ETHNOPHARMACOLOGICAL RELEVANCE:Chemotherapy-induced myelosuppression is a common and severe complication in clinical oncology treatment. Chemotherapeutic agents trigger this condition by damaging bone marrow mesenchymal stem cells (BMSCs) and disrupting hematopoietic microenvironment homeostasis. Danggui Jixueteng Decoction (DJD), a classical blood-tonifying and blood-activating formula, has been confirmed to alleviate post-chemotherapy myelosuppression, but its specific molecular mechanisms in protecting BMSCs remain unclear. OBJECTIVE:This study aims to clarify the molecular mechanisms whereby DJD-containing serum alleviates chemotherapy-induced BMSCs injury, identify key signaling pathways and targets for its myeloprotection, and provide evidence supporting DJD for treating chemotherapy-induced myelosuppression. MATERIALS AND METHODS:UHPLC-Orbitrap-MS analyzed DJD's chemical constituents, including blood-entry prototypes and metabolites. A carboplatin (CBP) -induced cell injury model was established. Different concentrations of DJD-containing serum were applied. Functional, proteomic, Western blot, molecular docking, cellular thermal shift assay (CETSA) and molecular dynamics simulation (MD) were used for detection and verification. RESULTS:107 chemical components and 38 blood-entry components of DJD were identified. DJD-containing serum concentration-dependently reversed the aforementioned damaging effects of CBP, significantly improved mitochondrial function, suppressed excessive mitophagy and ferroptosis, and effectively restored AKT/FOXO3a pathway signaling function. Molecular docking, CETSA and MD validated that tanshinol B stably binds to FOXO3a and enhances its thermal stability. CONCLUSION:This study demonstrates that DJD-containing serum protects BMSCs and maintains hematopoietic microenvironment homeostasis by targeting the AKT/FOXO3a signaling pathway, thereby repairing its abnormally inhibited state, suppressing CBP-induced excessive mitophagy, and inhibiting subsequent ferroptosis. This study provides novel insights and experimental evidence for targeted intervention of chemotherapy-induced bone marrow injury using traditional Chinese medicine.

This study aimed to investigate the chemical constituents of Xuebijing Injection and compare differences in its systemic exposure components among patients with severe pneumonia, sepsis, and acute pancreatitis during the steady-state blood concentration phase. Using ultra-high-performance liquid chromatography-mass spectrometry, compounds were identified and analyzed based on retention time, accurate molecular weight, secondary mass spectrometry fragmentation patterns, and comparisons with reference standards and databases. A total of 55 chemical constituents were identified in Xuebijing Injection, primarily flavonoids, organooxygen compounds, prenol lipids, and isobenzofurans. In patient plasma, 16 components were detected in severe pneumonia patients, comprising 7 prototypes, 6 Phase I metabolites, and 3 Phase II metabolites; 32 components were found in acute pancreatitis patients, including 12 prototypes, 10 Phase I metabolites, and 10 Phase II metabolites; and 24 components were identified in sepsis patients, consisting of 8 prototypes, 9 Phase I metabolites, and 4 Phase II metabolites. Acute pancreatitis patients exhibited the highest number of systemic exposure components, followed by sepsis and severe pneumonia patients. Hydroxysafflor yellow A, paeoniflorin, and neocnidilide glucuronidation were consistently detected at relatively high concentrations across all groups. This study demonstrates the utility of ultra-high-performance liquid chromatography-mass spectrometry for rapid profiling of the chemical composition of Xuebijing Injection and its blood-exposed components, providing a reference for elucidating its pharmacodynamic material basis and mechanism of action.

