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BACKGROUND: Postmenopausal osteoporosis (PMOP) is a systemic bone disease characterized by low bone mass and microstructural damage. Morinda Officinalis (MO) contains various components with anti-PMOP activities. Morinda Officinalis-derived extracellular vesicle-like particles (MOEVLPs) are new active components isolated from MO, and no relevant studies have investigated their anti-osteoporosis effect and mechanism. PURPOSE: To investigate the alleviating effect of MOEVLPs on PMOP and the underlying mechanism. METHODS: Differential centrifugation and ultracentrifugation were used to isolate MOEVLPs from MO. Transmission electron microscopy (TEM), flow nano analyzer, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), agarose gel electrophoresis, and thin-layer chromatography were employed to characterize MOEVLPs. PMOP mouse models were utilized to examine the anti-PMOP effect of MOEVLPs. H&E and immunohistochemical staining were used for drug safety and osteogenic effect assessment. Mouse embryo osteoblast precursor cells (MC3T3-E1) were used in vitro experiments. CCK-8 kit, alizarin red staining, proteomic, bioinformatic analyses, and western blot were used to explore the mechanism of MOEVLPs. RESULTS: In this study, MOEVLPs from MO were successfully isolated and characterized. Animal experiments demonstrated that MOEVLPs exhibited specific femur targeting, were non-toxic to the heart, liver, spleen, lung, kidney, and aorta, and possessed anti-PMOP properties. The ability of MOEVLPs to strengthen bone formation was better than that of alendronate. In vitro experiments, results revealed that MOEVLPs did not significantly enhance osteogenic differentiation in MC3T3-E1 cells. Instead, MOEVLPs promoted the proliferation of MC3T3-E1 cells. Proteomic and bioinformatic analyses suggested that the proliferative effect of MOEVLPs was closely associated with the mitogen-activated protein kinase (MAPK) signaling pathway, particularly the altered expression of cAMP response element-binding protein (CREB) and ribosomal S6 kinase 1 (RSK1). Western blot results further confirmed these findings. CONCLUSION: Our studies successfully isolated high-quality MOEVLPs and demonstrated that MOEVLPs can alleviate PMOP by promoting osteoblast proliferation through the MAPK pathway. MOEVLPs have the potential to become a novel and natural anti-PMOP drug.
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Vesículas Extracelulares , Sistema de Sinalização das MAP Quinases , Morinda , Osteoporose Pós-Menopausa , Animais , Morinda/química , Camundongos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Feminino , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Humanos , Modelos Animais de DoençasRESUMO
Context: Schizophrenia is a common and clinically disabling mental disorder. Many patients with schizophrenia smoke. Research on the effects of smoking on schizophrenia's symptoms are inconsistent. Objective: The study intended to investigate the smoking status of patients with stable schizophrenia to determine the effects of smoking on schizophrenia-related symptoms. Design: The research team performed an case-control study. Setting: The study took place at Beijing Huilongguan Hospital in Beijing, Changping District, China. Participants: Participants were 160 patients at the hospital who had been diagnosed with stable schizophrenia between April 2018 and March 2020. Groups: The research team divided participants into two groups based on their current smoking status: (1) a smoking group with 72 participants and (2) a nonsmoking group with 88 participants. Outcome Measures: The research team: (1) examined the types of antipsychotic drugs that participants received; (2) used a schizophrenia-related scale, the Positive and Negative Syndrome Scale (PANSS), to examine participants' status; (3) examined the smoking habits of the smoking group; and (4) analyzed the correlation between the PANSS score and the smoking group's smoking index. Results: No significant difference existed between the groups in the type of medicine used (P > .05). The smoking group's PANSS total (P = .014), positive symptom (P = .039), and negative symptom (P = .003) scores were significantly lower than those of the nonsmoking group (P < .05). No significant difference existed between the groups in the general psychopathological symptom score (P > .05). The smoking group started smoking between 13 and 24 years of age, with an mean age of 19.11 ± 4.10 years. The group smoked 10-30 cigarettes/d, with a mean smoking amount of 18.4 ± 3.1 cigarettes/d, and the smoking index was 344.7 ± 48.0. The smoking group's smoking index was significantly negatively correlated with the positive symptom, negative symptom, and total PANSS scores (all P = .000). No correlation existed between the smoking index and the general psychopathological symptom score (P > .05). Conclusions: Smoking patients with stable schizophrenia generally exhibit fewer symptoms than nonsmoking patients, which relate to the alleviation of mental tension that smoking can provide.
