Protective and curative effects of unconjugated bilirubin on gene expression of LOX-1 and iNOS in the heart of rats receiving high-fat diet and low dose streptozotocin: a histomorphometric approach.

BACKGROUND: Atherosclerosis is a chronic inflammatory condition affecting the large arteries and is a major cause of cardiovascular diseases (CVDs) globally. Increased levels of adhesion molecules in cardiac tissue serve as prognostic markers for coronary artery occlusion risk. Given the antioxidant properties of bilirubin and its inverse correlation with atherosclerosis, this study aimed to assess the beneficial effects of bilirubin on atherosclerotic indices and heart structure in high-fat diet-fed diabetic rats with atherosclerosis. METHODS: Atherosclerosis was induced in three out of five groups of adult male Sprague Dawley rats through a 14-week period of high-fat diet (HFD) consumption and a single low dose of streptozotocin (STZ) (35 mg/kg). The atherosclerotic rats were then treated with intraperitoneal administration of 10 mg/kg/day bilirubin for either 6 or 14 weeks (treated and protected groups, respectively), or the vehicle. Two additional groups served as the control and bilirubin-treated rats. Subsequently, the mRNA expression levels of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), lectin-like LDL receptor 1 (LOX-1), and the inducible nitric oxide synthase (iNOS) were analyzed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Histopathological and stereological analyses were performed to assess changes in the heart structure. RESULTS: Bilirubin significantly decreased the expression of VCAM-1, ICAM-1, LOX-1, and iNOS genes in the treated group. Moreover, bilirubin mitigated pathological damage in the left ventricle of the heart. Stereological analysis revealed a decrease in the left ventricle and myocardium volume, accompanied by an increase in vessel volume in rats treated with bilirubin. CONCLUSION: These findings demonstrate that mild hyperbilirubinemia can protect against the progression of atherosclerosis and heart failure by improving lipid profile, modulating adhesion molecules, LOX-1, and iNOS gene expression levels.

ß-Hydroxybutyrate and melatonin suppress maladaptive UPR, excessive autophagy and pyroptosis in Aß 1-42 and LPS-Induced SH-SY5Y cells.

BACKGROUND: Alzheimer's disease is a neurological disease characterized by the build-up of amyloid beta peptide (Aß) and lipopolysaccharide (LPS), which causes synapse dysfunction, cell death, and neuro-inflammation. A maladaptive unfolded protein response (UPR), excessive autophagy, and pyroptosis aggravate the disease. Melatonin (MEL) and hydroxybutyrate (BHB) have both shown promise in terms of decreasing Aß pathology. The goal of this study was to see how BHB and MEL affected the UPR, autophagy, and pyroptosis pathways in Aß1-42 and LPS-induced SH-SY5Y cells. MATERIALS AND METHODS: Human neuroblastoma SH-SY5Y cells were treated with BHB, MEL, or a combination of the two after being exposed to A ß1-42 and LPS. Cell viability was determined using the MTT test, and gene expression levels of UPR (ATF6, PERK, and CHOP), autophagy (Beclin-1, LC3II, P62, and Atg5), and pyroptosis-related markers (NLRP3, TXNIP, IL-1ß, and NFκB1) were determined using quantitative Real-Time PCR (qRT-PCR). For statistical analysis, one-way ANOVA was employed, followed by Tukey's post hoc test. RESULTS: BHB and MEL significantly increased SH-SY5Y cell viability in the presence of A ß1-42 and LPS. Both compounds inhibited the expression of maladaptive UPR and autophagy-related genes, as well as inflammatory and pyroptotic markers caused by Aß1-42 and LPS-induced SH-SY5Y cells. CONCLUSION: BHB and MEL rescue neurons in A ß1-42 and LPS-induced SH-SY5Y cells by reducing maladaptive UPR, excessive autophagy, and pyroptosis. More research is needed to fully comprehend the processes behind their beneficial effects and to discover their practical applications in the treatment of neurodegenerative disorders.

Confinement of Dirac fermions in gapped graphene.

