Search

ABSTRACTMoraxella catarrhalis is a major cause of chronic obstructive pulmonary disease. Toll-like receptor 2 (TLR2) plays an important role in the inflammatory response in host respiratory epithelial cells. M. catarrhalis induces an inflammatory immune response in respiratory epithelial cells that is mostly dependent on TLR2. However, the mechanisms by which this pathogen adheres to and invades the respiratory epithelium are not well understood. The present study aimed to reveal the role of TLR2 in M. catarrhalis adhesion to and invasion into alveolar epithelial cells, using molecular techniques. Pretreatment with the TLR2 inhibitor TLR2-IN-C29 enhanced M. catarrhalis adhesion to A549 cells but reduced its invasion, whereas the agonist Pam3CSK4 reduced both M. catarrhalis adhesion and invasion into A549 cells. Similarly, M. catarrhalis 73-OR strain adhesion and invasion were significantly reduced in TLR2−/− A549 cells. Moreover, the lung clearance rate of the 73-OR strain was significantly higher in TLR2−/− C57/BL6J mice than in wild-type (WT) mice. Histological analysis showed that inflammatory responses were milder in TLR2−/− C57/BL6J mice than in WT mice, which was confirmed by a decrease in cytokine levels in TLR2−/− C57/BL6J mice. Overall, these results indicate that TLR2 promoted M. catarrhalis adhesion and invasion of A549 cells and lung tissues and mediated inflammatory responses in infected lungs. This study provides important insights into the development of potential therapeutic strategies against M. catarrhalis and TLR2-induced inflammatory responses.

BackgroundThis study aimed to explore the distribution of intestinal and pharyngeal microbiota on the first day of life in preterm infants and compare the composition of microbiota in infants delivered by cesarean section or vaginally.MethodsThis study included 44 late preterm infants with a gestational age of 34–36 + 6 weeks. Stool and throat swab samples were collected from the preterm infants on the first day of life. The infants were divided into cesarean section and vaginal delivery groups. Illumina NovaSeq high-throughput sequencing technology was used to sequence the V3-V4 hypervariable region of the 16S rRNA gene of all bacteria in the samples. Venn diagram was used to identify shared operational taxonomic units (OTUs) in the intestines and pharynges. Microbial analysis was conducted at the phylum and genus levels, and α and β diversity comparisons were performed.Results(1) Gestational age may have significantly affected the microbial colonization of the intestines and pharynges of preterm infants on the first day after birth (p ≤ 0.001). (2) More OTUs were detected in the pharynx than in the intestines, both have a total of 819 shared OTUs. Proteobacteria, Firmicutes, and Bacteroidota were the dominant phyla in both. At the genus level, Streptococcus had a lower relative abundance in stool samples (0.5%) compared to throat samples (0.5% vs. 22.2%, p = 0.003). 3) The relative abundance of Streptococcus in pharyngeal samples was 26.2% in the cesarean section group much higher than the 3.8% in the vaginal delivery group (p = 0.01).ConclusionThe early postnatal period is a critical time for the establishment of an infant's microbiota. Gestational age at birth may influence microbial colonization, while birth weight, gender, and mode of delivery do not. The intestinal and pharyngeal microbiota composition of preterm infants on the first day after birth showed high similarity, but larger samples are needed for further validation.

Abstract Acute pancreatitis (AP) is currently among the most prevalent digestive diseases. The pathogenesis of AP remains elusive, and there is no specific treatment. Therefore, identifying novel therapeutic targets is imperative for effective management and prevention of AP. In this study, we conducted a comprehensive transcriptomic analysis of peripheral blood from patients with AP and the pancreatic tissue from a mouse model of AP. Our analyses revealed that mouse model of AP exhibited a higher enrichment of mitogen-activated protein kinase signaling, endocytosis, apoptosis and tight junction pathways than the control. Subsequent weighted gene co-expression network analysis identified 15 gene modules, containing between 50 and 1000 genes each, which demonstrated significant correlations within samples from patients with AP. Further screening identified four genes (ACSL4, GALNT3, WSB1, and IL1R1) that were significantly upregulated in severe acute pancreatitis (SAP) in both human and mouse samples. In mouse models of SAP, ACSL4 was significantly upregulated in the pancreas, whereas GALNT3, WSB1, and IL1R1 were not. Lastly, we found that a commercially available ACSL4 inhibitor, PRGL493, markedly reduced IL-6 and TNFα expression, alleviated pancreatic edema and necrosis, and diminished the infiltration of inflammatory cells. In conclusion, this study comprehensively depicts the key genes and signaling pathways implicated in AP and suggests the potential of ACSL4 as a novel therapeutic target for SAP. These findings provide valuable insights for further exploration of therapeutic strategies for SAP.

