Modeling and biological evaluation of pegmolesatide, a novel and potent erythropoiesis-stimulating agent.

Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO.

Experimental observation of the sequence of tibial plateau chondrocyte and matrix degeneration in spontaneous osteoarthritis in Guinea pigs.

BACKGROUND: To observe the sequence of chondrocyte degeneration and matrix degradation in the superficial surface cartilage of the tibial plateau in guinea pigs with spontaneous knee osteoarthritis (OA). METHODS: Sixty guinea pigs were euthanized at the ages of 8 months (n = 20),10 months (n = 20) and 12 months (n = 20) respectively. The degree of degeneration of the tibial plateau cartilage was evaluated by Osteoarthritis Research Society International (OARSI) score. The levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the chondrocytes were detected by immunohistochemistry (IHC). The serum concentration of CTX-II was measured and compared. Western blot analysis was used to detect the levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the cartilage tissue. RESULTS: The OARSI scores both in 8-month-old group and 10-month-old group were lower than that in the 12-month-old group. The levels of Aggrecan in articular chondrocyte were higher both in 8-month-old group and 10-month-old group than that in 12-month-old group. The level of Collagen X increased with the age of guinea pigs. And the levels of MMP-13 and caspase-3 both in 10-month-old group and 12-month-old group were higher than those in 8-month-old group. The concentration of CTX-II in serum increased significantly in 12 months old group. CONCLUSION: The superficial chondrocytes of the tibial plateau first appeared to be hypertrophic and then apoptotic, and the matrix was further degraded when spontaneous knee osteoarthritis occurred in guinea pigs. Changes in the physiological state of chondrocytes are the initiating factors in the pathogenesis of knee OA.

Prospective observation: Clinical utility of plasma Epstein-Barr virus DNA load in EBV-associated gastric carcinoma patients.

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.

Effectiveness of Lifestyle and Drug Intervention on Hypertensive Patients: a Randomized Community Intervention Trial in Rural China.

BACKGROUND: Strict medication guidance and lifestyle interventions to manage blood pressure (BP) in hypertensive patients are typically difficult to follow. OBJECTIVE: To evaluate the 1-year effectiveness of lifestyle and drug intervention in the management of rural hypertensive patients. DESIGN: Randomized community intervention trial. PARTICIPANTS: The control group comprised 967 patients who received standard antihypertensive drug intervention therapy from two communities, whereas the intervention group comprised 1945 patients who received antihypertensive drug and lifestyle intervention therapies from four communities in rural China. MAIN MEASURES: Data on lifestyle behaviors and BP measurements at baseline and 1-year follow-up were collected. A difference-in-difference logistic regression model was used to assess the effect of the intervention. KEY RESULTS: BP control after the 1-year intervention was better than that at baseline in both groups. The within-group change in BP control of 59.3% in the intervention group was much higher than the 25.2% change in the control group (P < 0.001). Along with the duration of the follow-up period, systolic and diastolic BP decreased rapidly in the early stages and then gradually after 6 months in the intervention group (P < 0.001). In the intervention group, drug therapy adherence was increased by 39.5% (from 48.1% at 1 month to 87.6% at 1 year) (P < 0.001), more in women (45.6%) than in men (31.2%; P < 0.001). The net effect of the lifestyle intervention improved the rate of BP control by 56.1% (70.8% for men and 44.7% for women). For all physiological and biochemical factors, such as body mass index, waist circumference, lipid metabolism, and glucose control, improvements were more significant in the behavioral intervention group than those in the control group (all P < 0.001). CONCLUSION: The addition of lifestyle intervention by physicians or nurses helps control BP effectively and lowers BP better than usual care with antihypertensive drug therapy alone.

Adventitial Cell Atlas of wt (Wild Type) and ApoE (Apolipoprotein E)-Deficient Mice Defined by Single-Cell RNA Sequencing.

