Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway.

Surgical brain injury (SBI), induced by neurosurgical procedures or instruments, has not attracted adequate attention. The pathophysiological process of SBI remains sparse compared to that of other central nervous system diseases thus far. Therefore, novel and effective therapies for SBI are urgently needed. In this study, we found that neutrophil extracellular traps (NETs) were present in the circulation and brain tissues of rats after SBI, which promoted neuroinflammation, cerebral edema, neuronal cell death, and aggravated neurological dysfunction. Inhibition of NETs formation by peptidylarginine deiminase (PAD) inhibitor or disruption of NETs with deoxyribonuclease I (DNase I) attenuated SBI-induced damages and improved the recovery of neurological function. We show that SBI triggered the activation of cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING), and that inhibition of the cGAS-STING pathway could be beneficial. It is worth noting that DNase I markedly suppressed the activation of cGAS-STING, which was reversed by the cGAS product cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP, cGAMP). Furthermore, the neuroprotective effect of DNase I in SBI was also abolished by cGAMP. NETs may participate in the pathophysiological regulation of SBI by acting through the cGAS-STING pathway. We also found that high-dose vitamin C administration could effectively inhibit the formation of NETs post-SBI. Thus, targeting NETs may provide a novel therapeutic strategy for SBI treatment, and high-dose vitamin C intervention may be a promising translational therapy with an excellent safety profile and low cost.

Comparing the wound healing potential of natural rubber latex serum and F1-protein: An in vivo approach.

Chronic wounds pose significant health concerns. Current treatment options include natural compounds like natural rubber latex (NRL) from Hevea brasiliensis. NRL, particularly the F1 protein fraction, has demonstrated bioactivity, biocompatibility, and angiogenic effects. So far, there is no study comparing F1 protein with total NRL serum, and the necessity of downstream processing remains unknown. Here, we evaluated the angiogenic potential of F1 protein compared to total NRL serum and the need for downstream processing. For that, ion exchange chromatography (DEAE-Sepharose), antioxidant activity, physicochemical characterization, cell culture in McCoy fibroblasts, and wound healing in Balb-C mice were performed. Also, the evaluation of histology and collagen content and the levels of inflammatory mediators were quantified. McCoy fibroblast cell assay showed that F1 protein (0.01 %) and total NRL serum (0.01 %) significantly increased cell proliferation by 47.1 ± 11.3 % and 25.5 ± 2.5 %, respectively. However, the AA of F1 protein (78.9 ± 0.8 %) did not show a significant difference compared to NRL serum (77.0 ± 1.1 %). F1 protein and NRL serum were more effective in wound management in rodents. Histopathological analysis confirmed accelerated healing and advanced tissue repair. Similarly, the F1 protein (0.01 %) increased collagen, showing that this fraction can stimulate the synthesis of collagen by fibroblastic cells. Regarding cytokines production (IL-10, TNF-α, IFN-γ), F1 protein and NRL serum did not exert an impact on the synthesis of these cytokines. Furthermore, we did not observe statistically significant changes in dosages of enzymes (MPO and EPO) among the groups. Nevertheless, Nitric Oxide dosage was reduced drastically when the F1 protein (0.01 %) protein was applied topically. These findings contribute to the understanding of F1 protein and NRL serum properties and provide insights into cost-effectiveness and practical applications in medicine and biotechnology. Therefore, further research is needed to assess the economic feasibility of downstream processing for NRL-based herbal medicine derived from Hevea brasiliensis.

Perceived COVID-19 Stress and Suicidal Ideation Among College Students: Meditation Roles of Family Cohesion and Unmet Interpersonal Needs.

Purpose: Few studies examined variables that might explain the link between perceived COVID-19 stress and suicidal ideation. The present study tested a multiple-sequence mediation model with family cohesion, thwarted belongingness, and perceived burdensomeness as mediators. Methods: The current study surveyed 1098 college students in China using questionnaires concerning perceived COVID-19 stress, family cohesion, unmet interpersonal needs, and suicide ideation. Results: Perceived COVID-19 stress was significantly associated with family cohesion, thwarted belongingness, perceived burdensomeness, and suicidal ideation. Family cohesion, thwarted belongingness, and perceived burdensomeness mediated the relationship between perceived COVID-19 stress and suicidal ideation separately. These factors also had multiple sequence-mediated effects between perceived COVID-19 stress and suicidal ideation. Conclusion: The study revealed pathways from perceived COVID-19 stress to suicidal ideation and suggested that interventions to increase family cohesion and reduce one's unmet interpersonal needs were beneficial in decreasing individuals' suicidal ideation.

