Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128

Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.

Adult neurogenesis:a real hope or a delusion?

Adult neurogenesis,the process of creating new neurons,involves the coordinated division,migration,and differentiation of neural stem cells.This process is restricted to neurogenic niches located in two distinct areas of the brain:the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle,where new neurons are generated and then migrate to the olfactory bulb.Neurogenesis has been thought to occur only during the embryonic and early postnatal stages and to decline with age due to a continuous depletion of neural stem cells.Interestingly,recent years have seen tremendous progress in our understanding of adult brain neurogenesis,bridging the knowledge gap between embryonic and adult neurogenesis.Here,we discuss the current status of adult brain neurogenesis in light of what we know about neural stem cells.In this notion,we talk about the importance of intra cellular signaling molecules in mobilizing endogenous neural stem cell prolife ration.Based on the current understanding,we can declare that these molecules play a role in targeting neurogenesis in the mature brain.However,to achieve this goal,we need to avoid the undesired proliferation of neural stem cells by controlling the necessary checkpoints,which can lead to tumorigenesis and prove to be a curse instead of a blessing or hope.

Axon guidance in regeneration of the mature central nervous system:step by step

Unlocking axon regeneration in the injured central nervous system:In adult mammals,central nervous system(CNS)neurons fail to regenerate a?ter a lesion,whether it is traumatic–after spinal cord injury for example–or in the case of neurodegenerative diseases.This causes axons to degenerate and neurons to die.

Exercise sustains the hallmarks of health

Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.

Light-controlled phosphorylation in the TrkA-Y785 site by photosensitive UAAs activates the MAPK/ERK signaling pathway

Background:This paper aims to establish a light-controlled phosphorylation detection method at the Y785 site of tropomyosin receptor kinase A(TrkA)receptor in mammalian cells by using genetic code expansion technology and detecting the effects of optical activation of this site on the downstream MAPK/ERK pathway.The study is based on the current situation that the regulatory mechanism of TrkA phosphorylation has not been fully elucidated.Methods:Two photosensitive unnatural amino acids,p-azido-L-phenylalanine(AzF)and photo-caged tyrosine(ONB)were introduced into the TrkA-Y785 site by genetic code expansion technology and site-directed mutagenesis.Western blotting and laser confocal imaging were conducted to analyze the effects of this site on activating the MAPK/ERK pathway and nerve cell differentiation before and after photostimulation.Results:Our results supplemented the light-controlled results of the TrkA-Y785 site based on our previous research and verified that Y785 also makes important contributions in regulating the MAPK/ERK pathway.Conclusion:This study demonstrated the significant contributions of the TrkAY785 site in regulating the ERK pathway by precisely controlling the phosphorylation state of a single tyrosine site.

Upper gastrointestinal bleeding due to left side portal hypertension after pancreatic surgery

Left-side portal hypertension(LSPH)is a rare cause of intraabdominal venous hypertension.In most of cases,LSPH is due to pancreatic diseases,especially chronic pancreatitis,but it is also described in other abdominal diseases(i.e.,retroperitoneal fibrosis or perineal abscess)after abdominal surgery(i.e.,pancreatic surgery,liver transplantation)or endovascular procedures[1–4].

Long-Term Persistent Absolute Insulin Secretion Deficiency in Diabetes Induced by Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are today an immense hope in the management of cancers. However, since their widespread use, many cases of insulin-requiring diabetes appearing suddenly, as fulminant diabetes have been reported. Here, we describe 4 cases that occurred at different times after the beginning of immune checkpoint inhibitor therapy with Nivolumab alone or associated with Ipilimumab. There are 3 cases of newly diagnosed diabetes and 1 case of known type 2 diabetes formerly quite well balanced with Metformin. The clinical and biological characteristics of these patients are quite similar. They were all insulin-requiring at the discovery of diabetes and remained so throughout their follow-up. This type of diabetes which looks like type 1 diabetes seems rather to be a new entity.

How to deal with right hepatic artery coming from the superior mesenteric artery during minimally invasive pancreaticoduodenectomy: A systematic review

Background: Anatomical variations in the liver arterial supply are quite common and can affect the surgical strategy when performing a minimally invasive pancreaticoduodenectomy(MIPD). Their presence must be preemptively detected to avoid postoperative liver and biliary complications. Data sources: Following the PRISMA guidelines and the Cochrane protocol we conducted a systematic review on the management of an accessory or replaced right hepatic artery(RHA) arising from the superior mesenteric artery when performing an MIPD. Results: Five studies involving 118 patients were included. The most common reported management of the aberrant RHA was conservative(97.0%);however, patients undergoing aberrant RHA division without reconstruction did not develop liver or biliary complications. No differences in postoperative morbidity or long-term oncological related overall survival were reported in all the included studies when comparing MIPD in patients with standard anatomy to those with aberrant RHA. Conclusions: MIPD in patients with aberrant RHA is feasible without increase in morbidity and mortality. As preoperative strategy is crucial, we suggested planning an MIPD with an anomalous RHA focusing on preoperative vascular aberrancy assessment and different strategies to reduce the risk of liver ischemia.

