Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Mesenchymal stem cells (MSCs)-based regenerative therapy is currently regarded as an alternative approach to salvage the acute myocardial infarcted hearts. However, the efficiency of MSCs transplantation is limited by lower survival rate of engrafted MSCs. In previous study, we found that 1.0 μg/ml Lipopolysaccharide (LPS) could protect MSCs against apoptosis induced by oxidative stress and meanwhile enhance the proliferation of MSCs. Therefore, in the present study, we firstly preconditioned MSCs with 1.0 μg/ml LPS, then transplanted MSCs into ischemic myocardium, and observed the survival and cardiac protective capacity of MSCs in a rat model of acute myocardial infarction. Furthermore, we tried to explore the underlying mechanisms and the role of Toll-like receptor-4 (TLR4) in the signal pathway of LPS-induced cardiac protection.</p> <p>Methods and results</p> <p>Acute myocardial infarction model was developed by left anterior descending coronary artery ligation. 60 rats were divided into 4 groups randomly and given an intramyocardial injection of one of the following treatments: 30 μl PBS (control group), 3 × 10⁶wild MSCs/30 μl (wMSCs group), 3 × 10⁶LPS-preconditioned wild MSCs/30 μl (LPS-wMSCs group), or 3 × 10⁶LPS-preconditioned TLR4 gene deleted MSCs/30 μl (LPS-tMSCs group). After 3 weeks, LPS-preconditioned wild MSCs transplantation ameliorated cardiac function and reduced fibrosis of infarcted myocardium. Vascular density was markedly increased in LPS-wMSCs group compared with other three groups. Survival rate of engrafted MSCs was elevated and apoptosis of myocardium was reduced in infarcted heart. Expression of vascular endothelial growth factor (VEGF) and phospho-Akt was increased in the infarcted myocardium after transplantation of LPS-preconditioned MSCs.</p> <p>Conclusion</p> <p>LPS preconditioning enhanced survival of engrafted MSCs, stimulated expression of VEGF and activated PI3K/Akt pathway. LPS preconditioning before MSCs transplantation resulted in superior therapeutic neovascularization and recovery of cardiac function. LPS preconditioning provided a novel strategy in maximizing biologic and functional properties of MSCs.</p

Learning to find topic experts in Twitter via different relations

Singapore National Research Foundatio

Gap Junctions Contribute To Ictal/Interictal Genesis In Human Hypothalamic Hamartomas

Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patient\u27s HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients

Experimental Study on Unconfined Compressive Strength of Basalt Fiber Reinforced Clay Soil

In order to study the mechanism and effect of basalt fiber reinforced clay soil, a series of unconfined compressive strength tests conducted on clay soil reinforced with basalt fiber have been performed under the condition of optimum water content and maximum dry density. Both the content and length of basalt fiber are considered in this paper. When the effect of content is studied, the 12 mm long fibers are dispersed into clay soil at different contents of 0.05%, 0.1%, 0.15%, 0.20%, 0.25%, 0.30%, and 0.35%. When the effect of length is researched, different lengths of basalt fibers with 4 mm, 8 mm, 12 mm, and 15 mm are put into soil at the same content of 0.05%. Experimental results show that basalt fiber can effectively improve the UCS of clay soil. And the best content and length are 0.25% and 12 mm, respectively. The results also show that the basalt fiber reinforced clay soil has the “poststrong” characteristic. About the reinforcement mechanism, the fiber and soil column-net model is proposed in this paper. Based on this model and SEM images, the effect of fiber content and length is related to the change of fiber-soil column and formation of effective fiber-soil net

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020

Persistent sulfate formation from London Fog to Chinese haze

Sulfate aerosols exert profound impacts on human and ecosystem health, weather, and climate, but their formation mechanism remains uncertain. Atmospheric models consistently underpredict sulfate levels under diverse environmental conditions. From atmospheric measurements in two Chinese megacities and complementary laboratory experiments, we show that the aqueous oxidation of SO2 by NO2 is key to efficient sulfate formation but is only feasible under two atmospheric conditions: on fine aerosols with high relative humidity and NH3 neutralization or under cloud conditions. Under polluted environments, this SO2 oxidation process leads to large sulfate production rates and promotes formation of nitrate and organic matter on aqueous particles, exacerbating severe haze development. Effective haze mitigation is achievable by intervening in the sulfate formation process with enforced NH3 and NO2 control measures. In addition to explaining the polluted episodes currently occurring in China and during the 1952 London Fog, this sulfate production mechanism is widespread, and our results suggest a way to tackle this growing problem in China and much of the developing world