Analysis of the efficacy of prophylactic tranexamic acid in preventing postpartum bleeding: systematic review with meta-analysis of randomized clinical trials.

BACKGROUND: Postpartum Hemorrhage (PPH) is one of the main causes of maternal mortality, mainly in the poorest regions of the world, drawing attention to the need for strategies for preventing it. This study aims to evaluate the efficacy of prophylactic administration of Tranexamic Acid (TXA) in decreasing blood loss in pregnant women in delivery, preventing PPH. METHODS: Systematic review of randomized clinical trials. We searched for publications in PubMed, EMBASE and Cochrane Library databases, with the uniterms "postpartum, puerperal hemorrhage" and "tranexamic acid", published between January of 2004 and January of 2020. The eligibility criteria were trials published in English with pregnant women assessed during and after vaginal or cesarean delivery about the effect of prophylactic use of TXA on bleeding volume. The random-effects model was applied with the DerSimonian-Laird test and the Mean Difference (MD) was calculated for continuous variables together with each 95% CI. This systematic review was previously registered in the PROSPERO platform under the registration n° CRD42020187393. RESULTS: Of the 630 results, 16 trials were selected, including one with two different doses, performing a total of 6731 patients. The intervention group received a TXA dose that varied between 10 mg.kg-1 and 1g (no weight calculation). The TXA use was considered a protective factor for bleeding (MD: -131.07; 95% CI: -170.00 to -92.78; p = 0.000) and hemoglobin variation (MD: -0.417; 95% CI: -0.633 to -0.202; p = 0.000). In the subgroup analysis related to the cesarean pathway, the effect of TXA was even greater. CONCLUSION: The prophylactic use of tranexamic acid is effective in reducing the post-partum bleeding volume. PROSPERO REGISTRATION ID: CRD42020187393.

Analysis of the efficacy of prophylactic tranexamic acid in preventing postpartum bleeding: systematic review with meta-analysis of randomized clinical trials

Abstract Background Postpartum Hemorrhage (PPH) is one of the main causes of maternal mortality, mainly in the poorest regions of the world, drawing attention to the need for strategies for preventing it. This study aims to evaluate the efficacy of prophylactic administration of Tranexamic Acid (TXA) in decreasing blood loss in pregnant women in delivery, preventing PPH. Methods Systematic review of randomized clinical trials. We searched for publications in PubMed, EMBASE and Cochrane Library databases, with the uniterms "postpartum, puerperal hemorrhage" and "tranexamic acid", published between January of 2004 and January of 2020. The eligibility criteria were trials published in English with pregnant women assessed during and after vaginal or cesarean delivery about the effect of prophylactic use of TXA on bleeding volume. The random-effects model was applied with the DerSimonian-Laird test and the Mean Difference (MD) was calculated for continuous variables together with each 95% CI. This systematic review was previously registered in the PROSPERO platform under the registration n° CRD42020187393. Results Of the 630 results, 16 trials were selected, including one with two different doses, performing a total of 6731 patients. The intervention group received a TXA dose that varied between 10 mg.kg−1 and 1g (no weight calculation). The TXA use was considered a protective factor for bleeding (MD: -131.07; 95% CI: -170.00 to -92.78; p= 0.000) and hemoglobin variation (MD: -0.417; 95% CI: -0.633 to -0.202; p= 0.000). In the subgroup analysis related to the cesarean pathway, the effect of TXA was even greater. Conclusion The prophylactic use of tranexamic acid is effective in reducing the post-partum bleeding volume. PROSPERO registration ID CRD42020187393.

Rutin improves glutamate uptake and inhibits glutamate excitotoxicity in rat brain slices.

Rutin is an important flavonoid consumed in the daily diet. It is also known as vitamin P and has been extensively investigated due to its pharmacological properties. On the other hand, neuronal death induced by glutamate excitotoxicity is present in several diseases including neurodegenerative diseases. The neuroprotective properties of rutin have been under investigation, although its mechanism of action is still poorly understood. We hypothesized that the mechanisms of neuroprotection of rutin are associated with the increase in glutamate metabolism in astrocytes. This study aimed to evaluate the protective effects of rutin with a focus on the modulation of glutamate detoxification. We used brain organotypic cultures from post-natal Wistar rats (P7-P9) treated with rutin to evaluate neural cell protection and levels of proteins involved in the glutamate metabolism. Moreover, we used cerebral cortex slices from adult Wistar rats to evaluate glutamate uptake. We showed that rutin inhibited the cell death and loss of glutamine synthetase (GS) induced by glutamate that was associated with an increase in glutamate-aspartate transporter (GLAST) in brain organotypic cultures from post-natal Wistar rats. Additionally, it was observed that rutin increased the glutamate uptake in cerebral cortex slices from adult Wistar rats. We conclude that rutin is a neuroprotective agent that prevents glutamate excitotoxicity and thereof suggest that this effect involves the regulation of astrocytic metabolism.

