Evolution and Domestication of a Novel Biosynthetic Gene Cluster Contributing to the Flavonoid Metabolism and High-Altitude Adaptability of Plants in the Fagopyrum Genus.

The diversity of secondary metabolites is an important means for plants to cope with the complex and ever-changing terrestrial environment. Plant biosynthetic gene clusters (BGCs) are crucial for the biosynthesis of secondary metabolites. The domestication and evolution of BGCs and how they affect plant secondary metabolites biosynthesis and environmental adaptation are still not fully understood. Buckwheat exhibits strong resistance and abundant secondary metabolites, especially flavonoids, allowing it to thrive in harsh environments. A non-canonical BGC named UFGT3 cluster is identified, which comprises a phosphorylase kinase (PAK), two transcription factors (MADS1/2), and a glycosyltransferase (UFGT3), forming a complete molecular regulatory module involved in flavonoid biosynthesis. This cluster is selected during Tartary buckwheat domestication and is widely present in species of the Fagopyrum genus. In wild relatives of cultivated buckwheat, a gene encoding anthocyanin glycosyltransferase (AGT), which glycosylates pelargonidin into pelargonidin-3-O-glucoside, is found inserted into this cluster. The pelargonidin-3-O-glucoside can help plants resist UV stress, endowing wild relatives with stronger high-altitude adaptability. This study provides a new research paradigm for the evolutionary dynamics of plant BGCs, and offers new perspectives for exploring the mechanism of plant ecological adaptability driven by environmental stress through the synthesis of secondary metabolites.

Gypensapogenin A-Liposomes Efficiently Ameliorates Hepatocellular Lipid Accumulation via Activation of FXR Receptor.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases encountered in clinical practice, which is characterized by the excessive accumulation of triglycerides (steatosis), and a variety of metabolic abnormalities including lipid metabolism and bile acid metabolism are closely related to NAFLD. In China, Gynostemma pentaphyllum is used as functional food and Chinese medicine to treat various diseases, especially NAFLD, for a long time. However, the active components that exert the main therapeutic effects and their mechanisms remain unclear. In this study, Gypensapogenin A was isolated from the total saponins of G. pentaphyllum and prepared as a liposomal delivery system. Gypensapogenin A liposomes could activate FXR, inhibit the expression of CYP7A1 and CYP8B1, increase the expression of CYP27A1, modulate the ratio of CA and CDCA, decrease the content of CA, and increase the content of CDCA, thus forming a virtuous cycle of activating FXR to play a role in lowering blood lipid levels.

Nomogram for assistant diagnosing acute suppurative cholangitis: a case-control study.

BACKGROUND: Acute suppurative cholangitis (ASC) lacks sensitive and specific preoperative diagnostic criteria. Some researchers suggest treating ASC as severe cholangitis. This study aimed to explore the relationship between the Tokyo Guidelines 2018 (TG18) grading system for acute cholangitis (AC) and the diagnosis of acute suppurative cholangitis (ASC), searching for independent risk factors of ASC and develop a nomogram to discriminate ASC from acute nonsuppurative cholangitis (ANSC) accurately. METHODS: After applying the inclusion and exclusion criteria, 401 patients with acute cholangitis (AC) were retrospectively analyzed at Nanjing First Hospital between January 2015 and June 2023. SPSS version 27.0 and R studio software were used to analyze data obtained from medical records. The results were validated in a prospective cohort of 82 AC patients diagnosed at Nanjing First Hospital between July 2023 and February 2024. RESULTS: Among the 401 patients, 102 had suppurative bile (the ASC group; AC grade I: 40 [39.2%], AC grade II: 27 [26.5%], AC grade III: 35 [34.3%]), whereas 299 did not have (the ANSC group; AC grade I: 157 [52.5%], AC grade II: 92 [30.8%], AC grade III: 50 [16.7%]). The specificity of ASC for diagnosing moderate-to-severe cholangitis is 79.7%. Multivariate logistic regression analysis identified concurrent cholecystitis, CRP, PCT, TBA, and bile duct diameter as independent risk factors for suppurative bile, and all of these factors were included in the nomogram. The calibration curve exhibited consistency between the nomogram and the actual observation, and the area under the curve was 0.875 (95% confidence interval: 0.835-0.915), sensitivity was 86.6%, and specificity was 75.5%. CONCLUSION: Suppurative bile is a specific indicator for diagnosing moderate-to-severe cholangitis. However, diagnosing ASC with AC grade II and AC grade III has the risk of missed diagnosis as the sensitivity is only 60.8%. To improve the diagnostic rate of ASC, this study identified concurrent cholecystitis, CRP, PCT, TBA, and preoperative bile duct diameter as independent risk factors for ASC, and a nomogram was developed to help physicians recognize patients with ASC.

