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Background: Quantification of urinary tissue inhibitor of metalloproteinase?2 (TIMP?2) and insulin?like growth factor binding protein (IFGBP?7), which is commercially known as NephroCheck�(NC) test have been suggested as promising tools for the early detection of acute kidney injury (AKI) after cardiac surgery involving cardio?pulmonary bypass (CPB). Objectives: The aim of the present study was to test the hypothesis that single value of postoperative NC test performed at 4 hours after surgery can predict AKI in off?pump coronary artery bypass grafting (OPCABG) surgery. Setting and Design: This prospective single?center study was conducted at the tertiary cardiac center in India from December 2017 to November 2018. Methods: Ninety adult patients of both sex undergoing elective OPCABG were included. Anesthesia was standardized to all patients. Urine samples were collected preoperatively and at 4 hours after surgery for NC test. Urine output, serum creatinine, estimated glomerular filtration rate (eGFR) were also measured. AKI staging was based on kidney disease improving global outcomes (KDIGO) guidelines. Statistical Analysis: To assess the predictability of NC test for the primary endpoint, area under the receiver operating characteristic curve (ROC), was calculated. Results: Thirteen patients developed AKI in the study cohort (14.4%) out of which 7 patients (7.8%) developed stage 2/3 AKI and the remaining stage 1 AKI. Baseline renal parameters were similar between AKI and non?AKI group. The area under curve (AUC) of NC test at 4 hours after surgery was 0.60 [95% confidence interval (CI): 0.42?0.77]. Postoperative NC test performed at 4 hours after surgery did not predict AKI in this study population (P = 0.24). There were no significant differences in duration of mechanical ventilation, length of intensive care stay and hospital stay between the two groups (P > 0.05). Conclusion: NephroCheck� test performed at 4 hours after surgery did not identify patients at risk for developing AKI following OPCABG surgery
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Mitochondrial dynamics are a contraversal issue in hepatocellular carcinoma. The present study tries to illustrate the role of mitochondrial dynamics proteins (mitofusin-2 (Mfn2) and YME1L) in hepatocarcinogenesis. Five groups were used: the control group and three HCC groups (after 8, 16, and 24 weeks from DENA induction). The last group was treated with Sorafenib (SP) (10 mg/kg), via oral gavage for 4 weeks after cancer induction. This study revealed that Mfn-2 was downregulated and YME1l was overexpressed in different HCC groups. This dysregulation of mitochondrial dynamics proteins was associated with high hepatic levels of cyclin D1, MMP-9, and MDA and overexpression of ki67 as well as decreasing the hepatic expression of tissue inhibitor of matrix metalloproteinase-3 (Timp-3) and Bax. To confirm the possible role of Mfn2 and YME1L in HCC, we assessed the effect of sorafenib on these parameters and its related HCC characteristics. Sorafenib corrected the level of Mfn2 and YME1L and decreased tumor cell proliferation as well. We also elucidated that mitochondrial dynamics proteins (Mfn2 and YME1L) could be a good therapeutic target for HCC.
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Objective: To investigate the main mechanisms of pulmonary fibrosis following silica nanoparticles (SiNPs) exposure through constructing the macrophage-fibroblast model in vitro, which simulated the process of pulmonary fibrosis. Methods: In January 2021, human mononuclear leukemia cells (THP-1) were treated with 0, 25, 50, 100 μg/ml SiNPs for 24 h. The supernatant of THP-1 cells was collected and applied to human embryonic lung fibroblast cells (MRC-5) which divided into control and low, medium and high dose groups at the logarithmic growth stage for 24 h. MRC-5 cell viability was detected by CCK8. The hydroxyproline (Hyp), interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) expression were detected in the supernatants of MRC-5. The changed proteins were detected by liquid-phase mass spectrometry in high dose group. GeneCard database were applied to identity the differential pulmonary fibrosis proteins in high dose group. Gene Ontology (GO) was performed to identity the key biological process in differential pulmonary fibrosis proteins of high dose group. The String database was used to construct the protein-protein interactions (PPI) network of differential pulmonary fibrosis proteins. The APP of CytoHubba was applied to calculate the key protein of differential pulmonary fibrosis proteins in PPI network. Correlation coefficients between key differential pulmonary fibrosis proteins were calculated using Pearson correlation analysis. Western blotting was applied to detect the expression of key proteins of differential pulmonary fibrosis proteins in different groups. Results: CCK8 results showed that MRC-5 cell viability was increasing in low, medium and high dose groups compared with control group (P<0.05). The expression levels of Hyp and IL-1β in different group were increased compared with control group, the expression levels of IL-6 and TNF-α were increased in high dose group compared with control group (P<0.05). GeneCard database identified 26 differential pulmonary fibrosis proteins, which were mainly involved in extracellular matrix hydrolysis, cell inflammatory response, tissue repair, cell proliferation, inflammation response by GO analysis. The APP of CytoHubba was calculated that matrix metalloproteinase 9 (MMP9) and tissue inhibitor metalloproteinase 1 (TIMP1) played an important role in PPI network. The results of correlation analysis showed that MMP9 was correlated with the expression of matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 3 (MMP3), TIMP1 and epidermal growth factor receptor (EGFR) (r=0.97, 0.98, 0.94, 0.93, P<0.05). Western blotting results showed that TIMP1 protein expression was increased in low, medium and high dose groups, while MMP9 protein expression was increased only in high dose group (P<0.05) . Conclusion: Differential expression proteins related with pulmonary fibrosis in MRC-5 cells mainly regulate biological processes of extracellular matrix hydrolysis, tissue repair, and cellular inflammation response following SiNPs exposure. MMP9 and TIMP1 may be the key proteins, which affected the fibrosis process in vitro pulmonary fibrosis model.