We explore the electronic transport characteristics of gapped graphene subjected to a perpendicular magnetic field and scalar potential barriers. Employing the Dirac-Weyl Hamiltonian and the transfer-matrix method, we calculate the transmission and conductance of the system. Our investigation delves into the impact of the energy, the gap energy parameter ( Δ ) and the magnetic flux parameters, including the number of magnetic barriers (N), the magnetic field strength (B) and the width of the magnetic barriers. We demonstrate that manipulating energy and total magnetic flux parameters allow precise control over the range of incident angle variation. Moreover, adjusting the tunable parameter Δ effectively confines quasiparticles within the magnetic system under study. Notably, an increase in N results in a strong wave vector filtering effect. The resonance effects and the peaks in the transmission and conductance versus Δ are observed for N > 1 . The tunability of the system's transport properties, capable of being toggled on or off, is demonstrated by adjusting Δ and B. As Δ or B increases, we observe suppression of the transmission and conductance beyond critical parameter values.

Catharanthine, an anticancer vinca alkaloid: an in silico and in vitro analysis of the autophagic system as the major mechanism of cell death in liver HepG2 cells.

Catharanthine, a component of the anticancer drug vinblastine along with vindoline, disrupts the cell cycle by interfering with mitotic spindle formation. Apart from their antioxidant properties, vinca alkaloids like catharanthine inhibit phosphodiesterase activity and elevate intracellular cAMP levels. The aim of this study was to investigate how catharantine affects apoptosis and autophagy. This study conducted experiments on HepG2 liver carcinoma cells with varying doses of catharanthine to evaluate cell death rates and viability and determine the IC50 concentration via MTT assays. The apoptotic and autophagic effects of catharanthine were assessed using flow cytometry with annexin V and PI staining, while the expression of autophagy-related genes was analyzed through quantitative PCR. Additionally, molecular docking and molecular dynamics simulations were employed to further investigate catharanthine's impact on autophagy mechanisms. The study showed that catharanthine reduced oxidative stress and triggered apoptosis in HepG2 cells in a dose-dependent manner. Catharanthine also upregulated the expression of autophagy-related genes like LC3, Beclin1, and ULK1. Notably, catharanthine increased sirtuin-1 levels, a known autophagy inducer, while decreasing Akt expression compared to untreated cells. Molecular docking results indicated rapamycin had a stronger binding affinity with FRB (-10.7 KJ/mol-1) than catharanthine (-7.3 KJ/mol-1). Additionally, molecular dynamics simulations revealed that catharanthine interacted effectively with the FRB domain of mTOR, displaying stability and a strong binding affinity, although not as potent as rapamycin. In summary, besides its cytotoxic and pro-apoptotic effects, catharanthine activates autophagy signaling pathways and induces autophagic necrosis by inhibiting mTOR.

Boosting wound healing in diabetic rats: The role of nicotinamide riboside and resveratrol in UPR modulation and pyroptosis inhibition.

BACKGROUND: Diabetes-related skin ulcers provide a substantial therapeutic issue, sometimes leading to amputation, needing immediate practical treatments for efficient wound care. While the exact mechanisms are unknown, pyroptosis and deregulation of the unfolded protein response (UPR) are known to exacerbate inflammation. Nicotinamide Riboside (NR) and Resveratrol (RV), which are known for their Nicotinamide adenine dinucleotide (NAD+) boosting and anti-inflammatory properties, are being studied as potential treatments. The purpose of this study was to shed light on the underlying molecular mechanisms and explore the medical application of NR and RV in diabetic wound healing. METHODS: 54 male Sprague-Dawley rats divided into control, diabetic (DM), Gel Base, DM-NR, DM-RV, and DM-NR + RV. Rats were orally administered 50 mg/kg/day of RV and 300 mg/kg/day of NR for 5 weeks. Following diabetes induction, their wounds were topically treated with 5 % NR and RV gel for 15 days. The wound closure rate, body weight, and serum lipid profiles were examined. Gene expression study evaluated UPR and pyroptosis-related genes (BIP, PERK, ATF6, IRE1α, sXBP1, CHOP, NLRP3, caspase-1, NFκB, and IL1-ß) in wound tissues, alongside histological assessment of cellular changes. RESULTS: NR and RV treatments greatly enhanced wound healing. Molecular investigation demonstrated UPR and pyroptosis marker modifications, suggesting UPR balance and anti-inflammatory effects. Histological investigation demonstrated decreased inflammation and increased re-epithelialization. The combination of NR and RV therapy had better results than either treatment alone. CONCLUSION: This study shows that NR and RV have therapeutic promise in treating diabetic wounds by addressing UPR dysregulation, and pyroptosis. The combination therapy is a viable strategy to improving the healing process, providing a multimodal intervention for diabetic skin ulcers. These findings pave the way for additional investigation and possible therapeutic applications, giving hope for better outcomes in diabetic wound care.

