Astragalus Polysaccharide Enhances Voriconazole Metabolism under Inflammatory Conditions through the Gut Microbiota.

Background and Aims: Voriconazole (VRC), a widely used antifungal drug, often causes hepatotoxicity, which presents a significant clinical challenge. Previous studies demonstrated that Astragalus polysaccharide (APS) can regulate VRC metabolism, thereby potentially mitigating its hepatotoxic effects. In this study, we aimed to explore the mechanism by which APS regulates VRC metabolism. Methods: First, we assessed the association of abnormal VRC metabolism with hepatotoxicity using the Roussel Uclaf Causality Assessment Method scale. Second, we conducted a series of basic experiments to verify the promotive effect of APS on VRC metabolism. Various in vitro and in vivo assays, including cytokine profiling, immunohistochemistry, quantitative polymerase chain reaction, metabolite analysis, and drug concentration measurements, were performed using a lipopolysaccharide-induced rat inflammation model. Finally, experiments such as intestinal biodiversity analysis, intestinal clearance assessments, and Bifidobacterium bifidum replenishment were performed to examine the ability of B. bifidum to regulate the expression of the VRC-metabolizing enzyme CYP2C19 through the gut-liver axis. Results: The results indicated that APS does not have a direct effect on hepatocytes. However, the assessment of gut microbiota function revealed that APS significantly increases the abundance of B. bifidum, which could lead to an anti-inflammatory response in the liver and indirectly enhance VRC metabolism. The dual-luciferase reporter gene assay revealed that APS can hinder the secretion of pro-inflammatory mediators and reduce the inhibitory effect on CYP2C19 transcription through the nuclear factor-κB signaling pathway. Conclusions: The study offers valuable insights into the mechanism by which APS alleviates VRC-induced liver damage, highlighting its immunomodulatory influence on hepatic tissues and its indirect regulatory control of VRC-metabolizing enzymes within hepatocytes.

Development of a prediction model for predicting the prevalence of nonalcoholic fatty liver disease in Chinese nurses: the first-year follow data of a web-based ambispective cohort study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is gradually becoming a huge threat to public health. With complex working characteristics, female nurses had been found with high risk of NAFLD. To develop and validate a prediction model to predict the prevalence of NAFLD based on demographic characteristics, work situation, daily lifestyle and laboratory tests in female nurses. METHODS: This study was a part of the Chinese Nurse Cohort Study (The National Nurse Health Study, NNHS), and data were extracted from the first-year follow data collected from 1st June to 1st September 2021 by questionnaires and physical examination records in a comprehensive tertiary hospital. The questionnaires included demographic characteristics, work situation and daily lifestyle. Logistic regression and a nomogram were used to develop and validate the prediction model. RESULTS: A total of 824 female nurses were included in this study. Living situation, smoking history, monthly night shift, daily sleep time, ALT/AST, FBG, TG, HDL-C, UA, BMI, TBil and Ca were independent risk factors for NAFLD occurance. A prediction model for predicting the prevalence of NAFLD among female nurses was developed and verified in this study. CONCLUSION: Living situation, smoking history, monthly night shift, daily sleep time, ALT/AST, FBG, TG, UA, BMI and Ca were independent predictors, while HDL-C and Tbil were independent protective indicators of NAFLD occurance. The prediction model and nomogram could be applied to predict the prevalence of NAFLD among female nurses, which could be used in health improvement. TRIAL REGISTRATION: This study was a part of the Chinese Nurse Cohort Study (The National Nurse Health Study, NNHS), which was a ambispective cohort study contained past data and registered at Clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04572347 ) and the China Cohort Consortium ( http://chinacohort.bjmu.edu.cn/project/102/ ).

Metabolic Disease and Risk of Thyroid Disease: Evidence from the National Nurse Health Cohort in China.

