ObjectiveTo explore the effects of Yimei Baijiang formula （YMBJF） on colitis-associated colorectal cancer （CAC） and the nuclear factor kappaB （NF-κB） signaling pathway in mice. MethodsSixty male Balb/c mice of 4-6 weeks old were randomized into 6 groups： Normal， model， capecitabine （0.83 g·kg^-1）， and low-， medium-， and high-dose （4.63， 9.25， 18.50 g·kg^-1， respectively） YMBJF. The mouse model of CAC was established by combining azoxymethane （AOM， 10 mg·kg^-1） and dextran sulfate sodium （DSS， 2%）. At the 5^th week after the start of modeling， the capecitabine group and the YMBJF groups were respectively administrated with the corresponding doses of drugs by gavage once a day for a total of 6 weeks. The body weights and general conditions of mice were measured and observed， and the disease activity index （DAI） was scored. The tumors in the colorectal tissue were counted， and the colorectal length was measured. The histological features of the colorectal tissue in each group of mice were observed by hematoxylin-eosin （HE） staining. The levels of inflammatory cytokines including interleukin-6 （IL-6）， interleukin-1β （IL-1β）， and tumor necrosis factor-α （TNF-α） in the serum were determined by enzyme-linked immunosorbent assay （ELISA）. The expression and localization of proliferating cell nuclear antigen-67 （Ki67）， proliferating cell nuclear antigen （PCNA）， and phosphorylated nuclear transcription factor-κB p65 （p-NF-κB p65） proteins were observed by immunohistochemistry （IHC）. The apoptosis of tumor cells was observed by the TUNEL assay. The mRNA levels of IL-6，IL-1β， TNF-α， nuclear transcription factor-κB p65 （NF-κB p65）， NF-κB inhibitor alpha （IκBα）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax） in the colorectal tissue were quantified by Real-time polymerase chain reaction（Real-time PCR）. The protein levels of NF-κB p65， phosphorylated （p）-NF-κB p65， IκBα， p-IκBα， Bcl-2， and Bax in the colorectal tissue were determined by Western blot. ResultsCompared with the model group， each YMBJF group showed decreases in DAI and tumor number （P0.01）， and the medium-dose and high-dose YMBJF groups showed increases in colorectal length （P0.05）. In addition， each YMBJF group showed alleviated colorectal mucosal pathological injury， declined levels of IL-6， IL-1β， and TNF-α in the serum （P0.05）， reduced expression of Ki67 and PCNA （P0.01）， and down-regulated expression of p-NF-κB p65 （P0.05）. The apoptosis in the medium-dose and high-dose YMBJF groups increased （P0.01）. Each YMBJF group and the capecitabine group showed down-regulated mRNA levels of IL-1β， TNF-α， IL-6， NF-κB p65， and Bcl-2 （P0.05） and up-regulated mRNA levels of IκBα and Bax （P0.05）. The mRNA level of IκBα was up-regulated， and that of Bcl-2 was down-regulated （P0.05） in the high-dose YMBJF group. The protein levels of p-IκBα and Bcl-2 were down-regulated （P0.05） in each YMBJF group. The protein levels of IκBα and Bax were up-regulated in the medium-dose and high-dose YMBJF groups （P0.01）， while those of NF-κB p65 and p-NF-κB p65 were down-regulated （P0.05）. ConclusionYMBJF can reduce the number of tumors， reduce the levels of inflammatory factors， promote tumor cell apoptosis， and inhibit tumor cell proliferation by regulating the direct effector molecules of the NF-κB signaling pathway in the mouse model of CRC.

