An Investigation of Coxsackie and Adenovirus Receptor in the Human Pancreatic Beta Cells

Human pancreatic beta cells are susceptible to infection by enteroviruses, especially Coxsackie B viruses, and such infections could contribute to the development of Type 1 diabetes. Enteroviruses gain entry via cell surface receptors, one of which, the Coxsackie and Adenovirus receptor (CAR), is a transmembrane cell adhesion protein which serves as a key entry receptor for Coxsackie B viruses and is thought to be localised mainly within regions where contacts are formed between adjacent cells. CAR exists as at least 5 isoforms and this study has examined their expression profile and distribution in the human pancreas utilising; formalin-fixed paraffin-embedded pancreatic sections from non-diabetic individuals, type 1 diabetes patients and a human tissue microarray. Isolated human islets, human pancreatic beta and ductal cell lines were also studied. Immunological and molecular approaches were employed to examine the expression and cellular localisation of the known CAR isoforms in human pancreas. One specific isoform of CAR (CAR-SIV) with a unique C terminal PDZ binding domain, was highly expressed in human beta cells at the protein level. Surprisingly, it was distributed in a punctate manner mainly within the cytoplasm of the cells, rather than at the cell surface. In human beta cells, within the cytoplasm CAR-SIV co-localised with ZnT8, PC1/3 and insulin but less so with proinsulin suggesting that CAR-SIV is associated with insulin secretory granules. Immunogold labelling and electron microscopic analysis revealed that CAR-SIV is localised both to maturing insulin secretory granules and to fully mature, dense-core (insulin) secretory granules. Intriguingly, CAR-SIV colocalises and interacts with a cytosolic protein, PICK1, which plays a role in the budding, maturation and trafficking of insulin secretory granules. On this basis, a model is proposed whereby CAR-SIV and PICK1 interact to regulate the maturation and trafficking of insulin secretory granules. Overall, this study suggests that the specialised role and subcellular localisation of CAR-SIV in human beta cells may contribute to their sensitivity to enteroviral infection following externalisation of the protein at the cell surface, during insulin exocytosis.FFWGJDRFPEVNETJDRFMR

The radio-protective effects of n-Hexane extracts of Telfairia occidentalis Hook. f. and Cucumeropsis mannii Naud. seed oils on the liver of irradiated male Wistar rats

The human population is predisposed to some considerable amounts of radiation especially ionizing radiation which may negatively impact their metabolic processes. Herbal extracts can mitigate these harmful effects. Therefore, this study aims to investigate the protective effect of n-Hexane extracts of Telfairia occidentalis and Cucumeropsis mannii seeds oils against radiation-mediated oxidative stress in Wistar rats. Sixty male rats were randomly distributed into six groups of six animals each and n-hexane extracts of T. occidentalis and C. mannii were administered at a dose of 2.4 or 4.8 mg/kg b. wt., orally for 7 days before irradiation and 10 days after irradiation, when they were sacrificed. Lipid peroxidation was measured, hepatic antioxidant status; SOD, CAT, GSH, Gpx and GST were estimated. The activities of liver enzymes: ALT, AST and ALP were measured and histological examination of sections of the liver was carried out. Radiation significantly increased MDA levels, SOD, GPx, AST, ALT and ALP activities but reduced body weights, total proteins, CAT, GSH and GST activities. Administration of the extracts significantly reduces the levels of MDA, SOD, GPx, ALT, AST and ALP activities while they increase the activities of CAT, GSH and GST at a dosage of 4.8 mg/kg. Histological examination showed increased levels of toxicity in radiated and groups administered 2.4 mg/kg extracts. From these findings, extracts of T. occidentalis and C. mannii at 4.8 mg/kg b. wt are effective herbal remedies in the prevention and amelioration of the consequences of oxidative stress due to exposure to ionizing radiation

Fungal Growth and Mycotoxins Production: Types, Toxicities, Control Strategies, and Detoxification

Fungal growth and the production of mycotoxins are influenced by several factors. Environmental conditions such as temperature, water activity, and humidity affect mycotoxin production and fungal growth. Other factors such as pH, fungal strain, and substrate also play roles. Common mycotoxins include aflatoxins, fumonisins, trichothecenes, sterigmatocystin (STC), citrinin, ergot alkaloids, ochratoxins, zearalenones (ZEAs), patulin, deoxynivalenol (DON), Alternaria toxins, tremorgenic mycotoxins, fusarins, cyclochlorotine, sporidesmin, 3-nitropropionic acid, etc. These toxins cause many health conditions in animals and humans, including death. A comprehensive approach starting from the field before planting, continuing throughout the entire food chain is required to control mycotoxin contamination. Good practices, such as proper field practices before and after planting, good harvest practices and postharvest handling, and proper drying and storage measures, help reduce mycotoxin contamination. Several physical, biological, and chemical techniques have been applied to help reduce/eliminate mycotoxin contamination. Food processing also play slight role in mycotoxins removal

