Patients with depression are more likely to have chronic gastrointestinal (GI) symptoms than the general population, but such symptoms are considered only somatic symptoms of depression and lack special attention. There is a chronic lack of appropriate diagnosis and effective treatment for patients with depression accompanied by GI symptoms, and studying the association between depression and GI disorders (GIDs) is extremely important for clinical management. There is growing evidence that depression is closely related to the microbiota present in the GI tract, and the microbiota-gut-brain axis (MGBA) is creating a new perspective on the association between depression and GIDs. Identifying and treating GIDs would provide a key opportunity to prevent episodes of depression and may also improve the outcome of refractory depression. Current studies on depression and the microbially related gut-brain axis (GBA) lack a focus on GI function. In this review, we combine preclinical and clinical evidence to summarize the roles of the microbially regulated GBA in emotions and GI function, and summarize potential therapeutic strategies to provide a reference for the study of the pathomechanism and treatment of depression in combination with GI symptoms.
Humans ; Gastrointestinal Microbiome/physiology* ; Depression/microbiology* ; Gastrointestinal Diseases/physiopathology* ; Brain ; Animals ; Brain-Gut Axis ; Gastrointestinal Tract/microbiology*

OBJECTIVES: To investigate the effects of formulated granules of Tianma Gouteng Yin (TGY) on motor deficits in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced subacute Parkinson's disease (PD) and explore the possible molecular mechanisms. METHODS: Ninety C57BL/6 mice were randomized equally into 6 groups, including a control group, a PD model group, a NEC-1 (6.5 mg/kg) treatment group, two TGY treatment groups at 5 and 2.5 g/kg, and a Madopar (76 mg/kg) treatment (positive control) group. Mouse models of PD were established by intraperitoneal injection of MPTP (30 mg/kg) for 5 consecutive days with the corresponding treatments for 15 days. The mice were randomly selected for motor function tests. Western blotting was used to detect the changes in expressions of TH, α-syn, RIPK1, RIPK3 and MLKL in the striatum of the mice. Network pharmacology analysis and molecular docking studies were performed to explore TGY-mediated regulation of the necroptosis pathway for PD treatment. RESULTS: Compared with those in the control group, the PD model mice exhibited obvious motor deficits with significantly increased α-syn protein expression and lowered TH protein expression in the striatum. Treatment with NEC-1 obviously improved motor deficits, inhibited the necroptosis pathway, and alleviated the changes in TH and α‑syn proteins in PD mice. Network pharmacology and molecular docking analyses suggested that the therapeutic effect of TGY in PD was associated with the modulation of RIPK1, a key protein in the necroptosis pathway. In PD mouse models, TGY treatment at the two doses significantly improved motor deficits of the mice, increased TH expression, and decreased the expressions of α-syn and necroptosis-related proteins in the striatum. CONCLUSIONS TGY can effectively inhibit the necroptosis pathway, increase TH expression and decrease α-syn expression in the striatum to improve motor deficits in PD mice.
Animals ; Mice, Inbred C57BL ; Mice ; Necroptosis/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Parkinson Disease/drug therapy* ; Disease Models, Animal ; Male

Ketosis is an energy metabolism disorder occurring frequently in periparturient dairy cows,primarily attributed to elevated non-esterified fatty acid(NEFA)levels resulting from nega-tive energy balance(NEB).Excessive NEFA will be incompletely oxidated into large amounts of ketone bodies or be re-esterified and deposit in the liver as a consequence of hepatic limited oxida-tive capacity,ultimately leading to ketosis and fatty liver.Hypoxic microenvironments are com-monly found during the progression of various liver diseases.Hypoxia inducible factor-2 alpha(HIF-2 alpha)has been identified as a crucial regulator of lipid metabolism.However,it is still un-clear the association between HIF-2α and disrupted lipid metabolism in the livers of in ketotic cows.This study aims to investigate the effect of high concentrations of NEFA on HIF-2α expres-sion and cellular oxygen homeostasis through bovine liver tissue and primary hepatocytes.In vivo,hepatic triglyceride(TAG)content was assessed to determine the extent of hepatic lipid accumula-tion,and HIF-2α protein and mRNA levels were analyzed by immunohistochemistry staining,Western blot and qRT-PCR assay in liver tissue samples from dairy cows;in vitro,bovine primary hepatocytes were treated with different concentrations of NEFA.Oil Red O staining and TAG con-tent assay were performed to determine hepatocellular steatosis extent,and immunofluorescence staining.Western blot,and qRT-PCR were performed to analyze HIF-2α expression,in addition,lu-minescent oxygen sensor[Ru(dpp)3]Cl2 was added to indicate intracellular oxygen levels.These results showed a significant increase in TAG content and elevated HIF-2α expression in the liver tissue of ketotic cows,and high concentrations of NEFA induced lipid accumulation,upregulation of HIF-2α expression,and intracellular hypoxia in bovine primary hepatocytes.These findings sug-gested that HIF-2α was significantly"activated"in the liver of ketotic cows and high concentration of NEFA-induced bovine primary hepatocytes,and that high concentrations of NEFA induced in-tracellular hypoxia in vitro.This study provides a potential molecular target for further investiga-tion of the mechanism underlying hepatic lipid metabolism disorders in ketotic cows.

