Single-cell landscape revealed immune characteristics associated with disease phases in brucellosis patients.

A comprehensive immune landscape for Brucella infection is crucial for developing new treatments for brucellosis. Here, we utilized single-cell RNA sequencing (scRNA-seq) of 290,369 cells from 35 individuals, including 29 brucellosis patients from acute (n = 10), sub-acute (n = 9), and chronic (n = 10) phases as well as six healthy donors. Enzyme-linked immunosorbent assays were applied for validation within this cohort. Brucella infection caused a significant change in the composition of peripheral immune cells and inflammation was a key feature of brucellosis. Acute patients are characterized by potential cytokine storms resulting from systemic upregulation of S100A8/A9, primarily due to classical monocytes. Cytokine storm may be mediated by activating S100A8/A9-TLR4-MyD88 signaling pathway. Moreover, monocytic myeloid-derived suppressor cells were the probable contributors to immune paralysis in acute patients. Chronic patients are characterized by a dysregulated Th1 response, marked by reduced expression of IFN-γ and Th1 signatures as well as a high exhausted state. Additionally, Brucella infection can suppress apoptosis in myeloid cells (e.g., mDCs, classical monocytes), inhibit antigen presentation in professional antigen-presenting cells (APCs; e.g., mDC) and nonprofessional APCs (e.g., monocytes), and induce exhaustion in CD8+ T/NK cells, potentially resulting in the establishment of chronic infection. Overall, our study systemically deciphered the coordinated immune responses of Brucella at different phases of the infection, which facilitated a full understanding of the immunopathogenesis of brucellosis and may aid the development of new effective therapeutic strategies, especially for those with chronic infection.

Injectable GelMA Hydrogel Microspheres with Sustained Release of Platelet-Rich Plasma for the Treatment of Thin Endometrium.

Platelet-rich plasma (PRP) intrauterine infusion has been demonstrated to be effective in treating thin endometrium and achieving pregnancy. However, the rapid release of growth factors limits its effectiveness in clinical applications, and thus, multiple intrauterine infusions are often required to achieve therapeutic efficacy. In this study, a GelMA hydrogel microsphere biomaterial is developed using droplet microfluidics to modify the delivery mode of PRP and thus prolong its duration of action. Its biocompatibility is confirmed through both in vivo and in vitro studies. Cell experiments show that PRP-loaded microspheres significantly enhance cell proliferation, migration, and angiogenesis. In vivo experiments show that the effects of PRP-loaded microspheres on repairing the endometrium and restoring fertility in mice could achieve the impact of triple PRP intrauterine infusions. Further mechanistic investigations reveal that PRP could facilitate endometrial repair by regulating the expression of E2Fs, a group of transcription factors. This study demonstrates that hydrogel microspheres could modify the delivery of PRP and prolong its duration of action, enabling endometrial repair and functional reconstruction. This design avoids repeated intrauterine injections of PRP in the clinic, reduces the number of patient visits, and provides a new avenue for clinical treatment of thin endometrium.

Delivering Microrobots in the Musculoskeletal System.

Disorders of the musculoskeletal system are the major contributors to the global burden of disease and current treatments show limited efficacy. Patients often suffer chronic pain and might eventually have to undergo end-stage surgery. Therefore, future treatments should focus on early detection and intervention of regional lesions. Microrobots have been gradually used in organisms due to their advantages of intelligent, precise and minimally invasive targeted delivery. Through the combination of control and imaging systems, microrobots with good biosafety can be delivered to the desired area for treatment. In the musculoskeletal system, microrobots are mainly utilized to transport stem cells/drugs or to remove hazardous substances from the body. Compared to traditional biomaterial and tissue engineering strategies, active motion improves the efficiency and penetration of local targeting of cells/drugs. This review discusses the frontier applications of microrobotic systems in different tissues of the musculoskeletal system. We summarize the challenges and barriers that hinder clinical translation by evaluating the characteristics of different microrobots and finally point out the future direction of microrobots in the musculoskeletal system.

The amino acid sensor methionyl-tRNA synthetase is required for methionine-induced milk protein synthesis in a domestic pigeon model.

