Apoptotic Factors Research Articles

Preventive effect of quercetin-Loaded nanophytosome against autistic-like damage in maternal separation model: The possible role of Caspase-3, Bax/Bcl-2 and Nrf2

The autism is an abnormality in the neuronal advance which starts before age 3 recognized by defective behaviors. This study aimed to make quercetin-loaded nanophytosomes (QNP) on behavioral deficits, cerebellar oxidative stress and apoptosis in an autistic-like model caused by maternal separation (MS). The newborn rats are randomly categorized into seven groups, including control, positive control, disease, and diseases treated with quercetin (10 and 40 mg/kg) and QNP (10 and 40 mg/kg). Pups exposed to MS for 3 h per day from postnatal days (PND) 1–9 showed behavioral impairment in adult rats compared to control group. The oral administration of quercetin and QNP was constantly started after the lactation period (21 postnatal days) for three weeks. Autistic-like behaviors, antioxidant parameters, and Nrf2, Bax/Bcl-2, and Caspase-3 expressions were surveyed in the cerebellum. Quercetin (40 mg/kg) treated improved some behavioral disorders. Also, the improvement of oxidative stress parameters, Nrf2 and apoptotic factors gene expression was observed in the cerebellum of quercetin (40 mg/kg) treated (p < 0.01). QNP treatment (10 and 40 mg/kg) significantly ameliorated anxiety-like behaviors, line crossing, and grooming index (p < 0.001), lipid peroxidation (p < 0.001), and increased catalase (CAT) (p < 0.001), superoxide dismutase (SOD) (p < 0.001), glutathione peroxidase (GPx) (p < 0.001) activity, and glutathione (GSH) levels (p < 0.05). Moreover, QNP significantly reduced Caspase-3 and Bax expression (p < 0.001), but increased Bcl-2, and Nrf2 expressions (p < 0.001). These findings indicated that QNP due to its high bioavailability was more effective than quercetin can be reduced autistic-like behavior, oxidative and apoptotic damages in the model of MS rats.

In Vivo Toxicity of Oral Administrated Nano-SiO2: Can Food Additives Increase Apoptosis?

Nano-silicon dioxide (nano-SiO2) has a great deal of application in food packaging, as antibacterial food additives, and in drug delivery systems but this nanoparticle, despite its wide range of utilizations, can generate destructive effects on organs such as the liver, kidney, and lungs. This study is aimed at investigating the toxicological effects of nano-SiO2 through apoptotic factors. For this purpose, 40 female rats in 4 groups (n = 10) received 300, 600, and 900mg/kg/day of nano-SiO2 at 20-30nm size orally for 20days. Relative expression of Caspase3, Bcl-2, and BAX genes in kidney and liver was evaluated in real time-PCR. The results indicated the overexpression of BAX and Caspase3 genes in the liver and kidney in groups receiving 300 and 900mg/kg/day of nano-SiO2. Bcl-2 gene was up-regulated in the liver and kidney at 600mg/kg/day compared to the control group. Overexpression of the Bcl-2 gene in the kidney in 300 and 900mg/kg/day recipient groups was observed (P ≤ 0.05). Histopathological examination demonstrated 600mg/kg/day hyperemia in the kidney and lungs. In addition, at 900mg/kg/day were distinguished scattered necrosis and hyperemia in the liver. The rate of epithelialization in the lungs increased. The nano-SiO2 at 300 and 900mg/kg/day can induce more cytotoxicity in the liver and lung after oral exposure. However, cytotoxicity of nano-SiO2 at 600mg/kg/day in the kidney and lung was noticed. Hence, the using of nano-SiO2 as an additive and food packaging should be more considered due to their deleterious effects.

Effects of limonin treatment on the survival of random skin flaps in mice.

