Cadmium-induced endothelial dysfunction mediated by asymmetric dimethylarginine.

Cadmium (Cd) is a naturally occurring toxic heavy metal with no known essential biological functions. Exposure to Cd increases the risk of cardiovascular disease by disrupting vascular homeostasis at the endothelium. The aim of the study was to evaluate the effect of chronic low-dose Cd on vascular structure and function. Fifty adult male Sprague Dawley rats were grouped and assigned to one of two treatments for 14 weeks. The control group received normal water for 14 weeks while the Cd-treated group received 15 mg Cd/kg B.W. as CdCl in water for 10 weeks. A subset of the Cd-treated group received 15 mg Cd/kg B.W. as CdCl in water for 10 weeks followed by 4 weeks of normal water. Results show an overall decline in vascular function and structure. Withdrawal of Cd treatment showed a considerable restoration of vascular structure and vasorelaxation function. Additionally, asymmetric dimethylarginine (ADMA) bioavailability was found to be lowered over time. Interestingly, the expression of eNOS in the Cd-treated group was found to be significantly elevated during the exposure by more than 3-fold in comparison with that in the control group. This protein expression was similar to the control group after the withdrawal of Cd treatment. Taken together, the results suggest that ADMA, an eNOS inhibitor, may play a role in altering endothelial function in the presence of cadmium. In conclusion, the findings indicate that even at low doses, Cd leads to endothelial dysfunction mediated by ADMA.This work was supported by grant from Qatar University (QUCP-CAS-BES-15/16, 2016)

Gut Microbiota Dysbiosis and Their Impact on Biochemical and Inflammatory Profiles in Cafeteria Diet Fed Sprague Dawley Rats

Gut microbiota plays a major role in regulating the host metabolism and immune system. However, the structure of microbiome population is altered constantly by diverse factors including diet and environment. In particular, the gut microbiome dynamics is influenced by diet composition and their associated metabolites. Many studies in the recent past reported on diet induced dysbiosis in the gut microbiome, the modulating ratio between Firmicutes and Bacteroidetes plays a central role in maintaining the microbiome diversity in the gut and their abundance regulates obese conditions. Although there are several reports on gut microbial dysbiosis (Firmicutes/Bacteroidetes) at phylum level but only few of them highlight at the genera level. In the present study, we focused more on the impact of cafeteria diet (CAF) with respect to the gut microbiome richness at the genera level in SD rats. Three weeks old Sprague Dawley (SD) rats were fed with normal chow diet and cafeteria diet (CAF). After 10 weeks, serum, tissue samples (small intestine and cecum), cecum fecal and fecal pellet were collected. Biochemical analysis from serum, Gene expression analysis of pro-inflammatory markers from tissues and microbiome analysis from fecal samples were analysed. CAF diet fed rat in the present study developed obesity with increased body weight, few of them developed the resistance to weight gain (WGR) and these animal shows significantly increased abundance of Bacteriodetes-Prevotella compared to obese animals. This study suggests that detailed research needed to address the contribution of microbiota abundance at the genera level. We further explored the influence of diet induced microbiota changes on immune response; increase in Bacteroidetes leads to increased LPS and this in turn elicit immune reaction in the gut. Moreover, variation in gut microbiota also affects the gut barrier function (Tight junction proteins) and increase metabolic endotoxemia that leads to activation of innate immune system and low-grade inflammation. Further studies on these lines targeting the microbiota changes in the gut at the genera level is warranted to gain more knowledge

Early-Life Sugar Consumption Affects the Microbiome in Juvenile Mice

Scope: The composition of the gut microbiota is influenced by the dietary nutrient. Sugar has been linked with many metabolic health disorders such as heart disease, metabolic syndrome, and immune disorders. Long-term consumption of sugar influences the landscape of gut microbiota by altering the gut microbial population called dysbiosis. This study aims to evaluate the impact of long-term consumption of high sugar diet (HSD) on the diversity of gut microbiota. Methods and results: CD1 mice are given high concentration of sugar for 15 weeks followed by a recovery period of 10 weeks. Real-time polymerase chain reaction and 16S rRNA next-generation sequencing methods employ to identify microbiome diversity. The results show that Firmicutes and Bacteroidetes are the predominant phyla in control, cecum, and fecal samples. Firmicutes population are gradually increased in treated samples even after the recovery period, whereas Bacteroidetes abundance slightly reduces throughout the study. Conclusion: The present study shows that the impact of long period of high sugar diet consumption alters the diversity of normal gut flora which can be restored after 10 weeks of sugar withdrawal. This indicates that the intervention of healthy and nutritious diet influences gut microbes and this can be beneficial in reducing the implication of early life metabolic disorders such as obesity.The authors would like to acknowledge LARC for their support and LARC vivarium team, for their support in animal care and husbandry. The research is funded by Qatar University

