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Aim: This study was aimed at investigating the cytotoxic effect of a novel combination of doxorubicin (DOX) and nano-formulation of Santolina chamaecyparissus L. essential oil (SCEO-NANO) on hepatic (HepG2) and colon (HT29) cancer cell lines. Methods: A nano-emulsion was prepared by high-pressure homogenisation, then analysed by zetasizer and Fourier transform infrared spectroscopy. HepG2 and HT29 cells were used in in vitro tests for apoptosis detection. Results: Formulated droplet size increased in DOX@SCEO-NANO/DOX to 11.54 ± 0.02 with uniform distribution (PDI = 0.13 ± 0.01), when compared with SCEO-NANO (size: 8.91 ± 0.02 nm; PDI = 0.1 ± 0.02). In both cells, DOX@SCEO-NANO/DOX led to a considerable reduction in colony formation. Compared to DOX, apoprotein proteins were overexpressed in HepG2 cells, showing increases of 8.66-fold for caspase-3 and 4.24-fold for the Bax/Bcl-2 ratio. In HT29 cells, ROS-dependent necrosis and apoptosis were seen. Comparing DOX@SCEO-NANO/DOX versus DOX, greater levels of caspase-3 and the Bax/Bcl-2 ratio were observed. Conclusion: The DOX@SCEO-NANO/DOX formulation showed potential for targeted eradication of colon adenocarcinoma and hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]

Radiotherapy is used in the treatment of ≈50% of patients with cancer. However, tumor repopulation is a major cause of treatment failure after radiotherapy. It is observed that apoptotic tumor following ionizing radiation (IR) accelerated the growth of surviving tumor cells. Here a Gasdermin E and Tannic acid‐based nanoassembly (GT) loaded with manganese tetroxide (Mn3O4) (termed as Mn3O4@GT) is developed to suppress tumor repopulation and improve the treatment outcome of radiotherapy. Mn3O4@GT enables an increase in the reactive oxygen species accumulation in tumor cells, enhancing radiotherapy‐mediated tumor killing. What's more, it can hijack activated caspase 3 to induce tumor pyroptosis, reversing apoptosis‐mediated tumor repopulation. In vivo results shows that Mn3O4@GT significantly reduced the IR induced tumor repopulation by 2.7 fold, resulting in 92% complete regression of tumors. In addition, Mn3O4@GT can sensitize tumors to anti‐PD‐L1 therapy by inducing immunogenic pyroptosis with 85% regression of distant tumors. The caspase 3‐hijacking nanosystem holds a great potential for improving the clinical benefits of radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin derived AL amyloidosis and transthyretin derived ATTR amyloidosis are the most common forms of cardiac amyloidosis. Both may present with cardiac arrhythmias, heart failure, and extracardiac symptoms. Disease outcome is often fatal. Recently, it was proposed that amyloid may cause cardiac inflammation. Here we tested the hypothesis that immune cell infiltration in cardiac tissue correlates with clinicopathological patient characteristics. Patients and methods: Myocardial biopsies from 157 patients with cardiac amyloidosis (46.5% AL, 53.3% ATTR) were immunohistochemically assessed for the presence and amount of T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO). Amyloid load, cardiomyocyte diameter, apoptosis (Caspase 3), necrosis (complement 9), and various clinical parameters were assessed and correlated with immune cell density. Results: Myocardial tissue was infiltrated with T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO) with variable amounts. Significant correlations were found between the number of macrophages and NYHA class. No correlations were found between the presence and amount of T lymphocytes, neutrophils and clinicopathological patient characteristics. Conclusion: The significant correlation between cardiac macrophage density and heart failure points towards a significant role of macrophages in disease pathology. [ABSTRACT FROM AUTHOR]

Despite the efficacy of highly active antiretroviral therapy in controlling the incidence and mortality of AIDS, effective interventions for HIV-1-induced neurological damage and cognitive impairment remain elusive. In this study, we found that HIV-1 infection can induce proteolytic cleavage and aberrant aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological protein associated with various severe neurological disorders. The HIV-1 accessory protein Vpu was found to be responsible for the cleavage of TDP-43, as ectopic expression of Vpu alone was sufficient to induce TDP-43 cleavage, whereas HIV-1 lacking Vpu failed to cleave TDP-43. Mechanistically, the cleavage of TDP-43 at Asp89 by HIV-1 relies on Vpu-mediated activation of Caspase 3, and pharmacological inhibition of Caspase 3 activity effectively suppressed the HIV-1-induced aggregation and neurotoxicity of TDP-43. Overall, these results suggest that TDP-43 is a conserved host target of HIV-1 Vpu and provide evidence for the involvement of TDP-43 dysregulation in the neural pathogenesis of HIV-1. Synopsis: HIV-1 Vpu triggers the cleavage of TDP-43 by stimulating Caspase 3 activation. The cleavage products generated can induce the cytoplasmic aggregation and inactivation of TDP-43, thereby exerting neurotoxic effects. HIV-1 infection promotes the cleavage and cytoplasmic aggregation of TDP-43 proteins. Vpu contributes to HIV-1-mediated cleavage of TDP-43 by enhancing Caspase 3 activity. TDP-43 fragments function as dominant-negative mutants and promote the aggregation of full-length TDP-43. Vpu serves as a neurotoxic factor during HIV-1 infection by inactivating TDP-43. HIV-1 Vpu triggers the cleavage of TDP-43 by stimulating Caspase 3 activation. The cleavage products generated can induce the cytoplasmic aggregation and inactivation of TDP-43, thereby exerting neurotoxic effects. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion injury (IRI) is unavoidable during kidney transplant and it is responsible for delayed or non-function after kidney transplantation. Cysteamine is the standard drug in the management of nephropathic cystinosis and its extra-renal complications. Thus, we designed this study to investigate its potential against renal reperfusion injury. Results: Significant elevation of H2O2, MDA, and nitrite and reduced GPx, GSH, and protein thiol in the Ischemia-reperfusion injury rats was reversed by cysteamine (50 and 100 mg/kg). Serum MPO, TNF-a, IL-1ß, creatinine, and AOPP were significantly elevated in IRI while rats treated with cysteamine revealed a significant decrease (p < 0.05) in the activities of these proinflammatory and renal injury markers. Conclusion: Based on its activity against inflammation, apoptosis, and free radical-induced stress, cysteamine has great potential to be used as a kidney transplant pre-operative drug to prevent renal reperfusion injury. [ABSTRACT FROM AUTHOR]

It has been documented that caspase 3 activity is necessary for skeletal muscle regeneration, but how its activity is regulated is largely unknown. Our previous report shows that intracellular TMEM16A, a calcium activated chloride channel, significantly regulates caspase 3 activity in myoblasts during skeletal muscle development. By using a mouse line with satellite cell (SC)-specific deletion of TMEM16A, we examined the role of TMEM16A in regulating caspase 3 activity in SC (or SC-derived myoblast) as well as skeletal muscle regeneration. The mutant animals displayed apparently impaired regeneration capacity in adult muscle along with enhanced ER stress and elevated caspase 3 activity in Tmem16a−/− SC derived myoblasts. Blockade of either excessive ER stress or caspase 3 activity by small molecules significantly restored the inhibited myogenic differentiation of Tmem16a−/− SCs, indicating that excessive caspase 3 activity resulted from TMEM16A deletion contributes to the impaired muscle regeneration and the upstream regulator of caspase 3 was ER stress. Our results revealed an essential role of TMEM16A in satellite cell-mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14–16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects. Methods: To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI. Results: The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p < 0.001), as determined by cell-based assays. ESL treatment led to significant enhancement of apoptosis (p < 0.01), as determined by flow cytometry, and upregulation of genes involved in cell apoptosis, such as the Bax/Bcl2 ratio at RNA (p < 0.05) and protein levels (5.37-fold). Flow cytometric analysis of ESL-treated cells revealed G2/M phase cell cycle arrest. ESL-treated cells demonstrated 2.49-fold upregulation of p21 alongside, 0.22-fold downregulation of cyclin B1, and 0.34-fold downregulation of cyclin-dependent kinase-1 at the protein level. Administration of ESL (30 mg/kg) to male rats bearing C6 intracranial tumors also suppressed the tumor volume and weight (p < 0.01). Conclusions: Based on these novel findings, ESL has the potential for further experimental and clinical studies in glioblastoma. [ABSTRACT FROM AUTHOR]