Random skin flap is commonly used in plastic and reconstructive surgery, however, distal part of skin flap often occurs ischemia and necrosis. Limonin, with bioactivities of anti-inflammation, anti-apoptosis and anti-oxidative stress, may be effective for skin flap survival. In our study, random flap model was performed in mice to explore the role of limonin in the survival of skin flap. On postoperative day 7, the necrosis of skin flaps was observed, while visualization of blood flow below the tissue surface was detected through Laser Doppler blood flow imaging (LDBFI). Then flap tissues were acquired to assess and levels of angiogenesis, apoptosis and oxidative stress. The results showed that limonin decreased necrosis and edema of skin flaps compared with the control group, with more blood flow in the flap under LDBFI detection. Limonin treatment also increased the mean vessels density, elevated the expression levels of angiogenic proteins (matrix metallopeptidase 9, vascular endothelial growth factor, Cadherin5) and antioxidant proteins [superoxide dismutase 1 (SOD1), endothelial nitric oxide synthase, heme oxygenase], and reduced the expression of apoptotic factors (BAX, CYC, Caspase3). In summary, limonin could effectively enhance the survival of random skin flap, the potential mechanism may attribute to the induction of angiogenesis, and inhibition of apoptosis and oxidative stress.

Glyoxal-derived advanced glycation end-products, Nε-carboxymethyl-lysine, and glyoxal-derived lysine dimer induce apoptosis-related gene expression in hepatocytes.

Advanced glycation end-products (AGEs) are proteins or lipids that have been glycated nonenzymatically by reducing sugars and their derivatives such as methylglyoxal. AGEs are known to cause inflammation, oxidative stress, and diseases in the human body. The toxic effects of AGEs and their structures on the origin of the protein being modified have not been well studied. Five different types of AGEs: AGE1 (glucose-derived), AGE2 (glyceraldehyde-derived), AGE3 (glycolaldehyde-derived), AGE4 (methylglyoxal-derived), and AGE5 (glyoxal-derived); were used to examine the effect of AGEs on HepG2 cells. AGE2 through 5 increase the production of reactive oxygen species (ROS) in liver cells, an initiating factor for apoptosis. At the mRNA and protein levels, AGE5 treatment showed the greatest increase in expression of apoptosis-related factors such as Bax, p53, and Caspase 3. Quantitative analysis revealed that Nε-carboxymethyl-lysine (CML) and glyoxal-lysine dimer (GOLD) were the important types of AGE5. The ROS generation and the expression of apoptotic factors both increased when cells were treated with CML and GOLD. These findings suggest that AGE5 treatment activates the apoptosis-related gene expression in hapatocytes, with CML and GOLD as potential major AGE compounds.

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.

Mapping the metabolic characteristics of probiotic-fermented Ganoderma lucidum and its protective mechanism against Cd-induced nephrotoxicity.

An animal model of Cd-induced kidney damage was designed to investigate the nephroprotective potential of the probiotic-fermented Ganoderma lucidum (FGL) via metabonomic analysis. The results showed that FGL enhanced sugar and amino acid metabolism. The interaction of Ganoderma lucidum (GL) and probiotics efficiently elevated short-chain fatty acid production following gut microbiota fermentation. The current data revealed that the FGL intervention alleviated Cd-induced nephrotoxicity via elevating the activity of antioxidant enzymes and decreasing the levels of pro-inflammatory and apoptotic factors. Based on transcriptome analysis, FGL intervention mediated renal dysfunction via decreasing the expressions of Nos2, Tnfsf14, S100a9, Map3k6 and Hk3, which were involved in oxidative stress, inflammatory response and the apoptosis process. The current study highlights a new approach for achieving positive nephroprotection via natural product intervention.

Aqueous Extract of Cinnamon (Cinnamomum spp.): Role in Cancer and Inflammation.

