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MicroRNA-125b (miR-125b) reduces myocardial infarct area and restrains myocardial ischemia reperfusion injury (I/R). In this study, we aimed to investigate the effect of bone marrow mesenchymal stem cell (BMSC)-derived exosomes carrying miR-125b on I/R rats. The myocardial I/R model in rats was constructed by ligation of the left anterior descending coronary artery (LAD). Rats were randomly divided into I/R and Sham group. Lv-cel-miR-67 (control) or Lv-miR-125b was transfected into BMSCs. Exosomes were extracted from transfected BMSCs, and separately named BMSC-Exo-67, BMSC-Exo-125b, and BMSC-Exo. MTT assay and flow cytometry were used to detect the viability and apoptosis of I/R myocardium cells, respectively. The expression of cell apoptosis proteins and the levels of inflammatory factors were examined by Western blot and ELISA assay, respectively. The target relationship between miR-125b and SIRT7 was predicted by using StarBase3.0, and was confirmed by using dual-luciferase reporter gene assay. qRT-PCR, immunohistochemistry staining, and Western blot were used to evaluate the expression of SIRT7 in myocardium tissues in I/R rats. BMSC-derived exosomes were successfully isolated and identified by TEM and positive expression of CD9 and CD63. The expression of miR-125b was down-regulated in I/R myocardium tissues and cells. BMSC-Exo-125b significantly up-regulated miR-125b in I/R myocardium cells. The intervention of BMSC-Exo-125b significantly increased the cell viability, decreased the apoptotic ratio, down-regulated Bax and caspase-3, up-regulated Bcl-2, and decreased the levels of IL-1β, IL-6, and TNF-α in I/R myocardium cells. SIRT7 was a target of miR-125b, and BMSC-Exo-125b significantly down-regulated SIRT7 in myocardium cells. In addition, the injection of BMSC-Exo-125b alleviated the pathological damages and down-regulated SIRT7 in myocardium tissues of I/R rats. BMSC-derived exosomes carrying miR-125b protected against myocardial I/R by targeting SIRT7.

Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4 + T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy. Overcoming the suppressive tumor microenvironment (TME) is crucial to improving the efficacy of cancer therapy. Here the authors show that, in mouse cancer models, administration of exogenous IL-16 establishes a Th1-dominant TME via regulation of glutamine catabolism and triggers a Th1 cell-macrophage crosstalk, enhancing anti-tumor immune responses and the efficacy of immunotherapy.

PurposeTo evaluate the potential association between the lowering of low-density lipoprotein cholesterol (LDL-C) with contemporary lipid-lowering medicines and cognitive function.MethodsRandomized controlled trials (RCTs) in databases including PubMed, Embase, and the Web of Science and all databases in the Cochrane Library and ClinicalTrials.gov were collected from inception to January 1, 2020. The cognitive function of patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, statins and ezetimibe was evaluated using meta-analysis.ResultsA total of 2910 studies were obtained from databases and other sources. Thirty-three studies were selected by screening, including 11 studies on alirocumab, 9 studies on evolocumab, 11 studies on statins and 2 studies on ezetimibe. In our study, a total of 128,691 patients with no cognitive impairment were divided into an intervention group (66,330 patients) and a control group (62,361 patients). The data were subjected to a random-effects model or a fixed-effects model for meta-analysis. The contemporary lipid-lowering medicines significantly reduced LDL-C in terms of both percentage (WMD: −45.06%, 95% CI −50.12% to −40.00%, P < 0.001) and absolute value (WMD: −64.01 mg/dL, 95% CI −72.25 to −55.78, P < 0.001). Compared with the control group, patients receiving treatment with contemporary lipid-lowering medicines did not show a significant difference in the rate of neurocognitive disorder (RR: 1.02, 95% CI 0.90 to 1.16, I2 = 0.0%, p = 0.696). Subgroup analysis was performed according to the intervention and LDL-C stratification. The result of this subgroup analysis was consistent with the main findings. Regarding global cognitive performance, no difference in major cognition was found among the pooled data (SMD: 0.02, 95% CI −0.01 to 0.04, P = 0.002), except for psychomotor speed (SMD: 0.09, 95% CI 0.02 to 0.16, P = 0.0024).ConclusionsContemporary lipid-lowering medicines were not associated with cognitive impairment in RCTs. A low LDL-C level did not influence the incidence of cognitive disorder or global cognitive performance.

