Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

BACKGROUND: Urolithiasis is a widespread disease with a high prevalence worldwide. This study aims to evaluate the disease burden of urolithiasis and its trends from 1990 to 2021 globally, based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 database. METHODS: The numbers and age-standardized rates (ASRs) of incidence, disability-adjusted life years (DALYs), and mortality of urolithiasis were extracted from GBD 2021 to represent the disease burden. Joinpoint regression analyses were conducted to assess the temporal trends in the burden of urolithiasis. The male-to-female ASR ratio indices were used to evaluate sex disparities. Additionally, we explored the relationship between the ASR ratio and the sociodemographic index (SDI). RESULTS: The total numbers of incidence, DALY, and mortality of urolithiasis were 105,983,780 cases (95% uncertainty interval [UI] = 88,349,356-128,645,155 cases), 693,444 cases (95% UI = 567,765-850,490 cases), and 17,672 cases (95% UI = 13,932-21,241 cases), respectively, in 2021. There is an increasing trend in the number of these measures globally, whereas the ASRs have decreased over the past 30 years. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) were significantly higher in males than in females in 2021. The sex disparities in the age-standardized DALY rate (ASDR) and ASMR of urolithiasis were negatively correlated with the SDI. In 2021, the ASIR of urolithiasis was 964.70 (95% UI = 801.26-1175.09) per 100,000 people in China, which is much lower than the global average (1242.84 [95% UI = 1034.94-1506.99] per 100,000 people). Compared with the global average, a more pronounced decline in ASIR was observed in China from 1793.16 (1446.0-2235.14) in 1990 to 964.70 (801.26-1175.09) per 100,000 people in 2021. CONCLUSIONS Urolithiasis poses a significant healthcare burden worldwide. More robust global and national strategies are warranted to address the prevention and treatment, especially in low SDI countries and regions.
Humans ; Urolithiasis/mortality* ; Male ; Female ; Incidence ; Global Burden of Disease ; Disability-Adjusted Life Years ; Adult ; Middle Aged ; Risk Factors ; Sex Factors

The chemical constituents were systematically separated from the roots of Berberis polyantha by various chromatographic methods, including silica gel column chromatography, HP20 column chromatography, polyamide column chromatography, reversed-phase C_(18) column chromatography, and preparative high-performance liquid chromatography. The structures of the compounds were identified by physicochemical properties and spectroscopic techniques(1D NMR, 2D NMR, UV, MS, and CD). Four phenylpropanoids were isolated from the methanol extract of the roots of B. polyantha, and they were identified as(2R)-1-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone-O-β-D-glucopyranoside(1), methyl 4-hydroxy-3,5-dimethoxybenzoate(2),(+)-syringaresinol(3), and syringaresinol-4-O-β-D-glucopyranoside(4). Compound 1 was a new compound, and other compounds were isolated from this plant for the first time. The anti-inflammatory activity of these compounds was evaluated based on the release of nitric oxide(NO) in the culture of lipopolysaccharide(LPS)-induced RAW264.7 macrophages. At a concentration of 10 μmol·L~(-1), all the four compounds inhibited the LPS-induced release of NO in RAW264.7 cells, demonstrating potential anti-inflammatory properties.
Plant Roots/chemistry* ; Animals ; Mice ; Berberis/chemistry* ; RAW 264.7 Cells ; Macrophages/immunology* ; Drugs, Chinese Herbal/isolation & purification* ; Nitric Oxide/metabolism* ; Molecular Structure ; Anti-Inflammatory Agents/isolation & purification*