Background: The Klebsiella oxytoca complex is an opportunistic pathogen that has been recently identified as an actual complex. However, the characteristics of each species remain largely unknown. We aimed to study the clinical prevalence, antimicrobial profiles, genetic differences, and interaction with the host of each species of this complex. Methods: One hundred and three clinical isolates of the K. oxytoca complex were collected from 33 hospitals belonging to 19 areas in China from 2020 to 2021. Species were identified using whole genome sequencing based on average nucleotide identity. Clinical infection characteristics of the species were analyzed. Comparative genomics and pan-genome analyses were performed on these isolates and an augmented dataset, including 622 assemblies from the National Center for Biotechnology Information. In vitro assays evaluating the adhesion ability of human respiratory epithelial cells and survivability against macrophages were performed on randomly selected isolates. Results: Klebsiella michiganensis (46.6%, 48/103) and K. oxytoca (35.92%, 37/103) were the major species of the complex causing human infections. K. michiganensis had a higher genomic diversity and larger pan-genome size than did K. oxytoca. K. michiganensis isolates with blaoxy-5 had a higher resistance rate to various antibiotics, antimicrobial gene carriage rate, adhesion ability to human respiratory epithelial cells, and survival rate against macrophages than isolates of other species. Conclusion: Our study revealed the genetic diversity of K. michiganensis and firstly identified the highly antimicrobial-resistant profile of K. michiganensis carrying blaoxy-5.

Abstract Systemic lupus erythematosus (SLE), a severe autoimmune disorder, is characterized by systemic inflammatory response, autoantibody accumulation and damage to organs. The dysregulation of double-negative (DN) T cells is considered as a crucial commander during SLE. Neddylation, a significant type of protein post-translational modification (PTM), has been well-proved to regulate T cell-mediated immune response. However, the function of neddylation in SLE is still unknown. Here, we reported that neddylation inactivation with MLN4924, a specific inhibitor of NEDD8-activating enzyme E1 (NAE1), or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development. Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells, contributing to the apoptosis of the accumulated DN T cells in lupus mice. Then double knockout (KO) lupus-prone mice (Ube2m -/- Bim -/- lpr) were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression. Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression. Clinically, we also found that in SLE patients, the proportion of DN T cells was raised and their apoptosis was reduced. Moreover, compared to healthy groups, SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels. Meantime, the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients. Altogether, our findings provide the direct evidence about the function of neddylation during lupus, suggesting a promising therapeutic approach for this disease.

ObjectiveTo analyze the clinical epidemiological characteristics including clinical features, disease prognosis of pneumococcal meningitis (PM), and drug sensitivity of S. pneumoniae isolates in Chinese children.MethodsA retrospective analysis was performed on the clinical, laboratory microbiological data of 160 hospitalized children less than 15 years of age with PM from January 2019 to December 2020 in 33 tertiary hospitals in China.ResultsA total of 160 PM patients were diagnosed, including 103 males and 57 females The onset age was 15 days to 15 years old, and the median age was 1 year and 3 months. There were 137 cases (85.6%) in the 3 months to

ObjectiveTo investigate whether an incubation time of 5 days (Aerobic/F, Anaerobic/F) and 14 days (Myco/F) blood culture bottles is sufficient to prevent false-negative results.MethodsWe evaluated 1,244 blood bottles (344 patients) defined as negative by the BACTEC™ FX system. We also reviewed published cases and our own cases of bloodstream infection caused by Cryptococcus neoformans and simulated different scenarios, including different inoculation concentrations, bottle types, and clinical isolates.ResultsTwo bottles (0.16%) were found to contain C. neoformans when subcultured and Gram stained. A 5-day protocol with Aerobic/F bottles was insufficient for the growth of C. neoformans in some cases, and C. neoformans grew better in Myco/F bottles than in Aerobic/F bottles.ConclusionSubculturing and Gram staining after a 5-day protocol were important for the detection of C. neoformans, and Myco/F bottles should be collected for the blood culture of C. neoformans.

Abstract Background Aneuploidy is the most frequent cause of early-embryo abortion. Any defect in chromosome segregation would fail to satisfy the spindle assembly checkpoint (SAC) during mitosis, halting metaphase and causing aneuploidy. The mitotic checkpoint complex (MCC), comprising MAD1, MAD2, Cdc20, BUBR1 and BUB3, plays a vital role in SAC activation. Studies have confirmed that overexpression of MAD2 and BUBR1 can facilitate correct chromosome segregation and embryo stability. Research also proves that miR-125b negatively regulates MAD1 expression by binding to its 3′UTR. However, miR-125b, Mad1 and Bub3 gene expression in aneuploid embryos of spontaneous abortion has not been reported to date. Methods In this study, embryonic villi from miscarried pregnancies were collected and divided into two groups (aneuploidy and euploidy) based on High-throughput ligation-dependent probe amplification (HLPA) and Fluorescence in situ hybridization (FISH) analyses. RNA levels of miR-125b, MAD1 and BUB3 were detected by Quantitative real-time PCR (qRT-PCR); protein levels of MAD1 and BUB3 were analysed by Western blotting. Results statistical analysis (p

