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Background: The present study investigated the function of G protein-coupled receptor kinase 2 (GRK2) in acute liver injury (ALI) by cisplatin, and investigated the protective effect of pharmacological inhibition of GRK2., Methods: ALI models were generated in global adult hemizygous (ALI-Grk2 ± ) mice and wild-type (WT) mice. Liver biochemistry parameters and histopathology were used to evaluate the severity of ALI and the protective effect of pharmacological inhibition of GRK2. GRK2-siRNA was used to knock down the expression of GRK2 in AML12 cells in vitro., Results: ALI model mice exhibited increased blood levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and abnormal liver pathology accompanied by imbalanced L-glutathione (GSH) levels. Cisplatin administration upregulated GKR2, p-GRK2 and NADPH oxidase 4 (NOX4) expression in the liver tissues of ALI model mice. Compared to WT mice injected with cisplatin, Grk2 ± mice that received cisplatin showed significant improvements in liver function and pathological performance, decreased NOX4 levels, reduced endoplasmic reticulum (ER) stress, and diminished liver cell apoptosis. In vitro, the transfection of AML12 cells with siRNA significantly reduced NOX4 expression and inhibited cisplatin-induced reactive oxygen species production, ER stress (increased levels of GRP94, GRP78, p-elF2α and CHOP) and apoptotic death. Moreover, pharmacological treatment with drugs that inhibit GRK2 (CP-25 or paroxetine) significantly ameliorated cisplatin-induced ALI by improving liver pathological manifestations, inhibiting oxidative stress and ER stress, and reducing liver cell apoptosis. Similar results were observed in vitro., Conclusions: GRK2 mediates the development of cisplatin-induced ALI by modulating NOX4 and ER stress. Pharmacological inhibition of GRK2 with CP-25 or paroxetine effectively alleviated ALI. GRK2 can be used as a potential target for the prevention and treatment of liver injury., Competing Interests: Declarations Ethics approval and consent to participate The present study was approved by the Subcommittee of the Institute of Clinical Pharmacology, Ethical Committee on Animal Research of Anhui Medical University (No. PZ-2021–015; Date: May 8th, 2021) and conducted according to the U.K. Animals (Scientific Procedures) Act, 1986 and our institutional guidelines for the care and use of animals. Consent for publication No applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Diabetes mellitus commonly causes endothelial cell and smooth muscle cell death in penile cavernous tissue., Aim: The study sought to study the mode of cell death in the penile cavernous tissue in type 1 diabetic rats., Methods: A total of 36 Sprague Dawley rats 10 weeks of age were randomly divided into 2 groups: a normoglycemic group and type 1 diabetic group (intraperitoneal injection of Streptozotocin (STZ), 60 mg/kg). We randomly selected 6 rats from each group for tests at the end of 11, 14, and 18 weeks of age, respectively. All rats were able to eat and drink freely. The ratio of maximum intracavernous pressure to mean arterial pressure, concentration of serum testosterone, level of nitric oxide in the penile cavernosum, and expression of active caspase-1 (pyroptosis) and active caspase-3 (apoptosis) were determined., Outcomes: At the end of weeks 4 and 8 of type 1 diabetes, the proportions of endothelial cells and smooth muscle cells undergoing apoptosis and pyroptosis in penile cavernous tissue are different., Results: The ratio of maximum intracavernous pressure to mean arterial pressure and nitric oxide levels were significantly lower in the 4- and 8-week diabetic groups than in the normoglycemic group (P < .01). Penile endothelial cell pyroptosis (5.67 ± 0.81%), smooth muscle cell apoptosis (23.72 ± 0.48%), total cell pyroptosis (9.67 ± 0.73%), and total apoptosis (10.52 ± 1.45%) were significantly greater in the 4-week diabetic group than in the normoglycemic group (P < .01). The proportion of endothelial cell pyroptosis (24.4 ± 3.69%), endothelial cell apoptosis (22.13 ± 2.43%), total cell pyroptosis (14.75 ± 0.93%), and total apoptosis (14.82 ± 1.08%) in the penile tissues of the 8-week diabetic group were significantly greater than those in the normoglycemic group (P < .01).The 8-week survival proportions of diabetic endothelial cells (38.86 ± 8.85%) and smooth muscle cells (44.46 ± 2.94%) was significantly lower than the 4-week survival proportions of endothelial cells (93.17 ± 8.07%) and smooth muscle cells (75.12 ± 4.76%) (P < .05)., Clinical Translation: Inhibition of cell death by different methods at different stages may be the key to the treatment of type 1 diabetes-induced erectile dysfunction., Strengths and Limitations: The effect of type 1 diabetes on other types of cell death in penile cavernous tissue needs further study., Conclusion: The mode of death of endothelial cells in the cavernous tissue of the penis in the early stage in diabetic rats is dominated by pyroptosis, and the death of smooth muscle cells is dominated by apoptosis. Endothelial cell and smooth muscle cell death are not consistent at different stages of diabetes progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Colorectal cancer (CRC) is the second most deadly cancer worldwide. Although various treatments for CRC have made progress, they have limitations. Therefore, the search for new effective molecular targets is important for the treatment of CRC. p20BAP31 induces apoptosis through diverse pathways and exhibits greater sensitivity in CRC. Therefore, a comprehensive exploration of the molecular functions of p20BAP31 is important for its application in anti-tumor therapy. In this study, we showed that exogenous p20BAP31 was still located in the ER and significantly activated the unfolded protein response (UPR) through the PERK pathway. The activation of the PERK pathway is prominent in p20BAP31-induced reactive oxygen species (ROS) accumulation and apoptosis. We found, for the first time, that p20BAP31 leads to ER stress and markedly attenuates tumor cell growth in vivo. Importantly, mechanistic investigations indicated that p20BAP31 competitively binds to GRP78 from PERK and causes hyperactivation of the UPR. Furthermore, p20BAP31 upregulates the expression of GRP78 by promoting HSF1 nuclear translocation and enhancing its binding to the GRP78 promoter. These findings reveal p20BAP31 as a regulator of ER stress and a potential target for tumor therapy, and elucidate the underlying mechanism by which p20BAP31 mediates signal transduction between ER and mitochondria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum (ER) membrane protein involved in apoptosis and autophagy by communication with ER and mitochondria. BAP31 is cleaved by caspase-8 and generates a proapoptotic fragment, p20BAP31, which has shown to induce ER stress and apoptosis through multiple pathways. In this study, we found that p20BAP31 significantly increased the agglomeration of LC3 puncta, suggesting the occurrence of autophagy. Therefore, it is meaningful to explore the mechanism of p20BAP31-induced autophagy, and further analyze the relationships among p20BAP31-induced autophagy, ER stress and apoptosis. The data showed that p20BAP31 induced autophagy by inhibition of the PI3K/AKT/mTOR signaling in colorectal cells. ER stress inhibitor 4-PBA and PERK siRNA alleviated p20BAP31-induced autophagy; in turn, autophagy inhibitors 3-MA and CQ did not affect p20BAP31-induced ER stress, suggesting that p20BAP31-induced ER stress is the upstream of autophagy. We also discovered that ROS inhibitor NAC inhibited p20BAP31-induced autophagy. Furthermore, inhibition of autophagy by CQ suppressed p20BAP31-induced apoptosis and ameliorated cell proliferation. Importantly, p20BAP31 markedly reduced the tumor size in vivo, and significantly enhanced the autophagy levels in the tumor tissues. Collectively, p20BAP31 initiates autophagy by inhibiting the PI3K/AKT/mTOR signaling and activating the PERK-mediated ROS accumulation, further promotes p20BAP31-induced apoptosis and ultimately results in cell death. This study comprehensively reveals the potential mechanism of p20BAP31-induced cell death, which may provide new strategies for antitumor therapy.