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ObjectiveTo investigate the effect and mechanism of pachymic acid （PA） in Poria on the invasion and metastasis of renal carcinoma cells. MethodThe effect of PA （0， 20， 40， 80， 160 μmol·L-1） on cell viability was detected by cell counting kit-8（CCK-8）， and the dose of PA was selected for subsequent experiments. The effect of PA （0， 20， 40， 80 μmol·L-1） on cell proliferation was evaluated by colony formation assay. The effect of PA （0， 20， 40， 80 μmol·L-1） on cell adhesion ability was observed by cell adhesion assay. The effect of PA （0， 20， 40， and 80 μmol·L-1） on cell invasion and metastasis was investigated by Wound healing assay and Transwell invasion assay. The inhibitory effect of PA （0， 20， 40， 80 μmol·L-1） on cell motility was further observed and verified by high-content imaging technology. The effects of PA （0， 20， 40， 80 μmol·L-1） on the expression of matrix metalloproteinase （MMP）/tissue inhibitor of metalloproteinasas （TIMP） related to invasion and metastasis and Smads were detected by Western blot. ResultCCK-8 results showed that compared with the blank group， the PA groups showed decreased cell viability（P<0.01）， with the half-maximal inhibitory concentration （IC50） of ACHN cells of 70.42 μmol·L-1 at 24 h. Colony formation assay showed that the number of cell clonal groups in the PA groups was reduced compared with that in the blank group（P<0.01）. Cell adhesion assay showed that compared with the blank group， the PA groups displayed reduced cell adhesion（P<0.01）. Wound healing assay showed that the wound healing rate of cells in the PA groups was lower than that in the blank group （P<0.05，P<0.01）. Transwell invasion assay showed that compared with the blank group， the number of transmembrane cells in PA groups was reduced（P<0.01）. High-content imaging showed that the cumulative migration distance of cells in the PA groups was shorter than that in the blank group（P<0.01）. The results of Western blot showed that the protein expression of MMP-2 and MMP-9 in the PA groups decreased （P<0.01）， and TIMP-1 protein expression increased （P<0.01） compared with those in the blank group. In addition， compared with the blank group， the PA groups showed decreased protein expression of Smad2 and Smad3 （P<0.01）. ConclusionPA can inhibit the invasion and metastasis of renal carcinoma cells presumably through regulating the homeostasis of MMP/TIMP by Smad2/3.
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Objective:To conduct a systematic review of clinical manifestations, treatment, and associated genotyping of Sorsby fundus dystrophy (SFD).Methods:An evidence-based medicine study. Sorsby fundus dystrophy, anti-vascular endothelial growth factor therapy, choroidal neovascularization, macular neovascularization, and TIMP3 gene were hereby used as search terms. Relevant literature was searched in CNKI, Wanfang, PubMed of the National Library of Medicine, and Embase of the Netherlands. The time span for literature searching ranged from the establishment of the database to April 2022, and two reviewers independently screened the literature and extracted relevant data, with duplicates, incomplete or irrelevant articles, and review articles excluded. SPSS26.0 software was used for analysis. The 95% confidence interval ( CI) was used as an estimate of the effect size. The clinical manifestations, treatment and related pathogenic genes of SFD were counted and recorded. Results:According to the search strategy, 157 pieces of literature were initially retrieved, and 49 eyes of 35 patients from 16 articles were finally included for analysis, among which, 17 patients were male, 13 patients were female, and 5 patients were unknown gender; 16 involved left eyes, 19 involved right eyes, and 14 involved unidentified eyes. The age of the disease onset was 42.33±2.19 years (28-59) years old. There were 19 cases with a positive family history, and the total positive rate was 54.3% (19/35, 95% CI 36%-72%). There were 31 cases of gene mutation, all of which were TIMP3. In the included literature, there were 2 and 2 cases with no mutation and unreported loci, respectively, with a total positive rate of 93.9% (31/33, 95% CI 85%-100%). Among the 31 cases with gene mutation, 22, 4, 1, and 4 cases were in the UK, Germany, Switzerland, and Chinese, respectively, and the detection rates were all 100% (22/22, 4/4, 1/1, 4/4). The clinical manifestations of SFD were mainly yellow-white deposits in the fundus and choroidal neovascularization (CNV) in the macula, thereby leading to a decrease in central vision, followed by the expansion of the deposits to the periphery, the further development of CNV, and a severe decline in vision caused by peripheral retinal and choroidal atrophy. The treatment methods for SFD include photodymatic therapy, anti-VEGF drugs, glucocorticoids, vitamin A, etc., among which, anti-VEGF drugs were considered the first-line treatment, and the combined treatment was provided with a better prognosis than a single treatment. Conclusions:Variations in the TIMP3 gene cause SFD, the fundus characteristic manifestations of which, are yellowish-white deposits and CNV, which develop from the center to the periphery, thus resulting in progressive decline of visual acuity. Current studies have shown that combined therapy presents a better prognosis than monotherapy.