This study was conducted to investigate whether methionyl-tRNA synthetase (MetRS) is a mediator of methionine (Met)-induced crop milk protein synthesis via the janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signalling pathway in breeding pigeons. In Experiment 1, a total of 216 pairs of breeding pigeons were divided into three groups (control, Met-deficient, and Met-rescue groups). In Experiments 2 and 3, forty pairs of breeding pigeons from each experiment were allocated into four groups. The second experiment included a control group and three MetRS inhibitor (REP8839) groups. The third experiment included a Met-deficient group, Met-sufficient group, REP8839 + Met-deficient group and REP8839 + Met-sufficient group. Experiment 1 showed that Met supplementation increased crop development, crop milk protein synthesis, the protein expression of MetRS and JAK2/STAT5 signalling pathway, and improved squab growth. Experiment 2 showed that crop development, crop milk protein synthesis and the protein expression of MetRS and the JAK2/STAT5 signalling pathway were decreased, and squab growth was inhibited by the injection of 1·0 mg/kg body weight REP8839, which was the selected dose for the third experiment. Experiment 3 showed that Met supplementation increased crop development, crop milk protein synthesis and the expression of MetRS and JAK2/STAT5 signalling pathway and rescued squab growth after the injection of REP8839. Moreover, the co-immunoprecipitation results showed that there was an interaction between MetRS and JAK2. Taken together, these findings indicate that MetRS mediates Met-induced crop milk protein synthesis via the JAK2/STAT5 signalling pathway, resulting in improved squab growth in breeding pigeons.

HMGB1 Modulates High Glucose-Induced Erroneous Differentiation of Tendon Stem/Progenitor Cells through RAGE/ß-Catenin Pathway.

The association of tendinopathy with diabetes has been well recognized. Tendon stem/progenitor cells (TSPCs) play critical roles in tendon repair, regeneration, and homeostasis maintenance. Diabetic TSPCs exhibit enhanced erroneous differentiation and are involved in the pathogenesis of diabetic tendinopathy, whereas the underlying mechanism of the erroneous differentiation of TSPCs remains unclear. Here, we showed that high glucose treatment promoted the erroneous differentiation of TSPCs with increased osteogenic differentiation capacity and decreased tenogenic differentiation ability, and stimulated the expression and further secretion of HMGB1 in TSPCs and. Functionally, exogenous HMGB1 significantly enhanced the erroneous differentiation of TSPCs, while HMGB1 knockdown mitigated high glucose-promoted erroneous differentiation of TSPCs. Mechanistically, the RAGE/ß-catenin signaling was activated in TSPCs under high glucose, and HMGB1 knockdown inhibited the activity of RAGE/ß-catenin signaling. Inhibition of RAGE/ß-catenin signaling could ameliorate high glucose-induced erroneous differentiation of TSPCs. These results indicated that HMGB1 regulated high glucose-induced erroneous differentiation of TSPCs through the RAGE/ß-catenin signaling pathway. Collectively, our findings suggest a novel essential mechanism of the erroneous differentiation of TSPCs, which might contribute to the pathogenesis of diabetic tendinopathy and provide a promising therapeutic target and approach for diabetic tendinopathy.

Pooled and global burdens and trends of five common cancers attributable to diet in 204 countries and territories from 1990 to 2019: an analysis of the Global Burden of Disease Study.

OBJECTIVE: Increasing evidence has shown that dietary behaviors are closely correlated with the carcinogenesis and progression of many types of cancer. However, few studies have assessed the global diet-related burden of cancer. This study aimed to estimate the pooled burdens and trends of five types of cancers attributable to dietary behaviors. METHODS: Data regarding cancer attributable to dietary behaviors were extracted from the Global Burden of Disease study 2019, including the death cases and age-standardized death rates, and disability-adjusted life years (DALYs) estimated according to diseases, age, sex, the socio-demographic index (SDI) and location. RESULTS: According to the Global Burden of Disease study 2019, five types of cancer were affected by dietary behaviors: colon and rectum cancer; tracheal, bronchus and lung cancer; stomach cancer; esophageal cancer and breast cancer. Unhealthy dietary behaviors for cancer caused a total of 605.4 thousand deaths and 13951.3 thousand DALYs globally. The burden of cancer attributable to dietary risks was higher for men than for women. The highest age-standardized death rates in 2019 were observed in southern Latin America, and the lowest rates were observed in North Africa and the Middle East. The greatest increases in the age-standardized death rates, from 1990 to 2019, were found in Western Sub-Saharan Africa, with the greatest decreases in Central Asia. The highest attributable proportions of death or DALYs were colon and rectum cancer. The greatest diet-related cancer burden was observed in regions with a high-middle SDI. CONCLUSION: Global age-standardized deaths and DALYs rates attributable to diet-related cancer are considerable and cause a substantial burden. Successful population-wide initiatives targeting unhealthy dietary behaviors would reduce this burden.

