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1.
Expert Opin Investig Drugs ; : 1-10, 2024 Jul 12.
Article in English | MEDLINE | ID: mdl-38988285

ABSTRACT

BACKGROUND: Considering the rise of new SARS-CoV-2 variants that have reduced the efficacy of COVID-19 vaccines, the development of new antiviral medications for the disease has become increasingly necessary. In this study, ASC10, a novel antiviral prodrug, was studied in a phase 1 trial in healthy Chinese participants. RESEARCH DESIGN AND METHODS: Part 1 involved 60 participants, receiving 50-800 mg ASC10 or placebo twice daily for 5.5 days. Part 2, with 12 participants, explored ASC10 dosing in the fed/fasting states. RESULTS: ASC10-A, the main pharmacologically active metabolite, rapidly appeared in plasma (Tmax: 1.00-2.00 h) and decreased (t1/2: 1.10-3.04 h) without accumulation. The Cmax and area under the plasma concentration - time curve (AUC) of ASC10-A increased dose-dependently (50-800 mg BID) over 5.5 days, with no accumulation. The Tmax was slightly delayed in the fed state; however, the Cmax and AUC were similar between the fed and fasting states. Adverse events (AEs) were comparable (ASC10/placebo, 66.7%) and mostly mild (95%). CONCLUSION: ASC10 was demonstrated to be safe and well tolerated and exhibited dose-proportional exposure and minimal food effects. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05523141.

2.
Hepatology ; 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38976867

ABSTRACT

BACKGROUND AIMS: Studies have shown that blocking the PD-1/PD-L1 pathway may lead to a potential cure for HBV infections. ASC22 (Envafolimab) is a humanized, single-domain PD-L1 antibody administered subcutaneously. This study aimed to evaluate the efficacy and safety of ASC22 in virally suppressed chronic hepatitis B (CHB) patients on nucleos(t)ide analogs (NAs). APPROACH AND RESULTS: This randomized, single-blind, phase IIb trial enrolled CHB patients in two cohorts for a 24-week treatment with ASC22 or placebo (PBO) once every 2 weeks and 24-week follow-up. In total, 60, 59, and 30 patients were treated with 1.0, 2.5 mg/kg ASC22 and PBO, respectively. The mean HBsAg changes from baseline at week 24 and 24 week follow-up periods were -0.309 (p<0.001) and -0.272 (p<0.023) log10 IU/mL in the 1.0 mg/kg ASC22 group, -0.231 (p=0.007) and -0.205 (p=0.12) log10 IU/mL in the 2.5 mg/kg ASC22 group, and-0.003 and -0.063 log10 IU/mL in the PBO group, respectively (ITT population). Three out of ten patients with baseline HBsAg levels ≤100 IU/mL in the 1.0 mg/kg group obtained on-treatment HBsAg loss. Most AEs were mild (97.9%). There were no study drug-related serious AEs in the 1.0 mg/kg ASC22 group. CONCLUSIONS: Subcutaneous administration of 1.0 mg/kg ASC22 Q2W for 24 weeks was shown to be safe and well tolerated in virally suppressed CHB patients on NAs and can induce HBsAg decline, especially in patients with HBsAg ≤100 IU/mL.

3.
Adv Biol (Weinh) ; 8(1): e2300315, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37759403

ABSTRACT

Systemic sclerosis (SSc) is an immune-mediated rheumatic disease that is characterized by fibrosis of the skin and internal organs and vasculopathy with poor prognosis. Dangui Huoxue Preparation (DHP) is a clinically effective traditional Chinese herbal formula for the treatment of SSc in the hospital. This study aims to investigate the therapeutic effects and underlying molecular mechanisms of DHP in the treatment of SSc. SSc mice models are induced by bleomycin (BLM). Tissues of DHP group, normal control group, and positive control drug Sanqi Tongshu Capsule (STC) group are collected for inflammation, fibrosis, and vasculopathy. Also, the human dermal fibroblasts (HDF) stimulated with TGF-ß1 are analyzed for in vitro study. The expression levels of MCP-1, IFN-γ, IL-1ß, IL-10, Fizz1, iNOS, and IL12p40, and the mRNA levels of Col1a1, Col1a2, Col3a1, and Col5a1 are significantly decreased in all DHP groups and STC group compare with those in the BLM group. The main drug of DHP inhibits the proliferation and migration of HDF, reduces Ctgf, Itgb3, Itgb5 expression, and also inhibits the Smad3 pathway. In conclusion, DHP can ameliorate SSc skin inflammation, fibrosis, and vasculopathy, possibly suppressing the TGF-ß1/Smad3 signaling pathway through extracellular and intracellular mechanisms.


