Dulaglutide rescues the elevated testicular dysfunction in a mouse model of high-fat diet-induced obesity.

Obesity is a well-known risk factor for testicular function; however, dulaglutide's effect on the testis in obesity has received little attention. Currently, clinicians prescribe the antidiabetic drug dulaglutide only off-label for weight management in non-diabetics. Investigating the impact of this novel compound on obesity is critical for determining whether it has any disruptive effects on testicular cells. We used a well-known animal model of high-fat diet-induced obesity in this investigation, and testicular dysfunction was determined by sperm DNA damage, spermatocyte chromosomal abnormalities, and spermiogram analysis. Following a 12-week high-fat diet challenge, mice were randomly assigned to dulaglutide (0.6 mg/kg/day) or saline treatments for five weeks. Testes and sperm cells were collected 24 h after the last dulaglutide injection. Untreated obese mice had a lower testes/body weight ratio, more sperm DNA damage, diakinesis-metaphase I chromosomal abnormalities, a lower sperm count/motility, more cell morphological defects, and an altered testicular redox balance. In obese mice, dulaglutide injection efficiently restored all disturbed parameters to their control levels. Dulaglutide injection into healthy mice exhibited no significant harmful effects at the applied regimen. As a result, we infer that dulaglutide therapy might bring obese men additional benefits by recovering testicular dysfunction induced by obesity.

Heavy metals accumulation in the meat, kidney and liver of cattle, broilers and goats sold in Quetta, northwestern city of Balochistan, Pakistan.

1. It was assumed that the concentrations of arsenic (As), chromium (Cr), cobalt (Co), lead (Pb), manganese (Mn) and mercury (Hg) in the meat, kidney and liver of cattle, broilers and goats within Quetta city potentially exceeded the permissible limits for heavy metal content. Risk assessment of these heavy metals on human health were estimated based on daily intake (EDI), target hazard quotient (THQ) and hazard index (HI).2. Samples of the meat, liver and kidney of cattle, broilers and goats were collected from butcher shops and slaughterhouses in 20 different areas of Quetta city. Overall, 180 samples were analysed, each for six heavy metals. After acid digestion of meat samples, heavy metals analysis was carried out via atomic absorption spectroscopy.3. The results varied in levels depending upon the species and organ type. The average concentrations of As, Pb and Hg were within the established reference limits of the Australia New Zealand Food Authority (ANZFA 2015) and the European Commission (EC, 2006), although some samples exceeded these limits. Compared with the kidney and meat, the liver was the primary tissue for Cr, Pb and Hg bioaccumulation. Metals concentration were mostly within the normal range in samples from cattle and goats, while the Mn concentration was elevated in broilers.4. The estimated daily intake (EDI) revealed that the intake of As, Co, Pb and Hg was mainly derived from goat and cattle products, whereas broiler samples were more contaminated with Cr and Mn. The EDIs of Cr and Hg in adults exceeded the oral reference dose, referring to potential adverse effects. The EDIs for Co and Mn were low, suggesting that additional intake sources were necessary. Except for As, none of the determined elements had a target hazard quotient (THQ) above 1.

Semaglutide ameliorated autism-like behaviors and DNA repair efficiency in male BTBR mice by recovering DNA repair gene expression.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.

Dulaglutide reduces oxidative DNA damage and hypermethylation in the somatic cells of mice fed a high-energy diet by restoring redox balance, inflammatory responses, and DNA repair gene expressions.

Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide's expediency in treating obesity and its associated complications.