BACKGROUND: Previous studies have shown that metabolic diseases are risk factors for thyroid disease; most studies are cross-sectional design. We aimed to evaluate the causal relationship between thyroid and metabolic diseases in a cohort of Chinese nurses. METHODS: We conducted an ambispective cohort study of the National Nurses' Health Study. Thyroid disease data based on ultrasonography from 2017 to 2021 were collected. We described thyroid disease incidence and the risk factors associated with a cluster of metabolic factors. We used the Mann‒Whitney U test, repeated-measures ANOVA and multivariable Cox proportional hazard regression to analyze the data. RESULTS: A total of 1529 female nurses without thyroid disease were enrolled in 2017, of which, complete data were available for 1269 nurses. In 2018-2020, thyroid nodule incidence ranged from 32.8%-46.3%, thyroiditis incidence was 13.4%-14.3%, and goiter incidence was 4.1%-29.1%, thyroid adenoma and thyroid tumors incidence were 0.1%-0.5% and 1%-1.5%. We also found that NAFLAD was an independent risk factor for thyroid adenoma (p = .003). The age at diagnosis was an independent risk factor for goiter (p <. 001) and thyroid nodules (p < .001). Fasting blood glucose was an independent risk factor for thyroid tumors (p = .004). The age at diagnosis (p = .003), Body Mass Index (p = .006) and menopause (p = .031) were risk factors for thyroiditis. CONCLUSION: Thyroid disease incidence among nurses is increasing. Age at diagnosis, BMI, fasting blood glucose, and nonalcoholic fatty liver disease are independent risk factors for different types of thyroid disease. This study provides evidence for future studies to further explore the pathogenesis and prevention of thyroid diseases.

Liver Protection of a Low-Polarity Fraction from Ficus pandurata Hance, Prepared by Supercritical CO2 Fluid Extraction, on CCl4-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Ferroptosis Mediated by Strengthened Antioxidation.

Ficus pandurata Hance (FPH) is a Chinese herbal medicine widely used for health care. This study was designed to investigate the alleviation efficacy of the low-polarity ingredients of FPH (FPHLP), prepared by supercritical CO2 fluid extraction technology, against CCl4-induced acute liver injury (ALI) in mice and uncover its underlying mechanism. The results showed that FPHLP had a good antioxidative effect determined by the DPPH free radical scavenging activity test and T-AOC assay. The in vivo study showed that FPHLP dose-dependently protected against liver damage via detection of ALT, AST, and LDH levels and changes in liver histopathology. The antioxidative stress properties of FPHLP suppressed ALI by increasing levels of GSH, Nrf2, HO-1, and Trx-1 and reducing levels of ROS and MDA and the expression of Keap1. FPHLP significantly reduced the level of Fe2+ and expression of TfR1, xCT/SLC7A11, and Bcl2, while increasing the expression of GPX4, FTH1, cleaved PARP, Bax, and cleaved caspase 3. The results demonstrated that FPHLP protected mouse liver from injury induced by CCl4 via suppression of apoptosis and ferroptosis. This study suggests that FPHLP can be used for liver damage protection in humans, which strongly supports its traditional use as a herbal medicine.

Recent Progress in Electrochemical Nano-Biosensors for Detection of Pesticides and Mycotoxins in Foods.

Pesticide and mycotoxin residues in food are concerning as they are harmful to human health. Traditional methods, such as high-performance liquid chromatography (HPLC) for such detection lack sensitivity and operation convenience. Efficient, accurate detection approaches are needed. With the recent development of nanotechnology, electrochemical biosensors based on nanomaterials have shown solid ability to detect trace pesticides and mycotoxins quickly and accurately. In this review, English articles about electrochemical biosensors in the past 11 years (2011-2022) were collected from PubMed database, and various nanomaterials are discussed, including noble metal nanomaterials, magnetic metal nanoparticles, metal-organic frameworks, carbon nanotubes, as well as graphene and its derivatives. Three main roles of such nanomaterials in the detection process are summarized, including biomolecule immobilization, signal generation, and signal amplification. The detection targets involve two types of pesticides (organophosphorus and carbamate) and six types of mycotoxins (aflatoxin, deoxynivalenol, zearalenone, fumonisin, ochratoxin A, and patulin). Although significant achievements have been made in the evolution of electrochemical nano-biosensors, many challenges remain to be overcome.

