Blocking CXCR4-CARM1-YAP axis overcomes osteosarcoma doxorubicin resistance by suppressing aerobic glycolysis.

Osteosarcoma, recognized for its aggressiveness and resistance to chemotherapy, notably doxorubicin, poses significant treatment challenges. This comprehensive study investigated the CXCR4-CARM1-YAP signaling axis and its pivotal function in controlling aerobic glycolysis, which plays a crucial role in doxorubicin resistance. Detailed analysis of Dox-resistant 143b/MG63-DoxR cells has uncovered the overexpression of CXCR4. Utilizing a combination of molecular biology techniques including gene silencing, aerobic glycolysis assays such as Seahorse experiments, RNA sequencing, and immunofluorescence staining. The study provides insight into the mechanistic pathways involved. Results demonstrated that disrupting CXCR4 expression sensitizes cells to doxorubicin-induced apoptosis and alters glycolytic activity. Further RNA sequencing revealed that CARM1 modulated this effect through its influence on glycolysis, with immunofluorescence of clinical samples confirming the overexpression of CXCR4 and CARM1 in drug-resistant tumors. Chromatin immunoprecipitation studies further highlighted the role of CARM1, showing it to be regulated by methylation at the H3R17 site, which in turn affected YAP expression. Crucially, in vivo experiments illustrated that CARM1 overexpression could counteract the tumor growth suppression that resulted from CXCR4 inhibition. These insights revealed the intricate mechanisms at play in osteosarcoma resistance to doxorubicin and pointed toward potential new therapeutic strategies that could target this metabolic and signaling network to overcome drug resistance and improve patient outcomes.

Engineering Bimetallic Polyphenol for Mild Photothermal Osteosarcoma Therapy and Immune Microenvironment Remodeling by Activating Pyroptosis and cGAS-STING Pathway.

The immunosuppressive tumor microenvironment (ITME) of osteosarcoma (OS) poses a significant obstacle to the efficacy of existing immunotherapies. Despite the attempt of novel immune strategies such as immune checkpoint inhibitors and tumor vaccines, their effectiveness remains suboptimal due to the inherent difficulty in mitigating ITME simultaneously from both the tumor and immune system. The promotion of anti-tumor immunity through the induction of immunogenic cell death and activation of the cGAS-STING pathway has emerged as potential strategies to counter the ITME and stimulate systemic antitumor immune responses. Here, a bimetallic polyphenol-based nanoplatform (Mn/Fe-Gallate nanoparticles coated with tumor cell membranes is presented, MFG@TCM) which combines with mild photothermal therapy (PTT) for reversing ITME via simultaneously inducing pyroptosis in OS cells and activating the cGAS-STING pathway in dendritic cells (DCs). The immunostimulatory pathways, through the syngeneic effect, exerted a substantial positive impact on promoting the secretion of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, which favors remodeling the immune microenvironment. Consequently, effector T cells led to a notable antitumor immune response, effectively inhibiting the growth of both primary and distant tumors. This study proposes a new method for treating OS using mild PTT and immune mudulation, showing promise in overcoming current treatment limitations.

Physical activity modifies the association of the composite dietary antioxidant index with all-cause mortality in the US osteoarthritis population.

Background: It remains unclear how antioxidant intake affects all-cause mortality in osteoarthritis (OA) patients. In this prospective cohort study, we aim to explore the association of the Composite Dietary Antioxidant Index (CDAI) with all-cause mortality and investigate the interaction of physical activity (PA) and CDAI on all-cause mortality in OA populations. Methods: A total of 3,197 adults with OA in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018 were included in this study. Death outcomes were obtained from National Death Index (NDI) records. Multivariable Cox regression analyses with cubic spines were applied to estimate the association of CDAI with all-cause mortality. The interaction between CDAI and PA on all-cause mortality was further assessed in stratified analysis and interaction tests. Results: The hazard ratios for all-cause mortality were 0.95 (0.77-1.17) for Q2, 0.75 (0.59-0.97) for Q3, and 0.71 (0.55-0.92) for Q4 (P for trend <0.001), compared with the lowest quartile of CDAI. A negative linear association was found between CDAI and all-cause mortality. In the stratified analyses, CDAI was negatively associated with all-cause mortality in the insufficient PA group. While in the low and sufficient PA group, there were nonlinear relationships of CDAI with all-cause mortality. Conclusion: A negative linear relationship was observed between CDAI and all-cause mortality in OA patients, and this association was significantly modified by PA. Higher intake of dietary antioxidants might be the interventional objective to reduce the risk of all-cause mortality in the US OA population.