Objective: This study was to investigate the functional role of RNA methyltransferase METTL3, an enzyme catalyzes the formation of N6-methyladenosine (m6A) on the target mRNA, in the development of osteoarthritis (OA) and the underlying mechanism., Methods: Cytokine IL-1β was used to stimulate the chondroprogenitor cell line ATDC5 cells to mimic the inflammatory condition in vitro. The level of METTL3 mRNA and m6A as well as inflammatory cytokines were detected by qRT-PCR. Cell activity was detected by CCK-8. The rate of apoptotic cell was measured by flow cytometry. Western blot was used to detect the levels of NF-κB signaling molecules and collagen in cells. Methylation inhibitor cycloleucine and methyl donor betaine were used to treat collagenase-induced OA mice., Results: In IL-1β-treated ATDC5 cells, the METTL3 mRNA levels and the percentage of m6A methylated mRNA of total mRNA were increased in a dose-dependent manner. Silencing of METTL3 by shRNA reduced the percentage of IL-1β-induced apoptosis, suppressed IL-1β-induced increased inflammatory cytokines levels and activation of NF-κB signaling in chondrocytes. Moreover, silencing of METTL3 promotes degradation of extracellular matrix (ECM) by reducing the expression of MMP-13 and Coll X, elevating the expression of Aggrecan and Coll II. In a OA mouse model induced by collagenase, injection of methylation inhibitor cycloleucine or methyl donor betaine does not affects METTL3 mRNA expression, but significantly inhibits or promotes the total level of m6A as well as inflammatory condition and ECM degradation, respectively., Conclusion: METTL3 has a functional role in mediates osteoarthritis progression by regulating NF-κB signaling and ECM synthesis in chondrocytes that shed insight on developing preventive and curative strategies for OA by focusing on METTL3 and mRNA methylation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neuronal apoptosis is regarded as one of the most important pathophysiological changes of intracerebral hemorrhagic (ICH) stroke-a major public health problem that leads to high mortality rates and functional dependency. Mitogen-and stress-activated kinase (MSK) 1 is implicated in various biological functions in different cell types, including proliferation, tumorigenesis and responses to stress. Our previous study showed that MSK1 phosphorylation (p-MSK1) is related to the regulation of LPS-induced astrocytic inflammation, and possibly acts as a negative regulator of inflammation. In this study, we identified a specific interaction between MSK1 and MRKβ (MLK-related kinase)-a member of the MAPK pathway-during neuronal apoptosis. In an ICH rat model, western blotting and immunohistochemical analysis revealed that both MRKβ and phosphorylation of MSK1 (p-MSK1 Ser376) were significantly upregulated in cells surrounding the hematoma. Triple-immunofluorescent labeling demonstrated the co-localization of MRKβ and p-MSK1 in neurons, but not astrocytes. Furthermore, MRKβ was partially transported into the nucleus, and interacted with p-MSK1 in hemin-treated neurons. Immunoprecipitation showed that MRKβ and p-MSK1 exhibited an enhanced interaction during the pathophysiology process. Utilizing small interfering RNAs to knockdown MRKβ or MSK1, we verified that MSK1 Ser376 is a phosphorylation site targeted by MRKβ. We also observed that the phosphorylation of NF-κB p65 at Ser276 was mediated by the MRKβ-p-MSK1 complex. Furthermore, it was found that the neuronal apoptosis marker, active caspase-3, was co-localized with MRKβ and p-MSK1. In addition, flow cytometry analysis revealed that knockdown of MRKβ or MSK1 specifically resulted in increased neuronal apoptosis, which suggested that the MRKβ-p-MSK1 complex might exert a neuroprotective function against ICH-induced neuronal apoptosis. Taken together, our data suggest that MRKβ translocated into the nucleus and phosphorylated MSK1 to protect neurons via phosphorylation of p65-a subunit of nuclear factor κB.

