981,665 results on '"APOPTOSIS"'
Search Results
2. A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response
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Leibel, Sandra L, McVicar, Rachael N, Murad, Rabi, Kwong, Elizabeth M, Clark, Alex E, Alvarado, Asuka, Grimmig, Bethany A, Nuryyev, Ruslan, Young, Randee E, Lee, Jamie C, Peng, Weiqi, Zhu, Yanfang P, Griffis, Eric, Nowell, Cameron J, James, Brian, Alarcon, Suzie, Malhotra, Atul, Gearing, Linden J, Hertzog, Paul J, Galapate, Cheska M, Galenkamp, Koen MO, Commisso, Cosimo, Smith, Davey M, Sun, Xin, Carlin, Aaron F, Sidman, Richard L, Croker, Ben A, and Snyder, Evan Y
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Medical Microbiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Stem Cell Research ,Infectious Diseases ,Lung ,Coronaviruses ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Emerging Infectious Diseases ,2.1 Biological and endogenous factors ,Infection ,Inflammatory and immune system ,Humans ,SARS-CoV-2 ,COVID-19 ,Virus Internalization ,Organoids ,COVID-19 Drug Treatment ,Induced Pluripotent Stem Cells ,Angiotensin-Converting Enzyme 2 ,Inflammation ,Cytokines ,Apoptosis ,inflammation ,lung organoids ,macropinocytosis ,surfactant - Abstract
The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.
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- 2024
3. Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules
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Kadiyala, Gayatri Nikhila, Telwatte, Sushama, Wedrychowski, Adam, Janssens, Julie, Kim, Sun Jin, Kim, Peggy, Deeks, Steven, Wong, Joseph K, and Yukl, Steven A
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Infectious Diseases ,Sexually Transmitted Infections ,Genetics ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,Infection ,Humans ,Indoles ,HIV Infections ,Pyrroles ,Leukocytes ,Mononuclear ,Proviruses ,apoptosis ,Bcl-2 ,DNA ,HIV ,IAP ,interferon ,mTOR ,PD-1 ,proteasome ,RIG-I ,TLR7 ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectivesSome drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses.DesignTo investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals.MethodsWe tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay).ResultsObatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects.ConclusionObatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.
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- 2024
4. Inhibiting liver autophagy and promoting hepatocyte apoptosis by 'Schistosoma japonicum' infection
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Yu, Zhihao, Jiang, Tingting, Xu, Fangfang, Jing, Zhang, Hu, Yuan, and Cao, Jianping
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- 2024
5. IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy.
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Moyer, Cassandra, Lanier, Amanda, Qian, Jing, Coleman, Darian, Hill, Jamal, Vuligonda, Vidyasagar, Sanders, Martin, Mazumdar, Abhijit, and Brown, Powel
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Humans ,Animals ,Breast Neoplasms ,Female ,Receptor ,ErbB-2 ,Mice ,Cell Line ,Tumor ,Xenograft Model Antitumor Assays ,Drug Synergism ,Cellular Senescence ,Cell Proliferation ,Apoptosis ,Trastuzumab ,Drug Resistance ,Neoplasm ,Retinoids - Abstract
PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action. EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy. RESULTS: IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib-resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44%, respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2-targeted mAbs, tyrosine kinase inhibitors, and antibody-drug conjugates. CONCLUSIONS: These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.
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- 2024
6. Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury.
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Lin, Hugo, Liang, Chan-Jung, Yang, Ming-Yu, Chen, Phang-Lang, Wang, Tzu-Ming, Chen, Yen-Hua, Shih, Yao-Hsiang, Liu, Wangta, Chiu, Chien-Chih, Chiang, Chih-Kang, Lin, Chang-Shen, and Lin, Han-Chen
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AKI ,ATP synthase ,Maleic acid ,Mitochondria ,Animals ,Humans ,Male ,Mice ,Acute Kidney Injury ,Apoptosis ,Cell Line ,Epithelial Cells ,Kidney Tubules ,Proximal ,Maleates ,Mice ,Inbred C57BL ,Mitochondria ,Mitochondrial Proton-Translocating ATPases ,Reactive Oxygen Species - Abstract
Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p
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- 2024
7. Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma.
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Zheng, Jianwei, Wang, Qianqian, Chen, Jianghe, Cai, Guodi, Zhang, Zhenhua, Zou, Hongye, Zou, June, Liu, Qianqian, Ji, Shufeng, Shao, Guoli, Li, Hong, Li, Sheng, Chen, Hongwu, Lu, LinLin, Yuan, Yanqiu, Liu, Peiqing, and Wang, Junjian
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Osteosarcoma ,Humans ,Oxidative Phosphorylation ,Mitochondria ,Nuclear Receptor Subfamily 1 ,Group F ,Member 3 ,Cell Line ,Tumor ,Animals ,Bone Neoplasms ,Mice ,Reactive Oxygen Species ,Apoptosis ,Gene Expression Regulation ,Neoplastic ,Ferroptosis ,Mice ,Nude ,Male ,Cell Proliferation ,RNA-Binding Proteins - Abstract
Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1β and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.
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- 2024
8. Pretreatment with IL-15 and IL-18 rescues natural killer cells from granzyme B-mediated apoptosis after cryopreservation.
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Berjis, Abdulla, Muthumani, Deeksha, Aguilar, Oscar, Pomp, Oz, Johnson, Omar, Finck, Amanda, Engel, Nils, Chen, Linhui, Plachta, Nicolas, Scholler, John, Lanier, Lewis, June, Carl, and Sheppard, Neil
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Granzymes ,Interleukin-15 ,Killer Cells ,Natural ,Apoptosis ,Humans ,Interleukin-18 ,Animals ,Cryopreservation ,Mice ,Cell Line ,Tumor ,CRISPR-Cas Systems - Abstract
Human natural killer (NK) cell-based therapies are under assessment for treating various cancers, but cryopreservation reduces both the recovery and function of NK cells, thereby limiting their therapeutic feasibility. Using cryopreservation protocols optimized for T cells, here we find that ~75% of NK cells die within 24 h post-thaw, with the remaining cells displaying reduced cytotoxicity. Using CRISPR-Cas9 gene editing and confocal microscopy, we find that cryopreserved NK cells largely die via apoptosis initiated by leakage of granzyme B from cytotoxic vesicles. Pretreatment of NK cells with a combination of Interleukins-15 (IL-15) and IL-18 prior to cryopreservation improves NK cell recovery to ~90-100% and enables equal tumour control in a xenograft model of disseminated Raji cell lymphoma compared to non-cryopreserved NK cells. The mechanism of IL-15 and IL-18-induced protection incorporates two mechanisms: a transient reduction in intracellular granzyme B levels via degranulation, and the induction of antiapoptotic genes.
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- 2024
9. Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
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Winstel, Volker, Abt, Evan, Le, Thuc, and Radu, Caius
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Staphylococcus aureus ,apoptosis ,infectious disease ,macrophages ,microbiology ,Animals ,Humans ,Staphylococcus aureus ,Deoxycytidine Kinase ,Abscess ,Staphylococcal Infections ,Anti-Infective Agents ,Mammals - Abstract
Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87, a clinical-stage anticancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates Staphylococcus aureus abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (R)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (R)-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients.
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- 2024
10. The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer.
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Hagi, Takaomi, Vangveravong, Suwanna, Takchi, Rony, Gong, Qingqing, Goedegebuure, S, Tiriac, Herve, Van Tine, Brian, Powell, Matthew, Hawkins, William, and Spitzer, Dirk
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Humans ,Animals ,Mice ,Female ,Antineoplastic Agents ,Apoptosis ,Ovarian Neoplasms ,Inhibitor of Apoptosis Proteins ,Caspases ,Cell Line ,Tumor - Abstract
Cancer selective apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian cancer cell lines in comparison with the individual components (S2 and IAPinh) as well as their equimolar mixtures (S2 + IAPinh) both in vitro and in preclinical models of pancreatic and ovarian cancer. Mechanistic studies of S2/IAPinh-mediated cell death were investigated in vitro and in vivo using syngeneic and xenograft mouse models of murine pancreatic and human ovarian cancer, respectively. S2/IAPinh demonstrated markedly improved pharmacological activity in cancer cell lines and primary organoid cultures when compared to the controls. In vivo testing demonstrated a marked reduction in tumor growth rates and increased survival rates when compared to the respective control groups. The predicted mechanism of action of S2/IAPinh was confirmed through assessment of apoptosis pathways and demonstrated strong target degradation (cellular inhibitor of apoptosis proteins-1 [cIAP-1]) and activation of caspases 3 and 8. Taken together, S2/IAPinh demonstrated efficacy in models of pancreatic and ovarian cancer, two challenging malignancies in need of novel treatment concepts. Our data support an in-depth investigation into utilizing S2/IAPinh for the treatment of cancer.
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- 2024
11. The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex.
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Leon, Walter, Steffen, David, Dale-Huang, Fiona, Rakela, Benjamin, Breevoort, Arnar, Romero-Rodriguez, Ricardo, Hasenstaub, Andrea, Weiner, Joshua, Alvarez-Buylla, Arturo, and Stryker, Michael
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GABAergic ,inhibitory neurons ,medial ganglionic eminence ,neuronal elimination ,transplantation ,Mice ,Animals ,Humans ,Protocadherins ,Interneurons ,Neurons ,Apoptosis ,Protein Isoforms ,Cerebral Cortex - Abstract
Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.
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- 2024
12. Stress response silencing by an E3 ligase mutated in neurodegeneration.
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Haakonsen, Diane, Heider, Michael, Ingersoll, Andrew, Vodehnal, Kayla, Witus, Samuel, Uenaka, Takeshi, Wernig, Marius, and Rapé, Michael
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Apoptosis ,Ataxia ,Cell Survival ,Dementia ,Mitochondria ,Mitochondrial Proteins ,Multiprotein Complexes ,Mutation ,Neurodegenerative Diseases ,Protein Stability ,Protein Transport ,Proteolysis ,Stress ,Physiological ,Ubiquitin ,Ubiquitin-Protein Ligases ,Ubiquitination - Abstract
Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.
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- 2024
13. Engrailed‐1 Promotes Pancreatic Cancer Metastasis
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Xu, Jihao, Roe, Jae‐Seok, Lee, EunJung, Tonelli, Claudia, Ji, Keely Y, Younis, Omar W, Somervile, Tim DD, Yao, Melissa, Milazzo, Joseph P, Tiriac, Herve, Kolarzyk, Anna M, Lee, Esak, Grem, Jean L, Lazenby, Audrey J, Grunkemeyer, James A, Hollingsworth, Michael A, Grandgenett, Paul M, Borowsky, Alexander D, Park, Youngkyu, Vakoc, Christopher R, Tuveson, David A, and Hwang, Chang‐Il
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Pancreatic Cancer ,Genetics ,Rare Diseases ,Biotechnology ,Digestive Diseases ,Humans ,Transcription Factors ,Pancreatic Neoplasms ,Gene Expression Regulation ,Carcinoma ,Pancreatic Ductal ,apoptosis ,cancer progression ,cancer therapeutics ,developmental transcription factor ,Engrailed-1 ,epigenetic reprogramming ,ERK signaling ,metastasis ,pancreatic ductal adenocarcinoma - Abstract
Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.
