Spilanthes filicaulis (Schumach. & Thonn.) C.D. Adams leaves protects against streptozotocin-induced diabetic nephropathy.

BACKGROUND AND OBJECTIVE: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. METHODS: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. RESULTS: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). CONCLUSION: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.

Synergistic Action of Virgin Coconut Oil and Clomiphene in Reversing Endocrine Dysregulation in Letrozole-Model of Polycystic Ovarian Syndrome in Rats: Role of Nrf2/HMOX-1 Pathway.

Polycystic ovarian syndrome (PCOS) is an endocrine disorder in women's reproductive age. Currently, the pathophysiology of PCOS is unclear, and the limited treatment options are unsatisfactory. Virgin coconut oil (VCO) is functional food oil associated with pharmacological effects in reproductive disorders. Therefore, we aimed to evaluate whether VCO could enhance clomiphene (CLO) therapy against PCOS in female rats. Rats were randomly divided: (1) Control, (2) PCOS model, (3) PCOS + CLO, (4) PCOS + VCO, and (5) PCOS + CLO + VCO. The PCOS was induced via daily letrozole (1 mg/kg, orally) administration for 21 days. After the PCOS induction, CLO, VCO, and CLO + VCO were administered from days 22 to 36. Serum levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estrogen, progesterone, and prolactin were estimated. Polymerase chain reaction gene expression for nuclear factor-erythroid-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), catalase (CAT), glutathione reductase (GSR), LH receptor (LHr), androgen receptor (AR), tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and caspase-3 were analyzed. The letrozole-induced PCOS caused considerable increases in GnRH, LH, prolactin, estrogen, and testosterone, whereas FSH decreased significantly compared to the control. The gene expression of Nrf2, HO-1, CAT, and GSR were markedly diminished, while IL-1ß, TNF-α, caspase-3, AR, and LHr prominently increased compared to control. Interestingly, the CLO and VCO separately exerted anti-inflammatory and endocrine balance effects. However, VCO-enhanced CLO effect in LH, prolactin and testosterone, Nrf2, HO-1, CAT, GSR, and AR. VCO may synergize with CLO to depress hyperandrogenism and oxidative inflammation in PCOS.

GC-MS chemical profiling, antioxidant, anti-diabetic, and anti-inflammatory activities of ethyl acetate fraction of Spilanthes filicaulis (Schumach. and Thonn.) C.D. Adams leaves: experimental and computational studies.

Introduction: This study aimed to investigate the chemical profile of GC-MS, antioxidant, anti-diabetic, and anti-inflammatory activities of the ethyl acetate fraction of Spilanthes filicaulis leaves (EFSFL) via experimental and computational studies. Methods: After inducing oxidative damage with FeSO4, we treated the tissues with different concentrations of EFSFL. An in-vitro analysis of EFSFL was carried out to determine its potential for antioxidant, anti-diabetic, and anti-inflammatory activities. We also measured the levels of CAT, SOD, GSH, and MDA. Results and discussion: EFSFL exhibited anti-inflammatory properties through membrane stabilizing properties (IC50 = 572.79 µg/ml), proteinase inhibition (IC50 = 319.90 µg/ml), and inhibition of protein denaturation (IC50 = 409.88 µg/ml). Furthermore, EFSFL inhibited α-amylase (IC50 = 169.77 µg/ml), α-glucosidase (IC50 = 293.12 µg/ml) and DPP-IV (IC50 = 380.94 µg/ml) activities, respectively. Our results indicated that induction of tissue damage reduced the levels of GSH, SOD, and CAT activities, and increased MDA levels. However, EFSFL treatment restores these levels to near normal. GC-MS profiling shows that EFSFL contains 13 compounds, with piperine being the most abundant. In silico interaction of the phytoconstituents using molecular and ensembled-based docking revealed strong binding tendencies of two hit compounds to DPP IV (alpha-caryophyllene and piperine with a binding affinity of -7.8 and -7.8 Kcal/mol), α-glucosidase (alpha-caryophyllene and piperine with a binding affinity of -9.6 and -8.9 Kcal/mol), and to α-amylase (piperine and Benzocycloheptano[2,3,4-I,j]isoquinoline, 4,5,6,6a-tetrahydro-1,9-dihydroxy-2,10-dimethoxy-5-methyl with a binding affinity of -7.8 and -7.9 Kcal/mol), respectively. These compounds also presented druggable properties with favorable ADMET. Conclusively, the antioxidant, antidiabetic, and anti-inflammatory activities of EFSFL could be due to the presence of secondary metabolites.

