A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS).

Polycystic ovarian syndrome (PCOS) is a prevailing endocrine and metabolic disorder occurring in about 6-20% of females in reproductive age. Most symptoms of PCOS arise early during puberty. Since PCOS involves a combination of signs and symptoms, thus it is considered as a heterogeneous disorderliness. The most accepted diagnostic criteria is Rotterdam criteria which involves two of the latter three features: (a) hyperandrogenism, (b) oligo- or an-ovulation, and (c) polycystic ovaries. The persistent hormonal imbalance leads to multiple small antral follicles formation and irregular menstrual cycle, ultimately causing infertility among females. Insulin resistance, cardiovascular diseases, abdominal obesity, psychological disorders, infertility, and cancer are also related to PCOS. These pathophysiologies associated with PCOS are interrelated with each other. Hyperandrogenism causes insulin resistance and hyperglycemia, leading to ROS formation, oxidative stress, and abdominal adiposity. In consequence, inflammation, ROS production, insulin resistance, and hyperandrogenemia also increase. Elevation of AGEs in the body either produced endogenously or consumed from diet exaggerates PCOS symptoms and is also related to ovarian dysfunction. This review summarizes how AGE formation, inflammation, and oxidative stress are significantly essential in PCOS progression. Alterations during prenatal development like exposure to excess AMH, androgens, or toxins (bisphenol-A, endocrine disruptors, etc.) may also be the etiologic mechanism behind PCOS. Although the etiology of this disorder is unclear, environmental and genetic factors are primarily involved. Physical inactivity, as well as unhealthy eating habits, has a vital role in the progression of PCOS. This review outlines a collection of specific genes phenotypically linked with PCOS. Furthermore, beneficial effect of metformin in maintaining endocrine abnormalities and ovarian function is also mentioned. Kisspeptin is a protein which helps in onset of puberty and increases GnRH pulsatile release during ovulation as well as role of KNDy neurons in GnRH pulsatile signal required for reproduction are also elaborated. This review also focuses on the immunology related to PCOS involving chronic low-grade inflammation, and how the alterations within the follicular microenvironment are intricated in the development of infertility in PCOS patients. How PCOS develops following antiepileptic and psychiatric medication is also expanded in this review. Initiation of antiandrogen treatment in early age (≤ 25 years) might be helpful in spontaneous conception in PCOS women. The role of BMP (bone morphogenetic proteins) in folliculogenesis and their expression in oocytes and granulosa cells are also explained. GDF8 and SERPINE1 expression in PCOS is given in detail.

Inhibitory effect of baicalein against glycation in HSA: an in vitro approach.

Hyperglycaemia accelerates the aging process significantly. Diabetes problems can be mitigated by inhibiting glycation. To learn more about glycation and antiglycation mediated by methyl glyoxal and baicalein, we studied human serum albumin as a model protein. A Methylglyoxal (MGO) incubation period of seven days at 37 degrees Celsius induced glycation of Human Serum Albumin.s Hyperchromicity, decreased tryptophan and intrinsic fluorescence, increased AGE-specific fluorescence, and reduced mobility were all seen in glycated human serum albumin (MGO-HSA) in sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Fourier transform infrared spectroscopy (FT-IR) and then far ultraviolet dichroism were used to detect secondary and tertiary structural perturbations (CD). The Congo red assay (CR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) all verified the presence of amyloid-like clumps. Structure (carbonyl groups on ketoamine moieties) (CO), physiological problems including diabetes mellitus, and cardiovascular disease, etc. are linked to the structural and functional changes in glycated HSA, as proven by these studies.Communicated by Ramaswamy H. Sarma.

Biochanin obstructs human serum albumin from non-enzymatic glycation: an in vitro approach.

