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Osteoarthritis (OA) is a common degenerative joint disease urgently needing effective treatments. Bone marrow mesenchymal stromal cell-derived exosomes (Exo) are considered good drug carriers whereas they have limitations such as fast clearance and low retention. This study aimed to overcome the limitations of Exo in drug delivery using multiple strategies. Novel photocrosslinking spherical gelatin methacryloyl hydrogel (GelMA)-encapsulated cartilage affinity WYRGRL (W) peptide-modified engineered Exo were developed for OA treatment and the performance of the engineered Exo (W-Exo@GelMA) loaded with a small inhibitor LRRK2-IN-1 (W-Exo-L@GelMA) was investigated in vitro and in vivo. The W-Exo-L@GelMA showed an effective targeting effect on chondrocytes and a pronounced action on suppressing catabolism and promoting anabolism in vitro. Moreover, W-Exo-L@GelMA remarkably inhibited OA-related inflammation and immune gene expression, rescuing the IL-1β-induced transcriptomic responses. With enhanced retention in the joint, W-Exo-L@GelMA demonstrated superior anti-OA activity and cartilage repair ability in the OA murine model. The therapeutic effect was validated in the cultured human OA cartilage. In conclusion, photocrosslinking spherical hydrogel-encapsulated targeting peptide-modified engineered Exo exhibit notable potential in OA therapy. Engineering Exo by a series of strategies enhanced the targeting ability and retention and cartilage-targeting and Exo-mediated drug delivery may offer a novel strategy for OA treatment. Clinical trial registration : Not applciable. Graphical Abstract

Although patients with renal collecting duct carcinoma (CDC) benefit from surgery, the value of cytoreductive nephrectomy (CNx) for the prognosis of patients with metastatic CDC remains unclear. Hence, in this study, we used data from Surveillance, Epidemiology, and End Results (SEER) registry to investigate the prognostic factors and the impact of CNx on the outcomes in patients with metastatic CDC. Data of 521 patients, diagnosed with CDC between 2000 and 2018, were retrieved from the SEER database. Kaplan–Meier method and log-rank tests were used to compare the survival differences between the CNx group and non-surgical group. Multivariate Cox regression analysis was used to identify the risk factors associated with overall survival (OS) and cancer-specific survival (CSS) for patients with metastatic CDC. Moreover, multivariate Cox regression analysis guided by directed acyclic graphs (DAG) was used to unfold the impact of CNx and chemotherapy on OS and CSS. 86 patients were identified to have metastatic CDC. The median OS and CSS time were 5 and 6 months, respectively. The OS rates at 1-, 2- and 5-years were 24.4%, 15.1% and 2.3%, respectively. Whereas, the CSS rates at 1-, 2- and 5-years were 27.0%, 17.9% and 2.8%, respectively. Old patients and those receiving CNx or chemotherapy exhibited better survival outcomes. The multivariate regression model identified non-surgical treatment as the only independent prognostic factor for both, OS and CSS. However, DAG-guided multivariate Cox regression model showed that both, CNx and chemotherapy, were associated with both, OS and CSS. Patients with metastatic CDC exhibited worse clinical outcomes. However, CNx improved the prognosis of patients with metastatic CDC. Additionally, surgical resection of visible lesions and suitable chemotherapy were identified as alternative treatment strategies.