Background Alzheimer’s disease (AD) affects a large number of people worldwide; its pathological mechanisms are complex, and there is a lack of effective treatments. HM568, a honokiol derivative, has been shown in previous studies to have therapeutic potential for Parkinson’s disease, but its efficacy and mechanisms of action in other neurodegenerative diseases remain unclear. Objective This study aims to investigate the effects and mechanisms of HM568 on Alzheimer's disease through reverse virtual screening and experimental validation. Methods Reverse virtual screening using AutoDock Vina was performed to identify potential targets of HM568. KEGG, Gene Ontology (GO), and protein–protein interaction (PPI) analyses, together with molecular dynamics simulations, were conducted to explore the associated mechanisms. A D-galactose/AlCl₃-induced AD mouse model and an Aβ₂₅–₃₅-injured PC12 cell model were established. Behavioral tests, histopathological staining, biochemical assays, ELISA, cellular functional analyses, Western blotting, and RT-qPCR were used to evaluate the effects of HM568. Results Reverse virtual screening identified voltage-dependent anion channel 1 (VDAC1) as a key AD-related target of HM568, showing strong binding (−9.83 kcal/mol) and stable interactions during 100 ns simulations. In vivo, HM568 improved the overall condition and cognition of AD mice. Body weight gain was increased by approximately 72% relative to the model group, and Morris water maze performance was markedly improved (P < 0.05–0.001). HM568 also reduced hippocampal neuronal damage, increased antioxidant enzyme activities, and decreased brain levels of inflammatory cytokines, Aβ₁₋₄₂, and AChE activity (all P < 0.05). In vitro, HM568 dose-dependently inhibited Aβ₂₅–₃₅ aggregation and reduced apoptosis of Aβ₂₅–₃₅-injured PC12 cells from 36.13% to 12.56% at 4 μM (P < 0.001). Furthermore, HM568 significantly suppressed ROS accumulation, restored mitochondrial membrane potential, increased ATP production, and upregulated mitochondrial respiratory chain complexes I and IV. These protective effects were accompanied by reduced VDAC1 expression and modulation of apoptosis-related genes, including decreased Cytc, Bax, Caspase-3, and Caspase-9 and increased Bcl-2. Conclusion HM568 exerts a neuroprotective effect by inhibiting the abnormal overexpression of VDAC1 and improving mitochondrial function, thereby suppressing neuronal apoptosis. This establishes an experimental foundation for developing and applying honokiol derivatives in neurodegenerative disease treatment while providing novel insights and directions for future anti-AD drug development.

Background Real-world evidence of achieving Treat-to-Target and Minimal Disease Activity targets in moderate-to-severe atopic dermatitis with dupilumab remains limited. Objective To evaluate real-world treatment goal attainment among Chinese patients with moderate-to-severe atopic dermatitis treated with dupilumab. Methods A multicenter retrospective study enrolled patients with moderate-to-severe atopic dermatitis treated with dupilumab. Results The achievement rates for >= 75% improvement in Eczema Area and Severity Index, >= 4-point reduction in Peak Pruritus Numeric Rating Scale, >= 4-point reduction in Dermatology Life Quality Index, and all three Treat-to-Target criteria at 4 weeks were 38.5%, 37.9%, 48.5%, and 16.6%, respectively, increasing to 67.3%, 64.1%, 59.4%, and 38.3% at 12 weeks. >= 90% improvement in Eczema Area and Severity Index, Peak Pruritus Numeric Rating Scale <= 1, Dermatology Life Quality Index <= 1, and all three Minimal Disease Activity criteria achievement rates at 4 weeks were 20.5%, 14.6%, 23.9%, and 10.5%, respectively, which improved to 46.7%, 27.4%, 30.0%, and 18.3% at 12 weeks. Conclusions The results support the feasibility of implementing target-oriented treatment strategies in daily clinical practice.

Parkinson's disease (PD) is closely associated with PARP1 overactivation. Although our previously developed compound HM568 has been shown to alleviate PD pathology, its mechanism of action remained unknown. In this study, we show that HM568 significantly improves behavioral deficits, prevents the loss of dopaminergic neurons, and restores blood–brain barrier integrity and mitochondrial morphology in MPTP/MPP+-induced PD models. Proteomic analysis then indicated that the effects of HM568 were enriched in mitochondrial respiratory chain complexes. Building on this clue, we confirmed in cellular models that HM568 counteracts MPP+-induced inhibition of complexes I, III, and IV, thereby restoring mitochondrial function. Further mechanistic exploration uncovered that HM568 acts by elevating intracellular NAD+ levels, downregulating PARP1 protein expression, and inhibiting its enzymatic activity. Molecular docking indicated a high binding affinity between HM568 and PARP1 (-10.38 kcal/mol). Molecular dynamics simulations provided structural insights into HM568's selective inhibition advantage for PARP1 over PARP2. Our study demonstrates that HM568 corrects mitochondrial dysfunction and energy metabolism imbalance possibly through inhibition of PARP1 and modulation of NAD⁺ metabolism, providing a mechanistic foundation for its potential as a therapeutic agent for Parkinson's disease.

