RESUMO
BACKGROUND: This study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model. METHODS: A total of 18 adult female mice (Parkes strain), aged 4-5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days. RESULTS: This study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice. CONCLUSION: The ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS.
Assuntos
Antraquinonas , Arildialquilfosfatase , Modelos Animais de Doenças , Resistência à Insulina , Síndrome do Ovário Policístico , Animais , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Feminino , Camundongos , Antraquinonas/farmacologia , Antraquinonas/uso terapêutico , Arildialquilfosfatase/metabolismo , Letrozol , Receptores de Adiponectina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adiponectina/metabolismoRESUMO
BACKGROUND: Panax ginseng (PG) is a plant that contains ginsenosides, which are considered adaptogens that confer cellular protection. However, the impact of PG on pituitary-ovarian dysfunction and subsequent infertility is unknown. This study investigated the hypothesis that PG would attenuate pituitary-ovarian dysfunction associated with mobile phone's Radiofrequency Electromagnetic Radiation (RF-EMR) in experimental rat models and the possible involvement of a cAMP Response Element Modulator (CREM)-dependent pathway. METHODS: Twenty adult female Wistar rats were divided randomly into four groups, each consisting of five rats. The control group was administered a vehicle (distilled water) orally, while the P. ginseng group received 200 mg/kg of P. ginseng extract orally. The RF-EMR group was exposed to 900MHz radiation, and the RF-EMR + PG group was exposed to the same radiation while also being treated with 200 mg/kg of P. ginseng orally. These treatments were administered daily for a period of 56 days. RESULTS: The RF-EMR group exhibited significant reductions in serum levels of LH, FSH, estradiol, and progesterone compared to the control group. Moreover, levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were significantly lower in the RF-EMR group compared to the control. Additionally, there was a notable decrease in the expression of the CREM gene, accompanied by disrupted pituitary/ovarian morphology in the RF-EMR group compared to the control. However, the administration of PG mitigated these changes. CONCLUSION: The findings of this study indicate that P. ginseng extract shields against pituitary-ovarian impairment linked to RF-EMR exposure from cell phones by boosting antioxidant capacity and promoting the CREM-dependent pathway.
RESUMO
Androgen excess and metabolic abnormality largely contribute to the pathogenesis of polycystic ovarian syndrome (PCOS), which primarily precipitates ovarian dysfunction and infertility in reproductive-age women. Impaired mitochondrial function and epigenetic alteration have been linked to the development of PCOS. However, it is unknown whether acetate would exert a therapeutic effect on ovarian mitochondrial dysfunction in PCOS. Herein, the study hypothesized that acetate reverses ovarian mitochondrial dysfunction in experimental PCOS rat model, possibly through modulation of mitofusin-2 (MFn2). Eight-week-old female Wistar rats were randomized into four groups (n = 5). Induction of PCOS was performed by 1 mg/kg letrozole (p.o.), administered for 21 days. Thereafter, the rats were treated with acetate (200 mg/kg; p.o.) for 6 weeks. The PCOS rats demonstrated androgen excess, multiple ovarian cysts, elevated anti-mullerian hormone and leptin and decreased SHBG, adiponectin and 17-ß estradiol with corresponding increase in ovarian transforming growth factor-ß1. Additionally, inflammation (tumor growth factor and nuclear factor-kB), elevated caspase-6, decreased hypoxia-inducible factor-1α and elevated histone deacetylase-2 (HDAC2) were observed in the ovaries of PCOS rats, while mitochondrial abnormality with evidence of decreased adenosine triphosphate synthase and MFn2 was observed in rats with PCOS. Treatment with acetate reversed the alterations. The present results collectively suggest that acetate ameliorates ovarian mitochondrial abnormality, a beneficial effect that is accompanied by MFn2 with consequent normalization of reproductive-endocrine profile and ovarian function. Perhaps, the present data provide hope for PCOS individuals that suffer infertility.
