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Long-term chronic inflammation after Achilles tendon injury is critical for tendinopathy. Platelet-rich plasma (PRP) injection, which is a common method for treating tendinopathy, has positive effects on tendon repair. In addition, tendon-derived stem cells (TDSCs), which are stem cells located in tendons, play a major role in maintaining tissue homeostasis and postinjury repair. In this study, injectable gelatine methacryloyl (GelMA) microparticles containing PRP laden with TDSCs (PRP–TDSC–GM) were prepared by a projection-based 3D bioprinting technique. Our results showed that PRP–TDSC–GM could promote tendon differentiation in TDSCs and reduce the inflammatory response by downregulating the PI3K–AKT pathway, thus promoting the structural and functional repair of tendons in vivo. Graphical Abstract

Osteoporosis, characterized by reduced bone mass, aberrant bone architecture, and elevated bone fragility, is driven by a disruption of bone homeostasis between bone resorption and bone formation. However, up to now, no drugs are perfect for osteoporosis treatment due to different defects. In this study, we demonstrated that norcantharidin (NCTD) could inhibit osteoclast formation and bone resorption by attenuating the ERK, ROS and NLRP3 inflammasomes pathways in vitro . Moreover, our in vivo study further confirms its preventive effects on estrogen-deficiency bone loss by inhibiting osteoclast formation and functions. Therefore, we could conclude that NCTD might be a potential candidates for the prevention and treatment of osteoporosis.

Osteoarthritis is a worldwide joint disease caused by abnormal chondrocytic metabolism. However, traditional therapeutic methods aimed at anti-inflammation for early-stage disease are palliative. In the present study, we demonstrated that cepharanthine (CEP), extracted from the plant Stephania cepharantha , exerted protective medicinal efficacy on osteoarthritis for the first time. In our in vitro study, CEP suppressed the elevated expression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and inducible nitric oxide synthase (iNOS) stimulated by IL-1β or TNF-α by inhibiting the activation of MAPK and NF-κB signaling pathways, and upregulated the protein expression of aggrecan, collagen II, and Sox9. Also, CEP could reverse the reduced level of cellular autophagy in IL-1β or TNF-α–induced chondrocytes, indicating that the protective effect of CEP on osteoarthritis was achieved by restoring MAPK/NF-κB-mediated autophagy. Furthermore, in a murine OA model, CEP mitigated cartilage degradation and prevented osteoarthritis in the CEP-treated groups versus the OA group. Hence, our results revealed the therapeutic prospect of CEP for anti-osteoarthritic treatment.

Background Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAF V600E -mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAF V600E mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype. Aim This study aims to develop a precise therapeutic system for BRAF V600E CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAF V600E . Method We first obtained engineered cells capable of stably producing EVs loaded with BRAF V600E nucleic acid drugs (siBRAF V600E ). Next, BRAF V600E -mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAF V600E and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms. Result EVs-siBRAF V600E specifically inhibited BRAF V600E CRC but didn’t affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAF V600E exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models. Conclusion The therapeutic EVs we constructed are effective and specific for the BRAF V600E -mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAF V600E mutation.

BackgroundHeat shock protein 47 (HSP47) is crucial for protein quality control and tumor progression. While its role in cancer biology is well established, its impact on cancer immunity remains poorly understood. In this study, we aim to elucidate how HSP47 inhibition modulates immune evasion, with a specific focus on the CD155/T-cell immunoreceptor with Ig and ITIM domains (TIGIT) axis in osteosarcoma (OS).MethodsWe used OS cell lines and mouse models to examine the effects of HSP47 inhibition on tumor growth and immune response. Expression levels of CD155, TIGIT, and other immune checkpoint molecules were analyzed throughflow cytometry, immunofluorescence, and western blotting. We also assessed the therapeutic effects of combining HSP47 inhibition with CD155 blockade or nuclear factor-kappa B (NF-κB) inhibitors in preclinical models.ResultsInhibition of HSP47 resulted in increased expression of the immune checkpoint molecule CD155, which impaired the antitumor activity of CD8+ T cells through the TIGIT receptor. Mechanistically, HSP47 inhibition reduced TRAF2 ubiquitination, leading to enhanced NF-κB signaling and upregulation of CD155 in OS cells. Combining HSP47 inhibition with anti-TIGIT antibodies or the NF-κB inhibitor bortezomib significantly suppressed OS progression and improved survival in mouse models.ConclusionsHSP47 inhibition promotes immune evasion by upregulating CD155 via the TRAF2-NF-κB pathway, which impairs CD8+ T cell-mediated antitumor immunity. The combination of HSP47 inhibition with CD155/TIGIT blockade enhances therapeutic efficacy, suggesting a promising strategy for combination cancer therapies.

