Xanthenone, ACE2 activator, counteracted gentamicin-induced nephrotoxicity in rats: Impact on oxidative stress and ACE2/Ang-(1-7) signaling.

Nephrotoxicity is a rapid deterioration of kidney function due to exposure to nephrotoxic drugs as gentamicin. Gentamicin increases the generation of reactive oxygen species (ROS) leading to inflammatory responses and nuclear factor-κB (NF-κB) activation. The renal renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression through the classic ACE/Ang-II/AT1 axis and its antagonist, ACE2/Ang-(1-7)/Mas axis which exerts an important role in the kidney. The present study evaluates the protective effects of the angiotensin-converting enzyme 2 (ACE2) activator; xanthenone; against experimental nephrotoxicity induced by gentamicin. Rats were divided into 4 groups, normal control, xanthenone (2 mg/kg, s.c), gentamicin (100 mg/kg, i.p. for one week) and xanthenone + gentamicin groups. Blood urea nitrogen (BUN) and serum creatinine levels were measured. The kidney tissues were used for estimating glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), NF-κB, Angiotensin II (AngII), and Ang-(1-7). In addition, histopathological examination and Western blot analysis of ACE2 expression were done. Xanthenone significantly restored serum levels of BUN and creatinine. Xanthenone exerted significant antioxidant effect as revealed by increased GSH content and SOD activity together with reduced MDA content. It exerted anti-inflammatory effect by significant reduction in TNF-α, NF-κB and IL-6 expression compared to gentamicin group. Xanthenone increased Ang-(1-7) and ACE2 expression while significantly decreased Ang-II expression. Histopathologically, xanthenone markedly counteracted gentamicin-induced renal aberrations. Activation of ACE2/Ang-(1-7) by xanthenone produced significant antioxidant and anti-inflammatory effects that counteracted gentamicin-induced nephrotoxicity.

Thymoquinone mitigate ischemia-reperfusion-induced liver injury in rats: a pivotal role of nitric oxide signaling pathway.

Oxidative and nitrosative stress-induced endothelial cell damage play an essential role in the pathogenesis of hepatic ischemia-reperfusion (IR) injury. IR is associated with reduced eNOS expression and exacerbated by superimposed stress. NOSTRIN induces intracellular endothelial nitric oxide synthase (eNOS) translocation and inducible nitric oxide synthase (iNOS) increases nitric oxide (NO) production. Our aim was to assess hepatic expression of iNOS, eNOS, and NOSTRIN in IR with or without N-acetylcysteine (NAC) or thymoquinone (TQ) pretreatment and to compare their hepatoprotective effects. Surgical induction of IR was performed by occlusion of hepatic pedicle for 30 min with mini-clamp and reperfused for 30 min. The effects of TQ (20 mg/kg/day) or NAC (300 mg/kg/day) administered orally for 10 days were evaluated by serum ALT and AST, oxidative stress parameters, NO production, and histopathological analysis. Also, localization and expression of iNOS, eNOS, and NOSTRIN were assessed by immunofluorescence. TQ or NAC pretreatment significantly decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and myeloperoxidase (MPO) activities, malondialdehyde (MDA) level, and NO production. In addition, they restored the depleted GSH content and alleviated histopathological changes. Furthermore, they up-regulated eNOS and down-regulated iNOS and NOSTRIN expressions. TQ exerts its hepatoprotective effect, at least in part, by nitric oxide signaling pathway through modulation of iNOS, eNOS, and NOSTRIN expressions as well as suppression of oxidative stress.

Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity.

BACKGROUND: Hesperidin, a naturally occurring flavonoid, exerts many clinically appreciable effects such as anti-oxidant, anti-allergic and anti-inflammatory actions. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced acute hepatotoxicity in rats. METHODS: Hesperidin (100 or 200mg/kg po) was given to rats one day before cisplatin (7.5mg/kg, ip) injection. All animals were sacrificed 5 days after cisplatin injection and blood samples were collected for determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, triglycerides (TG) and total cholesterol levels. Liver samples were used for the determination of malondialdehyde (MDA), glutathione (GSH), total nitrate and nitrite contents. Western blot analysis was used for the assessment of NF-κB and p-Akt expression and histopathological examination was also performed. RESULTS: Results showed that hesperidin significantly reduced cisplatin-induced elevations in serum ALT and AST activities, TG and total cholesterol levels. It also reduced cisplatin-induced oxidative stress by significant reduction in liver MDA and NO content and elevation of GSH content. In addition, hesperidin significantly counteracted cisplatin-induced increased NF-κB expression and decreased p-Akt expression. Histopathological examination revealed that hesperidin greatly protected liver against cisplatin-induced injury. Moreover hesperidin did not inhibit the cytotoxic effect of cisplatin on cancer cells as determined by MTT assay. CONCLUSION: Hesperidin decreased cisplatin-induced functional and histopathological liver damage in a dose-dependent manner without affecting its potential cytotoxic effect.