Stereotactic radiation therapy is a crucial approach in the treatment of tumors. However, the precision of stereotactic radiation therapy is influenced by important factors such as fractional tumor motion, image-guided resolution, and the utilization of adaptive techniques. Different image-guided methods and motion management strategies exhibit varying degrees of control over radiation-related toxicity. With the clinical application of magnetic resonance accelerator, it is still unclear whether its excellent soft tissue imaging contrast, adaptive radiotherapy technology, and real-time motion management of the moving target can bring better toxicity control for patients. Hence, the advantages of magnetic resonance accelerator in mitigating radiation-related toxicity, its clinical applications, and the reported post-treatment toxic reactions were comprehensively reviewed in this article.

Objective:To assess the clinicopathological characteristics of non-muscle-invasive bladder cancers (NMIBC) with high expression of human epidermal growth factor receptor 2 (HER2) and to examine the prognostic values of HER2 expression in NMIBC patients with intravesical anthracycline instillation.Methods:A total of 221 NMIBC samples diagnosed between January 1, 2017 and April 15, 2024 were collected. Their clinical, diagnostic and treatment features were analyzed. The expression of HER2 protein and the Ki-67 proliferation index were assessed using immunohistochemistry (IHC). For the patients with HER2 high-expression (IHC 3+), the clinical pathological features (age, gender, tumor grade, Ki-67 expression level, tumor size, and tumor number) were compared with those without (i.e., HER2 IHC 0/1+/2+). The impact of HER2 expression on the recurrence-free survival (RFS) of patients with intravesical anthracycline (epirubicin or pirarubicin) instillation after transurethral resection of bladder tumor (TURBT) was evaluated.Results:Among the 221 NMIBC patients, 30 (13.6%) were HER2 IHC 3+, 142 (64.3%) HER 2+, 46 (20.8%) HER2 1+, and 3 (1.4%) HER2 IHC 0. The proportion of high-grade tumors in patients with HER2 high-expression was higher than that in patients without (83.3% versus 44.5%, P<0.001). Additionally, a high Ki-67 index (≥20%) was more commonly noted in HER2 high-expression tumors ( P=0.003). In the patients treated with intravesical anthracycline instillation, HER2 high-expression was associated with a shorter RFS ( P<0.001). Conclusion:HER2 high-expression seems to be not only associated with worse clinicopathological features of NMIBC but also a poor RFS in NMIBC patients treated with anthracycline instillation after TURBT.

Objective:To explore the expression of chemokine ligand 1(CCL1)in oral squamous cell carcinoma(OSCC)and its effect on the proliferation,migration and invasion of human oral tongue squamous cell carcinoma cells(HSC-4).Methods:28 OSCC tissue samples and clinical characteristic data of patients were collected at the Affiliated Stomatological Hospital of Southwest Medical University between January 2018 and June 2020,as well as 10 normal gingival tissue samples removed during the extraction of impacted teeth.OSCC cells HSC-4 were cultured routinely and divided into the control group(without virus),the NC group(transfected with control lentiviral vector),the shCCL1 group(transfected with knockdown CCL1 lentiviral vector),and the CCL1 group(culture medium containing 60 ng/mL CCL1 recombinant protein).Immunohistochemistry and WB were used to detect the expression of CCL1 in OSCC tissues and cells,and analyze the correlation between its expression level and the clinical features of patients.qPCR,CCK-8 assay,plate cloning assay,cell scratch test,Transwell assay and flow cytometry were used to detect the expression of CCL1 mRNA,the proliferation,migration and invasion abilities and the apoptosis of HSC-4 cells respectively.Results:CCL1 protein was highly expressed in OSCC tissues and HSC-4 cells(all P<0.01)and its expression was related to the clinical stage of tumors(P<0.05).The expression of CCL1 in HSC-4 cells was successfully knocked down(P<0.000 5).Knocking down the expression of CCL1 could inhibit the proliferation(P<0.05 or P<0.01),migration and invasion(all P<0.05)of HSC-4 cells,and promote its apoptosis(all P<0.05).CCL1 recombinant protein treatment resulted in the opposite effects(P<0.05,P<0.01,P<0.000 1).Conclusion:CCL1 is highly expressed in OSCC and its expression is correlated with the clinical stage of OSCC.CCL1 may take part in regulating the proliferation,migration,invasion and apoptosis of HSC-4 cells.

