Pancreatic Antioxidative Defense and Heat Shock Proteins Prevent Islet of Langerhans Cell Death After Chronic Oral Exposure to Cadmium LOAEL Dose.

Cadmium, a hazardous environmental contaminant, is associated with metabolic disease development. The dose with the lowest observable adverse effect level (LOAEL) has not been studied, focusing on its effect on the pancreas. We aimed to evaluate the pancreatic redox balance and heat shock protein (HSP) expression in islets of Langerhans of male Wistar rats chronically exposed to Cd LOAEL doses, linked to their survival. Male Wistar rats were separated into control and cadmium groups (drinking water with 32.5 ppm CdCl2). At 2, 3, and 4 months, glucose, insulin, and cadmium were measured in serum; cadmium and insulin were quantified in isolated islets of Langerhans; and redox balance was analyzed in the pancreas. Immunoreactivity analysis of p-HSF1, HSP70, HSP90, caspase 3 and 9, and cell survival was performed. The results showed that cadmium exposure causes a serum increase and accumulation of the metal in the pancreas and islets of Langerhans, hyperglycemia, and hyperinsulinemia, associated with high insulin production. Cd-exposed groups presented high levels of reactive oxygen species and lipid peroxidation. An augment in MT and GSH concentrations with the increased enzymatic activity of the glutathione system, catalase, and superoxide dismutase maintained a favorable redox environment. Additionally, islets of Langerhans showed a high immunoreactivity of HSPs and minimal immunoreactivity to caspase associated with a high survival rate of Langerhans islet cells. In conclusion, antioxidative and HSP pancreatic defense avoids cell death associated with Cd accumulation in chronic conditions; however, this could provoke oversynthesis and insulin release, which is a sign of insulin resistance.

Hepatic Insulin Resistance Model in the Male Wistar Rat Using Exogenous Insulin Glargine Administration.

Metabolic diseases are a worldwide health problem. Insulin resistance (IR) is their distinctive hallmark. For their study, animal models that provide reliable information are necessary, permitting the analysis of the cluster of abnormalities that conform to it, its progression, and time-dependent molecular modifications. We aimed to develop an IR model by exogenous insulin administration. The effective dose of insulin glargine to generate hyperinsulinemia but without hypoglycemia was established. Then, two groups (control and insulin) of male Wistar rats of 100 g weight were formed. The selected dose (4 U/kg) was administered for 15, 30, 45, and 60 days. Zoometry, a glucose tolerance test, insulin response, IR, and the serum lipid profile were assessed. We evaluated insulin signaling, glycogenesis and lipogenesis, redox balance, and inflammation in the liver. Results showed an impairment of glucose tolerance, dyslipidemia, hyperinsulinemia, and peripheral and time-dependent selective IR. At the hepatic level, insulin signaling was impaired, resulting in reduced hepatic glycogen levels and triglyceride accumulation, an increase in the ROS level with MAPK-ERK1/2 response, and mild pro-oxidative microenvironmental sustained by MT, GSH, and GR activity. Hepatic IR coincides with additions in MAPK-p38, NF-κB, and zoometric changes. In conclusion, daily insulin glargine administration generated a progressive IR model. At the hepatic level, the IR was combined with oxidative conditions but without inflammation.

Pancreas-Liver-Adipose Axis: Target of Environmental Cadmium Exposure Linked to Metabolic Diseases.

Cadmium has been well recognized as a critical toxic agent in acute and chronic poisoning cases in occupational and nonoccupational settings and environmental exposure situations. Cadmium is released into the environment after natural and anthropogenic activities, particularly in contaminated and industrial areas, causing food pollution. In the body, cadmium has no biological activity, but it accumulates primarily in the liver and kidney, which are considered the main targets of its toxicity, through oxidative stress and inflammation. However, in the last few years, this metal has been linked to metabolic diseases. The pancreas-liver-adipose axis is largely affected by cadmium accumulation. Therefore, this review aims to collect bibliographic information that establishes the basis for understanding the molecular and cellular mechanisms linked to cadmium with carbohydrate, lipids, and endocrine impairments that contribute to developing insulin resistance, metabolic syndrome, prediabetes, and diabetes.

