Depletion of hepatic glutathione and adenosine by glucocorticoid exposure in Wistar rats is pregnancy-independent.

Liver diseases have gained increasing attention due to their substantial impact on health, independently as well as in association with cardio-metabolic disorders. Studies have suggested that glutathione and adenosine assist in providing protection against oxidative stress and inflammation while glucocorticoid (GC) therapy has been associated with chronic inflammatory disorders, even in pregnancy. The implications of Glucocorticoid exposure on maternal health and fetal growth is a concern, however, the possible role of glutathione and adenosine has not been thoroughly investigated. The study therefore hypothesize that exposure to glucocorticoids leads to depletion of hepatic glutathione and adenosine levels, contributing to oxidative stress and tissue injury. Additionally, we aim to investigate whether the effects of glucocorticoids on hepatic health are pregnancy dependent in female rats. Twelve Pregnant and twelve age-matched non-pregnant rats were used for this study; an exogenous administration of glucocorticoid (Dex: 0.2 mg/kg) or vehicle (po) was administered to six pregnant and six non-pregnant rats from gestational day 14 to 19 or for a period of 6 days respectively. Data obtained showed that GC exposure led to a decrease in hepatic glucose-6-phosphate dehydrogenase, glutathione peroxidase, GSH/GSSG ratio and adenosine content in both pregnant and non-pregnant rats. In addition, increased activities of adenosine deaminase and xanthine oxidase, along with increased production of uric acid and increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine transferase, alkaline phosphatase and gamma-glutamyl transferase were observed. In summary, the study indicates that GC-induced liver damage is underlined by depleted hepatic adenosine and glutathione levels as well as elevated markers of tissue inflammation and/or injury. Furthermore, the findings suggest that the effects of GC exposure on hepatic health are pregnancy independent.

Low-dose spironolactone combats dyslipidemia and hepatic inflammation by modulating PCSK9 in rat model of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder among women and it is associated with overt metabolic derangement. Circulating lipids are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) which blocks low density lipoprotein (LDL) receptors especially in the liver. The liver is highly vulnerable in dyslipidemia as lipid accumulation leads to progression of non-alcoholic fatty liver disease (NAFLD). An array of scientific endeavours hold that low-dose spironolactone (LDS) is beneficial as intervention for PCOS traits, but this claim is yet to be fully elucidated. The aim of this study was to investigate the effect of LDS on dyslipidemia and hepatic inflammation in rats with letrozole (LET)-induced PCOS and to assess the possible involvement of PCSK9 in these effects. Eighteen female Wistar rats were randomly assigned into 3 groups. The control group received vehicle (distilled water; p.o.), LET-treated group received letrozole (1 mg/kg; p.o.), LET+LDS-treated group received LET plus LDS (0.25 mg/kg, p.o.) for 21 days. Exposure to LET increased body and hepatic weights, plasma and hepatic total cholesterol (TC), TC/HDL, LDL, interleukin-6, MDA, PCSK9, ovarian degenerated follicles and hepatic NLRP3 intensity, reduced GSH and normal ovarian follicles. Interestingly, LDS averted dyslipidemia, NLRP3-dependent hepatic inflammation and ovarian PCOS traits. It is evident herein that LDS ameliorates PCOS traits and combats dyslipidemia and hepatic inflammation in PCOS by a PCSK9-dependent mechanism.

Acetate-mediated-obestatin modulation attenuates adipose-hepatic dysmetabolism in high fat diet-induced obese rat model.

