scholarly journals Effect of DHT-Induced Hyperandrogenism on the Pro-Inflammatory Cytokines in a Rat Model of Polycystic Ovary Morphology

Medicina ◽  
2020 ◽  
Vol 56 (3) ◽  
pp. 100
Author(s):  
Abhaya Krishnan ◽  
Sridhar Muthusami ◽  
Loganayaki Periyasamy ◽  
Jone A. Stanley ◽  
Vasudevan Gopalakrishnan ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Model System ◽  
Reproductive Age ◽  
Albino Rats ◽  
Low Grade ◽  
Tnf Α ◽  
Inflammatory State

Background and Objectives: Polycystic ovary syndrome (PCOS) is one of the most prevalent disorders among women of reproductive age. It is considered as a pro-inflammatory state with chronic low-grade inflammation, one of the key factors contributing to the pathogenesis of this disorder. Polycystic ovary is a well-established criterion for PCOS. The present investigation aimed at finding the role of hyperandrogenism, the most important feature of PCOS, in the development of this inflammatory state. To address this problem, we adopted a model system that developed polycystic ovary morphology (PCOM), which could be most effectively used in order to study the role of non-aromatizable androgen in inflammation in PCOS. Materials and Methods: Six rats were used to induce PCOM in 21-days-old female Wistar albino rats by using a pre-determined release of dihydrotestosterone (DHT), a potent non-aromatizable androgen, achieved by implanting a DHT osmotic pump, which is designed to release a daily dose of 83 μg. Results: After 90 days, the rats displayed irregular estrous cycles and multiple ovarian cysts similar to human PCOS. Elevated serum inflammatory markers such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the presence of a necrotic lesion in the liver, osteoclast in the femur, multinucleated giant cells and lymphocytes in the ovary based on histopathological observation of DHT-treated rats clearly indicated the onset of inflammation in the hyperandrogenic state. Our results show no significant alterations in serum hormones such as luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin, and cortisol between control and hyperandrogenised rats. DHT was significantly elevated as compared to control. mRNA studies showed an increased expression level of TNF-α and IL-1β, further, the mRNA expression of urocortin 1 (Ucn-1) was stupendously elevated in the liver of hyperandrogenised rats. Conclusions: Thus, results from this study provide: (1) a good PCOM model system in order to study the inflammatory changes in PCOS aspects, (2) alteration of inflammatory markers in PCOM rats that could be either due to its direct effect or by the regulation of various inflammatory genes and markers in the liver of hyperandrogenic state suggesting the regulatory role of DHT, and (3) alteration in stress-related protein in the liver of PCOM rats.

scholarly journals PCOS: A Chronic Disease that Fails to Produce Adequately Specialized Pro-Resolving Lipid Mediators (SPMs)

2021 ◽  
Author(s):  
Pedro-Antonio Regidor ◽  
Xavier de la Rosa ◽  
Anna Mueller ◽  
Manuela Sailer ◽  
Fernando Gonzalez Santos ◽  
...  
Keyword(s):  
Polycystic Ovary ◽  
Initial Response ◽  
Lipid Mediators ◽  
Reproductive Age ◽  
Lipid Mediator ◽  
Low Grade ◽  
Healthy Women ◽  
Inflammatory State ◽  
Inflammatory Molecules ◽  
Resolution Processes