Amphotericin B-loaded natural latex dressing for treating Candida albicans wound infections using Galleria mellonella model.

Amphotericin B (AmB) is the gold standard for antifungal drugs. However, AmB systemic administration is restricted because of its side effects. Here, we report AmB loaded in natural rubber latex (NRL), a sustained delivery system with low toxicity, which stimulates angiogenesis, cell adhesion and accelerates wound healing. Physicochemical characterizations showed that AmB did not bind chemically to the polymeric matrix. Electronic and topographical images showed small crystalline aggregates from AmB crystals on the polymer surface. About 56.6% of AmB was released by the NRL in 120 h. However, 33.6% of this antifungal was delivered in the first 24 h due to the presence of AmB on the polymer surface. The biomaterial's excellent hemo- and cytocompatibility with erythrocytes and human dermal fibroblasts (HDF) confirmed its safety for dermal wound application. Antifungal assay against Candida albicans showed that AmB-NRL presented a dose-dependent behavior with an inhibition halo of 30.0 ± 1.0 mm. Galleria mellonella was employed as an in vivo model for C. albicans infection. Survival rates of 60% were observed following the injection of AmB (0.5 mg.mL-1) in G. mellonella larvae infected by C. albicans. Likewise, AmB-NRL (0.5 mg.mL-1) presented survival rates of 40%, inferring antifungal activity against fungus. Thus, NRL adequately acts as an AmB-sustained release matrix, which is an exciting approach, since this antifungal is toxic at high concentrations. Our findings suggest that AmB-NRL is an efficient, safe, and reasonably priced ($0.15) dressing for the treatment of cutaneous fungal infections.

M supported on Al-defective Al2-δO3 (M = Fe, Co, Ni, Cu, Ag, Au) as catalysts for acetylene semi-hydrogenation: a theoretical perspective.

Semi-hydrogenation of acetylene is of great importance for both industry and academia. High prices and limited supplements of noble metals leave room for developing base metal catalysts. Experiments revealed the atomically dispersed Cu supported by Al2O3 with excellent long-term stability and high ethylene selectivity, but the physical nature has rarely been investigated theoretically. DFT calculations and microkinetic modeling revealed that the surface OH species could stabilize Cu1/Al2-δO3 and enhance its catalytic performance. The selectivity of ethylene formation decreases with increasing copper clusters (e.g., Cu1/Al2-δO3> Cu4/Al2-δO3> Cu8/Al2-δO3), meaning that the atomically dispersed copper may be a potential candidate for acetylene semi-hydrogenation. The structures of a series of single site catalysts M1/Al2-δO3 (M = Fe, Co, Ni, Ag, Au) are similar to that of Cu1/Al2-δO3, but their performances in catalyzing acetylene semi-hydrogenation are different. M1/Al2-δO3 (M = Ag, Au) shows higher selectivity than Cu1/Al2-δO3, while M1/Al2-δO3 (M = Fe, Co, Ni) demonstrates a higher turnover frequency (TOF) of ethylene than Cu1/Al2-δO3. Moreover, our results indicate that the Ni1-Cu1/Al2-δO3 alloy shows both high activity and ethylene selectivity. The present results show a compensation between the reactivity and the selectivity, suggesting that alloys of VIIIB metals with IB metals like Ni1-Cu1/Al2-δO3 may be efficient candidate catalysts in acetylene selective hydrogenation.

Eco-sustainable coatings based on chitosan, pectin, and lemon essential oil nanoemulsion and their effect on strawberry preservation.

Films and coatings manufactured with bio-based renewable materials, such as biopolymers and essential oils, could be a sustainable and eco-friendly alternative for protecting and preserving agricultural products. In this work, we developed films and coatings from pectin and chitosan to protect strawberries (Fragaria x ananassa Duch.) from spoilage and microbial contamination. We developed three coatings containing equal amounts of glycerol and Sicilian lemon essential oil (LEO) nanoemulsion. We identified seventeen chemicals from LEO by GC-MS chromatogram, including d-limonene, α-Pinene, ß-Pinene, and γ-Terpinene. The pectin and chitosan coatings were further characterized using different physicochemical, mechanical, and biological methods. The films demonstrated satisfactory results in strength and elongation at the perforation as fruit packaging. In addition, the coatings did not influence the weight and firmness of the strawberry pulps. We observed that 100 % essential oil was released in 1440 min resulting from the erosion process. Also, the oil preserved the chemical stability of the films. Antioxidant activity (AA), measured by Electron Paramagnetic Resonance (EPR), showed that the coatings loaded with 2 % LEO nanoemulsion (PC + oil) showed that almost 50 % of AA from LEO nanoemulsion was preserved. The chitosan and the pectin-chitosan coatings (PC + oil) inhibited filamentous fungi and yeast contaminations in strawberries for at least 14 days, showing a relationship between the AA and antimicrobial results.

