A novel selenium analog of HDACi-based twin drug induces apoptosis and cell cycle arrest via CDC25A to improve prostate cancer therapy.

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo. Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

Cocaine and amphetamine-regulated transcript improves myocardial ischemia-reperfusion injury through PI3K/AKT signalling pathway.

Myocardial ischemia-reperfusion injury (MIRI) is a common clinic scenario that occurs in the context of reperfusion therapy for acute myocardial infarction. It has been shown that cocaine and amphetamine-regulated transcript (CART) can ameliorate cerebral ischemia-reperfusion (I/R) injury, but the effect of CART on MIRI has not been studied yet. Here, we revealed that CART protected the heart during I/R process by inhibiting apoptosis and excessive autophagy, indicating that CART would be a potential drug candidate for the treatment of MIRI. Further analysis showed that CART upregulated the activation of phospho-AKT, leading to downregulation of lactate dehydrogenase (LDH) release, apoptosis, oxidative stress and excessive autophagy after I/R, which was inhibited by PI3K inhibitor, LY294002. Collectively, CART attenuated MIRI through inhibition of cardiomyocytes apoptosis and excessive autophagy, and the protective effect was dependent on PI3K/AKT signalling pathway.

A-A Strategy Enables Desirable Performance of All-Polymer Solar Cells Fabricated with Nonhalogenated Solvents.

Most polymer acceptors have been designed by applying a D (electron-rich unit)-A (electron-deficient unit) strategy, which are principally processed with halogenated solvents to fabricate all-polymer solar cells (all-PSCs). Two novel polymer acceptors, containing an A-A type backbone, were designed and synthesized, which can be readily dissolved in o-xylene. The polymer PY-FBTA, comprising a Y6 derivative as the first A unit and a benzotriazole derivative as the second A unit, shows smaller dihedral angles in the backbone, stronger molecular interactions, higher LUMO level, more complementary absorption spectrum, and better morphology with PM6 than the polymer PY-DPP comprising a diketopyrrolopyrrole derivative as the second A unit. Accordingly, the PM6:PY-FBTA all-PSC achieves a higher PCE of 13.95% than the all-PSC based on PM6:PY-DPP (9.51%) for thoroughly improved Jsc (22.34 mA cm-2), Voc (0.963 V), and FF (64.84%) values, which are fabricated with o-xylene as the solvent. This work demonstrates that the A-A structure is a desirable strategy for designing polymer acceptors for efficient all-PSCs prepared with nonhalogenated solvents.

The Association of Serum Neurofilament Light Chain and Acute Ischaemic Stroke Is Influenced by Effective Revascularization.

Objective: To explore associations of serum neurofilament light chain (sNfL) at admission with clinical deficits and the long-term prognosis of acute ischaemic stroke (AIS). Methods: We recruited 110 AIS patients with serum sampled at hospital arrival. The concentrations of sNfL were detected by a Simoa HD-1 analyser. We first investigated the determinants of sNfL levels at admission within the study population. Associations of sNfL levels with National Institutes of Health Stroke Scale (NIHSS) scores and modified Rankin Scale (mRS) scores were then tested. We further divided the patients into revascularized and nonrevascularized groups, and the associations of sNfL levels with NIHSS and mRS scores were assessed in these subgroups. Results: Age, sex, stroke history, and the time between the onset of illness and arrival at the hospital were independent influencing factors of sNfL levels within the study population. The sNfL levels at admission were correlated with the NIHSS scores 7 days after stroke (p = 0.004) across all subjects but showed no correlation with the NIHSS scores at admission (p = 0.293) or the mRS scores 6 months after stroke (p = 0.065). Further analysis revealed that in the nonrevascularized group of AIS patients, the sNfL levels at admission were positively correlated with NIHSS scores (NIHSS at admission, p = 0.005; NIHSS 7 days after stroke, p = 0.003) and negatively correlated with mRS scores (p = 0.011). Conclusion: sNfL levels at admission could be a potential biomarker for predicting clinical deficits and prognosis in the natural course of AIS.

Polymerized Naphthalimide Derivatives as Remarkable Electron-Transport Layers for Inverted Organic Solar Cells.

