Neurodegenerative Effects Research Articles

Genetically Proxied Angiotensin‐Converting‐Enzyme Inhibition is Potentially Causal for Alzheimer Disease: A Mendelian Randomization Study

AbstractBackgroundAngiotensin‐converting enzyme (ACE) has been implicated in the pathogenesis of Alzheimer disease (AD), in which ACE plays a role in metabolizing Amyloid Beta (AB). Genetic variants in the ACE locus have also been associated with AD. The effect of ACE inhibitors on AD risk remains unclear. We sought to investigate the potential causal relationship between ACE inhibition and AD and other neurodegenerative disorders using a mendelian randomization (MR) approach.MethodA genetic proxy for ACE inhibition (MR exposure) was generated using 17 single nucleotide polymorphisms (SNPs) in the ACE gene that were previously associated with lower ACE blood levels in a candidate gene study (n = 4,147; adjusted‐P < 0.05). Summary genome‐wide association study (GWAS) statistics for AD (111,326 cases, 677,663 controls), Frontotemporal dementia (FTD) (3526 cases, 9402 controls) and Lewy body dementia (LBD) (cases 2591, controls 4027) were used as proxies for the MR outcomes. Inverse weighted variance MR was performed to test the potentially causal relationship between the exposure and outcomes. Sensitivity analyses were completed to test the robustness of the results.ResultACE inhibition was significantly associated with increased risk of AD (OR = 1.07, P = 0.0000005); with robust and consistent effects in all sensitivity analyses. Using leave one out method; rs4343 (A allele) showed the strongest effect. rs4343 is in mild linkage disequilibrium with the SNP associated at genome wide significant level with AD rs4277405 (R2 0.35). Rerunning the MR analysis on the AD cohort after removing rs4343 continued to show significant results (OR = 1.04, P = 0.02). ACE inhibition was also associated with increased risk for FTD (OR = 1.16, P = 0.009), but the findings were not robust in some sensitivity analyses, possibly due to lower sample size of FTD cohort. ACE inhibition was not associated with LBD.ConclusionThis is the first study to provide robust genetic evidence for the potentially causal relationship between ACE inhibition in the blood and the diagnosis of AD. These results should encourage further investigation of the potential neurodegenerative side effects of ACE inhibition; and further suggest ACE related pathways as pharmacological targets for treatment and/or prevention of AD.

Reduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity

While the endocrine function of white adipose tissue has been extensively explored, comparatively little is known about the secretory activity of less-investigated fat depots. Here, we use proteomics to compare the secretory profiles of male murine perivascular depots with those of canonical white and brown fat. Perivascular secretomes show enrichment for neuronal cell-adhesion molecules, reflecting a higher content of intra-parenchymal sympathetic projections compared to other adipose depots. The sympathetic innervation is reduced in the perivascular fat of obese (ob/ob) male mice, as well as in the epicardial fat of patients with obesity. Degeneration of sympathetic neurites is observed in presence of conditioned media of fat explants from ob/ob mice, that show reduced secretion of neuronal growth regulator 1. Supplementation of neuronal growth regulator 1 reverses this neurodegenerative effect, unveiling a neurotrophic role for this protein previously identified as a locus associated with human obesity. As sympathetic stimulation triggers energy-consuming processes in adipose tissue, an impaired adipose-neuronal crosstalk is likely to contribute to the disrupted metabolic homeostasis characterising obesity.

Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration.

