Objective: The precise mechanisms driving intervertebral disc degeneration (IVDD) development remain unclear, but evidence suggests a significant involvement of gut microbiota (GM) and blood metabolites. We aimed to investigate the causal relationships between GM, IVDD, and blood metabolites using Mendelian randomization (MR) analysis. Methods: We utilized the summary statistics of GM from the MiBioGen consortium, 1400 blood metabolites from the genome-wide association studies (GWAS) Catalog, and IVDD data from the FinnGen repository, which are sourced from the largest GWAS conducted to date. Employing bidirectional MR analyses, we investigated the causal relationships between GM and IVDD. Additionally, we conducted 2 mediation analyses, 2-step MR and multivariable MR (MVMR), to identify potential mediating metabolites. Results: Five bacterial genera were causally associated with IVDD, while IVDD did not show a significant causal effect on GM. In the 2-step MR analysis, Eubacteriumfissicatenagroup, RuminococcaceaeUCG003, Lachnoclostridium, and Marvinbryantia genera, along with metabolites X-24949, Pimeloylcarnitine/3-methyladipoylcarnitine (C7-DC), X-24456, histidine, 2-methylserine, Phosphocholine, and N-delta-acetylornithine, were all significantly associated with IVDD (all p < 0.05). MVMR analysis revealed that the associations between Eubacteriumfissicatenagroup genus and IVDD were mediated by X-24949 (8.1%, p = 0.024); Lachnoclostridium genus and IVDD were mediated by histidine (18.1%, p = 0.013); and RuminococcaceaeUCG003 genus and IVDD were mediated by C7-DC (-7.5%, p = 0.041). Conclusion The present MR study offers evidence supporting the causal relationships between several specific GM taxa and IVDD, as well as identifying potential mediating metabolites.

Objective: The precise mechanisms driving intervertebral disc degeneration (IVDD) development remain unclear, but evidence suggests a significant involvement of gut microbiota (GM) and blood metabolites. We aimed to investigate the causal relationships between GM, IVDD, and blood metabolites using Mendelian randomization (MR) analysis. Methods: We utilized the summary statistics of GM from the MiBioGen consortium, 1400 blood metabolites from the genome-wide association studies (GWAS) Catalog, and IVDD data from the FinnGen repository, which are sourced from the largest GWAS conducted to date. Employing bidirectional MR analyses, we investigated the causal relationships between GM and IVDD. Additionally, we conducted 2 mediation analyses, 2-step MR and multivariable MR (MVMR), to identify potential mediating metabolites. Results: Five bacterial genera were causally associated with IVDD, while IVDD did not show a significant causal effect on GM. In the 2-step MR analysis, Eubacteriumfissicatenagroup, RuminococcaceaeUCG003, Lachnoclostridium, and Marvinbryantia genera, along with metabolites X-24949, Pimeloylcarnitine/3-methyladipoylcarnitine (C7-DC), X-24456, histidine, 2-methylserine, Phosphocholine, and N-delta-acetylornithine, were all significantly associated with IVDD (all p < 0.05). MVMR analysis revealed that the associations between Eubacteriumfissicatenagroup genus and IVDD were mediated by X-24949 (8.1%, p = 0.024); Lachnoclostridium genus and IVDD were mediated by histidine (18.1%, p = 0.013); and RuminococcaceaeUCG003 genus and IVDD were mediated by C7-DC (-7.5%, p = 0.041). Conclusion The present MR study offers evidence supporting the causal relationships between several specific GM taxa and IVDD, as well as identifying potential mediating metabolites.

