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Systemic lupus erythematosus (SLE) is an autoimmune disorder that commonly affects the skin, kidneys, joints, and various other systemic tissues, with its development intricately linked to the process of immunosenescence. Quercetin (QC), a phytochemical that occurs naturally, demonstrates many different biological capabilities, such as antibacterial, antioxidant, and anti-inflammatory activities. Our investigation found that QC effectively reduced kidney damage and relieved mesenteric lymph nodes (mLNs) swelling in MRL/lpr lupus mice. Moreover, QC has been found to decrease the number of senescent follicular helper T (Tfh) cells, a pivotal kind of T cells that contribute to the progression of SLE. In vitro, QC exhibited the capacity to modulate mRNA expression levels, with the downregulation of IL-6, IL21-AS1, IL-27, BCL6, and BCL2L12, and the upregulation of FOXP1 and BIM. This modulation resulted in the suppression of Tfh cells differentiation and the enhancement of apoptosis in senescent CD4+ T cells. In addition, the HuProtTM Human Proteome Microarray revealed that QC can directly bind to BCL-2 protein and therefore promote the apoptosis of senescent CD4+ T cell. As a result, our investigative elucidate the potent inhibitory action of QC on the ontogeny of Tfh cells, along with its capacity to abrogate the immunosenescent phenotype. This positions QC as a promising therapeutic strategy for treating SLE. [ABSTRACT FROM AUTHOR]

Background: Various medicinal plants and their bioactive compounds exhibited promising anticancer activities by inducing apoptosis, inhibiting angiogenesis, and modulating several signaling pathways in cancer cells. This study aims to assess whether two medicinal plant extracts have anticancer properties, Suaeda Palaestina and Zygophyllum album. Methods: This study used Ehrlich solid tumor mice as its in vivo model. We divided male mice into five groups (n = 5 per group). Group I was used as a control for Ehrlich ascites carcinoma (EAC). Groups 2 and 3 were given Z. album extract 180 mg/kg and 360 mg/kg body weight intraperitoneally. Groups 4 and 5 were given the same dose of S. palaestina and treated three times a week for 2 weeks, starting on day 10 after EAC implantation. After 3 weeks, we collected blood samples and thigh skeletal muscle, homogenized them, and processed them for analysis. The results showed that Ehrlich solid rats (EST) treated with low-dose dichloromethane extracts from Z. album and S. palaestina had significantly smaller tumor sizes than the control group. Protein expression levels of p53, caspase 3, and Bcl-2 were quantified by western blotting. Results: The extracts from both plants induced the hunger mechanism, leading to increased expression of p53 and caspase 3 and decreased expression of Bcl-2 at the protein level in EST mice treated with Z. album and S. palaestina. In addition, the comet assay indicated that these plants have a genotoxic potential for solid tumor cells. The T3 and T4 levels in EST blood samples revealed that both plants had significantly reduced the concentration of T3 and significantly increased T4 compared to the EST mice untreated group. Furthermore, these results showed that Z. album and S. palaestina had antiproliferative effects in EST mice through apoptosis-mediated genotoxicity. Conclusions: These findings indicated that S. palaestina and Z. album could be considered potential natural sources of anticancer agents. [ABSTRACT FROM AUTHOR]

5-Demethylnobiletin is the active ingredient in citrus polymethoxyflavones that could inhibit the proliferation of several tumor cells. However, the anti-tumor effect of 5-Demethylnobiletin on glioblastoma and the underlying molecular mechanisms are remains unknown. In our study, 5-Demethylnobiletin markedly inhibited the viability, migration and invasion of glioblastoma U87-MG, A172 and U251 cells. Further research revealed that 5-Demethylnobiletin induces cell cycle arrest at the G0/G1 phase in glioblastoma cells by downregulating Cyclin D1 and CDK6 expression levels. Furthermore, 5-Demethylnobiletin significantly induced glioblastoma cells apoptosis by upregulating the protein levels of Bax and downregulating the protein level of Bcl-2, subsequently increasing the expression of cleaved caspase-3 and cleaved caspase-9. Mechanically, 5-Demethylnobiletin trigged G0/G1 phase arrest and apoptosis by inhibiting the ERK1/2, AKT and STAT3 signaling pathway. Furthermore, 5-Demethylnobiletin inhibition of U87-MG cell growth was reproducible in vivo model. Therefore, 5-Demethylnobiletin is a promising bioactive agent that might be used as glioblastoma treatment drug. [ABSTRACT FROM AUTHOR]

Apoptosis is an evolutionarily conserved cell death pathway that plays a crucial role in maintaining tissue homeostasis, orchestrating organismal development, and eliminating damaged cells. Dysregulation of apoptosis can contribute to the pathogenesis of malignant tumors and neurodegenerative diseases. Anticancer drugs typically possess the capacity to induce apoptosis in tumor cells. The Bcl-2 protein family, consisting of 27 members in humans, serves as the key regulator of mitochondrial function. This family can be divided into two functional groups: anti-apoptotic proteins (e.g., Bcl-2, Bcl-xl, Mcl-1) and pro-apoptotic proteins (e.g., Bad, Bax). Mcl-1 exerts its function by binding pro-apoptotic Bcl-2 proteins thereby preventing apoptosis induction. Overexpression of Mcl-1 not only correlates closely with tumorigenesis but also associates significantly with resistance towards targeted therapy and conventional chemotherapy. Effective induction of apoptosis can be achieved through inhibition or interference with Mcl-1. Thus, this mini review discusses existing Mcl-1 inhibitors. [ABSTRACT FROM AUTHOR]

Breast cancer is the predominant form of cancer among women and ranks as the second most prevalent cancer globally, affecting both developed and less developed countries. Presently, accessible cancer treatment methods either employ recently created, secure, and efficient chemotherapeutic medications or directly target innovative pathways that cause apoptosis. One of the indirect strategies for treating this fatal illness has mostly depended on its essential role in cell cycle arrest and apoptosis induction, as well as the antagonistic interaction between the Bcl-2 and Mcl-1 proteins, in order to avert major health repercussions. We reported that newly synthesized fused chromenopyrimidines (3a and 4a) showed potential cell cycle arrest and dual Bcl-2 and Mcl-1 inhibitory characteristics. Bcl-2 and Mcl-1 were the targets of a molecular docking procedure. The previous docking results are in line with the biological data and suggest that 3a may have promising anti-cancer activity. [ABSTRACT FROM AUTHOR]

Despite significant advances in prenatal medicine, spontaneous miscarriage remains one of the most common and serious pregnancy complications, affecting an increasing number of women. Since many aspects of the pathogenesis of spontaneous miscarriage remain unexplained, the aim of this study has been to assess the involvement of the NLRP3 inflammasome as a potential causative factor. The concentrations of NLRP3, IL-1β, IL-18, and cytochrome C in the serum of patients after miscarriage were measured by means of the immunoenzymatic method. In the placental tissue, the expression of NLRP3, IL-1β, IL-18, and Caspase-1 as well as that of the classical apoptosis biomarkers Fas, FasL, Bcl-2, and Ca was evaluated by means of immunohistochemistry techniques. Additionally, in whole blood, the concentrations of elements crucial for pregnancy progression, such as Ca, K, Mg, and Na, were examined by means of the ICP-OES method. Significantly higher concentrations of NLRP3 and IL-18 were demonstrated in the serum of patients with miscarriage as compared to the control group. In the placental tissue samples, a higher expression of IL-1β, IL-18, and Caspase-1 proteins was noted in women who had experienced miscarriage as compared to the control group. At the same time, a significantly lower expression of FasL and Bcl-2 proteins as well as Ca deposits was observed in women after miscarriage as compared to those with a normal pregnancy outcome. Significantly lower concentrations of Ca and K were recorded in the blood of patients with spontaneous miscarriage as compared to pregnant women. The analysis of the results x indicated a greater involvement of the inflammasome in women with spontaneous miscarriage associated with oxidative–antioxidative imbalance than in the case of miscarriage related to NET formation. Our research has provided evidence for the involvement of the inflammasome in the process of spontaneous miscarriage and identifies a new direction for diagnostics that includes NLRP3 as a preventive element in prenatal care, particularly in light of the steadily declining number of pregnancies and the increasing number of reproductive failures. [ABSTRACT FROM AUTHOR]

