Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

Polycystic ovarian syndrome (PCOS) is the most common endocrine–metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology and pathogenesis; however, their causative role in PCOS development requires further investigation. As a low-grade chronic inflammation disease, PCOS patients have permanently elevated levels of inflammatory markers (TNF-α, CRP, IL-6, IL-8, IL-18). In this review, we summarise recent data regarding the role of mtDNA mutations and mitochondrial malfunctions in PCOS pathogenesis. Furthermore, we discuss recent papers dedicated to the identification of novel biomarkers for early PCOS diagnosis. Finally, traditional and new mitochondria-targeted treatments are discussed. This review intends to emphasise the key role of oxidative stress and chronic inflammation in PCOS pathogenesis; however, the exact molecular mechanism is mostly unknown and requires further investigation.     

Oxidative Stress,Plant Natural Antioxidants,and Obesity

Oxidative stress is important in the pathophysiology of obesity, altering regulatory factors of mitochondrial activity, modifying the concentration of inflammation mediators associated with a large number and size of adipocytes, promoting lipogenesis, stimulating differentiation of preadipocytes to mature adipocytes, and regulating the energy balance in hypothalamic neurons that control appetite. This review discusses the participation of oxidative stress in obesity and the important groups of compounds found in plants with antioxidant properties, which include (a) polyphenols such as phenolic acids, stilbenes, flavonoids (flavonols, flavanols, anthocyanins, flavanones, flavones, flavanonols, and isoflavones), and curcuminoids (b) carotenoids, (c) capsaicinoids and casinoids, (d) isothiocyanates, (e) catechins, and (f) vitamins. Examples are analyzed, such as resveratrol, quercetin, curcumin, ferulic acid, phloretin, green tea, Hibiscus Sabdariffa, and garlic. The antioxidant activities of these compounds depend on their activities as reactive oxygen species (ROS) scavengers and on their capacity to prevent the activation of NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells), and reduce the expression of target genes, including those participating in inflammation. We conclude that natural compounds have therapeutic potential for diseases mediated by oxidative stress, particularly obesity. Controlled and well-designed clinical trials are still necessary to better know the effects of these compounds.     

Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation

Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.     

Inflammation,Oxidative Stress,Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

Atherosclerosis is a leading cause of cardiovascular diseases (CVD) worldwide and intimately linked to aging. This pathology is characterized by chronic inflammation, oxidative stress, gradual accumulation of low-density lipoproteins (LDL) particles and fibrous elements in focal areas of large and medium arteries. These fibrofatty lesions in the artery wall become progressively unstable and thrombogenic leading to heart attack, stroke or other severe heart ischemic syndromes. Elevated blood levels of LDL are major triggering events for atherosclerosis. A cascade of molecular and cellular events results in the atherosclerotic plaque formation, evolution, and rupture. Moreover, the senescence of multiple cell types present in the vasculature were reported to contribute to atherosclerotic plaque progression and destabilization. Classical therapeutic interventions consist of lipid-lowering drugs, anti-inflammatory and life style dispositions. Moreover, targeting oxidative stress by developing innovative antioxidant agents or boosting antioxidant systems is also a well-established strategy. Accumulation of senescent cells (SC) is also another important feature of atherosclerosis and was detected in various models. Hence, targeting SCs appears as an emerging therapeutic option, since senolytic agents favorably disturb atherosclerotic plaques. In this review, we propose a survey of the impact of inflammation, oxidative stress, and senescence in atherosclerosis; and the emerging therapeutic options, including thioredoxin-based approaches such as anti-oxidant, anti-inflammatory, and anti-atherogenic strategy with promising potential of senomodulation.     

