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Of note, EP treatment resulted in the translocation of β-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/β-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4 and c-Myc while also inhibiting anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.A relatively large number of diabetic patients risk complications of clinical depression that lead to poorer quality of life, however the precise mechanisms for diabetes-associated depression are not fully understood. Links between hyperglycemia-induced oxidative stress and NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation have been reported in the pathogenesis of diabetes. The present study aimed to elucidate the contribution of NLRP3-mediated apoptotic/pyroptotic neuronal cell death to diabetes-associated depression. We found that depressive-like behavior in streptozotocin (STZ)-induced diabetic mice was associated with hippocampal NLRP3 inflammasome activation. Hyperglycemia increased reactive oxygen species (ROS) production, thus leading to NLRP3 inflammasome activation in hippocampal neurons. It was found that STZ treatment induced apoptotic and pyroptotic cell death in the hippocampus as evidenced by increases of cleaved caspase 3 positive hippocampal neurons, TUNEL-positive cells, protein levels of p53, Bax, Puma, and the cleaved GSDMD N-terminal fragment, all of which were decreased in NLRP3 deficient mice. Using murine hippocampal neuronal cell line HT22, we found that high glucose induced apoptotic and pyroptotic cell death in a NLRP3 inflammasome-dependent manner in vitro. In addition, NLRP3 deficiency alleviated depressive-like behavior in STZ-induced diabetic mice. Our results suggest that hyperglycemia results in apoptosis and pyroptosis of hippocampal neuron cells in a NLRP3-dependent manner, which was associated with the depressive phenotypes evoked by STZ-induced diabetes. The study identifies a novel function of NLRP3 activation in high glucose-induced neuronal cell death, which sheds further light on the pathogenesis and new therapeutic targets of diabetes-associated depression.Accumulating evidence support the critical role of endogenous orexin system in modulation of various physiological functions. Among these, regulation of pain and wakefulness have extensively been investigated, however, by independent series of studies each focusing a distinct side. It is now well established that orexins induce potent analgesic effect via affecting their receptors within several specific brain structures. These mainly include locus coeruleus (LC), lateral paragigantocellularis (LPGi), ventral tegmental area (VTA), dorsal raphe nucleus (DRN), periaquiductal gray (PAG) and tuberomammillary nuclei (TMN). On the other hand, increased activity of orexinergic neurons enhances general wakefulness. Interestingly, a review of literature reveals that brain regions underlying orexin-mediated analgesia are most probably the site of action for orexin wake-promoting effects as well. The present study first pieces together the existing evidence supporting the rationale for the possibility of sleep-pain coregulation by orexin system and then suggests several shared mechanisms through which orexin can control the two mentioned processes. Furthermore, this study explains how imbalanced orexinergic transmission can cause progressive dysregulation of sleep-pain processing.Mitochondria is a key cellular organelle, which is tightly supervised by multiple oversight cellular mechanisms regulating mitochondrial biogenesis and mitochondria maintenance and/or elimination. Selective autophagy of mitochondria, id est mitophagy, is one of the cellular mechanisms controlling mitochondria homeostasis. The nematode Caenorhabditis elegans has recently emerged as a powerful model organism to study the roles and functions of mitophagy. We present here the current knowledge on cellular and molecular mechanisms underlying the selective elimination of mitochondria by autophagy in C. elegans in the context of developmental processes, aging and adaptive responses to various stresses.This review was conducted with the following goals To quantify the severity of mood and anxiety symptoms emerging during acute abstinence from tobacco (1). To explore sex differences related to the experience of specific symptoms (2). To investigate the early time course of symptoms (3). A meta-analysis was performed from 28 studies assessing mood and anxiety symptoms during the earliest phases of tobacco abstinence (up to 24 hrs post-quit) conducted from 1999 to 2019. Results revealed a significant (p less then 0.0001) increase in 'anxiety', 'anger/irritability', 'depressed mood /sadness', and composite negative affect ('NA') in the 24 hours following smoking cessation. The largest effect size was detected for 'anxiety' (0.63). A qualitative analysis was performed to investigate sex differences and the time course of the specific symptoms. Results indicated that female smokers may experience worse mood symptoms compared to male smokers and that these symptoms may emerge within 3 hrs post-quit. Smoking cessation programs should implement sex-tailored interventions in order to improve