Aflatoxin B1 exposure deteriorates immune abnormalities in a BTBR T+ Itpr3tf/J mouse model of autism by increasing inflammatory mediators' production in CD19-expressing cells.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficiencies in communication, repetitive and stereotyped behavioral patterns, and difficulties in reciprocal social engagement. The presence of immunological dysfunction in ASD has been well established. Aflatoxin B1 (AFB1) is a prevalent mycotoxin found in food and feed, causing immune toxicity and hepatotoxicity. AFB1 is significantly elevated in several regions around the globe. Existing research indicates that prolonged exposure to AFB1 results in neurological problems. The BTBR T+ Itpr3tf/J (BTBR) mice, which were used as an autism model, exhibit the primary behavioral traits that define ASD, such as repeated, stereotyped behaviors and impaired social interactions. The main objective of this work was to assess the toxic impact of AFB1 in BTBR mice. This work aimed to examine the effects of AFB1 on the expression of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 by CD19+ B cells in the spleen of the BTBR using flow cytometry. We also verified the impact of AFB1 exposure on the mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain of BTBR mice using real-time PCR. The findings of our study showed that the mice treated with AFB1 in the BTBR group exhibited a substantial increase in the presence of CD19+Notch-1+, CD19+IL-6+, CD19+MCP-1+, CD19+iNOS+, CD19+GM-CSF+, and CD19+NF-κB p65+ compared to the mice in the BTBR group that were treated with saline. Our findings also confirmed that administering AFB1 to BTBR mice leads to elevated mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain, in comparison to BTBR mice treated with saline. The data highlight that exposure to AFB1 worsens immunological abnormalities by increasing the expression of inflammatory mediators in BTBR mice.

Navigating board dynamics: Configuration analysis of corporate governance's factors and their impact on bank performance.

This research utilizes the fsQCA technique to investigate how a combination of corporate governance conditions or factors collectively influences the performance of banks. Examining key elements such as board size, busy directors, independent directors, CEO duality, and women on the board, the research employs data collected from the annual reports of 30 banks spanning from 2010 to 2020. The necessary condition analysis (NCA) underscores that no individual condition or factor is indispensable for the ultimate outcome. Nevertheless, the sufficiency analysis reveals distinct solutions, each representing a unique set of conditions or factors sufficient to generate the outcome. The study concludes that the relationship between corporate governance characteristics and bank performance is complex and multifaceted, with neither ROA nor ROE reliant on a singular input condition or factor. The theoretical contributions of the findings align with or partially support various theories and propositions within the realm of corporate governance. Notably, the application of fsQCA contributes to enhance the methodological understanding of corporate governance studies in existing literature.

Beyond regression: Unpacking research of human complex systems with qualitative comparative analysis.

This study underscores the effectiveness of Qualitative Comparative Analysis (QCA) when compared to conventional regression analysis (CRA) in the investigation of complex human systems. Utilizing historical secondary cross-national data from Lipset & Man (1960) spanning 18 countries, where CRA may be impractical, the research emphasizes the superior performance of QCA, specifically utilizing both crisp set QCA and fuzzy set QCA. The dataset includes variables such as democracy survival and its precursors, such as gross national product per capita, urbanization, literacy rate, and industrial labor force. In contrast to conventional regression results indicating an insignificant relationship between democracy survival and its antecedents, crisp set QCA identifies two distinct combinations of antecedents associated with high levels of democracy survival, albeit with limited solution coverage. Meanwhile, fuzzy set qualitative comparative analysis (fsQCA) reveals five combinations of antecedents linked to robust democracy survival, providing adequate solution coverage and consistency. These findings suggest that fsQCA excels in capturing the intricacies of real-life scenarios in human complex systems, offering more robust empirical solutions compared to crisp set QCA and conventional regression. As a result, researchers may find value in integrating fsQCA into their new projects focused on human complex systems.

Dapagliflozin suppresses diabetes-induced oxidative DNA damage and hypermethylation in mouse somatic cells.

Diabetes mellitus is a complex metabolic disorder resulting from the interplay of environmental, genetic, and epigenetic factors that increase the risk of cancer development. However, it is unclear whether the increased cancer risk is due to poor glycemic control or the use of some antidiabetic medications. Therefore, we investigated the genetic and epigenetic changes in somatic cells in a mouse model of diabetes and studied whether multiple exposures to the antidiabetic medication dapagliflozin influence these changes. We also elucidated the mechanism(s) of these ameliorations. The micronucleus test and modified comet assay were used to investigate bone marrow DNA damage and methylation changes. These assays revealed that dapagliflozin is non-genotoxic in the tested regimen, and oxidative DNA damage and hypermethylation were significantly higher in diabetic mice. Spectrophotometry also evaluated oxidative DNA damage and global DNA methylation, revealing similar significant alterations induced by diabetes. Conversely, the dapagliflozin-treated diabetic animals significantly reduced these changes. The expression of some genes involved in DNA repair and DNA methylation was disrupted considerably in the somatic cells of diabetic animals. In contrast, dapagliflozin treatment significantly restored these disruptions and enhanced DNA repair. The simultaneous effects of decreased oxidative DNA damage and hypermethylation levels suggest that dapagliflozin can be used as a safe antidiabetic drug to reduce DNA damage and hypermethylation in diabetes, demonstrating its usefulness in patients with diabetes to control hyperglycemia and decrease the development of its subsequent complications.