The effect of quercetin on adipogenesis, lipolysis, and apoptosis in 3T3-L1 adipocytes: The role of SIRT1 pathways.

Background: Lipotoxicity, caused by adipocyte triglyceride over-accumulation, contributes to obesity-related comorbidities such as hypertension, type 2 diabetes, coronary heart disease, respiratory dysfunction, and osteoarthritis. This study focuses on determining how sirtuin-1 (SIRT-1) mediates quercetin's (QCT) effect on 3T3-L1 adipocytes. Key aspects of this study include preventing adipogenesis, inducing lipolysis, and stimulating adipocyte apoptosis. Methods: 3T3-L1 adipocytes underwent treatment with varying QCT doses, lipopolysaccharide (LPS), and the SIRT-1 inhibitor EX-527, followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide [MTT] assay for cell viability assessment. Furthermore, quantitative real-time polymerase chain reaction measured mRNA expression levels of adipogenesis markers (fatty acid synthase [FASN] and peroxisome proliferator-activated receptor gamma [PPARγ]), lipolysis markers (adipose triglyceride lipase [ATGL] and hormone-sensitive lipase [HSL]), and apoptosis markers (B-cell lymphoma2 [Bcl-2], Bcl-2 Associated -X-protein [BAX] and Caspase-3). Results: The data showed that LPS + QCT significantly reduced cell viability in a dose- and time-dependent manner, unaffected by LPS + QCT + EX-527. Treatment with LPS + QCT did not affect FASN and PPARγ expression but significantly increased ATGL and HSL mRNA expression compared with LPS alone. Interestingly, EX-527 reversed the effects of LPS + QCT on lipogenesis and lipolysis markers completely. QCT enhanced apoptosis in a SIRT-1 independent pattern. Conclusion: The data suggest that QCT suppresses adipogenesis while increasing lipolysis via SIRT-1. However, QCT's effects on apoptosis appear to be independent of SIRT-1. These findings provide further evidence for QCT's effects on adipocytes, particularly its interaction with SIRT-1.

Quercetin declines LPS induced inflammation and augments adiponectin expression in 3T3-L1 differentiated adipocytes SIRT-1 dependently.

BACKGROUND: Inflammation is an important factor contributing to obesity-induced metabolic disorders. Different investigations confirm that local inflammation in adipose issues is the primary reason for such disorder, resulting in low-grade systemic inflammation. Anti-inflammatory, antioxidant, and epigenetic modification are among the varied properties of Quercetin (QCT) as a natural flavonoid. OBJECTIVE: The precise molecular mechanism followed by QCT to alleviate inflammation has been unclear. This study explores whether the anti-inflammatory effects of QCT in 3T3-L1 differentiated adipocytes may rely on SIRT-1. METHODS: The authors isolated 3T3-L1 pre-adipocyte cells and exposed them to varying concentrations of QCT, lipopolysaccharide (LPS), and a selective inhibitor of silent mating type information regulation 2 homolog 1 (SIRT-1) called EX-527. After determining the optimal dosages of QCT, LPS, and EX-527, they assessed the mRNA expression levels of IL-18, IL-1, IL-6, TNF-α, SIRT-1, and adiponectin using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: The study showed considerable cytotoxic effects of LPS (200 ng/mL) + QCT (100 µM) + EX-527 (10 µM) on 3T3-L1 differentiated adipocytes after 48 h of incubation. QCT significantly upregulated the expression levels of adiponectin and SIRT-1 (p < 0.0001). However, introducing SIRT-1 inhibitor (p < 0.0001) reversed the impact of QCT on adiponectin expression. Additionally, QCT reduced SIRT-1-dependent pro-inflammatory cytokines in 3T3-L1 differentiated adipocytes (p < 0.0001). CONCLUSION: This study revealed that QCT treatment reduced crucial pro-inflammatory cytokines levels and increased adiponectin levels following LPS treatment. This finding implies that SIRT-1 may be a crucial factor for the anti-inflammatory activity of QCT.

