The gut microbiota is regarded as the "eighth organ" of the human body and plays a critical regulatory role in the occurrence and progression of various diseases. Ulcerative colitis （UC） is a chronic inflammatory bowel disease with a complex etiology and a tendency toward recurrent episodes. In recent years， studies have shown that gut microbiota dysbiosis plays a key role in its pathological processes. Meanwhile， an increasing number of studies have demonstrated that imbalances in the gut microbiota and abnormalities in its metabolites are closely associated with the development of atrial fibrillation （AF）. Although UC and AF belong to diseases of the digestive system and cardiovascular system， respectively， both exhibit systemic inflammatory characteristics and are often accompanied by gut microbiota dysregulation and abnormal metabolic products. However， systematic investigations into the mechanisms by which gut microbiota-derived metabolites act in these two diseases remain limited. Based on this， the present study adopts literature review and theoretical analysis methods， taking the "gut microbiota-gut-heart" axis as the entry point， to systematically summarize the signaling networks of three key classes of metabolites， i.e.， short-chain fatty acids （SCFAs）， bile acids （BAs）， and trimethylamine N-oxide （TMAO）， in the comorbidity mechanism of UC and AF. The findings indicate that these metabolites may activate key inflammatory pathways， such as NF-κB and NLRP3， thereby synergistically mediating intestinal barrier dysfunction and systemic inflammation and constructing a potential comorbidity network. On this basis， potential intervention strategies for the treatment of UC-AF comorbidity， including probiotic intervention and fecal microbiota transplantation， are further discussed. This study aims to provide new theoretical evidence and research perspectives for prevention and treatment strategies of cross-system diseases.

Prescription optimization is a crucial aspect in the study of traditional Chinese medicine （TCM） compounds. In recent years， the introduction of mathematical methods， data mining techniques， and artificial neural networks has provided new tools for elucidating the compatibility rules of TCM compounds. The study of TCM compounds involves numerous variables， including the proportions of different herbs， the specific extraction parts of each ingredient， and the interactions among multiple components. These factors together create a complex nonlinear dose-effect relationship. In this context， it is essential to identify methods that suit the characteristics of TCM compounds and can leverage their advantages for effective application in new drug development. This paper provided a comprehensive review of the cutting-edge optimization experimental design methods applied in recent studies of TCM compound compatibilities. The key technical issues， such as the optimization of source material selection， dosage optimization of compatible herbs， and multi-objective optimization indicators， were discussed. Furthermore， the evaluation methods for component effects were summarized during the optimization process， so as to provide scientific and practical foundations for innovative research in TCM and the development of new drugs based on TCM compounds.

Extracellular vesicles (EVs) are crucial for facilitating intercellular communication, promoting cell migration, and orchestrating the immune response. Recently, EVs can diagnose and treat tumors. EVs can be measured as biomarkers to provide information about the type of disease and therapeutic efficacy. Furthermore, EVs with lower immunogenicity and better biocompatibility are natural carriers of chemicals and gene drugs. Herein, we review the molecular composition, biogenesis, and separation methods of EVs. We also highlight the important role of EVs from different origins as biomarkers and drug delivery systems in tumor therapy. Finally, we provide deep insights into how EVs play a role in reversing the immunosuppressive microenvironment.

Plant-derived extracellular vesicles (PDEVs), describe a group of nanoparticles released by plants. These particles are characterized by a lipid bilayer structure containing various proteins, lipids, nucleic acids, and unique metabolites. Although the study on PDEVs is relatively new, having only been around for ten years, they have shown promising development prospects in both basic research and clinical transformation areas. Evidence suggests that PDEVs have excellent application prospects in regulating inflammation and treating tumors. Their distinctive, vesicle-mimicking architecture and stellar biocompatibility render them prime candidates for ferrying various anti-cancer agents, including RNA, proteins, and conventional chemotherapy drugs. Increasingly, studies have shown that PDEVs can be engineered as an innovative platform for combination cancer immunotherapy. Consequently, this paper provides an extensive summary of current developments in engineering methods and strategies for PDEVs in cancer treatment and combined cancer immune therapeutics. The essential characteristics of PDEVs, including the biogenesis process and components, as well as their anti-tumor activity and mechanism, are summarized. Finally, the in vivo safety of PDEVs as delivery vectors and the challenges of scale-up production and clinical transformation are discussed.