PURPOSE: Approximately 650 million of world adult population is affected by obesity, which is characterized by adipose and hepatic metabolic dysfunction. Short chain fatty acids (SCFAs) have been linked to improved metabolic profile. However, the effect of SCFAs, particularly acetate on adipose-hepatic dysfunction is unclear. Therefore, the present study investigated the role of acetate on adipose-hepatic metabolic dysfunction and the possible involvement of obestatin in high fat diet-induced obese Wistar rats. METHODS: Adult male Wistar rats (160-190 g) were allotted into groups (n = 6/group): Control, acetate-treated, obese and obese + acetate-treated groups received vehicle (distilled water), sodium acetate (200 mg/kg), 40% HFD and 40% HFD plus sodium acetate respectively. The administration lasted for 12 weeks. RESULTS: HFD caused increased body weight gain and visceral adiposity, insulin resistance, hyperinsulinemia and increased pancreatic-ß cell function and plasma/hepatic triglyceride and total cholesterol as well as decreased adipose triglyceride and total cholesterol, increased plasma, adipose, and hepatic malondialdehyde, TNF-α, uric acid, lactate production and plasma/adipose but not gamma-glutamyl transferase and decreased plasma, adipose, and hepatic nitric oxide, glucose-6-phosphate dehydrogenase (G6PD), glutathione (GSH) and obestatin concentration compared to the control group. Notwithstanding, treatment with acetate attenuated the alterations. CONCLUSIONS: The results demonstrate that high fat diet-induced obesity is characterized with adipose and hepatic lipid dysmetabolism, which is associated with obestatin suppression. Findings also suggest that acetate provide protection against adipose and hepatic metabolic perturbations by restoring obestatin as well as G6PD/GSH-dependent antioxidant system.

Dexamethasone increases renal free fatty acids and xanthine oxidase activity in female rats: could there be any gestational impact?

Dexamethasone (DEX) is used for various conditions in female and even during pregnancy. We tested the hypothesis that DEX exposure in female rats would lead to renal free fatty acid (FFA) accumulation with elevated xanthine oxidase (XO) activity that would be aggravated by pregnancy. Twenty-four female rats (n = 6/group) were randomly assigned to non-pregnant (NPR), DEX-exposed non-pregnant (NPR + DEX), pregnant (PRE) and DEX-exposed pregnant (PRE + DEX), respectively. NPR and PRE rats received vehicle (po) while NPR + DEX and PRE + DEX groups received DEX (0.2 mg/kg; po), between gestational days 14 and 19. Data showed that DEX exposure caused increased plasma creatinine, urea, renal FFA accumulation, lipid peroxidation, aminotranferases, depressed glutathione, increased activity of XO, and elevated uric acid in both pregnant and non-pregnant rats. The findings of this study indicate that DEX exposure would cause renal FFA accumulation and glutathione depletion that are accompanied by increased activity of XO/uric acid independently of gestation. The study also implies that DEX-induced renal damage could be worsened by gestation.

Allopurinol and valproic acid improve cardiac triglyceride and Na+-K+-ATPase activity independent of circulating aldosterone in female rats with glucose intolerance.

Context: Studies have shown that cardiac triglyceride accumulation and impaired Na+-K+-ATPase activity are linked to diabetes- related cardiovascular disease, particularly in women.Objectives: We hypothesised that allopurinol (ALL) and valproic acid (VPA) treatment would improve cardiac triglyceride and Na+-K+-ATPase activity independent of circulating aldosterone in Combined Oral Contraceptive (COC)-induced dysglycemiaMaterials and methods: Rats received COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel; po) with or without ALL (1 mg; po) and VPA (20 mg; po) for 6 weeks.Results: COC-treatment led to impaired glucose tolerance, accumulated abdominal fat, dyslipidemia, elevated plasma MDA, PAI-1 and aldosterone levels and also reduced plasma nitric oxide bioavailability and cardiac Na+-K+-ATPase activity. However, either ALL or VPA treatment ameliorated these alterations comparably independent of elevated aldosterone levelDiscussion and conclusion: Our results suggest that either ALL or VPA would improve cardiac TG and Na+-K+-ATPase activity comparably in COC-treated rats, regardless of circulating aldosterone level.

Suppression of Adenosine Deaminase and Xanthine Oxidase Activities by Mineralocorticoid and Glucocorticoid Receptor Blockades Restores Renal Antioxidative Barrier in Oral Contraceptive-Treated Dam.