Discovery of a New-Generation S-Adenosylmethionine-Noncompetitive Covalent Inhibitor Targeting the Lysine Methyltransferase Enhancer of Zeste Homologue 2.

The first-generation enhancer of zeste homologue 2 (EZH2) inhibitors suffer from several limitations, such as high dosage, cofactor S-adenosylmethionine (SAM) competition, and acquired drug resistance. Development of covalent EZH2 inhibitors that are noncompetitive with cofactor SAM offers an opportunity to overcome these disadvantages. The structure-based design of compound 16 (BBDDL2059) as a highly potent and selective covalent inhibitor of EZH2 is presented in this context. 16 inhibits EZH2 enzymatic activity at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition. The kinetic assay revealed that 16 is noncompetitive with the cofactor SAM, providing the basis for its superior activity over noncovalent and positive controls by reducing competition with cofactor SAM and offering a preliminary proof for its covalent inhibition nature. Mass spectrometric analysis and washout experiments firmly establish its covalent inhibition mechanism. This study demonstrates that covalent inhibition of EZH2 can offer a new opportunity for the development of promising new-generation drug candidates.

Aloe vera-loaded natural rubber latex dressing as a potential complementary treatment for psoriasis.

Psoriasis is a disease that causes keratinocytes to proliferate ten times faster than normal, resulting in chronic inflammation and immune cell infiltration in the skin. Aloe vera (A. vera) creams have been used topically for treating psoriasis because they contain several antioxidant species; however, they have several limitations. Natural rubber latex (NRL) has been used as occlusive dressings to promote wound healing by stimulating cell proliferation, neoangiogenesis, and extracellular matrix formation. In this work, we developed a new A. vera-releasing NRL dressing by a solvent casting method to load A. vera into NRL. FTIR and rheological analyzes revealed no covalent interactions between A. vera and NRL in the dressing. We observed that 58.8 % of the loaded A. vera, present on the surface and inside the dressing, was released after 4 days. Biocompatibility and hemocompatibility were validated in vitro using human dermal fibroblasts and sheep blood, respectively. We observed that ~70 % of the free antioxidant properties of A. vera were preserved, and the total phenolic content was 2.31-fold higher than NRL alone. In summary, we combined the antipsoriatic properties of A. vera with the healing activity of NRL to generate a novel occlusive dressing that may be indicated for the management and/or treatment of psoriasis symptoms simply and economically.

Divergent impacts on the gut microbiome and host metabolism induced by traditional Chinese Medicine with Cold or Hot properties in mice.