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]

Background and Objectives: Cisplatin is a chemotherapeutic drug that is frequently used with hyperthermic intraperitoneal chemotherapy (HIPEC). Cisplatin-induced gonadotoxicity leads to a depletion of the ovarian reserve, causing premature ovarian insufficiency. This study aimed to investigate the impact of hyperthermia on cisplatin-induced ovarian toxicity and to determine whether sevoflurane or desflurane could be a more appropriate choice of anesthetic for reducing ovarian toxicity in HIPEC procedures. Materials and Methods: A total of 24 New Zealand rabbits were randomly divided into 4 groups as follows: Group H: HIPEC (cisplatin 7 mg/kg), Group HS: HIPEC (cisplatin 7 mg/kg) + 3% sevoflurane (2 h), Group HD: HIPEC (cisplatin 7 mg/kg) + 6% desflurane (2 h), and Group C: Control (Saline). Two catheters were placed in the abdominal cavity, the upper and lower quadrants. The perfusate was heated to 42 °C and given intraperitoneally for 90 min at a rate of 4 mL/min by catheters. Ovarian tissues were collected for Hematoxylin and Eosin staining and immunohistochemical analysis. Results: The primary follicle number was significantly decreased in Group H and HD compared to the C group (p < 0.05). Bax expression was high in Group H, according to all groups (p < 0.0001). Bax expression significantly decreased after sevoflurane, compared to group H (p = 0.012). The bcl-2 expression decreased in all groups compared to the C group. Bcl-2 expression was increased with sevoflurane compared to the H group (p = 0.001). Caspase 3 and p53 expression increased in all groups compared to the C group. p53 expression was decreased with sevoflurane and desflurane compared to the H group (p = 0.002, p = 0.008, respectively). Conclusions: The application of cisplatin with the intraoperative HIPEC method caused ovarian damage. According to our results, sevoflurane anesthesia could be a better option in mitigating cell death I the n ovarian reserve (follicle count) and apoptosis in the HIPEC procedures. We think that our findings should be supported by large series of clinical and experimental studies. [ABSTRACT FROM AUTHOR]

Abstract Background: Immunoglobulin derived AL amyloidosis and transthyretin derived ATTR amyloidosis are the most common forms of cardiac amyloidosis. Both may present with cardiac arrhythmias, heart failure, and extracardiac symptoms. Disease outcome is often fatal. Recently, it was proposed that amyloid may cause cardiac inflammation. Here we tested the hypothesis that immune cell infiltration in cardiac tissue correlates with clinicopathological patient characteristics. Patients and methods: Myocardial biopsies from 157 patients with cardiac amyloidosis (46.5% AL, 53.3% ATTR) were immunohistochemically assessed for the presence and amount of T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO). Amyloid load, cardiomyocyte diameter, apoptosis (Caspase 3), necrosis (complement 9), and various clinical parameters were assessed and correlated with immune cell density. Results: Myocardial tissue was infiltrated with T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO) with variable amounts. Significant correlations were found between the number of macrophages and NYHA class. No correlations were found between the presence and amount of T lymphocytes, neutrophils and clinicopathological patient characteristics. Conclusion: The significant correlation between cardiac macrophage density and heart failure points towards a significant role of macrophages in disease pathology.

Abstract Pesticides like atrazine which are frequently present in everyday surroundings, have adverse impacts on human health and may contribute to male infertility. The work aimed to analyze the histological and biochemical effects of atrazine on the testis in adult albino rats and whether co-administration with resveratrol could reverse the effect of atrazine. Forty adult male albino rats in good health participated in this study. They were categorized at random into four groups: the Group Ӏ received water through a gastric tube for two months every day, the Group ӀӀ received resveratrol (20 mg/kg body weight (b.w.)) through a gastric tube for two months every day, the Group ӀӀӀ received atrazine (50 mg/kg bw) through a gastric tube for two months every day, the Group ӀV received concomitant doses of atrazine and resveratrol for two months every day. The testes of the animals were then carefully removed and prepared for biochemical, immunohistochemical, light, and electron microscopic studies. Atrazine exposure led to a significant decrease in serum testosterone hormone level, upregulation of caspase 3 and iNOS mRNA levels, destructed seminiferous tubules with few sperms in their lumens, many collagen fibres accumulation in the tunica albuginea and the interstitium, abnormal morphology of some sperms as well as many vacuolations, and damaged mitochondria in the cytoplasm of many germ cells. Concomitant administration of resveratrol can improve these adverse effects. It was concluded that atrazine exposure is toxic to the testis and impairs male fertility in adult rat and coadministration of resveratrol guards against this toxicity.

Background and objectives: As the global geriatric population continues to grow, degenerative-related disorders such as impaired cognitive function, keep increasing. This is partly due to the aging process, which triggers an inflammaging phenomenon, characterized by elevated levels of transforming growth factor-β (TGF-β) and caspase 3 cytokines. Moringa oleifera stands out as a solution, known for its antioxidant, anti-inflammatory, and anti-aging properties. This study aimed to assess the effects of M. oleifera leaves extract and physical activity on the levels of TGF-β, caspase 3, and cognitive function in geriatric mice model. Methods: Thirty mice were divided into five groups. The C1 group served as the negative control (given standardized food and water), while C2 was the positive control (treated with D-galactose 150 mg/kg BW/day intraperitoneally for eight weeks, followed by swimming for 30 minutes 2x/week, four weeks). The T1, T2, and T3 treatment groups received D-galactose 150 mg/kg BW/day for eight weeks and M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg/day, respectively, along with a similar swimming session. At the end of the study, the mice were assessed for cognitive function using the Y-maze test, and then TGF-β and caspase 3 levels were measured. Results: The differences in TGF-β and caspase 3 levels between groups were statistically significant (p0.05). Conclusion: Moringa oleifera leaves extract significantly influenced TGF-β and caspase 3 levels but did not affect the cognitive function of the geriatric mice model.

Heterogenous immune responses to checkpoint blockade therapy remain a major challenge to early prediction of treatment efficacy. Current methods of evaluating treatment efficacy in tumors are ineffective in accurately monitoring the disease status after immunotherapy early on. This study reports an immune response monitoring strategy that longitudinally reports on two crucial protease activities involved in T cell‐mediated target cell death, granzyme B (GrzB) and downstream caspase 3 (Casp3), during and after immune checkpoint antibody treatment. Specifically, activatable nanoreporters are engineered to sensitively and selectively capture the activity of GrzB and Casp3 enzymes in tumor cells triggered by cytotoxic T cells in real‐time, providing a direct readout of the tumor response to immune checkpoint inhibitors (ICIs). Furthermore, incorporating 3D tumor‐derived organoids and ex vivo cultures on microfluidic devices with nanoreporters enables high‐throughput screening of various ICIs and their combinations in immunocompetent tumor models. These findings suggest that efficient monitoring of dynamic immunological processes in the tumor microenvironment could help uncover mechanisms associated with ICI response or resistance. It is further anticipated that combining the dual‐sensing nanoreporter with tumor‐derived organoid‐on‐chip technology could lead to an early prediction of treatment outcomes with high fidelity and accelerate the development of optimal treatment in immuno‐oncology. [ABSTRACT FROM AUTHOR]

Pesticides like atrazine which are frequently present in everyday surroundings, have adverse impacts on human health and may contribute to male infertility. The work aimed to analyze the histological and biochemical effects of atrazine on the testis in adult albino rats and whether co-administration with resveratrol could reverse the effect of atrazine. Forty adult male albino rats in good health participated in this study. They were categorized at random into four groups: the Group Ӏ received water through a gastric tube for two months every day, the Group ӀӀ received resveratrol (20 mg/kg body weight (b.w.)) through a gastric tube for two months every day, the Group ӀӀӀ received atrazine (50 mg/kg bw) through a gastric tube for two months every day, the Group ӀV received concomitant doses of atrazine and resveratrol for two months every day. The testes of the animals were then carefully removed and prepared for biochemical, immunohistochemical, light, and electron microscopic studies. Atrazine exposure led to a significant decrease in serum testosterone hormone level, upregulation of caspase 3 and iNOS mRNA levels, destructed seminiferous tubules with few sperms in their lumens, many collagen fibres accumulation in the tunica albuginea and the interstitium, abnormal morphology of some sperms as well as many vacuolations, and damaged mitochondria in the cytoplasm of many germ cells. Concomitant administration of resveratrol can improve these adverse effects. It was concluded that atrazine exposure is toxic to the testis and impairs male fertility in adult rat and coadministration of resveratrol guards against this toxicity. [ABSTRACT FROM AUTHOR]