Neurodegeneration leads to multiple early changes in cognitive, emotional, and social behaviours and ultimately progresses to dementia. The dysregulation of calcium is one of the earliest potentially initiating events in the development of neurodegenerative diseases. A primary neuronal target of calcium is the small sensor and effector protein calmodulin that, in response to calcium levels, binds to and regulates hundreds of calmodulin binding proteins. The intimate and entangled relationship between calmodulin binding proteins and all phases of Alzheimer's disease has been established, but the relationship to other neurodegenerative diseases is just beginning to be evaluated. Risk factors and hallmark proteins from Parkinson's disease (PD; SNCA, Parkin, PINK1, LRRK2, PARK7), Huntington's disease (HD; Htt, TGM1, TGM2), Lewy Body disease (LBD; TMEM175, GBA), and amyotrophic lateral sclerosis/frontotemporal disease (ALS/FTD; VCP, FUS, TDP-43, TBK1, C90rf72, SQSTM1, CHCHD10, SOD1) were scanned for the presence of calmodulin binding domains and, within them, appropriate binding motifs. Binding domains and motifs were identified in multiple risk proteins, some of which are involved in multiple neurodegenerative diseases. The potential calmodulin binding profiles for risk proteins involved in HD, PD, LBD, and ALS/FTD coupled with other studies on proven binding proteins supports the central and potentially critical role for calmodulin in neurodegenerative events.

Carbonaceous Nanoparticle Air Pollution: Toxicity and Detection in Biological Samples.

Among the different air pollutants, particulate matter (PM) is of great concern due to its abundant presence in the atmosphere, which results in adverse effects on the environment and human health. The different components of PM can be classified based on their physicochemical properties. Carbonaceous particles (CPs) constitute a major fraction of ultrafine PM and have the most harmful effects. Herein, we present a detailed overview of the main components of CPs, e.g., carbon black (CB), black carbon (BC), and brown carbon (BrC), from natural and anthropogenic sources. The emission sources and the adverse effects of CPs on the environment and human health are discussed. Particularly, we provide a detailed overview of the reported toxic effects of CPs in the human body, such as respiratory effects, cardiovascular effects, neurodegenerative effects, carcinogenic effects, etc. In addition, we also discuss the challenges faced by and limitations of the available analytical techniques for the qualitative and quantitative detection of CPs in atmospheric and biological samples. Considering the heterogeneous nature of CPs and biological samples, a detailed overview of different analytical techniques for the detection of CPs in (real-exposure) biological samples is also provided. This review provides useful insights into the classification, toxicity, and detection of CPs in biological samples.

Anti-nonspecific hydrophilic hydrogel for efficient capture of N-glycopeptides from Alzheimer's disease patient's serum

A novel magnetic super-hydrophilic zwitterionic hydrogel (MagG@PCBAA) was prepared via a cross-linking reaction. The MagG@PCBAA hydrogel displayed high sensitivity (0.5 fmol/μL), superior selectivity (molar ratio BSA:HRP = 10,000:1), satisfactory recovery rate (119.1 ± 1.9%), stable reusability (10 times) and high load capacity (300 mg/g). Furthermore, the MagG@PCBAA hydrogel also exhibited an excellent capability for specific capture of glycopeptides from serum of normal control and Alzheimer's disease patient. 147 glycopeptides allocated to 72 glycoproteins were captured from serum of normal control and 187 glycopeptides allocated to 84 glycoproteins were enriched from serum of Alzheimer's disease patient analyzed by Nano-LC-MS/MS. Based on gene ontology analysis, 36 primitive glycoproteins captured from the serum of Alzheimer's disease patient were significantly involved in various of neurodegenerative disease-related events, including glycoprotein binding, antigen binding and serine-type endopeptidase activity, acute-phase response, lipid transport and cholesterol metabolic process.

Chronic exposure to methadone induces activated microglia and astrocyte and cell death in the cerebellum of adult male rats.