BACKGROUND: Traditional Chinese Medicine (TCM) has been practiced and developed in China over thousands of years under the guidance of a series of complicated traditional theories. Herbs within TCM usually are classified according to their different properties ranging from cold, cool, warm to hot, which are simplified as Cold and Hot properties. TCM with either Cold or Hot properties are used in various formulae designed for the purpose of restoring the balance of patients. Emerging evidence has highlighted that an altered gut microbiota or host metabolism are critically involved in affecting the healing properties of TCM. However, at present the exact influences and crosstalk on the gut microbiota and host metabolism remain poorly understood. METHODS: In the present study, the divergent impacts of six TCMs with either Cold or Hot properties on gut microbiome and host metabolism during short- or long-term intervention in mice were investigated. Six typical TCMs with Hot or Cold properties including Cinnamomi Cortex (rougui, RG), Zingiberis Rhizoma (ganjiang, GJ), Aconiti Lateralis Radix Praeparata (fuzi, FZ), Rhei Radix et Rhizoma (dahuang, DH), Scutellariae Radix (huangqin, HQ), and Copitdis Rhizoma (huanglian, HL) were selected and orally administered to male C57BL/6J mice for a short- or a long-term (7 or 35 days). At the end of experiments, serum and cecal contents were collected for metabolomic and gut microbiome analyses using gas chromatography-tandem mass spectrometry (GC-MS) or 16S ribosomal deoxyribonucleic acid (16S rDNA) sequencing. RESULTS: The results revealed that the gut microbiome underwent divergent changes both in its composition and functions after short-term intervention with TCM possessing either Cold or Hot properties. Interestingly, the number of changed genus and bacteria pathways was reduced in Hot_LT, but was increased in Cold_LT, especially in the HL group. Increased α diversity and a reduced F/B ratio revealed the changes in Hot_ST, but a reduced Shannon index and increased altered bacteria function was evident in Cold_LT. The serum metabolic profile showed that the influence of TCM on host metabolism was gradually reduced over time. Glycolipid metabolism related pathways were specifically regulated by Hot_ST, but also surprisingly by Cold_LT. Reduced lactic acid in Cold_ST, increased tryptophan concentrations and decreased proline and threonine concentrations in Cold_LT perhaps highlighting the difference between the two natures influence on serum metabolism. These metabolites were closely correlated with altered gut microbiota shown by further correlation analyses. CONCLUSION: The results indicated that TCM properties could be, at least partially characterized by an alteration in the gut microbiota and metabolic profile, implying that the divergent responses of gut microbiome and host metabolism are involved in different responses to TCM.

Interrelation between homocysteine metabolism and the development of autism spectrum disorder in children.

Evidence is emerging that dysregulation of circulating concentrations of homocysteine, an important intermediate in folate and vitamin B12 metabolism, is associated with autism spectrum disorder (ASD), but comprehensive assessments and correlations with disease characteristics have not been reported. Multivariate ordinal regression and restricted cubic spline (RCS) models were used to estimate independent correlations between serum homocysteine, folate, and vitamin B12 levels and clinical outcomes and severity of children with ASD. After adjusting for confounding factors, serum homocysteine levels were significantly higher in children with ASD than in healthy controls (ß: 0.370; 95% CI: 0.299~0.441, p < 0.001). Moreover, homocysteine had a good diagnostic ability for distinguishing children with ASD from healthy subjects (AUC: 0.899, p < 0.001). The RCS model indicated a positive and linear association between serum homocysteine and the risk of ASD. The lowest quartile of folate was positively associated with ASD severity (OR: 4.227, 95% CI: 1.022~17.488, p = 0.041) compared to the highest quartile, and serum folate showed a negative and linear association with ASD severity. In addition, decreased concentrations of folate and vitamin B12 were associated with poor adaptive behavior developmental quotients of the Gesell Developmental Schedules (p < 0.05). Overall, an increased homocysteine level was associated with ASD in a linear manner and is thus a novel diagnostic biomarker for ASD. Decreased concentrations of folate and vitamin B12 were associated with poor clinical profiles of children with ASD. These findings suggest that homocysteine-lowering interventions or folate and vitamin B12 supplementation might be a viable treatment strategy for ASD.

Identification of molecular mechanisms underlying the therapeutic effects of Xintong granule in coronary artery disease by a network pharmacology and molecular docking approach.

Coronary artery disease (CAD) is a cardiovascular disease characterized by atherosclerosis, angiogenesis, thrombogenesis, inflammation, etc. Xintong granule (XTG) is considered a practical therapeutic strategy in China for CAD. Although its therapeutic role in CAD has been reported, the molecular mechanisms of XTG in CAD have not yet been explored. A network pharmacology approach including drug-likeness (DL) evaluation, oral bioavailability (OB) prediction, protein-protein interaction (PPI) network construction and analysis, and Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses was used to predict the active ingredients, potential targets, and molecular mechanisms of XTG associated with the treatment of CAD. Molecular docking analysis was performed to investigate the interactions between the active compounds and the underlying targets. Fifty-one active ingredients of XTG and 294 CAD-related targets were screened for analysis. Gene Ontology enrichment analysis showed that the therapeutic targets of XTG in CAD are mainly involved in blood circulation and vascular regulation. KEGG pathway analysis indicated that XTG intervenes in CAD mainly through the regulation of fluid shear stress and atherosclerosis, the AGE-RAGE signaling pathway in diabetic complications, and the relaxin signaling pathway. Molecular docking analysis showed that each key active ingredient (quercetin, luteolin, kaempferol, stigmasterol, resveratrol, fisetin, gamma-sitosterol, and beta-sitosterol) of XTG can bind to the core targets of CAD (AKT1, JUN, RELA, MAPK8, NFKB1, EDN1, and NOS3). The present study revealed the CAD treatment-related active ingredients, underlying targets, and potential molecular mechanisms of XTG acting by regulating fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, and relaxin signaling pathway.