Objective: The precise mechanisms driving intervertebral disc degeneration (IVDD) development remain unclear, but evidence suggests a significant involvement of gut microbiota (GM) and blood metabolites. We aimed to investigate the causal relationships between GM, IVDD, and blood metabolites using Mendelian randomization (MR) analysis. Methods: We utilized the summary statistics of GM from the MiBioGen consortium, 1400 blood metabolites from the genome-wide association studies (GWAS) Catalog, and IVDD data from the FinnGen repository, which are sourced from the largest GWAS conducted to date. Employing bidirectional MR analyses, we investigated the causal relationships between GM and IVDD. Additionally, we conducted 2 mediation analyses, 2-step MR and multivariable MR (MVMR), to identify potential mediating metabolites. Results: Five bacterial genera were causally associated with IVDD, while IVDD did not show a significant causal effect on GM. In the 2-step MR analysis, Eubacteriumfissicatenagroup, RuminococcaceaeUCG003, Lachnoclostridium, and Marvinbryantia genera, along with metabolites X-24949, Pimeloylcarnitine/3-methyladipoylcarnitine (C7-DC), X-24456, histidine, 2-methylserine, Phosphocholine, and N-delta-acetylornithine, were all significantly associated with IVDD (all p < 0.05). MVMR analysis revealed that the associations between Eubacteriumfissicatenagroup genus and IVDD were mediated by X-24949 (8.1%, p = 0.024); Lachnoclostridium genus and IVDD were mediated by histidine (18.1%, p = 0.013); and RuminococcaceaeUCG003 genus and IVDD were mediated by C7-DC (-7.5%, p = 0.041). Conclusion The present MR study offers evidence supporting the causal relationships between several specific GM taxa and IVDD, as well as identifying potential mediating metabolites.

Objective: The precise mechanisms driving intervertebral disc degeneration (IVDD) development remain unclear, but evidence suggests a significant involvement of gut microbiota (GM) and blood metabolites. We aimed to investigate the causal relationships between GM, IVDD, and blood metabolites using Mendelian randomization (MR) analysis. Methods: We utilized the summary statistics of GM from the MiBioGen consortium, 1400 blood metabolites from the genome-wide association studies (GWAS) Catalog, and IVDD data from the FinnGen repository, which are sourced from the largest GWAS conducted to date. Employing bidirectional MR analyses, we investigated the causal relationships between GM and IVDD. Additionally, we conducted 2 mediation analyses, 2-step MR and multivariable MR (MVMR), to identify potential mediating metabolites. Results: Five bacterial genera were causally associated with IVDD, while IVDD did not show a significant causal effect on GM. In the 2-step MR analysis, Eubacteriumfissicatenagroup, RuminococcaceaeUCG003, Lachnoclostridium, and Marvinbryantia genera, along with metabolites X-24949, Pimeloylcarnitine/3-methyladipoylcarnitine (C7-DC), X-24456, histidine, 2-methylserine, Phosphocholine, and N-delta-acetylornithine, were all significantly associated with IVDD (all p < 0.05). MVMR analysis revealed that the associations between Eubacteriumfissicatenagroup genus and IVDD were mediated by X-24949 (8.1%, p = 0.024); Lachnoclostridium genus and IVDD were mediated by histidine (18.1%, p = 0.013); and RuminococcaceaeUCG003 genus and IVDD were mediated by C7-DC (-7.5%, p = 0.041). Conclusion The present MR study offers evidence supporting the causal relationships between several specific GM taxa and IVDD, as well as identifying potential mediating metabolites.

Colorectal cancer stands as a leading cause of cancer-related morbidity and mortality globally,with liver metastases being a significant determinant of patient prognosis.Conventional diagnostic methods,includ-ing imaging studies and biomarker testing,frequently exhibit inadequate sensitivity and specificity,underscoring the necessity for more advanced technologies.Recent advancements in genomics,transcriptomics,proteomics,me-tabolomics,and epigenomics have revolutionized our understanding of the biological mechanisms driving colorectal cancer.These methodologies enable comprehensive analyses of genetic mutations,gene expression profiles,protein modifications,and metabolic reprogramming,all of which are pivotal to the metastatic process.This article high-lights the advanced capabilities of artificial intelligence(AI)technologies in processing complex multi-omics data,thereby enhancing diagnostic accuracy and supporting personalized treatment strategies.It also addresses the challenges AI encounters in multi-omics analyses,such as ensuring data quality,improving model interpretability,and facilitating clinical translation.Additionally,it explores the potential integration of emerging technologies like single-cell sequencing and spatial omics into large-scale,multicenter studies to further enhance the clinical utility of these tools.