Insights into the Metabolite Profiles of Two Camellia (Theaceae) Species in Yunnan Province through Metabolomic and Transcriptomic Analysis.

Tea (Camellia sinensis) falls into the family Theaceae, is a valuable commercial crop, and tea products made from its buds and young leaves are favored by consumers all over the world. The more common Thea plant is Camellia sinensis (C. sinensis), but its most important relative, Camellia taliensis (C. taliensis), is also utilized by locals in the area of cultivation to manufacture tea. In this investigation, C. taliensis (DL) and C. sinensis (QJZ) were characterized in terms of their agronomic traits, physicochemical indices, metabolomics, and transcriptomics. The leaf area of DL is larger than that of QJZ; the color of DL's buds and leaves is yellowish-green, while that of QJZ's is green. DL's buds and leaves are more densely velvety than those of QJZ. The HPLC results indicated that the physicochemical contents varied considerably between the two samples, with DL having greater concentrations of EGCG and GABA than QJZ, while QJZ had remarkably higher concentrations of C, CA, and EGC than DL. A total of 2269 metabolites and 362,190,414 genes were positively identified, with the number of DAMs and DEGs being 1001 and 34,026, respectively. The flavonoids, phenolic acids, and alkaloid metabolites were dramatically different between the two tea group plants. Bioinformatics profiling revealed that the DAMs and DEGs of the two tea group plants interacted with each other and were involved in metabolic pathways, including "biosynthesis of secondary metabolites", "biosynthesis of amino acids", "biosynthesis of cofactors", "phenylpropanoid biosynthesis", and "flavonoid biosynthesis". Overall, these results provide statistical support for germplasm conservation and production for both C. taliensis and C. sinensis.

Deciphering the impairment of perimenopausal insomnia on visual search from a neurocognitive processing perspective.

STUDY OBJECTIVES: Perimenopausal insomnia (PMI) is associated with observable performance impairments in visual search tasks. This study examines how various cognitive processing stages contribute to search performance delays in PMI compared to healthy controls (HCs). METHODS: We recruited 76 participants diagnosed with PMI and 63 HCs. Event-related potentials (ERPs) were recorded as participants engaged in a visual search task, reporting the orientation of a color popout target within an array of ellipses. We analyzed group differences in behavioral performance and ERP components across cognitive processing stages. RESULTS: Compared to HCs, PMI patients exhibited behavioral response delays, although accuracy was not different between groups. Electrophysiological analyses revealed group differences across several ERP components. Firstly, the N1 component's amplitude increased bilaterally, suggesting enhanced visual sensory processing. Secondly, a slower and smaller N2pc indicated reduced attentional orienting. Thirdly, a decreased SPCN amplitude pointed to deficits in target discrimination. Fourthly, an increased amplitude of the stimulus-locked LRP, with unchanged latency, suggested heightened neural inputs for maintaining motor initiation speed. Fifthly, prolonged response-locked LRP latency indicated slower motor execution. Finally, these changes in ERP components, along with significant correlations between LRP components and insomnia symptoms, suggest potential neural biomarkers for PMI. CONCLUSIONS: Our findings provide high-temporal-resolution insights into the neurocognitive disruptions associated with PMI, highlighting how sleep disturbances affect cognitive processing in visual tasks. These insights enhance our understanding of PMI and contribute to discussions on neural mechanisms driving behavioral performance in various conditions.

The utilization of chitosan/Bletilla striata hydrogels to elevate anti-adhesion, anti-inflammatory and pro-angiogenesis properties of polypropylene mesh in abdominal wall repair.

