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Introduction: Migraine, a common disorder marked by severe and repetitive headaches, has been linked to the involvement of the NMDA receptor (NMDAR), a receptor responsible for glutamate signaling. Moringa oleifera (M. oleifera), recognized for its anti-inflammatory properties and therapeutic potential in various conditions, has been investigated. This study aims to assess the efficacy and precise mechanisms of M. oleifera for the treatment of migraine, for which evidence is limited. Methods: Rats were stratified into four distinct groups. The control group did not undergo the migraine-induction protocol. Post-induction, the "sumatriptan" group was administered sumatriptan injections, the "treatment" group received oral M. oleifera extract, and the "vehicle" group was provided with oral solvent treatment. Behavioral evaluations encompassing Von Frey's and hot plate assessments, in addition to qPCR analysis targeting Nr2a, Nr2b, Bax, Bcl-2, and Caspase-3, were conducted. Results: Von Fery's and hot plate tests revealed a notable decrease in triggering pressure and temperature within the vehicle group when compared to the other groups (both ps < 0.001). The Nr2a expression levels in both the vehicle and treatment cohorts exhibited significantly higher values than those observed in the control group (p < 0.001, p = 0.001) and the sumatriptan group (p < 0.001, p = 0.002). Conversely, no substantial alterations in Nr2b or Bcl-2 expression levels were observed across the study groups (p = 0.404, p = 0.976). Notably, heightened expressions of Caspase-3 and Bax were evident in the vehicle group relative to the other groups (p = 0.013, p = 0.010). Conclusions: Moringa oleifera extract appears to mitigate symptoms of migraine by inhibiting apoptosis, suggesting potential efficacy in migraine treatment; however, additional research investigating a wider range of pathways is necessary. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

We aimed to investigate the protective effects of low dose cyclosporin A (CsA) on ischemia–reperfusion (IR) injury in rat the kidney and on the apoptotic and necroptotic mechanisms involved. 1. Control group (received a single intraperitoneal (i.p.) dose of 1 ml sterile saline 15 min before the surgical procedure), 2. IR group (was subjected to 30 min of bilateral kidney ischemia followed by 90 min of reperfusion; and received a single i.p. dose of 1 ml sterile saline 15 min before the IR procedure, 3. IR + CsA group (received a single i.p. dose of 3 mg/kg CsA 15 min before the IR procedure. Renal functions (renal perfusion pressures, and serum urea-creatinine levels), kidney histological scores, MDA levels, and TNF-α, caspase-3, RIP1, RIP3, MLKL, CaMKII and CypD protein expressions were also measured. Renal perfusion pressures (PP), serum urea and creatinine levels, renal tissue MDA levels, and the protein expression levels of TNF-α, caspase-3, RIP1, RIP3, MLKL, CAMKII and CypD were significantly increased in the IR group compared to the control group (p < 0.05), Additionally, there were significant decreases in all the parameters in the IR + CsA group compared to those in the IR group (p < 0.05). Furthermore, histopathological analyses revealed significantly higher kidney injury scores in the IR group compared to the control group, and low dose CsA treatment improved the injury. A single low dose of CsA injection 15 min before IR, demonstrated a protective effect on bilateral renal IR injury and a reduction in apoptotic and necroptopic markers which is resulted in improvement of renal functions. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) is an intermittent hypoxia disorder associated with cognitive dysfunction, including learning and memory impairments. There is evidence that alterations in protease activity and neuronal activation are associated with cognitive dysfunction, are dependent on sex, and may be brain region-specific. However, the mechanisms mediating OSA-induced cognitive impairments are unclear. Therefore, we used a rat model of OSA, chronic intermittent hypoxia (CIH) to investigate protease activity (e.g., calpain and caspase-3) on spectrin, a cytoskeletal protein associated with neurotransmitter release, and neuronal activation (early growth response protein 1, EGR-1) in brain regions associated with learning and memory. Methods: Male and female Sprague Dawley rats were exposed to CIH or room air (normoxic) for 14 days. We quantified protease activity and cleaved spectrin products, along with EGR-1 protein expression in hippocampal subregions (CA1, CA3), cortical regions [entorhinal cortex (ETC), retrosplenial cortex (RSC), cerebellar cortex (CC)], and subcortical regions [raphe nucleus (RN), locus coeruleus (LC)] associated with learning and memory. Within each group, Pearson correlations of calpain activity, caspase-3 activity, and EGR-1 expression were performed between brain regions. Sex differences within normoxic and CIH correlations were examined. Results: CIH dysregulated calpain activity in male ETC, and female CA1 and RSC. CIH dysregulated caspase-3 activity in male RN, and female CA1 and RSC. CIH decreased calpain and caspase-3 cleavage products in male ETC. CIH decreased calpain-cleaved spectrin in male RSC but increased these products in female RSC. EGR-1 expression was decreased in male and female RN. Correlational analysis revealed CIH increased excitatory connections in males and increased inhibitory connections in females. EGR-1 expression in males shifted from negative to positive correlations. Conclusions: Overall, these data indicate CIH dysregulates protease activity and impairs neuronal function in a brain region- and sex-dependent manner. This indicates that males and females exhibit sex-specific vulnerabilities to mild OSA. These findings concur with our previous behavioral studies that demonstrated memory impairment in CIH-exposed rats. Plain Language summary: Many adults have a sleeping condition called sleep apnea, which can cause memory problems. Importantly, these memory problems can be linked to specific parts of the brain, such as the hippocampus, which is responsible for the formation of memories and ability to remember these memories. The hippocampus is connected to multiple other parts of the brain, so memory problems could also be due to changes in these other brain regions. Though sleep apnea is more common in men than women, it is likely that the brains of men and women respond to sleep apnea differently. To determine which brain regions are impacted by sleep apnea and how male or female sex could alter this effect, we exposed adult male and female rats to chronic intermittent hypoxia (CIH), which is a rat model of sleep apnea. We measured the effect of CIH by looking at the activation of brain cells and proteases, which are specialized proteins that cut other proteins into smaller pieces to change how they work. We found that CIH effects were unique to specific parts of the brain, and these effects were mainly observed in female rats. CIH also changed the way that enzyme and brain cell activity in certain brain regions was related to other brain regions. These results mean that not only does sleep apnea change the way parts of the brain function, but these changes are different for males and females. This indicates that men and women could experience sex-specific memory problems from sleep apnea. Highlights: This is the first study to examine the role of sex in CIH-induced protease dysregulation in the rat brain and to examine sex differences in calpain and caspase-3 activity in rats. CIH predominantly dysregulated protease activity in memory-associated brain regions of female rats, which may indicate a sex-specific vulnerability to mild OSA. CIH only impaired EGR-1 expression in the raphe nucleus, regardless of sex, with no effect observed in other brain regions. CIH altered the sex-specific correlational relationships of protease activity and neuronal activation between brain regions. CIH increased excitatory neuronal activity between brain regions in males but not females. [ABSTRACT FROM AUTHOR]