Cinnamon (Cinnamomum spp.; family Lauraceae), a plant widely used as a spice and flavoring agent and in the perfume industry, has high therapeutic value. However, the components and chemical properties of cinnamon extracts vary depending on the part of the plant, the method, and the solvent used for extraction. Green extraction methods using safe and green solvents have gained increased interest in recent years. Water is an environmentally friendly and safe green solvent widely used for preparing cinnamon extracts. This review focuses on the various preparation techniques for the aqueous extract of cinnamon, its major bioactive components, and their beneficial roles in different pathological conditions, specifically cancer and inflammation. The aqueous extract of cinnamon contains several bioactive compounds, such as cinnamaldehyde, cinnamic acid, and polyphenols, and exerts anticancer and anti-inflammatory properties by altering key apoptotic and angiogenic factors. The whole extract is a better anticancer and anti-inflammatory agent than the purified fractions, indicating a synergistic effect between various components. Studies have indicated that aqueous cinnamon extract has immense therapeutic potential, and to better understand its synergistic effects, extensive characterization of the aqueous extract and its potential to be used with other therapies should be explored.

Effects of Rosa roxburghii Tratt on Ulcerative Colitis: An Integrated Analysis of Network Pharmacology and Experimental Validation.

Rosa roxburghii Tratt is a traditional Chinese plant that has been used to treat different inflammatory diseases. The purpose of this study was to investigate the mechanism of action of Rosa roxburghii Tratt extract (RRTE) against ulcerative colitis (UC) using network pharmacology and experimental validation. HPLC-Q/Orbitrap MS was used to rapidly identify the substances contained in RRTE after extracting the active components from the fruit. Then, network pharmacology combined with molecular docking was used to explore the critical target and potential mechanism of RRTE against UC using the active ingredients in RRTE as the research object. Data are presented in a visual manner. Finally, the pharmacological effects of RRTE in alleviating UC were further verified using a DSS-induced UC model of NCM460. The results showed that 25 components in RRTE were identified. A total of 250 targets of the active components and 5376 targets associated with UC were collected. Furthermore, a systematic analysis of the Protein-Protein Interaction (PPI) networks suggests that epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), and serine/threonine kinase 1 (AKT1) are critical targets for RRTE in the treatment of UC. A comprehensive regulatory network analysis showed that RRTE alleviated UC through the EGFR-mediated PI3K/Akt pathway, and molecular docking showed that active components could strongly bind to EGFR, PIK3R1, and AKT1. In addition, RRTE alleviated dextran sulfate sodium salt (DSS)-induced cell injury and significantly decreased the protein expression levels of EGFR, PIK3R1, and p-AKT in NCM460 cells in vitro. Furthermore, RRTE significantly regulated the expression of the apoptosis-related proteins Apoptotic protease-activating factor 1 (Apaf1), cleaved caspase-3, B-cell lymphoma-2 (Bcl2), and Bcl2 associated X protein (Bax). In conclusion, the components of RRTE are complex, and RRTE can relieve UC through the EGFR-mediated PI3K/Akt pathway.

P53 upregulated by HIF-1α promotes gastric mucosal epithelial cells apoptosis in portal hypertensive gastropathy.

Portal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of gastrointestinal bleeding. Mucosal apoptosis is an essential pathological feature of PHG. However, whether HIF-1α and p53 are involved in mucosal apoptosis and whether HIF-1α induces PHG by mediating p53 remains unclear. Gastric mucosal injury and apoptosis were examined in PHG patients and animal models. The mechanisms of HIF-1α- and p53-mediated apoptosis were analyzed. The GES-1 cell line was used to elucidate the underlying mechanisms using siRNA knockdown of HIF-1α and p53 in a hypoxic environment in vitro. Epithelial apoptosis, HIF-1α, and p53 were markedly induced in the gastric mucosa of PHG. Apoptosis was attenuated in mice with HIF-1α- and p53-specific inhibitors. Apoptotic signaling factors were markedly induced in the gastric mucosa of PHG. Inhibition of p53 demonstrably attenuated the mucosal apoptosis; however, it did not affect HIF-1α expression. Conversely, targeted deletion of HIF-1α significantly inhibited p53 expression and attenuated the injury and p53-mediated apoptosis. Bax and Bcl-2 expression can be upregulated and downregulated by p53, respectively, to increasecleaved caspase-3 expression, which can be regulated by HIF-1α. These results indicate that HIF-1α regulates the p53-induced mucosal epithelial apoptotic signaling pathway and that HIF-1α and p53 are potential therapeutic targets for PHG.

