Puerarin improves Dioscorea bulbifera L.-induced liver injury by regulating drug transporters and the Nrf2/NF-κB/Bcl-2 signaling pathway.

PURPOSE: Investigate the protective effect and mechanism of Puerarin (PU) against Dioscorea bulbifera L. (DB)-induced liver injury. MATERIALS AND METHODS: The protective effect of PU against DB-induced liver injury was evaluated by the present animal experiment, which assessed the pathological changes in the liver of mice and detected Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (AKP), as well as inflammation and oxidative stress-related indexes. Finally, the transcription and expression of related proteins were detected using western blot and quantitative reverse transcription (PCR) techniques. RESULTS: PU significantly increased body weight, reduced liver index, and attenuated pathological changes in the liver compared to the DB group. It also decreased levels of AST, ALT, AKP, tumor necrosis factor-α, interleukin-1ß, and malondialdehyde while increasing interleukin-10 levels and superoxide dismutase activity. Additionally, it upregulated inhibitor of NF-κB (IκB-α), B-cell lymphoma-2 (Bcl-2), Nuclear respiratory factor 2 (Nrf2), and Heme oxygenase 1 (HO-1) expression while down-regulating p-NF-κB p65 and bcl2-associated x (Bax) expression in the liver. Furthermore, PU upregulated protein and gene expression levels of Multidrug resistance-associated protein2, bile salt export pump, p-glycoprotein, and UDP-glucuronyltransferase 1A1 (UGT1A1) as well. CONCLUSION: PU mitigates DB-induced liver injury by regulating the expression of drug transporters and modulating the Nrf2/NF-κB/Bcl-2 signaling pathway.

Border-like cell formation mediated by SgPG1 confers aluminum resistance in Stylosanthes guianensis.

Stylosanthes is an important forage legume in tropical areas with strong resistance to aluminum (Al) toxicity, though knowledge of mechanisms underlying this resistance remains fragmentary. We found that border-like cells (BLCs) were constitutively produced surrounding the root tips of all 54 examined Stylosanthes guianensis genotypes, but not the Stylosanthes viscose genotype TF0140. In genotypic comparisons under Al conditions, the S. guianensis genotype RY#2 retained significantly more Al in BLCs and thereby showed higher relative root growth than TF0140. Formation of BLCs accompanied changes in cell wall pectin epitopes and differential expression of genes involved in pectin metabolism, including a polygalacturonase (SgPG1). The expression pattern of SgPG1 was consistent with the formation of BLCs in both RY#2 and TF0140. SgPG1 was localized in cell walls and exhibited high activities mediating demethyl-esterified homogalacturonan degradation. Overexpressing SgPG1 changed cell wall pectin epitopes, enhanced BLCs production, and Al resistance in both Arabidopsis and Stylosanthes hairy roots. Furthermore, combining protein-DNA binding assays in vitro and in vivo, a bHLH transcription factor SgbHLH19 was demonstrated to be the upstream regulator of SgPG1. Our study demonstrates that S. guianensis Al resistance mainly relies on BLCs, whose formation involves cell wall pectin epitope modification by SgPG1.

Itm2a expression marks periosteal skeletal stem cells that contribute to bone fracture healing.

The periosteum contains skeletal stem/progenitor cells that contribute to bone fracture healing. However, the in vivo identity of periosteal skeletal stem cells (P-SSCs) remains unclear, and membrane protein markers of P-SSCs that facilitate tissue engineering are needed. Here, we identified integral membrane protein 2A (Itm2a) enriched in SSCs using single-cell transcriptomics. Itm2a+ P-SSCs displayed clonal multipotency and self-renewal and sat at the apex of their differentiation hierarchy. Lineage-tracing experiments showed that Itm2a selectively labeled the periosteum and that Itm2a+ cells were preferentially located in the outer fibrous layer of the periosteum. The Itm2a+ cells rarely expressed CD34 or Osx, but expressed periosteal markers such as Ctsk, CD51, PDGFRA, Sca1, and Gli1. Itm2a+ P-SSCs contributed to osteoblasts, chondrocytes, and marrow stromal cells upon injury. Genetic lineage tracing using dual recombinases showed that Itm2a and Prrx1 lineage cells generated spatially separated subsets of chondrocytes and osteoblasts during fracture healing. Bone morphogenetic protein 2 (Bmp2) deficiency or ablation of Itm2a+ P-SSCs resulted in defects in fracture healing. ITM2A+ P-SSCs were also present in the human periosteum. Thus, our study identified a membrane protein marker that labels P-SSCs, providing an attractive target for drug and cellular therapy for skeletal disorders.