Neuronal apoptosis is an important process of secondary brain injury which is induced by neurochemical signaling cascades after traumatic brain injury (TBI). Present study was designed to investigate whether FOS-like antigen 1 (Fra-1) is involved in the neuronal apoptosis. Western blot analysis and immunohistochemistry in a rat TBI model revealed a significant increase in the expression of Fra-1 in the ipsilateral brain cortex, which was in parallel with increase in the expression of active caspase-3. With immunofluorescence double-labeling, Fra-1 was colocalized with active caspase-3 and with NeuN, a neuronal marker. In an in vitro cell injury model, H 2 O 2 exposure induced cell apoptosis and reduced cell viability and at the same time, a similar increased expression of active caspase-3, p53 and Fra-1 was found in PC12 cells. Down-regulation of Fra-1 through transfection with Fra-1 siRNA remarkably elevated cell viability, reduced the expression of active caspase-3 and p53, and decreased apoptosis of PC12 cells after H 2 O 2 exposure. Taken together, present findings suggest that Fra-1 may be involved in the induction of neuronal apoptosis through up-regulating p53 signaling pathway and that this action may contribute to the secondary neuropathological process after TBI.

Background/aims: Autophagy is an evolutionarily conserved catabolic mechanism to maintain energy homeostasis and to remove damaged cellular components, which plays an important role in the survival of various cells. Inhibiting autophagy is often applied as a new strategy to halt the growth of cancer cells., Methods: The effect of FOXO1 gene on cellular function and apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methylthiazoletetrazolium (MTT) assay, western blot, DCFDA mitochondrial membrane potential, and ATP content measurement. FOXO1 siRNA was applied to down-regulate FOXO1 expression in QBC939 cells., Results: Here we reported that FOXO1, acetylation of FOXO1 (Ac-FOXO1) and the following interaction between Ac-FOXO1 and Atg7 regulated the basal and serum starvation (SS)-induced autophagy as evidenced by light chain 3 (LC3) accumulation and p62 degration. Either treatment with FOXO1 siRNA or resveratrol, a sirt1 agonist, inhibited autophagic flux, resulting in oxidative stress, mitochondrial dysfunction (MtD) and apoptosis in QBC939 cells, which were attenuated by enhancing autophagy with rapamycin. On the contrary, inhibiting autophagic flux with 3-MA worsened all these effects in QBC939 cells., Conclusions: Taken together, our study for the first time identified FOXO1 as a potential therapeutic target to cure against human cholangiocarcinoma via regulation of autophagy, oxidative stress and MtD., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: A series of reports revealed that autophagy and apoptosis exerted detrimental effects on the pathology of cardiac ischemia/reperfusion (I/R) injury. Ginsenoside compound K (CK), a major intestinal metabolite underlying the pharmacological actions of orally administered ginseng, has a protective effect against myocardial I/R injury. However, the molecular mechanisms by which CK protects against I/R injury remain unclear. In this study, we hypothesized that the cardioprotective effects of CK against I/R injury are mediated by inhibiting autophagy/apoptosis-related signaling pathways in H9c2 cardiomyocyte cells., Methods: H9c2 cells were incubated with CK and exposed to I/R. Cell viability and damage was analyzed by MTT and lactate dehydrogenase assays. Reactive oxygen species (ROS) generation, mitochondrial damage, and cell apoptosis were analyzed by flow cytometry and TUNEL staining. The expression of autophagy, apoptosis, and related signaling proteins was analyzed by Western blotting and immunofluorescence staining., Results: CK pretreatment promoted cell viability and attenuated ROS accumulation and intracellular mitochondrial damage induced by I/R injury Moreover, CK reduced autophagy by regulating the formation of phagocytic precursors to autophagosomes and also inhibited apoptosis through a mitochondrial-mediated pathway. Additionally the cardioprotective effect