Ecdysone-controlled nuclear receptor ERR regulates metabolic homeostasis in the disease vector mosquito Aedes aegypti.

Hematophagous mosquitoes require vertebrate blood for their reproductive cycles, making them effective vectors for transmitting dangerous human diseases. Thus, high-intensity metabolism is needed to support reproductive events of female mosquitoes. However, the regulatory mechanism linking metabolism and reproduction in mosquitoes remains largely unclear. In this study, we found that the expression of estrogen-related receptor (ERR), a nuclear receptor, is activated by the direct binding of 20-hydroxyecdysone (20E) and ecdysone receptor (EcR) to the ecdysone response element (EcRE) in the ERR promoter region during the gonadotropic cycle of Aedes aegypti (named AaERR). RNA interference (RNAi) of AaERR in female mosquitoes led to delayed development of ovaries. mRNA abundance of genes encoding key enzymes involved in carbohydrate metabolism (CM)-glucose-6-phosphate isomerase (GPI) and pyruvate kinase (PYK)-was significantly decreased in AaERR knockdown mosquitoes, while the levels of metabolites, such as glycogen, glucose, and trehalose, were elevated. The expression of fatty acid synthase (FAS) was notably downregulated, and lipid accumulation was reduced in response to AaERR depletion. Dual luciferase reporter assays and electrophoretic mobility shift assays (EMSA) determined that AaERR directly activated the expression of metabolic genes, such as GPI, PYK, and FAS, by binding to the corresponding AaERR-responsive motif in the promoter region of these genes. Our results have revealed an important role of AaERR in the regulation of metabolism during mosquito reproduction and offer a novel target for mosquito control.

Circ-Bptf Ameliorates Learning and Memory Impairments via the miR-138-5p/p62 Axis in APP/PS1 Mice.

Alzheimer's disease (AD) is a common age-associated progressive neurodegenerative disorder that is implicated in the aberrant regulation of numerous circular RNAs (circRNAs). Here, we reported that circ-Bptf, a conserved circRNA derived from the Bptf gene, showed an age-dependent decrease in the hippocampus of APP/PS1 mice. Overexpression of circ-Bptf significantly reversed dendritic spine loss and learning and memory impairment in APP/PS1 mice. Moreover, we found that circ-Bptf was predominantly localized to the cytoplasm and upregulated p62 expression by binding to miR-138-5p. Furthermore, the miR-138-5p mimics reversed the decreased expression of p62 induced by the silencing of circ-Bptf. Together, our findings suggested that circ-Bptf ameliorated learning and memory impairments via the miR-138-5p/p62 axis in APP/PS1 mice. It may act as a potential player in AD pathogenesis and therapy.

Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52.

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Predictors of functional dependence at one year in acute ischemic stroke with large vessel occlusion.

BACKGROUND: In China, the current status of clinical treatment of eLVO and the factors affecting its long-term prognosis are unclear. OBJECTIVE: This study aims to explore the predictive factors of functional outcomes at one year in patients of acute ischemic stroke with emergent large vessel occlusion (eLVO). METHODS: We retrospectively collected 536 patients who underwent treatments for eLVO. Primary outcomes included one-year functional outcomes and delayed functional independence (DFI). The logistic regression was performed to predict the primary outcome. RESULTS: 431 (85%) survivors participated in the one-year follow-up. In the multivariate logistic analysis adjusted for baseline characteristics, the following factors were found to be significant predictors of functional dependence at one year: old age (aOR = 1.042, 95% CI=1.01-1.076, p = 0.011), low Alberta stroke program early CT score (ASPECTS) (aOR = 0.791, 95% CI=0.671-0.933, p = 0.005), unsuccessful reperfusion (aOR = 0.168, 95% CI=0.048-0.586, p = 0.005), poor medication compliance (aOR = 0.022, 95% CI=0.007-0.072, p < 0.001), and complicated with stroke-associated pneumonia (SAP) (aOR = 2.269, 95% CI=1.103-4.670, p = 0.026). We also found that men (aOR = 3.947, 95% CI=1.15-13.549, p = 0.029) had better medication adherence (aOR = 14.077, 95% CI=1.736-114.157, p = 0.013), and going to rehabilitation centers (aOR = 5.197, 95% CI=1.474-18.327, p = 0.010) were independent predictors of DFI. CONCLUSION: The significant predictors of functional dependence at one year were: old age, low ASPECTS, unsuccessful reperfusion, poor medication adherence, and combination with SAP. Men, good medication adherence, and going to rehabilitation centers contributed to getting delayed functional independence.