Objective To investigate the relationship between daily intake of monounsaturated fatty acids(MUFAs)and polyunsaturated fatty acids(PUFAs)and non-alcoholic fatty liver disease(NAFLD),and to determine the threshold values of daily MUFAs and PUFAs intake for NAFLD risk.Methods Date were collected from the Dryad database.We enrolled a total of 1 068 healthy subjects aged 18 years and older(534 in the control group and 534 with NAFLD group)who had physical check-up in the Affiliated Nanping First Hospital of Fujian Medical University from April 2015 to August 2017.Comprehensive medical histories were obtained through questionnaires;information on dietary intake was collected using a semi-quantitative food frequency questionnaire and daily MUFAs and PUFAs intake were calculated.Baseline characteristics were compared between the two groups,and Logistic regression and restricted cubic spline(RCS)analyses were used to explore the relationship between daily MUFAs or PUFAs intake and NAFLD.Results Compared with the control group,the prevalence of hypertension,tea drinking,body mass index(BMI),daily energy intake,and daily MUFAs and PUFAs intakes were significant higher in patients with NAFLD(all P＜0.05),but the proportion of physical activities was significantly lower(P＜0.05).Logistic regression analysis revealed that after adjusting other confounding factors such as age,gender and BMI,for every 10 g increase in daily MUFAs or PUFAs intake,the risk of NAFLD increased by 53％(95％ CI:1.25-1.87,P＜0.001)and 3.30 times(95％ CI:2.98-6.20,P＜0.001),respectively.RCS indicated an approximately linear relationship between daily MUFAs intake and NAFLD(P for nonlinearity=0.064)and a nonlinear relationship between daily PUFAs intake and NAFLD(P for nonlinearity＜0.05).Subgroup analysis results were generally consistent,and there was statistical evidence of interactions between MUFAs and factors such as gender,hypertension and education level,with interaction between PUFAs and BMI observed(P＜0.05).Conclusion Increased daily intake of MUFAs or PUFAs is significantly associated with an increased risk of NAFLD,and further research is needed to clarify their specific roles in hepatic lipid accumulation.

Objective:To construct and validate a prognostic prediction model for patients with ovarian metastases from colorectal cancer after radical resection.Methods:A retrospective case series analysis was conducted on the clinical and pathological data of 81 patients with colorectal cancer and ovarian metastases who underwent radical resection for ovarian metastases at the Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, between January 2014 and December 2023. The patients were all female, with an age ( M(IQR)) of 49(13) years (range: 22 to 79 years). The primary tumor was located in the colon in 60 cases (74.1%) and in the rectum in 21 cases (25.9%). Univariate and multivariate Cox regression analyses were used to identify independent risk factors affecting prognosis. A risk scoring system was constructed, and patients were assigned to high-risk and low-risk groups based on their risk scores. The predictive performance of the scoring system was assessed, and 5-fold cross-validation was performed to evaluate the model′s stability on the internal dataset. Results:Among the 81 patients with ovarian metastases, a high proportion had T4 stage (58 cases, 71.6%), lymph node positivity (68 cases, 84.0%), and colon cancer (60 cases, 74.1%). Preoperative imaging suggested unilateral ovarian metastasis in 15 patients (23.4%), but pathological examination after bilateral oophorectomy confirmed bilateral ovarian metastases. Among the 17 patients who initially underwent unilateral oophorectomy, 11 developed contralateral ovarian metastases at varying times postoperatively. Univariate Cox proportional hazards regression analysis revealed that positive lymph node ratio ( HR=2.68,95% CI:1.41 to 5.09, P=0.003), N stage ( HR=2.07,95% CI:1.08 to 3.95, P=0.028),maximum diameter of metastatic tumors ( HR=2.27,95% CI:1.04 to 4.96, P=0.040),and peritoneal metastasis or ascites at the time of ovarian metastasis ( HR=2.04,95% CI:1.02 to 4.08, P=0.043) were significantly associated with overall survival in patients with ovarian metastasis from colorectal cancer. Multivariate regression analysis identified that positive lymph node ratio ( HR=3.34,95% CI:1.08 to 10.34, P=0.037) and maximum diameter of metastatic tumors ( HR=2.65,95% CI:1.19 to 5.88, P=0.017) were independent prognostic factors for overall survival following radical oophorectomy in patients with ovarian metastasis from colorectal cancer. Based on the regression coefficients from the multivariate analysis for variables (ovarian metastatic tumor diameter ≥6 cm, positive lymph node ratio ≥0.3,and presence of peritoneal metastasis or ascites), a risk scoring system was developed. Using the optimal cutoff value (154 points) for the risk score,patients were divided into high-risk (19 cases) and low-risk (62 cases) groups. Kaplan-Meier survival curves demonstrated that the high-risk group had significantly lower median overall survival (27 months) and median disease-free survival (22 months) compared to the low-risk group (median overall survival 90 months,median disease-free survival not reached; both P<0.01). Receiver operating characteristic curve analysis showed that the area under the curve(AUC) for predicting 1-,3-,and 5-year overall survival was 0.731(95% CI:0.563 to 0.899), 0.703(95% CI:0.573 to 0.833), and 0.776(95% CI: 0.657 to 0.894), respectively. The AUC for predicting 1-,3-, and 5-year disease-free survival was 0.724(95% CI:0.397 to 0.993),0.710(95% CI:0.514 to 0.906),and 0.688(95% CI:0.478 to 0.898),respectively,indicating good performance of the model.The decision curve analysis showed that the model has good clinical net benefit and the results of the 5-fold cross-validation showed that the model demonstrated stability in the internal dataset. Conclusions:When performing radical resection for ovarian metastasis from colorectal cancer,bilateral oophorectomy should be considered to minimize the risk of postoperative recurrence. Patients with ovarian metastasis from colorectal cancer,characterized by a metastatic tumor diameter ≥6 cm,a positive lymph node ratio ≥0.3,and the presence of peritoneal metastasis or ascites, tend to have a poorer prognosis. Based on these findings,a clinical prognostic scoring system for radical resection of ovarian metastasis from colorectal cancer has been developed to stratify patients into different risk groups and may assist in postoperative risk assessment and management.