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To promote the development of extracellular vesicles of herbal medicine especially the establishment of standardization, led by the National Expert Committee on Research and Application of Chinese Herbal Vesicles, research experts in the field of herbal medicine and extracellular vesicles were invited nationwide with the support of the Expert Committee on Research and Application of Chinese Herbal Vesicles, Professional Committee on Extracellular Vesicle Research and Application, Chinese Society of Research Hospitals and the Guangdong Engineering Research Center of Chinese Herbal Vesicles. Based on the collation of relevant literature, we have adopted the Delphi method, the consensus meeting method combined with the nominal group method to form a discussion draft of "Consensus statement on research and application of Chinese herbal medicine derived extracellular vesicles-like particles (2023)". The first draft was discussed in online and offline meetings on October 12, 14, November 2, 2022 and April and May 2023 on the current status of research, nomenclature, isolation methods, quality standards and research applications of extracellular vesicles of Chinese herbal medicines, and 13 consensus opinions were finally formed. At the Third Academic Conference on Research and Application of Chinese Herbal Vesicles, held on May 26, 2023, Kewei Zhao, convenor of the consensus, presented and read the consensus to the experts of the Expert Committee on Research and Application of Chinese Herbal Vesicles. The consensus highlights the characteristics and advantages of Chinese medicine, inherits the essence, and keeps the righteousness and innovation, aiming to provide a reference for colleagues engaged in research and application of Chinese herbal vesicles at home and abroad, decode the mystery behind Chinese herbal vesicles together, establish a safe, effective and controllable accurate Chinese herbal vesicle prevention and treatment system, and build a bridge for Chinese medicine to the world.
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ETHNOPHARMACOLOGICAL RELEVANCE: Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating gastric discomfort, burning epigastric pain, and gastric reflux for hundreds of years and has shown promise for treating gastric ulcers (GUs). However, the active components and mechanism of action against GUs remain unclear. AIM OF THE STUDY: The aim of this study was to explore the active components of WJW and elucidate the underlying mechanism involved in treating GUs. MATERIALS AND METHODS: Initially, cell viability was measured by a cell counting kit 8 (CCK-8) assay to evaluate the efficacy of WJW-containing serum in vitro. The gastric ulcer index, ulcer inhibition rate, hematoxylin and staining (H&E), and periodic acid-Schiff (PAS) staining were used to evaluate the therapeutic effect of WJW in vivo. Subsequently, the levels of inflammatory factors and oxidative stress factors were determined using an enzyme-linked immunosorbent assays (ELISA) on in vitro and in vivo samples. Additionally, UPLC-Q Exactive Plus Orbitrap HRMS was used to analyze the components that were absorbed into the blood of WJW and its metabolites. Network pharmacology and metabolomics were subsequently used to identify the targets and pathways. Real-time quantitative PCR (RTâqPCR) and Western blotting were used to verify the mRNA and protein levels of the key targets and pathways. Finally, the active components were identified by molecular docking to verify the binding stability of the components and key targets. RESULTS: WJW-containing serum ameliorated ethanol-induced damage in GES-1 cells and promoted cell healing. WJW-containing serum reduced IL-6, TNF-α, MDA, and LDH levels while increasing IL-10, SOD, and T-AOC levels in the cells. Moreover, WJW treatment resulted in decreased IL-6, TNF-α, and MDA levels and increased IL-10, SOD, PGE2, and NO levels in GUs rats. In addition, eight components of WJW were absorbed into the blood. The network pharmacology results revealed 192 common targets for blood entry components and GUs, and KEGG analysis revealed that apoptosis signaling pathways were the main pathways involved in WJW activity against GUs. Metabolomic screening was used to identify 13 differential metabolites. There were 23 common targets for blood entry components, GUs, and differential metabolites, with the key targets TNF (TNF-α), AKT1, PTGS2 (COX2) and MAPK1. WJW significantly inhibited the expression of Bax, Caspase-9, Caspase-3, cleaved Caspase-9, cleaved Caspase-3, TNF-α, COX2, and p-p44/42 MAPK while promoting the expression of Bcl-2 and p-AKT1. Molecular docking revealed that the active components of WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. CONCLUSIONS: WJW treatment reduces inflammation and oxidative stress injury and inhibits apoptosis signaling pathways. The main active components are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. In this paper, we provide a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms.