p-coumaric acid (p-CA), a common plant phenolic acid with multiple bioactivities, has a lipid-lowering effect. As a dietary polyphenol, its low toxicity, with the advantages of prophylactic and long-term administration, makes it a potential drug for prophylaxis and the treatment of nonalcoholic fatty liver disease (NAFLD). However, the mechanism by which it regulates lipid metabolism is still unclear. In this study, we studied the effect of p-CA on the down-regulation of accumulated lipids in vivo and in vitro. p-CA increased a number of lipase expressions, including hormone-sensitive lipase (HSL), monoacylglycerol lipase (MGL) and hepatic triglyceride lipase (HTGL), as well as the expression of genes related to fatty acid oxidation, including long-chain fatty acyl-CoA synthetase 1 (ACSL1), carnitine palmitoyltransferase-1 (CPT1), by activating peroxisome proliferator-activated receptor α, and γ (PPARα and γ). Furthermore, p-CA promoted adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and enhanced the expression of the mammalian suppressor of Sec4 (MSS4), a critical protein that can inhibit lipid droplet growth. Thus, p-CA can decrease lipid accumulation and inhibit lipid droplet fusion, which are correlated with the enhancement of liver lipases and genes related to fatty acid oxidation as an activator of PPARs. Therefore, p-CA is capable of regulating lipid metabolism and is a potential therapeutic drug or health care product for hyperlipidemia and fatty liver.

Context Dexamethasone (DXM) has an anti-immunoinflammatory effect, and is often used in acute kidney injury (AKI). However, the effects of DXM on albumin (ALB) have not been fully studied. Objective To investigate the effects of DXM on ALB production and renal function. Materials and methods Male Wistar rats were divided into normal and DXM groups (0.25, 0.5, 1 mg/kg for 5 days) (n = 15) for a dose-dependent study. Rats were divided into normal group and DXM groups (0.5 mg/kg for 3, 5, 7 days) (n = 9) for a time-dependent study. In AKI experiment, rats were divided into normal (saline), cisplatin (CP, 5 mg/kg, i.v.), CP + DXM groups (0.25, 0.5 and 1 mg/kg, i.m.) (n = 16). The blood and the organs were isolated for analysis. Results In normal, serum ALB (sALB) and serum total protein (sTP) increased in DXM group with sALB increased 19.8–32.2% (from small to large dosages); and 30.2–32.5.6% (from 3 to 7 days of DXM); sTP 15.7–22.6% and 14.2–24.3%; urine ALB (uALB) 31.5–392.3%, and 1047.2–1390.8%; urine TP (uTP) 0.68–173.1% and 98.0–504.9%, compared with normal groups. DXM increased the mRNA expression of Cebp and Hnf, suppressing podocin. In AKI, DXM decreased serum BUN (53.7%), serum Cre (73.4%), sALB (30.0%), sTP (18.7%), uALB (74.5%), uTP (449.3%), rescuing the suppressed podocin in kidney. Conclusions DXM acts on Cebp and Hnf and promotes ALB production. This finding helps to evaluate the rationale of DXM for kidney injury.

Anemoside B4 (B4) is a saponin that is extracted from Pulsatilla chinensis (Bge.), and Regel exhibited anti-inflammatory, antioxidant, antiviral, and immunomodulatory activities. However, its hypoglycemic activity in diabetes mellitus has not been evaluated. Here, we explored the effect of B4 on hyperglycemia and studied its underlying mechanism of lowering blood glucose based on hyperglycemic rats in vivo and L6 skeletal muscle cells (L6) in vitro. The rats were fed a high-fat diet (HFD) for one month, combined with an intraperitoneal injection of 60 mg/kg streptozotocin (STZ) to construct the animal model, and the drug was administrated for two weeks. Blood glucose was detected and the proteins and mRNA were expressed. Our study showed that B4 significantly diminished fasting blood glucose (FBG) and improved glucose metabolism. In addition, B4 facilitated glucose utilization in L6 cells. B4 could enhance the expression of glucose transporter 4 (GLUT4) in rat skeletal muscle and L6 cells. Mechanistically, B4 elevated the inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Furthermore, we confirmed the effect of B4 on glucose uptake involved in the enhancement of GLUT4 expression in part due to PI3K/AKT signaling by using a small molecule inhibitor assay and constructing a GLUT4 promoter plasmid. Taken together, our study found that B4 ameliorates hyperglycemia through the PI3K/AKT pathway and promotes GLUT4 initiation, showing a new perspective of B4 as a potential agent against diabetes.

Abstract Cisplatin (CP), an anticancer drug, often causes kidney damage. However, the mechanism of CP‐induced acute kidney injury (AKI) is not completely understood. AKI was induced by intravenous injection (i.v.) of cisplatin at doses of 5, 8, and 10 mg/kg. Anemoside B4 (B4) (20 mg/kg, i.m.) and dexamethasone (DXM) (0.5 mg/kg, i.v.) were used for AKI treatment. Biochemical indicators were assessed using an automatic biochemical analyzer, protein expression was analyzed by western blotting, and morphological changes in the kidney were examined by PAS staining. The serum creatinine (Cre) and blood urea nitrogen (BUN) levels did not change significantly in the first 2 days but abruptly increased on the third day after CP injection. The serum albumin (ALB) and total protein (TP) levels decreased in both a time‐ and dose‐dependent manner. The urine protein level increased, the clearing rate of Cre decreased distinctly, and morphologic changes appeared in a dose‐dependent manner. The protein expression of p53/caspase‐3, NLRP3, IL‐6, and TNF‐α was obviously upregulated on day 3; concurrently, nephrin and podocin were downregulated. The expression of LC3II and p62 was upregulated significantly as the CP dose increased. B4 and DXM obviously decreased the BUN and Cre levels after 3 or 5 days of treatment. AKI appeared distinctly in a time‐dependent manner at 2 to 5 days after the administration of 5 mg/kg CP and in a dose‐dependent manner upon the administration of 5, 8, and 10 mg/kg CP. The third day was a significant time point for renal deterioration, and treatment with B4 and DXM within the first 3 days provided significant protection against AKI.