Anti-colorectal cancer of Ardisia gigantifolia Stapf. and targets prediction via network pharmacology and molecular docking study.

BACKGROUND: Ardisia gigantifolia Stapf. (AGS), a Chinese folk medicine widely grows in the south of China and several studies reported that AGS could inhibit the proliferation of breast cancer, liver cancer, and bladder cancer cell lines. However, little is known about its anti-colorectal cancer (CRC) efficiency. METHODS: In the present study, a combination of MTT assay, network pharmacological analysis, bioinformatics, molecular docking, and molecular dynamics simulation study was used to investigate the active ingredients, and targets of AGS against CRC, as well as the potential mechanism. RESULTS: MTT assay showed that three kinds of fractions from AGS, including the n-butanol extract (NBAGS), ethyl acetate fraction (EAAGS), and petroleum ether fraction (PEAGS) significantly inhibited the proliferation of CRC cells, with the IC50 values of 197.24, 264.85, 15.45 µg/mL on HCT116 cells, and 523.6, 323.59, 150.31 µg/mL on SW620 cells, respectively. Eleven active ingredients, including, 11-O-galloylbergenin, 11-O-protocatechuoylbergenin, 11-O-syringylbergenin, ardisiacrispin B, bergenin, epicatechin-3-gallate, gallic acid, quercetin, stigmasterol, stigmasterol-3-o-ß-D-glucopyranoside were identified. A total of 173 targets related to the bioactive components and 21,572 targets related to CRC were picked out through database searching. Based on the crossover targets of AGS and CRC, a protein-protein interaction network was built up by the String database, from which it was concluded that the core targets would be SRC, MAPK1, ESR1, HSP90AA1, MAPK8. Besides, GO analysis showed that the numbers of biological process, cellular component, and molecular function of AGS against CRC were 1079, 44, and 132, respectively, and KEGG pathway enrichment indicated that 96 signaling pathways in all would probably be involved in AGS against CRC, among which MAPK signaling pathway, lipid, and atherosclerosis, proteoglycans in cancer, prostate cancer, adherens junction would probably be the major pathways. The docking study verified that AGS had multiple ingredients and multiple targets against CRC. Molecular dynamics (MD) simulation analysis showed that the binding would be stable via forming hydrogen bonds. CONCLUSION: Our study showed that AGS had good anti-CRC potency with the characteristics of multi-ingredients, -targets, and -signaling pathways.

Polysaccharides from Garlic Protect against Liver Injury in DSS-Induced Inflammatory Bowel Disease of Mice via Suppressing Pyroptosis and Oxidative Damage.

Inflammatory bowel disease (IBD), a widespread intestinal disease threatening human health, is commonly accompanied by secondary liver injury (SLI). Pyroptosis and oxidative stress act as an important role underlying the pathophysiology of SLI, during which a large number of proinflammatory cytokines and oxidative intermediates can be produced, thereby causing the liver severely damaged. Suppression of pyroptosis and oxidative damage can be considered one of the critical strategies for SLI therapy. Garlic, a natural food with eatable and medicinal functions, is widely used in people's daily life. There is no study about the alleviation of garlic against IBD accompanied with SLI. This study is aimed at investigating the efficacy of the polysaccharides from garlic (PSG) in treating IBD and SLI, as well as its pharmacological mechanism. The results showed that PSG significantly alleviated dextran sulfate sodium-induced IBD determined by evaluating the bodyweight loss, disease activity index, colon length, and colonic pathological examination of mice. PSG significantly reduced the colonic inflammation by reversing the levels of myeloperoxidase, diamine oxidase activity, iNOS, and COX2 and strengthened the intestinal barrier by increasing the expressions of ZO1, occludin, and MUC2 of IBD mice. Furthermore, PSG strongly alleviated SLI determined by assessing the liver morphological change, liver index, levels of ALT and AST, and liver pathological change of mice. Mechanically, PSG reduced the high levels of LPS, IL-1ß, IL18, NLRP3, gasdermin D, caspase 1, ASC, TLR4, MyD88, NF-κB, phospho-NF-κB, while it increased IL-10 in the livers of mice, indicating that PSG alleviated SLI by suppressing inflammation and pyroptosis. Additionally, PSG significantly inhibited the oxidative damage in the liver tissues of SLI mice by reducing the levels of ROS, MDA, Keap-1, 8-OHDG, and phospho-H2AX and increasing the levels of GPX4, SOD2, HO1, NQO1, and Nrf2. These findings suggested that the garlic polysaccharides could be used to treat IBD accompanied with SLI in humans.