Juvenile hormone acts on male accessory gland function via regulating l-asparaginase expression and triacylglycerol mobilization in Aedes aegypti.

Hormones control the reproductive development of Aedes aegypti mosquitoes. The adult male reproductive process and mating behavior require adequate nutrients and energy. Understanding the molecular mechanism linking hormones, energy metabolism, and reproduction in male mosquitoes is important. In this study, we found that the size of the male accessory gland, an essential part of the male reproductive system, gradually increased after eclosion. However, it was significantly reduced in male mosquitoes deficient in methoprene-tolerant (Met), the receptor of juvenile hormone. Likewise, egg hatchability of females that mated with Met-depleted males showed the same downward trend. The mRNA level of the gene encoding accessory gland protein, l-asparaginase (ASNase), was reduced in Met dsRNA-treated males. Electrophoretic mobility shift assay and quantitative reverse transcription-PCR results revealed that Met was capable of binding directly to the promoter of ASNase and activated its transcription. RNA interference of ASNase in males resulted in the reduction of egg hatchability of the females with which they mated. These results showed that Met influenced the fecundity of male mosquitoes by directly upregulating the expression of the ASNase gene. Moreover, the levels of triacylglycerol and the sizes of lipid droplets were decreased by 72-78 h after eclosion in the fat body cells, whereas both of them increased in Met-depleted male mosquitoes, indicating that Met knockdown reduced lipid catabolism. These data demonstrate that Met might influence the egg hatchability of females by regulating lipid metabolism and the development of the male accessory gland in male mosquitoes.

Degradation of 3-chlorocarbazole in water by sulfidated zero-valent iron/peroxymonosulfate system: Kinetics, influential factors, degradation products and pathways.

As an emerging class of organic contaminants, polyhalogenated carbazoles (PHCZs) have been increasingly detected all over the world since 1980s. Due to the environmental persistence, bioaccumulation, and dioxin-like toxicity, PHCZs have aroused widespread concerns in recent years. However, efficient approach for the degradation of PHCZs is quite limited so far. Therefore, in this study, an advanced oxidation process (AOP), sulfidated zero-valent iron/peroxymonosulfate (S-ZVI/PMS) system was used to degrade 3-chlorocarbazole (3-CCZ), which is one of the mostly detected PHCZs congeners. The degradation of 3-CCZ was systematically studied under different conditions by varying the molar ratio of S/Fe, the dosage of S-ZVI or PMS, pH and temperature. The results indicated that S-ZVI/PMS was an effective strategy for PHCZs treatment. The 20-min degradation efficiency of 3-CZZ was up to 96.6% with the pseudo-first-order rate constant of 0.168 min-1 under the conditions of 5 mg/L 3-CZZ, 0.3 g/L S-ZVI (S/Fe = 0.2), 1.0 mM PMS, pH 5.8 and 25 °C. HCO3-, Cl- and humic acid (HA) showed inhibitory effects to different degrees. Results of the electron paramagnetic resonance (EPR) and scavenging experiments clarified the dominant role of •OH, followed by 1O2 and SO4•─. The product analysis and DFT calculation revealed three degradation pathways of 3-CCZ, namely hydroxylation, dechlorination and C-N bond cleavage, which largely alleviated the toxicity of the parent compound. This study showed the effectiveness of S-ZVI/PMS system in PHCZs treatment and provided a comprehensive investigation on the degradation behaviors of PHCZs in AOPs.

Drug Repurposing: An Alternative Strategy to Treat COVID-19.

In order to curve the ongoing trend of the COVID-19 pandemic and save more lives, effective treatments against COVID-19 are urgently needed. Compared to developing new drugs, which may take too much time, it's more efficient and cost-effective to repurpose existing drugs in the treatment of COVID-19. Fortunately, some of the shared features of COVID-19 and other wellknown diseases make it possible to use old strategies to combat this new challenge. In this paper, we reviewed various possible strategies of drug repurposing in the treatment of COVID-19 and explored the possible scientific mechanisms behind each strategy.

Corrigendum: Early-Onset Depression in Stroke Patients: Effects on Unfavorable Outcome 5 Years Post-stroke.

[This corrects the article DOI: 10.3389/fpsyt.2021.556981.].

Early-Onset Depression in Stroke Patients: Effects on Unfavorable Outcome 5 Years Post-stroke.