[Comparative study on short and long-term intervention impacts of six Chinese herbs with cold or heat property on lipid and energy metabolism in mice].

This study selected three typical Chinese herbs with cold property(Rhei Radix et Rhizoma, Scutellariae Radix, and Coptidis Rhizoma) and another three with heat property(Cinnamomi Cortex, Zingiberris Rhizoma, and Aconiti Lateralis Radix Praeparata) to observe their regulatory effects on metabolism in animal organism, especially on lipid and energy metabolism in mice after a short-(7 d) and long-term(35 d) intervention. The mRNA expression levels of lipid metabolism genes in epididymal adipose tissue and liver were determined by real-time PCR. The oxygen consumption, carbon dioxide production, and energy consumption were detected by metabolic system. After the short-term intervention, the Chinese herbs with heat property significantly reduced epididymal adipose tissue index and elevated the expression levels of acetyl-CoA carboxylase(ACC), lipoprotein lipase(LPL), and carnitine-palmityl transferase 1(CPT-1) in liver and epididymal adipose tissues. However, those with cold property promoted the expression of above-mentioned genes in epididymal adipose tissue. After the long-term intervention, cold and heat Chinese herbs had no significant effect on epididymal adipose tissue index of animals, while cold Chinese herbs could increase carbon dioxide production and energy consumption and reduce activity. These findings demonstrated that the short-term intervention effects of cold and heat Chinese herbs on animal metabolism were significantly stronger than the long-term intervention effects. Specifically, the short-term intervention with cold Chinese herbs enhanced the lipid metabolism in epididymal adipose tissue, while the heat Chinese herbs promoted lipid metabolism in epididymal adipose tissue and liver. The long-term intervention with cold and heat Chinese herbs resulted in no obvious change in lipid level, but long-term intervention with cold Chinese herbs accelerated energy consumption of the body. This study preliminarily observed the effects of cold and heat Chinese herbs on normal animal physiology from lipid and energy metabolism, which would provide reference for explaining the biological basis of Chinese herbs with cold or heat property based on biological response.

Exploring the Multicomponent Synergy Mechanism of Yinzhihuang Granule in Inhibiting Inflammation-Cancer Transformation of Hepar Based on Integrated Bioinformatics and Network Pharmacology.

Background: The Chinese patent drug Yinzhihuang granule (YZHG) is used to treat hepatitis B. This research is aimed at exploring the multicomponent synergistic mechanism of YZHG in the treatment of inflammation-cancer transformation of hepar and at providing new evidence and insights for its clinical application. Methods: To retrieve the components and targets of Yinzhihuang granules. The differentially expressed genes (DEGs) of hepar inflammation-cancer transformation were obtained from TTD, PharmGKB, and GEO databases. Construct the compound-prediction target network and the key module network using Cytoscape 3.7.1. Results: The results show that hepatitis B and hepatitis C shared a common target, MMP2. CDK1 and TOP2A may play an important role in the treatment with YZHG in hepatitis B inflammatory cancer transformation. KEGG pathway enrichment showed that key genes of modules 1, 2, and 4 were mainly enriched in the progesterone-mediated oocyte maturation signaling pathway and oocyte meiosis signaling pathway. Conclusion: The multicomponent, multitarget, and multichannel pharmacological benefits of YZHG in the therapy of inflammation-cancer transition of hepar are directly demonstrated by network pharmacology, providing a scientific basis for its mechanism.

The effect of vitamin D supplementation in treatment of children with autism spectrum disorder: a systematic review and meta-analysis of randomized controlled trials.

