Effects of initiating time and dosage of Panax notoginseng on mucosal microvascular injury in experimental colitis

AIM To investigate the effects of Panax notoginseng(PN) on microvascular injury in colitis, its mechanisms, initial administration time and dosage.METHODS Dextran sodium sulfate(DSS)-or iodoacetamide(IA)-induced rat colitis models were used to evaluate and investigate the effects of ethanol extract of PN on microvascular injuries and their related mechanisms. PN administration was initiated at 3 and 7 d after the model was established at doses of 0.5, 1.0 and 2.0g/kg for 7 d. The severity of colitis was evaluated by disease activity index(DAI). The pathological lesions were observed under a microscope. Microvessel density(MVD) was evaluated by immunohistochemistry. Vascular permeability was evaluated using the Evans blue method. The serum concentrations of cytokines, including vascular endothelial growth factor(VEGF)A121, VEGFA165, interleukin(IL)-4, IL-6, IL-10 and tumor necrosis factor(TNF)-α, were detected by enzymelinked immunosorbent assay. Myeloperoxidase(MPO) and superoxide dismutase(SOD) were measured to evaluate the level of oxidative stress. Expression of hypoxia-inducible factor(HIF)-1α protein was detected by western blotting.RESULTS Obvious colonic inflammation and injuries of mucosa and microvessels were observed in DSS-and IA-induced colitis groups. DAI scores, serum concentrations of VEGFA121, VEGFA165, VEGFA165/VEGFA121, IL-6 and TNF-α, and concentrations of MPO and HIF-1α in the colon were significantly higher while serum concentrations of IL-4 and IL-10 and MVD in colon were significantly lower in the colitis model groups than in the normal control group. PN promoted repair of injuries of colonic mucosa and microvessels, attenuated inflammation, and decreased DAI scores in rats with colitis. PN also decreased the serum concentrations of VEGFA121, VEGFA165, VEGFA165/VEGFA121, IL-6 and TNF-α, and concentrations of MPO and HIF-1α in the colon, and increased the serum concentrations of IL-4 and IL-10 as well as the concentration of SOD in the colon. The efficacy of PN was dosage dependent. In addition, DAI scores in the group administered PN on day 3 were significantly lower than in the group administered PN on day 7.CONCLUSION PN repairs vascular injury in experimental colitis via attenuating inflammation and oxidative stress in the colonic mucosa. Efficacy is related to initial administration time and dose.

Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review

Coronavirus disease 2019(COVID-19)causes acute microvascular thrombosis in both venous and arterial structures which is highly associated with increased mortality.The mechanisms leading to thromboembolism are still under investigation.Current evidence suggests that excessive complement activation with severe amplification of the inflammatory response(cytokine storm)hastens disease progression and initiates complement-dependent cytotoxic tissue damage with resultant prothrombotic complications.The concept of thromboinflammation,involving overt inflammation and activation of the coagulation cascade causing thrombotic microangiopathy and end-organ damage,has emerged as one of the core components of COVID-19 pathogenesis.The complement system is a major mediator of the innate immune response and inflammation and thus an appealing treatment target.In this review,we discuss the role of complement in the development of thrombotic microangiopathy and summarize the current data on complement inhibitors as COVID-19 therapeutics.

Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

Thrombotic microangiopathy(TMA)is an uncommon but serious complication that not only affects native kidneys but also transplanted kidneys.This review is specifically focused on post-transplant TMA(PT-TMA)involving kidney transplant recipients.Its reported prevalence in the latter population varies from 0.8%to 14%with adverse impacts on both graft and patient survival.It has many causes and associations,and the list of etiologic agents and associations is growing constantly.The pathogenesis is equally varied and a variety of pathogenetic pathways lead to the development of microvascular injury as the final common pathway.PT-TMA is categorized in many ways in order to facilitate its management.Ironically,more than one causes are contributory in PT-TMA and it is often difficult to pinpoint one particular cause in an individual case.Pathologically,the hallmark lesions are endothelial cell injury and intravascular thrombi affecting the microvasculature.Early diagnosis and classification of PT-TMA are imperative for optimal outcomes but are challenging for both clinicians and pathologists.The Banff classification has addressed this issue and has developed minimum diagnostic criteria for pathologic diagnosis of PT-TMA in the first phase.Management of the condition is also challenging and still largely empirical.It varies from simple maneuvers,such as plasmapheresis,drug withdrawal or modification,or dose reduction,to lifelong complement blockade,which is very expensive.A thorough understanding of the condition is imperative for an early diagnosis and quick treatment when the treatment is potentially effective.This review aims to increase the awareness of relevant stakeholders regarding this important,potentially treatable but under-recognized cause of kidney allograft dysfunction.