ObjectiveTo explore the effects of Yimei Baijiang formula （YMBJF） on colitis-associated colorectal cancer （CAC） and the nuclear factor kappaB （NF-κB） signaling pathway in mice. MethodsSixty male Balb/c mice of 4-6 weeks old were randomized into 6 groups： Normal， model， capecitabine （0.83 g·kg^-1）， and low-， medium-， and high-dose （4.63， 9.25， 18.50 g·kg^-1， respectively） YMBJF. The mouse model of CAC was established by combining azoxymethane （AOM， 10 mg·kg^-1） and dextran sulfate sodium （DSS， 2%）. At the 5^th week after the start of modeling， the capecitabine group and the YMBJF groups were respectively administrated with the corresponding doses of drugs by gavage once a day for a total of 6 weeks. The body weights and general conditions of mice were measured and observed， and the disease activity index （DAI） was scored. The tumors in the colorectal tissue were counted， and the colorectal length was measured. The histological features of the colorectal tissue in each group of mice were observed by hematoxylin-eosin （HE） staining. The levels of inflammatory cytokines including interleukin-6 （IL-6）， interleukin-1β （IL-1β）， and tumor necrosis factor-α （TNF-α） in the serum were determined by enzyme-linked immunosorbent assay （ELISA）. The expression and localization of proliferating cell nuclear antigen-67 （Ki67）， proliferating cell nuclear antigen （PCNA）， and phosphorylated nuclear transcription factor-κB p65 （p-NF-κB p65） proteins were observed by immunohistochemistry （IHC）. The apoptosis of tumor cells was observed by the TUNEL assay. The mRNA levels of IL-6，IL-1β， TNF-α， nuclear transcription factor-κB p65 （NF-κB p65）， NF-κB inhibitor alpha （IκBα）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax） in the colorectal tissue were quantified by Real-time polymerase chain reaction（Real-time PCR）. The protein levels of NF-κB p65， phosphorylated （p）-NF-κB p65， IκBα， p-IκBα， Bcl-2， and Bax in the colorectal tissue were determined by Western blot. ResultsCompared with the model group， each YMBJF group showed decreases in DAI and tumor number （P0.01）， and the medium-dose and high-dose YMBJF groups showed increases in colorectal length （P0.05）. In addition， each YMBJF group showed alleviated colorectal mucosal pathological injury， declined levels of IL-6， IL-1β， and TNF-α in the serum （P0.05）， reduced expression of Ki67 and PCNA （P0.01）， and down-regulated expression of p-NF-κB p65 （P0.05）. The apoptosis in the medium-dose and high-dose YMBJF groups increased （P0.01）. Each YMBJF group and the capecitabine group showed down-regulated mRNA levels of IL-1β， TNF-α， IL-6， NF-κB p65， and Bcl-2 （P0.05） and up-regulated mRNA levels of IκBα and Bax （P0.05）. The mRNA level of IκBα was up-regulated， and that of Bcl-2 was down-regulated （P0.05） in the high-dose YMBJF group. The protein levels of p-IκBα and Bcl-2 were down-regulated （P0.05） in each YMBJF group. The protein levels of IκBα and Bax were up-regulated in the medium-dose and high-dose YMBJF groups （P0.01）， while those of NF-κB p65 and p-NF-κB p65 were down-regulated （P0.05）. ConclusionYMBJF can reduce the number of tumors， reduce the levels of inflammatory factors， promote tumor cell apoptosis， and inhibit tumor cell proliferation by regulating the direct effector molecules of the NF-κB signaling pathway in the mouse model of CRC.

As a pivotal strategy to alleviate the shortage of organ donors, xenotransplantation has achieved remarkable advances in both pre-clinical and clinical studies in recent years, driven by continuous optimization of gene modification techniques and immunosuppressive regimens. Nevertheless, clinical translation still confronts formidable challenges, including rejection and heightened infection risks, which severely compromise long-term graft survival. Consequently, the role of immunosuppressive regimens in xenotransplantation has become increasingly prominent. This article summarizes the mechanisms underlying xenogeneic immune rejection, the latest developments in immunosuppressive regimens, cutting-edge strategies for inducing immune tolerance and the major hurdles facing clinical xenotransplantation. It delves into potential optimization strategies and directions for future clinical research, aiming to offer theoretical insights and practical guidance for the safe and effective application of clinical xenotransplantation.