Radical-Scavenging and Subchondral Bone-Regenerating Nanomedicine for Osteoarthritis Treatment.

Osteoarthritis (OA) is characterized by cartilage degradation and subchondral bone remodeling. However, most available studies focus on either cartilage degradation or subchondral bone lesion, alone, and rarely pay attention to the synergy of these two pathological changes. Herein, a dual-functional medication is developed to simultaneously protect cartilage and achieve subchondral bone repair. Black phosphorus nanosheets (BPNSs), with a strong reactive oxygen species (ROS)-scavenging capability and high biocompatibility, also present a notable promoting effect in osteogenesis. BPNSs efficiently eliminate the intracellular ROS and, thus, protect the inherent homeostasis between cartilage matrix anabolism and catabolism. RNA sequencing results of BPNSs-treated OA chondrocytes further reveal the restoration of chondrocyte function, activation of antioxidant enzymes, and regulation of inflammation. Additional in vivo assessments solidly confirm that BPNSs inhibit cartilage degradation and prevent OA progression. Meanwhile, histological evaluation and microcomputed tomography (micro-CT) scanning analysis verify the satisfying disease-modifying effects of BPNSs on OA. Additionally, the excellent biocompatibility of BPNSs enables them as a competitive candidate for OA treatment. This distinct disease-modifying treatment of OA on the basis of BPNSs provides an insight and paradigm on the dual-functional treatment strategy focusing on both cartilage degradation and subchondral bone lesion in OA and explores a broader biomedical application of BPNS nanomedicine in orthopedics.

Enhanced mild-temperature photothermal therapy by pyroptosis-boosted ATP deprivation with biodegradable nanoformulation.

BACKGROUND: Mild-temperature photothermal therapy (mild PTT) is a safe and promising tumor therapeutic modality by alleviating the damage of healthy tissues around the tumor due to high temperature. However, its therapeutic efficiency is easily restricted by heat shock proteins (HSPs). Thus, exploitation of innovative approaches of inhibiting HSPs to enhance mild PTT efficiency is crucial for the clinical application of PTT. RESULTS: Herein, an innovative strategy is reported: pyroptosis-boosted mild PTT based on a Mn-gallate nanoformulation. The nanoformulation was constructed via the coordination of gallic acid (GA) and Mn2+. It shows an acid-activated degradation and releases the Mn2+ and GA for up-regulation of reactive oxygen species (ROS), mitochondrial dysfunction and pyroptosis, which can result in cellular ATP deprivation via both the inhibiton of ATP generation and incresed ATP efflux. The reduction of ATP and accumulation of ROS provide a powerful approach for inhibiting the expression of HSPs, which enables the nanoformulation-mediated mild PTT. CONCLUSIONS: Our in-vitro and in-vivo results demonstrate that this strategy of pyroptosis-assited PTT can achieve efficient mild PTT efficiency for osteosarcoma therapy.

Photothermal-triggered immunogenic nanotherapeutics for optimizing osteosarcoma therapy by synergizing innate and adaptive immunity.