Assuntos
Infertilidade , Doenças Mitocondriais , Síndrome do Ovário Policístico , Humanos , Feminino , Ratos , Animais , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Letrozol/efeitos adversos , Androgênios/efeitos adversos , Ratos Wistar , Infertilidade/complicações , Mitocôndrias/metabolismo , Acetatos/efeitos adversosRESUMO
In addition to the clinical manifestation of polycystic ovarian syndrome (PCOS), life-threatening diseases, especially hypertension and cardiovascular disease (CVD) are emerging critical complications of PCOS. Changes in cardiac energy remains an independent risk factor of CVD. Histone deacetylase (HDAC) inhibitors, including acetate has received attention for its beneficial role in energy regulation. Herein we hypothesized that acetate improves cardiac energy homeostasis in experimentally induced PCOS. Female Wistar rats (8-week-old) were divided into groups. To induce PCOS, 1 mg/kg of letrozole was given for 21 days. After confirmation of PCOS, acetate (200 mg/kg) was administered for 6 weeks. Rats with PCOS showed multiple ovarian cysts with androgen excess and decreased SHBG. The rats also manifested impaired glucose tolerance/hyperinsulinemia and hypertriglyceridemia. Increased systemic oxidative stress (malondialdehyde)/inflammatory (NF-kB/SDF-1) markers and nitric oxide deficiency (NO/eNOS) were observed. Though, the body weight was increased without affecting the cardiac mass index of PCOS rats. Nevertheless, there was an increase in cardiac triglyceride and oxidative stress/inflammatory markers with consequent cardiac injury, revealed by decreased levels of SIRT-1/HIF-1α and increased levels of CTGF/TGFß-1 and plasma troponin T. These led to cardiac ATP depletion with increased AMP and AMP/ATP ratio. These alterations were accompanied by elevated levels of mTOR and HDAC2, which were reversed when treated with acetate. The present results interestingly suggest that HDAC2 inhibition by acetate reversed cardiac energy depletion and attendant cardiomorbidities in experimental PCOS model. A beneficial effect that is accompanied by suppressed expression of mTOR.
Assuntos
Doenças Cardiovasculares , Síndrome do Ovário Policístico , Humanos , Ratos , Feminino , Animais , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Ratos Wistar , Doenças Cardiovasculares/etiologia , Serina-Treonina Quinases TOR , Acetatos/uso terapêutico , Trifosfato de Adenosina , Histona Desacetilase 2RESUMO
Polycystic ovarian syndrome (PCOS) is a known endocrine disorder that has affected many women of childbearing age, and is accompanied by various neurodegenerative conditions. Hence, this study investigates the impact of butyrate in reversing hypothalamic-related disorder, possibly through γ aminobutyric acid (GABA) in a rat model of PCOS. Eight-week-old female Wistar rats were allotted into four groups (n = 5), which include control, butyrate, letrozole, and letrozole + butyrate groups. PCOS was induced by administering 1 mg/kg of letrozole (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. Rats with PCOS were characterized by elevated levels of plasma insulin and testosterone. Increases in plasma and hypothalamic triglyceride levels, inflammatory biomarker (SDF-1), apoptotic marker (caspase-6), and decreased plasma GnRH were observed. Additionally, a decrease in hypothalamic GABA was revealed. Nevertheless, the administration of butyrate attenuated these alterations. The present study suggests that butyrate ameliorates hypothalamic inflammation in an experimental model of PCOS, a beneficial effect that is accompanied by enhanced GABA production.