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- 2024
14. Manuka Honey Inhibits Human Breast Cancer Progression in Preclinical Models
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Márquez-Garbán, Diana C, Yanes, Cristian D, Llarena, Gabriela, Elashoff, David, Hamilton, Nalo, Hardy, Mary, Wadehra, Madhuri, McCloskey, Susan A, and Pietras, Richard J
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Women's Health ,Breast Cancer ,Cancer ,5.1 Pharmaceuticals ,Humans ,Honey ,Breast Neoplasms ,Female ,Animals ,Apoptosis ,MCF-7 Cells ,Cell Proliferation ,Signal Transduction ,Mice ,Xenograft Model Antitumor Assays ,Mice ,Nude ,Leptospermum ,TOR Serine-Threonine Kinases ,Proto-Oncogene Proteins c-akt ,Antineoplastic Agents ,STAT3 Transcription Factor ,Disease Progression ,AMP-Activated Protein Kinases ,Cell Line ,Tumor ,Phosphorylation ,Manuka honey ,breast cancer ,estrogen receptor-positive breast cancer ,triple-negative breast cancer ,in vivo xenografts ,AMP kinase signaling ,mTOR ,STAT3 ,Food Sciences ,Nutrition and Dietetics ,Clinical sciences ,Nutrition and dietetics ,Public health - Abstract
Manuka honey (MH) exhibits potential antitumor activity in preclinical models of a number of human cancers. Treatment in vitro with MH at concentrations ranging from 0.3 to 5.0% (w/v) led to significant dose-dependent inhibition of proliferation of human breast cancer MCF-7 cells, but anti-proliferative effects of MH were less pronounced in MDA-MB-231 breast cancer cells. Effects of MH were also tested on non-malignant human mammary epithelial cells (HMECs) at 2.5% w/v, and it was found that MH reduced the proliferation of MCF-7 cells but not that of HMECs. Notably, the antitumor activity of MH was in the range of that exerted by treatment of MCF-7 cells with the antiestrogen tamoxifen. Further, MH treatment stimulated apoptosis of MCF-7 cells in vitro, with most cells exhibiting acute and significant levels of apoptosis that correlated with PARP activation. Additionally, the effects of MH induced the activation of AMPK and inhibition of AKT/mTOR downstream signaling. Treatment of MCF7 cells with increased concentrations of MH induced AMPK phosphorylation in a dose-dependent manner that was accompanied by inhibition of phosphorylation of AKT and mTOR downstream effector protein S6. In addition, MH reduced phosphorylated STAT3 levels in vitro, which may correlate with MH and AMPK-mediated anti-inflammatory properties. Further, in vivo, MH administered alone significantly inhibited the growth of established MCF-7 tumors in nude mice by 84%, resulting in an observable reduction in tumor volume. Our findings highlight the need for further research into the use of natural compounds, such as MH, for antitumor efficacy and potential chemoprevention and investigation of molecular pathways underlying these actions.
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- 2024
15. The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma
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Feichtenschlager, Valentin, Chen, Linan, Zheng, Yixuan James, Ho, Wilson, Sanlorenzo, Martina, Vujic, Igor, Fewings, Eleanor, Lee, Albert, Chen, Christopher, Callanan, Ciara, Lin, Kevin, Qu, Tiange, Hohlova, Dasha, Vujic, Marin, Hwang, Yeonjoo, Lai, Kevin, Chen, Stephanie, Nguyen, Thuan, Muñoz, Denise P, Kohwi, Yoshinori, Posch, Christian, Daud, Adil, Rappersberger, Klemens, Kohwi-Shigematsu, Terumi, Coppé, Jean-Philippe, and Ortiz-Urda, Susana
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Humans ,Mice ,Animals ,Melanoma ,RNA ,Long Noncoding ,Apoptosis ,Oligonucleotides ,Antisense ,Cell Line ,Tumor ,Membrane Proteins ,GTP Phosphohydrolases ,T-RECS ,lncRNA ,MAPK-pathway ,hnRNPA2/B1 ,Antisense oligonucleotides ,HT-KAM ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.
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- 2024
16. Extracorporeal Shockwave Therapy Alleviates Inflammatory Pain by Down-Regulating NLRP3 Inflammasome in Experimental Chronic Prostatitis and Chronic Pelvic Pain Syndrome.
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Bae, Woong, Shin, Dongho, Piao, Jun, Kim, Soomin, Choi, Yong, Park, Bong, Jung, Hyun, Sorkhi, Samuel, Chawla, Saager, Cheon, Chung, Kang, Dae, Choi, Jong, Park, Sang-Hyuck, Kim, Sae, and Rajasekaran, Mahadevan
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Apoptosis ,Extracorporeal shockwave therapy ,Inflammasomes ,Prostatitis - Abstract
PURPOSE: To evaluate the anti-inflammatory and antioxidative effects of extracorporeal shockwave therapy (ESWT) on prostatitis and explore the mechanism of alleviating pain. MATERIALS AND METHODS: For in vitro testing, RWPE-1 cells were randomly divided into 5 groups: (1) RWPE-1 group (normal control), (2) LPS group (lipopolysaccharide inducing inflammation), (3) 0.1ESWT group (treated by 0.1 mJ/mm² energy level), (4) 0.2ESWT group (treated by 0.2 mJ/mm² energy level), and (5) 0.3ESWT group (treated by 0.3 mJ/mm² energy level). After ESWT was administered, cells and supernatant were collected for ELISA and western blot. For in vivo testing, Sprague-Dawley male rats were randomly divided into 3 groups: (1) normal group, (2) prostatitis group, and (3) ESWT group (n=12 for each). Prostatitis was induced by 17 beta-estradiol and dihydrotestosterone (DHT) administration. Four weeks after ESWT, the pain index was assessed for all groups and prostate tissues were collected for immunohistochemistry, immunofluorescence, apoptosis analysis and, western blot. RESULTS: Our in vitro studies showed that the optimal energy flux density of ESWT was 0.2 mJ/mm². In vivo, ESWT ameliorated discomfort in rats with prostatitis and inflammation symptoms were improved. Compared to normal rats, overexpressed NLRP3 inflammasomes triggered apoptosis in rats with prostatitis and this was improved by ESWT. TLR4-NFκB pathway was overactive after experimental prostatitis, compared to normal and ESWT groups, and prostatitis induced alterations in BAX/BAK pathway were inhibited by ESWT. CONCLUSIONS: ESWT improved CP/CPPS by reducing NLRP3 inflammasome and ameliorated apoptosis via inhibiting BAX/BAK pathway in a rat model. TLR4 may play a key role in bonding NLRP3 inflammasome and BAX/BAK pathways. ESWT might be a promising approach for the treatment of CP/CPPS.
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- 2024
17. Green synthesis, characterization, and antiparasitic effects of gold nanoparticles against 'Echinococcus granulosus' protoscoleces
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Raziani, Yosra, Shakib, Pegah, Rashidipour, Marzieh, Cheraghipour, Koroush, Yadegari, Javad Ghasemian, and Mahmoudvand, Hossein
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- 2023
18. 苦参碱对椎间盘退变大鼠髓核细胞凋亡的影响.
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王 冲, 孔 丽, 崔学超, and 鲍铁周
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BACKGROUND: Nucleus pulposus cell apoptosis is the main pathological basis for intervertebral disc degeneration, and inflammation and peroxidation are important factors leading to apoptosis in the nucleus pulposus. Studies have shown that matrine has antioxidant, senescent, inflammatory and apoptotic effects, and may be a potential drug for the treatment of disc degeneration. OBJECTIVE: To investigate the effect of matrine on apoptosis of nucleus pulposus cells in rats with intervertebral disc degeneration by regulating the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) signaling pathway. METHODS: (1) Nucleus pulposus cells of rats at a logarithmic phase were randomly separated into a control group, a model group, a low-dose matrine group, a high-dose matrine group, an empty group, and a high-dose matrine+cGAS overexpression group. Except for the control group, cell models of intervertebral disc degeneration were established in the other groups through oxygen-glucose deprivation. At the same time of modeling, the low-dose and high-dose groups were treated with 0.4 and 0.8 mmol/L matrine, respectively, and the empty group was transfected with the empty plasmid, while the high-dose+cGAS overexpression group was treated with 0.8 mmol/L matrine with the transfection of the cGAS overexpression plasmid. After 24 hours of treatment, cell activity and apoptosis, intracellular levels of reactive oxygen species, superoxide dismutase, tumor necrosis factor α and interleukin 1β, and intracellular expression of apoptotic proteins and cGAS-STING pathway proteins were detected. (2) Sixty Sprague-Dawley rats were randomized into six groups (n=10 per group): control group, model group, low-dose matrine group, high-dose matrine group, empty group, and high-dose+cGAS overexpression group. After 12 weeks of modeling, 60 and 120 mg/kg matrine were given by gavage in the low-dose and high-dose matrine groups, respectively (once a day), and the empty plasmid was injected into the tail vein in the empty group (2 times/week), while the high-dose+cGAS overexpression group was given 120 mg/kg matrine by gavage and injected with cGAS overexpression plasmid to the tail vein. Treatment in each group was given consecutively for 3 weeks. Samples were taken after drug administration and assayed for apoptosis, levels of reactive oxygen species, superoxide dismutase, tumor necrosis factor α and interleukin 1β, as well as apoptotic protein and cGAS-STING pathway protein expression. RESULTS AND CONCLUSION: Compared with the control group, in the model group, cell activity and superoxide dismutase levels were decreased (P < 0.05), and apoptosis rate, levels of reactive oxygen species, tumor necrosis factor α and interleukin 1β, and the expression of cGAS, STING, cleaved caspase-3 and Bax proteins were elevated (P < 0.05). Matrine dose-dependently ameliorated the above changes in each index due to cellular modeling (P < 0.05), whereas cGAS overexpression partially antagonized the ameliorative effect of high-dose matrine. Similar results to the in vitro cellular experiments were obtained in animal experiments. These results indicate that matrine could inhibit inflammation and oxidative stress by blocking the cGAS-STING signaling, which in turn attenuates apoptosis and elevates the activity of nucleus pulposus cells in rats with intervertebral disc degeneration. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Flavone and 3-hydroxyflavone supplementation in cryopreservation medium protects canine sperm against apoptosis and lipid peroxidation.