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Abstract Introduction: The high incidence of sports injuries in elite athletes is a concern in sports medicine. A broad vision of sport injuries in Colombia and its pathophysiology can be achieved in the scope of genomics, which could respond to numerous sports injuries from the Identification of single nucleotide polymorphism that lead to disabilities that affect the health of athletes and often distance them from the field of play. Objective: To determine the association of single nucleotide polymorphisms in various genes with sports injuries in soccer. Material and methods: We searched in the databases PubMed, ScienceDirect and EBSCO for studies published in the last 6 years to January 2020, including studies in English and Portuguese, corresponding to case-control clinical studies, where the experimental group were soccer practitioners and controls were supposedly healthy people. The final papers were assessed for quality and bias using the Jadad scoring scale or Oxford quality scoring system. From the data obtained, heterogeneity was identified with the I2 test and the Q statistic, for the estimation of the effect in the cohort studies the odds ratio and p value <0.05 were used, obtaining the forest plots of each gen. Results: 10 out of 1928 studies were selected, finding a degree of heterogeneity in all studies, such as the risk of injury to ACNT3 SNP (OR = 0.98, 95% CI 0.64-1.50), MMP (OR = 1.16, 95% CI 0.86 - 1.58, p = 0.33), TIMP2 (OR 1.03 95% CI 0.65-1.63), VEFGA (OR 0.98 95% CI 0.70-1.37). Conclusion: The studies showed moderate heterogeneity with statistical significance for the ACTN3 and TIM SNPs, providing a pathway for future studies that relate to sports injuries. MÉD.UIS.2021;34(3): 9-18.
Resumen Introducción: La alta incidencia de lesiones deportivas en atletas de élite es una preocupación en medicina deportiva. Se puede lograr una visión amplia sobre las lesiones deportivas en Colombia y sobre su fisiopatología desde el ámbito de la genómica, la cual podría responder a numerosas lesiones deportivas a partir de la Identificación de polimorfismos de nucleótido único que conducen a discapacidades que afectan la salud de los deportistas y frecuentemente los distancian del campo de juego. Objetivo: Determinar la asociación entre polimorfismos de nucleótido único en varios genes con lesiones deportivas en el fútbol. Materiales y métodos: Se realizó búsqueda en las bases de datos PubMed, ScienceDirect y EBSCO de estudios publicados en los últimos 6 años hasta enero de 2020, incluyendo estudios en inglés y portugués, correspondientes a estudios clínicos de casos y controles, donde el grupo experimental fueran practicantes de fútbol y los controles fueran personas presumiblemente saludables. Se evaluó la calidad y el sesgo de los artículos finales mediante la escala de puntuación de Jadad o el sistema de puntuación de calidad de Oxford. A partir de los datos obtenidos se identificó la heterogeneidad con la prueba de I2 y el estadístico Q, para la estimación del efecto en los estudios de cohorte se utilizaron odds ratio y valor p <0.05, obteniendo los forest plot de cada gen. Resultados. 10 de los 1928 estudios fueron seleccionados, se encontró un grado de heterogeneidad en todos los estudios, como el riesgo de lesión de los polimorfismos de nucleótido único para ACNT3 (OR = 0,98; IC del 95%: 0.64-1.50), MMP (OR = 1.16; IC del 95%: 0.86-1.58, p = 0.33), TIMP2 (OR = 1,03; IC del 95%: 0,65-1,63), VEFGA (OR = 0,98; IC del 95%: 0,70-1,37). Conclusión. Los estudios mostraron una heterogeneidad moderada con significancia estadística para los polimorfismos de nucleótido único de ACTN3 y TIM, lo que proporciona una vía para futuros estudios en relación con lesiones deportivas. MÉD.UIS.2021;34(3): 9-18.