Objective- Vascular adventitia encompasses progenitors and is getting recognized as the major site of inflammation in early stage of atherosclerosis. However, the cellular atlas of the heterogeneous adventitial cells, the intercellular communication, the cellular response of adventitia to hyperlipidemia, and its contribution to atherosclerosis have been elusive. Approach and Results- Single-cell RNA sequencing was applied to wt (wild type) and ApoE (apolipoprotein E)-deficient aortic adventitia from 12-week-old C57BL/6J mice fed on normal laboratory diet with early stage of atherosclerosis. Unbiased clustering analysis revealed that the landscape of adventitial cells encompassed adventitial mesenchyme cells, immune cells (macrophages, T cells, and B cells), and some types of rare cells, for example, neuron, lymphatic endothelial cells, and innate lymphoid cells. Seurat clustering analysis singled out 6 nonimmune clusters with distinct transcriptomic profiles, in which there predominantly were stem/progenitor cell-like and proinflammatory population (Mesen II). In ApoE-deficient adventitia, resident macrophages were activated and related to increased myeloid cell infiltration in the adventitia. Cell communication analysis further elucidated enhanced interaction between a mesenchyme cluster and inflammatory macrophages in ApoE-deficient adventitia. In vitro transwell assay confirmed the proinflammatory role of SCA1+ (stem cell antigen 1 positive) Mesen II population with increased CCL2 (chemokine [C-C motif] ligand 2) secretion and thus increased capacity to attract immune cells in ApoE-deficient adventitia. Conclusions- Cell atlas defined by single-cell RNA sequencing depicted the heterogeneous cellular landscape of the adventitia and uncovered several types of cell populations. Furthermore, resident cell interaction with immune cells appears crucial at the early stage of atherosclerosis.

Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease with high heritability. Although several predisposing genes have been linked to IPAH, the genetic aetiology remains unknown for a large number of IPAH cases. METHODS: We conducted an exome-wide gene-based burden analysis on two independent case-control studies, including a total of 331 IPAH cases and 10 508 controls. Functional assessments were conducted to analyse the effects of genetic mutations on protein biosynthesis and function. RESULTS: The gene encoding human bone morphogenetic protein 9 (BMP9) was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (OR 18.8; p=1.9×10-11). This association was authenticated in the independent replication cohort (p=1.0×10-5). Collectively, the rare coding mutations in BMP9 occurred in 6.7% of cases, ranking this gene second to BMPR2, comprising a combined significance of 2.7×10-19 (OR 21.2). Intriguingly, the patients with BMP9 mutations had lower plasma levels of BMP9 than those without. Functional studies showed that the BMP9 mutations led to reduced BMP9 secretion and impaired anti-apoptosis ability in pulmonary arterial endothelial cells. CONCLUSION: We identify BMP9 as an IPAH culprit gene.

The removal of Rhodamine B by H2O2 or ClO2 combined with hydrodynamic cavitation.

Rhodamine B (RhB), widely used as an industrial dye, is a toxic organic that is hazardous to human health and can cause water pollution. In this study, the removal rate of RhB was investigated by the following methods: hydrodynamic cavitation (HC) operated individually, and HC combined with oxidants H2O2 or ClO2. The effect of different operating parameters including pressure (2-6 bar) and initial pH (2-8) on the extent of degradation was investigated using an orifice plate as the cavitation device to achieve maximum removal of RhB. Under the parameters of HC, the effect of different loadings was investigated: H2O2 (n(RhB):n(H2O2) was varied from 1:17.60 to 1:211.28) and ClO2 (n(RhB):n(ClO2) was varied from 1:8.87 to 1:177.53). A combination of cavitation and H2O2 or ClO2 resulted in degradations of 80.6% and 95.3%. The results indicated that the combination of HC and oxidants was better than the individual HC process for the degradation of RhB. When combining HC with H2O2 or ClO2, the synergistic coefficients of 62.54 and 74.79 were obtained. The combination of HC and ClO2 was proven to be more effective for the removal of RhB compared to HC alone and the hybrid process of HC and H2O2.

Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare systemic disorder associated with considerable metabolic dysfunction. Although enormous metabolomic studies on PAH have been emerging, research remains lacking on metabolic reprogramming in experimental PAH models. We aim to evaluate the metabolic changes in PAH and provide new insight into endogenous metabolic disorders of PAH. METHOD: A single subcutaneous injection of monocrotaline (MCT) (60 mg kg- 1) was used for rats to establish PAH model. Hemodynamics and right ventricular hypertrophy were adopted to evaluate the successful establishment of PAH model. Plasma samples were assessed through targeted metabolomic profiling platform to quantify 126 endogenous metabolites. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to discriminate between MCT-treated model and control groups. Metabolite Set Enrichment Analysis was adapted to exploit the most disturbed metabolic pathways. RESULTS: Endogenous metabolites of MCT treated PAH model and control group were well profiled using this platform. A total of 13 plasma metabolites were significantly altered between the two groups. Metabolite Set Enrichment Analysis highlighted that a disruption in the urea cycle pathway may contribute to PAH onset. Moreover, five novel potential biomarkers in the urea cycle, adenosine monophosphate, urea, 4-hydroxy-proline, ornithine, N-acetylornithine, and two candidate biomarkers, namely, O-acetylcarnitine and betaine, were found to be highly correlated with PAH. CONCLUSION: The present study suggests a new role of urea cycle disruption in the pathogenesis of PAH. We also found five urea cycle related biomarkers and another two candidate biomarkers to facilitate early diagnosis of PAH in metabolomic profile.

Quadratus femoris muscle pedicle bone flap transplantation in the treatment of femoral neck fracture for Chinese young and middle-aged patients: A systematic review and meta-analysis.

PURPOSE: To compare the efficacy of quadratus femoris muscle pedicle bone flap transplantation combined with hollow compression screw fixation versus AO hollow compression screw fixation in the treatment of femoral neck fracture for Chinese young and middle-aged patients. METHODS: Case-controlled studies (CCTs) were used to compare the two operative methods in the treatment of femoral neck fractures. Data were retrieved from the Cochrane Library, Pubmed Database, CNKI, Chinese Biomedical Database. Wanfang Data published during the period of January 2005 to December 2014. Methodological quality of the trials was critically assessed, and relevant data were extracted. Statistical Software Revman 5.0 was used for data-analysis. RESULTS: Eight articles were included in the meta-analysis. The results showed that there was statistical significance in the rate of fracture healing [OR = 5.43, 95% CI (2.89, 10.20), p < 0.05], the rate of good function of hip joint [OR = 5.12, 95% CI (3.21, 8.17), p < 0.05], the rate of femoral head necrosis [OR = 4.21, 95% CI (2.02, 8.76), p < 0.05], the time of fracture healing [WMD = -46.85, 95% CI (-65.13, -28.56), p < 0.05] between the two groups. CONCLUSIONS: For the treatment of femoral neck fractures, the transplantation of quadratus femoris muscle pedicle bone flap combined with hollow compression screw; fixation is superior to the AO hollow compression screw fixation in terms of the rate; of fracture healing, the rate of good function of hip joint, the rate of femoral head; necrosis and the time of fracture healing.

Ilioinguinal approach versus Stoppa approach for open reduction and internal fixation in the treatment of displaced acetabular fractures: A systematic review and meta-analysis.

PURPOSE: To compare the efficacy and safety of open reduction and internal fixation through ilioinguinal approach and Stoppa approach for the treatment of displaced acetabular fractures. METHODS: Case-controlled trials (CCTs) published from January 2010 to August 2015 that compared the ilioinguinal approach and Stoppa approach in the management of displaced acetabular fractures were retrieved from the databases of Cochrane Library, Pubmed, CNKI, and so on. Methodological quality of the trials was critically assessed. Statistical software RevMan 5.0 was used for data analysis. RESULTS: Eight articles were included in the meta-analysis. Through comparing the efficacy and safety of ilioinguinal approach and Stoppa approach in the treatment of displaced acetabular fracture, statistical significance was found in the average operation time [WMD = 68.29, 95% CI (10.52, 126.05), p < 0.05] and the median intraoperative blood loss [WMD = 142.26, 95% CI (9.30, 275.23), p < 0.05]. However, there existed no statistical significance in the fracture end reset satisfaction rate [RR = 0.63, 95% CI (0.17, 2.37), p > 0.05], the early complications rate [RR = 0.89, 95% CI (0.33, 2.40), p > 0.05], the late complications rate [RR = 0.91, 95% CI (0.27, 3.01), p > 0.05], and Harris hip score good function rate [RR = 0.52, 95% CI (0.25, 1.10), p > 0.05]. CONCLUSION: Though both techniques can obtain satisfactory clinical functions in the treatment of displaced acetabular fractures, Stoppa approach is superior to the ilioinguinal approach in terms of operation time and intraoperative blood loss.