Improved therapy for clear cell renal cell carcinoma: beta-hydroxybutyrate and quercetin target hypoxia-induced angiogenesis and multidrug resistance.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a form of kidney cancer characterized by dysregulated angiogenesis and multidrug resistance. Hypoxia-induced tumor progression plays a crucial role in ccRCC pathogenesis. Beta-hydroxybutyrate (BHB) and quercetin (QCT) have shown potential in targeting angiogenesis and drug resistance in various cancer types. This study investigates the combined effects of BHB and QCT in hypoxia-induced Caki-1 cells. METHODS: Caki-1 cells were subjected to normoxic and hypoxic conditions and treated with BHB, QCT, or a combination of both. Cell-viability was assessed using the MTT assay, and mRNA expression levels of key angiogenesis-related genes (HIF-1α/2α, VEGF, Ang-1, Ang-2, and MDR4) were quantified through real-time PCR during 24 and 48 h. RESULTS: BHB and QCT treatments, either alone or in combination, significantly reduced cell-viability in Caki-1 cells (p < 0.05). Moreover, the combined therapy demonstrated a potential effect in downregulating the expression of angiogenesis-related genes and MDR4 in hypoxia-induced cells, with a marked reduction in HIF-1α/2α, VEGF, Ang-1, and MDR4 expression (p < 0.05). The expression of Ang-2 increases significantly in presence of BHB combined QCT treatment. CONCLUSION: This study highlights the promising potential of a combination therapy involving BHB and QCT in mitigating angiogenesis and MDR4 expression in hypoxia-induced ccRCC cells. These findings support further investigation into the underlying mechanisms and warrant clinical studies to evaluate the therapeutic value of this combined treatment for ccRCC patients. This research provides new insights into addressing the challenges posed by angiogenesis and drug resistance in ccRCC.

Bioinformatics-Guided Discovery of miRNAs Involved in Apoptosis Modulated by Parthenolide Combined with Vincristine in The NALM6 Cell Line.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is a highly heterogeneous leukemia. Despite the current improvement in conventional chemotherapy and high survival rates, the outcomes remain challenging. Sesquiterpen extracted from the Tanacetum parthenium, parthenolide, is a potential anticancer agent that can modulate the expression of miRNAs and induce apoptosis. The objective of this study was to investigate the effect of parthenolide in combination with vincristine and alone on the apoptosis rate and expression of miR-125b-5p, miR-181b-5p, and miR-17-5p in the NALM6 cell line. MATERIALS AND METHODS: In this experimental study, cell viability and metabolic activity were determined through MTT assay and PI staining. Flow cytometry was applied to evaluate the rate of apoptosis. The expression of miRNAs was assessed using real-time polymerase chain reaction. Bioinformatic analyses, including Cytoscape, RNAhybrid, and signaling pathway analysis were employed to investigate the association of miR-17-5p, miR-181b-5p and miR-125b- 5p with apoptosis. Further, molecular docking served to validate the modulation of these miRNAs by parthenolide and vincristine treatment. RESULTS: The MTT assay indicated that 7.7 µM of parthenolide decreased the metabolic activity to 50% after 48 hours. PI staining analysis indicated that at concentrations below the half maximal inhibitory concentration, parthenolide caused 50% cell death. Flow cytometric analysis indicated that parthenolide (1.925 µM) in combination with vincristine (1.2 nM) induced apoptosis in 83.2% of the cells. Real-time quantitative reverse transcription polymerase chain reaction (qRTPCR) analysis showed significant changes in the expression levels of miR-17-5p, miR-125b-5p, and miR-181b-5p. Moreover, the combination therapy downregulated the expression of miRNAs significantly. This was consistent with our bioinformatic analysis demonstrating that the studied miRNAs are regulators of apoptosis. Finally, molecular docking validated the modulation of the miRNAs by parthenolide and vincristine. CONCLUSION: Parthenolide in combination with vincristine triggers apoptosis at a high rate in the NALM6 cell line. Moreover, this combination therapy can decrease the expression of miR-17-5p, miR-181b-5p, and miR-125b-5p.

Immunoinformatics Approach to Design a Chimeric CD70-Peptide Vaccine against Renal Cell Carcinoma.