Aflatoxin B1 exposure exacerbates chemokine receptor expression in the BTBR T+ Itpr3tf/J Mouse Model, unveiling insights into autism spectrum disorder: A focus on brain and spleen.

OBJECTIVE: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant difficulties in social interaction, communication, and repeated stereotypic behaviour. Aflatoxin B1 (AFB1) is the most potent and well-known mycotoxin in various food sources. Despite its propensity to generate significant biochemical and structural changes in human and animal tissues, the influence of AFB1 on ASD has yet to be thoroughly studied. Mounting evidence indicates that chemokine receptors play a crucial function in the central nervous system and are implicated in developing several neuroinflammatory disorders. Chemokine receptors in individuals with ASD were elevated in the anterior cingulate gyrus astrocytes, cerebellum, and brain. METHODS: The BTBR T+Itpr3tf/J (BTBR) mice are inbred strains that exhibit strong and consistently observed deficits in social interactions, characterized by excessive self-grooming and limited vocalization in social contexts. We examined the impact of AFB1 on CCR3-, CCR7-, CCR9-, CXCR3-, CXCR4-, and CXCR6-expressing I-A/I-E+ cells in the spleen of the BTBR mouse model of autism. We evaluated the mRNA levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 chemokine receptors in the brain. RESULTS: The exposure to AFB1 in BTBR mice resulted in a significant rise in the number of I-A/I-E+CCR3+, I-A/I-E+CCR7+, I-A/I-E+CCR9+, I-A/I-E+CXCR3+, I-A/I-E+CXCR4+, and I-A/I-E+CXCR6+ cells. Furthermore, exposure to AFB1 increased mRNA expression levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 in the brain. CONCLUSIONS: These findings highlight that AFB1 exposure increases the expression of chemokine receptors in BTBR mice, indicating the necessity for further research into AFB1's role in the development of ASD.

Network pharmacology and experimental insights into STAT3 inhibition by novel isoxazole derivatives of piperic acid in triple negative breast cancer.

STAT3 is a crucial member within a family of seven essential transcription factors. Elevated STAT3 levels have been identified in various cancer types, notably in breast cancer (BC). Consequently, inhibiting STAT3 is recognized as a promising and effective strategy for therapeutic intervention against breast cancer. We herein synthesize a library of isoxazole (PAIs) from piperic acid [2E, 4E)-5-(2H-1,3-Benzodioxol-5-yl) penta-2,4-dienoic acid] on treatment with propargyl bromide followed by oxime under prescribed reaction conditions. Piperic acid was obtained by hydrolysis of piperine extracted from Piper nigrum. First, we checked the binding potential of isoxazole derivatives with breast cancer target proteins by network pharmacology, molecular docking, molecular dynamic (MD) simulation and cytotoxicity analysis as potential anti-breast cancer (BC) agents. The multi-source databases were used to identify possible targets for isoxazole derivatives. A network of protein-protein interactions (PPIs) was generated by obtaining 877 target genes that overlapped gene symbols associated with isoxazole derivatives and BC. Molecular docking and MD modelling demonstrated a strong affinity between isoxazole derivatives and essential target genes. Further, the cell viability studies of isoxazole derivatives on the human breast carcinoma cell lines showed toxicity in all breast cancer cell lines. In summary, our study indicated that the isoxazole derivative showed the significant anticancer activity. The results highlight the prospective utility of isoxazole derivatives as new drug candidates for anticancer chemotherapy, suggesting route for the continued exploration and development of drugs suitable for clinical applications.

Synthesis, biological profile and computational insights of new derivatives of benzo [B][1,4] diazepines as prospective anticancer agents for inhibiting the CDK-2 protein.

