It is commonly assumed that aging and chronic low-grade inflammation compromise adaptive immunity, particularly the function and metabolism of CD4+ T cells. The preceding are key regulators of immune responses. These immunological alterations contribute to increased susceptibility to infections, diminished vaccine efficacy and the progression of age-related diseases. In contrast, adolescence and young adulthood tend to be characterized by more robust immune responses, though these are heavily influenced by modifiable lifestyle factors such as habitual physical activity, level of cardiorespiratory fitness, diet and body adiposity. Emerging evidence suggests that sustained physical activity throughout life may preserve CD4+ T cell competence by favourably modulating their metabolic programming. The current narrative review explores how lifelong physical exercise impacts CD4+ T cell metabolism, with particular emphasis on the developmental window of adolescence and the long-term benefits of early and sustained physical training across the lifespan. Molecular mechanisms linking exercise to metabolic reprogramming of T cells were summarised in parallel with attenuation of immunosenescence and inflammation over the lifespan. This review suggests that lifelong exercise may reprogram CD4+ T cell metabolism, enhancing oxidative phosphorylation at rest and glycolytic control upon activation, thereby improving Th17/Treg balance, reducing chronic inflammation and enabling effective effector T cell responses. In this context, exercise initiated early in life may act as a critical modulator by promoting optimal immune function from childhood and establishing a functional peak that helps preserve immune competence during aging. Lifelong and early-life exercise may reprogram CD4+ T cell metabolism, strengthening immune balance and preserving immune function during aging.
Inflammatory arthritis (IA) is a group of autoimmune diseases characterised by joint inflammation and progressive damage, thus impairing the patient's quality of life. The JAK/STAT pathway inhibitor Tofacitinib has been successfully introduced into the clinic to treat patients with IA, however its direct effect on T cell responses is widely unknown. This study aims to assess the effect of Tofacitinib on T cell activation, polyfunctionality, proliferation and metabolism. The effect of Tofacitinib on T cells from peripheral blood, synovial fluid and synovial tissue was evaluated with multidimensional flow cytometric analysis. T cell proliferation was assessed by flow cytometry and T cell metabolism was examined by qPCR and Seahorse XF analyser. To investigate the effect of Tofacitinib on T cell polarisation, naïve T cells were differentiated into Th1, Th2 and Th17 with specific cytokine cocktails. Soluble mediators were evaluated by MSD multiplex analysis. Tofacitinib significantly inhibited T helper cell activation as evidenced by a marked reduction in the frequency of PD-1/CD69/CD25-positive cells (p < 0.01). Reduced activation was consistent with impairment of pathogenic polyfunctionality of peripheral blood and synovial tissue-derived T cells. The impact of Tofacitinib on T cell plasticity was further substantiated by reduced T cell polarisation towards Th1 (p < 0.05), Th2 (p < 0.05), Th17 (p < 0.05) and a reduction in genes associated with T cell functions. The attenuation of pathogenic T cell responses is linked to metabolic adaptation, with Tofacitinib leading to a switch in metabolic capacity, mainly ascribed to the CD4-CD8+ T cell compartment. Tofacitinib strongly alters T cell responses and potentially limits T cell pathogenicity by decreasing their activation, polyfunctionality, differentiation, and metabolic potential in both the circulation and the joints of patients with inflammatory arthritis.
Food allergy (FA) has become increasingly prevalent, affecting daily life. Probiotics alleviate FA by modulating immune-microbiome interactions. Nevertheless, the key metabolites and mechanisms by which L. plantarum alleviates FA remain unclear. In this study, L. plantarum demonstrated the ability to improve FA by modulating regulatory T/Th1/Th2 balance, modulating gut microbial composition, and regulating gut metabolites. Tropomyosin sensitization was associated with decreased levels of 5-hydroxyindole-3-acetic acid (5-HIAA) in cecum contents, a phenomenon also observed in the serum of FA mice and patients. In vitro experiments showed that tryptophan (Trp), tryptamine, tryptophol, kynurenine, 5-HIAA, and indole-3-acetamide inhibited RBL-2H3 cell degranulation; however, this inhibitory effect was attenuated by the aryl hydrocarbon receptor (AhR) antagonist CH223191. Moreover, in vivo results indicated that dietary supplementation with 5-HIAA or Trp downregulated IgE and cytokine levels in an AhR-dependent manner. This study provided evidence for the positive role of Trp metabolites in alleviating FA.