Alleviation of Fufang Fanshiliu decoction on type II diabetes mellitus by reducing insulin resistance: A comprehensive network prediction and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Fanshiliu decoction (FFSLD) is a Chinese herbal medicine prescription that has been used in type 2 diabetes mellitus (T2DM), while the underlying mechanism remains unclear. AIM OF THE STUDY: To validate the efficacy and explore the potential mechanisms of FFSLD in treating T2DM via integrating a network pharmacological approach and experimental evaluation. MATERIALS AND METHODS: T2DM mice model induced by high-fat diet feeding combined with streptozotocin injection was selected to investigate the alleviation of FFSLD against T2DM, via detecting the levels of glucose, insulin, glucagon (GC), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Network pharmacological analysis was used to predict the potential mechanisms, including the pharmacokinetics and drug-likeness screening, active ingredients and potential targets prediction, network analysis, and enrichment analysis. The candidate bioactive molecules of FFSLD, and targets information excavated through TCMSP, Uniprot, GeneCards, OMIM databases, were combined for comprehensive analysis by constructing "drug-compound-target-disease" and "protein-protein interaction" networks. Enrichment analysis was performed via Gene Ontology (GO) and Koto Encyclopedia of Genes and Genomes (KEGG) databases. HepG2 insulin-resistance (IR) cells model induced by high glucose was used to verify the potential mechanisms of FFSLD against T2DM which were predicted by the network pharmacology. RESULTS: The animal study showed that FFSLD significantly decreased the blood glucose, and reversed the abnormal levels of insulin, GC, TG, TC, HDL-C, and LDL-C in T2DM mice. Network pharmacological analysis indicated that 106 active compounds of FFSLD might be correlated with 628 targets in treating T2DM, and the mechanism would probably be related to insulin resistance that harbored a high response value (P = 5.88844 E-33) though regulating Akt1, ESR1, oxidoreductase activity, and JAK/STAT signalings. Experimental validation showed that FFSLD reduced the ROS level, up-regulated the expressions of p-AKT, Nrf-2, and ESR1, and down-regulated the expressions of JAK2, STAT3, and Keap-1 in the HepG2-IR cells model. CONCLUSIONS: This study demonstrated that the therapeutic effect of FFSLD on T2DM was related to IR alleviation. The underlying mechanisms were associated with the regulation of PI3K/AKT, JAK/STAT, oxidative stress, and ESR signaling pathways.

Ficus pandurata Hance Inhibits Ulcerative Colitis and Colitis-Associated Secondary Liver Damage of Mice by Enhancing Antioxidation Activity.