Methadone is a centrally-acting synthetic opioid analgesic widely used in the methadone maintenance therapy (MMT) programs throughout the world. Considering its neurotoxic effects particularly on the cerebellum, this study aims to address the behavioral and histological alterations in the cerebellar cortex associated with methadone administration. Twenty-four adult male albino rats were randomized into two groups of control and methadone treatment. Methadone was subcutaneously administered (2.5-10mg/kg) once a day for two consecutive weeks. The functional and structural changes in the cerebellum were compared to the control group. Our data revealed that treating rats with methadone not only induced cerebellar atrophy, but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. We further demonstrated that treating rats with methadone increased complexity of astrocyte processes and decreased complexity of microglia processes. Our result showed that methadone impaired motor coordination and locomotor performance and neuromuscular activity. Additionally, relative gene expression of TNF-α, caspase-3 and RIPK3 increased significantly due to methadone. Our findings suggest that methadone administration has a neurodegenerative effect on the cerebellar cortex via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

An in-silico insight into the predictive interaction of Apolipoprotein-E with Epstein-Barr virus proteins and their probable role in mediating Alzheimer’s disease

Recent reports suggest that persistent Epstein-Barr virus (EBV) infection and its recurrent reactivation could instigate the formation of proteinaceous plaques in the brain: a hallmark of Alzheimer’s disease (AD). Interestingly, a major genetic risk factor of AD, the apolipoprotein E (ApoE), could also influence the outcome of EBV infection in an individual. The ApoE is believed to influence the proteinaceous plaque clearance from the brain, and its defective functioning could result in the aggregate deposition. The persistent presence of EBV infection in a genetically predisposed individual could create a perfect recipe for severe neurodegenerative consequences. Therefore, in the present study, we investigated the possible interactions between ApoE and various EBV proteins using computational tools. Our results showed possibly stable de-novo interactions between the C-terminal domain of ApoE3 and EBV proteins: EBV nuclear antigen-1 (EBNA1) and BamHI Z fragment leftward open reading frame-1 (BZLF1). The EBNA1 protein of EBV plays a crucial role in establishing latency and replication of the virus. Whereas BZLF1 is involved in the lytic replication cycle. The proposed interaction of EBV proteins at the ligand-binding site of ApoE3 on CTD could interfere with- its capability to sequester amyloid fragments and, hence their clearance from the brain giving rise to AD pathology. This study provides a new outlook on EBV’s underexplored role in AD development and paves the way for novel avenues of investigation which could further our understanding of AD pathogenesis. Communicated by Ramaswamy H. Sarma

Air pollution exposure during pregnancy and childhood, APOE ε4 status and Alzheimer polygenic risk score, and brain structural morphology in preadolescents

BackgroundAir pollution exposure is associated with impaired neurodevelopment, altered structural brain morphology in children, and neurodegenerative disorders. Differential susceptibility to air pollution may be influenced by genetic features. ObjectivesTo evaluate whether the apolipoprotein E (APOE) genotype or the polygenic risk score (PRS) for Alzheimer's Disease (AD) modify the association between air pollution exposure during pregnancy and childhood and structural brain morphology in preadolescents. MethodsWe included 1186 children from the Generation R Study. Concentrations of fourteen air pollutants were calculated at participants’ home addresses during pregnancy and childhood using land-use-regression models. Structural brain images were collected at age 9–12 years to assess cortical and subcortical brain volumes. APOE status and PRS for AD were examined as genetic modifiers. Linear regression models were used to conduct single-pollutant and multi-pollutant (using the Deletion/Substitution/Addition algorithm) analyses with a two-way interaction between air pollution and each genetic modifier. ResultsHigher pregnancy coarse particulate matter (PMcoarse) and childhood polycyclic aromatic hydrocarbons exposure was differentially associated with larger cerebral white matter volume in APOE ε4 carriers compared to non-carriers (29,485 mm3 (95% CI 6,189; 52,781) and 18,663 mm3 (469; 36,856), respectively). Higher pregnancy PMcoarse exposure was differentially associated with larger cortical grey matter volume in children with higher compared to lower PRS for AD (19436 mm3 (825, 38,046)). DiscussionAPOE status and PRS for AD possibly modify the association between air pollution exposure and brain structural morphology in preadolescents. Higher air pollution exposure is associated with larger cortical volumes in APOE ε4 carriers and children with a high PRS for AD. This is in line with typical brain development, suggesting an antagonistic pleiotropic effect of these genetic features (i.e., protective effect in early-life, but neurodegenerative effect in adulthood). However, we cannot discard chance findings. Future studies should evaluate trajectorial brain development using a longitudinal design.