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Berberina , Medicamentos de Ervas Chinesas , Glucosídeos , Monoterpenos , Úlcera Gástrica , Animais , Ratos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Caspase 3 , Caspase 9 , Interleucina-10 , Ciclo-Oxigenase 2 , Interleucina-6 , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fator de Necrose Tumoral alfa , Superóxido Dismutase , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
Fufang Xiling Jiedu capsule (FXJC), a traditional Chinese medicine that evolved from "Yinqiao Powder", is widely used for the treatment of cold and influenza. However, due to a lack of in vivo metabolism research, the chemical components responsible for the therapeutic effects still remain unclear. Hence, this study aimed to describe the metabolic profiles of the FXJC in rat plasma, urine, and feces. A combined data mining strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was employed and 201 xenobiotics, including 117 prototype components and 84 metabolites were detected. Phenolic acids, flavonoids, triterpenes, and lignans were prominent ingredients absorbed in vivo, and the major metabolic pathways of the detected metabolites were glucuronidation, sulfation, methylation, and oxidation. This is the first systematic study on the metabolism of the FXJC in vivo, providing valuable information for future studies on the efficacy, toxicity, and mechanism of the FXJC.
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Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , Ratos , Animais , Espectrometria de Massas em Tandem/métodos , Ratos Sprague-Dawley , Cromatografia Líquida de Alta Pressão/métodos , Administração Oral , Medicamentos de Ervas Chinesas/análise , MetabolomaRESUMO
OBJECTIVE: To explore the anti-tumor effect of safflower yellow (SY) against hepatocellular carcinoma (HCC) and the underlying potential mechanism. METHODS: An in vitro model was established by mixing Luc-Hepa1-6 cells and CD3+CD8+ T cells, followed by adding programmed cell death protein 1 (PD-1) antibody (Anti-mPD-1) with or without SY. The apoptosis was detected by flow cytometry and the level of inflammatory cytokines was determined by enzyme-linked immunosorbent assay. The protein levels of programmed cell death 1 ligand 1 (PD-L1), chemokine ligand (CCL5), C-X-C motif chemokine ligand 10 (CXCL10) were measured by Western blot. An in situ animal model was established in mice followed by treatment with anti-mPD-1 with or without SY. Bioluminescence imaging was monitored with an AniView 100 imaging system. To establish the FAK-overexpressed Luc-Hepa1-6 cells, cells were transfected with adenovirus containing pcDNA3.1-FAK for 48 h. RESULTS: The fluorescence intensity, apoptotic rate, release of inflammatory cytokines, and CCL5/CXCL10 secretion were dramatically facilitated by anti-mPD-1 (P<0.01), accompanied by an inactivation of PD-1/PD-L1 axis, which were extremely further enhanced by SY (P<0.05 or P<0.01). Increased fluorescence intensity, elevated percentage of CD3+CD8+ T cells, facilitated release of inflammatory cytokines, inactivated PD-1/PD-L1 axis, and increased CCL5/CXCL10 secretion were observed in Anti-mPD-1 treated mice (P<0.01), which were markedly enhanced by SY (P<0.05 or P<0.01). Furthermore, the enhanced effects of SY on inhibiting tumor cell growth, facilitating apoptosis and inflammatory cytokine releasing, suppressing the PD-1/PD-L1 axis, and inducing the CCL5/CXCL10 secretion in Anti-mPD-1 treated mixture of Luc-Hepa1-6 cells and CD3+CD8+ T cells were abolished by FAK overexpression (P<0.01). CONCLUSION: SY inhibited the progression of HCC by mediating immunological tolerance through inhibiting FAK.