of CK against I/R injury was mainly through the activation of the PI3K-Akt signaling pathway., Conclusions: CK pretreatment inhibits autophagy-mediated apoptosis induced by I/R injury through the activation of the PI3K-Akt signaling pathway, which reveals that CK may be one of the key bioactive ingredients of ginseng for the treatment of myocardial I/R injury., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Angiopoietin-like 4 (ANGPTL4) is a potential anti-apoptotic agent for various cells. We examined the protective effect of ANGPTL4 on hypoxia/serum deprivation (SD)-induced apoptosis of MSCs, as well as the possible mechanisms. MSCs were obtained from rat bone marrow and cultured in vitro. Apoptosis was induced by hypoxia/SD for up to 24 hr, and assessed by flow cytometry and TUNEL assay. Expression levels of Akt, ERK1/2, focal adhesion kinase (FAK), Src, Bcl-2, Bax, cytochrome C and cleaved caspase-3 were detected by Western blotting. Integrin β1 mRNA was detected by qRT-PCR. Mitochondrial membrane potential was assayed using a membrane-permeable dye. Hypoxia/SD-induced apoptosis was significantly attenuated by recombinant rat ANGPTL4 in a concentration dependent manner. Moreover, ANGPTL4 decreased the hypoxia/SD-induced caspase-3 cleavage and the cytochrome C release, but increased the Bcl-2/Bax ratio and the mitochondrial membrane potential. Decreased expression of integrin β1, the ANGPTL4 receptor was observed during hypoxia/SD conditions, however, such decrease was reversed by ANGPTL4. In addition, ANGPTL4 induced integrin β1-associated FAK and Src phosphorylation, which was blocked by anti-integrin β1 antibody. ANGPTL4 also reversed the hypoxia/SD-induced decrease of Akt and ERK 1/2 phosphorylation, and the effect of ANGPTL4 was abolished by inhibitors of either integrins, ERK1/2, or phosphatidylinositol 3-kinase (PI3K). Blocking integrinβ1, Akt or ERK largely attenuated anti-apoptotic effect of ANGPTL4. ANGPTL4 protects MSCs from hypoxia/SD-induced apoptosis by interacting with integrins to stimulate FAK complex, leading to downstream ERK1/2 and PI3K/Akt signaling pathways and mimicking the pathway in which MSCs contact with the extracellular matrix.

Erectile dysfunction (ED) is one of the most common male diseases, which seriously affects the patient's quality of life. The risk factors of ED include aging, diabetes, hypertension, hyperlipidemia, and unhealthy lifestyle, and its exact mechanism remains unclear. The apoptosis of endothelial cells in the corpus cavernosum penis may reduce NOS activity, block NO synthesis, and affect penile erection, and the mechanisms of their apoptosis vary with different causes of ED. This article updates the relationship between the apoptosis of endothelial cells and the development of ED.

Background and Purpose: Ischemic postconditioning (Postcond) is defined as a series of intermittent interruptions of blood flow in the early phase of reperfusion that mechanically alters the hydrodynamics of reperfusion. A recent study showed that Postcond reduced infarct size in cerebral ischemia/reperfusion (I/R) injury. However, little is known about the mechanisms of Postcond in cerebral I/R injury. In the present study, we investigated the effects of Postcond in focal cerebral I/R injury in the rat middle cerebral artery occlusion model., Methods: Adult male Sprague-Dawley rats were treated with Postcond after 60 minutes of occlusion (beginning of reperfusion). Neurologic scores and infarct volumes were assessed at 24 and 72 hours. Oxidative stress was evaluated by malondialdehyde assay, and apoptosis-related molecules were studied by Western blotting., Results: Postcond treatment upregulated Bcl-2 and heat-shock protein 70 expression and downregulated cytochrome c release to the cytosol, Bax translocation to the mitochondria, and caspase-3 activity. Postcond treatment also reduced infarct volumes and oxidative stress levels and improved neurologic scores compared with the I/R-only group., Conclusions: These findings indicate that Postcond inhibits focal cerebral I/R injury. This neuroprotective effect is likely achieved by antiapoptotic mechanisms.