Anti-CCP2 is an adjunct to, not a surrogate for, rheumatoid factor in the diagnosis of rheumatoid arthritis: diagnostic utility of anti-CCP2 antibodies in Egyptian patients with rheumatoid arthritis.

OBJECTIVES: To examine the diagnostic utility of the second generation of anti-cyclic citrullinated peptide (anti-CCP2) antibodies versus rheumatoid factor (RF) in rheumatoid arthritis (RA), and to study the association between anti-CCP2 and RA disease parameters. METHODS: Fifty consecutive Egyptian patients with RA, 37 patients with other rheumatic diseases, and 10 healthy controls were recruited for testing for anti-CCP2 and immunoglobulin M (IgM) rheumatoid factor (RF). Assessment measures included the Disease Activity Score (DAS28) for disease activity, the Health Assessment Questionnaire - Disability Index (HAQ-DI) for disability and the Short Erosion Narrowing Score (SENS) for radiological damage. RESULTS: The sensitivities of anti-CCP2 and IgM-RF in RA patients were 70% and 52%, with specificities of 91.5% and 89.4%, respectively. There was 73.2% agreement between anti-CCP2 and RF for all groups tested (kappa = 0.42, p<0.001) but agreement was only 66% for RA patients (kappa = 0.31, p<0.05). Anti-CCP2 had superior diagnostic properties [sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)] than RF, but using both RF and anti-CCP2 enhanced the sensitivity to 78%, when either test was positive, and the specificity to 100%, with a PPV of 1, when both tests were positive. Anti-CCP2 titre was significantly correlated with disease severity [rheumatoid nodules, rheumatoid factor (RF), and radiological damage] and HAQ-DI (p<0.05) but not with parameters of disease activity. CONCLUSION: Anti-CCP2 has superior diagnostic and prognostic properties in RA compared with RF. It should not replace RF as a serological test; however, since using both tests modestly increases sensitivity and markedly enhances specificity, so that diagnosis of RA is highly probable when both tests are positive.

Rheumatic manifestations of psoriasis.

Psoriatic arthritis was described as a distinct rheumatic disease in the 1960s, and subsequently grouped among the spondyloarthropathies. Recently, other rheumatic manifestations of psoriasis, such as enthesopathy and osteoperiostitis, were recognized. This study attempts to examine the rheumatological and radiological manifestations of Psoriasis and their association with skin and nail disease. Eighty-one psoriatic outpatients were interviewed consecutively during 6 months. Questionnaires and indices were carried out to assess the extent and severity of skin and nail involvement, as well as the activity and severity of peripheral and axial rheumatic manifestations. Radiological examination of the hands, feet, spine and pelvis was also done for all patients. Fifty-nine psoriatic outpatients (73%) had rheumatic manifestations clinically and/or radiologically (Psoriatic arthropathy "PsA"). Clinical peripheral arthritis was found in 14 (23.7%) of the patients with PsA, being oligoarticular in 11, polyarticular in two, and exclusively of the distal interphalangeal (DIP) joints in one patient. Sacroiliitis and/or spondylitis were found in 38 (64.4%), enthesopathy in 36 (61%), dactylitis in two (3.3%), radiological DIP involvement in 24 (40.6%), and radiological osteoperiostitis in 49 (83%) of patients with PsA. Most PsA patients had more than one rheumatic manifestation, while four patients (6.7%) had isolated enthesopathy without any other rheumatic manifestations. Subungual hyperkeratosis of the nails was significantly correlated with PsA (p<0.05), as well as with clinical arthritis, enthesopathy, and DIP involvement (p<0.01), while other types of skin and nail lesions were correlated with selected rheumatic manifestations. The performance of existing criteria for PsA was poor, as individual sets favored either sensitivity or specificity. Psoriatic arthropathy (PsA), occurring in about three-quarters of hospital outpatients with psoriasis, is more common than previously thought. More sensitive and specific criteria for the diagnosis and classification of PsA need to be developed, taking into account the recently described clinical and radiological manifestations.

Depression and depressive symptoms in rheumatoid arthritis patients: an analysis of their occurrence and determinants.