Background and objectives: As the global geriatric population continues to grow, degenerativerelated disorders such as impaired cognitive function, keep increasing. This is partly due to the aging process, which triggers an inflammaging phenomenon, characterized by elevated levels of transforming growth factor-β (TGF-β) and caspase 3 cytokines. Moringa oleifera stands out as a solution, known for its antioxidant, anti-inflammatory, and anti-aging properties. This study aimed to assess the effects of M. oleifera leaves extract and physical activity on the levels of TGF-β, caspase 3, and cognitive function in geriatric mice model. Methods: Thirty mice were divided into five groups. The C1 group served as the negative control (given standardized food and water), while C2 was the positive control (treated with D-galactose 150 mg/kg BW/day intraperitoneally for eight weeks, followed by swimming for 30 minutes 2x/week, four weeks). The T1, T2, and T3 treatment groups received D-galactose 150 mg/kg BW/day for eight weeks and M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg/day, respectively, along with a similar swimming session. At the end of the study, the mice were assessed for cognitive function using the Y-maze test, and then TGF-β and caspase 3 levels were measured. Results: The differences in TGF-β and caspase 3 levels between groups were statistically significant (p<0.05); however, no significant differences were observed in the cognitive function in any group (p>0.05). Conclusion: Moringa oleifera leaves extract significantly influenced TGF-β and caspase 3 levels but did not affect the cognitive function of the geriatric mice model. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is a significant hepatic condition that has gained worldwide attention. Kaempferol (Kae), renowned for its diverse biological activities, including anti-inflammatory, antioxidant, anti-aging, and cardio-protective properties, has emerged as a potential therapeutic candidate for non-alcoholic steatohepatitis (NASH). Despite its promising therapeutic potential, the precise underlying mechanism of Kae's beneficial effects in NASH remains unclear. Therefore, this study aims to clarify the mechanism by conducting comprehensive in vivo and in vitro experiments. Results: In this study, a murine model of non-alcoholic steatohepatitis (NASH) was established by feeding C57BL/6 female mice a high-fat diet for 12 weeks. Kaempferol (Kae) was investigated for its ability to modulate systemic inflammatory responses and lipid metabolism in this model (20 mg/kg per day). Notably, Kae significantly reduced the expression of NLRP3-ASC/TMS1-Caspase 3, a crucial mediator of liver tissue inflammation. Additionally, in a HepG2 cell model induced with palmitic acid/oleic acid (PA/OA) to mimic NASH conditions, Kae demonstrated the capacity to decrease lipid droplet accumulation and downregulate the expression of NLRP3-ASC/TMS1-Caspase 3 (20 µM and the final concentration to 20 nM). These findings suggest that Kae may hold therapeutic potential in the treatment of NASH by targeting inflammatory and metabolic pathways. Conclusions: These findings suggest that kaempferol holds potential as a promising therapeutic intervention for ameliorating non-alcoholic fatty liver disease (NAFLD). [ABSTRACT FROM AUTHOR]

Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors—BAY 61–3606 and R406—on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3β expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.

BackgroundIschemia-reperfusion injury (IRI) is unavoidable during kidney transplant and it is responsible for delayed or non-function after kidney transplantation. Cysteamine is the standard drug in the management of nephropathic cystinosis and its extra-renal complications. Thus, we designed this study to investigate its potential against renal reperfusion injury.ResultsSignificant elevation of H2O2, MDA, and nitrite and reduced GPx, GSH, and protein thiol in the Ischemia-reperfusion injury rats was reversed by cysteamine (50 and 100 mg/kg). Serum MPO, TNF-α, IL-1β, creatinine, and AOPP were significantly elevated in IRI while rats treated with cysteamine revealed a significant decrease (p < 0.05) in the activities of these pro-inflammatory and renal injury markers.ConclusionBased on its activity against inflammation, apoptosis, and free radical-induced stress, cysteamine has great potential to be used as a kidney transplant pre-operative drug to prevent renal reperfusion injury.

Monocytes are peripheral leukocytes that function in innate immunity. Excessive triglyceride (TG) accumulation causes monocyte death and thus can compromise innate immunity. However, the mechanisms by which TG mediates monocyte death remain unclear to date. Thus, this study aimed to elucidate the mechanisms by which TG induces monocyte death. Results showed that TG induced monocyte death by activating caspase-3/7 and promoting poly (ADP-ribose) polymerase (PARP) cleavage. In addition, TG induced DNA damage and activated the ataxia telangiectasia mutated (ATM)/checkpoint kinase 2 and ATM-and Rad3-related (ATR)/checkpoint kinase 1 pathways, leading to the cell death. Furthermore, TG-induced DNA damage and monocyte death were mediated by caspase-2 and -8, and caspase-8 acted as an upstream molecule of caspase-2. Taken together, these results suggest that TG-induced monocyte death is mediated via the caspase-8/caspase-2/DNA damage/executioner caspase/PARP pathways. [BMB Reports 2023; 56(3): 166-171].

Background: Human papillomavirus is an infection that causes malignancy because of persistency and modulation of apoptotic pathways, especially caspase-3. Factors that can increase persistency, recurrency, and malignancy of HPV infection include HIV infection with low CD4 levels. There is disagreement or deep molecular understanding of the induction and modulation of apoptosis in HIV-mediated CD4+ T cell depletion, especially in CA. However, it is necessary to see how CD4+ levels can influence caspase-3, so it may open up new avenues for supporting investigation to consider the presence of malignancy or therapeutic strategies regarding CD4+ can induce apoptosis. Purpose: This study aimed to determine whether there is a correlation between CD4+ levels and caspase-3 expression in condyloma acuminata with HIV reactive patients. Methods: This is an analytic observational study with a cross-sectional design. The research was conducted at Dr. Moewardi General Hospital from August to December 2023. Nineteen patients with condyloma acuminata and HIV reactive were included in this study with a consecutive sampling technique. The expression of caspase-3 was assessed using immunohistochemical staining, looking at the percentage of stained cell nuclei and cytoplasm and CD4+ levels with flow cytometry examination—data analysis using Pearson correlation. Results: Respondents in this study were primarily men, self-employed with heterosexual orientation and genito-genital-oral sexual intercourse. The statistical analysis showed no significant relationship (p: 0.300, r: -0.251) between CD4+ levels and caspase-3 expression. Conclusions: While not statistically significant, CD4+ level is reduced in correlation with increased caspase-3 expressions.

Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress responses induced by drugs. To address this question, we engineered a HeLa cell line to express caspase-3 inducibly and combined it with a quantitative caspase activity reporter. While high caspase activity levels killed all cells and very low levels allowed all cells to live, doses of caspase activity sufficient to kill 15 to 30% of cells nevertheless allowed 70 to 85% to survive. At these doses, neither the rate, nor the peak level, nor the total amount of caspase activity could accurately predict cell death versus survival. Thus, cells can survive direct executioner-caspase activation, and variations in cellular state modify the outcome of potentially lethal caspase activity. Such heterogeneities may underlie incomplete tumor cell killing in response to apoptosis-inducing cancer treatments.

