Molecular mechanisms underlying the neuroprotection of environmental enrichment in Parkinson’s disease

Parkinson’s disease is the most common movement disorder,affecting about 1%of the population over the age of 60 years.Parkinson’s disease is characterized clinically by resting tremor,bradykinesia,rigidity and postural instability,as a result of the progressive loss of nigrostriatal dopaminergic neurons.In addition to this neuronal cell loss,Parkinson’s disease is characterized by the accumulation of intracellular protein aggregates,Lewy bodies and Lewy neurites,composed primarily of the proteinα-synuclein.Although it was first described almost 200 years ago,there are no disease-modifying drugs to treat patients with Parkinson’s disease.In addition to conventional therapies,non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders.Among such strategies,environmental enrichment,comprising physical exercise,cognitive stimulus,and social interactions,has been assessed in preclinical models of Parkinson’s disease.Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression,enhancing the expression of neurotrophic factors and modulating neurotransmission.In this review article,we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson’s disease,highlighting its influence on the dopaminergic,cholinergic,glutamatergic and GABAergic systems,as well as the involvement of neurotrophic factors.We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson’s disease,highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.

Mesenchymal Stem Cells Express Low Levels of Cardiomyogenic Genes and Show Limited Plasticity towards Cardiomyogenic Phenotype

Mesenchymal stem cell differentiation towards osteogenic, chondrogenic and adipogenic lineages have been extensively described and reproduced in the literature. In contrast, cardiomyogenic differentiation still remains largely controversial. In this study the authors aim to shed new light into this unclear phenomenon and test whether BMMSC （bone marrow mesenchymal stem cells） and ATMSC （adipose tissue derived mesenchymal stem cells） are able to differentiate into functional cardiomyocytes, investigating two differentiation protocols. AT and BMMSC behaved differently when cultured in differentiation media and presented lower levels of proliferation and alkaline phosphatase production, expression of cardiomyocyte-specific transcription factors such as GATA-4, Nkx2-5 and proteins such as ct and 13 Myosin Heavy Chains. Furthermore, MSC started to express higher levels of Connexin-43 and c~ sarcomeric actinin protein. Unfortunately, though, MSC did not present cardiomyocyte-like electrophysiological properties. In order to analyze a possible explanation for such limited plasticity, the authors decided to address the issue using a quantitative approach. Gene expression was quantified by Real time PCR, and, for the first time, the authors show that a possible explanation for limited plasticity of MSC is that even though differentiated cells presented differential gene expression, the levels of key cardiomyogenic genes did not reach expression levels presented by adult cardiomyocytes, nor were maintained along differentiation, reaching peaks at 4 days of stimulation, and decaying thereafter.

Study of the Fibriolytic Inhibition and Clinical Prognosis in Acute Coronary Syndrome Patients Complicated with Type II Diabetes Mellitus

Objectives To study the status of fibrinolytic inhibition in patients of acute coronary syndrome(ACS) complicated with type II diabetes mellitus (NIDDM) and to evaluate the effect of fibrinolytic inhibition to the clinical prognosis. Methods Type II diabetes mellitus was defined by ADA 1997/WHO 1998 criteria. The subjects were divided into treatment groups that included 39 patients of ACS with 20 cases of acute myocardiac infarction (AMI), 36 patients of ACS + NIDOM with 20 cases of AMI. Twenty cases of healthy people were randomized to control group. The plasma level of tissue type plas-minogen activator (t - PA), plasminogen activator inhibitor type - 1 (PAI - 1) and plasma D - dimer were detected by using elisa technique. The index of statue in fibrinolysis was detected with the plasma level of D -dimer and the rate of PAI - 1/D - dimer in percentage. This index was used to evaluate the fibrinolytic inhibition and the clinical outcome in all the patients with AMI in treatment groups. The clinical outcome in patients with AMI consisted of the rate of reperfusion, the incidences of re - infarction, severi-ous arrhythmia, pump failure and death in the early period of AMI. Results The plasma level of PAI - 1 and D - dimer was higher in the two treatment groups than that in the control group ( P < 0. 01). The plasma level of PAI - 1 significantly higher in ACS + NIDDM patients than that in ACS ( P < 0. 05), but the plasma level of D - dimer raised from basic level was significantly lower in ACS + NIDDM than that in ACS ( P < 0. 05) . The rate of PAI - 1 /D - dimer in percentage was significantly higher in ACS + NIDDM than that in ACS or in control group ( P < 0. 01). For AMI patients in two treatment groups, the rate of reperfusion after the thrombolytic therapy was significantly lower in ACS + NIDDM than that in ACS( P < 0. 01) . The rate of incidences in pump failure was significantly higher in ACS + NIDDM than that in ACS too ( P < 0. 05). The morbidity of severious arrhythmia, re - infarction and the mortality were also higher in ACS + NIDDM; however the difference was not significant (P<0. 05) . Conclusions The plasma level of D - dimer combined with the rate of PAI - 1 /D - dimer in percentage could be used to be the evidence and the index to evaluate the status of fibrinolytic inhibition in patients of ACS + NIDDM, and could be used to evaluate the effect of the fibrinolytic inhibition to the outcome of treatment and clinical prognosis in ACS patient.