Subject(s)
Scleroderma, Systemic , Transforming Growth Factor beta1 , Humans , Animals , Mice , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/adverse effects , Disease Models, Animal , Fibrosis , Scleroderma, Systemic/chemically induced , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/genetics , Inflammation/drug therapy , Inflammation/genetics , Bleomycin/toxicity , Bleomycin/therapeutic use
4.
Front Genet ; 14: 1202561, 2023.
Article in English | MEDLINE | ID: mdl-37501723

ABSTRACT

Background: Systemic sclerosis (scleroderma; SSc), a rare and heterogeneous connective tissue disease, remains unclear in terms of its underlying causative genes and effective therapeutic approaches. The purpose of the present study was to identify hub genes, diagnostic markers and explore potential small-molecule drugs of SSc. Methods: The cohorts of data used in this study were downloaded from the Gene Expression Complex (GEO) database. Integrated bioinformatic tools were utilized for exploration, including Weighted Gene Co-Expression Network Analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) regression, gene set enrichment analysis (GSEA), Connectivity Map (CMap) analysis, molecular docking, and pharmacokinetic/toxicity properties exploration. Results: Seven hub genes (THY1, SULF1, PRSS23, COL5A2, NNMT, SLCO2B1, and TIMP1) were obtained in the merged gene expression profiles of GSE45485 and GSE76885. GSEA results have shown that they are associated with autoimmune diseases, microorganism infections, inflammatory related pathways, immune responses, and fibrosis process. Among them, THY1 and SULF1 were identified as diagnostic markers and validated in skin samples from GSE32413, GSE95065, GSE58095 and GSE125362. Finally, ten small-molecule drugs with potential therapeutic effects were identified, mainly including phosphodiesterase (PDE) inhibitors (BRL-50481, dipyridamole), TGF-ß receptor inhibitor (SB-525334), and so on. Conclusion: This study provides new sights into a deeper understanding the molecular mechanisms in the pathogenesis of SSc. More importantly, the results may offer promising clues for further experimental studies and novel treatment strategies.

5.
Arthritis Res Ther ; 24(1): 148, 2022 06 21.
Article in English | MEDLINE | ID: mdl-35729674

ABSTRACT

BACKGROUND: Calpains are a family of calcium-dependent thiol proteases that participate in a wide variety of biological activities. In our recent study, calpain is increased in the sera of scleroderma or systemic sclerosis (SSc). However, the role of calpain in interstitial lung disease (ILD) has not been reported. ILD is a severe complication of SSc, which is the leading cause of death in SSc. The pathogenesis of SSc-related ILD remains incompletely understood. This study investigated the role of myeloid cell calpain in SSc-related ILD. METHODS: A novel line of mice with myeloid cell-specific deletion of Capns1 (Capns1-ko) was created. SSc-related ILD was induced in Capns1-ko mice and their wild-type littermates by injection 0.l mL of bleomycin (0.4 mg/mL) for 4 weeks. In a separate experiment, a pharmacological inhibitor of calpain PD150606 (Biomol, USA, 3 mg/kg/day, i.p.) daily for 30 days was given to mice after bleomycin injection on daily basis. At the end of the experiment, the animals were killed, skin and lung tissues were collected for the following analysis. Inflammation, fibrosis and calpain activity and cytokines were assessed by histological examinations and ELISA, and immunohistochemical analyses, western blot analysis and Flow cytometry analysis. RESULTS: Calpain activities increased in SSc-mouse lungs. Both deletion of Capns1 and administration of PD150606 attenuated dermal sclerosis as evidenced by a reduction of skin thickness and reduced interstitial fibrosis and inflammation in bleomycin model of SSc mice. These effects of reduced calpain expression or activity were associated with prevention of macrophage polarization toward M1 phenotype and consequent reduced production of pro-inflammatory cytokines including TNF-α, IL-12 and IL-23 in lung tissues of Capns1-ko mice with bleomycin model of SSc. Furthermore, inhibition of calpain correlated with an increase in the protein levels of PI3K and phosphorylated AKT1 in lung tissues of the bleomycin model of SSc mice. CONCLUSIONS: This study for the first time demonstrates that the role of myeloid cell calpain may be promotion of macrophage M1 polarization and pro-inflammatory responses related PI3K/AKT1 signaling. Thus, myeloid cell calpain may be a potential therapeutic target for bleomycin model of SSc-related ILD.