Inflammatory bowel disease (IBD), a global disease threatening human health, is commonly accompanied by secondary liver damage (SLD) mediated by the gut-liver axis. Oxidative stress acts a critical role in the onset of IBD, during which excessive oxidation would destroy the tight junctions between intestinal cells, promote proinflammatory factors to penetrate, and thereby damage the intestinal mucosa. Ficus pandurata Hance (FPH) is widely used for daily health care in South China. Our previous study showed that FPH protected acute liver damage induced by alcohol. However, there is no study reporting FPH treating ulcerative colitis (UC). This study is designed to investigate whether FPH could inhibit UC and reveal its potential mechanism. The results showed that FPH significantly alleviated the UC disease symptoms including the body weight loss, disease activity index (DAI), stool consistency changing, rectal bleeding, and colon length loss of UC mice induced by dextran sulfate sodium (DSS) and reversed the influences of DSS on myeloperoxidase (MPO) and diamine oxidase activity (DAO). FPH suppressed UC via inhibiting the TLR4/MyD88/NF-κB pathway and strengthened the gut barrier of mice via increasing the expressions of ZO-1 and occludin and enhancing the colonic antioxidative stress property by increasing the levels of T-SOD and GSH-Px and the expressions of NRF2, HO-1, and NQO1 and reducing MDA level and Keap1, p22-phox, and NOX2 expressions. Furthermore, FPH significantly inhibited SLD related to colitis by reducing the abnormal levels of the liver index, ALT, AST, and cytokines including TNFα, LPS, LBP, sCD14, and IL-18 in the livers, as well as decreasing the protein expressions of NLRP3, TNFα, LBP, CD14, TLR4, MyD88, NF-κB, and p-NF-κB, suggesting that FPH alleviated UC-related SLD via suppressing inflammation mediated by inhibiting the TLR4/MyD88/NF-κB pathway. Our study firstly investigates the anticolitis pharmacological efficacy of FPH, suggesting that it can be enlarged to treat colitis and colitis-associated liver diseases in humans.

Dihydroartemisinin is potential therapeutics for treating late-stage CRC by targeting the elevated c-Myc level.

Currently, no frontline treatment is effective for the late-stage colorectal cancer (CRC). Understanding the molecular differences in different stages of CRC can help us to identify the critical therapeutic targets for designing therapeutic strategy. Our data show that c-Myc protein is highly expressed in late-stage CRC when compared with early-stage CRC in both clinical samples and in cell lines representing different cancer stages. Given that c-Myc is a well-known oncogenic driver in CRC, its high expression in the late-stage CRC may represent a critical therapeutic target for treating the cancer. Dihydroartemisinin treatment significantly increases c-Myc protein degradation and hence reduces its expression in CRC. The treatment also reduces CRC cell viability. Interestingly, dihydroartemisinin exhibits a more potent growth-inhibitory effect in late-stage CRC than the early-stage CRC. The treatment also possesses potent growth-inhibitory effects in mouse models bearing c-Myc-overexpressed CRC. The reduced c-Myc level and its reduced transcriptional activity reduce the expressions of acetyl-CoA carboxylase, fatty acid synthase, carnitine-palmitoyltransferase-1, and medium-chain acyl-CoA dehydrogenase in the cancer cells. Lipidomics study also shows that dihydroartemisinin treatment changes the metabolic phenotypes in CRC, reduces oxygen consumption, respiration, and ATP production, hence reduces the cell proliferation and induces apoptosis. Our study provides strong pharmacological evidence to support the translation of dihydroartemisinin for the treatment of late-stage CRC by targeting c-Myc.

NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation.

The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.

Clinical Evidence-Guided Anti-rheumatoid Arthritis Study of Shuji Tablet in Adjuvant-Induced Arthritis Rats and Mechanism Exploration via Network Pharmacological Approach.