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Humans , Soccer , Polymorphism, Genetic , Wounds and Injuries , Matrix MetalloproteinasesABSTRACT
Objective:This study is to investigate the predictive value of serum levels of TIMP-2 and insulin-like growth factor-binding protein 7(IGFBP7) in patients with DCD(donation after cardiac death) kidney transplantation.Methods:A prospective research design was used to select DCD kidney transplant patients admitted to the Li Huili Hospital of Ningbo University from January 2018 to October 2020.Inclusion criteria: ①Complete data; ②There were no serious complications affecting the function of the transplanted kidney in the early postoperative period.Exclusion criteria: ①Incomplete data; ②Patients were unable or unwilling to cooperate with the study; ③Severe complications affecting the function of the transplanted kidney occurred early after the operation.The ELASE method was used to quantitatively detect the serum TIMP-2 and IGFBP7 levels at 6, 12, 24, 48, 72 hours and 7 days after renal transplantation, and monitor the serum creatinine values during the same period and 21 days after the operation. According to the occurrence of DGF, the measured values of TIMP-2 and IGFBP7 at different time points and their product's ability to predict the occurrence of DGF after kidney transplantation were analyzed. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic efficacy of TIMP-2 and IGFBP7 for DGF.Results:A total of 33 patients were enrolled, 7 patients (21.2%) in the DGF group and 26 patients (78.8%) in the non-DGF group. Between the two groups, the donor glomerular filtration rate were [98.5(15.8-132.5)ml/(min·1.73m 2) and 79.1(60.6-102.5)ml/(min·1.73m 2)], recipient gender (male/female: 3/4 cases and 10/16 cases), recipient age [48(34-56) Years old and 45(23-61) years old], the recipient's preoperative creatinine [1114.0(731.4-1293.0)μmol/L and 858.4(657.6-1051.9)μmol/L], the recipient's preoperative urea nitrogen [15.0(13.2-19.6)mmol/L and 17.3(13.6-20.9)mmol/L], receptor preoperative albumin [43.5(38.5-45.3)mmol/L and 41.2(37.5-46.1) mmol/L], recipient dialysis method [hemodialysis/peritoneal dialysis: 3/4 cases and 9/17 cases], warm ischemia time [6(5-7) and 5(4-6) min, there was no statistically significant difference] ( P>0.05). The values of serum IGFBP7 and TIMP-2×IGFBP7 in the DGF group were higher than those in the non-DGF group at all time points ( F=15.753, P=0.040; F=13.000, P=0.024), while serum TIMP-2 was not significant between the two groups difference ( F=1.157, P=0.075). For the diagnostic value of DGF, the AUC of serum IGFBP7 at 48 h after surgery was 0.863 (95% CI 0.696-1.000, P=0.004). When 5.97 ng/ml was used as the cut-off value, the sensitivity was 85.7% and the specificity was 80.8 %. The AUC of TIMP-2×IGFBP7 at 48 hours after surgery was 0.819 (95% CI 0.641-0.996, P=0.011). When 62.06(ng/ml) 2 was used as the cutoff value, the sensitivity was 71.4% and the specificity was 80.8%.There was no statistical difference in the area under the curve between the two ( P>0.05). There were differences in the dynamic trend of serum IGFBP7 and creatinine in the DGF group. Serum IGFBP7 at 7 days after surgery was positively correlated with creatinine at 21 days after surgery. Conclusion:Serum IGFBP7 and TIMP-2×IGFBP7 could predict the occurrence of DGF after DCD donor kidney surgery. The predictive value changes with time. Among them, 48h and 7d after surgery are the most valuable. However, serum TIMP-2 has not been found to have predictive value in this study.
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Abstract; Aim To explore the effect of icariin (ISO) in mice. Methods C57BL/6 mice were ran- (ICA) on myocardial fibrosis induced by isoproterenol domly divided into control group, ISO group, low-dose (15 mg • kg"1), middle-dose (30 mg • kg"1) and high-dose (60 mg • kg"1) of ICA-treated group and Losartan-treated group ( 9 mg • kg"1 ). The control group was subcutaneously injected with normal saline, and the other groups were subcutaneously injected with ISO (5 mg • kg"1, qd) continuously 14 days to established the myocardial fibrosis model. The ICA-treated groups and Losartan-treated group were simultaneously intragastrically administered of ICA or Losartan, respectively. And the other groups received the same a- mount of double distilled water. The left ventricular e- jection fraction (LVEF) and the left ventricular fraction shortening rate ( LVFS) were evaluated by the small animal ultrasound. The heart mass index (HMI) was calculated. The left ventricular collagen deposition was detected by Masson staining. The protein expressions of a-SMA, MMP-2, MMP-9 and TIMP-1 in the left ventricular tissue were detected by Western blot. Results ICA (30, 60 mg • kg"1) and Losartan could inhibit the decreased LVEF and LVFS, the increased HMI and left ventricular collagen deposition, the up- regulated a-SMA and MMP-9 protein expression, the down-regulated MMP-2 and TIMP-1 protein expression in the left ventricular tissues induced by ISO. Conclusions ICA can improve myocardial fibrosis induced by ISO in mice, and the underlying mechanism may be related to the regulation of the protein expression of a- SMA and MMPs/TIMP-1.
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Up-regulation of MMP-2 and MMP-9 plays a significant role in promoting cancer progression by degradingthe components of the extracellular matrix, thereby enhancing the migration of tumor cells. Although the antiproliferative and apoptotic effect of Annona muricata is well established, its effect on MMP-2 and MMP-9, amajor target in several types of cancers, has not been studied. Powdered samples of various parts of A.muricata like fruit, stem, seed, and twig extracted using aqueous methanol showed significant dose-dependentinhibition of MMP-2 and MMP-9 in a highly metastatic fibrosarcoma cell line, HT1080. Additionally, theseextracts also up-regulated the expression of several endogenous inhibitors of MMP-2 and MMP-9 likeREversion-inducing Cysteine-rich protein with Kazal motifs (RECK) and Tissue Inhibitor of Metalloproteinase-2 (TIMP-2). Furthermore, primary cells developed from tumor tissues obtained from patients notexposed to chemotherapy, also exhibited similar results. Remarkably, the inhibition of MMP-2 and MMP-9observed was tumor specific, with the A. muricata fruit extract showing only 2% inhibition in cells obtainedfrom normal tissues, when compared to 60% inhibition observed in cells obtained from tumor samples. Thepresent study elucidates a novel mechanism by which A. muricata extracts selectively exhibit their anti-canceractivity in tumor cells by down-regulating MMP-2 and MMP-9 that are important biomarkers in cancer.
