Ramipril protects the endothelium from high glucose-induced dysfunction through CaMKKß/AMPK and heme oxygenase-1 activation.

This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKß (Ca(2+)/calmodulin-dependent protein kinase kinase-ß) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKß/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKß or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-ß, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function.

Research Hotspots and Effectiveness of Transcranial Magnetic Stimulation in Pain: A Bibliometric Analysis.

Transcranial magnetic stimulation, as a relatively new type of treatment, is a safe and non-invasive method for pain therapy. Here, we used CiteSpace software to visually analyze 440 studies concerning transcranial magnetic stimulation in pain research from 2010 to 2021, indexed by Web of Science, to clarify the research hotspots in different periods and characterize the process of discovery in this field. The United States ranked first in this field. Lefaucheur JP, Fregni F, and Andrade ACD made great contributions to this field of study. The most prolific institution was University of São Paulo. The four main hot keywords were neuropathic pain, motor cortex, connectivity, and non-invasive brain stimulation. There were three main points that were generally accepted: (1) definite analgesic effect of high-frequency rTMS of M1 contralateral to pain side in neuropathic pain; (2) there are inconclusive recommendations regarding rTMS of the dorsolateral prefrontal cortex (DLPFC) in fibromyalgia and neuropathic pain; (3) there is low-quality evidence that single doses of high-frequency rTMS of the motor cortex may have short-term effects on chronic pain. This bibliometric analysis indicated that prospective, multi-center, large-sample, randomized controlled trials are still needed to further verify the effectiveness of various transcranial magnetic stimulation parameters in pain research.

Research Hotspots and Frontiers of Transcranial Direct Current Stimulation in Stroke: A Bibliometric Analysis.

Background: Over the past decade, many studies in the field of transcranial direct current stimulation (tDCS) in stroke have been published in scholarly journals. However, a scientometric analysis focusing on tDCS after stroke is still missing. The purpose of this study is to deliver a bibliometric analysis to investigate the global hotspots and frontiers in the domain of tDCS in stroke from 2012 to 2021. Methods: Articles and reviews related to tDCS in stroke were retrieved and obtained from the Web of Science core collection database from 2012 to 2021. Data visualization and analysis were conducted by using CiteSpace, VOSviewer, and Microsoft Excel 2019. Results: Finally, 371 publications were included in the scientometric analysis, including 288 articles and 83 reviews. The results showed that the number of publications per year increased from 15 to 68 in the last 10 years. Neurosciences was the main research hotspot category (n = 201). Frontiers in Human Neuroscience was the most published journal with 14 papers. The most productive author, institution, and country were Fregni F (n = 13), the League of European Research Universities (n = 37), and the United States of America (n = 98), respectively. A burstness analysis of keywords and the literature indicated that current studies in the field of tDCS in stroke focused on poststroke aphasia, tDCS combined with robotic therapy, and anatomical parameters. Conclusion: The research of tDCS in stroke is predicted to remain a research hotspot in the future. We recommend investigating the curative effect of other different tDCS closed-loop rehabilitation methods for different stroke dysfunctions. In conclusion, this bibliometric study presented the hotspots and trends of tDCS in stroke over the last decade, which may help researchers manage their further studies.

Diaporine Potentiates the Anticancer Effects of Oxaliplatin and Doxorubicin on Liver Cancer Cells.