Targeting redox imbalance in neurodegeneration: characterizing the role of GLP-1 receptor agonists.

Reactive oxygen species (ROS) have emerged as essential signaling molecules regulating cell survival, death, inflammation, differentiation, growth, and immune response. Environmental factors, genetic factors, or many pathological condition such as diabetes increase the level of ROS generation by elevating the production of advanced glycation end products, reducing free radical scavengers, increasing mitochondrial oxidative stress, and by interfering with DAG-PKC-NADPH oxidase and xanthine oxidase pathways. Oxidative stress, and therefore the accumulation of intracellular ROS, determines the deregulation of several proteins and caspases, damages DNA and RNA, and interferes with normal neuronal function. Furthermore, ROS play an essential role in the polymerization, phosphorylation, and aggregation of tau and amyloid-beta, key mediators of cognitive function decline. At the neuronal level, ROS interfere with the DNA methylation pattern and various apoptotic factors related to cell death, promoting neurodegeneration. Only few drugs are able to quench ROS production in neurons. The cross-linking pathways between diabetes and dementia suggest that antidiabetic medications can potentially treat dementia. Among antidiabetic drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been found to reduce ROS generation and ameliorate mitochondrial function, protein aggregation, neuroinflammation, synaptic plasticity, learning, and memory. The incretin hormone glucagon-like peptide-1 (GLP-1) is produced by the enteroendocrine L cells in the distal intestine after food ingestion. Upon interacting with its receptor (GLP-1R), it regulates blood glucose levels by inducing insulin secretion, inhibiting glucagon production, and slowing gastric emptying. No study has evidenced a specific GLP-1RA pathway that quenches ROS production. Here we summarize the effects of GLP-1RAs against ROS overproduction and discuss the putative efficacy of Exendin-4, Lixisenatide, and Liraglutide in treating dementia by decreasing ROS.

Methyltransferase 3 beta (DNMT3B) inhibition by decitabine promotes endometrial carcinoma cell apoptosis by autophagy induction

Autophagy regulates endometrial cancer cell apoptosis and inhibits endometrial cancer development; however, the specific underlying mechanisms are unclear. The effects of DNA methylation on endometrial cancer cell autophagy were explored in HEC-1B cells using decitabine, a DNA methylase inhibitor. Real-time fluorescence quantitative PCR (RT-qPCR) and western blot (WB) analyses were used to detect the mRNA and protein expression of DNA methylase (DNMT3B), autophagy-related genes LC3B and Beclin-1, and apoptosis-related genes Bax and Bcl-2. High-purity and high-quality RNA was obtained by nano-magnetic bead extraction, to ensure highly accurate RT-qPCR and WB results. MTT cell viability assay, scratch assay, and Transwell migration assay were utilized to detect the proliferation and migration of HEC-1B cells. The results showed that decitabine significantly inhibited the expression of DNMT3B protein and mRNA, with 25 μM decitabine being the most effective. In subsequent experiments, this concentration of decitabine was used. The low DNMT3B expression significantly inhibited the expression of Beclin-1 and LC3B proteins (***P &lt;0.001 and *P &lt;0.05) and mRNA (*P &lt;0.05 and *P &lt;0.05). Decitabine promoted the mRNA and protein expression of apoptotic factor Bax (*P &lt; 0.05 and *P &lt; 0.05), while inhibiting the mRNA protein expression of anti-apoptotic factor Bcl-2 (***P &lt;0.001 and *P &lt;0.05). MTT assay results showed decreased proliferation of HEC-1B cells following inhibition of DNMT3B expression by decitabine, which was significantly different from that of the NC group (*P &lt;0.05). The results of the cell scratch and Transwell migration assays showed reduced migration ability of HEC-1B cells compared to that observed in the NC group (**P &lt;0.01 and *P &lt;0.05). These results show that decitabine inhibits DNMT3B expression, and low DNMT3B levels regulate the expression of autophagy- and apoptosis-related factors, thereby inhibiting the proliferation and migration of endometrial cancer cells.

Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells.

Uveal melanoma (UM) is the principal type of intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease with very poor survival. There are few drugs available to treat the primary or metastatic UM. This study was undertaken to evaluate the anti-cancer effect of lapatinib and corroborate the potential of HER2 inhibition in the treatment of UM. The anti-UM activity of lapatinib was assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing, invasion and colony formation assays. Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling. The anti-UM activity of lapatinib was further evaluated in a UM xenograft mouse model. Lapatinib decreased the viability of four UM cell lines (IC50: 3.67-6.53 µM). The antiproliferative activity of lapatinib was corroborated in three primary cell lines isolated from UM patient tumors. In UM cell lines, lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration, invasion and reproductive cell growth. Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling leading to the altered expression of apoptotic factors and cell cycle mediators in UM cell lines. Importantly, lapatinib suppressed tumourigenesis in mice carrying UM cell xenografts. Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM. Lapatinib is active in primary and metastatic UM as a clinically approved HER2 inhibitor. The activity of lapatinib in UM patients could be evaluated in future clinical trials.

Pharmacokinetic Characteristics of Bisdemethoxycurcumin and Its Mechanism of Reversing Cardiomyocyte Apoptosis

To investigate the pharmacokinetic characteristics of bisdemethoxycurcumin in vivo and the reversal effect of phosphatidylinositol 3-kinase/protein kinase B/caspase-9 signaling pathway on thapsigargininduced cardiomyocyte apoptosis in neonatal rat. Demethoxycurcumin and bisdemethoxycurcumin were intragastrically administered to adult Sprague–Dawley rats. Plasma was collected and the drug concentration was measured by high performance liquid chromatography. The pharmacokinetic parameters of the drug were calculated by Drug and Statistics 2.1.1 pharmacokinetic software. After that, primary cardiomyocytes from Sprague–Dawley neonatal rats were isolated and cultured, and they were divided into three groups; control (conventional culture without any drug treatment), model (endoplasmic reticulum stress model obtained by treatment with 1 mg/ml thapsigargin for 24 h), demethoxy curcumin group (treated with 1 μmol/l thapsigargin and 10 μmol/l demethoxy curcumin for 24 h at the same time) and bisdemethoxycurcumin group (treated with 1 μmol/l thapsigargin and 10 μmol/l bisdemethoxycurcumin for 24 h at the same time). Cell survival activity was measured by cell counting kit-8 assay. Western blot was used to detect the expression of intracellular apoptotic factors Bcl-2-associated X, B-cell lymphoma protein 2 and B-cell lymphoma protein 2/Bcl-2-associated X protein and the expression levels of phosphatidylinositol 3-kinase/protein kinase B/caspase-9 signaling pathway molecules phosphatidylinositol 3-kinase, protein kinase B, caspase-3 and caspase-9 protein. The results showed that the main pharmacokinetic parameters area under the timeconcentration curve 0-12 h, mean residency time 0-12 h, maximum plasma concentration, time to maximum plasma concentration of demethoxycurcumin and bisdemethoxycurcumin were (1.35±0.36) μg/ml•h and (1.01±0.14) μg/ml•h, (4.05±0.53) h and (3.43±0.21) h, (0.46±0.09) μg/ml and (0.45±0.11) μg/ml, (0.14±0.00) h and (0.20±0.00) h, respectively. In contrast with the model group, the survival activity of demethoxycurcumin and bisdemethoxycurcumin groups was significantly increased, the apoptosis rate was significantly decreased; the lactate dehydrogenase, malondialdehyde content and reactive oxygen species level were decreased, the superoxide dismutase activity was increased, the Bcl-2-associated X, caspase-3 and caspase-9 protein expression was decreased and the B-cell lymphoma protein 2/Bcl-2-associated X, phosphatidylinositol 3-kinase and protein kinase B protein expression was increased (p<0.05). However, bisdemethoxycurcumin was slightly superior to demethoxycurcumin in improving the above indicators, but the difference was not statistically meaningful (p>0.05). In summary, demethoxy curcumin and bisdemethoxycurcumin can mediate phosphatidylinositol 3-kinase/protein kinase B/caspase-9 signaling pathway to reduce thapsigargin-induced endoplasmic reticulum stress injury in cardiomyocytes, which in turn plays a protective role in cardiomyocytes.