Context: Lipopolysaccharide (LPS) is often used to induce immunoinflammatory reactions. TLR4/NFκB and NLRP3 signalling are major factors for inflammation. Dexamethasone (DXM) has an anti-immunoinflammatory effect. Objective: To investigate the inflammatory reaction in pathological changes of organs and the expression of inflammatory signalling during LPS infection. Materials and methods: ICR mice were divided into control group (n = 9), LPS group (n = 15) and LPS + DXM group (n = 14). LPS (10 mg/kg) was injected intravenously in LPS group and LPS + DXM group, normal saline was injected to the control group; DXM (0.5 mg/kg) was given by intragastric administration. 12 h after LPS, the blood was collected and the organs were isolated for biochemical analysis, protein expression, and morphological examination. Results: The results showed that BUN, Cre, ALT, AST in the LPS group increased distinctly by 81.42, 67.84, 40.53 and 36.05%, respectively, and CK, ALP, TP and ALB decreased by 71.37, 60.6, 12.57 and 19.73%, respectively, compared with the control group. In the morphologic observation, local necrosis in the liver, arterial vasodilation in the heart and kidney, alveolar secretions and pulmonary interstitial in the lungs, and mucosal shedding in the small and large intestines, the expression of TLR4-NFκB signalling were up-regulated distinctly whereas NLRP3 signalling was less broadly affected. DXM can decrease BUN and Cre, downregulate the expression of TLR4-NFκB signalling, but has no effect on the organ damage based on morphology. Conclusion: Acute injuries induced by LPS are extensive. The inflammatory damage in small and large intestines, liver and kidney was more severe than other organs. TLR4-NFκB signalling was the major response to LPS stress.

The balance between coagulation and fibrinolysis is essential for a successful pregnancy. This study aimed to explore the genetic variant of +1040C/T in the coding region of thrombin-activatable fibrinolysis inhibitor (TAFI) gene in women with recurrent spontaneous abortion (RSA) and in unrelated healthy controls and to investigate the possible association between TAFI +1040C/T polymorphism and RSA. Peripheral blood samples were collected from 137 Chinese patients with RSA and 103 unrelated healthy Chinese controls. The TAFI +1040C/T polymorphism was analyzed using SNaPshot SNP typing after DNA extraction. The frequency of the C allele was lower in RSA patients compared with the controls (0.78 vs 0.84). A subanalysis of the TAFI +1040C/T polymorphism in the 2 populations of RSA women (groups 2RSA and >2RSA) showed that the +1040CT genotype was significantly higher and the +1040CC genotype was significantly lower than from that found in controls. The allele +1040C was associated with a reduced risk of RSA in both group 2RSA (OR = 0.418, 95%CI, 0.255-0.685) and group >2RSA (OR = 0.473, 95%CI, 0.274-0.819) compared with controls. Our data indicate a protective role for TAFI +1040C allele against RSA, and may be associated with the genetic susceptibility of RSA.

Background: The CACNA1A gene encodes the voltage-dependent P/Q-type calcium channel subunit alpha-1A, which is widely expressed throughout the CNS. The biological roles of the P/Q channel are diverse and the phenotypic spectrum caused by CACNA1A mutations is wide. The aim of this study is to demonstrate its phenotypic diversity and analyze the genotype-phenotype correlations in a cohort of Chinese patients.Methods: Patients with hemiplegic migraine, cerebellar ataxia, developmental delay, or epilepsy without known causes were tested by trios whole-exome sequencing. Patients with pathogenic CACNA1A gene variants were recruited. The clinical information of the patients was collected, and the association between the genotype and the phenotype was investigated.Results: In total, eight patients (six females and two males) were found to have CACNA1A gene variants. All the variants were de novo including six missense variants and one frameshift variant. Four de novo missense variants were found in five patients located in the S4, S5, or S6 transmembrane segments of Domain II and III (p.R1352Q, p.G701V, p.A713T, p.V1393M). All of them were correlated with severe phenotypes, including three with sporadic hemiplegic migraine type 1 and epilepsy, and two with developmental and epileptic encephalopathy. The other two missense variants, p.Y62C and p.F1814L, located in the cytoplasmic side of the N-terminus and C-terminus, respectively. The variant p.Y62C was associated with severe hemiconvulsion-hemiplegia-epilepsy syndrome, and p.F1814L was associated with relatively mild phenotypes. All the missense variants were speculated as gain-of-function (GOF) mutations. The only frameshift variant, p.Q681Rfs*100, a lose-of-function (LOF) mutation, was found in a patient with episodic ataxia type 2. Meanwhile, all the patients had developmental delay ranging from mild to severe, as well as cerebellar ataxia including one with congenital ataxia, one with episodic ataxia, and six with non-progressive ataxia.Conclusions:CACNA1A variants could lead to a wide spectrum of neurological disorders including epileptic or non-epileptic paroxysmal events, cerebellar ataxia, and developmental delay. The variants could be both GOF and LOF mutations. There appeared to be some correlations between genotypes and phenotypes.

