Leflunomide-induced cardiac injury in adult male mice and bioinformatic approach identifying Nrf2/NF-κb signaling interplay.

Leflunomide (LFND) is an immunosuppressive and immunomodulatory disease-modifying antirheumatic drug (DMARD) that was approved for treating rheumatoid arthritis. LFND-induced cardiotoxicity was not fully investigated since its approval. We investigated the cardiac injury in male mice and identified the role of nuclear factor erythroid 2-related factor 2/nuclear factor-κ B (Nrf2/NF-κB) signaling. Male albino mice were assigned into five groups as control, vehicle, and LFND (2.5, 5, and 10 mg/kg). We investigated cardiac enzymes, histopathology, and the mRNA expression of Nrf2, NF-κB, BAX, and tumor necrosis factor-α (TNF-α). The bioinformatic study identified the interaction between LFND and Nrf2/NF-κB signaling; this was confirmed by amelioration in mRNA expression (0.5- to 0.34-fold decrease in Nrf2 and 2.6- to 4.61-fold increases in NF-κB genes) and increased (1.76- and 2.625-fold) serum creatine kinase (CK) and 1.38- and 2.33-fold increases in creatine kinase-MB (CK-MB). Histopathological results confirmed the dose-dependent effects of LFND on cardiac muscle structure in the form of cytoplasmic, nuclear, and vascular changes in addition to increased collagen deposits and apoptosis which were increased compared to controls especially with LFND 10 mg/kg. The current study elicits the dose-dependent cardiac injury induced by LFND administration and highlights, for the first time, dysregulation in Nrf2/NF-κB signaling.

Comparing the Efficacy of Local Corticosteroid Injection, Platelet-Rich Plasma, and Extracorporeal Shockwave Therapy in the Treatment of Pes Anserine Bursitis: A Prospective, Randomized, Comparative Study.

Background: Pes anserine bursitis (PAB) is one of the most common causes of painful knee syndromes. This study aimed at examining the efficacy of local corticosteroid injection, platelet-rich plasma (PRP) injection, and extracorporeal shock wave therapy (ESWT) as different modalities to alleviate pain and enhance function in patients with pes anserine bursitis (PAB). Methods: A prospective, randomized, comparative study was conducted on 180 patients diagnosed with chronic PAB. They were equally divided into three groups as follows: Group I received a local corticosteroid injection of 40 mg of methylprednisolone acetate/1 ml; Group II received a PRP injection; and in Group III, ESWT was used. Outcome measures included the visual analog scale (VAS), Western Ontario and McMaster Universities (WOMAC) pain score, WOMAC physical function score, and Ritchie articular index (RAI) for tenderness, which were recorded at the baseline, after 1 week, and after 8 weeks. Results: Before the application of procedures, there was a statistically significant increase in the WOMAC pain score in the local corticosteroid group compared to the PRP group and the ESWT group (P < 0.001). After the application of procedures, there was a statistically significant improvement in the 1-week and 8-week WOMAC pain score, WOMAC physical function score, and VAS in the local corticosteroid group in comparison to the PRP group and the ESWT group. (P < 0.001). Moreover, RAI for tenderness shows statistically significant improvement at 8 weeks in the local corticosteroid groups compared to the PRP groups (P < 0.001) and ESWT groups (P < 0.001). Similarly, a statistically significant difference was found between the PRP and ESWT groups (P=0.023). Conclusion: Our data suggest that in patients with PAB, local corticosteroid injection is more efficient than PRP injection and ESWT for reducing pain and enhancing function.

Non-alcoholic fatty liver disease is associated with decreased bone mineral density in upper Egyptian patients.