Nitrogen inputs promote wetland carbon dioxide and nitrous oxide emissions in China: a meta-analysis.

Nitrogen is the most limiting nutrient in wetland ecosystems. Changing in nitrogen nutrient status has a great effect on wetland carbon and nitrogen cycling. However, there is much uncertainty as to wetland greenhouse gas emissions response to nitrogen inputs in China. In this study, we synthesized 177 paired observations from 27 studies of greenhouse gases emissions related to nitrogen additions across wetland in China. The results showed nitrogen inputs significantly contributed to wetland carbon dioxide (CO2) and nitrous oxide (N2O) emissions but had no significant effect on methane (CH4). We further analyze the relationship between greenhouse gases emissions and soil properties, climate factors under nitrogen inputs. Regression analyses introducing explanatory variables showed that high nitrogen inputs (12 g N m-2 yr-1-24 g N m-2 yr-1) contributed more significantly to wetland CO2 and N2O emissions. Compared to other wetland types, alpine peatlands have a greater impact on CO2 and N2O emissions following nitrogen input. In addition, high altitude (> 1500 m and ≤ 3500 m) could promote wetland CO2 and N2O emissions more significantly after nitrogen input, but ultra-high altitude (> 3500 m) reduced CO2 emissions. CO2 and N2O emissions were more significantly promoted when mean annual temperature (MAT) was positive, and CO2 emissions increased with increasing mean annual precipitation (MAP). Wetland CO2 emissions can be significantly promoted when soil is acidic, while N2O emissions can be significantly promoted when soil is alkaline. N2O emissions increased with increasing of soil total nitrogen (TN) and soil organic carbon (SOC) contents. These findings highlight the characteristics of wetland greenhouse gas emissions following nitrogen input, and improve our ability to predict greenhouse gas emissions and help meet carbon neutrality targets.

The tonoplast-localized OsTIP2;1 is involved in aluminum detoxification in rice.

Aluminum (Al) stress is a significant issue in acidic soils, severely affecting crop growth and yield. Rice is notably resilient to Al toxicity, yet the internal tolerance mechanisms remain inadequately addressed. Here, we examined the role of OsTIP2;1, a tonoplast-bound intrinsic protein (TIP), in rice's internal Al detoxification. Our findings reveal that OsTIP2;1 expression was quickly and explicitly activated by Al ions in roots but not in shoots. The OsTIP2;1-GFP protein localizes to the tonoplast in plant and yeast cells. Non-functional ostip2;1 rice mutants were more vulnerable to Al toxicity. In the roots, the ostip2;1 mutants exhibited considerably lower levels of Al in the cell sap, primarily the vacuolar contents, than in the wild-type plant. Moreover, the ostip2;1 mutants showed reduced Al accumulation in the roots but increased translocation to the shoots. Heterologous expression of tonoplast-localized OsTIP2;1 in yeast led to enhanced Al tolerance, suggesting that OsTIP2;1 facilitates Al sequestration to the vacuole. These findings indicate that OsTIP2;1 mediates internal detoxification by transporting Al into the vacuole in the root and restricting its transport to above-ground tissues, thus contributing to Al resistance in rice.

Patient-derived ovarian cancer organoid carries immune microenvironment and blood vessel keeping high response to cisplatin.

Ovarian cancer is high recurrence and mortality malignant tumor. The most common ovarian cancer was High-Grade Serous Ovarian Cancer. However, High-Grade Serous Ovarian Cancer organoid is rare, which organoid with patient immune microenvironment and blood vessels even absence. Here, we report a novel High-Grade Serous Ovarian Cancer organoid system derived from patient ovarian cancer samples. These organoids recapitulate High-Grade Serous Ovarian Cancer organoids' histological and molecular heterogeneity while preserving the critical immune microenvironment and blood vessels, as evidenced by the presence of CD34 + endothelial cells. Whole exome sequencing identifies key mutations (CSMD3, TP53, GABRA6). Organoids show promise in testing cisplatin sensitivity for patients resistant to carboplatin and paclitaxel, with notable responses in cancer proteoglycans and p53 (TP53) signaling, like ACTG/ACTB1/AKT2 genes and BBC3/MDM2/PERP. Integration of immune microenvironment and blood vessels enhances potential for novel therapies like immunotherapies and angiogenesis inhibitors. Our work may provide a new detection system and theoretical basis for ovarian cancer research and individual therapy.