Colitis is not fully curable, although currently, some treatment options are being adopted. In this study, we investigated the effects of pineapple leaf phenols (PLPs), natural phenol products from pineapple leaves, on DSS-induced colitis in mice. The results showed that PLPs dramatically decreased the inflammatory response by inhibiting NF-κB activation and the secretion of pro-inflammatory factors. Moreover, PLPs provided protection against DSS-induced acute colitis by maintaining epithelial integrity. Caffeic and P-coumaric acids had similar effects and could be the active components responsible for PLPs’ effect on colitis. These results indicate that the oral administration of PLPs might be considered as a therapeutic strategy in the treatment of patients with colitis. However, further research on clinical applications and the exact effect of PLPs on colitis is required.

Accumulating evidence suggests that natural medicines have notable curative effects on neurological conditions, such as migraine, that are mediated by regulating the gut microbial flora. A natural medicine pair used in traditional Chinese medicine, Gastrodia elata Blume and Uncaria rhynchophylla (Miq.) Miq. ex Havil. (GU), have shown excellent effect in treating migraine, yet the role of gut microbes in the therapeutic effect of GU in chronic migraine (CMG) is unknown. Here, we performed a 16S rRNA gene sequencing and metabolomics study of the effects of GU in a nitroglycerin (NTG)-induced rat model of CMG. Our results showed that the gut microbial community structure changed significantly and was similar to that of control rats after GU administration in CMG rats. Specifically, GU increased the relative abundance of Bacteroides and Coprococcus and reduced the abundance of Prevotella_1 and Escherichia-Shigella in CMG rats. The metabolomics profiles of the plasma and ileum contents of CMG rats obtained with an ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) revealed similar biomarkers in both samples, and GU treatment reduced 3-indoxyl sulfate, glutamic acid, L-tyrosine, and L-arginine levels, and increased 5-HIAA, L-tryptophan, and linoleic acid levels in plasma. Correlation analysis showed that the affected bacteria were closely related to amino acid metabolism. Most importantly, GU treatment hardly affected biomarkers in feces samples after inhibiting the activity of gut microbes. Collectively, these findings indicate that structural changes in gut flora are closely related to host metabolism and that regulating the gut microbial community structure and function may be one of the important mechanisms underlying the therapeutic effects of GU in migraine.

Functional dyspepsia (FD) is a common chronic gastrointestinal disorder with a complex, undefined mechanism. Clustering of patients with FD in families highlights the role of genetic factors in the pathogenesis of FD. We performed a systematic review and meta-analysis to clarify the associations between specific gene polymorphisms and FD susceptibility. PubMed, EMBASE, the Cochrane Library, and HuGE database were searched. An additive model was adopted to determine whether previous studied genes are associated with FD susceptibility. Carriers of minor allele in GNB3 825C>T (OR=1.15, 95% CI 0.99-1.34, P=0.07), SCL6A4 5HTTLPR (OR=0.92, 95% CI 0.75-1.12, P=0.40), and CCK-1R 779T>C (OR=0.86, 95% CI 0.72-1.03, P=0.09) genes failed to demonstrate susceptibility to FD. In a subgroup analysis, only minor allele (T) in GNB3 825C>T was associated with an increased susceptibility to the epigastric pain syndrome subtype (OR=1.34, 95% CI 1.10-1.63, P=0.003). Our meta-analysis based on available studies using an additive model failed to show that GNB3, SCL6A4, and CCK-1R polymorphisms are associated with FD susceptibility.

Alterations in gut microbiota are postulated to be an etiologic factor in the pathogenesis of irritable bowel syndrome (IBS). To determine whether IBS patients in China exhibited differences in their gut microbial composition, fecal samples were collected from diarrhea-predominant IBS (IBS-D) and healthy controls and evaluated by 16S ribosomal RNA gene sequence and quantitative real-time PCR. A mouse model of postinfectious IBS (PI-IBS) was established to determine whether the altered gut microbiota was associated with increased visceral hypersensitivity. The results indicated that there were significant differences in the bacterial community profiles between IBS-D patients and healthy controls. Prevotella was more abundant in fecal samples from IBS-D patients compared with healthy controls (p

Small intestinal bacterial overgrowth (SIBO) has been implicated in the pathogenesis of irritable bowel syndrome (IBS). Psychosocial factors and low-grade colonic mucosal immune activation have been suggested to play important roles in the pathophysiology of IBS. In total, 94 patients with IBS and 13 healthy volunteers underwent a 10 g lactulose hydrogen breath test (HBT) with concurrent Tc99m scintigraphy. All participants also completed a face-to-face questionnaire survey, including the Hospital Anxiety and Depression Scale, Life Event Stress (LES), and general information. Serum tumour necrosis factor-α, interleukin- (IL-) 6, IL-8, and IL-10 levels were measured. The 89 enrolled patients with IBS and 13 healthy controls had no differences in baseline characteristics. The prevalence of SIBO in patients with IBS was higher than that in healthy controls (39% versus 8%, resp.; p=0.026). Patients with IBS had higher anxiety, depression, and LES scores, but anxiety, depression, and LES scores were similar between the SIBO-positive and SIBO-negative groups. Psychological disorders were not associated with SIBO in patients with IBS. The serum IL-10 level was significantly lower in SIBO-positive than SIBO-negative patients with IBS.

