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Mesenchymal stem cells (MSCs) have been increasingly applied into clinical therapy. Exosomes are small (30–100 nm in diameter) membrane vesicles released by different cell types and possess the similar functions with their derived cells. Human umbilical cord MSC-derived exosomes (hucMSC-Ex) play important roles in liver repair. However, the effects and mechanisms of hucMSC-Ex on liver injury development remain elusive. Mouse models of acute and chronic liver injury and liver tumor were induced by carbon tetrachloride (CCl4) injection, followed by administration of hucMSC-Ex via the tail vein. Alleviation of liver injury by hucMSC-Ex was determined. We further explored the production of oxidative stress and apoptosis in the development of liver injury and compared the antioxidant effects of hucMSC-Ex with frequently used hepatic protectant, bifendate (DDB) in liver injury. hucMSC-Ex alleviated CCl4-induced acute liver injury and liver fibrosis and restrained the growth of liver tumors. Decreased oxidative stress and apoptosis were found in hucMSC-Ex-treated mouse models and liver cells. Compared to bifendate (DDB) treatment, hucMSC-Ex presented more distinct antioxidant and hepatoprotective effects. hucMSC-Ex may suppress CCl4-induced liver injury development via antioxidant potentials and could be a more effective antioxidant than DDB in CCl4-induced liver tumor development.

We investigated the correlation between Triglyceride-glucose (TyG) index and cardiovascular disease (CVD) mortality in type 2 diabetes mellitus (T2DM) population across different obesity classications using a cohort study. We analyzed 7867 T2DM participants from the National Health and Nutrition Examination Survey 1999–2018, categorizing them into obese or non-obese group by body mass index (BMI) and waist circumference (WC). Cox regression models were used to estimate the correlation between TyG index and CVD mortality risk, comparing the results across the two obesity classifications. Over a 9.1-year follow-up, 691 CVD deaths occurred. Among non-obese T2DM participants (BMI-defined), the hazard ration for CVD mortality was 1.73 in the fourth quartile group of TyG index compared with the first quartile group. Conversely, among obese T2DM participants (WC-defined), the fourth quartile group of TyG index held a 1.51-fold risk of CVD mortality compared with the first quartile group. The association between obesity and higher CVD risk was observed in WC-defined obesity but not in BMI-defined obesity. A totally opposite relationship appeared between TyG index and CVD mortality based on how obesity was defined using BMI or WC in the T2DM participants, suggesting a reevaluation of BMI’s accuracy in predicting mortality risk.

Betula platyphylla , belonging to the cold-specialized lineage Betulaceae, exhibits a unique reproductive strategy where staminate catkins emerge in the first summer and undergo an overwintering process, culminating in flowering in the following year. However, the underlying regulatory mechanism remains unclear. In this study, we investigated the male germline development of B. platyphylla in four distinct stages: microsporocytes in Oct. (S1), uninuclear microspores from Dec. (S2) to Mar. of the following year (S3), and bicellular microspores in Apr. (S4). We performed RNA sequencing on mature pollen and the four stages of staminate catkins. Using weighted gene co-expression network analysis (WGCNA), we identified five highly correlated gene modules with distinct expression profiles. These modules exhibited strong correlations with sugar metabolism, cell cycle, flowering, and cell wall dynamics, highlighting their dynamic roles during male germline developmental stages. During the overwintering process, we observed that the expression of transcription factors such as BpDUO1 and BpAMS at the appropriate developmental stages, suggests their significant roles in male germline development. The expression patterns of BpFLC and BpFT suggest their potential involvement in temperature perception during male reproductive development. These findings offer valuable insights into the reproductive success of plants adapting to cold environments.

Aims/Introduction Distal symmetric polyneuropathy (DSPN) is a common complication of type 2 diabetes mellitus, but the underlining mechanisms have not yet been elucidated. The current study was designed to screen the feature metabolites classified as potential biomarkers, and to provide deeper insights into the underlying distinctive metabolic changes during disease progression. Materials and Methods Plasma metabolite profiles were obtained by the ultra‐high liquid chromatography coupled to tandem mass spectrometry method from healthy control participants, patients with type 2 diabetes mellitus and patients with DSPN. Potential biomarkers were selected through comprehensive analysis of statistically significant differences between groups. Results Overall, 938 metabolites were identified. Among them, 12 metabolites (dimethylarginine, N6‐acetyllysine, N‐acetylhistidine, N,N,N‐trimethyl‐alanylproline betaine, cysteine, 7‐methylguanine, N6‐carbamoylthreonyladenosine, pseudouridine, 5‐methylthioadenosine, N2,N2‐dimethylguanosine, aconitate and C‐glycosyl tryptophan) were identified as the specific biomarkers. The content of 12 metabolites were significantly higher in the DSPN group compared with the other two groups. Additionally, they showed good performance to discriminate the DSPN state. Correlation analyses showed that the levels of 12 metabolites might be more closely related to the glucose metabolic changes, followed by the levels of lipid metabolism. Conclusions The finding of the 12 signature metabolites might provide a novel perspective for the pathogenesis of DSPN. Future studies are required to test this observation further. We found taht 12 signature metabolites might provide novel perspective for the pathogenesis of DSPN. Future studies are needed to test this observation further.

