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Antioxidants (Basel, Switzerland) Nov 2021Statins may exert protective effects against oxidative stress by upregulating specific antioxidant mechanisms. We conducted a systematic review and meta-analysis of the... (Review)
Review
Statins may exert protective effects against oxidative stress by upregulating specific antioxidant mechanisms. We conducted a systematic review and meta-analysis of the effect of statins on three key antioxidant enzymes: glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. The electronic databases PubMed, Web of Science, and Scopus were searched from inception to July 2021. The risk of bias was assessed with the Joanna Briggs Institute Critical Appraisal Checklist and certainty of evidence was assessed using the GRADE framework. In 15 studies, reporting 17 treatment arms in 773 patients (mean age 53 years, 54% males), statins significantly increased the concentrations of both GPx (standardized mean difference, SMD = 0.80, 95% confidence interval, CI 0.13 to 1.46, = 0.018; high certainty of evidence) and SOD (SMD = 1.54, 95% CI 0.71 to 2.36, < 0.001; high certainty of evidence), but not catalase (SMD = -0.16, 95% CI -0.51 to 0.20, = 0.394; very low certainty of evidence). The pooled SMD values were not altered in sensitivity analysis. There was no publication bias. In conclusion, statin treatment significantly increases the circulating concentrations of GPx and SOD, suggesting an antioxidant effect of these agents (PROSPERO registration number: CRD42021271589).
PubMed: 34829712
DOI: 10.3390/antiox10111841 -
Journal of Diabetes and Metabolic... Dec 2019There is controversial data regarding the effects of dietary antioxidative supplements on diabetic retinopathy (DR). We conducted a systematic review of both... (Review)
Review
PURPOSE
There is controversial data regarding the effects of dietary antioxidative supplements on diabetic retinopathy (DR). We conducted a systematic review of both observational and randomized controlled clinical trials (RCTs) to clarify whether they are effective or not.
METHODS
All observational and RCTs conducted by antioxidative supplements on DR published up to 1 January 2018 in PubMed, Web of Sciences, Scopus and Cochrane Library databases were included. Exclusion criteria were animal studies, and studies conducted in Type 1 diabetes mellitus (T1DM), children or pregnant women. Main outcome measures were reporting the incidence or progression of DR in T2DM by assessment of visual fields, and measurements of oxidative and antioxidative biomarkers. The quality of reporting of included articles and risk of bias were assessed.
RESULTS
Finally, we reached 14 observational studies and 7 RCTs that conducted on 256,259 subjects. Due to severe methodological heterogeneity, only qualitative synthesis was carried. All studies were reported a significantly lower level of antioxidants and higher level of oxidative stress biomarkers in DR compared with others. There was an inverse significant correlation between vitamin C and malondialdehyde (MDA) (r = -0.81) or DNA damage (r = -0.41). These figures were statistically significant between vitamin E and MDA (r = 0.77) or superoxide dismutase (r = 0.44). Coefficient of correlation between MDA and zinc (-0.82), coenzyme Q10 (0.56), and magnesium (-0.73) was significant. Multi-oxidants trials were shown non-significant beneficial effects on DR.
CONCLUSIONS
Although our study supports the positive effects of antioxidative supplements on DR, more high quality studies are needed to confirm.
PubMed: 31890694
DOI: 10.1007/s40200-019-00434-x -
The International Journal of... Jun 2017People with schizophrenia and other psychosis show increased proinflammatory and prooxidative status. However, the few studies that have specifically assessed oxidative... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
People with schizophrenia and other psychosis show increased proinflammatory and prooxidative status. However, the few studies that have specifically assessed oxidative and inflammatory markers in early onset psychosis (onset before age 18) have shown contradictory results.
METHODS
Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews and meta-analyses were used to conduct a systematic literature search to detect studies comparing inflammatory and oxidative markers in early onset psychosis patients and healthy controls.