Background: Post-stroke depression (PSD) constitutes an essential complication of stroke and is associated with high-risk unfavorable outcome after stroke. The main objective of this prospective study was to determine the relationship between early-onset PSD (1 month after stroke) and functional outcomes 5 years after baseline enrollment. Methods: Four hundred thirty-six patients who met the criteria were included in this study from October 2013 to February 2015. The follow-up time for each patient was ~5 years, with follow-up every 3 months. Patients received questionnaires including the 17-item Hamilton Depression Scale (HAMD), the Mini-Mental State Examination (MMSE), the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the Barthel Index (BI). Results: Of the 436 patients, 154 (35.3%) patients with the prevalence of PSD status at baseline, 26 (7.2%) patients with the prevalence of PSD status, and 73 (20.1%) had an unfavorable outcome 5 years after stroke. The odds ratio (OR) for unfavorable outcome at 5 years in the PSD group was ~2.2 relative to the non-PSD group after adjusting for potential risk factors [OR = 2.217, 95% confidence interval (CI) = 1.179-4.421, P = 0.015]. In the early-onset PSD group, HAMD scores were independently associated with 5-year unfavorable outcome rates (OR = 1.168, 95% CI = 1.015-1.345, P = 0.031). Conclusions: Our findings indicate that early-onset PSD status in Chinese patients is an independent risk factor for unfavorable outcome 5 years after stroke, and that the severity of PSD is also related to unfavorable outcome.

Removal of perfluorooctanoic acid (PFOA) from aqueous solution by amino-functionalized graphene oxide (AGO) aerogels: Influencing factors, kinetics, isotherms, and thermodynamic studies.

Perfluorooctanoic acid (PFOA) is an emerging organic pollutant that has become ubiquitous in waterways and is difficult to be removed from wastewater using traditional treatment methods. In this study, amino-functionalized graphene oxide (AGO) aerogels were prepared as a potential remediation tool for water contaminated by PFOA. The structure of the prepared absorbent material was characterized by Fourier transform infrared spectroscopy, Raman spectroscopy, scanning electron microscope, and X-ray diffraction. The use of various adsorption times, temperatures, solution pH, and absorbent amount were investigated to determine optimum conditions for PFOA adsorption. Adsorption kinetics and thermodynamics of the absorbent were analyzed as well. AGO aerogels exhibited a high adsorption capacity of PFOA (1575 mg∙g-1) and high removal efficiency (99.95%) in a solution containing 10 mg PFOA L-1, likely due to the interconnected porous microstructures and amino groups of the AGO aerogels. The adsorption kinetics and isotherm of PFOA were well-fitted using pseudo-second-order and the Freundlich modelling. The adsorption mechanism of PFOA onto AGO aerogels followed spontaneous, exothermic, and physical processes. This study shows the potential of this material to remove PFOA from PFOA-contaminated waters effectively by providing insight into the understanding of the adsorption mechanisms of PFOA onto AGO aerogels.

Functional predication of differentially expressed circRNAs/lncRNAs in the prefrontal cortex of Nrf2-knockout mice.

In the central nervous system, nuclear factor erythroid-2-related factor 2 (Nrf2) protects neurons from oxidant injury, thereby ameliorating neurodegeneration. We explored the key circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) involved in Nrf2-induced neuroprotection. We used microarrays to examine the circRNAs (DEcircRNAs), lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) differentially expressed between Nrf2 (+/+) and Nrf2 (-/-) mice and identified DEcircRNA/DElncRNA-miRNA-DEmRNA interaction networks. In total, 197 DEcircRNAs, 685 DElncRNAs and 356 DEmRNAs were identified in prefrontal cortical tissues from Nrf2 (-/-) mice. The expression patterns of selected DEcircRNAs (except for mmu_circ_0003404) and DElncRNAs in qRT-PCR analyses were generally consistent with the microarray analysis results. Functional annotation of the DEmRNAs in the DEcircRNA/DElncRNA-miRNA-DEmRNA networks indicated that five non-coding RNAs (mmu_circ_0000233, ENSMUST00000204847, NONMMUT024778, NONMMUT132160 and NONMMUT132168) may contribute to Nrf2 activity, with the help of mmu_circ_0015035 and NONMMUT127961. The results also revealed that four non-coding RNAs (cicRNA.20127, mmu_circ_0012936, ENSMUST00000194077 and NONMMUT109267) may influence glutathione metabolism. Additionally, 44 DEcircRNAs and 7 DElncRNAs were found to possess coding potential. These findings provide clues to the molecular pathways through which Nrf2 protects neurons.

Cardiac parameters affect prognosis in patients with non-large atherosclerotic infarction.