Mitochondria-targeting agents, known as mitocans, are emerging as potent cancer therapeutics due to pronounced metabolic and apoptotic adaptations in the mitochondria of cancer cells. ONC212, an imipridone-family compound initially identified as a ClpP agonist, is currently under investigation as a potential mitocan with demonstrated preclinical efficacy against multiple malignancies. Despite this efficacy, the molecular mechanism underlying the cell death induced by ONC212 remains unclear. This study systematically investigates the mitochondrial involvement and signaling cascades associated with ONC212-induced cell death, utilizing HeLa and A549 cancer cells. Treated cancer cells exhibited characteristic apoptotic features, such as annexin-V positivity and caspase-3 activation; however, these occurred independently of typical mitochondrial events like membrane potential loss (ΔΨm) and cytochrome c release, as well as caspase-8 activation associated with the extrinsic pathway. Additionally, ONC212 treatment increased the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, which impeded apoptosis, as the overexpression of Bcl-2-GFP and Bcl-xL-GFP significantly reduced ONC212-mediated cell death. Furthermore, combining a sub-lethal dose of the Bcl-2/Bcl-xL inhibitor Navitoclax with ONC212 markedly augmented caspase-3 activation and cell death, still without any notable ΔΨm loss or cytochrome c release. Moreover, inhibition of caspase-9 activity unexpectedly augmented, rather than attenuated, caspase-3 activation and the subsequent cell death. Collectively, our research identifies ONC212 as an atypical mitochondrial-independent, yet Bcl-2/Bcl-xL-inhibitable, caspase-3-mediated apoptotic cell death inducer, highlighting its potential for combination therapies in tumors with defective mitochondrial apoptotic signaling. [ABSTRACT FROM AUTHOR]

Minocycline (Min), as an antibiotic, possesses various beneficial properties such as anti-inflammatory, antioxidant, and anti-apoptotic effects. Despite these known qualities, the precise cardioprotective effect and mechanism of Min in protecting against sepsis-induced cardiotoxicity (SIC) remain unspecified. To address this, our study sought to assess the protective effects of Min on the heart. Lipopolysaccharide (LPS) was utilized to establish a cardiotoxicity model both in vivo and in vitro. Min was pretreated in the models. In the in vivo setting, evaluation of heart tissue histopathological injury was performed using hematoxylin and eosin (H&E) staining and TUNEL. Immunohistochemistry (IHC) was employed to evaluate the expression levels of NLRP3 and Caspase-1 in the heart tissue of mice. During in vitro experiments, the viability of H9c2 cells was gauged utilizing the CCK8 assay kit. Intracellular ROS levels in H9c2 cells were quantified using a ROS assay kit. Both in vitro and in vivo settings were subjected to measurement of oxidative stress indexes, encompassing glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Additionglly, myocardial injury markers like lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) activity were quantified using appropriate assay kits. Western blotting (WB) analysis was conducted to detect the expression levels of NOD-like receptor protein-3 (NLRP3), caspase-1, IL-18, and IL-1β, alongside apoptosis-related proteins such as Bcl-2 and Bax, and antioxidant proteins including superoxide dismutase-1 (SOD-1) and antioxidant proteins including superoxide dismutase-1 (SOD-2), both in H9c2 cells and mouse heart tissues. In vivo, Min was effective in reducing LPS-induced inflammation in cardiac tissue, preventing cell damage and apoptosis in cardiomyocytes. The levels of LDH and CK-MB were significantly reduced with Min treatment. In vitro studies showed that Min improved the viability of H9C2 cells, reduced apoptosis, and decreased ROS levels in these cells. Further analysis indicated that Min decreased the protein levels of NLRP3, Caspase-1, IL-18, and IL-1β, while increasing the levels of SOD-1 and SOD-2 both in vivo and in vitro. Min alleviates LPS-induced SIC by suppressing the NLRP3/Caspase-1 signalling pathway in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, with its high morbidity and mortality rates, is a significant global health burden. Traditional treatments—surgery, chemotherapy, and radiotherapy—are widely used but come with drawbacks such as recurrence, metastasis, and significant side effects, including damage to healthy tissues. To address these limitations, new therapeutic strategies are being developed. Peroxidases (POD) can catalyze excess H2O2 in the tumor microenvironment to generate reactive oxygen species (ROS), which induce cancer cell apoptosis by disrupting redox homeostasis and modulating apoptosis-related proteins. However, natural enzymes face challenges like poor stability, high cost, and sensitivity to environmental conditions, limiting their application in breast cancer treatment. Nanozymes, nanomaterials with enzyme-like activity, offer a promising alternative by overcoming these limitations. Methods: In this study, we successfully prepared Au@Pd nanozymes with peroxidase activity by depositing metallic Pd on Au nanoparticles (Au NPs) synthesized using a trisodium citrate reduction method and ascorbic acid reduction. The in vitro validation was conducted through a series of experiments, including ROS detection, flow cytometry, CCK-8 assay, DNA damage assessment, live/dead cell staining, Western blot (WB), and qPCR. Tumor treatment was performed via tail vein injection of the drug, followed by HE staining of the treated tissues and biochemical analysis of the blood. Results: Au@Pd nanozymes can effectively accumulate at the tumor site through the EPR effect and exert peroxidase-like activity, catalyzing the excess H2O2 in the tumor microenvironment to produce ROS. This triggers apoptosis pathways and DNA damage, leading to the downregulation of the anti-apoptotic protein Bcl-2, upregulation of the pro-apoptotic protein Bax, and induction of apoptosis-related genes, demonstrating strong anti-tumor effects. Conclusions: This study developed an efficient nanozyme-mediated catalytic therapy strategy targeting the tumor microenvironment for the treatment of breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: Improved technologies for chromatin accessibility sequencing such as ATAC-seq have increased our understanding of gene regulation mechanisms, particularly in disease conditions such as cancer. Methods: This study introduces a computational tool that quantifies and establishes connections between chromatin accessibility, transcription factor binding, transcription factor mutations, and gene expression using publicly available colorectal cancer data. The tool has been packaged using a workflow management system to allow biologists and researchers to reproduce the results of this study. Results: We present compelling evidence linking chromatin accessibility to gene expression, with particular emphasis on SNP mutations and the accessibility of transcription factor genes. Furthermore, we have identified significant upregulation of key transcription factor interactions in colon cancer patients, including the apoptotic regulation facilitated by E2F1, MYC, and MYCN, as well as activation of the BCL-2 protein family facilitated by TP73. Conclusion: This study demonstrates the effectiveness of the computational tool in linking chromatin accessibility to gene expression and highlights significant transcription factor interactions in colorectal cancer. The code for this project is openly available on GitHub. [ABSTRACT FROM AUTHOR]

This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1′s interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities. To target these protein–protein interactions, VDAC1-derived peptides have been developed. This review focuses specifically on cell-penetrating VDAC1-based peptides that were developed and used as a "decoy" to compete with VDAC1 for its VDAC1-interacting proteins. These peptides interfere with VDAC1 interactions, for example, with metabolism-associated proteins such as hexokinase (HK), or with anti-apoptotic proteins such as Bcl-2 and Bcl-xL. These and other VDAC1-interacting proteins are highly expressed in many cancers. The VDAC1-based peptides in cells in culture selectively affect cancerous, but not non-cancerous cells, inducing cell death in a variety of cancers, regardless of the cancer origin or genetics. They inhibit cell energy production, eliminate cancer stem cells, and act very rapidly and at low micro-molar concentrations. The activity of these peptides has been validated in several mouse cancer models of glioblastoma, lung, and breast cancers. Their anti-cancer activity involves a multi-pronged attack targeting the hallmarks of cancer. They were also found to be effective in treating non-alcoholic fatty liver disease and diabetes mellitus. Thus, VDAC1-based peptides, by targeting VDAC1-interacting proteins, offer an affordable and innovative new conceptual therapeutic paradigm that can potentially overcome heterogeneity, chemoresistance, and invasive metastatic formation. [ABSTRACT FROM AUTHOR]

Acetamiprid (ACMP) is a neonicotinoid insecticide that poses a significant threat to the environment and mankind. Oxidative stress and mitochondrial dysfunction are considered prime contributors to ACMP-induced toxic effects. Meanwhile, berberine (BBR) a natural plant alkaloid, is a topic of interest because of its therapeutic and prophylactic actions. Therefore, this study evaluated the effects of BBR on ACMP-mediated alterations in mitochondrial functions and apoptosis in rat liver tissue. Male Wistar rats were divided into four groups: (I) control, (II) BBR-treated, (III) ACMP-exposed, and (IV) BBR+ACMP co-treated groups. The doses of BBR (150 mg/kg b.wt) and ACMP (1/10 of LD50, i.e., 21.7 mg/kg b.wt) were given intragastrically for 21 consecutive days. The results showed that the administration of ACMP diminished mitochondrial complex activity, downregulated complex I (ND1 and ND2) and complex IV (COX1 and COX4) subunit mRNA expression, depleted the antioxidant defense system, and induced apoptosis in rat liver. BBR pre-treatment significantly attenuated ACMP-induced mitochondrial dysfunction by maintaining mitochondrial complex activity and upregulating ND1, ND2, COX1, and COX4 mRNA expression. BBR reversed ACMP-mediated apoptosis by diminishing Bax and caspase-3 and increasing the Bcl-2 protein level. BBR also improved the mitochondrial antioxidant defense system by upregulating mRNA expression of PGC-1α, MnSOD, and UCP-2 in rat liver tissue. This study is the first to evaluate the protective potential of BBR against pesticide-induced mitochondrial dysfunction in liver tissue. In conclusion, BBR offers protection against ACMP-induced impairment in mitochondrial functions by maintaining the antioxidant level and modulating the apoptotic cascade. [ABSTRACT FROM AUTHOR]