Peri-operative score for elderly patients with resectable hepatocellular carcinoma

BACKGROUND Liver resection is the mainstay for a curative treatment for patients with resectable hepatocellular carcinoma(HCC),also in elderly population.Despite this,the evaluation of patient condition,liver function and extent of disease remains a demanding process with the aim to reduce postoperative morbidity and mortality.AIM To identify new perioperative risk factors that could be associated with higher 90-and 180-d mortality in elderly patients eligible for liver resection for HCC considering traditional perioperative risk scores and to develop a risk score.METHODS A multicentric,retrospective study was performed by reviewing the medical records of patients aged 70 years or older who electively underwent liver resection for HCC;several independent variables correlated with death from all causes at 90 and 180 d were studied.The coefficients of Cox regression proportional-hazards model for sixmonth mortality were rounded to the nearest integer to assign risk factors'weights and derive the scoring algorithm.RESULTS Multivariate analysis found variables(American Society of Anesthesiology score,high rate of comorbidities,Mayo end stage liver disease score and size of biggest lesion)that had independent correlations with increased 90-and 180-d mortality.A clinical risk score was developed with survival profiles.CONCLUSION This score can aid in stratifying this population in order to assess who can benefit from surgical treatment in terms of postoperative mortality.

Interest of Cardiac Rehabilitation in Patients with Heart Disease in a Cardiology Department in Senegal

Cardiac rehabilitation helps improve the prognosis and quality of life for patients with heart disease. To show its interest in the African context, in the management of heart disease, a prospective study was carried out. Its objective was to evaluate the effects of physical rehabilitation on cardiac function. Methods: Patients were evaluated at the beginning and at the end of cardiovascular rehabilitation by cardiovascular, biological, and echocardiographic parameters including the size of the heart chambers, the kinetics of the walls, and the systolic function of the ventricles. Results: The study involved 12 patients, 67% of whom were men. After cardiac rehabilitation, the mean hemodynamic constants had not been significantly modified. However, a significant decrease in Total-Cholesterol, LDL-Cholesterol and triglyceride levels was noted. Mean fasting blood sugar decreased from 1.25 ± 0.48 g/L to 0.92 ± 0.18 g/L and glycated hemoglobin from 7.72% ± 0.01% to 6.45% ± 0.008%. The echocardiographic parameters studied showed an improvement in the dilation of the heart chambers in 8.33% of the patients, the normalization of the ejection fraction of the left ventricle in 16% patients, the improvement of the kinetic disorders in 16% of patients and recovery of right ventricular systolic function in all patients. Conclusion: Cardiac rehabilitation as a secondary preventive measure for cardiovascular disease has contributed significantly to improving the clinico-biological parameters of the disease.

Overview of macroautophagy regulation in mammalian cells

Macroautophagy 是 multistep， vacuolar，在 lysosomal 分隔空间终止的降级小径，和它具有在织物动态平衡的基本重要性。在这评论，我们在我们 autophagosomes 的形成的理解根据最近的进展考虑 macroautophagy，它是扣押的 double-membrane-bound 液泡细胞质的货物并且把他们送到 lysosomes。在大多数情况中，这最后的步被成熟步在哪个 autophagosomes 与 endocytic 小径交往期间先于。AuTophaGy 相关的基因的发现极大地关于为 autophagosome 形成负责的机制增加了我们的知识，并且也在 autophagosome 成熟的分子的方面的理解有进步。最后，因为 Atg 建筑群的活动被蛋白质 kinases 指向的发现， autophagy 的规定现在更好被理解，并且由于经由在调整 autophagy 基因的表示的抄写因素的原子规定的重要性。

Recent advances in cytokines:Therapeutic implications for inflammatory bowel diseases

Inflammatory bowel diseases(IBDs) are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems.Cytokines are essential mediators between activated immune and non-immune cells,including epithelial and mesenchymal cells.They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells.The physiology of IBD is becoming a very attractive field of research for development of new therapeutic agents.These include cytokines involved in intestinal immune inflammation.This review will focus on mechanisms of action of cytokines involved in IBD and new therapeutic opportunities for these diseases.

Brain-gut-microbiota axis in Parkinson's disease

Parkinson's disease(PD) is characterized by alphasynucleinopathy that affects all levels of the braingut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological,neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding.Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gutmicrobiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.

Vascular endothelial dysfunction and pharmacological treatment

The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smo-king, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide(NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.

Hepatitis C virus: Virology, diagnosis and management ofantiviral therapy

Hepatitis C virus (HCV) infects approximately 170 million individuals worldwide. Prevention of HCV infection complications is based on antiviral therapy with the combination of pegylated interferon alfa and ribavirin. The use of serological and virological tests has become essential in the management of HCV infection in order to diagnose infection, guide treatment decisions and assess the virological response to antiviral therapy. Anti- HCV antibody testing and HCV RNA testing are used to diagnose acute and chronic hepatitis C. The HCV genotype should be systematically determined before treatment, as it determines the indication, the duration of treatment, the dose of ribavirin and the virological monitoring procedure. HCV RNA monitoring during therapy is used to tailor treatment duration in HCV genotype 1 infection, and molecular assays are used to assess the end-of-treatment and, most importantly the sustained virological response, i.e. the endpoint of therapy.