BACKGROUND: Although large artery atherosclerosis (LAA) is the most common type of cerebral infarction, non-LAA is not uncommon. The purpose of this paper is to investigate the prognosis of patients with non-LAA and to establish a corresponding nomogram. PATIENTS AND METHODS: Between June 2016 and June 2017, we had 1101 admissions for acute ischemic stroke (AIS). Of these, 848 were LAA and 253 were non-LAA. Patients were followed up every 3 months with a minimum of 1 year of follow-up. After excluding patients who were lost follow-up and patients who did not meet the inclusion criteria, a total of 152 non-LAA patients were included in this cohort study. After single-factor analysis and multifactor logistic regression analysis, the risk factors associated with prognosis were derived and different nomograms were developed based on these risk factors. After comparison, the best model is derived. RESULTS: Logistics regression found that the patient's National Institutes of Health Stroke Scale (NIHSS) score, ejection fraction (EF), creatine kinase-MB (CK-MB), age, neutrophil-to-lymphocyte ratio (NLR), aspartate aminotransferase (AST), and serum albumin were independently related to the patient's prognosis. We thus developed three models: model 1: single NIHSS score, AUC = 0.8534; model 2, NIHSS + cardiac parameters (CK-MB, EF), AUC = 0.9325; model 3, NIHSS + CK-MB + EF + age + AST + NLR + albumin, AUC = 0.9598. We compare the three models: model 1 vs model 2, z = - 2.85, p = 0.004; model 2 vs model 3, z = - 1.58, p = 0.122. Therefore, model 2 is considered to be the accurate and convenient model. CONCLUSIONS: Predicting the prognosis of patients with non-LAA is important, and our nomogram, built on the NIHSS and cardiac parameters, can predict the prognosis accurately and provide a powerful reference for clinical decision making.

Notochordal-Cell-Derived Exosomes Induced by Compressive Load Inhibit Angiogenesis via the miR-140-5p/Wnt/ß-Catenin Axis.

Angiogenesis is a pathological signature of intervertebral disc degeneration (IDD). Accumulating evidence has shown that notochordal cells (NCs) play an essential role in maintaining intervertebral disc development and homeostasis with inhibitive effect on blood vessel in-growth. However, the anti-angiogenesis mechanism of NCs is still unclear. In the current study, we, for the first time, isolated NC-derived exosomes (NC-exos) and showed their increased concentration following compressive load cultures. We further found that NC-exos from 0.5 MPa compressive load cultures (0.5 MPa/NC-exos) inhibit angiogenesis via transferring high expressed microRNA (miR)-140-5p to endothelial cells and regulating the downstream Wnt/ß-catenin pathway. Clinical evidence showed that exosomal miR-140-5p expression of the nucleus pulposus is negatively correlated with angiogenesis in IDD. Finally, 0.5 MPa/NC-exos were demonstrated to have a therapeutical impact on the degenerated disc with an anti-angiogenesis effect in an IDD model. Consequently, our present findings provide insights into the anti-angiogenesis mechanism of NC-exos, indicating their therapeutic potential for IDD.

Author Correction: The roles of p38 MAPK → COX2 and NF-κB → COX2 signal pathways in age-related testosterone reduction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Efficacy and safety of acupuncture therapy for urinary incontinence in women: A systematic review and meta- analysis.

BACKGROUND: Urinary incontinence (UI), affects women more frequently than men, with a prevalence to 30-40% of perimenopausal women and almost 50% among women aged over 70 years. caused severe psychological burden and bringing negatively impact to the quality of life, increased caregiver burden and economic cost. Acupuncture is often used to treat them. We aim to conduct a systematic review to evaluate the efficacy of acupuncture for women experiencing UI. METHODS: The following electronic databases will be searched from inception to Jan. 2020: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Traditional Chinese Medicine, Chinese Biomedical Literature Database (CBM), Wan-Fang Database and Chinese Scientific Journal Database (VIP database).All published randomized controlled trials in English or Chinese related to acupuncture for urinary incontinence in women will be included. The primary outcome will be the change from baseline in the amount of urine leakage measured by the 1-hour pad test. Adverse events will be the secondary outcome. Study selection, data extraction, and assessment of study quality will be performed independently by two reviewers. RevMan V.5.3.5 software will be used for the assessment of risk of bias and data synthesis. RESULTS: This study will provide a high-quality synthesis of current evidence of acupuncture for UI from the 1-hour pad test. CONCLUSION: The conclusion of our study will provide an evidence to judge whether acupuncture is an effective intervention for patients suffered from UI. PROSPERO REGISTRATION NUMBER: CRD42019133195.

Amplified cardiorespiratory activity by hypoxia in conscious spontaneously hypertensive rats.

