Curcumin reverses diabetic nephropathy in streptozotocin-induced diabetes in rats by inhibition of PKCβ/p66Shc axis and activation of FOXO-3a

This study investigated if the nephroprotective effect of Curcumin in streptozotocin-induced type 1 diabetes mellitus (DM) in rats involves downregulation/inhibition of p⁶⁶Shc and examined the underlying mechanisms. Rats were divided into 4 groups (n = 12/group) as control, control + Curcumin (100 mg/kg), T1DM, and T1DM + Curcumin. Curcumin was administered orally to control or diabetic rats for 12 weeks daily. As compared to diabetic rats, Curcumin didn't affect either plasma glucose or insulin levels but significantly reduced serum levels of urea, blood urea nitrogen, and creatinine, and concurrently reduced albumin/protein urea and increased creatinine clearance. It also prevented the damage in renal tubules and mitochondria, mesangial cell expansion, the thickness of the basement membrane. Mechanistically, Curcumin reduced mRNA and protein levels of collagen I/III and transforming growth factor- β-1 (TGF-β1), reduced inflammatory cytokines levels, improved markers of mitochondrial function, and suppressed the release of cytochrome-c and the activation of caspase-3. In the kidneys of both control and diabetic rats, Curcumin reduced the levels of reactive oxygen species (ROS), increased mRNA levels of manganese superoxide dismutase (MnSOD) and gamma-glutamyl ligase, increased glutathione (GSH) and protein levels of Bcl-2 and MnSOD, and increased the nuclear levels of nuclear factor2 (Nrf2) and FOXO-3a. Besides, Curcumin reduced the nuclear activity of the nuclear factor-kappa B (NF-κB), downregulated protein kinase CβII (PKCβII), NADPH oxidase, and p⁶⁶Shc, and decreased the activation of p⁶⁶Shc. In conclusion, Curcumin prevents kidney damage in diabetic rats by activating Nrf2, inhibiting Nf-κB, suppressing NADPH oxidase, and downregulating/inhibiting PKCβII/p⁶⁶Shc axis.     

Human amniotic fluid stem cells can improve cerebral vascular remodelling and neurological function after focal cerebral ischaemia in diabetic rats

Diabetes causes vascular injury and carries a high risk of ischaemic stroke. Human amniotic fluid stem cells ( hAFSCs) can enhance cerebral vascular remodelling and have the potential to improve neurological function after stroke in diabetic rats. Five groups of female rats were examined: (1) normal control, (2) type 1 diabetic (T1DM) rats induced by streptozotocin injection (DM), (3) non-DM rats receiving 60-minute middle cerebral artery occlusion (MCAO), (4) T1DM rats receiving 60-minute MCAO (DM + MCAO) and (5) T1DM rats receiving 60-minute MCAO and injection with 5 × 10⁶ hAFSCs at 3 h after MCAO (DM + MCAO + hAFSCs). Neurological function was examined before, and at 1, 7, 14, 21 and 28 days, and cerebral infarction volume and haemorrhage, cerebral vascular density, angiogenesis and inflammatory were examined at 7 and 28 days after MCAO. hAFSCs treatment caused a significant improvement of neurological dysfunction, infarction volume, blood-brain barrier leakage, cerebral arterial density, vascular density and angiogenesis and a reduction of brain haemorrhage and inflammation compared with non-treatment. Our results showed that the effect of hAFSCs treatment against focal cerebral ischaemia may act through the recovery of vascular remodelling and angiogenesis and the reduction of inflammation in ischaemic brain.     