In the current work, a new series of benzo[b][1, 4] diazepines (A-1 to C-4) was synthesized and screened against three different human cancer cell lines, HepG2 (hepatocellular carcinoma), HeLa (cervical cancer) and MCF-7 (breast cancer), by employing MTT (MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The outcomes of in vitro screening revealed that all the compounds exhibited momentous anticancer activity, most notably against the MCF-7 cell line by B1-4 compounds. Further, network pharmacology, UALCAN analysis, molecular docking, molecular dynamics (MD) simulations and density functional theory calculations were conducted to explore expression analysis, pharmacokinetics, toxicity profiles and binding interactions of the B1-4 compounds. By UALCAN, we explored the expression analysis of CDK-2 in 19 cancers. Through UALCAN, Pan-cancer analysis revealed that the expression of CDK-2 in 19 cancers was statistically significant. Among the 19 cancers, the CDK-2 expression was significantly upregulated in breast cancer (BRCA), cervical cancer (CESC) and lung carcinoma (LUSC) than normal tissues. Enzyme-docking examination revealed that B1-4 compounds exhibited significant binding affinity against the CDK-2 (PDB ID: 5IEV) drug target protein. Furthermore, MD simulations supported the docking results, which confirmed that the ligand + protein complex was in a stable conformation throughout the simulation time of 100 nanoseconds. Therefore, the present study demonstrates the potential of these benzo [b][1,4] diazepines as promising drug candidates against cancer.Communicated by Ramaswamy H. Sarma.

A new series of benzodiazepine molecules were designed and synthesized as CDK-2 inhibitors.In vitro anticancer potential against HepG2, HeLa and MCF-7 cancer cells were assessed.Network pharmacology; expression analysis; in silico docking; molecular dynamics simulation; molecular mechanics­generalized Born and surface area; and absorption, distribution, metabolism, excretion and toxicity studies were carried out.This study overall revealed the anticancer activity of benzodiazepines by integrating network pharmacology, molecular modeling and in vitro experiments.

Oral glutamine: Is there a role in the amelioration of radiation-induced mucositis? A prospective case-control study at a tertiary care centre in North India.

BACKGROUND: The most frequently occurring painful and dose-limiting side effect of radiation therapy (RT) to the head and neck region is oral mucositis (OM). Several studies demonstrated that glutamine may reduce the severity and the duration of OM significantly during RT and chemo-radiotherapy in patients with head and neck cancer (HNC). MATERIALS AND METHODS: Between January 2021 and August 2022, a prospective single institutional case-control study compared the efficacy and safety of oral glutamine on radiation-induced mucositis in patients with HNC. Of 60 biopsy-proven patients with HNC, 30 patients in the study arm received oral glutamine suspension (10 g in 500 mL of water) orally once daily, 2 hours before RT, receiving definitive or adjuvant RT and chemo-radiotherapy, while as 30 patients in the control arm received placebo with the same dose and schedule (n = 30 in the study arm and n = 30 in the control arm). RESULTS AND ANALYSIS: A total of 27 (90%) in the glutamine arm and 28 (93.33%) patients in the control arm developed mucositis. Grade 3 mucositis (13.33%) and Grade 4 mucositis (6.66%), respectively, were significantly less ( P = .040 and P = .004) in the glutamine arm. The mean duration of grade 3 and grade 4 mucositis was significantly less in the glutamine arm (8.94 days in the study arm vs. 14.54 in the control arm; P = .0001). The mean time of onset of OM was significantly delayed in the glutamine arm in comparison to the control arm with P < .001. CONCLUSION: Glutamine delays the onset of OM and decreases the severity of OM in patients of HNC receiving RT with or without chemotherapy.

Optimizing the fabrication of electrospun nanofibers of prochlorperazine for enhanced dissolution and permeation properties.