Objective: The effect of vitamin D supplementation on the risk of Autism Spectrum Disorder (ASD) is conflicting. The aim of this study was to estimate the efficacy of vitamin D supplementation on ASD in children.Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) in which vitamin D supplementation was used as a therapy in children with ASD. The PubMed, PsychINFO, Cochrane CENTRAL library, Web of Science, and Cinahl databases were searched from inception to March 20, 2019, for all publications on vitamin D and ASD with no restrictions. Studies involving individuals aged <18 years diagnosed with ASD and with all functional outcomes assessed by measurement scales for ASD were included. Mean differences were pooled, and a meta-analysis was performed using a random-effects model due to differences between the individual RCTs.Results: There were five RCTs with 349 children with ASD in the review, of which three RCTs were included in the meta-analysis. Vitamin D supplementation indicated a small but significant improvement in hyperactivity scores (pooled MD: -3.20; 95% CI: [-6.06, -0.34]) with low heterogeneity (I2 = 10%, p = 0.33), but there were no other statistically significant differences in ASD symptoms between groups as measured by validated scales.Conclusion: Vitamin D supplementation appears to be beneficial for hyperactivity but not for core symptoms or other co-existing behaviors and conditions of ASD. Future RCTs with large sample sizes examining the effect of vitamin D supplementation on ASD among individuals with low serum vitamin D levels at baseline are needed.

Integrated analysis of mRNA-seq and miRNA-seq reveals the advantage of polyploid Solidago canadensis in sexual reproduction.

BACKGROUND: The invasion of Solidago canadensis probably related to polyploidy, which may promotes its potential of sexual reproductive. S. canadensis as an invasive species which rapidly widespread through yield huge numbers of seed, but the mechanism remains unknown. To better understand the advantages of sexual reproduction in hexaploid S. canadensis, transcriptome and small RNA sequencing of diploid and hexaploid cytotypes in flower bud and fruit development stages were performed in this study. RESULTS: The transcriptome analysis showed that in the flower bud stage, 29 DEGs were MADS-box related genes with 14 up-regulated and 15 down-regulated in hexaploid S. canadensis; 12 SPL genes were detected differentially expressed with 5 up-regulated and 7 down-regulated. In the fruit development stage, 26 MADS-box related genes with 20 up-regulated and 6 down-regulated in hexaploid S. canadensis; 5 SPL genes were all up-regulated; 28 seed storage protein related genes with 18 were up-regulated and 10 down-regulated. The weighted gene co-expression network analysis (WGCNA) identified 19 modules which consisted of co-expressed DEGs with functions such as sexual reproduction, secondary metabolism and transcription factors. Furthermore, we discovered 326 miRNAs with 67 known miRNAs and 259 novel miRNAs. Some of miRNAs, such as miR156, miR156a and miR156f, which target the sexual reproduction related genes. CONCLUSION: Our study provides a global view of the advantages of sexual reproduction in hexaploid S. canadensis based on the molecular mechanisms, which may promote hexaploid S. canadensis owing higher yield and fruit quality in the process of sexual reproduction and higher germination rate of seeds, and finally conductive to diffusion, faster propagation process and enhanced invasiveness.

Investigation on the mechanisms of guiqi huoxue capsule for treating cervical spondylosis based on network pharmacology and molecular docking.

BACKGROUND: Guiqi huoxue capsule (GQHXC) is a patented Chinese medicine used for treating a liver and kidney deficiency and blood stasis syndrome due to qi deficiency. It is caused by cervical spondylosis (cervical spondylotic radiculopathy (CSR), mixed cervical spondylosis mainly composed of nerve root type). Its underlying mechanisms need, however, to be further clarified. METHODS: In this study, collecting compounds, predicting therapeutic targets, constructing networks, and analyzing biological functions and pathways were based on network pharmacology analysis. In addition, molecular docking verification was engaged to assess the binding potential of selected target-compound pairs. RESULTS: We established 5 networks: compound-putative target network of GQHXC, protein-protein interaction (PPI) network related to CSR, compound-CSR target network, potential therapeutic targets PPI network, and herb-compound-target-pathway network. Network analysis indicated that 7 targets (tumor necrosis factor [TNF], interleukin 6 [IL6], nitric oxide synthase 3 [NOS3], Interleukin-8 [CXCL8], prostaglandin-endoperoxide synthase 2 [PTGS2], vascular endothelial growth factor A [VEGFA], and AP-1 transcription factor subunit [JUN]) might be the therapeutic targets of GQHXC in CSR. Moreover, molecular docking verification showed that TNF, IL6, NOS3, CXCL8, PTGS2, VEGFA, and JUN had a good is interaction with the corresponding compounds. Furthermore, enrichment analysis indicated that GQHXC might exert a curative role in CSR by regulating some important pathways, such as TNF signaling pathway, NF-kappa B signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and so on. CONCLUSION: Our study preliminarily explained the underlying mechanisms of GQHXC for treating CSR, and molecular docking verification was adopted as an additional verification. These findings laid a valuable foundation for experimental research and further application of GQHXC in the clinical treatment of CSR.