OBJECTIVE: We tested the hypothesis that postpartum combined oral contraceptive (COC) treatment would induce oxidative stress via the adenosine deaminase-xanthine oxidase pathway in the kidney. We also sought to determine whether mineralocorticoid receptor (MR) or glucocorticoid receptor (GR ) blockade would suppress the activities of ADA and xanthine oxidase caused by postpartum COC treatment in the kidney. METHODS: Twenty-four Wistar dams were randomly assigned to 4 groups (n = 6/group). Dams received vehicle (po), COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel; po), COC with GR blockade (mifepristone; 80.0 mg/kg; po), and COC with MR blockade (spironolactone; 0.25 mg/kg; po) daily between 3rd and 11th week postpartum. RESULTS: Data showed that postpartum COC caused increased plasma creatinine and urea, increased renal triglyceride/high-density lipoprotein ratio, free fatty acid accumulation, alanine aminotransferase, gamma-glutamyltransferase, uric acid, and activities of renal XO and ADA. On the other hand, postpartum COC resulted in decreased plasma albumin, renal glutathione, and Na+-K+-ATPase activity with no effect on lactate production. However, MR or GR blockade ameliorated the alterations induced by postpartum COC treatment. The present results demonstrate that MR or GR blockade ameliorates postpartum COC-induced increased activities of ADA and xanthine oxidase and restores glutathione-dependent antioxidative defense. CONCLUSION: These findings implicate the involvements of GR and MR in renal dysfunctions caused by COC in dams via disrupted glutathione antioxidative barrier.

Rescue effect of sodium acetate in diabetes mellitus-associated testicular dysfunction is accompanied by PCSK9 modulation.

Diabetes mellitus (DM) is a global health burden, affecting about 463 million of the adult population worldwide. Approximately 94% of diabetic male individuals develop varying degrees of testicular disorders (TDs), which usually result in hypogonadism, hypotestosteronemia and defective spermatogenesis and steroidogenesis. Short chain fatty acids (SCFAs) have shown potential benefits in metabolic health. However, its effect on TD associated with DM is not clear. Howbeit, the present study investigated the hypothesis that SCFAs, acetate would ameliorate TD accompanying DM, possibly by suppressing proprotein convertase subtilisin/kexin type 9 (PCSK9). Male Wistar rats (210-240 g) were allotted into groups (n = 6/group): control (vehicle; po), DM with/without 200 mg/kg (po) of sodium acetate (SAc). Diabetes was induced by streptozotocin 65 mg/kg (iv) after a dose of nicotinamide (110 mg/kg). Semen/biochemical and histological analyses were performed with appropriate methods. In addition to hyperglycemia, hyperinsulinemia and reduced insulin sensitivity, DM led to increased serum and testicular triglyceride or total cholesterol/high-density lipoprotein cholesterol ratio, low-density lipoprotein cholesterol, malondialdehyde, TNF-α, IL-6 and PCSK9 as well as reduced high-density lipoprotein cholesterol and glutathione. Moreover, DM caused TD which is characterized by altered sperm parameters, disrupted tissue architecture, atrophied seminiferous tubules, deleterious spermatogonia, disappearance of lumen and cellular degeneration as well as decreased luteinizing hormone and testosterone. However, the administration of SAc attenuated these alterations. The study demonstrates that DM-induced TD is accompanied by elevated PCSK9. The results however suggest that SAc rescues testicular disorder/dysfunction associated with DM by suppression of PCSK9 and improvement of insulin sensitivity.

Treatment with acetate during late pregnancy protects dams against testosterone-induced renal dysfunction.

Cardiometabolic diseases are complicated by renal damage. Gestational hyperandrogenism causes gestational metabolic dysfunction that is associated with fetal and maternal tissue derangements as well as post-partum maternal androgen excess. Acetate (Ace) conferred hepatoprotection in pregnant rats exposed to excess testosterone (Tes). The effect of excess androgenic exposure on maternal kidney during and after pregnancy is not clear. Therefore, this study investigated the effect of late gestational and post-gestational testosterone exposure on renal functions and plausible renoprotective role of gestational Ace treatment in dams. Thirty pregnant Wistar rats were grouped (n = 10/group) and treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) with or without acetate (200 mg/kg sodium acetate; p.o) between gestational days 14 and 19. Data were obtained from half of the animals on gestational day 20. Data were also obtained from the other half (dams) after treatment of animals which received Tes with or without prior gestational acetate treatment with post-gestational Tes (sc; 0.5 mg/kg) for the last 6 days of an 8-week postpartum period. Biochemical and statistical analyses were performed with appropriate methods and SPSS statistical software respectively. Late gestational excess Tes led to low placental weight (p = 0.0001, F = 205.7), poor fetal outcomes, creatinine (p = 0.0001, F = 385.4), urea (p = 0.0001, F = 300.9) and renal uric acid (UA) (p = 0.0001, F = 123.2), gamma-glutamyl transferase (GGT) (p = 0.004, F = 26.9), malondialdehyde (p = 0.0001, F = 45.96), and lactate dehydrogenase (LDH) (p = 0.0002, F = 150.7). Postpartum Tes exposure also caused elevated plasma testosterone (p = 0001, F = 22.15), creatinine (p = 0.0002, F = 15.2), urea (p = 0.01, F = 13.8) and renal UA (p = 0.0001, 226.8), adenosine deaminase (p = 0001, F = 544.7), GGT (p = 0.0002, F = 401.4) and LDH (p = 0.01, F = 23.7). However, gestational acetate treatment ameliorated the renal effects of gestational and post-gestational Tes exposure. Taken together, gestational acetate would pre-programme dams against renal dysfunction caused by Tes exposure.