Background Frailty is a common geriatric syndrome associated with many adverse health outcomes. Identifying the risk factors of frailty is crucial and the insulin resistance (IR) is considered as a potential target. The estimated glucose disposal rate (eGDR) is a simple and reliable surrogate marker of IR. Associations of eGDR with frailty have not been explored. This study aimed to investigate the associations of eGDR with frailty progression. Methods We used data from two prospective cohorts of the China Health and Retirement Longitudinal Study (CHARLS) and Health and Retirement Study (HRS). The eGDR was calculated as follows: eGDR (mg/kg/min) = 21.158 − (0.09×waist circumference) − (3.407×hypertension) − (0.551×glycosylated hemoglobin A 1c ) [waist circumference (cm), hypertension (yes = 1/no = 0), and glycosylated hemoglobin A 1c (%)]. Participants were divided into three categories by tertiles of eGDR. Frailty index (FI) was calculated every two years and used to assess the degree of frailty which ranged from 0 to 100. Frailty progression was assessed by repeated measurements of FI during follow-up. Linear mixed-effect models were used to analyze the associations of eGDR with frailty progression. Results 8872 participants from CHARLS (mean age: 58.9 years, female: 53.3%) and 5864 participants from HRS (mean age: 67.0 years, female: 59.0%) were included. The median follow-up periods were 7.0 years in the CHARLS and 12.8 years in the HRS, respectively. Compared to participants with lower tertile (T1) of eGDR, those with upper tertile (T3) of eGDR showed decelerated FI progression (CHARLS, β: -0.294, 95%CI -0.390 to -0.198, P  < 0.001; HRS, β: -0.378, 95%CI -0.474 to -0.281, P  < 0.001). Continuous eGDR was also associated with FI progression for significant deceleration in FI progression with per 1 SD increase in eGDR (CHARLS, β: -0.142, 95%CI -0.181 to -0.103, P  < 0.001; HRS, β: -0.170, 95%CI -0.209 to -0.130, P  < 0.001). These associations were still observed after excluding baseline frail participants. Furthermore, the associations of eGDR with FI progression were consistent among participants with and without diabetes. Conclusion Regardless of diabetes or not, a higher level of eGDR was associated with the decelerated frailty progression. Our findings highlight the role of eGDR in frailty progression and recommend taking effective interventions to improve eGDR for preventing frailty progression. Graphical abstract The estimated glucose disposal rate and frailty progression. CHARLS, China Health and Retirement Longitudinal Study; HRS, Health and Retirement Study; eGDR, the estimated glucose disposal rate; FI, frailty index.

An active lifestyle protects against cardiovascular diseases, yet its mechanisms in modulating the cardiac immune environment and preserving cardiac function remain unclear. Here, we identify a subpopulation of monocyte-derived cardiac macrophages, termed iNOS + Arg1 + macrophages, which simultaneously express pro-inflammatory and pro-reparative genes in exercised male mice. Inhibiting either pro-inflammatory iNOS or pro-reparative Arg1 in these macrophages counters the exercise-induced cardiac function preservation. Mechanistically, exercise enhances glycolysis in monocytes, increasing lactate production and driving histone lactylation at H3K18, mediated by p300 as the relevant lactyltransferase and counterbalanced by HDAC2 as deacetylase. H3K18la accelerates the transition of cardiac macrophages to a pro-reparative state, restoring immune homeostasis and preserving cardiac function. Notably, human monocytes from physically active individuals exhibit elevated levels of Pan-Kla and H3K18la compared to those from sedentary individuals. Importantly, adoptive transfer of highly histone-lactylated monocytes restores cardiac function in sepsis-induced cardiomyopathy, which might translate into a promising therapeutic strategy for cardiomyopathy. Active lifestyle has considerable cardiac health benefits, but the metabolic and immunological background need further investigation. Here the authors show that a cardiac macrophage population, characterised by simultaneous pro-inflammatory and reparative properties, accumulate upon exercise, and these cells restore cardiac health upon transfer in a mouse model of sepsis-induced cardiomyopathy.