Pathogenesis of hepatitis B virus infection

Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.

Hepatic arterial infusion of gemcitabine-oxaliplatin in a large metastasis from colon cancer

Hepatic arterial infusion (HAI) of chemotherapy can be performed in cases of liver-confined metastatic disease,resulting in increased local drug concentrations.Here we report the case of a 61-year-old man who presented with an isolated large unresectable liver metastasis of colon cancer after failure of surgery and multiple administration of systemic chemotherapy.The patient was treated with a combination of gemcitabine and oxaliplatin using HAI.The tolerance was excellent and a radiological complete response was obtained after 8 cycles of HAI.The rationale for the use of gemcitabine and oxaliplatin as well as that for the combination of the 2 drugs is discussed in this paper.HAI of gemcitabine-oxaliplatin should be evaluated in further clinical trials.

Pre-diagnostic levels of adiponectin and soluble vascular cell adhesion molecule-1 are associated with colorectal cancer risk

AIM: To examine the relationships between pre-diagnostic biomarkers and colorectal cancer risk and assess their relevance in predictive models.METHODS: A nested case-control study was designed to include all first primary incident colorectal cancer cases diagnosed between inclusion in the SUpplémentation en VItamines et Minéraux AntioXydants cohort in 1994 and the end of follow-up in 2007. Cases (n = 50) were matched with two randomly selected controls (n = 100). Conditional logistic regression models were used to investigate the associations between pre-diagnostic levels of hs-CRP, adiponectin, leptin, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1, E-selectin, monocyte chemoattractant protein-1 and colorectal cancer risk. Area under the receiver operating curves (AUC) and relative integrated discrimination improvement (RIDI) statistics were used to assess the discriminatory potential of the models. RESULTS: Plasma adiponectin level was associated with decreased colorectal cancer risk (P for linear trend = 0.03). Quartiles of sVCAM-1 were associated with increased colorectal cancer risk (P for linear trend = 0.02). No association was observed with any of the other biomarkers. Compared to standard models with known risk factors, those including both adiponectin and sVCAM-1 had substantially improved performance for colorectal cancer risk prediction (P for AUC improvement = 0.01, RIDI = 26.5%). CONCLUSION: These results suggest that pre-diagnostic plasma adiponectin and sVCAM-1 levels are associated with decreased and increased colorectal cancer risk, respectively. These relationships must be confirmed in large validation studies.

Trends in incidence and management of cancer of the ampulla of Vater

AIM:To provide trends in incidence,management and survival of cancer of the ampulla of Vater in a welldefined French population.METHODS:Data were obtained from the populationbased digestive cancer registry of Burgundy over a34-year period.Age-standardized incidence rates were computed using the world standard population.Average annual variations in incidence rates were estimated using a poisson regression.A univariate and multivariate relative survival analysis was performed.RESULTS:Age-standardized incidence rates were0.46 and 0.30 per 100000 inhabitants for men and women,respectively.Incidence rate increased from0.26(1976-1984)to 0.58(2003-2009)for men and remained stable for women.Resection for cure was performed in 48.3%of cases.This proportion was stable over the study period.Among cases with curative resection,pancreatico-duodenectomy was performed in94.0%of cases and ampullectomy in 6.0%of cases.A total of 50.8%of cancers of the ampulla of Vater were diagnosed at an advanced stage.Their proportion remained stable throughout the study period.The overall1-and 5-year relative survival rates were 60.2%and27.7%,respectively.Relative survival did not vary over time.Treatment and stage at diagnosis were the most important determinants of survival.The 5-year relative survival rate was 41.5%after resection for cure,9.5%after palliative surgery and 6.7%after symptomatic treatment.In multivariate analysis,only stage at diagnosis significantly influenced the risk of death.CONCLUSION:Cancer of the ampulla of Vater is still uncommon,but its incidence increased for men in Burgundy.Diagnosis is often made at an advanced stage,dramatically worsening the prognosis.

Circulating tumor cell isolation:the assets of filtration methods with polycarbonate track-etched filters

Circulating tumor cells(CTCs) arise from primary or secondary tumors and enter the bloodstream by active or passive intravasation.Given the low number of CTCs,enrichment is necessary for detection.Filtration methods are based on selection of CTCs by size using a filter with 6.5 to 8 μm pores.After coloration,collected CTCs are evaluated according to morphological criteria.Immunophenotyping and fluorescence in situ hybridization techniques may be used.Selected CTCs can also be cultivated in vitro to provide more material.Analysis of genomic mutations is difficult because it requires adapted techniques due to limited DNA materials.Filtration-selected CTCs have shown prognostic value in many studies but multicentric validating trials are mandatory to strengthen this assessment.Other clinical applications are promising such as follow-up,therapy response prediction and diagnosis.Microfluidic emerging systems could optimize filtration-selected CTCs by increasing selection accuracy.