Notes

[Memory of procedures and also methods inside injury lowering: a job interview with Fatima Machado].
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Epidemiological studies indicate that pre-menopausal women are more protected against the development of CVDs compared to men of the same age. Selleck WM-8014 This effect is attributed to the action/effects of sex steroid hormones on the cardiovascular system. In this context, estrogen modulates cardiovascular function in physiological and pathological conditions, being one of the main physiological cardioprotective agents. Here we describe the common pathways and mechanisms by which estrogens modulate the retrograde and anterograde communication between the nucleus and mitochondria, highlighting the role of genomic and non-genomic pathways mediated by estrogen receptors. Additionally, we discuss the presumable role of bromodomain-containing protein 4 (BRD4) in enhancing mitochondrial biogenesis and function in different CVD models and how this protein could act as a master regulator of estrogen protective activity. Altogether, this review focuses on estrogenic control in gene expression and molecular pathways, how this activity governs nucleus-mitochondria communication, and its projection for a future generation of strategies in CVDs treatment.Alzheimer's disease (AD) is a destructive neurodegenerative disease with the progressive dysfunction, structural disorders and decreased numbers of neurons in the brain, which leads to long-term memory impairment and cognitive decline. There is a growing consensus that the development of AD has several molecular mechanisms similar to those of other neurodegenerative diseases, including excessive accumulation of misfolded proteins and neurotoxic substances produced by hyperactivated microglia. Nonetheless, there is currently a lack of effective drug candidates to delay or prevent the progression of the disease. Based on the excellent regenerative and reparative capabilities of stem cells, the application of them to repair or replace injured neurons carries enormous promise. Dental pulp stem cells (DPSCs), originated from ectomesenchyme of the cranial neural crest, hold a remarkable potential for neuronal differentiation, and additionally express a variety of neurotrophic factors that contribute to a protective effect on injured neuronal cells. Notably, DPSCs can also express immunoregulatory factors to control neuroinflammation and potentiate the regeneration and recovery of injured neurons. These extraordinary features along with accessibility make DPSCs an attractive source of postnatal stem cells for the regeneration of neurons or protection of existing neural circuitry in the neurodegenerative diseases. The present reviews the latest research advance in the pathophysiology of AD and elaborate the neurodifferentiation and neuroprotective properties of DPSCs as well as their application prospects in AD.Cellular growth is a fundamental process of life and must be precisely controlled in multicellular organisms. Growth is crucially controlled by the number of functional ribosomes available in cells. The production of new ribosomes depends critically on the activity of RNA polymerase (RNAP) II in addition to the activity of RNAP I and III, which produce ribosomal RNAs. Indeed, the expression of both, ribosomal proteins and proteins required for ribosome assembly (ribosomal biogenesis factors), is considered rate-limiting for ribosome synthesis. Here, we used genetic screening to identify novel transcriptional regulators of cell growth genes by fusing promoters from a ribosomal protein gene (Rpl18) and from a ribosomal biogenesis factor (Fbl) with fluorescent protein genes (RFP, GFP) as reporters. Subsequently, both reporters were stably integrated into immortalized mouse fibroblasts, which were then transduced with a genome-wide sgRNA-CRISPR knockout library. Subsequently, cells with altered reporter activity were isolated by FACS and the causative sgRNAs were identified. Interestingly, we identified two novel regulators of growth genes. Firstly, the exon junction complex protein RBM8A controls transcript levels of the intronless reporters used here. By acute depletion of RBM8A protein using the auxin degron system combined with the genome-wide analysis of nascent transcription, we showed that RBM8A is an important global regulator of ribosomal protein transcripts. Secondly, we unexpectedly observed that the glycolytic enzyme aldolase A (ALDOA) regulates the expression of ribosomal biogenesis factors. Consistent with published observations that a fraction of this protein is located in the nucleus, this may be a mechanism linking transcription of growth genes to metabolic processes and possibly to metabolite availability.Embryonic stem cells (ESCs), which are characterized by the capacity for self-renewal and pluripotency, hold great promise for regenerative medicine. Increasing evidence points to the essential role of mitophagy in pluripotency regulation. Our recent work showed that PINK1/OPTN take part in guarding ESC mitochondrial homeostasis and pluripotency. Evaluating mitophagy in ESCs is important for exploring the relationships between mitochondrial homeostasis and pluripotency. ESCs are smaller in size than adult somatic cells and the mitophagosomes in ESCs are difficult to observe. Many methods have been employed-for example, detecting colocalization of LC3-II and mitochondria-to evaluate mitophagy in ESCs. However, it is important to define an objective way to detect mitophagy in ESCs. Here, we evaluated two commonly used fluorescence-based imaging methods to detect mitophagy in ESCs. By using autophagy- or mitophagy-defective ESC lines, we showed that the