The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn’s disease (CD), ulcerative colitis (UC), celiac disease, and irritable bowel syndrome (IBS). Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploring in vitro and in vivo model system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK-) and myosin light chain kinase- (MLCK-) mediated pathways are involved in the regulation of intestinal permeability. With this perspective, we aim to summarize the current state of knowledge regarding the role of inflammation and ROCK-/MLCK-mediated pathways leading to intestinal hyperpermeability in gastrointestinal disorders. In the near future, it may be possible to specifically target these specific pathways to develop novel therapies for gastrointestinal disorders associated with increased gut permeability.

In this study, we investigated hypolipidemic mechanisms of the ethanolic extract of Ananas comosus L. leaves (AC) in mice and then determined its activities in related enzymes. The results showed that AC (0.40 g/kg) significantly inhibited the increase in serum triglycerides by 40% in fructose-fed mice. In mice induced by alloxan and high-fat diets, serum total cholesterol remained at a high level (180 – 220 mg/dl) within 7 days of removing high-fat diets but reached normal level (120 – 140 mg/dl) after AC (0.40 g/kg per day) treatment. Also, AC (0.40 and 0.80 g/kg) significantly inhibited serum lipids from the increase in Triton WR-1339-induced hyperlipidemic mice. AC (0.01 – 100 µg/ml) selectively activated lipoprotein lipase (LPL) activity by 200% – 400% and significantly inhibited 3-hydroxyl-methyl glutaryl coenzyme A (HMGCoA) reductase activity by 20% – 49% in vitro. Furthermore, 2 months of fenofibrate (0.20 g/kg) administration particularly increased mice liver weights (0.0760 ± 0.0110 g/g) while AC (0.40 g/kg) had no effect (0.0403 ± 0.0047). Taken together, these results suggest that AC will be a new potential natural product for the treatment of hyperlipidemia that exerts its actions through mechanisms of inhibiting HMGCoA reductase and activating LPL activities. Its action mechanisms differentiate from those with fibrates but may be partly similar to those with statins. It is hopeful that AC may serve as the adjuvant for fibrates. Keywords:: Ananas comosus L., hyperlipidemia, lipoprotein lipase, phenol, 3-hydroxyl-methyl glutaryl coenzyme A (HMGCoA) reductase

Berberine (BBR) is an established natural DNA intercalator with numerous pharmacological functions. However, currently there are neither detailed reports concerning the distribution of this alkaloid in living cells nor reports concerning the relationship between BBR's association with DNA and the function of DNA. Here we report that the distribution of BBR within the nucleus can be observed 30 minutes after drug administration, and that the content of berberine in the nucleus peaks at around 4 µmol, which is twelve hours after drug administration. The spatial conformation of DNA and chromatin was altered immediately after their association with BBR. Moreover, this association can effectively suppress the transcription of DNA in living cell systems and cell-free systems. Electrophoretic mobility shift assays (EMSA) demonstrated further that BBR can inhibit the association between the TATA binding protein (TBP) and the TATA box in the promoter, and this finding was also attained in living cells by chromatin immunoprecipitation (ChIP). Based on results from this study, we hypothesize that berberine can suppress the transcription of DNA in living cell systems, especially suppressing the association between TBP and the TATA box by binding with DNA and, thus, inhibiting TATA box-dependent gene expression in a non-specific way. This novel study has significantly expanded the sphere of knowledge concerning berberine's pharmacological effects, beginning at its paramount initial interaction with the TATA box.

Aerobic glycolysis is a prominent feature of cancer. Here, we reported that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells SKVO3 and ES-2 by increased production of ATP, lactic acid, extracellular acidification (ECAR), and increased expression of PKM2, LDHA, GLUT1 and GLUT3. Further study showed that over-expression of IGFBP3, the target of miR-19a-3p, decreases aerobic glycolysis in ovarian cancer cells, while knockdown of IGFBP3 expression increases aerobic glycolysis. The rescue assay suggested that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through targeting IGFBP3. Moreover, over-expression of miR-19a-3p or silencing of IGFBP3 expression promoted activation of AKT, which is important for aerobic glycolysis in cancer cells, indicating that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through the IGFBP3/PI3K/AKT pathway. This suggests that miR-19a-3p and IGFBP3 may serve as potential treatment targets of ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Pulmonary arteriovenous malformation (PAVM), also known as pulmonary arteriovenous fistula, is a rare vascular developmental anomaly. Most cases of PAVM are associated with hereditary hemorrhagic telangiectasia (HHT). Hemothorax associated with PAVM is even rarer, and management concerning this complication still challenges. Case presentation A 55-year-old man with sudden onset of dyspnea and chest pain was admitted to our hospital. He had a medical history of epistaxis, intraperitoneal germ cell tumor and PAVM. Chest unenhanced CT revealed the left-sided pleural effusion together with partial passive atelectasis and gradual increase at the interval of six days. Diagnostic thoracocentesis further revealed hemorrhagic effusion. CT angiography (CTA) showed tortuously dilated lumen of the left lower pulmonary artery and PAVM with the formation of aneurysm. Due to his family's refusal of surgery, the patient underwent transcatheter embolization therapy. However, the left pleural effusion did not significantly reduce and there was a slow drop in hemoglobin value even after interventional treatment, indicating the possibility of ongoing active bleeding. Eventually, the patient received lobectomy of the left lower lobe with a satisfactory outcome. Conclusions Massive hemothorax resulting from PAVM rupture into the pleural space can lead to fatal outcomes. CTA can accurately diagnose this pathologic condition. Transcatheter embolization is frequently used in the treatment of PAVM, but it may be challenging to achieve the desirable effect in patients with hemothorax. Combined with our case and literature review, direct radical surgery can lead to a successful outcome when PAVM complicated with hemothorax and a large diameter of the draining vein.