Effects of Qishen Yiqi Dripping Pills(芪参益气滴丸) in Reducing Myocardial Injury and Preserving Microvascular Function in Patients Undergoing Elective Percutaneous Coronary Intervention:A Pilot Randomized Study

Objectives：To evaluate the effect of treatment with Qishen Yiqi Dripping Pills（芪参益气滴丸,QSYQ） on myocardial injury and myocardial microvascular function in patients undergoing elective percutaneous coronary intervention（PCI）.Methods：Eighty patients undergoing elective PCI were randomly assigned to QSYQ and control groups.The QSYQ group received QSYQ at a dosage of 0.5 g 3 times daily（3–7 days before PCI and then daily for 1 month） and regular medication,which comprised of aspirin,clopidogrel,statin,β-blocker,and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker in the absence of contradiction.The control group received only the regular medication.The index of microcirculatory resistance（IMR） was measured at maximal hyperemia after PCI.The fractional flow reserve was measured before and after the procedure.Troponin Ⅰ levels were obtained at baseline and 20–24 h after the procedure.Results：Pre-PCI troponin Ⅰ levels between the two groups were similar（0.028±0.05 vs.0.022±0.04 ng/m L,P=0.55）.However,postPCI troponin Ⅰ levels in the QSYQ group were significantly lower than that in the control group（0.11±0.02 vs.0.16±0.09 ng/m L,P〈0.01）.IMR values were significantly lower in the QSYQ group as compared to the control group（16.5±6.1 vs.31.2±16.0,P〈0.01）.Multivariate analysis identified QSYQ treatment as the only independent protective factor against IMR 〉32（odds ratio=0.29,95% confidence interval：0.11–0.74,P=0.01）.Conclusion：The present study demonstrated the benefit of QSYQ in reducing myocardial injury and preserving microvascular function during elective PCI.

电针改善糖尿病肾病模型小鼠肾微血管损伤

Objective:Renal microvascular injury,as the result of diabetic toxicity,plays a vital role in the pathogenesis of diabetic kidney disease(DKD)during diabetes progression.Here,we investigated whether electroacupuncture(EA)could ameliorate renal microvascular impairment to prevent DKD and its underlying mechanism.Methods:The male db/db mice with Leprdb mutation were used as the model of type 2 diabetes mellitusinduced DKD and treated with EA at"Zusanli(ST36)"and"Weiwanxiashu(EX-B3)"acupoints for 4 weeks.Age-matched wild-type mice were used as control group.Renal protection of EA was evaluated by mouse urine production,water consumption,renal index and tubules dilation.Two-photon microscope imaging was applied to visualize renal microvascular blood flow in vivo.Immunostaining and western blot analysis were used to detect the glomerular alternations and inflammatory signaling.Results:EA significantly attenuated renal dysfunction in db/db mice.The protective effect of EA on renal microvascular recovery was observed both in function and structure analysis.Firstly,EA restored the renal microvascular blood flow in db/db mice.Then,glomerular hypertrophy and glomerular barrier destruction were suppressed after EA,as respectively demonstrated by the reduction of glomerular dilation,Collagen IV and Claudin-1 deposits.In mechanism,EA suppressed the diabetes-induced inflammatory response in renal microvessels,presenting as the downregulation of inflammatory cytokines interleukin-1β(IL-1β)and tumor necrosis factor(TNF-α),intercellular cell adhesion molecule-1(ICAM-1)activation,and macrophage infiltration after EA treatment.Conclusion:These findings indicated the benefits of EA against renal microvascular impairment and DKD progression,which was associated with the action of anti-inflammation,and supported EA as a promising modality for DKDmanagement.