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Background: At present, there is a dearth of comprehensive data at the global, national, and regional levels regarding the adult non-alcoholic fatty liver disease (NAFLD) prevalence. This cross-sectional study aims at ascertaining the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH), utilizing body mass index (BMI) as a determining factor. Methods: Based on the NHANES database, sigmoidal fitting curves were generated to establish the relationship between BMI and the risk of NAFLD/NASH. Utilizing BMI data from the NCD Risk Factor Collaboration (NCD-RisC) database at both global and regional levels, the prevalence of NAFLD/NASH among adults was estimated from 1975 to 2016, encompassing global, regional, and national perspectives. Additionally, projections were made to forecast the prevalence of adult NAFLD/NASH from 2017 to 2030. Results: In 2016, the global prevalence of NAFLD was 41.12% for males and 37.32% for females, while the global prevalence of NASH was 15.79% for males and 16.48% for females. The prevalence of NAFLD/NASH increased with higher BMI in both genders. Over the period from 1975 to 2016, there has been a gradual increase in the global prevalence of NAFLD/NASH in adults, and this trend is expected to continue between 2017 and 2030. In males, the prevalence of adult NAFLD/NASH was found to be highest in High-income Western countries, while it was highest in Central Asia, Middle East, and North African countries after 1995. Conclusions: The prevalence of adult NAFLD/NASH has been observed to increase annually, with significant variations in burden across different countries and regions.
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Two uncommon epoxyquinols, pyrrolocytosporin A (1) and cytosporin E2 (2), along with the known cytosporin Y1 (3), were isolated from the solid defined medium of the Arctic-derived fungus Eutypella sp. D-1. Their structures were established through comprehensive analyses of spectroscopic and electronic circular dichroism data. Structurally, compound 1 represented the first nitrogen-containing epoxyquinol characterized by a pyrrole fused cytosporin framework, while compound 2 contained an uncommon cyclic carbonate functionality. The antibacterial, immunosuppressive, anti-inflammatory, and cytotoxic activities of all compounds were evaluated. Among the three metabolites, only compound 1 exhibited inhibitory effects on nitric oxide production induced by lipopolysaccharide with an IC50 value of 6.55â µM. Additionally, only compound 2 displayed inhibitory activity against ConA-induced T-cell proliferation with an IC50 value of 9.85â µM.
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Proliferação de Células , Lipopolissacarídeos , Óxido Nítrico , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico/metabolismo , Proliferação de Células/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Animais , Camundongos , Linfócitos T/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Pirróis/química , Pirróis/farmacologia , Pirróis/isolamento & purificação , Estrutura Molecular , Conformação Molecular , Células RAW 264.7 , Relação Dose-Resposta a DrogaRESUMO
Aims: The population pharmacokinetic (PPK) model-based machine learning (ML) approach offers a novel perspective on individual concentration prediction. This study aimed to establish a PPK-based ML model for predicting tacrolimus (TAC) concentrations in Chinese renal transplant recipients. Methods: Conventional TAC monitoring data from 127 Chinese renal transplant patients were divided into training (80%) and testing (20%) datasets. A PPK model was developed using the training group data. ML models were then established based on individual pharmacokinetic data derived from the PPK basic model. The prediction performances of the PPK-based ML model and Bayesian forecasting approach were compared using data from the test group. Results: The final PPK model, incorporating hematocrit and CYP3A5 genotypes as covariates, was successfully established. Individual predictions of TAC using the PPK basic model, postoperative date, CYP3A5 genotype, and hematocrit showed improved rankings in ML model construction. XGBoost, based on the TAC PPK, exhibited the best prediction performance. Conclusion: The PPK-based machine learning approach emerges as a superior option for predicting TAC concentrations in Chinese renal transplant recipients.