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Carcinoma Hepatocelular , Chalcona/análogos & derivados , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linfócitos T CD8-Positivos , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Ligantes , Camundongos Endogâmicos , Citocinas/metabolismoRESUMO
The Lamiaceae family is renowned for its terpenoid-based medicinal components, but Leonurus, which has traditional medicinal uses, stands out for its alkaloid-rich composition. Leonurine, the principal active compound found in Leonurus, has demonstrated promising effects in reducing blood lipids and treating strokes. However, the biosynthetic pathway of leonurine remains largely unexplored. Here, we present the chromosome-level genome sequence assemblies of Leonurus japonicus, known for its high leonurine production, and Leonurus sibiricus, characterized by very limited leonurine production. By integrating genomics, RNA sequencing, metabolomics, and enzyme activity assay data, we constructed the leonurine biosynthesis pathway and identified the arginine decarboxylase (ADC), uridine diphosphate glucosyltransferase (UGT), and serine carboxypeptidase-like (SCPL) acyltransferase enzymes that catalyze key reactions in this pathway. Further analyses revealed that the UGT-SCPL gene cluster evolved by gene duplication in the ancestor of Leonurus and neofunctionalization of SCPL in L. japonicus, which contributed to the accumulation of leonurine specifically in L. japonicus. Collectively, our comprehensive study illuminates leonurine biosynthesis and its evolution in Leonurus.
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Lamiaceae , Leonurus , Leonurus/genética , Multiômica , Extratos VegetaisRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Diarrhea is a frequently encountered gastrointestinal complication in clinical practice, and E. coli is one of the main causative agents. Although Qingjie decoction (QJD) has been shown to be highly effective in treating diarrhea by eliminating heat-toxin, the underlying molecular mechanisms and pathways of QJD remain unclear. AIM OF REVIEW: The aim of this research was to explore the effects and fundamental mechanism of QJD on diarrhea induced by E.coli in rats. MATERIALS AND METHODS: Initially, we used UHPLC-MS/MS analysis to identify the chemical composition of QJD. Then, we constructed a visualization network using network pharmacology. Next, we utilized metabolomics to identify differentially expressed metabolites of QJD that are effective in treating diarrhea. RESULTS: The chemical composition of QJD was analyzed using UHPLC-MS/MS, which identified a total of 292 components. Using a network pharmacology approach, 127 bioactive compounds of QJD were screened, targeting 171 potential diarrhea treatment targets. TNF-α, IL-6, IL-1ß, and CAT were identified as important targets through visualizing the PPI network. Enrichment analysis demonstrated significant enrichment in the TNF signaling pathway, IL-17 signaling pathway, and PI3K-Akt signaling pathway. QJD showed beneficial effects, such as increased body weight, decreased fecal water content, and reduced inflammatory cell infiltration in the duodenum and colon, as well as maintaining the structure of the duodenum and colon. Metabolomic analysis revealed 32 differentially expressed metabolites in the control, model and QJD-H groups, including glucose, valine, and cysteine. Functional analysis indicated that differential metabolites were related to energy metabolism, including glucose metabolism, TCA cycle, and amino acid metabolism. CONCLUSION: QJD significantly increased body weight, decreased water content in feces, relieved inflammatory cell infiltration, maintained the structure of duodenum and colon. Combining network analysis and metabolomics, QJD exerted therapeutic effects by inhibiting inflammation and oxidative stress, regulating glucose metabolism, tricarboxylic acid metabolism, and amino acid metabolism.
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Medicamentos de Ervas Chinesas , Animais , Ratos , Escherichia coli , Fosfatidilinositol 3-Quinases , Espectrometria de Massas em Tandem , Metabolômica , Metabolismo Energético , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Cisteína , Glucose , Inflamação , Peso Corporal , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
Scutellaria baicalensis Georgi, a member of the Lamiaceae family, is a widely utilized medicinal plant. The flavones extracted from S. baicalensis contribute to numerous health benefits, including anti-inflammatory, antiviral, and anti-tumor activities. However, the incomplete genome assembly hinders biological studies on S. baicalensis. This study presents the first telomere-to-telomere (T2T) gap-free genome assembly of S. baicalensis through the integration of Pacbio HiFi, Nanopore ultra-long and Hi-C technologies. A total of 384.59 Mb of genome size with a contig N50 of 42.44 Mb was obtained, and all sequences were anchored into nine pseudochromosomes without any gap or mismatch. In addition, we analysed the major cyanidin- and delphinidin-based anthocyanins involved in the determination of blue-purple flower using a widely-targeted metabolome approach. Based on the genome-wide identification of Cytochrome P450 (CYP450) gene family, three genes (SbFBH1, 2, and 5) encoding flavonoid 3'-hydroxylases (F3'Hs) and one gene (SbFBH7) encoding flavonoid 3'5'-hydroxylase (F3'5'H) were found to hydroxylate the B-ring of flavonoids. Our studies enrich the genomic information available for the Lamiaceae family and provide a toolkit for discovering CYP450 genes involved in the flavonoid decoration.
