Extracellular vesicles (EVs) are pivotal mediators of intercellular communication within the tumor immune microenvironment (TME). They are broadly categorized into exosomes, microvesicles, and apoptotic bodies based on their distinct biogenesis pathways. Exosomes originate from the endosomal system via multivesicular body fusion, microvesicles bud directly from the plasma membrane, and apoptotic bodies are released during programmed cell death. By shuttling diverse bioactive cargoes—including proteins, lipids, and nucleic acids such as mRNA, miRNA, and DNA—EVs exert dual modulatory effects on tumor initiation, progression, and immune evasion. Importantly, EVs exhibit remarkable compositional heterogeneity that is intrinsically linked to their cellular origin. Tumor-derived EVs (TDEVs) are typically enriched with immunosuppressive molecules like PD-L1, TGF‑β, and miR-21, which promote tumor immune escape and metastasis. In contrast, EVs derived from immune cells, such as dendritic cells or cytotoxic T lymphocytes, often carry immunostimulatory components including antigens, co-stimulatory molecules, and granzymes, thereby potentiating anti-tumor immunity. This review systematically delineates the biogenesis and molecular composition of EVs, with a particular emphasis on their dynamic regulatory functions within the TME. Specifically, we discuss how EVs mediate intricate crosstalk between immune and tumor cells, facilitating signal transfer that reshapes immune surveillance. For instance, TDEVs can induce macrophage polarization toward an M2-like pro-tumor phenotype, while also suppressing natural killer cell cytotoxicity and dendritic cell maturation. The clinical utility of EV-associated biomarkers in liquid biopsy is increasingly recognized. Circulating EVs carry tumor-specific molecular signatures that mirror the genetic and proteomic alterations of primary tumors, enabling non-invasive early diagnosis, molecular subtyping, and real-time monitoring of therapeutic responses. Their natural biocompatibility, low immunogenicity, and intrinsic ability to traverse biological barriers make them ideal candidates for drug delivery systems. This review explores cutting-edge applications, including the use of EVs in immune checkpoint blockade therapy—for instance, engineered EVs displaying anti-PD-1 antibodies or carrying siRNA to silence immunosuppressive genes. Moreover, EV-based tumor vaccines are being developed, leveraging dendritic cell-derived EVs loaded with tumor antigens to elicit potent T cell responses. The feasibility of loading EVs with therapeutic molecules such as chemotherapeutic agents, oncolytic viruses, or CRISPR-Cas9 components is also under active investigation. The advent of engineered EVs has further expanded their therapeutic potential. Through surface modification or cargo encapsulation, EVs can be tailored for targeted delivery and controlled release, enhancing precision immunotherapy. However, several hurdles impede clinical translation. Current isolation and purification methods, such as ultracentrifugation and size-exclusion chromatography, suffer from low yield and purity. Distinguishing EV subpopulations remains technically challenging due to overlapping size and marker expression. Moreover, the lack of standardized protocols for EV production, characterization, and quality control poses significant barriers to regulatory approval and clinical adoption. Looking forward, the convergence of multi-omics technologies with artificial intelligence offers a powerful approach to decipher EV heterogeneity and identify robust diagnostic signatures. Machine learning algorithms can integrate proteomic, transcriptomic, and lipidomic data from large patient cohorts to construct predictive models for cancer diagnosis and prognosis. Concurrently, advances in bioengineering are enabling the design of next-generation EVs with enhanced targeting specificity, on-demand drug release, and reduced off-target effects. Future efforts should also focus on establishing good manufacturing practice (GMP)‑compliant production processes and conducting rigorous preclinical and clinical evaluations. In summary, this review provides a comprehensive overview of EV biology, their multifaceted roles in the TME, and their transformative potential in cancer diagnostics and therapeutics. By addressing current challenges and leveraging emerging technologies, EV-based strategies are poised to revolutionize precision oncology.