Assuntos
Síndrome do Ovário Policístico , Humanos , Feminino , Ratos , Animais , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/induzido quimicamente , Letrozol , Ácido Butírico/efeitos adversos , Ratos Wistar , Ácido gama-Aminobutírico , Modelos Teóricos , Modelos Animais de DoençasRESUMO
BACKGROUND: Polycystic ovarian syndrome (PCOS) is a multifactorial condition with metabolic-related complications, such as diabetic nephropathy and chronic renal disorder, which are the leading cause of renal transplant globally. Protective effects of histone deacetylase (HDAC) inhibitors (HDACi) have been documented in metabolic-linked pathologies. Nonetheless, the current study investigated the restorative role of HDACi, butyrate in experimental PCOS-induced renal disorder. MATERIALS AND METHODS: Female Wistar rats (8-week-old) were divided into groups; control, butyrate-treated, letrozole and letrozole + butyrate-treated groups. To induce PCOS, 1 mg/kg of letrozole was given (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. RESULTS: Rats with PCOS revealed disruption in glucose homeostasis (hyperinsulinemia and impaired glucose tolerance and insulin resistance) and presented with the phenotypes of PCOS (hyperandrogenism, multiple ovarian cysts and elevated LH/FSH ratio). Increased plasma and renal triglycerides and inflammatory (TNF-α/SDF-1/NF-κB) markers were observed with elevated levels of TGFß-1, renal lipid peroxidation and redox imbalance (GGT, GSH, HIF-1α). Interestingly, animals with PCOS reported increased body weight as well as renal mass. Whereas, heightened levels of plasma urea, creatinine and creatine kinase indicating renal dysfunction, characterized by renal apoptosis (Caspase-6) and increased HDAC2 levels. Notwithstanding, administration of butyrate averted the alterations. CONCLUSION: The present investigation demonstrates that PCOS declines renal function, which is accompanied by renal inflammation, apoptosis and fibrosis. The study further suggests that butyrate, an HDAC2i restores renal function by suppressing renal SDF-1 with subsequent attenuation of renal inflammation, apoptosis and fibrosis.
Assuntos
Butiratos , Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Ratos , Butiratos/uso terapêutico , Fibrose , Inflamação/tratamento farmacológico , Letrozol , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/patologia , Ratos WistarRESUMO
The role of short chain fatty acid, acetate in cardiac mitochondrial dysfunction especially in PCOS individuals is unknown. Therefore, the present study investigated the modulatory role of GPCRs (41 and 43) by acetate on cardiac mitochondrial status in PCOS rat model. Eight-week-old female Wistar rats were randomly allotted into four groups (n = 5). Polycystic ovarian syndrome was induced by administering letrozole (1 mg/kg p.o.) once daily for 21 days, thereafter the animals were treated with 200 mg/kg (oral gavage) of acetate for six weeks. Letrozole-induced PCOS rats showed elevated circulating testosterone and anti-mullerian hormone, with multiple ovarian cysts. In addition, these rats also manifested insulin resistance, hyperinsulinemia, and increased plasma triglyceride (TG), TG/HDLc and decreased HDLc, as well as elevated level of cardiac TG, glycogen, glycogen synthase, and plasma/cardiac NF-kB, TNF-α, and SDF-1. Cardiac MDA and caspase-6 increased, while plasma/cardiac NrF2 decreased in PCOS animals. A decrease in mitochondrial ATP synthase, ATP/AMP ratio, CPT2 and SDH, and increased HDAC2 were observed in PCOS rats with decreased level of GPCR 41 and 43 when compared with control. Immunohistochemical evaluation of cardiac tissue also showed decrease expression of PROKR1 in PCOS rats compared with control rats. However, treatment with acetate reversed these systemic, cardiac and mitochondrial anomalies. The present results suggest the therapeutic benefit of acetate, an HDAC2i against cardiac mitochondrial dysfunction in PCOS rat model, by attenuating cardiac inflammation, oxidative stress and apoptosis and these effects are accompanied by modulation of GPCR41 and 43 as well as increased expression of PROKR1.