Myocardial infarction (MI) is the leading cause of death worldwide. Exogenous delivery of nitric oxide (NO) shows great potential in MI treatment. However, the burst generation of reactive oxygen species (ROS) in ischemic microenvironment of MI oxidize NO to harmful peroxynitrite (ONOO − ). It renders secondary damage to cardiomyocyte, causing the failure of NO based therapies. Herein, we proposed an ROS responsive peptide-drug conjugates (PDCs) to overcome the dilemma of NO based therapy. The conjugated cardiac injury targeting peptide (CTP) in the PDC (named CTP-PBA-ISN) promoted selective accumulation of drugs in MI sites. Besides, controlled release of NO prodrug isosorbide mononitrate (ISN) was achieved by pathological ROS triggered hydrolysis of boronate ester. Meanwhile the antioxidant byproduct 4-hydroxybenzyl alcohol further scavenges the overwhelming ROS, reducing the production of RNS and improving the bioavailability of NO. The CTP-PBA-ISN efficiently inhibited myocardial apoptosis, improved myocardial function, and ameliorated adverse cardiac remodeling post-MI in mice by relief of oxidative stress, promotion of angiogenesis and restoration of mitochondrial homeostasis and function. These findings prove that the synergic ROS regulation is essential in maximizing therapeutic effects of NO. Our CTP-PBA-ISN may serve as a valuable inspiration for development of other treatments of myocardial infarction and other ischemic diseases.

Knowledge of the antibody response to the third dose of inactivated SARS-CoV-2 vaccines is crucial because it is the subject of one of the largest global vaccination programs. This study integrated microsampling with optical biosensors to profile neutralizing antibodies (NAbs) in fifteen vaccinated healthy donors, followed by the application of machine learning to predict antibody response at given timepoints. Over a nine-month duration, microsampling and venipuncture were conducted at seven individual timepoints. A refined iteration of a fiber optic biolayer interferometry (FO-BLI) biosensor was designed, enabling rapid multiplexed biosensing of the NAbs of both wild-type and Omicron SARS-CoV-2 variants in minutes. Findings revealed a strong correlation (Pearson r of 0.919, specificity of 100%) between wild-type variant NAb levels in microsamples and sera. Following the third dose, sera NAb levels of the wild-type variant increased 2.9-fold after seven days and 3.3-fold within a month, subsequently waning and becoming undetectable after three months. Considerable but incomplete evasion of the latest Omicron subvariants from booster vaccine-elicited NAbs was confirmed, although a higher number of binding antibodies (BAbs) was identified by another rapid FO-BLI biosensor in minutes. Significantly, FO-BLI highly correlated with a pseudovirus neutralization assay in identifying neutralizing capacities (Pearson r of 0.983). Additionally, machine learning demonstrated exceptional accuracy in predicting antibody levels, with an error level of <5% for both NAbs and BAbs across multiple timepoints. Microsample-driven biosensing enables individuals to access their results within hours of self-collection, while precise models could guide personalized vaccination strategies. The technology’s innate adaptability means it has the potential for effective translation in disease prevention and vaccine development.