Profiling nitric oxide metabolites in patients with idiopathic pulmonary arterial hypertension.

Intact nitric oxide (NO) signalling is critical to maintaining appropriate pulmonary vascular tone. NO bioavailability is reduced in patients with pulmonary arterial hypertension. This study aimed to examine the impact of NO plasma metabolites (NOx) relative to haemodynamic dysfunction and mortality in patients with idiopathic pulmonary arterial hypertension (IPAH).A total of 104 consecutive adult IPAH patients who had undergone genetic counselling when first diagnosed were enrolled in this prospective study.The median concentration of NOx (µmol·L-1) was significantly lower in IPAH patients compared with healthy subjects, and was decreased further in 19 carriers of the bone morphogenetic protein-receptor type-2 (BMPR2) mutation compared to non-carriers. Reduced concentrations of NOx were correlated with mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR) and cardiac output. Compared with higher baseline NOx concentrations, patients with a NOx concentration of ≤10 µmol·L-1 had a markedly worse survival. After adjustment for clinical features, a BMPR2 mutation and haemodynamics, a lower NOx level remained an increased risk of mortality.Patients with IPAH had lower levels of plasma NOx, which correlated inversely with mPAP, PVR and survival. Plasma NOx may be an important biomarker and prognostic indicator, suggesting that reduced NO synthesis contributes to the pathogenesis of IPAH.

Percutaneous poking reduction and fixation versus open reduction and fixation in the treatment of displaced calcaneal fractures for Chinese patients: A systematic review and meta-analysis.

PURPOSE: To compare the efficacy of percutaneous poking reduction and fixationwith open reduction and fixation in the treatment of displaced calcaneal fractures. METHODS: Reports of studies using case-controlled trials (CCT) to compare the percutaneous poking reduction and fixation with the open reduction and fixation in the management of calcaneal fractures were retrieved from the Cochrane Library, PubMed Database, CNKI, Chinese Biomedical Database, Wanfang Data (from January of 2005 to August of 2015). Methodological quality of the trials was critically assessed, and relevant data were extracted. Statistical software Revman 5.0 was used for data-analysis. RESULTS: Fifteen articles were included in the meta-analysis. Comparison of the efficacy of percutaneous poking reduction and fixation with open reduction and fixation in the treatment of calcaneal fractures revealed statistical significance in the incidence of complications after operation [RR = 0.32, 95% CI (0.20, 0.5), p < 0.05]. However, there were neither statistical significance in the degrees of recovery for calcaneal Bohler angle [WMD = -1.65, 95% CI (-3.43, 0.14), p > 0.05] and calcaneal Gissane angle [WMD = -3.21, 95% CI (-6.75, 0.33), p > 0.05], nor statistical significance in the rate of good foot function after operation [RR= 0.95, 95% CI (0.90, 1.00), p > 0.05]. CONCLUSION: For the treatment of calcaneal fractures, percutaneous poking reduction and fixation is su- perior to open reduction and fixation in terms of the incidence of postoperative complications. But both techniques can obtain satisfactory clinical function.