In Vitro Evaluation of Sida pilosa Retz (Malvaceae) Aqueous Extract and Derived Fractions on Schistosoma mansoni

Sida pilosa Retz. (Malvaceae) is a medicinal plant used in Africa for the treatment of dysmenorrhea, lower abdominal pains and intestinal helminthiasis. S. pilosa aqueous extract and derived fractions were investigated for their bioactivity against Schistosoma mansoni. The aqueous extract from S. pilosa aerial parts (1.25 - 40 mg/mL) and derived fractions (n-hexane, DCM, EtOAc and n-BuOH: 0.25 - 8 mg/mL) were tested on adult S. mansoni maintained in a GMEN culture medium. Praziquantel was used as the reference drug. After 24 h of incubation, worms were monitored for their viability and egg output. The antioxidant activity of S. pilosa was evaluated by the ability to scavenge the 2,2-diphenyl-1-picrylhydrazyl free radicals. The chemical composition of the n-BuOH fraction was investigated by HPLC-MS analysis. S. pilosa aqueous extract and fractions significantly increased worm mortality in a concentration-dependent manner. The n-BuOH fraction was the most active with a LC50 of 1.25 mg/mL. Significant reduction of motor activity (25% to 100%) was recorded for surviving worms incubated in different concentrations of the extract and fractions. Incubation of S. mansoni in different concentrations of S. pilosa extract and fractions led to significant reduction of egg laying (52% to 100%). The aqueous extract and derived fractions exhibited antioxidant activity in a concentration-dependent manner. The highest antioxidant activity was found with the EtOAc fraction, followed by the DCM and n-BuOH fractions. HPLC-MS analysis of the n-butanol fraction revealed the presence of two indoloquinoline alkaloids. This study disclosed the schistosomicidal activity of the n-butanol fraction from S. pilosa aqueous extract. This activity is probably related to the indoloquinoline alkaloids identified in the fraction.

Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system （RAS） have progressively assumed an important role. Angiotensin （Ang） II acts as a profibrotic mediator and Ang-（1-7）, the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-（1-7）- Mas receptor axis.

Lactobacillus bulgaricus inhibits colitis-associated cancer via a negative regulation of intestinal inflammation in azoxymethane/dextran sodium sulfate model

BACKGROUND Colitis-associated cancer(CAC)accounts for 2%-3%of colorectal cancer(CRC)cases preceded by inflammatory bowel diseases(IBD)such as Crohn's disease and ulcerative colitis.Intestinal microbiota has been reported to play a central role in the pathogenesis of IBD and CAC.Recently,numerous prebiotics and probiotics have being investigated as antitumor agents due to their capacity to modulate inflammatory responses.Previous studies have indicated that lactic acid bacteria could be successfully used in managing sporadic CRC,however little is known about their role in CAC.AIM To investigate the effect of the probiotic Lactobacillus bulgaricus(L.bulgaricus)during the development of an experimental model of colitis associated colon cancer(CAC).METHODS C57BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg),followed by three cycles of sodium dextran sulphate diluted in water(5%w/v).Probiotic group received daily L.bulgaricus.Intestinal inflammation was determined by scoring clinical signs.Cytokines levels were determined from colon and/or tumor samples by ELISA BD OptEIATM kits.The level of significance was set at P<0.05.Graphs were generated and statistical analysis performed using the software GraphPad Prism 6.0.RESULTS L.bulgaricus treatment inhibited of total tumor volume and mean size of tumors.In addition,the probiotic also attenuated the clinical signs of intestinal inflammation inducing a decrease in intestinal and tumor levels of IL-6,TNF-α,IL-17,IL-23 and IL-1β.CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC.L.bulgaricus regulates the inflammatory response and preventing CAC.

