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Abstract Background Stroke is the leading cause of death in middle-aged and elderly people in China. Insulin resistance (IR) and sarcopenia are both closely associated with metabolic diseases. However, the relationship between these two indicators and stroke has not been fully investigated. The aim of this study was to investigate the relationship between IR and sarcopenia and the risk of new-onset stroke. Methods Using longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018, Cox proportional hazards models were used to determine the association between IR surrogate indicators and sarcopenia status with stroke incidence. Results In the present study, during a median 7 years of follow-up, we included 7009 middle-aged and elderly residents, of whom 515 presented with stroke incidence. After adjustment for potential confounders, both baseline IR surrogates and sarcopenia independently predicted stroke risk. In addition, co-morbidities had a higher risk of stroke than other groups. The positive association between TyG-WC and sarcopenia on stroke risk was particularly significant [HR (95% CI): 2.03 (1.52, 2.70)]. In subgroups of different ages and sexes, the combination of IR and sarcopenia is associated with the highest risk of stroke. Conclusions We found that IR and sarcopenia synergistically increase the incidence of stroke in older adults. This finding provides new perspectives for stroke detection and intervention and highlights the importance of early detection and management of IR and sarcopenia in older adults.

ObjectiveThe correlation between surrogate insulin resistance (IR) indices and sarcopenic obesity (SO) remains uncertain. This study aimed to assess the association between six IR surrogates—triglyceride-glucose (TyG), TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), triglyceride-to-high-density lipoprotein-cholesterol ratio (TG/HDL), metabolic score for insulin resistance (METS-IR), and Chinese visceral adiposity index (CVAI)—and SO risk in a middle-aged and older population in China.MethodsThe study employed longitudinal data obtained from the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2015, involving 6,395 participants. We used multivariate logistic regression models to examine the link between six surrogates and SO. Nonlinear relationships were evaluated using restricted cubic spline analysis, and subgroup analyses were conducted for validation. Receiver operating characteristic (ROC) curves were used to assess predictive capabilities.ResultsOver the course of a 4-year follow-up period, 319 participants (5.0%) developed SO. In the fully adjusted model, all six surrogates were significantly associated with SO. The adjusted odds ratios (ORs) with a 95% confidence interval (95% CI) per standard deviation increase were 1.21 (1.08–1.36) for TyG, 1.56 (1.39–1.75) for TyG-WC, 2.04 (1.81–2.31) for TyG-WHtR, 1.11 (1.01–1.21) for TG/HDL, 1.67 (1.50–1.87) for METS-IR, and 1.74 (1.55–1.97) for CVAI. Notably, TyG-WC, TyG-WHtR, TG/HDL, METS-IR, and CVAI exhibited nonlinear correlations with SO. Conversely, TG/HDL did not exhibit a significant association during subgroup analysis. Furthermore, TyG-WHtR had a significantly larger area under the receiver operating characteristic curve than other indices.ConclusionThe results indicated that TyG, TyG-WC, TyG-WHtR, METS-IR, and CVAI were significantly and positively associated with SO incidence. Meanwhile, TyG-WC, TyG-WHtR, METS-IR, and CVAI showed nonlinear relationships with SO. Specifically, TyG-WHtR may be the most appropriate indicator for predicting SO among middle-aged and older Chinese adults.

BackgroundResearch has demonstrated that sarcopenia and visceral obesity are significant risk factors for chronic disease in middle-aged and older adults. However, the relationship between sarcopenia, the cardiac metabolic index (CMI), a novel measure of visceral obesity, and cardiometabolic multimorbidity (CMM) remains unclear. In this study, data from the China Longitudinal Study of Health and Retirement (CHARLS) were analyzed to investigate the association between sarcopenia and CMI with CMM in the middle-aged and older adult population.MethodsThe study included 4,959 participants aged 45 and over. Sarcopenia was defined using the criteria of the Asian Sarcopenia Working Group 2019. CMM is defined as having two or more of the following conditions: physician-diagnosed heart disease, diabetes, stroke, and/or hypertension. CMI was calculated using the formula: CMI = (TG/HDL-C) × WHtR. To explore the association between CMI and sarcopenia and CMM, cox proportional risk regression models were used.ResultsThe median age of all participants was 57 years, with 47.1% being male. Over the 8-year follow-up, 1,362 individuals developed CMM. The incidence of CMM was 8.7/1,000 person-years in the group without sarcopenia or high CMI, 17.37/1,000 person-years in those with high CMI, 14.22/1,000 person-years in the sarcopenia group, and 22.34/1,000 person-years in the group with both conditions. After adjusting for covariates, the group with both sarcopenia and high CMI had a significantly increased risk of CMM (HR 2.48, 95% CI 1.12-5.51) and heart disease (HR 2.04, 95% CI 1.05-3.98). Among those over 65 years, sarcopenia was discovered to be associated with an increased risk of CMM [HR (95% CI: 4.83 (1.22, 19.06)]. The risk of CMM was further increased to 7.31-fold (95% CI:1.72, 31.15) when combined with high CMI.ConclusionsThe combination of sarcopenia and high CMI is associated with an increased risk of developing CMM. Early identification and intervention of sarcopenia and CMI not only enable the development of targeted therapeutic strategies but also provide potential opportunities to reduce the morbidity and mortality of CMM.