Therapeutic Potential of Date Palm Pollen for Testicular Dysfunction Induced by Thyroid Disorders in Male Rats

Hyper- or hypothyroidism can impair testicular function leading to infertility. The present study was designed to examine the protective effect of date palm pollen (DPP) extract on thyroid disorder-induced testicular dysfunction. Rats were divided into six groups. Group I was normal control. Group II received oral DPP extract (150 mg kg^-1), group III (hyperthyroid group) received intraperitoneal injection of L-thyroxine (L-T4, 300μg kg^-1; i.p.), group IV received L-T4 plus DPP extract, group V (hypothyroid group) received propylthiouracil (PTU, 10 mg kg^-1; i.p.) and group VI received PTU plus DPP extract. All treatments were given every day for 56 days. L-T4 or PTU lowered genital sex organs weight, sperm count and motility, serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T), testicular function markers and activities of testicular 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD). Moreover, L-T4 or PTU increased estradiol (E2) serum level, testicular oxidative stress, DNA damage and apoptotic markers. Morphometric and histopathologic studies backed these observations. Treatment with DPP extract prevented LT4- or PTU induced changes. In addition, supplementation of DPP extract to normal rats augmented sperm count and motility, serum levels of LH, T and E2 paralleled with increased activities of 3β-HSD and 17β-HSD as well as testicular antioxidant status. These results provide evidence that DPP extract may have potential protective effects on testicular dysfunction induced by altered thyroid hormones.     

The susceptibility to autoxidation of erythrocytes in diabetic mice: Effects of melatonin and pentoxifylline

Oxidative stress had a great importance in development of complications in diabetes. We investigated effects of melatonin and pentoxifylline in diabetic mice. Swiss albino mice (n = 40) were divided into four groups: alloxan‐induced diabetes mellitus (DM), alloxan‐induced diabetes with melatonin supplementation (DM + MLT), alloxan‐induced diabetes with pentoxifylline supplementation (DM + PTX), and control. Glutathione‐peroxidase (GSH‐Px) activity, malondialdehyde (MDA) and reduced glutathione (GSH) levels, and susceptibility to oxidation of erythrocytes were measured. MDA levels were higher than control in the DM and DM + MLT. The DM had more MDA level than the DM + MLT and DM + PTX (P < 0.001). After in vitro oxidation, MDA levels of all groups were found higher than the control. However, they were significantly lower than the DM in DM + PTX and DM + MLT (P < 0.001). Although GSH levels of the DM and DM + PTX were less than the control, GSH‐Px activity of the DM was lower than the control and DM + PTX (P < 0.05). We suggest that there is increased oxidative stress and compromised antioxidant status of erythrocytes in diabetes; however, it can be effectively prevented by melatonin or pentoxifylline supplementation.     

Urolithin A prevents streptozotocin-induced diabetic cardiomyopathy in rats by activating SIRT1

This study examined the cardiac anti-cardiomyopathy (DC) protective effect of urolithin A in streptozotocin (STZ)-treated rats and investigated if this protection involves activation of SIRT1 signaling. Diabetes was induced first STZ (65 mg/kg, i.p.) before starting the experiments. Adult male rats (n = 8/group) were treated for 8 weeks as control (non-diabetic), control + urolithin A (2.5 mg/kg/i.p.), STZ, STZ + urolithin A, and STZ + urolithin A + Ex-527 (1 mg/kg/i.p.) (a SIRT1 inhibitor). With no effect on fasting glucose and insulin levels, urolithin A improved left ventricular (LV) function and structure and reduced heart weight and serum levels of cardiac markers in STZ-treated rats. Also, it prevented collagen deposition, reduced mRNA levels of Bax, cleaved caspaspe3, collagen 1A1, transforming growth factor-β1 (TGF-β1), and Smad3 but enhanced those of Bcl2 in the LVs of diabetic rats. However, urolithin A suppressed the generation of reactive oxygen species (ROS), activated the nuclear factor erythroid 2–related factor 2 (Nrf2), and increased the levels of manganese superoxide dismutase (MnSOD) and total glutathione (GSH) in the LVs of the non-diabetic and diabetic rats, In parallel, it suppressed the cardiac activity of NF-nuclear factor-kappa beta p65 (κB p65) and reduced levels of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Coincided with these events, urolithin A promoted higher activity, mRNA, and total/nuclear protein levels of SIRT1 and lowered the levels of acetyl-FOXO1, Nrf2, NF-κB, and p53. All these benefits of urolithin A were prevented by Ex-527. In conclusion, urolithin A protects against DC by activating SIRT signaling.     

