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1.
Future Microbiol ; 15: 1747-1758, 2020 12.
Article in English | MEDLINE | ID: mdl-33404263

ABSTRACT

COVID-19 caused by SARS-CoV-2, is an international concern. This infection requires urgent efforts to develop new antiviral compounds. To date, no specific drug in controlling this disease has been identified. Developing the new treatment is usually time consuming, therefore using the repurposing broad-spectrum antiviral drugs could be an effective strategy to respond immediately. In this review, a number of broad-spectrum antivirals with potential efficacy to inhibit the virus replication via targeting the virus spike protein (S protein), RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) that are critical in the pathogenesis and life cycle of coronavirus, have been evaluated as possible treatment options against SARS-CoV-2 in COVID-19 patients.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , SARS-CoV-2/drug effects , Virus Replication/drug effects , Chymases/drug effects , Coronavirus Papain-Like Proteases/drug effects , Coronavirus RNA-Dependent RNA Polymerase/drug effects , Drug Repositioning , Humans , Virus Internalization/drug effects
2.
Nat Commun ; 10(1): 706, 2019 02 11.
Article in English | MEDLINE | ID: mdl-30742008

ABSTRACT

Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly, including at the BBB. Here we show that JEV activates MCs, leading to the release of granule-associated proteases in vivo. MC-deficient mice display reduced BBB permeability during JEV infection compared to congenic wild-type (WT) mice, indicating that enhanced vascular leakage in the brain during JEV infection is MC-dependent. Moreover, MCs promoted increased JEV infection in the central nervous system (CNS), enhanced neurological deficits, and reduced survival in vivo. Mechanistically, chymase, a MC-specific protease, enhances JEV-induced breakdown of the BBB and cleavage of tight-junction proteins. Chymase inhibition reversed BBB leakage, reduced brain infection and neurological deficits during JEV infection, and prolonged survival, suggesting chymase is a novel therapeutic target to prevent JEV encephalitis.


Subject(s)
Chymases/metabolism , Encephalitis Virus, Japanese/pathogenicity , Encephalitis, Japanese/immunology , Encephalitis, Japanese/metabolism , Mast Cells/metabolism , Mast Cells/virology , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/virology , Brain/pathology , Brain/virology , Cell Line , Central Nervous System/pathology , Central Nervous System/virology , Chymases/drug effects , Cytokines/metabolism , Disease Models, Animal , Encephalitis, Japanese/mortality , Humans , Immunity, Innate , Male , Mast Cells/immunology , Mast Cells/pathology , Mice , Mice, Inbred C57BL , Morbidity , Permeability , Survival Analysis , Tight Junction Proteins
3.
Med Sci Monit ; 23: 3404-3411, 2017 Jul 13.
Article in English | MEDLINE | ID: mdl-28704345

ABSTRACT

BACKGROUND Tissues fibrosis is caused by ischemia-reperfusion injury (IRI) and results in organ dysfunction. In this study, we aimed to investigate whether fibrosis occurs after uterine ischemia-reperfusion injury, and to investigate the effects of puerarin (Pur) on the fibrosis process in rats. MATERIAL AND METHODS Twenty-four female Wistar rats were randomly divided into three groups (8 in each group): the control group rats only received operation without uterine ischemic, the IRI group and the IRI + Pur group rats received 30-minutes ischemia and 2-weeks of reperfusion. Pur was orally administered at the onset of reperfusion. Picrosirius red staining was used to assess uterine fibrosis. Immunohistochemistry was used to detect the expression levels of transforming growth factor (TGF)-ß and a-smooth muscle actin (α-SMA). Western blotting was used to evaluate the expression of chymase, TGF-ß, α-SMA, and the activity of the Wnt/ß-catenin pathway. RESULTS Uterine fibrosis in the IRI+Pur group was significantly decreased compared with the IRI group. In addition, immunohistochemistry reveals that TGF-ß and a-SMA were decreased in the IRI+Pur group compared with the IRI group. Western blotting results showed that Pur significantly suppresses the increase in chymase, α-SMA, TGF-ß, and b-catenin expression levels induced by IRI. CONCLUSIONS The results indicated that IRI could induce uterine fibrosis and that Pur had an improvement effect on IRI-induced uterine fibrosis by downregulating the activity of mast cell chymase, TGF-ß,  α-SMA, and the Wnt/ß-catenin pathway.


