The impact of digital healthcare systems on pain and body function in patients with knee joint pain: a systematic review and meta-analysis.

The digital healthcare (DH) system has recently emerged as an advanced rehabilitation approach that promotes rehabilitation training based on virtual reality (VR) and augmented reality (AR). The purpose of this meta-analysis study is to review and assess the impact of DH systems on pain and physical function among patients diagnosed with knee joint pain. Between January 2003 and September 2023, studies that met the listed inclusion criteria were gathered from Scopus, PubMed, Web of Science, and EBSCO databases. The analysis of standardized mean difference (SMD) was carried out with 95% confidence interval (95% CI) (PROSPERO registration number: CRD42023462538). Eight research papers were selected, which collectively involved 194 males and 279 females. The meta-analysis outcomes revealed that DH intervention significantly improved balance (SMD, 0.41 [0.12, 0.69], p < 0.05) and pain level (SMD, - 1.10 [- 2.02, - 0.18], p < 0.05). The subgroup analysis of the pain level showed varied outcomes for the TKA (SMD, - 0.22 [- 0.49, 0.04], p = 0.10) or OA patients (SMD, - 2.80 [- 3.83, - 1.78], p < 0.05) Next, this study found no significant effect of DH intervention on knee joint range of motion (ROM) (SMD, 0.00 [- 0.76, 0.76], p = 1.00) and walking velocity (SMD, 0.04 [- 0.22, 0.29], p = 0.77) in patients with knee joint pain. The meta-analysis review conducted in this study revealed that DH intervention may potentially improve balance among the patients with knee joint pain. It may also alleviate the pain level particularly among OA patients.

The Effects of Combined Exercise with Citrulline Supplementation on Body Composition and Lower Limb Function of Overweight Older Adults: A Systematic Review and Meta-Analysis.

The combined exercise with citrulline (CIT) supplementation is a potential adjuvant treatment approach to address the declining body composition and lower limb function of overweight older adults. However, research on this approach is limited. Thus, this study performed a meta-analysis review to explore the effects of combined exercise with CIT supplementation on body composition and lower limb function among overweight older adults. The search strategy and manuscript development of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Eligible studies were first searched through four databases (Web of Science, Scopus, PubMed, and EBSCO) from January 2003 until April 2023, followed by screening. The main inclusion criteria for the article selection are as follows: 1) Randomized Controlled Trial studies; 2) Participants aged over 55; 3) Studies involved exercise with CIT supplementation for the experimental group and exercise with Placebo (PLA) supplementation for the control group; 4) Body composition and lower limb function were measured at pre- and post-intervention. Subsequently, the Cochrane risk of bias assessment tool was utilized to evaluate the selected studies' quality. The Standardized Mean Difference (SMD) was chosen as the suitable effect scale index, and the mean differences of the data from the selected articles were analyzed using Revman 5.4 software with a 95% Confidence Interval (CI). A total of seven studies fulfilled the inclusion criteria and were selected for the meta-analysis. The included studies involved 105 males and 198 females, where 157 belonged to the PLA group and 146 from the CIT group. Significant improvements were observed among overweight older adults with CIT supplementation in 6-Minute Walking Test (6MWT) (P = 0.04, I2 = 4%), SMD (95% CI) = -0.28 (-0.54, -0.01), and Lower Limb Strength (LLS) (P < 0.01, I2 = 30%), SMD (95% CI) = -0.38 (-0.65, -0.12) compared to those with PLA supplementation. Combined exercise with CIT supplementation could be an effective non-pharmaceutical intervention to improve the physical function of overweight older adults by increasing their muscle strength.

Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis.

OBJECTIVE: The pathogenesis of sepsis is complex, and the sepsis-induced systemic proinflammatory phase is one of the key drivers of organ failure and consequent mortality. Akkermansia muciniphila (AKK) is recognised as a functional probiotic strain that exerts beneficial effects on the progression of many diseases; however, whether AKK participates in sepsis pathogenesis is still unclear. Here, we evaluated the potential contribution of AKK to lethal sepsis development. DESIGN: Relative abundance of gut microbial AKK in septic patients was evaluated. Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) injection were employed to establish sepsis in mice. Non-targeted and targeted metabolomics analysis were used for metabolites analysis. RESULTS: We first found that the relative abundance of gut microbial AKK in septic patients was significantly reduced compared with that in non-septic controls. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably reduced sepsis-induced mortality in sepsis models. Metabolomics analysis and germ-free mouse validation experiments revealed that live AKK was able to generate a novel tripeptide Arg-Lys-His (RKH). RKH exerted protective effects against sepsis-induced death and organ damage. Furthermore, RKH markedly reduced sepsis-induced inflammatory cell activation and proinflammatory factor overproduction. A mechanistic study revealed that RKH could directly bind to Toll-like receptor 4 (TLR4) and block TLR4 signal transduction in immune cells. Finally, we validated the preventive effects of RKH against sepsis-induced systemic inflammation and organ damage in a piglet model. CONCLUSION: We revealed that a novel tripeptide, RKH, derived from live AKK, may act as a novel endogenous antagonist for TLR4. RKH may serve as a novel potential therapeutic approach to combat lethal sepsis after successfully translating its efficacy into clinical practice.