Background: Rheumatoid arthritis (RA) is a kind of chronic autoimmune disease with several tissues damaged. Shuji tablet (SJT) is a prescription approved for treating lumbago and leg pain in the clinic. However, the efficacy of SJT against RA is still unknown. This study aims to evaluate the therapeutic effect of SJT on adjuvant-induced arthritis (AIA) rats and explore the mechanism via a network pharmacological approach. Methods: AIA rats were treated with SJT for 30 days at the dosages of 3.6, 1.8, and 0.9 g/kg, respectively, and the anti-RA effect was determined by measuring paw swelling, systemic symptoms score, arthritis index, and histopathological change. ELISA assay was used to evaluate the level of inflammatory cytokines in serum. The mechanism exploration and target prediction of SJT against RA were performed via a network pharmacological approach. Results: SJT showed excellent alleviation on AIA rats, with evidence of reducing paws swelling, decreasing systemic symptoms score, and arthritis index. Furthermore, SJT significantly reduced the serum cytokines of IL-6, IL-1ß, TNF-α in AIA rats. Histopathological examination showed SJT remarkably reduced synovial hyperplasia, cartilage damage, and inflammatory infiltration in the secondary-side paws. According to network pharmacological analysis, 208 candidate compounds and 445 potential targets of SJT were identified, and 4465 RA therapy-related targets were searched out. Subsequently, 292 target genes of SJT were speculated to be associated with RA treatment, among which the top 5 "response values" targets were STAT3, AKT1, JUN, HSP90AA1, TNF. GO and KEGG enrichment analysis suggested that 45 signaling pathways were associating with SJT treating RA. The top 10 signaling pathways were PI3K-Akt, MAPK, AGE-RAGE pathway in diabetic complications, Ras, HIF-1, TNF, Chemokine, IL-17, FoxO, and Rap1. Conclusion: Our experimental study showed that SJT significantly alleviated rheumatoid arthritis of AIA rats. Network pharmacology showed that the key targets of SJT against RA probably were STAT3, AKT1, JUN, HSP90AA1, TNF, and the potential mechanism was associated with modulation on the signaling pathways of PI3K-Akt, MAPK, Ras, AGE-RAGE, HIF-1, TNF, chemokine, IL-17, FoxO, Rap 1. Our study strongly provides evidence for Shuji tablet in RA therapy and would enlarge its application in the clinic.

Toll-like receptor 4 is a master regulator for colorectal cancer growth under high-fat diet by programming cancer metabolism.

Although high-fat diet (HFD) has been implicated in the development of colorectal cancer (CRC), the critical signaling molecule that mediates the cancer growth is not well-defined. Identifying the master regulator that controls CRC growth under HFD can facilitate the development of effective therapeutics for the cancer treatment. In this study, the global lipidomics and RNA sequencing data show that, in the tumor tissues of CRC-bearing mouse models, HFD not only increases tumor weight, but also the palmitic acid level and TLR4 expression, which are reduced when HFD is replaced by control diet. These concomitant changes suggest the roles of palmitic acid and TLR4 in CRC growth. Subsequent studies show that palmitic acid regulates TLR4 expression in PU.1-dependent manner. Knockdown of PU.1 or mutations of PU.1-binding site on TLR4 promoter abolish the palmitic acid-increased TLR4 expression. The role of palmitic acid/PU.1/TLR4 axis in CRC growth is further examined in cell model and animal models that are fed either HFD or palmitic acid-rich diet. More importantly, iTRAQ proteomics data show that knockdown of TLR4 changes the metabolic enzyme profiles in the tumor tissues, which completely abolish the HFD-enhanced ATP production and cancer growth. Our data clearly demonstrate that TLR4 is a master regulator for CRC growth under HFD by programming cancer metabolism.

The Human Cytomegalovirus US31 Gene Predicts Favorable Survival and Regulates the Tumor Microenvironment in Gastric Cancer.

Human cytomegalovirus (HCMV) is an oncogenic virus associated with tumorigenesis. Our previous study revealed that the HCMV US31 gene interacted with NF-κB2 and mediated inflammation through macrophages. However, there are few reports on the role of US31 in gastric cancer (GC). The aim of this study was to investigate the expression of the US31 gene in GC tissue and assess its role in the occurrence and development of GC. US31 expression in 573 cancer tissues was analyzed using immunohistochemistry. Results showed that US31 was significantly associated with tumor size (P = 0.005) and distant metastasis (P < 0.001). Higher US31 expression indicated better overall survival in GC patients. Overexpression of US31 significantly inhibited the proliferation, migration, and invasion of GC cells in vitro (P < 0.05). Furthermore, expression levels of CD4, CD66b, and CD166 were positively correlated with US31, suggesting that it was involved in regulating the tumor immune microenvironment of GC. RNA sequencing, along with quantitative real-time polymerase chain reaction, confirmed that the expression of US31 promoted immune activation and secretion of inflammatory cytokines. Overall, US31 inhibited the malignant phenotype and regulated tumor immune cell infiltration in GC; these results suggest that US31 could be a potential prognostic factor for GC and may open the door for a new immunotherapy strategy.