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Partyka, Agnieszka, Kostrzewa Susłow, Edyta, Dymarska, Monika, Ligocka, Zuzanna, Smalec, Barbara, Kalinin, Jarosław, Meco, Michele, and Niżański, Wojciech
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FROZEN semen , *SPERMATOZOA , *SEMEN analysis , *BEAGLE (Dog breed) , *APOPTOSIS , *PEROXIDATION , *SEMEN - Abstract
Cryopreservation is a pivotal technique in safeguarding genetic material across diverse species, despite its inherent challenges linked to induced spermatozoa damage, notably apoptosis and lipid peroxidation (LPO). Given the insufficient antioxidant defense of spermatozoa against LPO, there is a rising interest in integrating additional additives into extenders to ameliorate mammalian semen quality. Among these additives, flavonoids have garnered considerable attention due to their potent antioxidative properties. Hence, our study aimed to assess the efficacy of flavone (FL) and 3-hydroxyflavone (3-OH =) supplementation in the cryopreservation medium to protect canine sperm against the damaging impacts of freezing and ensure the preservation of their reproductive potential. Semen was collected from five Beagle stud dogs and then pooled. Then, the sample was divided into 7 groups, each treated with 1) 0 mM, 2) 0.1 mM FL, 3) 0.2 mM FL, 4) 0.4 mM FL, 5) 0.1 mM 3-OH = , 6) 0.2 mM 3-OH = , 7) 0.4 mM 3-OH =. Semen samples were subjected to cryopreservation in French straws and glycerol as a cryoprotectant. In the frozen thawed semen, sperm motility parameters by CASA system and sperm membrane integrity, acrosome status, mitochondrial activity, DNA fragmentation, early apoptosis with capacitation, and LPO were assessed using flow cytometry just after thawing (0 h) and 4 h post thaw. Results reveal significant increase in the proportion of live spermatozoa with undamaged acrosomes in the FL 0.1 and 3-OH = 0.2 groups at 0 h post thaw. At this time point, 3-OH = 0.1 significantly reduced the DNA fragmentation index (DFI) compared to the FL 0.1 and 0.2 groups. However, after the next 4 h, 3-OH = 0.4 exhibited the lowest (P < 0.05) DFI compared to FL 0.2 and 3-OH = 0.1. Additionally, 3-OH = 0.4 showed the highest (P < 0.05) proportion of non apoptotic and non capacitated spermatozoa compared to FL 0.1 0 h post-thaw. Simultaneously, the same group demonstrated significant reduction in apoptotic and capacitated sperm cells, at 0 h and 4 h post-thaw. Moreover, 3-OH = at 0.1 (0 h and 4 h) and 0.2 mM (4 h) significantly enhances the proportion of live sperm without LPO post thaw. Whitin the FL groups, only 0.4 FL significantly increased the percentage of live sperm without LPO. No significant effect of the tested substances was observed on sperm motility, cell membrane integrity, or mitochondrial activity. These findings highlight the promising role of flavone and 3-hydroxyflavone in enhancing sperm resilience during cryopreservation, suggesting their protective function against acrosome damages, capacitation, apoptosis and lipid peroxidation. [Display omitted] • lFlavone (FL) and 3-hydroxyflavone (3-OH =) were used to supplement the extender for canine semen cryopreservation for the first time. • Using FL 0.1 mM and 3-OH = 0.2 mM increased (P < 0.05) the proportion of live spermatozoa with undamaged acrosomes. • Using 3-OH = 0.1 and 0.4 mM significantly reduced the DNA fragmentation index of spermatozoa. • Using 3-OH = 0.4 mM significantly reduced apoptosis and capacitation of sperm cells. • Using FL 0.4 mM and 3-OH = 0.1 and 0.2 mM significantly protected the sperm against lipid peroxidation. [ABSTRACT FROM AUTHOR]
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- 2024
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20. Plumbagin induces G2/M arrest and apoptosis and ferroptosis via ROS/p38 MAPK pathway in human osteosarcoma cells.
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Li, Jintang, Gao, Hang, Wang, Ping, Sun, Chao, Wei, Zhilin, Yi, Xingcheng, Yu, Shuyuan, Zhang, Yanan, and Li, Shuqiang
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CELL cycle ,PLUMBAGIN ,MITOGEN-activated protein kinases ,RNA sequencing ,CELLULAR signal transduction ,CELL death - Abstract
Plumbagin (PLB), a naphthoquinone compound, has been proven to have anti-cancer properties in different types of cancers. However, the anti-tumor actions as well as molecular processes in osteosarcoma (OS) remain unclear. This study investigates the underlying mechanisms of PLB in human OS cells in vitro. Our study showed that PLB significantly inhibited the proliferation of human OS cells in a time- and dosage-dependent manner. RNA sequencing data revealed that the efficacy of PLB is related to cell cycle, cell death, and p38 MAPK signaling pathway in KHOS-240S cells. Further studies indicated that PLB triggers G2/M phase arrest, mitochondrial-dependent apoptosis, as well as ferroptosis in human OS cells. Mechanistically, PLB treatment increased ROS generation that activates the p38 MAPK signaling pathway. BIRB 796, a p38 MAPK inhibitor, partly reversed PLB-induced phase arrest of G2/M and cell death. Furthermore, N-acetylcysteine (NAC), a ROS scavenger, significantly decreased G2/M phase arrest and cell death and reversed p38 MAPK activation caused by PLB. In conclusion, PLB induces arrest G2/M arrest, apoptosis as well as ferroptosis in human OS cells via ROS generation and p38 MAPK activation. There is potential for PLB to be an effective treatment for OS. • PLB induces G2/M arrest, apoptosis, and ferroptosis in human osteosarcoma cells. • The anti-osteosarcoma effect of Plumbagin is related to the ROS/p38 MAPK pathway. • PLB could be a promising therapeutic agent for osteosarcoma. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Unravelling the mechanism of apoptosis induced by copper(II) complexes of NN2-pincer ligands in lung cancer cells.
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Das, Athulya and Sankaralingam, Muniyandi
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CANCER cells , *LIGANDS (Biochemistry) , *COPPER , *LIGANDS (Chemistry) , *LUNG cancer , *APOPTOSIS - Abstract
The invention of efficient chemotherapeutic drugs is essential for human health and development. Keeping this in mind, a series of copper(II) pincer complexes, 1-4, of ligands L1(H) = 2-morpholino-N-(quinolin-8-yl)acetamide, L2(H) = 2-di-n-propylamino-N-(quinolin-8-yl)acetamide, L3(H) = 2-di-n-buty-lamino-N-(quinolin-8-yl)acetamide and L4(H) = 2-di-n-benzylamino-N-(quinolin-8-yl)acetamide have been synthesized, characterized, and utilized for inhibiting cancer proliferation. Complexes 1-4 showed very efficient activity against lung (A549) and breast (MCF-7) cancer cells, which are the most frequently diagnosed cancers according to the WHO. Among them, 1 was highly active against lung cancer cells with an IC50 value of 8 µM, showing no toxicity towards common L929 fibroblast cell lines (IC50 > 1000 μM). Moreover, AO-EB staining inferred that this cellular demise was attributed to apoptosis, which was determined to be 25.91% of cells by flow cytometry at the IC50 concentration. Furthermore, carboxy-H2DCFDA staining revealed the involvement of ROS in the mechanism. Interestingly, JC-1 dye staining revealed a change in the potential of the mitochondrial membrane, which indicates the enhanced production of ROS in mitochondria. A deep search for the mechanism through in silico studies guided us to the fact that complexes 1-4 might perturb the function of complex I in mitochondria. Furthermore, the studies can be expanded towards clinical applications mainly with morpholine appended complex 1. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Targeting NPM1 inhibits proliferation and promotes apoptosis of hepatic progenitor cells via suppression of mTOR signalling pathway.
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Wang, Ping, Wang, Min, Liu, Lin, Li, Hongyi, Liu, Helin, Ren, Jiangbo, Liu, Tianhui, Cong, Min, Zhu, Zhijun, Zhao, Xinyan, Sun, Liying, and Jia, Jidong
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Background: Hepatic progenitor cells serve not only as the origin of combined hepatocellular cholangiocarcinoma (cHCC-CCA) but are also responsible for malignancy recurrence after surgical resection. Nucleophosmin 1 (NPM1) has been implicated in cancer metastasis and poor prognosis. This study aimed to determine the expression of NPM1 by hepatic progenitor cells in cHCC-CCA and the effects of targeting NPM1 on hepatic progenitor cells and BEL-7402 cells with characteristics of both progenitor cells and cHCC-CCA. Methods: First, NPM1 was detected by RT‒PCR, western blotting, and double-immunofluorescence staining in cHCC-CCA tissues. NPM1 expression was subsequently analysed in rat hepatic progenitor cells cultured in vitro and in interleukin 6 (IL6)-treated cells. The effects and mechanism of NPM1 on hepatic progenitor cells were determined by knocking down NPM1 and performing RNA sequencing analysis. Finally, NSC348884, a small-molecule inhibitor that disrupts NPM1 dimer formation, was used to confirm the function of NPM1 in BEL-7402 cells. Results: Both human hepatic progenitor cells in cHCC-CCA tissues and rat in vitro cultured hepatic progenitor cells highly expressed NPM1. IL6, a cytokine involved in the malignant transformation of hepatic progenitor cells, dose-dependently increased NPM1 and PCNA expression. Knocking down NPM1 reduced IL6R transcription (P < 0.0001) and inhibited the proliferation (P = 0.0065) of hepatic progenitor cells by suppressing the mTOR signalling pathway and activating the apoptosis pathway. Furthermore, knocking down NPM1 in hepatic progenitor cells resulted in more apoptotic cells (7.33 ± 0.09% vs. 3.76 ± 0.13%, P < 0.0001) but fewer apoptotic cells in the presence of NSC348884 (47.57 ± 0.49% vs. 63.40 ± 0.05%, P = 0.0008) than in the control cells, suggesting that low-NPM1-expressing cells are more resistant to NSC348884. In addition, NSC348884 induced the apoptosis of BEL-7402 cells with an IC50 of 2.77 μmol/L via the downregulation of the IL-6R and mTOR signalling pathways and inhibited the growth of BEL-7402 cells in a subcutaneous xenograft tumour model (P = 0.0457). Conclusions: Targeting NPM1 inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA. [ABSTRACT FROM AUTHOR]
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- 2024
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23. LncRNA ACVR2B-as1 interacts with ALDOA to regulate the self-renewal and apoptosis of human spermatogonial stem cells by controlling glycolysis activity.