Objective To investigate the effects and mechanisms of combined prescriptions of essential oils from five traditional Chinese medicinal herbs,namely peppermint,turmeric,ginger,Tibetan fennel,and cumin,on symptoms related to functional abdominal pain syndrome(FAPS).Methods Gas chromatography-mass spectrometry(GC-MS)was employed to analyze the chemical constituents of five essential oils,while network pharmacology was utilized to predict the key targets and signaling pathways associated with these essential oils in alleviating functional abdominal pain syndrome.A formula design methodology centered on these core targets and signaling pathways was developed for creating new prescriptions.Molecular docking technology was conducted to predict its the underlying mechanisms.Subsequently,animal experiments were performed to assess pharmacological activity,including hot plate tests and acetic acid-induced writhing assays to validate the analgesic effects of the newly formulated prescription,as well as xylene-induced ear swelling tests to evaluate its anti-inflammatory properties.The impact of the essential oil formulation on intestinal peristaltic function was examined through intestinal propulsion experiments.Additionally,enzyme-linked immunosorbent assay(ELISA)methods were employed to measure levels of serotonin(5-HT),prostaglandin E2(PGE2),and gamma-aminobutyric acid(GABA)in brain tissue.Western blot analysis was conducted to determine protein expression levels of TPH1 and SERT in the intestine,along with TPH2 and SERT in the brain.Results The main chemical components in five essential oils were identified and screened(peppermint:12,turmeric:8,ginger:14,cumin:2,fennel:6).Based on the network pharmacology analysis,four new essential oil prescriptions were successfully designed according to the complementary relationship between the five essential oils in improving functional abdominal pain syndrome at the target level,including 4 new prescription named Prescription A,B,C and D,these four prescriptions were all based on ginger and turmeric essential oils,with other essential oils serving as supplements or enhancements.The results of animal experiments showed that Prescription D could significantly reduce the writhe frequency of mice(P<0.05),all the four groups could significantly prolong the pain threshold of mice(P<0.05),and Prescription C had a significant effect on reducing the degree of ear swelling(P<0.05).The prescription of essential oil did not significantly affect the function of peristalsis and the speed of propulsion.The levels of 5-HT and PGE2 in the brain tissue were significantly inhibited(P<0.05),and the level of GABA was significantly increased(P<0.05).Prescription C could reduce the expression of TPH1 in the intestinal tissue(P<0.05),Prescription A,C and D could reduce the expression of TPH2,and all groups had a tendency to increase the expression of SERT in the brain tissue.Conclusion In summary,the therapeutic effects of the four novel prescriptions composed of the five essential oils demonstrated potential in improving symptoms related to FAPS,the mechanism might be through modulating abnormalities in the brain-gut axis system.