Renal cell carcinoma (RCC) accounts for the majority of cancer-related deaths worldwide. Overexpression of CD70 has been linked to advanced stages of RCC. Therefore, this study aims to develop a multiepitope vaccine targeting the overexpressed CD70 using immunoinformatics techniques. In this investigation, in silico multiepitope vaccines were constructed by linking specific CD70 protein epitopes for helper T lymphocytes and CD8+ T lymphocytes. To enhance immunogenicity, sequences of cell-penetrating peptide (CPP), penetratin (pAntp), along with the entire sequence of tumor necrosis factor-α (TNF-α), were attached to the N-terminal and C-terminal of the CD70 epitopes. Computational assessments were performed on these chimeric vaccines for antigenicity, allergenicity, peptide toxicity, population coverage, and physicochemical properties. Furthermore, refined 3D constructs were subjected to a range of analyses, encompassing structural B-cell epitope prediction and molecular docking. The chosen vaccine construct underwent diverse assessments such as molecular dynamics simulation, immune response simulation, and in silico cloning. All vaccines comprised antigenic, nontoxic, and nonallergenic epitopes, ensuring extensive global population coverage. The vaccine constructs demonstrated favorable physicochemical characteristics. The binding affinity of chimeric vaccines to the TNF receptor remained relatively stable, influenced by the alignment of vaccine components. Molecular docking and dynamics analyses predicted stable interactions between CD70-CPP-TNF and the TNF receptor, indicating potential efficacy. In silico codon optimization and cloning of the vaccine nucleic acid sequence were accomplished using the pET28a plasmid. Furthermore, this vaccine displayed the capacity to modulate humoral and cellular immune responses. Overall, the results suggest therapeutic potential for the chimeric CD70-CPP-TNF vaccine against RCC. However, validation through in vitro and in vivo experiments is necessary. This trial is registered with NCT04696731 and NCT04046445.

Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth.

The incidence of nonalcoholic fatty liver disease (NAFLD) is on the rise, mirroring a global surge in diabetes and metabolic syndrome, as its major leading causes. NAFLD represents a spectrum of liver disorders, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Mechanistically, we know the unfolded protein response (UPR) as a protective cellular mechanism, being triggered under circumstances of endoplasmic reticulum (ER) stress. The hepatic UPR is turned on in a broad spectrum of liver diseases, including NAFLD. Recent data also defines molecular mechanisms that may underlie the existing correlation between UPR activation and NAFLD. More interestingly, subsequent studies have demonstrated an additional mechanism, i.e. autophagy, to be involved in hepatic steatosis, and thus NAFLD pathogenesis, principally by regulating the insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. All these findings suggest possible mechanistic roles for autophagy in the progression of NAFLD and its complications. Both UPR and autophagy are dynamic and interconnected fluxes that act as protective responses to minimize the harmful effects of hepatic lipid accumulation, as well as the ER stress during NAFLD. The functions of UPR and autophagy in the liver, together with findings of decreased hepatic autophagy in correlation with conditions that predispose to NAFLD, such as obesity and aging, suggest that autophagy and UPR, alone or combined, may be novel therapeutic targets against the disease. In this review, we discuss the current evidence on the interplay between autophagy and the UPR in connection to the NAFLD pathogenesis.

Targeting apoptosis and unfolded protein response: the impact of ß-hydroxybutyrate in clear cell renal cell carcinoma under glucose-deprived conditions.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) plays a significant role in the mortality associated with kidney cancer. Targeting biological processes that inhibit cancer growth opens up new treatment possibilities. The unfolded protein response (UPR) and apoptosis have crucial roles in RCC progression. This study investigates the impact of ß-hydroxybutyrate (BHB) on ccRCC cells under glucose deprivation resembling as a ketogenic diet. METHOD: Caki-1 ccRCC cells were exposed to decreasing glucose concentrations alone or in combination with 10 or 25 mM BHB during 48 and 72 h. Cell viability was determined using MTT assay. The mRNA expression level of apoptosis-and UPR-related markers (Bcl-2, Bax, caspase 3, XBP1s, BIP, CHOP, ATF4, and ATF6) were assayed by qRT-PCR. RESULTS: Cell viability experiments demonstrated that combining different doses of BHB with decreasing glucose levels initially improved cell viability after 48 h. Nevertheless, this trend reversed after 72 h, with higher impacts disclosed at 25 mM BHB. Apoptosis was induced in BHB-treated cells as caspase-3 and Bax were increased and Bcl-2 was downregulated. BHB supplementation reduced UPR-related gene expression (XBP1s, BIP, CHOP, ATF4, and ATF6), revealing a possible mechanism by which BHB affects cell survival. CONCLUSION: This research emphasizes the dual effect of BHB, initially suppressing cell- survival under glucose deprivation but eventually triggering apoptosis and suppressing UPR signaling. These data highlight the intricate connection between metabolic reprogramming and cellular stress response in ccRCC. Further research is recommended to explore the potential of BHB as a therapeutic strategy for managing ccRCC.