AbstractDespite the efforts to treat cancer with chemotherapeutic agents targeting different mechanisms, cancer is still one of the most important health problems today. The increase in cancer incidence has led researchers to discover new, effective, and selective molecules. For this purpose, novel thiosemicarbazide (3a–3i) and 1,3,4-thiadiazole derivatives (4a–4i) were synthesized from clopidogrel bisulfate and their cytotoxic activities were investigated against glioblastoma (U87) cell line and healthy fibroblast (L929) cell line by MTT assay. Among the synthesized compounds; 3b, 3g, 4b, 4d, and 4i exhibited higher cytotoxic activities than the standard drug paclitaxel against U87 cancer cells. Cell apoptosis was detected by Bax, Bcl-2, caspase-3 activity, and Annexin V assay. The results displayed that compounds 3b, 3g, 4b, 4d, and 4i induced apoptosis in U87 cells. Moreover, all compounds were investigated for DNA methyltransferase (DNMT) activity in U87 cells. DNMT enzyme activity was decreased in these compounds’ treated cells. Cyclohexyl ring-bearing compound 4d, which showed the highest activity against U87 cells, was the most potent inhibitor of DNMT with an IC50 value of 5.78 ± 1.07 µM compared to paclitaxel (82.05 ± 4.67 µM). Molecular docking studies were also performed to identify the interactions between the compounds and the active sites of DNMT. [ABSTRACT FROM AUTHOR]

Gentamicin-induced nephrotoxicity limits its therapeutic use as an effective aminoglycoside. Herbal drugs have a distinct place in the world of pharmaceuticals since they are safe, effective, and cost-efficient. Acacia nilotica (L.) has long been recognized for its antihypertensive, antioxidant, anti-inflammatory, and antiplatelet aggregatory benefits in traditional medicine. Still, the protective effect of Acacia nilotica on gentamicin-induced nephrotoxicity is still unknown. Thus, the goal of this research was to examine the protection of ethanolic extract of Acacia nilotica (ANE) against nephrotoxicity triggered by Gentamicin. Thirty-six rats were randomly divided into six groups containing six rats in each group. The distilled water were given in control group. The rats in groups two and three were administered metformin and gentamicin respectively. In groups five and six, rats were administered ANE at doses of 100 and 200 mg/kg. Ten days of daily treatments were given. The urea, creatinine, uric acid, and LDH levels were analyzed on serum, whereas histological evaluation, MDA, GSH, SOD, CAT, TNF-α, IL-6, and caspase-3, were performed on kidney tissue on day 11. The gentamicin-treated group exhibited a significantly elevated MDA, and lower levels of antioxidant enzymes. Kidney function markers, inflammatory markers and caspase-3 expression were significantly elevated in the gentamicin-treated group. ANE significantly restored kidney function biomarkers, upregulated biochemical levels, inhibited TNF-α, caspase-3, cytokine expression, and reduced histological lesions. In conclusion, ANE has the ability to prevent gentamicin-induced nephrotoxicity and reduce nephrotoxic damage. As such, it may represent an effective therapy for patients receiving gentamicin treatment. [ABSTRACT FROM AUTHOR]

Exposure to Pb, a toxic heavy metal, is a risk factor for renal damage. Borax, an essential trace element in cellular metabolism, is a naturally occurring compound found in many foods. This study investigated the effects of sodium tetraborate (ST), a source of borax, on renal oxidative stress and inflammation in rats exposed to Pb. Wistar Albino rats (n = 24) were divided into four groups: Control (0.5 mL, i.p. isotonic), Pb (50 mg/kg/day/i.p.), ST (4.0 mg/kg/day/oral), and Pb + ST groups. At the end of the five-day experimental period, kidney tissue samples were obtained and analyzed. Histopathologically, the Pb-induced damage observed in the Pb group improved in the Pb + ST group. Immunohistochemically, Pb administration increased the expression of inducible nitric oxide synthase, cyclooxygenase-2, and caspase-3. When evaluated biochemically, Pb application inhibited catalase and glutathione peroxidase (GSH-Px) enzyme activities and activated superoxide dismutase enzyme activity. An increase in malondialdehyde levels was considered an indicator of damage. ST application increases glutathione peroxidase enzyme activity and decreased malondialdehyde levels. These results indicate that ST might play a protective role against Pb-induced renal damage via the upregulation of renal tissue antioxidants and cyclooxygenase-2, inducible nitric oxide synthase, and caspase-3 immunoexpression. [ABSTRACT FROM AUTHOR]

