Inhibition Of Apoptosis Research Articles

Synergy of zinc oxide nanoparticles to losartan attenuates kidney injury induced by unilateral ureteral obstruction through modulation of the TNF-α/IL6 and BAX/BCL2 signaling pathways.

Although the relief of ureteral obstruction seems to be a radical treatment for obstructive uropathy (OU), progressive kidney damage is the result because of the associated increased apoptosis and fibrosis. Therefore, it is urgent to find a complementary renoprotective therapy against partially obstructed uropathy cascades. Thus, this study investigated the renoprotective effects of both losartan (LOS) and zinc oxide nanoparticles (ZnONPs) in partial unilateral ureteral obstruction (PUUO). In controlled (n = 16) and shamed (n = 16) study, 64 healthy male Sprague-Dawley rats, both PUUO and right nephrectomy (RNX) were induced. The rats were equally allocated into four groups according to treatment protocol: (1) PUUO group (no treatment), (2) ZnONPs group, (3) LOS group and (4) ZnONPs/LOS group. Antioxidant status and gene expression were assessed in renal tissues. Moreover, histologic and immunohistochemical examinations were performed. LOS and ZnONPs significantly mitigated the PUUO-induced renal injury, by significant (P < 0.0001) suppressing of oxidative stress (MDA and TOS), upregulating of antioxidant gene (SOD) and antiapoptotic gene (BCL2), and downregulating the expression of inflammatory cytokines (TNF-α, and IL6), apoptotic gene (Bax) and fibrotic marker (β-Catenin). The combination of both agents offered a more powerful renoprotective effect with additional significant upregulation of the antioxidant marker (TAC, P < 0.0001). Both losartan and ZnONPs and specially their combination have synergistic action in protecting the kidney against PUUO-induced chronic renal cascades through improvement the renal function tests, amelioration of oxidative stress, inhibition of induced apoptosis and fibrosis with marked renal regeneration which highlights the possible application of these drugs as a complementary therapies for different chronic renal degenerative diseases.

NDUFA11 may be the disulfidptosis-related biomarker of ischemic stroke based on integrated bioinformatics, clinical samples, and experimental analyses

BackgroundProgrammed cell death plays an important role in neuronal injury and death after ischemic stroke (IS), leading to cellular glucose deficiency. Glucose deficiency can cause abnormal accumulation of cytotoxic disulfides, resulting in disulfidptosis. Ferroptosis, apoptosis, necroptosis, and autophagy inhibitors cannot inhibit this novel programmed cell death mechanism. Nevertheless, the potential mechanisms of disulfidptosis in IS remain unclear.MethodsThe GSE16561 dataset was used to screen for differentially expressed disulfidptosis-related biomarkers (DE-DRBs). A correlation between the DE-DRBs was detected. The optimal machine-learning (ML) model and predictor molecules were determined. The GSE58294 dataset was used to verify the accuracy of the optimal ML model. The DE-DRB expression was detected in the blood of patients with IS. Based on IS models, experimental analyses were performed to verify DE-DRB expression and the correlation between DE-DRBs.ResultsLeucine-rich pentatricopeptide repeat-containing (LRPPRC) and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 (NDUFA11) were identified as DE-DRBs. The NADH: ubiquinone oxidoreductase core subunit S1 (NDUFS1) interacted with NDUFA11 and LRPPRC. The support vector machine (SVM) model was identified as the optimal ML model. The NDUFA11 expression level in the blood of patients with IS was 20.9% compared to that in normal controls. NDUFA11 expression was downregulated in the in vitro/in vivo models of IS. The number of formed complexes of NDUFS1 and NDUFA11 decreased in the in vitro/in vivo models of IS.ConclusionThis research suggests that NDUFA11 is a specific DRB for IS and demonstrates alterations in the disulfidptosis-related protein complexes NDUFS1-NDUFA11.