Background: The Warburg effect is considered as a hallmark of various types of cancers, while the regulatory mechanism is poorly understood. Our previous study demonstrated that miR-194-5p directly targets and regulates insulin-like growth factor1 receptor (IGF1R). In this study, we aimed to investigate the role of miR-194-5p in the regulation of the Warburg effect in ovarian cancer cells. Methods: The stable ovarian cell lines with miR-194-5p overexpression or silencing IGF1R expression were established by lentivirus infection. ATP generation, glucose uptake, lactate production and extracellular acidification rate (ECAR) assay were used to analyze the effects of aerobic glycolysis in ovarian cancer cells. Gene expression was analyzed by quantitative polymerase chain reaction (qPCR) and western blot. Immunohistochemistry assays were performed to assess the expression of the IGF1R protein in ovarian cancer tissues. Results: Overexpression of miR-194-5p or silencing IGF1R expression in ovarian cancer cells decreases ATP generation, glucose uptake, lactate production, and ECAR and inhibits both the mRNA and protein expression of PKM2, LDHA, GLUT1, and GLUT3. While the knockdown of miR-194-5p expression led to opposite results. Overexpression of miR-194-5p or silencing IGF1R expression suppressed the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, whose activation can sustain aerobic glycolysis in cancer cells, and the knockdown of miR-194-5p expression promoted the activation of the PI3K/AKT pathway. Conclusion: Our results suggest that miR-194-5p can inhibit the Warburg effect by negative regulation of IGF1R and further repression of the PI3K/AKT pathway, which provides a theoretical basis for further test of miR-194-5p as a target in the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Broncho-esophageal fistula (BEF) secondary to esophageal diverticulum is a rare clinical condition, which is often misdiagnosed for a long time. The aim of our study is to summarize and clarify the advantages of MSCT in diagnosing BEF secondary to esophageal diverticulum. Methods We retrospectively analyzed patients clinically diagnosed with BEF from January 2005 to January 2022 at Jilin University First Hospital. Only those patients with BEF secondary to esophageal diverticulum and complete clinical data met our enrolled standard. All patients’ clinicopathologic characteristics and MSCT features were systemically evaluated. Results 17 patients were eligible for our cohort study, including male 10 and female 7. The patient’s mean age was 42.3 ± 12.5. The chronic cough occurred in all seventeen patients and bucking following oral fluid intake was documented in nine patients. MSCT distinctly suggested the fistulous tract between the bronchi and the esophagus in all patients. The mean diameter of the orifices in the wall of the esophagus was 4.40 ± 1.81 mm. The orifice in the midthoracic esophagus side was 15 cases and 2 cases at the lower thoracic esophagus. The involved bronchus included 13 cases at the right lower lobe bronchus, 1 at the right middle lobe bronchus and 3 at the left lower lobe bronchus. The contrast agent was observed in the pulmonary parenchyma in 10 of 13 patients who underwent esophagogram. No definite fistula was observed in 3 of 11 who underwent gastroscopy, while the intra-operative findings supported the existence of fistula. Conclusions BEF secondary to esophageal diverticulum tends to occur between the midthoracic esophagus and the right lower lobe bronchus. Compared with esophagography and gastroscopy, MSCT shows more comprehensive information about the fistulous shape, size, course and lung involvement, which are helpful for establishing diagnosis and guiding subsequent treatment.

Abstract Objective To summarize the clinical characteristics and imaging manifestations of patients with nonketotic hyperglycemic hemichorea (NH‐HC) and to explore the possible pathogenesis, diagnosis. and treatment of the disease in order to improve the understanding of this disease and avoid misdiagnosis. Methods Retrospective analysis was performed on the case data of five patients with NH‐HC admitted to our hospital in recent years. The patients were treated in the department of endocrinology, department of neurology, and department of neurosurgery in our hospital, respectively. Meanwhile, relevant literatures were consulted for further learning. Results NH‐HC is usually presented as a triad of nonketotic hyperglycemia, lateral chorea, and typical imaging manifestations of head magnetic resonance imaging or computed tomography, but the clinical manifestations are not the same, and imaging features may also be different, presenting a diversified trend in clinical practice. All five patients were given glucose‐lowering drugs and improved with or without combination of drugs to control symptoms of chorea. Conclusion NH‐HC is a rare complication of diabetes, characterized by hyperglycemia and hemichorea. How to identify the extreme situation and make fast judgment is a top priority. Timely and correct control of blood glucose is the key to the treatment, and when necessary, application of dopamine receptor antagonists in patients with combination therapy can accelerate improvement of the clinical symptoms. The prognosis of NH‐HC is good, the clinician should strengthen comprehensive understanding of this disease to avoid missed diagnosis or misdiagnosis and enable patients to get more timely and effective treatment.