This study aims to explore the mechanism of lung and gut protection by Tanreqing Capsules on the mice infected with influenza virus based on "the lung-gut axis". A total of 110 C57BL/6J mice were randomized into control group, model group, oseltamivir group, and low-and high-dose Tanreqing Capsules groups. Ten mice in each group underwent body weight protection experiments, and the remaining 12 mice underwent experiments for mechanism exploration. Mice were infected with influenza virus A/Puerto Rico/08/1934(PR8) via nasal inhalation for the modeling. The lung tissue was collected on day 3 after gavage, and the lung tissue, colon tissue, and feces were collected on day 7 after gavage for subsequent testing. The results showed that Tanreqing Capsules alleviated the body weight reduction and increased the survival rate caused by PR8 infection. Compared with model group, Tanreqing Capsules can alleviate the lung injury by reducing the lung index, alleviating inflammation and edema in the lung tissue, down-regulating viral gene expression at the late stage of infection, reducing the percentage of neutrophils, and increasing the percentage of T cells. Tanreqing Capsules relieved the gut injury by restoring the colon length, increasing intestinal lumen mucin secretion, alleviating intestinal inflammation, and reducing goblet cell destruction. The gut microbiota analysis showed that Tanreqing Capsules increased species diversity compared with model group. At the phylum level, Tanreqing Capsules significantly increased the abundance of Firmicutes and Actinobacteria, while reducing the abundance of Bacteroidota and Proteobacteria to maintain gut microbiota balance. At the genus level, Tanreqing Capsules significantly increased the abundance of unclassified＿f＿Lachnospiraceae while reducing the abundance of Bacteroides, Eubacterium, and Phocaeicola to maintain gut microbiota balance. In conclusion, Tanreqing Capsules can alleviate mouse lung and gut injury caused by influenza virus infection and restore the balance of gut microbiota. Treating influenza from the lung and gut can provide new ideas for clinical practice.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Lung/metabolism* ; Mice, Inbred C57BL ; Capsules ; Orthomyxoviridae Infections/virology* ; Gastrointestinal Microbiome/drug effects* ; Male ; Humans ; Female ; Influenza A virus/physiology* ; Influenza, Human/virology*

This paper aimed to investigate the therapeutic effect and mechanism of action of the Yiqi Fumai Formula(YQFM), a kind of traditional Chinese medicine(TCM), on mice with experimental heart failure based on the "heart-gut axis" theory. Based on the network pharmacology integrated with the group collaboration algorithm, the active ingredients were screened, a "component-target-disease" network was constructed, and the potential pathways regulated by the formula were predicted and analyzed. Next, the model of experimental heart failure was established by intraperitoneal injection of adriamycin at a single high dose(15 mg·kg~(-1)) in BALB/c mice. After intraperitoneal injection of YQFM(lyophilized) at 7.90, 15.80, and 31.55 mg·d~(-1) for 7 d, the protective effects of the formula on cardiac function were evaluated using indicators such as ultrasonic electrocardiography and myocardial injury markers. Combined with inflammatory factors in the cardiac and colorectal tissue, as well as targeted assays, the relevant indicators of potential pathways were verified. Meanwhile, 16S rDNA sequencing was performed on mouse fecal samples using the Illumina platform to detect changes in gut flora and analyze differential metabolic pathways. The results show that the administration of injectable YQFM(lyophilized) for 7 d significantly increased the left ventricular end-systolic internal diameter, fractional shortening, and ejection fraction of cardiac tissue of mice with experimental heart failure(P<0.05). Moreover, markers of myocardial injury were significantly decreased(P<0.05), indicating improved cardiac function, along with significantly suppressed inflammatory responses in cardiac and intestinal tissue(P<0.05). Additionally, the species of causative organisms was decreased, and the homeostasis of gut flora was improved, involving a modulatory effect on PI3K-Akt signaling pathway-related inflammation in cardiac and colorectal tissue. In conclusion, YQFM can affect the "heart-gut axis" immunity through the homeostasis of the gut flora, thereby exerting a therapeutic effect on heart failure. This finding provides a reference for the combination of TCM and western medicine to prevent and treat heart failure based on the "heart-gut axis" theory.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Heart Failure/microbiology* ; Mice ; Mice, Inbred BALB C ; Male ; Disease Models, Animal ; Gastrointestinal Microbiome/drug effects* ; Heart/physiopathology* ; Humans ; Signal Transduction/drug effects*

Melicope pteleifolia is a plant belonging to the Melicope genus of the Rutaceae family. Known for a bitter taste and cold nature, its stems and tender branches with leaves possess properties of clearing heat, detoxifying, dispelling wind, and removing dampness and can be used to treat sore throat, malaria, jaundice hepatitis, rheumatic bone pain, eczema, dermatitis, and sores and ulcers. In this study, 19 compounds were isolated from the chloroform and n-butanol extracts of M. pteleifolia leaves by using liquid chromatography-mass spectrometry(LC-MS) and proton nuclear magnetic resonance(~1H-NMR)-guided separation techniques. The compounds were identified as isoleptonol(1), leptaones B-E(2-5), friedelin(6), evodionol(7), ethyl p-hydroxybenzoate(8), litseachromolaevane A(9), quercetin-7,3',4'-trimethyl ether(10), kokusaginin(11), 8-(1-hydroxyethyl)-5,6,7-trimethoxy-2,2-dimethyl-2H-1-benzopyran(12), ethyl p-hydroxycinnamate(13), 3-hydroxy-9-methyl-6H-benzo\[c\]chromen-6-one(14), agrimonolide(15), 7-hydroxycoumarin(16), scopoletin(17), isoscutellarein(18), and agrimonolide 6-O-glucoside(19). Among these, the new compounds included one chromene and four meroterpenoid(1-5). The anti-inflammatory activities of the newly identified compounds 1-5 were screened in vitro, showing that the five compounds(1-5) exhibited inhibitory effects on nitric oxide(NO) production in BV2 cells induced by lipopolysaccharide(LPS)/interferon(IFN)-γ, with IC_(50) values ranging from 12.25 to 36.48 μmol·L~(-1).
Anti-Inflammatory Agents/isolation & purification* ; Mice ; Animals ; Rutaceae/chemistry* ; Drugs, Chinese Herbal/isolation & purification* ; Macrophages/immunology* ; Nitric Oxide/immunology*