Despite advances in surgery and chemotherapy, the survival of patients with osteosarcoma (OS) has not been fundamentally improved over the last two decades. Microvesicles (MVs) have a high cargo-loading capacity and are emerging as a promising drug delivery nanoplatform. The aim of this study was to develop MVs as specifically designed vehicles to enable OS-specific targeting and efficient treatment of OS. Herein, we designed and constructed a nanoplatform (YSA-SPION-MV/MTX) consisting of methotrexate (MTX)-loaded MVs coated with surface-carboxyl Fe3O4 superparamagnetic nanoparticles (SPIONs) conjugated with ephrin alpha 2 (EphA2)-targeted peptides (YSAYPDSVPMMS, YSA). YSA-SPION-MV/MTX showed an effective targeting effect on OS cells, which was depended on the binding of the YSA peptide to EphA2. In the orthotopic OS mouse model, YSA-SPION-MV/MTX effectively delivered drugs to tumor sites with specific targeting, resulting in superior anti-tumor activity compared to MTX or MV/MTX. And YSA-SPION-MV/MTX also reduced the side effects of high-dose MTX. Taken together, this strategy opens up a new avenue for OS therapy. And we expect this MV-based therapy to serve as a promising platform for the next generation of precision cancer nanomedicines. Graphical Abstract

Hand osteoarthritis (OA) is a chronic progressive disease characterized by disabling pain in the hand, with a high clinical burden. This study is designed to assess the epidemiological patterns of hand OA from 1990 to 2019 and analyze its secular trends based on sex, age, and socio-demographic index (SDI) at global, regional, and national levels. Data on the incidence and disability-adjusted life years (DALYs) of hand OA were extracted from the 2019 Global Burden of Disease (GBD), and their respective age-standardized rates (ASRs) were calculated. The estimated annual percentage changes (EAPCs) in ASR were calculated to assess the prevalent trends of the incidence and DALYs of hand OA over the recent three decades. The relationship between ASR and SDI was analyzed by Pearson's correlation analysis. The incidence of hand OA increased from 371.30 million in 1990 to 676.02 million in 2019, increasing by 82.07%, whereas its age-standardized incidence rate (ASIR) decreased, with a downward trend [EAPC = -0.34; 95% confidence interval: -0.39--0.28]. With the changes in age, the incidence of hand OA exhibited a unimodal distribution before 70 years of age, peaking at 50-54 years, while its incidence had an upward trend in the >70 years age groups. Overall, hand OA-related DALYs increased in the recent 30 years. Meanwhile, its annual age-standardized DALY rate decreased, with EAPCs of -0.35 (95% CI, -0.38 --0.32). The DALYs increased with age. In 2019, the ASIR and age-standardized DALY rate were positively associated with the SDI regions. The incidence and DALYs presented predominance in female patients. The burden of hand OA over the recent three decades displayed obvious geographical diversity. The incident cases of hand OA increased globally from 1990 to 2019, while the ASIR and age-standardized DALY rate decreased. However, in many countries and regions, there was a rising trend of ASR related to incidence and DALYs. In addition, the prevalence revealed geographical, sex, and age diversity. Thus, governments and medical institutions should reallocate medical resources based on the epidemiological characteristics of hand OA.

Osteoarthritis (OA) is a common articular ailment presented with cartilage loss and destruction that is common observed in the elderly population. Physalin A (PA), a natural bioactive withanolide, exerts anti-inflammatory residences in more than a few diseases; however, little is known about its efficacy for OA treatment. Here, we explored the therapeutic effects and potential mechanism of PA in mouse OA. After the in vitro administration of PA, the expression of inflammation indicators including inducible nitric oxide synthase and cyclooxygenase-2 was low, indicating that PA could alleviate the IL-1β-induced chondrocyte inflammation response. Moreover, PA reduced IL-1β-induced destruction of the extracellular matrix by upregulating the gene expression of anabolism factors, including collagen II, aggrecan, and sry-box transcription factor 9, and downregulating the gene expression of catabolic factors, including thrombospondin motif 5 and matrix metalloproteinases. In addition, the chondroprotective effect of PA was credited to the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, in vivo experiments showed that intra-articular injection of PA could alleviate cartilage destruction in a mouse OA model. However, the anti-inflammatory, anabolism enhancing, catabolism inhibiting, and MAPK and NF-κB signaling pathway inhibiting properties of PA on IL-1β-induced chondrocytes could be reversed when integrin αVβ3 is knocked down by siRNA. In conclusion, our work demonstrates that PA exhibits a chondroprotective effect that may be mediated by integrin αVβ3. Thus, PA or integrin αVβ3 might be a promising agent or molecular target for the treatment of OA.