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Eight new 12,8-eudesmanolide sesquiterpenes, eutypellaolides A-H (1-8), and two new eudesmane-type sesquiterpenes, eutypellaolides I-J (9-10), along with four known 12,8-eudesmanolide compounds 11-14, were isolated from the culture extract of the polar fungus Eutypella sp. D-1 by one strain many compounds (OSMAC) approach. The structures of these compounds were determined through comprehensive spectroscopic data and experimental and calculated ECD analysis. Antibacterial, immunosuppressive, and PTP1B inhibition activities of these compounds were evaluated. Compounds 1 and 11 exhibited strong inhibitory activities against Bacillus subtilis and Staphylococcus aureus, with each showing an MIC value of 2 µg/mL. Compound 9 displayed weak immunosuppressive activity against ConA-induced T-cell proliferation with an inhibitory rate of 61.7% at a concentration of 19.8 µM. Compounds 5, 11, and 14 exhibited weak PTP1B inhibition activities with IC50 values of 44.8, 43.2, and 49.5 µM, respectively.
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A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1-3 and 11-12) from rice medium and eight cytosporins (compounds 2 and 4-11) from solid defined medium. The structures of the seven new compounds, eutypelleudesmane A (1), cytosporin Y (2), cytosporin Z (3), cytosporin Y1 (4), cytosporin Y2 (5), cytosporin Y3 (6), and cytosporin E1 (7), were elucidated by analyzing their detailed spectroscopic data. Structurally, cytosporin Y1 (4) may be a key intermediate in the biosynthesis of the isolated cytosporins, rather than an end product. Compound 1 contained a unique skeleton formed by the ester linkage of two moieties, cytosporin F (12) and the eudesmane-type sesquiterpene dihydroalanto glycol. Additionally, the occurrence of cyclic carbonate moieties in compounds 6 and 7 was found to be rare in nature. The antibacterial, immunosuppressive, and cytotoxic activities of all compounds derived from Eutypella sp. D-1 were evaluated. Unfortunately, only compounds 3, 6, 8, and 10-11 displayed immunosuppressive activity, with inhibitory rates of 62.9%, 59.5%, 67.8%, 55.8%, and 68.7%, respectively, at a concentration of 5 µg/mL.
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Antineoplásicos , Sesquiterpenos , Xylariales , Estrutura Molecular , Xylariales/química , Antineoplásicos/farmacologia , Antibacterianos/farmacologiaRESUMO
Egg yolk immunoglobulin (IgY) and LL37, potent antibacterial substances, can fight against periodontitis. This work aimed to develop a locally injectable hydrogel for potential co-delivery of special IgY and LL37-loaded solid lipid nanoparticles (LL37-SLNs) to synergistically inhibit the proliferation of oral pathogens, thus relieving periodontal inflammation and redness. The formulation of thermosensitive hydrogel loaded with IgY and LL37-SLNs was developed by adopting the Quality by Design approach. Then the formulations were optimized by two-factor three-level full factorial design by Design-Expert software. Finally, the optimized formulation was characterized and estimated in vitro and in vivo. In vitro release and antibacterial activity studies have revealed that the optimized formulation was homogeneous and can be released slowly, with sustainably antibacterial power. And the physical and chemical composition analysis and morphological observations further confirmed the sustained-release capability. On the other hand, in vivo studies proved that the optimized formulation significantly decreased gingival redness, bleeding, and plaque formation, avoided excessive resorption of alveolar bone, and reduced the levels of inflammatory factor in periodontitis rats. In conclusion, the optimized thermosensitive hydrogel loaded with IgY and LL37-SLNs may be a promising local sustained-release preparation for the effective treatment of periodontal diseases.