The study aims to analyze the chemical constituents of Xuefu Zhuyu Wan (XZW) based on LC-MS and explore the mechanism of XZW in treating postoperative cognitive dysfunction (POCD) through network pharmacology and identify its potential quality marker (Q-marker). The chemical components of XZW were analyzed by LC-MS, and the corresponding targets were predicted by SwissTargetPrediction. Then POCD targets were obtained by GeneCards, OMIM, PharmGKB, and TTD database, and the "components-targets" and protein-protein interaction (PPI) maps were drawn by Cytoscape 3.9.1. The visualization of GO and KEGG enrichment analysis was obtained by micro-information. Finally, the content of network pharmacology prediction was preliminarily verified by molecular docking. Eighteen compounds were identified in XZW using LC-MS. SwissTargetPrediction predicted 443 compound targets. Among these, there are 352 common targets between the drug and the disease. Using Cytoscape 3.9.1, the main active components were screened as inophyllum E, liquiritigenin, pyrethrin, albiflorin, isoliquiritigenin, prunasin, meranzin, ligustilide, isoglycyrol, and dibutylphenol. PPI analysis identified the top 10 core proteins as: glyceraldehyde-phosphate dehydrogenase (GAPDH), protein kinase B (AKT1), tumor necrosis factor (TNF), src protein (SRC), epidermal growth factor receptor (EGFR), caspase 3 (CASP3), estrogen receptor (ESR1), prostaglandin peroxidase synthase 2 (PTGS2), matrix metalloenzyme 9 (MMP9), and transcription factor (JUN). KEGG enrichment analysis revealed 166 pathways, including the neuroactive ligand-receptor interaction pathway. Molecular docking shows that the active components have a good affinity with the core targets. It is predicted that liquiritigenin, isoglycyrol, inophyllum, and albiflorin could serve as Q-marker for XZW in the treatment of POCD. The chemical constituents of XZW were obtained by preliminary analysis, and the possible pharmacodynamic substances and their mechanism in treating POCD were discussed. The Q-marker of XZW in treating POCD was predicted, which provided basis for its clinical application and drug development.

BACKGROUND:The ingredients of traditional Chinese medicine (TCM) are complex and diverse and are often identified using the TCM systems pharmacology (TCMSP) database. However, the ingredients in this database exhibit significant homogeneity, which limits the comprehensive understanding of TCM's ingredient diversity and biological activity. Consequently, liquid chromatography-mass spectrometry (LC-MS) has become a key tool for the precise identification of TCM components. METHODS:In this study, the LC-MS was used to identify the components of a TCM herb. The identified components were then compared with the component data in the TCMSP database. A network pharmacological prediction of the components was subsequently performed. RESULTS:An analysis of the four herb formula prescriptions (Ganmai Dazao decoction, Bazhen granule, Shaoyao Gancao decoction, and Zixue san) was conducted, revealing significant discrepancies between the LC-MS identification results and the components in the TCMSP database. The database components were found to be highly homogeneous. CONCLUSION:This study underscores the pivotal function of LC-MS in the analysis of components of TCM, particularly in addressing issues of database homogeneity. The employment of LC-MS technology enhances the precision of ingredient identification and streamlines the identification of potential pharmacodynamic ingredients, thereby propelling TCM toward a more contemporary standing.

