Dexamethasone-treated Rats Research Articles

Dendrobine Ameliorates Glucocorticoid-Induced Osteoporosis by Promoting Osteogenesis through JNK/p38 MAPK Pathway Activation and GR Nuclear Translocation Inhibition.

Glucocorticoid-induced osteoporosis (GIOP) is the common reason for secondary osteoporosis. Dendrobine (DEN) is the major biologically active component of Dendrobium officinale with anti-inflammatory and antiaging properties. Whether DEN could alleviate osteogenic inhibition in GIOP rats is still unknown. The influence on osteogenic function caused by DEN on dexamethasone-treated bone marrow mesenchymal stem cells and rats was observed. The in vitro results showed that DEN reversed the inhibition of osteogenic differentiation by dexamethasone. Moreover, DEN supplementation attenuated dexamethasone-induced bone loss in vivo. DEN activated JNK and p38 MAPK pathways and restrained GR nuclear translocation, which could be prevented by the JNK (SP600125) or p38 (SB203580) pathway inhibitor. This study verified that DEN alleviated dexamethasone-induced nuclear translocation of GR, and inhibition of osteogenesis via JNK and p38 pathways, laying the foundation for DEN as a therapeutic agent for GIOP.

Black pepper (Piper nigrum L.) essential oil counteracts dexamethasone-induced hepatic injury via modulating PGC-1α/ PPAR-α pathway in rats

We previously characterized the volatile compounds of black pepper (Piper nigrum) essential oil (BPEO) and demonstrated its mitigating effect against dexamethasone-induced pancreatic damage. Herein, we investigated the protective effect of the oil against dexamethasone-induced hepatotoxicity in rats and pinned the possible underlying mechanisms. In the in vivo experiment, male Wistar rats were divided into five groups. The first group served as the normal control receiving a saline solution (Control). The second group was subjected to hepatic damage through dexamethasone exposure (Dexa) at 10 mg/kg. The third group received both dexamethasone and metformin (Met) at a dose of 50 mg/kg. The remaining two groups were exposed to dexamethasone along with black pepper oil administration at low and high doses (BPEO, 0.5 mL/kg and 1 mL/kg). We showed that BPEO offset toxicity manifestations, as indicated by reducing monocyte infiltration, hepatocyte degeneration and vacuolation, and reduction of ALT and AST levels. Moreover, relative to the dexamethasone-treated rats, BPEO declined the number of PGC-1α positive hepatocytes and activated the expression of PPAR-α in the liver. BPEO showed comparable hepatoprotective potency to the standard drug, metformin, especially at the higher dose tested (1 mL/kg). This study showcases the promising potential of BPEO in thwarting dexamethasone-induced adverse effects on the liver by alleviating hepatic biomarkers hikes and preventing histopathological changes and fibrosis. Finally, it opens a new avenue on the potential role of BPEO in modulating steroid-induced hepatic injury through the PGC-1α/ PPAR-α pathway.

Saroglitazar mitigated NASH-associated hepatic injury in dexamethasone-treated rats via modulating autophagy, apoptosis, and necroptosis

This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats.Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined.SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group.SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.

The Effects of Probiotic Bacillus Spores on Dexamethasone-Treated Rats.

Glucocorticoids are effective anti-inflammatory and immunosuppressive agents. Long-term exposure is associated with multiple metabolic side effects. Spore-forming probiotic bacteria have shown modulatory properties regarding glycolipid metabolism and inflammation. The aim of this study was to evaluate, for the first time, the effects of Bacillus species spores (B. licheniformis, B. indicus, B. subtilis, B. clausii, and B. coagulans) alone and in combination with metformin against dexamethasone-induced systemic disturbances. A total of 30 rats were randomly divided into 5 groups: group 1 served as control (CONTROL), group 2 received dexamethasone (DEXA), group 3 received DEXA and MegaSporeBiotic (MSB), group 4 received DEXA and metformin (MET), and group 5 received DEXA, MSB, and MET. On the last day of the experiment, blood samples and liver tissue samples for histopathological examination were collected. We determined serum glucose, total cholesterol, triglycerides, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), catalase, total antioxidant capacity (TAC), and metformin concentration. DEXA administration caused hyperglycemia and hyperlipidemia, increased inflammation cytokines, and decreased antioxidant markers. Treatment with MSB reduced total cholesterol, suggesting that the administration of Bacillus spores-based probiotics to DEXA-treated rats could ameliorate metabolic parameters.