Increasing the tolerance of mothers with children with autism: the effectiveness of cognitive therapy based on mindfulness - experimental research.

Introduction and importance: Autism spectrum disorder significantly impacts the life and psychosocial health of the family, resulting in high levels of anxiety, stress, isolation, and indecisiveness among parents. This study aimed to determine the effectiveness of cognitive therapy based on mindfulness in increasing the tolerance of mothers of children with autism. Case presentation: The study used a semi-experimental pre-test-post-test design with a control group. The study population comprised mothers referred to autism centers in Tehran. Eighty mothers were randomly divided into two groups, with 40 in each group. The Connor and Davidson Resilience Scale was used to measure the level of tolerance in both groups in the pre-test and post-test stages. The experimental group underwent cognitive therapy group therapy based on mindfulness, comprising eight sessions of 120 min. On the other hand, the control group did not receive any intervention. Clinical discussion: The results of the study showed that the tolerance scores of the experimental group significantly increased after the intervention, in both the post-test and follow-up stages. Conclusion: Therefore, the results of this research emphasize the importance of using this intervention in increasing the tolerance of mothers of children with autism spectrum disorder and creating new horizons in the clinical interventions of these people.

Adipose triglyceride lipase gene expression in peripheral blood mononuclear cells of subjects with obesity and its association with insulin resistance, inflammation and lipid accumulation in liver.

Introduction: Adipose triglyceride lipase (ATGL) is a crucial enzyme responsible for the release of fatty acids from various tissues. The expression of ATGL is regulated by insulin and this enzyme is linked to Insulin resistance (IR). On the other hand, ATGL-mediated lipolysis is connected to macrophage function and thus, ATGL is involved in inflammation and the pathogenesis of lipid-related disorders. This study aimed to investigate the correlation between ATGL, obesity, Metabolic Syndrome (MetS), and inflammation. Methods: A total of 100 participants, including 50 individuals with obesity and 50 healthy participants, were recruited for this study and underwent comprehensive clinical evaluations. Blood samples were collected to measure plasma lipid profiles, glycemic indices, and liver function tests. Additionally, peripheral blood mononuclear cells (PBMCs) were isolated and used for the assessment of the gene expression of ATGL, using real-time PCR. Furthermore, PBMCs were cultured and exposed to lipopolysaccharides (LPS) with simultaneous ATGL inhibition, and the gene expression of inflammatory cytokines, along with the secretion of prostaglandin E2 (PGE2), were measured. Results: The gene expression of ATGL was significantly elevated in PBMCs obtained from participants with obesity and was particularly higher in those diagnosed with MetS. It exhibited a correlation with insulin levels and Homeostatic Model Assessment for IR (HOMA-IR), and it was associated with lipid accumulation in the liver. Stimulation with LPS increased ATGL expression in PBMCs, while inhibition of ATGL attenuated the inflammatory responses induced by LPS. Conclusions: Obesity and MetS were associated with dysregulation of ATGL. ATGL might play a role in the upregulation of inflammatory cytokines and act as a significant contributor to the development of metabolic abnormalities related to obesity.

A Review of the Potential Role of CoQ10 in the Treatment of Hepatocellular Carcinoma.

The coenzyme ubiquinone-10 (CoQ10) is not only an important part of the electron transport chain of the mitochondrial inner membrane but also has complex biological functions beyond mitochondrial respiration. It is a natural nutrient that is not only produced by the body but is also found in foods, such as meat, eggs, fish, and vegetable oils. Because some types of cancer reduce CoQ10 blood levels, the use of CoQ10 supplements is recommended for the treatment of cancer patients. The anti-cancer effects of CoQ10 supplementation have been reported in several cancers, including colon and breast cancer. CoQ10 scavenges free radicals to reduce oxidative stress and minimize tissue damage. CoQ10 protects the body from damage caused by chemotherapy drugs by reducing the production of inflammatory cytokines and other inflammatory factors. Recent studies suggest that CoQ10 may be a supplement to pharmacotherapy for hepatocellular carcinoma. This article examines the effects of CoQ10 in hepatocellular carcinoma.

