Shagufta Moin

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.

Histamine, Histamine Receptors, and their Role in Immunomodulation: An Updated Systematic Review

Histamine, a biological amine, is considered as a principle mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. It stimulates different biological activities through differen- tial expression of four types of histamine receptors (H1R, H2R, H3R and H4R) on secretion by effector cells (mast cells and basophils) through various immunological or non-immunological stimuli. Since H4R has been discovered very re- cently and there is paucity of comprehensive literature covering new histamine receptors, their antagonists/agonists, and role in immune regulation and immunomodulation, we tried to update the current aspects and fill the gap in existing litera- ture. This review will highlight the biological and pharmacological characterization of histamine, histamine receptors, their antagonists/agonists, and implications in immune regulation and immunomodulation.

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.

Role of Pro-Inflammatory Cytokines and Biochemical Markers in the Pathogenesis of Type 1 Diabetes: Correlation with Age and Glycemic Condition in Diabetic Human Subjects.

Background Type 1 diabetes mellitus is a chronic inflammatory disease involving insulin producing β-cells destroyed by the conjoined action of auto reactive T-cells, inflammatory cytokines and monocytic cells. The aim of this study was to elucidate the status of pro-inflammatory cytokines and biochemical markers and possible correlation of these factors towards outcome of the disease. Methods The study was carried out on 29 T1D subjects and 20 healthy subjects. Plasma levels of oxidative stress markers, enzymatic and non-enzymatic antioxidants were estimated employing biochemical assays. The levels of pro-inflammatory cytokines such as by IL-1β & IL-17 in the serum were determined by ELISA, while the expression of TNF-α, IL-23 & IFN-γ was ascertained by qRT-PCR. Results The onset of T1D disease was accompanied with elevation in levels of Plasma malondialdehyde, protein carbonyl content and nitric oxide while plasma vitamin C, reduced glutathione and erythrocyte sulfhydryl groups were found to be significantly decreased in T1D patients as compared to healthy control subjects. Activity of antioxidant enzymes, superoxide dismutase, catalase, glutathione reductase and glutathione-s-transferase showed a significant suppression in the erythrocytes of T1D patients as compared to healthy subjects. Nevertheless, the levels of pro-inflammatory cytokines IL-1β and IL-17A were significantly augmented (***p≤.001) on one hand, while expression of T cell based cytokines IFN-γ, TNF-α and IL-23 was also up-regulated (*p≤.05) as compared to healthy human subjects. Conclusion The level of pro-inflammatory cytokines and specific biochemical markers in the serum of the patient can be exploited as potential markers for type 1 diabetes pathogenesis. The study suggests that level of inflammatory markers is up-regulated in T1D patients in an age dependent manner.

The effect of type 2 diabetes mellitus and smoking on periodontal parameters and salivary matrix metalloproteinase-8 levels.

The present study was carried out to evaluate the effect of type 2 diabetes mellitus (DM) and smoking on periodontal parameters and on the levels of salivary matrix metalloproteinase (MMP-8). One hundred and twenty five subjects were divided into five groups: group 1, systemically and periodontally healthy subjects (n = 25); group 2, systemically healthy subjects but with chronic periodontitis (n = 25); group 3, subjects with type 2 DM and chronic periodontitis (n = 25); group 4, smokers with chronic periodontitis (n = 25); group 5, diabetic-smokers with chronic periodontitis (n = 25). MMP-8 level in saliva was estimated by enzyme linked immunosorbent assay (ELISA) using Quantikine human total MMP-8 immunoassay kit. The result showed that the clinical periodontal parameters and the mean levels of the salivary MMP-8 were significantly higher for diabetic-smokers than other study groups. A highly significant positive correlation (r) between MMP-8 and periodontal parameters was also observed in diabetic-smoker patients. The findings suggest that diabetic-smokers have increased periodontal breakdown and are associated with an increased extent and severity of periodontitis. (J Oral Sci 58, 1-6, 2016).

Anti-inflammatory activity of roots of Cichorium intybus due to its inhibitory effect on various cytokines and antioxidant activity

Background: Cichorium intybus L. commonly known as chicory is one of the important medicinal plants commonly used in Ayurvedic system of medicine. It is commonly used for the treatment of diseases involving a khapa and pitta doshas. Traditionally, C. intybus is used for the treatment of inflammatory conditions, but there are only few in vitro studies reporting the anti-inflammatory activity of roots of chicory. Objective: Evaluation of anti-inflammatory activity of roots of chicory and mechanisms involved in it using in vivo models of inflammation. Materials and Methods: Albino Wistar rats of either sex weighing 150-200 g were used. Ethanolic and aqueous extracts of roots of chicory were prepared with the help of Soxhlet′s apparatus. The anti-inflammatory activity was studied using carrageenan-induced paw edema method and cotton pellet granuloma method. Levels of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-1 and activity of antioxidant enzymes such as catalase (CAT) and glutathione peroxidase (GPx) were estimated. Results: Chicory roots demonstrated significant dose-dependent decrease in paw edema in carrageenan-induced paw edema method. Chicory roots diminished the serum TNF-α, IL-6, and IL-1 levels. They also significantly attenuated the malonylaldehyde levels and increased the activities of CAT and GPx in paw tissue. Similarly, chicory roots demonstrated a significant decrease in granuloma formation in cotton pellet induced granuloma method. Conclusion: Chicory roots possess anti-inflammatory activity, and this might be due to the inhibition of various cytokines, antioxidant effects, and their free radical scavenging activity.

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-1β, 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.

Normal delivery induced stress alters glutathione peroxidase and TNF-α in elderly primigravidas mononuclear cells

To probe the glutathione peroxidase (GPx) activity coupled to ROS and TNF-α levels in younger versus elderly primigravidas. Monocytes were isolated from blood of young and elderly primigravidas after 12 hrs, 24 hrs and 14 days postpartum. Age-matched healthy female donors served as controls. Thereafter, the above monocytes were subjected to evaluation of GPx activity, levels of pro-inflammatory cytokine TNF-α and reactivity/specificity towards anti-TNF-α antibody. Suppression in GPx activity with simultaneous enhancement of TNF-α levels in monocytes was observed after 12 hrs and 24 hrs of spontaneous labor pain-induced maternal delivery through normal vaginal route. Conversely, an enhancement of GPx activity and decrease in TNF-α levels were observed on day 14 of postpartum, thereby indicating reversal of the impaired neutralizing mechanisms. The antioxidant network combating ROS was stronger in younger primigravidas. Capability of TNF-α and ROS suppression was somewhat lesser in elderly primigravidas even 14 days of postpartum via normal vaginal route. The capability of GPx activity enhancement with simultaneous suppression in ROS and TNF-α, decreases in elderly primigravidas. This may act as one of the important parameters leading to a variety of complications encountered by elderly primigravidas.

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.

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

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.