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Layered black phosphorus (LBP) is drawing increasing attention because of its excellent potential in biomedical applications. Properties and bioeffects of LBP depend on its layer number (LN). However, the variation of LN during applications, especially in organisms, is largely unknown. Herein, LBP is found to be exfoliated by human serum albumin (HSA) after the formation of protein coronas. The sorption of HSA on LBP exhibits multiple intermediate equilibrium and size-dependent capacity and is distinguished from traditional multilayer sorption. The loss of LN for LBP increases with the increase of HSA concentrations, e.g., 2, 4, and 6 layers of LBP are exfoliated at 35, 135, and 550 mg/L HSA, respectively. The energy distribution shows that at low HSA concentrations, exfoliation is mainly driven by electrostatic and hydrogen bond interactions. With middle or high HSA concentrations, exfoliation is mainly driven by p-π or hydrophobic interactions, respectively. Layer exfoliation causes the continuous emergence of an unsaturated LBP surface available for adsorbing further HSA, breaking previous sorption saturations. The complete exfoliation of LBP weakens cytotoxicity and promotes internalization to the A-549 cell line compared with pristine or less exfoliated LBP. This finding unveils the exfoliation mechanism of proteins toward LBP and is of benefit to evaluating application performance and biosafety of LBP.
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Fósforo , Albumina Sérica Humana , Humanos , Albumina Sérica Humana/químicaRESUMO
KEY MESSAGE: By integrating QTL fine mapping and transcriptomics, a candidate gene responsible for oil content in rapeseed was identified. The gene is anticipated to primarily function in photosynthesis and photosystem metabolism pathways. Brassica napus is one of the most important oil crops in the world, and enhancing seed oil content is an important goal in its genetic improvement. However, the underlying genetic basis for the important trait remains poorly understood in this crop. We previously identified a major locus, OILA5 responsible for seed oil content on chromosome A5 through genome-wide association study. To better understand the genetics of the QTL, we performed fine mapping of OILA5 with a double haploid population and a BC3F2 segregation population consisting of 6227 individuals. We narrowed down the QTL to an approximate 43 kb region with twelve annotated genes, flanked by markers ZDM389 and ZDM337. To unveil the potential candidate gene responsible for OILA5, we integrated fine mapping data with transcriptome profiling using high and low oil content near-isogenic lines. Among the candidate genes, BnaA05G0439400ZS was identified with high expression levels in both seed and silique tissues. This gene exhibited homology with AT3G09840 in Arabidopsis that was annotated as cell division cycle 48. We designed a site-specific marker based on resequencing data and confirmed its effectiveness in both natural and segregating populations. Our comprehensive results provide valuable genetic information not only enhancing our understanding of the genetic control of seed oil content but also novel germplasm for advancing high seed oil content breeding in B. napus and other oil crops.
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Brassica napus , Humanos , Brassica napus/genética , Brassica napus/metabolismo , Locos de Características Quantitativas , Estudo de Associação Genômica Ampla , Melhoramento Vegetal , Sementes/química , Óleos de Plantas/análiseRESUMO
Garlic, an asexually propagated crop, is the second important bulb crop after the onion and is used as a vegetable and medicinal plant. Abundant and diverse garlic resources have been formed over thousands of years of cultivation. However, genome variation, population structure and genetic architecture of garlic agronomic traits were still not well elucidated. Here, 1 100 258 single nucleotide polymorphisms (SNPs) were identified using genotyping-by-sequencing in 606 garlic accessions collected from 43 countries. Population structure, principal component and phylogenetic analysis showed that these accessions were divided into five subpopulations. Twenty agronomic traits, including above-ground growth traits, bulb-related and bolt-related traits in two consecutive years were implemented in a genome-wide association study. In total, 542 SNPs were associated with these agronomic traits, among which 188 SNPs were repeatedly associated with more than two traits. One SNP (chr6: 1896135972) was repeatedly associated with ten traits. These associated SNPs were located within or near 858 genes, 56 of which were transcription factors. Interestingly, one non-synonymous SNP (Chr4: 166524085) in ribosomal protein S5 was repeatedly associated with above-ground growth and bulb-related traits. Additionally, gene ontology enrichment analysis of candidate genes for genomic selection regions between complete-bolting and non-bolting accessions showed that these genes were significantly enriched in 'vegetative to reproductive phase transition of meristem', 'shoot system development', 'reproductive process', etc. These results provide valuable information for the reliable and efficient selection of candidate genes to achieve garlic genetic improvement and superior varieties.