Up-regulation of hexokinase1 in the right ventricle of monocrotaline induced pulmonary hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with a glycolytic shift during heart metabolism. An increase in glycolytic metabolism can be detected in the right ventricle during PAH. Expression levels of glycolysis genes in the right ventricle during glycolysis that occur in monocrotaline (MCT)-induced pulmonary hypertension (PH) remain unknown. METHODS: PH was induced by a single subcutaneous injection of MCT (50 mg/kg) into rats, eventually causing right heart failure. Concurrently, a control group was injected with normal saline. The MCT-PH rats were randomly divided into three groups according to MCT treatment: MCT-2 week, 3 week, and 4 week groups (MCT-2w, 3w, 4w). At the end of the study, hemodynamics and right ventricular hypertrophy were compared among experimental groups. Expression of key glycolytic candidate genes was screened in the right ventricle. RESULTS: We observed an increase in mean pulmonary arterial pressure, right ventricular systolic pressure and right ventricular hypertrophy index three weeks following MCT injection. Alterations in the morphology and structure of right ventricular myocardial cells, as well as the pulmonary vasculature were observed. Expression of hexokinase 1 (HK1) mRNA began to increase in the right ventricle of the MCT-3w group and MCT-4w group, while the expression of lactate dehydrogenase A (LDHA) was elevated in the right ventricle of the MCT-4w group. Hexokinase 2(HK2), pyruvate dehydrogenase complex α1 (PDHα1), and LDHA mRNA expression showed no changes in the right ventricle. HK1 mRNA expression was further confirmed by HK1 protein expression and immunohistochemical analyses. All findings underlie the glycolytic phenotype in the right ventricle. CONCLUSIONS: There was an increase in the protein and mRNA expression of hexokinase-1 (HK1) three and four weeks after the injection of monocrotaline in the right ventricle, intervention of HK1 may be amenable to therapeutic intervention.

[Effect of a novel selective S1P1 agonist, Syl948, on mouse skin transplantation].

Syl948 is a synthesized selective S1P1 agonist with novel structure. HTRF-IP1 test indicated that Syl948-P, the active form of Syl948 in vitro, has strong activity against S1P1 (EC50: 83 +/- 16 nmol x L(-1)), but its effect on S1P3 was very weak (EC50: 1 026 +/- 90 nmol x L(-1)). In SD rats, oral administration of Syl948 10 mg x kg(-1) significantly decreased the peripheral blood lymphocytes (PBL), with the maximal PBL inhibition rate of 63%, which was as similar as equal dose of fingolimod (FTY720). Oral administration of Syl948 10 mg x kg(-1) had no effect on heart rate of SD rats, which was better than FTY720. Daily oral administration with Syl948 (2 or 4 mg x kg(-1)) significantly prolonged the survival time of the allografts of skin slice on mice. In summary, the above results demonstrated that Syl948 has great selectivity in vitro and good activity in vivo, which indicated its potential use as an anti-rejection drug in skin transplantation.

[Design, synthesis and biological evaluation of fingolimod analogues containing diphenyl ether moiety].

A novel series of fingolimod analogues containing diphenyl ether moiety were designed and synthesized based on the modification of immunosuppressive agent fingolimod used in the treatment of multiple sclerosis. Compounds were evaluated in vivo for lymphopenic activity and heart rate affection. Most compounds showed moderate lymphopenic activity. It is worth noting that compounds 6c, 6d and 14c-14e showed considerable immunosuppressive activities comparable to fingolimod. And compound 14e had no effect on heart rate.

Untargeted metabolomics reveal the metabolic profile of normal pulmonary circulation.

BACKGROUND: As an important place of material exchange, the homeostasis of the pulmonary circulation environment and function lays an essential foundation for the normal execution of various physiological functions of the body. Small metabolic molecules in the circulation can reflect the corresponding state of the pulmonary circulation. METHODS: We enrolled patients with Patent Foramen Ovale and obtained blood from the pulmonary arteries and veins through heart catheterization. UPLC-MS based untargeted metabolomics was used to compare the changes and metabolic differences of plasma between pulmonary vein and pulmonary artery. RESULTS: The plasma metabolomics revealed that pulmonary artery had a different metabolomic profile compared to venous. 1060 metabolites were identified, and 61 metabolites were differential metabolites. Purine, Amino acids, Nicotinamide, Tetradecanedioic acid and Bile acid were the most markedly. CONCLUSION: The differential metabolites are mostly related to immune inflammation and damage repaired. It is suggested that the pulmonary circulation is always in a steady state of injury and repair while pathological changes may be triggered when the homeostasis is broken. These changes play an important role in revealing the development process and etiology of lung homeostasis and related diseases. Relevant metabolites can be used as potential targets for further study of pulmonary circulation homeostasis.