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Xu, Zhipeng, Lv, Cai, Gao, Jun, Cui, Yinghong, Liu, Wei, He, Zuping, and He, Leye
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Human spermatogonial stem cells (SSCs) have significant applications in reproductive medicine and regenerative medicine because of their great plasticity. Nevertheless, it remains unknown about the functions and mechanisms of long non-coding RNA (LncRNA) in regulating the fate determinations of human SSCs. Here we have demonstrated that LncRNA ACVR2B-as1 (activin A receptor type 2B antisense RNA 1) controls the self-renewal and apoptosis of human SSCs by interaction with ALDOA via glycolysis activity. LncRNA ACVR2B-as1 is highly expressed in human SSCs. LncRNA ACVR2B-as1 silencing suppresses the proliferation and DNA synthesis and enhances the apoptosis of human SSCs. Mechanistically, our ChIRP-MS and RIP assays revealed that ACVR2B-as1 interacted with ALDOA in human SSCs. High expression of ACVR2B-as1 enhanced the proliferation, DNA synthesis, and glycolysis of human SSCs but inhibited their apoptosis through up-regulation of ALDOA. Importantly, overexpression of ALDOA counteracted the effect of ACVR2B-as1 knockdown on the aforementioned biological processes. Collectively, these results indicate that ACVR2B-as1 interacts with ALDOA to control the self-renewal and apoptosis of human SSCs by enhancing glycolysis activity. This study is of great significance because it sheds a novel insight into molecular mechanisms underlying the fate decisions of human SSCs and it may offer innovative approaches to address the etiology of male infertility. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Effects of different slaughtering methods on the energy metabolism, apoptosis process and quality of grouper (Epinephelus fuscoguttatus) during cold storage at 4 °C.
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Zhao, Xin, Xu, Zhilong, Liu, Yu, Mei, Jun, and Xie, Jing
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BACKGROUND RESULTS CONCLUSION The aquatic processing industry is increasingly aware of the need to ensure that slaughtering is carried out under high welfare standards, so there is a need to explore the impact of slaughter methods on fish fillets. This study aimed to investigate the effects of different slaughtering methods (M1, lethality by hammering; M2, gas mixture causing death; M3, lethality by clove oil anesthesia + ice slurry; M4, lethality by ice slurry; M5, lethality by gradient cooling) on the energy metabolism, apoptosis and flesh mass in grouper (Epinephelus fuscoguttatus).Therefore, 120 fish (24 per treatment) were slaughtered by the five methods. The results showed that the succinate dehydrogenase (SDH) enzyme activity of M5 sample was higher. The serum glucose level of M2 samples and DAPI staining fluorescence of M2 samples were the highest, indicating that the stress response of M2 was strong. In addition, the texture, pH, total volatile basic nitrogen (TVB‐N), thiobarbituric acid (TBA) and K value results showed M5 samples had better flesh quality.Gradient cooling lethality had the least effect on oxidative damage and apoptosis in grouper during cold storage as the gradient cooling lethality had the least effect on antioxidant enzyme activities. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]
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- 2024
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25. BCL-2 and BOK regulate apoptosis by interaction of their C-terminal transmembrane domains.
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Beigl, Tobias B, Paul, Alexander, Fellmeth, Thomas P, Nguyen, Dang, Barber, Lynn, Weller, Sandra, Schäfer, Benjamin, Gillissen, Bernhard F, Aulitzky, Walter E, Kopp, Hans-Georg, Rehm, Markus, Andrews, David W, Pluhackova, Kristyna, and Essmann, Frank
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The Bcl-2 family controls apoptosis by direct interactions of pro- and anti-apoptotic proteins. The principle mechanism is binding of the BH3 domain of pro-apoptotic proteins to the hydrophobic groove of anti-apoptotic siblings, which is therapeutically exploited by approved BH3-mimetic anti-cancer drugs. Evidence suggests that also the transmembrane domain (TMD) of Bcl-2 proteins can mediate Bcl-2 interactions. We developed a highly-specific split luciferase assay enabling the analysis of TMD interactions of pore-forming apoptosis effectors BAX, BAK, and BOK with anti-apoptotic Bcl-2 proteins in living cells. We confirm homotypic interaction of the BAX-TMD, but also newly identify interaction of the TMD of anti-apoptotic BCL-2 with the TMD of BOK, a peculiar pro-apoptotic Bcl-2 protein. BOK-TMD and BCL-2-TMD interact at the endoplasmic reticulum. Molecular dynamics simulations confirm dynamic BOK-TMD and BCL-2-TMD dimers and stable heterotetramers. Mutation of BCL-2-TMD at predicted key residues abolishes interaction with BOK-TMD. Also, inhibition of BOK-induced apoptosis by BCL-2 depends specifically on their TMDs. Thus, TMDs of Bcl-2 proteins are a relevant interaction interface for apoptosis regulation and provide a novel potential drug target. Synopsis: The Bcl-2 family proteins BCL-2 and BOK interact via their transmembrane domains (TMDs) at the endoplasmic reticulum (ER). The TMD interaction interface is critical for the inhibition of BOK-induced apoptosis. BOK and BCL-2 directly interact via their C-terminal transmembrane domains in the ER membrane. Molecular-dynamics simulations reveal formation of higher order oligomers and mutation studies verify the relevance of predicted key residues in the BCL-2-TMD and BOK-TMD interaction interface. Inhibition of BOK-induced cell death by BCL-2 depends on TMD interaction thus exemplifying functional impact of TMD interaction on apoptosis regulation. The Bcl-2 family proteins BCL-2 and BOK interact via their transmembrane domains (TMDs) at the endoplasmic reticulum. The TMD interaction interface is critical for the inhibition of BOK-induced apoptosis. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Investigating the relationship between lymphocyte cells apoptosis and DNA damage and oxidative stress and therapeutic and clinical outcomes of COVID-19 elderly patients.
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Abiri, Elaheh, Mirzaii, Mehdi, Moghbeli, Majid, Atashi, Amir, and Harati, Ahad ali
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Background: While COVID-19 has been controlled and deaths have decreased, the long-term consequences of COVID-19 remain a challenge we face today. This study was conducted to determine the relationship between the apoptosis of lymphocyte cells with DNA damage and oxidative stress and the therapeutic and clinical outcomes of elderly patients with COVID-19. Methods: This study was conducted from April 2020 to May 2021 (the period of severe attacks of the epidemic peak of COVID-19) and September 2022 (the post-COVID-19 period). The study groups included elderly patients with COVID-19 hospitalized in the ICU and normal wards of the hospital as well as elderly patients with influenza. A polymerase chain reaction was used to check the validity of the studied diseases. The Annexin V/Propidium Iodide method was used to evaluate the level of apoptosis. Genotoxic effects and DNA damage were assessed by the comet assay method. Total antioxidant status (TAS), total oxidant status (TOS), and myeloperoxidase activity (MPO) were measured by photometric methods. Results: The highest level of apoptosis in peripheral blood lymphocytes and the highest level of DNA damage were observed at both times in the intubated-ICU and non-intubated-ICU groups. In all groups, there was a significant increase in peripheral blood lymphocyte apoptosis levels and DNA damage levels compared to the healthy control group (p < 0.01). The level of apoptosis and DNA damage decreased significantly in the post-COVID-19 period (p < 0.01). In the investigation of oxidative stress biomarkers, the oxidative stress index, including TOS and MPO levels, increased in patients (p < 0.01), and the TAS level decreased (p < 0.01). Conclusion: It shows that the apoptosis of lymphocyte cells, DNA damage, and oxidative stress can be effective in prognostic decisions and is a suitable predictor for diagnosing the condition of patients with viral infections such as COVID-19 and influenza. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Uncover the anticancer potential of lycorine.
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Zhang, Yan-Ming, Li, Ting, Xu, Chun-Cao, Qian, Jia-Yu, Guo, Hongwei, Zhang, Xiaolei, Zhan, Zha-Jun, and Lu, Jin-Jian
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IN vitro studies , *LIVER tumors , *SAFETY , *ALKALOIDS , *STOMACH tumors , *MELANOMA , *AUTOPHAGY , *RESEARCH funding , *BREAST tumors , *OVARIAN tumors , *APOPTOSIS , *IN vivo studies , *COLORECTAL cancer , *PANCREATIC tumors , *MICE , *SYSTEMATIC reviews , *MEDLINE , *MOLECULAR structure , *ANIMAL experimentation , *CELL death , *TUMORS , *ONLINE information services ,BLADDER tumors ,CERVIX uteri tumors - Abstract
Background: Natural products have a long history in drug discovery. Lycorine is an alkaloid derived from Amaryllidaceae plants, demonstrating significant pharmacological potential. Lycorine and its hydrochloride salt, lycorine hydrochloride, have shown outstanding anticancer effects both in vitro and in vivo. Purpose: This review aims to comprehensively summarize recent research advancements regarding the anticancer potential of lycorine and lycorine hydrochloride. It intends to elucidate current research limitations, optimization strategies, and future research directions to guide clinical translation. Methods: Various databases, e.g., Web of Science, PubMed, and Chinese National Knowledge Infrastructure, are systematically searched for relevant articles using keywords such as lycorine, cancer, pharmacokinetics, and toxicity. The retrieved literature is then categorized and summarized to provide an overview of the research advancements in the anticancer potential of lycorine and lycorine hydrochloride. Results: Lycorine and lycorine hydrochloride demonstrate significant anticancer activities against various types of cancer both in vitro and in vivo, employing diverse mechanisms such as inducing cell cycle arrest, triggering cellular senescence, regulating programmed cell death, inhibiting angiogenesis, suppressing metastasis, and modulating immune system. Furthermore, pharmacokinetic profiles and toxicity data are summarized. Additionally, this review discusses the druggability, limitations, optimization strategies, and target identification of lycorine, offering insights for future preclinical studies. Conclusion: The anticancer effects and safety profile of lycorine and lycorine hydrochloride suggest promising potential for clinical applications. Further research on their in-depth mechanisms and optimization strategies targeting their limitations will enhance the understanding and druggability of lycorine and lycorine hydrochloride. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Mechanisms of chondrocyte cell death in osteoarthritis: implications for disease progression and treatment.