Injectable self-assembled GDF5-containing dipeptide hydrogels for enhanced tendon repair.

Owing to the tissue characteristics of tendons with few blood vessels and cells, the regeneration and repair of injured tendons can present a considerable challenge, which considerably affects the motor function of limbs and leads to serious physical and mental pain, along with an economic burden on patients. Herein, we designed and fabricated a dipeptide hydrogel (DPH) using polypeptides P11-4 and P11-8. This hydrogel exhibited self-assembly characteristics and could be administered in vitro. To endow the hydrogel with differentiation and regeneration abilities, we added different concentrations of growth differentiation factor 5 (GDF5) to form GDF5@DPH. GDF5@DPH promoted the aggregation and differentiation of tendon stem/progenitor cells and promoted the regeneration and repair of tendon cells and collagen fibers in injured areas. In addition, GDF5@DPH inhibited inflammatory reactions in the injured area. Owing to its injectable properties, DPH can jointly inhibit adhesion and scar hyperplasia between tissues caused by endogenous inflammation and exogenous surgery and can provide a favorable internal environment for the regeneration and repair of the injured area. Overall, the GDF5@DPH system exhibits considerable promise as a novel approach to treating tendon injury.

Supramolecular Hydrogel Dexamethasone-Diclofenac for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) severely affects patients' quality of life and is commonly treated with glucocorticosteroids injections, like dexamethasone, which may have side effects. This study aimed to create a novel low dose of twin-drug hydrogel containing dexamethasone and diclofenac and explore its potential as a drug delivery system for an enhanced anti-inflammatory effect. Its characterization involved rheology, transmission electron microscope (TEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). Furthermore, the hydrogel demonstrated thixotropic properties. The hydrogel exhibited no cytotoxicity against RAW 264.7 macrophages. Furthermore, the hydrogel demonstrated a significant anti-inflammatory efficacy by effectively downregulating the levels of NO, TNF-α, and IL-6 in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. The co-delivery approach, when intra-articularly injected in adjuvant-induced arthritis (AIA) rats, significantly alleviated chronic inflammation leading to reduced synovitis, delayed bone erosion onset, and the downregulation of inflammatory cytokines. The biocompatibility and adverse effect evaluation indicated good biological safety. Furthermore, the hydrogel demonstrated efficacy in reducing NF-κB nuclear translocation in LPS-induced RAW 264.7 macrophages and inhibited p-NF-kB, COX-2, and iNOS expression both in RAW 264.7 macrophages and the joints of AIA rats. In conclusion, the findings indicate that the hydrogel possesses potent anti-inflammatory activity, which effectively addresses the limitations associated with free forms. It presents a promising therapeutic strategy for the management of RA.

The effect of metformin combined with liraglutide on gut microbiota of Chinese patients with type 2 diabetes / El efecto de la metformina combinada con liraglutida sobre la microbiota intestinal de pacientes chinos con diabetes tipo 2