Muscle fiber characteristics and apoptotic factor differences in beef Longissimus lumborum and Psoas major during early postmortem

This study was conducted to study muscle fiber characteristics and apoptotic factor differences within 24 h postmortem of bovine longissimus lumborum (LL) and psoas major (PM). Compared to LL, PM had a higher proportion of type I fibers and lower proportion of type II fibers. PM also had higher ROS levels. For bcl-2 family proteins, anti-apoptotic BCL-2 level was lower and pro-apoptotic BAX level was higher in PM. For caspases, at 1 h postmortem, gene and protein expression level of caspase-3 and caspase-9 was higher in PM than that of LL. The levels of DNA damage apoptotic factors ABL1, AIF and ENDOG was higher in PM than in LL. The results suggested that apoptotic gene and protein expression were different in muscles with different fiber type composition. These findings provided insights into muscle fiber and apoptotic factor differences during early postmortem in bovine PM and LL.

Inhibition of CCR2 attenuates neuroinflammation and neuronal apoptosis after subarachnoid hemorrhage through the PI3K/Akt pathway

BackgroundNeuroinflammation and neuronal apoptosis are closely associated with a poor prognosis in patients with subarachnoid hemorrhage (SAH). We investigated the role of C–C motif chemokine receptor 2 (CCR2) in SAH.MethodsPre-processed RNA-seq transcriptome datasets GSE167110 and GSE79416 from the Gene Expression Omnibus (GEO) database were screened for genes differentially expressed between mice with SAH and control mice, using bioinformatics analysis. The endovascular perforation model was performed to establish SAH. RS504393 (a CCR2 antagonist) and LY294002 (PI3K inhibitor) were administered to explore the mechanism of neuroinflammation after SAH. SAH grading, neurological scoring, brain water content and blood–brain barrier (BBB) permeability determination, enzyme-linked immunosorbent assay (ELISA), western blotting, and immunofluorescence were performed. An in vitro model of SAH was induced in H22 cells by hemin treatment. The protective mechanism of CCR2 inhibition was studied by adding RS504393 and LY294002. Clinical cerebrospinal fluid (CST) samples were detected by ELISA.ResultsExpression of CCR2 was upregulated in both datasets and was identified as a hub gene. CCR2 expression was significantly upregulated in the cytoplasm of neurons after SAH, both in vitro and in vivo. RS significantly reduced the brain water content and blood–brain barrier permeability, alleviated neuroinflammation, and reduced neuronal apoptosis after SAH. Additionally, the protective effects of CCR2 inhibition were abolished by LY treatment. Finally, the levels of CCR2, inflammatory factors, and apoptotic factors were elevated in the CSF of patients with SAH. CCR2 levels were associated with patient outcomes at the 6-month follow-up.ConclusionCCR2 expression was upregulated in both in vitro and in vivo SAH models. Additionally, inhibition of CCR2, at least partly through the PI3K/AKT pathway, alleviated neuroinflammation and neuronal apoptosis in vivo and in vitro. CCR2 levels in the CSF have a moderate diagnostic value for 6-month outcome prediction in patients with SAH.