PURPOSE: Lateral patellar compression syndrome (LPCS) is characterized by a persistent abnormally high stress exerted on the lateral articular surface of the patella due to lateral patellar tilt without dislocation and lateral retinaculum contracture, leading to anterior knee pain. The purpose of this study is to evaluate the efficacy and prognosis of lateral retinaculum release (LRR) combined with chondroplasty in the treatment of LPCS. METHODS: This retrospective study evaluated 40 patients who underwent LRR combined with chondroplasty for LPCS between 2020 and 2021. The assessment included improvement in postoperative tenderness and knee joint function. Patients were evaluated using the Lysholm, Tegner, and International Knee Documentation Committee 2000 scoring systems, as well as the visual analog scale, both preoperatively and postoperatively, with the paired comparisons analyzed using a t-test. Additionally, intraoperative observations were made regarding knee joint lesions, including cartilage damage and osteophyte formation, with analysis by the Chi-square test. RESULTS: The visual analog scale score for tenderness showed a significant decrease after surgery (p < 0.001). Evaluation of knee joint function also indicated significant improvements, as demonstrated by increased Lysholm, Tegner, and International Knee Documentation Committee 2000 scores postoperatively (p < 0.001, p = 0.011, p < 0.001, respectively). Furthermore, all LPCS patients included in the study presented with cartilage injuries and osteophyte formation. Significant differences were noted in the incidence of cartilage damage and osteophyte formation at different locations within the knee among patients with LPCS. CONCLUSION LRR combined with chondroplasty is an effective surgical approach for treating patients with LPCS, with satisfactory recovery observed at the 1-year follow-up. Additionally, the incidence of cartilage damage and osteophyte formation in LPCS patients varies significantly depending on the specific location within the knee joint.
Humans ; Male ; Female ; Retrospective Studies ; Adult ; Middle Aged ; Patella/surgery* ; Knee Joint/physiopathology* ; Recovery of Function ; Young Adult ; Treatment Outcome ; Cartilage, Articular/surgery* ; Adolescent

OBJECTIVE: To investigate the regulatory effect of Wip1 phosphatase on hematopoietic function in the mouse spleen. METHODS: Wip1 knockout mice were bred, and the effect of Wip1 deletion on the proportion and number of hematopoietic stem/progenitor cells, as well as their mature subsets in mouse spleen was detected by flow cytometry. The Proteome Profiler^TM antibody array was used to analyze the role of Wip1 deletion on the expression of inflammatory cytokines in CD45^highCD11b⁺ myeloid cells sorted from mouse spleen. RESULTS: Wip1 deletion resulted in smaller size and significant reduction of cell number in the mouse spleen. The absolute numbers of hematopoietic stem/progenitor cells were decreased. Meanwhile, the absolute number of T and B lymphocytes also significantly declined. However, the proportion of erythroid progenitors and erythroid cells at various stage significantly increased, but the number of mature erythroid cells decreased. Furthermore, the myeloid cells and their subsets neutrophils, monocytes, CD45^highCD11b⁺ and CD45^lowCD11b⁺ were all reduced. CD45^highCD11b⁺ myeloid cells displayed proinflammatory phenotype in the spleen. CONCLUSION Wip1 gene deletion impairs normal hematopoietic function in the mouse spleen, leading to a significant reduction of mature hematopoietic cells of various lineages, and proinflammatory phenotype in CD45^highCD11b⁺ myeloid cells.
Animals ; Mice ; Spleen/cytology* ; Mice, Knockout ; Hematopoietic Stem Cells/cytology* ; Myeloid Cells/cytology* ; Protein Phosphatase 2C ; Hematopoiesis ; Flow Cytometry