Subject(s)
Lung Diseases, Interstitial , Scleroderma, Systemic , Animals , Bleomycin/toxicity , Calpain , Cytokines/metabolism , Disease Models, Animal , Fibrosis , Inflammation/pathology , Lung/pathology , Lung Diseases, Interstitial/etiology , Macrophages/metabolism , Mice , Myeloid Cells/metabolism , Phenotype , Phosphatidylinositol 3-Kinases/metabolism , Scleroderma, Systemic/pathology
6.
Front Genet ; 12: 633059, 2021.
Article in English | MEDLINE | ID: mdl-34290731

ABSTRACT

Systemic sclerosis (SSc) is an immune-mediated connective tissue disease characterized by fibrosis of multi-organs, and SSc-related interstitial lung disease (SSc-ILD) is a leading cause of morbidity and mortality. To explore molecular biological mechanisms of SSc-ILD, we constructed a competing endogenous RNA (ceRNA) network for prediction. Expression profiling data were obtained from the Gene Expression Omnibus (GEO) database, and differential expressed mRNAs and miRNAs analysis was further conducted between normal lung tissue and SSc lung tissue. Also, the interactions of miRNA-lncRNA, miRNA-mRNA, and lncRNA-mRNA were predicted by online databases including starBase, LncBase, miRTarBase, and LncACTdb. The ceRNA network containing 11 lncRNAs, 7 miRNAs, and 20 mRNAs were constructed. Based on hub genes and miRNAs identified by weighted correlation network analysis (WGCNA) method, three core sub-networks-SNHG16, LIN01128, RP11-834C11.4(LINC02381)/hsa-let-7f-5p/IL6, LINC01128/has-miR-21-5p/PTX3, and LINC00665/hsa-miR-155-5p/PLS1-were obtained. Combined with previous studies and enrichment analyses, the lncRNA-mediated network affected LPS-induced inflammatory and immune processes, fibrosis development, and tumor microenvironment variations. The ceRNA network, especially three core sub-networks, may be served as early biomarkers and potential targets for SSc, which also provides further insights into the occurrence, progression, and accurate treatment of SSc at the molecular level.

7.
Clin Exp Rheumatol ; 39 Suppl 131(4): 66-76, 2021.
Article in English | MEDLINE | ID: mdl-33253093

ABSTRACT

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease clinically characterised by skin and internal organs fibrosis with high mortality. However, the pathogenesis of SSc is still controversial and the effect of the current treatment is far from satisfactory. We aimed to find out novel candidate genes related to the pathological process in SSc. METHODS: In this study, the weighted correlation network analysis (WGCNA) was conducted to identify the key module and hub genes most related to SSc in GSE58095, a microarray dataset from the Gene Expression Omnibus (GEO) database. Also, the key module was analysed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then we validated hub genes in other datasets (GSE32413, GSE125362, GSE45485, GSE76885, GSE95065). The serum of 37 patients with SSc and 25 healthy control subjects (HCs) were recruited and detected by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Five interested genes (IGFBP7, LRRC32, STMN2, C1QTNF5, CPXM1) were up-regulated in SSc microarray datasets from the GEO. And the level of serum IGFBP7, which encodes a secreted protein, was upregulated in SSc patients-also in dcSSc patients and SSc with ILD patients. CONCLUSIONS: Among the five interested genes, the IGFBP7 was a novel candidate gene for SSc and may be served as potential target and early biomarker for accurate treatment, which also provides further insights into the pathogenesis of SSc at the molecular level.