Two polymerized naphthalimide derivatives, named as N-TBHOB and N-DBH, are prepared by quaternization. They exhibit excellent performance as electron-transport layers (ETLs) in inverted organic solar cells (i-OSCs). The results indicate N-TBHOB with a reticulated structure owns a superior performance on electron extraction, electron transport, thickness tolerance, and less carrier recombination compared with N-DBH with linear structure. The i-OSCs based on N-TBHOB with PTB7-Th:PC71 BM as the active layer achieve power conversion efficiencies (PCEs) of 10.72% and 10.03% under the thickness of 11 and 48 nm respectively, which indicates N-TBHOB possesses better thickness tolerance than most of organic ETLs in i-OSCs. N-TBHOB also shows more competent performance than N-DBH and ZnO in nonfullerene i-OSCs for comprehensively improved Jsc , Voc , and fill factor (FF) values. Its i-OSC with PM6:Y6 blend presents a high PCE of 16.78%. The study provides an efficient strategy to prepare ETLs by combining conjugated and nonconjugated units with a reticulated structure in the backbone for high-performance i-OSCs.

Corrigendum: Association Between Metabolic Syndrome and Mild Parkinsonian Signs Progression in the Elderly.

[This corrects the article DOI: 10.3389/fnagi.2021.722836.].

Association Between Metabolic Syndrome and Mild Parkinsonian Signs Progression in the Elderly.

Background: This study investigated the impact of metabolic syndrome on the progression from mild parkinsonian signs (MPS) to Parkinson's disease (PD). Methods: A total of 1,563 participants with MPS completed 6 years of follow-up. The diagnosis of metabolic syndrome was made according to Adult Treatment Panel III of the National Cholesterol Education Program. The evaluations of MPS and PD were based on the motor portion of the Unified Parkinson's Disease Rating Scale. Cox proportional hazard models were used to identify the association between metabolic syndrome and PD conversion. Results: Of the 1,563 participants, 482 (30.8%) with MPS developed PD at the end of the follow-up. Metabolic syndrome (HR: 1.69, 95% CI: 1.29-2.03) was associated with the risk of PD conversion. Metabolic syndrome was associated with the progression of bradykinesia (HR: 1.85, 95% CI: 1.43-2.34), rigidity (HR: 1.36, 95% CI: 1.19-1.57), tremor (HR: 1.98, 95% CI: 1.73-2.32), and gait/balance impairment (HR: 1.66, 95% CI: 1.25-2.11). The effect of metabolic syndrome on the progression of bradykinesia and tremor was nearly two fold. Participants treated for two or three to four components of metabolic syndrome, including high blood pressure, high fasting plasma glucose, hypertriglyceridemia, and low HDL-C, had a lower risk of PD conversion. Conclusion: Metabolic syndrome increased the risk of progression from MPS to PD. Participants treated for two or more components of metabolic syndrome had a lower risk of PD conversion.

White matter hyperintensities and the progression from mild parkinsonian signs to parkinsonism and Parkinson's disease.

This study investigated the impact of white matter hyperintensities (WMHs) on the progression from mild parkinsonian signs (MPS) to parkinsonism and Parkinson's disease (PD). Participants with MPS completed 5 years of follow-up. WMHs were divided into periventricular WMHs and deep WMHs according to magnetic resonance imaging scans. The diagnosis of MPS, parkinsonism, and PD was based on the motor portion of the Unified Parkinson's Disease Rating Scale. Cox proportional hazard models were used to identify the association between WMHs and MPS progression. Of the 636 participants, 166 (26.1%) with MPS developed parkinsonism and PD after follow-up. After adjusting for potential factors, severe WMHs were associated with an increased risk of MPS progression, moderate and severe periventricular WMHs and severe deep WMHs were associated with the risk of MPS progression, and severe WMHs were associated with the progression of gait/balance impairment, bradykinesia, and rigidity. Additionally, participants treated for vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia had a lower risk of MPS progression.

The Efficacy and Safety of DFN-15 for the Treatment of Migraine: A Meta-Analysis of Randomized Controlled Studies.

