Histamine modulates nitric oxide release by microglia and dopaminergic neuronal survival

Microglia cells, the resident immune cells in the brain, play a critical role in the development and progression of several neurodegenerative diseases. Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons (DA) in the substantia nigra (SN), striatal dopamine depletion and motor impairments. Accumulating clinical and experimental evidences suggest that neuroinflammation plays a critical role in the pathogenesis of PD through the activation of microglia cells and the subsequent production of a vast array of inflammatory mediators, including nitric oxide (NO). Histamine (HIS), an amine that acts as a neurotransmitter and inflammatory mediator, has been reported to play a role in the pathogenesis of PD. Indeed, alterations in the histaminergic innervations in the striatum and SN and increased histamine concentrations in the blood, striatum and SN were found in PD patients. Based on these data, our aim was to uncover the effects of histamine on microglia cells derived from the SN of Wistar rats and then evaluate whether soluble factors released by microglia previously stimulated with histamine could modulate dopaminergic neuronal survival. Firstly, microglia cell cultures were used to study the effects of HIS and its receptors on NO production, which was measured by the Griess assay. We demonstrated that HIS triggered an increase of NO production as compared with control, an effect mediated by histamine H4 receptor (H4R) activation. Interestingly, in the presence of an inflammatory context, mimicked by lipopolysaccharide (LPS), HIS inhibited LPS-induced NO production not only by H4R but, possibly through histamine H1 receptor (H1R) activation. Then, conditioned medium derived from microglia cells (MCM) challenged with HIS and/or LPS was collected to evaluate its effects on the viability of DA neurons present in neuron-astrocyte midbrain co-cultures. In fact, conditioned medium derived from microglia cells exposed to LPS or HIS induced a decrease in the number of Tyrosine Hydroxylase positive neurons; whereas this noxious effect was abolished when MCM obtained from microglia challenged with HIS plus LPS was used. Curiously, the same effects were observed when HIS and/or LPS were added directly on neuron-astrocyte midbrain co-cultures. Together, our results suggest that HIS per se acts as a pro-inflammatory mediator, whereas, in an inflammatory context, HIS has a putative anti-inflammatory profile that can protect dopaminergic neurons

BALANÇO ENERGÉTICO DE BIOCOMBUSTÍVEIS

A crescente preocupação da sociedade em minimizar o uso de combustíveis fósseis na tentativa de diminuir alterações climáticas e emissões de CO2 conduz ao maior interesse na produção de energias e combustíveis limpos, como biodiesel, bioetanol, biogás, biohidrogênio e biocombustíveis sólidos. Contudo, na obtenção de tais, ainda há a utilização de combustíveis fósseis e baseando-se nisto, o objetivo do presente trabalho é analisar a sustentabilidade de alguns sistemas bioenergéticos, por meio do balanço energético, responsável por analisar toda energia incrementada na obtenção do produto de interesse, desde o plantio da cultura, fertilização, colheita e processamento, até síntese do produto final e energia contida neste, investigando com base nisto a viabilidade de cada processo

Preclinical assessment of mesenchymal-stem-cell-based therapies in spinocerebellar ataxia type 3

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)—or Machado–Joseph disease (MJD)—is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation—particularly in the cerebellum and basal ganglia—while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.This research was funded by the National Ataxia Foundation (NAF) and by Portuguese national funds, through the Foundation for Science and Technology (FCT)—projects UIDB/50026/2020, UIDP/50026/2020, POCI-01-0145-FEDER-029206, and through the Santa Casa Neuroscience Awards (Santa Casa da Misericórdia Lisboa)—project MC-04/17. Additionally, this project was funded by the ICVS Scientific Microscopy Platform, a member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122). S.C.S. received an individual fellowship within the project TUBITAK/0007/2014. The FCT funded individual fellowships to J.S C., A.N.-C., B.M.- P., F.G.T., R.L., S.M., N.A.S., C.S.-C., and S.D.-S. (SFRH/BD/140624/2018, SFRH/BPD/118779/2016, SFRH/BD/120124/2016, SFRH/BPD/118408/2016, PD/BDE/127836/2016, CEECIND/01902/2017, CEECIND/04794/2017, CEECIND/03887/2017, and CEECIND/00685/2020)

Avaliação da Cicatrização Óssea Troclear de coelhos utilizando implantes à base de Policaprolactona, Beta-Trifosfato de cálcio e Wollastonita ou Bredigita associados ou não à Vancomicina / Evaluation of the Trochlear Bone Scarring of rabbits using implants based on Polycaprolactone, Calcium Beta-Trifosphate and Wollastonite or Bredigit associated or not with Vancomycin

O objetivo deste trabalho foi avaliar a cicatrização óssea troclear de coelhos pelo uso de scaffolds à base de policaprolactona (PCL), beta-trifosfato de cálcio (?-TCP) e wallostonita (W) ou bredigita (BRE) associados ou não à vancomicina (VANCO). Foram utilizados 12 coelhos adultos, sendo 8 machos e 4 fêmeas, mestiços da linhagem Nova Zelândia, pesando em média 3,0 kg. Os animais tiveram seus membros divididos por sorteio em quatro grupos de acordo com a composição do biomaterial implantado. Os implantes foram introduzidos na tróclea femoral dos animais de acordo com o grupo experimental. Foram realizadas avaliações clínico-ortopédicas, radiográficas e histopatológica. Os animais apresentaram evolução clínica normal sem alterações da marcha ou atrofia muscular. Na avaliação radiográfica foi observada gradativa redução da reação inflamatória em comparação as avaliações dos 30 e 60 dias, sugerindo biocompatibilidade dos implantes em ambos os grupos, não foi observada diferença entre os grupos. Na avaliação histológica e morfométrica, os grupos com implantes PCL/?-TCP/W/VANCO e PCL/?-TCP/BRE/VANCO em sua composição apresentaram maior quantidade de tecido neoformado ao redor dos implantes do que os grupos PCL/?-TCP/W e PCL/?-TCP/BRE