Lipid peroxidation from oxidative stress is considered a major contributor to age-related macular degeneration (AMD). The retina is abundant with circulating low-density lipoproteins (LDL), which are taken up by LDL receptor (LDLR) in the RPE and Müller cells. The purpose of this study is to investigate the role of LDLR in the NaIO3-induced model of dry AMD. Confluent primary human RPE (hRPE) and LDLR-silenced ARPE-19 cells were stressed with 150 µM tert-butyl hydroperoxide (tBH) and caspase 3/7 activation was determined. WT and Ldlr-/- mice were administered NaIO3 (20 mg/kg) intravenously. On day 7, fundus imaging, OCT, ERG, and retinal thickness were measured. Histology, TUNEL, cleaved caspase 3 and lipid accumulation were assessed. Treatment of hRPE with tBH markedly decreased LDLR expression. Caspase 3/7 activation was significantly increased in LDLR-silenced ARPE-19 cells treated with tBH. In Ldlr-/- mice, NaIO3 administration resulted in significant (a) retinal thinning, (b) compromised photoreceptor function, (c) increased percentage of cleaved caspase 3 positive and apoptotic cells, and (d) increased lipid droplet accumulation in the RPE, Bruch membrane, choroid, and sclera, compared to WT mice. Our findings imply that LDLR loss leads to lipid accumulation and impaired retinal function, which may contribute to the development of AMD.

Novel approaches are required to address the urgent need to develop lipid-based carriers of paclitaxel (PTX) and other hydrophobic drugs for cancer chemotherapy. Carriers based on cationic liposomes (CLs) with fluid (i.e., chain-melted) membranes (e.g., EndoTAG-1) have shown promise in preclinical and late-stage clinical studies. Recent work found that the addition of a cone-shaped poly(ethylene glycol)-lipid (PEG-lipid) to PTX-loaded CLs (CLsPTX) promotes a transition to sterically stabilized, higher-curvature (smaller) nanoparticles consisting of a mixture of PEGylated CLsPTX and PTX-containing fluid lipid nanodiscs (nanodiscsPTX). These CLsPTX and nanodiscsPTX show significantly improved uptake and cytotoxicity in cultured human cancer cells at PEG coverage in the brush regime (10 mol % PEG-lipid). Here, we studied the PTX loading, in vivo circulation half-life, and biodistribution of systemically administered CLsPTX and nanodiscsPTX and assessed their ability to induce apoptosis in triple-negative breast-cancer-bearing immunocompetent mice. We focused on fluid rather than solid lipid nanodiscs because of the significantly higher solubility of PTX in fluid membranes. At 5 and 10 mol % of a PEG-lipid (PEG5K-lipid, molecular weight of PEG 5000 g/mol), the mixture of PEGylated CLsPTX and nanodiscsPTX was able to incorporate up to 2.5 mol % PTX without crystallization for at least 20 h. Remarkably, compared to preparations containing 2 and 5 mol % PEG5K-lipid (with the PEG chains in the mushroom regime), the particles at 10 mol % (with PEG chains in the brush regime) showed significantly higher blood half-life, tumor penetration, and proapoptotic activity. Our study suggests that increasing the PEG coverage of CL-based drug nanoformulations can improve their pharmacokinetics and therapeutic efficacy.

Background: Familial Alzheimer's disease (FAD) presenilin 1 E280A (PSEN 1 E280A) is characterized by functional impairment and the death of cholinergic neurons as a consequence of amyloid-β (Aβ) accumulation and abnormal phosphorylation of the tau protein. Currently, there are no available therapies that can cure FAD. Therefore, new therapies are urgently needed for treating this disease. Objective: To assess the effect of sildenafil (SIL) on cholinergic-like neurons (ChLNs) harboring the PSEN 1 E280A mutation. Methods: Wild-type (WT) and PSEN 1 E280A ChLNs were cultured in the presence of SIL (25μM) for 24 h. Afterward, proteinopathy, cell signaling, and apoptosis markers were evaluated via flow cytometry and fluorescence microscopy. Results: We found that SIL was innocuous toward WT PSEN 1 ChLNs but reduced the accumulation of intracellular Aβ fragments by 87%, decreased the non-physiological phosphorylation of the protein tau at residue Ser202/Thr205 by 35%, reduced the phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by 63%, decreased oxidized DJ-1 at Cys106-SO3 by 32%, and downregulated transcription factor TP53 (tumor protein p53), BH-3-only protein PUMA (p53 upregulated modulator of apoptosis), and cleaved caspase 3 (CC3) expression by 20%, 32%, and 22%, respectively, compared with untreated mutant ChLNs. Interestingly, SIL also ameliorated the dysregulation of acetylcholine-induced calcium ion (Ca2+) influx in PSEN 1 E280A ChLNs. Conclusions: Although SIL showed no antioxidant capacity in the oxygen radical absorbance capacity and ferric ion reducing antioxidant power assays, it might function as an anti-amyloid and antiapoptotic agent and functional neuronal enhancer in PSEN 1 E280A ChLNs. Therefore, the SIL has therapeutic potential for treating FAD. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a substance that can harm the environment and human health by interfering with the normal functioning of the body's hormonal system. It is commonly found in various plastic‐based products such as cosmetics, canned foods, beverage containers, and medical equipment and as well as it can also be absorbed by inhalation. There have been limited studies on the effects of BPA on lung fibroblasts, and it is still unclear how high levels of BPA can impact respiratory system cells, particularly the lungs and trachea. In this research, we aimed to investigate the cell cycle disruption potential of BPA on respiratory system cells by examining healthy trachea and lung cells together for the first time. The findings indicated that BPA exposure can alter the healthy cells' morphology, leading to reduced cellular viability that has been assessed by MTT and SRB assays. BPA treatment was able to activate caspase3 as expected, which could cause apoptosis in treated cells. Although the highest dose of BPA did not increase the apoptotic rate of rat trachea cells, it remarkably caused them to become necrotic (52.12%). In addition to quantifying the induction of apoptosis and necrosis by BPA, cell cycle profiles were also determined using flow cytometry. Thereby, BPA treatment unexpectedly inhibited the cell cycle's progression by causing G2/M cell cycle arrest in both lung and tracheal cells, which hindered cell proliferation. The findings of the study suggested that exposure to BPA could lead to serious respiratory problems, even respiratory tract cancers via alterations in the cell cycle. [ABSTRACT FROM AUTHOR]

In the present work, the synthesis of new ethacrynic acid (EA) derivatives containing nitrogen heterocyclic, urea, or thiourea moieties via efficient and practical synthetic procedures was reported. The synthesised compounds were screened for their anti-proliferative activity against two different cancer cell lines, namely, HL60 (promyelocytic leukaemia) and HCT116 (human colon carcinoma). The results of the in vitro tests reveal that compounds 1–3, 10, 16(a–c), and 17 exhibit potent anti-proliferative activity against the HL60 cell line, with values of the percentage of cell viability ranging from 20 to 35% at 1 μM of the drug and IC50 values between 2.37 μM and 0.86 μM. Compounds 2 and 10 showed a very interesting anti-proliferative activity of 28 and 48% at 1 μM, respectively, against HCT116. Two PyTAP-based fluorescent EA analogues were also synthesised and tested, showing good anti-proliferative activity. A test on the drug-likeness properties in silico of all the synthetised compounds was performed in order to understand the mechanism of action of the most active compounds. A molecular docking study was conducted on two human proteins, namely, glutathione S-transferase P1-1 (pdb:2GSS) and caspase-3 (pdb:4AU8) as target enzymes. The docking results show that compounds 2 and 3 exhibit significant binding modes with these enzymes. This finding provides a potential strategy towards developing anticancer agents, and most of the synthesised and newly designed compounds show good drug-like properties. [ABSTRACT FROM AUTHOR]

Background: Attention has recently focused on mitochondrial-mediated apoptosis as a signaling pathway that is disrupted in many diseases involving excessive cell proliferation. Medicinal plants that induce apoptosis may be useful in chemoprevention. Cajanus cajan (C. cajan) is cultivated in East and West Africa. It is used in folk medicine for the treatment of liver injury, anemia, dysentery, measles, jaundice, and tumor. Purpose: This study aims to investigate the in vitro antioxidant and mitochondrial-mediated apoptotic effects of C. cajan. Methods: The mitochondrial permeability transition (mPT), mitochondrial ATPase activity, (2, 2-diphenylpicrylhydrazyl) DPPH radical-scavenging activity, total antioxidant capacity, and total phenol and apoptotic biomarkers were assessed while the phytochemicals present in the extract were determined by gas chromatography-mass spectrometry (GC–MS). Methanol extract of Cajanus cajan (MECC) triggered mitochondrial-mediated apoptosis by induction of pore opening, enhancement of mitochondrial ATPase activities, and increased immunohistochemical expression of caspase 3, caspase 9, and cytochrome c. Results: MECC triggered mitochondrial-mediated apoptosis by induction of pore opening and increased expression of caspase 3, caspase 9, and cytochrome c. Enhancement of ATPase activities inhibition of lipid peroxidation and DPPH scavenging activity of DPPH were observed. Conclusions: These findings suggest that C. cajan-induced mitochondrial-mediated apoptosis in normal rat liver through the induction of mPT and eventual release of cytochrome c which is a prelude to the progression of apoptosis. Hence, certain bioactive components of C. cajan may be useful in chemoprevention and management of conditions associated with insufficient apoptosis. [ABSTRACT FROM AUTHOR]