Investigating the molecular mechanism of vitexin targeting CDK1 to inhibit colon cancer cell proliferation via GEO chip data mining, computer simulation, and biological activity verification.

The objective of this study is to explore the antiproliferative activity of the traditional Chinese medicine monomer vitexin on colon cancer HCT-116 cells and its underlying mechanism. The in vitro antiproliferative activity of vitexin on colon cancer HCT-116 cells was evaluated using the CCK-8 assay. Potential drug targets for colon cancer were identified through GEO chip data mining, and molecular docking using Schrödinger software was conducted. Molecular dynamics simulations were employed to deeply analyze the interaction between candidate compounds and target proteins. Flow cytometry was employed to examine the cell cycle. The impact of vitexin on the expression of CDK1/cyclinB proteins in HCT-116 cells was assessed through Western blot analysis, immunofluorescence, and CDK inhibition assay. Vitexin exhibited inhibitory effects on colon cancer HCT-116 cells, with a half inhibitory concentration (IC50) value of 203.27 ± 9.85 µmol/L. The analysis of differential gene expression in GEO and TCGA datasets, along with the GENECARD dataset of related disease genes, identified 91 disease targets, including "CDK1." Vitexin induced cell cycle arrest in the G2/M phase of HCT-116 cells. Molecular docking revealed a strong interaction between Vitexin and CDK1 (Docking score - 9.497), with molecular dynamics simulations confirming the stability of the Vitexin-CDK1 complex and comparable inhibitory effects to Flavopiridol. Vitexin can inhibit the expression of CDK1/cyclin B proteins in HCT-116 cells, with an IC50 of 58.06 ± 3.07 µmol/L. Vitexin may inhibit colon cancer HCT-116 cell proliferation by suppressing CDK1/cyclin B expression, leading to cell cycle arrest in the G2/M phase.

Molecular characterization and phylogenetic analyses of MetAP2 gene and protein of Nosema bombycis isolated from Guangdong, China.

Background: Pebrine, caused by microsporidium Nosema bombycis, is a devastating disease that causes serious economic damages to the sericulture industry. Studies on development of therapeutic and diagnostic options for managing pebrine in silkworms are very limited. Methionine aminopeptidase type 2 (MetAP2) of microsporidia is an essential gene for their survival and has been exploited as the cellular target of drugs such as fumagillin and its analogues in several microsporidia spp., including Nosema of honeybees. Methods: In the present study, using molecular and bioinformatics tools, we performed in-depth characterization and phylogenetic analyses of MetAP2 of Nosema bombycis isolated from Guangdong province of China. Results: The full length of MetAP2 gene sequence of Nosema bombycis (Guangdong isolate) was found to be 1278 base pairs (bp), including an open reading frame of 1,077 bp, encoding a total of 358 amino acids. The bioinformatics analyses predicted the presence of typical alpha-helix structural elements, and absence of transmembrane domains and signal peptides. Additionally, other characteristics of a stable protein were also predicted. The homology-based 3D models of MetAP2 of Nosema bombycis (Guangdong isolate) with high accuracy and reliability were developed. The MetAP2 protein was expressed and purified. The observed molecular weight of MetAP2 protein was found to be ~43-45 kDa. The phylogenetic analyses showed that MetAP2 gene and amino acids sequences of Nosema bombycis (Guangdong isolate) shared a close evolutionary relationship with Nosema spp. of wild silkworms, but it was divergent from microsporidian spp. of other insects, Aspergillus spp., Saccharomyces cerevisiae, and higher animals including humans. These analyses indicated that the conservation and evolutionary relationships of MetAP2 are closely linked to the species relationships. Conclusion: This study provides solid foundational information that could be helpful in optimization and development of diagnostic and treatment options for managing the threat of Nosema bombycis infection in sericulture industry of China.

Charged Gold Nanoparticles for Target Identification-Alignment and Automatic Segmentation of CT Image-Guided Adaptive Radiotherapy in Small Hepatocellular Carcinoma.