Phycocyanin (PC) is a key light-harvesting pigment protein in the phycobilisome of cyanobacteria and rhodophyta, and is currently the only natural blue pigment successfully commercialized. However, its application is limited by complex biosynthetic and degradative regulation, which constrain efficient CO2-based green production. Here, using Synechocystis sp. PCC 6803 as a photosynthetic chassis, the phycocyanobilin (PCB) precursor network was then systematically reconstructed to overcome key biosynthetic bottlenecks. For the first time in cyanobacteria, the C4 synthesis pathway of 5-aminolevulinic acid (5-ALA) was introduced together with enhancement of the native 5-ALA supply route. Combined with ferrochelatase (Ppfc)-mediated redirection of metabolic flux, this strategy expanded and stabilized the tetrapyrrole metabolic pool, resulting in a synergistic enhancement of PCB biosynthesis. In parallel, modulation of apophycocyanin expression was incorporated to better coordinate chromophore supply with phycobiliprotein assembly. In addition, genetic suppression of phycobilisome degradation under high light conditions effectively prolonged the functional half-life of PC. The multimodule engineered strain achieved a PC content of 124.62 mg g-1 under gas-bubbling cultivation, corresponding to a 66.92% increase over the wild-type, accompanied by improved photosystem II (PSII) photochemical efficiency, enhanced electron transport, and elevated photoprotective pigment levels. These results demonstrate that efficient PC biosynthesis emerges from coordinated, system-level engineering of the photosynthetic network rather than amplification of a single metabolic node. This work establishes a scalable paradigm for CO2-driven green manufacturing of pigment proteins and the construction of robust photosynthetic cell factories.
To investigate the chemical constituents of Shiqi Waigan Granules and their metabolic distribution in rats. An off-line two-dimensional liquid chromatography-mass spectrometry approach was employed to identify the constituents of Shiqi Waigan Granules. A UPLC-QTOF-MS method was established to analyze the distribution of prototype compounds and metabolites in rat plasma, heart, liver, lung, kidney, spleen and brain after oral administration, and to elucidate the metabolic pathways. (1) A total of 315 compounds were successfully identified in Shiqi Waigan Granules. Compared with conventional one-dimensional LC, the off-line 2D system amplified trace compounds and resolved more isomers, enabling a more systematic and refined characterization of the chemical profile. (2) Based on plasma pharmacochemistry and Phase I and II metabolic pathways, 66 prototype compounds and 102 metabolites were tentatively identified in rat plasma. (3) Most constituents were detected in liver, kidney, lung and spleen, whereas fewer were found in heart and brain. Shiqi Waigan Granules are mainly composed of flavonoids, terpenoids, organic acids, lignans, phenolics, phenylpropanoids and glycosides. In vivo, these constituents primarily undergo hydrolysis, reduction, hydroxylation, carboxylation, sulfation, glucuronidation and composite reactions, and are widely distributed as either prototype compounds or their Phase I/II metabolites.