Polyoxidovanadates as a pharmacological option against brain aging.

The world population is aging rapidly, and chronic diseases associated are cardiometabolic syndrome, cancer, and neurodegenerative diseases. Oxidative stress and inflammation are typical hallmarks in them. Polyoxidovanadates (POVs) have shown interesting pharmacological actions against chronic diseases. This work aimed to evaluate the POV effect on hippocampal neuroinflammation, redox balance, and recognition memory in the aging of rats. Rats 18 months old were administered a daily dose of sodium metavanadate (MV), decavanadate (DV), Metformin (Metf), or MetfDeca for two months. Results showed that short-term and long-term recognition memory improved by 28 % and 16 % (DV), 19 % and 20 % (Metf), and 21 % and 27 % (MetfDeca). In hippocampi, reactive oxygen species, IL-1ß, and TNF-α, after DV, Metf, and MetfDeca decreased at similar concentrations to young adult control, while lipid peroxidation substantially ameliorated. Additionally, superoxide dismutase and catalase activity increased by 41 % and 42 % (DV), 39 % and 41 % (Metf), and 75 % and 73 % (MetfDeca). POV treatments reduced Nrf2 and GFAP immunoreactivity in CA1 (70-87.5 %), CA3 (60-80 %), and DG (57-89 %). Metformin treatment showed a minor effect, while MV treatment did not improve any parameters. Although DV, Metf, and MetfDeca treatments showed similar results, POVs doses were 16-fold fewer than Metformin. In conclusion, DV and MetfDeca could be pharmacological options to reduce age-related neuronal damage.

ROS and ERK Pathway Mechanistic Approach on Hepatic Insulin Resistance After Chronic Oral Exposure to Cadmium NOAEL Dose.

Cadmium is a critical toxic agent in occupational and non-occupational settings and acute and chronic environmental exposure situations that have recently been associated with metabolic disease development. Until now, the no observed adverse effect level (NOAEL) of cadmium has not been studied regarding insulin resistance development. Therefore, we aimed to monitor whether chronic oral exposure to cadmium NOAEL dose induces insulin resistance in Wistar rats and investigate if oxidative stress and/or inflammation are related. Male Wistar rats were separated into control (standard normocalorie diet + water free of cadmium) and cadmium groups (standard normocalorie diet + drinking water with 15 ppm CdCl2). At 15, 30, and 60 days, oral glucose tolerance, insulin response, and insulin resistance were analyzed using mathematical models. In the liver glycogen, triglyceride, pro- and anti-inflammatory cytokines, cadmium, zinc, metallothioneins, and redox balance were quantified. Immunoreactivity analysis of proteins involved in metabolic and mitogenic insulin signaling was performed. The results showed that a cadmium NOAEL dose after 15 days of exposure causes ROS and mitogenic arm of insulin signaling to increase while hepatic glycogen diminishes. At 30 days, Cd accumulation accentuated ROS production, hepatic triglyceride overaccumulation, and mitogenic signals that develop insulin resistance. Finally, inflammation and lipid peroxidation appear after 60 days of Cd exposure, while lipids and carbohydrate homeostasis deteriorate. In conclusion, environmental exposure to cadmium NAOEL dose causes hepatic Cd accumulation and ROS overproduction that chronically declines the antioxidant defense, deteriorates metabolic homeostasis associated with the mitogenic pathway of insulin signaling, and induces insulin resistance.

Clinical monitored in subjects metabolically healthy and unhealthy before and during a SARS-CoV-2 infection- A cross-sectional study in Mexican population.