Because of the challenges posed by anatomical uncertainties and the low resolution of plain computed tomography (CT) scans, implementing adaptive radiotherapy (ART) for small hepatocellular carcinoma (sHCC) using artificial intelligence (AI) faces obstacles in tumor identification-alignment and automatic segmentation. The current study aims to improve sHCC imaging for ART using a gold nanoparticle (Au NP)-based CT contrast agent to enhance AI-driven automated image processing. The synthesized charged Au NPs demonstrated notable in vitro aggregation, low cytotoxicity, and minimal organ toxicity. Over time, an in situ sHCC mouse model was established for in vivo CT imaging at multiple time points. The enhanced CT images processed using 3D U-Net and 3D Trans U-Net AI models demonstrated high geometric and dosimetric accuracy. Therefore, charged Au NPs enable accurate and automatic sHCC segmentation in CT images using classical AI models, potentially addressing the technical challenges related to tumor identification, alignment, and automatic segmentation in CT-guided online ART.

The effect and mechanism of palmar ginseng in type 2 diabetic cognitive impairment.

Objective: To investigate the therapeutic effect of palmar ginseng on cognitive impairment in rats with type 2 diabetes, evaluate its neuroprotective effects, and explore its underlying mechanism. Methods: A rat model of diabetic cognitive impairment (DCI) was established by feeding with homemade high-fat, high-sugar chow combined with intraperitoneal injection of streptozotocin (STZ). Rats were continually fed high-fat, high-sugar chow for 60 days after successful induction of the model. Palmar ginseng was administered via gavage. The Morris test was performed after 30 days of treatment. At the end of the test, blood samples were collected, and the activities of IL-6, IL-10, TNF-α, and IL-1ß in rat serum. Pathological changes in hippocampal tissues were observed by Haematoxylin-eosin (HE) staining of the brain, activation of microglia in hippocampal tissues was detected by immunofluorescence, and the expression of PI3K/Akt/mTOR and JAK2/STAT3 proteins in the hippocampal tissues by Western blot. Results: During the administration of palmar Ginseng, the body weight and blood glucose levels of DCI rats were measured weekly, with results showing that Palmar Ginseng effectively reduced blood glucose levels and body weight of DCI rats. Behavioural tests in the water maze indicated that palmar ginseng effectively improved the learning and memory ability of DCI rats. HE and immunofluorescence staining showed that palmar ginseng improved DCI in rats, ameliorated hippocampal neuronal damage, and improved microglial activation. ELISA showed that palmar ginseng significantly reduced the expression of pro-inflammatory factors in the serum of DCI rats. Increased expression of anti-inflammatory factors was observed, and Western blot analysis showed that Palmar Ginseng regulated PI3K/Akt/mTOR and JAK2/STAT3 protein expression, promoted the phosphorylation of PI3K/Akt/mTOR, and inhibited JAK2/STAT3 protein phosphorylation in rat hippocampal tissues as well as in BV2 cells. Conclusions: Palmar ginseng may improve the onset and development of DCI by upregulating the phosphorylation of proteins in the PI3K/Akt/mTOR pathway.

Preparation of a Polymeric Phosphoramide Flame-Retardant and Its Effect on the Flame-Retardant Properties of Epoxy Resin.

The flammability of epoxy resins and knowing how to achieve curing are particularly important factors during use. A novel approach for enhancing the fire resistance and reducing the smoke emission of epoxy resin during the curing process is suggested, which involves the utilization of a three-source integrated polymerization intumescent flame-retardant. In this study, the synthesis of poly 4,4-diaminodiphenylsulfone spirocyclic pentaerythritol bisphosphonate (PCS) is achieved through using solution polymerization, utilizing 4,4'-diaminodiphenylsulfone (DDS) and spirocyclic pentaerythritol bisphosphorate disphosphoryl chloride (SPDPC) as initial components. Following that, the EP underwent the inclusion of PCS to examine its resistance to heat, its ability to prevent flames, its effectiveness in reducing smoke and its curing effect. Compared to the unmodified epoxy resin, the addition of PCS can not only cure the epoxy resin, but also decompose before the epoxy resin and has a good carbonization effect. With the addition of 7 wt.% PCS, the LOI value can achieve 31.2% and successfully pass the UL-94 test with a V-0 rating. Moreover, the cone calorimeter experiment demonstrated a noteworthy decline of 59.7% in the maximum heat release rate (pHRR), 63.7% in overall heat release (THR), and 42.3% in total smoke generation (TSP). Based on the examination of TG-FTIR and SEM findings, there is ample evidence to suggest that PCS, functioning as a phosphorus-nitrogen intumescent flame-retardant that combines three origins, has the potential to exhibit a favorable flame-retardant impact in both its gas and condensed phases.