Introduction: Polycystic Ovary Syndrome (PCOS) is an endocrinologic disorder that affects 5-15 % of women of their reproductive age and is a frequent cause of infertility. Major symptoms include hyperandrogenism, ovulatory dysfunction, a characteristic multi-follicular morphology of the ovary, an elevated ratio of LH/FSH, and often obesity and/or insulin resistance. PCOS also represents a state of chronic low-grade inflammation that is closely interlinked with the metabolic features. Inflammatory processes consist of the acute inflammatory response and resolution processes initiated concomitantly. "Classical" pro-inflammatory lipid mediators like prostaglandins (PG), leukotrienes (LT), or thromboxanes (TX) are derived from arachidonic acid (AA) and are crucial for the initial response. Resolution processes are driven by four families of so-called specialized pro-resolving mediators (SPMs): resolvins, maresins, lipoxins, and protectins. SPM biosynthesis starts from the essential polyunsaturated fatty acids DHA, DPA, or EPA via certain hydroxylated intermediates (18-HEPE, 17-HDHA, 14-HDHA). The present study aimed to establish lipid mediator profiles of PCOS patients compared to healthy women to identify differences in their resolutive and pro-inflammatory lipid parameters. Material and Methods: Blood samples were taken (20 ml), separated into plasma and serum, and analyzed by HPLC/MS-QQQ. Fifteen female patients (18-45 years) were diagnosed with PCOS according to Rotterdam criteria, and five healthy women, as comparator group, were recruited for the study. The main outcome measures were: Pro-inflammatory lipid mediators (PG, LT, TX) and their precursor AA; SPMs (Resolvins, Maresins, Protectins, Lipoxins), their precursors EPA, DHA, DPA, and their active biosynthesis pathway intermediates (18-HEPE, 17-HDHA, 14-HDHA). Ratio [(sum of pro-inflammatory molecules)/sum of SPMs]. Results: The level of pro-inflammatory parameters in serum was significantly higher in PCOS-affected women. The ratio [(sum of pro-inflammatory molecules) / (sum of SPMs plus hydroxylated intermediates)] reflecting the inflammatory state was significantly lower in the group of healthy women. Conclusion: There is a strong pro-inflammatory state in PCOS patients. Further research will clarify whether supplementation with SPMs or their precursors may improve this state.

scholarly journals PCOS: a Chronic Disease That Fails to Produce Adequately Specialized Pro-resolving Lipid Mediators (SPMs).

2022 ◽  
Author(s):  
Pedro-Antonio Regidor ◽  
Xavier de la Rosa ◽  
Anna Mueller ◽  
Manuela Sailer ◽  
Fernando Gonzalez Santos ◽  
...  
Keyword(s):  
Polycystic Ovary ◽  
Initial Response ◽  
Lipid Mediators ◽  
Reproductive Age ◽  
Lipid Mediator ◽  
Low Grade ◽  
Healthy Women ◽  
Inflammatory Parameters ◽  
Inflammatory State ◽  
Inflammatory Molecules

Abstract Introduction: Polycystic Ovary Syndrome (PCOS) is an endocrinologic disorder that affects 5-15 % of women of their reproductive age and is a frequent cause of infertility. Major symptoms include hyperandrogenism, ovulatory dysfunction, and often obesity and/or insulin resistance. PCOS also represents a state of chronic low-grade inflammation that is closely interlinked with the metabolic features. "Classical" pro-inflammatory lipid mediators like prostaglandins (PG), leukotrienes (LT), or thromboxanes (TX) are derived from arachidonic acid (AA) and are crucial for the initial response. Resolution processes are driven by four families of so-called specialized pro-resolving mediators (SPMs): resolvins, maresins, lipoxins, and protectins. The study aimed to establish lipid mediator profiles of PCOS patients compared to healthy women to identify differences in their resolutive and pro-inflammatory lipid parameters. Material and Methods: Fifteen female patients (18-45 years) were diagnosed with PCOS according to Rotterdam criteria, and five healthy women, as comparator group, were recruited for the study. The main outcome measures were: Pro-inflammatory lipid mediators (PG, LT, TX) and their precursor AA; SPMs (Resolvins, Maresins, Protectins, Lipoxins), their precursors EPA, DHA, DPA, and their active biosynthesis pathway intermediates (18-HEPE, 17-HDHA, 14-HDHA).Results: The level of pro-inflammatory parameters in serum was significantly higher in PCOS-affected women. The ratio [(sum of pro-inflammatory molecules) / (sum of SPMs plus hydroxylated intermediates)] reflecting the inflammatory state was significantly lower in the group of healthy women.Conclusion: There is a strong pro-inflammatory state in PCOS patients. Further research will clarify whether supplementation with SPMs or their precursors may improve this state.