Objective: To investigate the protective effects and underlying mechanisms of sodium pyruvate (SP) on RBC storage lesions using an oxidative damage model. Methods: Six units of leukocyte-depleted suspended RBCs (discarded for non-infectious reasons within three days post-collection) were randomly assigned to four groups: negative control (NS), positive control (PS), experimental group 1 (SP1), and experimental group 2 (SP2). Oxidative stress was induced in the PS group by the addition of hydrogen peroxide (H O ), while SP1 and SP2 received SP supplementation at different concentrations (25 mM and 50 mM, respectively) in the presence of H O . After 1 hour of incubation, RBC morphology was assessed microscopically, and biochemical indicators including glutathione (GSH), malondialdehyde (MDA), methemoglobin (MetHb), adenosine triphosphate (ATP), and Na /K -ATPase activity were measured. Results: RBCs in the PS group exhibited pronounced morphological damage, including cell shrinkage and echinocyte formation, whereas both SP-treated groups showed significantly reduced structural injury. SP treatment led to elevated GSH levels and decreased concentrations of MDA and MetHb, suggesting attenuation of oxidative stress. Additionally, SP enhanced intracellular ATP levels and Na /K -ATPase activity, thereby contributing to membrane stability. Notably, the SP2 group (50 mM) demonstrated superior protective effects compared to SP1 (25 mM). Conclusion: Sodium pyruvate effectively attenuates oxidative storage lesions in RBCs, primarily through its antioxidant properties, energy metabolism supporting ability, and celluar membrane stabilizing function. These findings suggest SP as a promising additive for enhancing the quality and safety of stored RBCs.

Traditional Chinese Medicine (TCM), as a treasure of the Chinese nation, plays a significant role in maintaining public health. In 2019, the Central Committee of the Communist Party of China and the State Council proposed for the first time the establishment of a TCM registration and evaluation evidence system that integrates TCM theory, "personal experience" and clinical trials (referred to as the "Three-in-One" System) to promote the inheritance and innovation of TCM. Subsequently, the National Medical Products Administration issued several guiding principles to advance the improvement and implementation of this system. Owing to the complexity of its implementation, there are still differing understandings within the TCM industry regarding the positioning of the "Three-in-One" Registration and Evaluation Evidence System, as well as the connotation and value orientation of the "personal experience." To address this, Academician WANG Qi, President of the TCM Association, China International Exchange and Promotion Association for Medical and Healthcare and TCM master, led a group of academicians, TCM masters, TCM pharmacology experts and clinical TCM experts to convene a "Seminar on Promoting the Implementation of the ′Three-in-One′ Registration and Evaluation Evidence System for Chinese Medicinals." Through extensive discussions, an expert consensus was formed, clarifying the different roles of the TCM theory, "personal experience" and clinical trials within the system. It was further emphasized that the "personal experience" is the core of this system, and its data should be derived from clinical practice scenarios. In the future, the improvement of this system will require collaborative efforts across multiple fields to promote the high-quality development of the Chinese medicinal industry.

BACKGROUND: Spatiotemporal disparities exist in the disease burden of non-communicable diseases (NCDs) attributable to kidney dysfunction, which has been poorly assessed. The present study aimed to evaluate the spatiotemporal trends of the global burden of NCDs attributable to kidney dysfunction and to predict future trends. METHODS: Data on NCDs attributable to kidney dysfunction, quantified using deaths and disability-adjusted life-years (DALYs), were extracted from the Global Burden of Diseases Injuries, and Risk Factors (GBD) Study in 2019. Estimated annual percentage change (EAPC) of age-standardized rate (ASR) was calculated with linear regression to assess the changing trend. Pearson's correlation analysis was used to determine the association between ASR and sociodemographic index (SDI) for 21 GBD regions. A Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2040. RESULTS: Between 1990 and 2019, the absolute number of deaths and DALYs from NCDs attributable to kidney dysfunction increased globally. The death cases increased from 1,571,720 (95% uncertainty interval [UI]: 1,344,420-1,805,598) in 1990 to 3,161,552 (95% UI: 2,723,363-3,623,814) in 2019 for both sexes combined. Both the ASR of death and DALYs increased in Andean Latin America, the Caribbean, Central Latin America, Southeast Asia, Oceania, and Southern Sub-Saharan Africa. In contrast, the age-standardized metrics decreased in the high-income Asia Pacific region. The relationship between SDI and ASR of death and DALYs was negatively correlated. The BAPC model indicated that there would be approximately 5,806,780 death cases and 119,013,659 DALY cases in 2040 that could be attributed to kidney dysfunction. Age-standardized death of cardiovascular diseases (CVDs) and CKD attributable to kidney dysfunction were predicted to decrease and increase from 2020 to 2040, respectively. CONCLUSION NCDs attributable to kidney dysfunction remain a major public health concern worldwide. Efforts are required to attenuate the death and disability burden, particularly in low and low-to-middle SDI regions.
Humans ; Noncommunicable Diseases/epidemiology* ; Global Burden of Disease ; Disability-Adjusted Life Years ; Male ; Female ; Risk Factors ; Middle Aged ; Kidney Diseases/epidemiology* ; Bayes Theorem ; Adult ; Aged ; Global Health ; Quality-Adjusted Life Years