Landscape of human organoids: Ideal model in clinics and research.

In the last decade, organoid research has entered a golden era, signifying a pivotal shift in the biomedical landscape. The year 2023 marked a milestone with the publication of thousands of papers in this arena, reflecting exponential growth. However, amid this burgeoning expansion, a comprehensive and accurate overview of the field has been conspicuously absent. Our review is intended to bridge this gap, providing a panoramic view of the rapidly evolving organoid landscape. We meticulously analyze the organoid field from eight distinctive vantage points, harnessing our rich experience in academic research, industrial application, and clinical practice. We present a deep exploration of the advances in organoid technology, underpinned by our long-standing involvement in this arena. Our narrative traverses the historical genesis of organoids and their transformative impact across various biomedical sectors, including oncology, toxicology, and drug development. We delve into the synergy between organoids and avant-garde technologies such as synthetic biology and single-cell omics and discuss their pivotal role in tailoring personalized medicine, enhancing high-throughput drug screening, and constructing physiologically pertinent disease models. Our comprehensive analysis and reflective discourse provide a deep dive into the existing landscape and emerging trends in organoid technology. We spotlight technological innovations, methodological evolution, and the broadening spectrum of applications, emphasizing the revolutionary influence of organoids in personalized medicine, oncology, drug discovery, and other fields. Looking ahead, we cautiously anticipate future developments in the field of organoid research, especially its potential implications for personalized patient care, new avenues of drug discovery, and clinical research. We trust that our comprehensive review will be an asset for researchers, clinicians, and patients with keen interest in personalized medical strategies. We offer a broad view of the present and prospective capabilities of organoid technology, encompassing a wide range of current and future applications. In summary, in this review we attempt a comprehensive exploration of the organoid field. We offer reflections, summaries, and projections that might be useful for current researchers and clinicians, and we hope to contribute to shaping the evolving trajectory of this dynamic and rapidly advancing field.

Resveratrol attenuates cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in the rat mesenteric artery.

Cyclosporin A, an immunosuppressive agent, is extensively utilized for the prevention of transplant rejection and treat autoimmune disease in the clinic, despite its association with a high risk of hypertension development among patients. Resveratrol is a kind of non-flavonoid phenolic compound that widely exists in many plants. The aim of the present study was to investigate the mechanism by which resveratrol ameliorates cyclosporin A-induced hypertension. The arterial rings of the mesentery were incubated with cyclosporin A and resveratrol in vitro. Rats were administered cyclosporin A and/or resveratrol for 3 weeks in vivo. Blood pressure was measured via the tail arteries. Vasoconstriction curves were recorded using a sensitive myograph. The protein expression was evaluated through Western blotting. This study demonstrated that resveratrol mitigated the cyclosporin A-induced increase in blood pressure in rats. Furthermore, resveratrol markedly inhibited the cyclosporin A-induced upregulation of thromboxane A2 receptor-mediated vasoconstriction in the rat mesenteric artery both in vitro and in vivo. Moreover, resveratrol activated AMPK/SIRT1 and inhibited the MAPK/NF-κB signaling pathway. In conclusion, resveratrol restored the cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in rats.

Revealing the active ingredients and mechanism of P. sibiricumm in non-small-cell lung cancer based on UPLC-Q-TOF-MS/MS, network pharmacology, and molecular docking.

