The zoonotic cryptosporidiosis is globally distributed,one of the major diarrheal diseases in humans and animals.Cryptosporidium oocysts are also one of the major environmental concerns,making it a pathogen that fits ...The zoonotic cryptosporidiosis is globally distributed,one of the major diarrheal diseases in humans and animals.Cryptosporidium oocysts are also one of the major environmental concerns,making it a pathogen that fits well into the One Health concept.Despite its importance,fully effective drugs are not yet available.Anti-cryptosporidial drug discovery has historically faced many unusual challenges attributed to unique parasite biology and technical burdens.While significant progresses have been made recently,anti-cryptosporidial drug discovery still faces a major obstacle:identification of systemic drugs that can be absorbed by patients experiencing watery diarrhea and effectively pass through electron-dense(ED)band at the parasite-host cell interface to act on the epicellular parasite.There may be a need to develop an in vitro assay to effectively screen hits/leads for their capability to cross ED band.In the meantime,non-systemic drugs with strong mucoadhesive properties for extended gastrointestinal exposure may represent another direction in developing anti-cryptosporidial therapeutics.For developing both systemic and non-systemic drugs,a non-ruminant animal model exhibiting diarrheal symptoms suitable for routine evaluation of drug absorption and anti-cryptosporidial efficacy may be very helpful.展开更多
The loss of endothelial connective integrity and endothelial barrier dysfunction can lead to increased vascular injury, which is related to the activation of endothelial inflammasomes. There are evidences that low con...The loss of endothelial connective integrity and endothelial barrier dysfunction can lead to increased vascular injury, which is related to the activation of endothelial inflammasomes. There are evidences that low concentrations of aspirin can effectively prevent cardiovascular diseases. We hypothesized that low-dose aspirin could ameliorate endothelial injury by inhibiting the activation of NLRP3 inflammasomes and ultimately prevent cardiovascular diseases. Microvascular endothelial cells were stimulated by lipopolysaccharide(2 μg/mL) and administrated by 0.1–2 mmol/L aspirin. The wild type mice were stimulated with LPS(100 μg/kg/day), and 1 h later treated with aspirin(12.5, 62.5, or125 mg/kg/day) and dexamethasone(0.0182 mg/kg/day) for 7 days. Plasma and heart were harvested for measurement of ELISA and immunofluorescence analyses. We found that aspirin could inhibit NLRP3 inflammasome formation and activation in vitro in dose-dependent manner and has correlation between the NLRP3 inflammasome and the ROS/TXNIP pathway. We also found that low-concentration aspirin could inhibit the formation and activation of NLRP3 inflammasome and restore the expression of theendothelial tight junction protein zonula occludens-1/2(ZO1/2). We assume that aspirin can ameliorate the endothelial layer dysfunction by suppressing the activation of NLRP3 inflammasome.展开更多
基金supported in part by grants from the National Key Research and Development Program of China 2017YFC1601206(J.Y.)the National Institutes of Health,USA R01AI125362(G.D.C.).
文摘The zoonotic cryptosporidiosis is globally distributed,one of the major diarrheal diseases in humans and animals.Cryptosporidium oocysts are also one of the major environmental concerns,making it a pathogen that fits well into the One Health concept.Despite its importance,fully effective drugs are not yet available.Anti-cryptosporidial drug discovery has historically faced many unusual challenges attributed to unique parasite biology and technical burdens.While significant progresses have been made recently,anti-cryptosporidial drug discovery still faces a major obstacle:identification of systemic drugs that can be absorbed by patients experiencing watery diarrhea and effectively pass through electron-dense(ED)band at the parasite-host cell interface to act on the epicellular parasite.There may be a need to develop an in vitro assay to effectively screen hits/leads for their capability to cross ED band.In the meantime,non-systemic drugs with strong mucoadhesive properties for extended gastrointestinal exposure may represent another direction in developing anti-cryptosporidial therapeutics.For developing both systemic and non-systemic drugs,a non-ruminant animal model exhibiting diarrheal symptoms suitable for routine evaluation of drug absorption and anti-cryptosporidial efficacy may be very helpful.
基金supported by the National Key Research and Development Program of China(No.2017YFC1700400)National Natural Science Foundation of China(Nos.81603587 and 81603668)+4 种基金Guangdong Natural Science Funds for Distinguished Young Scholar(No.2018B030306027,China)Science and Technology Development Plan of Guangdong Province(2017A020211016,China)Science&Technology Award for Young-Aged Talents of China Association of Traditional Chinese Medicine(No.CACM-2017-QNRC2-C12)the National Institutes of Health of USA(No.HL122769)Project of Guangzhou University of Chinese Medicine(No.A1-AFD018171Z11020,China)
文摘The loss of endothelial connective integrity and endothelial barrier dysfunction can lead to increased vascular injury, which is related to the activation of endothelial inflammasomes. There are evidences that low concentrations of aspirin can effectively prevent cardiovascular diseases. We hypothesized that low-dose aspirin could ameliorate endothelial injury by inhibiting the activation of NLRP3 inflammasomes and ultimately prevent cardiovascular diseases. Microvascular endothelial cells were stimulated by lipopolysaccharide(2 μg/mL) and administrated by 0.1–2 mmol/L aspirin. The wild type mice were stimulated with LPS(100 μg/kg/day), and 1 h later treated with aspirin(12.5, 62.5, or125 mg/kg/day) and dexamethasone(0.0182 mg/kg/day) for 7 days. Plasma and heart were harvested for measurement of ELISA and immunofluorescence analyses. We found that aspirin could inhibit NLRP3 inflammasome formation and activation in vitro in dose-dependent manner and has correlation between the NLRP3 inflammasome and the ROS/TXNIP pathway. We also found that low-concentration aspirin could inhibit the formation and activation of NLRP3 inflammasome and restore the expression of theendothelial tight junction protein zonula occludens-1/2(ZO1/2). We assume that aspirin can ameliorate the endothelial layer dysfunction by suppressing the activation of NLRP3 inflammasome.