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Nanopartículas , Periodontite , Ratos , Animais , Hidrogéis , Imunoglobulinas , Preparações de Ação Retardada , Periodontite/tratamento farmacológico , Nanopartículas/química , Portadores de Fármacos , Tamanho da PartículaRESUMO
Prodigiosin (PG) is a secondary metabolite of microorganisms with anticancer, antimalarial, antibacterial and immunomodulatory effects. However, the modulatory effects on gut microbiome and intestinal immune microenvironment have never been explored in the ulcerative colitis (UC) mice model. In this study, 2.5% dextran sulfate sodium (DSS) induced UC mice model was constructed to investigate the effects of PG derived from a chromium-resistant Serratia sp. on the intestinal flora and inflammatory response. The results showed that prodigiosin administration attenuated the DSS-induced UC symptoms, including preventing the reduction of colonic length and DSS-induced mortality. Furthermore, prodigiosin ameliorated the DSS-induced gut microbiota community dysbiosis by restoring the abundance of Bacteroidota. At the genus level, the declined abundance of Bifidobacterium, Allobaculum and Akkermannia in UC mice was elevated by the treatment of PG. Pathological results by H&E staining showed that PG prevented the appearance of distortion and atrophy of crypt and neutrophil infiltration in a dose-dependent manner. RT-PCR revealed that the expression levels of the inflammatory factors IL-1ß, IL-6 and IL-10 were significantly suppressed, and the expression of the intestinal tight junction protein Claudin-1, Occludin and ZO-1 were upregulted in PG-treated UC mice. Conclusively, our results revealed that prodigiosin effectively prevented inflammatory response and protected intestinal barrier integrity of DSS-induced colitis mice via modulating gut microbiota community structure, suppressing inflammatory factors' expression, and accelerating the expression of intestinal tight junction protein. These results will provide new insights into the interaction of prodigiosin with intestinal microbiota homeostasis and its application in clinical against inflammatory bowel disease.
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Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Animais , Camundongos , Prodigiosina/uso terapêutico , Sulfato de Dextrana/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Proteínas de Junções Íntimas/metabolismo , Homeostase , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Two new polyketides, palitantins B and C (1 and 2), along with one known related compound (+)-palitantin (3) were obtained from the culture of the Antarctic fungus Geomyces sp. 3-1. The structures of the new compounds were elucidated by detailed analysis of HRESIMS, NMR, CD, and ECD data. Compound 3 showed potent PTP1B inhibitory activity with an IC50 value of 7.9 µM (ursolic acid as positive control, IC50 = 8.3 µM).
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Ascomicetos , Policetídeos , Cicloexanóis , Cicloexanonas , Estrutura Molecular , Policetídeos/farmacologiaRESUMO
PURPOSE: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an independent risk factor for cardiovascular diseases, including hypertension. In our previous study, it was demonstrated that oral microbiota alteration in patients with OSAHS, particularly in the genera Aggregatibacter and Porphyromonas, may influence the development of hypertension. Continuous positive airway pressure (CPAP) is the main therapy for OSAHS and OSAHS-associated hypertension. However, the role of oral microbiota post CPAP treatment remains unknown. METHODS: We conducted 16S rDNA pyrosequencing and bioinformatic analyses to compare the bacterial composition of oral specimens from patients with OSAHS before and after overnight CPAP treatment. RESULTS: This approach enabled a relatively comprehensive description of oral microbiota, with decreases in Gemella and increases in Staphylococcus, f_Lachnospiraceae, Parabacteroides, and f_Ruminococcaceae after CPAP treatment. CONCLUSION: Alteration of oral microbiota may shed new insight on the underlying pathogenesis of OSAHS-associated hypertension.
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Hipertensão , Microbiota , Apneia Obstrutiva do Sono , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Hipertensão/terapia , Projetos Piloto , Apneia Obstrutiva do Sono/terapia , SíndromeRESUMO
The Arctic fungus Eutypella sp. D-1, previously found to produce a variety of cytotoxic cyclopropyl-fused and cyclobutyl-fused pimarane diterpenoids when grown in the defined medium, was induced to produce unusual metabolites by growing on solid rice medium. A chemical investigation on the rice medium extract led to the isolation of four new meroterpenoids, eutypellacytosporins A-D (1-4), along with the known biogenetically related compound cytosporin D (5). The structures of the new compounds were elucidated by their detailed spectroscopic analysis and modified Mosher's method. Compounds 1-4 may be formed by the 12,32-ester linkage of two moieties, cytosporin D (5) and decipienolide A or B. All isolated compounds, except 5, showed weak cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cell lines with IC50 values ranging from 4.9 to 17.1 µM.