Purpose To summarize the clinicopathological features of pheochromocytoma and paraganglioma(PPGL)and discuss the potential correlation between SDHB immunophenotype and prognosis in PPGLs.Methods A retrospective analysis was conducted on 30 samples of PPGL along with their corresponding clinicopathological informa-tion,SDHB immunophenotype characteristics,and the risk of recurrence and metastasis.Results The study included 20 extra-adrenal paragangliomas and 10 pheochromocytoma cases.The male-to-female ratio was 13∶17,with a mean age of 56(range from 21 to 79).Four cases recurred,one case resulted in death and five cases failed to follow-up.All recurrent or fatal cases were paraganglioma patients.Among the 30 cases,3 had multiple nodular lesions,and the re-maining cases were single nodule.The neck was the most frequent site for paraganglioma(6/20),followed by retroper-itoneum(5/20).Histologically,the tumors displayed a variable"zellballen"architecture with a highly vascularized stroma.The chief cells had abundant pale eosinophilic cytoplasm and slightly to moderately atypical nuclei,and pe-ripherally located sustentacular cells.Positive immunoreactivity with markers of neuroendocrine cells,including Syn,CgA,and GATA3,was found in tumor chief cells,which were nonreactive for CK.The sustentacular cells exhibited positive immunoreactivity for the S-100 protein.SDHB deficiency was demonstrated in 12 of 30 cases,with only one case being pheochromocytoma.The recurrence rate in SDHB-deficient group was higher than that in the positive group(33.3％vs 6.7％).Only one case of paraganglioma developed distant metastasis and death.Conclusion SDHB de-ficiency was predominantly observed in paragangliomas and serverd as an indipentent factor for metastatic risk in PPGLs.It was closely associated with younger age at onset,invasiveness,extra-adrenal tumorgenesis,and a high rate of tumor recurrence.