Various serum proteins, like Human Serum Albumin (HSA) and others, are susceptible to glycation and the formation of Advanced Glycation End Products (AGEs). Diabetes and other diseases are associated with AGE development. Recently, isoflavones have been studied for their therapeutic benefits. In the present study, we glycated HSA with Methylglyoxal (MGO) with and without the test compound, i.e., Biochanin A (BCA), to test its antiglycating capacity. We studied the biochemical and biophysical effects of glycation on HSA with and without BCA and also took the help of the in silico technique. Analytical methods included intrinsic and extrinsic fluorescence, polyacrylamide gel electrophoresis (PAGE), UV spectroscopy, far UV circular dichroism, and others. For structural comprehension, TEM and SEM were used. Molecular docking and simulation were employed to observe BCA-HSA's site-specific interaction. Since HSA is a therapeutically relevant protein involved in many disorders, this study's findings are important.Communicated by Ramaswamy H. Sarma.

Synergistic effect of chlorogenic acid and vitamin D3 (cholecalciferol) on in-vitro glycation may assist in prevention of Polycystic Ovarian Syndrome (PCOS) progression - A biophysical, biochemical and in-silico study.

Advanced glycation end products (AGEs) are formed through non-enzymatic glycation, that have been linked to various diseases, including polycystic ovarian syndrome (PCOS) playing a critical role leading to secondary comorbidities such as diabetes-related problems, cardiovascular complications, infertility, etc. As a result, there has been a lot of research into AGE-inhibiting phytochemicals for the remediation and obstruct progression of glycation-related illnesses. The current study is based on in-vitro protein model, in which human serum albumin have been used to investigate the cumulative effect of chlorogenic acid (CGA) and cholecalciferol (vitamin D) on glycation and evaluate their inhibitory impact on AGEs production in the presence of methylglyoxal. Through the application of several biochemical and biophysical techniques, we were able to examine the synergistic impact of both the compounds on albumin structure and its biochemical properties during different stages of glycation. According to Nitro-blue tetrazolium assay results indicate that CGA and vitamin D inhibited fructosamine (early glycation product) production. Moreover, free thiol and lysine residues were significantly increased whereas protein carbonyl levels were significantly decreased. Additive effect of CGA and vitamin D were associated with reduced AGEs fluorescence and increased tryptophan and tyrosine fluorescence. Amadori-albumin after treatment showed some evidence of regaining its alpha-helicity as measured by far-UV CD spectrum. Furthermore, secondary structural alterations were confirmed by Fourier transform infrared spectroscopy (FTIR). ANS (1-anilinonaphthalene-8-sulfonic acid) fluorescence spectra also displayed less revelation of hydrophobic patches. Bilirubin binding capacity was also restored which showed functional recovery of HSA. The electrophoretic mobility was also restored which is portrayed by SDS-PAGE. Additionally, to predict the anti-aggregation potential of CGA and vitamin D, congo red assay and ThT fluorescence was performed which reveal low aggregate formation after treatment. These results corroborated with scanning electron microscopy and confocal microscopy. Docking and simulation results also reveal spontaneous binding of CGA and vitamin D on subdomain IIA of HSA favoring their binding thermodynamically. All the findings suggest that chlorogenic acid and cholecalciferol given in combination might help in prevention of PCOS progression and its related complications.

Cardiac glycoside digoxin ameliorates pro-inflammatory cytokines in PBMCs of rheumatoid arthritis patients in vitro.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by hyperplasia of the synovial membrane along with persistent inflammation of joints. Earlier studies suggest the crucial role of Th1 and Th17 subsets of T-helper cells in the pathogenesis of RA. Digoxin, a cardiac glycoside, is widely used in the treatment of heart failure. Keeping into consideration the potential of digoxin to regulate inflammatory responses in the host, we assessed its effect on the peripheral blood mononuclear cells (PBMCs) of RA patients. The PBMCs were incubated with a varying amount (10-500 nM) of digoxin for 24 h at 37 °C. There was a significant reduction in the population of Th17 cells upon treatment with digoxin. On the other hand, the digoxin treatment failed to modify the expression of T-bet and IFN-γ at both proteins as well as mRNA level in the treated PBMCs. The cardiac glycoside also inhibited transcription factor ROR-γt in the Th17 cells. We also found a decrease in the levels of IL-1ß, IL-6, IL-17, and IL-23 cytokines in the culture supernatant of digoxin treated PBMCs isolated from RA patients. The data of the present study suggest the preferential role of digoxin in suppressing the differentiation of Th17 cells in RA patients.