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Guan, Mengqi, Yu, Qingyuan, Zhou, Guohui, Wang, Yan, Yu, Jianan, Yang, Wei, and Li, Zhenhua
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OSTEOARTHRITIS treatment , *AUTOPHAGY , *RESEARCH funding , *DISEASE management , *APOPTOSIS , *MORPHOGENESIS , *CARTILAGE cells , *CELL death , *OSTEOARTHRITIS , *MOLECULAR biology , *DISEASE progression - Abstract
Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration, destruction, and excessive ossification of articular cartilage. The prevalence of OA is rising annually, concomitant with the aging global population and increasing rates of obesity. This condition imposes a substantial and escalating burden on individual health, healthcare systems, and broader social and economic frameworks. The etiology of OA is multifaceted and not fully understood. Current research suggests that the death of chondrocytes, encompassing mechanisms such as cellular apoptosis, pyroptosis, autophagy, ferroptosis and cuproptosis, contributes to both the initiation and progression of the disease. These cell death pathways not only diminish the population of chondrocytes but also exacerbate joint damage through the induction of inflammation and other deleterious processes. This paper delineates the morphological characteristics associated with various modes of cell death and summarizes current research results on the molecular mechanisms of different cell death patterns in OA. The objective is to review the advancements in understanding chondrocyte cell death in OA, thereby offering novel insights for potential clinical interventions. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Hirocidins, Cytotoxic Metabolites from Streptomyces hiroshimensis, Induce Mitochondrion‐Mediated Apoptosis.
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Han, Esther J., Jeong, Myungeun, Lee, Seoung Rak, Sorensen, Erik J., and Seyedsayamdost, Mohammad R.
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STREPTOMYCES , *WHOLE genome sequencing , *DRUG discovery , *METABOLITES , *SMALL molecules , *APOPTOSIS , *CANCER cells - Abstract
Recent advances in whole genome sequencing have revealed an immense microbial potential for the production of therapeutic small molecules, even from well‐known producers. To access this potential, we subjected prominent antimicrobial producers to alternative antiproliferative assays using persistent cancer cell lines. Described herein is our discovery of hirocidins, novel secondary metabolites from Streptomyces hiroshimensis with antiproliferative activities against colon and persistent breast cancer cells. Hirocidin A is an unusual nine‐membered carbocyclic maleimide and hirocidins B and C are relatives with an unprecedented, bridged azamacrocyclic backbone. Mode of action studies show that hirocidins trigger mitochondrion‐dependent apoptosis by inducing expression of the key apoptotic effector caspase‐9. The discovery of new cytotoxins contributes to scaffold diversification in anticancer drug discovery and the reported modes of action and concise total synthetic route for variant A set the stage for unraveling specific targets and biochemical interactions of the hirocidins. [ABSTRACT FROM AUTHOR]
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- 2024
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30. 环状 RNA hsa-circ-0001360 在同型半胱氨酸诱导人脐静脉内皮细胞凋亡中的作用.
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况园军, 于素美, 钟颖怡, 章旭红, 马胜超, 杨安宁, 郝银菊, 熊建团, 焦 运, and 姜怡邓
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BACKGROUND: Increased homocysteine level induces apoptosis of human umbilical vein endothelial cells, but the mechanism remains unclear. OBJECTIVE: To investigate the role of hsa-circ-0001360 in human umbilical vein endothelial cell apoptosis induced by homocysteine. METHODS: In vitro cultured human umbilical vein endothelial cells were divided into control group, homocysteine group, interference control group, interference control + homocysteine group, hsa-circ-0001360 interference group, hsa-circ-0001360 + homocysteine interference group, overexpression control group, overexpression control + homocysteine group, hsa-circ-0001360 overexpression group and hsa-circ-0001360 + homocysteine overexpression group. All groups were treated with 100 μmol/L homocysteine. After 72 hours of intervention, the expressions of apoptosis-related proteins Bax, Bcl-2, and Caspase-3 were detected by western blot assay. The apoptotic rate was detected by flow cytometry. Quantitative real-time PCR was used to detect the expression of hsacirc-0001360. RESULTS AND CONCLUSION: (1) Compared with the control group, the expression of Caspase-3 and Bax was significantly increased (P < 0.01), and the expression of Bcl-2 was significantly decreased (P < 0.01), and the apoptotic rate was significantly increased (P < 0.01) in the homocysteine group. (2) Compared with control group, the expression of hsa-circ-0001360 was significantly increased in the homocysteine group (P < 0.01). (3) The expression of hsa-circ-0001360 was significantly higher in the cytoplasm than that in the nucleus (P < 0.01). (4) Compared with the interference control C group and interference control + homocysteine group, the expressions of Caspase-3 and Bax were significantly decreased (P < 0.01), while the expression of Bcl-2 was significantly increased (P < 0.01); the apoptotic rate was significantly decreased (P < 0.01) in sh-hsa-circ-0001360 interference group and sh-hsa-circ-0001360 + homocysteine interference group. (5) Compared with overexpression control group and overexpression control + homocysteine group, the expressions of Caspase-3 and Bax were significantly increased (P < 0.01), while the expression of Bcl-2 was significantly decreased (P < 0.01); the apoptotic rate was significantly increased (P < 0.01) in the hsa-circ-0001360 overexpression group and the hsa-circ-0001360 + homocysteine overexpression group. (6) In conclusion, hsa-circ-0001360 can promote the apoptosis of human umbilical vein endothelial cells induced by homocysteine. [ABSTRACT FROM AUTHOR]
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- 2024
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31. 灵孢多糖对过氧化氢致 SH-SY5Y 细胞凋亡及线粒体功能障碍的调控.
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李雁冰, 王记委, 刘晓琴, 郭敏芳, 牛晓洁, 孟 涛, 苏 琴, 王瀚斌, 杨立志, 马存根, and 尉杰忠
- Abstract
BACKGROUND: Current studies have confirmed that Ganoderma lucidum polysaccharides can promote nerve regeneration in neurodegeneration-related diseases. The occurrence of neurodegenerative diseases is closely related to mitochondrial dysfunction, but the role of Ganoderma lucidum polysaccharides on the regulation of apoptosis and mitochondrial function in neurodegenerative diseases is not yet clarified. OBJECTIVE: To explore the regulatory effects and mechanisms of Ganoderma lucidum polysaccharides on apoptosis and mitochondrial dysfunction in H2O2- induced SH-SY5Y cells. METHODS: SH-SY5Y cells were divided into three groups: control group, H2O2 group, and Ganoderma lucidum polysaccharides group. Cells in the control group were normally cultured. Cells in the H2O2 group were treated with 300 μmol/L H2O2 for 24 hours. In the Ganoderma lucidum polysaccharides group, the intervention with 300 μg/L Ganoderma lucidum polysaccharides was conducted first for 1-2 hours, followed by the addition of 300 μmol/L H2O2 for 24 hours. The mitochondrial membrane potential was detected by JC-1 kit. Apoptosis was detected by TUNEL staining kit. The activities of malondialdehyde and superoxide dismutase were detected by malondialdehyde test kit and superoxide dismutase test kit, respectively. The apoptosis and expression of mitochondrial dynamics-related proteins were detected by immunofluorescence staining and western blot assay. RESULTS AND CONCLUSION: (1) Compared with the control group, the mitochondrial membrane potential and superoxide dismutase activity were significantly reduced, as well as apoptotic rate and malondialdehyde levels were significantly increased in the H2O2 group (P < 0.05). After treatment with Ganoderma lucidum polysaccharides, the membrane potential and superoxide dismutase activities were significantly increased, and apoptotic rate and malondialdehyde levels were significantly reduced compared with the H2O2 group (P < 0.05). (2) The expression levels of pro-apoptotic proteins Bax and Caspase-3 were significantly increased, but the expression of anti-apoptotic protein Bcl-2 was significantly decreased in the H2O2 group compared with the control group (P < 0.05). Compared with the H2O2 group, the levels of Bax and Caspase-3 were significantly decreased, but the expression of anti-apoptotic protein Bcl-2 was significantly increased in the Ganoderma lucidum polysaccharides group (P < 0.05). (3) Compared with the control group, the expression of mitochondrial splitting proteins Fis1 and p-Drp1 was significantly increased, but the expression of mitochondrial fusion proteins OPA1, Mfn1, and Mfn2 was decreased in the H2O2 group (P < 0.05). Compared with the H2O2 group, Fis1 and p-Drp1 expression was significantly reduced, but the expression levels of OPA1, Mfn1, and Mfn2 were significantly increased in the Ganoderma lucidum polysaccharides group (P < 0.05). (4) The above results confirm that Ganoderma lucidum polysaccharides can attenuate H2O2-induced oxidative stress damage and apoptosis in SH-SY5Y cells by ameliorating mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]
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- 2024
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32. Salicylaldehyde-derived piperazine-functionalized hydrazone ligand-based Pt(II) complexes: inhibition of EZH2-dependent tumorigenesis in pancreatic ductal adenocarcinoma, synergism with PARP inhibitors and enhanced apoptosis.
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Lv, Zhimin, Ali, Amjad, Zou, Cheng, Wang, Zerui, Ma, Minglu, Cheng, Na, Shad, Man, Hao, Huifang, Zhang, Yongmin, and Rahman, Faiz-Ur
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LIGANDS (Chemistry) , *PANCREATIC duct , *POLY(ADP-ribose) polymerase , *DOXORUBICIN , *CANCER cell growth , *PIPERAZINE , *APOPTOSIS , *ANTINEOPLASTIC agents - Abstract
Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1–L8) and Pt(II) complexes (C1–C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1–C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1–C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Quercetin ameliorates oxidative stress-induced apoptosis of granulosa cells in dairy cow follicular cysts by activating autophagy via the SIRT1/ROS/AMPK signaling pathway.
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Duan, Hongwei, Wang, Fang, Wang, Ke, Yang, Shuai, Zhang, Rong, Xue, Chen, Zhang, Lihong, Ma, Xiaofei, Du, Xianghong, Kang, Jian, Zhang, Yong, Zhao, Xingxu, Hu, Junjie, and Xiao, Longfei
- Abstract
Background: Follicular cysts contribute significantly to reproductive loss in high-yield dairy cows. This results from the death of follicular granulosa cells (GCs) caused by oxidative stress. Quercetin is known to have significant antioxidant and anti-apoptotic effects. However, the effect of quercetin on follicular cysts has yet been elucidated. Therefore, this study aimed to explore the anti-oxidant and anti-apoptosis effects and potential molecular mechanisms of quercetin in H2O2-induced primary cow GCs and 3-nitropropionic acid (3-NPA)-induced mouse model of oxidative stress and thus treat ovarian cysts in dairy cows. Results: In this study, compared with estrus cows, cows with follicular cysts showed heightened levels of oxidative stress and increased follicular cell apoptosis, while autophagy levels were reduced. A model of oxidative stress was induced in vitro by H2O2 and showed significant increases in apoptosis together with reduced autophagy. These effects were significantly ameliorated by quercetin. Effects similar to those of quercetin were observed after treatment of cells with the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC). Further investigations using chloroquine (autophagy inhibitor), rapamycin (autophagy activator), selisistat (SIRT1 inhibitor), and compound C (AMPK inhibitor) showed that chloroquine counteracted the effects of quercetin on oxidative stress-induced apoptosis, while rapamycin had the same effect as quercetin. In addition, the SIRT1/AMPK pathway inhibitors antagonized quercetin-mediated mitigation of the effects of oxidative stress on increased apoptosis and reduced autophagy. Consistent with the results in vitro, in mouse ovarian oxidative stress model induced by 3-NPA, quercetin activated autophagy through the SIRT1/AMPK signaling pathway, while alleviating oxidative stress damage and inhibiting apoptosis in mouse ovaries. Conclusions: These findings indicate that quercetin can inhibit apoptosis in GCs and restore ovarian function by activating autophagy through the SIRT1/ROS/AMPK signaling pathway, suggesting a new direction for the treatment of ovarian follicular cysts in high-yield dairy cows. [ABSTRACT FROM AUTHOR]
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- 2024
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34. PANoptosis and cardiovascular disease: The preventive role of exercise training.