A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNA-seq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5' untranslated regions (5'UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
Animals ; Humans ; Cardiomegaly/physiopathology* ; Ribosomes/physiology* ; Protein Biosynthesis/physiology* ; Mice ; Cardiomyopathy, Dilated/genetics* ; Ribosome Profiling

This study aims to delve into the influences and underlying mechanisms of Banxia Xiexin Decoction(BXD) on the proliferation, apoptosis, invasion, and migration of colon cancer cells. Firstly, the components of BXD in blood were identified by UPLC-MS/MS, and subsequently the content of these components were determined by HPLC. Then, different concentrations of BXD were used to treat both the normal intestinal epithelial cells(NCM460) and the colon cancer cells(HT29 and HCT116). The cell viability and apoptosis were examined by the cell counting kit-8(CCK-8) and flow cytometry, respectively. Western blot was employed to determine the expression of the apoptosis regulators B-cell lymphoma-2(Bcl-2) and Bcl-2-associated X(Bax). The cell wound healing assay and Transwell assay were employed to measure the cell migration and invasion, respectively. Additionally, Western blot was employed to determine the expression levels of epithelial-mesenchymal transition(EMT)-associated proteins, including epithelial cadherin(E-cadherin), neural cadherin(N-cadherin), and vimentin. The protein and mRNA levels of the factors in the poly(ADP-ribose) glycohydrolase(PARG)/poly(ADP-ribose) polymerase 1(PARP1)/nuclear factor kappa-B p65(NF-κB p65) signaling pathway were determined by Western blot and RT-qPCR, respectively. The results demonstrated that following BXD intervention, the proliferation of HT29 and HCT116 cells was significantly reduced. Furthermore, BXD promoted the apoptosis, enhanced the expression of Bcl-2, and suppressed the expression of Bax in colon cancer cells. At the same time, BXD suppressed the cell migration and invasion and augmented the expression of E-cadherin while diminishing the expression of N-cadherin and vimentin. In addition, BXD down-regulated the protein and mRNA levels of PARG, PARP1, and NF-κB p65. In conclusion, BXD may inhibit the malignant phenotypes of colon cancer cells by mediating the PARG/PARP1/NF-κB signaling pathway.
Colonic Neoplasms/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Phenotype ; Signal Transduction/drug effects* ; Cell Proliferation/drug effects* ; Apoptosis ; Cell Movement/drug effects* ; Neoplasm Invasiveness ; HCT116 Cells ; Proto-Oncogene Proteins c-bcl-2/biosynthesis* ; Humans ; Poly (ADP-Ribose) Polymerase-1 ; Glycoside Hydrolases ; bcl-2-Associated X Protein ; NF-kappa B p50 Subunit

Diterpenoid ferruginol is a key intermediate in biosynthesis of active ingredients such as tanshinone and carnosic acid.However, the traditional process of obtaining ferruginol from plants is often cumbersome and inefficient. In recent years, the increasingly developing gene editing technology has been gradually applied to the heterologous production of natural products, but the production of ferruginol in microbe is still very low, which has become an obstacle to the efficient biosynthesis of downstream chemicals, such as tanshinone. In this study, miltiradiene was produced by integrating the shortened diterpene synthase fusion protein,and the key genes in the MVA pathway were overexpressed to improve the yield of miltiradiene. Under the shake flask fermentation condition, the yield of miltiradiene reached about(113. 12±17. 4)mg·L~(-1). Subsequently, this study integrated the ferruginol synthase Sm CYP76AH1 and Sm CPR1 to reconstruct the ferruginol pathway and thereby realized the heterologous synthesis of ferruginol in Saccharomyces cerevisiae. The study selected the best ferruginol synthase(Il CYP76AH46) from different plants and optimized the expression of pathway genes through redox partner engineering to increase the yield of ferruginol. By increasing the copy number of diterpene synthase, CYP450, and CPR, the yield of ferruginol reached(370. 39± 21. 65) mg·L~(-1) in the shake flask, which was increased by 21. 57-fold compared with that when the initial ferruginol strain JMLT05 was used. Finally, 1 083. 51 mg·L~(-1) ferruginol was obtained by fed-batch fermentation, which is the highest yield of ferruginol from biosynthesis so far. This study provides not only research ideas for other metabolic engineering but also a platform for the construction of cell factories for downstream products.
Saccharomyces cerevisiae/genetics* ; Diterpenes/metabolism* ; Metabolic Engineering ; Fermentation ; Abietanes

