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The quadridentate tetraaza ligand (H2L) containing dioxime function groups and its palladium (II) complex [PdL] were synthesized and structurally characterized by analytical and various spectroscopic techniques (MS‐ES, 1HNMR, FTIR, UV–Vis, and PXRD in addition to SEM and EDX analysis). Processing powder X‐ray diffraction data and DFT calculations coupled with spectroscopic measurements revealed slightly distorted square planar stereochemistry. The anticancer activity of the newly synthesized dioxime palladium (II) complex, [PdL], has been studied and the findings of this study emphasize that [PdL] complex potentially combats cancer by exhibiting diverse cytotoxic impacts. These effects include reduced cell mitosis, decreased metastasis of MDA‐MB‐231 cancer cells, inhibition of topoisomerase II, and induction of apoptotic cell death. In conclusion, the present palladium (II) complex could be a potential therapeutic drug in breast cancer because it can reduce topoisomerase II expression, which is essential in metastasis. This inhibition also reduces the expression of CDK1, which plays an important role in cell cycle regulation. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age globally. Emerging evidence suggests that the dysregulation of microRNAs (miRNAs) and gut dysbiosis are linked to the development of PCOS. In this study, the effects of Lacticaseibacillus paracasei subsp. paracasei DSM 27449 (DSM 27449) were investigated in a rat model of PCOS induced by letrozole. The administration of DSM 27449 resulted in improved ovarian function, reduced cystic follicles, and lower serum testosterone levels. Alterations in miRNA expressions and increased levels of the pro-apoptotic protein Bax in ovarian tissues were observed in PCOS-like rats. Notably, the administration of DSM 27449 restored the expression of miRNAs, including miR-30a-5p, miR-93-5p, and miR-223-3p, leading to enhanced ovarian function through the downregulation of Bax expressions in ovarian tissues. Additionally, 16S rRNA sequencing showed changes in the gut microbiome composition after letrozole induction. The strong correlation between specific bacterial genera and PCOS-related parameters suggested that the modulation of the gut microbiome by DSM 27449 was associated with the improvement of PCOS symptoms. These findings demonstrate the beneficial effects of DSM 27449 in ameliorating PCOS symptoms in letrozole-induced PCOS-like rats, suggesting that DSM 27449 may serve as a beneficial dietary supplement with the therapeutic potential for alleviating PCOS. [ABSTRACT FROM AUTHOR]

Traditional therapies often struggle with specificity and resistance in case of cancer treatments. It is therefore important to investigate new approaches for cancer treatment based on nanotechnology. Zinc oxide nanoparticles (ZnONPs) are known to exhibit anti-cancer properties by inducing oxidative stress, apoptosis, and cell cycle arrest. Methotrexate (MTX) a known anti-folate shows specificity to folate receptors and interrupts healthy functioning of cells. This study proposes the use of previously characterized biocompatible Methotrexate loaded Zinc oxide nanoparticles (MTX-ZnONPs) as a dual action therapeutic strategy against breast cancer cell lines, MCF-7 (MTX-sensitive) and MDA-MB-231 (MTX-resistant). To elucidate the cytotoxicity mechanism of MTX-ZnONPs an in depth In vitro study was carried out. In vitro assays, including cell cycle analysis, apoptosis assay, and western blot analysis to study the protein expression were performed. Results of these assays, further supported the anti-cancer activity of MTX-ZnONPs showing apoptotic and necrotic activity in MCF-7 and MDA-MB-231 cell line respectively. In vivo acute oral toxicity study to identify the LD50 in animals revealed no signs of toxicity and mortality up to 550 mg kg−1 body weight of animal, significantly higher LD50 values than anticipated therapeutic levels and safety of the synthesized nanosystem. The study concludes that MTX-ZnONPs exhibit anti-cancer potential against breast cancer cells offering a promising strategy for overcoming resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Research efforts over the past decade have uncovered new insights into functions of erythropoietin that point to new roles beyond erythropoiesis. Recent studies have demonstrated that erythropoietin is implicated in tissue protection, regeneration, and reproduction. In this context, the present study reveals for the first time that erythropoietin inhibits cell death by apoptosis and enhances the fertilizing capacity of bovine spermatozoa. Erythropoietin (EPO), a hormone secreted mainly by the kidney, exerts its biological function by binding to its cell-surface receptor (EpoR). The presence of EPO and EpoR in the male and female reproductive system has been verified. Therefore, some of the key properties of EPO, such as its antioxidant and antiapoptotic effects, could improve the fertilizing capacity of spermatozoa. In the present study, the effect of two different concentrations of EPO (10 mIU/μL and 100 mIU/μL) on bovine sperm-quality parameters was evaluated during a post-thawing 4-h incubation at 37 °C. EPO had a positive effect on sperm motility, viability, and total antioxidant capacity. Moreover, EPO inhibited apoptosis, as it reduced both BCL2-associated X apoptosis regulator (Bax)/B-cell lymphoma 2 (Bcl-2) ratio and cleaved cysteine-aspartic proteases (caspases) substrate levels in a dose-dependent manner. In addition, EPO induced sperm capacitation and acrosome reaction in spermatozoa incubated in capacitation conditioned medeia. These results establish a foundation for the physiological role of EPO in reproductive processes and hopefully will provide an incentive for further research in order to fully decipher the role of EPO in sperm physiology and reproduction. [ABSTRACT FROM AUTHOR]

Titanium dioxide nanoparticles (TiO2-NPs) are one of the most popular nanoscale materials and have a wide range of applications in the manufacturing industry; nonetheless, researchers' focus has been directed to the detrimental consequences of TiO2-NPs. The current study was designed to assess the potential hazardous effects of chemically synthesized TiO2-NPs on the placenta and feto-maternal kidneys of rats. On the other hand, the probable positive impact of TiO2-NPs made after green synthesis was also evaluated. HepG2 cell lines were used to assess the cytotoxicity of chemical and green TiO2-NPs. Five groups of fifty pregnant female rats were formed (n=10). The first (control) group received distilled water. The second and third groups were orally given 100 and 300 mg/kg body weight (bw) of chemical TiO2-NPs, respectively. The fourth and fifth groups were orally given 100 and 300 mg/kg bw of green synthesized TiO2-NPs, respectively. On gestational day 20 (GD 20), blood and tissues were collected for biochemical and histological studies. Our findings revealed that chemical TiO2-NPs induced apoptosis in HepG2 cells at high concentrations, while there was no observed toxicity for green TiO2-NPs. The chemically treated TiO2-NPs groups showed a significant decrease in the level of HDL and a significant increase in cholesterol, LDL-cholesterol, and triglyceride levels. Renal tissues showed necrosis with exfoliation of lining epithelial cells, degenerated tubules, and glomerulonephritis. While the placenta was atrophied and hyalinized. Moreover, Bax expression significantly increased in the renal tubular cells and the villi of the placenta. Contrariwise, green TiO2-NPs-treated groups showed a significant rise in HDL levels with a significant reduction in triglycerides and LDL levels, while cholesterol levels were unaffected. Also, renal tissues showed mild degenerative changes in the glomeruli and renal tubules; thus, noticeable regeneration of epithelium lining tubules was detected in the maternal kidney. Bax showed a minimal reaction in the renal tubules and the villi of the placenta. It concluded that in contrast to chemical TiO2-NPs, biosynthesized TiO2-NPs with garlic showed a positive impact on the biochemical profile and histological investigations. [ABSTRACT FROM AUTHOR]

Background and Objectives: PIN1 is overexpressed in several human cancers, including prostate cancer, breast cancer, and oral squamous carcinomas. Juglone (J), derived from walnut, was reported to selectively inhibit PIN1 by modifying its sulfhydryl groups. In this study, the potential effects of juglone, also known as PIN1 inhibitor, on oral cancer and carcinogenesis were investigated at the molecular level. Materials and Methods: 4-Nitroquinoline N-oxide (4-NQO) was used to create an oral cancer model in animals. Wistar rats were divided into five groups: Control, NQO, Juglone, NQO+J, and NQO+J*. The control group received the basal diet and tap water throughout the experiment. The NQO group received 4-NQO for 8 weeks in drinking water only. The Juglone group was administered intraperitoneally in a juglone solution for 10 weeks (1 mg/kg/day). The NQO+J group received 4-NQO in drinking water for 8 weeks, starting 1 week after the cessation of 4-NQO treatment. They were then administered intraperitoneally in a juglone solution for 10 weeks. (1 mg/kg/day). NQO+J* group: received 4 NQO for 8 weeks in drinking water and administered intraperitoneally in a juglone solution for 10 weeks (1 mg/kg/day). They were sacrificed at the end of the 22-week experimental period. The tongue tissues of the rats were isolated after the experiment, morphological changes were investigated by histological examinations, and the molecular apoptotic process was investigated by rt-qPCR and western blot. Results: Histological results indicate that tumors are formed in the tongue tissue with 4-NQO, and juglone treatment largely corrects the epithelial changes that developed with 4-NQO. It has been determined that apoptotic factors p53, Bax, and caspases are induced by the effect of juglone, while antiapoptotic factors such as Bcl-2 are suppressed. However, it was observed that the positive effects were more pronounced in rats given juglone together with 4-NQO. Conclusions: The use of PIN1 inhibitors such as juglone in place of existing therapeutic approaches might be a promising and novel approach to the preservation and treatment of oral cancer and carcinogenesis. However, further research is required to investigate the practical application of such inhibitors. [ABSTRACT FROM AUTHOR]