RESUMO
This study hypothesized that acetate breaks the vicious cycle driving adipose-hepatic metabolic dysregulation in a rat model of polycystic ovarian syndrome (PCOS), possibly by suppression of nuclear factor-kappaB (NF-κB)/NOD-like receptor protein 3 (NLRP3) inflammasome. Female Wistar rats (8-week-old) were randomly allocated into four groups of n =6/group, which received vehicle, sodium acetate (200 mg), letrozole (1 mg/kg), and letrozole plus sodium acetate, respectively. The animals were treated by oral gavage, once daily for a period of 21 days. The PCOS animals were insulin-resistant, hyperandrogenic, and hypoestrogenic with decreased sex-hormone binding globulin. In addition, the hepatic tissue had increased lipid profile and decreased glycogen synthesis, while the adipose tissue showed decreased lipid profile with elevated glycogen synthesis. Besides, the results also showed increased malondialdehyde, γ-glutamyl transferase, lactate dehydrogenase, and inflammatory mediators with corresponding decrease in antioxidant defense in the hepatic and adipose tissues. Immunohistochemical evaluation also demonstrated severe expression with Bcl2-associated X protein/NLRP3 antibodies. Nonetheless, concomitant acetate supplementation attenuated these derangements. The present data collectively suggest that acetate ameliorates adipose-hepatic glycolipid dysregulation in experimental PCOS model by attenuating androgen excess and NF-κB/NLRP3 immunoreactivity.
Assuntos
Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Ratos , Glicogênio , Letrozol , Lipídeos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Ratos Wistar , Acetato de Sódio , Subunidade p50 de NF-kappa B/metabolismoRESUMO
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.
Assuntos
Dislipidemias , Síndrome do Ovário Policístico , Humanos , Ratos , Feminino , Animais , Pró-Proteína Convertase 9/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Espironolactona , Letrozol , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Wistar , Dislipidemias/induzido quimicamente , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Receptores de LDL , Inflamação/tratamento farmacológicoRESUMO
Polycystic ovary syndrome (PCOS), an intricate and multifaceted metabolic-endocrine disorder that typically affects 6-20% of women of reproductive age and accounts for 70-80% of all occurrences of infertility globally. In this study we focussed on the effect of diacerein (DIC) on steroidogenesis and follicle development in addition to the basic metabolic and endocrine problems which are associated with PCOS. Eighteen mature female parkes strain mice were separated into three groups at random with 6 animals in a group as follows: Group I, received water and normal diet for 66 days; group II received letrozole (LETZ) (6 mg/kg bw) for the induction of PCOS; Group III received LETZ (6 mg/kg) for 3 weeks followed by the administration of DIC (35 mg/kg) for 45 days. In our study we observed that mice with PCOS had irregular estrous cycle with increased LH/FSH, estrogen level and decline in expression of Kitl, Bmp, Cyp11a1, CYP19a1, Ar, lhr, Fshr and Esr1 as well as decreased SOD and CAT activity in ovary. Moreover, we observed increase in the expression of CYP17a1, as well as increase in serum cholesterol, triglycerides, testosterone, LH, VEGF and insulin levels. All these changes were reversed after the administration of DIC in PCOS mice. Diacerin administration reversed abnormalities in mice with PCOS by modulating the regulation of genes which are related to steroidogenesis and folliculogenesis.
Assuntos
Síndrome do Ovário Policístico , Humanos , Feminino , Camundongos , Animais , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/genética , Letrozol/efeitos adversos , Estrogênios , Modelos Animais de DoençasRESUMO
Various endocrinometabolic diseases, inclusively polycystic ovarian syndrome (PCOS) has been linked with increased risk of renal dysfunction with attendant cardiovascular disease (CVD) in women of reproductive age. Short chain fatty acids (SCFAs) especially acetate have been suggested as an immunometabolic modulator. However, the impact of SCFAs, particularly acetate on renal disorder in PCOS individuals is unknown. The present study therefore hypothesized that acetate would circumvent renal dysfunction in a rat model of PCOS, probably by suppressing NF-κB-dependent mechanism. Eight-week-old female Wistar rats were randomly distributed into four groups (n = 6), which received vehicle, sodium acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole plus sodium acetate, respectively. The administrations were done by oral gavage once daily for a duration of 21 days. Animals with PCOS showed insulin resistance, lipid dysmetabolism, hyperandrogenism, hyperleptinemia and hypoadiponectinemia. Besides, the result also revealed increased renal malondialdehyde, lactate production, inflammatory mediators (NF-κB and TNF-α), urea and creatinine concentration. Immunohistochemical evaluation of renal tissue also demonstrated severe expression of apoptosis and inflammation with BAX/NLRP3 antibodies. However, supplementation with acetate significantly attenuated these anomalies. Collectively, the present results suggest that acetate abolishes renal dysfunction in experimentally induced PCOS animals by attenuating androgen excess, apoptosis, oxidative stress and NF-κB/NLRP3 immunoreactivity.