多囊卵巢综合症的内分泌变化观察

目的通过观察多囊卵巢综合症患者的机体内分泌变化探讨治疗多囊卵巢综合症的有效方法。方法选择46例多囊卵巢综合症患者,给予克罗米芬联合二甲双胍治疗,3个周期后观察患者性激素水平、糖代谢水平、卵巢体积变化情况及临床常见症状改善情况。结果治疗后性激素水平与治疗前比较,有极显著性差异(P<0.01),糖代谢水平、卵巢体积、多毛、痤疮及月经不调症状与治疗前比较,有显著性差异(P<0.05)。结论在多囊卵巢综合症的治疗中观察内分泌变化情况,提示联合用药能更好的调节性激素分泌,改善糖代谢水平,缩小卵巢体积,改善临床症状,提高有效率。     

Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.     

Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques

As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6–7 months. A cross-over experimental design enabled use of the same monkeys in each treatment phase. Insulin treatment unexpectedly normalized follicular phase duration in PCOS-like, but not control, females. In response to an intramuscular injection of 200 IU hCG, neither prenatally androgenized nor control females demonstrated ovarian hyperandrogenic responses while receiving insulin. An intravenous GnRH (100 ng/kg) injection also did not reveal evidence of hypergonadotropism. Taken together, these results suggest that experimentally induced adult hyperinsulinemia, alone, is insufficient to induce PCOS-like traits in female rhesus monkeys and to amplify intrinsic PCOS-like pathophysiology.     

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

Overweight and obesity during pregnancy have been associated with increased birth weight, childhood obesity, and noncommunicable diseases in the offspring, leading to a vicious transgenerational perpetuating of metabolic derangements. Key components in intrauterine developmental programming still remain to be identified. Obesity involves chronic low-grade systemic inflammation that, in addition to physiological adaptations to pregnancy, may potentially expand to the placental interface and lead to intrauterine derangements with a threshold effect. Animal models, where maternal inflammation is mimicked by single injections with lipopolysaccharide (LPS) resembling the obesity-induced immune profile, showed increased adiposity and impaired metabolic homeostasis in the offspring, similar to the phenotype observed after exposure to maternal obesity. Cytokine levels might be specifically important for the metabolic imprinting, as cytokines are transferable from maternal to fetal circulation and have the capability to modulate placental nutrient transfer. Maternal inflammation may induce metabolic reprogramming at several levels, starting from the periconceptional period with effects on the oocyte going through early stages of embryonic and placental development. Given the potential to reduce inflammation through inexpensive, widely available therapies, examinations of the impact of chronic inflammation on reproductive and pregnancy outcomes, as well as preventive interventions, are now needed.     

Components of the Complement Cascade Differ in Polycystic Ovary Syndrome

Complement pathway proteins are reported to be increased in polycystic ovary syndrome (PCOS) and may be affected by obesity and insulin resistance. To investigate this, a proteomic analysis of the complement system was undertaken, including inhibitory proteins. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls). SOMALogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). The alternative pathway of the complement system was primarily overexpressed in PCOS, with increased C3 (p < 0.05), properdin and factor B (p < 0.01). In addition, inhibition of this pathway was also seen in PCOS, with an increase in CFHR5, factor H and factor I (p < 0.01). Downstream complement factors iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with an inflammatory cytokine release, were increased (p < 0.01). Hyperandrogenemia correlated positively with properdin and iC3b, whilst insulin resistance (HOMA-IR) correlated with iC3b and factor H (p < 0.05) in PCOS. BMI correlated positively with C3d, factor B, factor D, factor I, CFHR5 and C5a (p < 0.05). This comprehensive evaluation of the complement system in PCOS revealed the upregulation of components of the complement system, which appears to be offset by the concurrent upregulation of its inhibitors, with these changes accounted for in part by BMI, hyperandrogenemia and insulin resistance.     