Protection of Ficus pandurata Hance against acute alcohol-induced liver damage in mice via suppressing oxidative stress, inflammation, and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ficus pandurata Hance (FPH) is a traditional Chinese herbal medicine, which is commonly used for liver protection in the folk of Southeast China. However, the medicinal part and pharmacological mechanism have not been clarified yet. AIM OF THE STUDY: This study aims to investigate the medicinal part of FPH for liver protection and uncover the potential mechanism. MATERIALS AND METHODS: Acute alcoholic liver damage (ALD) mice model induced by intragastric administration with 50% alcohol was used to evaluate the liver protection of FPH. Different parts of FPH, including the root (FPHR), stem (FPHS), leaf (FPHL), and whole plant (FPHWP), were selected to investigate the liver-protected efficacy and determine which part is the medicinal part. Acute oral toxicity (AOT) test was performed to determine the acute toxicity of FPH on Kunming mice. The liver-protected effect of FPH was determined by evaluating the liver function, liver morphological changes, and liver pathological changes. The underlying mechanism was investigated by evaluating the effect on oxidative stress, inflammation, and apoptosis in liver tissues via ELISA, H&E staining, Western Blot, and TUNEL staining assays. RESULTS: In the screening test for medicinal parts of FPH, all of the extracts from FPHR, FPHS, FPHL, and FPHWP could alleviate the acute ALD of mice, including reducing abnormal levels of AST, ALT, and relative liver weight. Especially, the alleviated efficacies of FPHS and FPHL were better than those of FPHWP and FPHR, showing that the aerial part (FPHAP, including the stem and leaf), is probably the medicinal part of FPH against acute ALD. In the AOT test, FPHAP at the maximum administration dosage (480 g/kg, calculated based on the quantity of crude material) did not induce obvious abnormality and death of mice, and had no significant influence on body weight, as well as the relative organ weight, showing that the maximum tolerated dose (MTD) of FPHAP was 480 g/kg on Kunming mice. In the anti-acute ALD study, FPHAP significantly reduced the levels of AST, ALT, LDH, ROS, MDA, TNF-α, IL-1ß, IL-18, and IL-6, alleviated the morphology of liver injury, increased the levels of SOD and GSH, up-regulated the expressions of Nrf-2, HO-1 and NQO1, and reduced apoptosis of liver cells in acute ALD mice, indicating that FPHAP could significantly alleviate acute ALD by suppressing oxidative stress, inflammation, and apoptosis. CONCLUSIONS: FPH could protect acute alcohol-induced liver damage of mice by suppressing oxidative stress, inflammation, and apoptosis. Our study provides scientific evidence for the therapeutic effect of Ficus pandurata Hance in acute ALD mice and suggests its potential development in humans for liver protection, supporting its traditional application.

Structural characterization and immunomodulatory mechanisms of two novel glucans from Morchella importuna fruiting bodies.

