Network Pharmacology and Molecular Docking Analysis to Explore the Mechanism of Huaiqihuang-Mediated Alleviation of Henoch–Schönlein Purpura Nephritis

Objective Henoch–Schönlein purpura nephritis (HSPN) is considered a major cause of chronic renal failure and is the most common secondary glomerular disease in children. Huaiqihuang (HQH), a traditional Chinese herbal formula, exhibits therapeutic effects against HSPN in clinical practice. However, the potential molecular targets and mechanisms underlying HSPN treatment remain unclear. Methods By constructing a protein-protein interaction (PPI) network, core targets related to HQH and HSPN were identified. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways were analyzed to identify the main pathways related to HSPN based on the core targets. To screen the main active ingredients of HQH against HSPN, an ingredient-target-pathway network was constructed using the top 10 main pathways associated with HSPN. Then, molecular docking was performed to explore the interactions and binding patterns between molecules and proteins. Results Clinical data showed that HQH combined with conventional medicine significantly reduced 24-hour urine protein excretion, urine microalbumin levels, and erythrocyte counts in the urine sediment of HSPN patients. By constructing PPI models, 15 potential core targets were identified. The top 10 main pathways showed higher enrichment ratios, including the cytokine–cytokine receptor interaction and signaling pathways related to NOD-like receptor, IL-17, etc. Through the ingredient-target-pathway network and molecular docking, we revealed that five active ingredients of HQH had good affinities with three core targets, AKT1, MMP9, and SERPINE1, which may be vital in treating HSPN. Conclusions The study preliminarily explored the active ingredients, targets, and pathways involved in HQH therapy for HSPN. The mechanism of HQH therapy may be attributed to the modulation of inflammatory response, immune response, and oxidative stress. Combined with clinical data, our results indicate that HQH is highly effective in treating HSPN.

[1]  Jian-ping Liu,et al.  Chinese patent herbal medicine Huaiqihuang for Henoch-Schonlein purpura nephritis in children: a systematic review of randomized controlled trials , 2021, BMC Complementary Medicine and Therapies.

[2]  Yan Jin,et al.  The Efficacy of Tripterygium Glycosides Combined with LMWH in Treatment of HSPN in Children , 2021, Evidence-based complementary and alternative medicine : eCAM.

[3]  J. Floege,et al.  Key metalloproteinase-mediated pathways in the kidney , 2021, Nature Reviews Nephrology.

[4]  Jingmeng Sun,et al.  Huaiqihuang (HQH) granule alleviates cyclophosphamide-induced nephrotoxicity via suppressing the MAPK/NF-κB pathway and NLRP3 inflammasome activation , 2021, Pharmaceutical biology.

[5]  Min Zhao,et al.  Investigation of the effect of Huaiqihuang granules via adjuvant treatment in children with relapsed systemic lupus erythematosus. , 2021, American journal of translational research.

[6]  Wei Liu,et al.  Clinical effect of combined western medicine and traditional Chinese medicine on children with Henoch-Schönlein purpura nephritis. , 2021, American journal of translational research.

[7]  H. Y. Lin,et al.  Tubular mitochondrial AKT1 is activated during ischemia reperfusion injury and has a critical role in predisposition to chronic kidney disease. , 2020, Kidney international.

[8]  Wei Huang,et al.  Targeting STAT3 in Cancer Immunotherapy , 2020, Molecular cancer.

[9]  Xu-tao Lin,et al.  Effects of Huaier Extract on Ameliorating Colitis-Associated Colorectal Tumorigenesis in Mice , 2020, OncoTargets and therapy.

[10]  Mingyi Zhao,et al.  The Effect of Chinese Traditional Medicine Huaiqihuang (HQH) on the Protection of Nephropathy , 2020, Oxidative medicine and cellular longevity.

[11]  Xiangmei Chen,et al.  Identification and Validation of Potential Biomarkers and Their Functions in Acute Kidney Injury , 2020, Frontiers in Genetics.