Effect of high-intensity interval training on aerobic capacity and fatigue among patients with prostate cancer: a meta-analysis.

OBJECTIVE: This study focused on evaluating whether high-intensity interval training (HIIT) had an effect on aerobic capacity and fatigue among patients with prostate cancer (PCa) and exploring its effect on the immune system of PCa patients. METHODS: To investigate the potential effect of HIIT on patients with prostate cancer, a meta-analysis was carried out. From January 2012 to August 2022, studies that met predefined criteria were searched in the Scopus, PubMed, Web of Science, and EBSCO databases. Analysis of the standardized mean differences was performed using Review Manager 5.4.1 software with a 95% confidence interval. RESULTS: This review examined a total of 6 articles. There were 215 male patients with PCa involved, and the mean age was 64.4 years. According to the results of the meta-analysis, the HIIT group (n = 63) had greater VO2peak (P<0.01) than the control group (CON) (n = 52) (P = 0.30, I2 = 19% in the heterogeneity test; MD, 1.39 [0.50, 2.27]). Moreover, fatigue was significantly different (P<0.01) between the HIIT (n = 62) and CON (n = 61) groups (P = 0.78, I2 = 0% in the heterogeneity test; SMD, -0.52 [-0.88, -0.16]). Furthermore, among PCa patients, HIIT showed higher efficacy (P < 0.01) in decreasing PSA than the CON regimen (P=0.22, I2 = 34% in the heterogeneity test; MD, -1.13 [-1.91, -0.34]). CONCLUSIONS: HIIT improves aerobic capacity, fatigue, and PSA levels among PCa patients but does not significantly affect IL-6 or TNF-α content. Therefore, HIIT may be a novel and potent intervention scheme for PCa patients.

A critical review on retaining antibiotics in liquid digestate: Potential risk and removal technologies.

Substantial levels of antibiotics remain in liquid digestate, posing a significant threat to human safety and the environment. A comprehensive assessment of residual antibiotics in liquid digestate and related removal technologies is required. To this end, this review first evaluates the potential risks of the residual antibiotics in liquid digestate by describing various anaerobic digestion processes and their half-lives in the environment. Next, emerging technologies for removing antibiotics in liquid digestate are summarized and discussed, including membrane separation, adsorption, and advanced oxidation processes. Finally, this study comprehensively and critically discusses these emerging technologies' prospects and challenges, including techno-economic feasibility and environmental impacts.

TLR7 modulating B-cell immune responses in the spleen of C57BL/6 mice infected with Schistosoma japonicum.

B cells played an important role in Schistosoma infection-induced diseases. TLR7 is an intracellular member of the innate immune receptor. The role of TLR7 on B cells mediated immune response is still unclear. Here, C57BL/6 mice were percutaneously infected by S. japonicum for 5-6 weeks. The percentages and numbers of B cells increased in the infected mice (p < 0.05), and many activation and function associated molecules were also changed on B cells. More splenic cells of the infected mice expressed TLR7, and B cells were served as the main cell population. Moreover, a lower level of soluble egg antigen (SEA) specific antibody and less activation associated molecules were found on the surface of splenic B cells from S. japonicum infected TLR7 gene knockout (TLR7 KO) mice compared to infected wild type (WT) mice (p < 0.05). Additionally, SEA showed a little higher ability in inducing the activation of B cells from naive WT mice than TLR7 KO mice (p < 0.05). Finally, the effects of TLR7 on B cells are dependent on the activation of NF-κB p65. Altogether, TLR7 was found modulating the splenic B cell responses in S. japonicum infected C57BL/6 mice.

Ikzf2 Regulates the Development of ICOS+ Th Cells to Mediate Immune Response in the Spleen of S. japonicum-Infected C57BL/6 Mice.