Polypropylene (PP) mesh is commonly used in abdominal wall repair due to its ability to reduce the risk of organ damage, infections and other complications. However, the PP mesh often leads to adhesion formation and does not promote functional tissue repair. In this study, we synthesized one kind of aldehyde Bletilla striata polysaccharide (BSPA) modified chitosan (CS) hydrogel based on Schiff base reaction. The hydrogel exhibited a porous network structure, a highly hydrophilic surface and good biocompatibility. We wrapped the PP mesh inside the hydrogel and evaluated the performance of the resulting composites in a bilateral 1 × 1.5 cm abdominal wall defect model in rats. The results of gross observation, histological staining and immunohistochemical staining demonstrated the positive impact of the CS hydrogel on anti-adhesion and wound healing effects. Notably, the addition of BSPA to the CS hydrogel further improved the performance of the composites in vivo, promoting wound healing by enhancing collagen deposition and capillary rearrangement. This study suggested that the BSPA-modified CS hydrogel significantly promoted the anti-adhesion, anti-inflammatory and pro-angiogenesis properties of PP meshes during the healing process. Overall, this work offers a novel approach to the design of abdominal wall repair patches.

Unveiling the secrets of gastrointestinal mucous adenocarcinoma survival after surgery with artificial intelligence: A population-based study.

BACKGROUND: Research on gastrointestinal mucosal adenocarcinoma (GMA) is limited and controversial, and there is no reference tool for predicting postoperative survival. AIM: To investigate the prognosis of GMA and develop predictive model. METHODS: From the Surveillance, Epidemiology, and End Results database, we collected clinical information on patients with GMA. After random sampling, the patients were divided into the discovery (70% of the total, for model training), validation (20%, for model evaluation), and completely blind test cohorts (10%, for further model evaluation). The main assessment metric was the area under the receiver operating characteristic curve (AUC). All collected clinical features were used for Cox proportional hazard regression analysis to determine factors influencing GMA's prognosis. RESULTS: This model had an AUC of 0.7433 [95% confidence intervals (95%CI): 0.7424-0.7442] in the discovery cohort, 0.7244 (GMA: 0.7234-0.7254) in the validation cohort, and 0.7388 (95%CI: 0.7378-0.7398) in the test cohort. We packaged it into Windows software for doctors' use and uploaded it. Mucinous gastric adenocarcinoma had the worst prognosis, and these were protective factors of GMA: Regional nodes examined [hazard ratio (HR): 0.98, 95%CI: 0.97-0.98, P < 0.001)] and chemotherapy (HR: 0.62, 95%CI: 0.58-0.66, P < 0.001). CONCLUSION: The deep learning-based tool developed can accurately predict the overall survival of patients with GMA postoperatively. Combining surgery, chemotherapy, and adequate lymph node dissection during surgery can improve patient outcomes.

New natural protein tyrosine phosphatase 1B inhibitors from Gynostemma pentaphyllum.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. Gynostemma pentaphyllum is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from G. pentaphyllum, and their structures were elucidated by spectroscopic methods including HR-ESI-MS,1H and 13C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds 7∼10 were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.

Molecular network mechanism of Shexiang Huayu Xingnao granules in treating intracerebral hemorrhage.

We aim to explore the pharmacological efficacy and molecular network mechanism of Shexiang Huayu Xingnao granules (SX granules) in the treatment of intracerebral hemorrhage (ICH) based on experiments and network pharmacology. After the ICH model establishment, the behavioral functions of rats were assessed by the modified neurological severity score (mNSS), the wire suspension test, and the rotarod test. Brain histomorphological changes were observed using 2,3,5-triphenyl tetrazolium chloride (TTC), hematoxylin-eosin (HE), Nissl, and TdT-mediated dUTP nick end labeling (TUNEL) combined with neuronal nuclear (NEUN) immunofluorescence staining. The cross-targets of SX granules and ICH were obtained using network pharmacology, gene ontology (GO) enrichment analysis, and Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway analysis were performed. Then, the obtained Hub genes were verified using real-time quantitative polymerase chain reaction (RT-qPCR). The mNSS score was reduced and the duration to remain wire suspended increased in the SX group. In the morphological experiment, SX granules reduced brain tissue damage, neuronal apoptosis, and the number of astrocytes in the ICH rats. Moreover, 607 targets of drug-disease intersection were obtained by network pharmacology, and 10 Hub genes were found. SX granules regulated the expression of HRAS, MAPK3, and STAT3 in ICH condition. In conclusion, SX granules improved behavioral dysfunction, abnormal alterations in brain tissue, and cell morphology in ICH rats, and potential molecular mechanism was linked with the expression of multiple genes.

Chemical characterization and comparative analysis of different parts of Cocculus orbiculatus through UHPLC-Q-TOF-MS.