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Kordi, Negin, Sanaei, Masoumeh, Akraminia, Peyman, Yavari, Sajad, Saydi, Ali, Abadi, Fatemeh Khamis, Heydari, Naser, Jung, Friedrich, and Karami, Sajad
- Abstract
Regulated cell death, including pyroptosis, apoptosis, and necroptosis, is vital for the body’s defense system. Recent research suggests that these three types of cell death are interconnected, giving rise to a new concept called PANoptosis. PANoptosis has been linked to various diseases, making it crucial to comprehend its mechanism for effective treatments. PANoptosis is controlled by upstream receptors and molecular signals, which form polymeric complexes known as PANoptosomes. Cell death combines necroptosis, apoptosis, and pyroptosis and cannot be fully explained by any of these processes alone. Understanding pyroptosis, apoptosis, and necroptosis is essential for understanding PANoptosis. Physical exercise has been shown to suppress pyroptotic, apoptotic, and necroptotic signaling pathways by reducing inflammatory factors, proapoptotic factors, and necroptotic factors such as caspases and TNF-alpha. This ultimately leads to a decrease in cardiac structural remodeling. The beneficial effects of exercise on cardiovascular health may be attributed to its ability to inhibit these cell death pathways. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1/FLVCR1-mediated mitochondrial homeostasis.
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Qu, Yan, Meng, Bowen, Cai, Simin, Yang, Benyi, He, Yifan, Fu, Chaoran, Li, Xiangxia, Li, Peiyi, Cao, Zeyuan, Mao, Xueli, Teng, Wei, and Shi, Songtao
- Abstract
Over 50 billion cells undergo apoptosis each day in an adult human to maintain tissue homeostasis by eliminating damaged or unwanted cells. Apoptotic deficiency can lead to age-related diseases with reduced apoptotic metabolites. However, whether apoptotic metabolism regulates aging is unclear. Here, we show that aging mice and apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) mice exhibit decreased apoptotic levels along with increased aging phenotypes in the skeletal bones, which can be rescued by the treatment with apoptosis inducer staurosporine (STS) and stem cell-derived apoptotic vesicles (apoVs). Moreover, embryonic stem cells (ESC)-apoVs can significantly reduce senescent hallmarks and mtDNA leakage to rejuvenate aging bone marrow mesenchymal stem cells (MSCs) and ameliorate senile osteoporosis when compared to MSC-apoVs. Mechanistically, ESC-apoVs use TCOF1 to upregulate mitochondrial protein transcription, resulting in FLVCR1-mediated mitochondrial functional homeostasis. Taken together, this study reveals a previously unknown role of apoptotic metabolites in ameliorating bone aging phenotypes and the unique role of TCOF1/FLVCR1 in maintaining mitochondrial homeostasis. [ABSTRACT FROM AUTHOR]
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- 2024
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36. Key subdomains of mesencephalic astrocyte-derived neurotrophic factor attenuate myocardial ischemia/reperfusion injury by JAK1/STAT1/NF-κB signaling pathway.
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Dong, Haibin, Jia, Wenjuan, Wang, Chunxiao, Teng, Da, Xu, Bowen, Ding, Xiaoning, Yang, Jun, Zhong, Lin, and Gong, Lei
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Background: Myocardial ischemia/reperfusion (I/R) injury is a common pathological process in clinical practice. Developing effective therapeutic strategies to reduce or prevent this injury is crucial. The article aimed to investigate the role and mechanism of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its key subdomains in modulating myocardial I/R-induced cardiomyocyte apoptosis. Methods: MANF stable knockout cell line and MANF mutant overexpression plasmids were constructed. The effects of MANF and mutants on apoptosis and endoplasmic reticulum (ER) stress related proteins were evaluated in hypoxia/reoxygenation-induced HL-1 cardiomyocytes by western blot, immunofluorescence, Tunel and flow cytometry. Echocardiography, ELISA, TTC and Masson were used to observe the effects of recombinant MANF protein (rMANF) on cardiac function in myocardial I/R mice. Results: This study observed increased expression of MANF in both myocardial infarction patients and I/R mice. MANF overexpression in cardiomyocytes decreased ER stress-induced apoptosis, while MANF knockout exacerbated it. rMANF improved cardiac function in I/R mice by reducing injury and inflammation. This study specifically demonstrates that mutations in the α-helix of MANF were more effective in reducing ER stress and cardiomyocyte apoptosis. Mechanistically, MANF and the α-helix mutant attenuated I/R injury by inhibiting the JAK1/STAT1/NF-κB signaling pathway in addition to reducing ER stress-induced apoptosis. Conclusion: These findings highlight MANF and its subdomains as critical regulators of myocardial I/R injury, offering promising therapeutic targets with significant clinical implications for I/R-related diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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37. Apoptosis and cuproptosis Co-activated Copper-based metal-organic frameworks for cancer therapy.
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Li, Kun, Wu, Leilei, Wang, Han, Fu, Zi, Gao, Jiani, Liu, Xiucheng, Fan, Yongfei, Qin, Xichun, Ni, Dalong, Wang, Jing, and Xie, Dong
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NON-small-cell lung carcinoma , *IRON-sulfur proteins , *COPPER ions , *MITOCHONDRIAL proteins , *METAL-organic frameworks , *COPPER - Abstract
Lung cancer, predominantly non-small cell lung cancer (NSCLC), remains a significant global health challenge, with limited therapeutic options for patients with KRAS-mutated tumors. Herein, a copper-based metal-organic framework (Cu-MOF) was applied as a novel cuproptosis-mediated nanoplatform for lung cancer therapy. Cu-MOF would disassemble and liberate copper ions under the acidic microenvironment of lysosomes of cancer cells, initiating a cascade of cellular events. The released copper ions catalyzes the Fenton reaction, generating hydroxyl radicals that induce oxidative damage, leading to cytoskeletal disruption and activation of caspase-3, ultimately triggering apoptosis. Simultaneously, with the mediation of the key regulatory factor FDX1, we found that the copper ions binding to the mitochondrial protein DLAT could result in the loss of iron-sulfur cluster proteins and aggregation of lipoylated proteins, which culminated in proteotoxic stress-induced cuproptosis. The pronounced anti-tumor effects of Cu-MOF with apoptosis and cuproptosis were confirmed both in vitro and in vivo experiments. Such dual induction of apoptosis and cuproptosis by Cu-MOF presents a promising therapeutic strategy for NSCLC, particularly for KRAS-mutated tumors, and expands potential applications of Cu-based nanomateirals for other cancers. [ABSTRACT FROM AUTHOR]
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- 2024
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38. GSH-responsive polymeric micelles-based augmented photoimmunotherapy synergized with PD-1 blockade for eliciting robust antitumor immunity against colon tumor.
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Huang, Chenlu, Yang, Xinyu, Li, Huidong, Zhang, Li, Guo, Qing, Yu, Qingyu, Wang, Hai, Zhang, Linhua, and Zhu, Dunwan
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TOLL-like receptor agonists , *APOPTOSIS , *INDOLEAMINE 2,3-dioxygenase , *IMMUNE checkpoint inhibitors , *PHOTODYNAMIC therapy - Abstract
Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What's more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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39. 沉默 miR-126 对关节软骨细胞增殖、凋亡 和炎症反应的影响及其机制.
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何至, 许凯, 裴新武, 颜端国, and 严林
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Objective To investigate the effects of silencing miR-126 on proliferation, apoptosis, and inflammatory response of osteoarticular chondrocytes and their mechanism. Methods Human osteoarticular chondrocytes HC-a were cultured in vitro. HC-a cells in the third generation, which were in the logarithmic growth phase and had good growth status, were randomly divided into the control group, IL-1β group, IL-1β + miR-NC group, and IL-1β + miR-126 inhibitor group, respectively. Cells in the IL-1β + miR-NC group and IL-1β + miR-126 inhibitor group were transfected with miR-NC and miR-126 inhibitor, respectively. Except for the control group, the other three groups were treated with 10 ng/mL IL-1β induction to construct the cell models of osteoarthritis (OA) . The cells of each group were collected, and the expression of miR-126 was detected by RT-qPCR, cell proliferation activity was detected by CCK-8, apoptosis rate was detected by flow cytometry, and inflammatory factors TNF-α, IL-6 and IFN-γ in the culture supernatant were detected by ELISA. The expression levels of SIRT1 and Caspase-3 proteins were detected by Western blotting. Results Compared with the control group, the relative expression of miR-126 increased, the cell proliferation activity decreased, apoptosis rate increased, the levels of TNF-α, IL-6 and IFN-γ in culture supernatance increased, the relative expression of SIRT1 protein decreased, and the relative expression of Caspase-3 protein increased in the IL-1β group (all P<0. 05) . Compared with the IL-1β + miR-NC group, the relative expression decreased, cell proliferation activity increased, apoptosis rate decreased, the levels of TNF-α, IL-6 and IFN-γ in culture supernatant decreased, the relative expression of SIRT1 protein increased, and the relative expression of Caspase-3 protein decreased in the miR-126 inhibitor group (all P<0. 05) . There were no significant differences in the above indexes between IL-1β group and IL-1β + miR-NC group (all P>0. 05) . Conclusion Silencing miR-126 can promote the proliferation of OA cells and inhibit apoptosis and inflammation, which may be related to the regulation of SIRT1 protein expression. [ABSTRACT FROM AUTHOR]
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- 2024
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40. Cardioprotective effect of Vitamin D on cardiac hypertrophy through improvement of mitophagy and apoptosis in an experimental rat model of levothyroxine -induced hyperthyroidism.