Cardiac and Renal SARS-CoV-2 Viral Entry Protein Regulation by Androgens and Diet: Implications for Polycystic Ovary Syndrome and COVID-19

The susceptibility and the severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with hyperandrogenism, obesity, and preexisting pulmonary, metabolic, renal, and cardiac conditions. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with obesity, hyperandrogenism, and cardiometabolic dysregulations. We analyzed cardiac, renal, circulatory, and urinary SARS-CoV-2 viral entry proteins (ACE2, TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) and androgen receptor (AR) expression, in a peripubertal androgen exposure model of PCOS. Peripubertal female mice were treated with dihydrotestosterone (DHT) and low (LFD) or high (HFD) fat diet for 90 days. HFD exacerbated DHT-induced increase in body weight, fat mass, and cardiac and renal hypertrophy. In the heart, DHT upregulated AR protein in both LFD and HFD, ACE2 in HFD, and ADAM17 in LFD. In the kidney, AR protein expression was upregulated by both DHT and HFD. Moreover, ACE2 and ADAM17 were upregulated by DHT in both diets. Renal TMPRSS2, furin, and cathepsin L were upregulated by DHT and differentially modulated by the diet. DHT upregulated urinary ACE2 in both diets, while neither treatment modified serum ACE2. Renal AR mRNA expression positively correlated with Ace2, Tmprss2, furin, cathepsin L, and ADAM17. Our findings suggest that women with PCOS could be a population with a high risk of COVID-19-associated cardiac and renal complications. Furthermore, our study suggests that weight loss by lifestyle modifications (i.e., diet) could potentially mitigate COVID-19-associated deleterious cardiorenal outcomes in women with PCOS.     

Controversies in the Pathogenesis,Diagnosis and Treatment of PCOS: Focus on Insulin Resistance,Inflammation, and Hyperandrogenism

Polycystic ovary syndrome (PCOS) is a heterogeneous and extremely common disease with symptoms that vary with the age of the patient, typically characterized by hyperandrogenism, chronic oligo-anovulation, and/or several metabolic disorders. The syndrome includes various phenotypes, and the pathogenesis is multifactorial, often involving insulin resistance. This feature is closely related to ovarian dysfunction, inflammation, hyperandrogenism, and metabolic disorders, which characterize and complicate the syndrome. Therapy currently considers both lifestyle improvements and medications, and must be tailored on a case-by-case basis. To date, the published studies have not arrived at a definition of the most suitable therapy for each individual case and many of the drugs used are still off-label. In this review, we discuss some controversial diagnostic and therapeutic aspects of PCOS, such as the role of insulin resistance, inflammation, and hyperandrogenism. We also evaluated the advantages and disadvantages of contraceptive therapy and antiandrogens.     

Oxidative Stress in Malaria: Potential Benefits of Antioxidant Therapy

Malaria is an infectious disease and a serious public health problem in the world, with 3.3 billion people in endemic areas in 100 countries and about 200 million new cases each year, resulting in almost 1 million deaths in 2018. Although studies look for strategies to eradicate malaria, it is necessary to know more about its pathophysiology to understand the underlying mechanisms involved, particularly the redox balance, to guarantee success in combating this disease. In this review, we addressed the involvement of oxidative stress in malaria and the potential benefits of antioxidant supplementation as an adjuvant antimalarial therapy.     

Pediatric Multisystem Syndrome Associated with SARS-CoV-2 (MIS-C): The Interplay of Oxidative Stress and Inflammation

Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (MIS-C) is characterized by persistent fever and evidence of single or multiorgan dysfunction, and laboratory evidence of inflammation, elevated neutrophils, reduced lymphocytes, and low albumin. The pathophysiological mechanisms of MIS-C are still unknown. Proinflammatory mediators, including reactive oxygen species and decreased antioxidant enzymes, seems to play a central role. Virus entry activates NOXs and inhibits Nrf-2 antioxidant response inducing free radicals. The biological functions of nonphagocytic NOXs are still under study and appear to include: defense of epithelia, intracellular signaling mechanisms for growth regulation and cell differentiation, and post-translational modifications of proteins. This educational review has the aim of analyzing the newest evidence on the role of oxidative stress (OS) in MIS-C. Only by relating inflammatory mediators to OS evaluation in children following SARS-CoV-2 infection will it be possible to achieve a better understanding of these mechanisms and to reduce long-term morbidity. The link between inflammation and OS is key to developing effective prevention strategies with antioxidants to protect children.     