Release of apoptosis inhibitor of macrophage (AIM) from pentameric IgM in serum predicts prognosis after hemodialysis initiation

BackgroundThe optimal timing for initiating dialysis and prognostic markers in chronic kidney disease (CKD) patients are under debate, with mortality and cardiovascular risks varying among patients. This study investigates whether the apoptosis inhibitor of macrophage (AIM), which is mostly bound to pentameric IgM, could serve as an effective indicator.MethodsWe prospectively followed 423 patients at dialysis initiation and 563 at various CKD stages. AIM dissociation from IgM and other serum components were measured in their serum samples. In vitro treatment of IgM-AIM complexes with their serum was conducted to assess AIM release from IgM. Survival analysis determined the associations of each variable with mortality and cardiovascular risk, and a cutoff value was calculated and validated using cross-validation.ResultsAIM dissociation from IgM increases with CKD progression and correlates with the serum uremic state, as shown by enhanced AIM release from IgM in vitro with sera from patients starting dialysis, but not those at earlier CKD stages. Patients at dialysis initiation with high proportion of serum IgM-free AIM (fAIM%) show elevated uremic toxins and other toxic metabolites, higher mortality, and increased cardiovascular risk compared to those with low fAIM%. This prognostic association is not seen with other CKD biomarkers, such as eGFR, creatinine, or inositol-phosphate. We determined the fAIM% cutoff of 46.27%, which predicts mortality two years post-dialysis initiation.ConclusionsThese findings suggest that the serum fAIM% could function as a prognostic marker at dialysis initiation and may have potential as a criterion for determining dialysis timing.

Advancements in the treatment of cerebral ischemia-reperfusion injury: Acupuncture combined with mesenchymal stem cells transplantation.

Cerebral ischemia-reperfusion injury (CIRI) constitutes a significant etiology of exacerbated cerebral tissue damage subsequent to intravenous thrombolysis and endovascular mechanical thrombectomy in patients diagnosed with acute ischemic stroke. The treatment of CIRI has been extensively investigated through a multitude of clinical studies. Acupuncture has been demonstrated to be effective in treating CIRI. Recent 5 years studies have identified potential mechanisms of acupuncture, including regulation of autophagy, promotion of angiogenesis, inhibition of inflammation and apoptosis, modulation of cell activation, neuroplasticity regulation, and promotion of nerve regeneration. The transplantation of mesenchymal stem cells (MSCs) can effectively suppress apoptosis, modulate immune responses, and enhance the proliferation and migration of endogenous neural stem cells (NSCs), thereby compensating for the NSCs deficiency following cerebral ischemia/reperfusion injury. The combination of acupuncture and MSCs transplantation demonstrates superiority over individual treatments, significantly enhancing the survival rate of MSCs. Moreover, it facilitates the secretion of various cytokines to promote their homing and differentiation into functional neurons, thereby providing a novel approach for clinical treatment of CIRI.

Conessine Attenuates Diabetic Nephropathy in Rats through Inhibition of Hyperglycemia-Induced Oxidative Stress, Inflammation and Apoptosis

Conessine Attenuates Diabetic Nephropathy in Rats through Inhibition of Hyperglycemia-Induced Oxidative Stress, Inflammation and Apoptosis

A novel therapeutic approach to doxorubicin-induced cardiotoxicity, with a particular emphasis on the potential cardioprotective properties of Vitis gracilis Wall.

Context: Doxorubicin, a potent chemotherapy drug, often leads to cardiotoxicity, limiting its clinical use. This study investigates the potential of Vitis gracilis Wall. nanoherbs (VGN) in mitigating doxorubicin-induced heart damage, aiming to provide insights into its therapeutic efficacy as a cardioprotective agent. Aims: To evaluate the therapeutic potential of VGN in mitigating doxorubicin-induced cardiotoxicity. Methods: The study comprised four treatment groups in male Wistar rats: D0 (negative control), D+ (doxorubicin 0.00038 mg/200 g body weight (BW)/day), DC (doxorubicin + Vitamin C 0.04 mg/200 g BW/d), D25 (doxorubicin + VGN at 25 mg/200 g BW/d), and D30 (doxorubicin + VGN at 30 mg/200 g BW/d). Key cardiac parameters, including LDH, CK-MB, TNF-alpha, IL-10, SOD, and caspase 3, were meticulously measured to assess cardioprotective effects. Statistical analyses were performed to evaluate the significance of observed changes, revealing a dose-dependent reduction in markers of cardiac injury (LDH, CK-MB) and inflammation (TNF-alpha) alongside enhancements in antioxidant defenses (SOD) and inhibition of apoptosis (caspase 3) with VGN administration. Results: The results showed promising reductions in markers of heart injury (LDH, CK-MB) and inflammation (TNF-alpha) specifically at a dose of 30 mg/200 g BW/d significantly (p&lt;0.05). In addition, doses of 30 mg/200 g BW/d of VGN showed potential to increase antioxidant defenses (SOD), IL-10, as well as inhibit apoptosis (caspase 3) (p&lt;0.05), highlighting the best multifaceted cardioprotective effects. Conclusions: The study demonstrates that V. gracilis has the potential to reduce doxorubicin-induced cardiotoxicity through its multifaceted cardioprotective effects. These effects include a reduction in markers of cardiac injury and inflammation at a dose of 30 mg/200 g BW/d, enhancement of antioxidant defenses, and inhibition of apoptosis.