Subject(s)
Isoflavones/pharmacology , Leiomyoma/drug therapy , Reperfusion Injury/pathology , Actins/drug effects , Animals , Chymases/drug effects , Female , Fibrosis , Isoflavones/metabolism , Isoflavones/therapeutic use , Kidney/pathology , Rats , Rats, Wistar , Reperfusion Injury/drug therapy , Transforming Growth Factor beta/metabolism , Wnt Signaling Pathway/drug effects , Wnt Signaling Pathway/physiology , beta Catenin/metabolism
4.
Am J Physiol Heart Circ Physiol ; 305(5): H644-50, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23812388

ABSTRACT

Angiotensin-(1-12) [ANG-(1-12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1-12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1-12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1-12) infusion lasting 5, 15, 30, or 60 min (n = 4-10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1-12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) (n = 7-13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1-12) (2 nmol·kg(-1)·min(-1)), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1-12). Infusion of ANG-(1-12) increased arterial pressure and plasma ANG-(1-12), ANG I, ANG II, and ANG-(1-7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1-12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1-12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1-7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1-12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1-7) degrading enzyme.


Subject(s)
Angiotensinogen/metabolism , Hypertension/metabolism , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/metabolism , Angiotensin I/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensinogen/administration & dosage , Angiotensinogen/pharmacology , Animals , Blood Pressure/drug effects , Chymases/antagonists & inhibitors , Chymases/drug effects , Chymases/metabolism , Disease Models, Animal , Hypertension/physiopathology , Infusions, Intravenous , Lisinopril/pharmacology , Male , Oligopeptides/pharmacology , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacology , Peptidyl-Dipeptidase A/drug effects , Rats , Rats, Inbred SHR , Rats, Inbred WKY
5.
Asian Pac J Cancer Prev ; 13(4): 1097-104, 2012.
Article in English | MEDLINE | ID: mdl-22799288

ABSTRACT

BACKGROUND/AIM: Pristimerin isolated from Celastrus and Maytenus spp can inhibit proteasome activity. However, whether pristimerin can modulate cancer metastasis is unknown. METHODS: The impacts of pristimerin on the purified and intracellular chymotrypsin proteasomal activity, the levels of regulator of G protein signaling 4 (RGS 4) expression and breast cancer cell lamellipodia formation, and the migration and invasion were determined by enzymatic, Western blot, immunofluorescent, and transwell assays, respectively. RESULTS: We found that pristimerin inhibited human chymotrypsin proteasomal activity in MDA-MB-231 cells in a dose-dependent manner. Pristimerin also inhibited breast cancer cell lamellipodia formation, migration, and invasion in vitro by up-regulating RGS4 expression. Thus, knockdown of RGS4 attenuated pristimerin-mediated inhibition of breast cancer cell migration and invasion. Furthermore, pristimerin inhibited growth and invasion of implanted breast tumors in mice. CONCLUSION: Pristmerin inhibits proteasomal activity and increases the levels of RGS4, inhibiting the migration and invasion of breast cancer cells.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Movement/drug effects , Proteasome Inhibitors/pharmacology , RGS Proteins/metabolism , Triterpenes/pharmacology , Actins/metabolism , Analysis of Variance , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/enzymology , Cell Line, Tumor , Chymases/drug effects , Chymases/metabolism , Dose-Response Relationship, Drug , Female , Humans , Leupeptins/pharmacology , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Pentacyclic Triterpenes , Proteasome Endopeptidase Complex/drug effects , Proteasome Endopeptidase Complex/metabolism , RGS Proteins/drug effects , RGS Proteins/genetics , RNA Interference , Random Allocation , Tumor Burden/drug effects , Up-Regulation
6.
J Diabetes Complications ; 24(3): 199-208, 2010.
Article in English | MEDLINE | ID: mdl-19230716

ABSTRACT

Diabetic cardiomyopathy is associated with high morbidity and mortality of heart failure. Overactivation of the local chymase-Ang II system plays a dominant role in diabetic cardiomyopathy. Astragalus polysaccharide (APS) is used in traditional Chinese medicine to boost immunity. To study the effect of APS on local system of chymase-Ang II in diabetic cardiomyopathy, we investigated APS/normal saline (NS)-administrated streptozotocin-induced diabetic hamsters. After APS/NS administration at a dose of 1 g/kg per day for 10 weeks, hemodynamic parameters, levels of insulin (INS), C-peptide (C-P), glycosylated serum protein (GSP), lipoproteins, myocardial enzymes, and Ang II (plasma and myocardial) were tested; myocardial collagen (type I and III), myocardial ultrastructure, and activities of matrix metalloproteinase (MMPs) were measured; activities and expression of cardiac chymase and ACE were detected by using quantitative real-time RT-PCR and RIA; protein expression of cardiac phosphoric extracellular signal-regulated kinase 1/2 (p-ERK1/2) was measured by Western blot. AP-administrated diabetic hamsters had lower levels of GSP, lipoproteins, myocardial enzymes, myocardial Ang II, expression of collagen I and I/ III, activities of pro-MMP-2 and MMP-2, activities and expression of chymase, and expression of p-ERK1/2 than NS-administrated diabetic hamsters and could better protect the myocardial ultrastructure. There was no difference in hemodynamic parameters between two groups. These results indicate that APS could inhibit diabetic cardiomyopathy in hamsters depending on the suppression of the local cardiac chymase-Ang II system.