The alcohol extraction of P. sibiricum has exhibited significant inhibitory effects on the production of free radicals and the proliferation of non-small-cell lung carcinoma (NSCLC) A549 cells. Despite the diverse components found in alcohol extraction of P. sibiricum and its multiple targets, the active components and associated targets remain largely unidentified. Hence, there is a need for additional investigation into the pharmacodynamic elements and mechanisms of action. This study aimed to analyze and identify the components responsible for the anti-tumor activity of alcohol extraction from P. sibiricum using UPLC-Q-TOF-MS/MS for the first time. Subsequently, the targets of the active components were predicted using the SwissTargetPrediction database, whereas the targets for NSCLC were sourced from the Online Mendelian Inheritance in Man database (OMIM) and the GeneCards database. Next, the targets of chemical composition were integrated with disease targets via Venny online. GO and KEGG pathway enrichment analyses were performed utilizing DAVID. Subsequently, a network analysis of "components-targets-pathways" was established using Cytoscape 3.8.2 and assessed with the "network analyzer" plug-in. Molecular docking was conducted utilizing Autodock 1.5.6. The study aimed to examine the anti-proliferative impacts and underlying mechanisms of alcohol extraction from P. sibiricum on NSCLC through in vivo and in vitro investigations utilizing an animal model of transplanted tumor, CCK8 assay, cell scratch test, RT-qPCR, and western blotting. The study unveiled that 17 active components extracted from P. sibiricum alcohol demonstrated anti-non-small cell lung cancer (NSCLC) effects through the modulation of 191 targets and various significant signaling pathways. These pathways include Endocrine resistance, PI3K/AKT, Chemical carcinogenesis-receptor activation, Proteoglycans in cancer, EGFR tyrosine kinase inhibitor resistance, AMPK signaling pathway, and other related signaling pathways. Network analysis and molecular docking results indicated that specific compounds such as (25S)-26-O-(ß-d-glucopyranosyl)-furost-5-en3ß,22α,26-triol3-O-ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranosyl-(1→4)-ß-d-glucopyranoside, Timosaponin H1, Deapi-platycodin D3, (3R)-5,7-dihydroxy-6,8-dimethyl-3-(4'-hydroxybenzyl)-chroman-4-one, Disporopsin, Funkioside F, Kingianoside E, Parisyunnanoside H, and Sibiricoside B primarily targeted 17 key proteins (BCL2, EGFR, ESR1, ESR2, GRB2, IGF1R, JUN, MAP2K1, MAPK14, MAPK8, MDM2, MMP9, mTOR, PIK3CA, RAF1, RPS6KB1, and SRC) collectively. In conclusion, the alcohol extraction of P. sibiricum demonstrated inhibitory effects on cell proliferation, induction of apoptosis, and inhibition of metastasis through various pathways.

Understanding Sorafenib-Induced Cardiovascular Toxicity: Mechanisms and Treatment Implications.

Tyrosine kinase inhibitors (TKIs) have been recognized as crucial agents for treating various tumors, and one of their key targets is the intracellular site of the vascular endothelial growth factor receptor (VEGFR). While TKIs have demonstrated their effectiveness in solid tumor patients and increased life expectancy, they can also lead to adverse cardiovascular effects including hypertension, thromboembolism, cardiac ischemia, and left ventricular dysfunction. Among the TKIs, sorafenib was the first approved agent and it exerts anti-tumor effects on hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) by inhibiting angiogenesis and tumor cell proliferation through targeting VEGFR and RAF. Unfortunately, the adverse cardiovascular effects caused by sorafenib not only affect solid tumor patients but also limit its application in curing other diseases. This review explores the mechanisms underlying sorafenib-induced cardiovascular adverse effects, including endothelial dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, dysregulated autophagy, and ferroptosis. It also discusses potential treatment strategies, such as antioxidants and renin-angiotensin system inhibitors, and highlights the association between sorafenib-induced hypertension and treatment efficacy in cancer patients. Furthermore, emerging research suggests a link between sorafenib-induced glycolysis, drug resistance, and cardiovascular toxicity, necessitating further investigation. Overall, understanding these mechanisms is crucial for optimizing sorafenib therapy and minimizing cardiovascular risks in cancer patients.