Pyroptosis is an inflammatory type of programmed cell death that mainly depends on the formation of plasma membrane pores by Gasdermin D (GSDMD) in mammals. However, the genetic deficiency of GSDMD in chicken renders avian pyroptosis elusive. Here, we show that infection of DF-1 cells (a chicken cell line) with infectious bursal disease virus (IBDV) induced cell death associated with chicken GSDME (chGSDME) cleavage, and so did cells with other RNA virus (VSV, AIV, or NDV) infections, indicating a broad role of chGSDME in RNA virus-induced pyroptosis in chicken. Furthermore, infection of DF-1 cells by IBDV or treatment of cells with Poly(I:C) initiated MDA5-mediated signaling pathway, followed by the activation of chCaspase-3/7 cleaving chGSDME at a specific site 270DAVD273. Moreover, knockdown or knockout of chGSDME expression in cells markedly reduced IBDV-induced pyroptosis and viral release. These results unravel the mechanisms of pyroptosis in chickens with RNA virus infection, providing important clues to uncover the role of GSDM proteins of different species in host response against pathogenic infection. IMPORTANCE Pyroptosis is an inflammatory type of programmed cell death that mainly depends on the function of GSDMD in mammals and plays a crucial role in the pathogenesis of viral infection, whereas the mechanism of pyroptosis in chicken remains elusive. Herein, we show that IBDV and other RNA virus induced pyroptosis through the chMDA5-CASP8/9-CASP3/7-chGSDME pathway. The finding advances our understanding of GSDM proteins of different species in host response against pathogenic infection. [ABSTRACT FROM AUTHOR]

Mycotoxins are toxic secondary metabolites of fungi that grow on food and feed matrices and significantly harm the health of humans and farm animals. Among the reported mycotoxigenic fungi, Fusarium graminearum has received wide attention due to its ability to produce multiple mycotoxins, including deoxynivalenol (DON), nivalenol (NIV), and zearalenone (ZEA) under diverse climatic conditions. The present study focused on proving in vitro cytotoxicity of F. graminearum toxins (DON, NIV, and ZEA) in H9c2 cells (Rattus norvegicus heart/myocardi). The effect of F. graminearum toxins (FGTs) on cell viability was studied by MTT, LDH, and live/dead cell assays. The cell viability decreased with increasing the quantity of FGTs and was noticed as dose-dependent. The cell viability assays indicated that DON was significantly more toxic than NIV, and both were considerably more toxic than ZEA. The toxicity mechanism of FGTs was revealed by estimating reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase-3 levels. The effect of FGTs on the generation of ROS was observed by fluorescent probe dichloro-dihydro-fluorescein diacetate (DCFH-DA), and the ROS levels were enhanced on the treatment of FGTs. The effect of FGTs on MMP was revealed by rhodamine 123 staining, and MMP levels were depleted with exposure to FGTs. Furthermore, the expression level of caspase-3 was determined by a caspase-3 detection kit, and its levels were enhanced by exposure to FGTs. The studies conclude that FGTs have a potent cytotoxic effect on H9c2 cells and induce death by oxidative stress-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype characterized by the lack of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors. TNBC cells are becoming more aggressive due to the high expression of manganese superoxide dismutase (MnSOD) antioxidants to suppress reactive oxygen species-induced apoptosis and promote oncogenic signaling. This study was aimed to evaluate the effects of MnSOD knockout (KO) on TNBC cell apoptosis by assessing the survivin, caspase-9, and caspase-3 expressions. BT-549 TNBC cells containing the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-edited MnSOD gene were used to evaluate the messenger RNA (mRNA) expressions of survivin using the RT-qPCR assay. The Western blot assay was used to measure protein expressions of survivin, caspase-9, and caspase-3. Interactions between MnSOD and apoptosis-related proteins were simulated using computational methods based on molecular docking analysis and protein-protein interaction network. This study revealed that MnSOD KO decreased the binding affinity between MnSOD and survivin, in line with the significant reduction of survivin mRNA and protein expressions whereas the protein expressions of caspase-9 and caspase-3 increased in MnSOD KO cells. Therefore, MnSOD plays a pivotal role in BT-549 cell apoptosis by modulating survivin, caspase-9, and caspase-3 gene expressions. This study provides insights into a novel therapeutic strategy to mitigate the aggressiveness of TNBC by disrupting MnSOD gene expression. Further studies should elaborate the MnSOD signaling pathways involving closely related apoptotic proteins. [ABSTRACT FROM AUTHOR]