Glucocorticoid-Induced Dose-Dependent Reproductive Impairments in Male Albino Rat

The present study is aimed at elucidating the effect of different doses of Dexamethasone (DEX) on testis and epididymis of male Wistar rats. Thirty-six rats were divided into six groups, each containing six rats: one control (CON), and five groups of rats treated with five (30 μg, 40 μg, 50 μg, 60 μg, 70 μg/100 g body weight) doses of dexamethasone intraperitoneally (i.p.) for twenty-one days. The results revealed a dose-dependent decrease in testes and epididymis weight. DEX-treated rats evidenced significant increase in TBARS levels, this being the highest in 70 μg/100 g body weight (bw) which could be a consequence of the highest level of free radical generation. The activity level of antioxidative enzymes Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH), and protein content significantly declined in dexamethasone-treated rats in a dose-dependent manner. Histological observation revealed different degrees of germ cell degeneration/alterations in testis and epididymis The present finding suggests that exposure to dexamethasone (70 μg/100 g bw) can potentially lead to severe impairments in male reproductive tissues (testis and epididymis) structure and function, which may consequently lead to male infertility.

Effects of pharmacological doses of niacin on subacute glucocorticoid-induced testicular damage in rats.

Glucocorticoid excess adversely affects male reproduction. This study evaluates effects of pharmacological doses of niacin on testicular structure and function in dexamethasone-treated rats. Adult rats (48) were randomly assigned to 6 equal groups: (1) Negative control (NC): normal rats; (2) Positive control (PC): dexamethasone at 7 mg/kg/day by intraperitoneal injections for 7 days; groups 3-6 (N50, N100, N200, and N400): dexamethasone and concomitant treatment with niacin at 50, 100, 200, and 400 mg/kg/day by oral gavages. Testicular weight and volume of PC rats were significantly lower than the NC group (p < .05). Testicular volume of rats in the N50 and N200 groups was statistically similar to the NC group. Significant decreases in serum testosterone with a slight LH increase were detected in the PC group. Nacin at 50 mg/kg reversed serum testosterone to NC levels and increased serum LH concentration. Niacin only slightly increased epididymal spermatozoa number while all groups of niacin-treated rats had significantly higher percentages of motile spermatozoa compared with the PC group. Hypospermatogenesis, germ cell degeneration and depletion, epithelial vacuolization, and degenerated Leydig cells were observed in PC rats. Lesions were relatively milder in niacin-treated rats. Johnsen scores were also significantly higher in niacin-treated rats. Niacin reduced apoptosis as shown by TUNEL assay. In conclusion, niacin administration at pharmacological doses dose-dependently ameliorates the destructive effects of dexamethasone on sperm motility, Johnsen score, and testicular cell apoptosis in rats with the latter can be considered a decisive mechanism for its positive effects on testis.

Attenuation of Skeletal Muscle Atrophy Induced by Dexamethasone in Rats by Teaghrelin Supplementation

Muscle atrophy caused by an imbalance between the synthesis and the degradation of proteins is a syndrome commonly found in the elders. Teaghrelin, a natural compound from oolong tea, has been shown to promote cell differentiation and to inhibit dexamethasone-induced muscle atrophy in C2C12 cells. In this study, the therapeutic effects of teaghrelin on muscle atrophy were evaluated in Sprague Dawley rats treated with dexamethasone. The masses of the soleus, gastrocnemius and extensor digitorum longus muscles were reduced in dexamethasone-treated rats, and the reduction of these muscle masses was significantly attenuated when the rats were supplemented with teaghrelin. Accordingly, the level of serum creatine kinase, a marker enzyme of muscle proteolysis, was elevated in dexamethasone-treated rats, and the elevation was substantially reduced by teaghrelin supplementation. A decrease in Akt phosphorylation causing the activation of the ubiquitin-proteasome system and autophagy for protein degradation was detected in the gastrocnemius muscles of the dexamethasone-treated rats, and this signaling pathway for protein degradation was significantly inhibited by teaghrelin supplementation. Protein synthesis via the mTOR/p70S6K pathway was slowed down in the gastrocnemius muscles of the dexamethasone-treated rats and was significantly rescued after teaghrelin supplementation. Teaghrelin seemed to prevent muscle atrophy by reducing protein degradation and enhancing protein synthesis via Akt phosphorylation.