Subject(s)
Astragalus propinquus , Cardiomyopathies/drug therapy , Chymases/drug effects , Diabetes Complications/drug therapy , Phytotherapy , Plant Preparations/therapeutic use , Polysaccharides/therapeutic use , Angiotensin II/analysis , Animals , Blood Glucose/analysis , Blood Proteins/analysis , Cardiomyopathies/enzymology , Collagen/analysis , Cricetinae , Diabetes Complications/enzymology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/enzymology , Extracellular Signal-Regulated MAP Kinases/analysis , Glycoproteins/analysis , Lipoproteins/analysis , Male , Matrix Metalloproteinase 2/analysis , Glycated Serum Proteins
7.
Br J Pharmacol ; 154(8): 1672-9, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18552882

ABSTRACT

BACKGROUND AND PURPOSE: Chronic inflammatory conditions, such as granulomas, are associated with angiogenesis. Mast cells represent the main cell type orchestrating angiogenesis, through the release of their granule content. Therefore, compounds able to modulate mast cell behaviour may be considered as a new pharmacological approach to treat angiogenesis-dependent events. Here, we tested the effect of selective cannabinoid (CB) receptor agonists in a model of angiogenesis-dependent granuloma formation induced by lambda-carrageenin in rats. EXPERIMENTAL APPROACH: Granulomas were induced by lambda-carrageenin-soaked sponges implanted subcutaneously on the back of male Wistar rats. After 96 h, implants were removed and granuloma formation was measured (wet weight); angiogenesis was evaluated by histological analysis and by the measurement of haemoglobin content. Mast cells in the granulomas were evaluated histologically and by RT-PCR and immunoblotting analysis for mast cell-derived proteins (rat mast cell protease-5 (rMCP-5) and nerve growth factor). Selective CB1 and CB2 receptor agonists(,) ACEA and JWH-015 (0.001-0.1 mg mL(-1)), were given locally only once, at the time of implantation. KEY RESULTS: The CB1 and CB2 receptor agonists decreased the weight and vascularization of granulomas after 96 h. This treatment also reduced mast cell number and activation in granulomatous tissue. Specifically, these compounds prevented the transcription and expression of rMCP-5, a protein involved in sprouting and advance of new blood vessels. CONCLUSION AND IMPLICATIONS: Modulation of mast cell function by cannabinoids reduced granuloma formation and associated angiogenesis. Therefore cannabinoid-related drugs may be useful in the management of granulomatous diseases accompanied by angiogenesis.


Subject(s)
Arachidonic Acids/pharmacology , Granuloma/pathology , Indoles/pharmacology , Neovascularization, Pathologic/drug therapy , Animals , Arachidonic Acids/administration & dosage , Carrageenan , Chymases/drug effects , Chymases/metabolism , Dose-Response Relationship, Drug , Gene Expression Regulation, Enzymologic/drug effects , Indoles/administration & dosage , Male , Mast Cells/drug effects , Mast Cells/metabolism , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Transcription, Genetic/drug effects
8.
Dig Dis Sci ; 53(5): 1311-5, 2008 May.
Article in English | MEDLINE | ID: mdl-17932768

ABSTRACT

Hypertension is commonly observed in alcoholics. Both the renin-angiotensin system (RAS) and the non-renin-angiotensin system (NRAS) have been implicated in the dynamics of blood pressure maintenance. In bilaterally nephrectomized rats, acetaldehyde has been reported to enhance the generation of the rate-limiting angiotensin I (ANG I) in the plasma, and in humans it inhibits the activity of several angiotensinases (A, B, and M) in the serum, thereby promoting a hypertensive set of reactions. We report here the results of a study on the effect of acetaldehyde upon cathepsin G and mast cell chymase. Acetaldehyde enhanced cathepsin G activity at all of the concentrations tested between 11.2 and 223.5 mM in a statistically significant manner. Since cathepsin G is one of several enzymes transforming ANG I into ANG II and is also capable of cleaving ANG II directly from angiotensinogen, we suggest that alcoholism, which will generate exogenous acetaldehyde from ingested alcohol, may be a contributory factor for an elevated cathepsin G activity and, consequently, hypertension via the NRAS. Chymase activity also is elevated in the presence of 440 mM acetaldehyde and diminished in the presence of 27 mM acetaldehyde. Since both enzymes also degrade ANG II, the degradative effects of each enzyme on ANG II may neutralize one another.


Subject(s)
Acetaldehyde/pharmacology , Cathepsins/drug effects , Chymases/drug effects , Serine Endopeptidases/drug effects , Alcoholism/blood , Alcoholism/physiopathology , Animals , Cathepsin G , Hypertension/blood , Hypertension/physiopathology , Rats , Renin-Angiotensin System
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