Protective effect of aldehyde dehydrogenase 2 against rat corneal dysfunction caused by streptozotocin-induced type I diabetes

Aldehyde dehydrogenase 2 plays a pivotal role in detoxifying aldehydes, and our previous study revealed that aldehyde dehydrogenase 2 could alleviate diabetic retinopathy-associated damage. We aimed to characterize the potential role of aldehyde dehydrogenase 2 in diabetic keratopathy. Twenty-four rats with streptozotocin-induced (60 mg/kg, single intraperitoneal injection) type 1 diabetes mellitus (T1DM) were divided the T1DM group and the T1DM + Alda1 (an activator of aldehyde dehydrogenase 2) group (5 mg/kg/d, intraperitoneal injection, 1/2/3 months), while an additional 12 healthy rats served as the control group. Corneal morphology was examined in vivo and in vitro at one, two, and three months after T1DM induction. Additionally, serum inflammatory factors were measured by ELISA, and the expression of corneal vascular endothelial growth factor A (VEGF-A) and aldehyde dehydrogenase 2 was measured by immunofluorescence staining. Corneal cell death was evaluated by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. Slit lamp analysis showed that the area of corneal epithelial cell injury in the T1DM + Alda1 group was significantly smaller than that in the T1DM group at one and two months after T1DM induction (all P < 0.05). OCT analysis and HE staining showed that the central corneal thickness (indication of corneal edema) and the epithelial keratinization level in the T1DM + Alda1 group was evidently decreased compared with those in the T1DM group (all P < 0.05). The serum inflammatory factors interleukin-1 and interleukin-6 were significantly upregulated in the T1DM group compared with the T1DM + Alda1 group at three months after T1DM induction (all P < 0.05), while there were no differences in SOD or TNF-α levels among all groups. Furthermore, corneal VEGF-A expression and corneal cell death in the T1DM + Alda1 group were dramatically reduced compared to those in the T1DM group (all P < 0.05). In conclusion, the aldehyde dehydrogenase 2 agonist Alda1 attenuated rat corneal dysfunction induced by T1DM by alleviating corneal edema, decreasing corneal cell death, and downregulating corneal VEGF-A expression.     

Zinc deficient diet exacerbates the testicular and epididymal damage in type 2 diabetic rat: Studies on oxidative stress-related mechanisms

Zinc (Zn) is one of the most important trace elements in the body and is required for insulin secretion and release. Zn is also required for the growth and development of the reproductive system. Alteration in the Zn levels can cause moderate to severe damage to various organs, including the reproductive system. Most of type 2 diabetic patients have altered Zn levels/signaling. So, here we investigated the role of Zn-deficient diet (ZDD) in type 2 diabetes. Type 2 diabetes in the rat was induced by the combination of high-fat diet (HFD) and a single low dose of streptozotocin (STZ, 35 mg/kg, i.p.). Control animals were fed normal pellet diet throughout the study, while ZDD was given for four consecutive weeks to the diabetic rats, which were earlier kept on HFD for 16 weeks. The present findings showed that ZDD further decreased the serum Zn, plasma insulin and serum testosterone levels, whereas it increased cholesterol, triglycerides, BUN, %HbA1c in diabetic rats. Oxidative stress in testes was increased by ZDD as evidenced by decreased glutathione, catalase and SOD1 levels. ZDD-induced several abnormalities in sperm head morphology, altered sperm decondensation, sperm chromatin and protamine content, along with significant histopathological alterations in testes and epididymis. Further, ZDD altered protein levels of MT, MTF-1, Keap1, Nrf2, Nf-κB, GPX4 and GPX5 levels in the testes and epididymis of diabetic rat. The present results demonstrated that dietary Zn deficiency could exacerbate type 2 diabetes-induced germ cell damage.     