RESULTS
Seven studies met criteria for the qualitative analysis. Four studies met criteria for meta-analysis, comprising an overall sample of 261 early onset psychosis patients and 246 healthy controls. Six independent meta-analyses were performed for catalase, glutathione, glutathione peroxidase, superoxide dismutase, total antioxidant status, and cell/DNA oxidative damage. No significant differences were found between early onset psychosis patients and controls in any of the parameters assessed. Heterogeneity among studies was high. Qualitative analysis of individual studies showed an association of inflammatory and oxidative markers with clinical, cognitive, and neurobiological outcomes, especially in longitudinal assessments.
CONCLUSIONS
Despite the lack of significant differences between early onset psychosis patients and controls in the oxidative markers assessed in the meta-analyses, results based on individual studies suggest that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first episodes of early onset psychosis.
Topics: Acute Disease; Humans; Inflammation; Oxidative Stress; Psychotic Disorders; Schizophrenia
PubMed: 28575316
DOI: 10.1093/ijnp/pyx015 -
The Cochrane Database of Systematic... Oct 2023Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring... (Review)
Review
BACKGROUND
Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring enzyme which provides a defense against such oxidant injury. Providing supplementary SOD has been tested in clinical trials to prevent BPD in preterm infants.
OBJECTIVES
To determine the efficacy and safety of SOD in the prevention and treatment of BPD on mortality and other complications of prematurity in infants at risk for, or having BPD.
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, and three trials registers on 22 September 2022 together with reference checking, citation searching and contact with study authors to identify additional studies.
SELECTION CRITERIA
Randomized, quasi-randomized and cluster-randomized controlled trials (RCTs) where the participants were preterm infants who had developed, or were at risk of developing BPD, and who were randomly allocated to receive either SOD (in any form, by any route, any dose, anytime) or placebo, or no treatment.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality, mortality prior to discharge, and BPD or death at 36 weeks' postmenstrual age. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for the dichotomous outcomes. We used GRADE to assess certainty of evidence for each outcome.
MAIN RESULTS
We included three RCTs (380 infants) on SOD administration in preterm infants at risk for BPD, and no studies in preterm infants with evolving BPD / early respiratory insufficiency. The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days (RR 1.09, 95% CI 0.94 to 1.26; RD 0.06, 95% CI -0.05 to 0.16, 1 study, 302 infants; I for RR and RD not applicable), BPD defined as oxygen at 36 weeks' postmenstrual age (RR 0.96, 95% CI 0.72 to 1.29; RD -0.01, 95% CI -0.11 to 0.09, 2 studies, 335 infants; I for RR and RD = 0%), neonatal mortality (RR 0.98, 95% CI 0.57 to 1.68; RD -0.00, 95% CI -0.08 to 0.07, 2 studies, 335 infants; I for RR and RD = 0%), and mortality prior to discharge (RR 1.20, 95% CI 0.53 to 2.71; RD 0.04, 95% CI -0.14 to 0.23, 2 studies, 78 infants; I for RR and RD = 0%). No studies reported BPD or death at 36 weeks' postmenstrual age. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage (RR 0.95, 95% CI 0.78 to 1.15; RD -0.03, 95% CI -0.15 to 0.08, 2 studies, 335 infants; Ifor RR = 0%, I for RD = 8%), and severe retinopathy of prematurity (ROP) (RR 0.97, 95% CI 0.57 to 1.65; RD -0.01, 95% CI -0.10 to 0.09, 1 study, 244 infants; I for RR and RD not applicable). No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. Certainty of evidence was very low for all outcomes. We identified no ongoing trials.