Background: Th cells (helper T cells) have multiple functions in Schistosoma japonicum (S. japonicum) infection. Inducible co-stimulator (ICOS) is induced and expressed in activated T lymphocytes, which enhances the development of B cells and antibody production through the ICOS/ICOSL pathway. It remains unclear about the role and possible regulating mechanism of ICOS+ Th cells in the spleen of S. japonicum-infected C57BL/6 mice. Methods: C57BL/6 mice were infected with cercariae of S. japonicum through the abdomen. The expression of ICOS, activation markers, and the cytokine production on CD4+ ICOS+ Th cells were detected by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR). Moreover, the differentially expressed gene data of ICOS+ and ICOS- Th cells from the spleen of infected mice were obtained by mRNA sequencing. Besides, Western blot and chromatin immunoprecipitation (ChIP) were used to explore the role of Ikzf2 on ICOS expression. Results: After S. japonicum infection, the expression of ICOS molecules gradually increased in splenic lymphocytes, especially in Th cells (P < 0.01). Compared with ICOS- Th cells, more ICOS+ Th cells expressed CD69, CD25, CXCR5, and CD40L (P < 0.05), while less of them expressed CD62L (P < 0.05). Also, ICOS+ Th cells expressed more cytokines, such as IFN-γ, IL-4, IL-10, IL-2, and IL-21 (P < 0.05). RNA sequencing results showed that many transcription factors were increased significantly in ICOS+ Th cells, especially Ikzf2 (P < 0.05). And then, the expression of Ikzf2 was verified to be significantly increased and mainly located in the nuclear of ICOS+ Th cells. Finally, ChIP experiments and dual-luciferase reporter assay confirmed that Ikzf2 could directly bind to the ICOS promoter in Th cells. Conclusion: In this study, ICOS+ Th cells were found to play an important role in S. japonicum infection to induce immune response in the spleen of C57BL/6 mice. Additionally, Ikzf2 was found to be one important transcription factor that could regulate the expression of ICOS in the spleen of S. japonicum-infected C57BL/6 mice.

Interferon Regulatory Factor 4 Regulates the Development of Polymorphonuclear Myeloid-Derived Suppressor Cells Through the Transcription of c-Myc in Cancer.

The accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles to achieve an appropriate anti-tumor immune response and successful tumor immunotherapy. MDSCs in tumor-bearing hosts are primarily polymorphonuclear (PMN-MDSCs). However, the mechanisms regulating the development of MDSCs remain poorly understood. In this report, we showed that interferon regulatory factor 4 (IRF4) plays a key role in the development of PMN-MDSCs, but not monocytic MDSCs. IRF4 deficiency caused a significant elevation of PMN-MDSCs and enhanced the suppressive activity of PMN-MDSCs, increasing tumor growth and metastasis in mice. Mechanistic studies showed that c-Myc was up-regulated by the IRF4 protein. Over-expression of c-Myc almost abrogated the effects of IRF4 deletion on PMN-MDSCs development. Importantly, the IRF4 expression level was negatively correlated with the PMN-MDSCs frequency and tumor development but positively correlated with c-Myc expression in clinical cancer patients. In summary, this study demonstrated that IRF4 represents a novel regulator of PMN-MDSCs development in cancer, which may have predictive value for tumor progression.

Characterization of γδT cells in lung of Plasmodium yoelii-infected C57BL/6 mice.

BACKGROUND: Malaria has high morbidity and mortality rates in some parts of tropical and subtropical countries. Besides respiratory and metabolic function, lung plays a role in immune system. γδT cells have multiple functions in producing cytokines and chemokines, regulating the immune response by interacting with other cells. It remains unclear about the role of γδT cells in the lung of mice infected by malaria parasites. METHODS: Flow cytometry (FCM) was used to evaluate the frequency of γδT cells and the effects of γδT cells on the phenotype and function of B and T cells in Plasmodium yoelii-infected wild-type (WT) or γδTCR knockout (γδT KO) mice. Haematoxylin-eosin (HE) staining was used to observe the pathological changes in the lungs. RESULTS: The percentage and absolute number of γδT cells in the lung increased after Plasmodium infection (p < 0.01). More γδT cells were expressing CD80, CD11b, or PD-1 post-infection (p < 0.05), while less γδT cells were expressing CD34, CD62L, and CD127 post-infection (p < 0.05). The percentages of IL-4+, IL-5+, IL-6+, IL-21+, IL-1α+, and IL-17+ γδT cells were increased (p < 0.05), but the percentage of IFN-γ-expressing γδT cells decreased (p < 0.05) post-infection. The pathological changes in the lungs of the infected γδT KO mice were not obvious compared with the infected WT mice. The proportion of CD3+ cells and absolute numbers of CD3+ cells, CD3+ CD4+ cells, CD3+ CD8+ cells decreased in γδT KO infected mice (p < 0.05). γδT KO infected mice exhibited no significant difference in the surface molecular expression of T cells compared with the WT infected mice (p > 0.05). While, the percentage of IFN-γ-expressing CD3+ and CD3+ CD8+ cells increased in γδT KO infected mice (p < 0.05). There was no significant difference in the absolute numbers of the total, CD69+, ICOS+, and CD80+ B cells between the WT infected and γδT KO infected mice (p > 0.05). CONCLUSIONS: The content, phenotype, and function of γδT cells in the lung of C57BL/6 mice were changed after Plasmodium infection. γδT cells contribute to T cell immune response in the progress of Plasmodium infection.