Background: Metformin (MET) is a first-line therapy for type-2 diabetes mellitus (T2DM). Liraglutide (LRG) is a glucagon-like peptide-1 receptor agonist used as a second-line therapy in combination with MET. Methods: We performed a longitudinal analysis comparing the gut microbiota of overweight and/or pre-diabetic participants (NCP group) with that of each following their progression to T2DM diagnosis (UNT group) using 16S ribosomal RNA gene sequencing of fecal bacteria samples. We also examined the effects of MET (MET group) and MET plus LRG (MET+LRG group) on the gut microbiota of these participants following 60 days of anti-diabetic drug therapy in two parallel treatment arms. Results: In the UNT group, the relative abundances of Paraprevotella (P = 0.002) and Megamonas (P = 0.029) were greater, and that of Lachnospira (P = 0.003) was lower, compared with the NCP group. In the MET group, the relative abundance of Bacteroides (P = 0.039) was greater, and those of Paraprevotella (P = 0.018), Blautia (P = 0.001), and Faecalibacterium (P = 0.005) were lower, compared with the UNT group. In the MET+LRG group, the relative abundances of Blautia (P = 0.005) and Dialister (P = 0.045) were significantly lower than in the UNT group. The relative abundance of Megasphaera in the MET group was significantly greater than in the MET+LRG group (P = 0.041). Conclusions: Treatment with MET and MET+LRG results in significant alterations in gut microbiota, compared with the profiles of patients at the time of T2DM diagnosis. These alterations differed significantly between the MET and MET+LRG groups, which suggests that LRG exerted an additive effect on the composition of gut microbiota.(AU)

Heterotopic mineralization (ossification or calcification) in aged musculoskeletal soft tissues: A new candidate marker for aging.

Aging can lead to various disorders in organisms and with the escalating impact of population aging, the incidence of age-related diseases is steadily increasing. As a major risk factor for chronic illnesses in humans, the prevention and postponement of aging have become focal points of research among numerous scientists. Aging biomarkers, which mirror molecular alterations at diverse levels in organs, tissues, and cells, can be used to monitor and evaluate biological changes associated with aging. Currently, aging biomarkers are primarily categorized into physiological traits, imaging characteristics, histological features, cellular-level alterations, and molecular-level changes that encompass the secretion of aging-related factors. However, in the context of the musculoskeletal soft tissue system, aging-related biological indicators primarily involve microscopic parameters at the cellular and molecular levels, resulting in inconvenience and uncertainty in the assessment of musculoskeletal soft tissue aging. To identify convenient and effective indicators, we conducted a comprehensive literature review to investigate the correlation between ectopic mineralization and age-related changes in the musculoskeletal soft tissue system. Here, we introduce the concept of ectopic mineralization as a macroscopic, reliable, and convenient biomarker for musculoskeletal soft tissue aging and present novel targets and strategies for the future management of age-related musculoskeletal soft tissue disorders.

Spatial separation of nitrifiers and denitrifiers promotes selection and enrichment of polyhydroxyalkanoates storing mixed cultures fed by crude glycerol and propionate wastewater.

Polyhydroxyalkanoates (PHA) recovery from industrial wastewater has been highlighted as a promising strategy for a circular bioeconomy. However, the high and varying level of nitrogen in wastewater makes enrichment of mixed microbial culture (MMC) low efficiency. In this study, spatial separation of nitrifiers and denitrifiers was adopted by adding biocarriers in MMC and decreasing the sludge retention time (SRT) to accelerate the enrichment of PHA-storing MMC fed by mixed wastewater containing glycerol and propionate. Nitrifiers and denitrifiers were sustained on biocarriers, obtaining a high total inorganic nitrogen removal and allowing a more efficient selective pressure of a high carbon and nitrogen ratio (C/N) under low SRT conditions. The maximum PHA cell content and relative abundance of PHA-storing bacteria were increased to 60.51 % (SRT 6 d) and 49.62 % (SRT 6 d) with the decrease of SRT, respectively. This study demonstrates an efficient way to highly enrich PHA-storing MMC from crude glycerol, which provide a relevant technical support for high-efficiency enrichment of PHA-storing bacteria in low C/N wastewater.

The effect of metformin combined with liraglutide on gut microbiota of Chinese patients with type 2 diabetes.