Gut Microbiota Dysbiosis in Cafeteria Diet Fed Sprague Dawley Rats

Diet plays a major role in the body physiology and metabolism. The quantity, nature and stability of the macronutrients present in the diet have a major impact on the composition of gut microbiota. Gut microbiota plays a major role in the body metabolism and leads to obese or lean phenotype. Bacteriodetes, Firmicutes, Proteobacteria and Actinobacteria are the major microbes that inhabit in the region of the gut. We made an attempt to study the effects of Cafeteria (CAF) diets and normal chow diets on diet consumption, weight gain, metabolism and composition of gut microbiota in fecal and cecum samples from three weeks old Sprague Dawley (SD) rats (n = 18/group) using 16S rDNA high throughput sequencing. Results revealed that distinctive diet based phenotypical changes were observed in some of the Cafeteria diet fed rats. Interestingly, some weight gain resistant (WGR) animals in Cafeteria diet fed groups show similar trend like that of control normal chow fed rats. Fecal microbiome analysis indicates that the ratio of Bacteriodetes is higher than the Firmicutes in cecum samples of Cafeteria diet fed rats whereas no significant difference is found in fecal samples of Cafeteria diet fed rats and as well as in control rats. Further analysis of other taxa at the level of family and genus of microbial abundance are also discussed. Our study suggests that contribution of gut microbiota towards obesity is not at the phylum level, and microbiome composition even at the level of species or strain may exert impact on the metabolism of the Cafeteria diet

Cadmium: An Emerging Role in Adipose Tissue Dysfunction

Cadmium (Cd) is a toxic heavy metal that is widespread in the environment due to the substantial anthropogenic inputs from the agriculture and industrial sectors. The toxic impact of Cd adversely affects human health and is linked with endocrine disruption, carcinogenicity, diabetes-related diseases, and metabolic disorder. One of the main characterizations of Cd is bioaccumulation where its half-life reaches 40 years with an unknown biological role. Several organs were found to be targets for Cd accumulation such as the liver, kidneys, and adipose tissue. Adipose tissue (AT) is a dynamic organ that plays a significant role in the body’s homeostasis through the maintenance of energy storage. Another vital function for AT is the secretion of adipokines which provides a metabolic cross-talk with the whole body’s organs. Cd is found to adversely impact the function of AT. This includes the disruption of adipogenesis, lipogenesis, and lipolysis. As a consequence, dysfunctional AT has disruptive patterns of adipokines secretions. The main adipokines produced from AT are leptin and adiponectin. Both were found to be significantly declined under the Cd exposure. Additionally, adipose tissue macrophages can produce either anti-inflammatory markers or pro-inflammatory markers depending on the local AT condition. Cadmium exposure was reported to upregulate pro-inflammatory markers and downregulate anti-inflammatory markers. However, the exact mechanisms of Cd’s adverse role on AT structure, function, and secretion patterns of adipokines are not totally clarified. Therefore, in this review, we present the current findings related to Cd detrimental effects on adipose tissues.Open Access funding provided by Qatar University

In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity

Impaired adipogenesis is associated with the development of insulin resistance and an increased risk of type 2 diabetes (T2D). GATA Binding Protein 3 (GATA3) is implicated in impaired adipogenesis and the onset of insulin resistance. Therefore, we hypothesize that inhibition of GATA3 could promote adipogenesis, restore healthy fat distribution, and enhance insulin signaling. Primary human preadipocytes were treated with GATA3 inhibitor (DNAzyme hgd40). Cell proliferation, adipogenic capacity, gene expression, and insulin signaling were measured following well-established protocols. BALB/c mice were treated with DNAzyme hgd40 over a period of 2 weeks. Liposomes loaded with DNAzyme hgd40, pioglitazone (positive), or vehicle (negative) controls were administered subcutaneously every 2 days at the right thigh. At the end of the study, adipose tissues were collected and weighed from the site of injection, the opposite side, and the omental depot. Antioxidant enzyme (superoxide dismutase and catalase) activities were assessed in animals’ sera, and gene expression was measured using well-established protocols. In vitro GATA3 inhibition induced the adipogenesis of primary human preadipocytes and enhanced insulin signaling through the reduced expression of p70S6K. In vivo GATA3 inhibition promoted adipogenesis at the site of injection and reduced MCP-1 expression. GATA3 inhibition also reduced omental tissue size and PPARγ expression. These findings suggest that modulating GATA3 expression offers a potential therapeutic benefit by correcting impaired adipogenesis, promoting healthy fat distribution, improving insulin sensitivity, and potentially lowering the risk of T2D.Qatar University H3P grant number QPH3P-BRC-2021-451 (MAE, HN, LM)

Claudin-1, A Double-Edged Sword in Cancer.