Retraction: Yiqi Fumai lyophilized injection attenuates doxorubicin-induced cardiotoxicity, hepatotoxicity and nephrotoxicity in rats by inhibition of oxidative stress, inflammation and apoptosis.

[This retracts the article DOI: 10.1039/C8RA07163B.].

Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1.

Doxorubicin (Dox) is a widely used antineoplastics although its clinical usage is greatly limited by its cardiotoxicity. Several studies have depicted an essential role for dampened mitophagy and mitochondrial injury in Dox cardiotoxicity. However, preventative measure to alleviate Dox-evoked cardiotoxicity via targeting mitophagy and mitochondrial integrity remains elusive. Urolithin A (UA) is a newly identified mitophagy inducer with antioxidant and anti-apoptotic properties although its effect on Dox-induced cardiotoxicity is unknown. This study was designed to explore the effect of UA on Dox cardiotoxicity and mechanisms involved. Our results indicated that UA alleviated Dox-induced cardiac dysfunction exhibited by echocardiographic parameters and histological analyses, and partially relieved Dox-induced apoptosis in vitro and in vivo, and mitochondrial dysfunction including ΔΨm dissipation and ROS production in vitro. The ability of UA to facilitate restoration of mitophagy in mice and H9C2s underscored its advantageous effects, manifested as upregulation of mitophagy-related proteins, including p62, LC3, PINK1 and Parkin, as well as the co-location between LC3 and mitochondria. Incubation with 3-MA nearly reversed the UA-evoked rise of mitophagy-related proteins, and inhibition of apoptosis. Given that knockdown of Ambra1 almost abolished UA-induced protective effect, the enhanced expression of Ambra1 owing to UA increased PINK1 levels by inhibiting its degradation via LONP1. Collectively, our results suggest that the cardioprotective properties of UA depend on the stimulation of PINK1-dependent mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. This highlights UA's potential as a valuable treatment option and its importance in cardioprotective strategies against Dox-induced cardiotoxicity.

α -lipoic acid supplementation reduces oxidative stress and inflammation in red skeletal muscle of insulin-resistant rats

α -lipoic acid (ALA) is an eight-carbon saturated fatty acid with strong antioxidant activity. Despite previous reports of ALA's protective properties in treating cardiovascular and metabolic diseases (including insulin resistance and diabetes), little is known about the compound's effects on skeletal muscle metabolism. In particular, the effect of ALA on glycooxidative and nitrosative damage in red muscles during insulin resistance is unknown. This study investigated the therapeutic potential of ALA on the antioxidant barrier as well as oxidative, nitrosative and carbonyl stress in the red skeletal muscle of rats with high-fat diet-induced insulin resistance. Male Wistar cmdb/outbred rats were divided into four equal groups: control diet (CTRL), high fat diet (HFD), CTRL+ALA (30 mg/kg body weight for 4 weeks; intragastrically) and HFD+ALA. Enzymatic and nonenzymatic antioxidant systems, protein and lipid glycoxidation, nitrosative stress, and selected inflammatory/apoptosis parameters were assessed using colorimetric, fluorimetric, and immune-enzymatic methods. ALA lowered body weight and glucose metabolism parameters in insulin-resistant rats. ALA not only strengthened enzymatic antioxidant defense (by increasing superoxide dismutase, catalase and glutathione peroxidase activity) but also stimulated the synthesis of non-enzymatic GSH. ALA supplementation inhibited lipid peroxidation (decreased lipid hydroperoxides and malondialdehyde content) and prevented protein oxidation (by lowering advanced oxidation protein products concentration) in red muscle. ALA's multifactorial actions on muscle tissue also included inhibition of inflammation and apoptosis, requiring further research to elucidate its effects in metabolic diseases.

Inhibition of osteocyte apoptosis does not prevent iron overload-induced bone resorption and bone loss.