The COVID-19 disease has forced us to consider the physiologic role of obesity and metabolically healthy and unhealthy status in response to SARS-CoV-2 infection. Hematological, coagulation, biochemical, and immunoinflammatory changes have been informed with a disparity in morbidity and mortality. Therefore, we aimed to investigate the influence of metabolic health on clinical features in a cross-sectional study in Mexican subjects with and without SARS-CoV-2 infection in non-severe stages after a rigorous classification of obese and non-obese subjects who were metabolically healthy and unhealthy. Four groups were formed: 1) metabolically healthy with normal BMI (MHN); 2) metabolically unhealthy with normal BMI (MUN); 3) metabolically healthy obese (MHO); 4) metabolically unhealthy obese (MUO). Serum proinflammatory (TNF-α, MCP-1, IL-1ß, and IL-6) and anti-inflammatory (TGF-ß, IL-1Ra, IL-4, and IL-10) cytokines, hematological parameters, coagulation, and acute phase components were evaluated. Our results showed that MHO people live with inflammaging. Meanwhile, MUN and MUO subjects develop metaflammation. Both inflammaging and metaflammation cause imperceptible modifications on hematological parameters, mainly in leukocyte populations and platelets, as well as acute phase and coagulation components. The statistical analysis revealed that many clinical features are dependent on metabolic health. In conclusion, MHO subjects seem to be transitioning from metabolically healthy to unhealthy, which is accelerated in acute processes, such as SARS-CoV-2 infection. Meanwhile, metabolically unhealthy subjects independently of BMI have a deteriorating immunometabolic status associated with a hyperinflammatory state leading to multi-organ dysfunction, treatment complications, and severe COVID-19 disease.

Oral Subacute Exposure to Cadmium LOAEL Dose Induces Insulin Resistance and Impairment of the Hormonal and Metabolic Liver-Adipose Axis in Wistar Rats.

Cadmium is a nonessential transition metal considered one of the more hazardous environmental contaminants. The population is chronically exposed to this metal at low concentrations, designated as the LOAEL (lowest observable adverse effect level) dose. We aimed to investigate whether oral subacute exposure to cadmium LOAEL disrupts hormonal and metabolic effects of the liver-adipose axis in Wistar rats. Fifty male Wistar rats were separated into two groups: control (standard normocalorie diet + water free of cadmium) and cadmium (standard normocalorie diet + drinking water with 32.5 ppm CdCl2). After 1 month, zoometry, a serum lipid panel, adipokines, and proinflammatory cytokines were evaluated. Tests of glucose and insulin tolerance (ITT) and insulin resistance were performed. Histological studies on structure, triglyceride distribution, and protein expression of the insulin pathway were performed in the liver and retroperitoneal adipose tissue. In both tissues, the cadmium, triglyceride, glycogen, and proinflammatory cytokine contents were also quantified. The cadmium group developed dyslipidemia, glucose intolerance, hyperinsulinemia, hyperleptinemia, inflammation, and selective insulin resistance in the liver and adipose tissue. In the liver, glycogen synthesis was diminished, while de novo lipogenesis increased, which was associated with low GSK3ß-pS9 and strong expression of SREBP-1c. Dysfunctional adipose tissue was observed with hypertrophy and lipolysis, without changes in SREBP-1c expression and low glycogen synthesis. Both tissues accumulated cadmium and developed inflammation. In conclusion, oral subacute cadmium LOAEL dose exposure induces inflammation, insulin signaling modifications, an early insulin resistance stage (insensibility), and impairment of the hormonal and metabolic liver-adipose axis in Wistar rats.

Sodium metavanadate treatment improves glycogen levels in multiple tissues in a model of metabolic syndrome caused by chronic cadmium exposure in Wistar rats.