Acute pancreatitis（AP） is one of the most common gastrointestinal diseases requiring urgent hospitalization, and its incidence is on the rise. This study aims to evaluate whether empagliflozin (EMPA) can alleviate AP in rats by inhibiting apoptosis. Eighteen SPF-grade SD male rats were randomly divided into three groups using a random number table method: control group (CON group), AP group, and AP+EMPA group, with six rats in each group. After successful establishment of the rat models, blood and pancreatic samples were collected. The serum markers tested included amylase (AMY), glucose (GLU), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels. Western blot analysis was used to detect the expression levels of Caspase-3 and Bcl2 in the pancreatic tissue, while immunohistochemistry and immunofluorescence were used to assess Caspase-3 expression in the pancreatic tissue. Pancreatic tissues were paraffin-embedded for hematoxylin-eosin (HE) staining and pathological scoring. One-way ANOVA was employed for statistical analysis of the data. The study found that the AP group had elevated serum AMY, GLU, inflammatory cytokine levels, and pathological scores compared to the CON group. In the pancreatic tissue, the apoptosis-related molecule Caspase-3 was elevated, while the expression level of Bcl2 was reduced compared to the CON group (P<0.05). However, EMPA treatment could reverse these changes. In conclusion, EMPA effectively ameliorates the pathological changes in the pancreatic tissue in a rat model of AP, and this protective effect may be related to the inhibition of apoptosis. This article aims to explore the potential therapeutic effects and molecular mechanisms of EMPA in AP, providing new insights for the effective prevention and treatment of this disease. [ABSTRACT FROM AUTHOR]

Moringa oleifera is a highly nutritious and water purifier plant that is widely utilized in the aquaculture sector. Tilapia fish has various advantageous characteristics endowing it appropriate for aquaculture. Thus, this current study is designed to evaluate the impact of Moringa oleifera MOAE aqueous extract supplementation at the levels of 0, 100, 200, and 400 mg/kg diet for 3 months on Nile tilapia, Oreochromis niloticus. Antioxidant capacity, reproductive hormones, cytokines, and gonadal histological and caspase-3 immune-histochemical changes are assessed. Outcomes revealed a significant (P < 0.05) decrease in the antioxidant (CAT, SOD, GSH, and GPx) readings plus a significant (P < 0.05) increase in the proinflammatory cytokines (TNFα, IL1-β) was recorded for the 400 mg MOAE/kg group. In addition, significant (P < 0.05) improvements in estradiol and testosterone concentrations were detected in the 200 mg MOAE group. However, gonadal histological alterations were detected in the 400 mg MOAE/kg group, while the best histo-architectures were recorded for the 200 mg MOAE/kg group. Associated Caspase-3 immunoexpression showed wide-ranging positive three cells indicating severe apoptotic features for the 400 mg MOAE/kg group. Consequently, 200 mg/kg diet MOAE dietary supplementation is suggested for enhancing immune-antioxidant traits and reproductive hormones and modulating cytokines, as well as gonadal activity enhancement of O. niloticus with caution when the level of MOAE exceeds 200 mg/kg diet. [ABSTRACT FROM AUTHOR]

Objective(s): Activating apoptosis and oxidative stress contributes to the pathogenesis of diabetes. Evening primrose oil (EPO) has been shown to regulate lipid profiles and hyperglycemia under metabolic conditions. This study aimed to examine the effect of EPO on miR-21 expression, oxidative stress, apoptosis, and histological changes in the pancreas of male rats with experimental diabetes induced by streptozotocin (STZ). Materials and Methods: Thirty-two Wistar rats were divided into four distinct groups: control, diabetic, diabetic + EPO, and EPO. EPO was administered orally at a dose of 500 mg/kg, and STZ was administered intraperitoneally at a dose of 35 mg/kg for 28 days. In the end, the effects of treatments were assessed by measuring expressions of miR-21 in the pancreas with real-time PCR, pancreatic histological and immunohistochemical changes examinations, and oxidative stress assessment. Results: In the diabetic group, miR-21 expression and the levels of caspase-3 and malondialdehyde (MDA) were increased compared to the control group, while insulin expression and superoxide dismutase activity (SOD) levels were decreased significantly. Treatment with EPO resulted in a reduction of miR-21 and caspase-3 expression, as well as MDA levels, and an increase in insulin expression and SOD levels compared to the diabetic group. Additionally, supplementation with EPO demonstrated the ability to restore pancreatic tissue features, serum insulin levels, and blood glucose fluctuations. Conclusion: Collectively, the protective impacts of EPO in diabetic rats may be linked to the inhibition of miR-21/caspase-3/oxidative stress pathway, leading to the restoration of pancreatic β-cell function and structure. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to demonstrate the protective effect of beta-carotene against STZ-induced DN in rats and explore the possible underlying mechanisms that may have mediated such condition. Material and Methods: Wistar rats were allocated into four groups. Normal group received distilled water for 3 weeks. The other three groups were rendered diabetic by an intraperitoneal dose of STZ (50 mg/kg), 48 h later, group 2: received the vehicle and served as control, groups (3 &4) received orally beta-carotene in doses of 10 and 20 mg/kg, respectively for 3 weeks. Then serum and renal tissue were collected for biochemical, molecular, immunohistopathological, and histopathological examination. Results: Beta-carotene ameliorated the reduction in body weight, reduced blood glucose, elevated serum insulin, reduced blood urea nitrogen, and serum creatinine levels. Beta-carotene elevated phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK)/AMPK, alleviated phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR, reduced interleukin 1 beta (IL-1β), increased Beclin 1, LC3II/LC3I, and reduced p62 renal contents. Moreover, it elevated renal SIRT1 gene expression and reduced renal tumor necrosis factor-alpha (TNF-α) and caspase-3 protein expressions. Conclusion: Beta-carotene exerted renoprotective effect against STZ-induced DN and histopathological alterations through alleviating hyperglycemia, attenuating inflammation, activating AMPK/SIRT1/autophagy pathway, and combating apoptosis. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the protective or therapeutic effect of thymoquinone (TQ) in a retinal degeneration rat model and its relationships with the retina ultrastructure, heme oxygenase 1 (HO-1), caspase-3, and RPE65 expressions and to determine whether TQ has a therapeutic effect at the biochemical level. Methods: A total of 25 adult Wistar albino rats were divided into the following treatment groups: saline (control: CONT), CO (corn oil), sodium iodate (SI), TQ + SI, and SI + TQ injection groups. Retina morphology, RPE65, HO-1, and caspase-3 expression levels were evaluated using immunohistochemistry, and optical density was determined using ImageJ. Ultrastructural evaluations were performed with electron microscopy. Thiol-disulfide homeostatic parameters were examined in serum samples. Results: Outer nuclear layer (ONL) thickness was significantly higher in the SI + TQ group compared to the SI group. The RPE65 expression significantly decreased in the SI group compared with the CONT and CO groups. A significant increase in RPE65 expression level and a significant decrease in caspase-3 expression level were found in the SI + TQ group compared with the SI group. The increase in HO-1 expression level was significantly higher in the TQ treatment groups, particularly in the SI + TQ group. In the SI and TQ + SI groups, the ONL thickness significantly decreased with a significant increase in caspase-3 expression compared to the CONT and CO groups. In the treatment groups, decreased organelle damage was observed on electron microscopy. In the SI + TQ group, the disulfide/native thiol and disulfide/total thiol ratios were significantly lower than all other groups, while the native/total thiol ratio was significantly higher than the other experimental groups. Conclusions: The present study provides evidence that continuous TQ treatment can increase HO-1 and RPE65 expression and decrease apoptosis (caspase-3 levels), thereby preserving the retina at the ultrastructural level. Moreover, TQ administration can maintain thiol/disulfide homeostasis in SI-induced retinal degeneration-modelled rats. [ABSTRACT FROM AUTHOR]

