We developed a novel class of hybrids (HP-1a-HP-1f) of telmisartan and 2-(1-hydroxypentyl)-benzoate (HPBA) as a ring-opening derivative of NBP. The most promising hybrid, HP-1c, exhibited more potent anti-inflammatory and neuroprotective effects in vitro and reduced brain infarct volume and improved neurological deficits in a rat model of transient focal cerebral ischemia when compared with telmisartan alone, NBP alone, or a combination of telmisartan and NBP. HP-1c had a therapeutic window of up to 24 h, ameliorated ischemic cerebral injury in permanent focal cerebral ischemia, and improved motor function. The beneficial effects of HP-1c in ischemic stroke were associated with microglial polarization to the M2 phenotype and reduced oxidative stress. HP-1c also shifted the M1/M2 polarization in a mouse neuroinflammatory model. The anti-inflammatory and anti-oxidative effects of HP-1c were associated with AMPK-Nrf2 pathway activation for neuroprotection. We showed that HP-1c penetrates the brain, has a plasma half-life of around 3.93 h, and has no toxicity in mice. Innovation and Conclusion: Our study results suggest that HP-1c, with dual AMPK- and Nrf2-activating properties, may have potential in further studies as a novel therapy for ischemic stroke. Antioxid. Redox Signal. 28, 141-163.

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The pandemic of coronavirus disease 2019 (COVID-19) resulted in a stringent lockdown in China to reduce the infection rate. We adopted a machine learning technique to analyze the air quality impacts of the COVID-19 lockdown from January to April 2020 for six megacities with different lockdown durations. Compared with the scenario without lockdowns, we estimated that the lockdown reduced ambient NO 2 concentrations by 36–53% during the most restrictive periods, which involved Level-1 public health emergency response control actions. Several cities lifted the Level-1 control actions during February and March, and the avoided NO 2 concentrations subsequently dropped below 10% in late April. Traffic analysis during the same periods in Beijing and Chengdu confirmed that traffic emission changes were a major factor in the substantial NO 2 reduction, but they were also associated with increased O 3 concentrations. The lockdown also reduced PM 2.5 concentrations, although heavy pollution episodes occurred on certain days due to the enhanced formation of secondary aerosols in association with the increased atmospheric oxidizing capacity. We also observed that the changes in air pollution levels decreased as the lockdown was gradually eased in various cities.

BackgroundDNA methylation is an important biological form of epigenetic modification, playing key roles in plant development and environmental responses.ResultsIn this study, we examined single-base resolution methylomes of Populus under control and drought stress conditions using high-throughput bisulfite sequencing for the first time. Our data showed methylation levels of methylated cytosines, upstream 2kp, downstream 2kb, and repeatitive sequences significantly increased after drought treatment in Populus. Interestingly, methylation in 100 bp upstream of the transcriptional start site (TSS) repressed gene expression, while methylations in 100-2000bp upstream of TSS and within the gene body were positively associated with gene expression. Integrated with the transcriptomic data, we found that all cis-splicing genes were non-methylated, suggesting that DNA methylation may not associate with cis-splicing. However, our results showed that 80% of trans-splicing genes were methylated. Moreover, we found 1156 transcription factors (TFs) with reduced methylation and expression levels and 690 TFs with increased methylation and expression levels after drought treatment. These TFs may play important roles in Populus drought stress responses through the changes of DNA methylation.ConclusionsThese findings may provide valuable new insight into our understanding of the interaction between gene expression and methylation of drought responses in Populus.

Voltage-gated sodium channels (VGSCs) are the basic ion channels for neuronal excitability, which are crucial for the resting potential and the generation and propagation of action potentials in neurons. To date, at least nine distinct sodium channel isoforms have been detected in the nervous system. Recent studies have identified that voltage-gated sodium channels not only play an essential role in the normal electrophysiological activities of neurons but also have a close relationship with neurological diseases. In this study, the latest research findings regarding the structure, type, distribution, and function of VGSCs in the nervous system and their relationship to neurological diseases, such as epilepsy, neuropathic pain, brain tumors, neural trauma, and multiple sclerosis, are reviewed in detail.

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BackgroundHistone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines.ObjectiveTo investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.MethodsALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-κB p65 in cytoplasm and nucleus was determined by Western blot analysis respectively.ResultsPretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-α, IL-1β and NO. Furthermore, the expression of NF-κB p65 in nucleus was markedly suppressed by butyrate pretreatment.ConclusionsButyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-κB activation.

Problem definition: This paper investigates the channel choice problem of an online platform that exerts service effort to enhance the demand in its sales channels. Academic/practical relevance: In the existing literature on the channel structure of an online retail platform, it is usually assumed that a manufacturer sells through either the platform’s agency or reselling channel but not both. In practice, many manufacturers sell the same products through both channels of the same online retail platform, a phenomenon that cannot be explained by the existing theory. Moreover, online retail platforms routinely invest in retail services that enhance the demand in their sales channels. Methodology: We develop a game-theoretic model to investigate the equilibrium channel choice, wholesale price, and retail quantity decisions. We also conduct sensitivity analysis to evaluate the impact of some parameters on the equilibrium. Results: We derive conditions under which each of the three channel structures (agency channel, reselling channel, and dual channel) emerges in equilibrium. We show that the wholesale price in the reselling channel is reduced because of the addition of the agency channel even when both channels are equally efficient, which extends the wholesale price effect because of the addition of a less efficient direct channel in the supplier encroachment literature. Our analysis highlights the flexibility of a dual channel for firms to shift sales between the two channels, which could increase the retail platform’s incentive to exert service effort. Managerial implications: Our study provides useful insights to managers to understand and make channel choice decisions in supply chains with manufacturers selling through online retail platforms.