Cocculus orbiculatus (L.) DC. (C. orbiculatus) is a medicinal herb valued for its dried roots with anti-inflammatory, analgesic, diuretic, and other therapeutic properties. Despite its traditional applications, chemical investigations into C. orbiculatus remain limited, focusing predominantly on alkaloids and flavonoids. Furthermore, the therapeutic use of C. orbiculatus predominantly focuses on the roots, leaving the stems, a significant portion of the plant, underutilized. This study employed ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) with in-house and online databases for comprehensive identification of components in various plant parts. Subsequently, untargeted metabolomics was employed to analyze differences in components across different harvest periods and plant sections of C. orbiculatus, aiming to screen for distinct components in different parts of the plant. Finally, metabolomic analysis of the roots and stems, which contribute significantly to the plant's weight, was conducted using chemometrics, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares discriminant analysis (OPLS-DA), and heatmaps. A total of 113 components, including alkaloids, flavonoids, and organic acids, were annotated across the root, stem, leaf, flower, and fruit, along with numerous previously unreported compounds. Metabolomic analyses revealed substantial differences in components between the root and stem compared to the leaf, flower, and fruit during the same harvest period. PLS-DA and OPLS-DA annotated 10 differentiating components (VIP > 1.5, P < 0.05, FC > 2 or FC < 0.67), with 5 unique to the root and stem, exhibiting lower mass spectrometric responses. This study provided the first characterization of 113 chemical constituents in different parts of C. orbiculatus, laying the groundwork for pharmacological research and advocating for the enhanced utilization of its stem.

Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.

The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.

Identification of m6A-related lncRNAs LINC02471 and DOCK9-DT as potential biomarkers for thyroid cancer.

Thyroid cancer (THCA) is the most common endocrine malignancy worldwide and has been rising at the fastest rate in recent years. Long-stranded non-coding RNAs (lncRNAs) and N6-methyladenosine (m6A) have been associated with immunotherapy efficacy and cancer prognosis. However, how m6A-associated lncRNAs (mrlncRNAs) affect the prognosis of patients with thyroid cancer is unclear. Therefore, this study utilized The Cancer Genome Atlas (TCGA) database to provide thyroid cancer-related transcriptomic data and related clinical data. The R program was used to identify m6A-related lncRNAs, and a risk model consisting of two lncRNAs (LINC02471 and DOCK9-DT) was obtained using least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Kaplan-Meier survival analysis and transient subject operating characteristics (ROC) were used for analysis. The results showed a substantial association between immune cell infiltration and risk scores. Independent analyses confirmed that the expression of LINC02471 and DOCK9-DT was significantly higher in thyroid cancer tissues than in normal tissues, suggesting that they may be useful biomarkers for thyroid cancer.

Quantitative analysis of six sesquiterpene glycosides from Dendrobium nobile Lindl. under different growth conditions by high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry in MRM mode.

INTRODUCTION: The sesquiterpene glycosides (SGs) from Dendrobium nobile Lindl. have immunomodulatory effects. However, there are no studies on the growth conditions affecting its contents and quantitative analysis methods. OBJECTIVE: In the present study, a quantitative analysis method for six SGs from D. nobile was established. We explored which growth conditions could affect the contents of SGs, providing a basis for the cultivation and clinical application of D. nobile. METHODS: Firstly, based on the optimization of mass spectrometry parameters and extraction conditions for six SGs in D. nobile, a method for the determination of the contents of six SGs was established using high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC-QqQ-MS/MS) in multiple reaction monitoring (MRM) mode. Then, the methodology of the established method was validated. Secondly, the established method was applied to determine the contents of six SGs from 78 samples of D. nobile grown under different growth conditions. Finally, chemometrics analysis was employed to analyze the results and select optimal growth conditions for D. nobile. RESULTS: The results indicated significant variations in the contents of SGs from D. nobile grown under different growth conditions. The primary factors influencing SG contents included age, geographical origin, altitude, and epiphytic pattern. CONCLUSION: Therefore, the established method for determining SG contents from D. nobile is stable. In particular, the SG contents were relatively high in samples of 3-year-old D. nobile grown at an altitude of approximately 500 m on Danxia rocks in Chishui, Guizhou.

Glutathionylation of a glycolytic enzyme promotes cell death and vigor loss during aging of elm seeds.