Objective:To investigate the variations and co-alteration of KRAS and HER-family genes in the patients with ampullary carcinoma.Methods:A total of 37 formalin-fixed paraffin-embedded primary ampullary carcinoma specimens, which were collected at Peking Union Medical College Hospital from April 2019 to October 2024 were analyzed for KRAS and HER-family gene mutations using next-generation sequencing (NGS). Immunohistochemistry (IHC) was performed for HER2 protein expression in HER2 mutation cases and fluorescence in situ hybridization (FISH) for further gene status in HER2 IHC 2+cases.Results:In our cohort (22 males, 15 females; 31-82 years old), KRAS gene mutations were detected in 51.4% (19/37) of cases, with G12D being the most frequent abnormality (7/19), followed by G12V (5/19) and Q61R (3/19). Other variants of KRAS gene included G12C, A146T, N116H, and Q61H (each 1/19). In this cohort, 27.0% (10/37) of cases harbored HER-family gene alterations with most frequently in HER2 (6/10) and HER3 genes (missense mutations mainly). Notably, 3 cases (8.1%, 3/37) with coexistence of KRAS and HER-family genes mutations were recognized in our series, including KRAS p.G12D/HER2 p.V842I/HER2 p.V777L (c.2329 G>T)/HER3 p.Asp581Asn, KRAS p.Q61R/HER4 p.D1018H and KRAS p.G12C/HER2 p.R678Q. Additionally, a mutation of HER3 p.V104L (c.310 G>C) was identified in our population. Moreover, 4 novel mutations including HER3 p.V296E, HER3 p.V920L (c.2758 G>T), HER3 p.Asp581Asn, and HER4 p.D1018H were detected. In 6 tumors with HER2 gene changes (16.2%, 6/37), 5 variants with the high proportion of HER2 p.S310Y (3/6) were revealed. A tumor (HER2 IHC 2+) with HER2 p.S310Y presented HER2 gene amplification confirmed by NGS and FISH, and another one (also HER2 IHC 2+) with HER2 p.L755S possessed HER2 gene amplification determined by FISH assay.Conclusion:In ampullary carcinoma, co-alteration of KRAS and HER-family genes is observed, and HER2 gene mutations account for more than half of HER-family gene abnormities, which may be accompanied by gene amplification.

Objective:To investigate the mutation of PIK3CA, AKT1 and PTEN genes in hormone receptor (HR)-positive and HER2-negative invasive breast cancer.Methods:A total of 44 formalin-fixed paraffin-embedded samples from HR-positive/HER2-negative female patients with breast cancer obtained between January 2020 and July 2024 in Peking Union Medical College Hospital were selected. The mutations of PIK3CA, AKT1 and PTEN genes were analyzed by next-generation sequencing (NGS), and the related clinicopathological characteristics were summarized.Results:In the cohort, 31 out of 44 cases (70.5%) exhibited alterations in the PIK3CA, AKT1 and PTEN genes. Of these, 83.9% (26/31) tumors harbored genetic abnormalities involving one gene, including 21 (47.7%, 21/44) PIK3CA, 2 (4.5%, 2/44) PTEN and 3 (6.8%, 3/44) AKT1 gene mutations. Mutations of both PIK3CA and PTEN genes were found in 16.1% (5/31) of specimens. Among the 26 cases with PIK3CA gene mutations, 13 variants were identified, including E542K, E545K, Q546K, H1047R, H1047L, G1049R, M1043I, C420R, P447_L455del, N345K, N345I, K711N and H1047L/V346G. In addition, 7 mutants of PTEN gene were determined (T319 *, T321Qfs *23, Q245 *, Q171H, L108P, Y68Ifs *6 and V343fs). For AKT1 gene mutation, only E17K was observed.Mutations of PIK3CA/AKT1/PTEN genes are more likely to occur over 40 year-old patients.In this cohort, the PIK3CA V346G mutation (co-existent PIK3CA H1047L) and the PTEN V343fs mutation were not found in previous publications. Conclusion:In addition to the predominance of common loci, PIK3CA and PTEN gene mutations also have rare loci mutations in the breast cancer, warranting further analysis with an expanded sample size.