AUTHORS' CONCLUSIONS
The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality and mortality prior to discharge compared to placebo. No studies reported BPD or death at 36 weeks' postmenstrual age and need for supplemental oxygen. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage and severe retinopathy of prematurity. No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. The effects of SOD in preterm infants has not been reported in any trial in the last few decades, considering that the most recent trial on SOD in preterm infants was conducted in 1997/1998, and no new studies are ongoing. In the light of the limited available evidence, new data from preclinical and observational studies are needed to justify the conduction of new RCTs. Observational studies might report how SOD is administered, including indication, dose and association with relevant outcomes such as mortality, BPD and long-term neurodevelopment.
Topics: Infant, Newborn; Infant; Humans; Retinopathy of Prematurity; Bronchopulmonary Dysplasia; Infant, Premature; Oxygen; Superoxide Dismutase; Randomized Controlled Trials as Topic
PubMed: 37811631
DOI: 10.1002/14651858.CD013232.pub2 -
Frontiers in Endocrinology 2023Male testicular dysfunction is a considerable complication of anti-cancer therapies, including chemotherapy and radiotherapy, partly due to the increased oxidative... (Meta-Analysis)
Meta-Analysis
Protective effects of exogenous melatonin therapy against oxidative stress to male reproductive tissue caused by anti-cancer chemical and radiation therapy: a systematic review and meta-analysis of animal studies.
BACKGROUND
Male testicular dysfunction is a considerable complication of anti-cancer therapies, including chemotherapy and radiotherapy, partly due to the increased oxidative stress caused by these treatments. Melatonin is an effective antioxidant agent that protects testicles against physical and toxic chemical stressors in animal models. This study aims to systematically review the melatonin's protective effects against anti-cancer stressors on rodential testicular tissue.
MATERIALS AND METHOD
An extensive search was conducted in Web of Science, Scopus, and PubMed for animal studies investigating exogenous melatonin's protective effects on rodent testicles exposed to anti-cancer chemicals and radiotherapeutic agents. Using the DerSimonian and Laird random-effect model, standardized mean differences and 95% confidence intervals were estimated from the pooled data. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022355293).
RESULTS
The meta-analysis included 38 studies from 43 studies that were eligible for the review. Rats and mice were exposed to radiotherapy (ionizing radiations such as gamma- and roentgen radiation and radioactive iodine) or chemotherapy (methotrexate, paclitaxel, busulfan, cisplatin, doxorubicin, vinblastine, bleomycin, cyclophosphamide, etoposide, Taxol, procarbazine, docetaxel, and chlorambucil). According to our meta-analysis, all outcomes were significantly improved by melatonin therapy, including sperm quantity and quality (count, motility, viability, normal morphology, number of spermatogonia, Johnsen's testicular biopsy score, seminiferous tubular diameter, and seminiferous epithelial height), serum level of reproductive hormones (Follicle-Stimulating Hormone and testosterone), tissue markers of oxidative stress (testicular tissue malondialdehyde, superoxide dismutase, glutathione peroxidase, catalase, glutathione, caspase-3, and total antioxidant capacity), and weight-related characteristics (absolute body, epididymis, testis, and relative testis to body weights). Most SYRCLE domains exhibited a high risk of bias in the included studies. Also, significant heterogeneity and small-study effects were detected.
CONCLUSION
In male rodents, melatonin therapy was related to improved testicular histopathology, reproductive hormones, testis and body weights, and reduced levels of oxidative markers in testicular tissues of male rodents. Future meticulous studies are recommended to provide a robust scientific backbone for human applications.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022355293, identifier CRD42022355293.
Topics: Humans; Male; Animals; Rats; Mice; Melatonin; Antioxidants; Iodine Radioisotopes; Semen; Thyroid Neoplasms; Oxidative Stress; Body Weight
PubMed: 37701901
DOI: 10.3389/fendo.2023.1184745 -
Reproduction & Fertility Jan 2022To summarize the currently available phase I and II clinical trials of the effects of nonoxynol-9 (N-9) on human sperm structure and functions. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To summarize the currently available phase I and II clinical trials of the effects of nonoxynol-9 (N-9) on human sperm structure and functions.