Cryptococcus neoformans is an environmental pathogen that remodels its cellular physiology to survive within mammals and, in susceptible hosts, cause life-threatening meningoencephalitis. Of the many distinctions between the external environment and mammalian tissues, CO2 concentration in the host is two orders of magnitude higher than in the environment and represents a critical stress for C. neoformans. C. neoformans strains that do not replicate at host CO2 concentrations are less virulent in mouse models of infection, further supporting CO2 tolerance as a virulence trait. To further understand the genetic determinants of C. neoformans CO2 tolerance, we performed a near genome-wide screen for deletion mutants with altered CO2 fitness using a competitive growth assay. A total of 301 of 4,692 deletion mutants showed altered CO2 tolerance (245 reduced fitness; 56 increased fitness) demonstrating the global effect of host CO2 on C. neoformans physiology. Based on this data set as well as a metabolomic analysis of C. neoformans adaptation to host CO2, we show that remodeling of central carbon metabolism, oxidative stress buffering, and membrane homeostasis represent an integrated response to CO2 stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO2-induced capsule formation leads to reduced cellular glucose which, in turn, triggers remodeling of central carbon metabolism toward utilization of alternative carbon sources and increased mitochondrial respiration/reactive oxygen generation. Thus, these data provide a near genome-wide profile of the genetic determinants of C. neoformans CO2 tolerance as well as a model for how this important environmental human fungal pathogen alters its physiology to proliferate in the host.
Translating high-resolution multiomics data into clinically actionable biomarkers is critical for overcoming therapeutic resistance and tumor heterogeneity in prostate adenocarcinoma (PRAD). To decode the complex immunosuppressive tumor microenvironment (TME) and identify robust prognostic targets, we developed a systematic biomarker discovery pipeline integrating single-cell RNA sequencing (scRNA-seq) mapping and high-dimensional network analysis. By deconvoluting scRNA-seq profiles from over 35,000 PRAD cells, nonnegative matrix factorization (NMF) of the malignant epithelial compartment revealed nine distinct transcriptional metaprograms (MPs). High-dimensional weighted gene coexpression network analysis (hdWGCNA) pinpointed PRAD-MP7 as the core proliferative engine and nominated the malignant-specific gene YBX1 as the master prognostic hub. To establish clinical utility evidence, we validated YBX1 across six independent global PRAD cohorts, where its overexpression robustly predicted poor overall survival (OS) and relapse-free survival (RFS). In vitro functional validation via siRNA-mediated knockdown in DU-145 and PC-3 cells significantly attenuated proliferative and invasive capacities, impairing cell viability and downregulating key progression markers (Ki-67, MMP2, and MMP9). Crucially, immunogenomic profiling mapped YBX1 expression to an "immune-excluded" TME, characterized by depleted CD8+ T cell and dendritic cell infiltration alongside elevated immune checkpoint networks. Serving as a bridge to clinical translation, YBX1 effectively predicted clinical responses in three immunotherapy cohorts and demonstrated broad resistance to 12 chemotherapeutic and targeted agents. Our multiomics integration pipeline highlights YBX1 as a dual-functional oncogene that couples malignant proliferation with immune evasion, establishing it as a highly translational biomarker and an actionable target for precision PRAD management.
Genetic predisposition and unhealthy lifestyles are well-known contributors to disorders of glucose and lipid metabolism, including type 2 diabetes, obesity, and metabolic dysfunction-associated fatty liver disease. However, these factors alone cannot fully explain the rapidly rising prevalence of these conditions. Emerging evidence highlights the pivotal role of the intrauterine environment in gestational diabetes mellitus (GDM) in shaping epigenetic modifications and metabolic reprogramming, thereby predisposing offspring to long-term metabolic complications. Exosomes have recently been identified as key mediators of maternal-fetal communication. In GDM, both the quantity and cargo (e.g., proteins, miRNAs) of exosomes are altered. These altered exosomes not only contribute to maternal glucose and lipid metabolic abnormalities but also act as a critical vector for transmitting adverse metabolic signals to the offspring. This exosome-mediated communication disrupts placental function and the development of fetal metabolic organs, ultimately programming the offspring for long-term metabolic disorders. In this review, we summarize the characteristic changes of maternal exosomes in GDM and explore the potential mechanism by which exosomes regulate offspring metabolism during maternal-fetal crosstalk. We also propose the possible direction of exosomes in application, providing insights into early-life strategies for the prevention of metabolic diseases.