Properties and Roles of γδT Cells in Plasmodium yoelii nigeriensis NSM Infected C57BL/6 Mice.

BACKGROUND: Many kinds of immune cells are involved in malaria infection. γδT cells represent a special type of immune cell between natural and adaptive immune cells that play critical roles in anti-parasite infection. METHODS: In this study, malaria infection model was constructed. Distribution of γδT cells in various immune organs and dynamic changes of γδT cells in the spleens of C57BL/6 mice after infection were detected by flow cytometry. And activation status of γδT cells was detected by flow cytometry. Then γδT cells in naive and infected mice were sorted and performed single-cell RNA sequencing (scRNA-seq). Finally, γδTCR KO mice model was constructed and the effect of γδT cell depletion on mouse T and B cell immunity against Plasmodium infection was explored. RESULTS: Here, splenic γδT cells were found to increase significantly on day 14 after Plasmodium yoelii nigeriensis NSM infection in C57BL/6 mice. Higher level of CD69, ICOS and PD-1, lower level of CD62L, and decreased IFN-γ producing after stimulation by PMA and ionomycin were found in γδT cells from infected mice, compared with naive mice. Moreover, 11 clusters were identified in γδT cells by scRNA-seq based t-SNE analysis. Cluster 4, 5, and 7 in γδT cells from infected mice were found the expression of numerous genes involved in immune response. In the same time, the GO enrichment analysis revealed that the marker genes in the infection group were involved in innate and adaptive immunity, pathway enrichment analysis identified the marker genes in the infected group shared many key signalling molecules with other cells or against pathogen infection. Furthermore, increased parasitaemia, decreased numbers of RBC and PLT, and increased numbers of WBC were found in the peripheral blood from γδTCR KO mice. Finally, lower IFN-γ and CD69 expressing CD4+ and CD8+ T cells, lower B cell percentage and numbers, and less CD69 expressing B cells were found in the spleen from γδTCR KO infected mice, and lower levels of IgG and IgM antibodies in the serum were also observed than WT mice. CONCLUSIONS: Overall, this study demonstrates the diversity of γδT cells in the spleen of Plasmodium yoelii nigeriensis NSM infected C57BL/6 mice at both the protein and RNA levels, and suggests that the expansion of γδT cells in cluster 4, 5 and 7 could promote both cellular and humoral immune responses.

Adjustments of γδ T Cells in the Lung of Schistosoma japonicum-Infected C56BL/6 Mice.

Many kinds of lymphocytes are involved in Schistosoma japonicum (S. japonicum) infection-induced disease. γδ T cells comprise a small number of innate lymphocytes that quickly respond to foreign materials. In this study, the role of γδ T cells in the lung of S. japonicum-infected C56BL/6 mice was investigated. The results demonstrated that S. japonicum infection induces γδ T cell accumulation in the lung, expressing higher levels of CD25, MHCII, CD80, and PDL1, and lower levels of CD127 and CD62L (P < 0.05). The intracellular cytokines staining results illustrated higher percentages of IL-4-, IL-10-, IL-21-, and IL-6-producing γδ T cells and lower percentages of IFN-γ-expressing γδ T cells in the lung of infected mice (P < 0.05). Moreover, the granuloma size in lung tissue was significantly increased in Vδ-/- mice (P < 0.05). In the lung of S. japonicum-infected Vδ-/- mice, both type 1 and type 2 immune responses were decreased significantly (P < 0.05). In addition, the expression of CD80 and CD69 on B cells was decreased significantly (P < 0.05), and the SEA-specific antibody was markedly decreased (P < 0.05) in the blood of infected Vδ-/- mice. In conclusion, this study indicates that γδ T cells could adjust the Th2 dominant immune response in the lung of S. japonicum-infected mice.

Changes of CD103-expressing pulmonary CD4+ and CD8+ T cells in S. japonicum infected C57BL/6 mice.