Botulinum toxin type A (BTXA) has the potential to treat androgenetic alopecia (AGA); however, its impact on the apoptosis of dermal papillary cells (DPCs) is not yet fully understood. Noncoding RNAs play a crucial role in AGA. In this study, we investigated the potential mechanism by which BTXA alleviates apoptosis induced by dihydrotestosterone (DHT) in DPCs. We assessed the mRNA levels of circ_0135062, miR-506-3p, and Bax using qRT–PCR. Binding interactions were analyzed using RNA pulldown and dual-luciferase assays. Cell viability was determined using a cell counting kit-8 assay, and cell apoptosis was assessed using flow cytometry, TUNEL assays, and western blotting. Our findings revealed that BTXA inhibited the apoptosis of DPCs treated with DHT. Moreover, circ_0135062 overexpression counteracted the protective effect of BTXA on DHT-treated DPCs. MiR-506-3p was found to interact with Bax and inhibit apoptosis in DPCs by suppressing Bax expression in response to DHT-induced damage. Furthermore, circ_0135062 acted as a sponge for miR-506-3p, thereby inhibiting the targeting of Bax expression by miR-506-3p. In conclusion, BTXA exhibited an antiapoptotic effect on DHT-induced DPC injury via the circ_0135062/miR-506-3p/Bax axis. Level of Evidence II This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

The mortality rate of acute-on-chronic liver failure (ACLF) remains significantly elevated; hence, this study aimed to investigate the impact of heat shock protein family B (small) member 1 (HSPB1) on ACLF in vivo and in vitro and the underlying mechanism. This study used the ACLF mouse model, and liver damage extent was studied employing Masson trichrome, hematoxylin and eosin (H&E), Sirius red staining, and serum biochemical indices. Similarly, hepatocyte injury in lipopolysaccharide (LPS)-induced L02 cells was evaluated using cell counting kit-8 assay, enzymatic activity, flow cytometry, and TUNEL assay, while the underlying mechanism was investigated using western blot. Results showed that the morphology of liver tissue in ACLF mice was changed and was characterized by cirrhosis, fibrosis, collagen fiber deposition, inflammatory cell infiltration, and elevated liver injury indices. Moreover, HSPB1 was upregulated in both ACLF patients and mice, where overexpressing HSPB1 was found to inhibit ACLF-induced liver damage. Similarly, the HSPB1 expression in LPS-treated L02 cell lines was also increased, where overexpressing HSPB1 was found to promote cell viability, inhibit liver injury-related enzyme activity, and suppress apoptosis. Mechanistic investigations revealed that HSPB1 was responsible for inhibiting p-P53 and Bax protein levels, where activated P53 counteracted HSPB1’s effects on cellular behaviors. In conclusion, HSPB1 attenuated ACLF-induced liver injury in vivo and inhibited LPS-induced hepatocyte damage in vitro, suggesting that HSPB1 may be a novel target for ACLF therapy.

Abstract Purpose The aim of the current study was to molecularly determine Bcl-2 and BAX gene mutations in HPV-associated squamous cell carcinoma of the cervix. Methods Formalin-fixed, paraffin-embedded tissue blocks, all consisting of squamous cell carcinoma of the cervix, were used for this study. The nucleic acid amplification technique and various steps for DNA sequencing, including DNA extraction and polymerase chain reaction, were used. Results Mutations were detected in the Bcl-2 gene of patients with squamous cell carcinoma of the cervix in the 10–860 bp region, while BAX gene mutations were detected in the 10–320 bp region. The nucleotide mutations in the Bcl-2 gene were A > G (50%), C > T (33.33%), and G > A > T (16.67%), while the BAX gene mutations were A > (16.67%), T > (16.67%), G > (16.67%), A > C (16.67%), T > G (16.67%), and T > C (16.67%). The mutations in the BAX gene were Indel (50%), Transversion (33.4%), and Transition (16.6%), while only the Transition mutation (100%) was detected in the Bcl-2 gene. The functional mutations in the BAX gene were only missense mutations (100%), but in the Bcl-2 gene, the functional mutations were missense (50%) and silent (50%) mutations. Conclusion Our findings revealed genomic mutations of different types and frequencies in the BAX and Bcl-2 genes in squamous cell carcinoma of the cervix, which should encourage further research to better understand these mutations and exploit them for clinical use.

Liwei Sun,1,* Hailong Bing,1,* Chenxi Zhang,1,* Lin Lin,2 Hongkai Lian,2 Qinjun Chu,1 Xiaogao Jin1,3 1Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China; 2Research of Trauma Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, People’s Republic of China; 3Department of Anesthesiology, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaogao Jin; Liwei Sun, Email jinxiaoagao@zzu.edu.cn; sunliwei2972@163.comObjective: Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether preconditioning with insulin and glucose protects the kidney against ischemia-reperfusion injury (IRI).Methods: Kidney IRI was performed in C57BL/6 mice by clamping the renal vessels for 30 min, followed by reperfusion for 24 h. A total subcutaneous 0.1 unit of insulin along with 10% glucose in drinking water was treated on the mice for 24 h before kidney IRI. The kidney function and injuries were investigated through the determination of BUN and Cr in blood plasma, as well as the apoptosis and the expression of P-AKT, BAX, and caspase-3 in the kidneys. The role of P-AKT in insulin-treated IRI kidneys was tested using an AKT inhibitor. The effects of the preconditional duration of insulin and glucose on IRI kidneys were investigated by expanding the treatment duration to 1, 3, and 6 days.Results: Preconditioning with insulin and glucose protected the kidney against IRI as manifested by a decrease in creatinine and BUN and a reduction of kidney tubular injury. The protection effect was mediated by P-AKT-BAX-caspase-3 signaling pathway resulting in suppression of apoptotic cell death. An AKT inhibitor partially reversed the protective effects of preconditional insulin. The preconditional duration for 1, 3, and 6 days had no differences in improving kidney functions and pathology.Conclusion: A short-term preconditioning with insulin and glucose protected the kidney from IRI through the activation of p-AKT and subsequent reduction of BAX-caspase-3-induced apoptosis. The short-term precondition provides a practicable strategy for protecting the kidney against predictable IRI, such as kidney transplant and major surgical operations with high risk of hypotension.Keywords: kidney, insulin, ischemia-reperfusion injury, AKT, Bax, caspase-3

Diabetes mellitus is a persistent metabolic condition marked by elevated blood glucose levels due to compromised insulin secretion or functionality. The search for natural antidiabetic agents has gained attention due to their potential effectiveness and safety profiles. Sessuvium portulacastrum, a coastal plant, has been traditionally used for various medicinal purposes. This study investigates the antidiabetic potential of Sessuvium portulacastrum aqueous extract by analyzing its inhibitory effects on key enzymes involved in carbohydrate metabolism and exploring its molecular interactions with critical target proteins. The aqueous extract of Sessuvium portulacastrum was prepared and used for in vitro analysis. The reduced activity of the extract against α-amylase and α-glucosidase enzymes, crucial in glucose absorption and postprandial hyperglycemia, was assessed. Molecular docking techniques were employed to explore the potential interactions between active compounds in the extract and diabetes-related proteins, including BAX, GSK3β, and CADH. The study revealed significant inhibition of both alpha-amylase and alpha-glucosidase enzymes by Sessuvium portulacastrum aqueous extract, indicating its potential to reduce glucose absorption and postprandial hyperglycemia. Moreover, the molecular docking analysis demonstrated strong binding interactions between active compounds in the extract and key proteins involved in diabetes-related pathways, namely apoptotic pathways, glycogen synthesis, and cell adhesion. The findings of this study highlight the promising antidiabetic potential of Sessuvium portulacastrum aqueous extract. Upcoming research should get an attention on isolating and characterizing the active compounds responsible for these effects on antidiabetic therapies from natural sources.