The biological significance of the transition metal molybdenum (Mo) lies in its function at the catalytic center of several enzymes that drive a wide spectrum of redox reactions underlying global biogeochemical cycles, yet a paradox persists. While modern life ubiquitously relies on Mo, geochemical evidence suggests that its availability in early Earth's anoxic oceans was extremely limited. Modern organisms can use Mo down to trace levels; however, the rates of Mo-dependent metabolisms slow down when Mo availability decreases, posing fundamental questions about the extent to which changing Mo abundances shaped the evolution of molybdoenzymes, and when early life began harnessing Mo. Here, we confront this evolutionary enigma by reconstructing the temporal and ecological emergence of molybdoenzymes, their transport systems, and biosynthetic pathways. In parallel, we examine biological tungsten (W) usage due to shared chemical properties and cofactor biosynthetic pathways with Mo. We provide molecular dating evidence of Mo/W utilization back to the Eo- to Mesoarchean (~3.7-3.1 Ga). These findings challenge prevailing assumptions about trace metal availability on the early Earth and underscore the profound antiquity and adaptability of Mo-based biochemistry in shaping early microbial evolution.
NLRX1, a mitochondrial NOD-like receptor (NLR) family protein, is a non-inflammasome-forming protein with diverse roles in cancer. While NLRX1 has been recognized as a tumor suppressor in colorectal and hepatocellular carcinomas, it appears to act as a tumor promoter in breast and head and neck cancers. This study explored the role of NLRX1 in prostate cancer (PCa), examining its impact on cell proliferation, apoptosis, migration, invasion, and tumor progression, as well as associated molecular mechanisms. Using TCGA data, the association between NLRX1 expression and PCa prognosis was evaluated. NLRX1 expression was upregulated under serum-free stress conditions. Silencing NLRX1 reduced cell proliferation in PC3 cells, but not in LNCaP cells. Additionally, NLRX1 knockdown inhibited migration and invasion, while promoting apoptosis under serum-free conditions. Mechanistically, NLRX1 knockdown reduced AKT and ERK phosphorylation in response to serum deprivation, EGF, and TGF-β, without affecting PDK1 activity under serum deprivation. Pharmacological data showed AKT and ERK as key regulators of viability and invasion, with AKT critical for growth and migration. Co-immunoprecipitation, confocal microscopic examination, domain binding, structural modeling, and molecular dynamics revealed a stable interaction between NLRX1's LRR domain and AKT's PH domain. NLRX1 facilitated cell proliferation, migration, invasion, and resistance to serum-free stress through direct interaction with AKT, highlighting NLRX1 as a promising biomarker for PCa progression.
Excess mortality in psychotic disorders is largely due to preventable cardiometabolic morbidity. Efforts to evaluate the link between the psychosis spectrum and cardiometabolic health have been confounded by early-life adversity (ELA) and biased sampling. This population-based study examined prospective associations between psychosis-spectrum status and cardiometabolic biomarkers at age 44-45, adjusting for ELA. We analyzed data from the 2002/03 biomedical sweep of the British National Child Development Study (n = 9377; age 44-45). Psychosis-spectrum status (exposure; n = 171) was defined using repeated screening across adulthood (ages 23 to 44-45), including self-reported diagnoses, antipsychotic medication use, or professional help-seeking for hallucinations. Cardiometabolic biomarkers at age 44-45 (outcomes) were compared between individuals on the psychosis spectrum and psychosis-free controls (comparator; n = 2448). Analyses were conducted using unimputed and multiply imputed datasets (n = 7391-9298), adjusting for 24 indicators of ELA. In both unimputed/imputed analyses, individuals on the psychosis spectrum had significantly worse cardiometabolic profiles. Adjusted results showed elevated abdominal obesity (exp(b), 1.404; 95% CI, 1.177-1.676; P < .001), higher glycated hemoglobin (B = 0.321; 95% CI, 0.089-0.553; P = .008), lower high-density lipoprotein cholesterol (B = -4.472; 95% CI, -7.782 to -1.162; P = .009), and increased fibrinogen (B = 4.542; 95% CI, 0.939-8.144; P = .015) compared to controls. Overcoming early-life confounders and biases that limited prior research, our study demonstrates a robust, independent association between psychosis-spectrum status and cardiometabolic dysfunction at age 44-45. These findings underscore the urgent need for comprehensive screening, treatment, and monitoring of cardiometabolic morbidity in psychosis, guided by a life-course perspective.