METHODS
A systematic review and meta-analysis aiming to evaluate the spermicidal activity of N-9 on motility, was conducted in PubMed, EMBASE, and Cochrane databases by 10 March 2021. The counted numbers of progressive motile (PR) sperm in cervical mucus and the vanguard sperm penetration distances were analyzed. Other effects on sperm structures and physiological activities were reviewed as well.
RESULTS
In the pooled results, percentages or counted numbers of PR sperm decreased after the treatment of N-9. Vanguard sperm penetration distance was shortened in treated groups. N-9 has been confirmed to damage the structures of sperm, as well as other organelles like acrosome and mitochondria. The physiological activities such as generation of reactive oxygen species, superoxide dismutase activity, acrosin activity, and hemizona binding were all inhibited in the reviewed studies.
CONCLUSIONS
N-9 has several impacts on sperm owing to its potency in reducing sperm motility and cervical mucus penetration, as well as other functional competencies.
LAY SUMMARY
Nonoxynol-9 (N-9) has been used worldwide as a spermicide to kill sperm for more than 60 years but can cause side effects including vaginal irritation and can increase the rate of contraceptive failure. A detailed analysis of published literature aiming to evaluate the spermicidal activity of N-9 on sperm was carried out. In the pooled results, N-9 reduced the number of active sperm and the distance they traveled. It also caused damage to the structures of sperm and to the way the sperm acted and interacted with the egg. In conclusion, N-9 impacts on sperm in a number of ways that lead to sperm death and dysfunction.
Topics: Female; Humans; Male; Nonoxynol; Semen; Sperm Motility; Spermatocidal Agents; Spermatozoa
PubMed: 35350652
DOI: 10.1530/RAF-21-0024 -
Frontiers in Endocrinology 2023Environmental pollution and infertility are two modern global challenges that agonize personal and public health. The causal relationship between these two deserves... (Meta-Analysis)
Meta-Analysis
Protective effects of melatonin against the toxic effects of environmental pollutants and heavy metals on testicular tissue: A systematic review and meta-analysis of animal studies.
BACKGROUND
Environmental pollution and infertility are two modern global challenges that agonize personal and public health. The causal relationship between these two deserves scientific efforts to intervene. It is believed that melatonin maintains antioxidant properties and may be utilized to protect the testicular tissue from oxidant effects caused by toxic materials.
METHODS
A systematic literature search was conducted in PubMed, Scopus, and Web of Science to identify the animal trial studies that evaluated melatonin therapy's effects on rodents' testicular tissue against oxidative stress caused by heavy metal and non-heavy metal environmental pollutants. Data were pooled, and standardized mean difference and 95% confidence intervals were estimated using the random-effect model. Also, the risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. (PROSPERO: CRD42022369872).
RESULTS
Out of 10039 records, 38 studies were eligible for the review, of which 31 were included in the meta-analysis. Most of them showed beneficial effects of melatonin therapy on testicular tissue histopathology. [20 toxic materials were evaluated in this review, including arsenic, lead, hexavalent chromium, cadmium, potassium dichromate, sodium fluoride, cigarette smoke, formaldehyde, carbon tetrachloride (CCl4), 2-Bromopropane, bisphenol A, thioacetamide, bisphenol S, ochratoxin A, nicotine, diazinon, Bis(2-ethylhexyl) phthalate (DEHP), Chlorpyrifos (CPF), nonylphenol, and acetamiprid.] The pooled results showed that melatonin therapy increased sperm count, motility, viability and body and testicular weights, germinal epithelial height, Johnsen's biopsy score, epididymis weight, seminiferous tubular diameter, serum testosterone, and luteinizing hormone levels, testicular tissue Malondialdehyde, glutathione peroxidase, superoxide dismutase, and glutathione levels. On the other hand, abnormal sperm morphology, apoptotic index, and testicular tissue nitric oxide were lower in the melatonin therapy arms. The included studies presented a high risk of bias in most SYRCLE domains.