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We have previously shown that Liang-Yan-Yi-Zhen-San (LYYZS), an ancient Chinese herbal formula, can promote the browning of white adipose tissue. In this study, we sought to determine which active ingredients of LYYZS mediated its effects on the browning of white adipose tissue. Employing ultra-high performance liquid chromatography-Q-Exactive HF mass spectrometry, a total of 52 LYYZS ingredients were identified. On this basis, 1,560 ingredient-related targets of LYYZS were screened using the HERB databases. Meanwhile, RNA sequencing analysis of the inguinal white adipose tissue of mice produced a total of 3148 genes that were significantly differentially expressed following LYYZS treatment and differentially expressed genes regarded as browning-related targets. Through the network pharmacological analysis, a total of 136 intersection targets were obtained and an ingredient-target-pathway network was established. According to network pharmacology analysis, 10 ingredients containing trans-cinnamaldehyde, genistein, daidzein, calycosin, arginine, coumarin, oleic acid, isoleucine, palmitic acid and tyrosine were regarded as active ingredients of browning of white adipose tissue. Integrated evaluation using chemical analysis, transcriptomics and network pharmacology provides an efficient strategy for discovering the active ingredients involved in how LYYZS promotes the browning of white adipose tissue.
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Medicamentos de Ervas Chinesas , Farmacologia em Rede , Animais , Camundongos , Cromatografia Líquida de Alta Pressão , Transcriptoma , Tecido Adiposo Marrom , Cromatografia Gasosa-Espectrometria de Massas , Tecido Adiposo Branco , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/químicaRESUMO
The Nitraria roborowskii Kom. (NRK) berries, as fruits of the genus Nitraria of the Zygophyllceae family, have been widely used as folk medicine. Modern pharmacological research has demonstrated that Nitraria berries had hypolipidemic, hypoglycemic, and immunomodulatory effects. However, more research needs to be reported on the chemical composition and biological activity of NRK. Hence, the phenolic compounds in the NRK berries were comprehensively analyzed and characterized by Ultra Performance Liquid Chromatography-Quadruple-Orbitrap MS system (UPLC-Q-Orbitrap MS) in this study. In total, 52â phenolics were identified, and all were reported for the first time. In addition, the hypolipidemic efficacy of NRK berries extract was studied in the hyperlipidemic mouse model. After treatment, the high dose group of NRK substantially reversed total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. Through lipidomics technology, 27 potential biomarkers were characterized. And there was a significant callback at 25 of them after NRK treatment by using statistical analysis methods. Pathway analysis results demonstrated that NRK might exert therapeutic effects by regulating glycerophospholipid and glycerolipid metabolism pathways. This study could provide firsthand information on NRK berries for their phenolic compounds and potential application in preventing and treating hyperlipidemia.
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Fenóis , Extratos Vegetais , Camundongos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Fenóis/farmacologia , ColesterolRESUMO
BACKGROUND: Previous studies have reported inconsistent results regarding the potential relationships between addictive behaviors and the risk of epilepsy. OBJECTIVE: To assess whether genetically predicted addictive behaviors are causally associated with the risk of epilepsy outcomes. METHODS: The causation between five addictive behaviors (including cigarettes per day, alcoholic drinks per week, tea intake, coffee intake, and lifetime cannabis use) and epilepsy was evaluated by using a two-sample Mendelian Randomization (MR) analysis. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (MR Egger, weighted median, simulation extrapolation corrected MR-Egger, and Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO)) were performed to complement IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. RESULTS: The IVW analysis method indicated an approximately 20% increased risk of epilepsy per standard deviation increase in lifetime cannabis use (odds ratio [OR], 1.20; 95% confidence interval [CI]), 1.02-1.42, P = 0.028). However, there is no causal association between the other four addictive behaviors and the risk of epilepsy (cigarettes per day: OR, 1.04; 95% CI, 0.92-1.18, P = 0.53; alcoholic drinks per week: OR, 1.31; 95% CI, 0.93-1.84, P = 0.13; tea intake: OR, 1.15; 95% CI, 0.84-1.56, P = 0.39; coffee intake: OR, 0.86; 95% CI, 0.59-1.23, P = 0.41). The other MR analysis methods and further leave-one-out sensitivity analysis suggested the results were robust. CONCLUSION: This MR study indicated a potential genetically predicted causal association between lifetime cannabis use and higher risk of epilepsy. As for the other four addictive behaviors, no evidence of a causal relationship with the risk of epilepsy was found in this study.