mito-Keima (mt-Keima) system is a suitable and effective way for detecting and quantifying mitophagy in ESCs. Our study provides evidence that mt-Keima is an effective tool to study mitophagy function in ESCs.Translational control at the initiation, elongation, and termination steps exerts immediate effects on the rate as well as the spatiotemporal dynamics of new protein synthesis, shaping the composition of the proteome. Translational control is particularly important for cells under stress as during viral infection or in disease conditions such as cancer and neurodegenerative diseases. Much has been learned about the control mechanisms acting at the translational initiation step under normal or pathological conditions. However, problems during the elongation or termination steps of translation can lead to ribosome stalling and ribosome collision, which will trigger ribosome-associated quality control (RQC) mechanism. Inadequate RQC may lead to the accumulation of faulty translation products that perturb protein homeostasis (proteostasis). Proteostasis signifies a cellular state in which the synthesis, folding, and degradation of proteins are maintained at a homeostatic state such that an intact proteome is prespandemic.Preeclampsia, a clinical syndrome mainly characterized by hypertension and proteinuria, with a worldwide incidence of 3-8% and high maternal mortality, is a risk factor highly associated with maternal and offspring cardiovascular disease. However, the etiology and pathogenesis of preeclampsia are complicated and have not been fully elucidated. Obesity, immunological diseases and endocrine metabolic diseases are high-risk factors for the development of preeclampsia. Effective methods to treat preeclampsia are lacking, and termination of pregnancy remains the only curative treatment for preeclampsia. The pathogenesis of preeclampsia include poor placentation, uteroplacental malperfusion, oxidative stress, endoplasmic reticulum stress, dysregulated immune tolerance, vascular inflammation and endothelial cell dysfunction. The notion that placenta is the core factor in the pathogenesis of preeclampsia is still prevailing. G protein-coupled receptors, the largest family of membrane proteins in eukaryotes and the largest drug target family to date, exhibit diversity in structure and function. Among them, the secretin/adhesion (Class B) G protein-coupled receptors are essential drug targets for human diseases, such as endocrine diseases and cardiometabolic diseases. Given the great value of the secretin/adhesion (Class B) G protein-coupled receptors in the regulation of cardiovascular system function and the drug target exploration, we summarize the role of these receptors in placental development and preeclampsia, and outlined the relevant pathological mechanisms, thereby providing potential drug targets for preeclampsia treatment.Glaucoma is a progressive, irreversible loss of retinal ganglion cells (RGCs) and axons that results in characteristic optic atrophy and corresponding progressive visual field defect. The exact mechanisms underlying glaucomatous neuron loss are not clear. The main risk factor for glaucoma onset and development is high intraocular pressure (IOP), however traditional IOP-lowering therapies are often not sufficient to prevent degeneration of RGCs and the vision loss may progress, indicating the need for complementary neuroprotective therapy. This review summarizes the progress for neuro protection in glaucoma in recent 5 years, including modulation of neuroinflammation, gene and cell therapy, dietary supplementation, and sustained-release system.Bromodomain and extra-terminal domain (BET) family proteins play important roles in regulating the expression of multiple proto-oncogenes by recognizing acetylation of histones and non-histone proteins including transcription factors, which subsequently promote tumor cell proliferation, survival, metastasis and immune escape. Therefore, BET family proteins are considered attractive therapeutic targets in various cancers. Currently, blocking of the BET proteins is a widely used therapeutic strategy for MYCN amplified high-risk neuroblastoma. Here, we summarized and reviewed the recent research progresses for the critical function of BET proteins, as an epigenetic reader, on tumorigenesis and the therapeutic potential of the BET/BRD4 inhibitors on MYCN amplified neuroblastoma. We also discussed the combined therapeutic strategies for BET inhibitor-resistant neuroblastoma.Cholesterol is an essential component of animal cells. Different regulatory mechanisms converge to maintain adequate levels of this lipid because both its deficiency and excess are unfavorable. Low cell cholesterol content promotes its synthesis and uptake from circulating lipoproteins. In contrast, its excess induces the efflux to high-density lipoproteins (HDL) and their transport to the liver for excretion, a process known as reverse cholesterol transport. Different studies suggest that an abnormal HDL metabolism hinders female fertility. HDL are the only lipoproteins detected in substantial amounts in follicular fluid (FF), and their size and composition correlate with embryo quality. Oocytes obtain cholesterol from cumulus cells via gap junctions because they cannot synthesize cholesterol de novo and lack HDL receptors. Recent evidence has supported the possibility that FF HDL play a major role in taking up excess unesterified cholesterol (UC) from the oocyte. Indeed, genetically modified mouse models wiregulated and largely unexplored system of cholesterol homeostasis controlling traffic between FF HDL and oocytes, with significant implications for female fertility.
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