BACKGROUND: Metformin (MET) is a first-line therapy for type-2 diabetes mellitus (T2DM). Liraglutide (LRG) is a glucagon-like peptide-1 receptor agonist used as a second-line therapy in combination with MET. METHODS: We performed a longitudinal analysis comparing the gut microbiota of overweight and/or pre-diabetic participants (NCP group) with that of each following their progression to T2DM diagnosis (UNT group) using 16S ribosomal RNA gene sequencing of fecal bacteria samples. We also examined the effects of MET (MET group) and MET plus LRG (MET+LRG group) on the gut microbiota of these participants following 60 days of anti-diabetic drug therapy in two parallel treatment arms. RESULTS: In the UNT group, the relative abundances of Paraprevotella (P = 0.002) and Megamonas (P = 0.029) were greater, and that of Lachnospira (P = 0.003) was lower, compared with the NCP group. In the MET group, the relative abundance of Bacteroides (P = 0.039) was greater, and those of Paraprevotella (P = 0.018), Blautia (P = 0.001), and Faecalibacterium (P = 0.005) were lower, compared with the UNT group. In the MET+LRG group, the relative abundances of Blautia (P = 0.005) and Dialister (P = 0.045) were significantly lower than in the UNT group. The relative abundance of Megasphaera in the MET group was significantly greater than in the MET+LRG group (P = 0.041). CONCLUSIONS: Treatment with MET and MET+LRG results in significant alterations in gut microbiota, compared with the profiles of patients at the time of T2DM diagnosis. These alterations differed significantly between the MET and MET+LRG groups, which suggests that LRG exerted an additive effect on the composition of gut microbiota.

General practitioners' attitudes towards and frequency of collaboration with pharmacists in China: a cross-sectional study.

BACKGROUND: Building interprofessional working relationships between general practitioners (GPs) and pharmacists is essential to ensure high-quality patient care. However, there is limited Chinese literature on GP-pharmacist collaboration, and few studies have explored GPs' experiences with pharmacist integration into general practices. This study aimed to investigate GPs' attitudes towards and frequency of collaboration with pharmacists in China. METHODS: This cross-sectional study used an online self-administered questionnaire integrating two scales, ATCI-GP and FICI-GP, which had been translated and validated to investigate 3,248 GPs from February 15 to March 15, 2023 across Zhejiang Province, China. Descriptive analyses were used, and the factors associated with GPs' frequency of collaboration with pharmacists were explored using logistic regression analysis. RESULTS: A total of 2,487 GPs (76.6%) responded and consented to participate in the survey; 52.3% were male and the mean age was 35.4 years. Most GPs agreed that they shared common goals and objectives with pharmacists when caring for patients (90.0%), and pharmacists were open to working with them on patients' medication management (80.8%). However, half of the GPs did not change or seldom changed the patient's medication on the pharmacist's advice (51.4%). Logistic regression analysis showed that GPs who were older and had more years of practice were more likely to agree that pharmacists were willing to collaborate, had common goals for treatment and that they would change the patient's medication on the advice of the pharmacist. GPs who had regular communication protocols (adjusted odds ratio1 [aOR1] = 1.88, 95% CI 1.45-2.45; aOR2 = 3.33, 95% CI 2.76-4.02), participated in joint continuing education (aOR1 = 1.87, 95% CI 1.44-2.43; aOR2 = 2.27, 95% CI 1.91-2.70), provided recommendations for medication review (aOR1 = 3.01, 95% CI 2.07-4.38; aOR2 = 3.50, 95% CI 2.51-4.86), and communicated with pharmacists during resident training (aOR1 = 2.15, 95% CI 1.78-2.60; aOR2 = 1.38, 95% CI 1.18-1.62) were associated with a more positive attitude towards and higher frequency of cooperation. CONCLUSIONS: GPs in China displayed a positive attitude towards cooperating with pharmacists, but they did not demonstrate a similar level of practice. As environmental determinants impact interdisciplinary collaboration, healthcare managers and policy-makers need to implement measures that foster a supportive environment conducive to interdisciplinary collaboration.

In Vitro Antibody-Dependent Enhancement of SARS-CoV-2 Infection Could Be Abolished by Adding Human IgG.