Neuroprotective Effect of the Mixture of Gastrodiae elata and Glycyrrhizae uralensis In Vitro

Background: This study investigated the effect of a mixture of Gastrodiae elata and Glycyrrhizae uralensis (GGW) on β-amyloid-induced neuronal damage in vitro. Methods: For finding the appropriate GGW ratio, we performed MTT assays using the ratios of 5:5, 6:4, 7:3, 8:2 and 9:1 in SK-N-SH cell and SH-SY-5Y cell. Treatment with β-amyloid (10 μM) caused cell death and overexpression of acetylcholinesterase (ACHE) in SH-SY-5Y cells. β-amyloid treatment increased the expression of mitogen-activated protein kinases (MAPKs). In addition, we detected the antioxidant activity of GGW using DCF-DA staining of SK-N-SH cells. To determine the effect of GGW on oxidative stress, we used a hydrogen peroxidase-induced in vitro model. Results: We selected the ratios of 5:5 and 7:3 mixtures with the least cytotoxicity. The 7:3 ratio of GGW (GGW73) decreased the mRNA expression of ACHE in SH-SY-5Y cell more than the 5:5 ratio of GGW (GGW55). GGW73 suppressed p-ERK protein expression in β-amyloid-treated SH-SY-5Y cells. Additionally, GGW73 regulated reactive oxygen species (ROS) in vitro. GGW73 treatment regulated apoptotic factors in β-amyloid-stimulated neuronal cells. Conclusions: These results suggest that GGW73 exerts neuroprotective and anti-inflammatory effects in vitro. These results also showed that GGW73 had a protective effect against H2O2 induced cell damage in an in vitro model. These results indicate the potential of GGW as a therapeutic agent for cognitive disorders.

Effect of Esculetin on Tert-Butyl Hydroperoxide-Induced Oxidative Injury in Retinal Pigment Epithelial Cells In Vitro.

Esculetin is a coumarin-derived compound with antioxidant and anti-inflammatory properties. The current study aims to evaluate the therapeutic implications of esculetin on retinal dysfunction and uncover the underlying mechanisms. Tert-butyl hydroperoxide (t-BHP) at a concentration of 300 μM was used to induce oxidative stress in human retinal pigment epithelial cell line (ARPE-19) cells. Esculetin at concentrations below 250 μM did not cause cytotoxicity to ARPE-19 cells. Cell viability analysis confirmed that t-BHP induced oxidative injury of ARPE-19 cells. However, ARPE-19 cells were protected from t-BHP-induced oxidative injury by esculetin in a concentration-dependent manner. As a result of the TUNEL assay to confirm apoptosis, esculetin treatment reduced the number of TUNEL-positive cells. Esculetin down-regulated the expression levels of Bax, Caspase-3, and PARP and up-regulated the expression level of Bcl2. Collectively, this study demonstrates that esculetin exerts potent antioxidant properties in ARPE-19 cells, inhibiting t-BHP-induced apoptosis under the regulation of apoptotic factors.

Melatonin ameliorates myocardial infarction in obese diabetic individuals: The possible involvement of macrophage apoptotic factors.

In recent days, the hike in obesity-mediated epidemics across the globe and the prevalence of obesity-induced cardiovascular diseasehas become one of the chief grounds for morbidity and mortality. This epidemic-driven detrimental events in the cardiac tissues start with the altered distribution and metabolism pattern of high-density lipoproteinand low-density lipoprotein (LDL) leading to cholesterol (oxidized LDL) deposition on the arterial wall and atherosclerotic plaque generation, followed by vascular spasms and infarction. Subsequently, obesity-triggered metabolic malfunctions induce free radical generation which may further trigger pro-inflammatory signaling and nuclear factor kappa-light-chain-enhancer of activated B cellstranscriptional factor, thus inducing interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase. This terrifying cardiomyopathy can be further aggravated in type 2 diabetes mellitus, thereby makingobese diabetic patients prone towardthe development of myocardial infarction (MI) or stroke in comparison to their nondiabetic counterparts. The accelerated oxidative stress and pro-inflammatory response induced cardiomyocyte hypertrophy, followed by apoptosis in obese diabetic individuals, causing progression of athero-thrombotic vascular disease. Being an efficient antioxidative and anti-inflammatory indolamine, melatonin effectively inhibits lipid peroxidation, pro-inflammatory reactions, thereby resolving free radical-induced myocardial damages along with maintaining antioxidant reservoir to preserve cardiovascular integrity. Prolonged melatonin treatment maintains balanced body weight and serum total cholesterolconcentration by inhibiting cholesterol synthesis and promoting cholesterol catabolism. Additionally, melatonin promotes macrophage polarization toward the anti-inflammatory state, providing a proper shield during the recovery period. Therefore, the protective role of melatonin in maintaining the lipid metabolism homeostasis and blocking the atherosclerotic plaque rupture could be targeted as the possible therapeutic strategy for the management of obesity-induced acute MI. This review aimed at orchestrating the efficacy of melatonin in ameliorating irrevocable oxidative cardiovascular damage induced by the obesity-diabetes correlation.