Acetate causes renoprotection like androgen and mineralocorticoid receptors blockade in testosterone-exposed pregnant rats.

The kidney plays a critical role in human health and deviation from its normal function can lead to severe morbidity and mortality. Exposure to excess testosterone in women has been linked to several disorders, including kidney disorder and acting undoubtedly through androgen receptor (AR), whereas the involvement of mineralocorticoid receptor (MR) is unclear. Likewise, the renal effect of sodium acetate (SAc) during late gestational exposure to testosterone is not well known. We hypothesized that SAc or MR blockade would protect the kidney of testosterone-exposed pregnant rats against glutathione and adenosine depletion. Twenty-five pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; p.o.), androgen receptor (AR) blocker, flutamide (Flu; 7.5 mg/kg; p.o.) or (MR) blocker, eplerenone (Eple; 0.5 mg/kg) between gestational days 14 and 19. Glutathione, adenosine and nitric oxide were decreased while uric acid (UA), xanthine oxidase (XO), malondialdehyde (MDA), lactate dehydrogenase activity and free fatty acids were increased in the kidneys of gestational rats exposed to testosterone. Also, plasma urea and creatinine were elevated. SAc and Eple reversed tested testosterone-induced effects in gestational rats. The exposure to testosterone impairs renal antioxidant defense via AR and MR during late gestation in pregnant rats. The study also provides evidence that sodium acetate protects the kidneys of gestational testosterone-exposed rats against defective antioxidant defense in like manner as MR or AR antagonist.

Late gestational testosterone exposure causes glucose deregulation and elevated cardiac VCAM-1 and DPP-4 activity in rats.

CONTEXT: Increased vascular cell adhesion molecule-1 (VCAM-1) has been reported to be a critical link between obesity and atherosclerotic cardiovascular diseases while dipeptidyl peptidase-4 (DPP-4) has been implicated in the development of disrupted glucose regulation and inflammation. OBJECTIVE: This study aimed to investigate the effect of gestational testosterone exposure on glucose metabolism, atherogenic dyslipidemia, as well as circulating and cardiac VCAM-1, oxidative stress biomarkers and DPP-4 activity in pregnant rats. METHODS: Pregnant Wistar rats received either vehicle or testosterone (0.5 mg/kg; sc) between gestational days 14 and 19. RESULTS: Gestational testosterone exposure caused impaired glucose homeostasis that was accompanied with atherogenic dyslipidemia, elevated circulating and cardiac levels of VCAM-1, uric acid, malondialdehyde as well as increased DPP-4 activity. However, nitric oxide levels were decreased. CONCLUSION: This study shows that gestational testosterone exposure causes glucose deregulation and atherogenic dyslipidemia that is accompanied by increased circulating and cardiac VCAM-1 and DPP-4 activity.

Sodium butyrate arrests pancreato-hepatic synchronous uric acid and lipid dysmetabolism in high fat diet fed Wistar rats.