To study the effects of recombinant human tumor necrosis factor-alpha (rhTNF-alpha) on HL-60 cells in vitro and in vivo, MTT and colony forming assay were used to examine the effects of rhTNF-alpha on proliferation of HL-60 cells; AO/EB (acridine orange-ethidium bromide) staining, Annexin-V flow cytometry analysis and TUNEL assay were used to detect apoptotic cells. The effect of rhTNF-alpha on xenograft growth of HL-60 cells was evaluated by tumor inhibition rate, histology, ultrastructure and TUNEL assay. The results showed that rhTNF-alpha inhibited the proliferation of HL-60 cells in a dose-dependent manner. Staining of cells with AO/EB revealed that rhTNF-alpha induced nuclear chromatin condensation and fragmentation. Positive Annexin V-FITC on cell membrane showed that rhTNF-alpha induced apoptosis of HL-60 cells in a dose-dependent manner. TUNEL assay showed that the apoptotic percentage of HL-60 cells reached 37.5% when incubated with 3200 U/ml rhTNF-alpha for 48 hours. In vivo rhTNF-alpha inhibited xenograft growth of HL-60 cells with the highest inhibition rate of 60.33%. Pathologically it was found that there were necrotic areas in the tumors of groups treated with rhTNF-alpha. There were more apoptotic cells in treatment groups than in that control group by transmission electron microscopy (TEM) and TUNEL assay. It is concluded that rhTNF-alpha is able to inhibit the proliferation of HL-60 cells and to induce apoptosis of HL-60 cells in vitro and in vivo.

Aim: To investigate the cellular effects of hybrid polar compound hexamethylene bisacetamide (HMBA) on the growth and apoptosis of human hepatocellular carcinoma cells and to provide the molecular mechanism for potential application of HMBA in the treatment of liver cancer., Methods: Effects of HMBA on the growth of human hepatocellular carcinoma SMMC-7721 cells were assayed by MTT chronometry. Apoptosis induced by HMBA was detected by phase-contrast microscopy, flow cytometry, propidium iodide staining and immunocytochemical analysis., Results: The growth of SMMC-7721 cells was significantly inhibited by HMBA, and the growth inhibitory rate was 51.1%, 62.6%, 68.7% and 73.9% respectively after treatment with 5.0, 7.5, 10.0 and 12.5 mmol/L of HMBA. In the cells treated with 10 mmol/L of HMBA for 72 h, the population of cells at sub-G(1) phase significantly increased, and the apoptotic bodies and condensed nuclei were detected. Moreover, treatment of SMMC-7721 cells with 10 mmol/L of HMBA down-regulated the expression of Bcl-2 anti-apoptotic protein, while slightly up-regulated the level of pro-apoptotic protein Bax., Conclusion: Treatment with 10.0 mmol/L of HMBA can significantly inhibit the growth and induce apoptosis of human hepatocellular carcinoma SMMC-7721 cells by decreasing the ratio of Bcl-2 to Bax.

Multifunctional nanocomposites (NC) can greatly enhance therapy outcomes by reducing tumor proliferative potential. We created a novel class of Zn_Mn_CMC_FA_sesamol NC in the current work to combat breast cancer (MDA-MB-231) cells. To understand how zinc (Zn), manganese (Mn), carboxymethylcellulose, and folic acid (FA) interact with sesamol, UV-Visible spectrophotometer and Fourier Transform Infrared spectroscopy were used to analyze the absorption behavior of the synthesized NC. The particle size of NC was confirmed by X-ray diffraction and dynamic light scattering. Scanning electron microscopy was used to assess the morphological features of these NCs. photoluminescence spectrum was used to analyze the optical and electron transition molecules of the sample. In addition to MTT analysis, acridine orange/ethidium bromide (AO/EtBr) analysis of reactive oxygen species (ROS) and nuclear staining with 4′,6-diamidino-2-phenylindole as well as flow cytometry were used to confirm the apoptotic activity of Zn_Mn_CMC_FA_sesamol NC on MDA-MB-231 cells. The results showed significant cytotoxicity, apoptosis induction on AO/EtBr, and increased ROS production in treated cells compared to control cells. The cell cycle analysis revealed that NCs triggered apoptosis and arrested the cell cycle in G0/G1 phases. As a conclusion, the created NC serves as a versatile platform for the successful molecularly targeted chemotherapeutic treatment of cancer.