Subject(s)
Insulin-Like Growth Factor Binding Proteins , Scleroderma, Systemic , Biomarkers , Collagen , Glycoproteins , Humans , Insulin-Like Growth Factor Binding Proteins/genetics , Membrane Proteins , Scleroderma, Systemic/diagnosis , Scleroderma, Systemic/genetics , Stathmin , Transcription Factors
8.
Front Genet ; 11: 816, 2020.
Article in English | MEDLINE | ID: mdl-32793290

ABSTRACT

Systemic sclerosis-associated with pulmonary arterial hypertension (SSc-PAH) is still a major cause of SSc related deaths. Early diagnosis and prompt treatment are crucial to reduce the mortality of patients with SSc-PAH. To screen the candidate biomarkers and potential therapeutic targets for SSc-PAH, we analyzed the data set (GSE33463 and GSE19617) for confirming key genes in peripheral blood mononuclear cells from SSc-PAH patients. A total of 105 SSc patients from gene expression omnibus (GEO) were included as discovery cohort (n = 69) and duplication cohort (n = 36) for screening hub genes by weighted gene co-expression network analysis (WGCNA). Furthermore, an independent validation cohort (n = 40), including healthy controls, SSc and SSc-PAH patients, was used for further validation by quantitative real-time polymerase chain reaction. The results showed that four key genes, including IFIT2, IFIT3, RSAD2, and PARP14, may serve as potential biomarkers in SSc-PAH. Also, they could be independent risk factors for SSc-PAH. In conclusion, the four key genes can be expected to become the potential therapeutic targets and early biomarkers for accurate therapy and diagnosis of SSc-PAH in the future, which also provides promising insights into the pathogenesis of SSc-PAH at the molecular level.

9.
Arthritis Res Ther ; 22(1): 110, 2020 05 11.
Article in English | MEDLINE | ID: mdl-32393322

ABSTRACT

BACKGROUND: Systemic sclerosis (SSc) or scleroderma is an intractable autoimmune disorder that affects multiple organs. The objectives were to investigate clinical correlations of serum calpain activity and high mobility group box 1 (HMGB1) levels with immunological and clinical traits. METHODS: A total of 31 patients with SSc, 20 age- and gender-matched healthy control subjects (HC), and 10 patients with other connective tissue diseases (CTD) were recruited in the study. We measured serum calpain activity and HMGB1 levels and analyzed the datasets (GSE40839, GSE48149, GSE76808, GSE81292, GSE33463, and GSE58095) from Gene Expression Omnibus (GEO) database to explore the potential mechanism by which calpain exerts its function through bioinformatics methods. RESULTS: Serum calpain activity was significantly increased in patients with SSc compared with those in HC and in patients with CTD and was correlated with serum HMGB1 levels, modified Rodnan skin score, erythrocyte sedimentation rate, mean platelet volume, and plateletcrit. Notably, serum calpain activity and HMGB1 levels in SSc patients with interstitial lung disease (ILD) were significantly higher than those in SSc patients without ILD. Serum calpain activity and HMGB1 levels could be the independent risk factors for SSc-ILD and novel biomarkers in patients with SSc. CONCLUSION: This is the first study that reports increased serum calpain activity and the correlation between calpain and HMGB1 in patients with SSc or SSc-ILD. The serum calpain activity and HMGB1 levels may serve as measures of ILD in patients with SSc. Also, calpain and HMGB1 could be potential therapeutic targets for patients with SSc or SSc-ILD in the future.


Subject(s)
Calpain/blood , HMGB1 Protein/blood , Lung Diseases, Interstitial , Scleroderma, Systemic , Adult , Aged , Biomarkers , Female , Humans , Male , Middle Aged
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