Chronic immunosuppressive therapy is currently the only effective method to prevent acute rejection of a transplanted organ. Unfortunately, the expected effect of treatment brings a number of grave side effects, one of the most serious being cardiovascular complications. In our study, we wanted to investigate how treatment with commonly used immunosuppressive drugs affects the occurrence of programmed cardiac cell death. For this purpose, five groups of rats were treated with different triple immunosuppressive regimens. Cardiac tissue fragments were subjected to the TUNEL assay to visualize apoptotic cells. The expression of Bcl-2 protein, Bax protein, caspase 3 and caspase 9 was also assessed. This study indicates that all immunosuppressive protocols used chronically at therapeutic doses result in an increased percentage of cells undergoing apoptosis in rat heart tissue. The greatest changes were recorded in the TMG (rats treated with tacrolimus, mycophenolate mofetil and glucocorticosteroids) and CMG (rats treated with cyclosporin A, mycophenolate mofetil and glucocorticosteroids) groups. The TRG (rats treated with rapamycin, tacrolimus and glucocorticosteroids) group showed the lowest percentage of apoptotic cells. The internal apoptosis pathway was confirmed only in the TMG group; in the remaining groups, the results indicate programmed cell death via the receptor pathway. [ABSTRACT FROM AUTHOR]

Hesperidin (Hes) functions as a strong antioxidant and anti-inflammatory to guard against damage to the heart, liver, and kidneys. Nevertheless, due to its restricted solubility and bioavailability, a delivery method is required for it to reach a specific organ. In this study, ion gelation was used to synthesize a chitosan/hesperidin nanoformulation. Numerous characterization techniques, such as zeta potential, particle size, XRD, TEM, SEM, and FTIR analyses, were used to corroborate the synthesis of hesperidin nanoparticles (Hes-NPs). Male albino mice were given a pretreatment dose of 100 mg/kg, PO, of Hes or Hes-NPs, which was administered daily for 14 days before the induction of doxorubicin nephrotoxicity on the 12th day. Kidney function (urea and creatinine levels) was measured. Lipid peroxidation (MDA) and antioxidant enzyme (CAT and SOD) activities were estimated. TNF-α, IL-1β, and VEGF content; histopathological examination of kidney tissue; and immunohistochemical staining of NF-κB, Caspase-3, BAX, Bcl-2, and TGF-β1 were evaluated. The gene expressions of Sirt-1, Bcl-2, VEGF, HIF1-α, and Kim-1 were also considered. The results showed that pretreatment with Hes or Hes-NPs reduced doxorubicin's nephrotoxic effects, with Hes-NPs showing the greatest reduction. Kidney enzyme and MDA content were lowered in response to the Hes or Hes-NP pretreatment, whereas antioxidant enzyme activities were increased. Hes or Hes-NP pretreatment suppressed the levels of TNF-α, IL-1β, VEGF, NF-κB, Caspase-3, BAX, and TGF-β1; however, pretreatment increased Bcl-2 protein levels. Furthermore, the gene expressions of Sirt-1, Bcl-2, VEGF, HIF1-α, and Kim-1 were considerably higher with Hes-NP than with Hes treatment. These results suggest that Hes-NP treatment might reduce DOX-induced nephrotoxicity in mice via modulating Sirt-1/HIF1-α/VEGF/NF-κB signaling to provide antioxidant, anti-inflammatory, and anti-apoptotic effects. [ABSTRACT FROM AUTHOR]

This study investigates the underlying mechanism through which dietary supplementation of pyrroloquinoline quinone disodium (PQQ) alleviates intestinal inflammation and cell apoptosis in piglets challenged with lipopolysaccharide (LPS). Seventy-two barrows were divided into three groups: control (CTRL), LPS challenged (LPS), and LPS challenged with PQQ supplementation (PQQ + LPS). On d 7, 11, and 14, piglets received intraperitoneal injections of LPS or 0.9% of NaCl (80 μg/kg). After a 4 h interval following the final LPS injection on d 14, blood samples were obtained, and all piglets were euthanized for harvesting jejunal samples. The results showed that dietary supplementation of PQQ improved the damage of intestinal morphology, increased the down-regulated tight junction proteins, and reduced the increase of serum diamine oxidase activity, the intestinal fatty acid binding protein, and TNF-α levels in piglets challenged with LPS (p < 0.05). The proteomics analysis revealed a total of 141 differentially expressed proteins (DEPs), consisting of 64 up-regulated DEPs and 77 down-regulated DEPs in the PQQ + LPS group compared to the LPS group. The KEGG pathway analysis indicated enrichment of the tight junction pathway and the apoptosis pathway (p < 0.05). Compared to the LPS group, the piglets in the PQQ + LPS group had increased levels of Bcl-2 protein, reduced positive apoptosis signals, and a decrease in the abundance of MKK 3/6 and p-p38 proteins (p < 0.05). In conclusion, dietary supplementation of PQQ could alleviate jejunal inflammatory damage and cell apoptosis in piglets challenged with LPS through the MKK3/6-p38 signaling pathway. [ABSTRACT FROM AUTHOR]

The cell signaling pathways involved in the antiproliferative activities of T. rosea inner bark remain unexplored. This study evaluated the apoptotic effects of two iridoids from the inner bark of T. rosea and apicidin on THP-1 cells. The cytotoxic effects of the extract and the pure compounds on THP-1 and Jurkat cells were also evaluated using the MTT assay. The apoptotic effect was determined by measuring the mitochondrial membrane potential. The expression of mRNA and MAPK kinase, Bax, and Bcl-2 proteins was detected by Western blotting and RT–qPCR, respectively. The extract and the compounds evaluated increased the percentage of apoptotic cells. Depolarization of the mitochondrial membrane was observed, and the number of cells in the G0/G1 phase increased. Catalposide and specioside significantly increased p38 protein expression, mostly in cells pretreated with apicidin. The p38 MAPK signaling pathway is at least one of the pathways by which the n-butanol extract obtained from Tabebuia rosea, catalposide, and specioside exerts its apoptotic effect on THP-1 cells, and this effect generates a response in the G0/G1 phase and subsequent cell death. In addition, there was depolarization of the mitochondrial membrane, an effect that was related to the participation of the proapoptotic protein Bax. [ABSTRACT FROM AUTHOR]

Cardiolipin (CL), a critical phospholipid situated within the mitochondrial membrane, plays a significant role in modulating intramitochondrial processes, especially in the context of certain cardiac pathologies; however, the exact effects of alterations in cardiolipin on septic cardiomyopathy (SCM) are still debated and the underlying mechanisms remain incompletely understood. This study highlights a notable increase in the expressions of ALCAT1 and PLSCR3 during the advanced stage of lipopolysaccharide (LPS)-induced SCM. This up-regulation potential contribution to mitochondrial dysfunction and cellular apoptosis—as indicated by the augmented oxidative stress and cytochrome c (Cytc) release—coupled with reduced mitophagy, decreased levels of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2) and lowered cell viability. Additionally, the timing of LPS-induced apoptosis coincides with the decline in both autophagy and mitophagy at the late stages, implying that these processes may serve as protective factors against LPS-induced SCM in HL-1 cells. Together, these findings reveal the mechanism of LPS-induced CL changes in the center of SCM, with a particular emphasis on the importance of pathological remodeling and translocation of CL to mitochondrial function and apoptosis. Additionally, it highlights the protective effect of mitophagy in the early stage of SCM. This study complements previous research on the mechanism of CL changes in mediating SCM. These findings enhance our understanding of the role of CL in cardiac pathology and provide a new direction for future research. [ABSTRACT FROM AUTHOR]

Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus) is one of the most commonly employed Lactobacillus in the food industry. Exopolysaccharides (EPS) of Lactobacillus, which are known to exhibit probiotic properties, are secondary metabolites produced during the growth of Lactobacillus. This study identified the structure of the EPS produced by L. bulgaricus 1.0207 and investigated the mitigation of L. bulgaricus 1.0207 EPS on H2O2-induced oxidative stress in IPEC-J2 cells. L. bulgaricus 1.0207 EPS consisted of glucose and galactose and possessed a molecular weight of 4.06 × 104 Da. L. bulgaricus 1.0207 EPS exhibited notable scavenging capacity against DPPH, hydroxyl radicals, superoxide anions, and ABTS radicals. Additionally, L. bulgaricus 1.0207 EPS enhanced cell proliferation, reduced intracellular reactive oxygen species (ROS) accumulation, increased activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC) elevated the relative expression of CAT, SOD, HO-1, NQO1, ZO-1, and Occludin genes. Moreover, L. bulgaricus 1.0207 EPS improved the expression of Nrf2, pNrf2, pNrf2/Nrf2, and Bcl-2 proteins, while decreasing the expression of Keap1, Caspase3, and Bax proteins, with the best effect at a concentration of 100 μg/mL. L. bulgaricus 1.0207 EPS mitigated H2O2-induced oxidative stress injury in IPEC-J2 cells by activating the Keap1/Nrf2 pathway. Meanwhile, L. bulgaricus 1.0207 EPS exhibited the potential to decrease apoptosis and restore the integrity of the gut barrier. The findings establish a theoretical foundation for the development and application of L.bulgaricus 1.0207 and its EPS. [ABSTRACT FROM AUTHOR]