A study integrated metabolomics and network pharmacology to investigate the effects of Shicao in alleviating acute liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Shicao is the aerial part of Achillea alpina L., a common herb found mainly in Europe, Asia, and North America. Traditional Chinese medicine has a history of thousands of years and is widely used to treat various diseases. AIM OF STUDY: To explore the hepatoprotective effects of Shicao on CCl4-induced acute liver injury. METHODS: A rat model of acute liver injury was established and liver function indices were assessed to evaluate the protective effect of Shicao on the liver. Untargeted metabolomics of the serum and liver tissues was conducted using UPLC-Q-TOF/MS to identify differential metabolites related to acute liver injury. A network of metabolite-reaction-enzyme-gene constituents was constructed using network pharmacology. Hub targets and key components of the effect of Shicao on acute liver injury were screened from the network. RESULTS: Compared to the model group, Shicao improved the degree of liver damage through the assessment of the liver index, ALT and AST levels, and hepatic pathology slices, demonstrating its hepatoprotective effect against acute liver injury in rats. 10 and 38 differential metabolites involved in acute liver injury were identified in serum and liver tissues, respectively. Most of these were regulated or restored following treatment with Shicao, which mainly consisted of bile acids, lipids, and nucleotides such as taurocholic acid, LysoPC (17:0), and adenosine diphosphate ribose. Through the network of metabolite-reaction-enzyme-gene-constituents, 10 key components and 5 hub genes, along with 7 crucial differential metabolites, were mainly involved in glycerophospholipid metabolism, purine metabolism, biosynthesis of unsaturated fatty acids, and primary bile acid biosynthesis, which may play important roles in the prevention of acute liver injury by Shicao. CONCLUSION: This study revealed that Shicao had protective effects against CCl4-induced liver injury in rats. It was speculated that the ingredients of Shicao might be closely related to the hub targets, thereby regulating the levels of key metabolites, affecting inflammatory response and oxidative stress and attenuate the liver injury consequently. This study provides a basis for further investigation of its therapeutic potential and the mechanism of action.

Substance basis and pharmacological mechanism of heat-clearing herbs in the treatment of ischaemic encephalopathy: a systematic review and network pharmacology.

BACKGROUND AND OBJECTIVE: Ischaemic encephalopathy is a common cerebrovascular disease caused by insufficient blood supply to the cerebral vessels. The ischaemic encephalopathy is closely associated with the development of many chronic diseases such as obesity, hypertension and diabetes. Neurotrophic therapy has become the main therapeutic strategy for ischaemic encephalopathy. However, neurotrophic drugs only slightly recover the neurological function of patients, and their long-term efficacy is uncertain. Previous reports revealed that the active ingredients of natural medicines play important roles in the treatment of cerebral ischemia. In this study, we reviewed clearing herbs with anti-ischaemic encephalopathy functions using the data from quantitative statistical and network pharmacological exploration methods. We also discussed the different bioactive components and pharmacological effects of these herbs. METHODS: First, we collected Chinese herbal prescriptions against ischaemic encephalopathy in four databases. Then, we statistically analysed the frequency of application of heat-clearing herbs to obtain the commonly used heat-clearing herbs against ischaemic encephalopathy, and classified them according to their efficacy according to the statistical results, to summarize the mechanism of anti-ischaemic effects of different bioactive components; Second, the network database was used to obtain the above components of heat-clearing Chinese medicines and their corresponding targets of action, disease targets of ischaemic stroke; Venny 2.1.0 was used to obtain component-disease target intersections; Cytoscape was used to construct the 'Drug-Active Ingredient-Target Network Graph '; DAVID was used for GO and KEGG enrichment analysis. RESULTS: Literature and database screening involved 149 prescriptions, with a total of 269 flavours of Chinese medicines and 20 flavours of single-flavour heat-clearing Chinese medicines; The top nine in terms of frequency of use were Radix Paeoniae Rubra、Rehmanniae Radix Praeparata、Figwort Root、Cortex Moutan、Scutellariae Radix、Coptidis Rhizoma、Gardeniae Fructus、Cassiae Semen、Lonicerae Japonicae Flos. The common components obtained from network pharmacology were beta-sitosterol, quercetin, and stigmasterol, which mainly act on key targets such as RELA, AKT1, JUN, PRKACA, PTGS2, RAF1 and CHUK; and their active ingredients are mainly involved in signalling pathways such as Calcium, PI3K-Ak, MAPK, cAMP, IL-17, HIF-1, TNF, T-cell receptor, NF-kappa B and JAK-STAT. CONCLUSIONS: Heat-clearing herbs are useful and promising for the protection against and prevention of ischemic encephalopathy. The results of the network pharmacological studies are similar to the mechanisms of anti-ischemic encephalopathy of the active ingredients of the purgative herbs we have listed; Thin either directly protects cerebrovascular tissues by improving vascular permeability and reducing the area of infarcted tissues, or produces protective effects through molecular signaling pathways. It can be seen that the components of heat-clearing Chinese medicines can exert cerebroprotective effects through multiple pathways, which provides us with a reference for further development and study of heat-clearing Chinese medicines in the treatment of ischemic cerebrovascular diseases.

Effects of restoration years on soil nitrogen and phosphorus in inland salt marshes.