Parkinson’s disease (PD) is the fastest growing neurodegenerative disease in the world at present. Neuroinflammation plays an important role in Parkinson's disease. In our study, we initially screened magnolol/honokiol derivatives synthesized by our group for their potential anti-neuroinflammatory properties. This was done using LPS-activated BV-2 microglial cell and MPP+-induced PC-12 cell models. Most of derivatives had increased anti-inflammatory activities and decreased toxicities compared to raw materials. Then, compounds were scored with inflammatory factors IL-1β, TNF-α and IL-6 by molecular docking in silico. Our studies revealed the strongest binding compound HM568 which binds with honokiol and metformin. Furthermore, HM568 showed no acute toxicity in mice through acute toxicity. And it is stable under high temperature, high humidity and strong light irradiation. Combining cell experiments and computer results, HM568 was considered for further in vivo pharmacological validations. Intraperitoneal injection administration of MPTP into C57BL/6 mice was utilized as Parkinson's animal model. Results showed that administration of HM568 for 14 days in MPTP-PD mice led to a significant alleviation in weight loss and movement disorders. Further HM568 could significantly down-regulate the expression levels of inflammatory factors IL-1β, IL-6 and TNF-α in brain tissue of the mouse model, reduce the level of caspase-3 and the ratio of Bcl-2/Bax, and up-regulate the level of transforming factor TGF-β, thus producing anti-apoptosis and anti-neuroinflammatory effects on neuronal cells. In terms of pathological features, HM568 could reduce the infiltration of neuronal cells and alleviate the development of lesions, promote the transformation of microglia from M1 negative phenotype to M2 type, and reverse the reduction of TH-positive immune cells in mouse neurons induced by MPTP. The administration of HM568 could reduce the abnormal accumulation of α-syn, and thus produce neuroprotective effect on MPTP-PD mice. Cell experiments, molecular docking and animal experiments thus depict HM568 as a promising agent to delay neuronal degeneration in PD, and its mechanism is related to anti-neuroinflammation.

Background: Accurate evaluation of atopic dermatitis (AD) severity is crucial to determine and adjust treatment options. Previous studies have found the product of Investigator's Global Assessment (IGA) and affected body surface area (BSA) to be a simple tool, which requires further verification. Objective: To determine the validity of IGA*BSA in assessing the severity of AD across all age, sex, BMI and disease severity groups. Method: We performed a retrospective study of AD using data from a national cohort (China Type II Inflammatory Skin Disease Clinical Research and Standardized Diagnosis and Treatment Project). Results: Overall, 3051 participants were included in the final analysis. IGA*BSA correlated better with objective measures than with subjective measures. IGA*BSA significantly correlated with Eczema Area and Severity Index (EASI) (r = 0.81), which was stronger than either IGA or BSA alone with EASI, regardless of age, sex, Body Mass Index (BMI), and disease severity groups. Besides, IGA*BSA mild, moderate, and severe groups were associated with significantly higher scores of other assessments and had moderate to fair concordance with other assessments severity strata. At follow-up, the concordance of improvement between IGA*BSA 50/75/90 and EASI 50/75/90 was observed (kappa = 0.65, 0.62, 0.58, respectively). Conclusion: IGA*BSA appears to be a valid objective assessment of AD severity and improvement over time across all age, sex, BMI, and disease severity subgroups in the clinical practice.

Danggui Jixueteng decoction (DJD) has been used to treat anemia for many years and has been shown to be effective. However, the mechanism of action and effective components are yet unknown. We want to search for pharmacodynamic components in DJD with therapeutic effects on myelosuppression after chemotherapy (MAC), utilizing a spectrum-effect connection study based on gray relational analysis and partial least-squares regression analysis. Transcriptome sequencing (RNA-Seq) was used to investigate the mechanism by which DJD treats MAC. In this study, fingerprints of different batches of DJD (S1-S10) were established by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), after which the resulting shared peaks were screened and identified. A total of 21 common peaks were screened through the fingerprints of different batches of DJD, and the similarity of each profile was greater than 0.92. The 21 shared peaks were identified by comparison with the standard sample and searching on a MassLynx 4.1 workstation. The rat model of MAC was established by intraperitoneal injection of cyclophosphamide, and DJD treatment was carried out in parallel with the establishment of the model. White blood cell count, red blood cell count, platelet count, interleukin-3, hemoglobin concentration, granulocyte-macrophage colony-stimulating factor, and nucleated cell count were used as efficacy indicators. Pharmacodynamic results indicated that DJD could effectively improve the pharmacodynamic indices of MAC rats. The results of gray relational analysis demonstrated eight peaks with high correlation with efficacy, which were 2, 7, 10, 14, 15, 16, 18, and 21, and the partial least-squares regression analysis showed four peaks with variable importance in projection values greater than 1, which were 10, 12, 13, and 19. RNA-Seq was used to identify DEGs in rat bone marrow cells, Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs were performed. The genes related to the effects of DJD on MAC were mainly involved in the phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K-Akt) signaling pathway, the mitogen-activated protein kinase signaling pathway, actin cytoskeleton regulation, focal adhesion, and Rap1 signaling pathways. The results of the RNA-Seq study were confirmed by a qPCR experiment. The effective compounds of DJD against MAC include albiflorin, paeoniflorin, gallopaeoniflorin, salvianolic acid H/I, albiflorin R1, salvianolic acid B, salvianolic acid E, benzoylpaeoniflorin, and C12H18N5O4. The mechanism by which DJD prevents and treats MAC might involve the control of the PI3K-Akt signaling pathway.