scholarly journals Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

2021 ◽  
Vol 22 (8) ◽  
pp. 3923
Author(s):  
Siarhei A. Dabravolski ◽  
Nikita G. Nikiforov ◽  
Ali H. Eid ◽  
Ludmila V. Nedosugova ◽  
Antonina V. Starodubova ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Polycystic Ovary ◽  
Low Grade ◽  
Causative Role ◽  
Mitochondrial Dysfunctions ◽  
Mtdna Mutations ◽  
Targeted Treatments ◽  
Tnf Α ◽  
Novel Biomarkers

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.

scholarly journals Metabolic and hormonal aspects of polycystic ovary syndrome: the impact of diet

2010 ◽  
Vol 69 (4) ◽  
pp. 628-635 ◽  
Author(s):  
Annalouise O'Connor ◽  
James Gibney ◽  
Helen M. Roche
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Overweight And Obesity ◽  
Dietary Guidelines ◽  
Dietary Fatty Acids ◽  
Reproductive Age ◽  
Low Grade ◽  
Ovary Syndrome ◽  
The Impact

Polycystic ovary syndrome (PCOS) is a common, chronic endocrine condition affecting young women of reproductive age. It is characterised by hyperandrogenaemia, and profound menstrual and ovulatory dysfunction with consequent sub-fertility. A clustering of metabolic aberrations is commonly associated with this condition and these include insulin resistance, disordered lipid metabolism and chronic low-grade inflammation. Overweight and obesity, as well as a degree of adipose tissue dysfunction, are present in a large proportion of women with PCOS, and where present, magnify the inherent hyperandrogenaemia characteristic of the condition, in addition to worsening the metabolic profile. Diet and lifestyle interventions are among the first-line treatments for PCOS, and weight reduction through energy restriction has been shown to exert positive influences on both metabolic and hormonal aspects of this condition. Alterations in carbohydrate amount and type have also been investigated, and more recently, dietary fatty acids, with a particular emphasis on PUFA, have been shown to have a positive impact within this population group. Although it is likely that diet is not the root cause of PCOS, it represents a modifiable variable with the potential to improve the health of women with this condition. Work to date has provided insights into the role of diet in PCOS; however, further work is required to determine the role of nutrients specifically within the context of PCOS, in order to develop more effective, evidence-based dietary guidelines for this condition.

scholarly journals In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rosangela Montanaro ◽  
Alessio D’Addona ◽  
Andrea Izzo ◽  
Carlo Ruosi ◽  
Vincenzo Brancaleone
Keyword(s):  
Inflammatory Markers ◽  
In Vitro Study ◽  
Inos Expression ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

scholarly journals Inflammation and reproductive function in women with polycystic ovary syndrome

2021 ◽  
Author(s):  
Leandro M Velez ◽  
Marcus Seldin ◽  
Alicia B Motta
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Chronic Inflammation ◽  
Polycystic Ovary ◽  
Essential Feature ◽  
Reproductive Function ◽  
Cardiovascular Complications ◽  
Reproductive Age ◽  
Metabolic Abnormalities ◽  
Ovary Syndrome ◽  
Inflammatory State