A botanical dietary supplement from white peony and licorice attenuates nonalcoholic fatty liver disease by modulating gut microbiota and reducing inflammation.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related metabolic disease that is highly associated with gut dysbiosis and inflammation. A botanical dietary supplement, mainly containing an herbal pair of white peony root and licorice as well as grape seeds and broccoli extracts (WLT), exerts auxiliary protection against chemical liver injury. However, it is unclear whether WLT protects against the development of NAFLD induced by a high energy diet. PURPOSE: To investigate the protective role of WLT against NAFLD development induced by a high-fat and high-sucrose (HFHS) diet and its mechanism of action. METHODS: We investigated the anti-NAFLD effects of WLT on a HFHS diet-induced NAFLD C57BL/6J mouse model by detecting the hepatic triglyceride (TG) level, performing histological examination of the liver tissue, and evaluating glucose tolerance and systemic inflammation. Then, we analyzed the impact of WLT on gut microbiota by 16S rRNA gene sequencing, followed by fecal microbiota transplantation. Furthermore, we performed hepatic transcriptomic analysis of mice with or without WLT treatment using the RNA sequencing approach. RESULTS: Our results showed that WLT supplement attenuated body weight gain, hepatic steatosis, glucose tolerance, and systemic inflammation in HFHS-fed mice. Moreover, WLT supplement altered the composition of gut microbiota, which contributed at least in part, to the anti-NAFLD effect. Meanwhile, WLT improved the intestinal integrity and comprehensively modulated the expression of hepatic genes in HFHS mice, particularly reducing the expression of genes in the toll-like receptor-mediated inflammatory pathway. CONCLUSION: WLT is protective against NAFLD formation induced by an HFHS diet, and its effect is associated with the modulation of gut microbiota and inflammation, highlighting the potential of WLT to reduce the risk of metabolic disorders as a functional dietary supplement.

Molecular Targets and Mechanisms of Scutellariae radix-Coptidis rhizoma Drug Pair for the Treatment of Ulcerative Colitis Based on Network Pharmacology and Molecular Docking.

This study aims to analyze the targets of the effective active ingredients of Scutellariae radix-Coptidis rhizoma drug pair (SCDP) in ulcerative colitis (UC) by network pharmacology and molecular docking and to explore the associated therapeutic mechanism. The effective active ingredients and targets of SCDP were determined from the TCMSP database, and the drug ingredient-target network was constructed using the Cytoscape software. The disease targets related to UC were searched in GeneCards, DisGeNET, OMIM, and DrugBank databases. Then, the drug ingredient and disease targets were intersected to construct a protein-protein interaction network through the STRING database. The Metascape database was used for the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the predicted targets of SCDP for UC. The Autodock software was used for molecular docking between the main active ingredient and the core target to evaluate the binding ability. SCDP has 43 effective active ingredients and 134 intersection targets. Core targets included AKT1, TP53, IL-6, VEGFA, CASP3, JUN, TNF, MYC, EGFR, and PTGS2. GO functional enrichment analysis showed that biological process was mainly associated with a cytokine-mediated signaling pathway, response to an inorganic substance, response to a toxic substance, response to lipopolysaccharide, reactive oxygen species metabolic process, positive regulation of cell death, apoptotic signaling pathway, and response to wounding. KEGG enrichment analysis showed main pathway concentrations were related to pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, bladder cancer, IL-17 signaling pathway, apoptosis, p53 signaling pathway, and PI3K-Akt signaling pathway. The drug active ingredient-core target-key pathway network contains 41 nodes and 108 edges, of which quercetin, wogonin, baicalein, acacetin, oroxylin A, and beta-sitosterol are important active ingredients; PTGS2, CASP3, TP53, IL-6, TNF, and AKT1 are important targets; and the pathways involved in UC treatment include pathways in cancer, PI3K-Akt signaling pathway, AGE-RAGE signaling pathway in diabetic, apoptosis, IL-17 signaling pathway and herpes simplex infection. The active ingredient has a good binding capacity to the core target. SCDP key active ingredients are mainly quercetin, wogonin, baicalein, acacetin, oroxylin A, and beta-sitosterol, which function mainly by regulating targets, such as PTGS2, CASP3, TP53, IL-6, TNF, and AKT1, and are associated with multiple signaling pathways as pathways in cancer, PI3K-Akt signaling pathway, apoptosis, IL-17 signaling pathways.