Despite being an approved antiemetic for more than five decades, the clinical usefulness of prochlorperazine is limited by its low solubility and inconsistent absorption in the gastrointestinal tract, which presents challenges for nanotherapeutic interventions. Here, we report the preparation of a highly soluble and permeable nanofiber formulation of prochlorperazine using the Quality-by-Design approach. The final nanofiber formulation with drug entrapment of 88.02 ± 1.14 % was obtained at 20.0 kV, with a flow rate of 0.5 ml/h and tip-to-collector distance of 19.9 cm. Physio-mechanical properties, such as thickness (0.42 ± 0.02 mm), pH resistance (7.04 ± 0.08), folding endurance (54 ± 5), and tensile strength (0.244 ± 0.02 N.mm-2), were appropriate for packaging and application to oromucosal surfaces. The content uniformity (93.48-106.63 %) and weight variation (<1.8 mg) of the optimal nanofiber formulation were within the permissible limits prescribed for orodispersible films. Microscopical investigations confirm a randomly deposited and dense network of woven nanofibers with an average diameter of 363 ± 5.66 nm. The drug particles were embedded homogeneously on the fiber in the nanoform (4.27 ± 1.34 nm). The spectral analysis using TEM-EDS shows diffraction peaks of sulfur and chlorine, the elemental constituents of prochlorperazine. The drug was amorphized in the nanofiber formulation, as led by the decline of the crystallinity index from 87.25 % to 7.93 % due to electrostatic destabilization and flash evaporation of the solvent. The enthalpy of fusion values of the drug in the nanofiber mat decreased significantly to 23.6 J/g compared to its pristine form, which exhibits a value of 260.7 J/g. The nanofibers were biocompatible with oral mucosal cells, and there were no signs of mucosal irritation compared to 1 % sodium lauryl sulfate. The fiber mats rapidly disintegrated within <1 s and released ≈91.49 ± 2.1 % of the drug within 2 min, almost 2-fold compared to the commercial Stemetil MD® tablets. Similarly, the cumulative amount of the drug permeated across the unit area of the oromucosal membrane was remarkably high (31.28 ± 1.30 µg) compared to 10.17 ± 1.11 µg and 13.10 ± 1.79 µg from the cast film and drug suspension. Our results revealed these nanofiber formulations have the potential to be fast-dissolving oromucosal delivery systems, which can result in enhanced bioavailability with an early onset of action due to rapid disintegration, dissolution, and permeation.

GSK3ß phosphorylates Six1 transcription factor and regulates its APC/CCdh1 mediated proteosomal degradation.

Sine oculis homeobox homolog 1 (Six1) is a developmentally important transcription factor that regulates cellular proliferation, apoptosis, and dissemination during embryogenesis. Six1 overexpression as reported in multiple cancers modulates expression of a repertoire of its target genes causing an increase in proliferation, metastasis and survival of cancer cells. Six1 exists as a cell cycle regulated nuclear phosphoprotein and its cellular turnover is regulated by APC/C (Anaphase promoting complex / Cyclosome) complex mediated proteolysis. However, the kinases that regulate Six1 proteolysis have not been identified and the mechanistic details that cause its overproduction in various cancers are lacking. Here, we report that Six1 is a physiological GSK3ß substrate. GSK3ß interacts with Six1 and phosphorylates it at Ser221 within the conserved consensus sequence in its carboxy terminus. Using pharmacological inhibition, siRNA mediated knockdown and protein overexpression of GSK3ß; we show that GSK3ß regulates Six1 protein stability. Pulse chase analysis of Six1 revealed that GSK3ß regulates its ubiquitin proteolysis such that Six1 phosphomimicking mutant (Six1S221E) for Ser221 site had dramatically increased half-life than its phosphodeficient (Six1S221A) and wild type variants. Furthermore, we demonstrate that GSK3ß rescues Six1 from APC dependent proteolysis by regulating its binding with APC/C co-activator protein Cdh1. Importantly, strong positive correlation exists between GSK3ß and Six1 protein levels throughout the cell cycle and in multiple cancers indicating that GSK3ß activation may in part contribute to Six1 overproduction in a subset of human cancers.

Cadmium exposure exacerbates immunological abnormalities in a BTBR T+ Itpr3tf/J autistic mouse model by upregulating inflammatory mediators in CD45R-expressing cells.

