Disruption of the intestinal mucosal barrier caused by gut dysbiosis and metabolic imbalance is the underlying pathology of inflammatory bowel disease (IBD). Traditional Chinese medicine Wuji Wan (WJW) is commonly used to treat digestive system disorders and showed therapeutic potential for IBD. In this interdisciplinary study, we aim to investigate the pharmacological effects of WJW against experimental colitis by combining functional metabolomics and gut-microbiota sequencing techniques. Treatment with WJW altered the profile of the intestinal microbiota and notably increased the abundance of Lactobacillus, thereby facilitating the conversion of tryptophan into indole-3-acetic acid (IAA) and indoleacrylic acid (IA). These indole derivatives activated the aryl hydrocarbon receptor (AhR) pathway, which reduced colonic inflammation and restored the expression of intestinal barrier proteins. Interestingly, the beneficial effects of WJW on gut barrier function improvement and tryptophan metabolism were disappeared in the absence of gut microbiota. Finally, pre-treatment with the AhR antagonist CH-223191 confirmed the essential role of IAA-mediated AhR activation in the therapeutic effects of WJW. Overall, WJW enhanced intestinal barrier function and reduced colonic inflammation in a murine colitis model by modulating Lactobacillus-IAA-AhR signaling pathway. This study provides novel insights into colitis pathogenesis and presents an effective therapeutic and preventive approach against IBD.

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Objective:To analyze the correlation between peripheral blood lymphocyte subsets, especially B cells, and the relapse of autoimmune encephalitis (AE).Methods:A retrospective analysis was conducted on patients with AE who were diagnosed and treated in Peking Union Medical College Hospital from January 2012 to January 2023. The clinical data including gender, age and changes in related indicators of CD19 +B cells, CD16/56 +NK cells, CD3 +T cells, CD4 +T cells, CD8 +T cells, IgG, IgA, and IgM before and after recurrence were analyzed.Binary Logistic regression analysis was applied to the study of correlation between AE recurrence and gender, age, CD19 +B cells, CD16/56 +NK cells, CD3 +T cells, CD4 +T cells, CD8 +T cells, IgG, IgA and IgM. The receiver operating characteristic (ROC) curves of the cells that affect AE recurrence (CD19 +B cells, CD16/56 +NK cells, CD3 +T cells, CD4 +T cells and CD8 +T cells) were plotted separately. Results:A total of 198 eligible AE patients were included, including 98 males and 100 females, aged (39.52±17.91) years. Among these patients, 78 cases had relapses, with a recurrence rate of 39.4%. The results of Logistic regression analysis showed that CD19 +B cells ( B=0.006, P<0.001), CD16/56 +NK cells ( B=0.004, P<0.05), CD3 +T cells ( B=-0.011, P<0.05), CD4 +T cells ( B=0.014, P<0.05) and CD8 +T cells ( B=0.010, P<0.05) were highly correlated with the relapse of AE. ROC curve analysis showed that CD19 +B cells (area under the curve: 0.833, P<0.001, critical value: 73.5/μl; sensitivity: 69.2%, specificity: 86.7%), CD3 +T cells (area under the curve: 0.784, P<0.001), CD4 +T cells (area under the curve: 0.808, P<0.001), and CD8 +T cells (area under the curve: 0.742, P<0.001) all had a certain predictive value for AE relapse. Among all the indicators, the area under the curve of CD19 +B cells was the largest, which had a higher value in predicting AE recurrence. Conclusion:The increase in peripheral blood CD19 +B cells has high predictive value for the relapse of AE.

Metabotropic glutamate receptor 5 (mGluR5) encephalitis is a rare type of anti-cell surface antigen antibody encephalitis mediated by autoimmune mechanisms. This article reported a case of anti-mGluR5 encephalitis. The patient was a 25-year-old young man with a history of Hodgkin′s lymphoma. Due to tumor recurrence, he developed encephalitis symptoms including fever, headache, mental and behavioral abnormalities, memory loss, consciousness disturbance, and seizures after checkpoint immunosuppressive therapy. He was finally diagnosed as anti-mGluR5 encephalitis by positive serum anti-mGluR5 antibodies. Finally, the symptoms alleviated after treatment with hormones and gamma globulin.

Objective:To analyze the clinical characteristics and prognosis of patients with stiff-person syndrome (SPS) associated with glutamic acid decarboxylase (GAD) antibodies.Methods:A retrospective analysis was conducted on demographic characteristics, clinical manifestations, auxiliary examination results, treatment, and prognosis of patients with GAD antibody-related SPS treated at Peking Union Medical College Hospital from January 2015 to July 2023.Results:A total of 33 patients were included, comprising 26 females (78.8%) and 7 males (21.2%), with an onset age of (42±12) years and a disease duration of 24.0 (10.5, 37.5) months. Two cases (6.1%) were diagnosed with tumors, including 1 case with invasive thymoma and 1 case with small cell lung cancer. The majority of patients (87.9%, 29/33) presented with stiffness of trunk and proximal limb muscles, 42.4% (14/33) of patients exhibited episodic spasm, and 54.5% (18/33) of patients were triggered by stimuli such as sound and light. Babinski or Chaddock reflexes were elicited in 33.3% (11/33) of patients. Some patients (36.4%, 16/33) had concurrent limbic encephalitis/epilepsy or cerebellar ataxia (referred to as complex SPS). The median cerebrospinal fluid (CSF) white blood cell count was 2×10 6/L [quartile: 1×10 6/L, 6×10 6/L; range: (0-30)×10 6/L], with mild elevation in 28.0% (7/25) of patients. Multi-channel surface electromyography in 14 out of 21 cases (66.7%) suggested synchronous contraction of agonist and antagonist muscles in a relaxed state. The modified Rankin Scale (mRS) score during the acute phase was 4 (3, 4). All patients received treatment with benzodiazepines or baclofen. Thirty patients (90.9%, 30/33) received first-line immunotherapy, 3 patients (9.1%, 3/33) received second-line immunotherapy with rituximab, and 14 (42.4%, 14/33) received mycophenolate mofetil as long-term immunotherapy. The follow-up period was 16 (10, 42) months, with a median best mRS score of 2; 66.7% (22/33) of patients had a favorable functional prognosis (mRS score≤2), and the recurrence rate was 30.0% (9/30). At the last follow-up, the median mRS score was 2, and 53.3% (16/30) of patients had a favorable functional prognosis. Prognosis was not significantly correlated with gender, age, clinical type, or CSF white blood cell level (all P>0.05). Conclusions:SPS is one of the main clinical phenotypes of GAD antibody-related neuroimmune diseases, commonly observed in middle-aged women, and exhibits a chronic progressive course. Only a minority of patients have concomitant tumors. The diagnosis relies on typical symptoms, GAD antibody testing, and electromyography examination. The initial immune therapy yields good results, but the prognosis for recurrent patients is poor.