High fat diet (HFD) is a risk factor for metabolic syndrome which is characterized by overt glucose dysmetabolism and tissue derangement. The liver and pancreas are important metabolic tissues with anatomical proximity sharing splanchnic and mesenteric circulation but it is unclear whether, there is an associated metabolic status between the two organs in health and disease. Uric acid (UA) hypersecretion and ectopic lipid accumulation are characteristic pathophysiology of an array of non-communicable diseases. Sodium butyrate (BUT) is reputed for therapeutic roles in metabolic derangement. Therefore, the present study investigated synchrony in hepatic and pancreatic UA and lipid metabolic status in HFD-induced glucose dysregulation and probed the beneficial effects of BUT. Twenty-four female Wistar rats were treated with normal rat chow and distilled water (po) or sodium butyrate (200 mg/kg; po) or high fat diet and distilled water (po) or high fat diet and sodium butyrate. Results showed that HFD increased plasma, pancreatic and hepatic triglyceride, triglyceride-glucose index, malondialdehyde, uric acid (UA), lactate dehydrogenase but reduced glucose-6-phosphate dehydrogenase. Histological analysis revealed hepatic and pancreatic architectural derangement and cellular degeneration in HFD-fed animals. However, BUT reversed the HFD-induced systemic, pancreatic and hepatic synchronous dysmetabolism with evidence of improved histology. HFD-induced lipid and UA alterations were synchronous in the pancreas and liver. BUT elicits beneficial effects on systemic and tissue HFD-induced deleterious metabolic changes which were synchronized in pancreas and liver of rats.

Suppression of uric acid and lactate production by sodium acetate ameliorates hepatic triglyceride accumulation in fructose-insulin resistant pregnant rats.

High fructose intake has been associated with perturbed lipid, uric acid and lactate homeostasis. However, consumption of fructose-sweetened beverages is not usually regulated during pregnancy. The effect of short-chain fatty acid (acetate) on the metabolic effects of high fructose intake during pregnancy is not known. We hypothesized that acetate prevents gestational fructose-induced hepatic triglyceride (TG) accumulation by suppressing uric acid and lactate production. Pregnant Wistar rats were randomly separated into three groups (n = 6/group) receiving drinking water (CON), 10 % (w/v) fructose drink (FRU) and 10 % (w/v) fructose with 200 mg/kg (w/w; p.o.) sodium acetate (FRU + ACE) daily for nineteen days. Fructose intake resulted in increased body weight gain, liver weight, fluid intake, visceral fat, insulin resistance, fasting blood glucose, insulin, plasma and hepatic TG, total cholesterol, free fatty acid, lipid peroxidation, adenosine deaminase, xanthine oxidase, uric acid, lactate, lactate dehydrogenase, and liver injury marker enzymes. However, gestational high fructose intake led to depressed plasma and hepatic glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant barrier, adenosine and food intake. All these effects except water intake and food intake were abated by sodium acetate. These results demonstrate that maternal fructose-enriched drink would cause hepatic TG accumulation that is associated with perturbed glucose, uric acid, lactate homeostasis, and G6PD-dependent antioxidant barrier. These results also demonstrate that acetate protects the liver against gestational fructose-induced TG accumulation by inhibiting uric acid and lactate production. Thus, acetate may be useful in the treatment of hyperuricemia- and hyperlactatemia-related disorders.

Dexamethasone causes defective glucose-6-phosphate dehydrogenase dependent antioxidant barrier through endoglin in pregnant and nonpregnant rats.

Glucocorticoid therapy has been associated with adverse cardiometabolic effects during pregnancy. Inflammation-mediated cardiac dysfunction, an independent risk factor for morbidity and mortality, has been linked to defective glucose-6-phosphate dehydrogenase (G6PD) dependent antioxidant defenses and increased endoglin expression. We therefore sought to investigate the effects of dexamethasone (DEX) on cardiac endoglin and G6PD-dependent antioxidant defense. Twenty-four rats were randomly assigned to nonpregnant (PRE(-)), DEX-exposed nonpregnant (PRE(-) + DEX), pregnant (PRE(+)), and DEX-exposed pregnant (PRE(+) + DEX) rats, respectively (n = 6 per group). PRE(-) and PRE(+) rats received vehicle (per oral (po)), while PRE(-) + DEX and PRE(+) + DEX groups were administered DEX (0.2 mg/kg po) between gestational days 14 and 19, respectively. Results showed that DEX caused increased cardiac pro-inflammatory markers (adenosine deaminase (ADA) activity, endoglin, vascular cell adhesion molecule-1 (VCAM-1), tissue injury markers (LDH, GGT, AST, ALT, and ALP), metabolic disturbances (elevated fasting plasma glucose, free fatty acid (FFA), lactate, cardiac FFA, and lactate) and depressed G6PD-dependent antioxidant defenses (G6PD activity, reduced glutathione/oxidized glutathione ratio, and nitric oxide) in pregnant and nonpregnant rats. The present study demonstrates that DEX led to increased cardiac endoglin and VCAM-1 that is accompanied by defective G6PD-dependent antioxidant defenses but not cardiac lipid accumulation in both pregnant and nonpregnant rats.