Autism spectrum disorder (ASD) is a neurodevelopmental illness characterized by behavior, learning, communication, and social interaction abnormalities in various situations. Individuals with impairments usually exhibit restricted and repetitive actions. The actual cause of ASD is yet unknown. It is believed, however, that a mix of genetic and environmental factors may play a role in its development. Certain metals have been linked to the development of neurological diseases, and the prevalence of ASD has shown a positive association with industrialization. Cadmium chloride (Cd) is a neurotoxic chemical linked to cognitive impairment, tremors, and neurodegenerative diseases. The BTBR T+ Itpr3tf/J (BTBR) inbred mice are generally used as a model for ASD and display a range of autistic phenotypes. We looked at how Cd exposure affected the signaling of inflammatory mediators in CD45R-expressing cells in the BTBR mouse model of ASD. In this study, we looked at how Cd affected the expression of numerous markers in the spleen, including IFN-γ, IL-6, NF-κB p65, GM-CSF, iNOS, MCP-1, and Notch1. Furthermore, we investigated the effect of Cd exposure on the expression levels of numerous mRNA molecules in brain tissue, including IFN-γ, IL-6, NF-κB p65, GM-CSF, iNOS, MCP-1, and Notch1. The RT-PCR technique was used for this analysis. Cd exposure increased the number of CD45R+IFN-γ+, CD45R+IL-6+, CD45R+NF-κB p65+, CD45R+GM-CSF+, CD45R+GM-CSF+, CD45R+iNOS+, and CD45R+Notch1+ cells in the spleen of BTBR mice. Cd treatment also enhanced mRNA expression in brain tissue for IFN-γ, IL-6, NF-κB, GM-CSF, iNOS, MCP-1, and Notch1. In general, Cd increases the signaling of inflammatory mediators in BTBR mice. This study is the first to show that Cd exposure causes immune function dysregulation in the BTBR ASD mouse model. As a result, our study supports the role of Cd exposure in the development of ASD.

Assessment of Blood Lead Level of School Children in 10 Cities of India: A Cross-Sectional Study.

OBJECTIVES: To assess the blood lead level (BLL) of school children in 10 cities of India. METHODS: This multi-centric cross-sectional study enrolled participants from randomly selected schools. Data on demographic details, socioeconomic status (SES) and anthropometric indicators was collected. Samples were collected for assessment of lead level in blood. Inductively coupled plasma-optical emission spectrometry technique was used to assess BLL. RESULTS: From April 2019 through February 2020, 2247 participants were recruited from sixty schools (62.6% government schools) with equal gender distribution. The overall median (interquartile range) BLL was 8.8 (4.8, 16.4) µg/dl. The highest median (interquartile range) BLL was in Manipal 30.6 (23.0, 46.7) and lowest in Dibrugarh 4.8 (3.2, 7.0). Overall, 82.5% of participants had BLL above ≤4 µg/dl. Significant negative correlation was observed between BLL and SES (correlation= -0.24, p <0.001), anthropometric indicators (correlation= -0.11, p <0.001), hemoglobin level (correlation= -0.045, p = 0.03) and multivariate regression model showed association with gender, SES and anthropometric indicators. CONCLUSIONS: BLL are elevated in urban school going children and there is intercity variation. Hence, urgent focus is needed to reduce exposure to lead in India.

Saxagliptin, a selective dipeptidyl peptidase-4 inhibitor, alleviates somatic cell aneugenicity and clastogenicity in diabetic mice.

Diabetes-related complications are becoming increasingly common as the global prevalence of diabetes increases. Diabetes is also linked to a high risk of developing cancer. This raises the question of whether cancer vulnerability is caused by diabetes itself or the use of antidiabetic drugs. Chromosomal instability, a source of genetic modification involving either an altered chromosomal number or structure, is a hallmark of cancer. Saxagliptin has been approved by the FDA for diabetes treatment. However, the detailed in vivo effects of prolonged saxagliptin treatment on chromosomal instability have not yet been reported. In this study, streptozotocin was used to induce diabetes in mice, and both diabetic and non-diabetic mice received saxagliptin for five weeks. Fluorescence in situ hybridization was conducted in combination with a bone marrow micronucleus test for measuring chromosomal instability. Our results indicated that saxagliptin is neither mutagenic nor cytotoxic, under the given treatment regimen. Diabetic mice had a much higher incidence of micronuclei formation, and a centromeric DNA probe was present inside the majority of the induced micronuclei, indicating that most of these were caused by chromosome nondisjunction. Conversely, diabetic mice treated with saxagliptin exhibited a significant decrease in micronuclei induction, which were centromeric-positive and centromeric-negative. Diabetes also causes significant biochemical changes indicative of oxidative stress, such as increased lipid peroxidation and decreased reduced/oxidized glutathione ratio, which was reversed by saxagliptin administration. Overall, saxagliptin, the non-mutagenic antidiabetic drug, maintains chromosomal integrity in diabetes and reduces micronuclei formation by restoring redox imbalance, further indicating its usefulness in diabetic patients.