This study investigated the effects of Rehmanniae Radix Praeparata on striatal neuronal apoptosis in rats with attention deficit hyperactivity disorder(ADHD) based on the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X protein(Bax)/caspase-3 signaling pathway. Twenty-four 3-week-old male spontaneously hypertensive rats(SHR) were randomly divided into a model group, a methylphenidate group(2 mg·kg~(-1)·d~(-1)), and a Rehmanniae Radix Praeparata group(2.4 mg·kg~(-1)·d~(-1)). Age-matched male Wistar Kyoto(WKY) rats were used as the normal control group, with 8 rats in each group. The rats were administered by gavage for 28 days. Body weight and food intake were recorded for each group. The open field test and elevated plus maze test were used to assess hyperactivity and impulsive behaviors. Nissl staining was used to detect changes in striatal neurons and Nissl bodies. Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) fluorescence staining was used to detect striatal cell apoptosis. Western blot was employed to detect the expression levels of Bcl-2, Bax, and caspase-3 proteins in the striatum. The results showed that compared with the model group, Rehmanniae Radix Praeparata significantly reduced the total movement distance, average movement speed, and central area residence time in the open field test, and significantly reduced the ratio of open arm entries, open arm stay time, and head dipping in the elevated plus maze test. Furthermore, it increased the number of Nissl bodies in striatal neurons, significantly downregulated the apoptosis index, significantly increased Bcl-2 protein expression and the Bcl-2/Bax ratio, and reduced Bax and caspase-3 protein expression. In conclusion, Rehmanniae Radix Praeparata can reduce hyperactivity and impulsive behaviors in ADHD rats. Its mechanism may be related to the regulation of the Bcl-2/Bax/caspase-3 signaling pathway in the striatum, enhancing the anti-apoptotic capacity of striatal neurons.
Animals ; Male ; Apoptosis/drug effects* ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Caspase 3/genetics* ; Proto-Oncogene Proteins c-bcl-2/genetics* ; bcl-2-Associated X Protein/genetics* ; Rehmannia/chemistry* ; Attention Deficit Disorder with Hyperactivity/physiopathology* ; Signal Transduction/drug effects* ; Neurons/cytology* ; Rats, Inbred SHR ; Rats, Inbred WKY ; Humans ; Corpus Striatum/cytology* ; Plant Extracts

A targeted metabolomics study was conducted on the bile acid profiles in the liver and feces of rats induced by a high-fat diet and intervened by ginsenoside Rb_1, along with the detection of FXR pathway gene expression in the liver, to explore and clarify its mechanism of action. The content of biochemical indicators in the serum were detected using an automatic biochemical analyzer. Hematoxylin and eosin(HE) staining and oil red O staining were used to detect pathological changes and lipid deposition in the liver. RT-PCR was used to detect the mRNA expression of FXR, small heterodimer partner(SHP), cholesterol 7 alpha-hydroxylase(CYP7A1), and sterol regulatory element-binding protein-1c(SREBP-1c) in the liver. Targeted bile acid metabolomics technology was employed to analyze changes in bile acid profiles in liver tissue and feces, and a correlation analysis was performed between key genes such as FXR, SHP, CYP7A1, SREBP-1c and differential bile acid metabolites. The results showed that ginsenoside Rb_1 significantly reduced the levels of total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C) in the serum, alleviated the large fat vacuoles and lipid deposition in the liver, increased the expression of FXR mRNA in the liver, and decreased the expression of SREBP-1c mRNA. The expression of CYP7A1 and SHP mRNA was increased, but the differences were not statistically significant. Targeted bile acid metabolomics showed that ginsenoside Rb_1 could restore the levels of 9 bile acids in the liver and 8 bile acids in the feces. Ginsenoside Rb_1 also increased the percentage of taurocholic acid(TCA) in the liver(56.78%) and the percentage of 12-ketolithocholic acid(12-KLCA) in the feces(26.10%). Pathway enrichment analysis revealed two pathways involved in bile acid metabolism: primary bile acid biosynthesis and taurine and hypotaurine metabolism. Correlation analysis showed that FXR, SHP, CYP7A1, and SREBP-1c were positively correlated with multiple differential bile acids. These results suggest that ginsenoside Rb_1 may intervene in lipid metabolism disorders induced by a high-fat diet by regulating the FXR pathway and modulating bile acid profiles in the liver and feces.
Animals ; Bile Acids and Salts/metabolism* ; Rats ; Ginsenosides/pharmacology* ; Male ; Receptors, Cytoplasmic and Nuclear/genetics* ; Liver/drug effects* ; Diet, High-Fat/adverse effects* ; Metabolomics ; Rats, Sprague-Dawley ; Feces/chemistry* ; Cholesterol 7-alpha-Hydroxylase/metabolism* ; Sterol Regulatory Element Binding Protein 1/genetics* ; Humans