[12]  Y. Wada,et al.  A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy , 2020, PloS one.

[13]  Qifeng Yang,et al.  Huaier Suppresses Breast Cancer Progression via linc00339/miR-4656/CSNK2B Signaling Pathway , 2019, Front. Oncol..

[14]  S. Ozen,et al.  Different histological classifications for Henoch-Schönlein purpura nephritis: which one should be used? , 2019, Pediatric Rheumatology.

[15]  Zhong-dong Hu,et al.  An immune-stimulating proteoglycan from the medicinal mushroom Huaier up-regulates NF-κB and MAPK signaling via Toll-like receptor 4 , 2019, The Journal of Biological Chemistry.

[16]  P. Zhou,et al.  Effects of Huaiqihuang Granules Adjuvant Therapy in Children with Primary Nephrotic Syndrome , 2019, Open life sciences.

[17]  Q. Ren,et al.  The change of Th17/Treg cells and IL-10/IL-17 in Chinese children with Henoch–Schonlein purpura , 2019, Medicine.

[18]  Quanyi Wang,et al.  Correlation between serum inflammatory factors TNF-α, IL-8, IL-10 and Henoch-Schonlein purpura with renal function impairment , 2018, Experimental and therapeutic medicine.

[19]  Huijuan Li,et al.  Huai Qi Huang corrects the balance of Th1/Th2 and Treg/Th17 in an ovalbumin-induced asthma mouse model , 2017, Bioscience reports.

[20]  A. Leung,et al.  Proteinuria in Children: Evaluation and Differential Diagnosis. , 2017, American family physician.

[21]  G. Hempel,et al.  The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy , 2016, Cancer Chemotherapy and Pharmacology.

[22]  Jianhua Mao,et al.  Huaiqihuang may protect from proteinuria by resisting MPC5 podocyte damage via targeting p-ERK/CHOP pathway. , 2016, Bosnian journal of basic medical sciences.

[23]  R. Coppo,et al.  Henoch–Schönlein purpura nephritis in children , 2014, Nature Reviews Nephrology.

[24]  Y. Huang,et al.  [Function of CD4(+) CD25(+) regulatory T cells in Henoch-Schonlein purpura nephritis in children]. , 2014, Zhonghua er ke za zhi = Chinese journal of pediatrics.

[25]  Wei Zhou,et al.  TCMSP: a database of systems pharmacology for drug discovery from herbal medicines , 2014, Journal of Cheminformatics.

[26]  Lei Li,et al.  Huai Qi Huang ameliorates proteinuria and hematuria in mild IgA nephropathy patients: a prospective randomized controlled study. , 2013, Journal of the Formosan Medical Association = Taiwan yi zhi.

[27]  Li Ru,et al.  [Clinical significance of serum levels of IGF-1 and IGFBP-3 in children with Henoch-Schonlein purpura or Henoch-Schonlein purpura nephritis]. , 2013, Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics.

[28]  Jing Zhang,et al.  A polysaccharide from the fungi of Huaier exhibits anti-tumor potential and immunomodulatory effects. , 2013, Carbohydrate polymers.

[29]  Tian-biao Zhou,et al.  Cut‐off values for serum matrix metalloproteinase‐9: Is there a threshold to predict renal involvement for Henoch–Schonlein purpura in children? , 2011, Nephrology.

[30]  [Evidence-based guidelines on diagnosis and treatment of childhood common renal diseases (II): evidence-based guideline on diagnosis and treatment of Henoch-Schonlein purpura nephritis]. , 2009, Zhonghua er ke za zhi = Chinese journal of pediatrics.

[31]  A. Hopkins Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[32]  A. Fogo,et al.  Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action. , 2006, Journal of the American Society of Nephrology : JASN.

[33]  J. Flynn,et al.  Treatment of Henoch-Schönlein Purpura Glomerulonephritis in Children with High-Dose Corticosteroids plus Oral Cyclophosphamide , 2001, American Journal of Nephrology.