Changes in serum inflammatory factor interleukin-6 levels and pathology of carotid vessel walls of rats with chronic periodontitis and diabetes mellitus after the periodontal intervention

ObjectiveThe effects of the periodontal intervention on rats with type-II diabetes mellitus (T2DM) and chronic periodontitis (CP) were explored through observing the changes in carotid artery pathology and interleukin-6 (IL-6) levels.MethodsThe rats were randomly divided into 5 groups, i.e. group A (the normal control group), group B (the T2DM control group), group C (the CP control group), group D (the T2DM + CP group), and group E (the periodontal intervention T2DM + CP group). Blood samples of rats were collected from angular veins respectively at the following 5 time nodes: 1 week before the intervention (T1), 1 week after the intervention (T2), 3 weeks after the intervention (T3), 5 weeks after the intervention (T4), and 7 weeks after the intervention (T5); IL-6 concentrations before and after the intervention were determined by the enzyme-linked immunosorbent assay (ELISA), and the pathology of carotid arteries were observed by the Hematoxylin-Eosin (HE) stain.ResultsThe pathological results of carotid arteries showed that the blood vessels of rats in group A were normal in morphology; most of the carotid artery vessel walls of rats in groups B, C, and D were significantly thickened and the fibers were disorderly arranged; the increased thickness of vessel walls of rats in group E was reduced, a small number of foam cells and inflammatory cells were observed, and the irregular arrangement of fibers was improved. In terms of the IL-6 concentrations, during the period of T1-T5, in groups B, C, and D, the IL-6 concentrations in rats were increased (P < 0.05); after the periodontal intervention, in group E, the IL-6 concentrations in rats were first increased then decreased (P < 0.05).ConclusionIn terms of the long-term effects, periodontal intervention may reduce the inflammations of patients with diabetes mellitus and periodontitis and improve the lesions of carotid arteries.     

Forskolin ameliorates mancozeb‐induced testicular and epididymal toxicity in Wistar rats by reducing oxidative toxicity and by stimulating steroidogenesis

In the present study, we have tested the beneficial effects of forskolin in protecting the mancozeb‐induced reproductive toxicity in rats. Adult male Wistar rats were exposed to either mancozeb (500 mg/kg body weight/day) or forskolin (5 mg/kg body weight/day) or both for 65 days and analyzed for spermatogenesis and steroidogenesis and testicular and epididymal oxidative toxicity. A significant decrease in daily sperm production, epididymal sperm count, motile, viable, and hypo‐osmotic swelling‐tail swelled sperm was observed in mancozeb‐treated rats. The activity levels of testicular 3β‐hydroxysteroid dehydrogenase and 17β‐hydroxysteroid dehydrogenase and circulatory testosterone levels were significantly decreased in mancozeb‐treated rats. Exposure to mancozeb resulted in a significant decrease in glutathione levels and superoxide dismutase and catalase activity levels with an increase in lipid peroxidation levels in the testes and epididymis. Coadministration of forskolin mitigated the mancozeb‐induced oxidative toxicity and suppressed steroidogenesis and spermatogenesis.     

Exposure to high fluoride concentration in drinking water will affect spermatogenesis and steroidogenesis in male albino rats

Sodium fluoride (NaF) administered orally to adult male rats at a dose level of 4.5 ppm and 9.0 ppm for 75 days caused significant decrease in the body weight, brain index and testicular index. A significant decrease in sperm count, sperm motility, sperm viability and sperm function (HOS positive) with increased sperm abnormalities was also observed in NaF-exposed male rats. The activity levels of testicular steroidogenic marker enzymes 3-hydroxysteroid dehydrogenase (3-HSD) and 17-hydroxysteroid dehydrogenase (17-HSD) were significantly decreased in NaF-treated rats indicating decreased steroidogenesis and in turn spermatogenesis in rats exposed to NaF.     