Assuntos
Resistência à Insulina , Nefropatias , Síndrome do Ovário Policístico , Animais , Feminino , Ratos , Modelos Animais de Doenças , Letrozol/uso terapêutico , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Síndrome do Ovário Policístico/metabolismo , Ratos Wistar , Acetato de SódioRESUMO
OBJECTIVES: Endocrine disorders in women of childbearing age, including polycystic ovarian syndrome (PCOS), have been linked to skeletal muscle insulin resistance with multiple post-receptor intracellular defects, disrupting metabolic flexibility. Short-chain fatty acids, such as acetate have been suggested as a metabolic modulator. However, the effects of acetate on aberrant metabolic switch in skeletal muscle of individuals with PCOS are unknown. This study therefore hypothesized that acetate would circumvent impaired metabolic switch in the skeletal muscle of a letrozole-induced PCOS rat model, probably by suppression of PDK4/NLRP3. METHODS: Eight-wk-old female Wistar rats were assigned into three groups (nâ¯=â¯6), which received vehicle, letrozole (1 mg/kg), and letrozole plus acetate (200 mg/kg), respectively. The administrations were done by oral gavage for 21 d. . RESULTS: Animals with PCOS had insulin resistance, increased testosterone, and leptin, as well as decreased adiponectin level. Additionally, the skeletal muscle was also characterized with increased lipid deposition, malondialdehyde, inflammatory mediators (nuclear factor-κB and tumor necrosis factor-α), lactate dehydrogenase, lactate/pyruvate ratio, HDAC and PDK 4 with corresponding decrease in glycogen synthesis, glutathione and NrF2. Besides, immunohistochemical evaluation showed severe expression of inflammasome and apoptosis in PCOS animals. Nonetheless, supplementation with acetate significantly attenuated these perturbations. CONCLUSIONS: The present results demonstrate aberrant metabolic switch in the skeletal muscle of PCOS animals, which is accompanied by excessive inflammation, oxidative stress and elevated levels of histone deacetylase and PDK4. The results suggested that histone deacetylase inhibitor, acetate circumvents impaired metabolic switch in the skeletal muscle of PCOS rats by suppression of PDK4/NLRP3 inflammasome.
Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico , Humanos , Ratos , Feminino , Animais , Síndrome do Ovário Policístico/induzido quimicamente , Letrozol/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Insulina/metabolismo , Ratos Wistar , Inflamassomos/metabolismo , Músculo Esquelético/metabolismo , Acetatos/metabolismoRESUMO
Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age. PCOS has been demonstrated to induce depressive-like behaviour. Epigenetic alterations such as histone deacetylation (HDAC) and DNA methylation have been suggested in major depression. However, their effects with respect to neuroinflammation are not clear. This study therefore investigated the pathogenic involvement of epigenetic changes in PCOS-associated depression and the protective role of HDACi, especially acetate. Virgin female Wistar rats (140 ± 10 g) were assigned into four groups: the groups received vehicle (control), acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole plus acetate, respectively. The administrations were done concomitantly by oral gavage for 21 days. Treatment with letrozole caused hyperandrogenism, hypoestrogenism, hyperinsulinemia and multiple ovarian cysts/degenerated follicles. In addition, these animals showed depressive-like behaviours and increased expression of HDAC2 and DNA methyltransferase in PFC and hippocampal tissues. Biochemical analyses showed elevated levels of NF-κB, malondialdehyde and acetylcholine (ACH) with glutathione depletion in PFC and hippocampus as well as elevated plasma malondialdehyde and impaired anti-oxidant system in letrozole-treated animals. Histological analysis of PFC and hippocampus showed neurodegeneration in letrozole-treated animals compared with control. However, these alterations were attenuated when treated with acetate. The study demonstrates that PCOS-associated depression is characterised by neuroinflammation and elevated ACH levels, accompanied by increased expression of HDAC2/DNA methyltransferase in PFC and hippocampus. Besides, the study suggests that acetate protects against PCOS-associated depression through suppression of prefrontal and hippocampal DNA methylation and prefrontal but not hippocampal HDAC2 expression.