COVID-19-related mental health burdens: Impact of educational level and relationship status Among low-Income earners of Western Uganda

Objective: The study aimed to investigate the relationship between mental health with the level of education, relationship status, and awareness on mental health among low-income earners in Western Uganda. Methods: This was a cross-sectional descriptive study carried out among 253 participants. Anxiety, anger, and depression were assessed using a modified generalized anxiety disorder (GAD-7), Spielberger\u27s State-Trait Anger Expression Inventory-2, and Beck Depression Inventory item tools, respectively. Results: The majority of our respondents were male (n = 150/253, 59.3), had a secondary level of education (104/253, 41.1), and were single (137/253, 54.2). No formal education and primary education (r2 = 47.4% and 6.4%, respectively) had a negative correlation with awareness of mental health care. In addition, no formal education had a positive correlation with anger and depression (r2 = 1.9% and 0.3%, respectively). Singleness in this study had a negative correlation with awareness of mental health care, anger, and depression (r2 = 1.9, 0.8, and 0.3%, respectively), and a positive correlation with anxiety (r2 = 3.9%). Conclusion: It is evident that education and relationship status influenced awareness on mental health care and mental health state among low-income earners in Western Uganda during the first COVID-19 lockdown. Therefore, policymakers should strengthen social transformation through the proper engagement of low-income earners in this COVID-19 era

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.</p

The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier

Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD

Elucidation of chemical profiles and molecular targets of Mondia whitei leave fractions bioactive as novel therapeutics: an in vitro and in silico assay

Abstract Background Mondia whitei root is often used in Africa as a local therapeutic agent for libido enhancement. The fractions of the M. whitei leaves (MWL) lack chemical characterization of their bioactive components and possible molecular targets. We characterized and investigated its molecular target as therapeutic agents in an in vitro and in silico assay. Mineral compositions, antioxidant, and GC-MS characterization were studied. The cytotoxicity effect was measured on HeLa and HT-29 cells by MTT assay. In silico potential inhibitors of Cathepsin B (CathB) as a cancer biomarker were determined. Results The flame photometry produced marked Na+ and K+. GC-MS revealed eighteen bioactive components. The fractions (chloroformic 47.00, ethanolic 45.52, and aqueous 40.13) of MWL caused a higher inhibition ratio compared to standards. The MWL showed a significant cytotoxic effect on the treated cell lines at concentrations of 150 and 200 μg/ml and 100, 150, and 200 μg/ml for HT-29 and HeLa cells, respectively. Ten bioactives (MWL 4, 5, 6, 8, 9, 10, 14, 15, 17, and 18) showed potential inhibition of CathB with binding affinities of −4.40 to −8.3 Kcal/Mol. However, MWL 4, 9, 14, and 17 which have higher binding affinities (−6.7, −7.1, −8.2, and −8.3, respectively) than the standard inhibitor (−6.5) were the lead molecules. Conclusion These chemical profiles and potential molecular targets unraveled in this study propose that MWL has a promising anticancer activity. Graphical Abstrac

Mycotoxins&rsquo; Toxicological Mechanisms Involving Humans, Livestock and Their Associated Health Concerns: A Review

Mycotoxins are well established toxic metabolic entities produced when fungi invade agricultural/farm produce, and this happens especially when the conditions are favourable. Exposure to mycotoxins can directly take place via the consumption of infected foods and feeds; humans can also be indirectly exposed from consuming animals fed with infected feeds. Among the hundreds of mycotoxins known to humans, around a handful have drawn the most concern because of their occurrence in food and severe effects on human health. The increasing public health importance of mycotoxins across human and livestock environments mandates the continued review of the relevant literature, especially with regard to understanding their toxicological mechanisms. In particular, our analysis of recently conducted reviews showed that the toxicological mechanisms of mycotoxins deserve additional attention to help provide enhanced understanding regarding this subject matter. For this reason, this current work reviewed the mycotoxins&rsquo; toxicological mechanisms involving humans, livestock, and their associated health concerns. In particular, we have deepened our understanding about how the mycotoxins&rsquo; toxicological mechanisms impact on the human cellular genome. Along with the significance of mycotoxin toxicities and their toxicological mechanisms, there are associated health concerns arising from exposures to these toxins, including DNA damage, kidney damage, DNA/RNA mutations, growth impairment in children, gene modifications, and immune impairment. More needs to be done to enhance the understanding regards the mechanisms underscoring the environmental implications of mycotoxins, which can be actualized via risk assessment studies into the conditions/factors facilitating mycotoxins&rsquo; toxicities