Objective:To investigate the regulatory role and mechanism of synaptic vesicle protein 2A (SV2A) in apoptosis of drug-resistant epilepsy neurons.Methods:One hundred and fifty specific pathogen-free (SPF) Sprague-Dawley (SD) rats were randomly numbered; 20 rats were selected as a normal control group (NC group), and the remaining 130 rats were subjected to chronic epilepsy models of lithium-pilocarpine. Phenobarbital and phenytoin sodium for 2 weeks were given to these rats after modeling; fanally, 94 rats with chronic epilepsy were divided into a drug-resistant group (phenobarbital and phenytoin sodium-resistant epilepsy [PRE] group, reduction in episodes<50%, n= 55) and a drug-sensitive group (phenobarbital and phenytoin sodium-sensitive epilepsy [PSE] group, reduction in episodes by≥50%, n=38). Rats in the PRE group were further randomly divided into 5 groups, namely a up-regulated-SV2A PRE group (UPRE group), a down-regulated-SV2A PRE group (DPRE group), a up-regulated-SV2A control group (UPRC group), a down-regulated-SV2A control group (DPRC group), and a non-transfected PRE group; different types of lentivirus were given to the first 4 groups via stereotactic brain injection. Ten days after lentiviral transfection, virus detection was performed; and 2 weeks after lentiviral transfection, occurrence of epileptic seizures was observed, and after that, rats were sacrificed and the hippocampal tissues were collected for subsequent experiments. Western blotting was used to detect the expressions of SV2A, cyclophilin A (CyPA), apoptosis-inducing factor (AIF), and superoxide dismutase 2 (SOD2) in the cell nucleus or mitochondria; coimmunoprecipitation experiment was performed to observe the interaction among SV2A, CyPA and AIF proteins; immunofluorescent co-staining was used to observe the CyPA/AIF localization; mitochondrial damage was detected by electron microscopy; ATP content in the hippocampal tissues was detected by luciferase method, 8-hydroxy-2-deoxyguanosine (8-OHDG) expression was detected by immunofluorescent staining, and neuronal apoptosis rate was calculated by double staining with neuron-specific nuclear protein (NeuN) and TUNEL. Results:(1) Confocal microscopy revealed that the hippocampal tissues in the 4 transfected groups showed green fluorescence inherent to the lentivirus, indicating successful viral infection. Compared with the UPRC group, the UPRE group had significantly reduced frequency of epileptic seizures and seizure duration ( P<0.05). (2) Western blotting showed that, in mitochondria, the UPRE group had significantly higher expressions of SV2A (0.475± 0.105 vs. 0.136±0.043), CyPA (0.473±0.041 vs. 0.175±0.047), AIF (0.443±0.058 vs. 0.131±0.037), and SOD2 (0.457±0.037 vs. 0.152±0.038) compared with the UPRC group ( P<0.05); the DPRE group had significantly decreased expressions of SV2A (0.038±0.013 vs. 0.184±0.047), CyPA (0.041±0.010 vs. 0.214±0.040), AIF (0.040±0.019 vs. 0.175±0.046), and SOD2 (0.043±0.017 vs. 0.187±0.039) compared with the DPRC group ( P<0.05). In the cell nucleus, the UPRE group had significantly lower expressions of AIF (0.336±0.084 vs. 0.649±0.209) and CyPA (0.331±0.086 vs. 0.620±0.162) compared with the UPRC group ( P<0.05); the DPRE group had statistically higher expressions of AIF (0.771± 0.180 vs. 0.519±0.144) and CyPA (0.738±0.223 vs. 0.488±0.091) compared with the DPRC group ( P< 0.05). (3) Co-immunoprecipitation experiment results showed that the bidirectional precipitation results of SV2A and AIF, SV2A and CyPA, and AIF and CyPA were all positive, suggesting existence of interactions. (4) Immunofluorescent co-staining showed that the fluorescence changes of CyPA and AIF were consistent. (5) Electron microscopy showed that mitochondria in the NC group had intact structure; mitochondria in the UPRE group, UPRC group, DPRC group and DPRE group showed swelling and cristae fragmentation; among them, injury in the UPRE group was relatively less severe than that in the UPRC group, while that in the DPRC group was more severe than that in the DPRE group. (6) Compared with the UPRC group, the UPRE group had statistically higher ATP content ( P<0.05); compared with the DPRC group, the DPRE group had significantly lower ATP content ( P<0.05).(7) Immunofluorescent staining results showed that the UPRE group had significantly lower 8-OHDG expression than the UPRC group ( P<0.05); compared with the DPRC group, the DPRE group had statistically higher 8-OHDG expression ( P<0.05). (8) The UPRE group had significantly lower NeuN-TUNEL double staining positive rate than the UPRC group ( P<0.05); compared with the DPRC group, the DPRE group had significantly higher NeuN-TUNEL double staining positive rate ( P<0.05). Conclusion:SV2A can play a role in the apoptosis of hippocampal neurons in rats with drug-resistant epilepsy by regulating the nuclear translocation of AIF/CyPA and mitochondrial damage.

Objective:To investigate the clinical, pathological, and molecular biological characteristics of gastric hepatoid adenocarcinoma (HAS) in order to provide reference for clinical treatment.Methods:Thirty-two patients diagnosed with hepatoid adenocarcinoma after radical gastrectomy for gastric cancer at Shanxi Cancer Hospital were included from January 2019 to December 2021. Immunohistochemistry, in situ hybridization, and next-generation sequencing (NGS) methods were used to analyze immune markers and molecular characteristics in the pathological tissues from 32 patients with HAS. Cox regression analysis and Kaplan-Meier method were used to analyze the prognostic factors of overall survival and disease-free survival.Results:Among the 32 patients with HAS, 26 were male, 6 were female; aged 28-77 years, with an median age 62.0 (53.8, 67.2) years. Fifteen cases of HAS were located in the cardia, 10 cases in the antrum, and 7 cases in the body of the stomach. The maximum diameter of the mass was 3-10 cm, and mainly ulcerative in gross. The immunohistochemistry and in situ hybridization results showed that the positive rates of AFP, SALLA4, and Glypican-3 were 68.8% (22/32), 68.8% (22/32), 78.1% (25/32), respectively; Seven patients had microsatellite status of dMMR. Two cases of HER2 gene amplification and 2 cases of EB virus positivity. The NGS results showed that HAS was often accompanied by multiple gene mutations, with 23 cases having ≥ 2 gene mutations and 6 cases having ≥10 gene mutations. The TP53 gene had the highest mutation frequency; 4 cases had genetic structural variations; 28 cases had copy number variation. In addition, there were 7 cases of MSI-H and 9 cases of TMB-H. Follow-up results showed that 12 cases died, 9 cases developed metastasis, and the shortest survival time was 5 months.Conclusions:Gastric HAS is a type of tumor with high invasiveness and poor prognosis. The combined detection of AFP, SALLA4 and Glypican-3 can improve the diagnostic rate of tumors. dMMR/MSI-H and TMB-H patients in HAS are significantly higher than those in ordinary gastric cancer, and the high frequency mutation genes in HAS are often accompanied by multiple potential therapeutic targets. Immunotherapy combined with chemotherapy and targeted therapy are expected to become the treatment direction of HAS.