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Shokri, Farid, Ramezani-Aliakbari, Khadijeh, Zarei, Mohammad, Komaki, Alireza, Raoufi, Safoura, Naddaf, Hanieh, and Ramezani-Aliakbari, Fatemeh
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Background: Mitochondria are known to be involved in mediating the calorigenic effects of thyroid hormones. With an abundance of these hormones, alterations in energy metabolism and cellular respiration take place, leading to the development of cardiac hypertrophy. Vitamin D has recently gained attention due to its involvement in the regulation of mitochondrial function, demonstrating promising potential in preserving the integrity and functionality of the mitochondrial network. The present study aimed to investigate the therapeutic potential of Vitamin D on cardiac hypertrophy induced by hyperthyroidism, with a focus on the contributions of mitophagy and apoptosis as possible underlying molecular mechanisms. Methods and results: The rats were divided into three groups: control; hyperthyroid; hyperthyroid + Vitamin D. Hyperthyroidism was induced by Levothyroxine administration for four weeks. Serum thyroid hormones levels, myocardial damage markers, cardiac hypertrophy indices, and histological examination were assessed. The assessment of Malondialdehyde (MDA) levels and the expression of the related genes were conducted using heart tissue samples. Vitamin D pretreatment exhibited a significant improvement in the hyperthyroidism-induced decline in markers indicative of myocardial damage, oxidative stress, and indices of cardiac hypertrophy. Vitamin D pretreatment also improved the downregulation observed in myocardial expression levels of genes involved in the regulation of mitophagy and apoptosis, including PTEN putative kinase 1 (PINK1), Mitofusin-2 (MFN2), Dynamin-related Protein 1 (DRP1), and B cell lymphoma-2 (Bcl-2), induced by hyperthyroidism. Conclusions: These results suggest that supplementation with Vitamin D could be advantageous in preventing the progression of cardiac hypertrophy and myocardial damage. [ABSTRACT FROM AUTHOR]
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- 2024
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41. The role of the miR-30a-5p/ BCL2L11 pathway in rosmarinic acid-induced apoptosis in MDAMB-231-derived breast cancer stem-like cells.
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Wei Wang, Yuefen Zhang, Xiaomin Huang, Dan Li, Qi Lin, Hailin Zhuang, and Hong Li
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Background: Rosmarinic acid (RA), a natural phenolic acid, exhibits promising anti-cancer properties. The abnormal expression of microRNA (miRNA) regulates the gene expression and plays a role as an oncogenic or tumor suppressor in TNBC. However, the biological role of RA in miR-30a-5p on BCL2L11 during MDA-MB-231 induced breast cancer stem-like cells (BCSCs) progression and its regulatory mechanism have not been elucidated. Objective: To investigate whether RA inhibited the silencing effect of miR-30a- 5p on the BCL2L11 gene and promoted apoptosis in BCSCs. Materials and Methods: We assessed the migration, colony formation, proliferation, cell cycle, and apoptosis of BCSCs after RA treatment using the wound-healing assay, colony formation assay, CCK-8 assay, and flowcytometry, respectively. The expression of mRNA and protein levels of BCL-2, Bax, BCL2L11, and P53 genes in BCSCs after RA treatment was obtained by real-time polymerase chain reaction and Western blot. DifferentialmiRNA expression in BCSCswas analyzed by high-throughput sequencing. Targetscan was utilized to predict the targets of miR-30a-5p. The dual luciferase reporter system was used for validation of the miR-30a-5p target. Results:Wound-healing assay, colony formation assay,CCK-8 assay, and cell cycle assay results showed that RA inhibited migration, colony formation and viability of BCSCs, and cell cycle arrest in the G0-G1 phase. At the highest dose of RA, we noticed cell atrophy, while the arrest rate at 100 μg/mL RA surpassed that at 200 μg/mL RA. Apoptotic cells appeared early (Membrane Associated Protein V FITC
+ , PI- ) or late (Membrane Associated Protein V FITC+ , PI+ ) upon administration of 200 µg/mL RA, Using high-throughput sequencing to compare the differences in miRNA expression, we detected downregulation ofmiR-30a-5p expression, and the results of dual luciferase reporter gene analysis indicated that BCL2L11 was a direct target of miR-30a-5p. Conclusion: RA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and enhanced apoptosis in BCSCs. [ABSTRACT FROM AUTHOR]- Published
- 2024
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42. Aquaporin 1 is renoprotective in septic acute kidney injury by attenuating inflammation, apoptosis and fibrosis through inhibition of P53 expression.
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Wuyang Lv, Jia Liao, Cuicui Li, Dongyang Liu, Xiaoxiao Luo, RuXue Diao, YuChen Wang, and Yingyu Jin
- Abstract
Sepsis associated Acute kidney injury (AKI) is a common clinical syndrome characterized by suddenly decreased in renal function and urinary volume. This study was designed to investigate the role of Aquaporin 1 (AQP1) and P53 in the development of sepsis-induced AKI and their potential regulatorymechanisms. Firstly, transcriptome sequencing analysis of mice kidney showed AQP1 expression was reduced and P53 expression was elevated in Cecal ligation and puncture (CLP)- induced AKI compared with controls. Bioinformatics confirmed that AQP1 expression was remarkably decreased and P53 expression was obviously elevated in renal tissues or peripheral blood of septic AKI patients. Moreover, we found in vivo experiments that AQP1mRNA levels were dramatically decreased and P53mRNA significantly increased following the increased expression of inflammation, apoptosis, fibrosis, NGAL and KIM-1 at various periods in septic AKI. Meanwhile, AQP1 and P53 protein levels increased significantly first and then decreased gradually in kidney tissue and serum of rats in different stages of septic AKI. Most importantly, in vivo and vitro experiments demonstrated that silencing of AQP1 greatly exacerbates renal or cellular injury by upregulating P53 expression promoting inflammatory response, apoptosis and fibrosis. Overexpression of AQP1 prevented the elevation of inflammation, apoptosis and fibrosis by down-regulating P53 expression in Lipopolysaccharide (LPS)-induced AKI or HK-2 cells. Therefore, our results suggested that AQP1 plays a protective role in modulating AKI and can attenuate inflammatory response, apoptosis and fibrosis via downregulating P53 in septic AKI or LPS-induced HK-2cells. The pharmacological targeting of AQP1mediated P53 expressionmight be identified as potential targets for the early treatment of septic AKI. [ABSTRACT FROM AUTHOR]
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- 2024
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43. Reversal of cadmium-induced toxicity in Meretrix meretrix as determined by alleviation of oxidative damage following short-term depuration.
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Jian Zhou, Huiqi Cai, Yuning Zhong, Yu Zheng, Yinuo Wu, Kueichieh Chang, Alan, and Xueping Ying
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OXIDATIVE stress ,OXYGEN detectors ,REACTIVE oxygen species ,HEAVY metals ,CLAMS ,BIVALVE shells - Abstract
Cadmium (Cd) is a toxic heavy metal that, when present as a pollutant in the marine environment, is readily accumulated by marine bivalves, causing oxidative stress and tissue damage. This study explored whether short-term depuration could reverse Cd
2+ -induced toxicity in the ovary of the clam Meretrix meretrix. Clams exposed to 3 mg L-1 Cd2+ for three days showed increased accumulated Cd2+ in their ovaries with obvious tissue damage as shown by loose structure and some apoptotic cells compared with non-exposed clams. Increased oxidative stress in the ovarian tissue was also obvious, as revealed by increased levels of oxidative indicators such as reactive oxygen species (ROS), malondialdehyde (MDA), DNA-protein crosslinking (DPC), and protein carbonylation (PCO) and increased expression levels of genes related to oxidative stress and apoptosis, which included the Bax, Bcl-2, caspase-3, HO-1, Hsp70, NQO1, Nrf2, and MT genes. When the clams were exposed to Cd2+ for three more days, the accumulated Cd2+ level in the ovary increased to more than 10-fold the level in the control clams, accompanied by more severe damage and cell death as well as oxidative stress. However, when the initial three-day Cd2+ exposure was followed by three days of depuration in Cd2+ -free seawater, the Cd2+ level in the ovary was reduced by as much as 20%, accompanied by some recovery of tissue damage and reduced oxidative stress, suggesting that short-term depuration may mitigate Cd2+ -induced toxicity in M. meretrix, allowing the clams to recover and potentially reducing the risk of Cd2+ exposure from consuming contaminated clams. [ABSTRACT FROM AUTHOR]- Published
- 2024
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44. Reactive oxygen species activate the Drosophila TNF receptor Wengen for damage-induced regeneration.
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Esteban-Collado, José, Fernández-Mañas, Mar, Fernández-Moreno, Manuel, Maeso, Ignacio, Corominas, Montserrat, and Serras, Florenci
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TUMOR necrosis factor receptors , *MITOGEN-activated protein kinases , *DROSOPHILA melanogaster , *REACTIVE oxygen species , *CELL survival - Abstract
Tumor necrosis factor receptors (TNFRs) control pleiotropic pro-inflammatory functions that range from apoptosis to cell survival. The ability to trigger a particular function will depend on the upstream cues, association with regulatory complexes, and downstream pathways. In Drosophila melanogaster, two TNFRs have been identified, Wengen (Wgn) and Grindelwald (Grnd). Although several reports associate these receptors with JNK-dependent apoptosis, it has recently been found that Wgn activates a variety of other functions. We demonstrate that Wgn is required for survival by protecting cells from apoptosis. This is mediated by dTRAF1 and results in the activation of p38 MAP kinase. Remarkably, Wgn is required for apoptosis-induced regeneration and is activated by the reactive oxygen species (ROS) produced following apoptosis. This ROS activation is exclusive for Wgn, but not for Grnd, and can occur after knocking down Eiger/TNFα. The extracellular cysteine-rich domain of Grnd is much more divergent than that of Wgn, which is more similar to TNFRs from other animals, including humans. Our results show a novel TNFR function that responds to stressors by ensuring p38-dependent regeneration. Synopsis: TNF receptors (TNFR) have been associated with pleiotropic pro-inflammatory functions ranging from apoptosis to survival. This study shows that the two Drosophila TNFRs, Wengen (Wgn) and Grindelwald (Gwd), are functionally divergent, playing opposing roles in response to apoptosis. Wgn is required for cell survival independently of the TNFα/Eiger, whereas Grnd promotes TNFα/Eiger-induced apoptosis. Wgn exerts its pro-survival role by signaling through the MAPK p38 during regeneration. Wgn, but not Grnd, is regulated by ROS generated in response to damage in a non-autonomous manner. The specialization of grnd and wgn for specific biological functions is supported by phylogenetic studies on their evolutionary origin. The two Drosophila TNFRs perform opposing functions in response to apoptosis and differ in their dependence on TNFα for activation. [ABSTRACT FROM AUTHOR]
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- 2024
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45. Tert‐butylhydroquinone promotes skin flap survival by inhibiting oxidative stress mediated by the Nrf2/HO‐1 signalling pathway.