In Vitro and In Vivo Nephroprotective Effects of Nelumbo nucifera Seedpod Extract against Cisplatin-Induced Renal Injury.

Cisplatin has been considered a chemotherapeutic drug for treating human tumors, and one of the noteworthy side effects of cisplatin is nephrotoxicity. Amelioration of cisplatin-induced nephrotoxicity is necessary. Lotus seedpod extract (LSE) mainly composed of quercetin-3-glucuronide has been revealed for antioxidant and anti-tumor effects. However, the effects of LSE on cisplatin-induced nephrotoxicity are still unknown. This study aims to explore the in vitro and in vivo protective effect and possible mechanism of LSE on cisplatin-induced nephrotoxicity. Results showed that co-treatment of LSE with cisplatin raised the viability of rat renal tubular epithelial NRK-52E cells and decreased oxidative stress and cell apoptosis when compared to the cells treated with cisplatin alone. The molecular mechanisms analyzed found that LSE could reduce the expressions of apoptotic factors, including Bax, Bad, t-Bid, and caspases. In the in vivo study, LSE improved the cisplatin-induced levels of serum markers of kidney function, glomerular atrophy, and the degree of apoptosis in the kidneys. This is the first study to display that LSE prevents cisplatin-induced nephrotoxicity by reducing oxidative stress and apoptosis. Thus, LSE could be a novel and natural chemoprotective agent for cisplatin chemotherapy in the future.

Comparison of the Pathogenicity of SARS-CoV-2 Delta and Omicron Variants by Analyzing the Expression Patterns of Immune Response Genes in K18-hACE2 Transgenic Mice.

The recently emerged variants of the severe acute respiratory coronavirus 2 (SARS-CoV-2) pose a threat to public health. Understanding the pathogenicity of these variants is a salient factor in the development of effective SARS-CoV-2 therapeutics. This study aimed to compare the expression patterns of genes involved in immune responses in K18-hACE2 mice infected with the wild-type, Delta, and Omicron SARS-CoV-2 variants. K18-hACE2 mice were intranasally infected with either wild-type (B.1), Delta (B.1.617.2), or Omicron (B.1.1.529) variants. On day 6 post-infection, lung, brain, and kidney tissues were collected from each variant-infected group. The mRNA expression levels of 39 immune response genes in all three groups were compared by RT-qPCR. Viral titers were measured using the median tissue culture infectious dose (TCID50) assay and expressed as Log10 TCID50/0.1 g. The statistical significance of the differences in gene expression was determined by one-way analysis of variance (ANOVA) (alpha = 0.05). The expression of toll-like receptors (TLRs) was upregulated in the lung and brain tissues of the wild-type- and Delta-infected groups but not in those of the Omicron-infected group. The highest expression of cytokines, including interleukin (IL)-1α, IL-1β, IL-17α, interferon, and tumor necrosis factors, was observed in the lungs of mice infected with the wild-type variant. Additionally, CCL4, CCL11, CXCL9, and CXCL10 were upregulated (>3-fold) in wild-type-infected mice, with markedly higher expressions in the brain than in the lungs. Most of the apoptotic factors were mainly expressed in the brain tissues of Omicron-infected mice (caspase 8, caspase 9, p53, Bax, Bak, BCL-2, and Bcl-XL), whereas neither the lung nor kidney showed more than 3-fold upregulation of these apoptotic factors. Collectively, our findings revealed that the wild-type SARS-CoV-2 variant exhibited the highest pathogenicity, followed by the Delta variant, then the Omicron variant.