The intestinal barrier is the primary defense that separates the host from the external environment, possessing several crucial physiological functions, including nutrient digestion, absorption, and protection against potentially harmful dietary antigens and pathogenic microorganisms. Nevertheless, various factors, such as diet, medications, circadian rhythm disturbances, gut microbiota, microbial metabolites, and genetic predisposition, can disrupt the intestinal barrier. Such disruption may lead to bacterial translocation, subsequently triggering enterohepatic and systemic inflammation. Impaired intestinal barrier has been implicated in the pathogenesis of numerous diseases, particularly chronic gut and liver diseases. In this review, we will summarize the fundamental functions of intestinal barrier and discuss clinical correlations between intestinal barrier dysfunction and diseases such as colitis, colorectal cancer, and chronic liver diseases including metabolic dysfunction-associated steatohepatitis, alcohol-associated liver disease, and primary sclerosing cholangitis. Additionally, we will also highlight some potential therapeutic strategies aimed at restoring barrier integrity to improve disease management.

OBJECTIVES: To assess the therapeutic effect of aucubin in mice with knee osteoarthritis (KOA) and investigate the underlying mechanism. METHODS: Sixty C57BL/6J mice were randomized equally into sham operation group, KOA model group, glucosamine (positive control) treatment group, and low-, medium-, and high-dose aucubin treatment groups (2, 4, and 8 mg/kg, respectively). KOA mouse models were established by transection of the anterior cruciate ligament (ACL), and the treatment was initiated on day 1 postoperatively and administered weekly for 8 weeks. Safranin O-fast green staining, immunohistochemistry, and microCT were used to evaluate the changes in cartilage pathology, inflammatory protein expression, and subchondral bone volume fraction (BV/TV). The expression levesl of COL2, SOX9, p-P65, IL-1β and MMP13 proteins in the cartilage tissues were detected using Western blotting. In a chondrocyte model with IL-1β treatment for mimicking KOA, the effect of aucubin on chondrogenic differentiation was observed with Alcian blue and Safranin O staining, and cellular COL2, SOX9 and TNF‑α mRNA expressions were detected with RT-qPCR. RESULTS: Compared with those in the model group, the mouse models receiving aucubin treatment showed significantly upregulated COL2 and SOX9 protein levels and downregulated p-P65, IL-1β and MMP13 expressions in the cartilage tissues. In the IL-1β-induced chondrocyte model, aucubin treatment significantly upregulated the mRNA expressions of SOX9 and COL2 but lowered the mRNA expression of TNF-α. Alcian blue and Safranin O staining confirmed that aucubin promoted the synthesis of cartilage extracellular matrix and enhanced chondrogenic differentiation of the cells. CONCLUSIONS Aucubin can effectively alleviate KOA in mice by inhibiting NF‑κB-mediated cartilage inflammation, promoting cartilage matrix synthesis, and improving subchondral bone microstructure.
Animals ; Mice, Inbred C57BL ; Mice ; Osteoarthritis, Knee/drug therapy* ; Signal Transduction/drug effects* ; NF-kappa B/metabolism* ; Iridoid Glucosides/therapeutic use* ; SOX9 Transcription Factor/metabolism* ; Chondrocytes/drug effects* ; Male ; Interleukin-1beta/metabolism* ; Matrix Metalloproteinase 13/metabolism* ; Collagen Type II/metabolism* ; Disease Models, Animal

Five new terpenoids, including two vibsane-type diterpenoids (1, 2) and three iridoid allosides (3-5), together with eight known ones, were isolated from the leaves and twigs of Viburnum odoratissimum var.sessiliflorum. Their planar structures and relative configurations were determined by spectroscopic methods, especially 2D NMR techniques. The sugar moieties of the iridoids were confirmed as β-D-allose by GC analysis after acid hydrolysis and acetylation. The absolute configurations of neovibsanin Q (1) and dehydrovibsanol B (2) were determined by quantum chemical calculation of their theoretical electronic circular dichroism (ECD) spectra and Rh₂(OCOCF₃)₄-induced ECD analysis. The anti-inflammatory activities of compounds 1, 3, 4, and 5 were evaluated using an LPS-induced RAW264.7 cell model. Compounds 3suppressed the release of NO in a dose-dependent manner, with an IC₅₀ value of 55.64 μmol·L^-1. The cytotoxicities of compounds 1-5 on HCT-116 cells were assessed and the results showed that compounds 2 and 3 exhibited moderate inhibitory activities with IC₅₀ values of 13.8 and 12.3 μmol·L^-1, respectively.
Terpenes/pharmacology* ; Viburnum/chemistry* ; Molecular Structure ; Diterpenes/chemistry* ; Plant Leaves/chemistry*

