Unraveling the molecular reason of opposing effects of α-mangostin and norfluoxetine on TREK-2 at the same binding site [[EQUATION]].

TWIK-related K(+) channel (TREK)-2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK-2 is of significance for the development of new analgesics. Recent studies have shown that α-Mangostin (α-MG) activates TREK-2, facilitating analgesic effects, yet the underlying molecular mechanisms remain elusive. Intriguingly, even though norfluoxetine (NFx) is known to inhibit TREK-2, α-MG is also observed to share the same binding site with NFx, and this implies that TREK-2 might be modulated in a highly complicated manner. Therefore, we examine the mechanism of how TREK-2 is activated by α-MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how α-MG and NFx exhibit opposing effects at the same binding site of TREK-2. These findings will broaden our understanding of TREK-2 modulation, providing clues for designing novel analgesic drugs.

Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications.

Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer. In this review, we synthesize recent findings regarding the structure and activating mechanisms of KCa channels. We also discuss the role of KCa channel modulators in therapeutic medicine. Finally, we identify the major reasons behind the delay in bringing these modulators to the pharmaceutical market and propose new strategies to promote their application.

Anti-Inflammatory Effects of Alphitolic Acid Isolated from Agrimonia coreana Nakai Extracts Are Mediated via the Inhibition of ICRAC Activity in T Cells.

Agrimonia pilosa Ledeb., an important medicinal herb in traditional East Asian medicine, is primarily used to treat abdominal pain, dysentery, and hemostasis. There are ten other reported species of Agrimonia plants, including Agrimonia coreana Nakai-a naturally growing species in South Korea-and Agrimonia eupatoria Linn. Although recent studies have isolated numerous active constituents and investigated their effects, the medicinal utility of this herb is not yet fully explored. Through patch-clamp recording, a previous study reported that Agrimonia plant extracts inhibit the function of Ca2+ release-activated Ca2+ channels (CRACs). Herein, we aimed to identify and isolate the main compounds in A. coreana responsible for CRAC inhibition while assessing the anti-inflammatory effects mediated by this inhibition. We demonstrated for the first time that alphitolic acid isolated from A. coreana has a dose-dependent inhibitory effect on CRAC activity and, thus, an inhibitory effect on intracellular calcium increase. Furthermore, analysis of human CD4+ T cell proliferation via the carboxyfluorescein diacetate succinimidyl ester method revealed that alphitolic acid inhibited T cell proliferation in a concentration-dependent manner. Our findings provide a theoretical basis for the potential therapeutic use of alphitolic acid in the treatment of inflammatory diseases.

Effects of nut consumption on blood lipid profile: A meta-analysis of randomized controlled trials.

BACKGROUND & AIMS: Several randomized controlled trials (RCTs) have assessed the effects of nut consumption on blood lipid profile. The aim of this study was to conduct a meta-analysis to quantitatively estimate the effects of nut consumption on blood lipid profile. METHODS AND RESULTS: The PubMed, EMBASE, Cochrane Library, and Google Scholar databases were systematically searched to identify RCTs examining the effects of nut intake on blood total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) from inception until March 2021. A random-effects model was used to pool standardized mean differences (SMDs) and 95% confidence intervals (CIs). Potential publication bias was assessed using Begg's test and Egger's test. Sensitivity analysis was performed to assess the impact of each individual study on the pooled results. The meta-analysis showed that nut consumption had no significant effect on the blood lipid profile. However, there was a significant reduction in TC (SMD: -2.89, 95% CI: -4.80, -0.98, I2 = 97.4) for pistachio consumption, and cashew consumption significantly increased HDL-C (SMD: 0.24, 95% CI: 0.04, 0.43, I2 = 0.0) compared with that in controls. There was no significant publication bias in the meta-analysis. The sensitivity analysis showed that removing one study at a time did not change the significance of the results. CONCLUSION: There was no overall effect of nut consumption on lipid profile, and the results may vary depending on nut type. We found that pistachio consumption may reduce TC levels, while cashew consumption increases HDL-C. REGISTRY NUMBER: PROSPERO CRD42021249147.

Night shift work and breast cancer risk: a meta-analysis of observational epidemiological studies.

Previous observational epidemiological studies have reported inconsistently the association between night shift work (NSW) and the risk of breast cancer (BC). This study aimed to investigate those associations by using a meta-analysis of observational epidemiological studies. We searched PubMed and EMBASE using keywords related to this topic from inception till November 2020. The pooled effect sizes such as odds ratio (OR), hazard ratio (HR) or relative risk (RR) with 95% confidence interval (CI) were calculated using a random-effects model. In the meta-analysis of a total of 32 observational studies including 13 case-control studies, 4 nested case-control studies and 15 cohort studies, NSW significantly increased the risk of BC (OR/RR/HR, 1.11; 95% CI, 1.04-1.20; I2 = 72.4%). In the subgroup meta-analysis by type of study, NSW was also associated with the increased risk of BC in case-control studies (OR, 1.34; 95% CI, 1.17-1.53; I2 = 63.8%). However, no significant association was found in both nested case-control studies (OR, 1.14; 95% CI, 0.89-1.46; I2 = 65.8%) and cohort studies (RR/HR, 0.98; 95% CI, 0.93-1.03; I2 = 25.3%). Besides, there was no significant association between NSW for over 20 years and the risk of BC (OR/RR/HR, 1.03; 95% CI, 0.95-1.11; I2 = 36.6%, n = 14). Given that cohort studies provide higher evidence than case-control studies, there is no association between NSW and the risk of BC.