Automated insulin delivery (AID) has been established as an effective therapy for individuals with type 1 diabetes. This analysis evaluates the clinical and economic outcomes of AID compared with multiple daily injections plus continuous glucose monitoring (MDI/CGM) in adults with type 2 diabetes. The IQVIA CORE Diabetes Model v10.0 was employed to simulate the impact of using the t:slim X2 insulin pump with Control-IQ+ technology (Control-IQ+) versus MDI/CGM over a 50-year period using data from the 2IQP randomized controlled trial (NCT05785832). Trial data informed cohort demographics, intervention effects and resource utilization while literature sources provided health state utilities and costs. Scenario analyses examined the effect of Control-IQ+ on reducing HbA1c based on alternative HbA1c progression estimates from the Swedish National Diabetes Registry and alternative resource use and treatment effects from real-world evidence. The base case analysis indicated that direct medical costs per individual for type 2 diabetes management with Control-IQ+ were $239 935 compared to $209 792 with MDI/CGM use. Control-IQ+ resulted in 0.51 additional quality-adjusted life years (QALYs: 10.36 vs. 9.85 for MDI/CGM), yielding an incremental cost-effectiveness ratio (ICER) of $59 417 per QALY, 95% CI: ($55 836, $62 998). In probabilistic sensitivity analyses, 89% of simulations produced ICERs below $100 000/QALY. ICERs across all scenarios remained below $100 000 per QALY. Control-IQ+ is associated with increased life expectancy, higher QALYs and reduced complication rates. These findings suggest that Control-IQ+ is cost-effective relative to MDI/CGM for managing patients with type 2 diabetes in the United States.
Liver diseases pose a significant global health burden. This review systematically elucidates the crucial role of exercise as a non-pharmacological intervention in the prevention and treatment of various liver conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), viral hepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Exercise effectively delays disease progression and improves patients' quality of life through multi-targeted mechanisms, such as improving glucose and lipid metabolism, enhancing insulin sensitivity, regulating immune-inflammatory responses, inhibiting hepatic stellate cell activation, and remodeling the tumor microenvironment. Future research should focus on developing individualized, precise exercise prescriptions and further exploring its molecular mechanisms by integrating multi-omics technologies, thereby providing innovative strategies for the comprehensive management of liver diseases.
Neurons depend on glucose to sustain their high energetic demands; yet, ketone bodies can serve as alternative substrates during ketogenic states. Here, we examined how β-hydroxybutyrate reshapes metabolism and function in human iPSC-derived neurons. Neurons generated from neuroepithelial stem cells were cultured in glucose-rich media or low-glucose media supplemented with β-hydroxybutyrate. We developed an electrochemical biosensor for ketone detection and validated its performance by cyclic voltammetry and amperometry, achieving linear sensitivity in the 0.01 to 0.1 mM range. Metabolic changes for neurons were assessed through glucose consumption and lactate production, and transcriptional profiling revealed reduced expression of selected metabolic and ketone-associated genes under ketone supplementation. Calcium imaging further showed lower firing rates in ketone exposed neurons compared with glucose conditions. Together, these results demonstrate how alternative energy substrates modulate neuronal metabolism and excitability, providing a framework to evaluate metabolic interventions for neurological disorders.