Effect of syringic acid and syringaldehyde on oxidative stress and inflammatory status in peripheral blood mononuclear cells from patients of myocardial infarction.

Oxidative stress and inflammation are considered as therapeutic targets in myocardial injury. The aim of the present study was to investigate the protective effect of syringic acid (SA) and syringaldehyde (SYD) on peripheral blood mononuclear cells (PBMCs) of myocardial infarction (MI) patients. PBMCs from MI patients were cultured in the presence and absence of SA and SYD. The level of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) was estimated. Reactive oxygen species (ROS) formation, oxidation of lipids, proteins, and activity of antioxidant enzymes were also quantified. To further determine biomolecular changes in treated PBMCs, Fourier transform infrared (FTIR) spectroscopic analysis was done. Molecular docking study was also conducted to evaluate the binding interaction of SA and SYD with various target proteins. SA and SYD treated PBMCs of MI patients showed decreased secretion of TNF-α, IL-6, and NO. Moreover, the content of ROS, level of lipid, and protein oxidation showed diminution by treatment with both the compounds. Enhanced antioxidant defense was also observed in treated PBMCs. The FTIR spectra of treated cells revealed safeguarding effect of SA and SYD on biomolecular structure. The molecular docking analysis displayed significant binding affinity of the two compounds towards TNF-α, IL-6, and antioxidant enzymes. Our findings demonstrated potent antioxidant and anti-inflammatory effects of SA and SYD on PBMCs of MI patients. Thus, SA and SYD supplementation might be beneficial in attenuating oxidative stress and inflammation in MI.

GRACE score of myocardial infarction patients correlates with oxidative stress index, hsCRP and inflammation.

BACKGROUND: Etiopathogenesis of myocardial infarction (MI) is contributed by oxidative injury and inflammatory response. The interplay of these processes determines outcomes in MI patients. However, studies showing the relationship of oxidative stress and inflammatory cytokines with prognosis and severity of MI are lacking. OBJECTIVE: The present study was designed to assess the degree of oxidative stress and inflammation in correlation with GRACE (Global Registry of Acute Coronary Events) risk score in patients of MI. METHODS: MI patients were segregated according to GRACE risk score and age. Blood samples of the patients were used for determination of level of total peroxide, Total Antioxidant Status (TAS), Oxidative Stress Index (OSI), pro-inflammatory molecules such as high sensitive C-reactive protein (hsCRP), Tumor Necrosis Factor α (TNFα), interleukin 1 ß (IL 1ß), interleukin 6 (IL 6), anti-inflammatory cytokine interleukin 10 (IL 10), and TNFα/IL 10 cytokine ratio. RESULTS: We found significant elevation in concentration of total peroxide, TAS and OSI in all MI patients than healthy volunteers, this elevation showed pronouncement with higher GRACE score (GS) and age. Alteration in pro-inflammatory and anti-inflammatory cytokines was seen in MI patients than control group, and this alteration displayed polarization with GS and age. CONCLUSION: MI patients with higher GS and age have greater degree of OSI and inflammation, and these biochemical parameters were significantly correlated with GS and thus disease severity.

Syringic acid protects from isoproterenol induced cardiotoxicity in rats.

