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expression of constitutively active STAT3 partially abolished the anti-proliferative, anti-migratory, and anti-invasive effects of shikonin. Conclusion The anti-melanoma activity of shikonin is at least partially attributed to the inhibition on STAT3 signaling. These findings provide new insights into the anti-melanoma molecular mechanisms of shikonin, suggesting its potential in melanoma treatment.The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARα, PPARγ, and PPARβ/δ, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARα activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARγ ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1β. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment.Dysfunction of human endothelial cells is an important trigger for atherosclerosis. Oxidative low-density lipoprotein (ox-LDL) usually was used to stimulate the dysfunction of human umbilical vein endothelial cells (HUVECs). LncRNA SNHG1 (small nucleolar RNA host gene 1) is a cerebral infarction-associated gene. The present study was designed to investigate the role of SNHG1 in ox-LDL-induced HUVECs. Cell viability was evaluated by CCK-8 and MTT assay. Cell apoptosis was detected by flow cytometry analysis. Cell inflammatory response was evaluated by detecting LDH, IL-6, IL-1β levels. The results revealed that up-regulation of SNHG1 attenuated ox-LDL-induced cell injury and inflammatory response in HUVECs. Next, mechanism assays including RNA immunoprecipitation (RIP) assay, luciferase reporter assay, and RNA pull-down assay, helped us to identify the interaction between miR-556-5 and SNHG1. GNAI2 (G protein subunit alpha i2) and PCBP1 (poly(rC) binding protein 1) were identified as the downstream targets of miR-556-5p. SNHG1 regulated dysfunctions of ox-LDL-induced HUVECs via sponging miR-556-5p and up-regulating GNAI2 and PCBP1. SNHG1 attenuated cell injury and inflammatory response in ox-LDL-induced HUVECs via up-regulating both GNAI2 and PCBP1 at a miR-556-5p dependent way.The selection of optimum statin intensity is inconclusive, and the association of plasma exposure of statins and metabolites with major adverse cardiovascular events (MACEs) is unclear. This study sought to compare the effect of low (quartile 1), intermediate (quartiles 2 and 3), and high (quartile 4) plasma exposure of statins and metabolites on MACE, re-ischemia events and death in patients with coronary artery disease (CAD) at 5 years. A total of 1,644 patients in atorvastatin (AT) cohort and 804 patients in rosuvastatin (RST) cohort were included, and their plasma concentration of statins and metabolites was categorized as low-, mid-, or high-group. The association between the plasma levels of statins and metabolites and the incidence of primary endpoint in patients was assessed by Cox proportional hazard models. Intensive AT exposure (Q4 > 5.32 ng/ml) was significantly associated with increased risk of death compared with low (hazard ratio [HR] 1.522; 95% confidence interval [CI] 1.035-1.061; P = 0.0022) or moderate exposure (HR 2.054; 95% CI 1.348-3.130; P = 0.0008). This association was also found in AT's five metabolites (all P less then 0.01). In patients with RST treatment, moderate RST concentration (0.53-4.29 ng/ml) versus low concentration had a significantly lower risk of MACE and re-ischemia events. (HR 0.532, 95% CI 0.347-0.815, P = 0.0061 and HR 0.505, 95% CI 0.310-0.823, P = 0.0061, respectively). A higher plasma exposure of AT and metabolites has a significantly higher risk of death, and moderate RST exposure has a significantly lower risk of MACE and re-ischemia events in Chinese patients with CAD. The harms of high plasma exposure should be considered when prescribing statins to patients because it may be a risk factor for having poor prognosis in patients with CAD.The movement of micro and macro molecules into and within a cell significantly governs several of their pharmacokinetic and pharmacodynamic parameters, thus regulating the cellular response to exogenous and endogenous stimuli. Trafficking of various pharmacological agents and other bioactive molecules throughout and within the cell is necessary for the fidelity of the cells but has been poorly investigated. Novel strategies against cancer and microbial infections need a deeper understanding of membrane as well as subcellular trafficking pathways and essentially regulate several aspects of the initiation and spread of anti-microbial and anti-cancer drug resistance. Furthermore, in order to avail the maximum possible bioavailability and therapeutic efficacy and to restrict the unwanted toxicity of pharmacological bioactives, these sometimes need to be functionalized with targeting ligands to regulate the subcellular trafficking and to enhance the localization. In the recent past the scenario drug targeting has livery of the active molecule in to the subcellular locations, the associated pathways of the subcellular drug delivery system, and the role of the carrier system in drug delivery techniques.Background Studies have emphasized the importance of geographical factors and general practitioner (GP) characteristics in influencing drug prescriptions. Objectives To (i) ascertain the prevalence rate (PR) of use of drugs in six therapeutic categories used for chronic conditions; (ii) assess how geographical characteristics and GP characteristics may influence drug prescribing. Methods This study is part of the EDU.RE.DRUG Project, a national collaborative project founded by Italian Medicine Agency (AIFA). Cross-sectional analyses were undertaken employing the pharmacy-claim databases of four local health units (LHUs) located in two Italian regions Lombardy and Campania. Six drug categories were evaluated proton-pump inhibitors; antibiotics; respiratory-system drugs; statins; agents acting on the renin-angiotensin system; psychoanaleptic drugs. The PR was estimated according to drug categories at the LHU level. A linear multivariate regression analysis was undertaken to evaluate the association between the PR and geographical area, age and sex of GPs, number of patients, and percentage of patients aged >65 per GP. Results LHUs in Campania showed a PR that was significantly higher than that in Lombardy. Antibiotics showed the highest PR in all the LHUs assessed, ranging from 32.5% in Lecco (Lombardy) to 59.7% in Naples-2 (Campania). Multivariate linear regression analysis confirmed the association of the PR with geographical area for all drug categories. Being located in Campania increased the possibility of receiving a drug prescription from the categories considered, with estimates more marked for antibiotics, proton-pump-inhibitors, and respiratory-system drugs. Conclusions This study provides information about the PR of medications used for treating common and costly conditions in Italy and highlighted a significant geographical variation. These insights could help to develop area-specific strategies to optimize prescribing behavior.Reduced pain tolerance may be one of the possible explanations for high prevalence of chronic pain among older people. We hypothesized that age-related alterations in pain tolerance are associated with functioning deterioration of the frontal cortex during normal aging. Twenty-one young and 41 elderly healthy participants underwent a tonic heat pain test, during which cerebral activity was recorded using electroencephalography (EEG). Elderly participants were divided into two subgroups according to their scores on executive tests, high performers (HPs; n = 21) and low performers (LPs; n = 20). Pain measures [exposure times (ETs) and perceived pain ratings] and cerebral activity were compared among the three groups. buy Ac-DEVD-CHO ETs were significantly lower in elderly LPs than in young participants and elderly HPs. Electroencephalographic analyses showed that gamma-band oscillations (GBOs) were significantly increased in pain state for all subjects, especially in the frontal sites. Source analysis showed that GBO increase in elderly LPs was contributed not only by frontal but also by central, parietal, and occipital regions. These findings suggest that better preservation of frontal functions may result in better pain tolerance by elderly subjects.In the last decades, several electrophysiological markers have been investigated to better understand how humans precede a signaled event. Among others, the pre-stimulus microstates' topography, representing the whole brain activity, has been proposed as a promising index of the anticipatory period in several cognitive tasks. However, to date, a clear relationship between the metrics of the pre-stimulus microstates [i.e., the global explained variance (GEV) and the frequency of occurrence (FOO)] and well-known electroencephalography marker of the anticipation (i.e., the alpha power reduction) has not been investigated. Here, after extracting the microstates during the expectancy of the semantic memory task, we investigate the correlations between the microstate features and the anticipatory alpha (8-12 Hz) power reduction (i.e., the event-related de-synchronization of the alpha rhythms; ERD) that is widely interpreted as a functional correlate of brain activation. We report a positive correlation between the occurrence of the dominant, but not non-dominant, microstate and both the mean amplitude of high-alpha ERD and the magnitude of the alpha ERD peak so that the stronger the decrease (percentage) in the alpha power, the higher the FOO of the dominant microstate. Moreover, we find a positive correlation between the occurrence of the dominant microstate and the latency of the alpha ERD peak, suggesting that subjects with higher FOO present the stronger alpha ERD closely to the target. These correlations are not significant between the GEV and all anticipatory alpha ERD indices. Our results suggest that only the occurrence of the dominant, but not non-dominant, microstate should be considered as a useful electrophysiological correlate of the cortical activation.Visual attention-related processes include three functional sub-processes alerting, orienting, and inhibition. We examined these sub-processes using reaction times, event-related potentials (ERPs), and their neuronal source activations during the Attention Network Test (ANT) in control children, attentional problems (AP) children, and reading difficulties (RD) children. During the ANT, electroencephalography was measured using 128 electrodes on three groups of Finnish sixth-graders aged 12-13 years (control = 77; AP = 15; RD = 23). Participants were asked to detect the direction of a middle target fish within a group of five fish. The target stimulus was either preceded by a cue (center, double, or spatial), or without a cue, to manipulate the alerting and orienting sub-processes of attention. The direction of the target fish was either congruent or incongruent in relation to the flanker fish, thereby manipulating the inhibition sub-processes of attention. Reaction time performance showed no differences between groups in alerting, orienting, and inhibition effects.