OBJECTIVE: To explore the early clinical efficacy of a three-stage external treatment with traditional Chinese medicine (TCM) in the treatment of talar bone contusion caused by acute ankle sprain. METHODS: A retrospective analysis was performed on 360 patients with primary lateral ankle sprain admitted from September 2021 to July 2024. Patients with talar bone contusion were selected based on MRI examination, and 73 cases were finally included. According to different treatment methods, they were divided into the observation group and the control group. The observation group consisted of 35 cases, including 16 males and 19 females, aged 24 to 37 years old with an average of (30.34±2.68) years old, and received the three-stage external TCM treatment combined with the "POLICE" protocol. The control group included 38 cases, including 18 males and 20 females, aged 24 to 35 years old with an average of (29.87±2.57) years old, and was treated with the "POLICE" protocol alone. The volume of bone marrow edema (BME) area shown by MRI before treatment and 6 weeks after treatment was measured using 3D Slicer software, and the BME improvement rate was calculated. The "Figure of 8" measurement method was used to assess ankle swelling before treatment and at 1 and 3 weeks after treatment. The visual analogue scale (VAS) was used to evaluate ankle pain before treatment and at 1 and 6 weeks after treatment. At 6 weeks after treatment, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and Karlsson ankle function score system were used to evaluate the improvement of ankle function. RESULTS: A total of 73 patients with talar bone contusion caused by ankle sprain completed the 6-week follow-up. At 6 weeks after treatment, the BME improvement rate in the observation group was (39.18±0.06)%, which was higher than (26.75±0.03)% in the control group, with a statistically significant difference (P<0.05). After 1 week of treatment, the VAS score in the observation group was (2.89±0.72) points, lower than (3.37±0.79) points in the control group, and the difference was statistically significant (P<0.05). The ankle swelling degree in the observation group was (50.20±3.19) cm, lower than (52.00±3.60) cm in the control group, with a statistically significant difference (P<0.05). After 3 weeks of treatment, there was no statistically significant difference in ankle swelling between the two groups. At 6 weeks after treatment, there was no statistically significant difference in VAS scores between the two groups. At 6 weeks after treatment, the AOFAS ankle-hindfoot score and Karlsson score in the observation group were (87.43±4.18) and (82.77±5.93) points, respectively, which were higher than (82.92±4.87) and (76.45±6.85) points in the control group, with statistically significant differences (P<0.05). According to the AOFAS ankle-hindfoot score, 8 cases were excellent and 27 cases were good in the observation group;2 cases were excellent, 33 cases were good, and 3 cases were fair in the control group. The difference between the two groups was statistically significant (χ²=7.089, P=0.029). CONCLUSION The three-stage external TCM treatment combined with the "POLICE" protocol has a significant early clinical efficacy. It can significantly reduce ankle pain and swelling in patients with bone contusion caused by acute lateral ankle sprain, promote the absorption of bone marrow edema, and accelerate the recovery of ankle function.
Ankle Injuries/drug therapy* ; Drugs, Chinese Herbal/administration & dosage* ; Talus/injuries* ; Retrospective Studies ; Administration, Cutaneous ; Magnetic Resonance Imaging ; Humans ; Male ; Female ; Young Adult ; Adult ; Contusions/etiology* ; Visual Analog Scale ; Musculoskeletal Pain/etiology* ; Recovery of Function/drug effects* ; Treatment Outcome ; Follow-Up Studies