Over the last decade, automatic chemical design frameworks for discovering molecules with drug-like properties have significantly progressed. Among them, the variational autoencoder (VAE) is a cutting-edge approach that models the tractable latent space of the molecular space. In particular, the usage of a VAE along with a property estimator has attracted considerable interest because it enables gradient-based optimization of a given molecule. However, although successful results have been achieved experimentally, the theoretical background and prerequisites for the correct operation of this method have not yet been clarified. In view of the above, we theoretically analyze and rigorously reconstruct the entire framework. From the perspective of parameterized distribution and the information theory, we first describe how the previous model overcomes the limitations of the beta VAE in discovering molecules with the desired properties. Furthermore, we describe the prerequisites for training the above model. Next, from the log-likelihood perspective of each term, we reformulate the objectives for exploring latent space to generate drug-like molecules. The distributional constraints are defined in this study, which will break away from the invalid molecular search. We demonstrated that our model could discover a novel chemical compound for targeting BCL-2 family proteins in de novo approach. Through the theoretical analysis and practical implementation, the importance of the aforementioned prerequisites and constraints to operate the model was verified. [ABSTRACT FROM AUTHOR]

Although clinical outcomes in chronic lymphocytic leukemia (CLL) have greatly improved with several approved small molecular inhibitors, acquired resistance does occur, leading to disease progression and eventual death. Thus, the effort to explore novel inhibitors and combination therapeutic regimens is needed. The inhibition of MDM2-p53 interaction to restore p53 function has been regarded as a potential strategy for treating different cancers. We investigated the effects of novel MDM2 inhibitor APG-115 in CLL. We found that APG-115 treatment upregulated the expression of p53, MDM2, and p21 at the mRNA and protein level. APG-115 inhibited cell proliferation, induced apoptosis, and arrested the cell cycle at G0/G1 stage. Moreover, APG-115 inhibited the expression of BCL-2, BCLxL, and MCL-1, and suppressed the activation of AKT and ERK signaling pathways. APG-115 combined with the BCL2 inhibitor, ABT-199 (venetoclax), led to further inhibition of the expression of BCL-2 family anti-apoptotic proteins and consequently enhanced cell death. Collectively, this study demonstrates that APG-115 activates p53 and thus inhibits multiple pro-survival mechanisms, which provides a rational explanation for APG-115 efficiency in inducing cell apoptosis in CLL. The synergistic effect of APG-115 with ABT-199 suggested a potential combination application in CLL therapy. [ABSTRACT FROM AUTHOR]

Anal cancer is uncommon, comprising 2.2% of gastrointestinal cancers. Squamous cell carcinoma (SCC) is the most common; while perianal basal cell carcinoma (BCC) is rare, representing only 0.2% of anorectal malignancies. BCC, associated with sun exposure and immunosuppression, often resembles benign conditions and manifests as perianal ulcers or masses. Histologically, BCC exhibits basaloid tumor cells with distinct patterns. Despite its rarity, accurate diagnosis is crucial. We expose a case study of a 59-year-old male, previously healthy, that presented with hematochezia and perianal pain, leading to a diagnosis of lower gastrointestinal bleeding. Colonoscopy was needed, and a biopsy revealed an ulcerated, indurated lesion involving the left lateral hemorrhoidal bundle, diagnosed as pigmented basaloid carcinoma. Microscopic examination showed malignant nests of cells with peripheral nuclear palisading, melanocytes, and melanin pigment. Immunohistochemistry confirmed positivity for p63, CK5/6, and BCL2. Respect the treatment, due to the involvement of the anal sphincteric muscle, radiotherapy was chosen. [ABSTRACT FROM AUTHOR]

Using plant extracts as photosensitizers in photodynamic therapy (PDT) represents a significant green approach toward sustainability. This study investigates beetroot juice (BRJ), betanin, and their liposomal formulations (Lip-BRJ, Lip-Bet) as photosensitizers in cancer PDT. BRJ was prepared, and its betanin content was quantified via HPLC. The p-nitrosodimethylaniline (RNO)/imidazole technique monitored the singlet oxygen formation. BRJ and betanin decreased the RNO absorbance at 440 nm by 12% and 9% after 45 min of irradiation, respectively. Furthermore, betanin interaction with Bcl-2 proteins was examined using binding free energy analysis and molecular dynamic simulation. The results revealed favorable interactions with ΔG values of −40.94 kcal/mol. Then, BRJ, betanin, Lip-BRJ, and Lip-Bet were tested as photosensitizers on normal (HEK 293) and human lung cancer (A549) cell lines. Irradiation significantly enhanced the cytotoxicity of Lip-Bet on HEK 293 cells (20% cell viability at 2000 µg/mL) and A549 cells (13% cell viability at 1000 µg/mL). For Lip-BRJ, irradiation significantly enhanced the cytotoxicity on HEK 293 cells at lower concentrations and on A549 cells at all tested concentrations. These results proved the positive effect of light and liposomal encapsulation on the anticancer activity of betanin and BRJ, suggesting the efficiency of liposomal beetroot pigments as green photosensitizers. [ABSTRACT FROM AUTHOR]

Recent global scientific attention has been directed towards eco-friendly synthesis and versatile applications of silver nanoparticles (AgNPs) due to their effectiveness against specific cells and tissues. This study aimed to develop a green synthesis method for AgNPs using ethanolic extract from Salvia sclarea aerial parts, and to assess their protective efficacy against streptozotocin (STZ)-induced diabetic nephropathy in rats. Additionally, antioxidant, anti-inflammatory, and apoptosis studies were conducted to understand their mode of action. Characterization via ultraviolet-visible (UV-Vis) spectroscopy, infrared (IR) spectroscopy, and X-ray diffraction (XRD) confirmed the formation of ethanol extract of Salvia sclarea silver nanoparticles (EESS AgNPs), with a distinctive absorption peak at 400 nm. Scanning electron microscopy (SEM) analysis revealed predominantly spherical and quasi-spherical shapes of the synthesized nanoparticles. The treatment procedure spanned for a period of 12 weeks in diabetic rats and were evaluated for inflammatory markers (tumor necrosis factor-α, antioxidant markers (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) and apoptosis markers (Bcl-2, Bax, cleaved-caspase-3). Results demonstrated that treatment with EESS AgNPs significantly reduced blood glucose levels compared to the diabetic group. Additionally, EESS AgNPs treatment led to a significant decrease in levels of pro-inflammatory cytokines TNF-α, IL-1β, and PKC-β in renal cells. Furthermore, EESS AgNPs effectively modulated antioxidant enzyme concentrations, including GSH, SOD, GPx, and CAT, bringing them to acceptable levels. Administration of EESS AgNPs also resulted in a significant decrease in protein levels of Bax and activated caspase-3, while increasing expression of the anti-apoptotic protein Bcl-2 in renal cells of STZ-induced diabetic rats. In conclusion, EESS AgNPs demonstrate potent anti-hyperglycemic effects, potentially mitigating diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress, apoptosis, and inflammation in renal cells of diabetic rats. [ABSTRACT FROM AUTHOR]

The ischemia–reperfusion process of a donor heart during heart transplantation leads to severe mitochondrial dysfunction, which may be the main cause of donor heart dysfunction after heart transplantation. Pyruvate carboxylase (PC), an enzyme found in mitochondria, is said to play a role in the control of oxidative stress and the function of mitochondria. This research examined the function of PC and discovered the signaling pathways controlled by PC in myocardial IRI. We induced IRI using a murine heterotopic heart transplantation model in vivo and a hypoxia–reoxygenation cell model in vitro and evaluated inflammatory responses, oxidative stress levels, mitochondrial function, and cardiomyocyte apoptosis. In both in vivo and in vitro settings, we observed a significant decrease in PC expression during myocardial IRI. PC knockdown aggravated IRI by increasing MDA content, LDH activity, TUNEL-positive cells, serum cTnI level, Bax protein expression, and the level of inflammatory cytokines and decreasing SOD activity, GPX activity, and Bcl-2 protein expression. PC overexpression yielded the opposite findings. Additional research indicated that reducing PC levels could block the Wnt/β-catenin pathway and glutamine metabolism by hindering the movement of β-catenin to the nucleus and reducing the activity of complex I and complex II, as well as ATP levels, while elevating the ratios of NADP+/NADPH and GSSG/GSH. Overall, the findings indicated that PC therapy can shield the heart from IRI during heart transplantation by regulating glutamine metabolism through the Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a sudden-onset disease of the digestive system caused by abnormal activation of pancreatic enzymes. Dual oxidase 2 (DUOX2) has been found to be elevated in the progression of a variety of inflammatory diseases. Therefore, we analyzed the specific roles of DUOX2 in AP development. Blood samples were collected from of AP patients and healthy people, and the caerulein- stimulated human pancreatic duct cells (H6C7) were utilized to establish an AP cell model. Cell growth and apoptosis were measured using an MTT assay and TUNEL staining. Additionally, RT-qPCR and western blot assays were conducted to assess the RNA and protein expressions of the cells. ELISA kits were used to determine TNF-α, IL-6, IL-8, and IL-1β levels. The interaction between DUOX2 and miR-605-3p was predicted using the Targetscan database and confirmed by dual-luciferase report assay. We found that DUOX2 increased while miR-605-3p decreased in the blood of AP patients and caerulein-stimulated H6C7 cells. DUOX2 was targeted by miR-605-3p. Furthermore, DUOX2 knockdown or miR-605-3p overexpression promoted cell viability, decreased the TNF-α, IL-6, IL-8, and IL-1β levels, and inhibited apoptosis rate in caerulein-stimulated H6C7 cells. DUOX2 knockdown or miR-605-3p overexpression also increased the Bcl-2 protein levels and down-regulated Bax, cleaved-caspase-1, NLRP3 and p-p65. Interestingly, DUOX2 overexpression reversed the miR-605-3p mimic function in the caerulein-treated H6C7 cells. In conclusion, our research demonstrated that DUOX2 knockdown relieved the injury and inflammation in caerulein-stimulated H6C7 cells. [ABSTRACT FROM AUTHOR]