Recent studies have shown that diaporine, a novel fungal metabolic product, has a strong in vitro and in vivo anticancer effect on human non-small-cell lung and breast cancers. In this study, three human hepatocarcinoma cell lines (HepG2, Hep3B, and Huh7) were used to evaluate the efficacy of diaporine alone and in combination with the standard cytotoxic drugs oxaliplatin and doxorubicin for the treatment of liver cancer. We demonstrated that diaporine, oxaliplatin, and doxorubicin triggered a concentration- and time-dependent decrease in the number of HepG2 cells. Diaporine at a concentration of 2.5 µM showed almost 100% inhibition of cell counts at 72 h. Similar effects were observed only with much higher concentrations (100 µM) of oxaliplatin or doxorubicin. Decreases in cell numbers after 48 h treatment with diaporine, oxaliplatin, and doxorubicin were also demonstrated in two additional hepatoma cell lines, Hep3B and Huh7. The combination of these drugs at low concentration for 48 h in vitro noticeably showed that diaporine improved the inhibitory effect on the number of cancer cells induced by oxaliplatin or doxorubicin. Additionally, this combination effectively inhibited colony growth in vitro. We found that inhibition of phosphorylation of ERK1/2 significantly increased when diaporine was used in combination with other agents. In addition, we also found that when diaporine was used in combination with doxorubicin or oxaliplatin, their proapoptotic effect greatly increased. We further revealed that the induction of apoptosis in hepatoma cells after treatment is due, at least in part, to the inhibition of phosphorylation of AKT, leading to the activation of caspase-3, inactivation of poly (ADP-ribose) polymerase (PARP), and subsequently to DNA damage, as indicated by the increased level of H2AX. Based on these findings, we suggest that diaporine in combination with the standard cytotoxic drugs oxaliplatin and doxorubicin may play a role in the treatment of liver cancer.

Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKß/AMPK/Nrf2 Pathway.

Clopidogrel (INN), an oral antiplatelet drug, has been revealed to have a number of biological properties, for instance, anti-inflammation and antioxidation. Oxidative stress plays an imperative role in inflammation, diabetes mellitus, atherosclerosis, and cancer. In the present study, human aortic endothelial cells (HAECs) were employed to explore the anti-inflammatory activity of INN. INN reduced TNFα-induced reactive oxygen species (ROS) generation and time-dependently prompted the expression and activity of heme oxygenase 1 (HO-1). Cellular glutathione (GSH) levels were augmented by INN. shHO-1 blocked the INN suppression of TNFα-induced HL-60 cell adhesion. The CaMKKß/AMPK pathway and Nrf2 transcriptional factor were implicated in the induction of HO-1 by INN. Additionally, TNFα dramatically augmented VCAM-1 expression at protein and mRNA levels. INN treatment strikingly repressed TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Compound C, an AMPK inhibitor, and shNrf2 abolished TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Our data suggest that INN diminishes TNFα-stimulated VCAM-1 expression at least in part via HO-1 induction, which is CaMKKß/AMPK pathway-dependent.

Evaluating the fall risk among elderly population by choice step reaction test.

Falls during daily activities are often associated with injuries and physical disabilities, thereby affecting quality of life among elder adults. Balance control, which is crucial in avoiding falls, is composed of two elements: muscle strength and central nervous system (CNS) control. A number of studies have reported that reduced muscle strength raises the risk of falling. However, to date there has been only limited research focused on the relationship between fall risk and the CNS. This study aimed to investigate the relationship between CNS and risk of falling among the elderly. A total of 140 elderly people (92 females and 48 males) were divided into faller and nonfaller groups based on questionnaire responses concerning falls in their daily life. Participants undertook a choice step reaction test in which they were required to respond to random visual stimuli using foot movements as fast as possible in the left or right directions. Response time was quantified as premotor time (PMT) and motor time (MT). In addition, the participants' electro-myography data were recorded during the choice step reaction test. A maximal isokinetic torque test was also performed. PMT was greater in the fallers than in the nonfallers group. There was a significant difference between fall status and direction on PMT. PMT of the left limb in nonfallers was faster than the right, but in fallers there was no difference between left and right limbs. A similar phenomenon was also observed for MT. There were significant differences between fallers and nonfallers in maximum isokinetic torque at knee and ankle joints. The correct rate of PMT was higher than other variables, such as MT and maximal isokinetic torque, in evaluating elderly fall risk by using logistic regression analyses. The results suggest that PMT in the choice step reaction test could be a useful parameter to assess risk of fall among elder adults. In addition, decreased maximal isokinetic torque was related to greater PMT and disappearance of asymmetry in older adults who were at higher risk of fall, especially in the lower limb.