Abstract Background Hepatocellular carcinoma (HCC) is a severe threat and a main reason for cancer-related deaths around the world. Drug resistance to sorafenib (Sorf), the effective HCC first-line therapy, is very common. A number of natural compounds, notably bee venom (BV), have been claimed to show a great impact against cancer when administered on its own or in conjunction with chemotherapy. Thus, this study aimed to investigate the anticancer effect of BV alone and/or combined with Sorf on HepG2 liver cancer cell lines. Methods Both mRNA and protein expressions of Bax, Bcl-2 and Beclin-1 were investigated by quantitative real-time PCR (qPCR) and western blot respectively, to examine the apoptotic and autophagic regulatory effects of BV and Sorf single treatments plus BV/Sorf combination on HepG2 cell lines. Results Our findings showed that BV and Sorf had considerable dose-dependent anti-proliferative effects on HepG2 cells whether administered alone or in combination, with the greatest impact for the combined therapies. Single BV and Sorf treatments showed IC50 of 93.21 and 7.28 μg/ml respectively, while combined treatment showed IC50 of 6.73 μg/ml BV + 6.73 μg/ml Sorf. Moreover, both the pro-apoptotic gene Bax and the autophagy-related gene Beclin-1 showed significant up-regulation in their mRNA expression, while the anti-apoptotic Bcl-2 mRNA gene expression showed significant down-regulation after BV/Sorf treatment as compared to either BV or Sorf single treatment. These qPCR results were further confirmed by western blot. Conclusions These findings indicate that BV synergistically potentiates the anticancer effect of Sorf on HepG2 cells through induction of apoptotic and autophagic machineries.

Abstract Background Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in vascular smooth muscle cell (VSMC) phenotypic switching, which is an early pathogenic event in various vascular remodeling diseases (VRDs). However, the underlying mechanism is not fully understood. Methods An IP‒LC‒MS/MS assay was conducted to identify new binding partners of G6PD involved in the regulation of VSMC phenotypic switching under platelet-derived growth factor-BB (PDGF-BB) stimulation. Co-IP, GST pull-down, and immunofluorescence colocalization were employed to clarify the interaction between G6PD and voltage-dependent anion-selective channel protein 1 (VDAC1). The molecular mechanisms involved were elucidated by examining the interaction between VDAC1 and apoptosis-related biomarkers, as well as the oligomerization state of VDAC1. Results The G6PD level was significantly elevated and positively correlated with the synthetic characteristics of VSMCs induced by PDGF-BB. We identified VDAC1 as a novel G6PD-interacting molecule essential for apoptosis. Specifically, the G6PD-NTD region was found to predominantly contribute to this interaction. G6PD promotes VSMC survival and accelerates vascular neointimal hyperplasia by inhibiting VSMC apoptosis. Mechanistically, G6PD interacts with VDAC1 upon stimulation with PDGF-BB. By competing with Bax for VDAC1 binding, G6PD reduces VDAC1 oligomerization and counteracts VDAC1–Bax-mediated apoptosis, thereby accelerating neointimal hyperplasia. Conclusion Our study showed that the G6PD–VDAC1–Bax axis is a vital switch in VSMC apoptosis and is essential for VSMC phenotypic switching and neointimal hyperplasia, providing mechanistic insight into early VRDs. Graphical Abstract

Side effects and risk of resistance are common consequences of colon cancer treatment based on chemotherapy. The medicinal plant originating in Indonesia, Lansium parasiticum bark extract (LPBE), has not been studied much. The purpose of this study is to identify the compounds present in LPBE and explain how the molecular mechanisms of the composite inhibit colon cancer cells. LC-MS/MS Liquid Chromatography Tandem Mass Spectrophotometry has been used to identify compounds in LPBE. The ADMET program is used to determine absorption profiles and bioavailability per oral. The tissue pharmacology approach uses Cytoscape 3.9.1, GeneCards, Disgenet, STRING 2.0.0, SRplot, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to predict the molecular anti-cancer mechanisms of these compounds. In vitro validation using PyRx Autodock Vina 9.0 and Biovia Discovery Studio with BAX (PDB ID:2YXJ), BCL2 (P DB ID:2W3L) and STAT3 receptors (PDB ID:6NJS). A total of 17 active compounds were identified through LC-MS/MS. The moronic acid compound showed the highest levels of 14.29% followed by 4-Morpholineacetic Acid 12.2% and ursolic aldehyde 8.37%. Pharmacological network analysis showed that the compounder works on the EGFR tyrosine kinase resistance path by targeting the BCL2, BAX, STAT3 genes. The results of the in silico validation support the results of tissue pharmacology findings. Ursolic aldehyde, and Moronic acid showed a higher affinity to the three receptors. Therefore, Lansium parasiticum bark extract (LPBE) is recommended for further study as a candidate anti-cancer drug both in vitro and in vivo.

Idiopathic pulmonary fibrosis is a progressive and age‐related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL‐2 and BCL‐XL, leading to BAX inactivation. We further showed that high levels of inactive BAX‐mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl‐valyl‐O‐methylaspartyl‐[2,6‐difluorophenoxy]‐methyl ketone (QVD‐OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1‐activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment. [ABSTRACT FROM AUTHOR]

The B‐cell lymphoma 2 (BCL2) family members, BCL2‐associated protein X (BAX) and BCL2 homologous antagonist killer (BAK), are required for programmed cell death via the mitochondrial pathway. When cells are stressed, damaged or redundant, the balance of power between the BCL2 family of proteins shifts towards BAX and BAK, allowing their transition from an inactive, monomeric state to a membrane‐active oligomeric form that releases cytochrome c from the mitochondrial intermembrane space. That oligomeric state has an essential intermediate, a symmetric homodimer of BAX or BAK. Here we describe crystal structures of dimers of the core domain of BAX, comprising its helices α2–α5. These structures provide an atomic resolution description of the interactions that drive BAX homo‐dimerisation and insights into potential interaction between core domain dimers and membrane lipids. The previously identified BAK lipid‐interacting sites are not conserved with BAX and are likely to determine the differences between them in their interactions with lipids. We also describe structures of heterodimers of BAK/BAX core domains, yielding further insight into the differences in lipid binding between BAX and BAK. [ABSTRACT FROM AUTHOR]

Background: The B-cell lymphoma 2 (BCL-2) protein is one of the members of the BCL-2 associated X (BAX) protein family that acts as an inducer of apoptosis. Objective: The present study aims to investigate the association between BAX and BCL-2 gene expression with reproductive outcome, in cases undergoing intracytoplasmic sperm injection. Materials and Methods: In this case-control study, 50 men were divided into healthy fertile and oligoasthenoteratozoospermic infertile men (n = 25/each). They were subjected to history taking, clinical examination, and semen analysis. Expression of BAX and BCL-2 genes were measured using real-time polymerase chain reaction. The DNA fragmentation index was measured using the sperm chromatin dispersion assay technique. Using World Health Organization criteria, sperm parameters were evaluated. Results: Evaluation of apoptosis-related genes showed that oligoasthenoteratozoospermic significantly increased mRNA expression of BAX, and significantly decreased mRNA expression of BCL-2, when compared with control. Moreover, the BAX/BCL-2 ratio was significantly higher in oligoasthenoteratozoospermic compared to the normozoospermic group (p = 0.01). Also, this study showed that the BAX and BCL-2 genes expression had a significant correlation with sperm quality, and DNA fragmentation in the oligoasthenoteratozoospermic group (p = 0.01). The oligoasthenoteratozoospermic men, had a considerably lower proportion of fertilization rate and good-quality embryos at the cleavage stage than the normozoospermic subjects (p = 0.01). A significant correlation was observed between the expression of BAX and BCL-2 genes, fertilization, and embryo quality (p = 0.01). Conclusion: We concluded that the sperm BAX/BCL-2 ratio demonstrates a significant correlation with fertilization rate and embryo quality. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a chronic, gynecological disorder, and the disease's pathogenesis is still debatable. Genes related to apoptosis have been revealed to be deregulated in endometriosis. Objective: This study investigates the relationship between polymorphic variants of Bax -248G>A and Bcl-2 -938C>A promoter regions with endometriosis risk in an Iranian population. Materials and Methods: In this case-control study, the polymorphisms of Bax -248G>A and Bcl-2 -938C>A promoter regions were analyzed in 127 Iranian cases and 125 controls who were referred to Ali-ibn-Abi Taleb Educational hospital, Zahedan, Iran between May 2022 and February 2023. The genotypic analysis was performed for all the subjects using the polymerase chain reaction-restriction fragment length polymorphism method. Results: The frequencies of mutant allele A carriers and the A allele of Bax -248G>A polymorphism showed about 2-fold significant increase of endometriosis risk (p = 0.04; p = 0.01, respectively). The frequencies of the mutant genotype AA and A allele carriers of Bcl-2 -938C>A polymorphism were approximately 4 and 2.5-fold higher in endometriosis compared to the control women, which were highly significant (p > 0.001). Moreover, the allele A frequency of Bcl-2 -938C>A was associated with a 2-fold higher risk of endometriosis (p > 0.001). Furthermore, the combination effects of these 2 single nucleotide polymorphisms showed that women with Bax -248G>A GG and Bcl-2 -938C>A AA variant alleles were associated with about 5 times higher risk of endometriosis (p > 0.001). Notably, a significant difference was observed in mutant allele distribution between minimal/mild (stage I and II) and moderate/severe (stage III and IV) women with endometriosis disease. Conclusion: The results of our study provide evidence that Bcl-2 -938C>A and Bax -248G>A single nucleotide polymorphisms might be associated with the risk of endometriosis. [ABSTRACT FROM AUTHOR]

BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death. [ABSTRACT FROM AUTHOR]

Bladder cancer stands as a prevailing neoplasm among men globally, distinguished for its pronounced malignancy attributed to invasiveness and metastatic proclivity. Tannic acid (TA), an organic compound in many plants, has garnered recent attention for its discernible anti-mutagenic attributes. This investigation endeavored to scrutinize the repercussions of TA on grade II bladder cancer, with a concerted focus on unraveling its anti-cancer mechanisms. The cytotoxic effects of TA on grade II bladder cancer cells were investigated using multiple techniques, including MTT assay, flow cytometry, TUNEL assay, and western blot. Our findings revealed that elevated concentrations of TA induced cytotoxic effects in grade II bladder cancer cells. Both flow cytometry and the TUNEL assay substantiated the dose-dependent capacity of TA to prompt apoptosis. Western blot analysis corroborated that TA treatment in bladder cancer cells resulted in the upregulation of cleaved caspase-3 expression and PARP. Furthermore, heightened TA dosage elicited an augmentation in the expression of pro-apoptotic proteins, namely Bax and Bak, alongside a reduction in the expression of the anti-apoptotic protein Bcl-2 within bladder cancer cells. This study confirms TA as a potential anticancer agent, demonstrably diminishing the viability of bladder cancer cells. TA exerts cytotoxicity through the activation of mitochondrial apoptotic pathways. Specifically, TA initiates the cleavage of PARP and caspase-3, concurrently augmenting the expression of pro-apoptotic proteins to facilitate apoptosis. Collectively, the present study indicates that TA effectively impedes the proliferation of bladder cancer cells by instigating apoptosis through the intrinsic mitochondrial pathway. [ABSTRACT FROM AUTHOR]

Breast cancer remains a significant challenge in oncology, necessitating the exploration of novel therapeutic options. This study investigates the anticancer effects of ethanol and n-hexane fractions derived from the methanol extract of the Leptastrea purpurea sponge on T47D breast cancer cells. Employing cytotoxicity assays (MTT and WST-1), mitochondrial transmembrane potential assays, and protein expression analysis of p53, Caspase-3, and Bax, we aimed to elucidate the mechanisms underlying their potential anticancer activity. LC-MS/MS analysis was utilized to identify active compounds within the fractions. The results of the experiment demonstrate that the ethanol fraction exhibits significant efficacy against T47D breast cancer cells, with an IC50 value of 25.36 μg/mL indicating potent cytotoxicity. At a concentration of 1508 μg/mL, it induces cell death in 95% of T47D cells, highlighting its specificity in targeting breast cancer cells. Comparative analysis with cisplatin reveals a 9.92% higher rate of cell death induced by the ethanol fraction, suggesting superior apoptosis induction capability. Flow cytometry results show increased p53 expression at concentrations of 754 and 1508 μg/mL, with a concentration-dependent pattern. Furthermore, notable increases in Bax protein expression at concentrations of 377 and 754 μg/mL suggest the involvement of the ethanol fraction in regulating apoptosis. In conclusion, the ethanol fraction demonstrates promising potential as a cytotoxic and apoptosis-inducing agent for breast cancer therapy. These findings underscore the importance of exploring natural products from marine sources as potential anticancer agents. [ABSTRACT FROM AUTHOR]

Splicing factor polyglutamine binding protein‐1 (PQBP1) is abundantly expressed in the central nervous system during development, and mutations in the gene cause intellectual disability. However, the roles of PQBP1 in cancer progression remain largely unknown. Here, it is shown that PQBP1 overexpression promotes tumor progression and indicates worse prognosis in ovarian cancer. Integrative analysis of spyCLIP‐seq and RNA‐seq data reveals that PQBP1 preferentially binds to exon regions and modulates exon skipping. Mechanistically, it is shown that PQBP1 regulates the splicing of genes related to the apoptotic signaling pathway, including BAX. PQBP1 promotes BAX exon 2 skipping to generate a truncated isoform that undergoes degradation by nonsense‐mediated mRNA decay, thus making cancer cells resistant to apoptosis. In contrast, PQBP1 depletion or splice‐switching antisense oligonucleotides promote exon 2 inclusion and thus increase BAX expression, leading to inhibition of tumor growth. Together, the results demonstrate an oncogenic role of PQBP1 in ovarian cancer and suggest that targeting the aberrant splicing mediated by PQBP1 has therapeutic potential in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a severe threat and a main reason for cancer-related deaths around the world. Drug resistance to sorafenib (Sorf), the effective HCC first-line therapy, is very common. A number of natural compounds, notably bee venom (BV), have been claimed to show a great impact against cancer when administered on its own or in conjunction with chemotherapy. Thus, this study aimed to investigate the anticancer effect of BV alone and/or combined with Sorf on HepG2 liver cancer cell lines. Methods: Both mRNA and protein expressions of Bax, Bcl-2 and Beclin-1 were investigated by quantitative real-time PCR (qPCR) and western blot respectively, to examine the apoptotic and autophagic regulatory effects of BV and Sorf single treatments plus BV/Sorf combination on HepG2 cell lines. Results: Our findings showed that BV and Sorf had considerable dose-dependent anti-proliferative effects on HepG2 cells whether administered alone or in combination, with the greatest impact for the combined therapies. Single BV and Sorf treatments showed IC50 of 93.21 and 7.28 μg/ml respectively, while combined treatment showed IC50 of 6.73 μg/ml BV + 6.73 μg/ml Sorf. Moreover, both the pro-apoptotic gene Bax and the autophagy-related gene Beclin-1 showed significant up-regulation in their mRNA expression, while the anti-apoptotic Bcl-2 mRNA gene expression showed significant down-regulation after BV/Sorf treatment as compared to either BV or Sorf single treatment. These qPCR results were further confirmed by western blot. Conclusions: These findings indicate that BV synergistically potentiates the anticancer effect of Sorf on HepG2 cells through induction of apoptotic and autophagic machineries. [ABSTRACT FROM AUTHOR]

Background: Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in vascular smooth muscle cell (VSMC) phenotypic switching, which is an early pathogenic event in various vascular remodeling diseases (VRDs). However, the underlying mechanism is not fully understood. Methods: An IP‒LC‒MS/MS assay was conducted to identify new binding partners of G6PD involved in the regulation of VSMC phenotypic switching under platelet-derived growth factor-BB (PDGF-BB) stimulation. Co-IP, GST pull-down, and immunofluorescence colocalization were employed to clarify the interaction between G6PD and voltage-dependent anion-selective channel protein 1 (VDAC1). The molecular mechanisms involved were elucidated by examining the interaction between VDAC1 and apoptosis-related biomarkers, as well as the oligomerization state of VDAC1. Results: The G6PD level was significantly elevated and positively correlated with the synthetic characteristics of VSMCs induced by PDGF-BB. We identified VDAC1 as a novel G6PD-interacting molecule essential for apoptosis. Specifically, the G6PD-NTD region was found to predominantly contribute to this interaction. G6PD promotes VSMC survival and accelerates vascular neointimal hyperplasia by inhibiting VSMC apoptosis. Mechanistically, G6PD interacts with VDAC1 upon stimulation with PDGF-BB. By competing with Bax for VDAC1 binding, G6PD reduces VDAC1 oligomerization and counteracts VDAC1–Bax-mediated apoptosis, thereby accelerating neointimal hyperplasia. Conclusion: Our study showed that the G6PD–VDAC1–Bax axis is a vital switch in VSMC apoptosis and is essential for VSMC phenotypic switching and neointimal hyperplasia, providing mechanistic insight into early VRDs. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a persistent metabolic condition marked by elevated blood glucose levels due to compromised insulin secretion or functionality. The search for natural antidiabetic agents has gained attention due to their potential effectiveness and safety profiles. Sessuvium portulacastrum, a coastal plant, has been traditionally used for various medicinal purposes. This study investigates the antidiabetic potential of Sessuvium portulacastrum aqueous extract by analyzing its inhibitory effects on key enzymes involved in carbohydrate metabolism and exploring its molecular interactions with critical target proteins. The aqueous extract of Sessuvium portulacastrum was prepared and used for in vitro analysis. The reduced activity of the extract against a-amylase and a-glucosidase enzymes, crucial in glucose absorption and postprandial hyperglycemia, was assessed. Molecular docking techniques were employed to explore the potential interactions between active compounds in the extract and diabetes-related proteins, including BAX, GSK3ß, and CADH. The study revealed significant inhibition of both alpha-amylase and alpha-glucosidase enzymes by Sessuvium portulacastrum aqueous extract, indicating its potential to reduce glucose absorption and postprandial hyperglycemia. Moreover, the molecular docking analysis demonstrated strong binding interactions between active compounds in the extract and key proteins involved in diabetes-related pathways, namely apoptotic pathways, glycogen synthesis, and cell adhesion. The findings of this study highlight the promising antidiabetic potential of Sessuvium portulacastrum aqueous extract. Upcoming research should get an attention on isolating and characterizing the active compounds responsible for these effects on antidiabetic therapies from natural sources. [ABSTRACT FROM AUTHOR]