Identification of pharmacologically potent antioxidant compounds for their use in preventive medicine is thrust area of current research. This study was undertaken with the aim of determining the protective role of syringic acid (SA) on isoproterenol (ISO) induced myocardial infarction (MI) in rats. SA was orally given to rats for 21 days at three different concentrations (12.5, 25 and 50 mg/kg). At 20th and 21st day, rats were subcutaneously injected with ISO and at the end of experimental period, rats were killed. ISO induced myocardial damage was averted by pre-co-treatment of SA, as decrease was found in serum level of marker enzymes (CKMB, LDH, AST, ALT), lipid peroxidation, protein carbonyl (PC) and proinflammatory cytokines (TNFα, IL 6). Furthermore, content of glutathione (GSH) and activities of antioxidant enzymes in heart tissue were significantly raised. Improvement in infarct size and erythrocyte (RBCs) morphology was also observed. The biochemical findings were supported by histopathological outcome and protective effect of SA was found to be dose dependent. The results of our study demonstrated that the cardioprotective potential of SA in rat model of ISO induced MI might be due to anti-lipid peroxidative and endogenous antioxidant system enhancement effects.

T helper cell subpopulations repertoire in peripheral blood and its correlation with sex of newly diagnosed arthritis patients: A gender based study.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder. Autoreactive T cells play a very significant role in the pathogenesis of RA. However, the exact mechanisms of disease severity and pathogenesis are poorly understood. We attempted to correlate T-helper cell activities with sexes of newly diagnosed patients with RA. The patients were divided based on their sex and disease severity. Examination of the expression of various factors using quantitative real-time PCR and FACS analysis of peripheral blood mononuclear cells revealed that T-bet, ROR-γt, Foxp3, and the level of cytokines associated with Th1 cells were almost identical among male and female patients with RA. Interestingly, there was a high correlation between Th17 expression and disease severity in female patients with RA. In general, there was no significant correlation between Th1 cell population and the disease severity in newly diagnosed patients with RA. In contrast, the frequency of both Th17 and Treg cells was higher in patients with more severe disease. The results suggested that, in patients with RA, the T-helper cell balance within peripheral blood was skewed towards the Th17 and Treg phenotypes. Besides Th17- and Treg-associated cytokines, elevated expression of IL-27/IL-23 cytokines might also be responsible for increased disease severity in female patients with RA.

Cinnamaldehyde and eugenol attenuates collagen induced arthritis via reduction of free radicals and pro-inflammatory cytokines.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease which leads to bone and cartilage erosion. Oxidative stress and pro-inflammatory cytokines plays crucial role in the pathophysiology of RA. Cinnamaldehyde and eugenol have a long history of medical use in various inflammatory disorders. PURPOSE: The drugs available for the treatment of RA are associated with various side effects. The present study was conducted to evaluate the anti-arthritic effects of cinnamaldehyde and eugenol in rat model of arthritis. METHODS: Type II collagen was intradermally injected to rats for the induction of arthritis. Cinnamaldehyde (10 and 20 mg/kg/day) and eugenol (10 and 20 mg/kg/day) were given orally for 15 days, starting from day 21 to 35. Dexamethasone treated rats served as positive control. Histological, radiological and scanning electron microscopic analysis were done to monitor the effect of compounds on collagen induced arthritis (CIA). Reactive oxygen species (ROS) formation, nitric oxide and antioxidant status were also determined. The markers of biomolecular oxidation (protein, lipid and DNA) and activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, catalase and glutathione reductase) were also evaluated in the joint homogenate and plasma of rats. For detecting inflammation, levels of TNF-α, IL-6 and IL-10 were monitored by ELISA. RESULTS: Our results showed anti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol in arthritic rats. Scanning electron microscopy, histopathological and radiological findings also confirmed the anti-arthritic effects of cinnamaldehyde and eugenol. Both the compounds were effective in bringing significant decrease in the levels of ROS, nitric oxide, markers of biomolecular oxidation and increase in enzymatic and non-enzymatic antioxidants. The levels of TNF-α, IL-6 and IL-10 were also ameliorated by cinnamaldehyde and eugenol treatment. Between the two phytochemicals used, eugenol was found to be more effective than cinnamaldehyde in reducing the severity of arthritis. CONCLUSION: Cinnamaldehyde and eugenol were effective in ameliorating oxidative stress and inflammation in arthritic rats. These findings indicate that cinnamaldehdye and eugenol have a great potential to be used as an adjunct in the management of RA.