Allopurinol reduces oxidative stress and activates Nrf2/p62 to attenuate diabetic cardiomyopathy in rats

Allopurinol (ALP) attenuates oxidative stress and diabetic cardiomyopathy (DCM), but the mechanism is unclear. Activation of nuclear factor erythroid 2‐related factor 2 (Nrf2) following the disassociation with its repressor Keap1 under oxidative stress can maintain inner redox homeostasis and attenuate DCM with concomitant attenuation of autophagy. We postulated that ALP treatment may activate Nrf2 to mitigate autophagy over‐activation and consequently attenuate DCM. Streptozotocin‐induced type 1 diabetic rats were untreated or treated with ALP (100 mg/kg/d) for 4 weeks and terminated after heart function measurements by echocardiography and pressure‐volume conductance system. Cardiomyocyte H9C2 cells infected with Nrf2 siRNA or not were incubated with high glucose (HG, 25 mmol/L) concomitantly with ALP treatment. Cell viability, lactate dehydrogenase, 15‐F2t‐Isoprostane and superoxide dismutase (SOD) were measured with colorimetric enzyme‐linked immunosorbent assays. ROS, apoptosis, was assessed by dihydroethidium staining and TUNEL, respectively. The Western blot and qRT‐PCR were used to assess protein and mRNA variations. Diabetic rats showed significant reductions in heart rate (HR), left ventricular eject fraction (LVEF), stroke work (SW) and cardiac output (CO), left ventricular end‐systolic volume (LVVs) as compared to non‐diabetic control and ALP improved or normalized HR, LVEF, SW, CO and LVVs in diabetic rats (all P < .05). Hearts of diabetic rats displayed excessive oxidative stress manifested as increased levels of 15‐F2t‐Isoprostane and superoxide anion production, increased apoptotic cell death and cardiomyocytes autophagy that were concomitant with reduced expressions of Nrf2, heme oxygenase‐1 (HO‐1) and Keap1. ALP reverted all the above‐mentioned diabetes‐induced biochemical changes except that it did not affect the levels of Keap1. In vitro, ALP increased Nrf2 and reduced the hyperglycaemia‐induced increases of H9C2 cardiomyocyte hypertrophy, oxidative stress, apoptosis and autophagy, and enhanced cellular viability. Nrf2 gene silence cancelled these protective effects of ALP in H9C2 cells. Activation of Nrf2 subsequent to the suppression of Keap1 and the mitigation of autophagy over‐activation may represent major mechanisms whereby ALP attenuates DCM.     

Excessive dietary calcium in the disruption of structural and functional status of adult male reproductive system in rat with possible mechanism

Calcium is essential for functioning of different systems including male reproduction. However, it has also been reported as chemo-castrative agent. The study has been undertaken to elucidate the effect of excessive dietary calcium on male reproductive system in animals with possible action. Adult male healthy rats fed CaCl(2) at different doses (0.5, 1.0 and 1.5 g%) in diet for 13 and 26 days to investigate reproductive parameters as well as the markers of oxidative stress. Significant alteration was found (P < 0.05) in testicular and accessory sex organs weight, epididymal sperm count, testicular steroidogenic enzyme (Δ(5) 3β-HSD and 17β-HSD) activities, serum testosterone, LH, FSH, LPO, activities of antioxidant enzymes, testicular histoarchitecture along with adrenal Δ(5) 3β-HSD activity with corticosterone level in dose- and time-dependent manner. Overall observations suggest that excessive dietary calcium enhances the generation of free-radicals resulting in structural and functional disruption of male reproduction.     