Aminochrome decreases NGF, GDNF and induces neuroinflammation in organotypic midbrain slice cultures.

Recent evidence shows that aminochrome induces glial activation related to neuroinflammation. This dopamine derived molecule induces formation and stabilization of alpha-synuclein oligomers, mitochondria dysfunction, oxidative stress, dysfunction of proteasomal and lysosomal systems, endoplasmic reticulum stress and disruption of the microtubule network, but until now there has been no evidence of effects on production of cytokines and neurotrophic factors, that are mechanisms involved in neuronal loss in Parkinson's disease (PD). This study examines the potential role of aminochrome on the regulation of NGF, GDNF, TNF-α and IL-1ß production and microglial activation in organotypic midbrain slice cultures from P8 - P9 Wistar rats. We demonstrated aminochrome (25 µM, for 24 h) induced reduction of GFAP expression, reduction of NGF and GDNF mRNA levels, morphological changes in Iba1+ cells, and increase of both TNF-α, IL-1ß mRNA and protein levels. Moreover, aminochrome (25 µM, for 48 h) induced morphological changes in the edge of slices and reduction of TH expression. These results demonstrate neuroinflammation, as well as negative regulation of neurotrophic factors (GDNF and NGF), may be involved in aminochrome-induced neurodegeneration, and they contribute to a better understanding of PD pathogenesis.

Aminochrome induces microglia and astrocyte activation.

Aminochrome has been suggested as a more physiological preclinical model capable of inducing five of the six mechanisms of Parkinson's Disease (PD). Until now, there is no evidence that aminochrome induces glial activation related to neuroinflammation, an important mechanism involved in the loss of dopaminergic neurons. In this study, the potential role of aminochrome on glial activation was studied in primary mesencephalic neuron-glia cultures and microglial primary culture from Wistar rats. We demonstrated that aminochrome induced a reduction in the number of viable cells on cultures exposed to concentration between 10 and 100µM. Moreover, aminochrome induces neuronal death determined by Fluoro-jade B. Furthermore, we demonstrated that aminochrome induced reduction in the number of TH-immunoreactive neurons and reactive gliosis, featured by morphological changes in GFAP+ and Iba1+ cells, increase in the number of OX-42+ cells and increase in the number of NF-κB p50 immunoreactive cells. These results demonstrate aminochrome neuroinflammatory ability and support the hypothesis that it may be a better PD preclinical model to find new pharmacological treatment that stop the development of this disease.

Autophagy protects against neural cell death induced by piperidine alkaloids present in Prosopis juliflora (Mesquite).

Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD) and autophagy on the mechanism of cell death induced by a total extract (TAE) of alkaloids and fraction (F32) from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL) and F32 (7.5 µg/mL) induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.

Autophagy protects against neural cell death induced by piperidine alkaloids present in Prosopis juliflora (Mesquite)

ABSTRACT Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD) and autophagy on the mechanism of cell death induced by a total extract (TAE) of alkaloids and fraction (F32) from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL) and F32 (7.5 µg/mL) induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.

Characteristic pattern of skeletal muscle remodelling in different mouse strains.

Muscular injury associated with local inflammatory reaction frequently occurs in sports medicine, but the individual response and capacity of regeneration vary among subjects. Inflammatory cytokines are probably implicated in activation of repair mechanisms by specifically influencing tissue microenvironment. This work aimed to compare muscle tissue repair in different mouse lineages. We used C57BL/6 and BALB/c mice genetically predisposed to either Type1 or Type2 cytokine production. The role of Type1 cytokines was also investigated in C57IFN-γ (IFNγ-KO) and C57IL-12 (IL12-KO) knockout mice. Participation of T lymphocytes was assessed in athymic BALB/c nude (nu/nu) mice. Muscular lesion was induced with bupivacaine injection in the Triceps brachii muscle. BALB/c mice showed marked collagen deposition and increased TGF-ß mRNA content, contrasting with mild fibrosis observed in C57BL/6 mice. C57-IFNγ-KO mice, exhibited pronounced fibrosis, but IL12-KO collagen deposition was similar to that of C57. Twenty-four hours after lesion, C57BL/6 and BALB/c(nu/nu) presented numerous regenerating myofibres and marked increase of metalloprotease-9 activity compared with BALB/c. These data support that skeletal muscle remodelling is greatly influenced by the genetic backgrounds, shedding light on the molecular mechanisms influencing differential muscular remodelling and tissue regeneration among individuals.