OBJECTIVE:Depression and sleep are closely related and tend to affect each other. To improve the sleep quality in depressed patients and the depression severity, there is an urgent need to find safer and more effective treatments - non-pharmacological interventions. This network meta-analysis aimed to investigate the effects of non-pharmacological interventions on improving sleep quality of patients with depression. METHODS:All published literature were searched from four databases (Pubmed, Embase, Cochrane, Web of Science) as of November 2022. The risk of bias of the included studies was assessed using the Cochrane Systematic Review Manual 2.0 bias risk assessment tool. The primary outcome was sleep quality and, the secondary outcome was depression severity. RESULTS:This study included 26 randomized controlled trials, involving 11 interventions and 3748 depressed patients. Cognitive-behavioral therapy (CBT) (SMD: 2.80; 95% CI: 1.63,3.96), aromatherapy (SMD: 3.95; 95% CI: 0.71,7.19), and acupuncture (SMD:3.49; 95% CI: 0.88,6.10) statistically and significantly improved sleep quality, compared to education only. CBT and acupuncture both were significantly more effective than education in depression severity. The cluster analysis showed that acupuncture, exercise, and cognitive-behavioral therapy were considered to be more effective non-pharmacological interventions. CONCLUSION:Non-pharmacological interventions are promising in the daily care of depressed patients. In future research, we should value the need for psychological and social aspects of psychiatric care and make better use of nonpharmacological interventions through the biopsychosocial model. (PROSPERO registration number: CRD42023402316).

To explore the metabolomics of fatty acids and biological information of related markers in a RAW264.7 cell inflammation model. RAW264.7 macrophage inflammation model was induced by LPS, and RAW264.7 cells were treated with non-steroidal anti-inflammatory drugs (NSAIDs). The fatty acid compositions were identified by GC-MS, combined with standard product spectrum information and NIST (National Institute of Standards and Technology) database. Using chemometrics and Analysis of Variance (ANOVA), the components with VIP > 1 and P < 0.05 were selected as significant difference markers, and combined with biological methods to explore the biological significance of them. GC-MS identified 21 fatty acids in RAW264.7 cells, and screened significant difference biomarkers in each group. Among these biomarkers, C20:5 and C22:6 had significant changes in pairwise comparison among each group. Through ELISA, polymerase chain reaction (PCR) and Western Blot methods, the mRNA and protein expressions of IL-1β, NLRP3, GPR120 and β-Arrestin-2 were up-regulated after RAW264.7 cells induced by LPS and nigericin, and decreased after drug intervention. It indicated that the signal pathway centered on NLRP3 inflammasome was involved in the anti-inflammatory process of ibuprofen. It was the first time to study fatty acid metabolomics in RAW264.7 cell inflammatory model by GC-MS combined with chemometrics. The anti-inflammatory mechanism of ibuprofen was explained from NLRP3 inflammasome perspective without precedent, which enriched the research on the signal pathway of ibuprofen anti-inflammatory mechanism.