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Terpenos/química , Terpenos/farmacologia , Xylariales/química , Antibacterianos , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Regiões Árticas , Linhagem Celular Tumoral , Meios de Cultura , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Humanos , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Bone morphogenetic proteins (BMPs) are the largest subfamily of the transforming growth factor-ß superfamily, and they play important roles in the development of numerous organs, including the inner ear. The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance. Here, we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.
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Proteínas Morfogenéticas Ósseas/fisiologia , Orelha Interna/embriologia , Padronização Corporal , Receptores de Proteínas Morfogenéticas Ósseas/fisiologia , Diferenciação Celular , Cóclea/embriologia , Proteínas Hedgehog/fisiologia , Humanos , Transdução de Sinais/fisiologia , Proteínas Smad/fisiologia , Vestíbulo do Labirinto/embriologia , Via de Sinalização WntRESUMO
Two new cyclohexanone derivatives, nectriatones A-B (1-2), and one new natural product, nectriatone C (3), together with three known phenolic sesquiterpene derivatives (4-6), were isolated from the culture of Nectria sp. B-13 obtained from high-latitude soil of the Arctic. The structures of all compounds were unambiguously elucidated by extensive spectroscopic analysis, as well as by comparison with the literature. These compounds were evaluated in cytotoxic and antibacterial activities. Compounds 1-6 showed cytotoxicities against SW1990, HCT-116, MCF-7, and K562 cells, with IC50 values in the range of 0.43 to 42.64 µM. Only compound 4 exhibited antibacterial activity against Escherichisa coli, Bacillus subtilis, and Staphylococcus aureus (MIC 4.0, 2.0, and 4.0 µg/ml, respectively).
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Nectria/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Regiões Árticas , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Sesquiterpenos/química , Microbiologia do SoloRESUMO
Three new pimarane diterpenes, eutypellenoids Aâ»C (1â»3), together with a known compound, eutypenoid C (4), were isolated from the culture extract of Eutypella sp. D-1 derived from the Arctic region. Compounds 1â»3 possessed an uncommon tetrahydrofuran-fused pimarane diterpene skeleton. The structures of all compounds were determined by detailed spectroscopic analysis, electronic circular dichroism (ECD) analysis, as well as a comparison with the literature data. Antibacterial, antifungal, and cytotoxic activities of these compounds were evaluated. Compound 2 displayed antibacterial activity against Staphylococcus aureus and Escherichia coli with MIC values of 8 and 8 µg/mL, respectively. Additionally, compound 2 showed antifungal activity against Candidaparapsilosis, Candida albicans, Candida glabrata, and Candida tropicalis with MIC values of 8, 8, 16, and 32 µg/mL, respectively. Furthermore, compound 2 exhibited moderate cytotoxic activity against HCT-116 cell line with IC50 value of 3.7 µM.
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Abietanos/química , Diterpenos/química , Xylariales/química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Regiões Árticas , Linhagem Celular Tumoral , Escherichia coli/efeitos dos fármacos , Fungos/efeitos dos fármacos , Furanos/química , Células HCT116 , Humanos , Testes de Sensibilidade Microbiana/métodos , Staphylococcus aureus/efeitos dos fármacosRESUMO
Seven new pimarane-type diterpene derivatives, libertellenones O-S (1-5) and eutypellenones A and B (6 and 7), together with two known compounds (8 and 9), were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures were elucidated from spectroscopic data, as well as experimental and calculated electronic circular dichroism (ECD) analysis. Structurally, compounds 1-5 possess a cyclopropyl-fused pimarane diterpene moiety, whereas compounds 6 and 7 share an unusual cyclobutyl-fused pimarane diterpene skeleton. Compounds 1-9 exhibited cytotoxicities against HeLa, MCF-7, HCT-116, PANC-1, and SW1990 cells, with IC50 values in the range of 0.3 to 29.4 µM. Compounds 6 and 7 could dose-dependently inhibit the activity of NF-κB and exhibited significantly inhibitory effects on nitric oxide production induced by lipopolysaccharide.