Si Miao Formula attenuates non-alcoholic fatty liver disease by modulating hepatic lipid metabolism and gut microbiota.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with few therapeutic options available currently. Traditional Chinese Medicine (TCM) has been practiced for thousands of years in China and Asian countries, and regarded as an important source for identifying novel medicines for diseases. Si Miao Formula (SMF) is a classical TCM formula for the treatment of gout disease by reducing serum uric acid concentrations, while high concentration of uric acid is also an independent risk factor for NAFLD. PURPOSE: To investigate the protective effect of SMF on NAFLD in a mouse model induced by a high fat/high sucrose (HFHS) diet. METHODS: Mice received a HFHS diet over a 16-week period to induce NAFLD with or without SMF intervention. Lipid levels were measured in both the liver and serum. Histopathological staining was used to evaluate the extent of hepatic lipid accumulation. Liver transcriptomics was used to enrich differentially expressed genes and to predict regulatory pathways after gene set enrichment analysis. 16S rRNA gene sequencing was used to determine the microbial composition. Genes of liver lipid metabolism, inflammation and intestinal tight junctions were detected by qRT-PCR analysis. RESULTS: SMF attenuated hepatic steatosis, reduced body weight gain and lipid concentrations, improved sensitivity to insulin and also tolerance to glucose, in mice fed an HFHS diet. Hepatic transcriptomics showed that SMF downregulated the biosynthesis of fatty acids and stimulated the insulin secretion pathway. SMF significantly altered the gut microbiota composition and in particular increased the proportion of Akkermansia muciniphila. In agreement with liver transcriptomics, SMF downregulated the expression of genes implicated in the metabolism of lipids (Acly, Fas, Acc, Scd-1) and pro-inflammatory cytokines (Il-1ß, Nlrp-3) in the livers. CONCLUSION: The results indicate that SMF attenuates HFHS diet-induced NAFLD and regulates hepatic lipid metabolism pathways. The anti-NAFLD effect of SMF was linked to modulation of the gut microbiota composition and in particular an increased relative abundance of Akkermansia muciniphila.

Based on Network Pharmacology to Explore the Molecular Targets and Mechanisms of Gegen Qinlian Decoction for the Treatment of Ulcerative Colitis.

BACKGROUND: Gegen Qinlian (GGQL) decoction is a common Chinese herbal compound for the treatment of ulcerative colitis (UC). In this study, we aimed to identify its molecular target and the mechanism involved in UC treatment by network pharmacology and molecular docking. Material and Methods. The active ingredients of Puerariae, Scutellariae, Coptis, and Glycyrrhiza were screened using the TCMSP platform with drug-like properties (DL) ≥ 0.18 and oral availability (OB) ≥ 30%. To find the intersection genes and construct the TCM compound-disease regulatory network, the molecular targets were determined in the UniProt database and then compared with the UC disease differential genes with P value < 0.005 and ∣log2 (fold change) | >1 obtained in the GEO database. The intersection genes were subjected to protein-protein interaction (PPI) construction and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. After screening the key active ingredients and target genes, the AutoDock software was used for molecular docking, and the best binding target was selected for molecular docking to verify the binding activity. RESULTS: A total of 146 active compounds were screened, and quercetin, kaempferol, wogonin, and stigmasterol were identified as the active ingredients with the highest associated targets, and NOS2, PPARG, and MMP1 were the targets associated with the maximum number of active ingredients. Through topological analysis, 32 strongly associated proteins were found, of which EGFR, PPARG, ESR1, HSP90AA1, MYC, HSPA5, AR, AKT1, and RELA were predicted targets of the traditional Chinese medicine, and PPARG was also an intersection gene. It was speculated that these targets were the key to the use of GGQL in UC treatment. GO enrichment results showed significant enrichment of biological processes, such as oxygen levels, leukocyte migration, collagen metabolic processes, and nutritional coping. KEGG enrichment showed that genes were particularly enriched in the IL-17 signaling pathway, AGE-RAGE signaling pathway, toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, transcriptional deregulation in cancer, and other pathways. Molecular docking results showed that key components in GGQL had good potential to bind to the target genes MMP3, IL1B, NOS2, HMOX1, PPARG, and PLAU. CONCLUSION: GGQL may play a role in the treatment of ulcerative colitis by anti-inflammation, antioxidation, and inhibition of cancer gene transcription.