Black pepper oil (Piper nigrum L.) mitigates dexamethasone induced pancreatic damage via modulation of oxidative and nitrosative stress

Dexamethasone acts as an immunosuppressive drug and has been used recently in the management of specific coronavirus disease 2019 (COVID-19) cases; however, various adverse effects could limit its use. In this work, we studied the mitigation effects of black pepper oil (BP oil) on glycemic parameters, dyslipidemia, oxidative and nitrosative stress and pancreatic fibrosis in dexamethasone-treated rats. Animals were divided into five groups that were treated with vehicle, dexamethasone (10 mg/kg, SC) or black pepper oil (BP oil, 0.5 mL, or 1 mL/kg) or metformin (50 mg/kg) plus dexamethasone for 4 consecutive days. Serum insulin, blood glucose, total cholesterol, triglycerides, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were higher in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic nitric oxide, inducible nitric oxide synthase and malondialdehyde levels were increased in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic endothelial nitric oxide synthase and reduced glutathione were declined in the dexamethasone group vs the control group. They were increased in BP oil and metformin groups relative to the dexamethasone group. Moreover, the pancreatic islets diameter and collagen deposition were assessed and found to be higher in the dexamethasone group vs the control group. BP oil and metformin groups showed to regress this effect. In conclusion, BP oil may alleviate hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia and pancreatic structural derangements and fibrosis by suppressing oxidative stress, increasing endogenous antioxidant levels, modulating nitric oxide signaling, preventing pancreatic stellate cells transition and collagen deposition.

Efficacy of Emilia coccinea aqueous extract on inhibition of α-amylase enzyme activity and insulin resistance in dexamethasone treated-rats

BackgroundDiabetes mellitus is one of the most common chronic metabolic diseases throughout the world, characterized by hyperglycemia and insulin resistance. The purpose of this study was to evaluate the effects of aqueous extract of Emilia coccinea (AEEC) leaves on dexamethasone-induced insulin resistance in rats and on in vitro α-amylase enzyme activity. MethodsInsulin resistance was induced by intraperitoneal injection of dexamethasone (1 mg/kg) for 8 days in rats. The animals were concomitant received extracts at doses of 107.5; 215; 430 mg/kg for this period. At the end of the treatment, blood glucose level, lipid profile, transaminases, triglyceride glucose (TyG) index, body mass and relative organ weight were evaluated. ResultsThe results showed that AEEC inhibits α-amylase enzyme with an IC50 of 34.10 μg/ml in vitro. AEEC significantly reduced blood glucose level, triglycerides, TyG index, total and LDL cholesterol, liver weight and increased HDL cholesterol. Moreover, it reduced ALAT and ASAT activity. These parameters were strongly modify by dexamethasone. ConclusionAEEC plays antidiabetic roles by ameliorating insulin resistance and reducing postprandial blood glucose level through α-amylase enzyme inhibition.

The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats

Ozone-induced lung injury/inflammation dissipates despite continued exposure for 3 or more days; however, the mechanisms of adaptation/habituation remain unclear. Since ozone effects are mediated through adrenal-derived stress hormones, which also regulate longevity of centrally-mediated stress response, we hypothesized that ozone-adaptation is linked to diminution of neuroendocrine stress-axes activation and glucocorticoid levels. Male Wistar-Kyoto-rats (12-week-old) were injected with vehicle or a therapeutically-relevant dexamethasone dose (0.01-mg/kg/day; intraperitoneal) for 1-month to determine if suppression of glucocorticoid signaling was linked to adaptation. Vehicle- and dexamethasone-treated rats were exposed to air or 0.8-ppm ozone, 4 h/day × 2 or 4 days to assess the impacts of acute exposure and adaptation, respectively. Dexamethasone reduced thymus and spleen weights, circulating lymphocytes, corticosterone and increased insulin. Ozone increased lavage-fluid protein and neutrophils and decreased circulating lymphocytes at day-2 but not day-4. Ozone-induced hyperglycemia, glucose intolerance and inhibition of beta-cell insulin release occurred at day-1 but not day-3. Ozone depleted circulating prolactin, thyroid-stimulating hormone, and luteinizing-hormone at day-2 but not day-4, suggesting central mediation of adaptation. Adrenal epinephrine biosynthesis gene, Pnmt, was up-regulated after ozone exposure at both timepoints. However, genes involved in glucocorticoid biosynthesis were up-regulated after day-2 but not day-4, suggesting that acute 1- or 2-day ozone-mediated glucocorticoid increase elicits feedback inhibition to dampen hypothalamic stimulation of ACTH release in response to repeated subsequent ozone exposures. Although dexamethasone pretreatment affected circulating insulin, lymphocytes and adrenal genes, it had modest effect on ozone adaptation. In conclusion, ozone adaptation likely involves lack of hypothalamic response due to reduced availability of circulating glucocorticoids.