OBJECTIVES: The efficacy of DFN-15 for pain control of migraine remains controversial. We conduct a systematic review and meta-analysis to explore the influence of DFN-15 versus placebo on pain control in migraine patients. PATIENTS AND METHODS: We search PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases through November 2019 for randomized controlled trials assessing the effect of DFN-15 versus placebo on pain control in migraine patients. This meta-analysis is performed using the random-effects model. RESULTS: Three randomized controlled trials are included in the meta-analysis. Overall, compared with the control group in migraine patients, lasmiditan treatment shows a positive impact on pain freedom at 2 hours (risk ratio [RR], 1.96; 95% confidence interval, 1.61-2.40; P < 0.00001), headache response at 2 hours (RR, 1.40; 95% CI, 1.25-1.57; P < 0.00001), and pain freedom at 24 hours (RR, 1.87; 95% CI, 1.33-2.62; P = 0.0003), but has no obvious influence or no substantial impact on no or mild disability level (RR, 1.21; 95% CI, 0.97-1.52; P = 0.09) or nausea (RR, 2.42; 95% CI, 0.53-11.01; P = 0.25). In addition, lasmiditan seems to result in the increase in dizziness (RR, 7.33; 95% CI, 1.83-29.30; P = 0.005) and paresthesia (RR, 5.17; 95% CI, 2.08-12.86; P = 0.0004). CONCLUSIONS: DFN-15 treatment may be effective and safe for pain control in migraine patients.

Phenolic compounds with antioxidant activity from strawberry leaves: a study on microwave-assisted extraction optimization.

A microwave-assisted extraction (MAE) technology developed to extract polyphenols from the strawberry leaves was optimized by response surface methodology (RSM). Box-Behnken design (BBD) with four-factor and three-level was used to estimate the effects of extraction time, microwave power, ethanol concentration, and liquid-solid ratio in strawberry leaf extracts on total phenolic content (TPC) and antioxidant capacity (DPPH and FRAP). The optimized conditions were extraction time of 40 s, ethanol concentration of 51.1%, microwave power of 300 W, and liquid-solid ratio of 61.6 mL/g. The TPC, inhibition percentage of DPPH radical, and FRAP were 89.21 mg GAE/g, 79.80%, and 34.62 mM FE/g under optimal conditions. The absolute errors between the experimental and predicted values were less than 5.00%, revealing that the model was fitted well. High Performance Liquid Chromatography (HPLC) analysis demonstrated that the major antioxidant polyphenols with the highest concentration extracted at the optimum conditions were sinapic acid and rutin. This study proves that the MAE technique can efficiently extract polyphenols with high antioxidant activity from strawberry leaves.

Analysis of risk factors for depression in Alzheimer's disease patients.

Purpose: Depression, which affects about 52% of Alzheimer's disease (AD) patients, can worsen cognitive impairment and increase mortality and suicide rates. We hope to provide clinical evidence for the prevention and treatment of depression in AD patients by investigating related risk factors of depression in AD patients.Methods: 158 AD inpatients of the Department of Neurology, Daping Hospital from September 2017 to March 2019 were enrolled. General information, laboratory tests, cognitive and emotional function assessments of the inpatients were collected. Logistic regression was used to analyze the risk factors of depression in AD patients, and the relationship between 17 Hamilton depression scale scores and HbA1c levels in AD patients was further analyzed.Results: The prevalence of age, gender, hypertension, hyperlipidemia, Type 2 diabetes mellitus (T2DM), and white matter lesions (WML) in the AD with depression group was significantly different from without depression group. Hypertension, T2DM, and WML are independent risk factors for depression in AD patients. The depression scores of AD patients with HbA1c>6.5% were significantly higher than AD patients with HbA1c ≤ 6.5%, and there were significant difference in depression scale scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is >6.5%, while no difference in depression scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is ≤6.5%.Conclusion: T2DM is an independent risk factor for AD patients with depression. Increased HbA1c levels aggravate depression in AD patients, and controlling HbA1c levels and anti-diabetes drugs can reduce the severity of depression in AD patients.

Effects of Metabolic Syndrome on Cognitive Impairment with White Matter Lesions.