Iron overload leads to apoptosis and increased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) in osteocytes, which in turn accelerates osteoclastogenesis. Since osteocytes are the main RANKL producers, we hypothesized that apoptotic osteocytes increase RANKL expression in osteocytes, which in turn stimulates osteoclastogenesis and bone resorption. In this study, alendronate or IG9402, a bisphosphonate (BP) analog which does not inhibit bone resorption, inhibited iron overload-induced osteocyte apoptosis and increased RANKL expression. Both BPs also prevented osteoblast apoptosis but did not inhibit the increase in osteoblastic RANKL. Alendronate, but not IG9402, prevented the increase in osteoclastogenesis and serum levels of the bone resorption marker C-telopeptide of type I collagen (CTX) in iron-overloaded mice. Alendronate also prevented the iron overload-induced reduction in femoral bone mineral density, disruption of bone microstructure, and weakness of bone strength. Although IG9402 did not prevent bone loss due to iron overload, it partially prevented reduction of strength, suggesting that osteocyte viability contributes to the maintenance of bone strength. In conclusion, although osteocyte apoptosis in the presence of iron overload leads to an increase in osteocytic RANKL production. However, blocking these events was not sufficient to inhibit iron overload-induced osteoclastogenesis and bone loss.

An Overview of the Dichotomous Role of Microbiota in Cancer Progression and Management.

It is a well-known fact that cancer is considered the second leading cause of mortality across the globe. Although the human oral cavity and intestine are the natural habitat of thousands of microbes, dysbiosis results in malignancies, such as oral squamous cell carcinoma and colorectal cancer. Amongst the intestinal microbes, H. pylori is a deadly carcinogen. Also, causative pathogens for the development of pancreatic and colorectal cancer are found in the oral cavity, such as Fusobacterium nucleatum and Porphyromonas gingivalis. Many periodontopathic micro- organisms, like Streptococcus sp., Peptostreptococcus sp., Prevotella sp., Fusobacterium sp., Porphyromonas gingivalis, and Capnocytophaga gingivalis, strongly have an impact on the development of oral cancers. Three basic mechanisms are involved in pathogen-mediated cancer development, like chronic inflammation-mediated angiogenesis, inhibition of cellular apoptosis, and release of carcinogenic by-products. Microbiota has a dichotomous role to play in cancer, i.e., microbiota can be used for cancer management too. Shreds of evidence are there to support the fact that microbiota enhances the chemotherapeutic drug efficacy. This review presents the possible mechanism of the oncogenic effect of microbiota with emphasis on the oral microbiome and also attempts to explain the intricate role of microbiota in cancer management.

Biocompatible ionized air alleviates rat osteoarthritis by modulating polarization from M1 to M2 macrophages

AbstractThe imbalance in the proportion of M1/M2 macrophage polarization is a crucial contributor to the persistent progression of osteoarthritis (OA). This study aimed to evaluate the effects of low-dose biocompatible ionized air (BIA) on macrophage polarization and its subsequent chondroprotective effects, thereby validating the potential of BIA in slowing the progression of OA. In vitro experiments demonstrated that BIA modulates the polarization of M1 macrophages toward the M2 phenotype via the ROS-mediated STAT6 pathway. This shift reduces the expression of pro-inflammatory mediators while increasing the expression of anti-inflammatory mediators and pro-chondrogenic factors, leading to an improved microenvironment surrounding chondrocytes. The direct benefits of this improved microenvironment include enhanced chondrocyte viability, inhibition of apoptosis, and reduced degradation of the extracellular matrix. In vivo studies in rats showed that BIA inhibited M1 macrophage infiltration in the synovium, upregulated the proportion of M2 macrophages, alleviated cartilage degeneration, and delayed OA progression. This gas-based regulatory strategy may open new avenues for the treatment of OA.

Bacteroides fragilis capsular polysaccharide A ameliorates ulcerative colitis in rat by recovering intestinal barrier integrity and restoring gut microbiota.