This review explores mesoporous silica nanoparticles (MSNs) as emerging nano-drug delivery systems for ocular diseases and provides a comprehensive overview of their application in ophthalmic drug delivery, including eye anatomy, ocular barriers, MSNs structural characteristics, synthesis approaches, surface functionalization strategies, drug-loading mechanisms, as well as recent advances in patents and clinical trials. Among all the senses, vision plays a crucial role in everyday life. Ocular disease causes visual impairment and significantly reduces the quality of life, resulting in expensive medical care. Currently used treatments mostly utilize traditional formulations, which are limited by the physiological and anatomical barriers of the eye. Nanotechnologies, particularly MSNs, have emerged as a promising approach to overcome these limitations by enhancing drug loading, targeted drug delivery, and sustained release. An extensive literature review on the synthesis, functionalization, toxicity, safety, and applications of MSNs was conducted using multiple databases, including relevant patents and research studies. The reviewed articles demonstrated that MSNs exhibited improved drug penetration, improved mucoadhesion which extends longer precorneal residence duration, clinical efficacy and acceptable safety profile. Several recent research papers and patents further support the potential of MSNs in treating several ocular disorders effectively. According to the extensive literature survey, MSN-based nanodrug delivery systems provide significant advantages over conventional ocular formulations by overcoming ocular obstacles and enhancing therapeutic effect. Further standardized and clinical research is needed to validate their safety, long-term stability, and clinical effectiveness. Overall, MSNs represent a promising platform with significant potential for ophthalmic drug delivery.
Objective: To investigate the efficacy and safety of 36 000 IU recombinant human erythropoietin (rhEPO) in the treatment of cancer-related anemia (CRA) and to evaluate whether 36 000 IU rhEPO can serve as a rational "reduced-dose alternative" to the 40 000 IU rhEPO regimen. Methods: The multicenter, open-label, non-inferiority, randomized controlled trial was conducted from March 2023 to July 2024 across 12 hospitals in China, including Liaoning Cancer Hospital. A total of 119 patients with CRA were enrolled and randomly assigned to receive the 36 000 IU rhEPO (n=61) or 40 000 IU rhEPO (n=58). The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline at weeks 9-13. Secondary efficacy endpoints included hematologic and other biochemical parameters, transfusion requirements, quality of life (QOL), which was assessed by QOL scores and Karnofsky performance status (KPS) scores, and overall survival. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). Results: The least-squares mean changes in Hb from baseline to weeks 9-13 were (12.9±2.3) g/L in the 36 000 IU group and (13.4±2.4) g/L in the 40 000 IU group. Analysis of covariance showed no statistically significant difference between groups (F=-0.21, P=0.836), with a between-group difference of (-0.5±2.5) g/L (95% CI: -5.4 g/L, 4.4 g/L). The lower limit of the 95% CI (-5.4 g/L) exceeded the predefined non-inferiority margin of -10 g/L, indicating non-inferiority of the 36 000 IU dose compared to the 40 000 IU. At week 13, the proportions of patients with Hb increase ≥10 g/L were 82.0% (50/61) in the 36 000 IU group and 86.2% (50/58) in the 40 000 IU group, with no significant difference between groups (Qmh=0.40, P=0.527). The average weekly transfusion rate was 2.0% in both groups. No significantly significant differences were observed between the two groups in terms of changes in hematocrit, reticulocyte percentage, folate, vitamin B12, albumin, iron metabolism markers, QOL