Osteoarthritis (OA) is one of the most prevalent chronic degenerative joint diseases affecting adults in their middle or later years. It is characterized by symptoms such as joint pain, difficulty in movement, disability, and even loss of motion. Moreover, the onset and progression of inflammation are directly associated with OA. In this research, we evaluated the impact of Flavokawain A (FKA) on osteoarthritis. In-vitro effects of FKA on murine chondrocytes have been examined using cell counting kit-8 (CCK-8), safranin o staining, western blot, immunofluorescence staining, senescence β-galactosidase staining, flow cytometry analysis, and mRFP-GFP-LC3 adenovirus infection. An in-vivo model of destabilization of the medial meniscus (DMM) was employed to investigate FKA’s effect on OA mouse. An analysis of bioinformatics was performed on FKA and its potential role in OA. It was observed that FKA blocked interleukin (IL)-1β-induced expression of inflammatory factors, i.e., cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) in chondrocytes. In addition, FKA also downregulated the catabolic enzyme expression, i.e., aggrecanase-2 (ADAMTS5) and matrix metalloproteinases (MMPs), and helped in the upregulation of the anabolic protein expression, i.e., type II collagen (Col2), Aggrecan, and sry-box transcription factor 9 (SOX9). Moreover, FKA ameliorated IL-1β-triggered autophagy in chondrocytes, and it was observed that the FKA causes anti-inflammatory effects by the mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathways inhibition. The results of immunohistochemical analysis and microcomputed tomography from the in vivo OA mouse model confirmed the therapeutic effect of FKA. Finally, we assessed the anti-arthritic impacts of FKA by conducting in vivo and in vitro analyses. We concluded that FKA can be employed as a useful therapeutic agent for OA therapy, but the findings require needs further clinical investigation.

Background. Urolithiasis is common worldwide and can predispose to urinary tract infections and renal failure. We aimed to explore the global, regional, and national burden of urolithiasis between 1990 and 2019, stratified by sex, age, and sociodemographic index (SDI). Methods. From 1990 to 2019, data on the number of incident cases of urolithiasis, associated deaths, and disability-adjusted life years (DALYs) were extracted from the 2019 Global Burden of Disease (GBD) study. The trends for the incidence rate, mortality, and DALYs were evaluated using estimated annual percentage changes (EAPCs). Results. The incidence of urolithiasis increased by 48.57%, from 77.78 million incident cases in 1990 to 115.55 million in 2019, while its age-standardized incidence rate (ASIR) decreased. The ASIR increased slightly in the low SDI regions (EAPC = 0.33; 95% confidence interval [CI]: 0.24–0.43), while ASIRs in other SDI regions decreased. The incidence of urolithiasis by age presented a unimodal distribution, with the peak observed in patients aged between 50 years and 70 years. Urolithiasis-related mortality and DALYs also increased over time. Yet, the age-standardized death rate (ASDR) decreased by 2.05% (95% CI, −2.25% to −1.85%) per year, and the annual age-standardized DALY rate decreased by 1.77% (95% CI, −1.92% to −1.63%). The mortality and DALYs increased with age. The incidence, mortality, and DALYs were greater in males than those in females. The burden of urolithiasis showed obvious differences in its regional distribution over the past three decades. Conclusion. From 1990 to 2019, ASIR, ASDR, and age-standardized DALY rate of urolithiasis have decreased. Yet, particularly significant differences exist in the geographic, age, and sex distribution. Thus, medical resources should be rationally allocated and adjusted according to the geographic and demographic distribution of urolithiasis.