Mineralocorticoid receptor blockade attenuates hyperandrogenic metabolic dysregulation in letrozole-induced PCOS rat model.

Purpose: Polycystic ovarian syndrome (PCOS) is a metabolic syndrome associated with mineralocorticoid receptor (MR) activation, which causes infertility in women of reproductive age. Spironolactone (SPL) is a MR blocker with inconclusive effect in the treatment of PCOS. Therefore, the present study hypothesized that low dose SPL would ameliorate metabolic dysfunction associated with PCOS. Methods: Female Wistar rats (8-week-old) were divided into 3 groups namely: Control, SPL, Letrozole (LET)-treated and LET + SPL-treated groups. The control group was given vehicle (distilled water), SPL-treated group received 0.25 mg/kg, LET-treated group received 1 mg/kg of LET and LET + SPL-treated group received a combination of LET and SPL. The administrations were done by oral gavage for 21 days uninterruptedly. Biochemical parameters such as lipid profile, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), γ-glutamyl transferase (GGT), lactate dehydrogenase (LDH), testosterone, 17-ß estradiol and glutathione peroxidase (GPx) were determined with appropriate assay methods. Results: Letrozole-treated group had a significant increase in ovarian weight, plasma and ovarian triglycerides, MDA/TNF-α, GGT/LDH and plasma testosterone while it decreased plasma 17-ß estradiol and plasma/ovarian high-density lipoproteins and GPx when compared with control group. In addition, histomorphological changes were observed in LET-treated group compared with control group. Nevertheless, administration of low dose SPL attenuated these perturbations. Conclusion: The present study therefore demonstrates that inhibition of mineralocorticoid receptor by low dose SPL ameliorates hyperandrogenic metabolic dysfunction in a rat model of PCOS. Therefore, low dose SPL is hereby suggested as a promising therapeutic agent in the management of PCOS.

Short chain fatty acid, acetate restores ovarian function in experimentally induced PCOS rat model.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is pathogenically characterized with hyperandrogenism and metabolic alterations, which often result in ovarian changes and infertility in women of reproductive age. Epigenetic changes have been linked to the development of PCOS. However, the involvement of epigenetic regulator, histone deacetylase (HDAC) in PCOS-driven ovarian dysfunction is not clear. Howbeit, the present study hypothesized that acetate, an HDAC inhibitor (HDACi) would protect against ovarian dysfunction in experimentally induced PCOS. MATERIALS AND METHODS: Female Wistar rats weighing 120-150 g were randomly divided into four groups (n = 6). The groups received vehicle, sodium acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole with acetate by oral gavage respectively. The administrations were done daily for 21 days. RESULTS: The rat model of PCOS had increased body weight and ovarian weight, 1-hr postload glucose and plasma insulin, testosterone and LH/FSH ratio as well as reduced insulin sensitivity and plasma 17-ß estradiol and sex hormone binding globulin. This model of PCOS in addition showed a significant increase in plasma and ovarian triglyceride, total cholesterol, TNF-α and HDAC, and ovarian malondialdehyde as well as a significant reduction in ovarian glutathione peroxidase/reduced glutathione and NrF2 with the histology of ovarian tissues showing disrupted morphology with significant increase in the number of degenerated follicles compared with control group. These alterations were however attenuated when treated with HDACi, acetate. CONCLUSION: Altogether, the present results suggest that acetate protects ovarian function with evidence of normal growing follicles and enhanced circulating 17-ß estradiol by inhibition of HDAC.

Low-dose spironolactone abates cardio-renal disorder by reduction of BAX/inflammasome expression in experimentally induced polycystic ovarian syndrome rat model.