Evidence of antibody-dependent enhancement (ADE) of other viruses has raised concerns about the safety of SARS-CoV-2 vaccines and antibody therapeutics. In vitro studies have shown ADE of SARS-CoV-2 infection. In this study, we also found that vaccination/convalescent sera and some approved monoclonal antibodies can enhance SARS-CoV-2 infection of FcR-expressing B cells in vitro. However, the enhancement of SARS-CoV-2 infection can be prevented by blocking Fc-FcR interaction through the addition of human serum/IgG or the introduction of mutations in the Fc portion of the antibody. It should be noted that ADE activity observed on FcR-expressing cells in vitro may not necessarily reflect the situation in vivo; therefore, animal and clinical data should be included for ADE evaluation.

WeChat official accounts' posts on medication use of 251 community healthcare centers in Shanghai, China: content analysis and quality assessment.

Background: The dissemination of online health information (OHI) on medication use via WeChat Official Accounts (WOAs) is an effective way to help primary care practitioners (PCPs) address drug-related problems (DRPs) in the community. Although an increasing number of primary care institutions in China have published WOA posts on medication use, their content and quality have not yet been assessed. Objective: This study aimed to explore the general features and content of WOA posts on medication use published by community healthcare centers (CHCs) in Shanghai, China and to assess their quality of content. It also aimed to explore the factors associated with the number of post views. Methods: From June 1 to October 31, 2022, two coauthors independently screened WOA posts on medication use published throughout 2021 by the CHCs in Shanghai. Content analysis was performed to analyze their general features (format, length, and source, etc.) and content (types of medicines and diseases). The QUEST tool was used to assess the quality of the posts. We compared the differences among posts published by CHCs in central urban areas and suburban areas, and used multiple linear regression to explore the factors associated with the number of post views. Results: A total of 236 WOAs of interest published 37,147 posts in 2021, and 275 (0.74%) of them were included in the study. The median number of post views was 152. Thirty percent of the posts were reviewed by the CHCs' staff before publication and only 6% provided information on PCPs' consultations. The most commonly mentioned medicines and diseases in the posts were Chinese patent medicines (37.1%) and respiratory diseases (29.5%). The posts frequently provided information on indications (77%) and usage (56%) but rarely on follow-up (13%) and storage (11%). Of the posts, 94.9% had a total QUEST score < 17 (full score = 28). The median number of post views and total post quality scores did not significantly differ among the CHCs in central urban and suburban areas. In the multiple linear regression model, the number of post views was associated with scores of complementarity (B = 56.47, 95% CI 3.05, 109.89) and conflict of interest (B = -46.40, 95% CI -56.21, -36.60). Conclusion: The quantity and quality of WOA posts on medication use published by CHCs in China need improvement. The quality of posts may partially impact the dissemination effect, but intrinsic causal associations merit further exploration.

Evaluation of the knowledge, awareness, and attitudes toward epilepsy among general practitioners in Eastern China.

OBJECTIVE: We aimed to assess the knowledge, awareness, and attitudes toward epilepsy among general practitioners (GPs) from community health service centers (CHCs) in Hangzhou, Eastern China. METHODS: One hundred twenty three GPs working at CHCs participated in this cross-sectional study in 2022. A custom-built electronic questionnaire, which comprised four domains, including 12 items for general condition data, 10 items for awareness (including first aid), a 16-item scale for attitudes, and 6 items for demographic data, was administered to the GPs. Descriptive statistics, the Mann-Whitney U test, the Kruskal-Wallis H test, and Spearman's rank correlation analysis were used to analyze the non-normal distribution of the data set. RESULTS: The GPs' average score on the awareness of epilepsy section was 18.14 ± 3.34 (aggregate score: 34), the first aid knowledge of epilepsy section scored 4.89 ± 1.54 (aggregate score: 7), and the epilepsy attitude section scored 62.28 ± 10.15 (aggregate score: 80). Age (rs = 0.218, P = 0.015), professional title (rs = 0.215, P = 0.017), and length of service (rs = 0.240, P = 0.008) correlated significantly with mean awareness of epilepsy scores. Age (rs = -0.234, P = 0.009) and educational background (rs = 0.199, P = 0.028) correlated significantly with attitudes toward epilepsy. Furthermore, when GPs faced newly diagnosed people with epilepsy (PWE), a referral was usually recommended (89.43%) and some would give Chinese traditional treatment (13.01%). In addition, the difficulties the GPs encountered in managing included PWE rarely appearing in the community (82.93%), the community lacking corresponding medical equipment (82.11%), and GPs lacking epilepsy-related experience (73.17%). CONCLUSION: The awareness and attitudes of GPs toward epilepsy in the CHCs were suboptimal. General practitioners age, professional title, length of service, and educational background influenced awareness and attitudes toward PWE. Effective public intervention programs, epilepsy training based on National Guidelines, and referral routes need to improve in China to enhance the care of PWE.