This review provides a comprehensive analysis of apoptotic signaling pathways in the context of bone metastatic lung cancer, emphasizing the intricate molecular mechanisms and microenvironmental influences. Beginning with an overview of apoptosis in cancer, the paper explores the specific molecular characteristics of bone metastatic lung cancer, highlighting alterations in apoptotic pathways. Focused discussions delve into key apoptotic signaling pathways, including the intrinsic and extrinsic pathways, and the roles of critical molecular players such as Bcl-2 family proteins and caspases. Microenvironmental factors, such as the tumor microenvironment, extracellular matrix interactions, and immune cell involvement, are examined in depth. The review also addresses experimental approaches and techniques employed in studying apoptotic signaling, paving the way for a discussion on current therapeutic strategies, their limitations, and future prospects. This synthesis contributes a holistic understanding of apoptosis in bone metastatic lung cancer, offering insights for potential therapeutic advancements. [ABSTRACT FROM AUTHOR]

Background: Among bone diseases, osteoporosis-like skeleton, such as trabecular thinning, fracture and so on, is the main pathological change of cadmium-induced osteoporosis(Cd-OP), accompanied by brittle bone and increased fracture rate. However, the mechanism underlying cadmiuminduced osteoporosis has remained elusive. Compound Lurong Jiangu Capsule (CLJC) is an experienced formula for the treatment of bone diseases, which has the effect of tonifying kidney and strengthening bones, promoting blood circulation and relieving pain. Objective: Network pharmacology and molecular docking technology combined with experiments were used to investigate the potential mechanism of CLJC in treating Cd-OP. Method: The active compounds and corresponding targets of each herb in CLJC were searched in the TCMSP and BATMAN-TCM databases. The DisGeNet, OMIM, and GeneCards databases searched for Cd-OP targets. The relationship between both of them was visualized by establishing an herbcompound- target network using Cytoscape 3.9.1 software. Gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed after determining the intersection of the targets from CLJC and Cd-OP. What's more, molecular docking was performed to validate the results. All of them were aim to obtain hud signaling pathways for further study. Finally, BAX, BCL-2, and CASPASE-3 were screened and selected for further experiments, which included bone imaging and reconstruction analysis (Micro-CT), hematoxylin-eosin Staining (HE), and western blot (WB). Results: 106 common targets from CLJC and Cd-OP targets were identified. KEGG pathway analysis suggested that multiple signaling pathways, such as the pathways in cancer, may play roles in treatment. Verification of the molecular docking was successful. Here we showed that Cd-OP displayed Tb.Th and Tb.N significantly reduced and even broke, irregular proliferation of bone cortex, uneven and loose trabecular bone arrangement, changed in apoptosis-related proteins, such as significant upregulation of CASPASE-3, BAX protein and significant downregulation of BCL-2 protein in vivo, while CLJC rescued these phenotypes. Conclusion: This study revealed that CLJC can reduce the expression of apoptosis-related proteins, and multiple components and multiple targets inhibit Cd-OP through apoptosis signaling pathway. [ABSTRACT FROM AUTHOR]

Male reproductive dysfunction is a clinical disease, with a large number of cases being idiopathic. Reproductive disorders have been found in obese (diet-induced obesity and diet-induced obesity-resistant) mice, but the mechanism behind the male reproductive dysfunction between them may be different. The purpose of this study was to explore the possible role and mechanism of miR-34c on sperm production in high-fat-diet-induced obesity-resistant (DIO-R) mice and GC-1 spg cells, which may differ from those in high-fat-diet-induced obesity (DIO) mice. In vivo and in vitro experiments were performed. C57BL/6J mice were fed a high-fat diet for 10 weeks to establish the DIO and DIO-R mouse model. GC-1 spg cells were used to verify the mechanism of miR-34c on sperm production. During in vivo experiments, sperm production damage was found in both DIO and DIO-R male mice. Compared to the control mice, significantly decreased levels of testosterone, LH, activities of acrosome enzyme (ACE), HAse, and activating transcription factor 1 (ATF1) were found in both DIO and DIO-R male mice (p < 0.05). Compared with the control group, the ratio of B-cell lymphoma-2 (Bcl-2)/bcl-2-associated X protein (Bax) in the DIO group was significantly decreased, and the expression level of cleaved caspase-3 was significantly increased (p < 0.05). Compared with the control group, the Bcl-2 protein expression level in the testes of the DIO-R group significantly decreased (p < 0.05). However, the Bax expression level increased. Thus, the Bcl-2/Bax ratio significantly decreased (p < 0.01); however, the factor-related apoptosis (Fas), Fas ligand (FasLG), cleaved caspase-8, caspase-8, cleaved caspase-3, and caspase-3 protein expression levels significantly increased (p < 0.05). Compared with the DIO group, in DIO-R mice, the activities of ACE, ATF1, Bcl-2, and Bcl-2/Bax's spermatogenesis protein expression decreased, while the apoptosis-promoting protein expression significantly increased (p < 0.05). During the in vitro experiment, the late and early apoptotic ratio in the miR-34c over-expression group increased. MiR-34c over-expression enhanced the expression of apoptosis-related proteins Fas/FasLG and Bax/Bcl-2 while inhibiting the expression of ATF1 and the sperm-associated protein in GC-1 spg cells. DIO and DIO-R could harm sperm production. DIO-R could impair sperm production by inducing the miR-34c-activated apoptosis and spermatogenesis pathway, which may be different from that of DIO. [ABSTRACT FROM AUTHOR]

Escherichia coli (E. coli) is commonly utilized as a vehicle for anti-tumor therapy due to its unique tumor-targeting capabilities and ease of engineering modification. To further explore the role of E. coli in tumor treatment, we consider that E. coli outer membrane vesicles (E. coli-OMVs) play a crucial role in the therapeutic process. Firstly, E. coli-OMVs were isolated and partially purified by filtration and ultracentrifugation, and were characterized using techniques such as nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western Blot (WB). The obtained extracellular nanoparticles, containing OMVs, were found to inhibited the growth of CT26 tumor in mice, while the expression of Bax protein was increased and the expression of Bcl-2 protein decreased. In vitro experiments showed that E. coli-OMVs entered CT26 cells and inhibited cell proliferation, invasion and migration. In addition, in the presence of E. coli-OMVs, we observed an increase in apoptosis rate and a decrease in the ratio of Bcl-2/Bax. These data indicate that E. coli-OMVs inhibits the growth of CT26 colon cancer by inducing apoptosis of CT26 cells. These findings propose E. coli-OMVs as a promising therapeutic drug for colorectal cancer (CRC), providing robust support for further research in related fields. [ABSTRACT FROM AUTHOR]