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Comportamento Aditivo , Cannabis , Epilepsia , Humanos , Café/efeitos adversos , Análise da Randomização Mendeliana , Comportamento Aditivo/genética , Agonistas de Receptores de Canabinoides , Epilepsia/epidemiologia , Epilepsia/genética , Chá , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: Alternative splicing complexity plays a vital role in carcinogenesis and cancer progression. Improved understanding of novel splicing events and the underlying regulatory mechanisms may contribute new insights into developing new therapeutic strategies for colorectal cancer (CRC). METHODS: Here, we combined long-read sequencing technology with short-read RNA-seq methods to investigate the transcriptome complexity in CRC. By using experiment assays, we explored the function of newly identified splicing isoform TIMP1 Δ4-5. Moreover, a CRISPR/dCasRx-based strategy to induce the TIMP1 exon 4-5 exclusion was introduced to inhibit neoplasm growth. RESULTS: A total of 90,703 transcripts were identified, of which > 62% were novel compared with current transcriptome annotations. These novel transcripts were more likely to be sample specific, expressed at relatively lower levels with more exons, and oncogenes displayed a characteristic to generate more transcripts in CRC. Clinical outcome data analysis showed that 1472 differentially expressed alternative splicing events (DEAS) were tightly associated with CRC patients' prognosis, and many novel isoforms were likely to be important determinants for patient survival. Among these, newly identified splicing isoform TIMP1 Δ4-5 was significantly downregulated in CRC. Further in vitro and in vivo assays demonstrated that ectopic expression of TIMP1 Δ4-5 significantly suppresses tumor cell growth and metastasis. Serine/arginine-rich splicing factor 1 (SRSF1) acts as a onco-splicing regulator through sustaining the inclusion of TIMP1 exon 4-5. Furthermore, CRISPR/dCasRx-based strategies designed to induce TIMP1 exon 4-5 exclusion have the potential to restrain the CRC growth. CONCLUSIONS: This data provides a rich resource for deeper studies of gastrointestinal malignancies. Newly identified splicing isoform TIMP1 Δ4-5 plays an important role in mediating CRC progression and may be a potential therapy target in CRC.
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Processamento Alternativo , Neoplasias Colorretais , Humanos , Splicing de RNA , Oncogenes , Bioensaio , Neoplasias Colorretais/genética , Fatores de Processamento de Serina-ArgininaRESUMO
Polysaccharides (TCMPs) derived from traditional Chinese medicines (TCMs), such as Ganoderma lucidum, Astragalus membranaceus, Lycium barbarum, and Panax ginseng, are considered to be the main active constituents in TCMs. However, the significant pharmacological effects of orally administered TCMPs do not align well with their poor pharmacokinetics. This article aims to review the literature published mainly from 2010 to 2022, focusing on the relationship between pharmacokinetics and pharmacological effects. It has been found that unabsorbed TCMPs can exert local pharmacological effects in the gut, including anti-inflammation, anti-oxidation, regulation of intestinal flora, modulation of intestinal immunity, and maintenance of intestinal barrier integrity. Unabsorbed TCMPs can also produce systemic pharmacological effects, such as anti-tumor activity and immune system modulation, by regulating intestinal flora and immunity. Conversely, some TCMPs can be absorbed and distributed to various tissues, especially the liver, where they exhibit tissue-protecting effects against inflammation and oxidative stress-induced damage and improve glucose and lipid metabolism. In future studies, it is important to improve quality control and experimental design. Furthermore, research on enhancing the oral bioavailability of TCMPs, exploring the activity of TCMP metabolites, investigating pharmacokinetic interactions between TCMPs and oral drugs, and developing oral drug delivery systems using TCMPs holds great significance.