Bacteroides fragilis (B. fragilis) is a Gram-negative, obligate anaerobic, commensal bacterium residing in the human gut and holds therapeutic potential for ulcerative colitis (UC). Previous studies have indicated that capsular polysaccharide A (PSA) of B. fragilis is a crucial component for its effectiveness, possessing various biological activities such as anti-inflammatory, anti-tumor, and immune-modulating effects. We previously isolated and characterized the B. fragilis strain ZY-312 from the feces of a healthy breastfed infant, and extracted its PSA, named TP2. In this study, we explored the impact of TP2 on colonic inflammation and delved into its potential mechanisms. Initially, we used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis in rats and found that TP2 treatment significantly ameliorated TNBS-induced weight loss, increased clinical scores, extensive ulcers, and intestinal epithelial damage in UC rats. Further analysis revealed that TP2 effectively restored the intestinal barrier integrity in UC rats by regulating the expression of Muc-2, tight junction proteins (ZO-1, occludin, claudin-1, and claudin-2), as well as apoptosis-related proteins Bcl-2, BAX, and Cleaved-Caspase-3. Additionally, TP2 suppressed the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL23, while promoting the secretion of anti-inflammatory cytokines IL-10 and IL-22, thereby inhibiting the occurrence of inflammation. TP2 also downregulated the phosphorylation levels of AKT and PI3K, effectively inhibiting the abnormal activation of the PI3K/AKT signaling pathway. More interestingly, 16S rRNA sequencing results showed that TP2 restored the ecological imbalance of the rat intestinal microbiota, with an increase in beneficial bacteria such as Lactobacillus and Limosilactobacillus observed in the treatment group. In conclusion, TP2 through the regulation of intestinal barrier-related cells and proteins, inhibition of apoptosis, modulation of inflammation-related cytokine levels, and control of abnormal activation of the PI3K/AKT signaling pathway, restores intestinal barrier integrity. Additionally, by reshaping the ecological imbalance of the gut microbiota, TP2 ultimately alleviates ulcerative colitis in rats.

Rosmarinic acid protects against cyclophosphamide-induced hepatotoxicity via inhibition of oxidative stress, inflammation, and apoptosis and upregulation of Nrf2 in mice.

Cyclophosphamide (CP) is widely used in chemotherapy to treat various types of cancer. However, it is toxic to the liver and other organs. Rosmarinic acid (RA) possesses anti-inflammatory, antioxidant, and cytoprotective properties. This study investigated the protective effects of RA against CP-induced liver injury in mice. Mice were treated with RA (25, 50, and 100mg/kg) for 15days and followed by a single injection of CP on day 16th. CP injection resulted in an elevation in serum AST, ALT, and ALP, along with multiple histopathological alterations in the liver. CP also induced increased levels of MDA and NO, associated with declined GSH, SOD and CAT. RA pretreatment prevented liver injury, alleviated the enhanced levels of MDA and NO, and restored antioxidants defenses, hence avoiding the oxidative injury in the liver. Moreover, RA pretreatment attenuated NF-κB p65 and proinflammatory cytokines levels. Liver of CP-injected mice also showed a decrease in Bcl2, accompanied with elevated BAX and caspase-3 expression, an effect that RA pretreatment alleviated. In addition, pretreatment of CP-administrated mice with RA restored the Nrf2 expression in the liver. Taken together, this study suggests a potential application value of RA in preventing CP hepatotoxicity and sheds light on the possible mechanism.

The 'Oma's of the Gammas-Cancerogenesis by γ-Herpesviruses.

Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), which are the only members of the gamma(γ) herpesviruses, are oncogenic viruses that significantly contribute to the development of various human cancers, such as Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, and primary effusion lymphoma. Oncogenesis triggered by γ-herpesviruses involves complex interactions between viral genetics, host cellular mechanisms, and immune evasion strategies. At the genetic level, crucial viral oncogenes participate in the disruption of cell signaling, leading to uncontrolled proliferation and inhibition of apoptosis. These viral proteins can modulate several cellular pathways, including the NF-κB and JAK/STAT pathways, which play essential roles in cell survival and inflammation. Epigenetic modifications further contribute to EBV- and KSHV-mediated cancerogenesis. Both EBV and KSHV manipulate host cell DNA methylation, histone modification, and chromatin remodeling, the interplay of which contribute to the elevation of oncogene expression and the silencing of the tumor suppressor genes. Immune factors also play a pivotal role in the development of cancer. The γ-herpesviruses have evolved intricate immune evasion strategies, including the manipulation of the major histocompatibility complex (MHC) and the release of cytokines, allowing infected cells to evade immune detection and destruction. In addition, a compromised immune system, such as in HIV/AIDS patients, significantly increases the risk of cancers associated with EBV and KSHV. This review aims to provide a comprehensive overview of the genetic, epigenetic, and immune mechanisms by which γ-herpesviruses drive cancerogenesis, highlighting key molecular pathways and potential therapeutic targets.

Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential

In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique zwitterionic amidine featuring a nido-cluster. We tested the anti-cancer potential of these prodrugs against murine colon adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29). The tests showed that diclofenac and the carborane-substituted oxindoles exhibited no cytotoxicity, the dichlorophenyl-substituted oxindole had moderate anti-cancer activity, while with the amidine this effect was strongly potentiated with activity mapping within low micromolar range. Compound 3 abolished the viability of selected colon cancer cell line MC38 preferentially through strong inhibition of cell division and moderate apoptosis accompanied by ROS/RNS depletion. Our findings suggest that carborane-based prodrugs could be a promising direction for new anti-cancer therapies. Inhibition assays for COX-1 and COX-2 revealed that while diclofenac had strong COX inhibition, the re-engineered carborane compounds demonstrated a varied range of anti-cancer effects, probably owing to both, COX inhibition and COX-independent pathways.

Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis.

Liver fibrosis is the common fate of NASH and poses a major health threat with very limited pharmacological treatments. This study aims to investigate the preventive effect of hinokitone (HO), an isolated compound from Agathis dammara, on NASH fibrosis and its underlying mechanism. To investigate the effect of HO on NASH fibrosis, C57BL/6 mice were either fed a high-fat diet (HFD) in conjunction with intraperitoneal injection of CCl4 for 8 weeks or single CCl4 for 14 days to establish mouse liver fibrosis model, and HO was administered by gavage simultaneously. To elucidate the underlying mechanisms, HepG2 cells were stimulated by palmitic acid (PA) or tumor necrosis factor α plus actinomycin-D (Act-D + TNFα) to induce hepatocyte apoptosis model. Furthermore, hepatocyte Farnesoid-X-receptor (FXR) specifically knocked out mice were established by the albumin-Cre-loxP recombination enzyme system to ascertain the role of FXR in the anti-NASH fibrosis effects of HO. The results showed that HO presented dose-dependent anti-liver fibrosis efficacy in NASH mice induced by HFD + CCl4 and CCl4-induced mouse liver fibrosis. Cellularly, HO significantly inhibited PA-induced lipotoxic apoptosis and Act-D + TNFα-induced exogenous apoptosis in hepatocytes, which in turn prevented HSC activation. Mechanistically, bioinformatics analysis and surface plasmon resonance assay had identified hepatocyte FXR as a target of HO. Specifically, HO directly bound to FXR and upregulated its protein level by inhibiting proteasomal degradation. In turn, HO attenuated hepatocyte lipid deposition through upregulating the FXR's downstream target genes SHP and CES1, and reduced cleaved-CASP8 level, thereby inhibiting hepatocyte apoptosis. Furthermore, HO lost its function in the inhibition of hepatocyte apoptosis and liver fibrosis when knockout hepatocyte FXR. In conclusion, HO has an inhibitory effect on NASH fibrosis. This effect is mediated by targeting upregulation of hepatocyte FXR, which in turn attenuates hepatocyte apoptosis and thus indirectly inhibits the activation of HSCs.

Impact of Nuclear Peripheral Chromatin Lamin LMNB1 Gene in the Proliferation and Migration of Glioma Cells.

The goal of this study is to explore the role of the LMNB1 gene in glioma. A cohort of 160 patients who underwent glioma surgery were randomly selected of this study. The LMNB1 expression was assessed employing immunohistochemical and real-time quantitative polymerase chain reaction methods. Initially, RNA interference technology was applied to suppress gene expression, followed by the evaluation of tumor cell proliferation, apoptosis, cell cycle dynamics, and migration. The underlying molecular mechanisms of LMNB1 function were examined by a human phospho-kinase array and immunoblotting. And we established the xenograft models to determine the effect of tumor growth as well as the degree of invasion in shLMNB1 mice. Elevated LMNB1 expression correlated with unfavorable overall survival and disease-free survival. A substantial inhibition in cell growth was observed subsequent to LMNB1 knockdown in SHG-44 and U251 glioma cells. SHG-44-shLMNB1 cells exhibited a reduction in the S phase population, along with an increase in cells in G1 and G2 phases. Similarly, shLMNB1 U251 cells showed fewer cells in the S phase and an elevation in cells in G1 phase. Notably, increased apoptosis was observed in U251-shLMNB1 cells and SHG-44-shLMNB1 cells. Wound healing and Transwell migration assays demonstrated a significant decrease in the migration rate of both SHG-44-shLMNB1 and U251-shLMNB1 cells. The phosphorylation levels of Akt1/2/3, as well as the expressions of PI3K, AKT, and p-AKT proteins, were reduced in the shLMNB1 group. Downregulation of LMNB1 repressed tumor progress in vivo. The silencing of LMNB1 was found to significantly reduce the proliferation of human glioma cells, induce apoptosis in tumor cells, impede the progression of the cell cycle, and inhibit the migration of tumor cells. Consequently, we hypothesize that LMNB1 promotes glioma cell proliferation through mechanisms involving the inhibition of tumor cell apoptosis, acceleration of the cell cycle, and enhancement of tumor cell migration. We found that LMNB1 exert critical roles in glioma progression may via regulation of PI3K/Akt signaling pathway. These observations suggest that LMNB1 holds clinical potential for diagnostic and prognostic applications in glioma, presenting novel targets for drug development.