Seed deterioration during storage is a major problem in agricultural and forestry production and for germplasm conservation. Our previous studies have shown that a mitochondrial outer membrane protein VOLTAGE-DEPENDENT ANION CHANNEL (VDAC) is involved in programmed cell death-like viability loss during the controlled deterioration treatment (CDT) of elm (Ulmus pumila L.) seeds, but its underlying mechanism remains unclear. In this study, we demonstrate that the oxidative modification of GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE (GAPDH) is functioned in the gate regulation of VDAC during the CDT of elm seeds. Through biochemical and cytological methods and observations of transgenic material [Arabidopsis (Arabidopsis thaliana), Nicotiana benthamiana, and yeast (Saccharomyces cerevisiae)], we demonstrate that cysteine S-glutathionylated UpGAPDH1 interacts with UpVDAC3 during seed aging, which leads to a mitochondrial permeability transition and aggravation of cell death, as indicated by the leakage of the mitochondrial proapoptotic factor cytochrome c and the emergence of apoptotic nucleus. Physiological assays and inductively coupled plasma mass spectrometry analysis revealed that GAPDH glutathionylation is mediated by increased glutathione, which might be caused by increases in the concentrations of free metals, especially Zn. Introduction of the Zn-specific chelator TPEN [(N,N,N',N'-Tetrakis (2-pyridylmethyl)ethylenediamine)] significantly delayed seed aging. We conclude that glutathionylated UpGAPDH1 interacts with UpVDAC3 and serves as a proapoptotic protein for VDAC-gating regulation and cell death initiation during seed aging.

Abnormal functional connectivity of the reward circuit associated with early satiety in patients with postprandial distress syndrome.

Postprandial distress syndrome (PDS) is the most common functional dyspepsia (FD) subtype. Early satiety is one of the cardinal symptoms of the PDS subtype in FD patients. The heterogeneity of symptoms in FD patients hampered therapy for patients based on specific symptoms, necessitating a symptom-based understanding of the pathophysiology of FD. To investigate the correlation between reward circuit and symptom severity of PDS patients, seed (Nucleus accumbens, NAc, a key node in the reward circuit) based resting-state functional connectivity (FC) was applied in the neuroimaging data analysis. The results demonstrated that the patients with PDS manifested strengthened FC between NAc and the caudate, putamen, pallidum, amygdala, hippocampus, thalamus, anterior cingulate cortex (ACC), and insula. Moreover, the FC between NAc and ACC, insula, thalamus, and hippocampus exhibited significant positive associations with symptom severity. More importantly, the strengthened FC between NAc and the ACC, insula, amygdala, and hippocampus were found associated with the early satiety symptom of patients with PDS. This study indicated that the altered FC of reward circuit regions may play a role in the pathophysiology of patients with PDS, and some of the aberrant NAc-based FC within the reward circuit were more related to the early satiety of patients with PDS. These findings improve our symptom-based understanding of the central pathophysiology of FD, lay the groundwork for an objective diagnosis of FD, and shed light on the precise prescription for treating FD based on symptoms.

Construction of in vitro liver-on-a-chip models and application progress.

The liver is the largest internal organ of the human body. It has a complex structure and function and plays a vital role in drug metabolism. In recent decades, extensive research has aimed to develop in vitro models that can simulate liver function to demonstrate changes in the physiological and pathological environment of the liver. Animal models and in vitro cell models are common, but the data obtained from animal models lack relevance when applied to humans, while cell models have limited predictive ability for metabolism and toxicity in humans. Recent advancements in tissue engineering, biomaterials, chip technology, and 3D bioprinting have provided opportunities for further research in in vitro models. Among them, liver-on-a-Chip (LOC) technology has made significant achievements in reproducing the in vivo behavior, physiological microenvironment, and metabolism of cells and organs. In this review, we discuss the development of LOC and its research progress in liver diseases, hepatotoxicity tests, and drug screening, as well as chip combinations. First, we review the structure and the physiological function of the liver. Then, we introduce the LOC technology, including general concepts, preparation materials, and methods. Finally, we review the application of LOC in disease modeling, hepatotoxicity tests, drug screening, and chip combinations, as well as the future challenges and directions of LOC.

Metabolites rapid-annotation in mice by comprehensive method of virtual polygons and Kendric mass loss filtering: A case study of Dendrobium nobile Lindl.

