Lynchfrom5942

Recent studies have shown that programmed cell death 4 (PDCD4) modulates distinct signal transduction pathways in different pathological conditions. Despite acute and chronic immune responses elicited by ischemia contributing to the functional deterioration of the kidney, the contributions and mechanisms of PDCD4 in acute kidney injury (AKI) have remained unclear. Using two murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI, we found that PDCD4 deficiency markedly ameliorated renal dysfunction and inflammatory responses in AKI mice. Consistently, upregulation of PDCD4 was also confirmed in the kidneys from patients with biopsy confirmed acute tubular necrosis from a retrospective cohort study. MT-802 solubility dmso Moreover, we found that overexpression of Fgr, a member of the tyrosine kinase family, dramatically aggravated renal injury and counteracted the protective effects of PDCD4 deficiency in AKI mice. We discovered that FGR upregulated NOTCH1 expression through activating STAT3. Most importantly, we further found that systemic administration of ponatinib, a tyrosine kinase inhibitor, significantly ameliorated AKI in mice. In summary, we identified that PDCD4 served as an important regulator, at least in part, of FGR/NOTCH1-mediated tubular apoptosis and inflammation in AKI mice. Furthermore, our findings suggest that ponatinib-mediated pharmacologic targeting of this pathway had therapeutic potential for mitigating AKI.The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (NTRK1, NTRK2 and NTRK3) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLCγ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.Enormous studies have corroborated that long non-coding RNAs (lncRNAs) extensively participate in crucial physiological processes such as metabolism and immunity, and are closely related to the occurrence and development of tumors, cardiovascular diseases, nervous system disorders, nephropathy, and other diseases. The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases. This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of lncRNAs from the role of disease coding to acting as drug candidates, including the current status and progress in preclinical research. Cutting-edge strategies for lncRNA modulation have been summarized, including the sources of lncRNA-related drugs, such as genetic technology and small-molecule compounds, and related delivery methods. The current progress of clinical trials of lncRNA-targeting drugs is also discussed. This information will form a latest updated reference for research and development of lncRNA-based drugs.Fibrosis is a pathological reparative process that can occur in most organs and is responsible for nearly half of deaths in the developed world. Despite considerable research, few therapies have proven effective and been approved clinically for treatment of fibrosis. Artemisinin compounds are best known as antimalarial therapeutics, but they also demonstrate antiparasitic, antibacterial, anticancer, and anti-fibrotic effects. Here we summarize literature describing anti-fibrotic effects of artemisinin compounds in in vivo and in vitro models of tissue fibrosis, and we describe the likely mechanisms by which artemisinin compounds appear to inhibit cellular and tissue processes that lead to fibrosis. To consider alternative routes of administration of artemisinin for treatment of internal organ fibrosis, we also discuss the potential for more direct oral delivery of Artemisia plant material to enhance bioavailability and efficacy of artemisinin compared to administration of purified artemisinin drugs at comparable doses. It is our hope that greater understanding of the broad anti-fibrotic effects of artemisinin drugs will enable and promote their use as therapeutics for treatment of fibrotic diseases.Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.The study aims to characterize the foods advertised in supermarket circulars in Belo Horizonte, Brazil, as well as to analyze the price and discounts applied to the products. Supermarket circulars were obtained from five supermarket chains during 2018. Foods were classified according to the NOVA classification system and the Pan-American Health Organization (PAHO) nutritional profile model. Advertised prices, with and without discount, were recorded. Ultra-processed foods responded for 66.9% of ads, followed by fresh or minimally processed foods with 19.9%, processed foods with 9.5%, and processed culinary ingredients with 3.7%. Only 3.5% of the products did not exceed any critical nutrients of the PAHO model. Processed foods had a higher cost (R$3.27/100 g) in relation to other food categories. Products excessive in trans-fat and sodium were statistically significant cheaper when compared to those that did not present inadequacy of these nutrients. The reverse was verified for foods excessive in saturated fat, in total fat and in added sugars. Processed culinary ingredients were more frequent on sale (27.7%), while processed foods were the least advertised with discount (15.9%). Products that were adequate in saturated fat, trans fat, total fat and added sugar were statistically significant more announced with discount. Processed culinary ingredients presented the lowest percentage of discount (13.5%). The study confirms the position of supermarket circulars in Brazil as an obstacle to healthy eating, due to the higher incidence of processed and ultra-processed food advertisements, although no greater financial stimulus was noted for these products.Food insecurity among college students has begun to be recognized as a pressing social issue. However, much of the research in this area to date is limited by factors like small sample sizes and convenience sampling. The objective of this study was to assess sociodemographic and health disparities among two- and four-year post-secondary students screening positive for food insecurity, using one of the largest relevant health surveillance databases available. This study included analyses of pooled annual data (2015-2018; n = 13,720) from students participating in state-based surveillance of 27 two- and four-year Minnesota post-secondary institutions. Food security was determined using a validated two-item screener. Disparities were examined across numerous factors including sociodemographic, economic, academic, institutional, nutrition and weight-related health risk and resiliency. In total, 24% of students experienced food insecurity. Findings highlighted stark disparities, with notably high positive screening rates of food insecurity among non-Hispanic Black (43%), transgender/non-binary (42%) and first-generation (33%) students. Food insecurity was significantly associated with nearly every adverse health factor examined, despite controlling for demographics (p less then 0.0001). Overall, these findings represent one of the largest peer-reviewed studies of college food insecurity to date and underscore robust differences between who experiences food insecurity and who does not. They also highlight troubling health risks that accompany food insecurity. Importantly, the COVID-19 pandemic has worsened these realities. To inform prevention efforts, additional research is urgently needed, including cohort studies, controlled trials, and quasi-experimental research based on rigorous evaluation of policy initiatives now being considered at institutional, state and federal levels.Coronavirus Disease 2019 (COVID-19) pandemic has affected millions of people worldwide with far-reaching socio-economic implications in society. The adoption of preventive practices by the public remains the mainstay in reducing the spread of COVID-19 but there is a dearth of validated tools to assess such infection prevention practices related to pandemics. This study was conducted to develop and validate a questionnaire for the assessment of preventive practices against COVID-19 in the general population. It was done following a standardized protocol involving questionnaire development through literature review, focused group discussions, in-depth interviews, expert opinion, and pre-testing. This was followed by the validation of the questionnaire through a cross-sectional survey on 108 individuals from diverse backgrounds in New Delhi, India in July 2020. Exploratory factor analysis was used to evaluate construct validity. Internal consistency was assessed by Cronbach's alpha coefficient. The developed questionnaire for assessing preventive practices consists of two sections the first section of 18 items to evaluate preventive practices and the second section of 19 items for assessing various reasons for deficiencies in the preventive practices.