Objective: The precise mechanisms driving intervertebral disc degeneration (IVDD) development remain unclear, but evidence suggests a significant involvement of gut microbiota (GM) and blood metabolites. We aimed to investigate the causal relationships between GM, IVDD, and blood metabolites using Mendelian randomization (MR) analysis. Methods: We utilized the summary statistics of GM from the MiBioGen consortium, 1400 blood metabolites from the genome-wide association studies (GWAS) Catalog, and IVDD data from the FinnGen repository, which are sourced from the largest GWAS conducted to date. Employing bidirectional MR analyses, we investigated the causal relationships between GM and IVDD. Additionally, we conducted 2 mediation analyses, 2-step MR and multivariable MR (MVMR), to identify potential mediating metabolites. Results: Five bacterial genera were causally associated with IVDD, while IVDD did not show a significant causal effect on GM. In the 2-step MR analysis, Eubacteriumfissicatenagroup, RuminococcaceaeUCG003, Lachnoclostridium, and Marvinbryantia genera, along with metabolites X-24949, Pimeloylcarnitine/3-methyladipoylcarnitine (C7-DC), X-24456, histidine, 2-methylserine, Phosphocholine, and N-delta-acetylornithine, were all significantly associated with IVDD (all p < 0.05). MVMR analysis revealed that the associations between Eubacteriumfissicatenagroup genus and IVDD were mediated by X-24949 (8.1%, p = 0.024); Lachnoclostridium genus and IVDD were mediated by histidine (18.1%, p = 0.013); and RuminococcaceaeUCG003 genus and IVDD were mediated by C7-DC (-7.5%, p = 0.041). Conclusion The present MR study offers evidence supporting the causal relationships between several specific GM taxa and IVDD, as well as identifying potential mediating metabolites.

Hypercholesterolemia is a significant risk factor for the development of atherosclerosis. 2',3',5'-Tri-O-acetyl-N ⁶-(3-hydroxyphenyl) adenosine (IMM-H007), a novel AMPK agonist, has shown protective effects in metabolic diseases. However, its impact on cholesterol and triglyceride metabolism in hypercholesterolemia remains unclear. In this study, we aimed to elucidate the effects and specific mechanisms by which IMM-H007 regulates cholesterol and triglyceride metabolism. To achieve this goal, we used Apoe ^-/- and Ldlr ^-/- mice to establish a hypercholesterolemia/atherosclerosis model. Additionally, hepatocyte-specific Ampka1/2 knockout mice were subjected to a 5-week high-cholesterol diet to establish hypercholesterolemia, while atherosclerosis was induced via AAV-PCSK9 injection combined with a 16-week high-cholesterol diet. Our results demonstrated that IMM-H007 improved cholesterol and triglyceride metabolism in mice with hypercholesterolemia. Mechanistically, IMM-H007 modulated the AMPKα1/2-LDLR signaling pathway, increasing cholesterol uptake in the liver. Furthermore, IMM-H007 activated the AMPKα1-FXR pathway, promoting the conversion of hepatic cholesterol to bile acids. Additionally, IMM-H007 prevented hepatic steatosis by activating the AMPKα1/2-ATGL pathway. In conclusion, our study suggests that IMM-H007 is a promising therapeutic agent for improving hypercholesterolemia and atherosclerosis through the activation of AMPKα.