Two novel glucans named MIPB50-W and MIPB50-S-1 were obtained from edible Morchella importuna with molecular weights (Mw) of 939.2 kDa and 444.5 kDa, respectively. MIPB50-W has a backbone of α-(1 → 4)-d-glucan, which was substituted at O-6 position by α-d-Glcp-(1→. Moreover, MIPB50-S-1 has a backbone of α-(1 → 4)-d-glucan, which was substituted at O-6 position by α-d-Glcp-(1 → 6)-α-d-Glcp-(1→. This is the first report about glucan found in Morchella mushrooms. Furthermore, MIPB50-W and MIPB50-S-1 strengthened the phagocytosis function and the promoted secretion of interleukins (IL)-6/tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO), which induced the activation of Toll-like receptor 2 (TLR2), TLR4 as well as mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways. Interestingly, MIPB50-S-1 performed the better immunomodulatory activity than that of MIPB50-W in almost all tests. Therefore, MIPB50-W and MIPB50-S-1 are potential immune-enhancing components of functional foods.

Berberine Suppresses Colonic Inflammation in Dextran Sulfate Sodium-Induced Murine Colitis Through Inhibition of Cytosolic Phospholipase A2 Activity.

Ulcerative colitis (UC) causes chronic inflammation and damage to the colonic mucosal layer. Recent studies have reported significant changes in phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) in UC patients and oral administration of PC has considerable therapeutic effects against UC, suggesting the metabolism of phosphatidylcholine may be involved in the UC development. Our previous work has demonstrated that berberine effectively suppresses inflammation and protects colonic mucosa injury in DSS-induced colitic mice. However, whether the therapeutic effects of berberine are attributed to its action on the PC metabolism remains unknown. In the present study, we have shown that berberine significantly reduces the lysophosphatidylcholine (LPC) levels in the sera of DSS-induced experimental colitis mice and LPS-stimulated macrophage RAW 264.7 cells. The cytosolic phospholipase A2a (PLA2G4A), an enzyme for hydrolyzing PC to LPC, was found to be up-regulated in the colon tissue of experimental colitis mice and inflamed macrophage RAW 264.7 cells. We then demonstrated berberine inhibits the phosphorylation of cytosolic phospholipase A2a (PLA2G4A) in the colon tissue of experimental colitis mice and inflamed macrophage RAW 264.7 cells. Subsequently, we revealed berberine suppressed the expression of pro-inflammatory factors including TNF-alpha and IL-6 through regulating PLA2G4A dysfunction in macrophage RAW 264.7 cells. Mechanistically, we found that berberine directly binds to PLA2G4A and inhibits MAPK/JNK signaling pathway to inhibit PLA2G4A activity in inflammatory status. Therefore, we concluded that berberine inhibits colonic PLA2G4A activity to ameliorate colonic inflammation in experimental colitic mice, suggesting modulation of the PC metabolism via PLA2G4A might be beneficial for establishing new therapies strategy for UC.

Arca subcrenata Polypeptides Inhibit Human Colorectal Cancer HT-29 Cells Growth via Suppression of IGF-1R/Akt/mTOR Signaling and ATP Production.

Arca subcrenata Lischke, widely scattering offshore at neritic regions, is very popular on dining table due to its edible and medical functional meatball. This study aims to investigate the suppression of a polypeptide fraction from A. subcrenata (PAS) on human colorectal cancer HT-29 cells, and its underlying mechanism. The results showed that PAS inhibited the growth of HT-29 cells with an IC50 value of 117 µg/ml after 48 h treatment, and significantly suppressed the tumor growth in nude mice bearing-xenografted HT-29 cells at the dosage of 63 mg/kg, with little influence on normal colon cells and normal colonic mucosa. PAS was then inspiringly found to induce apoptosis and G2/M phase arrest in HT-29 cells. The effect mechanism was involved in the inhibition of IGF-1/IGF-1R signaling activation, which was responsible for inactivating downstream Akt/mTOR pathway. Immunofluorescence assay also showed that PAS could reduce phosphorylation of IGF-1R (Tyr1165/1166). IGF-1, an IGF-1R activator, could reverse the suppression of PAS on IGF-1R phosphorylation. Furthermore, PAS significantly inhibited ATP production of HT-29 cells both in vitro and in vivo. Our results provide positive evidence that A. subcrenata has the potential to be a candidate for the treatment of colorectal cancer.