Dapagliflozin Mitigated Elevated Disomic and Diploid Sperm in a Mouse Model of Diabetes and Recover the Disrupted Ogg1, Parp1, and P53 Gene Expression.

Increases in numerical chromosomal syndromes were observed in children of diabetic mothers. However, the effects of diabetes on male reproduction, specifically numerical chromosomal aberrations (aneuploidy), have not been studied. Furthermore, despite the increasing use of dapagliflozin for diabetes treatment, no data exists on its ability to affect aneuploidy levels in germ cells. Thus, our investigation aimed to evaluate the effects of diabetes on spontaneous sperm aneuploidy and whether treatment with dapagliflozin influences the frequency of aneuploidy in the sperm of an experimental diabetic animal model. Our findings show that dapagliflozin has no aneugenic effects on the meiotic stages of spermatogenesis. In contrast, diabetes raised the frequency of aneuploidy, and dapagliflozin administration decreased the elevated levels of disomic and diploid sperm. The level of oxidative stress was markedly increased in diabetic mice, but were reduced by dapagliflozin treatment. Furthermore, the expression of some of DNA repair genes was disrupted in diabetic animals, whereas dapagliflozin therapy restored these disruptions and significantly enhanced DNA repair. Thus, dapagliflozin may effectively ameliorate diabetes-induced aneugenic effects on male meiosis and treating diabetic patients with dapagliflozin may effectively mitigate the transmission of diabetes-induced chromosomal defects to offspring.

Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice.

Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.

Aflatoxin B1 Exposure Aggravates Neurobehavioral Deficits and Immune Dysfunctions of Th1, Th9, Th17, Th22, and T Regulatory Cell-Related Transcription Factor Signaling in the BTBR T+Itpr3tf/J Mouse Model of Autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, reciprocal social interactions, restricted sociability deficits, and stereotyped behavioral patterns. Environmental factors and genetic susceptibility have been implicated in an increased risk of ASD. Aflatoxin B1 (AFB1) is a typical contaminant of food and feed that causes severe immune dysfunction in humans and animals. Nevertheless, the impact of ASD on behavioral and immunological responses has not been thoroughly examined. To investigate this phenomenon, we subjected BTBR T+Itpr3tf/J (BTBR) mice to AFB1 and evaluated their marble-burying and self-grooming behaviors and their sociability. The exposure to AFB1 resulted in a notable escalation in marble-burying and self-grooming activities while concurrently leading to a decline in social contacts. In addition, we investigated the potential molecular mechanisms that underlie the impact of AFB1 on the production of Th1 (IFN-γ, STAT1, and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A, IL-21, RORγT, and STAT3), Th22 (IL-22, AhR, and TNF-α), and T regulatory (Treg) (IL-10, TGF-ß1, and FoxP3) cells in the spleen. This was achieved using RT-PCR and Western blot analyses to assess mRNA and protein expression in brain tissue. The exposure to AFB1 resulted in a significant upregulation of various immune-related factors, including IFN-γ, STAT1, T-bet, IL-9, IRF4, IL-17A, IL-21, RORγ, STAT3, IL-22, AhR, and TNF-α in BTBR mice. Conversely, the production of IL-10, TGF-ß1, and FoxP3 by CD4+ T cells was observed to be downregulated. Exposure to AFB1 demonstrated a notable rise in Th1/Th9/Th22/Th17 levels and a decrease in mRNA and protein expression of Treg. The results above underscore the significance of AFB1 exposure in intensifying neurobehavioral and immunological abnormalities in BTBR mice, hence indicating the necessity for a more comprehensive investigation into the contribution of AFB1 to the development of ASD.