Nonalcoholic fatty liver disease (NAFLD) has been linked with a number of extra hepatic diseases and could be a potential risk factor of decreasing bone mineral density. To determine whether Upper Egyptian patients with NAFLD are at risk of developing osteoporosis. Cross sectional study was done on a total 100 individuals; 50 patients diagnosed with NAFLD (based on ultrasound imaging) crossed-matched with 50 individuals without NAFLD based on age, sex and body mass index. Bone mineral density, serum calcium and phosphorus levels, serum parathyroid hormone, serum vitamin D and fasting insulin level were assessed. Osteoporosis was prevalent in NAFLD patients versus to controls (19/50 vs. 0/50; P < 0.001). There was significant decrease in bone mineral density in NAFLD patients than controls (- 2.29 ± 0.4 vs. - 1.53 ± 0.1; P < 0.001). There was a statistical significance decrease in serum vitamin D and calcium levels in NAFLD patients than controls. Furthermore, vitamin D levels in the NAFLD group was a predictor for osteoporosis (OR 0.614; 95% CI 0.348-0.825). Patients with NAFLD tend to have a significant decrease in bone density, vitamin D, and serum calcium levels than controls.

Silent Lupus Nephritis: Renal Histopathological Profile and Early Detection with Urinary Monocyte Chemotactic Protein 1.

Objective: Lupus nephritis (LN) affects almost half of all individuals with systemic lupus erythematosus (SLE). Overt LN (OLN) symptoms might vary from asymptomatic microscopic hematuria to renal failure. However, when there are no clinical or laboratory indicators of renal involvement, some people with silent LN (SLN) may have pathological evidence of renal involvement identified by renal biopsy. Monocyte Chemotactic Protein 1 (MCP-1) is a chemotactic factor that promotes leukocyte migration to the kidney. MCP-1 urine levels (uMCP-1) have been demonstrated to be high in individuals with active LN. The purpose of this study was to discover the occurrence of SLN, as well as the possible variations between overt LN (OLN) and SLN across SLE patients based on the histopathological assessment, as well as the role of uMCP-1 in the early detection of SLN. Methods: An overall of 144 patients with SLE were included in the current research. Patients were subsequently divided into two groups: individuals who did not have clinical evidence of LN (84 patients) and those with OLN (60 patients). All the patients were subjected to the following investigations: uMCP-1, erythrocyte sedimentation rate (ESR), complement C3 (C3), complement C4 (C4), creatinine, albumin/creatinine ratio (uACR), creatinine clearance, quantitative assessment of proteinuria by 24-hour urine proteinuria (24hr UP) and percutaneous renal biopsy. Results: Sixty patients from group I (71.4%) showed glomerular lesions on renal biopsy (SLN), and class II was the predominant class. uMCP-1 had a sensitivity of 95.2% and a specificity of 98% in the detection of SLN, and uMCP-1 values were markedly higher in patients with OLN in comparison to SLN. Conclusion: The actual frequency of SLN may be higher than expected. High levels of uMCP-1 may have warranted the early activity of LN. uMCP-1 can be used as a non-invasive, useful tool for the prediction of LN.

Evaluating Gender Differences in Egyptian Fibromyalgia Patients Using the 1990, 2011, and 2016 ACR Criteria.

Background: Fibromyalgia (FM) is a common rheumatic illness distinguished by chronic pain, fatigue, cognitive problems, and functional disability. However, the differences between men and women have not yet been comprehensively studied, especially after the development of the last 2016 American College of Rheumatology (ACR) criteria. The aim of this study was to evaluate the gender differences in symptom characteristics, cognitive dysfunction, and disease severity in Egyptian FM patients considering both the ACR 1990, 2011, and the last 2016 ACR diagnostic criteria. Methods: This is a prospective cross-sectional study that was carried out on 352 patients with FM in the Rheumatology Department, Al-Azhar University Hospital in Egypt, in the period between January 1, 2020, and June 1, 2021. In addition to the number of tender points (TPC), data was collected on age, gender, body mass index (BMI), marital status, disease onset, duration, and diagnostic delay. The widespread pain index (WPI), the symptom severity scale (SSS), fatigue, cognitive dysfunction, sleep disturbance, awakening unrefreshed, headache, abdominal pain, and depression were evaluated and scored according to 2010 and 2016 ACR criteria. A visual analog scale (VAS) for pain, fatigue, stiffness, anxiety, and depression is included in the questionnaire. The total score ranges were produced using total score ranges ranging from 0 to 80 (excluding job items), with higher scores indicating a stronger negative effect and/or intensity of symptoms. The polysymptomatic distress scale (PDS) has been calculated by the summation of the SSS with the WPI. The Revised FM impact questionnaire (FIQR) has also been evaluated. Results: The study shows that females have a significantly higher prevalence of fatigue, cognitive dysfunction, sleep disturbance, headache, and abdominal pain (p < 0.05). Also, females showed significantly higher scores than males regarding WPI, SSS, and mean TPC (p = 0.004, 0.027, and 0.001, respectively). While there was no difference regarding the FIQR (p=0.93), PDS was significantly higher in women (p= 0.001). Conclusion: Female patients with FM had greater disease severity scores, symptomatology, and number of tender points. Whatever the criteria applied, the prevalence and intensity of the disease features are higher in females, which may underestimate the disease in male patients.

Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis.

Diabetic neuropathic pain (DNP) is a common diabetic complication that currently lacks an efficient therapy. The aim of the current work was to uncover the anti-allodynic and neuroprotective effects of memantine in a model of mouse diabetic neuropathy and its ameliorative effect on the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor-k B (NF-kB) inflammatory axis. Diabetes was prompted by an alloxan injection (180 mg/kg) to albino mice. On the ninth week after diabetes induction, DNP was confirmed. Diabetic mice were randomly allocated to two groups (six mice each); a diabetes mellitus (DM) group and DM+memantine group (10 mg/kg, daily) for five weeks. DNP-related behaviors were assessed in terms of thermal hyperalgesia and mechanical allodynia by hot-plate and von Frey filaments. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the spinal glutamate, interleukin-1 beta (IL-1ß), and tumor necrosis factor-α (TNF-α). The spinal levels of N-methyl-D-aspartate type 1 receptor (NMDAR1), HMGB1, TLR4, and phosphorylated NF-kB were assessed using Western blotting. Histopathological investigation of the spinal cord and sciatic nerves, together with the spinal cord ultrastructure, was employed for assessment of the neuroprotective effect. Memantine alleviated pain indicators in diabetic mice and suppressed excessive NMDAR1 activation, glutamate, and pro-inflammatory cytokine release in the spinal cord. The current study validated the ability of memantine to combat the HMGB1/TLR4/NF-kB axis and modulate overactive glutamate spinal transmission, corroborating memantine as an appealing therapeutic target in DNP.

Supplement With Calcium or Alendronate Suppresses Osteopenia Due to Long Term Rabeprazole Treatment in Female Mice: Influence on Bone TRAP and Osteopontin Levels.

BACKGROUND AND PURPOSE: Rabeprazole, a proton pump inhibitor (PPIs) is much endorsed to patients with increased gastric acidity. PPIs were accused to have osteoporotic effects on patients who chronically use them. The point of the current investigation was to decide the impact of rabeprazole on osteoporosis and to explore the modulatory effects of dietary calcium or alendronate on this side effect. METHODS: 80 female mice were alienated into four groups maintained for 18 weeks: [1] Vehicle group: given distilled water in 12 ml/kg, P.O. [2] Rabeprazole control group: given rabeprazole in a dose equals 10 mg/kg every 48 h, P.O. [3] Rabeprazole + calcium: given rabeprazole (10 mg/kg every 48 h) along with calcium supplement. [4] Rabeprazole + alendronate: given rabeprazole (10 mg/kg every 48 h) and alendronate (1 mg/kg per week, i.p.). Serum calcium, phosphorus and parathyroid hormone were measured. Both femurs were kept in paraformaldehyde, and then the right one was used for X-ray examination with analysis by Digora software and the left one for histopathological examination (H&E) and immunohistochemical stains for osteopontin and tartrate resistant acid phosphatase (TRAP). RESULTS: Calcium supplementation or administration of alendronate along with rabeprazole significantly restored the mean bone density as shown by X-ray analysis. Femurs from mice received rabeprazole showed widely separated, thin-walled bone trabeculae and increased number of osteoclasts. Calcium or alendronate with rabeprazole showed thick bone trabeculae without full recovery from rabeprazole induced damage. Adding calcium supplementation to rabeprazole did not affect the histological abnormalities related to osteoclasts meanwhile alendronate produced inactivation of osteoclasts. Both calcium and alendronate decreased the rabeprazole-induced increment in the femur osteopontin level. CONCLUSION: Calcium or alendronate can be recommended for female patients on PPI therapy who are at risk of osteopenia.