Inadequate immune response remains a critical cause of immunotherapy failure in various tumor treatments. Herein, we offer a new approach to achieve a cross-talk between innate and adaptive immune responses based on a new nanoplatform for photothermal therapeutics. The nanoplatform was formed by linking titanium carbide MXene with Mn2+-contained ovalbumin (OVA), where it can trigger efficient mt-DNA presentation and the release of OVA and Mn2+ upon the irradiation of near-infrared laser. More importantly, the released mt-DNA and Mn2+ synergistically activate innate immunity via the cGAS-stimulator of the interferon genes signaling pathway, and the OVA and protein antigens from tumor cells enhance adaptive immunity. Furthermore, in an osteosarcoma model, we observed that the proposed nanoplatform leads to the effective presentation of tumor antigens, which boost the maturation of dendritic cells (DCs) to the hilt and thus improve the infiltration of cytotoxic T lymphocyte in primary and distant tumors. Collectively, our work not only demonstrates a method for constructing a new nanoplatform for photothermal therapeutics but also provides a general strategy for synchronously activating innate and adaptive immunities to promote the maturation of DCs for antimetastasis tumor therapy.

Efficacy and safety of a self-developed home-based enhanced knee flexion exercise program compared with standard supervised physiotherapy to improve mobility and quality of life after total knee arthroplasty: a randomized control study.

BACKGROUND: This randomized controlled study compared standard supervised physiotherapy (SPT) with a self-developed, home-based, enhanced knee flexion exercise program involving a low stool (KFEH) in patients who underwent total knee arthroplasty (TKA). METHODS: Patients were recruited from July 2014 to December 2015 and randomly assigned to one of two groups: KFEH (n = 60) and SPT (n = 59). Outcomes (joint function) were evaluated according to the Knee Society Score (KSS), visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and range of motion (ROM) assessment at selected time points (preoperatively; 1 week; 1, 3, and 6 months; and 1 year after surgery). RESULTS: Pain and functional improvement were observed in both groups. Non-inferiority of KFEH was evident 12 months postoperatively; however, patients in the KFEH group exhibited better ROM at 1 month (P < 0.01). Absolute WOMAC and KSS scores were slightly better in the KFEH group, although the difference was not statistically significant. There was no difference in VAS scores and complication rates between the two groups. Additionally, the home program would save patient time and decrease the economic burden associated with in-hospital SPT. CONCLUSION: Considering rehabilitation and economic efficiency as well as the COVID pandemic, a home-based enhanced knee flexion exercise program for TKA rehabilitation is recommended.

LncRNA RP11-361F15.2 promotes osteosarcoma tumorigenesis by inhibiting M2-Like polarization of tumor-associated macrophages of CPEB4.

Long non-coding RNAs (lncRNAs) regulates the initiation and progression of osteosarcoma (OS), specifically lncRNA RP11-361F15.2 has been shown to play prominent roles in tumorigenesis. Previously, M2-Like polarization of tumor-associated macrophages (TAMs) has been identified to play a key role in cancer migration/invasion. Hence, it is essential to understand the role of RP11-361F15.2 in tumorigenesis and its association with M2-Like polarization of TAMs. The results indicate that RP11-361F15.2 is significantly increased in OS tissues, and its expression is positively correlated with cytoplasmic polyadenylation element binding protein 4 (CPEB4) expression and negatively associated with miR-30c-5p expression. Further, overexpression of RP11-361F15.2 increased OS cell migration/invasion and M2-Like polarization of TAMs in vitro, as well as promoted xenograft tumor growth in vivo. Mechanistically, luciferase reporter assays indicated that RP11-361F15.2 upregulated CPEB4 expression by competitively binding to miR-30c-5p. Further, we have identified that RP11-361F15.2 promotes CPEB4-mediated tumorigenesis and M2-Like polarization of TAMs through miR-30c-5p in OS. We also identified that RP11-361F15.2 acts as competitive endogenous RNA (ceRNA) against miR-30c-5p thereby binding and activating CPEB4. This RP11-361F15.2/miR-30c-5p/CPEB4 loop could be used as a potential therapeutic strategy for the treatment of OS.