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Background: It is well established that chronic exposure to tobacco induces head and neck cancers but the exact etiopathogenesis is not known. Though studies have shown expression of TIMP1, EPS8 and AXL in cancers, their role in tobacco-induced cancers is not known. We aimed this study to evaluate the role of these molecules in oral and oropharyngeal squamous cell cancers (SCC). Materials and Methods: In this single institutional study, 31 patients of oral and oropharyngeal SCC with history of chewing tobacco were included. Smokers were excluded from the study. After informed consent biopsies were taken from affected and contralateral normal mucosa. Paraffin blocks were made and tissue microarray (TMA) were constructed using these blocks. Immunohistochemistry (IHC) for TIMP1, EPS8, AXL kinase was carried out on these tissue microarrays. The intensity of staining was scored from 0 to 3+, related to expression of each of the three molecules. Results: The expression of TIMP1, EPS8 and AXL kinase was significantly more in the cancerous mucosa versus non-cancerous mucosa (P = 0.000 in all three) in oral and oropharyngeal SCC exposed to chewing tobacco. Conclusion: Immunohistochemical expression of these molecular markers in oral and oropharyngeal SCC correlated with their molecular based studies. Significant IHC expression of TIMP1, EPS8 and AXL establishes their role in the pathogenesis of oral and oropharyngeal squamous cell carcinomas. Novel targeted therapies may be researched that can detect and target these molecules at an earlier stage of pathogenesis of these tumors.
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Macroangiopathy is a complication of Type II Diabetes Mellitus (T2DM), which is mainly caused by fibrosis of blood vessels. Using T2DM rat models, we investigated whether the traditional Chinese medicine, Di-Dang Decoction (DDD), exhibited anti-fibrotic actions on great vessels. T2DM rats were randomly divided into non-intervention group, early-, middle-, late-stage DDD intervention groups and control groups, including pioglitazone group and aminoguanidine group. After administration of DDD to T2DM rats at different times, we detected the amount of extracellular matrix (ECM) deposition in the thoracic aorta. The results showed that early-stage intervention with DDD could effectively protect great vessels from ECM deposition. Considering that TGF-β1 is the master regulator of fibrosis, we further validated at the molecular level that, compared to middle- and late-stage intervention with DDD, early-stage intervention with DDD could significantly decrease the expression levels of factors related to the activated TGF-β1/Smad signalling pathway, as well as the expression levels of downstream effectors including CTGF, MMP and TIMP family proteins, which were directly involved in ECM remodelling. Therefore, early-stage intervention with DDD can reduce macrovascular fibrosis and prevent diabetic macroangiopathy.
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To investigate the effect of baicalin extracted from Qinbai Qingfei Concentrated Pills on the expressions of TGF-β1, mmp2 and timp2 in mice with pulmonary fibrosis induced by bleomycin. The Biacore technique was used to detect the specific binding between Qinbai Qingfei Concentrated Pills and TGF-β1, and the affinity components were enriched, regenerated and recovered by Biacore fishing. Then ultra-performance liquid chromatography and quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS) were used to determine whether the monomer was baicalin. Biacore was used to verify the affinity kinetics of baicalin, which was validated by pharmacodynamics in vivo. Totally 30 BALB/C mice were randomly divided into three groups: baicalin group, blank group and model group. The blank group was given sodium chloride injection(0.08 mL·kg~(-1)), while the model group and the baicalin group were injected with 4 mg·kg~(-1) bleomycin. The localization of TGF-β1, mmp2 and timp2 protein in the cells and the mRNA expressions of TGF-β1, mmp2 and timp2 were detected by RT-PCR 14 days later. The results of Biacore affinity analysis showed that the peak of binding response between Qinbai Qingfei Concentrated Pills and TGF-β1 protein reached 1 524.0 RU, with specific binding. The affinity constant K_D of baicalin and TGF-β1 was 1.620 06 μmol·L~(-1), which was determined by SPR kinetic analysis, suggesting a stable binding between baicalin and TGF-β1, which verified the results of angulation. The results of immunohistochemistry showed that the deposition of cellulose in baicalin group was significantly less than that in model group, the mRNA expressions of TGF-β1, mmp2 and timp2 were decreased in baicalin solution compared with the model group. Baicalin combined with TGF-β1 could inhibit the expressions of mmp2 and timp2 and delay the progress of pulmonary fibrosis.
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Animals , Mice , Flavonoids , Kinetics , Mice, Inbred BALB C , Pulmonary Fibrosis , Transforming Growth Factor beta1ABSTRACT
AIM: To investigate the regulation function of miR-106a on the proliferation of human ovarian granulosa cells, and to explore its possible target.METHODS: The expression of miR-106a in granulosa cells was regulated by cell transfection, and its expression level was detected by RT-PCR. The MTT assay was used to detect the cell proliferation activities of cells. Bioinformatics methods were used to predicted the possible target genes of miR-106a, which were verified them by double-luciferase assay. The expression of target protein was detected by Western blot. RESULTS:The expression of miR-106a in KGN cells was significantly higher than that of normal ovarian epithelial cell (IOSE80), the difference was statistically significant (P<0.05). The proliferation activity of KGN cells was significantly decreased after inhibiting the expression of miR-106a (P<0.05). The results of dual luciferase assay showed that miR-106a could directly target TIMP-2 gene. Western blot results showed that the expression level of TIMP-2 protein was significantly decreased after overexpression of miR-106a (P<0.05). CONCLUSION: miR-106a can promote the proliferation of KGN cell; The mechanism is related to the targeted reduction of TIMP-2 expression level.