Fighting against amyotrophic lateral sclerosis (ALS) with flavonoids: a computational approach to inhibit superoxide dismutase (SOD1) mutant aggregation.

Protein aggregation is a biological process that occurs when proteins misfold. Misfolding and aggregation of human superoxide dismutase (hSOD1) cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS). Among the mutations occurring, targeting the E21K mutation could be a good choice to understand the pathological mechanism of SOD1 in ALS, whereof it significantly reduces life hopefulness in patients. Naturally occurring polyphenolic flavonoids have been suggested as a way to alleviate the amyloidogenic behavior of proteins. In this study, computational tools were used to identify promising flavonoid compounds that effectively inhibit the pathogenic behavior of the E21K mutant. Initial screening identified Pelargonidin, Curcumin, and Silybin as promising leads. Molecular dynamics (MD) simulations showed that the binding of flavonoids to the mutated SOD1 caused changes in the protein stability, hydrophobicity, flexibility, and restoration of lost hydrogen bonds. Secondary structure analysis indicated that the protein destabilization and the increased propensity of ß-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Free energy landscape (FEL) analysis was also used to differentiate aggregation, and results showed that Silybin followed by Pelargonidin had the most therapeutic efficacy against the E21K mutant SOD1. Therefore, these flavonoids hold great potential as highly effective inhibitors in mitigating ALS's fatal and insuperable effects.Communicated by Ramaswamy H. Sarma.

Evaluating the incidence of ampC-ß-lactamase genes, biofilm formation, and antibiotic resistance among hypervirulent and classical Klebsiella pneumoniae strains.

AIM: Both immunocompetent and healthy individuals can become life-threateningly ill when exposed to the hypervirulent (hvKp) strains of Klebsiella pneumoniae (Kp). The main objectives of this study were to evaluate the presence of ampC-lactamase genes, biofilm formation, and antibiotic resistance in clinical strains of hvKp and cKp (classical K. pneumoniae). MATERIALS AND METHODS: Kp strains were collected from patients referred to Shahidzadeh Hospital in Behbahan City, Khuzestan Province, Iran. Several techniques were used to identify hvKp. The hypermucoviscosity phenotype was determined using the string test. Isolates that developed dark colonies on tellurite agar were assumed to be hvKp strains. If any of the iucA, iutA, or peg-344 genes were detected, the isolates were classified as hvKp. Phenotypic and genotypic detection of AmpC ß-lactamases of hvKp strains was performed by the combined disk method and polymerase chain reaction, respectively. In addition, crystal violet staining was used to determine the biofilm formation of these isolates. RESULTS: For this study, 76 non-duplicative isolates of Kp were collected. Overall, 22 (28.94%) strains had positive string test results, and 31 (40.78%) isolates were grown in tellurite-containing medium. The genes iucA and iutA or peg-344 were found in 23.68% of all Kp strains and in 50% of tellurite-resistant isolates, respectively. The most effective antibiotics against hvKp isolates were tetracycline (85.52%) and chloramphenicol (63.15%). Using the cefoxitin disc diffusion method, we observed that 56.57% (43/76) of the strains were AmpC producer. A total of 30.26% (n = 23/76) of the isolates tested positive for at least one ampC gene, including blaDHA (52.63%, n = 40), blaCIT (40.78%, n = 31), blaACC (19.76%, n = 15), blaMOX (25%, n = 19), and blaFOX (43.42%, n = 33). Biofilm formation analysis revealed that most hvKp isolates were weak (n = 6, 40%) and moderate (n = 5, 33.33%) biofilm producers. CONCLUSION: Healthcare practitioners should consider the possibility of the existence and acquisition of hvKp everywhere. The exact mechanisms of bacterial acquisition are also unknown, and it is unclear whether the occurrence of infections is related to healthcare or not. Thus, there are still many questions about hvKp that need to be investigated.

Assessment of global histone acetylation in pediatric and adolescent obesity: Correlations with SIRT1 expression and metabolic-inflammatory profiles.