Hepato- and Nephro-Effect of Sphenostylis stenocarpa– Formulated Diet on Dexamethasone-Treated Pregnant Rats

This study sought to investigate the effect of Sphenostylis stenocarpa-formulated diet on hepatic and renal parameters of dexamethasone-treated pregnant rats. Sphenostylis stenocarpa were locally sourced from a market in Ado Ekiti. They were milled into powder and used in formulating feed for experimental animals. Fifteen female pregnant rats were divided in three groups of five each. Animals in group A were exposed to standard animal feed only. This served as the control group. Those in group B were exposed to Sphenostylis stenocarpa-formulated diet + 0.3 mg/kg body weight of dexamethasone, while those in group C were exposed to Sphenostylis stenocarpa-formulated diet. At the end of the eight days treatment, animals were sacrificed and blood sample, liver and kidney were collected. Exposure of pregnant rats to dexamethasone was observed to significantly (p&lt;0.05) increased the activities of plasma aspartate amino transaminase (AST) and alanine amino transferase (ALT) as well as the concentrations of plasma total protein, bilirubin, creatinine and urea when compared with those in animals in the control as well as those fed with S. stenocarpa-formulated diet only. The results further showed that pregnant rats fed with S. stenocarpa-formulated diet only had no significant difference on plasma hepatic and renal biomarkers when compared with those in the control group. The results of liver and kidney homogenates are similar to those observed in the plasma. Exposure of animals to dexamethasone adversely unhinged hepatic and renal biomarkers investigated in the study. The study also revealed that P. biglobosa seed is beneficial to the health of the liver and kidney of pregnant female rats.

Effect of Consumption of Sphenostylis stenocarpa Seed-formulated Diet on Oxidative Stress Biomarkers of Dexamethasone-treated Pregnant Rats

Aim: The present study tends to examine the effect of consumption of Sphenostylis stenocarpa-formulated diet on oxidative stress biomarkers of dexamethasone-treated pregnant rats.&#x0D; Methodology: Sphenostylis stenocarpa was obtained locally from a market in Ado Ekiti. They were ground into powder and used to make feed for laboratory animals. Fifteen pregnant female rats were divided into three groups of five. Animals in group A were only fed standard animal feed. This served as the control group. Those in group B were exposed to Sphenostylis stenocarpa-formulated diet + 0.3 mg/kg body weight of dexamethasone, while those in group C were exposed to Sphenostylis stenocarpa-formulated diet. At the end of the eight days treatment, animals were sacrificed and blood sample, liver and kidney were collected.&#x0D; Results: The results revealed that treatment of animals with dexamethasone significantly increased (P&lt;0.05) the activities of SOD and CAT and the concentration of MDA but decreased the concentration of GSH in plasma, liver homogenate and kidney homogenate respectively when compared with those in animals in the control group as well as those fed with S. stenocarpa-formulated diet only. The result further showed that feeding of animals with S. stenocarpa-formulated diet only had no significant effect on oxidative stress biomarkers investigated when compared with those in the control group.&#x0D; Conclusion: It can be concluded that exposure of animals to dexamethasone induced oxidative stress in animals while S. stenocarpa-formulated diet possesses the potential to alleviate the effect of oxidative stress generation.

The effect of progesterone administration on the expression of metastasis tumor antigens (MTA1 and MTA3) in placentas of normal and dexamethasone-treated rats.

