Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine

Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known. While the pathophysiology and clinical consequences of ricin poisoning by the parenteral route, i.e., intramuscular penetration, have been described recently in various animal models, the preceding mechanism underlying the clinical manifestations of systemic ricin poisoning has not been completely defined. Here, we show that following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages. Increased levels of circulating VEGF and decreased expression of vascular VE-cadherin caused blood vessel impairment, thereby promoting hyperpermeability in various organs. Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage. Finally, by using side-stream dark field intravital microscopy imaging, we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels. These findings, which suggest that glycocalyx shedding and microcirculation dysfunction play a major role in the pathology of systemic ricin poisoning, may serve for the formulation of specifically tailored therapies for treating parenteral ricin intoxication.

Pathophysiology of Takotsubo Syndrome as A Bridge to Personalized Treatment

Takotsubo syndrome (TTS) consists of transient dysfunction of the left and/or right ventricle in the absence of ruptured plaque; thrombus or vessel dissection. TTS may be divided into two categories. Primary TTS occurs when the cause of hospitalization is the symptoms resulting from damage to the myocardium usually preceded by emotional stress. Secondary TTS occurs in patients hospitalized for other medical; surgical; anesthetic; obstetric or psychiatric conditions who have activation of their sympathetic nervous system and catecholamines release- they develop TTS as a complication of their primary condition or its treatment. There are several hypotheses concerning the cause of the disease. They include a decrease in estrogen levels; microcirculation dysfunction; endothelial dysfunction and the hypothesis based on the importance of the brain-heart axis. More and more research concerns the importance of genetic factors in the development of the disease. To date; no effective treatment or prevention of recurrent TTS has been found. Only when the pathophysiology of the disease is fully known; then personalized treatment will be possible.

Effect of Musk Tongxin Dropping Pill on Myocardial Remodeling and Microcirculation Dysfunction in Diabetic Cardiomyopathy

Objective. To explore the effect of Musk Tongxin Dropping Pill (MTDP) on myocardial remodeling and microcirculation dysfunction in diabetic cardiomyopathy (DCM). Methods. Forty male SD rats were randomly divided into control group (control group, n = 10), DCM model group (DCM group, n = 10), DCM model + pioglitazone group (DCM + PLZ group, n = 10), and DCM model + MTDP group (DCM + MTDP group, n = 10). An intraperitoneal single injection of 65 mg/kg streptozotocin (STZ) was used to establish rat model of DCM and the rats in control group were treated with the same dose of sodium citrate buffer solution. DCM + PLZ group was treated with 3 mg/kg/d PLZ by ig after modeling, DCM + MTDP group was treated with 22 mg/kg/d MTDP by ig, and DCM group was treated with 2 ml/kg/d sodium carboxymethyl cellulose (CMC-Na) by ig. The general condition of rats was continuously observed. After intervening for 3 weeks, the random blood glucose of rats was detected by tail vein, and the echocardiography examination was performed. Blood specimens were collected from the abdominal aorta, serum nitric oxide (NO) and endothelin-1 (ET-1) were detected to estimate endothelial function, and tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1β, malondialdehyde (MDA), and superoxide dismutase (SOD) were detected to observe the changes of inflammation and oxidative stress indexes. The heart mass index (HMI) was calculated through the ratio of heart mass (HM) to the corresponding body mass (BM). Myocardial pathological tissue staining was performed. Results. Compared with control group, blood glucose in other three groups was higher. Left ventricular end systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) in DCM group showed a significant increase, while left ventricular ejection fraction (LVEF) and heart rate (HR) in this group displayed an obvious decrease P < 0.01 . BM and HM in DCM group exhibited a reduction, and HM/BM × 103 revealed an apparent increase P < 0.01 . The levels of serum NO and SOD were distinctly downregulated P < 0.01 , and the levels of ET-1, MDA, TNF-α, IL-1β, and IL-6 were remarkably upregulated P < 0.01 . Compared with DCM group, a significant decrease was observed in LVSD and LVDD in DCM + MTDP group, while LVEF and HR obviously increased P < 0.05 . BM and HM indicated an apparent increase, but HM/BM ×103 reduced distinctly P < 0.01 . The levels of serum NO and SOD were markedly upregulated P < 0.05 , and the levels of ET-1, MDA, TNF-α, IL-1β, and IL-6 were significantly downregulated P < 0.05 . HE staining showed that myocardial cells arranged neatly in the control group but not in the DCM group. The intercellular space between myocardial cells in DCM group increased, accompanied by damage of myocardial fibers and infiltration of inflammatory cells. Masson staining displayed an increase in interstitial collagen fibers in DCM group. Carstairs staining showed that microembolization occurred in the myocardium in DCM group, while in DCM + MTDP and DCM + PLZ groups the corresponding myocardial pathological changes were significantly improved. Conclusions. MTDP might show a positive effect on myocardial remodeling and microcirculation dysfunction in DCM rats.