Abstract Polycystic Ovary Syndrome (PCOS) is one of the most frequent endocrinopathies, affecting 5–10% of women of reproductive age, and is characterized by the presence of ovarian cysts, oligo, or anovulation, and clinical or biochemical hyperandrogenism [1]. Metabolic abnormalities such as hyperinsulinemia, insulin resistance, cardiovascular complications, dyslipidemia, and obesity are frequently present in PCOS women [1]. Several key pathogenic pathways overlap between these metabolic abnormalities, notably chronic inflammation. The observation that this mechanism was shared led to the hypothesis that a chronic inflammatory state could contribute to the pathogenesis of PCOS [2]. Moreover, while physiological inflammation is an essential feature of reproductive events such as ovulation, menstruation, implantation, and labour at term [3], the establishment of chronic inflammation may be a pivotal feature of the observed reproductive dysfunctions in PCOS women [2]. Taken together, the present work aims to review the available evidence about inflammatory mediators and related mechanisms in women with PCOS, with an emphasis on reproductive function.

Role of the spleen in the development of steatohepatitis in high-fat-diet-induced obese rats

2012 ◽  
Vol 237 (4) ◽  
pp. 461-470 ◽  
Author(s):  
Megumi Inoue ◽  
Koro Gotoh ◽  
Masataka Seike ◽  
Takayuki Masaki ◽  
Koichi Honda ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Liver Tissue ◽  
Sham Operation ◽  
Low Grade ◽  
Sprague Dawley ◽  
High Fat ◽  
Obese Rats ◽  
Inflammatory State

Obesity is considered a systemic low-grade inflammatory state. Although the spleen is the main immune organ with a close anatomical relationship with the liver, its role in the progression of fatty liver disease remains uncertain. Therefore, we sought to clarify the functional role of the spleen in the development of steatohepatitis in high-fat (HF)-diet-induced obese rats. Male Sprague-Dawley rats were fed HF food and divided into two groups, a splenectomy (SPX) group and a sham-operation (Sham) group. The liver and abdominal white adipose tissue (WAT) were removed one and six months after surgery, and we evaluated the effects of SPX on WAT and HF-induced fatty liver. SPX rats exhibited worse dyslipidemia and inflammatory changes in WAT one month after surgery. Hepatic steatosis and inflammation were accelerated by SPX, based on the time after surgery. At one month after surgery, the tissue triglyceride content increased in SPX rats, compared with Sham controls ( P < 0.05). The liver histology also showed a worsening of steatosis in those rats. At six months after SPX, dramatic inflammatory and fibrotic changes were observed in liver tissue sections. Hepatic carnitine palmitoyltransferase-1 was suppressed at one and six months after SPX ( P < 0.05 for each). WAT and liver tissue levels of inflammatory markers such as tumor necrosis factor- α, and the expression of Kupffer cells were all increased at six months in SPX rats, compared with Sham controls ( P < 0.05 for each). Our results indicate that the preservation of the spleen contributes to the prevention of the progression of hepatic steatosis to steatohepatitis in obese rats.

scholarly journals The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1552
Author(s):  
Maria Sebastian-Valverde ◽  
Giulio M. Pasinetti
Keyword(s):  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Cellular Mechanisms ◽  
Pyrin Domain ◽  
Human Lifespan ◽  
Age Related ◽  
Inflammatory State ◽  
Chronic Activation ◽  
Receptor Family

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.

scholarly journals Curcumin Ameliorates Lead-Induced Hepatotoxicity by Suppressing Oxidative Stress and Inflammation, and Modulating Akt/GSK-3β Signaling Pathway

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 703 ◽  
Author(s):  
Ahlam Alhusaini ◽  
Laila Fadda ◽  
Iman H. Hasan ◽  
Enas Zakaria ◽  
Abeer M. Alenazi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Tissue Injury ◽  
Elevated Serum ◽  
Antioxidant Defenses ◽  
Exact Role ◽  
Toxic Heavy Metal ◽  
Tnf Α ◽  
Gsk 3Β

