WJD 5~h Anniversary Special Issues(1):Insulin Insulin and bone:Recent developments

While insulin-like growth factorⅠis a well-known anabolic agent in bone evidence is beginning to accumulate that its homologue,insulin,also has some anabolic properties for bone.There is specific evidence that insulin may work to stimulate osteoblast differentiation,which in turn would enhance production of osteocalcin,the osteoblast-produced peptide that can stimulate pancreaticβcell proliferation and skeletal muscle insulin sensitivity.It is uncertain whether insulin stimulates bone directly or indirectly by increasing muscle work and therefore skeletal loading.We raise the question of the sequence of events that occurs with insulin resistance,such as type 2 diabetes.Evidence to date suggests that these patients have lower serum concentrations of osteocalcin,perhaps reduced skeletal loading,and reduced bone strength as evidenced by microindentation studies.

Strategies to rescue steatotic livers before transplantation in clinical and experimental studies

The shortage of donor livers has led to an increased use of organs from expanded criteria donors. Included are livers with steatosis, a metabolic abnormality that increases the likelihood of graft complications posttransplantation. After a brief introduction on the etiology, pathophysiology, categories and experimental models of hepatic steatosis, we herein review the methods to rescue steatotic donor livers before transplantation applied in clinical and experimental studies. The methods span the spectrum of encouraging donor weight loss, employing drug therapy, heat shock preconditioning, ischemia preconditioning and selective anesthesia on donors, and the treatment on isolated grafts during preservation. These methods work at different stages of transplantation process, although share similar molecular mechanisms including lipid metabolism stimulation through enzymes or nuclear receptor e.g. , peroxisomal proliferator-activated receptor, or anti-inflammation through suppressing cytokines e.g. , tumor necrosis factor-α, or antioxidant therapies to alleviate oxidative stress. This similarity of molecular mechanisms implies possible future attempts to reinforce each approach by repeating the same treatment approach at several stages of procurement and preservation, as well as utilizing these alternative approaches in tandem.

Recognition of an additional mechanism leading to myocardial abnormalities

A growing body of evidence explicitly suggests the significant role of inflammatory processes in the development and progressive deterioration of vascular diseases and cardiomyopathies.1-3 In recent years, a large variety of infections have been reported to be associated with the development of cardiomyopathy; the pathogenic factors include rickets, bacteria, protozoa and other parasites,and also, at least 17 viruses.2。

Tracking of Labelled Stem Cells Using Molecular MR Imaging in a Mouse Burn Model <i>in Vivo</i>as an Approach to Regenerative Medicine

Therapies based on stem cell transplants offer significant potential in the field of regenerative medicine. Monitoring the fate of the transplanted stem cells in a timely manner is considered one of the main limitations for long-standing success of stem cell transplants. Imaging methods that visualize and track stem cells in vivo non-invasively in real time are helpful towards the development of successful cell transplantation techniques. Novel molecular imaging methods which are non-invasive particularly such as MRI have been of great recent interest. Hence, mouse models which are of clinical relevance have been studied by injecting contrast agents used for labelling cells such as super-paramagnetic iron-oxide (SPIO) nanoparticles for cellular imaging. The MR techniques which can be used to generate positive contrast images have been of much relevance recently for tracking of the labelled cells. Particularly when the off-resonance region in the vicinity of the labeled cells is selectively excited while suppressing the signals from the non-labeled regions by the method of spectral dephasing. Thus, tracking of magnetically labelled cells employing positive contrast in vivo MR imaging methods in a burn mouse model in a non-invasive way has been the scope of this study. The consequences have direct implications for monitoring labeled stem cells at some stage in wound healing. We suggest that our approach can be used in clinical trials in molecular and regenerative medicine.

Why so little effort to study anti-oxidant therapy in burns?

Given that oxidative stress is an inherent response to burn injury,it is puzzling as to why investigation into anti-oxidant therapy as an adjunct to burn treatment has been limited.Both the inflammatory response and the stress response to burn injury involve oxidative stress,and there has been some limited success in studies using gamma tocopherol and selenium to improve certain consequences of burns.Much remains to be done to investigate the number,doses and combinations of anti-oxidants,their efficacy,and limitations in improving defined outcomes after burn injury.