Triple negative breast cancers (TNBC) present a poor prognosis primarily due to their resistance to chemotherapy. This resistance is known to be associated with elevated expression of certain anti-apoptotic members within the proteins of the BCL-2 family (namely BCL-xL, MCL-1 and BCL-2). These regulate cell death by inhibiting pro-apoptotic protein activation through binding and sequestration and they can be selectively antagonized by BH3 mimetics. Yet the individual influences of BCL-xL, MCL-1, and BCL-2 on the sensitivity of TNBC cells to chemotherapy, and their regulation by cancer-associated fibroblasts (CAFs), major components of the tumor stroma and key contributors to therapy resistance remain to be delineated. Using gene editing or BH3 mimetics to inhibit anti-apoptotic BCL-2 family proteins in TNBC line MDA-MB-231, we show that BCL-xL and MCL-1 promote cancer cell survival through compensatory mechanisms. This cell line shows limited sensitivity to chemotherapy, in line with the clinical resistance observed in TNBC patients. We elucidate that BCL-xL plays a pivotal role in therapy response, as its depletion or pharmacological inhibition heightened chemotherapy effectiveness. Moreover, BCL-xL expression is associated with chemotherapy resistance in patient-derived tumoroids where its pharmacological inhibition enhances ex vivo response to chemotherapy. In a co-culture model of cancer cells and CAFs, we observe that even in a context where BCL-xL reduced expression renders cancer cells more susceptible to chemotherapy, those in contact with CAFs display reduced sensitivity to chemotherapy. Thus CAFs exert a profound pro-survival effect in breast cancer cells, even in a setting highly favoring cell death through combined chemotherapy and absence of the main actor of chemoresistance, BCL-xL. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) patients are treated with traditional chemotherapy, such as the taxane class of drugs. One such drug, paclitaxel (PTX), can be effective in treating TNBC; however, many tumors will develop drug resistance, which can lead to recurrence. In order to improve patient outcomes and survival, there lies a critical need to understand the mechanism behind drug resistance. Our lab made the novel observation that decreased expression of the Adenomatous Polyposis Coli (APC) tumor suppressor using shRNA caused PTX resistance in the human TNBC cell line MDA-MB-157. In cells lacking APC, induction of apoptosis by PTX was decreased, which was measured through cleaved caspase 3 and annexin/PI staining. The current study demonstrates that CRISPR-mediated APC knockout in two other TNBC lines, MDA-MB-231 and SUM159, leads to PTX resistance. In addition, the cellular consequences and molecular mechanisms behind APC-mediated PTX response have been investigated through analysis of the BCL-2 family of proteins. We found a significant increase in the tumor-initiating cell population and increased expression of the pro-survival family member Bcl-2, which is widely known for its oncogenic behavior. ABT-199 (Venetoclax), is a BH3 mimetic that specifically targets Bcl-2. ABT-199 has been used as a single or combination therapy in multiple hematologic malignancies and has shown promise in multiple subtypes of breast cancer. To address the hypothesis that APC-induced Bcl-2 increase is responsible for PTX resistance, we combined treatment of PTX and ABT-199. This combination treatment of CRISPR-mediated APC knockout MDA-MB-231 cells resulted in alterations in apoptosis, suggesting that Bcl-2 inhibition restores PTX sensitivity in APC knockout breast cancer cells. Our studies are the first to show that Bcl-2 functional inhibition restores PTX sensitivity in APC mutant breast cancer cells. These studies are critical to advance better treatment regimens in patients with TNBC. [ABSTRACT FROM AUTHOR]

Previous studies have shown that scutellarin inhibits the excessive activation of microglia, reduces neuronal apoptosis, and exerts neuroprotective effects. However, whether scutellarin regulates activated microglia-mediated neuronal apoptosis and its mechanisms remains unclear. This study aimed to investigate whether scutellarin can attenuate PC12 cell apoptosis induced by activated microglia via the JAK2/STAT3 signalling pathway. Microglia were cultured in oxygen–glucose deprivation (OGD) medium, which acted as a conditioning medium (CM) to activate PC12 cells, to investigate the expression of apoptosis and JAK2/STAT3 signalling-related proteins. We observed that PC12 cells apoptosis in CM was significantly increased, the expression and fluorescence intensity of the pro-apoptotic protein Bax and apoptosis-related protein cleaved caspase-3 were increased, and expression of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) was decreased. Phosphorylation levels and fluorescence intensity of the JAK2/STAT3 signalling pathway-related proteins JAK2 and STAT3 decreased. After treatment with scutellarin, PC12 cells apoptosis as well as cleaved caspase-3 and Bax protein expression and fluorescence intensity decreased. The expression and fluorescence intensity of Bcl-2, phosphorylated JAK2, and STAT3 increased. AG490, a specific inhibitor of the JAK2/STAT3 signalling pathway, was used. Our findings suggest that AG490 attenuates the effects of scutellarin. Our study revealed that scutellarin inhibited OGD-activated microglia-mediated PC12 cells apoptosis which was regulated via the JAK2/STAT3 signalling pathway. [ABSTRACT FROM AUTHOR]

The early stages of brain injury can induce acute liver injury, which can be recovered in the short term. Continued medication treatment during hospitalization for brain injury alleviates the prognosis and contributes to a high incidence of drug-induced liver injury (DILI). We hypothesize that there is an interaction between changes in the hepatic environment after brain injury and liver injury produced by intensive drug administration, leading to an upregulation of the organism's sensitivity to DILI. In this study, mice models of TBI were established by controlled cortical impact (CCI) and models of DILI were constructed by acetaminophen (APAP). All mice were divided into four groups: Sham, TBI, APAP, and TBI+APAP, and related liver injury indicators in liver and serum were detected by Western blot, Quantitative real-time PCR (qRT-PCR), and immunohistochemical staining. The results suggested that liver injury induced in the early stages of brain injury recovered in 3 days, but this state could still significantly aggravate DILI, represented by higher liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), oxidative stress (increase in malondialdehyde [MDA] concentration and deregulation of glutathione [GSH] and superoxide dismutase [SOD] activities), inflammatory response (activation of the HMGB1/TLR4/NF-κB signaling pathway, and increased messenger RNA [mRNA] and protein levels of pro-inflammatory cytokines including tumor necrosis factor alpha [TNF-α], interleukin [IL]-6, and IL-1β), and apoptosis (TUNEL assay, upregulation of Bax protein and deregulation of Bcl-2 protein). In summary, our results suggested that TBI is a potential susceptibility factor for DILI and exacerbates DILI. [ABSTRACT FROM AUTHOR]

Proteins of the Bcl-2 family regulate cellular fate via multiple mechanisms including apoptosis, autophagy, senescence, metabolism, inflammation, redox homeostasis, and calcium flux. There are several regulated cell death (RCD) pathways, including apoptosis and autophagy, that use distinct molecular mechanisms to elicit the death response. However, the same proteins/genes may be deployed in multiple biochemical pathways. In apoptosis, Bcl-2 proteins control the integrity of the mitochondrial outer membrane (MOM) by regulating the formation of pores in the MOM and apoptotic cell death. A number of prosurvival genes populate the genomes of viruses including those of the pro-survival Bcl-2 family. Viral Bcl-2 proteins are sequence and structural homologs of their cellular counterparts and interact with cellular proteins in apoptotic and autophagic pathways, potentially allowing them to modulate these pathways and determine cellular fate. [ABSTRACT FROM AUTHOR]

It is well known that Particulate Matter2.5 (PM2.5) has a major adverse effect on the organism. However, the health hazards of livestock farm PM2.5 to humans and animals are not yet known, and the role of miRNAs in the cellular damage induced by livestock farm PM2.5 is also unclear. Therefore, our study used cowshed PM2.5 to stimulate rat alveolar macrophage NR8383 to construct an in vitro injury model to investigate the effect of miR–122–5p on PM2.5-induced apoptosis in the NR8383. The level of apoptosis was quantified by flow cytometry and Hoechst 33342/PI double staining. Furthermore, the potential target gene Collagen type IV alpha (COL4A1) of miR–122–5p was identified through the use of bioinformatics methods. The results demonstrated a decline in cell viability and an increase in apoptosis with rising PM2.5 concentrations and exposure durations. The transfection of miR–122–5p mimics resulted in an upregulation of the pro-apoptotic protein Bcl–xL/Bcl–2 and activation of cleaved caspase–3 while inhibiting the anti-apoptotic protein B–cell lymphoma–2. The experimental data indicate that miR–122–5p is involved in the apoptotic process by targeting COL4A1. Furthermore, the overexpression of COL4A1 was observed to enhance the PM2.5-activated PI3K/AKT/NF–κB signaling pathway, which contributed to the inhibition of apoptosis. This finding offers a promising avenue for the development of therapeutic strategies aimed at mitigating cellular damage induced by PM2.5 exposure. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the intervention effect of curcumin on hepatic fibrosis in rodent models through systematic review and meta-analysis, in order to provide meaningful guidance for clinical practice. Methods: A systematic retrieval of relevant studies on curcumin intervention in rats or mice hepatic fibrosis models was conducted, and the data were extracted. The outcome indicators included liver cell structure and function related indicators, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB), ratio of albumin to globulin (A/G), total bilirubin (TBIL), bax protein, bcl-2 protein and index of liver, as well as the relevant indicators for evaluating the degree of hepatic fibrosis, such as hyaluronic acid (HA), laminin (LN), type I collagen (Collagen I), type III collagen (Collagen III), type III procollagen (PCIII), type III procollagen amino terminal peptide (PIIINP), type IV collagen (IV-C), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), α-Smooth muscle actin (α-SMA), hydroxyproline (HYP), platelet derived factor-BB (PDGF-BB), connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1), and oxidative stress-related indicators, such as superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px). These results were then analyzed by meta-analysis. Studies were evaluated for methodological quality using the syrcle's bias risk tool. Results: A total of 59 studies were included in the meta-analysis, and the results showed that curcumin can reduce the levels of ALT, AST, ALP, TBIL, bax protein, and index of liver in hepatic fibrosis models. It can also reduce HA, LN, Collagen I, Collagen III, PCIII, PIIINP, IV-C, TNF-α, α-SMA, HYP, PDGF-BB, CTGF, TGF-β1 and MDA, and increase the levels of ALB, A/G, SOD, and GSH-Px in the hepatic fibrosis models. However, the effects of curcumin on bcl-2 protein, IL-6 in hepatic fibrosis models and index of liver in mice were not statistically significant. Conclusion: The analysis results indicate that curcumin can reduce liver cell apoptosis by maintaining the stability of liver cell membrane, inhibit the activation and proliferation of hepatic stellate cells by reducing inflammatory response, and alleviate tissue peroxidation damage by clearing oxygen free radicals. [ABSTRACT FROM AUTHOR]