The successful treatment of Alzheimer's disease (AD) is still a big challenge. Rivastigmine is one of the most used drugs for the treatment of AD. The short half-life, lower bioavailability, and less concentration of the drug in the brain after oral delivery are considered the main drawbacks of rivastigmine. To improve these drawbacks, nanostructure-mediated drug delivery has gained more attention. This study investigates the effect of rivastigmine-loaded in optimized chitosan nano-particles (RS-CSNPs) as polymeric nano-carriers by different administration routes (oral and intranasal) on aluminum chloride (AlCl3)-induced Alzheimer-like disease in rat. The model was established by giving rats 100 mg/kg/b.wt of AlCl3 orally for 3 months. Then the experimental rats were treated with RS-CSNPs either orally or intranasally for 75 days. Histopathology, immunohistochemistry of Tau expression in brain tissue, and gene expression of Caspase-3, NF-κB, and Nrf-2 were carried out. The therapeutic agents used decreased the alterations observed in AlCl3 group with improvement in the neuronal viability. In addition to low expression of tau protein, down-regulation of caspase-3 and NF-κB genes and up-regulation of Nrf-2. RS-CSNPs alleviated the progression of AD presumably via blocking the inflammatory cascade and decreasing the oxidative stress process. The intranasal route is superior to the oral one and promising in AD management. [ABSTRACT FROM AUTHOR]

Few studies have investigated the joint toxicity mechanism of azole fungicides at different exposure times and relevant environmental concentrations. Fungicides can be found in higher concentrations than other agricultural chemicals in the whole environment due to their wide range of use and repetitive use. One of these fungicides, tebuconazole, acts as a chemical disrupting the synthesis of ergosterol found in the cell membranes of fungi and protozoa. It is aimed to investigate the effects of this mechanism of action on other living things exposed to tebuconazole in nature. In the study, 2.5 mg/L concentration of tebuconazole was applied to Van fish as a model organism, and sampling was performed at 24, 48, 72 and 96 hours. The liver and gill tissues of the sampled fish were taken, and the change of superoxide dismutase, glutathione peroxidase, catalase, malonedialdehyde, 8-hydroxy deoxyguanosine, and caspase-3 biomarkers were investigated. The results determined that the levels of antioxidant enzymes decreased with the increase of the exposure time to tebuconazole, and the levels of L-lipid peroxidation, 8-OHdG, and caspase-3 increased (P < 0.05). This study determined with different biomarkers that this fungicide caused oxidative stress in the tissues examined. [ABSTRACT FROM AUTHOR]