Objective:To summarize the therapeutic effect of deep brain stimulation (DBS) for dystonia.Methods:Detailed clinical information and peripheral blood of children with dystonia at Peking University First Hospital from April 2017 to July 2020 were collected.The motor scores of Burke-Fahn-Marsden Dystonia Rating Scale were recorded of the dystonia before and after the treatment of DBS.Whole-exome sequencing was performed on children with dystonia.Then the effect of DBS was evaluated.Results:A total of 32 cases of patients with dystonia treated with DBS were enrolled, including 16 males and 16 females.Twelve cases were treated with globus pallidus internus DBS, and 20 cases were treated with subthalamic nucleus DBS.Twenty cases (62.5%) with pathogenic gene mutations were detected.Pathogenic variants in PANK2 (9 cases), KMT2B(3 cases), GNAO1 (2 cases), GCDH (2 cases), PINK1(1 case), NDUFAF6(1 case), DYT27(1 case) and ADCY5(1 case) were found.The follow-up period was 1 month to 3 years and 8 months.Only 1 case had local infection due to improper home care.The postoperative improvement was 5.66%-95.92%. Conclusions:All patients have a certain degree of relief after DBS without obvious adverse reactions.DBS is an effective treatment for pediatric dystonia.

In the past 30 years, with the advancement of functional neurosurgery, neuroelectrophysiology and neuroimaging, deep brain stimulation (DBS), as a new tool for the treatment of dyskinesia, has been considered to have underwent the fastest development in this field.Many patients with dyskinesias have significantly improved their main clinical symptoms after treatment with DBS, some of the improvement are even dramatic.Due to its minimally invasive characteristics, reversibility and adjustability, DBS therapy has been increasingly used in the treatment of dystonia in children.Hereditary dystonia is the most common type of dyskinesia in children, and there is no effective treatment yet.Recently, some dyskinesia at home and abroad centers have carried out DBS treatment for pediatric hereditary dystonia and achieved some encouraging results.Now, the effect of DBS in the treatment of hereditary dystonia in children and the main process of DBS treatment were mainly discussed, and shared the experience based on the clinical practices of Multidisciplinary Collaborative Diagnosis and Treatment Center for Children′s Motor Disorders, Peking University First Hospital.

Objective: To evaluate the effect of ATP-binding cassette B subfamily member 1 transporter (ABCB1) C3435T genetic polymorphism on the efficacy of postoperative analgesia. Methods: One hundred American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients, aged 18-60 yr, scheduled for elective thoracoscopic lobectomy under general anesthesia, were enrolled in this study.The gene mutation of ABCB1 C3435T was detected, and the patients were divided into 3 groups according to the genotypes: wild homozygote group (CC group), mutation heterozygote (CT group) and mutation homozygote group (TT group). Patient-controlled intravenous analgesia was performed with sufentanil after operation.Visual analogue scale (VAS) scores at 24 and 48 h after operation, postoperative consumption of sufentanil, sleep quality score at 24 h after operation and state-trait anxiety score were recorded. Results: Compared with CC group, VAS scores at 24 h after operation and postoperative consumption of sufentanil were significantly decreased in TT and CT groups, and the state-trait anxiety score was significantly decreased in TT group and increased in CT group (P<0.05). Compared with TT group, VAS scores at 24 h after operation, postoperative consumption of sufentanil and the state-trait anxiety score were significantly increased in CT group (P<0.05). There was no significant difference in sleep quality scores among the three groups (P>0.05). Conclusion ABCB1 C3435T genetic polymorphism may be one of the mechanisms of the individual variation in the efficacy of postoperative analgesia.

Objective: To study the mutational characteristics of KCNT1 and its clinical features in children with early-onset epileptic encephalopathy. Methods: Retrospective analysis of clinical data of 175 children with early onset epilepsy from the Department of Pediatrics at Peking University First Hospital from January 2012 to December 2017. Gene-based analysis was performed on children with targeted capture second-generation sequencing and the source of mutations was verified by PCR-Sanger. The clinical features of children with KCNT1 mutation were summarized. Results: In 175 infants with early-onset epileptic encephalopathy, 6 children were found to have KCNT1 mutations, all of which were new mutations with an overall mutation rate of 3.4% (6/175). All the mutations were missense mutations. The age of onset was from 2 days to 32 days. Five children were diagnosed with epilepsy of infancy with migrating focal seizure, one case was diagnosed with epilepsy, focal seizures, focal seizures with generalization. A total of 6 children were treated with multi-antiepileptic drugs. The disease in 4 patients were partially controlled, while in 2 patients, the disease was not significantly alleviated. One patient died of "severe pneumonia" at one year and 4 months of age. Then, four cases were treated with quinidine. The seizure frequency had no change in 3 cases, the frequency decreased and then relapsed in 1 case. The case once ketogenic diet and failed. Ketogenic diet treatment was applied to 5 cases, no significant effect was achieved. All the 6 patients had severe developmental delay. They could not sit alone, follow the light and objects and had no language. Conclusions The mutation of KCNT1 gene is mainly de novo. The onset of the disease was early, and mostly occurs in neonate and early infancy. The main seizure type was epilepsy of infancy with migrating focal seizure. Patients usually had severe psychomotor developmental delay. Antiepileptic drugs are ineffective. The efficacy of quinidine was not significant. Though, it still need studies on a large sample.