Simple Summary: For nearly half a century, a mainstay and goal of medical oncology has been to identify novel anticancer drugs and therapeutic strategies to promote the effective elimination of cancer cells via apoptosis. In the past decade, however, single cell biology has revealed that apoptosis is not obligatorily a permanent cell fate. The purpose of this commentary is to briefly discuss laboratory and clinical studies that have revealed the dark side of apoptosis in treating patients with solid tumors. Most therapeutic strategies for solid tumor malignancies are designed based on the hypothesis that cancer cells evade apoptosis to exhibit therapy resistance. This is somewhat surprising given that clinical studies published since the 1990s have demonstrated that increased apoptosis in solid tumors is associated with cancer aggressiveness and poor clinical outcome. This is consistent with more recent reports demonstrating non-canonical (pro-survival) roles for apoptotic caspases, including caspase 3, as well as the ability of cancer cells to recover from late stages of apoptosis via a process called anastasis. These activities are essential for the normal development and maintenance of a healthy organism, but they also enable malignant cells (including cancer stem cells) to resist anticancer treatment and potentially contribute to clinical dormancy (minimal residual disease). Like apoptosis, therapy-induced cancer cell dormancy (durable proliferation arrest reflecting various manifestations of genome chaos) is also not obligatorily a permanent cell fate. However, as briefly discussed herein, compelling pre-clinical studies suggest that (reversible) dormancy might be the "lesser evil" compared to treacherous apoptosis. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic retinopathy is a neurodegenerative, microvascular, and sight-threatening impact of chronic uncontrolled diabetes. Avocado/soybean (ASB), a relatively new nutraceutical mixture, has acquired a significant role as a natural substitutional therapy for numerous diseases. Glibenclamide (Gli), a potent sulfonylurea, was confirmed as a diabetic therapy. Aim of the Study: To explore the protective effects of ASB versus glibenclamide on the diabetic rats' retina induced by streptozotocin (STZ). Materials and Methods: Forty rats were categorized into four groups: Normal control, Diabetic Control, Diabetes+Avocado soybean, and Diabetes+Glibenclamide. Retinal specimens were processed for histological, immunohistochemical, ultrastructural studies. Morphometrical and statistical studies were also performed. Results: Diabetic retinal specimens demonstrated evident disorganization of the retinal layers, degenerated retinal pigment epithelium, photoreceptors, and outer nuclear layers with appearance of empty spaces and multiple vacuolations. Most of ganglion cells were lost, others appeared with pycnotic nuclei. Together with a highly significant decrease (P< 0.001) of the total thickness, and the thickness of the outer and inner nuclear layers of the rats' retina, and the number of the ganglion cells. Immune expression of TNF-α, VEGF, caspase-3, and vimentin illustrated a highly significant elevation (P< 0.001). Ultrastructural findings of retinal pigmented cell layer illustrated; swollen degenerated mitochondria with cytoplasmic vacuolation. Degenerated photoreceptors, ganglion cells have indented irregular nucleus, destructed nuclear membrane, and vacuolated cytoplasm. ASB amends the diabetic retinopathy changes, structurally and immunohistochemically, more than glibenclamide Conclusion: ASB has a more, retinal-protective efficacy on DR, than glibenclamide. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common and malignant tumor, ranking as the third most common cancer in men and the second most common cancer in women. Pyroptosis, a recently described programmed cell death mechanism mediated by the GSDM family, has emerged as an immunogenic mechanism for chemotherapy drugs in tumor treatment. In this study, we discovered that Miltirone has the ability to reduce the viability of CRC cells (SW620 and HCT116) and cause the proteolytic cleavage of gasdermin E (GSDME) in CRC cells. It was also observed that inhibiting GSDME prevented pyroptotic cell death induced by Miltirone in SW620 and HCT116 cells. Furthermore, the main active component of Miltirone was found to effectively bind with caspase 3. SiRNA-mediated caspase 3 silencing and specific caspase 3 inhibitor Z-DEVD-FMK were shown to weaken Miltirone-induced GSDME-dependent cell death. The findings of the study suggest that Miltirone has the potential to inhibit the growth of CRC tumors in vivo by inducing pyroptotic cell death. This indicates that Miltirone could be a viable therapeutic agent for the treatment of CRC through GSDME-dependent pyroptosis. These results offer a promising new option for the clinical treatment of CRC.

Background: Hypothermia is neuroprotective after neonatal hypoxic-ischaemic brain injury. However, systemic cooling to hypothermic temperatures is a stressor and may reduce neuroprotection in awake pigs. We compared two experiments of global hypoxic-ischaemic injury in newborn pigs, in which one group received propofol–remifentanil and the other remained awake during post-insult hypothermia treatment. Methods: In both studies, newborn pigs were anaesthetised using halothane during a 45-min global hypoxic-ischaemic insult induced by reducing Fio2 and graded hypotension until a low-voltage

Most therapeutic strategies for solid tumor malignancies are designed based on the hypothesis that cancer cells evade apoptosis to exhibit therapy resistance. This is somewhat surprising given that clinical studies published since the 1990s have demonstrated that increased apoptosis in solid tumors is associated with cancer aggressiveness and poor clinical outcome. This is consistent with more recent reports demonstrating non-canonical (pro-survival) roles for apoptotic caspases, including caspase 3, as well as the ability of cancer cells to recover from late stages of apoptosis via a process called anastasis. These activities are essential for the normal development and maintenance of a healthy organism, but they also enable malignant cells (including cancer stem cells) to resist anticancer treatment and potentially contribute to clinical dormancy (minimal residual disease). Like apoptosis, therapy-induced cancer cell dormancy (durable proliferation arrest reflecting various manifestations of genome chaos) is also not obligatorily a permanent cell fate. However, as briefly discussed herein, compelling pre-clinical studies suggest that (reversible) dormancy might be the “lesser evil” compared to treacherous apoptosis.

AbstractMetastatic melanoma cancer stem cells are subpopulations linked to tumour development, immunoevasive behaviour, treatment resistance, and metastasis, all of which contribute to a poor prognosis. Photodynamic treatment (PDT) is an alternate strategy to cancer eradication that involves the generation of reactive oxygen species. As a carrier, nanoparticles enable efficient cellular uptake of photosensitizers, improving organelle accumulation and cancer cell targeted therapy. This study considered at the effect of PDT on CD133+ Melanoma Stem Cells utilising an Aluminium Phthalocyanine Gold Nanoparticle (AlPcS4Cl-AuNP) combination. A ligand exchange approach was used to conjugate AlPcS4Cl–PEG-AuNP-COOH and was characterised using UV-Vis, FTIR, DLS and Zeta Potential. Stem cells isolated from the A375 cell line irradiated with a laser at 673.2 nm with a fluency of 5 J/cm2 were evaluated. Furthermore, it was important to study if apoptosis was one of the mechanisms causing to cell death which was substantiated with Annexin V/PI, caspase 3 and p53 analysis. The nanoparticle conjugate mediated PDT promoted apoptotic cell death, showing increased expression of p53 and caspase-3. The study proposed a strategy aimed at extending the understanding of PDT in enhancing the therapy of melanoma, suggesting a probable improved cell death when AlPcS4Cl was conjugated to AuNPs.