their effectiveness, while future research should focus on alternative methods of nicotine administration.Hyperkinetic movement disorders comprise a variety of conditions characterized by involuntary movements, which include but are not limited to tardive dyskinesia, chorea associated with Huntington's Disease, and tic disorders. The class of medications that have been used to treat these conditions includes Vesicular Monoamine Transporter-2 (VMAT2) inhibitors. In 2008, the FDA approved tetrabenazine as a treatment for chorea associated with Huntington's Disease. Optimization of the pharmacology of tetrabenazine has since led to the approval of two new VMAT2 inhibitors, deutetrabenazine and valbenazine. The objective of this review is to provide background on the role of VMAT in monoamine neurotransmission, the mechanism of VMAT2 inhibition on the treatment of hyperkinetic disorders (specifically tardive dyskinesia and chorea associated with Huntington's Disease), the pharmacology and pharmacokinetics of the commercially available VMAT2 inhibitors, and a summary of the clinical data to support application of these medications.A standard method for growing Pseudomonas aeruginosa biofilm in the Drip Flow Biofilm Reactor was assessed in a 10-laboratory study. The mean log density was 9.29 Log10(CFU/cm2). The repeatability and reproducibility SDs were equal to 0.22 and 0.24, respectively, providing statistical confidence in data generated by the method.Background The CArdiac MARker Guidelines Uptake in Europe Study (CAMARGUE) initiated by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) aims to survey the current use of evidence-based guidelines for dyslipidemia testing in Europe. Methods In 2019 a web-based questionnaire was distributed via EFLM National Societies to clinical laboratories in Europe. Questions covered pre-analytics, analytical methods, measurement units, flagging of decision thresholds, and use of decision-enhancing comments. Results Returns were obtained from 452 laboratories from 28 countries. Most laboratories always use nonfasting blood samples for lipid assays (66%). Lipid profiles are reported in mmol/L by 59% of the laboratories, mainly from 14 countries promoting the use of SI units. Important differences in flagging of decision thresholds were observed, with less than half of the laboratories applying the guideline-recommended LDL cholesterol threshold. Only 17% of the laboratories add an alert comment when familial hypercholesterolemia is suspected and 23% when risk of pancreatitis from hypertriglyceridemia is high. Conclusions There are marked differences among laboratories in Europe in terms of pre-analytical, analytical, and post-analytical lipid management that could have an important clinical impact. This relates to different availability of assays or different laboratory practices on reporting and flagging of lipid profiles.Background Two out of three of family members experience symptoms of post-traumatic stress, depression, or anxiety lasting for months after the intensive care unit (ICU) stay. Interventions aimed at mitigating these symptoms have been unsuccessful. Research question To understand the emotional experiences of family members of critically ill patients and to identify coping strategies used by family members during the ICU stay. Study design and methods As part of a mixed methods study to understand sources of distress among ICU family members, semi-structured interviews were conducted with ICU family members. Family members completed surveys at the time of interview and at 90 days to assess for symptoms of depression, anxiety, and post-traumatic stress. Results Semi-structured interviews and baseline surveys were conducted with 40 ICU family members; 78% of participants (n = 31) completed follow-up surveys at 90 days. At the time of interview, 65% of family members had symptoms of depression, anxiety, or post-traumatic stress. At 90 days, 48% of surveyed family members had symptoms of psychological distress. Three primary emotions were identified among ICU family members sadness, anger, and fear. A diverse array of coping strategies was used by family members, including problem-solving, information seeking, avoidance/escape, self-reliance, support seeking, and accommodation. Interpretation This study emphasizes similarities in emotions but diversity in coping strategies used by family members in the ICU. Understanding the relationship between ICU experiences, emotional responses, and long-term psychological outcomes may guide targeted interventions to improve mental health outcomes of ICU family members.Background The outbreak of Covid-19 has vastly increased the operational burden on healthcare systems worldwide. LCL161 purchase For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources. Methods We performed an international multi-center study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the Quadripartite Equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources. Results Seventeen large- and medium- sized liver transplant centers from twelve countries across four continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach.
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