Background Osteoarthritis (OA) is characterized by cartilage degradation in the affected joints. Pomegranate fruit extract (PFE) inhibits cartilage degradation in vitro. Here we determined whether oral consumption of PFE inhibits disease progression in rabbits with surgically-induced OA. Methods OA was surgically induced in the tibiofemoral joints of adult NZW rabbits. In one group animals were fed PFE in water for 8 weeks post-surgery. In the second group, animals were fed PFE for 2 weeks before surgery andfor 8 weeks post-surgery.Histological assessment and scoring of the cartilage was per OARSI guidelines. Gene expression and MMPs activity were determined using qRT-PCR and fluorometric assay, respectively. IL-1β, MMP-13, IL-6, PGE2 and COL2A1 levels in synovial fluid/plasma/culture mediawere quantified using ELISA. Expression of active Caspase-3 and PARP p85 was determined by immunohistochemistry. Effect of PFE and inhibitors of MMP-13, MAPK and NF-κB was studied in IL-1β-stimulated rabbit articular chondrocytes. Results Safranin-O-staining and chondrocyte cluster formation was significantly reduced in the ACLT+PFE fed groups. Expression of MMP-3, MMP-9 and MMP-13 mRNAwas higher in the cartilage of rabbits given water alone but was significantly lower in the animals fed PFE. PFE-fed rabbits had lowerIL-6, MMP-13 and PGE2 levels in the synovial fluid and plasma respectively and showed higher expression of ACAN and COL2A1 mRNA. Significantly higher numbers of chondrocytes were positive for markers of apoptosisin the joints of rabbits with OA given water only compared to rabbits in the PFE-fed groups. PFE pretreatment significantly reduced IL-1β induced IL-6 and MMPs expression in rabbit articular chondrocytes. These effects were also mimicked using MMP-13, MAPK and NF-κB inhibitors in IL-1β-stimulated rabbit chondrocytes. In an in vitro activity assay, PFE blocked the activity of MMP-13.Like MAPK and NF-κB inhibitors, PFE was also effective in inhibiting IL-1β-induced PGE2 production in rabbit chondrocytes. PFE also reversed the inhibitory effect of IL-1β on COL2A1 mRNA and protein expression in IL-1β-stimulated rabbit chondrocytes. Conclusion Our data highlighted the chondroprotective effects of PFE oral consumption in a model of post-traumatic OA and suggests that PFE derived compounds may have potential value in the management of OA.

Pomegranate fruit extract (PE) rich in polyphenols have been shown to exert chondroprotective effects but the mechanism is not established. Here, we used an in vitro model of inflammation in OA to investigate the potential of PE to suppress IL-1β-stimulatedexpression of inflammatory cytokine IL-6, generation of reactive oxygen species (ROS) levels and investigated the mechanism of NF-κB inhibition by analyzing the activation of the kinases upstream of IκBα in primary human chondrocytes. Total and phosphorylated forms of kinases, and expression of IL-6 were determined at protein and mRNA levels by Western immunoblotting and Taqman assay respectively. DHR-123 staining estimated ROS generation. PE inhibited the mRNA and protein expression of IL-6, generation of ROS and inhibited the IL-1β-mediated phosphorylation of IKKβ, expression of IKKβ mRNA, degradation of IκBα, and activation and nuclear translocation of NF-κB/p65 in human chondrocytes. Importantly, phosphorylation of NF-κB-inducing kinase (NIK) was blocked by PE in IL-1β-treated human OA chondrocytes. Taken together, these data suggest that PE exerts the chondroprotective effect(s) by suppressing the production of IL-6 and ROS levels. Inhibition of NF-κB activation by PE was blocked via modulation of activation of upstream kinases in human OA chondrocytes.

Osteoarthritis (OA) is the most common degenerative joint disease characterized by enzymatic degradation of the cartilage extracellular matrix (ECM) causing joint pain and disability. There is no disease-modifying drug available for the treatment of OA. An ideal drug is expected to stop cartilage ECM degradation and restore the degenerated ECM. The ECM primarily contains type II collagen and aggrecan but also has minor quantities of other collagen fibers and proteoglycans. In OA joints, the components of the cartilage ECM are degraded by matrix-degrading proteases and hydrolases which are produced by chondrocytes and synoviocytes. Matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS5) are the major collagenase and aggrecanase, respectively, which are highly expressed in OA cartilage and promote cartilage ECM degradation. Current studies using various in vitro and in vivo approaches show that natural compounds inhibit the expression and activity of MMP-13, ADAMTS4, and ADAMTS5 and increase the expression of ECM components. In this review, we have summarized recent advancements in OA research with a focus on natural compounds as potential therapeutics for the treatment of OA with emphasis on the prevention of cartilage ECM degradation and improvement of joint health.

Multiple myeloma is a heterogeneous clonal malignant plasma cell disorder, which remains incurable despite the therapeutic armamentarium’s evolution. Bispecific antibodies (BsAbs) can bind simultaneously to the CD3 T-cell receptor and tumor antigen of myeloma cells, causing cell lysis. This systematic review of phase I/II/III clinical trials aimed to analyze the efficacy and safety of BsAbs in relapsed refractory multiple myeloma (RRMM). A thorough literature search was performed using PubMed, Cochrane Library, EMBASE, and major conference abstracts. A total of 18 phase I/II/III studies, including 1283 patients, met the inclusion criteria. Among the B-cell maturation antigen (BCMA)-targeting agents across 13 studies, the overall response rate (ORR) ranged between 25% and 100%, with complete response/stringent complete response (CR/sCR) between 7 and 38%, very good partial response (VGPR) between 5 and 92%, and partial response (PR) between 5 and 14%. Among the non-BCMA-targeting agents across five studies, the ORR ranged between 60 and 100%, with CR/sCR seen in 19–63%, and VGPR in 21–65%. The common adverse events were cytokine release syndrome (17–82%), anemia (5–52%), neutropenia (12–75%), and thrombocytopenia (14–42%). BsAbs have shown promising efficacy against RRMM cohorts with a good safety profile. Upcoming phase II/III trials are much awaited, along with the study of other agents in concert with BsAbs to gauge response.

Immunoglobulin M monoclonal gammopathy is detected in Waldenström macroglobulinemia (WM), a rare lymphoplasmacytic lymphoma with serum immunoglobulin M. We report three rare presentations with focus on diagnostic and management challenges of type I cryoglobulinemia, type II cryoglobulinemia, and Bing–Neel syndrome. In approximately 10% of WM cases, macroglobulins can precipitate to cryoglobulins. Type I and II cryoglobulinemia, representing 10–15% and 50–60% of WM cases, respectively, present with vasculitis and renal failure. Bing–Neel syndrome, representing 1% of WM patients, is a rare neurological complication with lymphoplasmacytic infiltration in the brain. WM diagnosis includes bone marrow biopsy, immunophenotypic analysis, and MYD88 L265P mutation. We initiated management of cryoglobulinemia with dexamethasone, rituximab, and cyclophosphamide; in Bing–Neel, bortezomib and dexamethasone, followed by a Bruton tyrosine kinase inhibitor.