Temporal gradients limit the accumulation of neutrophils toward sources of chemoattractant

Neutrophil trafficking during inflammation is a highly orchestrated process,coordinating neutrophil recruitment,sterilization of the wound,and inflammation resolution.Although the chemotactic signals guiding neutrophil recruitment to sites of inflammation are relatively well understood,our knowledge of mechanisms controlling cessation of neutrophil recruitment and return to normal tissue physiology remains incomplete.To gain insights into these processes,we designed a microfluidic device with an array of chemoattractant reservoirs,which mimics the microenvironment in infected tissues,when multiple clusters of microbes are present.We monitored the temporal dynamics of neutrophil recruitment toward the chemoattractant reservoirs at single cell resolution,for 3 h.We observed robust neutrophil recruitment that reached a plateau after 1.5 h,despite the continuous presence of strong chemoattractant gradients around the reservoirs.The timing of the plateau was dependent on the geometry of the devices and was independent from the number of neutrophils.On the basis of these observations,we ruled out sub-population sensitivity,chemoattractant scavenging,and production of a self-limiting stop signal as potential mechanisms underpinning the plateau in neutrophil recruitment.We found a strong correlation between the temporal stabilization of concentration changes and the plateau in neutrophils recruitment.These results suggest that dynamic aspects of chemoattractant gradients are key for maximizing recruitment during the acute phase of infections and limiting the accumulation of neutrophils as soon as the infection is contained.

Effects of enteral nutrition with different energy supplies on metabolic changes and organ damage in burned rats

Background:Enteral nutrition(EN)is an important treatment for burn patients.However,severe gastrointestinal damage caused by major burns often leads to EN intolerance.Trophic EN solves this problem basically,but how to transition from trophic EN to standard EN smoothly is still a challenge in burn clinical nutrition.The aim of this study is to investigate the effects of EN with different energy supplies on metabolic changes,organ damage and prognosis in burned rats.Methods:Different feeding regimens were designed based on the continuous monitoring of resting energy expenditure in rats.Thirty-two Sprague-Dawley rats were randomly divided into a normal control group,burn+50%REE group,burn+75%REE group and burn+100%REE group.At the end of a nutritional treatment cycle(14th day),nuclear magnetic resonance spectroscopy,blood biochemistry analysis and quantification of subscab bacteria were performed to explore the differences in metabolic changes,degrees of organ damage and prognoses between the groups.Results:Sixteen metabolites involving seven metabolic pathways were identified from the different energy supply groups.After burn injury,resting energy consumption and body weight loss increased obviously.Meanwhile,weight loss was inversely related to energy supply.The greatest changes in the degree of organ damage,the level of plasma proteins,lipids and endotoxins,as well as the quantification of subscab bacteria were observed in the 50%REE group,followed by the 75 and 100%groups.Conclusions:Achieving an early balance between energy supply and expenditure is conducive to mitigating metabolic disorders and improving prognosis after burn injury.

Burn injury differentially alters whole-blood and organ glutathione synthesis rates: An experimental model

Previous studies from our laboratories revealed a reduced rate of whole-blood (WB) glutathione (GSH) synthesis in severely burned patients. To determine whether WB GSH metabolism is an indicator of the status of GSH metabolism in one or more of the major organs, we used a burn rabbit model to determine GSH concentrations and rates of synthesis in WB, liver, lungs, kidney, and skeletal muscle. L-[1-13C]-cysteine was infused intravenously for 6 h in rabbits at 3 days post-burn and in sham burn controls. WB and organ 13C-enrichment of cysteine and GSH was determined by gas chromatography/mass spectrometry. Plasma cysteine metabolic flux was increased significantly (P < 0.01) following burn injury. WB, liver, and lung GSH concentrations (P = 0.054, P < 0.05, and P < 0.05, respectively) and fractional rates of GSH synthesis (P < 0.05, P< 0.01, and P< 0.05, respectively) were reduced at 3 days post-burn. Kidney was unaffected. There also appears to be an increased rate of GSH transport out of the liver after burn injury. Hence, there is a differential impact of burn injury on tissue and organ GSH status, with WB qualitatively reflecting the changes in lung and liver. It will be important to determine whether these changes are due to alterations in the intrinsic capacity for GSH synthesis and/or availability of amino acid precursors of GSH.