scores, KPS scores, or overall survival (all P＞0.05). Regarding safety, the incidence of TEAE was 80.3% (49/61) in the 36 000 IU group and 84.5% (49/58) in the 40 000 IU group, with nausea, fever, and fatigue being the most common symptoms (incidence＞5%). No drug-related serious adverse events were reported, and there were no significant differences between the groups (P＞0.05). Conclusions: The 36 000 IU dose of rhEPO is non-inferior to the 40 000 IU dose in terms of efficacy and has a favorable safety profile for the treatment of CRA. These findings support the use of 36 000 IU rhEPO as a reasonable clinical option for managing CRA. 目的： 探索36 000 IU重组人促红细胞生成素（rhEPO）治疗肿瘤相关性贫血（CRA）的有效性和安全性，评估36 000 IU rhEPO能否成为40 000 IU rhEPO的合理“减量替代”。 方法： 采用多中心、开放标签、非劣效、随机对照试验设计，于2023年3月至2024年7月在辽宁省肿瘤医院等中国12家医院开展。共纳入119例CRA受试者，根据rhEPO给药剂量规格随机分为36 000 IU组（n=61）和40 000 IU组（n=58）。主要疗效指标为第9～13周血红蛋白（Hb）水平较基线的变化值，次要疗效指标包括血细胞比容等血液生化指标、输血需求、生活质量［生活质量（QOL）评分和卡氏功能状态（KPS）评分］及总生存时间。安全性指标为治疗期不良事件（TEAE）发生率。 结果： 36 000 IU组和40 000 IU组受试者在第9～13周Hb较基线变化值的最小二乘均值分别为（12.9±2.3）g/L与（13.4±2.4）g/L，协方差分析显示组间差异无统计学意义（F=-0.21，P=0.836），组间差值为（-0.5±2.5）g/L（95% CI：-5.4～4.4 g/L），95% CI下限（-5.4 g/L）高于预设的非劣效界值（-10 g/L），表明36 000 IU组相对于40 000 IU组具有非劣效性。在第13周时，36 000 IU组和40 000 IU组Hb升高≥10 g/L的受试者比例分别为82.0%（50/61）和86.2%（50/58），差异无统计学意义（Qmh=0.40，P=0.527），且两组平均周输血率均为2.0%。两组受试者治疗前后的血细胞比容、网织红细胞百分比、叶酸、维生素B12、白蛋白、铁代谢指标、QOL评分、KPS评分以及总生存时间差异均无统计学意义（均P＞0.05）。在安全性方面，36 000 IU组和40 000 IU组TEAE发生率分别为80.3%（49/61）与84.5%（49/58），以恶心、发热和乏力症状为主（发生比例高于5%），均未报告任何药物相关严重不良事件，组间差异无统计学意义（均P＞0.05）。 结论： 36 000 IU rhEPO在治疗CRA方面对比40 000 IU rhEPO具有非劣效性，且安全性良好，36 000 IU剂量可作为临床治疗CRA的合理选择。.
L-theanine, a nitrogen compound uniquely synthesized in tea plant roots, is a core determinant of tea flavor and a key carrier for nitrogen. Its metabolic dynamics are tightly linked to root development, yet whether auxin signaling participates in regulating theanine biosynthesis and the underlying molecular mechanisms remain unclear. This study aims to elucidate the molecular pathways and key regulatory factors governing auxin signaling in the regulation of root-specific theanine biosynthesis in tea seedlings. Changes in free amino acids (FAA), ethylamine, and endogenous hormone contents in roots, stems, and leaves of tea seedlings across five developmental stages (S1-S5) were detected by HPLC, GC-MS, and LC-MS, respectively. A theanine biosynthesis regulatory network was constructed by integrating time-series transcriptome and weighted gene co-expression network analysis (WGCNA). Additionally, exogenous indole-3-acetic acid (IAA) treatment, yeast one-hybrid assays, in vivo function validation, and DAP-seq were employed to screen and characterize key regulatory factors. During tea seedling radicle development, theanine content rapidly increase from 10% to over 80% of the total FAA. Multi-Omics correlation analysis revealed a feedback inhibition relationship between rapid theanine biosynthesis and auxin signaling levels. Exogenous IAA treatment and in vivo/in vitro assays confirmed that the CsZAT6/CsZAT12-CsAlaDC modules, which respond to auxin signaling, exert bidirectional regulation on theanine metabolism: CsZAT6 positively regulates theanine biosynthesis by activating the expression of CsAlaDC (the rate-limiting enzyme for ethylamine production), while CsZAT12 negatively regulates theanine biosynthesis by repressing CsAlaDC expression. This study uncovered that CsZAT6 and CsZAT12, as core response factors to auxin signaling, differentially regulate CsAlaDC expression to modulate theanine biosynthesis rate and nitrogen flux allocation during tea seedlings radicle development. These findings explore the feedback regulatory mechanism between auxin signaling and theanine metabolism, providing novel molecular insights into the unique nitrogen nutrition distribution system centered on theanine in tea plants.