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Medicamentos de Ervas Chinesas , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Disponibilidade Biológica , Astragalus propinquus , Polissacarídeos/farmacologiaRESUMO
Plant-derived nanovesicles (NVs) and extracellular vesicles (EVs) are the next generation of nanocarrier platforms for biotherapeutics and drug delivery. EVs exist not only in the extracellular space, but also within the cell wall. Due to the limitations of existing isolation methods, the EVs extraction efficiency is low, and a large amount of plant material is wasted, which is of concern for rare and expensive medicinal plants. We proposed and validated a novel method for isolation of plant EVs by enzyme degradation of the plant cell wall to release the EVs. The released EVs can easily be collected. The new method was used for extraction of EVs from the roots of Morinda officinalis (MOEVs). For comparison, nanoparticles from the roots (MONVs) were extracted using the grinding method. The new method yielded a greater amount of MOEVs, and the vesicles had a smaller diameter compared to MONVs. Both MOEVs and MONVs were readily absorbed by endothelial cells without cytotoxic effect and promoted the expression of miR-155. The promotion of miR-155 by MOEVs was dose-dependent. More importantly, we found that MOEVs and MONVs were enriched toward bone tissue. These results support our hypothesis that EVs in plants could be efficiently extracted by enzymatic cell wall digestion and confirm the potential of MOEVs as therapeutic agents and drug carriers.
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Vesículas Extracelulares , MicroRNAs , Células Endoteliais , Espaço Extracelular , Osso e OssosRESUMO
Ruscogenin (RUS), a major effective steroidal sapogenin derived from Ophiopogon japonicas, has been reported to alleviate myocardial ischemia (MI), but its cardioprotective mechanism is still not completely clear. In this study, we observed that RUS markedly reduced MI-induced myocardial injury, as evidenced by notable reductions in infarct size, improvement in biochemical markers, alleviation of cardiac pathology, amelioration of mitochondrial damage, and inhibition of myocardial apoptosis. Moreover, RUS notably suppressed oxygen-glucose deprivation (OGD)-triggered cell injury and apoptosis. Notably, RUS demonstrated a considerable decrease of the interaction between myosin IIA and F-actin, along with the restoration of mitochondrial fusion and fission balance. We further confirmed that the effects of RUS on MI were mediated by myosin IIA using siRNA and overexpression techniques. The inhibition of myosin IIA resulted in a significant improvement of mitochondrial fusion and fission imbalance, while simultaneously counteracting the beneficial effects of RUS. By contrast, overexpression of myosin IIA aggravated the imbalance between mitochondrial fusion and fission and partially weakened the protection of RUS. These findings suggest that myosin IIA is essential or even a key functional protein in the cardioprotection of RUS. Overall, our results have elucidated an undiscovered mechanism involving myosin IIA-dependent mitochondrial fusion and fission balance for treating MI. Furthermore, our study has uncovered a novel mechanism underlying the protective effects of RUS.
Assuntos
Isquemia Miocárdica , Miosina não Muscular Tipo IIA , Espirostanos , Humanos , Dinâmica Mitocondrial , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/genética , Espirostanos/farmacologia , Espirostanos/uso terapêutico , Apoptose/genéticaRESUMO
The production scalability and increasing demand for nano-black phosphorus materials (nano-BPs) inevitably lead to their environmental leakage, thereby raising the risk of human exposure through inhalation, ingestion, dermal, and even intravenous pathways. Consequently, a systematic evaluation of their potential impacts on human health is necessary. This Review outlines recent progress in the understanding of various biological responses to nano-BPs. Attention is particularly given to the inconsistent toxicological findings caused by a wide variation of nano-BPs' physicochemical properties, toxicological testing methods, and cell types examined in each study. Additionally, cellular uptake and intracellular trafficking, cell death modes, immunological effects, and other biologically relevant processes are discussed in detail, providing evidence for the potential health implications of nano-BPs. Finally, we address the remaining challenges related to the health risk evaluation of nano-BPs and propose a broader range of applications for these promising nanomaterials.