Eman A. Ahmed

Background: Rheumatoid arthritis (RA) is a long‐term inflammatory disease linked to higher mortality, joint degeneration, and long‐term disability. This study evaluated the anti‐inflammatory, antioxidant, and immunomodulatory effects of Capsicum annuum (CAP) hydroethanolic extract and bee venom (BV) in Freund’s complete adjuvant (FCA)‐induced RA in rats. Methods: Forty‐eight rats were divided into six groups: normal control (NC), RA control, and RA groups orally treated with methotrexate (MTX) (0.25 mg/kg), CAP (100 mg/kg), BV (0.25 mg/kg), and CAP (100 mg/kg) + BV (0.25 mg/kg). RA was induced by intradermal injection of FCA (100 μL/rat) into a footpad of the right hind paw at two consecutive days, and treatments were administered for 3 weeks. The study assessed serum rheumatoid factor (RF), anticyclic citrullinated peptide (ACCP) antibodies (ACPAs), tumor necrosis factor‐alpha (TNF‐α), interleukin‐4 (IL‐4), oxidative stress markers such as lipid peroxidation, and antioxidant parameters including superoxide dismutase (SOD) and reduced glutathione (GSH). Additionally, mRNA expression of various genes (inducible nitric oxide synthase [ iNOS ], endothelial nitric oxide synthase [ eNOS ], interleukin‐1β [ IL-1β ], TNF-α , matrix metalloproteinase‐1 [ MMP-1 ], matrix metalloproteinase‐3 [ MMP-3 ], and glutathione reductase [ GR ]) were analyzed, alongside histopathological evaluation. Results: The data showed that CAP and/or BV significantly reduced serum inflammatory and oxidative stress biomarkers, enhanced the antioxidant defense system, and improved the histopathological changes of ankle joint. Gene expression analysis revealed downregulation of iNOS , eNOS , IL-1β , TNF-α , MMP-1 , and MMP-3 gene expression, with upregulation of the GR gene expression. The combined CAP + BV treatment demonstrated the most potent antiarthritic effect. Conclusion: CAP and BV exhibit promising potential for alleviating RA in rats, with their combined application showing the greatest efficacy. The antiarthritic effects may be mediated via suppression of oxidative stress and inflammation and enhancement of the antioxidant defense system in addition to the modulatory effects on MMP-1 and MMP-3 gene expression. Further clinical research is essential to evaluate their safety and effectiveness in human RA management.

Type 1 diabetes mellitus (T1DM) was established to be ameliorated by islet transplantation, but the shortage of the transplanted human islet tissue and the use of immunosuppressive drugs to inhibit the rejection of allogeneic grafts make this type of therapy is limited. Nowadays, therapy with stem cells is one of the most promising future treatments. This kind of therapy could have a profound impact on both replacement, as well as regenerative therapies, to improve or even cure various disorders, including diabetes mellitus. Flavonoids have also been shown to possess anti-diabetic effects. Thus, this study aims to evaluate the effectiveness of the bone marrow-derived mesenchymal stem cells (BM-MSCs) and hesperetin in the treatment of a T1DM rat model. T1DM was induced in male Wistar rats that had been starved for 16 h via intraperitoneal injection of STZ at a dose of 40 mg/kg body weight (b.wt.). After 10 days of STZ injection, the diabetic rats were allocated into four groups. The first diabetic animal group was considered a diabetic control, while the other three diabetic animal groups were treated for six weeks, respectively, with hesperetin (given orally at a dose of 20 mg/kg b.wt.), BM-MSCs (injected intravenously at a dose of 1 × 10⁶ cells/rat/week), and their combination (hesperetin and BM-MSCs). The use of hesperetin and BM-MSCs in the treatment of STZ-induced diabetic animals significantly improved the glycemic state, serum fructosamine, insulin and C-peptide levels, liver glycogen content, glycogen phosphorylase, glucose-6-phosphatase activities, hepatic oxidative stress, and mRNA expressions of NF-κB, IL-1β, IL-10, P53, and Bcl-2 in pancreatic tissue. The study suggested the therapy with both hesperetin and BM-MSCs produced marked antihyperglycemic effects, which may be mediated via their potencies to ameliorate pancreatic islet architecture and insulin secretory response, as well as to decrease hepatic glucose output in diabetic animals. The improvement effects of hesperetin and BM-MSCs on the pancreatic islets of diabetic rats may be mediated via their antioxidant, anti-inflammatory, and antiapoptotic actions.