With significant advancements in high-resolution mass spectrometry, there has been a substantial increase in the amount of chemical component data acquired from natural products. Therefore, the rapid and efficient extraction of valuable mass spectral information from large volumes of high-resolution mass spectrometry data holds crucial significance. This study illustrates a targeted annotation of the metabolic products of alkaloid and sesquiterpene components from Dendrobium nobile (D. nobile) aqueous extract in mice serum through the integration of an in-houses database, R programming, a virtual metabolic product library, polygonal mass defect filtering, and Kendrick mass defect strategies. The research process involved initially establishing a library of alkaloids and sesquiterpenes components and simulating 71 potential metabolic reactions within the organism using R programming, thus creating a virtual metabolic product database. Subsequently, employing the virtual metabolic product library allowed for polygonal mass defect filtering, rapidly screening 1705 potential metabolites of alkaloids and 3044 potential metabolites of sesquiterpenes in the serum. Furthermore, based on the chemical composition database of D. nobile and online mass spectrometry databases, 95 compounds, including alkaloids, sesquiterpenes, and endogenous components, were characterized. Finally, utilizing Kendrick mass defect analysis in conjunction with known alkaloids and sesquiterpenes targeted screening of 209 demethylation, methylation, and oxidation products in phase I metabolism, and 146 glucuronidation and glutathione conjugation products in phase II metabolism. This study provides valuable insights for the rapid and accurate annotation of chemical components and their metabolites in vivo within natural products.

Early results of the integrative epigenomic-transcriptomic landscape of colorectal adenoma and cancer.

BACKGROUND: Aberrant methylation is common during the initiation and progression of colorectal cancer (CRC), and detecting these changes that occur during early adenoma (ADE) formation and CRC progression has clinical value. AIM: To identify potential DNA methylation markers specific to ADE and CRC. METHODS: Here, we performed SeqCap targeted bisulfite sequencing and RNA-seq analysis of colorectal ADE and CRC samples to profile the epigenomic-transcriptomic landscape. RESULTS: Comparing 22 CRC and 25 ADE samples, global methylation was higher in the former, but both showed similar methylation patterns regarding differentially methylated gene positions, chromatin signatures, and repeated elements. High-grade CRC tended to exhibit elevated methylation levels in gene promoter regions compared to those in low-grade CRC. Combined with RNA-seq gene expression data, we identified 14 methylation-regulated differentially expressed genes, of which only AGTR1 and NECAB1 methylation had prognostic significance. CONCLUSION: Our results suggest that genome-wide alterations in DNA methylation occur during the early stages of CRC and demonstrate the methylation signatures associated with colorectal ADEs and CRC, suggesting prognostic biomarkers for CRC.

Hypolipidemic effect and gut microbiota regulation of Gypenoside aglycones in rats fed a high-fat diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynostemma pentaphyllum (Thunb.) Makino has traditional applications in Chinese medicine to treat lipid abnormalities. Gypenosides (GPs), the main bioactive components of Gynostemma pentaphyllum, have been reported to exert hypolipidemic effects through multiple mechanisms. The lipid-lowering effects of GPs may be attributed to the aglycone portion resulting from hydrolysis of GPs by the gut microbiota. However, to date, there have been no reports on whether gypenoside aglycones (Agl), the primary bioactive constituents, can ameliorate hyperlipidemia by modulating the gut microbiota. AIM OF THE STUDY: This study explored the potential therapeutic effects of gypenoside aglycone (Agl) in a rat model of high-fat diet (HFD)-induced hyperlipidemia. METHODS: A hyperlipidemic rat model was established by feeding rats with a high-fat diet. Agl was administered orally, and serum lipid levels were analyzed. Molecular techniques, including RT-polymerase chain reaction (PCR) and fecal microbiota sequencing, were used to investigate the effects of Agl on lipid metabolism and gut microbiota composition. RESULTS: Agl administration significantly reduced serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and mitigated hepatic damage induced by HFD. Molecular investigations have revealed the modulation of key lipid metabolism genes and proteins by Agl. Notably, Agl treatment enriched the gut microbiota with beneficial genera, including Lactobacillus, Akkermansia, and Blautia and promoted specific shifts in Lactobacillus murinus, Firmicutes bacterium CAG:424, and Allobaculum stercoricanis. CONCLUSION: This comprehensive study established Agl as a promising candidate for the treatment of hyperlipidemia. It also exhibits remarkable hypolipidemic and hepatoprotective properties. The modulation of lipid metabolism-related genes, along with the restoration of gut microbiota balance, provides mechanistic insights. Thus, Agl has great potential for clinical applications in hyperlipidemia management.