The fetus is strongly dependent on nutrients from the mother, including polyunsaturated fatty acids (PUFA). In adult animals, n-3 PUFA ameliorates stroke-mediated brain injury, but the modulatory effects of different PUFA content in maternal diet on focal arterial stroke in neonates are unknown. This study explored effects of maternal n-3 or n-6 enriched PUFA diets on neonatal stroke outcomes. Pregnant mice were assigned three isocaloric diets until offspring reached postnatal day (P) 10-13: standard, long-chain n-3 PUFA (n-3) or n-6 PUFA (n-6) enriched. Fatty acid profiles in plasma and brain of mothers and pups were determined by gas chromatography-mass spectrometry and cytokines/chemokines by multiplex protein analysis. Transient middle cerebral artery occlusion (tMCAO) was induced in P9-10 pups and cytokine and chemokine accumulation, caspase-3 and calpain-dependent spectrin cleavage and brain infarct volume were analyzed. The n-3 diet uniquely altered brain lipid profile in naïve pups. In contrast, cytokine and chemokine levels did not differ between n-3 and n-6 diet in naïve pups. tMCAO triggered accumulation of inflammatory cytokines and caspase-3-dependent and -independent cell death in ischemic-reperfused regions in pups regardless of diet, but magnitude of neuroinflammation and caspase-3 activation were attenuated in pups on n-3 diet, leading to protection against neonatal stroke. In conclusion, maternal/postnatal n-3 enriched diet markedly rearranges neonatal brain lipid composition and modulates the response to ischemia. While standard diet is sufficient to maintain low levels of inflammatory cytokines and chemokines under physiological conditions, n-3 PUFA enriched diet, but not standard diet, attenuates increases of inflammatory cytokines and chemokines in ischemic-reperfused regions and protects from neonatal stroke.

Objective To explore the mechanism of miR-421 affecting the occurrence and development of depression. Methods A depressive rat model was established by single intraperitoneal injection of lipopolysaccharide (LPS), and depressive behavior was detected by glucose preference test and open-field test. miRNA microarray chips and RT-PCR were used to analyze the expression level of miR-421 in hippocampus of the depressed rats. TargetScan database and mi RDB database were used to predict the target genes of miR-421. Dual luciferase reporter gene assay was used to observe the binding of miR-421 to the target genes. The impact of over-expression and inhibition of miR-421 on target genes was observed, then the influence of over-expression and inhibition of target genes on downstream factors was observed, and the related mechanism of miR-421 on depression was explored. Results miRNA microarray chips and RT-PCR assay showed that miR-421 was highly expressed in the hippocampus of the depressed rats (P < 0.001), Inhibition of miR-421 expression could significantly restore the body weight and exercise ability of the depressed rats (P < 0.001). Binding targets of Menin and miR-421 were predicted by TargetScan database, and interaction between Menin and miR-421 was demonstrated by dual-luciferase reporter gene assay. Menin expression was down-regulated while miR-421 was overexpressed (P < 0.001), whereas it was up-regulated as miR-421 was inhibited (P < 0.001). qPCR indicated that expressions of Caspase-3 and NF-kB in he hippocampus of the depressed rats was significantly increased (P < 0.001), and IL-1p expression in the hippocampus was significantly increased (P < 0.01). When the expression of Menin was inhibited, the expressions of Caspase-3, NF-kB and IL-ip were increased (P < 0.001), while the expressions of Caspase-3, NF-kB and IL-ip were decreased when Menin was overexpressed (P < 0.001). Conclusions Inhibition of miR-421 expression can increase Menin expression, decrease Caspase-3 content, and reduce neuroinflammatory response, thereby improving depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: Many reports on the use of aspartame revealed that it releases metabolites which in turn cause brain adverse effect on rats. Our aim was to investigate the impact of aspartame on histopathology and ultrastructure of rat frontal cortex and assess the efficacy of Adipose-Mesenchymal Stem Cells (AD-MSCs) to ameliorate this effect after chronic aspartame administration (40 mg/kg per body weight). Methods: to investigate the effects of aspartame, methotrexate and folate deficient diet was used to induce folate deficiency in rats to imitate the human methanol metabolic process. The animals were distributed into four groups; control group, MTX control, MXT/Aspartame and MXT/aspartame/AD-MSCs group. The histopathology and ultrastructure of frontal cortex along with its cell's expression of Caspase-3 and GFAP were assessed. The used AD-MSCs were characterized by immunohistochemical detection of CD73, CD105 and CD45 markers and tracked in frontal cortex by PCR. Results: White matter density was significantly reduced in MTX/aspartame animals, evidence of gliosis, pyramidal cell intracellular and extracellular vacuolations and Significant increase in Caspase-3 and GFAP stained neuron. Disorganization of ultrastructure organelles and oedematous astrocyte plates around blood vessels were evident when compared to control animals. Almost restoration of the frontal cortex architecture and ultrastructure was established in the MXT//aspartame/AD-MSCs together with significant decrease in Caspase-3 and GFAP stained neuron compared to MXT//aspartame group. Conclusions: AD-MSCs transplantation could mitigate the degenerative impact of aspartame metabolites on the rat frontal cortex. [ABSTRACT FROM AUTHOR]

Background: Organ ischemia-reperfusion (IR) is a common clinical condition associated with various situations such as trauma surgery, organ transplantation, and myocardial ischemia. Current therapeutic methods for IR injury have limitations, and nanotechnology, particularly zinc oxide nanoparticles (ZnO NPs), offers new approaches for disease diagnosis and treatment. In this study, we investigated the protective and anti-apoptotic effects of ZnO NPs in liver ischemia-reperfusion (IR) injury in rats. Methods: Forty-eight male rats were divided into six groups: sham, ZnO5, ZnO10, ischemiareperfusion (IR), IR+ZnO5, and IR+ZnO10. The protective effect of ZnO NPs was evaluated by liver enzymes (AST, ALT, Bilirubin, ALP), biochemical (TAC, TNF-a, and MDA), molecular examinations (Bcl2, BAX), and histopathological evaluations (H&E, TUNEL). Results: Pre-treatment with ZnO5 and ZnO10 improved hepatic function in IR liver injury, attenuated the levels of oxidants (P = 0.03) and inflammatory mediators, and reduced apoptosis (P = 0). ZnO10 was found to have a greater effect on ischemic reperfusion injury than ZnO5 did. Histopathological examination also showed a dose-dependent decrease in alterations in the IR+ZnO5 and IR+ZnO10 groups. Conclusion: Administration of ZnO5 and ZnO10 improved liver function after IR. The findings of this study suggest that ZnO NPs have a protective effect against oxidative stress and apoptosis in liver ischemia-reperfusion injury in rats. These results may have important implications for developing advanced methods in ischemia-reperfusion treatment. [ABSTRACT FROM AUTHOR]

Food additives such as carboxy methyl chitosan (CMC) and mannan (MOS) may have detoxification effect on aflatoxins (AFs). The current study aimed to investigate the role of chitosan and/or mannan in reducing the toxicity of AFs in broiler chickens (cobb500), through improving biochemical, hematological, oxidative stress, and antioxidant parameters. Furthermore, we investigated the impact on histopathological parameters and immune gene expression analysis (caspase 3 and interleukin 1-β). Five equal groups of 50 broilers each were selected (n=10); (G1) given the basal diet, (G2) basal diet intoxicated with 100 ppb AFs kg-1diet; (G3) given as basal diet intoxicated with 100 ppb AFs kg-1diet and supplemented with MAN (1 g kg-1 diet); (G4) given basal diet intoxicated with 100 ppb AFs kg-1diet and supplemented with CMC (0.5 g kg-1 diet) ; and (G5) given basal diet intoxicated with 100 ppb AFs kg-1diet and supplemented with MAN (1 g kg-1 diet)and CMC (0.5 g kg-1 diet). The current study's findings showed that the administration of both MAN and CMC brought hematological parameters back to the level of control. Chicks treated with MAN and/or CMC after being intoxicated with aflatoxins showed a considerable improvement in both renal and hepatic indicators with a notable improvement in antioxidant indicators in the groups receiving CMC and MAN supplements after being exposed to aflatoxicosis. Additionally, chicks treated with MAN and/or COS after being intoxicated with aflatoxins showed a considerable improvement in the gene expression of Caspase-3 and IL-1β. Furthermore, supplemental MAN and/or CMC decreased aflatoxin accumulation in the tissues of the muscles, liver, and kidneys. The groups G3, G4, and G5 showed notable improvements in the hepatic parenchymal architecture in their liver sections. The results of this study confirmed the hypothesis that adding natural additives such mannan and chitosan might enhance the antioxidant capacity and vital parameters of broilers exposed to 100 ppb aflatoxins. [ABSTRACT FROM AUTHOR]