This study aimed at investigating the effects of Chinese herbal compound Qi Kui granules on urine protein and inflammatory markers in patients with type 2 diabetic nephropathy (DN) based on the treatment of regular western medication.A randomized,parallel controlled method was involved in the present trial,and patients diagnosed with type 2 DN were randomly divided into the Chinese herb group and the control group.Regular treatment of angiotensin Ⅱ receptor blocker (ARB) in western medicine was administered in the two groups with the additional treatment of Qi Kui granules for the Chinese herb group.All the patients revisited the doctor every 4 weeks during the observation period within a 12-week course of the observation.Urinary albumin to creatinine ratio (UACR),urinary albumin excretion rate (UAER) and inflammatory cytokines in the two groups were determined.As a result,seventy-two patients in aggregate were included in the study,while 32 patients of the control group and 31 patients of the Chinese herb group effectively accomplished the observation.After the 12-week treatments,UACR and UAER were significantly decreased in the two groups (P ＜ 0.01),while the efficacy of the Chinese herb group was better than that of the control group (P ＜ 0.05).Compared with the control group,the levels of serum IL-6,tumor necrosis factor α (TNF-α),transforming growth factor f1 (TGF-f1) and urinary monocyte chemoattractant protein (MCP-1) / Cr significantly decreased after the 12-week treatment (P ＜ 0.01).It was concluded that the Chinese herbal compound Qi Kui granules successfully mitigated proteinuria in DN patients.The improvement of glomerular inflammation for renoprotection should be the mechanism behind this.

OBJECTIVETo analyze the ultra microstructures and the expression of platelet peroxidase (PPO) of megakaryocytes from bone marrow, their clinical manifestations and laboratory characteristics in patients with acute megakaryoblastic leukemia (AMKL).

METHODSKaryocytes from bone marrow of 22 AMKL patients were divided into two parts by lymphocyte separation liquid, one part was used to prepare the ordinary transmission electron microscope specimens to observe the morphological structures of megakaryocytes, the other was used to prepare the histochemical specimens of platelet peroxidase to analyze the positive reaction of PPO in AMKL, which were coupled with the patients' data of with bone marrow morphology, cell chemistry, and chromosome karyotype examination.

RESULTSMegakaryocytes from 17 of 22 patients were in the first stage, less than 20 µm in diameter, the nucleis were round, the cytoplasm contained microtubules, membranous vesicles and minute dense granules, no demarcation membrane system and surface-connected canalicular system, less dense granules and α-granules; Megakaryocytes in 5 cases were mainly in the first stage, while containing second and third stage megakaryocytes; the positive rate of PPO in megakaryocytes of 22 patients was 0-80%. The primitive and naive megakaryocytes were found in bone marrow smears of 22 cases, CD41 staining of the megakaryocytes was detected in the primitive and naive megakaryocytes, and more complex chromosome karyotype anomalies were observed.

CONCLUSIONThe majority of megakaryocytes in AMKL patients were the first stage ones, the rest were second and third stage ones, and the positive PPO reaction was significantly different. CD41 staining of the megakaryocytes was specific with complex chromosome karyotypeswere.

Blood Platelets ; enzymology ; Bone Marrow ; pathology ; Cell Count ; Chromosome Aberrations ; Chromosome Disorders ; Humans ; Karyotyping ; Leukemia, Megakaryoblastic, Acute ; diagnosis ; pathology ; Megakaryocytes ; pathology ; Peroxidase ; metabolism ; Staining and Labeling

Magnetotactic bacteria (MTB), a group of phylogenetically diverse organisms that use their unique intracellular magnetosome organelles to swim along the Earth's magnetic field, play important roles in the biogeochemical cycles of iron and sulfur. Previous studies have revealed that the bacterial actin protein MamK plays essential roles in the linear arrangement of magnetosomes in MTB cells belonging to the Proteobacteria phylum. However, the molecular mechanisms of multiple-magnetosome-chain arrangements in MTB remain largely unknown. Here, we report that the MamK filaments from the uncultivated 'Candidatus Magnetobacterium casensis' (Mcas) within the phylum Nitrospirae polymerized in the presence of ATP alone and were stable without obvious ATP hydrolysis-mediated disassembly. MamK in Mcas can convert NTP to NDP and NDP to NMP, showing the highest preference to ATP. Unlike its Magnetospirillum counterparts, which form a single magnetosome chain, or other bacterial actins such as MreB and ParM, the polymerized MamK from Mcas is independent of metal ions and nucleotides except for ATP, and is assembled into well-ordered filamentous bundles consisted of multiple filaments. Our results suggest a dynamically stable assembly of MamK from the uncultivated Nitrospirae MTB that synthesizes multiple magnetosome chains per cell. These findings further improve the current knowledge of biomineralization and organelle biogenesis in prokaryotic systems.
Actins ; chemistry ; metabolism ; Adenosine Triphosphate ; metabolism ; Bacteria ; classification ; metabolism ; Bacterial Proteins ; chemistry ; metabolism ; Magnetospirillum ; classification ; metabolism ; Nucleotides ; metabolism ; Phylogeny ; Substrate Specificity