Rheumatoid arthritis (RA) is an autoimmune syndrome affecting joint spaces, leading to the disabled state. Currently, there is no optimal therapy for RA except for systemic immunosuppressants that have variable undesirable effects after long-term use. Hence, the need for other treatment modalities has emerged in an attempt to develop a treating agent that is effective but without bad effects. Bone marrow-derived mesenchymal stem cells (BM-MSCs) may be an alternative medicine since they may differentiate into a variety of mesenchymal tissues including bone and cartilage. Indomethacin (IMC) could be suggested as an analgesic, anti-inflammatory, and antirheumatic potential agent against the course of RA since it possesses significant palliative effects and antipyretic properties. Therefore, our target of this study was to explore and compare the effect of BM-MSCs ( cells/rat at the 1^st, 6^th, 12^th, and 18^th days) and IMC (2 mg/kg b.w./day for 3 weeks) either alone or in combination on arthritic rats. The model of rheumatoid arthritis in rats was induced by subcutaneous injection of 0.1 mL/rat CFA into the footpad of the right hind paw. The BM-MSC intravenous injection and IMC oral administration significantly reduced the elevated right hind leg paw diameter and circumference, serum anti-CCP, and ankle joint articular tissue expressions of TNF-α, iNOS, MMP-9, and TGF-β1 while they significantly increased the lowered articular IL-10 expression in CFA-induced arthritic rats. The combinatory effect of the two treatments was the most potent. In conclusion, the treatment of RA with BM-MSCs and IMC together is more effective than the treatment with either BM-MSCs or IMC. The Th1 cytokine (TNF-α), Th2 cytokine (IL-10), iNOS, MMP-9, and TGF-β1 are important targets for mediating the antiarthritic effects of BM-MSCs and IMC in CFA-induced arthritis in rats.

Rheumatoid arthritis (RA) is a disorder triggered by autoimmune reactions and related with chronic inflammation and severe disability. Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) have shown a hopeful immunomodulatory effect towards repairing cartilage and restoring joint function. Additionally, indomethacin (IMC), a nonsteroidal compound, has been considered as a potent therapeutic agent that exhibits significant antipyretic properties and analgesic effects. The target of the current research is to assess the antiarthritic efficacy of BM-MSCs (10⁶ cells/rat at 1, 6, 12 and 18 days) and IMC (2mg/kg body weight/day for 3 weeks) either alone or concurrently administered against complete Freunds adjuvant-induced arthritic rats. Changes in paw volume, body weight, gross lesions, and antioxidant defense system, as well as oxidative stress, were assessed. The Th1 cytokine (IL-1β) serum level and Th2 cytokine (IL-4) and Nrf-2 ankle joint expression were detected. In comparison to normal rats, it was found that the CFA-induced arthritic rats exhibited significant leukocytosis and increase in paw volume, LPO level, RF, and IL-1β serum levels. In parallel, arthritic rats that received BM-MSCs and/or IMC efficiently exhibited decrease in paw edema, leukocytosis, and enhancement in the antioxidant enzymatic levels of SOD, GPx, GST, and GSH in serum besides upregulation of Nrf-2 and anti-inflammatory IL-4 expression levels in the ankle articular joint. Likewise, these analyses were more evidenced by the histopathological sections and histological score. The data also revealed that the combined administration of BM-MSC and IMC was more potent in suppressing inflammation and enhancing the anti-inflammatory pathway than each agent alone. Thus, it can be concluded that the combined therapy with BM-MSC and IMC may be used as a promising therapeutic choice after assessing their efficacy and safety in human beings with RA, and the antiarthritic effects may be mediated via modulatory effects on Th1/Th2 cytokines, ozidative stress, and Nrf-2.