Green prescription is a written prescription aimed at improving health by promoting physical activity and improving diet， with advantages such as high cost-effectiveness， strong feasibility， and minimal harm to patients. The theory of traditional Chinese medicine （TCM） green prescription integrates the health philosophy of "following rule of yin and yang， and adjusting ways to cultivating health"， the exercise philosophy of balancing yin-yang and the five elements， and the dietary philosophy of moderation and balance， which embody core TCM concepts such as treating disease before its onset and harmony between humans and nature. It has also developed traditional exercise practices like Tai Chi， Baduanjin， Wuqinxi， Yi-Gin-Ching， and Qigong， as well as dietary adjustments like medicated diet and herbal wines. However， it is believed that the TCM green prescription currently suffers from insufficient evidence-based research， low patient awareness and acceptance， and weak basic research. Based on this， it is proposed that large-sample clinical trials should be conducted in the future to improve the quality of evidence-based medicine， basic research can be carried out with the help of artificial intelligence and other methods in research design， the hospital information system （HIS） can be used for control at the implementation level， and publicity and patient education can be strengthened through the new media， so as to promote the development and application of the TCM green prescriptions in the field of global health treatment.

Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe-S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.

Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

Phages, as obligate bacterial and archaeal parasites, constitute a virus group of paramount ecological significance due to their exceptional abundance and genetic diversity. These biological entities serve as critical regulators in Earth's ecosystems, driving biogeochemical cycles, energy fluxes, and ecosystem services across terrestrial and marine environments. Within soil microbiomes, phages function as microbial "dark matter," maintaining the soil-plant system balance through precise modulation of the microbial community structure and functional dynamics. Despite the growing research interests in soil phages in recent years, the proportion of such studies in environmental virology remains disproportionately low, which is primarily attributed to researchers' limited familiarity with the research methodologies for phage microecology, incomplete technical frameworks, and inherent challenges posed by soil environmental complexity. To address these challenges, this review synthesizes cutting-edge methodologies for soil phage investigation from four aspects: (1) tangential flow filtration (TFF)-based phage enrichment strategies; (2) integrated quantification approaches combining double-layer agar plating, epifluorescence microscopy, and flow cytometry; (3) multi-omics analytical pipelines leveraging metagenomics and viromics datasets; and (4) computational frameworks merging machine learning algorithms with eco-evolutionary theory for deciphering phage-host interaction networks. Through comparative analysis of methodological principles, technical merits, and application scopes, we establish a comprehensive workflow for soil phage research. Future research in this field should prioritize: (1) construction of soil phage resource libraries, (2) exploration of RNA phages based on transcriptomes, (3) functional characterization of unknown genes, and (4) deep integration and interaction validation of multi-omics data. This systematic methodological synthesis provides critical technical references for addressing fundamental challenges in characterizing soil phages regarding the community structure, functional potential, and interaction mechanisms with hosts.
Bacteriophages/physiology* ; Soil Microbiology ; Ecosystem ; Microbiota ; Metagenomics/methods*

There are different views on the theory of “spleen governs time”， which is still a hot spot in the study of Zangxiang （藏象） theory. Based on Zangxiang time-space view， it is found that the thinking mode of the spleen governing time theory follows space-time logic. It is believed that the different time views of the spleen governing time are all formed based on the space view that the spleen belongs to earth and resides in the center， and the zang time theory is developed with the unified time and space logic. Guided by Zangxiang time-space view， the origin of the spleen belonging to earth and residing in the center is traced， and the theoretical connotation and its clinical application of spleen governing time under different time-space logic are explored with reference to the four season and five zang theory， five season and five zang theory， six season and six zang theory， and eight season and eight zang theory.