Dexamethasone (DEX) induces intrauterine growth restriction (IUGR)in pregnant rats. IUGR can occur due to apoptosis of trophoblasts, which is believed to be inhibited by progesterone (P4). A group of genes called MTAs play a role in proliferation and apoptosis. MTA1 upregulates trophoblasts proliferation and differentiation, while MTA3 downregulates proliferation and induces apoptosis. Hence, we hypothesized that during IUGR, placental MTA1 decreases and MTA3 increases and this is reversed by P4 treatment. Pregnant Sprague-Dawley rats were divided into 4 groups based on daily intraperitoneal injections: control (C, saline), DEX (DEX, 0.2mg/kg/day), DEX and P4 (DEX + P4, DEX: 0.2mg/kg/day, P4: 5mg/kg/day) and P4-treated (P4, 5mg/kg/day) groups. Injections were started on 15 dg until the day of dissection (19 or 21 dg). Gene and protein expressions of MTA1 and MTA3 were studied in the labyrinth (LZ) and basal (BZ) zones using real-time PCR and Western blotting, respectively. DEX treatment induced 18% reduction in fetal body weight (p < 0.001) and 30% reduction in placental weight (p < 0.01). Maternal P4 level was also significantly lower in DEX treated groups (p < 0.05). MTA1 expression was decreased in the LZ (gene, p < 0.001) and BZ (protein p < 0.01), while MTA3 protein expression was upregulated in the LZ with DEX treatment (p < 0.001). These changes were reversed with P4 treatment. The findings of the present study indicate that DEX induces IUGR through changing the expression of placental MTA1 and MTA3 antigens and P4 improved pregnancy outcome by preventing the changes in MTAs expression.

Effect of Parkia biglobosa seed on lipid profile of dexamethasone-treated pregnant rats

This study was aimed at evaluating the effect of Parkia biglobosa seed on dexamethasone-treated pregnant rats. Locust bean seeds were purchased from an open market in Ado Ekiti, Nigeria. It was processed and ground into powder which was subsequently used in formulating feed for experimental animals. Fifteen female pregnant rats were divided in three groups of five each. Animals in group A were exposed to standard animal feed only. This served as the control group. Those in group B were exposed to animal feed mixed with locust beans + 0.3 mg/kg body weight of dexamethasone, while those in group C were exposed to animal feed mixed with locust beans. At the end of eight days treatment, animals were sacrificed and blood sample was collected into EDTA bottles and centrifuged. Plasma was separated and used for the determination of glucose and lipid profile. Exposure of animals to dexamethasone was observed to significantly (p&lt;0.05) increased the concentration of plasma glucose concentration when compared with the control as well as animals treated with P. biglobosa only. Animals treated with dexamethasone along with P. biglobosa were observed to have higher concentrations of triglyceride, total cholesterol, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) when compared with those in animals in the control group as well as those treated with P. biglobosa only. Observations from this study revealed that dexamethasone adversely perturbed and unhinged plasma glucose and lipid profile in female pregnant rats while P. biglobosa-formulated diet was observed to be a potent hypoglycemic and hypolipidemic agent.

Effect of Parkia biglobosa seed on lipid profile of dexamethasone-treated pregnant rats

Effect of Parkia biglobosa seed on lipid profile of dexamethasone-treated pregnant rats

1α,25-(OH)2 vitamin D3 prevents insulin resistance and regulates coordinated exocytosis and insulin secretion