The impact of low-dose spironolactone (LSPL) on polycystic ovarian syndrome (PCOS)-associated cardio-renal disorder is unknown. Therefore, the present study hypothesized that LSPL would ameliorate cardio-renal disorders in experimental PCOS animals. Eight-week-old female Wistar rats were allotted into three groups. The control group received vehicle (distilled water; per os (p.o.)), the letrozole (LET)-treated group designated as PCOS group received LET (1 mg/kg; p.o.), and PCOS+LSPL received LET and LSPL (0.25 mg/kg, p.o.). The treatment was done once daily for 21 days uninterrupted. The experimental PCOS rats were characterized with insulin resistance, as well as elevated testosterone and luteinizing hormone/follicle-stimulating hormone, with a significant increase in cardiac and renal lipid profile, oxidative stress, inflammatory biomarkers (nuclear factor-κB and tumor necrosis factor-α), lactate dehydrogenase and lactate content and decrease in cardiac and renal antioxidant system (glutathione peroxidase and reduced glutathione) compared with the control rats. In addition, immunohistochemical assessment of cardiac and renal tissue showed significant expression of inflammasome and B-cell lymphoma-2 associated X-protein (BAX) in animals with PCOS. Nevertheless, these perturbations were attenuated following the administration of LSPL. Collectively, the present results suggest that LSPL attenuates PCOS-associated cardio-renal disorders by reduction of oxidative stress and BAX/inflammasome expression.

Melatonin supplementation preserves testicular function by attenuating lactate production and oxidative stress in high fat diet-induced obese rat model.

Metabolic syndrome, including obesity has been documented as a critical factor in male reproductive dysfunction with subsequent reduction in male fertility. The therapeutic potential of melatonin has been demonstrated against oxidative stress-induced pathologies. Therefore, the present study investigated the effects of melatonin on testicular dysfunction associated with high fat diet (FD)-induced obese rat model, and the possible involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ). Adult male Wistar rats (n = 6/group) were used: control group received vehicle (normal saline), obese group received 40% FD, melatonin-treated group received melatonin (4 mg/kg), and obese plus melatonin group received melatonin and 40% FD and the treatment lasted for 12 weeks. High fat diet caused increased body weight and testicular triglyceride, total cholesterol, malondialdehyde, γ-glutamyl transferase, lactate production and lactate/pyruvate ratio as well as decreased glutathione/glutathione peroxidase, nitric oxide and PPAR-γ and circulating testosterone. Nevertheless, all these alterations were attenuated when supplemented with melatonin. Taken together, these results demonstrates that FD-induced obesity causes testicular dysfunction. In addition, the results suggest that melatonin supplementation protects against obesity-associated testicular dysfunction and this effect is accompanied by upregulation of PPAR-γ.

Antidiabetic Activity of Elephant Grass (Cenchrus Purpureus (Schumach.) Morrone) via Activation of PI3K/AkT Signaling Pathway, Oxidative Stress Inhibition, and Apoptosis in Wistar Rats.

Ethnopharmacological Relevance: The management of diabetes over the years has involved the use of herbal plants, which are now attracting interest. We assessed the antidiabetic properties of aqueous extract of C. purpureus shoots (AECPS) and the mechanism of action on pancreatic ß-cell dysfunction. Methods: This study was conducted using Thirty-six 36) male Wistar rats. The animals were divided into six equal groups (n = 6) and treatment was performed over 14 days. To induce diabetes in the rats, a single dose of 65 mg/kg body weight of alloxan was administered intraperitoneal along with 5% glucose. HPLC analysis was carried out to identified potential compounds in the extract. In vitro tests α-amylase, and α-glucosidase were analyzed. Body weight and fasting blood glucose (FBG) were measured. Biochemical parameters, such as serum insulin, liver glycogen, hexokinase, glucose-6-phosphate (G6P), fructose-1,6-bisphosphatase (F-1,6-BP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-ĸB), were analyzed. Additionally, mRNA expressions of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), B-cell lymphoma 2 (Bcl-2), and proliferating cell nuclear antigen (PCNA) were each evaluated. Results: This in vitro study showed inhibitory potency of Cenchrus purpureus extract (AECPS) as compared with the positive controls. AECPS showed a gradual decrease in alloxan-induced increases in FBG, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL-c), G6P, F-1,6-BP, malondialdehyde (MDA), IL-6, TNF-α, and NF-ĸB and increased alloxan-induced decreases in liver glycogen, hexokinase, and high density lipoprotein (HDL-c). The diabetic control group exhibited pancreatic dysfunction as evidenced by the reduction in serum insulin, homeostasis model assessment of ß-cell function (HOMA-ß), expressions of PI3K/AKT, Bcl-2, and PCNA combined with an elevation in homeostatic model assessment of insulin resistance (HOMA-IR). High performance liquid chromatography (HPLC) revealed 3-O-rutinoside, ellagic acid, catechin, rutin, and kaempferol in AECPS. Conclusion: AECPS showed efficient ameliorative actions against alloxan-induced pancreatic dysfunction, oxidative stress suppression as well as, inflammation, and apoptosis via the activation of PI3K/AKT signaling pathways.