Objective:To analyze the clinicopathological factors affecting the prognosis of patients after curative resection of lung metastases (LMs) from colorectal cancer (CRC) and to construct a clinical risk scoring (CRS) model.Methods:This study retrospectively collected clinicopathological data and follow-up information on 132 patients who underwent radical resection of LMs from CRC at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2010 and December 2020. We analyzed the clinicopathological factors influencing patient prognosis using univariate and multivariate Cox proportional hazards regression models, and we developed a risk stratification model for prognostic prediction.Results:The median follow-up duration for the cohort of 132 patients was 54.2 months. During this period, 61 patients (46.2%) experienced recurrence or distant metastasis, resulting in a 5-year DFS rate of 54.1%. Additionally, 33 patients (25.0%) died, corresponding to a 5-year overall survival (OS) rate of 76.7%. Univariate Cox proportional hazards regression model analysis indicated that ten clinicopathological factors were significantly associated with OS (all P＜0.05). These factors include the total number of lymph nodes (LNs) dissected from the primary tumor (PT) <16, the number of negative LNs from the PT <13, pN(+) of the PT, logarithmic odds of positive lymph nodes (LODDS) of the PT ≥-1.1, lymph nodes ratio (LNR) of the PT ≥0.02, preoperative carcinoembryonic antigen (CEA) level before LMs resection ≥10 ng/ml, the presence of hilar/mediastinal LN metastasis, the number of LMs ≥2, the maximum diameter of LMs ≥2.5 cm, and the necessity for hilar/mediastinal lymphadenectomy. Multivariate Cox proportional hazards regression analysis identified the number of negative LNs <13 ( HR=3.01, 95% CI: 1.28-7.03, P=0.011), pN(+) of the PT ( HR=5.04, 95% CI: 1.51-16.84, P=0.009), preoperative CEA level before LMs resection ≥10 ng/ml ( HR=5.39, 95% CI: 1.80-16.19, P=0.003), the number of LMs ≥2 ( HR=2.47, 95% CI: 1.09-5.60, P=0.030), and the necessity for hilar/mediastinal lymphadenectomy ( HR=2.74, 95% CI: 1.15-6.52, P=0.023) as independent prognostic risk factors. Patients were categorized based on independent risk factors, revealing statistically significant differences in OS across the groups with CRS scores of ≤2, 3～4, and ≥5 ( P＜0.001). Conclusions:Independent risk factors associated with LMs from CRC patients include the number of negative LNs <13, pN(+) of the PT, preoperative CEA level before LMs resection ≥10 ng/ml, the number of LMs ≥2, and the necessity for hilar/mediastinal lymphadenectomy. Patients scoring 3 or higher on the CRS model may warrant cautious assessment for the appropriateness of direct surgical treatment.

BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G-Protein-Coupled Receptor Kinase 2/metabolism* ; Arthritis, Rheumatoid/immunology* ; Animals ; Dendritic Cells/metabolism* ; Paroxetine/therapeutic use* ; Proto-Oncogene Proteins c-akt/metabolism* ; Mice ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Lymphocyte Activation/drug effects* ; Female ; T-Lymphocytes/metabolism* ; Middle Aged

In recent years,the clinical implementation of next-generation sequencing(NGS)has demonstrated the critical driving role of spe-cific myeloid-related gene mutations in the clonal evolution of myelodysplastic syndrome(MDS).These molecular genetic abnormalities not only correlate significantly with disease prognosis but also provide actionable molecular targets for precision medicine-era therapies.In cur-rent clinical practice,the Revised International Prognostic Scoring System(IPSS-R)remains the primary tool for guiding risk-adapted treat-ments in patients with MDS.However,real-world outcomes in certain patients still deviate from IPSS-R predictions,highlighting the need to integrate molecular genetic features into traditional prognostic models for enhanced accuracy.This article systematically reviews recent ad-vances in understanding MDS genetic mutations,focusing on their pivotal roles in driving malignant clonal evolution,optimizing risk stratific-ation,and developing personalized treatments.