Anti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol on mononuclear cells of rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is an autoimmune disorder affecting joints and frequently characterized by initial local and later systemic inflammation. The present study was conducted with the aim to determine the anti-inflammatory and antioxidant effects of cinnamaldehyde and eugenol in the peripheral blood mononuclear cells (PBMC) of RA patients. PBMCs obtained from RA patients were treated with varying concentrations of cinnamaldehyde and eugenol. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were monitored in the 24-h culture supernatant of PBMCs. Reactive oxygen species formation, biomolecular oxidation and the activities of antioxidant enzymes were also determined. FTIR analysis was done to determine structural alterations in the PBMCs. Molecular docking was performed to gain an insight into the binding mechanism of eugenol and cinnamaldehyde with pro-inflammatory cytokines. The levels of pro-inflammatory cytokines and markers of oxidative stress were found to be elevated in the PBMC culture of RA patients as compared to the healthy controls. Cinnamaldehyde and eugenol have significantly reduced the levels of cytokines. Reactive oxygen species formation, biomolecular oxidation and antioxidant defense response were also ameliorated by treating PBMCs with both the compounds. FTIR results further confirms cinnamaldehyde and eugenol mediated protection to biomolecules of PBMCs of RA patients. Molecular docking results indicates interaction of cinnamaldehyde and eugenol with key residues of TNF-α and IL-6. Cinnamaldehyde and eugenol were found to exert potent anti-inflammatory and anti-oxidant effects on the PBMC culture of RA patients. So, these compounds may be used as an adjunct in the management of RA.

Role of hydrotherapy in the amelioration of oxidant-antioxidant status in rheumatoid arthritis patients.

AIM: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease. Reactive oxygen species (ROS) are involved in the pathophysiology of RA. Moderate intensity exercises have been reported to have anti-oxidant and anti-inflammatory effects. The aim of this study was to evaluate the effect of hydrotherapy on oxidant-antioxidant status in RA patients. METHODS: Forty RA patients and 30 age- and sex-matched healthy controls were included in this study. RA patients were subdivided into two groups: the first group (n = 20) received treatment with conventional RA drugs, while the second group (n = 20) received hydrotherapy along with the conventional drugs for a period of 12 weeks. Disease Activity Score of 28 joints (DAS-28), ROS level, protein oxidation, lipid peroxidation, DNA damage and the activities of antioxidant enzymes were evaluated before and after 12 weeks of treatment. RESULTS: RA patients showed a significant change in the oxidative stress biomarkers (ROS, P < 0.01; ferric reducing antioxidant potential, P < 0.001; malondialdehyde, P < 0.01; protein carbonyl, P < 0.001; tail length, P < 0.05) and decrease in the activities of anti-oxidant enzymes (superoxide dismutase [SOD], P < 0.01; glutathione peroxidase [GPx], P < 0.001). Conventional drug treatment has not produced any significant change in these parameters. However, cotreatment of drugs with hydrotherapy has decreased protein, lipid and DNA oxidation by increasing the activities of antioxidant enzymes (SOD and GPx). CONCLUSION: Our results indicate that hydrotherapy along with drugs has reduced the severity of disease (DAS-28) by ameliorating the oxidant-antioxidant status in RA patients. Thus, in addition to conventional drugs, RA patients should be advised to have hydrotherapy (moderate intensity exercise) in their treatment regimen.

Elevated DNA Damage, Oxidative Stress, and Impaired Response Defense System Inflicted in Patients With Myocardial Infarction.