Salinomycin, a naturally occurring polyether ionophore antibiotic isolated from Streptomyces albus, has been demonstrated potent cytotoxic activity against a variety of cancer cell lines. In particular, it exhibits selective targeting of cancer stem cells. However, systemic toxicity, drug resistance and low bioavailability of the drug significantly limit its potential applications. In this study, the C20‐epi‐isothiocyanate of salinomycin was designed and synthesized, and then reacted with amines as a versatile synthon to assemble a series of salinomycin thiourea derivatives, which improved the druggability of salinomycin. The antiproliferative activities of the compounds were evaluated in vitro against A549, HepG2, HeLa, 4T1, and MCF‐7 cancer cell lines using the CCK‐8 assay. The pharmacological results showed that some salinomycin thiourea derivatives exhibited excellent inhibitory activity against at least one of the tested tumor cells and high selectivity. Further mechanistic studies showed that compound 9 f, containing a 3,5‐difluorobenzyl moiety, could directly induce apoptosis, probably by increasing caspase‐9 protein expression and cell cycle arrest in G1 phase in a concentration dependent manner. [ABSTRACT FROM AUTHOR]

Prolonged skin exposure to ultraviolet radiation can lead to development of several acute and chronic diseases, with UVA exposure considered a primary cause of dermal photodamage. We prepared a wild ginseng adventitious root extract (ARE) that could alleviate UVA irradiation‐induced NIH‐3T3 cell viability decline. After employing a series of purification methods to isolate main active components of ARE, adventitious root protein mixture (ARP) was identified then tested for protective effects against UVA irradiation‐induced NIH‐3T3 cell damage. The results showed that ARP treatment significantly reduced UVA‐induced cell viability decline and confirmed that the active constituent of ARP was the protein, since proteolytic hydrolysis and heat treatment each eliminated ARP protective activity. Moreover, ARP treatment markedly inhibited UVA‐induced apoptosis, cell cycle arrest and DNA fragmentation, while also significantly reversing UVA effects (elevated Bax levels, reduced Bcl‐2 expression) by reducing Bax levels and increasing Bcl‐2 expression. Mechanistically, ARP promoted Akt phosphorylation regardless of UVA exposure, thus confirming ARP resistance to inactivation by UVA light. Notably, in the presence of Akt inhibitor SC0227, ARP could no longer counteract UVA‐induced cell viability decline and DNA fragmentation. Additionally, our results demonstrated that ARP treatment protected UVA‐irradiated NIH‐3T3 cells by preventing UVA‐induced reduction of collagen‐I expression. Taken together, these results suggest that ARP treatment of NIH‐3T3 cells effectively mitigated UVA‐induced cell viability decline by activating intracellular Akt to reduce UVA‐induced DNA damage, leading to reduced rates of apoptosis and cell cycle arrest after UVA exposure and restoring collagen expression to normal levels. [ABSTRACT FROM AUTHOR]

The role of long non‐coding RNAs (lncRNAs) in kidney diseases has been gradually discovered in recent years. LINC00963, as an lncRNA, was found to be involved in chronic renal failure. However, the role and molecular mechanisms of LINC00963 engaged in acute kidney injury (AKI) were still unclear. In this study, we established rat AKI models by ischaemia and reperfusion (I/R) treatment. Urea and creatinine levels were determined, and histological features of kidney tissues were examined following HE staining. CCK8 assay was chosen to assess the viability of hypoxia‐induced HK‐2 cells. Dual‐luciferase reporter gene assays were performed to verify the target relationship between LINC00963 and microRNA. The mRNA and protein levels were assayed by RT‐qPCR and Western blot, respectively. Annexin V‐FITC/PI and TUNEL staining were used to evaluate apoptosis. LINC00963 was highly expressed in the cell and rat models, and miR‐128‐3p was predicted and then verified as a target gene of LINC00963. Knockdown of LINC00963 reduced acute renal injury both in vitro and in vivo. LINC00963 activated the JAK2/STAT1 pathway to aggravate renal I/R injury. LINC00963 could target miR‐128‐3p to reduce G1 arrest and apoptosis through JAK2/STAT1 pathway to promote the progression of AKI. [ABSTRACT FROM AUTHOR]