Ischemic stroke causes a lack of oxygen and glucose supply to brain, eventually leads to severe neurological disorders. Retinoic acid is a major metabolic product of vitamin A and has various biological effects. The PI3K-Akt signaling pathway is an important survival pathway in brain. Phosphorylated Akt is important in regulating survival and apoptosis. We examined whether retinoic acid has neuroprotective effects in stroke model by regulating Akt and its downstream protein, Bad. Moreover, we investigated the relationship between retinoic acid and Bcl-2 family protein interactions. Animals were intraperitoneally administered vehicle or retinoic acid (5 mg/kg) for four days before surgery and ischemic stroke was induced by middle cerebral artery occlusion (MCAO) surgery. Neurobehavioral tests were performed 24 h after MCAO and cerebral cortical tissues were collected. Cresyl violet staining and TUNEL histochemistry were performed, Western blot and immunoprecipitation analysis were performed to elucidate the expression of various proteins. Retinoic acid reduced neurological deficits and histopathological changes, decreased the number of TUNEL-positive cells, and alleviated reduction of phospho-PDK1, phospho-Akt, and phospho-Bad expression caused by MCAO damage. Immunoprecipitation analysis showed that MCAO damage reduced the interaction between phospho-Bad and 14-3-3, which was attenuated by retinoic acid. Furthermore, retinoic acid mitigated the increase in Bcl-2/Bad and Bcl-xL/Bad binding levels and the reduction in Bcl-2/Bax and Bcl-xL/Bax binding levels caused by MCAO damage. Retinoic acid alleviated MCAO-induced increase of caspase-3 and cleaved caspase-3 expression. We demonstrate that retinoic acid prevented apoptosis against cerebral ischemia through phosphorylation of Akt and Bad, maintenance of phospho-Bad and 14-3-3 binding, and regulation of Bcl-2 family protein interactions. [ABSTRACT FROM AUTHOR]

Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel "two birds with one stone" technique for amplifying enzyme‐mediated tumor apoptosis and enzyme‐promoted metabolic clearance is proposed and achieved using GOx‐functionalized rhenium nanoclusters‐doped polypyrrole (Re@ReP‐G). Re@ReP‐G reduces ATP production while increasing H2O2 concentrations in the tumor microenvironment through GOx‐induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti‐apoptotic Bcl‐2 proteins, the upregulation of pro‐apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser‐induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, H2O2 catalyzes the conversion of rhenium nanoclusters in Re@ReP‐G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP‐G‐based "two birds with one stone" therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms. [ABSTRACT FROM AUTHOR]

[Display omitted] This study involved the preparation of Metal Organic Frameworks (MOF)-derived Co 8 FeS 8 @Co 1-x S nanoenzymes with strong interfacial interactions. The nanoenzymes presented the peroxidase (POD)-like activity and the oxidation activity of reduced glutathione (GSH). Accordingly, the dual activities of Co 8 FeS 8 @Co 1-x S provided a self-cascading platform for producing significant amounts of hydroxyl radical (•OH) and depleting reduced glutathione, thereby inducing tumor cell apoptosis and ferroptosis. More importantly, the Co 8 FeS 8 @Co 1-x S inhibited the anti-apoptosis protein B-cell lymphoma-2 (Bcl-2) and activated caspase family proteins, which caused tumor cell apoptosis. Simultaneously, Co 8 FeS 8 @Co 1-x S affected the iron metabolism-related genes such as Heme oxygenase-1 (Hmox-1), amplifying the Fenton response and promoting apoptosis and ferroptosis. Therefore, the nanoenzyme synergistically killed anti-apoptotic tumor cells carrying Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Furthermore, Co 8 FeS 8 @Co 1-x S demonstrated good biocompatibility, which paved the way for constructing a synergistic catalytic nanoplatform for an efficient tumor treatment. [ABSTRACT FROM AUTHOR]

The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML. [ABSTRACT FROM AUTHOR]

The primary objective of the present study was to produce metal complexes of H4DAP ligand (N,N'-((pyridine-2,6-diylbis(azanediyl))bis(carbonothioyl))dibenzamide) derived from 2,6-diaminopyridine and benzoyl isothiocyanate with either ML or M2L stoichiometry. There are three distinct coordination complexes obtained with the formulas [Co(H2DAP)]·H2O, [Ni2(H2DAP)Cl2(H2O)2]·H2O, and [Cu(H4DAP)Cl2]·3H2O. The confirmation of the structures of all derivatives was achieved through the utilization of several analytical techniques, including FT-IR, UV–Vis, NMR, GC–MS, PXRD, SEM, TEM analysis, and QM calculations. Aiming to analyze various noncovalent interactions, topological methods such as QTAIM, NCI, ELF, and LOL were performed. Furthermore, the capacity of metal–ligand binding was examined by fluorescence emission spectroscopy. An in vitro investigation showed that the viability of MDA-MB-231 and HepG-2 cells was lower when exposed to the manufactured Cu2+ complex, in comparison to the normal cis-platin medication. The compounds were further evaluated for their in vitro antibacterial activity. The Ni2+ complex has shown promising activity against all tested pathogens, comparable to the reference drugs Gentamycin and Ketoconazole. Furthermore, a computational docking investigation was conducted to further examine the orientation, interaction, and conformation of the recently created compounds on the active site of the Bcl-2 protein. [ABSTRACT FROM AUTHOR]

Introduction: As the most common aggressive primary brain tumor, glioblastoma is inevitably a recurrent malignancy whose patients' prognosis is poor. miR-143 and miR-145, as tumor suppressor miRNAs, are downregulated through tumorigenesis of multiple human cancers, including glioblastoma. These two miRNAs regulate numerous cellular processes, such as proliferation and migration. This research was intended to explore the simultaneous replacement effect of miR-143, and miR-145 on in vitro tumorgenicity of U87 glioblastoma cells. Methods: U87 cells were cultured, and transfected with miR-143-5p and miR-145-5p. Afterward, the changes in cell viability, and apoptosis induction were determined by MTT assay and Annexin V/PI staining. The accumulation of cells at the cell cycle phases was assessed using the flow cytometry. Wound healing and colony formation assays were performed to study cell migration. qRT-PCR and western blot techniques were utilized to quantify gene expression levels. Results: Our results showed that miR-143-5p and 145-5p exogenous upregulation cooperatively diminished cell viability, and enhanced U-87 cell apoptosis by modulating Caspase-3/8/9, Bax, and Bcl-2 protein expression. The combination therapy increased accumulation of cells at the sub-G1 phase by modulating CDK1, Cyclin D1, and P53 protein expression. miR-143/145-5p significantly decreased cell migration, and reduced colony formation ability by the downregulation of c-Myc and CD44 gene expression. Furthermore, the results showed the combination therapy of these miRNAs could remarkably downregulate phosphorylated-AKT expression levels. Conclusion: In conclusion, miR-143 and miR-145 were indicated to show cooperative anti-cancer effects on glioblastoma cells via modulating AKT signaling as a new therapeutic approach. [ABSTRACT FROM AUTHOR]

BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial porin VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2–BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy. BAK and BAX execute apoptotic cell death by increasing the permeability of the mitochondria outer membrane, and this is regulated by interactions with the mitochondrial channel protein VDAC2. This study maps the key residues involved in the BAK:VDAC2 interaction and demonstrate that this interaction can be targeted to either promote or inhibit apoptosis. [ABSTRACT FROM AUTHOR]

To investigate the potential protective impact of miR-10a-modified HUMSCs-derived exosomes on both premature ovarian failure and the functionality of ovarian granulosa cells in a POF model. Methods: KGN cells were co-cultured with cisplatin-diaminedichloroplatinum (II) (10 μM) for 24 h to establish an in vitro POF model. The cells were distributed into three distinct groups: the control group, the POF group, and the POF + HUCMSC group. The plasmid sh-NC, sh-miR-10 a and miR-10 a mimic were transfected into KGN cells. After co-cultured with HUCMSC-EVs for 48 h, they were divided into HUCMSC group, sh-miR-10 a-HUMSCs-exosomes group and miR-10 a-HUMSCs-exosomes group. Flow cytometry was adopted to assess the impact of HUMSCs surface immune antigens and miR-10a-HUCMSCs-exosomes on KGN cell apoptosis. Additionally, the evaluation of cell proliferation was carried out through CCK-8 and EDU assays. Western blot analysis was utilized to detect the Caspase-3, Bax, and Bcl-2 proteins levels. Furthermore, the levels of TNF-α, IL-6, IL-10, MDA, SOD, and CAT were quantified using ELISA. Results: Compared with the Control group, the POF group inhibited the growth of ovarian granulosa cells (P< 0.01), reduced the number of EDU cells (P< 0.01), and increased the protein expression of Caspase-3 (P< 0.05) and Bax (P< 0.01). HUMSCs treatment significantly down-regulated the expression of IL-6, TNF-α and MDA, while up-regulating the expression of IL-10, SOD and CAT (P< 0.01); the overexpression of miR-10a promoted cell growth, besides, the introduction of miR-10a-HUMSCs-derived exosomes led to an elevation in the proliferation rate of OGCs affected by POF and concurrently suppressed the apoptosis rate. Conclusion: HUMSCs-derived exosomes modified by miR-10a have protective effects on premature ovarian failure and ovarian granulosa cell function in POF model. [ABSTRACT FROM AUTHOR]