ABSTRACTObjective To identify biomarkers that can predict the recurrence of the central nervous system (CNS) in children with acute lymphoblastic leukemia (ALL).Materials and Methods The transcriptome and clinical data of ALL in children were downloaded from the TARGET database. Transcriptome data were analyzed by bioinformatics method to identify core (hub) genes and establish a risk assessment model. Univariate Cox analysis was performed on each clinical data, and multivariate Cox regression analysis was performed on the obtained results and risk score. The children ALL phase I samples from TARGET database were used for validation.Results Univariate multivariate Cox analysis of 10 hub genes identified showed that PPARG (HR = 0.78, 95%CI = 0.67–0.91, p = 0.007), CD19 (HR = 1.15, 95%CI = 1.05–1.26, p = 0.003) and GNG12 (HR = 1.25, 95%CI = 1.04–1.51, p = 0.017) had statistical differences. The risk score was statistically significant in univariate (HR = 3.06, 95%CI = 1.30–7.19, p = 0.011) and multivariate (HR = 1.81, 95%CI = 1.16–2.32, p = 0.046) Cox regression analysis. The survival analysis results of the high and low-risk groups were different when the validation dataset was substituted into the model (p = 0.018). Then, we constructed a Nomogram which had a concordance index of survival prediction of 0.791(95%CI= 0.779-0.803). In addition, the CNS involvement grading status at first diagnosis CNS3 vs. CNS1 (HR = 5.74, 95%CI = 2.01–16.4, p = 0.001), T cell vs B cell (HR = 1.63, 95% CI = 1.06-2.49, p = 0.026) were also statistically significant.Conclusions PPARG, GNG12, and CD19 may be predictors of CNS relapse in childhood ALL.

Over recent years, C-X-C motif ligand 7 (CXCL7) has received widespread attention as a chemokine involved in inflammatory responses. Abnormal production of the chemokine CXCL7 has been identified in different inflammatory diseases; nevertheless, the exact role of CXCL7 in the pathogenesis of inflammatory diseases is not fully understood. Persistent infection or chronic inflammation can induce tumorigenesis and progression. Previous studies have shown that the pro-inflammatory chemokine CXCL7 is also expressed by malignant tumor cells and that binding of CXCL7 to its cognate receptors C-X-C chemokine receptor 1 (CXCR1) and C-X-C chemokine receptor 2 (CXCR2) can influence tumor biological behavior (proliferation, invasion, metastasis, and tumor angiogenesis) in an autocrine and paracrine manner. CXCL7 and its receptor CXCR1/CXCR2, which are aberrantly expressed in tumors, may represent new targets for clinical tumor immunotherapy.

Heavy metal (HM) exposure remains a global occupational and environmental problem that creates a hazard to general health. Even low-level exposure to toxic metals contributes to the pathogenesis of various metabolic and immunological diseases, whereas, in this process, the gut microbiota serves as a major target and mediator of HM bioavailability and toxicity. Specifically, a picture is emerging from recent investigations identifying specific probiotic species to counteract the noxious effect of HM within the intestinal tract via a series of HM-resistant mechanisms. More encouragingly, aided by genetic engineering techniques, novel HM-bioremediation strategies using recombinant microorganisms have been fruitful and may provide access to promising biological medicines for HM poisoning. In this review, we summarized the pivotal mutualistic relationship between HM exposure and the gut microbiota, the probiotic-based protective strategies against HM-induced gut dysbiosis, with reference to recent advancements in developing engineered microorganisms for medically alleviating HM toxicity.