The effects of resveratrol on cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein levels in diabetic rat kidneys

Cyclooxygenase (COX), which have the isoforms of COX-1 and COX-2, is the key enzyme of prostaglandins biosynthesis. Especially, COX-2 is induced in inflammatory disease such as Diabetes Mellitus (DM). Resveratrol (RSV), a natural antioxidant, has a beneficial role in prevention of inflammatory disease. We investigated the changes of COX-1 and COX-2 mRNA expression and protein level in diabetic rat kidney after RSV treatment. Three months-old, 44 Wistar albino male rats, which were divided into six groups such as control group, sodium citrate buffer (sham control) group, diabetic group (DM), Dimethyl Sulfoxide induced control group, RSV treated sham control group (RSV) and RSV treated diabetic group (DM + RSV) were used for the study. Experimental diabetes was induced by intraperitoneal injection of 55 mg/kg Streptozotocin. After the induction of chronic diabetes 10 mg/kg per day RSV was administered intraperitoneally for 4 weeks. In this study. RSV has no significant effect on COX-1 mRNA expression in diabetic rat kidney (P > 0.05). Immunohistochemical study showed that COX-1 expression was slightly inhibited in RSV group and was not significantly supressed in DM + RSV group. When comparing control and treated groups, there were no significant differences in COX-2 mRNA or protein levels (P > 0.05). In conclusion, our results indicate that resveratrol do not significantly affect COX gene and protein expression. Therefore, different therapy strategies such as combination with other antidiabetic drugs may tried in STZ induced animal model for reducing diabetic symptoms and altering COX-1 and COX-2 mRNA or protein levels.     

Astaxanthin Ameliorates high-fat diet-induced cardiac damage and fibrosis by upregulating and activating SIRT1

This study evaluated the protective effect of astaxanthin (ASX) against high-fat diet (HFD)-induced cardiac damage and fibrosis in rats and examined if the mechanism of protection involves modulating SIRT1. Rat were divided into 5 groups (n = 10/group) as: 1) control: fed normal diet (3.82 kcal/g), 2) control + ASX (200 mg/kg/orally), 3) HFD: fed HFD (4.7 kcal/g), 4) HFD + ASX (200 mg/kg/orally), and HFD + ASX + EX-527 (1 mg/kg/i.p) (a selective SIRT1 inhibitor). All treatments were conducted for 14 weeks. Administration of ASX reduced cardiomyocyte damage, inhibited inflammatory cell infiltration, preserved cardiac fibers structure, prevented collagen deposition and protein levels of TGF-β 1 in the left ventricles (LVs) of HFD-fed rats. In the LVs of both the control and HFD-fed rat, ASX significantly reduced levels of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and p-smad2/3 (Lys19) but increased the levels of glutathione (GSH), catalase, and manganese superoxide dismutase (MnSOD). Concomitantly, it increased the nuclear activity of Nrf2 and reduced that of NF-κB p65. Furthermore, administration of ASX to both the control and HFD-fed rats increased total and nuclear levels of SIRT1, stimulated the nuclear activity of SIRT1, and reduced the acetylation of Nrf2, NF-κB p65, and Smad3. All these cardiac beneficial effects of ASX in the HFD-fed rats were abolished by co-administration of EX-527. In conclusion, ASX stimulates antioxidants and inhibits markers of inflammation under basal and HFD conditions. The mechanism of protection involves, at least, activation SIRT1 signaling.     

Ameliorative effects of Anchomanes difformis aqueous extract against oxidative stress in the testes and epididymis of streptozotocin-induced diabetic male Wistar rats