CONCLUSION
In conclusion, our study demonstrated amelioration of testicular histopathological characteristics, reproductive hormonal panel, and tissue markers of oxidative stress. Melatonin deserves scientific attention as a potential therapeutic agent for male infertility.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022369872.
Topics: Animals; Male; Melatonin; Environmental Pollutants; Semen; Testis; Antioxidants
PubMed: 36793277
DOI: 10.3389/fendo.2023.1119553 -
Alpha Psychiatry Mar 2022Brain's aerobic energy metabolism, abundance of the fatty acids and unsaturated lipids, generation of Reactive Oxygen Species (ROS) by hormones, physiological roles of... (Review)
Review
OBJECTIVE
Brain's aerobic energy metabolism, abundance of the fatty acids and unsaturated lipids, generation of Reactive Oxygen Species (ROS) by hormones, physiological roles of transition metals (i.e., iron and copper), and free radicals in the nervous system may cause inclination to oxidative stress in psychiatric disorders. Electroconvulsive therapy (ECT) may cause oxidative stress by the electrical field or by the induced seizure. It was aimed to review the literature in terms of the influence of ECT on levels of oxidant and antioxidant compounds.
METHODS
The literature search was performed with the keywords that were oxidative stress or "DNA damage" or "RNA damage" or "lipid peroxidase" or "superoxide dismutase" or "catalase" or "glutathione" or "nitrite" or "nitric oxide" and "electroconvulsive therapy" or "electroconvulsive shock" or "electroconvulsive seizure". Twenty of 1480 records were included.
RESULTS
Eleven studies were performed in human subjects, whereas 9 studies were performed in rats. Human studies are conducted with serum, plasma, or urine samples; rat studies include brain tissues from various sites. In rats, four independent studies showed increased levels of lipid oxidation markers, and four independent studies reported increased levels of oxidative stress markers in brain samples. In human studies, studies were performed with circulating blood samples and the results were more inconsistent.
CONCLUSION
Although some markers like superoxide dismutase or thioredoxin imply that ECT may increase the balance for oxidative stress, this notion is not supported by other markers of ECT. The current literature does not clearly suggest that the ECT is associated with oxidative stress in psychiatric disorders. Further studies with similar methods should be performed in big samples.
PubMed: 36426296
DOI: 10.5152/alphapsychiatry.2021.21584 -
Frontiers in Pharmacology 2023Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and end-stage renal failure (ESRF), and the control of disease progression and adverse...
Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and end-stage renal failure (ESRF), and the control of disease progression and adverse events during treatment needs to be improved. This study aimed to systematically evaluate the clinical efficacy and safety of Niaoduqing granules (NDQG) in the treatment of diabetic kidney disease (DKD). Randomized controlled trials (RCTs) of NDQG for DKD from Chinese and English databases up to 31 August 2022 were included. The quality of the literature was assessed using the risk of bias tool of the Cochrane Handbook. At a 95% confidence interval (CI), relative risk (RR) and Cohen's d were used for the categorical and continuous variables, respectively, and Stata 16.0 software was used for statistical analysis. A funnel plot and Egger's tests were used to assess publication bias. A total of 4,006 patients were included in 52 RCTs, including 1,987 cases in the control group and 2,019 cases in the treatment group. Compared with conventional treatment (CT), combined NDQG therapy is more effective in improving clinical efficiency [RR = 1.23, 