Objective:To investigate the effectiveness and safety of low-dose oral misoprostol solution for cervical ripening in late gestation.Methods:This was a prospective cohort study including 396 primiparas with singleton pregnancy who received low-dose oral misoprostol solution for cervical ripening (oral group) in Peking University Third Hospital from March to October 2022. They were further allocated to receive oral misoprostol alone (OA group, n=167) or oral misoprostol in combination with oxytocin/amniotomy (OC group, n=229). Moreover, 218 cases who received vaginal misoprostol for cervical ripening (vaginal group) during the same period in 2021 were reviewed (a retrospective cohort). Among them, 77 were given vaginal misoprostol alone (VA group) and 141 received vaginal misoprostol in combination with oxytocin/amniotomy (VC group). The OA group and VA group (72 and 73 cases) as well as the OC group and VC group (108 and 103 cases) were matched using propensity scores. Basic clinical information, hospital stay, duration of labor induction, uterine hyperstimulation, rate of labor initiation, vaginal delivery rate, rate of delivery within 24 h, duration of labor, neonatal condition, adverse pregnancy outcomes, and other information were compared between different groups. All data were statistically analyzed using independent sample t test, analysis of variance, nonparametric test, Chi-square test, or Fisher's exact probability test. Logistic regression model was used to analyze the factors affecting the labor initiation and the failure of labor induction. Results:The average hospital stay, the duration from medication to labor initiation and the duration from medication to vaginal delivery were significantly shorter in the oral group than those in the vaginal group [(5.4±2.4) vs. (6.5±2.6) d, (34.2±24.1) vs. (38.9±25.7) h, (45.8±25.8) vs. (53.4±27.8) h; t=5.24, 2.10 and 3.39; all P<0.05]. The total labor initiation rate and vaginal delivery rate in the oral group were significantly higher than those in the vaginal group [92.9% (368/396) vs. 83.5% (182/218), 72.2% (286/396) vs. 60.1% (131/218); χ 2=13.43 and 9.50; both P<0.05]. The incidence of failed induction of labor, uterine hyperstimulation, fetal distress, and intrauterine infection in the oral group were lower than those in the vaginal group [2.0% (8/396) vs. 6.9% (15/218), 4.3% (17/396) vs. 17.9% (39/218), 8.8% (35/396) vs. 14.7% (32/218), 1.3% (5/396) vs. 3.7% (8/218); χ 2=9.21, 31.36, 4.93 and 3.93; all P<0.05]. The duration from medication to labor initiation and to vaginal delivery in the OA group were higher than those in the VA group [(25.8±17.0) vs. (17.4±10.8) h, (37.2±18.8) vs. (29.7±13.5) h; t=3.49 and 2.74; both P<0.05]. There were no significant differences in the labor initiation rate, vaginal delivery rate, rate of delivery within 24 h or the incidence of failed induction of labor between the OA and VA groups (all P>0.05). Women in the VA group were more likely to develop uterine hyperstimulation than those in the OA group [19.2% (14/73) vs. 4.2% (3/72), χ2=7.89, P=0.005]. There were no significant differences in the duration from medication to labor initiation or to vaginal delivery between the VC and OC groups (both P>0.05), but the duration were significantly longer than those in the corresponding medication alone group (VC vs. VA groups: (49.7±24.6) vs. (17.4±10.8) h and (61.6±25.7) vs. (29.7±13.5) h, t=5.31 and 5.13, both P<0.05; OC vs. OA groups: (45.3±26.6) vs. (25.8±17.0) h and (56.1±27.2) vs. (37.2±18.8) h, t=10.35 and 9.78, both P<0.05]. The labor initiation rate, vaginal delivery rate and rate of delivery within 24 h in the OC group were higher than those in the VC group [88.9% (96/108) vs. 77% (87/113), 63.0% (68/108) vs. 47.8% (54/113), 10.3% (7/108) vs. 0.0% (0/113); χ 2=5.49, 5.14 and 7.56; all P<0.05]. The incidence of uterine hyperstimulation in the OC group was 4.6% (5/108), which was lower than that in the VC group [18.6% (21/113), χ 2=10.37, P=0.001]. Logistic regression analysis showed that oral misoprostol and gestational age were positively correlated with labor initiation [ OR (95% CI): 2.18 (1.24-3.90) and 1.43 (1.14-1.79)], while maternal age was negatively correlated with labor initiation [ OR (95% CI): 0.90 (0.82-0.98)]. Moreover, failed induction of labor was negatively correlated with oral misoprostol [ OR (95% CI): 0.37 (0.14-0.91)], but positively correlated with maternal age [ OR (95% CI): 1.21 (1.05-1.40)]. Conclusions:Oral administration of low-dose misoprostol solution is as effective as vaginal misoprostol in promoting cervical ripening. Besides, it can shorten the average hospital stay and reduce the incidence of uterine hyperstimulation, suggesting that low-dose oral misoprostol solution is relatively safer and can be used to promote cervical ripening in late gestation.