Vitamin D3 is associated with improvements in insulin resistance and glycemia. In this study, we investigated the short-term effect of 1α,25(OH)2 Vitamin D3 (1,25-D3) and cholecalciferol (vitamin D3) on the glycemia and insulin sensitivity of control and dexamethasone-induced insulin-resistance rats. 45Ca2+ influx responses to 1,25-D3 and its role in insulin secretion were investigated in isolated pancreatic islets from control rats. In vivo, 5 d treatment with 1,25-D3 (i.p.) prevented insulin resistance in dexamethasone-treated rats. Treatment with 1,25-D3 improved the activities of hepatic enzymes, serum lipids and calcium concentrations in insulin-resistant rats. 25-D3 (o.g.) does not affect insulin resistance. In pancreatic islets, 1,25-D3 increased insulin secretion and stimulated rapid response 45Ca2+ influx. The stimulatory effect of 1,25-D3 on 45Ca2+ influx was decreased by diazoxide, apamine, thapsigargin, dantrolene, 2-APB, nifedipine, TEA, PKA, PKC, and cytoskeleton inhibitor, while it was increased by glibenclamide and N-ethylmaleimide. The stimulatory effect of 1,25-D3 on 45Ca2+ influx involves the activation of L-type VDCC, K+-ATP, K+-Ca2+, and Kv channels, which augment cytosolic calcium. These ionic changes mobilize calcium from stores and downstream activation of PKC, PKA tethering vesicle traffic and fusion at the plasma membrane for insulin secretion. This is the first study highlighting the unprecedented role of 1,25-D3 (short-term effect) in the regulation of glucose homeostasis and on prevention of insulin resistance. Furthermore, this study shows the intracellular β-cell signal transduction of 1,25-D3 through the modulation of pivotal ionic channels and proteins exhibiting a coordinated exocytosis of vesicles for insulin secretion.

Dose-dependent and time-dependent metabolic, hemodynamic, and redox disturbances in dexamethasone-treated Wistar rats.

Dexamethasone is used experimentally to induce insulin resistance and type 2 diabetes. However, data concerning the dose, the duration of treatment, and the associated comorbidities are inconsistent. The aim of this study was to compare the effects of different doses of dexamethasone and the duration of treatment necessary for the development of a model of insulin resistance thatmimics the clinical condition with the associated comorbidities. Dexamethasone was administered intramuscularly to male Wistar rats, at doses of 500 and 1,000µg/kg/day for the subchronic treatment (eight consecutive days) and at doses of 5, 25, 50, and 100µg/kg/day in chronic treatment (28 consecutive days). Effects on body weight, metabolism, hemodynamics, renal function, and redox status were evaluated. Both treatments induced a progressive body weight loss that was drastic in subchronic treatment, improved glucose tolerance without affecting fasting glycemia. Doses of 1,000 and 100µg/kg were associated with hypertriglyceridemia, hypertension, and increased heart rate, cardiac and renal hypertrophy. Increased creatinemia associated with reduced creatinuria were observed in sub-chronic treatment while increased proteinuria and reduced creatinuria were noticed in chronic treatment. 1,000µg/kg dexamethasone caused an increase in hepatic, and renal malondialdehyde (MDA) and glutathione (GSH) coupled with a reduction in catalase activity. The dose of 100µg/kg induced a rise in GSH and catalase activity but reduced MDA levels in the kidney. Doses of 1,000µg/kg for subchronic and 100µg/kg for chronic treatment exhibited similar effects and are the best doses to respective time frames to induce the model.

Protective Effects of Garcinia kola Stem Barks Aqueous Extract on Metabolic Disorders and Oxidative Stress in Dexamethasone-Induced Insulin Resistance in Rat

Aim: To evaluate how the aqueous extract of Garcinia kola (GK) stem bark impacted dexamethasone-induced insulin resistance in male rats. Method: This work was completed in 2020. A phytochemical screening of the extract was first carried out. Using acute and subacute studies (11 days), the effect of the extract was evaluated at 100 mg/kg and 200 mg/kg, on dexamethasone-induced hyperglycemic rats. Glycemia was measured before and after treatment in both studies, while histological examination for isolated liver, kidneys and pancreas was performed, body weight and some internal organs determined, and biochemical assays. for blood samples were performed only for the subacute study. Results and Conclusion : An examination of the plant's chemistry showed the presence of alkaloids, phenolic compounds, flavonoids, saponins, coumarins, anthocyanins, and anthraquinones. GK extract decreased the Area Under Curve induced by dexamethasone (DEXA) injection both in the acute and in the subacute test. The extract and glibenclamide decrease the alanine amino transferase activity induced by DEXA. In both the glibenclamide and extract groups, total protein levels increased. The uric acid level in all dexamethasone-treated rats remains elevated when compared to the normal control group. Superoxide dismutase activity increased in both groups treated with the extract or glibenclamide. DEXA induced islet hypertrophy in the pancreas, vascular congestion, cytolysis, and vacuolation of hepatocytes. The kidney presented leucocyte infiltration and a decrease in glomerular cell density. All those abnormalities were improved by the administration of glibenclamide or the extract of Garcinia kola.