Nef-M1, a CXCR4 Peptide Antagonist, Enhances Apoptosis and Inhibits Primary Tumor Growth and Metastasis in Breast Cancer

Results from studies with animal models suggest that, in many cancers, CXCR4 is an important therapeutic target and that CXCR4 antagonists may be promising treatments for primary cancers and for metastases. The Nef protein effectively competes with CXCR4’s natural ligand, SDF-1α, and induces apoptosis. As described in this report, the Nef-M1 peptide (Nef protein amino acids 50 - 60) inhibits primary tumor growth and metastasis of breast cancer (BC). Four BC cell lines (MDA-MB-231, MDA-MB-468, MCF 7, and DU4475) and primary human mammary epithelium (HME) cells were evaluated for their response to the Nef protein and to the Nef-M1 peptide. The presence of CXCR4 receptors in these cells was determined by RT-PCR, Western blot (WB), and immunohistochemical analyses. The apoptotic effect of Nef-M1 was assessed by terminal transferase dUTP nick-end labeling (TUNEL). WBs was used to assess caspase 3 activation. BC xenografts grown in SCID mice were evaluated for the presence of CXCR4 and for their metastatic potential. CXCR4 was presented in MDA-MB-231, MCF 7, and DU 4475 BC cells but not in MDA-MB-468 BC or HME cells. Cells expressing CXCR4 and treated with Nef-M1 peptide or the Nef protein had higher rates of apoptosis than untreated cells. Caspase-3 activation increased in MDA-MB 231 cells treated with the Nef protein, the Nef 41 - 60 peptide, or Nef-M1. Nef-M1, administered to mice starting at the time of xenograft implantation, inhibited growth of primary tumors and metastatic spread. Untreated mice developed diffuse intraperitoneal metastases. We conclude that, in BCs, Nef-M1, through interaction with CXCR4, inhibits primary tumor growth and metastasis by causing apoptosis.

Murine model to study brain,behavior and immunity during hepatic encephalopathy

AIM:To propose an alternative model of hepatic encephalopathy(HE) in mice,resembling the human features of the disease.METHODS:Mice received two consecutive intraperitoneal injections of thioacetamide(TAA) at low dosage(300 mg/kg).Liver injury was assessed by serum transaminase levels(ALT) and liver histology(hematoxylin and eosin).Neutrophil infiltration was estimated by confocal liver intravital microscopy.Coagulopathy was evaluated using prolonged prothrombin and partial thromboplastin time.Hemodynamic parameters were measured through tail cuff.Ammonia levels were quantified in serum and brain samples.Electroencephalography(EEG) and psychomotor activity score were performed to show brain function.Brain edema was evaluated using magnetic resonance imaging.RESULTS:Mice submitted to the TAA regime developed massive liver injury,as shown by elevation of serum ALT levels and a high degree of liver necrosis.An intense hepatic neutrophil accumulation occurred in response to TAA-induced liver injury.This led to mice mortality and weight loss,which was associated with severe coagulopathy.Furthermore,TAA-treated mice presented with increased serum and cerebral levels of ammonia,in parallel with alterations in EEG spectrum and discrete brain edema,as shown by magnetic resonance imaging.In agreement with this,neuropsychomotor abnormalities ensued 36 h after TAA,fulfilling several HE features observed in humans.In this context of liver injury and neurological dysfunction,we observed lung inflammation and alterations in blood pressure and heart rate that were indicative of multiple organ dysfunction syndrome.CONCLUSION:In summary,we describe a new murine model of hepatic encephalopathy comprising multiple features of the disease in humans,which may provide new insights for treatment.