OBJECTIVE: To explore the relationship between metabolic syndrome (MetS) and cognitive impairment in elderly patients with white matter lesions (WML). METHODS: From -January 2016 to June 2017, a cross-sectional study was conducted on the clinical data of 358 WML patients over 65 years old in the Department of Neurology of the Daping Hospital. Mini-mental state examination scales were used to evaluate the cognitive function of the patients, and the cognitive impairment was diagnosed and grouped according to the scoring and diagnostic criteria. All WML patients were divided into the cognitive impairment group and normal cognition group. Clinical data of age, sex, education level, body mass index, abdominal circumference, smoking and alcohol consumption, blood pressure, fasting blood glucose, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were collected. Multivariate logistic regression analyses were performed to examine the relationship between MetS and cognitive impairment in WML patients. RESULTS: Compared with the normal cognition group, the proportion of MetS in the cognitive impairment group was significantly higher (χ2 = 11.211, p < 0.01), the proportion of MetS components such as elevated blood pressure, elevated blood glucose, elevated TG, decreased HDL-C and abdominal obesity in the cognitive impairment group was also higher (p < 0.01 or p < 0.05). After adjustment for age, sex, low education level, current smoking, daily drinking, severity of WML, MetS, and its components, multivariate logistic regression analysis showed that MetS was an independent risk factor for cognitive impairment in WML patients (OR 3.32, 95% CI 1.31-5.19). In addition, The greater the number of MetS components, the higher the risk of cognitive impairment in WML patients (ptrend < 0.01). CONCLUSION: MetS is an independent risk factor for cognitive impairment in patients with WML.

White-Matter Hyperintensities and Lacunar Infarcts Are Associated with an Increased Risk of Alzheimer's Disease in the Elderly in China.

BACKGROUND AND PURPOSE: This study investigated the contribution of white-matter hyperintensities (WMH) and lacunar infarcts (LI) to the risk of Alzheimer's disease (AD) in an elderly cohort in China. METHODS: Older adults who were initially cognitively normal were examined with MRI at baseline, and followed for 5 years. WMH were classified as mild, moderate, or severe, and LI were classified into a few LI (1 to 3) or many LI (≥4). Cognitive function was assessed using the Mini Mental State Examination and the Activities of Daily Living scale. RESULTS: Among the 2,626 subjects, 357 developed AD by the end of the 5-year follow-up period. After adjusting for age and other potential confounders, having only WMH, having only LI, and having both WMH and LI were associated with an increased risk of developing AD compared with having neither WMH nor LI. Moderate and severe WMH were associated with an increased risk of developing AD compared with no WMH. Furthermore, patients with many LI had an increased risk of developing AD compared with no LI. CONCLUSIONS: Having moderate or severe WMH and many LI were associated with an increased risk of developing AD, with this being particularly striking when both WMH and LI were present.

LincRNA Plays a Role in the Effect of CYP46A1 Polymorphism in Alzheimer's Disease - Related Pathology.

Polymorphism of the cholesterol-24S-hydroxylase (CYP46A1) gene is thought to be a risk factor for Alzheimer's disease (AD). A single nucleotide polymorphism (T/C) in intron 2, rs754203, has been confirmed to be implicated in AD. Rs754203 is located in the long intronic non-coding RNA (LincRNA) sequence, which has previously been shown to be involved in the pathology of many diseases. Thus, the present study aimed to investigate the role of LincRNA in the CYP46A1 gene expression and related AD pathology. SH-SY5Y cells with overexpressed TT or CC genotype CYP46A1 were used. Through RT-PCR, Western blot and ELISA assays, we found that LincRNA can affect the CYP46A1 gene expression and the production of 24-OHC and Aß. Overexpression of LincRNA can significantly inhibit CYP46A1 expression and 24-OHC production, as well as increasing the Aß expression level. Silencing of LincRNA confirmed the role that it plays in the regulation of CYP46A1, as well as the production of 24-OHC and Aß. In addition, this effect was stronger in the A type LincRNA than in the G type LincRNA. Results from dual luciferase assays show that LincRNA inhibited the activity of the CYP46A1 gene promoter. This study indicates a possible novel role of LincRNA and provides a new way to look into the relationship between CYP46A1 polymorphism and AD pathology. This may identify a novel pathway through which to explore AD therapy.

Metabolic syndrome contributes to cognitive impairment in patients with Parkinson's disease.