Melatonin ameliorates endocrine dysfunction and defective sperm integrity associated with high-fat diet-induced obesity in male Wistar rats.

Obesity (OBS) has been established as a link to male hypogonadism with consequent infertility. Previous studies have shown that melatonin (MEL) modulates hypothalamic-pituitary-gonadal function. The present study therefore investigated the hypothesis that MEL supplementation would attenuate spermatogenic and steroidogenic dysfunctions associated with obesity induced by high-fat diet (HFD). Twenty-four adult male Wistar rats (n = 6/group) were used: control group received vehicle (normal saline), obese group received 40% high-fat diet and distilled water, MEL-treated group received MEL (4 mg/kg), and OBS + MEL group received MEL and 40% HFD and the treatment lasted for 12 weeks. HFD caused increased body weight, glucose intolerance, plasma triglyceride and low-density lipoprotein cholesterol/ very low-density lipoprotein cholesterol and malondialdehyde, as well as decreased antioxidant capacity, high-density lipoprotein cholesterol, gonadotrophin-releasing hormone, follicle-stimulating hormone and testosterone and altered sperm parameters. However, all these alterations were attenuated when supplemented with MEL. Taken together, these results indicate that HFD exposure causes endocrine dysfunction and disrupted sperm parameters in obese animals, which are accompanied by lipid peroxidation/defective antioxidant capacity. In addition, the present results suggest that melatonin supplementation restores endocrine function and sperm integrity in obese rat model by suppression of oxidative stress-dependent mechanism.

The Biological Roles of Urea: A Review of Preclinical Studies.

Urea is an organic compound that has been reported to be effective against many pathological conditions. However, many other studies have reported the toxic effects of urea. These controversies on the biological roles of urea remain unresolved. This review aims to evaluate the biological roles of urea in experimental animals from data published in peer-reviewed journals. A PubMed search was conducted using the phrase, "urea application in experimental animals." A total of 13 publications that met the inclusion criteria were evaluated. The test substance, animal model, number of animals, doses, duration of treatment, and effects were recorded. Regarding the toxic effect, urea caused decreased excretion of other nitrogenous compounds, increased oxidative stress, decreased insulin, and impairment of beta-cell glycolysis. Furthermore, it caused endothelial dysfunction, loss of synapsis, and decreased olfaction. Regarding the therapeutic effects, urea caused increased growth, increased digestion, and decreased hepatic dysfunction. It also induced apoptosis of tumor cells and exerted neuroprotective properties. Products containing urea should be used with caution, especially in individuals with symptoms of chronic kidney disease. However, more studies are needed to elucidate the mechanisms of its therapeutic effects.

Hippocampus and Prefrontal Cortex Following the Use of Anti-Retroviral Therapy in Adult Wistar Rats: Therapeutic Role of Epigallocatechin Gallate.