The polarization of macrophages plays an important clinical role in the occurrence and development of many diseases. Photothermal therapy is a non-invasive treatment mode based on near-infrared light stimulation. The large surface of MXenes makes it have a high spectral band from UV to NIR region and high photothermal conversion efficiency, which has a very broad prospect in photothermal therapy. In this study, we report, for the first time, the integration of photothermal MXenes into gelatin methacryloyl (GelMA) hydrogels for macrophage polarization regulation. Macrophage M1 polarization was induced by photothermal effect to achieve immune reaction via heat-shock protein (HSP) 60, 70, and 90. This study indicated that we could propose immunomodulatory strategies based on the immunological characteristics of target diseases and provide ideas for the design and synthesis of new immunoregulatory biomaterials.

Osteoarthritis (OA) is a chronic progressive articular illness which commonly affects older-aged adults, presenting with cartilage inflammation and degradation. Rutaecarpine (RUT) has been shown to exert promising anti-inflammatory effects; however, the efficacy of RUT in the treatment of OA is debatable. The present study investigated the potential of RUT in alleviating OA in a mouse model. Treatment with RUT inhibited the inflammatory response and extracellular matrix degradation by suppressing process regulators in interleukin (IL)-1β-stimulated chondrocytes. Moreover, treatment with RUT in vitro upregulated the gene expression of anabolic agents, such as collagen type II, aggrecan and SRY-box transcription factor 9, indicating that RUT contributed to cartilage repair. Additionally, flow cytometric assays, and the measurement of β-galactosidase levels, autophagic flux and related protein expression revealed that RUT effectively attenuated IL-1β-induced chondrocyte apoptosis, senescence and autophagy impairment. In addition, bioinformatics analysis and in vitro experiments demonstrated that RUT protected cartilage by mediating the phosphoinositide-3-kinase (PI3K)/Akt/nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. The ameliorative effects of RUT on IL-1β-stimulated chondrocytes were abrogated when siRNA was used to knock down integrin αVβ3. Furthermore, the results of immunohistochemical analysis and microcomputed tomography confirmed the in vivo therapeutic effects of RUT in mice with OA. On the whole, the present study demonstrates that RUT attenuates the inflammatory response and cartilage degradation in mice with OA by suppressing the activation of the PI3K/AKT/NF-κB and MAPK pathways. Integrin αVβ3 may play a pivotal role in these effects.

Osteoarthritis (OA) is a chronic progressive articular illness which commonly affects older-aged adults, presenting with cartilage inflammation and degradation. Rutaecarpine (RUT) has been shown to exert promising anti-inflammatory effects; however, the efficacy of RUT in the treatment of OA is debatable. The present study investigated the potential of RUT in alleviating OA in a mouse model. Treatment with RUT inhibited the inflammatory response and extracellular matrix degradation by suppressing process regulators in interleukin (IL)-l[beta]-stimulated chondrocytes. Moreover, treatment with RUT in vitro upregulated the gene expression of anabolic agents, such as collagen type II, aggrecan and SRY-box transcription factor 9, indicating that RUT contributed to cartilage repair. Additionally, flow cytometric assays, and the measurement of [beta]-galactosidase levels, autophagic flux and related protein expression revealed that RUT effectively attenuated IL-1[beta]-induced chondrocyte apoptosis, senescence and autophagy impairment. In addition, bioinformatics analysis and in vitro experiments demonstrated that RUT protected cartilage by mediating the phosphoinositide-3-kinase (PI3K)/Akt/nuclear factor-[kappa]? (NF-[kappa]?) and mitogen-activated protein kinase (MAPK) pathways. The ameliorative effects of RUT on IL-1[beta]-stimulated chondrocytes were abrogated when siRNA was used to knock down integrin [alpha]V[beta]3. Furthermore, the results of immunohistochemical analysis and microcomputed tomography confirmed the in vivo therapeutic effects of RUT in mice with OA. On the whole, the present study demonstrates that RUT attenuates the inflammatory response and cartilage degradation in mice with OA by suppressing the activation of the PI3K/AKT/NF-[kappa]B and MAPK pathways. Integrin [alpha]V[beta]3 may play a pivotal role in these effects.