The rhizoma of Anemarrhenae asphodeloides has a long history of hypoglycemic use in Chinese traditional medicine. In this article, 400 μmol/L H2 O2 induced normal INS-1 pancreatic beta cells to establish experimental model of oxidative damage. Quercetin was used as a positive drug, and mangiferin and its ethanolic extract were selected as therapeutic agents in an oxidative damage model to evaluate the ameliorative effect of the active ingredients of Anemarrhenae asphodeloides rhizoma on oxidative damage in INS-1 pancreatic β-cells. Building a qualitative analysis method of membrane phospholipids of INS-1 pancreatic beta cells and identified 82 phospholipids based on the UPLC/Q-TOF MS technology, which could provide a database for further statistics analysis. OPLS-DA was used to screen the phospholipid biomarkers from the raw data. Exploring the biological significances of these biomarkers, and discussing the toxic effect of the effective components of Anemarrhena asphodeloides rhizoma, on oxidatively damaged INS-1 pancreatic beta cell.

Magnolol and Honokiol are the primary active components that have been identified and extracted from Magnolia officinalis, and several investigations have demonstrated that they have significant pharmacological effects. Despite their therapeutic benefits for a wide range of illnesses, research on and the implementation of these compounds have been hindered by their poor water solubility and low bioavailability. Researchers are continually using chemical methods to alter their structures to make them more effective in treating and preventing diseases. Researchers are also continuously developing derivative drugs with high efficacy and few adverse effects. This article summarizes and analyzes derivatives with significant biological activities reported in recent research obtained by structural modification. The modification sites have mainly focused on the phenolic hydroxy groups, benzene rings, and diene bonds. Changes to the allyl bisphenol structure will result in unexpected benefits, including high activity, low toxicity, and good bioavailability. Furthermore, alongside earlier experimental research in our laboratory, the structure-activity relationships of magnolol and honokiol were preliminarily summarized, providing experimental evidence for improving their development and utilization.

Quercetin is a naturally existing flavonoid with numerous physiological effects, including antitumor activity. It functions as an antitumor agent by inducing apoptosis and inhibiting tumor cell development, preventing tumor cell invasion and metastasis, and reversing tumor multidrug resistance. Quercetin has limited therapeutic usefulness due to its low water solubility, poor oral absorption, and low bioavailability. New quercetin derivatives are being developed and manufactured via a variety of methods to address inadequacies and for utilization in disease prevention and therapy. The synthesis and anticancer effects of quercetin derivatives, as well as the structure-activity relationship of quercetin derivatives, were explored, and the unique dosage forms of these derivatives were summarized to serve as a reference for future quercetin research and development. Quercetin, a kind of polyhydroxy flavonoid possesses antitumor, antioxidation, and anti-inflammatory properties, is a well-known cancer therapeutic agent and autophagy mediator. However, because of its poor fat solubility and low bioavailability, quercetin has limited development and use. Herin, the synthesis and anticancer effects of quercetin derivatives, as well as the structure-activity relationship of quercetin derivatives, were explored.image

To provide the basis for further development and research of drugs, non-clinical pharmacokinetics studies were conducted on HM475, which is composed of natural active molecules honokiol and metformin through cyclization. In this paper, HM475 was studied from six aspects by gavage and intraperitoneal injection: 1) Acute toxicity of HM475 in rats, 2) Pharmacokinetic characteristics of HM475 in rats, 3) Distribution characteristics of HM475 in heart, liver, spleen, lung, and kidney, small intestine, fat and brain of rats, 4) Main metabolic pathways of HM475 in rats, 5) Excretion of HM475 in rats, 6) Determination of protein binding rate of HM475 in bovine plasma, rabbit plasma, and rat plasma. Acute toxicity of HM475 on SD rats was evaluated by maximum dose method. The metabolic analysis method of HM475 in rats was first established by UPLC-Q-TOF-MS/MS technology, and the pharmacokinetic characteristics of oral administration and intraperitoneal injection were studied. Experimental results showed that HM475 had no obvious acute toxicity. The absolute oral bioavailability of HM475 was 38.45 %, and the drug concentration in plasma was higher than that in tissues. Combined with the process characteristics of HM475 in vivo, it is inferred that HM475 has enterohepatic circulation. In this study, non-clinical pharmacokinetics were systematically studied to provide data support for the clinical pharmacokinetics and pharmacodynamics of HM475, to more accurately predict the pharmacokinetic behavior of HM475 in human body and provide scientific data for the compound to enter clinical research.