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease, accompanied by liver lipid accumulation and inflammation. JianPi-QingHua formula (JPQH), a Chinese herbal formula, exhibits effects on obesity and T2DM. However, the hepatoprotective effect of JPQH has not been elucidated. To investigate the hepatoprotective effect of JPQH in NAFLD induced by a high-fat diet (HFD) in mice. C57BL/6J mice were divided into four groups and fed a normal-fat diet (ND), high-fat diet (HFD), HFD + JPQH (2.5 g/kg), or HFD + metformin (300 mg/kg) for 6 weeks, respectively. Furthermore, the body weight, epididymal fat mass, blood glucose, and liver weight were measured. Serum total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were performed. Hematoxylin and eosin staining and Oil Red O staining were observed in hepatic histopathological changes. Western blotting and quantitative real-time polymerase chain reaction were utilized to assess the key protein expression of hepatic lipid metabolism and inflammation. Compared with the HFD group, JPQH could reduce body weight, epididymal fat mass, blood glucose and liver weight (p < 0.05), and markedly decreased the levels of serum TC, TG, ALT, AST (p < 0.05). Additionally, JPQH improved liver pathological changes. Consistent with the hepatic histological analysis, JPQH intervention suppressed lipid accumulation and inflammatory responses. Mechanistically, JPQH boosted SIRT1/AMPK signalling, and attenuated NF-κB pathway, which suppressed inflammatory responses. These findings indicate that JPQH supplementation protected against HFD-induced NAFLD by regulating SIRT1/AMPK/NF-κB pathway, which provides a theoretical basis for the clinical treatment of patients with NAFLD.

Background Female inflorescence development from megasporogenesis to gametogenesis, and mature female gametophyte (FG), is a complex and important event in plant sexual reproduction. However, how this essential developmental process is regulated in birch remains obscure. This study conducted extensive morphological and transcriptomic analyses to reveal possible regulatory mechanisms during birch female inflorescence development. Results Histological analyses showed that birch exhibits a Polygonum-type embryo sac. During early ovule development, the ovule primordium emerges and subsequently differentiates into the archesporial cell (ASC), initiating megasporogenesis. The megaspore mother cell (MMC) then undergoes meiosis, generating a functional megaspore (FM) that develops into the mature embryo sac (MES). Transcriptomic profiling revealed upregulation of reactive oxygen species (ROS)-scavenging genes, including BpGSTU17 , BpGSTU19 , BpAPX1 , BpPRXIIE -1, BpSODCP , and BpFDX3 , at the MMC stage. At the MES stage, genes involved in both ROS synthesis and scavenging, such as BpACX , BpCuAOγ1 , BpGLO1 , BpRBOHH , BpUOX2 , BpFSD2 , BpCAT3 , BpGRX , BpNRX , and BpTRX , were significantly expressed. BpPAL , BpC4H , BpCSE , BpCoMT , BpCCoAOMT , BpCAD , BpF5H , BpLAC , BpXTH23 , and BpCESA , genes involved in the cell wall biosynthesis pathways including lignin, cellulose, hemicellulose and pectin, were also upregulated. Conclusion Our results suggest that ROS homeostasis affects the process of birch megasporogenesis. Genes related to ROS signaling and cell wall synthesis participate in embryo sac maturation.

Resistance to tyrosine kinase inhibitor (TKI) is a tough problem in the treatment of chronic myeloid leukemia in blastic phase (CML-BP), which was often associated with acquired mutations in the kinase domain and not eliminating the leukemic stem cells. The efficacy of TKI or combination with chemotherapy in CML-BP remains unsatisfactory. Chimeric antigen receptor T (CAR-T) cell immunotherapy may overcome TKI and chemotherapy resistance. However, lack of ideal targetable antigens is a major obstacle for treating patients with myeloid malignancies. CD38 is known to be expressed on most (acute myeloid leukemia) AML cells, and its lack of expression on hematopoietic stem cells renders it as a potential therapeutic target for myeloid CML-BP. We develop a CD38-directed CAR-T cell therapy for AML, and two patients with myeloid CML-BP were enrolled (NCT04351022). Two patients, harboring E255K and T315I mutation in the ABL kinase domain, respectively, were resistant to multiple TKIs (imatinib, dasatinib, nilotinib, and ponatinib) and intensive chemotherapy. The blasts in the bone marrow of two patients exhibited high expression of CD38. After tumor reduction chemotherapy and lymphodepletion chemotherapy, 1 × 10 7 CAR-T-38 cells per kilogram of body weight were administered. They achieved minimal residual disease–negative and BCR::ABL1 -negative complete remission and experienced grade II cytokine release syndrome manifesting as fever. Our data highlighted that CAR-T-38 cell therapy may overcome TKI and chemotherapy resistance in patients with myeloid CML-BP.