[Research progress of the selective sphingosine-1-phosphate receptor 1 agonists].

Sphingosine-1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions in both intracellular and extracellular compartments. It interacts with five G protein-coupled receptors subtypes (S1PR(1-5)) to generate multiple downstream signaling. Activation of S1PR1 has been validated to be involved in the process of immune modulation. Fingolimod (FTY720), the novel S1PR1 agonist, has been approved for the treatment of multiple sclerosis in clinical trials. The study towards discovery of selective S1PR1 agonists has become hot spot for immunological diseases. This article summarized the research progress of S1PR1 agonists, emphasizing their structure types, structure-activity relationship and direction of development.

Text Mining-Based Drug Discovery for Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: The current medical treatments for connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) do not show favorable efficiency for all patients, and identification of novel drugs is desired. Methods: Text mining was performed to obtain CTD- and PAH-related gene sets, and the intersection of the two gene sets was analyzed for functional enrichment through DAVID. The protein-protein interaction network of the overlapping genes and the significant gene modules were determined using STRING. The enriched candidate genes were further analyzed by Drug Gene Interaction database to identify drugs with potential therapeutic effects on CTD-PAH. Results: Based on text mining analysis, 179 genes related to CTD and PAH were identified. Through enrichment analysis of the genes, 20 genes representing six pathways were obtained. To further narrow the scope of potential existing drugs, we selected targeted drugs with a Query Score ≥5 and Interaction Score ≥1. Finally, 13 drugs targeting the six genes were selected as candidate drugs, which were divided into four drug-gene interaction types, and 12 of them had initial drug indications approved by the FDA. The potential gene targets of the drugs on this list are IL-6 (one drug) and IL-1ß (two drugs), MMP9 (one drug), VEGFA (three drugs), TGFB1 (one drug), and EGFR (five drugs). These drugs might be used to treat CTD-PAH. Conclusion: We identified 13 drugs targeting six genes that may have potential therapeutic effects on CTD-PAH.

Attenuation of cartilage pathogenesis in osteoarthritis by blocking the phosphorylation of tyrosine kinase Fyn to ß-catenin, AZD0530.

OBJECTIVE: To observe the effect of AZD0530 on the progression of knee OA after blocking ß-catenin phosphorylation and then dormancy of the Wnt/ß pathway by tyrosine kinase Fyn. METHODS: The levels of Fyn, ß-catenin, p-ß-catenin (Tyr142), the chondrocyte positive marker Aggrecan, and the chondrocyte negative marker MMP13 were observed in human knee tibial plateau chondrocytes in vivo and in vitro. Different doses of AZD0530 were used to treat chondrocytes of the human OA tibial plateau chondrocytes in vitro, and the degree of chondrocyte degeneration was observed. Different doses of AZD0530 were intraarticularly injected into OA rats to observe the degree of tibial plateau cartilage degeneration. RESULTS: When OA occurred in human knee, the levels of tyrosine kinase Fyn,ß-catenin and p-ß-catenin (Tyr142) in chondrocytes increased significantly.The level of Aggrecan decreased and MMP13 increased in chondrocytes. The levels of ß-catenin, p-ß-catenin (Tyr142) and MMP13 in chondrocytes decreased, while the level of Aggrecan increased after AZD0530 was used to intervene chondrocytes in vitro, which was positively correlated with the dose of AZD0530. Intra-articular injection of AZD0530 obviously attenuated the degeneration of articular cartilage, which was positively correlated with the dose of AZD0530. CONCLUSION: The level of Fyn in chondrocytes of human knee tibial plateau increased significantly when OA occurred. AZD0530 can inhibit tyrosine kinase Fyn from ß-catenin phosphorylation, a key Wnt/ß pathway protein, and then inhibit Wnt/ß pathway levels in chondrocytes. This finding also suggests that disruption of the Wnt/ß pathway with AZD0530 provides chondral protection in rat posttraumatic OA.