The objectives were to determine the differences in depressive symptoms and depression between rheumatoid arthritis (RA) and osteoarthritis (OA) patients, and to analyse the contribution of sociodemographic and clinical variables to depression in RA patients. The responses of 60 Egyptian RA patients and 40 patients with OA of the knees to the Symptom Checklist-90-R Depression subscale were compared. The proportions of patients from both groups confirmed by a psychiatric interview to be clinically depressed according to the DSM-III-R criteria were also compared. The contributions of sociodemographic and disease variables to depressive symptoms and clinical depression in RA patients were explored by multiple linear and logistic regression, respectively. RA patients showed significantly higher depression scores than OA patients (P = 0.001). The difference was unaffected by controlling for the effects of age, sex, disease duration and the sociodemographic covariates. A depressive disorder was clinically confirmed in 23% of RA patients and 10% of OA patients. The erythrocyte sedimentation rate (ESR), being unmarried and an urban residence were significant predictors of depressive symptoms (P < 0.05), while being unmarried (P < 0.05, OR = 2.1) and HAQ disability (P < 0.01, OR = 3.8) were significant predictors of clinical depression in RA patients. RA patients have significantly more depressive symptoms and tend to be more clinically depressed than OA patients. The contribution of some sociodemographic and clinical variables to depression in RA patients was modest, albeit significant.

A self-report Thompson articular index: what does it measure?

The aim of this study was to investigate the reliability and validity of the self-report Thompson articular index (ThAI) in Dutch patients with rheumatoid arthritis (RA). A rheumatologist assessed the ThAI in 43 patients with RA. Patients completed the self-report ThAI and the AIMS-2 questionnaire to assess physical function, pain, mood and level of tension. Blood samples were taken to measure the erythrocyte sedimentation rate (ESR). After 4 weeks, patients were sent a questionnaire for a repeat assessment of the self-report AI. The test-retest reliability of the self-report ThAI was adequate (ICC=0.83). There was low agreement between ThAI scores from patients and AI scores assessed by the rheumatologist (ICC=0.44). Self-report ThAI scores (mean=230.5) were significantly higher than the rheumatologist's scores (mean=110.8). Levels of agreement between patients and rheumatologist for individual joints were disappointing, ranging from 49% to 74% (Cohen's kappa from -0.02 to 0.48). The rheumatologist's ThAI scores correlated significantly with ESR (r=0.55) and physical function (r=0.44), but not with pain, mood or level of tension. Patients' scores correlated significantly with physical function (r=0.51), pain (r=0.43), and mood (r=0.36) but not with ESR or level of tension. In regression analyses the only significant predictor of the rheumatologist's ThAI scores was ESR, and for patients' scores physical function, thus showing that patients' responses are not confounded by mood or level of tension. In conclusion, the self-report ThAI is a reliable measure, but the validity is questionable because of the non-significant correlation with ESR and the low level of agreement between patients and rheumatologist. The results indicate that self-reported joint involvement is more closely related to physical function than to arthritic activity.

Epidemiological and clinical aspects relating to the variability of rheumatoid arthritis.

OBJECTIVE: To review epidemiological studies dealing with the temporal and geographic variability in the occurrence of rheumatoid arthritis (RA) and clinical studies that address the variability of severity and manifestations among populations. METHODS: An extensive search of the literature, including a Medline search, was completed. Studies addressing the origin, history, and trends in the occurrence of RA were reviewed first. Next, studies of the prevalence and incidence of RA in different populations were reviewed, and occurrence rates compared. Standardization was attempted by tabulating adult prevalence rates of studies using equivalent sets of criteria. Studies comparing RA patients from two populations were sought next. Finally, studies dealing with explanations of the presumed variability were reviewed. RESULTS: Temporal variability is indicated by paleopathological evidence that RA has existed in the New World since 4000 BC, whereas there is no evidence that it occurred in Europe before the 17th century, or in Africa before the 20th century. Epidemiological studies show a possible trend of decreasing incidence of RA in the United States and Western Europe, whereas reports from Africa note a rising incidence. In white populations of Europe and America, prevalence is approximately 1%, and incidence is 0.03%. Significantly higher rates are found in some North American Indians, and significantly lower rates in some Asian and African populations, even when the different population structures are taken into account. In the latter populations, different patterns of occurrence from those observed in whites emerge, such as greater female preponderance and a much younger peak age at onset. Direct standardized comparisons of two diverse populations of RA patients showed some differences in expression, severity, or manifestations of RA between populations. CONCLUSION: The occurrence and manifestations of RA are temporally and geographically variable.