Does cognitive aging follow an orchid and dandelion phenomenon?

Cognitive reserve reflects the brain’s intrinsic adaptive capacity against the neurodegenerative effects of aging. The maintenance or enhancement of the brain’s cognitive reserve plays a crucial role in mitigating the severity of pathologies associated with aging. A new movement, social prescribing, which focuses on prescribing lifestyle activities as a treatment for patients, is growing in popularity as a solution against aging pathologies. However, few studies have demonstrated a clear impact of lifestyle activities on individual cognitive health, outside of floor and ceiling effects. Understanding who benefits from which lifestyle factors remains unclear. Here, we investigated the potential effects of lifestyle activities on individuals’ cognitive health from more than 3,530 older adults using a stratification method and advanced analysis technique. Our stratification methods allowed us to observe a new result: older adults who had relatively average cognitive scores were not impacted by lifestyle factors. By comparison, older adults with very high or very low cognitive scores were highly impacted by lifestyle factors. These findings expand the orchid and dandelion theory to the aging field, regarding the biological sensitivity of individuals to harmful and protective environmental effects. Our discoveries demonstrate the role of individual differences in the aging process and its importance for social prescribing programs.

Multilayer Exponential Family Factor models for integrative analysis and learning disease progression.

Current diagnosis of neurological disorders often relies on late-stage clinical symptoms, which poses barriers to developing effective interventions at the premanifest stage. Recent research suggests that biomarkers and subtle changes in clinical markers may occur in a time-ordered fashion and can be used as indicators of early disease. In this article, we tackle the challenges to leverage multidomain markers to learn early disease progression of neurological disorders. We propose to integrate heterogeneous types of measures from multiple domains (e.g., discrete clinical symptoms, ordinal cognitive markers, continuous neuroimaging, and blood biomarkers) using a hierarchical Multilayer Exponential Family Factor (MEFF) model, where the observations follow exponential family distributions with lower-dimensional latent factors. The latent factors are decomposed into shared factors across multiple domains and domain-specific factors, where the shared factors provide robust information to perform extensive phenotyping and partition patients into clinically meaningful and biologically homogeneous subgroups. Domain-specific factors capture remaining unique variations for each domain. The MEFF model also captures nonlinear trajectory of disease progression and orders critical events of neurodegeneration measured by each marker. To overcome computational challenges, we fit our model by approximate inference techniques for large-scale data. We apply the developed method to Parkinson's Progression Markers Initiative data to integrate biological, clinical, and cognitive markers arising from heterogeneous distributions. The model learns lower-dimensional representations of Parkinson's disease (PD) and the temporal ordering of the neurodegeneration of PD.

Midazolam Prevents the Adverse Outcome of Neonatal Asphyxia.

Birth asphyxia (BA) is the most frequent cause of neonatal death as well as central nervous system (CNS) injury. BA is often associated with neonatal seizures, which only poorly respond to anti-seizure medications and may contribute to the adverse neurodevelopmental outcome. Using a non-invasive rat model of BA, we have recently reported that the potent benzodiazepine, midazolam, prevents neonatal seizures in ~50% of rat pups. In addition to its anti-seizure effect, midazolam exerts anti-inflammatory actions, which is highly relevant for therapeutic intervention following BA. The 2 major aims of the present study were to examine (1) whether midazolam reduces the adverse outcome of BA, and (2) whether this effect is different in rats that did or did not exhibit neonatal seizures after drug treatment. Behavioral and cognitive tests were performed over 14months after asphyxia, followed by immunohistochemical analyses. All vehicle-treated rats had seizures after asphyxia and developed behavioral and cognitive abnormalities, neuroinflammation in gray and white matter, neurodegeneration in the hippocampus and thalamus, and hippocampal mossy fiber sprouting in subsequent months. Administration of midazolam (1 mg/kg i.p.) directly after asphyxia prevented post-asphyctic seizures in ~50% of the rats and resulted in the prevention or decrease of neuroinflammation and the behavioral, cognitive, and neurodegenerative consequences of asphyxia. Except for neurodegeneration in the thalamus, seizures did not seem to contribute to the adverse outcome of asphyxia. The disease-modifying effect of midazolam identified here strongly suggests that this drug provides a valuable option for improving the treatment and outcome of BA. ANN NEUROL 2023;93:226-243.