Assuntos
Acetatos , Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Ratos , Acetatos/uso terapêutico , Modelos Animais de Doenças , DNA/metabolismo , Metilação de DNA , Histona Desacetilase 2/metabolismo , Letrozol/efeitos adversos , Malondialdeído , Metiltransferases/metabolismo , Doenças Neuroinflamatórias , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Ratos WistarRESUMO
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.
RESUMO
BACKGROUND OF STUDY: Globally, many reproductive aged women are affected by polycystic ovarian syndrome (PCOS), which is a common endocrine and metabolic disorder that is linked with adipose dysfunction and chronic low-grade inflammation. Spironolactone (SPL), a mineralocorticoid receptor blocker has been documented as a metabolic modulator. However, its immunomodulatory effect in PCOS is unknown. Therefore, the present study hypothesized that SPL would ameliorate adipose dysfunction and inflammation in experimental PCOS animals. MATERIALS AND METHODS: Female Wistar rats that were 8 weeks old were allocated into three groups. Group 1 received vehicle (distilled water; p.o.), group 2 received letrozole (1 mg/kg; p.o.) and group 3 received letrozole plus SPL (0.25 mg/kg, p.o.). The administration was performed once daily for 21 days. RESULTS: The experimental PCOS animals showed insulin resistance, hyperinsulinemia and hyperandrogenism as well as oxidative stress and elevated inflammatory biomarkers (NF-kB/TNF-/IL-6) as well as a significant decrease in triglycerides, total cholesterol, free fatty acids, GSH and G6PD in the adipose tissue of PCOS animals. In addition, immunohistochemical assessment of adipose tissue showed significant expression of BAX and inflammasome, indicating apoptosis and inflammation compared to control animals. Nevertheless, administration of SPL attenuated these perturbations. CONCLUSION: Altogether, the present study suggests that low-dose spironolactone confers protection against adipose dysfunction in experimental PCOS animals by attenuating inflammation, oxidative stress and cellular apoptosis.
Assuntos
Síndrome do Ovário Policístico , Tecido Adiposo/metabolismo , Animais , Apoptose , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Letrozol/efeitos adversos , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Ratos , Ratos Wistar , Espironolactona/efeitos adversosRESUMO
PURPOSE: Polycystic ovary syndrome (PCOS) is a complex reproductive event that is delineated by endocrine/metabolic disorders. Alteration of kisspeptin status in the hypothalamus and adipose tissue is critical to increased endocrine/metabolic derangements in PCOS individuals, aggravating the clinical manifestation of PCOS and its complications. Short chain fatty acids (SCFAs) are crucial modulators of metabolic homeostasis. However, the role of SCFAs, particularly acetate on hypothalamic-adipose kisspeptin status (HAKS) in PCOS model is unknown. The present study hypothesized acetate as a key player in restoration of deranged HAKS, associated with experimental PCOS model. METHODS: Three groups (n = 6/group) of female Wistar rats (120-150 g) were used. The groups were treated (po) for 21 days with vehicle, letrozole (1 mg/kg) with/without acetate (200 mg/kg) respectively. RESULTS: Letrozole-treated animals had impaired glucose homeostasis, elevated testosterone, leptin and LH/FSH ratio and decreased GnRH and adiponectin with ovarian tissues revealing degenerated follicles and disrupted morphology. These animals also showed increased concentration of hypothalamic triglyceride (TG)/total cholesterol (TC), free fatty acid (FFA), and decreased concentration of TG/TC/FFA in visceral adipose tissue (VAT) with an increase in hypothalamic and VAT malondialdehyde, NF-κB/TNF-α and decreased glutathione/G6PD and hypothalamic but not VAT kisspeptin. Immunohistochemical analysis revealed the expression of NLRP3 inflammasome in the hypothalamus and VAT and all these changes were attenuated by acetate. CONCLUSIONS: Altogether, the present results demonstrate that PCOS is characterized with hypothalamic-adipose inflammation, associated with immunohistochemical expression of NLRP3 with significant alteration of hypothalamic but not adipose kisspeptin. The results suggest that acetate restores kisspeptin status in PCOS animals. This beneficial effect is accompanied by repressed NLRP3 immunoreactivity.