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Wang, Kaitao, Wang, An, Deng, Jiapeng, Yang, Jialong, Chen, Guodong, Chen, Qingyu, Ye, Minle, and Lin, Dingsheng
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TRANSCRIPTION factors , *CELLULAR signal transduction , *DERMATOLOGIC surgery , *SURGICAL flaps , *FOOD additives - Abstract
Background and Purpose Experimental Approach Key Results Conclusion and Implications Skin flaps are among the most important means of wound repair in clinical settings. However, partial or even total distal necrosis may occur after a flap operation, with severe consequences for both patients and doctors. This study investigated whether
tert ‐butylhydroquinone (TBHQ), a known agonist of the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2), and an antioxidant, could promote skin flap survival.McFarlane skin flap models were established in male Sprague–Dawley rats and then randomly divided into control, low‐dose TBHQ, and high‐dose TBHQ treatment groups. On postoperative day 7, the survival and blood flow of the skin flaps were assessed. Using flap tissue samples, angiogenesis, inflammation, apoptosis, autophagy, and Nrf2/haem oxygenase 1 (HO‐1) signalling pathway activity were measured with immunohistochemical techniques and western blotting.TBHQ dose‐dependently stimulated the Nrf2/HO‐1 signalling pathway, inducing autophagy through the up‐regulation of LC3B and beclin 1 and concurrently suppressing p62 expression. Additionally, TBHQ hindered apoptosis by enhancing Bcl‐2 expression while inhibiting the expression of Bax. It suppressed inflammation by inhibiting the expression of interleukin 1β, interleukin 6, and tumour necrosis factor‐α and enhanced angiogenesis by promoting the expression of vascular endothelial growth factor.In summary, TBHQ promoted flap survival in rats by up‐regulating the Nrf2/HO‐1 signalling pathway. As TBHQ is already widely used as a food additive, it could offer an acceptable means of improving clinical outcomes following skin flap surgery in patients. [ABSTRACT FROM AUTHOR]- Published
- 2024
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46. The plant extract PNS mitigates atherosclerosis via promoting Nrf2‐mediated inhibition of ferroptosis through reducing USP2‐mediated Keap1 deubiquitination.
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Zhao, Yun, Zheng, Guobin, Yang, Shu, Liu, Shangjing, Wu, Yifan, Miao, Yaodong, Liang, Zhen, Hua, Yunqing, Zhang, Jing, Shi, Jia, Li, Dan, Cheng, Yanfei, Zhang, Yunsha, Chen, Yuanli, Fan, Guanwei, and Ma, Chuanrui
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FOAM cells , *APOPTOSIS , *IRON metabolism , *PLANT extracts , *CARDIOVASCULAR diseases , *UBIQUITINATION , *SAPONINS - Abstract
Background and purpose Experimental approach Key results Conclusion and implications Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (
Panax notoginseng saponins ), containing the main active ingredients ofPanax notoginseng , exhibits anti‐atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s).The anti‐atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE−/− mice. In vitro, the anti‐ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2−/− macrophages. Finally, the anti‐atherogenic effect of USP2 knockout was determined by using USP2−/− mice treated with high‐fat diet (HFD) and AAV‐PCSK9.PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis‐aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis‐aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro.PNS reduced USP2‐mediated Keap1 de‐ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti‐atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS. [ABSTRACT FROM AUTHOR]- Published
- 2024
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47. Tumor microenvironment-responsive manganese-based nano-modulator activate the cGAS-STING pathway to enhance innate immune system response.
- Author
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Liang, Xiayi, Wang, Duo, Zhao, Yuanquan, Wang, Xiaobo, Yao, Siyang, Huang, Wei, Yang, Yongyu, Dong, Xiaofeng, Zhang, Lei, and Yang, Jianrong
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KILLER cells , *TYPE I interferons , *APOPTOSIS , *REACTIVE oxygen species , *NATURAL immunity , *INTERFERON receptors - Abstract
Background: Manganese ions (Mn2+) combined with adjuvants capable of damaging and lysing tumor cells form an antitumor nano-modulator that enhances the immune efficacy of cancer therapy through the cascade activation of the cyclic GMP-AMP interferon gene synthase-stimulator (cGAS-STING) pathway, which underscores the importance of developing antitumor nano-modulators, which induce DNA damage and augment cGAS-STING activity, as a critical future research direction. Methods and Results: We have successfully synthesized an antitumor nano-modulator, which exhibits good dispersibility and biosafety. This nano-modulator is engineered by loading manganese dioxide nanosheets (M-NS) with zebularine (Zeb), known for its immunogenicity-enhancing effects, and conducting targeted surface modification using hyaluronic acid (HA). After systemic circulation to the tumor site, Mn2+, Zeb, and reactive oxygen species (ROS) are catalytically released in the tumor microenvironment by H+ and H2O2. These components can directly or indirectly damage the DNA or mitochondria of tumor cells, thereby inducing programmed cell death. Furthermore, they promote the accumulation of double-stranded DNA (dsDNA) in the cytoplasm, enhancing the activation of the cGAS-STING signalling pathway and boosting the production of type I interferon and the secretion of pro-inflammatory cytokines. Additionally, Zeb@MH-NS enhances the maturation of dendritic cells, the infiltration of cytotoxic T lymphocytes, and the recruitment of natural killer cells at the tumor site. Conclusions: This HA-modified manganese-based hybrid nano-regulator can enhance antitumor therapy by boosting innate immune activity and may provide new directions for immunotherapy and clinical translation in cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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48. Role of G protein coupled receptors in acute kidney injury.
- Author
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Lv, Liangjing, Liu, Yong, Xiong, Jiachuan, Wang, Shaobo, Li, Yan, Zhang, Bo, Huang, Yinghui, and Zhao, Jinghong
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G protein coupled receptors , *ACUTE kidney failure , *METABOLIC reprogramming , *LIGANDS (Biochemistry) , *APOPTOSIS , *PURINERGIC receptors , *PROSTAGLANDIN receptors - Abstract
Acute kidney injury (AKI) is a clinical condition characterized by a rapid decline in kidney function, which is associated with local inflammation and programmed cell death in the kidney. The G protein-coupled receptors (GPCRs) represent the largest family of signaling transduction proteins in the body, and approximately 40% of drugs on the market target GPCRs. The expressions of various GPCRs, prostaglandin receptors and purinergic receptors, to name a few, are significantly altered in AKI models. And the role of GPCRs in AKI is catching the eyes of researchers due to their distinctive biological functions, such as regulation of hemodynamics, metabolic reprogramming, and inflammation. Therefore, in this review, we aim to discuss the role of GPCRs in the pathogenesis of AKI and summarize the relevant clinical trials involving GPCRs to assess the potential of GPCRs and their ligands as therapeutic targets in AKI and the transition to AKI-CKD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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49. Targeting NLRP3 inhibits AML progression by inducing PERK/eIF2-mediated apoptosis.
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Luciano, Michela, Sieberer, Helene, Krenn, Peter W., Dang, Hieu-Hoa, Vetter, Julia, Neuper, Theresa, Amend, Diana, Blöchl, Constantin, Weichenberger, Christian X., Eglseer, Anna, Unger, Michael S., Andosch, Ancuela, Steiner, Philip, Neureiter, Daniel, Bauer, Renate, Hummer, Laura, Tesanovic, Suzana, Binder, Stephanie, Elmer, Dominik P., and Strandt, Helen
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RNA interference , *ACUTE myeloid leukemia , *SMALL interfering RNA , *MYELOID cells , *TRANSMISSION electron microscopy - Abstract
Background: Acute myeloid leukemia (AML) is characterized by the abnormal proliferation of myeloid precursor cells and presents significant challenges in treatment due to its heterogeneity. Recently, the NLRP3 inflammasome has emerged as a potential contributor to AML pathogenesis, although its precise mechanisms remain poorly understood. Methods: Public genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1β, IL-18, ASC, and NLRP3) in AML patients compared to healthy individuals. CRISPR/Cas9 technology was employed to generate NLRP3-deficient MOLM-13 AML cells, followed by comprehensive characterization using real-time PCR, western blotting, FACS analysis, and transmission electron and immunofluorescence microscopy. Proteomic analyses were conducted to identify NLRP3-dependent alterations in protein levels, with a focus on the eIF2 kinase PERK-mediated signaling pathways. Additionally, in vivo studies were performed using a leukemic mouse model to elucidate the pathogenic role of NLRP3 in AML. Results: Elevated expression of NLRP3 was significantly associated with diminished overall survival in AML patients. Genetic deletion, pharmacological inhibition and silencing by RNA interference of NLRP3 led to decreased AML cell survival through the induction of apoptosis. Proteomic analyses uncovered NLRP3-dependent alterations in protein translation, characterized by enhanced eIF2α phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2α phosphorylation reduced apoptosis by downregulating pro-apoptotic Bcl-2 family members. In vivo studies demonstrated reduced leukemic burden in mice engrafted with NLRP3 knockout AML cells, as evidenced by alleviated leukemic symptoms. Conclusion: Our findings elucidate the involvement of the NLRP3/PERK/eIF2 axis as a novel driver of AML cell survival. Targeting NLRP3-induced signaling pathways, particularly through the PERK/eIF2 axis, presents a promising therapeutic strategy for AML intervention. These insights into the role of the NLRP3 inflammasome offer potential avenues for improving the prognosis and treatment outcomes of AML patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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50. Green synthesis of copper oxide nanoparticles using walnut shell and their size dependent anticancer effects on breast and colorectal cancer cell lines.
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Abdollahzadeh, Hanieh, Pazhang, Yaghub, Zamani, Asghar, and Sharafi, Yousef
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COLORECTAL cancer , *CELL lines , *CANCER cells , *BREAST cancer , *ANTINEOPLASTIC agents , *COPPER oxide , *BREAST - Abstract
Metal oxide nanoparticles(NPs) contain unique properties which have made them attractive agents in cancer treatment. The CuO nanoparticles were green synthesized using walnut shell powder in different calcination temperatures (400°, 500°, 700°, and 900 °C). The CuO nanoparticles are characterized by FTIR, XRD, BET, SEM and DLS analyses. SEM and DLS analyses showed that by increasing the required calcination temperature for synthesizing the NPs, their size was increased. DPPH analysis displayed no significant anti-oxidative properties of the CuO NPs. The MTT analysis showed that all synthesized CuO NPs exhibited cytotoxic effects on MCF-7, HCT-116, and HEK-293 cell lines. Among the CuO NPs, the CuO-900 NPs showed the least cytotoxic effect on the HEK-293 cell line (IC50 = 330.8 µg/ml). Hoechst staining and real-time analysis suggested that the CuO-900 NPs induced apoptosis by elevation of p53 and Bax genes expression levels. Also, the CuO-900 NPs increased the Nrf-2 gene expression level in MCF-7 cells, despite the HCT-116 cells. As can be concluded from the results, the CuO-900 NPs exerted promising cytotoxic effects on breast and colon cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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