Evaluation of retinal and choroidal parameters as neurodegeneration biomarkers in patients with post-covid-19 syndrome

BackgroundTo investigate the neurodegenerative effects of post-COVID-19 syndrome. MethodsThis comparative, cross-sectional study included patients who had post-COVID-19 prolonged neurologic symptoms. The control group was selected from volunteer participants with similar age, sex, and spherical equivalent characteristics. After detailed ophthalmic examinations, spectral-domain optic coherence tomography (SD-OCT) analysis of the macula and peripapillary retinal nerve fiber layer (m-RNFL, p-RNFL respectively) were obtained. We also evaluated the choroidal parameters with the ImageJ software. Post-COVID-19 symptoms and disease severity of the patients were also questioned. ResultsThirty-four eyes of 20 patients, and 39 eyes of 23 healthy individuals were included in the study. Thinning was found in the inner superior quadrant of mRNFL (p < 0.05). More prominent and common thinning of retinal layers was observed in the ganglion cell layer (GCL) and inner plexiform layer (IPL) segments in the patient group. There was no difference between the groups in the calculated choroidal parameters (p > 0.05). In the regression models created, lung involvement was the most prominent parameter associated with thinning of the OCT layers. The other factors were male sex, and the presence of loss of taste and smell also led to deterioration in some parameters. ConclusionsWe detected an overall thinning of the GCL and IPL layers with no significant change in CMT, pRNFL, and CVI in the post-COVID-19 period, indicating the direct or indirect effect of SARS-CoV-2 on these layers, rather than a long-term neurodegenerative effect.

Neurotoxic effects of environmental contaminants—measurements, mechanistic insight, and environmental relevance

Pollution is a significant and growing concern for any population regardless of age because these environmental contaminants exhibit different neurodegenerative effects on persons of different ages. These environmental contaminants are the products of human welfare projects like industry, automobile exhaust, clinical and research laboratory extrudes, and agricultural chemicals. These contaminants are found in various forms in environmental matrices like nanoparticles, particulate matter, lipophilic vaporized toxicants, and ultrafine particulate matter. Because of their small size, they can easily cross blood-brain barriers or use different cellular mechanisms for assistance. Other than this, these contaminants cause an innate immune response in different cells of the central nervous system and cause neurotoxicity. Considering the above critiques and current needs, this review summarizes different protective strategies based on bioactive compounds present in plants. Various bioactive compounds from medicinal plants with neuroprotective capacities are discussed with relevant examples. Many in vitro studies on clinical trials have shown promising outcomes using plant-based bioactive compounds against neurological disorders.

Exposure of aluminium to C6 glioma cells modulates molecular and functional neurotoxic markers.

The risk of aluminium exposure to humans is very high as it may get into the human body through excessive dietary contaminants, inhalation of fine particulate matter, or through parenteral routes as a vaccine adjuvant and so forth. The increased level of aluminium in brain tissue has been shown to be associated with several neurodegenerative and neurotoxic adverse effects, including AD. However, the exact mechanism of aluminium-induced neurotoxicity is still unclear. Therefore, our study aimed to investigate the mechanism of neurotoxic and neurodegenerative effects through in vitro exposure of aluminium in rat glioma C6 cell line. The findings of our study have indicated that aluminium chloride exposure may lead to alteration in acetylcholine levels, increased oxidative imbalanceand induction of molecular structural and functional markers of neuronal inflammation. This study also demonstrated that aluminium exposure may lead to the induction of caspase-3 along with apoptotic cell death and a significant increase in amyloid-beta and hyperphosphorylated tau levels in C6 cells. Thus, this study may provide a mechanistic understanding of the regulation of neuroinflammatory and neurodegenerative biomarkers due to aluminium exposure.