Nasopharyngeal carcinoma （NPC） is a malignant tumor originating from the mucosal epithelium of the nasopharynx. In recent years， its incidence and mortality rates have shown a continuous upward trend， and there is still a lack of therapeutic regimens with both favorable efficacy and safety in clinical practice. Mitogen-activated protein kinase （MAPK） signaling pathway plays a key regulatory role in biological processes such as cell proliferation， differentiation， apoptosis and invasion. It is widely involved in the occurrence and progression of NPC， and serves as an important target in the research field of anti-NPC therapy. This article systematically elaborates on the mechanism of action of the MAPK signaling pathway in NPC， and reviews the research status regarding the anti-NPC effect of active components of traditional Chinese medicine （TCM） and TCM compound prescriptions by regulating this signaling pathway. The results show that TCM active components， including flavonoids （luteolin， maackiain， baicalein， etc.）， alkaloids （picrasidine Ⅰ， tetrandrine， etc.）， terpenoids （bakuchiol， cantharidic acid）， as well as traditional Chinese medicine compound formulas （such as Biyan jiedu capsules and Yiqi jiedu formula） can exert effects including inducing autophagy and apoptosis of NPC cells， promoting pyroptosis， reversing drug resistance， blocking epithelial-mesenchymal transition， weakening cell stemness and arresting cell cycle progression by regulating the MAPK signaling pathway， thereby inhibiting the occurrence and development of NPC through multiple pathways.

OBJECTIVE To investigate the mechanism of Xihuang pill （XHP） against diffuse large B-cell lymphoma （DLBCL）. METHODS The active ingredients of XHP and potential therapeutic targets for DLBCL were identified using TCMSP， GeneCards and DisGeNET databases. Protein-protein interaction networks were constructed using the String database and Cytoscape software to screen core components and core targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were then performed. The clinical relevance of core targets was analyzed using the GEPIA and PanCanSurvPlot databases. Molecular docking and molecular dynamics （MD） simulation were conducted to verify the interactions between core components and core targets， and the binding free energy was calculated using the molecular mechanics Poisson-Boltzmann surface area （MM-PBSA） method. The effects of XHP on DLBCL and the related molecular mechanisms were validated using CCK-8 assay， flow cytometry and Western blot. RESULTS Network pharmacology analysis identified 108 active ingredients of XHP and 410 potential therapeutic targets for DLBCL. Six core components （e.g.， 17 beta-estradiol， quercetin） and ten core targets [e.g.， tumor protein 53 （TP53）， proto-oncogene tyrosine-protein kinase Src （SRC）] were obtained. Enrichment analysis indicated that the anti-DLBCL effects of XHP were primarily associated with the apoptotic signaling pathway， the phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway and so on. Clinical correlation analysis revealed that TP53 and SRC expression were significantly up-regulated in DLBCL tissues and associated with poor patient prognosis （P＜0.05）. Molecular docking， MD simulations and MM-PBSA calculations confirmed that the SRC-quercetin complex had a mail：stronger and more stable binding affinity. In vitro experiments demonstrated that XHP concentration-dependently inhibited the proliferation of DLBCL cells； compared with control group， XHP medium- and high-dose groups could significantly induce the apoptosis of SU-DHL2 and SU-DHL4 cells， and significantly down- regulated the expressions of SRC protein， phosphorylated （p）-PI3K/PI3K and p-Akt/Akt in SU-DHL4 cells （P＜0.05）. CONCLUSIONS XHP may inhibit the proliferation and induce the apoptosis of DLBCL cells by regulating the SRC/PI3K/Akt signaling pathway.

Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

ObjectiveThis study aims to elucidate the potential mechanism of Zuojinwan in improving liver fibrosis through hepatic tissue metabolomics analysis. MethodsTwenty-four mice were randomly allocated into normal group， model group ， positive drug group （silymarin， 100 mg·kg^-1）， and Zuojinwan group （Zuojinwan solution， 2.5 g·kg^-1）， with per group six mice. Liver fibrosis model was induced via intraperitoneal injection of olive oil solution with 10% carbon tetrachloride （CCl₄） （0.5 μL·g^-1， three times weekly for 8 weeks） in all groups except the normal group. During the final 4 weeks， the silymarin group received silymarin （100 mg·kg^-1） by gavage thrice weekly， while the Zuojinwan group was administered Zuojinwan solution （2.5 g·kg^-1） under the same regimen. After the last administration， the levels of liver fibrosis indicators and liver injury markers in serum were detected. The pathological morphological changes of the liver tissues were observed. The levels of liver fibrosis markers α-smooth muscle actin （α-SMA） and Collagen Ⅰ（ColⅠ） were detected. Metabolomics was analyzed on mice's liver tissues. The mice's serum was collected for metabolomics analysis. ResultsCompared with the model group， Zuojinwan significantly improved indicators related to liver fibrosis and liver injury. Compared with the normal group， the model group showed significantly elevated levels of fibrosis markers such as laminin （LN）， hyaluronic acid （HA）， procollagen typeⅢ （PC-Ⅲ）， and type Ⅳ Collagen （Ⅳ-C）， while liver injury indicators such as alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， alkaline phosphatase （ALP）， lactate dehydrogenase （LDH）， and total bilirubin （TBIL）， exhibited a marked upward trend （P<0.05）. Compared with the model group， the silymarin group showed a significant decrease in the aforementioned indicators （P<0.05）. Notably， compared with the model group， the Zuojinwan group exhibited a significant reduction in all these indicators （P<0.05）， with efficacy comparable to that of the silymarin group. Zuojinwan reduced mRNA and protein levels of α-SMA and ColⅠ in the liver tissue. Metabolomics results revealed that compared with the model group， Zuojiinwan significantly reduced levels of glucose metabolism-related metabolites such as D-fructose 1，6-bisphosphate （FBP）， nicotinamide adenine dinucleotide phosphate （NADPH）， sodium beta-D-fructose 6-phosphate （F6P）， dihydroxyacetone phosphate （DHAP）， fumaric acid， and D-glucose 6-phosphate （G6P） （P<0.05）. Serum enzyme-linked immunosorbent assay （ELISA） was used to detect glucose metabolism indicators and further validate the regulatory effect of Zuojinwan on glucose metabolism. ConclusionThese results suggest that Zuojinwan may improve liver fibrosis by regulating the dysregulated levels of glucose metabolism during the progression of liver fibrosis.

Liver fibrosis is a chronic liver injury resulting from factors like viral hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis, fatty liver disease, and cholestatic liver disease. Liver transplantation is currently the gold standard for treating severe liver diseases. However, it is limited by a shortage of donor organs and the necessity for lifelong immunosuppressive therapy. Mesenchymal stem cells (MSCs) can differentiate into various liver cells and enhance liver function when transplanted into patients due to their differentiation and proliferation capabilities. Therefore, it can be used as an alternative therapy for treating liver diseases, especially for liver cirrhosis, liver failure, and liver transplant complications. However, due to the potential tumorigenic effects of MSCs, researchers are exploring a new approach to treating liver fibrosis using extracellular vesicles (exosomes) secreted by stem cells. Many studies show that exosomes released by stem cells can promote liver injury repair through various pathways, contributing to the treatment of liver fibrosis. In this review, we focus on the molecular mechanisms by which stem cell exosomes affect liver fibrosis through different pathways and their potential therapeutic targets. Additionally, we discuss the advantages of exosome therapy over stem cell therapy and the possible future directions of exosome research, including the prospects for clinical applications and the challenges to be overcome.

Background: The association of changes in metabolic syndrome (MetS) with cognitive function remains unclear. We explored this association using prospective and Mendelian randomization (MR) studies. Methods: MetS components including high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides were measured at baseline and two follow-ups, constructing a MetS index. Immediate, delayed memory recall, and cognitive function along with its dimensions were assessed by immediate 10- word recall test (IWRT) and delayed 10-word recall test (DWRT), and mini-mental state examination (MMSE), respectively, at baseline and follow-ups. Linear mixed-effect model was used. Additionally, the genome-wide association study (GWAS) of MetS was conducted and one-sample MR was performed to assess the causality between MetS and cognitive function. Results: Elevated MetS index was associated with decreasing annual change rates (decrease) in DWRT and MMSE scores, and with decreases in attention, calculation and recall dimensions. HDL-C was positively associated with an increase in DWRT scores, while SBP and FPG were negatively associated. HDL-C showed a positive association, whereas WC was negatively associated with increases in MMSE scores, including attention, calculation and recall dimensions. Interaction analysis indicated that the association of MetS index on cognitive decline was predominantly observed in low family income group. The GWAS of MetS identified some genetic variants. MR results showed a non-significant causality between MetS and decrease in DWRT, IWRT, nor MMSE scores. Conclusion Our study indicated a significant association of MetS and its components with declines in memory and cognitive function, especially in delayed memory recall.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.