Lead (Pb) is a toxic heavy metal pollutant with adverse effects on the liver and other body organs. Curcumin (CUR) is the principal curcuminoid of turmeric and possesses strong antioxidant and anti-inflammatory activities. This study explored the protective effect of CUR on Pb hepatotoxicity with an emphasis on oxidative stress, inflammation and Akt/GSK-3β signaling. Rats received lead acetate and CUR and/or ascorbic acid (AA) for seven days and samples were collected for analyses. Pb(II) induced liver injury manifested by elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), as well as histopathological alterations, including massive hepatocyte degeneration and increased collagen deposition. Lipid peroxidation, nitric oxide, TNF-α and DNA fragmentation were increased, whereas antioxidant defenses were diminished in the liver of Pb(II)-intoxicated rats. Pb(II) increased hepatic NF-κB and JNK phosphorylation and caspase-3 cleavage, whereas Akt and GSK-3β phosphorylation was decreased. CUR and/or AA ameliorated liver function, prevented tissue injury, and suppressed oxidative stress, DNA damage, NF-κB, JNK and caspase-3. In addition, CUR and/or AA activated Akt and inhibited GSK-3β in Pb(II)-induced rats. In conclusion, CUR prevents Pb(II) hepatotoxicity via attenuation of oxidative injury and inflammation, activation of Akt and inhibition of GSK-3β. However, further studies scrutinizing the exact role of Akt/GSK-3β signaling are recommended.

scholarly journals Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase Gene Expression in the Ovaries of Female Sprague Dawley Rats

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1244-1244
Author(s):  
Amanda Bries ◽  
Joe Webb ◽  
Brooke Vogel ◽  
Claudia Carrillo ◽  
Aileen Keating ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polycystic Ovary Syndrome ◽  
Mrna Expression ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Reproductive Age ◽  
Sprague Dawley ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Sd Rats

Abstract Objectives Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive age women and leads to hyperandrogenism, abnormal menstrual cycles, and polycystic ovaries. Moreover, PCOS has been associated with elevated serum homocysteine; however, the characterization of one-carbon metabolism (OCM) in PCOS remains incomplete. The aim of our research was to examine OCM in a genetic and chemically-induced rodent model of PCOS: 1) viable yellow Agouti (Avy) mice; and 2) letrozole (Let)-induced Sprague Dawley (SD) rats. Methods Five wk old female Avy mice (N = 18), their lean controls (N = 18), and SD rats (N = 36) were acclimated for one wk. Following acclimation, the animals were placed on a modified standard AIN93G diet (energy, %: 50.4, carbohydrate; 17.3, protein; and 32.3, fat). Rats were randomly assigned to Let (1 g/kg BW) treatment or vehicle (carboxymethylcellulose) control that was administered via a subcutaneously implanted slow-release pellet every 30-d. For both models, 12 animals were randomly assigned to be euthanized during proestrus at one of the following ages: 8, 16 or 24 wk. Bodyweight and estrous cycles were measured daily. Ovaries were collected to assess gene expression of OCM. These data were analyzed using linear mixed models to determine the main effects of age and treatment at a significance level of P &lt; 0.05. Results Letrozole significantly reduced the occurrence of proestrus and estrus stages (P = 0.0001 and P = 0.006, respectively). Additionally, Let-induced rats had increased BW compared to control rats, across all age groups (P &lt; 0.0001). In contrast, Avy mice weighed less than their controls by 24 wk of age (P &lt; 0.0001). Cystathionine-β synthase (CBS) mRNA expression was downregulated in the Let-induced vs. control rats at 16 (59%; P &lt; 0.05) and 24 (77%; P &lt; 0.01) wk of age. As expected, Cyp19A1, aromatase mRNA was downregulated in the Let-induced rats (P = 0.02). Interestingly, betaine-homocysteine s-methyltransferase (BHMT) mRNA increased as a function of age in Let-induced rats (P = 0.03). Conclusions These data demonstrate that Letrozole-induced PCOS temporally decreases ovarian CBS mRNA expression; whereas, BHMT mRNA is upregulated as a function of age. Funding Sources This work was supported by the National Institute of Child Health and Human Development.

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