BACKGROUND: Ischemic tissue damage in myocardial infarction (MI) is allied with the exaggerated production of reactive oxygen species (ROS) beyond the countering capability of chain-breaking radical scavengers, fallouts in the form of oxidatively burdened myocardial tissue. METHODS: One hundred and twenty five patients with MI were included in the study to evaluate the dynamics of redox status of patients by monitoring the antioxidant potential, biomarkers of oxidative stress, lipid indices, RBC membrane damage when compared to healthy individuals in patients with MI congregated on the basis of Global Registry of Acute Coronary Events (GRACE) score, risk factors, and age. RESULTS: Higher levels of malondialdehyde, 8-hydroxy-2-deoxyguanosine, lipid indices, ROS content, and membrane deterioration in erythrocytes were seen in patients with MI. Furthermore, reduced activities of erythrocyte antioxidant enzymes and lower concentrations of antioxidant molecules, plus reduced total antioxidant capacity, were observed in plasma of all patients with MI with respect to control. However, elevation in oxidative stress was found to be significantly marked in patients having GRACE score >100, risk factors, and MI >45 years when compared to patients with GRACE score ≤100, without risk factors, and MI ≤45 years, respectively. CONCLUSION: These findings indicate the existence of increased oxidative damage and reduced antioxidant potential in patients with MI have a potent relationship with their GRACE risk score, risk factors, and age.

Protective effect of syringaldehyde on biomolecular oxidation, inflammation and histopathological alterations in isoproterenol induced cardiotoxicity in rats.

BACKGROUND: Ischemic injury during myocardial infarction (MI) is responsible for increased deaths among patients with cardiovascular disorders. Recently, research has been directed for finding treatment using natural compounds. This study was performed to investigate the effects of syrigaldehyde (SYD), a phytochemical against isoproterenol (ISO) induced cardiotoxicity model. METHODS: For induction of MI, rats were intoxicated with two doses of ISO and were treated with SYD at three different concentrations (12.5, 25 & 50 mg/kg) both prior and simultaneous to ISO administration. RESULTS: ISO group revealed amplified activity of marker enzymes (CKMB, LDH, AST, ALT), increased oxidation of proteins and lipid molecules. Moreover, augmentation in pro-inflammatory markers was also found. The same group also displayed marked changes in histopathology and erythrocyte (RBCs) morphology. SYD treated groups showed diminished levels of serum markers enzymes, lipid peroxidation and protein carbonyl (PC) with increment in antioxidant defense in cardiac tissues of ISO administered rats. Our findings also revealed the modulatory effect of SYD on membrane bound ATPases, showing that SYD significantly improved the ISO induced changes in membrane fluidity. Furthermore, decline in infarct size, alleviation of structural RBC damage and improved myocardial histopathological outcome were observed in treated groups. In addition, mitigation of biochemical and histopathological changes by SYD was found to be dependent on its concentration. CONCLUSION: SYD had cardioprotective efficacy owing to its antioxidative and anti-inflammatory properties. Our results support incorporation of SYD in regular diet for prevention of MI.

Level of inflammatory cytokines in rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen species.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder. Reactive oxygen species (ROS) and pro-inflammatory cytokines have been believed to be involved in the etiopathogenesis of the disease. The aim of the study was to determine the correlation of inflammatory cytokines with 25-hydroxy vitamin D and ROS. METHODS: 100 RA patients and 50 healthy age and sex matched individuals were included in the study. Patients were further divided on the basis of presence or absence of rheumatoid factor and disease severity. Serum 25-hydroxy vitamin D levels were monitored by chemiluminescent immunoassay. 10% hematocrit was used to detect the level of ROS by spectro fluorometer. The levels of inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-10 and IL-17) were determined in plasma by ELISA. RESULTS: The level of 25-hydroxy vitamin D was found to be decreased in RA patients in comparison to the control group. However the level of ROS and inflammatory cytokines were found to be elevated in RA patients in comparison with the healthy controls, with the increase being more pronounced in seropositive and RA patients having high disease severity. Inflammatory cytokines showed negative correlation with 25-hydroxy vitamin D and positive correlation with ROS. CONCLUSION: This study for the first time shows the association of inflammatory cytokines with 25-hydroxy vitamin D and ROS in RA patients. The results suggest that 25-hydroxy vitamin D being an immune modulator is decreased in the serum of RA patients. Further ROS and cytokines play an important role in the pathogenesis of RA and are responsible for increasing the severity of disease.