Despite significant advances in cancer diagnosis and treatment, cancer is still a fatal disease due to a lack of prevention, early detection, and effective drugs. Therefore, there is a need to discover anticancer treatments that are specific to cancer cells and are affordable, safe, and tolerable for patients. Vitamin E is a potential candidate because of its safety. A growing body of evidence on the anti-cancer power of vitamin E has shifted the focus away from chemical drugs and antioxidants. The purpose of this study is to investigate the effect of vitamin E on the survival of colorectal cancer cell lines and the effect of this vitamin on two important genes involved in apoptosis. MTT test was performed on this cell line treated with different concentrations of vitamin E (500 to 33350 μg/ml). After determining the IC50 of this vitamin, RNA was extracted from cells treated with vitamin E and untreated cells, and then cDNA synthesis was performed. Using the specific primers of BAX and BCL2 genes and considering the GAPDH gene as the reference gene, Real-time PCR was performed and the results were analyzed. MTT test showed that vitamin E in low concentrations strengthens and increases the survival of the HT29 cell line, but at a concentration of 10000 μg/ml, it decreases the survival percentage of this cancer cell line. Analysis of gene expression also showed that vitamin E leads to increased transcription of both BAX and BCL2 genes. However, the increase in BCL2 transcription is several times higher than that of BAX. In general, the cytotoxicity and lethality of vitamin E in colorectal cancer cell line was proved and it was found that this toxicity is not through Bax and Bcl-2 genes and probably the apoptotic effect of this vitamin is through other ways such as reducing survivin expression. [ABSTRACT FROM AUTHOR]

One of the most common cancers in the world is oral squamous cell carcinoma. Increasing apoptotic activity is one method of treating cancer by reducing or stopping the uncontrolled growth of cancer cells. Known for its many health advantages and anti-tumor capabilities, Ant's Nest (Myrmecodia pendans) is a native of Papua, Indonesia. This study aimed to analyze the therapeutic effects of Ant's Nest extract on epithelial dysplasia in a carcinoma model through the immunoexpression of Caspase-3, Bax, and Bcl-2. The research was a pure experimental study using male Sprague Dawley rats, divided into control and treatment groups. The experimental animals were induced with 0.5% dimethylbenz(a)anthracene (DMBA) for 4 weeks, resulting in epithelial dysplasia. Subsequently, Ant's Nest water and ethanol extracts were administered orally at a dose of 6.3 mg dissolved in 0.5% CMC once a day for 4 weeks. Immunohistochemical examinations were conducted for Caspase-3, Bax, and Bcl-2 immunoexpression. The results of the study showed that there were notable variations in the immunoexpression of Bcl-2, Bax, and Caspase-3 between the treatment and control groups. The group that was given Ant's Nest water and ethanol extracts showed a decrease in Bcl-2 immunoexpression and an increase in Caspase-3 and Bax immunoexpression. We find that via modulating the immunoexpression of Caspase-3, Bax, and Bcl-2, Ant's Nest extract treatment promotes the process of apoptosis. [ABSTRACT FROM AUTHOR]

This current study reports, for the first time, on the potent cytotoxicity of (Z)-3-hexenyl-β-D-glucopyranoside, as well as its cellular and molecular apoptotic mechanisms against Panc1 cancer cells. The cytotoxicity of three compounds, namely (Z)-3-hexenyl-β-D-glucopyranoside (1), gallic acid (2), and pyrogallol (3), which were isolated from C. rotang leaf, was investigated against certain cancer and normal cells using the MTT assay. The cellular apoptotic activity and Panc1 cell cycle impact of compound (1) were examined through flow cytometry analysis and Annexin V-FITC cellular apoptotic assays. Additionally, RT-PCR was employed to evaluate the effect of compound (1) on the Panc1 apoptotic genes Casp3 and Bax, as well as the antiapoptotic gene Bcl-2. (Z)-3-hexenyl-β-D-glucopyranoside demonstrated the highest cytotoxic activity against Panc1 cancer cells, with an IC50 value of 7.6 µM. In comparison, gallic acid exhibited an IC50 value of 21.8 µM, and pyrogallol showed an IC50 value of 198.2 µM. However, (Z)-3-hexenyl-β-D-glucopyranoside displayed minimal or no significant cytotoxic activity against HepG2 and MCF7 cancer cells as well as WI-38 normal cells, with IC50 values of 45.8 µM, 108.7 µM, and 194. µM, respectively. (Z)-3-hexenyl-β-D-glucopyranoside (10 µM) was demonstrated to induce cellular apoptosis and cell growth arrest at the S phase of the cell cycle in Panc1 cells. These findings were supported by RT-PCR analysis, which revealed the upregulation of apoptotic genes (Casp3 and Bax) and the downregulation of the antiapoptotic gene Bcl-2. This study emphasizes the significant cellular potency of (Z)-3-hexenyl-β-D-glucopyranoside in specifically inducing cytotoxicity in Panc1 cells. [ABSTRACT FROM AUTHOR]

Proteins from the Bcl-2 family play an essential role in the regulation of apoptosis. However, they also possess cell death-unrelated activities that are less well understood. This prompted us to study apoptosis-unrelated activities of the Bax and Bak, pro-apoptotic members of the Bcl-2 family. We prepared Bax/Bak-deficient human cancer cells of different origin and found that while respiration in the glioblastoma U87 Bax/Bak-deficient cells was greatly enhanced, respiration of Bax/Bak-deficient B lymphoma HBL-2 cells was slightly suppressed. Bax/Bak-deficient U87 cells also proliferated faster in culture, formed tumours more rapidly in mice, and showed modulation of metabolism with a considerably increased NAD+/NADH ratio. Follow-up analyses documented increased/decreased expression of mitochondria-encoded subunits of respiratory complexes and stabilization/destabilization of the mitochondrial transcription elongation factor TEFM in Bax/Bak-deficient U87 and HBL-2 cells, respectively. TEFM downregulation using shRNAs attenuated mitochondrial respiration in Bax/Bak-deficient U87 as well as in parental HBL-2 cells. We propose that (post)translational regulation of TEFM levels in Bax/Bak-deficient cells modulates levels of subunits of mitochondrial respiratory complexes that, in turn, contribute to respiration and the accompanying changes in metabolism and proliferation in these cells. [ABSTRACT FROM AUTHOR]

Abstract Introduction Epilepsy is a common neurological disorder that presents with challenging mechanisms and treatment strategies. This study investigated the neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epileptic rats and explored its potential mechanisms. Methods Lithium chloride pilocarpine was used to induce an epileptic model in rats, and the effects of quinpirole on seizure symptoms and cognitive function were evaluated. The Racine scoring method, electroencephalography, and Morris water maze test were used to assess seizure severity and learning and memory functions in rats in the epileptic group. Additionally, immunohistochemistry and Western blot techniques were used to analyze the protein expression levels and morphological changes in glutamate receptor 2 (GluR2; GRIA2), BAX, and BCL2 in the hippocampi of rats in the epileptic group. Results First, it was confirmed that the symptoms in rats in the epileptic group were consistent with features of epilepsy. Furthermore, these rats demonstrated decreased learning and memory function in the Morris water maze test. Additionally, gene and protein levels of GluR2 in the hippocampi of rats in the epileptic group were significantly reduced. Quinpirole treatment significantly delayed seizure onset and decreased the mortality rate after the induction of a seizure. Furthermore, electroencephalography showed a significant decrease in the frequency of the spike waves. In the Morris water maze test, rats from the quinpirole treatment group demonstrated a shorter latency period to reach the platform and an increased number of crossings through the target quadrant. Network pharmacology analysis revealed a close association between quinpirole and GluR2 as well as its involvement in the cAMP signaling pathway, cocaine addiction, and dopaminergic synapses. Furthermore, immunohistochemistry and Western blot analysis showed that quinpirole treatment resulted in a denser arrangement and a more regular morphology of the granule cells in the hippocampi of rats in the epileptic group. Additionally, quinpirole treatment decreased the protein expression of BAX and increased the protein expression of BCL2. Conclusion The current study demonstrated that quinpirole exerted neuroprotective effects in the epileptic rat model induced by lithium chloride pilocarpine. Additionally, it was found that the treatment not only alleviated the rats' seizure symptoms, but also improved their learning and memory abilities. This improvement was linked to the modulation of protein expression levels of GLUR2, BAX, and BCL2. These findings provided clues that would be important for further investigation of the therapeutic potential of quinpirole and its underlying mechanisms for epilepsy treatment.