Late blight, caused by Phytophthora infestans, is the most devastating potato disease worldwide and results in catastrophic production losses. Reactive oxygen species (ROS) are signal molecules utilized at the early stage of plant immunity. Specifically, anionic peroxidases are reported to be involved in many plants' defense systems. However, there is limited information about the function of anionic peroxidase genes in potato immunity. Here, we report that StPOPA, a gene encoding a suberization-associated anionic peroxidase, was induced by P. infestans infection, mechanical damage, as well as jasmonic acid and ethylene treatments. Overexpression of StPOPA gene in potato enhanced potato resistance against P. infestans by promoting the accumulation of callose in the cell wall and ROS in the cytoplasm, and then the callose and ROS restricted the infection and spreading of the disease possibly by purposeful programmed cell death. Our results suggest that StPOPA plays a positive role in potato resistance to immunochallenge, and this gene could be used for the genetic improvement of resistance against potato late blight. [ABSTRACT FROM AUTHOR]

Skeletal muscle development is regulated by a series of regulatory factors, and also including noncoding RNA, especially microRNAs (miRNAs). Recently, miR‐148a has been found to be involved in murine C2C12 differentiation by targeting ROCK1. However, the function of miR‐148a‐3p for the proliferation and apoptosis of bovine muscle cells has not been determined. In this study, we found that miR‐148a‐3p was highly expressed in fetal bovine skeletal muscle and exhibited a decreasing trend in muscle cells during its growth phase. Functional studies indicated that gain of miR‐148a‐3p inhibited the proliferation of bovine muscle cells and promoted apoptosis. Conversely, interference with miR‐148a‐3p inhibitor promoted muscle cell proliferation and inhibited its apoptosis. Mechanistically, KLF6 was confirmed as a new potential target gene of miR‐148a‐3p by TargetScan software prediction and the dual‐luciferase assay verification. Additionally, after a gain or loss of KLF6, the function of KLF6 for muscle cell proliferation and apoptosis was opposite to that of miR‐148a‐3p. Collectively, these findings proposed a novel avenue whereby miR‐148a‐3p impeded bovine myoblast cell proliferation and promoted apoptosis through the posttranscriptional downregulation of KLF6. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common and malignant cancers with extremely high morbidity and mortality in both males and females. Although traditional lung cancer treatments are fast progressing, there are still limitations. Caveolin-1 (Cav-1), a main component of caveolae, participates in multiple cellular events such as immune responses, endocytosis, membrane trafficking, cellular signaling and cancer progression. It has been found tightly associated with lung cancer cell proliferation, migration, apoptosis resistance and drug resistance. In addition to this, multiple bioactive molecules have been confirmed to target Cav-1 to carry on their anti-tumor functions in lung cancers. Cav-1 can also be a predictor for lung cancer patients' prognosis. In this review, we have summarized the valuable research on Cav-1 and lung cancer in recent years and discussed the multifaceted roles of Cav-1 on lung cancer occurrence, development and therapy, hoping to provide new insights into lung cancer treatment. [ABSTRACT FROM AUTHOR]