This study was conducted to determine the antioxidant and anticancer activity of Salvia aramiensis Rech.f., which is a member of Lamiaceae, and its phenolic compounds. For this purpose, the phenolic compounds from the S. aramiensis methanol extract (SAME) were identified by LC-MS-MS. Antioxidant activities of SAME were determined by in vitro DPPH scavenging and metal chelating assays. The antiproliferative effect of SAME on lung cancer cells (A549) was determined by using the MTT assay. In addition, the levels of the pro-inflammatory cytokines IL6 and IL8, and apoptotic marker caspase-3 were determined using ELISA assays. As a result of LC-MS-MS screening, luteol was detected as the main compound of SAME. The DPPH scavenging and metal chelating activities of SAME were insignificant. In addition, it was observed that SAME reduces the viability of A549 cells. At doses of 25, 50, and 100 µg/mL, IL6 and IL8 levels increase, but at 200 µg/mL, a considerable decrease was observed. Caspase-3 levels also decreased at doses of 100 and 200 µg/mL. As a result, although SAME has weak antioxidant activities, it has significant antiproliferative and pro-inflammatory cytokine suppressing effects. Due to the decreased levels of caspase 3, the cytotoxic effect of SAME may be mediated by a caspase independent pathway. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) remains one of the most common cancers and is the third leading cause of cancer-related deaths despite conventional treatments. Chemerin is an endogenous adipocytokine that plays a role in cancer, apoptosis, oxidative stress, and inflammation processes. The aim of this study is to investigate intracellular chemerin signalling in apoptosis, oxidative stress, and inflammation in HT-29 cells treated with exogenous chemerin. The study aims to reveal how chemerin affects these processes and potentially triggers apoptosis in colon cancer cells. Cell viability was determined using the XTT cell proliferation assay after HT-29 cells were treated with 5, 20, and 40 nM chemerin for 48 hours. Oxidative stress (TOS, TAS) and inflammation markers (TNFα and IL1β) were measured using ELISA, while NF-kB mRNA expression was assessed with qRT-PCR. Additionally, CMKLR1, cytochrome c, and caspase-3 gene expressions were quantified using qRT-PCR. PTEN and Bax/Bcl-2 protein expressions were evaluated through Western blotting. Chemerin dose-dependently reduced CMKLR1 levels. Notably, low-dose chemerin increased TOS, OSI, TNFα, IL1β, and NF-kB levels, and low doses were more effective in reducing TAS compared to other doses. Administration of chemerin in human HT-29 cells also resulted in the up-regulation of PTEN, Bax, cytochrome c, and caspase-3, and the down-regulation of Bcl-2. Overall, the study data demonstrated that chemerin induces apoptosis in colon cancer cells by increasing oxidative stress and inflammation through intracellular PTEN, Bax/Bcl-2, cytochrome c, and caspase-3 signalling pathways. [ABSTRACT FROM AUTHOR]

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Chronic stress induces changes in the prefrontal cortex and hippocampus. Selenium nanoparticles (SeNPs) showed promising results in several neurological animal models. The implementation of SeNPs in chronic restraint stress (CRS) remains to be elucidated. This study was done to determine the possible protective effects of selenium nanoparticles on behavioral changes and brain oxidative stress markers in a rat model of CRS. 50 rats were divided into three groups; control group (n = 10), untreated CRS group (n = 10) and CRS-SeNPs treated group (n = 30). Restraint stress was performed 6 h./day for 21 days. Rats of CRS-SeNPs treated group received 1, 2.5 or 5 mg/kg SeNPs (10 rats each) by oral gavage for 21 days. Rats were subjected to behavioral assessments and then sacrificed for biochemical and histological analysis of the prefrontal cortex and hippocampus. Prefrontal cortical and hippocampal serotonin levels, oxidative stress markers including malondialdehyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx), tumor necrosis factor alpha (TNF-α) and caspase-3 were assessed. Accordingly, different doses of SeNPs showed variable effectiveness in ameliorating disease parameters, with 2.5 mg/kg dose of SeNPs showing the best improving results in all studied parameters. The present study exhibited the neuroprotective role of SeNPs in rats subjected to CRS and proposed their antioxidant, anti-inflammatory and anti-apoptotic effects as the possible mechanism for increased prefrontal cortical and hippocampal serotonin level, ameliorated anxiety-like and depressive-like behaviors and improved prefrontal cortical and hippocampal histological architecture. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a risk factor of chronic kidney disease, without specific treatment. This study investigated the effect of co‐treatment using erythropoietin‐derived helix B surface peptide (HBSP) and caspase‐3 small interfering RNA (CASP3siRNA) on preventing fibrosis post AKI in order to achieve better efficacy by different action mechanisms. Ischemia–reperfusion (IR) in mice was induced by clamping bilateral renal pedicles for 30 min followed by 2‐week reperfusion, with HBSP and/or CASP3siRNA administered at the onset of IR. Serum creatinine, apoptosis, active caspase‐3 and high mobility group protein B1 (HMGB1) in kidneys were decreased by HBSP, CASP3siRNA or both, with increased PCNA. α‐SMA expression and collagen I deposition were also reduced by CASP3siRNA and both. Most interestingly, the co‐treatment further reduced tubulointerstitial damage and fibrosis, but raised PCNA compared to CASP3siRNA. EPOR/βcR was reduced by HBSP, and positively correlated with Sirius red staining, whereas EPOR was unchanged. In TCMK‐1 cells, H2O2 raised apoptosis and α‐SMA were reduced by HBSP, while the same was occurred to HMGB1. However, HMGB1 was further increased by EPOR siRNA under H2O2 stimulation with/without HBSP treatment. In conclusion, this study demonstrated synergistic long‐term renoprotection post IR‐AKI by HBSP and CASP3siRNA, which may be due to co‐inhibiting inflammation and stimulating repair at early stage, and subsequently preventing fibrosis. [ABSTRACT FROM AUTHOR]