AbstractHerein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 μM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.

Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the second leading cause of mortality, with an incidence rate of about 2.6 million cases per year. Noscapine, a well-known alkaloid used as a cough suppressant, demonstrated anti-tumor effects by triggering apoptosis in various cancer cell lines and has the potential to become another ally against breast, ovarian, colon, and gastric cancer, among other types of malignancy. Apoptosis plays a crucial role in the treatment of cancer. Noscapine affected BAX, CASP8, CASP9, NFKBIA, and RELA gene and protein expression in the MCF-7 and MDA-MB-231 cell lines. Gene expression was higher in tumor than in normal tissue, including the BAX expression levels in lung, ovary, endometrium, colon, stomach, and glioblastoma patients; BCL2L1 expression in endometrium, colon, and stomach patients; CASP8 gene expression levels in lung, endometrium, colon, stomach, and glioblastoma patients; RELA in colon, stomach, and glioblastoma patients; and NFKBIA in glioblastoma patients. It can be concluded that noscapine affected genes and proteins related to apoptosis in cancer cell lines and several types of cancer patients. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionBreast cancer among women is the most frequently diagnosed cancer and the leading cause of death worldwide. There many advances in diagnosing and treating this disease, early diagnosis and treatment are still a significant challenge in the early stages. In recent years, microRNAs have attracted much attention in cancer diagnosis and treatment. However, the role of miR-146a in breast cancer is still controversial. We aimed to investigate the roles of miR-146a in apoptosis in breast cancer cells.A microarray dataset from the GEO database was selected, and using the GEO2R tool, the gene expression profile of this dataset was extracted. Then, the target scan database was used to explore the miR-146a target genes. The link between the signaling pathways was collected. We used miR-146a mimic, which was transfected to the MCF-7 cells to investigate the miR-146a roles in the apoptosis. The expression levels of miR-146a and BAX, BCL-2, and p-21(most essential genes in the apoptosis) were quantified by qPCR and western blot analysis.Our findings indicated that doxorubicin induces miR-146a expression. In addition, overexpression of miR-146a affected MCF-7 cell viability, induced apoptosis, and led to reduced expression levels of BCL-2 and P-21, as well as increased BAX expression levels.Considering the role of doxorubicin in inducing apoptosis and increasing the expression of miR-146a, it can be suggested that this miR is involved in inducing apoptosis in BC cells. In addition, miR-146a can be considered a therapeutic candidate. [ABSTRACT FROM AUTHOR]

Spermatogenesis is a finely regulated process that involves the interaction of several cellular mechanisms to ensure the proper development and maturation of germ cells. This study assessed autophagy contribution and its relation to apoptosis in fish spermatogenesis during starvation. To that end, Nile tilapia males were subjected to 0 (control), 7, 14, 21, and 28 days of starvation to induce autophagy. Testes samples were obtained for analyses of spermatogenesis by histology, electron microscopy, immunohistochemistry, and western blotting. Sperm quality was assessed using a computer-assisted sperm analysis (CASA) system. Data indicated a significant reduction in gonadosomatic index, seminiferous tubule area, and spermatozoa proportion in fish subject to starvation compared to the control group. Immunoblotting revealed a reduction of Bcl2 and Beclin 1 associated with increased Bax and Caspase-3, mainly after 21 and 28 days of starvation. LC3 and P62 indicated reduced autophagic flux in these starvation times. Immunolabeling for autophagic and apoptotic proteins occurred in all development stages of the germ cells, but protein expression varied throughout starvation. Beclin 1 and Cathepsin D decreased while Bax and Caspase-3 increased in spermatocytes, spermatids, and spermatozoa after 21 and 28 days. Autophagic and lysosomal proteins colocalization indicated the fusion of autophagosomes with lysosomes and lysosomal degradation in spermatogenic cells. The CASA system indicated reduced sperm motility and velocity in animals subjected to 21 and 28 days of starvation. Altogether, the data support autophagy acting at different spermatogenesis stages in Nile tilapia, with decreased autophagy and increased apoptosis after 21 and 28 days of starvation, which results in a decrease in the spermatozoa number and sperm quality. [Display omitted] • Starvation induces autophagy during spermatogenesis in Nile tilapia. • LC3, Beclin-1, and Cathepsin D are expressed in germ and somatic cells. • Prolonged starvation decreases autophagy and increases apoptosis in the testis. • Sperm motility and velocity are reduced with 21 and 28 days of starvation. [ABSTRACT FROM AUTHOR]

Introduction: Acrylamide (ACR) is commonly polluting the nearby environment as it is formed during high-temperature food cooking conditions. Several previous studies have confirmed its toxic potential on different body organs. Aim of the Work: The current study aims to investigate the possible hepatoprotection elicited by vitamin E (vit E), alphatocopherol, melatonin (MT), and combined vit E/MT in a rat model of ACR-induced liver toxicity. The putative mechanisms involved in such protection were also examined using histological and immunohistochemical studies. Material and Methods: Forty-nine male Wistar albino rats were divided into seven equal groups; control, vit E alone (100 mg/kg/d), MT alone (10 mg/kg/d), ACR-exposed (5 mg/kg/day), ACR/vit E-treated, ACR/MT-treated, and ACR/vit E/MT-treated groups. All treatments were given daily via oral gavage for 8 weeks. At the end of the study, blood samples were collected for measurement of the liver enzymes. Liver lobes were collected for preparation of the tissue homogenates to measure the hepatic concentrations of the oxidative/antioxidative markers. Also, liver samples were prepared for paraffin microtechniques and stained by Hematoxylin & Eosin (H & E) and Masson trichrome staining. Immunohistochemical assays for the detection of Bax, Bcl2, and iNOS immunoexpressions were performed. Results: ACR-exposed rats showed marked disruption of the biochemical assays, in addition to the hepatocytes disorganization and vacuolar degenerative changes observed in the H & E findings. Moreover, fibrotic changes in the Masson-stained sections and disturbed immunoexpressed proteins were noticed. Either vit E and/or MT treatment improved the histological and biochemical parameters with normalization in the combined therapy group. Conclusion: Vit E and or MT protected against ACR-mediated liver toxicity by reestablishing of the oxidant/antioxidant balance, downregulation of pro-apoptotic proteins, upregulation of anti-apoptotic proteins, and suppression of the inflammatory pathways. Both combined had a synergistic action. [ABSTRACT FROM AUTHOR]

Introduction: Bisphenol A (BPA) is an environmental contaminant with a global use as a plasticizer. Daily BPA exposure begins early prenatally and continues throughout a person's life without exact limit or safety raising alarms concerning overall health. Objective: To explore potential cardiotoxicity of orally administered BPA in adult rat, and to assess the outcome of recovery period following BPA stoppage. Materials and Methods: Forty-eight adult male albino rats were allocated into four groups (12 each); control negative, control positive, BPA-treated and recovered. For eight weeks, rats in the 3rd group received daily BPA (50 mg/kg body weight, via oral gavage). In the recovery group, animals obtained BPA, for the same dose and duration similar to that in the 3rd group, then left to convalesce without BPA administration for 4 weeks. At the experimental end, blood was collected to estimate serum Creatine kinase-MB(CK-MB) level and heart specimens were handled for histology, immunohistochemistry, and quantitative morphometry study. Results: BPA persuaded several histological, immunohistochemical and biochemical alterations manifested as cardiac fiber disruption, vascular congestion, hemorrhage, RBCs extravasation, inflammatory cell infiltration and fibrosis. Cardiomyocytes displayed dark acidophilic sarcoplasm, pyknosis and perinuclear vacuolation. Also, the mean area % for collagen fiber deposition, glycogen content, Bcl-2-associated X protein, Nuclear factor kappa B (NF-κB) and Vimentin immune-expressions were significantly high. Furthermore, mast cell number/mm2, MDA and CK-MB levels were enhanced meanwhile SOD, GSH and CAT levels were declined. After 4-week recovery, cardiomyocytes and vascular changes exhibited marked improvement and all previous metrics were directed toward normal values, though most of them were still demonstrating low significant differences contrasted to controls. Conclusion: BPA induced cardiac structural and functional alterations via ROS generation, apoptosis, inflammation and fibrosis with considerable self-recovery following BPA cessation denoting transitory adverse impact. However, the particular mechanisms underlying cardiotoxicity or recovery still require further study. [ABSTRACT FROM AUTHOR]