The contribution of prefrontal-hippocampal interactions to brain function of people infected with HIV may be aggravated by toxicities due to long-term use of antiretroviral agents. This study was designed to investigate the curative potential of Epigallotatechin gallate (EGCG) in the treatment of neurodegenerative disorders as a possible consequence of antiretroviral toxicity. Twenty-four adult male Wistar rats, weighing 80~100g, were divided into four groups and treated as follows: control A (distilled water), B (HAART), C (EGCG 2.5mg/kg), D (EGCG 2.5mg/kg) + HAART) Brain histology, immunohistochemistry, and oxidative stress markers such as superoxide dismutase (SOD), glutathione (GSH),catalase (CAT)  and malondialdehyde (MDA) were examined. The use of highly active antiretroviral therapy (HAART) showed extensive architectural deformation with pyknotic neuronal cells and obliterated neurons in the hippocampus and prefrontal cortex. Expression of inflammasome cells was also evident in this group. MDA levels increased significantly with a significant reduction in the levels of GSH, as well as antioxidant enzyme (SOD and CAT) activities compared to other treatment groups. Treatment with EGCG resulted in partial neuronal restoration of histopathological alterations, and modulation of NLRP3 inflammasome in the hippocampus and prefrontal cortex. EGCG also showed significant improvements in terms of increased antioxidant levels of SOD, GSH, CAT and a reduced MDA level and well-preserved brain architecture. Epigallocatechin gallate improves brain morphology and function with a reversal of HAART-induced alterations.

Acetate supplementation restores testicular function by modulating Nrf2/PPAR-γ in high fat diet-induced obesity in Wistar rats.

PURPOSE: Several studies have established impaired testicular function in obese male population, including the young males with childhood obesity, contributing to increased male infertility, which is a universal trend in the last few decades. Short chain fatty acids (SCFAs) have been recently demonstrated to inhibit progression to metabolic comorbidities. The present study therefore hypothesized that SCFAs, acetate attenuates testicular dysfunction in high fat diet (HFD)-induced obese rat model, possibly by modulating Nrf2/PPAR-γ. METHODS: Adult male Wistar rats weighing 160-190 g were randomly allotted into three groups (n = 6/group): The groups received vehicle (distilled water), 40% HFD and sodium acetate (200 mg/kg) plus 40% HFD respectively. The administration lasted for 12 weeks. RESULTS: HFD caused obesity, which is characterized with increased body weight and visceral adiposity and insulin resistance/hyperinsulinemia. In addition, it increased testicular lipid deposition, malondialdehyde, pro-inflammatory mediators, lactate/pyruvate ratio, γ-Glutamyl transferase, and circulating leptin as well as decreased testicular glutathione, nitric oxide, Nrf2, PPAR-γ and circulating follicle stimulating hormone and testosterone without a significant change in testicular lactate dehydrogenase, blood glucose and luteinizing hormone when compared to the control group. Nevertheless, administration of acetate reversed the HFD-induced alterations. CONCLUSION: The present results demonstrates that HFD causes obesity-driven testicular dysfunction, associated with testicular lipid deposition, oxidative stress, and inflammation. The study in addition suggests the restoration of testicular function in obese animals by acetate, an effect that is accompanied by elevated Nrf2/PPAR-γ.

Protective role of melatonin against adipose-hepatic metabolic comorbidities in experimentally induced obese rat model.

BACKGROUND: Adipose and hepatic metabolic dysfunctions are critical comorbidities that also aggravate insulin resistance in obese individuals. Melatonin is a low-cost agent and previous studies suggest that its use may promote metabolic health. However, its effects on some comorbidities associated with obesity are unknown. Herein, we investigated the hypothesis that melatonin supplementation would attenuate adipose-hepatic metabolic dysfunction in high fat diet (HFD)-induced obesity in male Wistar rats. MATERIALS AND METHODS: Twenty-four adult male Wistar rats (n = 6/group) were used: Control group received vehicle (normal saline), obese group received 40% high fat diet, melatonin-treated group received 4 mg/kg of melatonin, and obese plus melatonin group received 40% HFD and melatonin. The treatment lasted for 12 weeks. RESULTS: HFD caused increased food intake, body weight, insulin level, insulin resistance and plasma and liver lipid but decreased adipose lipid. In addition, HFD also increased plasma, adipose and liver malondialdehyde, IL-6, uric acid and decreased Glucose-6-phosphate dehydrogenase, glutathione, nitric oxide and circulating obestatin concentration. However, these deleterious effects except food intake were attenuated when supplemented with melatonin. CONCLUSION: Taken together, the present results indicate that HFD exposure causes adipose-hepatic metabolic disturbance in obese animals, which are accompanied by oxidative stress and inflammation. In addition, the present results suggest that melatonin supplementation attenuates adipose-hepatic metabolic dysfunction, accompanying obesity by suppression of oxidative stress/inflammation-dependent mechanism and increasing circulating obestatin.