Skin cancer is a widespread type of cancer representing 30% of all cancer types worldwide. Resveratrol (RSV) is an anticancer drug used for skin cancer treatment. Several limitations of RSV such as poor aqueous solubility, first-pass metabolism, and instability limit their topical use. The study aimed to develop and optimize RSV-loaded invasomes for topical administration as well as assess their efficacy in vivo. The optimized RSV-loaded invasomes showed small particle size (208.7 ± 74 nm), PDI (0.3 ± 0.03), high % entrapment efficiency (77.7 ± 6%), and negative zeta potential (−70.4 ± 10.9 mV). They showed an initial burst effect followed by controlled drug release for 24 h. RSV-loaded invasomal gel revealed the highest skin deposition percentage (65%) in ex vivo rat skin, the highest potency (low IC50 of 6.34 μg/mL), and the highest cellular uptake when tested on squamous cancerous cells (SCCs) when compared to other formulations. The antitumor effect of topical RSV-loaded invasomes was also evaluated in vivo in Ehrlich-induced mice models. The results revealed that RSV-loaded invasomal gel exhibited the smallest tumor volume with no signs of organ toxicity indicating its safety in skin cancer treatment. Upregulation of BAX and Caspase-3 gene levels and downregulation of NF-kB and BCL2 protein levels were demonstrated using RT-PCR and ELISA tests, respectively. Interestingly, the present study is the first to develop RSV-loaded invasomal gel for topical skin cancer treatment. According to our results, invasomes are considered promising lipid-based nanosystems for topical RSV delivery having high skin penetration ability and anticancer effect in the treatment of skin carcinoma. [ABSTRACT FROM AUTHOR]

Gliclazide (GLZ), an oral antihyperglycemic medication, has additional beneficial effects, such as anti-inflammatory and antioxidant properties, besides lowering blood glucose levels. In this study, the radioprotective effect of GLZ was evaluated against ionizing radiation (IR)-induced intestinal injury in mice. Eight groups of mice were randomized as follows: control, GLZ (5, 10, and 25 mg/kg), IR (6 Gy), and IR + GLZ (at 5, 10, and 25 mg/kg). GLZ was administered to the mice for eight consecutive days, after which they were exposed to X-rays at a single dose of 6 Gy. After irradiation, biochemical parameters, immunohistochemical, and histological examinations were conducted on the ileum of the mice. IR exposure increased the levels of malondialdehyde and protein carbonyl, while glutathione levels, as oxidative stress biomarkers, decreased. Apoptosis in ileum tissues was also assessed. Furthermore, histopathological changes were observed in the irradiated mice. GLZ treatment significantly mitigated these changes. The administration of GLZ resulted in a marked decrease in caspase-3 immunoreactivity in the ileum of irradiated mice. This preclinical study exhibited that GLZ has a radioprotective effect against intestinal injury by inhibiting oxidative stress and apoptosis.

Background: Hypopharyngeal carcinoma is an aggressive subtype of head and neck squamous cell carcinoma, characterized by poor prognosis and resistance to conventional therapies. Reversine, a 2,6-disubstituted purine derivative, exhibits anticancer properties by inducing apoptosis and inhibiting cell proliferation in various cancers. Methods: FaDu hypopharyngeal carcinoma cells were treated with reversine at concentrations of Control, 15 μM, and 30 μM. Cell viability was assessed using MTT and live/dead assays. Apoptotic features were analyzed by hematoxylin & eosin and DAPI staining, and DNA fragmentation assays. Immunoblotting was performed to evaluate caspase-3 and poly adenosine diphosphate-ribose polymerase (PARP) activation. Results: Reversine significantly reduced the viability of FaDu cells in a dose-dependent manner. Morphological changes, nuclear fragmentation, and DNA laddering confirmed apoptosis. Immunoblotting revealed increased levels of cleaved caspase-3 and PARP, indicating the activation of the intrinsic and extrinsic apoptotic pathways. Conclusion: Reversine effectively inhibited FaDu cell viability and induced apoptosis through intrinsic and extrinsic pathways, and represents a potential novel therapeutic agent for hypopharyngeal carcinoma. This study highlights a unique focus on subpharyngeal cancer, overcoming therapeutic resistance, and suggests its potential as an anticancer agent by targeting dual cell death pathways.

Background: The aim is to ameliorate the anticancer activity of topotecan (topoisomerase [TOPO]) by solubilizing it in a nanoemulsion (NE) delivery system containing avocado oil (AO), then to assess its cytotoxicity in MCF-7 breast, HCT116 colon, HeLa cervical, and HepG2 liver cancer cells. Methods: AO-NE formulation was developed using an ultrasonic homogenizer and characterized by a zeta-sizer and transmission electron microscope (TEM). The effects of the TOPO-AO-NE formula on viability, cellular and nuclear morphology of cancer cells, as well as TOPO cellular accumulation, inflammatory effects, apoptosis, and autophagy, were examined. Results: The nanosized particles of the AO-NE formula were negatively charged (114.83 ± 1.10 nm, −8.96 ± 0.14 mV) even after TOPO loading (75.44 ± 8.51 nm,−5.79 ± 0.38 mV). In contrast to free TOPO, TOPO-AO-NE exhibited significant anti-proliferation, clear apoptotic changes, improved TOPO cellular uptake and decreased IC50 from (12.65 ± 0.05, 15.78 ± 0.08, 26.82 ± 0.50, and 5.50 ± 0.50 μM) to (2.35 ± 0.05, 4.90 ± 0.05, 2.58 ± 0.08, and 4.87 ± 0.08 μM) in MCF-7, HCT116, HeLa, and HepG2 cells, respectively. In MCF-7 and HCT116 cells, cytotoxicity of TOPO-AO-NE was attributed to decreased IL-6 levels relative to a negative control, lessened autophagic LC-3 levels compared to free TOPO-treated cells, and induction of type-I apoptotic cell death. In HeLa cells, TOPO-AO-NE-induced apoptosis through autophagy inhibition and induction of type-I apoptosis. In HepG2 cells, AO-NE reduced IL-6 cytokines and induced both type-I-apoptotic and type-II-autophagic cell deaths in comparison with control cells. Conclusion: Loading TOPO in AO-NE has dramatically enhanced its’ antiproliferative effects in cancer cells.