Sepsis is a life-threatening condition in which early host responses critically determine organ dysfunction, yet strategies targeting this critical window remain limited. We investigated whether pre-septic modulation of host metabolism and gut microbiota could mitigate early organ injury in severe polymicrobial sepsis. Male Sprague-Dawley rats were pretreated for 4 weeks and then subjected to cecal ligation and perforation (CLP). Outcomes were assessed within the first 24 h after sepsis induction, with survival monitored for 7 days. Gut microbiota composition was analyzed at the group level before and after CLP. Early sepsis was characterized by adrenal catecholamine depletion, ileal villus shortening, colonic inflammatory activation, rapid gut microbiota restructuring, and hepatic oxidative stress with selective inflammatory transcriptional activation. Although pretreatments altered baseline gut microbiota composition and partially preserved commensal and short-chain fatty acid-associated taxa, they did not improve survival nor prevent early intestinal and hepatic injury. Early mortality occurred exclusively in meldonium-pretreated animals, indicating a potential trade-off of metabolic preconditioning under severe septic stress. Despite pretreatment-specific modulation of selected antioxidant enzymes, hepatic redox imbalance and stress-associated protein oxidation persisted during early sepsis. Collectively, these observations indicate an apparent dissociation at the group level between gut microbiota remodeling and early gut-liver injury. The first 24 h after sepsis onset thus emerge as a period of limited pharmacological plasticity, underscoring the need for therapeutic strategies that directly target the robust, systemic, host-driven stress mechanisms predominating during this early phase in severe sepsis.
Acute pancreatitis (AP) is a common emergency of the digestive system, with some cases progressing to severe acute pancreatitis (SAP), which threatens life. Intrapancreatic fat deposition (IPFD) denotes the abnormal infiltration of lipid and pathological proliferation of adipocytes in pancreatic parenchyma. It has been demonstrated to bear a close correlation with the heightened risk and progressive development of acute pancreatitis, whereas the specific molecular and cellular mechanisms underlying this association remain poorly understood. This article elaborates on the mechanisms through which IPFD exacerbates acute pancreatitis from the following four perspectives: 1. IPFD causes pancreatic cell damage via lipotoxicity, such as inducing multiple forms of cell death in pancreatic acinar cells, damaging endothelial cells to trigger microcirculatory disorders, and interfering with ductal cells leading to pancreatic duct obstruction. 2. IPFD prematurely activates pancreatic enzymes by inducing adipocyte dysfunction, thereby forming a vicious cycle. 3. IPFD amplifies inflammatory responses by interfering with endocrine regulation. 4. IPFD mediates pancreatic fibrotic dysfunction to amplify AP-associated injury. In addition, this article conducts a thorough review and raises the urgent key issues that remain to be addressed in current research on the association between IPFD and the development of AP, providing new insights for future clinical applications in the future.
Chili pepper (Capsicum annuum L.) produces specialized metabolites, notably the pungent capsaicin and the red capsanthin. Although their biosynthetic pathways are well characterized, the cellular architecture that underpins spatial regulation remains unclear. Here we present a spatiotemporal single-nucleus atlas of pepper development, integrating single-nucleus RNA sequencing and spatial transcriptomics, profiling 332,468 high-quality cells from 57 samples spanning seedlings to mature fruits. This resource reveals a multilayered organization and precisely maps metabolic genes to defined cell types and spatial regions. We further identify laminar patterning transcription factors, including WRKY6, ZAT10 and BTF3, whose layer-specific expression correlates with localized capsanthin accumulation. Our work establishes a framework for dissecting laminar control of specialized metabolism and provides a valuable reference for comparative studies across species. The atlas is openly accessible at http://Pepper-Cell-Atlas.com .