Relapse is a major limitation of chimeric antigen receptor (CAR) T-cell therapy. Here, we speculated that decitabine (DAC) in combination with fludarabine and cyclophosphamide (FC) as a lymphodepletion regimen may improve the efficacy of CD19/CD22 CAR T-cell therapy. Fourteen of 26 patients with relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) without remission before lymphodepletion treatment were treated with DAC (total dose 100 mg/m 2 in 3 days) followed by the FC regimen (DAC group), while twelve patients received the FC regimen (CON group). On Day 28 after CAR T-cells infusion, no significant differences in complete remission (CR) and minimal residual disease negative CR rates were found between both groups. However, there were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 92.3% (DAC) versus 41.7% (CON), P = 0.005 and 3-year LFS, 92.9% (DAC) versus 27.3% (CON), P < 0.001. There was no significant difference in the incidence of cytokine release syndrome between both groups. Median time to platelet and neutrophil counts recovery was similar in both groups. All adverse events were reversible and manageable. In conclusion, DAC in combination with the FC lymphodepletion regimen may be a new treatment option that can improve the efficacy of CAR T-cell therapy in r/r B-ALL.

Background Jianpi Qinghua Fomula (JPQHF), a clinically proven prescription,has been applied to cure insulin resistance(IR) and type 2 diabetes (T2DM) for more than 20 years. Here, we will unravel the underlying molecular mechanisms relevant to the therapeutic actions of JPQHF. Methods High-fat(HF)diet-induced obesity(DIO)mouse were established in our research, along with insulin resistance. After the administration of JPQHF 5 or 6 weeks, the parameters of the glucose and lipid metabolism were measured. Flow cytometry and Luminex were utilized to assess the inflammation in small intestine,whilst Western blot was used to determine the relative expression levels of the MAPK pathway-related proteins. The glucose and lipid transporter of small intestine was assessed by immunofluorescence and ELISA, and the expression of insulin signaling pathway was detected by Western blot. Results The metabolic phenotypes of DIO mouse were ameliorated after 6-week oral administration of JPQHF; Meanwhile,JPQHF downregulated levels of IL-1β,IL-6, TNF-α and IFN-γ but upregulated the ratio of M2/M1 macrophages in the small intestine. The elevated expressions of p-P38 MAPK/P38 MAPK、p-JNK/JNK and p-ERK1/2/ERK1/2 were reversed by JPQHF. Moreover, JPQHF enhanced expression of PI3K,p-AKT/AKT, p-IRS1/ IRS1, p-IRS2/ IRS2 and apoB48 in small intestine, and facilitated the translocation of GLUT2 to the basal side of small intestine epithelial cells. Conclusion JPQHF alleviates insulin resistance in DIO mice, and this effect may be associated with its restraining of inflammation of small intestine via attenuating MAPK pathway, and then diminishes small intestinal glucose and lipid absorption.

BackgroundIt is widely recognized that glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) are two key risk factors for albuminuria and renal function impairment in patients with type 2 diabetes mellitus (T2DM). Our study aimed to identify the specific numerical relationship of albumin/creatinine ratio (ACR) with HbA1c and SBP among a large population of adults with T2DM.MethodA total of 8,626 patients with T2DM were included in the data analysis from the National Health and Nutrition Examination Surveys (NHANES) (1999-2018). The multiple linear regressions were used to examine the associations of ACR with HbA1c and SBP. Generalized additive models with smooth functions were performed to identify the non-linear relations between variables and interactions were also tested.ResultsSignificantly threshold effects were observed between ACR and HbA1c or SBP after multivariable adjustment, with the risk threshold values HbA1c = 6.4% and SBP = 127 mmHg, respectively. Once above thresholds were exceeded, the lnACR increased dramatically with higher levels of HbA1c (β = 0.23, 95 CI%:0.14, 0.32, P < 0.001) and SBP (β = 0.03, 95 CI%:0.03, 0.04, P < 0.001). Subgroup analysis showed high protein diet was related to higher ACR. In addition, a higher risk of ACR progression was observed in central obesity participants with HbA1C ≥ 6.4% or hyperuricemia participants with SBP ≥ 127 mmHg among patients withT2DM.ConclusionWe identified thresholds of HbA1c and SBP to stratify patients with T2DM through rapid albuminuria progression. These might provide a clinical reference value for preventing and controlling diabetes kidney disease.