3D cell infiltration into porous scaffolds constitutes a fundamental prerequisite for bone tissue engineering. Though pore size and curvature are known to dictate this process, their mathematical coupling remains elusive. Herein, we identified a size‐dependent bone marrow‐derived mesenchymal stem cells 3D in‐growth pattern in which small pores promoted horizontal bridging, while large pores favored vertical cellular migration into the scaffold core. An analytical framework of Porous‐Fisher model was developed using a superposition approach tailored to boundary‐specific solutions. This approach not only enabled quantitative prediction of coverage rates through examination of grid dimensions and diffusion coefficients but also mathematically elucidated curvature and strategic geometric design. Furthermore, the prediction of cellular diffusion patterns on porous scaffolds was achieved through the alteration of boundary conditions and diffusion coefficients. Convex topological configurations were shown to accelerate cellular infiltration, whereas concave geometries permitted spatiotemporal modulation of tissue growth. Additionally, lower diffusion environments delayed coverage, suggesting scaffold designs with reduced pore sizes might benefit elderly patients. Consequently, the accuracy of model was in vivo validated by a rat cranial defect model. Overall, the mathematical model provided an effective way for ideal pore structure prediction in advance and propel the application of porous scaffolds in tissue engineering. This study identifies a fundamental pore size dependent pattern of three dimensional bone marrow derived mesenchymal stem cell (BMSC) infiltration within porous scaffolds, where small pores promote horizontal cellular bridging and large pores facilitate vertical migration. An analytical Porous Fisher mathematical framework is developed, employing a superposition approach tailored to boundary specific solutions. This model quantitatively predicts cellular coverage rates by examining grid dimensions and diffusion coefficients, while mathematically elucidating the role of pore curvature and geometric design. It reveals that convex topological configurations accelerate cellular infiltration, whereas concave geometries allow spatiotemporal modulation of tissue growth. The model further indicates that reduced diffusion environments delay coverage, suggesting scaffold designs with smaller pores may benefit elderly patients. Finally, the predictions are successfully validated in a rat cranial critical size defect model.

Selenium (Se) is an essential micronutrient that plays a critical role in anti-inflammatory processes and antioxidant defense system. In this study, we investigated the effects of dietary selenium deficiency on lipopolysaccharide (LPS)-induced mastitis in mouse models. Se content in the liver was assessed by fluorescent atomic absorption spectrometry. Glutathione peroxidase (GPx) activity in the blood, myeloperoxidase (MPO) activity, tumor necrosis actor alpha (TNF-α), and interleukin (IL)-1β in the supernatant of the mammary tissue were determined according to the corresponding kits. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions were evaluated by Western blotting. The results showed that the Se-deficient mouse model was successfully replicated, and selenium deficiency exacerbated mammary gland histopathology, increased the expressions of TNF-α and IL-1β, and facilitated the activation of iNOS and COX-2 in LPS-induced mouse mastitis. In conclusion, our studies demonstrated that selenium deficiency resulted in more severe inflammatory response in LPS-induced mouse mastitis.

Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAF -mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAF mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype. This study aims to develop a precise therapeutic system for BRAF CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAF . We first obtained engineered cells capable of stably producing EVs loaded with BRAF nucleic acid drugs (siBRAF ). Next, BRAF -mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAF and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms. EVs-siBRAF specifically inhibited BRAF CRC but didn't affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAF exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models. The therapeutic EVs we constructed are effective and specific for the BRAF -mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAF mutation.

Selenium, in the form of selenoproteins, plays a pivotal role in anti-inflammatory processes and antioxidant defense system. The aim of this study was to examine the effects of selenium on lipopolysaccharide (LPS)-induced inflammatory responses in bovine mammary epithelial cells (bMEC) and to investigate the potential mechanism. bMEC viability was measured by MTT assay. TNF-α, IL-1β, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) expressions were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The activation of nuclear factor-kappa B (NF-κB) was determined by Western blotting. The results showed that the mRNA expressions of these inflammatory factors were significantly inhibited by selenium in a dose-dependent manner. At protein levels, Western blot analysis demonstrated that selenium dose-dependently decreased NF-κB p65 translocating from the cytoplasm to the nucleus. Taken together, these results suggest that the anti-inflammatory property of selenium in LPS-stimulated primary bMEC may be attributed to the downregulation of NF-κB activation.