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Abietanos/isolamento & purificação , Xylariales/química , Abietanos/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Regiões Árticas , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HeLa , Humanos , Estrutura Molecular , Microbiologia do SoloRESUMO
A new furanone derivative, butanolide A (1), and a new sesquiterpene, guignarderemophilane F (2), together with six known compounds, were isolated from the fungus Penicillium sp. S-1-18 derived from Antarctic marine. The new structures were determined by spectroscopic studies such as 1D- and 2D-NMR and MS analyses. The absolute configuration of 1 was determined by the modified Mosher's method, while the absolute configuration of 2 was determined by calculated ECD spectroscopy. The isolated secondary metabolites were evaluated for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Compound 1 showed moderate inhibitory activity against PTP1B with IC50 value of 27.4 µM.
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Furanos/química , Penicillium/química , Sesquiterpenos/química , Regiões Antárticas , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura MolecularRESUMO
The biotransformation of total coumarins of Radix Glehniae by Lecanicillium attenuatum W-1-9 yielded three new products, lecaniside A (1), lecaniside B (2), and lecaniside C (3). The chemical structures of these metabolites were elucidated based on extensive spectral data, including 2D NMR and HRMS. The hydrogenation, dealkylation, glycosylation, and O-methylation reactions of these metabolites were observed in the present study. In the in vitro assays, compound 1 displayed a little PTP1B inhibitory activity.
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Apiaceae/metabolismo , Cumarínicos/química , Hypocreales/metabolismo , Apiaceae/química , Cromatografia Líquida de Alta Pressão , Cumarínicos/metabolismo , Meios de Cultura , Medicamentos de Ervas Chinesas/química , Hypocreales/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Raízes de Plantas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidoresRESUMO
BACKGROUND: Inhibition of aging of vascular endothelial cells (VECs) may delay aging and prolong life. The goal of this study was to prepare anti-CD31 monoclonal antibody conjugated PEG-modified liposomes containing the AU-rich region connecting factor 1 (AUF1) gene (CD31-PILs-AUF1) and to explore the effects of targeting CD31-PILs-AUF1 to aging VECs. METHODS: The mean particle sizes of various PEGylated immunoliposomes (PILs) were measured using a Zetasizer Nano ZS. Gel retardation assay was used to confirm whether PILs had encapsulated the AUF1 plasmid successfully. Fluorescence microscopy and flow cytometry were used to quantify binding of CD31-PILs-AUF1 to target cells. Flow cytometry was also used to analyze the cell cycles of aging bEnd3 cells treated with CD31-PILs-AUF1. We also developed an aging mouse model by treating mice with D-galactose. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The malondialdehyde (MDA) and the superoxide dismutase (SOD) levels were detected by commercial kits. Hematoxylin-eosin (HE) staining was used to determine whether treatment with CD31-PILs-AUF1 was toxic to the mice. RESULTS: CD31-PILs-AUF1 specifically could targeted bEnd3 VECs and increased the percentage of cells in the S and G2/M phases of aging bEnd3 cells. ELISA showed that content of the IL-6 and TNF-α decreased in CD31-PILs-AUF1 group. The level of SOD increased, whereas MDA decreased in the CD31-PILs-AUF1 group. Additionally, CD31-PILs-AUF1 was not toxic to the mice. CONCLUSION: CD31-PILs-AUF1 targets VECs and may delay their senescence.
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We isolated and identified a new sesquiterpene lactone which we named eut-Guaiane sesquiterpene (1), along with four cytochalasins from the fungus Eutypella sp. derived from the soil of high latitude of Arctic. The new structure was determined by spectroscopic studies such as 1D and 2D NMR and MS analyses, while the known compounds were identified by comparison of the NMR data with those in literatures. New compound 1 exhibited strong antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus. Besides, it showed a little cytotoxicity against SGC7901 cell line.