Introduction: Epilepsy is a common neurological disorder that presents with challenging mechanisms and treatment strategies. This study investigated the neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epileptic rats and explored its potential mechanisms. Methods: Lithium chloride pilocarpine was used to induce an epileptic model in rats, and the effects of quinpirole on seizure symptoms and cognitive function were evaluated. The Racine scoring method, electroencephalography, and Morris water maze test were used to assess seizure severity and learning and memory functions in rats in the epileptic group. Additionally, immunohistochemistry and Western blot techniques were used to analyze the protein expression levels and morphological changes in glutamate receptor 2 (GluR2; GRIA2), BAX, and BCL2 in the hippocampi of rats in the epileptic group. Results: First, it was confirmed that the symptoms in rats in the epileptic group were consistent with features of epilepsy. Furthermore, these rats demonstrated decreased learning and memory function in the Morris water maze test. Additionally, gene and protein levels of GluR2 in the hippocampi of rats in the epileptic group were significantly reduced. Quinpirole treatment significantly delayed seizure onset and decreased the mortality rate after the induction of a seizure. Furthermore, electroencephalography showed a significant decrease in the frequency of the spike waves. In the Morris water maze test, rats from the quinpirole treatment group demonstrated a shorter latency period to reach the platform and an increased number of crossings through the target quadrant. Network pharmacology analysis revealed a close association between quinpirole and GluR2 as well as its involvement in the cAMP signaling pathway, cocaine addiction, and dopaminergic synapses. Furthermore, immunohistochemistry and Western blot analysis showed that quinpirole treatment resulted in a denser arrangement and a more regular morphology of the granule cells in the hippocampi of rats in the epileptic group. Additionally, quinpirole treatment decreased the protein expression of BAX and increased the protein expression of BCL2. Conclusion: The current study demonstrated that quinpirole exerted neuroprotective effects in the epileptic rat model induced by lithium chloride pilocarpine. Additionally, it was found that the treatment not only alleviated the rats' seizure symptoms, but also improved their learning and memory abilities. This improvement was linked to the modulation of protein expression levels of GLUR2, BAX, and BCL2. These findings provided clues that would be important for further investigation of the therapeutic potential of quinpirole and its underlying mechanisms for epilepsy treatment. [ABSTRACT FROM AUTHOR]

Purpose: Globally, sepsis, which is a major health issue resulting from severe infection-induced inflammation, is the fifth biggest cause of death. This research aimed to evaluate, for the first time, the molecular effects of gabapentin's possible nephroprotective potential on septic rats by cecal ligation and puncture (CLP). Methods: Sepsis was produced by CLP in male Wistar rats. Evaluations of histopathology and renal function were conducted. MDA, SOD, GSH, TNF-α, IL-1β, and IL-6 levels were measured. qRT-PCR was utilized to determine the expression of Bax, Bcl-2, and NF-kB genes. The expression of Nrf-2 and HO-1 proteins was examined by western blotting. Results: CLP caused acute renal damage, elevated the blood levels of creatinine, BUN, TNF-α, IL-1β, and IL-6, reduced the expression of Nrf-2 and HO-1 proteins and the Bcl-2 gene expression, and upregulated NF-kB and Bax genes. Nevertheless, gabapentin dramatically diminished the degree of the biochemical, molecular, and histopathological alterations generated by CLP. Gabapentin reduced the levels of proinflammatory mediators and MDA, improved renal content of GSH and SOD, raised the expression of Nrf-2 and HO-1 proteins and Bcl-2 gene, and reduced the renal expression of NF-kB and Bax genes. Conclusion: Gabapentin mitigated the CLP-induced sepsis-related acute kidney injury through up-regulating Nrf-2/HO-1 pathway, repressing apoptosis, and attenuating the oxidative stress status by reducing the levels of the proinflammatory mediators and enhancing the antioxidant status. [ABSTRACT FROM AUTHOR]

Background and purpose: Apoptosis is involved in the occurrence and development of acute ischemic stroke (AIS). This study aimed to assess whether Chuanzhitongluo (CZTL), a multi-target and multi-pathway compound preparation, plays a neuroprotective role in AIS by modulating neuronal apoptosis via the PI3K/AKT signaling pathway. Methods: A mouse model of AIS was established by photochemical processes. Cerebral infarction volume was measured by 2% staining with 2, 3, and 5-triphenyl tetrazole chloride (TTC). Neuron apoptosis was assessed by TUNEL staining. Apoptosis RNA arrays were used to detect changes in apoptosis-related gene expression profiles. Western blotting was used to detect proteins involved in the PI3K/AKT signaling pathway. Results: The study demonstrated that CZTL could potentially mitigate neuronal apoptosis in AIS mice. This appears to be achieved via the up-regulation of certain genes such as BCL-2 , Birc6 , and others, coupled with the down-regulation of genes like BAX , Bid , and Casp3. Further validation revealed that CZTL could enhance the expression of BCL-2 and reduce the expression of Cleaved Caspase-3 and BAX at both the gene and protein levels. The study also found that CZTL can enhance the phosphorylation level of the PI3K/AKT signaling pathway. In contrast to these findings, the PI3K inhibitor LY294002 notably amplified neuronal apoptosis in AIS mice. Conclusions: These findings imply that CZTL's ability to inhibit neuronal apoptosis may be linked to the activation of AIS's PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Glaucoma is one of the leading causes of acquired blindness and characterized by retinal ganglion cell (RGC) death. MicroRNAs are small noncoding RNAs that degrade their target mRNAs. Apoptosis is one of the common mechanisms leading to neuronal death in many neurodegenerative diseases, including glaucoma. In the present study, we identified microRNAs that modulate RGC death caused by the intravitreal injection of N-methyl-d-aspartic acid (NMDA). We found an upregulation of miR-29b and downregulation of miR-124 in the retina of the NMDA-injected eyes. The intravitreal injection of an miR-29b inhibitor 18 h before NMDA injection reduced RGC death and the downregulation of myeloid cell leukemia 1 (MCL-1), an anti-apoptotic factor, induced by intravitreal NMDA. The intravitreal injection of an miR-124 mimic 18 h before NMDA injection also reduced RGC death and the upregulation of B-cell/chronic lymphocytic leukemia lymphoma 2 (bcl-2)-associated X protein (Bax) and bcl-2 interacting protein (Bim), pro-apoptotic factors, induced by intravitreal NMDA. These data suggest that expressional changes in microRNA are involved in the excitotoxicity of RGCs, and that complement and/or inhibition of microRNA may be a potential therapeutic approach for the diseases related to the excitotoxicity of RGCs, such as glaucoma and retinal central artery occlusion. [ABSTRACT FROM AUTHOR]

Two novel steroidal saponins, trilliumosides K (1) and L (2), were isolated from the rhizomes of Trillium govanianum led by bioactivity-guided phytochemical investigation along with seven known compounds: govanoside D (3), protodioscin (4), borassoside E (5), 20-hydroxyecdysone (6), 5,20-hydroxyecdysone (7), govanic acid (8), and diosgenin (9). The structure of novel compounds 1-2 was established using analysis of spectroscopic data including 1D and 2D nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-ESI-MS) data. All isolated compounds were evaluated for in vitro cytotoxic activity against a panel of human cancer cell lines. Compound 1 showed significant cytotoxic activity against the A-549 (Lung) and SW-620 (Colon) cancer cell lines with IC50 values of 1.83 and 1.85 μΜ, respectively whereas the IC50 value of Compound 2 against the A-549 cell line was found to be 1.79 μΜ. Among the previously known compounds 3, 5, and 9, the cytotoxic IC50 values were found to be in the range of 5-10 μΜ. Comprehensive anti-cancer investigation revealed that Compound 2 inhibited in vitro migration and colony-forming capability in the A-549 cell line. Additionally, the mechanistic analysis of Compound 2 on the A-549 cell line indicated distinctive alterations in nuclear morphology, increased reactive oxygen species (ROS) production, and decreased levels of mitochondrial membrane potential (MMP). By upregulating the pro-apoptotic protein BAX and downregulating the anti-apoptotic protein BCL-2, the aforementioned actions eventually cause apoptosis, a crucial hallmark in cancer research, which activates Caspase-3. To the best of our knowledge, this study reports the first mechanistic anticancer evaluation of the compounds isolated from the rhizomes of T. govanianum with remarkable cytotoxic activity in the desired micromolar range. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to investigate the synergistic and separate cytotoxicity effects of carboplatin (a chemotherapy medication) and Lactobacillus plantarum cell lysate supernatant (CLS) in the SK-OV-3 ovarian cancer cell line and the expression change of apoptotic Bax and anti-apoptotic Bcl-2 genes. Materials and Methods: L. Plantarum CLS at concentrations of 0.05, 0.1, 0.15, 0.25, 0.5, 1, 1.25, and 1.5 mg/ml and carboplatin at concentrations of 0.1, 0.5, 1, 2, 2.5, 5, 10, 20, 40, and 50 μg/ml were prepared. Separate and synergistic toxicity effects of carboplatin and L. Plantarum CLS at different concentrations were investigated on the SK-OV-3 cell line at intervals of 24, 48, and 72 h using the MTT method. Also, the expression level of Bax and Bcl-2 genes in the treated SK-OV-3 cell line was analyzed using Real-time PCR. Results: In the current study, the highest increases of toxicities in the separate and synergistic application of carboplatin and L. Plantarum CLS were seen after 48-h treatment against cancer cells. These toxicities were time-dependent, and with increasing time from 24 to 72 h, their cytotoxicity increased. The results of the MTT test showed that drug and probiotics synergism could cause the highest decrease in the survival rate of the SK-OV-3 cell line in 72, 48, and 24 h, respectively. This synergism led to a 2.8-fold decrease in the expression of the Bcl-2 gene and a 3.5-fold increase in the Bax gene compared to the control group. Carboplatin alone decreased Bcl-2 by 1.4 times and increased Bax by 1.5 times, and CLS alone decreased Bcl-2 by 3.2 times and increased Bax by 1.2 times. Discussion and Conclusion: We concluded the combination of an L. Plantarum CLS (0.1 mg/ml) and carboplatin (0.5 μg/ml) has induced apoptosis in the SK-OV-3 cell line. L. plantarum .CLS can be used as adjunctive therapy with carboplatin through increased toxicity and changes in apoptosis gene expressions. [ABSTRACT FROM AUTHOR]