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BACKGROUND: Skeletal muscle injury is the most common sports injury, which can develop fibrosis and then impair muscle function. Varieties of fibrotic factors are involved in the repair of skeletal muscle and effectively regulate the process of tissue fibrosis. OBJECTIVE: To establish a rat model of acute gastrocnemius strain, observe the changes of fibrotic factors in the recovery of injury and explore the possible roles of fibrotic factors. METHODS: Totally 112 male Sprague-Dawley rats were randomly divided into control group (n=56) and injury group (n=56). The left gastrocnemius muscle was injured by a rat gastrocnemius pull-off device in the injury group. Each group was further subdivided into immediately group, 2 days group, 4 days group, 7 days group, 14 days group, 21 days group and 28 days group depending on the sampling time points. There were eight rats in each subgroup. The control group did not receive any intervention. The left gastrocnemius muscle of the injury group was strained by specialized equipment. Muscle fiber injury and inflammation were observed by hematoxylin-eosin staining. The expression of transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), and matrix metalloproteinase tissue inhibitor 1 (TIMP-1) were detected by western blot. The experiment was approved by the Sports Science Experimental Ethics Committee of Beijing Sport University. RESULTS AND CONCLUSION: Hematoxylin-eosin staining results showed that the muscle fibers of the gastrocnemius muscle arranged disorderedly and inflammatory cells were aggregated in the injury group. Compared with the control group, protein expression levels of TGF-β1 and CTGF significantly increased in the injury group from the 2nd day throughout the recovery (P 0.05). TIMP-1 expression significantly increased from the 7th day until the 28th day (P < 0.05). These findings indicate that TGF-β1/CTGF signal pathway may be successively activated during the recovery of skeletal muscle strain, triggering the occurrence and development of skeletal muscle fibrosis. Meanwhile, MMP-1 and TIMP-1 protein may be activated to participate in the recovery of injury.
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OBJECTIVE: To investigate the application of NBNA and TIMP in the follow-up of preterm infants,and to as⁃sess the value of them in early diagnosis of abnormal motor development of preterms. METHODS: Databases including Pubmed,Embase and Cochrane Library,China National knowledge internet,and Wanfang data were searched for studies about neuro-behavior or motor assessments with NBNA or TIMP. The methodological quality of the included studies was assessed with COSMIN checklist,then the predictive validity of NBNA and TIMP were compared. RESULTS: Ultimately,16 studies were included,5 of which were about the application of NBNA in follow-up of preterm infants. But many fac⁃tors might pose threat to methodological quality. As for TIMP,11 studies were included,9 of which showed that with a satisfying predictive validity(sensitivity:0.50 to 1.00;specificity:0.68 to 1.00)or moderate correlation(r:0.36 to 0.44)for the neurodevelopmental scores after half a year old. TIMP is helpful in making early diagnosis for neurodevelopmental disability. CONCLUSION: With satisfying predictive validity for long-term neurological development outcomes of the pre⁃term infants,TIMP is considered as an alternative method of assessing functional movements in preterms.
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OBJECTIVE： To study the effects of Dengzhan shengmai capsules combined with isosorbide mononitrate on serum TIMP-1 and MMP-9 levels， blood lipid level and cardiac function in patients with unstable angina pectoris （UAP）. METHODS： Totally 198 UAP patients admitted to our hospital from Apr. 2016 to Apr. 2019 were selected， and divided into observation group （n＝102） and control group （n＝96） according to therapy plan. Control group received Isosorbide mononitrate tablets 40 mg， qd， orally； observation group additionally received Dengzhan shengmai capsules， 2 capsules per time， tid， orally， on the basis of control group. Both groups received treatment for consecutive 4 weeks. The clinical efficacy， serum levels of MMP-9 and TIMP-1， blood lipid indexes [low density lipoprotein cholesterol （LDL-C）， high density lipoprotein cholesterol （HDL-C）， triglyceride （TG）， total cholesterol （TC）]， cardiac function indexes [end-diastolic volume （EDV）， left ventricular ejection fraction （LVEF）， end-systolic volume （ESV）] and ADR were compared between 2 groups. RESULTS： The total response rate of observation group was significantly higher than control group （91.18％ vs. 70.83％， P＜0.05）. Before treatment， there was no statistical significance in the levels of ESV， MMP-9， TIMP-1， TC， LDL-C， TG， HDL-C， EDV and LVEF between 2 groups （P＞0.05）. After treatment， the levels of MMP-9， TC， LDL-C， TG， ESV and EDV in 2 groups were decreased significantly in both groups， and the observation group was significantly lower than the control group （P＜0.05）； meanwhile， the levels of TIMP-1， HDL-C and LVEF in 2 groups were increased significantly， and the observation group was significantly higher than control group （P＜0.05）. There was no statistical significance in the incidence of total ADR in 2 groups （P＞0.05）. CONCLUSIONS： Dengzhan shengmai capsules combined with isosorbide mononitrate show good clinical efficacy for UAP， which can effectively reduce serum MMP-9 level and increase serum TIMP-1 level， reduce blood lipid levels， as well as improve cardiac function for UAP patients， with good safety.