Combined effect of metformin and gallic acid on inflammation, antioxidant status, endoplasmic reticulum (ER) stress and glucose metabolism in fructose-fed streptozotocin-induced diabetic rats.

Over time, diabetes patients usually need combination therapy involving two or more agents, including phytonutrients to attain therapeutic targets. The purpose of this research is to elucidate the combined effect of metformin and gallic acid (GA) on glucose metabolism, inflammation as well as oxidative and endoplasmic reticulum (ER) stresses in fructose-fed diabetic rats. Thirty-five rats of Wistar strain were arbitrarily distributed into five groups, each containing seven animals as follows: normal control, diabetic control, groups administered 100 mg/kg bw metformin only, 50 mg/kg bw gallic acid only and a combination of both. Experimental animals were made diabetic by single injection of 40 mg/kg streptozotocin (intraperitoneally) subsequent to 14 days administration of 10 % fructose prior. Treatment of rats continued for 21 days following diabetes confirmation. Glucose and insulin levels as well as lipid profile were evaluated in the serum, while activities of catalase and superoxide dismutase were estimated in both liver and pancreas. In addition, levels of malondialdehyde, interleukin-6 and tumor necrosis factor-alpha, as well as expression of activating transcription factor-4 were evaluated in liver and pancreas of diabetic rats. Activities of glucose-6-phosphatase and glucokinase were also determined in liver of diabetic animals. Metformin only, GA only and combination of metformin and GA significantly improved antioxidant status and glucose homeostasis while inflammation and endoplasmic reticulum stress were significantly ameliorated in diabetic rats. Metformin/GA combination appeared to improve glucose metabolism by increasing insulin level and ameliorating the dysregulated activities of glucose metabolizing enzymes and ER stress better than either metformin only or GA only. It could be concluded that coadministration of metformin/GA produced a combined effect in ameliorating diabetes in Wistar rats and could be considered in treatment of diabetes.

High fructose-enriched diet synergistically exacerbates endocrine but not metabolic changes in letrozole-induced polycystic ovarian syndrome in Wistar rats.

BACKGROUND: Polycystic Ovarian Syndrome (PCOS) is a multifactorial endocrine-metabolic disorder that highly contributes to the prevalence of infertility globally. The increased consumption of refined carbohydrate, particularly fructose has been associated with pandemic metabolic disorders, including in women of reproductive age. However, the effects of high fructose consumption (FRD) on endocrine and metabolic disorders associated with PCOS are not clear. Therefore, this study investigated the effects of FRD on endocrine/metabolic changes in letrozole-induced PCOS in Wistar rats. MATERIALS AND METHODS: Twenty-eight adult female Wistar rats were randomly allotted into 4 groups and treated with vehicle, letrozole (LET; 0.5 mg/kg), FRD (D-fructose chow pellet mixture) and LET + FRD. The treatment lasted for 21days. RESULTS: Data showed a significant increase in ovarian weight, liver weight, luteinising hormone (LH), testosterone and decrease in follicle stimulating hormone as well as moderate histopathological changes in the fallopian tube, uterus and liver of animals with PCOS. FRD-treated group showed a significant increase in ovarian weight and liver weight but no significant alteration in hormonal profile or histopathological changes in uterus and fallopian tube. However, FRD significantly altered hormonal profile with consequent histopathological changes in fallopian tube and uterus but FRD did not alter ovarian/liver weight or blood glucose in animals with PCOS when compared with animals without PCOS. CONCLUSION: The present results demonstrate that FRD synergistically aggravates endocrine but not metabolic changes in PCOS, suggesting that FRD might deteriorate endocrine-related phenotypes in PCOS.