Background: For patients with acute myeloid leukemia (AML), the long-term survival rate is still very low. This study examines the effects on AML cell lines of an indole chemical in its free and liposomal forms. Material and Method: In this experimental case control study, an AML-originated KG-1 cell line was cultured in RPMI 1640 medium. The cells were treated with the free and liposomal forms of an indole compound (C18H10N2F6O) at different concentrations of 20, 40, 100, 200, and 400 μg/mL after they attained the proper confluence. The cellular metabolic activity was examined by an MTT assay. The expression of BAX and BCL-2 genes was investigated by q-PCR to assess the apoptotic effect of that compound. The analysis was also done between each experimental group and the control group using t-test. P<0.05 was assumed significant. Results: Based on the MTT assay, the lethal effective dose of free indole was found to be 245.1 μg/ml and 164.8 μg/ml in 24 and 48 hours, respectively. The corresponding values for liposomal indole were 47.2 μg/ml and 40.6 μg/ml. Furthermore, treatment with free and liposomal forms of indole resulted in a decline in the expression level of the BCL-2 gene. However, in the case of the liposomal compound, this decrease was only statistically significant after 48 hours of treatment (P < 0.05). Furthermore, the expression of BAX gene increased after treatment with both free and liposomal forms of indole, but it significantly increased only after treatment with the liposomal compound (p < 0.05). Conclusion: These results suggest that an indole derivative, especially when liposomal, causes apoptosis in AML cells, hence exhibiting cytotoxic effects. To confirm the potential usefulness of this indole derivative as a therapeutic agent for inhibiting tumor progression in the setting of human malignancies, more studies on physiologically relevant models are necessary. [ABSTRACT FROM AUTHOR]

Background: Terminalia arjuna is an evergreen tree commonly referred as Arjuna, widely distributed in India and is a prominent member of the genus Terminalia. It has been discovered that the various plant parts, including the root, leaf, bark, fruits, and seeds have unique medicinal property. Among them, bark part is found to have and plethora of bioactive compounds and rich in medicinal property, especially for its cardiovascular properties. Materials and Methods: In the current investigation we have developed a standardized extract of T. arjuna bark called Cardiboost, which contains 1% arjunolic acid. Cardiboost was used to examine in vitro thrombin and ACE enzyme inhibition. Additionally, MTT assay was used to measure cell viability of H9c2 cardiomyocytes, western blot experiments were performed to measure the levels of antioxidative enzyme levels CAT and SOD and the expressions of cell apoptosis regulatory proteins PARP1, Casp antiapoptotic properties to elucidate Cardiboost ability to prevent H9c2 cardiomyocytes cells suffering from oxidative damage induced by H2O2. Results: Cardiboost, exhibited potent thrombin and ACE inhibition property, with IC50 values of 111.88µg/mL and 196.66 µg/mL respectively, Furthermore, Cardiboost, averted the cell death and significantly increased the levels of antioxidant enzymes CAT and SOD which was subsided in presence of H2O2, and Cardiboost protected the mitochondrial events and reduced the apoptotic effects in H2O2-induced oxidative stress. Conclusion: Cardiboost could shield H9c2 cardiomyocytes from oxidative stress and may also be used as a medicinal product to prevent oxidative stress in cardiac damage. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a highly prevalent joint disorder characterized by progressive degeneration of articular cartilage, subchondral bone remodeling, osteophyte formation, synovial inflammation, and meniscal damage. Although the etiology of OA is multifactorial, pro-inflammatory processes appear to play a key role in disease pathogenesis. Previous studies indicate that electroacupuncture (EA) exerts chondroprotective, anti-inflammatory, and analgesic effects in preclinical models of OA, but the mechanisms underlying these potential therapeutic benefits remain incompletely defined. This study aimed to investigate the effects of EA on OA development in a rat model, as well as to explore associated molecular mechanisms modulated by EA treatment. Forty rats were divided into OA, EA, antagomiR-214, and control groups. Following intra-articular injection of monosodium iodoacetate to induce OA, EA and antagomiR-214 groups received daily EA stimulation at acupoints around the knee joint for 21 days. Functional pain behaviors and chondrocyte apoptosis were assessed as outcome measures. The expression of microRNA-214 (miR-214) and its downstream targets involved in apoptosis and nociception, BAX and TRPV4, were examined. Results demonstrated that EA treatment upregulated miR-214 expression in OA knee cartilage. By suppressing pro-apoptotic BAX and pro-nociceptive TRPV4, this EA-induced miR-214 upregulation ameliorated articular pain and prevented chondrocyte apoptosis. These findings suggested that miR-214 plays a key role mediating EA's therapeutic effects in OA pathophysiology, and represents a promising OA treatment target for modulation by acupuncture.

Abstract Splicing factor polyglutamine binding protein‐1 (PQBP1) is abundantly expressed in the central nervous system during development, and mutations in the gene cause intellectual disability. However, the roles of PQBP1 in cancer progression remain largely unknown. Here, it is shown that PQBP1 overexpression promotes tumor progression and indicates worse prognosis in ovarian cancer. Integrative analysis of spyCLIP‐seq and RNA‐seq data reveals that PQBP1 preferentially binds to exon regions and modulates exon skipping. Mechanistically, it is shown that PQBP1 regulates the splicing of genes related to the apoptotic signaling pathway, including BAX. PQBP1 promotes BAX exon 2 skipping to generate a truncated isoform that undergoes degradation by nonsense‐mediated mRNA decay, thus making cancer cells resistant to apoptosis. In contrast, PQBP1 depletion or splice‐switching antisense oligonucleotides promote exon 2 inclusion and thus increase BAX expression, leading to inhibition of tumor growth. Together, the results demonstrate an oncogenic role of PQBP1 in ovarian cancer and suggest that targeting the aberrant splicing mediated by PQBP1 has therapeutic potential in cancer treatment.

Despite the health benefits of herbals, random misuse of such therapy without consult tends to participate in public health issues. This study describes the nephro-and pulmonary toxicity effects of heavy consumption of garlic (Allium sativum) during developmental period. Two groups of ten healthy pregnant female Albino rats each were formed from the 20 in total. Gavages of distilled water were administered to the control group. Since garlic group rats orally received garlic aqueous extract (GAE) 1 ml/rat daily from gestational day (GD) 6 to 19. Kidney functions and lipid biomarkers were assayed along with histopathological investigations. Our results confirmed that the group that received garlic had significantly increased serum levels of urea, cholesterol, triglycerides and LDL. Moreover, the foetal and maternal tissues of the kidney and lung exhibited a varying degree of histopathological manifestations characterized by kidney necrosis and lung haemorrhage, severe congestion, and thickening of the blood vessels. Renal and pulmonary fibrosis were detectable by Masson’s trichrome. A positive expression of the foetal kidney and placental tissues towards Bax protein was noticed. In conclusion, depending on existing findings, the administration of higher concentrations of garlic could explode renal and pulmonary toxicity and decrease the rat’s weight.