Activation of peripheral respiratory chemoreceptors provokes respiratory and cardiovascular reflexes, providing a novel understanding of pathogenic mechanism of hypertension. Here we hypothesize that activation of peripheral respiratory chemoreceptors by hypoxia causes enhanced cardiorespiratory activity in conscious spontaneously hypertensive rats (SHRs). Using whole body plethysmography in combination with radio telemetry, pulmonary ventilation, arterial blood pressure and heart rate were examined in SHRs and Wistar-Kyoto (WKY) rats. We found that exposure to hypoxia induced greater increases in tidal volume and minute ventilation volume in SHRs compared to WKY rats. In addition, hypoxia caused a robust increase in arterial blood pressure and heart rate in SHRs relative to WKY counterparts. After carotid body denervation, the hypoxic ventilatory response was significantly decreased in both SHRs and WKY rats, but without significant difference between the two strains; moreover, the differences of arterial blood pressure and heart rate changes during hypoxic exposure were statistically insignificant between SHRs and WKY rats. It is concluded that hypoxia remarkably potentiates cardiorespiratory activity in the SHRs, suggesting an enhanced sensitivity of carotid bodies to hypoxia.

The roles of p38 MAPK → COX2 and NF-κB → COX2 signal pathways in age-related testosterone reduction.

In our study, we explored changes in the redox status and inflammatory response in the testes of the SAMP8 model of varying ages (2, 4, 8, 10 months old) compared with control mice SAMR1 by the methods of immunohistochemical staining, Western blotting, RT-PCR and Luminex multi-analyte cytokine profiling. We found that as ROS and inflammation levels increased during aging, steroidogenic enzymes (StAR and P450scc) reduced and led to the decline of testosterone production eventually. The pathways of P38 MAPK → COX2 and NF-κB → COX2 were detected by using specific inhibitors of SB203580 and Bay 11-7082 in isolated Leydig cells. These results indicated that activation of both p38 MAPK → COX2 and NF-κB → COX2 signaling pathways are functionally linked to the oxidative stress response and chronic inflammation during aging, and mediate their inhibitory effects on testosterone production.

Patients' self-perceived burden, caregivers' burden and quality of life for amyotrophic lateral sclerosis patients: a cross-sectional study.

AIMS AND OBJECTIVES: This study surveys the quality of life of amyotrophic lateral sclerosis patients and the factors associated with amyotrophic lateral sclerosis patients' self-perceived burden and their caregivers' burden. BACKGROUND: Burdens of patients with amyotrophic lateral sclerosis and their caregivers in Chinese population are largely unknown. DESIGN: A cross-sectional study was conducted among 81 pairs of amyotrophic lateral sclerosis patients and their caregivers. METHODS: Amyotrophic lateral sclerosis patients' self-perceived burden and caregivers' burden were assessed by the Self-Perceived Burden Scale and Zarit-Burden Interview, respectively. Quality of life of amyotrophic lateral sclerosis patients was measured using the World Health Organization Quality of Life-Bref. The amyotrophic lateral sclerosis Functional Rating Scale-Revised questionnaire was used to estimate patients' physical function. RESULTS: Both patients and caregivers reported a mild to moderate burden. The World Health Organization quality of life-Bref scores were decreased in respondents with lower amyotrophic lateral sclerosis Functional Rating Scale-Revised, higher Self-Perceived Burden Scale and higher Zarit-Burden Interview scores. Self-Perceived Burden Scale scores were associated with patients' knowledge of amyotrophic lateral sclerosis, respiratory function and female sex. Zarit-Burden Interview scores were associated with caregivers' age, patients' motor function and out-of-pocket payment. CONCLUSION: With increase in amyotrophic lateral sclerosis patients' self-perceived burden and caregivers' burden, quality of life of amyotrophic lateral sclerosis patients decreased. Female patients, who had known more about the disease, and those with severe respiratory dysfunction were subject to higher self-perceived burden. Older caregivers and caregivers of patients with severe motor dysfunction and more out-of-pocket payment experienced more care burdens. RELEVANCE TO CLINICAL PRACTICE: Our study suggests that paying more attention to female amyotrophic lateral sclerosis patients might benefit patients in China or other South-East Asian countries under the Confucian concept of ethics. There is an urgent demand to expand medical insurance coverage to cover amyotrophic lateral sclerosis in China and other developing countries. Long and adequate supports are needed for relieving caregiver's burden. To improve the quality of life of patients, relieving the patients' SBP and caregivers' burden is likely to be not only required, but also essential.