OBJECTIVES: Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. RESULTS: The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T_1/2), area under the curve (AUC), time to reach maximum concentration (T_max). Compared with the control group, AUC was increased by 23.5%, T_max and T_1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. CONCLUSIONS Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
Humans ; Diabetes Mellitus, Type 2/drug therapy* ; Metformin/therapeutic use* ; Acidosis, Lactic ; Tandem Mass Spectrometry ; Hypoxia ; Glucose

Objective To investigate the therapeutic effect of targeting and killing CD248-positive myofibroblasts on bleomycin-induced pulmonary fibrosis in mice. Methods IgG78-DM1, an antibody-maytansine 1 (DM1) conjugate targeting CD248, was prepared. The drug conjugation efficiency was measured and calculated by UV spectrophotometer, and the identification of IgG78-DM1 was performed through SDS-PAGE and Western blot analysis. In vitro, the binding activity of IgG78-DM1 on CD248-positive myofibroblasts was detected by flow cytometry and the cytotoxicity of IgG78-DM1 to CD248-positive myofibroblasts was evaluated by CCK-8 assay. In vivo, C57BL/6 male mice were randomly divided into control group, idiopathic pulmonary fibrosis group, human IgG-DM1 (hIgG-DM1) control group, and IgG78-DM1 treatment group. Then, the mouse models with pulmonary fibrosis induced by bleomycin were constructed. Two weeks later, the animal models were intravenously injected with IgG78-DM1. After the treatment of two weeks, lung tissues were collected for Masson staining and Sirius Red staining to evaluate the degree of pulmonary fibrosis. Real-time fluorescence quantitative PCR was used to measure the expression levels of CD248, as well as markers of fibroblastic activation including alpha-smooth muscle actin (α-SMA) and type I collagen alpha 1 (COL1A1). The safety of IgG78-DM1 was preliminarily assessed by conducting liver and kidney function tests. Results IgG78-DM1 was successfully prepared, and its drug conjugation ratio was 3.2. The antibody structure remained stable after conjugation, allowing effective binding and cytotoxicity against CD248-positive myofibroblasts. After treatment with IgG78-DM1, the degree of pulmonary fibrosis in mice significantly reduced, accompanied by the decrease of the expression of CD248, α-SMA, and COL1A1. The liver and kidney function of the mice remained at normal levels compared to the normal control group. Conclusion IgG78-DM1 effectively inhibits pulmonary fibrosis in mice by targeting and killing CD248-positive myofibroblasts. The safety of this strategy is preliminarily assessed.
Humans ; Animals ; Mice ; Male ; Mice, Inbred C57BL ; Pulmonary Fibrosis/drug therapy* ; Myofibroblasts ; Antibodies ; Bleomycin ; Antigens, Neoplasm ; Antigens, CD

Metformin is the most common first-line oral hypoglycemic drug ，but there are large individual differences in pharmacokinetic parameters and pharmacodynamics during clinical use. The dosage of some patients should be adjusted to achieve satisfactory therapeutic effect. Pharmacokinetic parameters of metformin are affected by many factors ，including respects of transporter gene polymorphism ，drug interaction ，intestinal flora ，plateau hypoxia and physiological function and so on. In order to guide the clinical individualized use of metformin ，this study reviews the research progress on the influencing factors of metformin pharmacokinetics.