Hyperglycemia is a central trait of diabetes mellitus (DM) and is linked to an increase in free radical generation and oxidative stress in the testes, resulting in testicular tissue damage and male infertility. Synthetic medicines are commonly used to manage diabetes; however, they are costly and associated with adverse effects. As a result, the search for a safer and affordable alternative from medicinal plants that contain antioxidants has become imperative to scavenge free radicals caused by hyperglycaemia, thereby alleviating male reproductive dysfunction. Therefore, the present aimed to investigate the ameliorative effects of Anchomanes difformis aqueous extract against oxidative stress in the testes and epididymis of streptozotocin-induced diabetic male Wistar rats. A total of 64 male Wistar rats (eight weeks old) weighing 180 ± 10 mg/kg were divided into seven groups at random. Type 2 diabetic mellitus (T2DM) was induced by streptozotocin (STZ) and a 10% fructose injection intraperitoneally using 40 mg/kg body weight rats. The levels of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, and ferric reducing antioxidant (FRAP) as well as 2, 2-diphenyl-1-picrylhydrazyl (DPPH) values were used to establish the testicular oxidative status. It was found that A. difformis extract significantly (p < 0.05) lowered MDA levels in diabetic rats. Both CAT and SOD activity were significantly (p < 0.05) lower following induction of DM and increased (p < 0.05) after treating with A. difformis. The findings of this study show that A. difformis extract could be a promising source of lead compounds for the development of a therapeutic agent to treat male infertility caused by DM complications.     

Ameliorative effect of ellagic acid and Vitamin C against malathion-induced toxicity in testis of adult Wistar rats

The pesticide malathion (MT), an organophosphate, is highly neurotoxic and causes cholinergic disorders as well as cytotoxicity, genotoxicity, mutagenicity, carcinogenicity and reproductive toxicity. Our purpose was to study the effect of ellagic acid (EA) and Vitamin C on the testis against MT-induced toxicity in the rats. Thirty-six adult Wistar rats were employed, separated into six groups and were given treatment for 14 days. The toxicity of MT on the testis was evaluated using a variety of physical parameters, such as mortality rate and body weight, as well as biochemical parameters, such as total protein, total cholesterol, serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase, and haematological parameters, such as counts of red blood cells, haemoglobin (Hb) and white blood cells, as well as mean corpuscular volume, mean corpuscular Hb, and mean corpuscular Hb concentration. At the end of the experiment, rats were killed and a histological examination of the testis was performed. A sperm count technique and an analysis of sperm motility were used to determine the sperm quality. Biochemical indicators, sperm count, motility, viability and morphology were significantly decreased with MT. When compared with MT and the control group, EA and Vitamin C administration significantly increased sperm motility and count (p < 0.05). After receiving EA and Vitamin C, biochemical indicators and histological characteristics are also intensified. The results of the current investigation show that EA and Vitamin C can both reduce increased levels of biochemical markers and improve pathological alterations in the testis brought on by MT treatment.     

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Oxidative stress and inflammation play a central role in the progression and complications of chronic kidney disease (CKD) and are, in part, due to impairment of the Nrf2 system, which regulates the expression of antioxidant and detoxifying molecules. Natural Nrf2-inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However, owing to adverse outcomes a clinical trial of a synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via covalent modification of reactive cysteine residues in the Nrf2 repressor molecule, Keap1. In addition to Nrf2, Keap1 suppresses IKKB, the positive regulator of NF-κB. Treatment with a BARD analog, dh404, at 5–20 mg/kg/day in diabetic obese Zucker rats exacerbates, whereas its use at 2 mg/kg/day in 5/6 nephrectomized rats attenuates, CKD progression. We, therefore, hypothesized that deleterious effects of high-dose BARD are mediated by the activation of NF-κB. CKD (5/6 nephrectomized) rats were randomized to receive dh404 (2 or 10 mg/kg/day) or vehicle for 12 weeks. The vehicle-treated group exhibited glomerulosclerosis; interstitial fibrosis and inflammation; activation of NF-κB; upregulation of oxidative, inflammatory, and fibrotic pathways; and suppression of Nrf2 activity and its key target gene products. Treatment with low-dose dh404 restored Nrf2 activity and expression of its target genes, attenuated activation of NF-κB and fibrotic pathways, and reduced glomerulosclerosis, interstitial fibrosis, and inflammation. In contrast, treatment with a high dh404 dosage intensified proteinuria, renal dysfunction, and histological abnormalities; amplified upregulation of NF-κB and fibrotic pathways; and suppressed the Nrf2 system. Thus therapy with BARD analogs exerts a dose-dependent dimorphic impact on CKD progression.