Rashid Lateef,1,2 Israr Ahmad,2 Abbas Ali Mahdi,3 Neha Lohia,1 Hisham A Alhadlaq,4 Mohd Javed Akhtar,4 Maqusood Ahamed4 1School of Life and Basic Sciences, Jaipur National University, Jaipur, Rajasthan, 302017, India; 2Department of Biotechnology, Era University, Lucknow, Uttar Pradesh, 226003, India; 3Department of Biochemistry, Era University, Lucknow, Uttar Pradesh, 226003, India; 4King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, 11451, Saudi ArabiaCorrespondence: Maqusood Ahamed, King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, 11451, Saudi Arabia, Email mahamed@ksu.edu.saBackground: Researchers have shown substantial interest in bismuth oxide/reduced graphene oxide (Bi2O3/RGO) nanocomposites due to their superior features that are not achievable by each material alone. The growing applications and manufacturing of Bi2O3/RGO nanocomposites have raised concerns regarding their potential human health risks. This work was designed to explore the possible toxicity mechanisms of Bi2O3/RGO nanocomposites in two distinct mammalian cell lines, normal rat kidney cells (NRK52E) and human liver cancer cells (HepG2).Methods: Bi2O3/RGO nanocomposites were prepared by a simple hydrothermal technique. X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and dynamic light scattering (DLS) were used to characterize the synthesized nanocomposites. The cytotoxicity of Bi2O3/RGO nanocomposites in NRK52E and HepG2 cells was examined by MTT cell viability assay. Reactive oxygen species (ROS) and glutathione (GSH) were measured as the biomarkers of oxidative stress. The apoptosis study was carried out by measuring several parameters, including cell cycle and caspase-3.Results: High-quality Bi2O3/RGO nanocomposites of &ap;33– 38 nm size without impurities, where crystalline Bi2O3 particles are evenly attached to the RGO sheets. Bi2O3/RGO nanocomposites exhibit cytotoxic effects on NRK52E and HepG2 cells, which were dose- and time-dependent. Interestingly, NRK52E exhibited marginally higher vulnerability to Bi2O3/RGO nanocomposites compared to HepG2. Bi2O3/RGO nanocomposites also cause a dose-dependent increase in ROS production and a decrease in GSH levels. Exposing NRK52E and HepG2 cells to Bi2O3/RGO nanocomposites results in activation of the caspase-3 enzyme and chromosomal condensation. The apoptotic response of Bi2O3/RGO nanocomposites against both types of cells was further confirmed by AO-EB dual staining and altered cell cycle.Conclusion: This study demonstrated that the toxicity of Bi2O3/RGO nanocomposites in both NRK52E and HepG2 cells is attributed to their ability to produce ROS, leading to apoptosis and cell cycle arrest as a consequence of oxidative stress. Keywords: Bi2O3/RGO nanocomposites, health effects, NRK52E, HepG2, Caspase-3, ROS, apoptosis

AIM: To assess the protective effect of adipose tissue-derived mesenchymal stem cells(ADSCs)exosomes on injured retinal ganglion cells(RGCs)by establishing an in vitro rat RGC pressure injury model.METHODS: ADSCs were cultured, and exosomes were extracted from the supernatant and identified. Rat RGCs were divided into a control group, pressure model groups(40, 80, 120 mmHg), and exosome-treated groups under different pressures. Cell proliferation activity was assessed using the CCK-8 assay. The mRNA expression levels of brain-derived neurotrophic factor(BDNF)and Caspase-3 in RGCs were detected by qPCR, and protein levels were measured by Western Blot.RESULTS: The CCK-8 assay showed that cell proliferation activity in the control group increased significantly at 48 h compared to 24 h(P0.05), and significantly decreased in the 80 and 120 mmHg pressure model groups(all P0.05). Caspase-3 mRNA expression increased in the 40 mmHg pressure model group without statistical significance(P>0.05), and significantly increased in the 80 and 120 mmHg pressure model groups(all P0.05). Western Blot analysis showed that BDNF protein expression decreased in the 40 mmHg pressure model group without statistical significance(P>0.05), and significantly decreased in the 80 and 120 mmHg pressure model groups(all P

Background and Aim: Alzheimer's disease (AD) is a major health challenge in the world today. The present study aimed to determine the effect of aerobic exercise and Melissa officinalis extract on the expression of p53, p21, and caspase-3 genes in male rats with AD. Methods: In this experimental study, 48 rats were randomly divided into 6 groups: control, AD, control + aerobic exercise, AD + aerobic exercise, AD + aerobic exercise + extract, and AD + extract. The AD model was induced by injecting amyloid beta 42-1 into the hippocampus. Aerobic exercise was performed for 8 weeks. Melissa officinalis extract was dissolved in 2 ml of distilled water at a dose of 100 mg/kg body weight and gavaged to rats for 8 weeks. Real-Time PCR was used to determine the expression levels of p53, p21, and caspase-3 genes. Results: After 8 weeks of aerobic exercise combined with Melissa officinalis extract, the expression of the p21 gene in the intervention groups significantly increased compared to the AD group (P