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target

Cadmium Toxicity: Oxidative Stress, Inflammation and Tissue Injury

Cadmium is a known environmental pollutant targeting various organs. Often implicated in cadmium toxicology is the formation of reactive oxygen species, overwhelming the free radical scavenging mechanisms and inducing oxidative stress. Acute cadmium intoxication has been shown to reduce antioxidant enzyme activity and induce oxidative stress. However, chronic intoxication has obscure outcomes in oxidative stress while the cell makes adjustments to overcome the toxicant load. Also linked with the occurrence of oxidative stress is inflammation. Stimulation of acute or chronic inflammation is mediated by different cascades. However, key events include activation of transcription factor, NF-κB and release of pro-inflammatory cytokines. Both oxidative stress and inflammation are implicated simultaneously in pathogenesis and induction of multi-organ tissue damage under cadmium exposure. This article reviews the impact of acute and chronic cadmium intoxication on inducing oxidative stress, inflammation and thereby inflicting tissue damag

Cadmium-induced endothelial dysfunction mediated by asymmetric dimethylarginine

Cadmium (Cd) is a naturally occurring toxic heavy metal with no known essential biological functions. Exposure to Cd increases the risk of cardiovascular disease by disrupting vascular homeostasis at the endothelium. The aim of the study was to evaluate the effect of chronic low-dose Cd on vascular structure and function. Fifty adult male Sprague Dawley rats were grouped and assigned to one of two treatments for 14 weeks. The control group received normal water for 14 weeks while the Cd-treated group received 15 mg Cd/kg B.W. as CdCl2 in water for 10 weeks. A subset of the Cd-treated group received 15 mg Cd/kg B.W. as CdCl2 in water for 10 weeks followed by 4 weeks of normal water. Results show an overall decline in vascular function and structure. Withdrawal of Cd treatment showed a considerable restoration of vascular structure and vasorelaxation function. Additionally, asymmetric dimethylarginine (ADMA) bioavailability was found to be lowered over time. Interestingly, the expression of eNOS in the Cd-treated group was found to be significantly elevated during the exposure by more than 3-fold in comparison with that in the control group. This protein expression was similar to the control group after the withdrawal of Cd treatment. Taken together, the results suggest that ADMA, an eNOS inhibitor, may play a role in altering endothelial function in the presence of cadmium. In conclusion, the findings indicate that even at low doses, Cd leads to endothelial dysfunction mediated by ADMA.Other Information Published in: Environmental Science and Pollution Research License: https://creativecommons.org/licenses/by/4.0See article on publisher's website: http://dx.doi.org/10.1007/s11356-020-08116-5</p

Chronic Cadmium Exposure Alters Cardiac Matrix Metalloproteinases in the Heart of Sprague-Dawley Rat

The aim of this study was to evaluate the role of chronic cadmium exposure in modulating cardiac matrix metalloproteinases (MMPs) in the heart of rats. Adult male Sprague-Dawley rats were exposed to 15 ppm CdCl2 in drinking water for 10 weeks followed by withdrawal of cadmium treatment for 4 weeks. Following the completion of the treatment, gene expression of inflammatory mediators (IL-1β, IL-6, IL-10, TNF-α and NF-κB), protein expression of MMP-2, MMP-9 and their respective inhibitors- TIMP-1 and TIMP-2, and gelatinolytic activity of MMP-2 and MMP-9 were determined. At the protein level, cadmium incites a differential effect on the expression and activity of gelatinases and their endogenous inhibitors in an exposure-dependent manner. Results also show that the administered cadmium dose elicits an inflammatory response until week 10 that slightly diminishes after 4 weeks. This study provides evidence of cadmium-induced imbalance in the MMP-TIMP system in the cardiac tissue. This imbalance may be mediated by cadmium-induced inflammation that could contribute to various cardiovascular pathologies