Cadmium, one of the more hazardous environmental contaminants, has been proposed as a metabolic disruptor. Vanadium has emerged as a possible treatment for metabolic diseases. Both metals are important in public health. We aimed to investigate whether vanadium treatment is effective against metabolic disturbances caused by chronic exposure to the lowest-observable adverse effect level of cadmium. Male Wistar rats were exposed to cadmium (32.5 ppm) in drinking water for 3 months. Metabolic complications such as overweight, visceral adipose gain, hyperglycemia, impaired glucose tolerance, and dyslipidemia were detected, and low glycogen levels and steatosis were observed in the tissues. Then, the control and treated animals were subdivided and treated with a solution of 5 µM NaVO3/kg/twice a week for 2 months. The control-NaVO3 group did not show zoometric or metabolic changes. A strong interaction of NaVO3 treatment over cadmium metabolic disruption was observed. The vanadium accumulation diminished cadmium concentration in tissues. Also, vanadium interaction improved glucose homeostasis. The major effect was observed on glycogen synthesis, which was fully recovered in all tissues analyzed. Additionally, vanadium treatment prevented overweight and visceral fat accumulation, improving BMI and the percentage of fat. However, NaVO3 treatment did not have an effect on dyslipidemia or steatosis. In conclusion, this work shows that vanadium administration has a strong effect against metabolic disturbances caused by chronic cadmium exposure, observing powerful interaction on glucose homeostasis.

The NOAEL Metformin Dose Is Ineffective against Metabolic Disruption Induced by Chronic Cadmium Exposure in Wistar Rats.

Previous studies have proposed that cadmium (Cd) is a metabolic disruptor, which is associated with insulin resistance, metabolic syndrome, and diabetes. This metal is not considered by international agencies for the study of metabolic diseases. In this study, we investigate the effect of metformin on Cd-exposed Wistar rats at a lowest-observed-adverse-effect level (LOAEL) dose (32.5 ppm) in drinking water. Metabolic complications in the rats exposed to Cd were dysglycemia, insulin resistance, dyslipidemia, dyslipoproteinemia, and imbalance in triglyceride and glycogen storage in the liver, muscle, heart, kidney, and adipose tissue. Meanwhile, rats treated orally with a No-observable-adverse-effect level (NOAEL) dose of metformin (200 mg/kg/day) showed mild improvement on serum lipids, but not on glucose tolerance; in tissues, glycogen storage was improved, but lipid storage was ineffective. In conclusion, metformin as a first-line pharmacological therapy must take into consideration the origin and duration of metabolic disruption, because in this work the NOAEL dose of metformin (200 mg/kg/day) showed a limited efficiency in the metabolic disruption caused by chronic Cd exposure.

Hepatic mobilization of zinc after an experimental surgery, and its relationship with inflammatory cytokines release, and expression of metallothionein and Zip14 transporter.

OBJECTIVE: To study the relationship between the release of inflammatory cytokines and mobilization of zinc into liver, and the expression of metallothionein and Zip14 transporter after an abdominal surgery in rats. MATERIALS: Thirty-five male Wistar rats were subjected to experimental surgical stress, then the subgroups of five animals were killed at 3, 6, 9, 12, 16, 20 and 24 h. Matched groups without surgery were used as controls. METHODS: Zinc levels were determined by AAS, intracellular zinc by zinquin and dithizone staining. Hepatic metallothionein was assayed by a Cd-saturation method, and IL-1ß, IL-6, and TNF-ß by immunoassays. Zip14 expression was analyzed by real-time RT-PCR, and protein level by immunohistochemistry and Western blot. RESULTS: Experimental surgery produced a hypozincemia, and the increase of hepatic zinc also produced the release of IL-1ß, IL-6 in serum, and the increase of hepatic MT. Histochemistry showed a decrease of free zinc at 3-6 h, but an increase at 9 h (zinquin); meanwhile, total intracellular zinc increased after 9 h (dithizone). RNAm and protein levels of Zip14 were elevated between 6 and 20 h after surgery. CONCLUSION: Biochemical changes described in this work could be part of the APR, and directed to respond to the damage produced during surgical trauma.