BACKGROUND: Epigenetic modifications, particularly histone acetylation-deacetylation and its related enzymes, such as sirtuin 1 (SIRT1) deacetylase, may have substantial roles in the pathogenesis of obesity and its associated health issues. This study aimed to evaluate global histone acetylation status and SIRT1 gene expression in children and adolescents with obesity and their association with metabolic and anthropometric parameters. METHODS: This study included 60 children and adolescents, 30 with obesity and 30 normal-weight. The evaluation consisted of the analysis of global histone acetylation levels and the expression of the SIRT1 gene in peripheral blood mononuclear cells, by specific antibody and real-time PCR, respectively. Additionally, insulin, fasting plasma glucose, lipid profile and tumor necrosis factor α (TNF-α) levels were measured. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Metabolic syndrome was determined based on the diagnostic criteria established by IDF. RESULTS: Individuals with obesity, particularly those with insulin resistance, had significantly higher histone acetylation levels compared to control group. Histone acetylation was positively correlated with obesity indices, TNF-α, insulin, and HOMA-IR. Additionally, a significant decrease in SIRT1 gene expression was found among obese individuals, which was negatively correlated with the histone acetylation level. Furthermore, SIRT1 expression levels showed a negative correlation with various anthropometric and metabolic parameters. CONCLUSION: Histone acetylation was enhanced in children and adolescents with obesity, potentially resulting from down-regulation of SIRT1, and could play a role in the obesity-associated metabolic abnormalities and insulin resistance. Targeting global histone acetylation modulation might be considered as an epigenetic approach for early obesity management.

Characterization of the Human Blood Virome in Iranian Multiple Transfused Patients.

Blood transfusion safety is an essential element of public health. Current blood screening strategies rely on targeted techniques that could miss unknown or unexpected pathogens. Recent studies have demonstrated the presence of a viral community (virobiota/virome) in the blood of healthy individuals. Here, we characterized the blood virome in patients frequently exposed to blood transfusion by using Illumina metagenomic sequencing. The virome of these patients was compared to viruses present in healthy blood donors. A total number of 155 beta-thalassemia, 149 hemodialysis, and 100 healthy blood donors were pooled with five samples per pool. Members of the Anelloviridae and Flaviviridae family were most frequently observed. Interestingly, samples of healthy blood donors harbored traces of potentially pathogenic viruses, including adeno-, rota-, and Merkel cell polyomavirus. Viruses of the Anelloviridae family were most abundant in the blood of hemodialysis patients and displayed a higher anellovirus richness. Pegiviruses (Flaviviridae) were only observed in patient populations. An overall trend of higher eukaryotic read abundance in both patient groups was observed. This might be associated with increased exposure through blood transfusion. Overall, the findings in this study demonstrated the presence of various viruses in the blood of Iranian multiple-transfused patients and healthy blood donors.

Status of Crimean-Congo haemorrhagic fever virus in ticks in Iran: A systematic review with meta-analysis.

Crimean-Congo haemorrhagic fever (CCHF) is a re-emerging viral haemorrhagic fever causing outbreaks in Iran in the last 15 years. In this systematic review and meta-analysis, the status of Crimean-Congo haemorrhagic fever virus (CCHFV) in ticks would be evaluated. PubMed, Google Scholar and Web of Science were searched for peer-reviewed original papers published between 2000 and 1 July 2022. We included papers that evaluated the prevalence of CCHFV in individual ticks using reverse transcription polymerase chain reaction (RT-PCR). The pooled prevalence of CCHFV was 6.0% (95% confidence interval [CI]: 4.5-7.9%), with heterogeneity (I2 = 82.706; P < 0.0001). The prevalence of CCHFV was higher related to regions with above sea level of 1001-1500m (6.4%; 95% CI: 4.3-9.5%), an average temperature of ≤15 °C (8.3%; 95% CI: 5.6-12.0%), latitude of ≥36° (8.1%; 95% CI: 5.2-12.3%), an annual rainfall of 101-300 mm (9.8%; 95% CI: 6.1-15.4%) and humidity of ≥61% (10.2%; 95% CI: 5.1-19.3%). Due to the importance of CCHF, it is better to do new epidemiologic studies on ticks by related organizations and adjacent regions of some provinces in which human cases have been previously reported.