The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome

Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.     

Resolvin D1 Decreases Severity of Streptozotocin-Induced Type 1 Diabetes Mellitus by Enhancing BDNF Levels,Reducing Oxidative Stress,and Suppressing Inflammation

Type 1 diabetes mellitus is an autoimmune disease characterized by increased production of pro-inflammatory cytokines secreted by infiltrating macrophages and T cells that destroy pancreatic β cells in a free radical-dependent manner that causes decrease or absence of insulin secretion and consequent hyperglycemia. Hence, suppression of pro-inflammatory cytokines and oxidative stress may ameliorate or decrease the severity of diabetes mellitus. To investigate the effect and mechanism(s) of action of RVD1, an anti-inflammatory metabolite derived from docosahexaenoic acid (DHA), on STZ-induced type 1 DM in male Wistar rats, type 1 diabetes was induced by single intraperitoneal (i.p) streptozotocin (STZ-65 mg/kg) injection. RVD1 (60 ng/mL, given intraperitoneally) was administered from day 1 along with STZ for five consecutive days. Plasma glucose, IL-6, TNF-α, BDNF (brain-derived neurotrophic factor that has anti-diabetic actions), LXA4 (lipoxin A4), and RVD1 levels and BDNF concentrations in the pancreas, liver, and brain tissues were measured. Apoptotic (Bcl2/Bax), inflammatory (COX-1/COX-2/Nf-κb/iNOS/PPAR-γ) genes and downstream insulin signaling proteins (Gsk-3β/Foxo1) were measured in the pancreatic tissue along with concentrations of various antioxidants and lipid peroxides. RVD1 decreased severity of STZ-induced type 1 DM by restoring altered plasma levels of TNF-α, IL-6, and BDNF (p < 0.001); expression of pancreatic COX-1/COX-2/PPAR-γ genes and downstream insulin signaling proteins (Gsk-3β/Foxo1) and the concentrations of antioxidants and lipid peroxides to near normal. RVD1 treatment restored expression of Bcl2/Pdx genes, plasma LXA4 (p < 0.001) and RVD1 levels and increased brain, pancreatic, intestine, and liver BDNF levels to near normal. The results of the present study suggest that RVD1 can prevent STZ-induced type 1 diabetes by its anti-apoptotic, anti-inflammatory, and antioxidant actions and by activating the Pdx gene that is needed for pancreatic β cell proliferation.     

Therapeutic Potentials of Low-Dose Tacrolimus for Aberrant Endometrial Features in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a major anovulatory infertility affecting a great proportion of women of childbearing age and is associated with obesity, insulin resistance and chronic inflammation. Poor endometrial receptivity and recurrent implantation failure are major hurdles to the establishment of pregnancy in women with PCOS. The accumulating body of evidence obtained from experimental and clinical studies suggests a link between inherent adaptive and innate immune irregularities and aberrant endometrial features in PCOS. The use of conventional therapeutic interventions such as lifestyle modification, metformin and ovarian stimulation has achieved limited clinical success in restoring ovulation and endometrial receptivity in women with PCOS. Unlike other immunosuppressive drugs prescribed in the clinical management of autoimmune and inflammatory disorders that may have deleterious effects on fertility and fetal development, preclinical studies in mice and in women without PCOS but with repeated implantation failure revealed potential therapeutic benefits for the use of low-dose tacrolimus in treating female infertility. Improved systemic and ovarian immune functions, endometrial progesterone receptor and coreceptor expressions and uterine vascular adaptation to pregnancy were among features of enhanced progesterone-receptor sensitivity in the low-dose tacrolimus-treated mouse model of the disease. In this review, we have compiled available experimental and clinical data in literature on endometrial progesterone resistance and current therapeutic options, as well as mechanisms of actions and reported outcomes relevant to the potential therapeutic benefits for the use of low-dose tacrolimus in treating PCOS-associated female infertility.