While the high-voltage direct current (HVDC) transmission system is in monopolar operation, it produces thousands of amperes of ground-return currents (GRCs). Accurate computation of the GRCs is essential for assessing safety implications for nearby industrial infrastructure. Current three-dimensional forward models of GRCs are typically constructed based on discrete differential equations, and their solving efficiency is constrained by the increased degrees of freedom resulting from the fine discretization grids in high-conductivity conductors and ground points. To address this issue, we present a new resistor network (RN) forward solver based on a multi-resolution grid approach. This solver utilizes an RN to avoid the massive degrees of freedom resulting from fine discretization of high-voltage conductors and enhances grid discretization efficiency near the surface grounding system through multi-resolution grids. We demonstrate, through multiple three-dimensional geoelectrical model cases, that the proposed method reduces the forward modeling misfit to 1% and possesses only 3‰ of the required discrete elements compared to traditional approaches. Furthermore, practical HVDC grid model analyses indicate the successful application of the proposed method for GRC analysis in complex geoelectric conditions.

Copyright of Journal of Chinese Pharmaceutical Sciences is the property of Journal of Chinese Pharmaceutical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Behcet's disease is a form of systematic vasculitis that affects vessels of various sizes anywhere in the body. Aortic pseudoaneurysm is the most hazardous lesion in Behcet's disease and is associated with high mortality rate once rupture. Case presentation In this report, we presented a patient with a known history of Behcet's disease, whose recurrent aortic-arch pseudoaneurysm eroding into the left main bronchus was identified after a 4-year duration of thoracic endovascular aortic repair for thoracic descending aortic pseudoaneurysm ruptured into the left lung. Repeated thoracic endovascular aortic repair combined with the chimney stent effectively controlled massive hemoptysis under the life-threatening circumstance, and the patient was in good condition at the 7-year follow-up. Conclusions Thoracic endovascular aortic repair can be used as an effective and problem-solving treatment approach for thoracic aortic aneurysms eroded into the lung, even recurrent pseudoaneurysm after thoracic endovascular aortic repair in BD patients. Among the imaging methods assessing the technical success, outcome and complications, computed tomography angiography offers a fast, accessible and sensitive imaging modality.

Abstract Osteoarthritis (OA) is a prevalent and distressing chronic degenerative joint disorder characterized by damaged articular cartilage and inflamed joints. Among risk factors, obesity has emerged as the second‐leading contributor to OA after age. Obesity is believed to play a key role in the development and progression of OA. This study aimed to investigate the role and underlying mechanisms of high‐fat diet (HFD)‐induced obesity in the development of OA. Our findings revealed that HFD could aggravate the destabilization of the medial meniscus (DMM)‐induced damage in the mouse model of obesity. Similar results were observed when macrophages obtained from HFD‐fed mice were cocultured with cartilage and subsequently stimulated with interleukin‐1β (IL‐1β). Mechanistically, we observed a decrease in the expression of intraarticular macrophagic FBW7, which was implicated in the aggravation of OA in the HFD‐fed animal. Furthermore, by modulating the immune status of macrophages, we found that reversing the macrophagic expression of FBW7 in these cells can alleviate the chondrocyte damage. In conclusion, this study provides novel insights into the pathological mechanisms underlying HFD‐related OA development by identifying the role of FBW7 in synovial macrophages. These findings open up new avenues for research and therapeutic interventions targeting HFD‐related OA.

Abstract Background Osteochondromas, also known as exostoses, are the most common benign tumors of bone and can be classified into isolated and multiple osteochondromas. A great majority of osteochondromas is asymptomatic, painless, slow-growing mass, and incidentally found. However, osteochondromas occurring in adolescence or in adult patients can grow in size and become symptomatic as a result of mechanical irritation of the surrounding soft tissues or peripheral nerves, spinal cord compression, or vascular injury. Case presentation We present a case of a 13-year-old girl with spontaneous hemothorax, the cause of which was identified by limited thoracotomy with the aid of video-assisted thoracic surgery to be bleeding from a diaphragmatic laceration incurred by a costal exostosis on the left sixth rib. Preoperative chest computed tomography (CT) depicted a bony projection arising from the rib and bloody effusion in the intrathoracic cavity, but was unable to discern the bleeding cause from the lung or the diaphragm. This case will highlight our awareness that costal exostosis possibly results in bloody pleural effusion. Meanwhile, English literatures about solitary costal exostosis associated with hemothorax were searched in PubMed and nineteen case reports were obtained. Combined our present case with available literature, a comprehensive understanding of this rare disease entity will further be strengthened. Conclusions Injury to the diaphragm is the primary cause of hemothorax caused by costal osteochondroma, including the present case. Thoracic CT scan can help establish a diagnosis of preoperative diagnosis of costal osteochondroma. Surgical intervention should be considered for those patients with symptomatic osteochondroma of the rib. Combined with our case and literature, prophylactic surgical removal of intrathoracic exostosis should be advocated even in asymptomatic patients with the presentation of an inward bony spiculation.