Although major advances have been achieved in the treatment of chronic myeloid leukemia (CML) by using tyrosine kinase inhibitors, patients relapse after withdrawal and need long-term medication. This reflects the CML clones have not been eliminated completely. The precise mechanisms for the maintenance of CML cells are not yet fully understood. The bone marrow microenvironment constitutes the sanctuary for leukemic cells. Mesenchymal stem cells (MSC) are an important component of the bone marrow microenvironment (BM). It plays an important role in the development and drug resistance of CML. Accumulating evidence indicates that exosomes play a vital role in cell-to-cell communication. We successfully isolated and purified exosomes from human bone marrow microenvironment-derived mesenchymal stem cells (hBMMSC-Exo) by serial centrifugation. In the present study, we investigated the effect of hBMMSC-Exo on the proliferation, apoptosis, and drug resistance of CML cells. The results demonstrated that hBMMSC-Exo had the ability to inhibit the proliferation of CML cells in vitro via miR-15a and arrest cell cycle in the G0/G1 phase. However, the results obtained from BALB/c nu/nu mice studies apparently contradicted the in vitro results. In fact, hBMMSC-Exo increased tumor incidence and promoted tumor growth in vivo. Further study showed the antiapoptotic protein Bcl-2 expression increased, whereas the Caspase3 expression decreased. Moreover, the in vivo study in the xenograft tumor model showed that hBMMSC-Exo promoted the proliferation and decreased the sensitivity of CML cells to tyrosine kinase inhibitors, resulting in drug resistance. These results demonstrated that hBMMSC-Exo supported the maintenance of CML cells and drug resistance in BM by cell-extrinsic protective mechanisms. They also suggested that hBMMSC-Exo might be a potential target to overcome the microenvironment-mediated drug resistance.

Mesenchymal stem cells (MSCs) are ubiquitously present in many tissues. Due to their unique advantages, MSCs have been widely employed in clinical studies. Emerging evidences indicate that MSCs can also migrate to the tumor surrounding stroma and exert complex effects on tumor growth and progression. However, the effect of MSCs on tumor growth is still a matter of debate. Several studies have shown that MSCs could favor tumor growth. On the contrary, other groups have demonstrated that MSCs suppressed tumor progression. Extracellular vesicles have emerged as a new mechanism of cell-to-cell communication in the development of tumor diseases. MSCs-derived extracellular vesicles (MSC-EVs) could mimic the effects of the mesenchymal stem cells from which they originate. Different studies have reported that MSC-EVs may exert various effects on the growth, metastasis, and drug response of different tumor cells by transferring proteins, messenger RNA, and microRNA to recipient cells. In the present review, we summarize the components of MSC-EVs and discuss the roles of MSC-EVs in different malignant diseases, including the related mechanisms that may account for their therapeutic potential. MSC-EVs open up a promising opportunity in the treatment of cancer with increased efficacy.

The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected with E. coli. When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF-β and less IL-1, IFN-γ, and TNF-α. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.

Chronic myeloid leukemia (CML) is caused by the fusion of the BCR activator of RhoGEF and GTPase activating protein (BCR) and ABL proto-oncogene, the nonreceptor tyrosine kinase (ABL) genes. Although the tyrosine kinase inhibitors (TKIs) imatinib (IM) and nilotinib (NI) have remarkable efficacy in managing CML, the malignancies in some patients become TKI-resistant. Here, we isolated bone marrow (BM)-derived mesenchymal stem cells (MSCs) from several CML patients by Ficoll-Hypaque density-gradient centrifugation for coculture with K562 and BV173 cells with or without TKIs. We used realtime quantitative PCR to assess the level of interleukin 7 (IL-7) expression in the MSCs and employed immunoblotting to monitor protein expression in the BCR/ABL, phosphatidylinositol 3-kinase (PI3K)/AKT, and JAK/STAT signaling pathways. We also used a xenograft tumor model to examine the in vivo effect of different MSCs on CML cells. MSCs from patients with IM-resistant CML protected K562 and BV173 cells against IM- or NI-induced cell death, and this protection was due to increased IL-7 secretion from the MSCs. Moreover, IL-7 levels in the BM of patients with IM-resistant CML were significantly higher than in healthy donors or IM-sensitive CML patients. IL-7 elicited IM and NI resistance via BCR/ABL-independent activation of JAK1/STAT5 signaling, but not of JAK3/STAT5 or PI3K/AKT signaling. IL-7 or JAK1 gene knockdown abrogated IL-7-mediated STAT5 phosphorylation and IM resistance in vitro and in vivo. Because high IL-7 levels in the BM mediate TKI resistance via BCR/ABL-independent activation of JAK1/ STAT5 signaling, combining TKIs with IL-7/JAK1/STAT5 inhibition may have significant utility for managing CML. [ABSTRACT FROM AUTHOR]