Effects of high doses of glucocorticoids on insulin-mediated vasodilation in the mesenteric artery of rats.

Several pathological conditions predict the use of glucocorticoids for the management of the inflammatory response; however, chronic or high dose glucocorticoid treatment is associated with hyperglycemia, hyperlipidemia, and insulin resistance and can be considered a risk factor for cardiovascular disease. Therefore, we investigated the mechanisms involved in the vascular responsiveness and inflammatory profile of mesenteric arteries of rats treated with high doses of glucocorticoids. Wistar rats were divided into a control (CO) group and a dexamethasone (DEX) group, that received dexamethasone for 7 days (2mg/kg/day, i.p.). Blood samples were used to assess the lipid profile and insulin tolerance. Vascular reactivity to Phenylephrine (Phe) and insulin, and O2•-production were evaluated. The intracellular insulin signaling pathway PI3K/AKT/eNOS and MAPK/ET-1 were investigated. Regarding the vascular inflammatory profile, TNF-α, IL-6, IL-1β and IL-18 were assessed. Dexamethasone-treated rats had decreased insulin tolerance test and endothelium-dependent vasodilation induced by insulin. eNOS inhibition caused vasoconstriction in the DEX group, which was abolished by the ET-A antagonist. Insulin-mediated relaxation in the DEX group was restored in the presence of the O2.- scavenger TIRON. Nevertheless, in the DEX group there was an increase in Phe-induced vasoconstriction. In addition, the intracellular insulin signaling pathway PI3K/AKT/eNOS was impaired, decreasing NO bioavailability. Regarding superoxide anion generation, there was an increase in the DEX group, and all measured proinflammatory cytokines were also augmented in the DEX group. In addition, the DEX-group presented an increase in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (TC) and reduced high-density lipoprotein cholesterol (HDL-c) levels. In summary, treatment with high doses of dexamethasone promoted changes in insulin-induced vasodilation, through the reduction of NO bioavailability and an increase in vasoconstriction via ET-1 associated with generation of O2•- and proinflammatory cytokines.

NOX-dependent reactive oxygen species production underlies arrhythmias susceptibility in dexamethasone-treated rats

Dexamethasone is the most clinically used glucocorticoid with an established role in the treatment of a wide spectrum of inflammatory-related diseases. While the therapeutic actions are well known, dexamethasone treatment causes a number of cardiovascular side effects, which are complex, frequent and, in some cases, clinically unnoticeable. Here, we investigated whether a therapeutic regimen of dexamethasone affects cardiac arrhythmogenesis, focusing on the contribution of Nox-derived reactive oxygen species (ROS). Male Wistar rats were treated with dexamethasone (2 mg/kg, i.p.) for 7 days. Afterward, hemodynamic measurements, autonomic modulation, left ventricular function, cardiac fibrosis, reactive oxygen species (ROS) generation, Nox protein expression, superoxide dismutase (SOD) and catalase activities, and arrhythmias incidence were evaluated. Here, we show that dexamethasone increases blood pressure, associated with enhanced cardiac and vascular sympathetic modulation. Moreover, a marked increase in the cardiac ROS generation was observed, whereas the enhanced SOD activity did not prevent the higher levels of lipid peroxidation in the dexamethasone group. On the other hand, increased cardiac Nox 4 expression and hydrogen peroxide decomposition rate was observed in dexamethasone-treated rats, while Nox 2 remained unchanged. Interestingly, although preserved ventricular contractility and β-adrenergic responsiveness, we found that dexamethasone-treated rats displayed greater interstitial and perivascular fibrosis than control. Surprisingly, despite the absence of arrhythmias at basal condition, we demonstrated, by in vivo and ex vivo approaches, that dexamethasone-treated rats are more susceptible to develop harmful forms of ventricular arrhythmias when challenged with pharmacological drugs or burst pacing-induced arrhythmias. Notably, concomitant treatment with apocynin, an inhibitor of NADPH oxidase, prevented these ectopic ventricular events. Together, our results reveal that hearts become arrhythmogenic during dexamethasone treatment, uncovering the pivotal role of ROS-generating NADPH oxidases for arrhythmias vulnerability.