95% confidence interval (1.17, 1.29), < 0.001, = 53.17%], kidney function (urinary albumin excretion rate [SMD = -0.90, 95% CI (-1.14, -0.66), < 0.001, = 78.19%], 24hUTP levels [SMD = -0.81, 95% CI (-1.08, -0.55), < 0.001, = 87.08%], blood urea nitrogen [SMD = -0.54, 95% CI (-0.69, -0.39), < 0.01, = 77.01%], SCr [SMD = -0.68, 95% CI (-0.90, -0.45), < 0.001, = 89.97%], CCr [SMD = 0.76, 95% CI (0.10,1.42), = 0.02, = 95.97%], and Cys-C [SMD = -1.32, 95% CI (-2.25, -0.40), = 0.01, = 93.44%]), the level of glucose metabolism (fasting blood glucose [SMD = -0.18, 95% CI (-0.38, 0.03), = 0.10, = 71.18%] and HbA1c [SMD = -0.42, 95% CI (-0.86, -0.02), = 0.06, = 81.64%]), the level of lipid metabolism (total cholesterol [SMD = -0.70, 95% CI (-1.01, -0.39), < 0.001, = 86.74%] and triglyceride [SMD = -0.61, 95% CI (-0.87,-0.36), < 0.001, = 80.64%]), inflammatory factors (Hs-CRP [SMD = -1.00, 95% CI (-1.54, -0.46), < 0.001, = 86.81%], IL-18 [SMD = -1.25, 95% CI (-1.58, -0.92), < 0.001, = 0], and TNF-α [SMD = -1.28, 95% CI (-1.64, -0.91), < 0.001, = 75.73%]), and indicators of oxidative stress (malondialdehyde [SMD = -0.88, 95% CI (-1.22, -0.54), < 0.001, = 66.01%] and advanced oxidation protein products [SMD = -0.92, 95% CI (-1.85, 0.00), < 0.001, = 90.68%]). In terms of improving uric acid [SMD = -1.59, 95% CI (-3.45, 0.27), = 0.09, = 94.67%], 2hPG [SMD = -0.04, 95% CI (-0.61, 0.53), = 0.89, = 84.33%], HDL-C [SMD = 0.71, 95% CI (0.02, 1.40), = 0.04, = 87.43%], Hb [SMD = 0.11, 95% CI (-0.10, 0.32), = 0.32, = 0.00]), and superoxide dismutase [SMD = 1.32, 95% CI (0.44, 2.20), < 0.001, = 93.48%], the effect is not obvious. Adjuvant treatment with NDQG did not increase the incidence of adverse reactions in the control group [SMD = 0.98, 95% CI (0.71, 1.34), = 0.89, = 1.59%]. Obvious publication bias was detected by funnel plot and Egger's test. Our meta-analysis showed that adjuvant treatment with NDQG has more advantages than conventional treatment alone in the DKD treatment, which could improve clinical efficiency, kidney function, the level of glucose metabolism, the level of lipid metabolism, inflammatory factors, and oxidative stress indicators. At the same time, it also showed that NDQG are relatively safe. However, more high-quality studies are needed to provide more reliable evidence for clinical use. : https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022373726, identifier CRD42022373726.
PubMed: 37475716
DOI: 10.3389/fphar.2023.1180751 -
Journal of Molecular Neuroscience : MN Nov 2020Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and is characterized by degeneration and axon loss from the upper motor neuron, that descends from... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and is characterized by degeneration and axon loss from the upper motor neuron, that descends from the lower motor neuron in the brain. Over the period, assorted outcomes from medical findings, molecular pathogenesis, and structural and biophysical studies have abetted in providing thoughtful insights underlying the importance of disease-causing genes in ALS. Consequently, numerous mechanisms were proposed for the pathogenesis of ALS, considering protein mutations, aggregation, and misfolding. Besides, the answers to the majority of ALS cases that happen to be sporadic still remain obscure. The application in discovering susceptibility factors in ALS contemplating the genetic factors is to be further dissevered in the future years with innovation in research studies. Hence, this review targets in revisiting the breakthroughs on the disease-causing genes related with ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; C9orf72 Protein; Genetic Predisposition to Disease; Humans; Profilins; RNA-Binding Protein FUS; Superoxide Dismutase-1
PubMed: 32415434
DOI: 10.1007/s12031-020-01569-w