Triglyceride/HDL-cholesterol ratio and plasminogen activator inhibitor-1 independently predict high pulse pressure in sickle cell trait and disease.

We hypothesised that TG/HDL-C ratio and PAI-1 would be associated with high pulse pressure (PP) in young adults with sickle cell trait (SCT) and sickle cell disease (SCD). We compared the clinical, biochemical, and cardiometabolic parameters among individuals with normal genotype (HbAA; n = 60), SCT (HbAS; n = 60), and SCD (HbSS; n = 60), all in steady state. Using multivariate linear regression analysis, high PP was positively related to TG/HDL-C ratio in SCT (ß = 0.307; p = .014) and PAI-1 (ß = 0.499; p = .001) in SCD. The curve of receiver operating characteristic also showed that TG/HDL-C ratio and PAI-1 are efficient predictors of high PP in SCT carriers and SCD patients, respectively. This study suggests that increased levels of TG/HDL-C ratio and PAI-1 may be salient risk factors that would promote the development of arterial stiffness and other CVD in SCT carriers and SCD patients.

Drospirenone-containing oral contraceptives do not affect glucose regulation and circulating corticosterone.

Background Combined oral contraceptive (COC) use has been associated with an increased risk of insulin resistance (IR) and other adverse cardiovascular events, despite efforts to reduce the dosage and/or progestin type. COC containing drospirenone (DRSP) is an analog of spironolactone, hence its antimineralocorticoid and antiandrogenic characteristics have been deemed beneficial, although the benefits and/or negative outcome of its usage have not been fully elucidated. We therefore hypothesized that COC with DRSP component will not affect glucose regulation and circulating corticosterone. Method Ten-week-old female Wistar rats were divided into three groups: control (CON), ethinylestradiol/drospirenone COC (EE/DRSP)-treated, and ethinylestradiol/levonorgestrel COC (EE/LN)-treated rats. The treatment lasted for 8 weeks. Results Results showed that with the exception of lipid profiles, EE/LN but not EE/DRSP COC treatment affected body weight, glucose tolerance, plasma insulin, corticosterone, (IR), and pancreatic ß-cell dysfunction. Conclusion Taken together, the findings showed that the beneficial effect of EE/DRSP could possibly be through the DRSP component. The result also implies that COCs containing DRSP may be a better and safer means of contraception than those with LN with less cardiovascular risks.

Very low dose spironolactone protects experimentally-induced polycystic ovarian syndrome from insulin-resistant metabolic disturbances by suppressing elevated circulating testosterone.

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women of reproductive age and hyperandrogenism is a prominent feature of PCOS resulting in infertility and increased risk of developing metabolic disorders including insulin resistance (IR), abdominal adiposity, glucose intolerance and cardiovascular diseases. Spironolactone (SPL), a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. In this study, we investigated the effects of SPL on IR and metabolic disturbances in letrozole-induced PCOS rats. Eighteen adults female Wistar rats were randomly divided into 3 groups and treated with vehicle, letrozole (LET; 1 mg/kg) and LET + SPL (SPL; 0.25 mg/kg), p.o. once daily for 21 consecutive days. Results showed that LET treatment induced PCOS characterised by elevated plasma testosterone and luteinizing hormone (LH) accompanied with increased body weight and visceral adiposity, IR, glucose intolerance, dyslipidemia and altered histomorphological ovaries. Treatment with SPL however attenuated the elevated testosterone in LET-induced PCOS model accompanied with a reversal in all the observed alterations. Taken together, analysis of the physical, biochemical and histological evidences shows that the protective effect of this very low dose spironolactone may be through its anti-androgenic mechanism.

Drospirenone-containing contraceptive exerts positive effects on cardiac uric acid and PAI-1 but not GSK-3: Improved safety profiles in contraception?