Statins protect human endothelial cells from TNF-induced inflammation via ERK5 activation.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) exert pleiotropic effects on the cardiovascular system, in part through a decrease in reactive oxygen species (ROS) formation and reduction of vascular inflammation. To elucidate the molecular mechanisms involved in these effects, we investigated the effect of statins on TNF-α-induced ROS production, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in human aortic endothelial cells (HAECs). Exposure of HAECs to TNF-α caused production of ROS via Rac-1 membrane translocation and activation. The Rac-1 activation and ROS liberation mediated TNF-stimulated NF-κB activation and the subsequent VCAM-1 and ICAM-1 expression. Extracellular-signal-regulated kinase 5 (ERK5) plays a central role in inhibiting endothelial inflammation. Immune complex kinase assay of protein extracts from HAECs treated with atorvastatin revealed increased ERK5 activity in a time- and dose-dependent manner. In addition, pretreatment with atorvastatin inhibited TNF-α-induced ROS production and VCAM-1 and ICAM-1 expression. Chemical or genetic inhibition of ERK5 ablated the statins inhibition of Rac-1 activation, ROS formation, NF-κB, VCAM-1 and ICAM-1 expression induced by TNF-α. Taken together, statins, via ERK5 activation, suppress TNF-stimulated Rac-1 activation, ROS generation, NF-κB activation and VCAM-1 and ICAM-1 expression in human ECs, which provides a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system.

Mechanomyography is more sensitive than EMG in detecting age-related sarcopenia.

The aim of this work was to investigate the effects of age-related sarcopenia on the time and frequency domain properties of lower extremity muscles' electromyographic and mechanomyographic activities. Healthy elderly (n=10, 64.5+/-4.5yr) and young (n=10, 22.6+/-2.8yr) were recruited as participants. Participants' lean thigh volumes (LTV) and 1 RM (one repetition maximum) leg strength of quadriceps and maximum speed knee extension with different load levels (45%, 60% and 75% 1 RM) were recorded. The root mean square (RMS) and the mean frequency (MF) of the surface electromyography (EMG(RMS), EMG(MF)) and mechanomyography (MMG(RMS), MMG(MF)) signals were collected at vastus lateralis during concentric contraction with different intensity levels. Compared to the young, the elderly had significantly less LTV, absolute and relative maximal force, as well as absolute and relative maximal power (p<.05). EMG(MF) of the elderly and the young increased monotonically from 45% to 75% 1 RM testing conditions. While the MMG(RMS) of the young increased with testing intensities, the MMG(RMS) of the elderly increased only from 45% to 60% but leveled off from 60% to 75% 1 RM testing conditions. The results indicate the declines of muscle mass, force and power production capacity with aging. The observations could be explained by neuromuscular performance and change of MU activation patterns may result from age-related sarcopenia. Aging affected muscle power more than muscle strength, which could be due to fast fiber reduction. This is supported by our observations that the MMG(RMS) differences between the young and the elderly across all three intensity level where EMG(RMS) was only different at the greatest intensity. We suggest that MMG could be used as an important measurement in studying muscle contraction in age-related sarcopenia.

Lower extremity joint torque predicted by using artificial neural network during vertical jump.

The purpose of this study was to develop an artificial neural network (ANN) for predicting lower extremity joint torques using the ground reaction force (GRF) and related parameters derived by the GRF during counter-movement jump (CMJ) and squat jump (SJ). Ten student athletes performed CMJ and SJ. Force plate and kinematic data were recorded. Joint torques were calculated using inverse dynamics and ANN. We used a fully connected, feed-forward network. The network comprised of one input layer, one hidden layer and one output layer. It was trained by error back-propagation algorithm using Steepest Descent Method. Input parameters of the ANN were GRF measurements and related parameters. Output parameters were three lower extremity joint torques. ANN model fitted well with the results of the inverse dynamics output. Our observations indicate that the model developed in this study can be used to estimate three lower extremity joint torques for CMJ and SJ based on ground reaction force data and related parameters.