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OBJECTIVE： To investigate the effects of Buyang huanwu decoction on the expression of MMPs and TIMPs in cardiac tissue of viral myocarditis （VMC） model mice. METHODS： Male BALb/c mice were randomly divided into control group， model group， positive control group [captopril， 100 mg/（kg·d）]， Buyang huanwu decoction low-dose， medium-dose and high-dose groups [6， 18， 36 g/（kg·d）]， with 24 mice in each group. Except for control group， other groups were given Coxsackie virus B3 once intraperitoneally to induce VMC model. After modeling， control group and model group were given constant volume of normal saline intragastrically； administration groups were given relevant medicine intragastrically； once a day， for consecutive 30 days. The general situation of mice in each group was observed. The day of inoculation was set at 0 d， heart mass to body mass ratio （HW/BW） was measured at 4， 10， 20， 30 d after inoculation. The morphological characteristics of myocardium were observed by HE staining， and the myocardial histopathological scores of myocardium were evaluated. The distribution of type Ⅰ and Ⅲ collagen in myocardium was observed by Abcam picrosirius red staining， and the ratio of type Ⅰ to Ⅲ collagen was calculated. At 30 d， relative expressions of MMP-1， MMP-3， MMP-9 and TIMP-1 in cardiac tissue were detected by Western blotting assay， and the ratio of MMPs to TIMPs was calculated. RESULTS： Compared with control group， mice in model group suffered from irritability， arch back， alleviation of stimulation response， reduction of body mass and even mental depression. Typical inflammatory changes and local interstitial hyperemia were observed in the myocardium， accompanied by a large number of lymphocyte infiltration and distribution of type Ⅰ and Ⅲ collagen. HW/BW （at different time points of 10-30 d）， myocardial histopathological score （at different time points of 4-30 d）， ratio of type Ⅰ and Ⅲ collagen （at different time points of 4-30 d）， the expression of MMP-1 and MMP-9， ratio of MMPs to TIMPs were increased significantly， while the expression of MMP-3 and TIMP-1 were decreased significantly （P＜0.05）. Compared with model group， above symptoms of mice in administration groups were improved to different extents. HW/BW [at different time points of 10-30 d in administration groups （except for 10 d in Buyang huanwu decoction low-dose group）]， myocardial histopathological score （at different time points of 10-30 d in administration groups）， ratio of type Ⅰand Ⅲ collagen （at different time points of 4-10 d in positive control group and Buyang huanwu decoction high-dose group， at different time points of 20-30 d in Buyang huanwu decoction low-dose and medium-dose groups）， the expression of MMP-1 （positive control group and Buyang huanwu decoction high-dose group） and MMP-9 （administration groups）， ratio of MMPs to TIMPs （administration groups） were decreased significantly， while the expression of MMP-3 （positive control group， Buyang huanwu decoction low-dose and high-dose groups） and TIMP-1 （administration groups） were increased significantly （P＜0.05）. CONCLUSIONS： Buyang huanwu decoction can inhibit myocardial fibrosis of VMC model mice by inhibiting myocardial collagen hyperplasia， regulating the expression of MMPs and TIMPs， improving MMPs/TIMPs imbalance.
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Objective:To explore the clinical efficacy of Modified Qingqi Huatan Wan in treatment of acute exacerbation of chronic obstructive pulmonary disease and its effect on inflammatory reaction, airway remodeling and thrombokinesis. Method:A total of 80 patients of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) were randomly divided into control group (40 cases) and therapy group (40 cases) by random number table. The control group was treated with conventional therapy. In addition to the therapy for the control group, the patients in therapy group also received modified Qingqi Huatan Wan. The treatment course was 14 days for both groups. Scores of traditional Chinese medicine(TCM) syndrome, chronic obstructive pulmonary disease and asthma physiology Score (CAPS), and chronic obstructive pulmonary disease patients self-assessment test questionnaire (CAT) were compared. The secondary indicators were pulmonary function, arterial blood gas analysis, and blood rheology indexes. In addition, the levels of serum nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), transforming growth factor-beta1 (TGF-β1) and plasma tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von-willebrand factor (v-WF), clinical efficacy and safety were evaluated. Result:The total clinical effective rate was 94.74% in therapy group,which was higher than 78.38% in control group (χ2=4.341,P2, serum NF-κB, IL-6, IL-8, MMP-2, TIMP-2, TGF-β1 and plasma PAI-1, v-WF in therapy group were lower than those in control group(P2, PaO2, FEV1, FEV1%, FEV1/FVC in therapy group were higher than those in control group(PPConclusion:Modified Qingqi Huatan Wan can control the symptoms safely, alleviate CAPS and lung function, effectively reduce the inflammatory response and inhibit the formation of airway remodeling and thrombosis, and its mechanism may be protect the lung tissue by reducing the level of inflammatory cytokines, regulating the balance of MMP-2/TIMP-2 and t-PA/PAI-1 and improving extracellular matrix and vascular endothelial function.