INTRODUCTION: Metabolic syndrome (MetS) increases the risk of cognitive impairment in normal aging but this has not been studied in Parkinson's Disease (PD). The purpose of this study was to investigate the impact of MetS on cognitive impairment in PD. METHODS: This study investigated subjects older than 60 years who were diagnosed with PD. They were enrolled into this study between January 2010 and December 2011, and followed for 5 years. The assessment of cognitive function in subjects with PD was based on the cognitive and neuropsychiatric tests, and MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III. The subjects were divided into three groups according to the cognitive function at the end of follow-up: PD with normal cognitive function (PD-NC), mild cognitive impairment in PD (PD-MCI) and PD dementia (PDD). RESULTS: Of the 787 subjects with PD included in our study, 255 (32.4%) were diagnosed with PD-MCI, and 105 (13.3%) were diagnosed with PDD. MetS was significantly associated with PD-MCI (odds radio [OR]: 1.45, 95% confidence interval [CI]: 1.17-1.72) and PDD (OR: 2.12, 95% CI: 1.57-2.83). The associations between MetS and the main cognition domains of PDD were statistically significant. The treatment of MetS was helpful in reducing the risk of PDD. CONCLUSIONS: We found that MetS increase the risk of cognitive impairment in patients with PD, and is significantly associated with the severity of cognitive impairment. The results suggest that the intervention against MetS is helpful in managing cognitive impairment in PD.

CYP46A1 and the APOEε4 Allele Polymorphisms Correlate with the Risk of Alzheimer's Disease.

Polymorphisms of the cholesterol-24S-hydroxylase (CYP46A1) and apolipoprotein E (APOE) genes are risk factors for Alzheimer's disease (AD). Plasma level of 24S-hydroxcholesterol (24-OHC), the metabolite of cholesterol, is thought to correlate with AD. The present study investigated the correlation between these genetic factors and blood 24-OHC and amyloid-beta (Aß) levels in AD patients. Association analysis, logistic regression, and linear regression were used to analyze the correlation of CYP46A1 and APOE genotypes with blood 24-OHC and Aß levels and AD risk. We found that the APOEε4 alleles were significantly higher in patients with AD and there was a potential synergistic interaction between the CYP46A1 C allele and APOEε4 allele in AD. Blood 24-OHC level and Aß level were significantly higher in AD patients than controls, indicating 24-OHC could be a marker in AD diagnosis. However, AD patients with the CYP46A1 TT, but not CC, genotype had higher 24-OHC levels, which indicated that there may be other mechanisms in the relationship between CYP46A1 polymorphisms and AD.

Metabolic syndrome is associated with increased risk of short-term post-procedural complications after carotid artery stenting.

The risk factors for post-procedural events after carotid artery stenting (CAS) have not been well established. The aim of this study was to investigate the association between metabolic syndrome (MetS) and the risk of post-CAS complications. A total of 358 consecutive patients who underwent CAS were enrolled in this prospective study. Patients' demographic data, clinical characteristics, and complications after CAS within 30 days were recorded. Logistic regression analysis was performed to identify possible risk factors for post-procedural complications after CAS. The incidence of complications after CAS within 30 days was 7.0%. Logistic regression analysis identified the following as independent risk factors for 30-day transient ischemic attacks, stroke, myocardial infarction, and death after CAS: metabolic syndrome (OR = 2.31, 95% CI 1.91-3.01, P = 0.004), diabetes (OR = 2.24, 95% CI 1.74-2.76, P = 0.026), symptomatic patient (OR = 1.73, 95% CI 1.23-3.05, P = 0.011), and age (OR = 1.87, 95% CI 1.35-2.57, P = 0.042). Among the components of MetS, central obesity (OR = 2.21, 95% CI 1.24-2.63, P = 0.006), low high-density lipoprotein cholesterol (HDL-C) (OR = 1.66, 95% CI 1.34-2.27, P = 0.022), and high fasting plasma glucose (OR = 2.32, 95% CI 1.85-2.74, P = 0.003) were associated with increased risk of 30-day complications after CAS. This present study suggests that patients with metabolic syndrome have significantly increased risk of complications after CAS within 30 days. Moreover, MetS patients with central obesity, high fasting plasma glucose, or low HDL-C have significantly increased risk of complications after CAS within 30 days.