The use of combined oral contraceptives (COC) have been associated with increased risk of adverse cardiovascular events and elevated cardiac and circulating plasminogen activator inhibitor-1 (PAI-1) and glycogen synthase kinase-3 (GSK-3) have been implicated in these events. Contraceptives containing drospirenone, a progestin with anti-androgenic actions may have a positive or neutral effect on cardiac PAI-1 and GSK-3 levels. Studies on the favorable effects of oral contraceptives containing drospirenone when compared with other androgenic contraceptives have not been fully elucidated. We therefore sought to compare the effect of a contraceptive containing ethinyl estradiol and drospirenone (DSP) with a contraceptive containing ethinyl estradiol and levonorgestrel (LVG) on cardiac uric acid (UA), PAI-1, GSK-3 and some hematological parameters. Ten weeks old female Wistar rats were divided into three groups; control (CON), LVG or DSP treated rats. The treatment lasted for 8 weeks. Results showed that LVG and not DSP treatment led to increase in plasma and cardiac tissue UA, plasma and cardiac PAI-1 as well as granulocyte-lymphocyte ratio (GLR) and platelet-lymphocyte ratio (PLR). However, the DSP treatment affected the circulating GSK-3. Taken together, the findings showed that LVG and not DSP affected cardiac UA and PAI-1. These results suggest that COC containing drospirenone appears to have positive effects on cardiac UA and PAI-1 levels but do not affect GSK-3, hence, COC containing drospirenone may be a better and safer means of contraception compared to androgenic contraceptives.

Involvement of glucocorticoid and mineralocorticoid receptors in lipid accumulation and depressed G6PD activity in the livers of rats treated with postpartum oral estrogen-progestin.

Postpartum contraception is an important step for preventing closely spaced pregnancy. Combined oral contraceptive (COC) has been linked to cardiometabolic disturbances. We therefore hypothesized that postpartum oral estrogen-progestin use induces hepatic lipid accumulation that is associated with glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation via adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA)-dependent pathway. Female Wistar rats weighing 130-150 g were mated to achieve timed pregnancy and delivery. Twenty-four (24) dams were randomly assigned to receive vehicle (po), COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel; po), COC with GR blockade (mifepristone; 80.0 mg/kg; po) and COC with MR blockade (spironolactone; 0.25 mg/kg; po) daily between 3rd and 11th week postpartum. Data showed that postpartum COC resulted in glucose dysregulation, increased visceral adiposity, liver weight, plasma corticosterone, aldosterone, circulating and hepatic free fatty acid (FFA), triglyceride (TG), adenosine deaminase (ADA), uric acid production, lactate production, and oxidative marker injury. On the other hand, G6PD-dependent antioxidant defenses were depressed by postpartum COC. However, these effects were attenuated by GR or MR blockade. Our data demonstrate that enhanced G6PD-dependent antioxidant defenses and suppressed ADA/XO/UA pathway in the liver by GR or MR blockade improves glucose dysregulation and hepatic TG accumulation induced by postpartum COC. This study implies a plausible involvement of GR and MR via defective G6PD-dependent antioxidant barrier and increased activity of ADA/XO/UA pathway in postpartum COC-induced hepatic lipid accumulation.

Mineralocorticoid receptor blockade attenuates disrupted glutathione-dependent antioxidant defense and elevated endoglin in the hearts of pregnant rats exposed to testosterone.

Elevated testosterone during late pregnancy has been linked to cardiac dysfunction and poor pregnancy outcomes. The role of mineralocorticoid receptor (MR) in testosterone-induced cardiac dysfunction has not been fully elucidated. The study was therefore designed to investigate the role of MR on gestational excess androgen-induced cardiac disrupted glutathione-dependent antioxidant system and elevated endoglin (Eng) linking it with pregnancy outcomes. Thirty-two pregnant Wistar rats were randomly allotted into four groups (n = 8/group) receiving (sc) olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with non-selective MR blocker (MRB), spironolactone (0.25 mg/kg; po) or selective MRB, and eplerenone (1.0 mg/kg; po) in late between gestational days 14 and 19. The results showed that testosterone exposure resulted in elevated fasting blood glucose, increased cardiac mass, free fatty acid, endoglin, malonaldehyde, oxidized glutathione, uric acid, and lactate production and cardiac injury marker enzymes. On the other hand, testosterone exposure caused reduction in cardiac adenosine, nitric oxide, glutathione, glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. However, MR blockade by spironolactone and or eplerenone attenuated the effects induced by testosterone exposure. Taken together, the findings from the current study demonstrates that lategestational testosterone induces poor pregnancy outcome that is accompanied by cardiac lipotoxicity,glutathione-dependent antioxidant defense depletion, increased endoglin, lactate and uric acid productionthrough MR activation.