Immunization with rPb27 Protects Mice from the Disruption of VEGF Signaling in Paracoccidioides brasiliensis Infection

VEGF （Vascular endothelial growth factor） signaling is critical for endothelial cell survival and maintenance of the vasculature. Deregulation of VEGF signaling contributes to the physiopathology of many diseases. However, the ways in which infection with Paracoccidioides brasiliensis affects VEGF signaling and the influence of immunization with rPb27 （recombinant protein Pb27） on VEGF signaling have not yet been studied. Animals were immunized with rPb27 and subsequently infected with a virulent strain of P. brasiliensis. The fungal load was evaluated by measuring CFU （colony-forming unit） and histology was performed to evaluate the inflammatory reaction. At the two time points analyzed, the PC （positive control） and TREAT （treated） animals had decreased levels of pulmonary VEGF compared to basal levels. However, in the immunized （Pb27） and treated mice （Pb27 ＋ TREAT）, VEGF expression remained unchanged after infection. In the case of VEGFR-2, the Pb27 and Pb27 ＋ TREAT groups showed increased levels of expression. Regarding the levels of the eNOS enzyme, only the Pb27 group did not reduce the expression levels relative to baseline. The immunization with rPb27 kept VEGF signaling, NO production and increased VEGFR-2 expression, after infection with P. brasiliensis. Thus, the authors infer that immunization with rPb27 protects mice from the disruption of VEGF signaling in Paracoccidioides brasiliensis infection.

Ursolic Acid Derivatives Induced Apoptosis and Reduces the NF-κB in Human Lung Adenocarcinoma Cells

Lung cancer is the major cause of death in the neoplastic diseases. In spite of the advances in the chemotherapy, the lung cancer treatments are still complex and costly, being necessary the seeking of new drugs. In this context, the ursolic acid (UA) becomes the target of studies that investigate its antitumor potential and, thus, structural modifications can enhance its biological activities. Eight UA semisynthetic derivative compounds (UAD1-8) were synthesized and evaluated their cytotoxic activity against human alveolar adenocarcinoma cells (A549). UAD1, UAD3, UAD5, UAD6 and UAD8 were able to reduce the viability of the A549 cells. Only UAD1 and UAD6 reduced the viability at 24 h, and only UAD3 didn’t reduce the NF-κB expression. The compound UAD1 showed the greater apoptosis induction. Moreover, the compound UAD1 showed better results than UA in all assays. The present study shows, for the first time, the action of these compounds in the apoptotic effect, in the expression of NF-κB and in the A549 cell line. The ursolic acid derivatives showed substantial results in the apoptosis, cytotoxicity and NF-κB inhibition of A549 cells, and further studies are necessary for the development of possible new therapeutic drugs.

Why not change classical treatments for glioblastoma in elderly patients?

In consideration of the poor results obtained with conventional treatments, a review of alternative treatments for elderly patients with glioblastoma was researched in this study. The proposal considers the elimination of human cytomegalovirus, modifying the immune response, arresting growths, blocking some signaling pathways, and modulating the effects of oxygen reactive species.

Intestinal microbiota and juvenile idiopathic arthritis:current understanding and future prospective

Background Juvenile idiopathic arthritis(JIA)characterized by arthritis of unknown origin is the most common childhood chronic rheumatic disease,caused by both host genetic factors and environmental triggers.Recent evidence has mounted to focus on the intestinal microbiota,a potentially recognized set of environmental triggers affecting JIA development.Here we offer an overview of recently published animal and human studies that support the impact of intestinal microbiota in JIA.Data sources We searched PubMed for animal and human studies publications with the search terms"intestinal microbiota or gut microbiota"and"juvenile idiopathic arthritis or juvenile chronic arthritis or juvenile rheumatoid arthritis or childhood rheumatoid arthritis or pediatric rheumatoid arthritis".Results Several comparative studies have demonstrated that intestinal microbial alterations might be triggers in disease pathogenesis.Alternatively,a slice of studies has suggested environmental triggers in early life might disrupt intestinal microbial colonization,including cesarean section,formula feeding,and antibiotic exposure.Aberrant intestinal microbiota may influence the development of JIA by mediating host immune programming and by altering mucosal permeability.Conclusions Specific microbial factors may contribute to the pathogenesis of JIA.Intensive studies,however,are warranted to investigate the causality between intestinal dysbiosis and JIA and the mechanisms behind these epidemiologic relationships.Studies are also needed to design the best interventional administrations to restore balanced intestinal microbial communities.