Sargassum polysaccharide attenuates osteoarthritis in rats and is associated with the up-regulation of the ITGß1-PI3K-AKT signaling pathway.

Background: Osteoarthritis (OA) presents a formidable challenge, characterized by as-yet-unclear mechanical intricacies within cartilage and the dysregulation of bone homeostasis. Our preliminary data revealed the encouraging potential of a Sargassum polysaccharide (SP), in promoting chondrogenesis. The aim of our study is to comprehensively assess the therapeutic effects of SP on OA models and further elucidate its potential mechanism. Methods: The protective effects of SP were initially evaluated in an inflammation-induced human chondrocyte (C28) cell model. CCK-8 assays, Alcian blue staining, RT-qPCR and Western blotting were used to verify the chondrogenesis of SP in vitro. To assess the efficacy of SP in vivo, surgically induced medial meniscus destabilization (DMM) OA rats underwent an 8-week SP treatment. The therapeutic effects of SP in OA rats were comprehensively evaluated using X-ray imaging, micro-computed tomography (µ-CT), histopathological analysis, as well as immunohistochemical and immunofluorescent staining. Following these assessments, we delved into the potential signaling pathways of SP in inflammatory chondrocytes utilizing RNA-seq analysis. Validation of these findings was conducted through RT-qPCR and western blotting techniques. Results: SP significantly enhance the viability of C28 chondrocytes, and increased the secretion of acidic glycoproteins. Moreover, SP stimulated the expression of chondrogenic genes (Aggrecan, Sox9, Col2a1) and facilitated the synthesis of Collagen II protein in C28 inflammatory chondrocytes. In vivo experiments revealed that SP markedly ameliorated knee joint stenosis, alleviated bone and cartilage injuries, and reduced the histopathological scores in the OA rats. µ-CT analysis confirmed that SP lessened bone impairments in the medial femoral condyle and the subchondral bone of the tibial plateau, significantly improving the microarchitectural parameters of the subchondral bone. Histopathological analyses indicated that SP notably enhanced cartilage quality on the surface of the tibial plateau, leading to increased cartilage thickness and area. Immunohistochemistry staining and immunofluorescence staining corroborated these findings by showing a significant promotion of Collagen II expression in OA joints treated with SP. RNA-seq analysis suggest that SP's effects were mediated through the regulation of the ITGß1-PI3K-AKT signaling axis, thereby stimulating chondrogenesis. Verification through RT-qPCR and Western blot analyses confirmed that SP significantly upregulated the expression of ITGß1, p110δ, AKT1, ACAN, and Col2a1. Notably, knock-down of ITGß1 using siRNA in C28 chondrocytes inhibited the expression of ITGß1, p110δ, AKT1, and ACAN. However, these inhibitory effects were not completely reversed by supplemental SP intervention. Conclusions: In summary, our findings reveal that SP significantly enhances chondrogenesis both in vitro and in vivo, alleviating OA progression both in bone and cartilage. The observed beneficial effects are intricately linked to the activation of the ITGß1-PI3K-AKT signaling axis. The translational potential of this article: Our research marks the first instance unveiling the advantageous effects and underlying mechanisms of SP in OA treatment. With its clinical prospects, SP presents compelling new evidence for the advancement of a next-generation polysaccharide drug for OA therapy.

Bio-responsive Au-miR-183 inhibitor enhances immunotherapy in hepatocellular carcinoma by inducing immunogenic cell death.

The treatment of advanced hepatocellular carcinoma (HCC) is limited, and immunotherapy is the current research focus of multi-disciplinary collaborative comprehensive treatment of HCC. Herein, we constructed a bio-responsive Au-miR-183 inhibitor (Au@miR-183i) delivery system targeting liver cancer stem cells (LCSCs), and adopted the strategy of combining αPD-L1 immunotherapy. The multifunctional Au@miR-183i nanocomplexes (NCs), which self-assemble based on the tumor microenvironment, consume NADPH and H2O2, leading to redox homeostasis disturbance, ROS accumulation, regulation of the LCSC niche, and induction of stemness regression. Moreover, self-assembled Au@miR-183i NCs specifically target the delivery of miR-183i to LCSCs, triggering the immunogenic cell death (ICD) effect, promoting the maturation of dendritic cells, inducing infiltration of CD8+ T cells, and facilitating the transformation of 'cold' tumors into 'hot' tumors. More importantly, consistent with the results in vitro, Au@miR-183i NCs demonstrated effective tumor targeting and strong ICD induction in vivo, assisted in enhancing αPD-L1 immunotherapy, and activated a robust systemic anti-tumor immune response in tumor-bearing mouse models. Overall, we provide a simple and universal therapeutic strategy by constructing a multifunctional bio-responsive Au@miR-183i NCs delivery system with LCSC targeting capability. Furthermore, nanocomplex-based ICD inducers have great promise in enhancing anti-tumor immunity and the PD-1/PD-L1 blocking efficacy in HCC, which provides a theoretical basis for effectively eliminating LCSCs and achieving a high-efficiency synergistic treatment strategy for HCC.

Expanding the therapeutic potential of Salvia miltiorrhiza: a review of its pharmacological applications in musculoskeletal diseases.

Salvia miltiorrhiz, commonly known as "Danshen" in Chinese medicine, has longstanding history of application in cardiovascular and cerebrovascular diseases. Renowned for its diverse therapeutic properties, including promoting blood circulation, removing blood stasis, calming the mind, tonifying the blood, and benefiting the "Qi", recent studies have revealed its significant positive effects on bone metabolism. This potential has garnered attention for its promising role in treating musculoskeletal disorders. Consequently, there is a high anticipation for a comprehensive review of the potential of Salvia miltiorrhiza in the treatment of various musculoskeletal diseases, effectively introducing an established traditional Chinese medicine into a burgeoning field. AIM OF THE REVIEW: Musculoskeletal diseases (MSDs) present significant challenges to healthcare systems worldwide. Previous studies have demonstrated the high efficacy and prospects of Salvia miltiorrhiza and its active ingredients for treatment of MSDs. This review aims to illuminate the newfound applications of Salvia miltiorrhiza and its active ingredients in the treatment of various MSDs, effectively bridging the gap between an established medicine and an emerging field. METHODS: In this review, previous studies related to Salvia miltiorrhiza and its active ingredients on the treatment of MSD were collected, the specific active ingredients of Salvia miltiorrhiza were summarized, the effects of Salvia miltiorrhiza and its active ingredients for the treatment of MSDs, as well as their potential molecular mechanisms were reviewed and discussed. RESULTS: Based on previous publications, Salvianolic acid A, salvianolic acid B, tanshinone IIA are the representative active ingredients of Salvia miltiorrhiza. Their application has shown significant beneficial outcomes in osteoporosis, fractures, and arthritis. Salvia miltiorrhiza and its active ingredients protect against MSDs by regulating different signaling pathways, including ROS, Wnt, MAPK, and NF-κB signaling. CONCLUSION: Salvia miltiorrhiza and its active ingredients demonstrate promising potential for bone diseases and have been explored across a wide variety of MSDs. Further exploration of Salvia miltiorrhiza's pharmacological applications in MSDs holds great promise for advancing therapeutic interventions and improving the lives of patients suffering from these diseases.