BACKGROUND: Recent studies have shown that CD103 is an important marker for tissue-resident memory T cells (TRM) which plays an important role in anti-infection. However, the role of CD103+ TRM was not elucidated in the progress of S. japonicum infection induced disease. METHODS: 6-8 weeks old C57BL/6 mice were infected by S. japonicum. Mice were sacrificed and the lungs were removed 5-6 weeks after infection. Immunofluorescent staining and Q-PCR were performed to identify the expression of CD103 molecule. Single cellular populations were made, percentages of CD103 on both CD4+ and CD8+ T lymphocytes were dynamical observed by flow cytometry (FCM). Moreover, the expression of memory T cells related molecules CD69 and CD62L, T cell function associated molecules CD107a, IFN-γ, IL-4, IL-9, and IL-10 were compared between CD103+ CD4+ and CD8+ T cells by FCM. RESULTS: CD103+ cells were emerged in the lung of both naive and S. japonicum infected mice. Both the percentage and the absolute numbers of pulmonary CD4+ and CD8+ cells were increased after S. japonicum infection (P < 0.05). The percentage of CD103+ cells in CD8+ T cells decreased significantly at the early stage of S. japonicum infection (P < 0.05). Increased CD69, decreased CD62L and CD107a expressions were detected on both CD4+ and CD8+ CD103+ T cells in the lungs of infected mice (P < 0.05). Compared to CD8+ CD103+ T cells, CD4+ CD103+ T cells from infected mice expressed higher level of CD69 and lower level CD62L molecules (P < 0.05). Moreover, higher percentage of IL-4+, IL-9+ and IL-10+ cells on CD4+ CD103+ pulmonary T cells was found in infected mice (P < 0.05). Significantly increased IL-4 and IL-9, and decreased IFN-γ expressing cells were detected in CD8+CD103+ cells of infected mice (P < 0.05). CONCLUSIONS: CD103-expressing pulmonary CD4+ and CD8+ T cells play important roles in mediating S. japonicum infection induced granulomatous inflammation in the lung.

Schistosoma japonicum Infection Promotes the Response of Tfh Cells Through Down-Regulation of Caspase-3-Mediating Apoptosis.

CD4+ T follicular helper (Tfh) cells, a new subset of immune cells, have been demonstrated to be involved in granulomatous responses to Schistosoma japonicum (S. japonicum) infection. However, the role and underlying mechanisms of Tfh cell aggregation in S. japonicum infection remain incompletely understood. In this study, we provide evidence that S. japonicum infection enhances the accumulation of Tfh cells in the spleen, lymph nodes, and peripheral blood of C57BL/6 mice. Infection-induced Tfh cells exhibited more potent effects directly on B cell responses than the control Tfh cells (P < 0.05). Furthermore, reduced apoptosis of Tfh cells was found both in S. japonicum infected mice and in soluble egg antigen (SEA) treated Tfh cells (P < 0.05). Mechanistic studies reveal that caspase-3 is the primary drivers of down-regulated apoptotic Tfh cell death in S. japonicum infection. In summary, this study demonstrates that Tfh cell accumulation might have an impact on the generation of immune responses in S. japonicum infection, and caspase-3 signaling mediated apoptosis down-regulation might responsible for the accumulation of Tfh cell in this course.

TLR7 Modulated T Cell Response in the Mesenteric Lymph Node of Schistosoma japonicum-Infected C57BL/6 Mice.

Toll-like receptors (TLRs) play an important role in regulating immune responses during pathogen infection. However, roles of TLRs on T cells reside in the mesenteric lymph node (MLN) were not be fully elucidated in the course of S. japonicum infection. In this study, T lymphocytes from the mesenteric lymph node (MLN) of S. japonicum-infected mice were isolated and the expression and roles of TLR2, TLR3, TLR4, and TLR7 on both CD4+ and CD8+ T cells were compared. We found that the expression of TLR7 was increased in the MLN cells of S. japonicum-infected mice, particularly in CD4+ and CD8+ T cells (P < 0.05). R848, a TLR7 agonist, could enhance the production of IFN-γ from MLN T cells of infected mice (P < 0.05), especially in CD8+ T cells (P < 0.01). In TLR7 gene knockedout (KO) mice, the S. japonicum infection caused a significant decrease (P < 0.05) of the expression of CD25 and CD69, as well as the production of IFN-γ and IL-4 inducted by PMA plus ionomycin on both CD4+ and CD8+ T cells. Furthermore, the decreased level of IFN-γ and IL-4 in the supernatants of SEA- or SWA-stimulated mesenteric lymphocytes was detected (P < 0.05). Our results indicated that S. japonicum infection could induce the TLR7 expression on T cells in the MLN of C57BL/6 mice, and TLR7 mediates T cell response in the early phase of infection.