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As life expectancy increases, the number of people affected by cancer is increasing. The available drugs still cause several adverse reactions, and it is important to look for less toxic drugs that act on resistant cancers. The present study evaluated the antitumor potential of acetogenins. Through a literature review, 44 acetogenins isolated from Annona muricata were selected and subjected to in silico studies to predict the physicochemical properties, pharmacokinetics (Preadmet and Admet lab), toxicity (Preadmet and Protox II) and molecular docking in caspase 3 (DockThor). For muricatacin, a literature review was carried out for antitumor activity and cytotoxicity. Only muricatacin met all physicochemical criteria, while all compounds showed high cutaneous and intestinal absorption (HIA), moderate permeability in Madin-Darby canine kidney and Caco2 cells, strongly bound plasma proteins, freely crossed the blood-brain barrier, inhibited CYP2C19, CYP2C9 and CYP3A4 and have an affinity for CYP3A4, being metabolized by it, an undesirable characteristic for antitumor drugs. All compounds were toxic in at least one model, while compound 28 was not carcinogenic in rats and mice. Compounds 13, 14, 15, 16, 17 and 28 were selected for molecular docking into Caspase 3. Docking showed hydrophobic interactions, hydrogen and covalent bonds performed to maintain the stability of caspase 3, and cis-uvariamicin IV stood out more through the energies and chemical bonds of this parameter. The chloroform fraction from the methanolic extract of the seeds showed activity against triple-negative breast cancer, both in vitro and in vivo, and only muricatacin has studies in which the antitumor activity was evaluated in vitro and showed to be very promising. In summary, muricatacin and cis-uvariamicin IV appear to be very promising as antitumors, especially cis-uvariamicin IV. [ABSTRACT FROM AUTHOR]

Metastatic melanoma cancer stem cells are subpopulations linked to tumour development, immunoevasive behaviour, treatment resistance, and metastasis, all of which contribute to a poor prognosis. Photodynamic treatment (PDT) is an alternate strategy to cancer eradication that involves the generation of reactive oxygen species. As a carrier, nanoparticles enable efficient cellular uptake of photosensitizers, improving organelle accumulation and cancer cell targeted therapy. This study considered at the effect of PDT on CD133+ Melanoma Stem Cells utilising an Aluminium Phthalocyanine Gold Nanoparticle (AlPcS4Cl-AuNP) combination. A ligand exchange approach was used to conjugate AlPcS4Cl-PEG-AuNP-COOH and was characterised using UV-Vis, FTIR, DLS and Zeta Potential. Stem cells isolated from the A375 cell line irradiated with a laser at 673.2nm with a fluency of 5 J/cm² were evaluated. Furthermore, it was important to study if apoptosis was one of the mechanisms causing to cell death which was substantiated with Annexin V/PI, caspase 3 and p53 analysis. The nanoparticle conjugate mediated PDT promoted apoptotic cell death, showing increased expression of p53 and caspase-3. The study proposed a strategy aimed at extending the understanding of PDT in enhancing the therapy of melanoma, suggesting a probable improved cell death when AlPcS4Cl was conjugated to AuNPs. [ABSTRACT FROM AUTHOR]

Aim: This study evaluated the effect of lead, with or without zinc co-administration, on steroidogenic and xanthine oxidase (XO)/uric acid (UA)/caspase 3-mediated apoptotic signaling in the testis. Materials and methods: Forty male Wistar rats were divided into four groups at random; vehicle-treated control, zinc-treated, lead-treated, and lead + zinc-treated groups. Results: Lead exposure significantly lowered overall weight gain, testicular, epididymal, seminal vesicle, and prostate weights. Also, lead decreased sperm count, viability and motility but increased the fraction of sperm with aberrant morphology. In addition, lead caused a marked rise in the level of UA and XO activity but a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), reduced glutathione (GSH) as well as total antioxidant capacity (TAC) levels, and super- oxide dismutase (SOD) and catalase activities. Furthermore, lead increased the testicular levels of nuclear factor kappa B (NFkB), interleukin-1beta (IL-1β), and tumour necrotic factor-alpha (TNF-α), which were associated with an increase in testicular caspase 3 activity and DNA frag- mentation as well as a decline in circulating gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and testicular 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD). These were associated with lead-induced degenerative changes in testicular tissues evidenced by shrunken seminiferous tubules, degeneration and sloughing of germ cells. Co-administration of zinc prevented lead-induced testicular injury by ameliorating oxidative stress, apoptosis, and inflammation through downregulation of XO/UA/caspase 3 pathway and upregulation of testicular 3β-HSD/17β-HSD. Conclusion: This study demonstrated that zinc protected against lead-induced testicular toxicity via the downregulation of XO/UA/caspase 3 signaling. [ABSTRACT FROM AUTHOR]

Introduction: Aluminum is a widespread metal in the environment and linked to several diseases, including cardiovascular disease. Regenerative cardiac telocytes can potentially alleviate numerous heart diseases. Aim of the Work: This study investigated the potential protective effect carvedilol on aluminum trichloride (AlCl3)-induced cardiac toxicity by examining its antioxidative, anti-inflammatory, anti-apoptotic and its impact on cardiac telocytes. Materials and Methods: Thirty adult male Wistar rats were randomly divided into three (10-rats) groups. Control group: saline. AlCl3 group: after two weeks of saline, (70 mg/kg/day) AlCl3 for four weeks. The Carvedilol+ AlCl3 group: (1 mg/ kg day) carvedilol for two weeks followed by AlCl3 for four weeks. All drugs were received as a single dose daily I.P. At the end of the experiment, blood biochemical antioxidants, inflammatory and aluminum level were assessed. Additionally cardiac tissue histology, immunohistochemistry (active caspase 3 and CD117 markers) and histomorphometry were performed. Results: Administration of AlCl3 significantly increase in cardiac malonaldehyde, nitric oxide, and tumor necrosis factor-alpha levels as well as both serum and cardiac aluminum levels. Heart and body weights and cardiac catalase levels were significantly decreased. Histologically AlCl3 induced degenerative and apoptotic changes in cardiac myocytes with a significant increase in apoptotic cells number and collagen fibers area percentage., However, myocardial telocytes is significantly decreased. Carvedilol administration ameliorated these abnormal biochemical, histological and immunohistochemical parameters. Conclusion: Carvedilol prophylactic administration protected against ALCL3 induced cardiotoxicity via downregulating cardiomyocyte apoptosis and fibrosis due to its antioxidant, anti-inflammatory, and anti-apoptotic effects and increased cardiac telocytes number and its regenerative capacity. [ABSTRACT FROM AUTHOR]

Background. Eccentric exercise may trigger mechanical stress, resulting in muscle damage that may decrease athletic performance. L-citrulline potentially prevents skeletal muscle damage after acute eccentric exercise. This study aimed to assess the dose-response effect of L-citrulline as a preventive therapy for skeletal muscle damage in mice after acute eccentric exercise. Methods. This is a controlled laboratory in vivo study with a post-test-only design. Male mice (BALB/c, n=25) were randomized into the following groups: a normal control (C1) (n=5); a negative control (C2) with downhill running and placebo intervention (n=5); treatment groups: T1 (n=5), T2 (n=5), and T3 (n=5), were subjected to downhill running and 250, 500, and 1,000 mg/kg of L-citrulline, respectively, for seven days. Blood plasma was used to determine the levels of TNNI2 and gastrocnemius muscle tissue NOX2, IL-6, and caspase 3 using ELISA. NF-χB and HSP-70 expressions were determined by immunohistochemistry. Results. Skeletal muscle damage (plasma TNNI2 levels) in mice after eccentric exercise was lower after 250 and 500 mg/kg of L-citrulline. Further, changes in oxidative stress markers, NOX2, were reduced after a 1,000 mg/kg dose. However, a lower level of change has been observed in levels of cellular response markers (NF-κB, HSP-70, IL-6, and caspase 3) after administration of L-citrulline doses of 250, 500, and 1,000 mg/kg. Conclusion. L-citrulline may prevent skeletal muscle damage in mice after acute eccentric exercise through antioxidant effects as well as inflammatory and apoptotic pathways. In relation to dose-related effects, it was found that L-citrulline doses of 250, 500, and 1,000 mg/kg significantly influenced the expression of NF-κB and HSP-70, as well as the levels of IL-6 and caspase 3. Meanwhile, only doses of 250 and 500 mg/kg had an impact on TNNI2 levels, and the 1,000 mg/kg dose affected NOX2 levels. [ABSTRACT FROM AUTHOR]