Assuntos
Kisspeptinas , Síndrome do Ovário Policístico , Animais , Feminino , Ratos , Acetatos/uso terapêutico , Kisspeptinas/metabolismo , Letrozol/farmacologia , Letrozol/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Ratos WistarRESUMO
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.
Assuntos
Síndrome do Ovário Policístico , Acetatos/farmacologia , Animais , Estradiol , Ácidos Graxos Voláteis , Feminino , Letrozol/farmacologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Ratos , Ratos WistarRESUMO
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.
Assuntos
Síndrome do Ovário Policístico , Animais , Modelos Animais de Doenças , Feminino , Humanos , Inflamassomos , Letrozol/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Ratos , Ratos Wistar , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Proteína X Associada a bcl-2RESUMO
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.
Assuntos
Melatonina , Doenças dos Roedores , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Dieta Hiperlipídica , Suplementos Nutricionais , Glutationa Peroxidase/metabolismo , Ácido Láctico/metabolismo , Masculino , Melatonina/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Obesidade/veterinária , Estresse Oxidativo , PPAR gama/metabolismo , Ratos , Ratos Wistar , Doenças dos Roedores/metabolismo , TestículoRESUMO
AIM: Endocrinometabolic disorders in women of reproductive age, including polycystic ovarian syndrome (PCOS) has contributed to increased prevalence of cardiovascular disease (CVD) risk and its attendant complications. Acetate, the most abundant endogenously produced short chain fatty acid has been linked to metabolic health. However, the impact of acetate on CVD-driven pathologies in PCOS is unknown. The present study therefore investigated the effects of acetate on cardiometabolic abnormalities associated with PCOS in rat model, and the possible involvement of PCSK9/NF-kB-dependent pathways. MATERIALS AND METHODS: Eight-week-old female Wistar rats were allotted into four groups (n = 6) and the groups received vehicle, acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole plus acetate respectively. The administrations were done once daily by oral gavage and lasted for 21 days. KEY FINDINGS: In letrozole-induced PCOS rats characterized with insulin resistance, glucose dysregulation, elevated plasma testosterone and decreased 17-ß estradiol as well as degenerated ovarian follicles, there was a significant increase in plasma and cardiac lipid/lipoproteins, lipid peroxidation, inflammatory mediators (NF-kB and TNF-α), γ-glutamyl transferase/lactate dehydrogenase and lactate content, PCSK9 and reduction in plasma and cardiac antioxidants (glutathione peroxidase and reduced glutathione) and plasma nitric oxide synthesis (eNOS and NO) compared with the control rats. In addition, immunohistochemical assessment of cardiac tissue showed severe expression of inflammasome in letrozole-induced PCOS rats compared with the control rats. Nevertheless, supplementation with acetate significantly attenuated these alterations. SIGNIFICANCE: The present results suggest that acetate protects against cardiac inflammation in a rat model of PCOS by suppression of PCSK9 and NF-kB-dependent mechanisms.