Based on the principle of molecular splicing and theory of traditional Chinese medicine pairs, a new multi-active compound (HM475) was synthesized by connecting metformin with honokiol, and its structure was characterized, which not only reduced the toxicity of raw materials, but also maintained the original activity, and had a certain significance in research and innovation. At the same time, quality control and preliminary activity evaluation were carried out, and the effect of HM475 on neuroinflammation was further explored, which provided a new idea for drug development of neurodegenerative diseases.

目的:应用网络药理技术从氨基酸代谢调控角度分析黄芪甲苷抗糖尿病肾损害网络分子机制.方法:基于前期代谢组学筛选出的与糖尿病肾病进展相关的氨基酸.使用KEGG、PubChem、TCMSP数据库,检索并提取氨基酸及黄芪甲苷的有效靶标基因,采用KEGG pathway数据库进行通路分析;应用Cytoscape绘制黄芪甲苷、氨基酸基因靶标蛋白互作网络图,并提取核心基因靶标.Cytoscape3.7.1软件内在的ClueGO应用进行疾病进展相关氨基酸基因靶标的通路、生物过程、细胞定位、分子功能进行富集分析,并绘制网络图.结果:本研究共分析了 10个与糖尿病肾病进展密切相关的氨基酸,提取基因靶标82个,参与KEGG通路62条.提取黄芪甲苷基因靶标24个.通过构建PPI网络,拟合黄芪甲苷和氨基酸基因靶标网络,提取核心靶标39个.富集分析结果表明黄芪甲苷和氨基酸核心基因靶标参与调控细胞应激、转录生长因子调控、蛋白质去乙酰化、RNA聚合酶调控、DNA结合调节、细胞周期调控、碳水化合物分解、糖酵解、细胞增殖染色质重塑等生物过程;涉及的细胞定位包括细胞周期蛋白、RNA聚合酶体复合物、常染色质、转录抑制因子、ATP酶复合物、PcG蛋白复合物、组蛋白甲基转移酶、组蛋白去乙酰化酶、SWI/SNF超家族复合物、Sin3复合物、CHD复合物;参与的分子功能有调控组蛋白去乙酰化、DNA转录因子结合、RNA聚合酶结合、转录因子活化、染色质DNA结合、泛素蛋白连接、p53连接、糖皮质受体结合等;核心基因靶标涉及的KEGG通路以调控细胞周期、癌症、自噬通路相关通路为主.结论:黄芪甲苷可能通过调节糖代谢、蛋白、DNA的转录后修饰,在细胞增殖、细胞周期、氧化应激、细胞自噬等多个分子功能层面实施保护糖尿病肾病肾脏的功能.

Diabetes is a worldwide metabolic disease with rapid growing incidence, characterized by hyperglycemia. Diabetic kidney disease (DKD), the leading cause of chronic kidney disease (CKD), has a high morbidity according to the constantly increasing diabetic patients and always develops irreversible deterioration of renal function. Though different in pathogenesis, clinical manifestations, and therapies, both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) can evolve into DKD. Since amino acids are both biomarkers and causal agents, rarely report has been made about its metabolism which lies in T1DM- and T2DM-related kidney disease. This study was designed to investigate artemether in adjusting renal amino acid metabolism in T1DM and T2DM mice. Artemether was applied as treatment in streptozotocin (STZ) induced T1DM mice and db/db T2DM mice, respectively. Artemether-treated mice showed lower FBG and HbA1c and reduced urinary albumin excretion, as well as urinary NAG. Both types of diabetic mice showed enlarged kidneys, as confirmed by increased kidney weight and the ratio of kidney weight to body weight. Artemether normalized kidney size and thus attenuated renal hypertrophy. Kidney tissue UPLC-MS analysis showed that branched-chain amino acids (BCAAs) and citrulline were upregulated in diabetic mice without treatment and downregulated after being treated with artemether. Expressions of glutamine, glutamic acid, aspartic acid, ornithine, glycine, histidine, phenylalanine and threonine were decreased in both types of diabetic mice whereas they increased after artemether treatment. The study demonstrates the initial evidence that artemether exerted renal protection in DKD by modulating amino acid metabolism.