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Objective: To observe the effects of different combinations of Gentianae Macrophyllae Radix (Qinjiao) on the ankle joint matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) of rheumatoid arthritis (RA) model rats with wind-cold-dampness arthralgia.Method: Eighty healthy SD rats were randomly divided into 8 groups, namely blank control group, collage Ⅱ model group, wind-cold-dampness syndrome model group, positive control group, single-taste Gentianae Macrophyllae Radix group, Gentianae Macrophyllae Radix-Clematidis Radix et Rhizoma group (GC group), Gentianae Macrophyllae Radix-Taxilli Herba group (GT group), Gentianae Macrophyllae Radix-Stephanlae Tetrandrae Radix group (GS group), with 10 rats in each group. Rat model of wind-cold-dampness RA was induced through the injection with type Ⅱ collagen emulsion and wind-cold-dampness stimulation. After the establishment of the model, the blank control group, collage Ⅱ model group and wind-cold-dampness syndrome model group were given normal saline, and the corresponding liquid medicine was given to each administration group. In the experiment, the thickness of the left posterior metatarsal of rats was measured every 3 days, and the swelling degree of metatarsal was calculated. The arthritis index (AI) was evaluated on the 38th day of the experiment. The serum rheamatoid factor(RF) content of rats was detected by enzyme linked immunosorbent assay (ELISA). The expressions of MMP-3 and TIMP-1 in ankle joint were detected by Western blot. The expressions of MMP-3 and TIMP-1 mRNA in ankle joint were detected by real-time fluorescence quantitative PCR (Real-time PCR).Result: Compared with the blank group, the swelling degree, AI score, serum RF content, MMP-3 protein expression and MMP-3 mRNA expression in ankle joints of coll age Ⅱ model group and model wind-cold-dampness syndrome group were significantly increased (PPPPPPConclusion: For rheumatoid arthritis with wind-cold-dampness arthralgia, mild and warm traditional Chinese medicine (TCM) has a better effect than the combination of mild and cold TCM or mild TCM drugs. The experimental results are basically consistent with the principle of "treating cold diseases with hot medicine". The mechanism of the compatibility in treating rheumatoid arthritis due to wind-cold-dampness arthralgia may be related to the reduction of MMP-3, the increase of TIMP-1 expression and the reduction of articular cartilage damage.
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Abstract Objective To evaluate whether the circulating level of tissue inhibitor of metalloproteinase- 4 (TIMP-4) in the period between 20 and 25 weeks of gestation is a predictor of preeclampsia. Methods We have performed a case-control study, nested in a prospective study cohort in Ribeirão Preto, in the state of São Paulo, Brazil. Of the 1,400 pregnant women evaluated between 20 and 25 weeks of gestation, 460 delivered in hospitals outside of our institution. Of the 940 pregnant women who completed the protocol, 30 developed preeclampsia. Healthy pregnant women (controls, n = 90) were randomly selected from the remaining 910 participants. From blood samples collected between 20 and 25 weeks of gestation, we performed a screening of 55 angiogenesis-related proteins in 4 cases and 4 controls. The protein TIMP-4 was the most differentially expressed between cases and controls. Therefore, wemeasured this protein in all cases (n = 30) and controls selected (n = 90). Results There were no differences in the plasma TIMP-4 levels of cases compared with controls (1,144 263 versus 1,160 362 pg/mL, respectively; p > 0.05). Conclusion Plasma TIMP-4 levels were not altered at 20 to 25 weeks of gestation, before the manifestation of clinical symptoms; therefore, they are not good predictors of the development of preeclampsia.
Resumo Objetivo Avaliar se o nível de inibidor tecidual de metaloproteinases tipo-4 (TIMP-4, na sigla em inglês) circulante no período entre 20 e 25 semanas de gestação é um preditor de preeclâmpsia. Métodos Foi realizado um estudo caso-controle aninhado em uma coorte de estudo prospectivo em Ribeirão Preto, São Paulo, Brasil. De 1.400 mulheres grávidas avaliadas entre 20 e 25 semanas de gestação, 460 tiveram parto em hospitais fora da nossa instituição. Das 940 gestantes que completaram o protocolo, 30 desenvolveram preeclâmpsia. Gestantes saudáveis (controles, n = 90) foram selecionadas aleatoriamente das 910 participantes restantes. A partir de amostras de sangue coletadas entre 20 e 25 semanas de gestação, foi realizada uma triagem de 55 proteínas relacionadas à angiogênese em 4 casos e 4 controles. A proteína TIMP-4 foi a mais diferentemente expressa entre os casos e os controles; portanto, medimos esta proteína em todos os casos (n = 30) e controles selecionados (n = 90). Resultados Não houve diferenças nos níveis plasmáticos de TIMP-4 nos casos em comparação com os controles (1.144 263 versus 1.160 362 pg/mL, respectivamente; p > 0,05). Conclusão Os níveis plasmáticos de TIMP-4 não foramalterados no período entre 20 e 25 semanas de gestação antes da manifestação dos sintomas clínicos; portanto, não são um bom preditor do desenvolvimento da preeclâmpsia.