Yunnan Province is the main planting area of the precious Chinese herbal medicines (CHM) Panax notoginseng; however, it locates the geological area with high soil heavy metals in China. The frequent land replacement due to continuous cropping obstacles and excessive application of chemicals makes P. notoginseng prone to be contaminated by heavy metals under the farmland P. notoginseng (FPn) planting. To overcome farmland shortage, understory P. notoginseng (UPn) was developed as a new ecological planting model featured by no chemicals input. However, this newly developed planting system requires urgently the soil–plant heavy metal characteristics and risk assessment. This study aimed to evaluate the pollution status of eight heavy metals in the tillage layer (0–20 cm), subsoil layer (20–40 cm) and the plants of UPn in Lancang County, Yunnan Province. Pollution index (Pi) showed that the contamination degree of heavy metals in the tillage layer and subsoil layer was Cd > Pb > Ni > Cu > Zn > Cr > Hg > As and Pb > Cd > Cu > Ni > Cr > Hg > Zn > As, respectively. Potential ecological risk index (PERI) for the tillage layer and subsoil layer was slight and middle, respectively. The exceeding standard rate of Cd, As, Pb, Hg, Cu in the UPn roots was 5.33%, 5.33%, 13.33%, 26.67% and 1.33%, respectively, while only Cd and Hg in the UPn leaves exceeded the standard 10% and 14%, respectively. The enrichment abilities of Cd and Hg in the roots and leaves of UPn were the strongest, while that of Pb was the weakest. The Hazard index (HI) and target hazard quotient (THQ) of eight heavy metals in the roots and leaves of UPn were less than 1.Therefore, our results prove that Upn has no human health risk and provide a scientific basis for the safety evaluation and extension of UPn.

As an essential trace mineral in mammals and the second most abundant metal in the Earth’s crust, iron acts as a double-edged sword in humans. Iron plays important beneficial roles in numerous biological processes ranging from deoxyribonucleic acid biosynthesis and protein function to cell cycle progression. However, iron metabolism disruption leads to widespread tissue degeneration and organ dysfunction. An increasing number of studies have focused on iron regulation pathways and have explored the relationship between iron and cardiovascular diseases. Ferroptosis, an iron-dependent form of programmed cell death, was first described in cancer cells and has recently been linked to heart diseases, including cardiac ischemia–reperfusion injury and doxorubicin-induced myocardiopathy. Here, we summarize recent advances in our understanding of iron homeostasis and heart diseases and discuss potential relationships between ferroptosis and cardiac ischemia–reperfusion injury and cardiomyopathy.

Diabetes is a well-known risk factor for atherosclerosis (AS), but the underlying molecular mechanism remains unknown. The dysregulated immune response is an important reason. High glucose is proven to induce foam cell formation under lipidemia situations in clinical patients. Exploring the potential regulatory programs of accelerated foam cell formation stimulated by high glucose is meaningful. Macrophage-derived foam cells were induced in vitro, and high-throughput sequencing was performed. Coexpression gene modules were constructed using weighted gene co-expression network analysis (WGCNA). Highly related modules were identified. Hub genes were identified by multiple integrative strategies. The potential roles of selected genes were further validated in bulk-RNA and scRNA datasets of human plaques. By transfection of the siRNA, the role of the screened gene during foam cell formation was further explored. Two modules were found to be both positively related to high glucose and ox-LDL. Further enrichment analyses confirmed the association between the brown module and AS. The high correlation between the brown module and macrophages was identified and 4 hub genes (Aldoa, Creg1, Lgmn, and Pkm) were screened. Further validation in external bulk-RNA and scRNA revealed the potential diagnostic and therapeutic value of selected genes. In addition, the survival analysis confirmed the prognostic value of Aldoa while knocking down Aldoa expression alleviated the foam cell formation in vitro. We systematically investigated the synergetic effects of high glucose and ox-LDL during macrophage-derived foam cell formation and identified that ALDOA might be an important diagnostic, prognostic, and therapeutic target in these patients.