Inland salt marsh wetlands have very important ecological functions in semi-arid areas. However, degradation and soil desertification have impacted these areas, making it necessary to study the impact of wetland restoration years on the soil quality of salt marsh wetland. We used remote sensing methods, field surveys, and inquiries to examine the seasonal profile effects of two-, four-, and six-year restoration periods on total nitrogen (TN), total phosphorus (TP) and the ratio of nitrogen to phosphorus (N:P) in P. australis and S. triqueter wetland natural states. Our results showed that soil TN in P. australis wetland in restored conditions was higher than that in natural conditions. The average soil TP of the S. triqueter wetlands at 0-10 cm, 10-20 cm, 20-30 cm, and 30-40 cm layers was 0.36 g/kg, 0.31 g/kg, 0.21 g/kg, and 0.17 g/kg s in September, respectively. The soil TP of the S. triqueter wetland increased slightly over the entire growing season. The restoration years had a great influence on the soil TP of the S. triqueter wetland from May to July. The soil TN in the P. australis wetland was almost restored to its natural condition in each layer during the six-year restoration period. The soil TP of the S. triqueter wetland was higher in the restored two-year period and showed a decreasing trend with an increased soil depth. Our conclusions can significantly guide the restoration of inland salt marsh wetlands.

Identification of Gonatophragmium mori Causing Mulberry Zonate Leaf Spot Disease and Characterization of Their Biological Enemies in Guangxi, China.

Mulberry zonate leaf spot disease (MZLSD) is an important fungal disease of mulberry trees, which seriously affects the productivity and quality of mulberry leaves. MZLSD has been widely reported in sericultural production areas in Guangxi, China, in recent years. In this study, the causal agent of MZLSD was isolated from symptomatic samples and identified as Gonatophragmium mori (Acrospermaceae) based on morphological characterization and molecular analyses using nucleotide sequences of the internal transcribed spacer (ITS) and large subunit ribosomal DNA (LSU rDNA). Pathogenicity tests confirmed that G. mori is the pathogen responsible for MZLSD. Furthermore, we isolated antagonistic endophytic bacteria (AEB) from healthy mulberry leaves. Plate confrontation experiments showed that the lipopeptide crude extracts (LPCE) of three endophytic bacteria can inhibit the growth of G. mori, and the diameter of the antibacterial circle reaches more than 60 mm when their concentration of LPCE is 200 mg/ml. Light microscopy and scanning electron microscopy revealed that LPCE caused drastic changes in mycelial morphology. Fluorescence microscopy and transmission electron microscopy showed that the LPCE-induced apoptosis-like cell death in G. mori hyphae. Finally, based on morphological and molecular features, we identified the three isolates as Bacillus subtilis DS07, B. subtilis DS32, and B. velezensis Q6, respectively. To our knowledge, this is the first time to identify G. mori by combining characterization and molecular analyses, and we provide timely information about the use of biocontrol agents for suppression of G. mori.

Discovery of a Novel Benzothiadiazine-Based Selective Aldose Reductase Inhibitor as Potential Therapy for Diabetic Peripheral Neuropathy.

Aldose reductase 2 (ALR2), an activated enzyme in the polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for complications of diabetes, especially in diabetic peripheral neuropathy (DPN). However, many of the ALR2 inhibitors have shown serious side effects due to poor selectivity over aldehyde reductase (ALR1). Herein, we describe the discovery of a series of benzothiadiazine acetic acid derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities in vivo. Compound 15c, carrying a carbonyl group at the 3-position of the thiadiazine ring, showed high potent inhibition against ALR2 (IC50 = 33.19 nmol/L) and ∼16,109-fold selectivity for ALR2 over ALR1. Cytotoxicity assays ensured the primary biosafety of 15c. Further pharmacokinetic assay in rats indicated that 15c had a good pharmacokinetic feature (t1/2 = 5.60 h, area under the plasma concentration time curve [AUC(0-t)] = 598.57 ± 216.5 µg/mL * h), which was superior to epalrestat (t1/2 = 2.23 h, AUC[0-t] = 20.43 ± 3.7 µg/mL * h). Finally, in a streptozotocin-induced diabetic rat model, 15c significantly increased the nerve conduction velocities of impaired sensory and motor nerves, achieved potent inhibition of d-sorbitol production in the sciatic nerves, and significantly increased the paw withdrawal mechanical threshold. By combining the above investigations, we propose that 15c might represent a promising lead compound for the discovery of an antidiabetic peripheral neuropathy drug.