HMGB1: a potential new target for tendinopathy treatment.

Tendinopathy describes a complex pathology of the tendon characterized by abnormalities in the microstructure, composition, and cellularity of the tendon, leading to pain, limitation of activity and reduced function. Nevertheless, the mechanism of tendinopathy has not been fully elucidated, and the treatment of tendinopathy remains a challenge. High mobility group box 1 (HMGB1), a highly conserved and multifaceted nuclear protein, exerts multiple roles and high functional variability and is involved in many biological and pathological processes. In recent years, several studies have suggested that HMGB1 is associated with tendinopathy and may play a key role in the pathogenesis of tendinopathy. Therefore, this review summarizes the expression and distribution of HMGB1 in tendinopathy, focuses on the roles of HMGB1 and HMGB1-based potential mechanisms involved in tendinopathy, and finally summarizes the findings on HMGB1-based therapeutic approaches in tendinopathy, probably providing new insight into the mechanism and further potential therapeutic targets of tendinopathy.

The Regulation of the AMPK/mTOR Axis Mitigates Tendon Stem/Progenitor Cell Senescence and Delays Tendon Aging.

Age-related tendon disorders are closely linked with tendon stem/progenitor cell (TSPC) senescence. However, the underlying mechanisms of TSPC senescence and promising therapeutic strategies for rejuvenation of TSPC senescence remain unclear. In this study, the senescent state of TSPCs increased with age. It was also verified that the AMPK inhibition/mTOR activation is correlated with the senescent state of TSPCs. Furthermore, a low dose of metformin mitigated TSPC senescence and restored senescence-related functions, including proliferation, colony-forming ability, migration ability and tenogenic differentiation ability at the early stage of aging. The protective effects of metformin on TSPCs were regulated through the AMPK/mTOR axis. An in vivo study showed that metformin treatment postpones tendon aging and enhances AMPK phosphorylation but reduces mTOR phosphorylation in a natural aging rat model. Our study revealed new insight and mechanistic exploration of TSPC senescence and proposed a novel therapeutic treatment for age-related tendon disorders by targeting the AMPK/mTOR axis at the early stage of aging.

Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells invivo.

HIV-specific chimeric antigen receptor (CAR) T-cells have been developed to target HIV-1 infected CD4+ T-cells that express HIV Env proteins. However, T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27 (3BE) CAR construct that enabled the expression of programmed cell death protein (PD-1) -blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env. Compared with T cells expressing 3BNC117-CAR alone, 3BE CAR-T cells showed greater cytotoxic activity against HIV Env+ cells with stronger proliferation capability, higher killing efficiency, and enhanced cytokine secretion in the presence of HIV Env-expressing cells. Furthermore, we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env â€‹+ â€‹cells in vivo without the occurrence of severe graft-versus-host disease (GvHD) in NSG mice. These data suggest that we have provided a feasible approach to the generation of "off-the-shelf" anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy, which can be a powerful therapeutic candidate for the functional cure of HIV.

The regulative effect and repercussion of probiotics and prebiotics on osteoporosis: involvement of brain-gut-bone axis.

Osteoporosis (OP) is a systemic disease characterized by decreased bone mass and degeneration of bone microstructure. In recent years, more and more researches have focused on the close relationship between gut microbiota (GM) and the occurrence and progression of OP, and the regulation of probiotics and prebiotics on bone metabolism has gradually become a research hotspot. Based on the influence of brain-gut-bone axis on bone metabolism, this review expounds the potential mechanisms of probiotics and prebiotics on OP from next perspectives: regulation of intestinal metabolites, regulation of intestinal epithelial barrier function, involvement of neuromodulation, involvement of immune regulation and involvement of endocrine regulation, so as to provide a novel and promising idea for the prevention and treatment of OP in the future.