Cytoprotective Effects and Intranuclear Localization of Sulfur-Containing Derivative of Buckminsterfullerene.

There is a growing interest in exploring the biological characteristics of nanoparticles and exploring their potential applications. However, there is still a lack of research into the potential genotoxicity of fullerene derivatives and their impact on gene expression in human cells. In this study, we investigated the effects of a water-soluble fullerene derivative, C60[C6H4SCH2COOK]5H (F1), on human embryonic lung fibroblasts (HELF). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used to study the cytotoxicity of F1; reactive oxygen species (ROS) level was determined with 2,7-DCFH-DA; gene expression level was evaluated by reverse transcription polymerase chain reaction (RT-PCR); protein expression level was determined by flow cytofluorometry; fluorescence microscopy was used for visualization; Mann-Whitney statistical U-test was used for data processing. The differences were considered significant at p < 0.01. F1 at a concentration of 0.3 mg/mL causes a short-term (up to 1 hour) increase in the number of double-strand breaks and oxidative DNA damage in HELF. Within 1 to 24 hours, F1 penetrates through the cell and nuclear membrane of HELF and localizes in the nucleus. In this case, the response of cells to DNA damage is activated: the functional activity of DNA repair genes, antioxidant and anti-apoptotic genes is increased within 24 hours. Due to the processes of activation of cell division and inhibition of apoptosis, an increase in the population of HELF cells in the presence of the fullerene derivative F1 is observed. F1 has a stabilizing effect on cell nuclei under the action of 1 Gy radiation. An increase in antioxidant protection, activation of repair genes, anti-apoptotic genes, progression of the cell cycle, and a decrease in the level of oxidative damage, and DNA breaks in cells indicates the cytoprotective properties of F1.

Astragalus Polysaccharide Mitigates Rhabdomyolysis-Induced Acute Kidney Injury via Inhibition of M1 Macrophage Polarization and the cGAS-STING Pathway.

This study aimed to examine the impact of APS on acute kidney injury induced by rhabdomyolysis (RIAKI), exploring its association with macrophage M1 polarization and elucidating the underlying mechanisms. C57BL/6J mice were randomly assigned to one of three groups: a normal control group, a RIAKI model group, and an APS treatment group. Techniques such as flow cytometry and immunofluorescence were employed to demonstrate that APS can inhibit the transition of renal macrophages to the M1 phenotype in RIAKI. Furthermore, the raw264.7 macrophage cell line was chosen and induced into the M1 phenotype to further examine the impact of APS on this model and elucidate the underlying mechanism. Administration of APS led to a significant decrease in UREA levels by 25.2% and CREA levels by 60.9% within the model group. Also, APS exhibited an inhibitory effect on the infiltration of M1 macrophages and the cGAS-STING pathway in kidneys within the RIAKI, subsequently leading to decreased serum concentrations of IL-1β, IL-6 and TNF-α by 44.5%, 12.9%, and 10.3%, respectively, consistent with the results of in vitro experiments. Furthermore, APS exhibited an anti-apoptotic effect on MPC5 cells when co-cultured with M1 macrophages. Astragalus polysaccharide (APS) potentially mitigated rhabdomyolysis-induced renal damage by impeding the M1 polarization of macrophages. This inherent mechanism might involve the suppression of the cGAS-STING pathway activation within macrophages. Furthermore, APS could endow protective effects on podocytes through the inhibition of apoptosis.