Redox signaling in rheumatoid arthritis and the preventive role of polyphenols.

Rheumatoid arthritis (RA) is an autoimmune, inflammatory joint disease whose exact cause is still not completely known. Reactive oxygen species (ROS) are believed to be involved in the pathogenesis of RA. ROS are produced mostly by the phagocytic cells during oxidative burst and oxidative phosphorylation. Lipids, proteins and nucleic acids get damaged by the overproduction of ROS. Damaging effects of ROS are taken care by the enzymatic and non-enzymatic defence system of the body. Overproduction or inadequate elimination of reactive species leading to oxidative stress has been positively correlated with the disease severity in RA patients. ROS activates signal transduction pathways involved in the inflammatory response in RA. Understanding the complex interplay between signaling pathways might be useful for the development of new and effective therapeutics for RA. In this review we discuss the involvement of reactive species in the pathogenesis of RA and their elimination by antioxidant defence system. Role of various antioxidants/polyphenols which looks quite promising in the treatment of RA have also been discussed.

Increased Reactive Oxygen Species Formation and Oxidative Stress in Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder. Highly reactive oxygen free radicals are believed to be involved in the pathogenesis of the disease. In this study, RA patients were sub-grouped depending upon the presence or absence of rheumatoid factor, disease activity score and disease duration. RA Patients (120) and healthy controls (53) were evaluated for the oxidant-antioxidant status by monitoring ROS production, biomarkers of lipid peroxidation, protein oxidation and DNA damage. The level of various enzymatic and non-enzymatic antioxidants was also monitored. Correlation analysis was also performed for analysing the association between ROS and various other parameters. METHODS: Intracellular ROS formation, lipid peroxidation (MDA level), protein oxidation (carbonyl level and thiol level) and DNA damage were detected in the blood of RA patients. Antioxidant status was evaluated by FRAP assay, DPPH reduction assay and enzymatic (SOD, catalase, GST, GR) and non-enzymatic (vitamin C and GSH) antioxidants. RESULTS: RA patients showed a higher ROS production, increased lipid peroxidation, protein oxidation and DNA damage. A significant decline in the ferric reducing ability, DPPH radical quenching ability and the levels of antioxidants has also been observed. Significant correlation has been found between ROS and various other parameters studied. CONCLUSION: RA patients showed a marked increase in ROS formation, lipid peroxidation, protein oxidation, DNA damage and decrease in the activity of antioxidant defence system leading to oxidative stress which may contribute to tissue damage and hence to the chronicity of the disease.

Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anti-citrullinated peptide antibodies. Initial phase of RA involves the activation of both T and B cells. Cytokines have a crucial role in the pathophysiology of RA as pro-inflammatory cytokines such as TNFα, IL-1, IL-17 stimulates inflammation and degradation of bone and cartilage. There occurs an imbalance between the pro- and anti-inflammatory cytokine activities which leads to multisystem immune complications. There occurs a decline in the number of Treg cells which may also play an important role in pathophysiology of the disease. In RA patients, serum or plasma level of cytokines may indicate the severity of disease. Cytokine gene polymorphism could be used as markers of susceptibility and severity of RA. Anti-cytokine agents seem to emerge as potent drug molecules to treat RA. Many clinical trials are ongoing and several positive results have been obtained. There is a need to develop potential anti-cytokine agents that target numerous pathways involved in the pathogenesis of RA. This review article describes the effector functions of pro- and anti-inflammatory cytokines and the role of cytokine gene polymorphism in the pathogenesis of RA. Anti-cytokine agents that are currently available and those that are still in clinical trials have also been summarized.