The variability in response to conventional prostate cancer (PC) therapies, coupled with the emergent issue of drug resistance, underscores the critical need for innovative treatment strategies. Aerobic physical exercise reduced incidence of several cancers, but the mechanism underlying these effects associated the nanoemulsion not fully understood. The application of a lipid nanoemulsion (LDE) delivery system for docetaxel (DTX), showing marked enhancement in therapeutic efficacy when combined with aerobic physical exercise. This novel intervention potentiates the antitumor activity of LDE-delivered DTX by augmenting nanoparticle internalization and inducing cell cycle arrest. Our findings reveal that this synergistic treatment not only significantly reduces prostate weight and mitigates adenocarcinoma proliferation but also attenuates anti-apoptotic BCL-2 protein expression. Concurrently, it elevates pro-apoptotic proteins and diminishes inflammatory markers. Metabolic profiling of the combined therapy group disclosed additional benefits, such as reduced lipid and plasma glucose levels. Collectively, our data illuminate the profound impact of integrating LDE-mediated DTX delivery with structured physical exercise, which together spearhead a dual-front assault on PC. This multimodal approach heralds a new paradigm in PC management, accentuating the promise of combined pharmacological and non-pharmacological interventions to elevate tumor suppressor protein activity and refine patient outcomes. [ABSTRACT FROM AUTHOR]

Background: As a natural extraction, astaxanthin is gaining increasing attention because of its safety and anti-tumor properties. It has been reported to participate in the progression of various types of cancer such as gastric cancer and ovarian cancer. Nevertheless, the role of astaxanthin in nasopharyngeal carcinoma (NPC) has not been investigated. Object: The study aimed to explore the anticancer mechanism of astaxanthin in regulating NPC cell proliferation, cell cycle progression, apoptosis, migration, and invasion. Methods: Human NPC cells (C666-1) were treated with different concentrations of astaxanthin (0, 1, 10, 20 mg/mL) followed by detection of cell viability. Then, C666-1 cell proliferation, apoptosis, cell cycle progression, invasion, and migration in response to 10 mg/mL astaxanthin, LY294002 (PI3K/AKT inhibitor) or parthenolide (PTL; NF-κB inhibitor) treatment were measured using cell counting kit-8 assay, colony forming assay, flow cytometry analyses, Transwell assay, and wound healing assay, respectively. Western blotting was performed to quantify protein levels of factors involved in PI3K/AKT and NF-κB signaling pathways, cell cycle phase markers (Cyclin D1, p21) and apoptotic markers (Bcl-2 and Bax). Results: C666-1 cell proliferation, invasion, and migration were significantly suppressed by astaxanthin while cell apoptosis and cell cycle arrest at G1 phase were effectively enhanced in the context of 10 mg/mL astaxanthin. Protein levels of p-AKT, p-P65 and p-IκB levels were suppressed by astaxanthin treatment. After LY294002 or PTL treatment, the suppressive impact of astaxanthin on C666-1 cell process was strengthened, accompanied by the more obvious decrease in cell activity and cell colony number, more enhanced cell apoptosis and G1 phase arrest, and further inhibited cell migration and invasion. Moreover, the inhibitory effect of astaxanthin on Cyclin D1 and Bcl-2 protein levels as well as the promoting impact of astaxanthin on p21 and Bax were also amplified in combination with LY294002 or PTL treatment. Conclusions: Astaxanthin significantly suppresses NPC cell proliferation, cell cycle arrest, migration, invasion while promoting cell apoptosis by inactivating PI3K/AKT and NF-κB pathways. The study first reveals the anticancer role of astaxanthin in NPC, providing a potential candidate for NPC treatment. [ABSTRACT FROM AUTHOR]

Introduction: BCL-2 family proteins are important for tumour cell survival and drug resistance in multiple myeloma (MM). Although proteasome inhibitors are effective anti-myeloma drugs, some patients are resistant and almost all eventually relapse. We examined the function of BCL-2 family proteins in stromal-mediated resistance to carfilzomib-induced cytotoxicity in MM cells. Methods: Co-cultures employing HS5 stromal cells were used to model the interaction with stroma.MMcells were exposed to CFZ in a 1-hour pulse method. The expression of BCL-2 family proteins was assessed by flow cytometry and WB. Pro-survival proteins: MCL-1, BCL-2 and BCL-XL were inhibited using S63845, ABT-199 and A-1331852 respectively. Changes in BIM binding partners were examined by immunoprecipitation and WB. Results: CFZ induced dose-dependent cell death ofMMcells, primarily mediated by apoptosis. Culture ofMMcells on HS-5 stromal cells resulted in reduced cytotoxicity to CFZ in a cell contact-dependent manner, upregulated expression of MCL-1 and increased dependency on BCL-XL. Inhibiting BCL-XL or MCL-1 with BH-3 mimetics abrogated stromal-mediated protection only at high doses, which may not be achievable in vivo. However, combining BH-3 mimetics at sub-therapeutic doses, which alone were without effect, significantly enhanced CFZ-mediated cytotoxicity even in the presence of stroma. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-XL and BIM, while blocking BCL-XL increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins. Conclusion: Stromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ. [ABSTRACT FROM AUTHOR]

Background and objective: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. Methods: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. Results: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). Conclusion: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways. [ABSTRACT FROM AUTHOR]

Testicular dysfunction is a prevalent health problem frequently reported in individuals with diabetes mellitus (DM). Oxidative-inflammatory reactions, hormonal and spermatic abnormalities often accompany this illness. Herbal remedies "particularly wild plants" including chicory (Chicorium Intybus) and purslane (Portulaca Oleracea) are emerging as popular agents for people dealing with these issues due to their ability to act as antioxidants, reduce inflammation, and exhibit antidiabetic effects. According to the collected data, the daily administration of chicory (Ch) seed-extract (250 mg/kg) or purslane (Pu) seed-extract (200 mg/kg) to streptozotocin (STZ)-induced diabetic rats (50 mg/kg) for 30 days resulted in the normalization of fasting blood glucose (FBG), serum fructosamine, insulin levels, and insulin resistance (HOMA-IR), as well as reducing lipid peroxidation end-product malondialdehyde (MDA) level, aldehyde oxidase (AO) and xanthene oxidase (XO) activities. While caused a considerable improvement in glutathione (GSH) content, superoxide dismutase (SOD), catalase (CAT) activity, and total antioxidant capacity (TAC) when compared to diabetic rats. Ch and Pu extracts had a substantial impact on testicular parameters including sperm characterization, testosterone level, vimentin expression along with improvements in body and testis weight. They also mitigated hyperlipidemia by reducing total lipids (TL), total cholesterol (TC) levels, and low-density lipoprotein cholesterol (LDL-C), while increasing high-density lipoprotein cholesterol (HDL-C). Furthermore, oral administration of either Ch or Pu notably attuned the elevated proinflammatory cytokines as tumor necrotic factor (TNF-α), C-reactive protein (CRP), and Interleukin-6 (IL-6) together with reducing apoptosis and DNA damage. This was achieved through the suppression of DNA-fragmentation marker 8OHdG, triggering of caspase-3 immuno-expression, and elevation of Bcl-2 protein. The histological studies provided evidence supporting the preventive effects of Ch and Pu against DM-induced testicular dysfunction. In conclusion, Ch and Pu seed-extracts mitigate testicular impairment during DM due to their antihyperglycemic, antilipidemic, antioxidant, anti-inflammatory, and antiapoptotic properties. [ABSTRACT FROM AUTHOR]

Venetoclax is a Bcl-2 homology domain 3 (BH3) mimetic currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) that has proven to be highly effective in reinstating apoptosis in leukemic cells through the highly selective inhibition of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). Clinically, venetoclax has provided lasting remissions through the inhibition of CLL and AML blasts. However, this activity has often come at the cost of grade III/IV neutropenia due to hematopoietic cells' dependence on Bcl-2 for survival. As life-threatening infections are an important complication in these patients, an effective management of neutropenia is indispensable to maximize patient outcomes. While there is general consensus over dose reduction and scheduling modifications to minimize the risk of neutropenia, the impact of these modifications on survival is uncertain. Moreover, guidelines do not yet adequately account for patient-specific and disease-specific risk factors that may predict toxicity, or the role combination treatment plays in exacerbating neutropenia. The objective of this review is to discuss the venetoclax-induced mechanism of hematological toxicity, the potential predictive risk factors that affect patient vulnerability to neutropenia, and the current consensus on practices for management of neutropenia. [ABSTRACT FROM AUTHOR]