Objective:To investigate the abnormalities of mesenchymal-epithelial transition factor (MET) gene in early-stage lung adenocarcinomas and to provide genetic bases for related clinical studies.Methods:A total of 630 cases of formalin-fixed and paraffin-embedded lung adenocarcinoma specimens with ALK and EGFR double-negativities were collected at Peking Union Medical College Hospital, Beijing, China between July 2020 and April 2022. Forty-three stage Ⅰ-ⅢA tumors with MET exon 14 skipping mutation identified by reverse transcription droplet digital PCR (RT-ddPCR) were identified and then evaluated for MET amplification using fluorescence in situ hybridization (FISH). MET amplification was determined using the ratio of MET to chromosome 7 enumeration probe (CEP7) or the mean of MET gene copy number (GCN).Results:Among the 43 samples with MET exon 14 skipping mutation, MET amplification was detected in 9 cases (9/43, 20.93%), including 1 case of MET/CEP7 ≥2 and GCN ≥5 (1/9), 8 cases of GCN≥5 (8/9), as well as 10 cases with high level of CEP7 (7.00-9.72) which included 5 cases with MET amplification. There were no significant differences in clinicopathological features between the two subgroups of tumors which harbored MET exon 14 skipping mutation with MET amplification versus those without ( P>0.05). Conclusions:Co-occurrence of MET exon 14 skipping mutation and MET amplification or high level of CEP7 is frequently observed in early-stage lung adenocarcinomas. The most common pattern of MET gene amplification is GCN ≥5.

Objective To explore the effects of Danlong Xingnao Prescription on the learning and memory ability of vascular dementia(VD)model rats based onPI3K/Akt/mTOR signaling pathway;To discuss its possible mechanism.Methods VD rat model was prepared using improved bilateral common carotid artery ligation method.Modeling rats were randomly divided into model group,nimodipine group and DanlongXingnao Prescription low-,medium-,high-dosage groups(3.7,7.4,14.8 g/kg),with 10 rats in each group.The sham-operation group only separated the arteries without ligation.Each medication group was given corresponding drugs by gavage,the sham-operation group and the model group were given equal amounts of physiological saline by gavage for 4 consecutive weeks.Morris water maze was used to test the learning and memory ability of rats,morphology of the hippocampus were observed by HE staining,immunohistochemistry was used to detect microvascular density and expression of vascular endothelial growth factor(VEGF),the activity of SOD,GSH-Px and the content of MDA in liver tissue were detected by biochemical method,RT-qPCR and Western blot were used to detect the mRNA and protein expression of PI3K,Akt,mTOR,hypoxia-inducible factor-1α(HIF-1α),VEGF,Bax and Bcl-2 in hippocampal tissue.Results Compared with the sham-operation group,the latency period of evasion was significantly prolonged,and the number of platform crossings was significantly reduced in the model group(P＜0.01),the cells in the hippocampal CA1 region had irregular morphology,loose arrangement,blurred boundaries,nucleolar condensation,and a large number of neuronal necrosis,the microvascular density and VEGF expression significantly increased(P＜0.01),the SOD and GSH-Px activity in hippocampal tissue decreased(P＜0.01),MDA content increased(P＜0.01),the expressions of HIF-1α,VEGF,Bax mRNA and protein in hippocampal CA1 region increased,and PI3K,Akt,mTOR,Bcl-2 mRNA and protein expression decreased(P＜0.01).Compared with the model group,the latency period of evasion were significantly shortened,and the number of platform crossings increased in the Danlong Xingnao Prescription groups(P＜0.05,P＜0.01),neuronal damage in hippocampal CA1 region was alleviated,microvascular density and VEGF expression increased(P＜0.05,P＜0.0 1),the activities of SOD and GSH-Px in hippocampal tissue increased(P＜0.05,P＜0.01),the content of MDA decreased(P＜0.05,P＜0.01),the mRNA and protein expressions of PI3K,Akt,mTOR,HIF-1α,VEGF,Bcl-2 in hippocampal CA1 region increased(P＜0.05,P＜0.01),the expression of Bax mRNA and protein decreased(P＜0.05,P＜0.01).Conclusion Danlong Xingnao Prescription can improve the learning and memory ability of VD model rats,promote angiogenesis,inhibit oxidative stress and apoptosis.The mechanism may be related to the up-regulation of PI3K/Akt/mTOR signaling pathway in hippocampal tissue.