Aflatoxins B1 (AFB1) a dangerous type of aflatoxin, poses a serious threat to human health. Meanwhile, Taraxasterol, a bioactive compound in dandelion, exhibits strong anti-inflammatory and antioxidant activity. Therefore, the aim of this study was to investigate the impact of AFB1 on the intrinsic and extrinsic pathways of apoptosis, as well as evaluate the protective role of taraxasterol in the TM3 Leydig cell line. Cell viability was evaluated using an MTT assay, measuring the effects of 3.6 µM AFB1 and varying concentrations of taraxasterol. Expression levels of Caspase 3,8, and 9 were analyzed with RT-qPCR, and flow cytometry was used to assess cell cycle progression and apoptotic alterations. The findings of this study demonstrated that exposure to 3.6 µM of AFB1 resulted in an upregulation of Caspase 3 and Caspase 9 expression, indicating an activation of apoptotic pathways in TM3 cells. Additionally, the analysis of apoptosis revealed a significant increase in cellular apoptosis at this AFB1 concentration. However, when TM3 cells were exposed to 5 µM of taraxasterol, a downregulation of Caspase 3 and Caspase 9 expression was observed, suggesting a protective effect against apoptosis. Moreover, the apoptotic rate in TM3 cells was reduced in the presence of 5 µM of taraxasterol. Consequently, this study highlights the potential of taraxasterol as a protective agent against AFB1-induced apoptosis and suggest its potential application in regulating cell survival and apoptosis-related processes. Further investigations are necessary to elucidate the underlying mechanisms and evaluate the clinical implications of taraxasterol in the context of fertility disorders and other conditions associated with AFB1 exposure.

Caspase (CASP) is a family of proteases involved in cleavage and activation of gasdermin, the executor of pyroptosis. In humans, CASP3 and CASP7 recognize the same consensus motif DxxD, which is present in gasdermin E (GSDME). However, human GSDME is cleaved by CASP3 but not by CASP7. The underlying mechanism of this observation is unclear. In this study, we identified a pyroptotic pufferfish GSDME that was cleaved by both pufferfish CASP3/7 and human CASP3/7. Domain swapping between pufferfish and human CASP and GSDME showed that the GSDME C-terminus and the CASP7 p10 subunit determined the cleavability of GSDME by CASP7. p10 contains a key residue that governs CASP7 substrate discrimination. This key residue is highly conserved in vertebrate CASP3 and in most vertebrate (except mammalian) CASP7. In mammals, the key residue is conserved in non-primates (e.g., mouse) but not in primates. However, mouse CASP7 cleaved human GSDME but not mouse GSDME. These findings revealed the molecular mechanism of CASP7 substrate discrimination and the divergence of CASP3/7-mediated GSDME activation in vertebrate. These results also suggested that mutation-mediated functional alteration of CASP probably enabled the divergence and specialization of different CASP members in the regulation of complex cellular activities in mammals.

Background Acute kidney injury (AKI) is a serious pathology that causes dysfunction in concentrating urine due to kidney damage, resulting in blood pressure dysregulation and increased levels of toxic metabolites. Dexpanthenol (DEX), a pantothenic acid analog, exhibits anti-inflammatory and anti-apoptotic properties in various tissues. This study investigated the protective effects of DEX against systemic inflammation-induced AKI. Methods Thirty-two female rats were randomly assigned to the control, lipopolysaccharide (LPS), LPS+DEX, and DEX groups. LPS (5 mg/kg, single dose on the third day, 6 h before sacrifice) and DEX (500 mg/kg/day for 3 days) were administered intraperitoneally. After sacrifice, blood samples and kidney tissues were collected. Hematoxylin and eosin, caspase-3 (Cas-3), and tumor necrosis factor alpha (TNF-α) staining were performed on the kidney tissues. The total oxidant status (TOS) and total antioxidant status were measured using spectrophotometric methods. Aquaporin-2 (AQP-2), silent information regulator 1 (SIRT1), and interleukin-6 (IL-6) were detected using quantitative reverse transcription-polymerase chain reaction analysis. Results Histopathological analysis revealed that DEX treatment ameliorated histopathological changes. In the LPS group, an increase in the blood urea nitrogen, creatinine, urea, IL-6, Cas-3, TNF-α, and TOS levels and oxidative stress index was observed compared with the control group, whereas AQP-2 and SIRT1 levels decreased. DEX treatment reversed these effects. Conclusions DEX was found to effectively prevent inflammation, oxidative stress, and apoptosis in the kidneys via the SIRT1 signaling pathway. These protective properties suggest DEX’s potential as a therapeutic agent for the treatment of kidney pathologies.

Abstract Background The aim of our study was to evaluate the expression of the CASP3 gene at both mRNA and protein levels in patients with depressive disorders and to determine the impact of caspase 3 in the pathogenesis of depression; Methods A total of 290 subjects, including 190 depressed patients and 100 healthy controls, participated in the study. Socio-demographic and clinical data were collected, and the severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Venous blood was collected and gene expression was evaluated using RT-PCR and ELISA at the mRNA and protein levels, respectively; Results The expression of the CASP3 gene was significantly lower in depressed patients compared to healthy controls at both the mRNA and protein levels. Additionally, a positive correlation was observed between CASP3 gene expression and disease duration as well as the number of depressive episodes; Conclusions Further studies are needed to investigate the role of caspase 3 in depressive disorders.

Protein homeostasis, including protein folding, refolding, and degradation, is thought to decline with aging. HSPB5 (also known as αB-crystallin) prevents target protein aggregation as a molecular chaperone and exhibits a cytoprotective function against various cell stresses. To elucidate the effect of HSPB5 on endoplasmic reticulum (ER) stress, we searched for novel binding proteins of HSPB5 using the proximity-dependent biotin labeling method. Proteins presumed to interact with HSPB5 in cells treated with the proteasome inhibitor MG132 were identified by a reversible biotin-binding capacity method combining tamavidin2-REV magnetic beads and mass spectrometry. We discovered a new binding protein for HSPB5, polo-like kinase 2 (PLK2), which is an apoptosis-related enzyme. The expression of PLK2 was upregulated by MG132 treatment, and it was co-localized with HSPB5 near the ER in L6 muscle cells. Inhibition of PLK2 decreased ER stress-induced phosphorylation of serine 19 in HSPB5 and increased apoptosis by activation of caspase 3 under ER stress. Overexpression of HSPB5 (WT) suppressed the ER stress-induced caspase 3 activity, but this was not observed with phospho-deficient HSPB5 (3A) mutants. These results clarify the role of HSPB5 phosphorylation during ER stress and suggest that the PLK2/HSPB5 pathway plays an essential role in cytoprotection against proteasome inhibition-induced ER stress.

The usage of cisplatin, a highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) inhibitors were shown to ameliorate this dose-limiting side effect, but both approaches have some pharmacological limitations. Analogues of EETs are an alternative avenue with unique benefits, but the current series of analogues face concerns regarding their structure and mimetic functionality. Hence, in this study, regioisomeric mixtures of four new ARA alkyl ethers were synthesized, characterized, and assessed as EET analogues against the concentration- and time-dependent toxicities of cisplatin in porcine proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy- (1), good for n-propoxy- (4), and excellent for ethoxy- (2) and i-propoxy- (3). Compounds 2 and 3 displayed cytoprotective effects comparable to that of an EET regioisomeric mixture (5) against high, acute cisplatin exposures but were more potent against low to moderate, chronic exposures. Compounds 2 and 3 (and 5) acted through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and caspase-3. This study demonstrates that alkoxy- groups are potent and more metabolically stable bioisostere alternatives to the epoxide within EETs that enable sEH-independent activity. It also illustrates the potential of ether-based mimics of EETs and other epoxy fatty acids as promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin without compromising its antineoplastic function.