A case of idiopathic hypertrophic spinal pachymeningitis is reported. The patient was a middle-aged female, with the course of disease more than 1 year. Clinical manifestations included recurrent fever,headache and backache, and the magnetic resonance imaging showed diffuse enhancement and thickening of the spinal dura mater. Dural biopsy pathology finally confirmed hypertrophic spinal pachymeningitis. After treatment with surgery and immunotherapy, the patient′s clinical symptoms improved.

This article reports a case of primary central nervous system lymphoma（PCNSL）. The patient was a young man with subacute onset，and the disease lasted for more than 8 months and had the main manifestations of gradually aggravated headache and dizziness. Cranial MRI showed ventricular dilatation，hydrocephalus，and meningeal enhancement. Dehydration treatment aiming to reduce intracranial pressure alleviated the symptom of headache in the early stage of the disease；the cerebrospinal fluid was tested positive for anti-GFAP antibodies，and the symptoms were improved temporarily after hormone treatment. However，the symptom of headache aggravated again after hormone reduction. Finally，the patient was diagnosed with PCNSL based on cerebrospinal fluid cytology and cerebrospinal fluid immunocytochemistry staining.

BACKGROUND/OBJECTIVES: To identify modifiable risk factors for type 2 diabetes mellitus and explore the relationship between diet sodium intake and blood glucose levels.MATERIALS/METHODS: Based on inclusion and exclusion criteria, we extracted, analyzed, and assessed the available crossover studies of dietary salt intake restriction and insulin resistance in PubMed, Web of Science, MEDLINE, Embase, Wanfang, and CNKI databases. RESULTS: We included 6 studies with 8 sets of data, covering 485 subjects. I2 statistics results showed insignificant heterogeneity among all data (I 2 = 39.2% < 50%). Thus, a fixed-effect model was adopted for the final pooled effect size. Weighted mean difference and its 95% confidence interval (CI) value was 0.193 (95% CI, 0.129–0.257), and the test of the overall effect showed P < 0.001. The results revealed that the blood glucose levels in the subjects in the low-salt intake group were significantly higher than those in the normal or high-salt intake groups. We also found no significant change occurred after the removal of any study through sensitivity analysis, which confirmed that the outcome we calculated was prudent and credible. The quantitative Egger’s test (P = 0.109 > 0.05) indicated that insignificant publication bias existed. CONCLUSION This meta-analysis highlights the relationship between dietary sodium intake and blood glucose levels. Our findings show that higher blood glucose levels might be expected in hypertensive or normal people with low-salt consumption compared to those with normal or high-salt consumption, although these differences were not clinically significant.Trial Registration: PROSPERO Identifier: CRD42021256998

Objective:To evaluate the significance of copy number variation (CNV) and metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) in the diagnosis of meningeal carcinomatosis (MC).Methods:Ten patients with MC diagnosed in the Department of Neurology of Peking Union Medical College Hospital from March 2022 to June 2022 were consecutively enrolled in this study. The patients were diagnosed according to the criteria of the Chinese expert consensus on the diagnosis of MC by the Chinese Society of Infectious Diseases and Cerebrospinal Fluid Cytology, and the diagnosis of MC was confirmed by CSF cytology. The control group included 10 patients who were diagnosed as autoimmune encephalitis or viral encephalitis. CSF mNGS and CNV analysis were performed simultaneously in all the patients.Results:Of the 10 patients with MC, 6 had lung adenocarcinoma, 4 had breast cancer. CSF mNGS and CNV analysis detected large CNV in 8 of 10 patients with MC, including 4 patients with breast cancer and 4 patients with lung cancer. The results of pathogenic microorganism analysis of CSF mNGS in all the patients were negative. Meanwhile, large CNV was not detected in the control group.Conclusions:CSF CNV can serve as a diagnostic marker for MC. The combination of mNGS and CNV analysis has demonstrated a high positive rate in the diagnosis of MC. The dual-omics analysis of pathogenic microorganisms and CNV has been proposed as a potential strategy to further expand the clinical utility of CSF mNGS in the realm of auxiliary diagnosis.

The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the canonical type IV exporter fold. Herein, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, or ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the transmembrane domains (TMDs), and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-electron microscopy (Cryo-EM) structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB. Moreover, the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle. This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.
Siderophores/metabolism* ; Iron/metabolism* ; Mycobacterium tuberculosis/metabolism* ; Cryoelectron Microscopy ; Adenosine Triphosphate/metabolism* ; ATP-Binding Cassette Transporters