Posttranslational S-nitrosylation modification regulates HMGB1 secretion and promotes its proinflammatory and neurodegenerative effects.

SUMMARYNuclear protein high-mobility group box 1 (HMGB1) can be actively secreted by activated immune cells and functions as a proinflammatory cytokine. Regulation of HMGB1 secretion is critical for treatment of HMGB1-mediated inflammation and related diseases. This study demonstrates that S-nitrosylation (SNO; the covalent binding of nitric oxide [NO] to cysteine thiols) by inducible nitric oxide synthase (iNOS)-derived NO at Cys106 is essential and sufficient for inflammation-elicited HMGB1 secretion. iNOS deletion or inhibition or Cys106Ser mutation prevents lipopolysaccharide (LPS)- and/or poly(I:C)-elicited HMGB1 secretion. NO donors induce SNO of HMGB1 and reproduce inflammogen-triggered HMGB1 secretion. SNO of HMGB1 promotes its proinflammatory and neurodegenerative effects. Intranigral HMGB1 injection induces chronic microglial activation, dopaminergic neurodegeneration, and locomotor deficits, the key features of Parkinson’s disease (PD), in wild-type, but not Mac1 (CD11b/CD18)-deficient, mice. This study indicates pivotal roles for SNO modification in HMGB1 secretion and HMGB1-Mac1 interaction for inflammatory neurodegeneration, identifying a mechanistic basis for PD development.

Is lithium neuroprotective? An updated mechanistic illustrated review.

Neurodegeneration is a pathological process characterized by progressive neuronal impairment, dysfunction, and loss due to mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis. Many studies have shown that lithium protects against neurodegeneration. Herein, we summarize recent clinical and laboratory studies on the neuroprotective effects of lithium against neurodegeneration and its potential to modulate mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis. Recent findings indicate that lithium regulates critical intracellular pathways such as phosphatidylinositol-3 (PI3)/protein kinase B (Akt)/glycogen synthase kinase-3 (GSK3β) and PI3/Akt/response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF). We queried PubMed, Web of Science, Scopus, Elsevier, and other related databases using search terms related to lithium and its neuroprotective effect in various neurodegenerative diseases and events from January 2000 to May 2022. We reviewed the major findings and mechanisms proposed for the effects of lithium. Lithium's neuroprotective potential against neural cell degeneration is mediated by inducing anti-inflammatory factors, antioxidant enzymes, and free radical scavengers to prevent mitochondrial dysfunction. Lithium effects are regulated by two essential pathways: PI3/Akt/GSK3β and PI3/Akt/CREB/BDNF. Lithium acts as a neuroprotective agent against neurodegeneration by preventing inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction using PI3/Akt/GSK3β and PI3/Akt/CREB/BDNF signaling pathways.

HDAC3 Inhibition Alleviates High-Glucose-Induced Retinal Ganglion Cell Death through Inhibiting Inflammasome Activation.

Purpose The exact effects of histone deacetylase 3 (HDAC3) inhibition in DR related retinal ganglion cells (RGCs) death remained unclear. This study is aimed at detecting the influence of HDAC3 on the high-glucose-induced retinal ganglion cell death. Methods The retinal HDAC3 expression in DR of different time points was analyzed by immunohistochemical assay and western blot. Besides, the expression of HDAC3 and both retinal thickness and RGC loss were analyzed. The effects of HDAC3 inhibitor on cell viability, oxidative stress, and apoptosis in high-glucose- (HG-) treated RGCs were analyzed. Both inflammatory and antioxidative factors were detected by ELISA. Results Advanced effects of HDAC3 inhibition on the expression of NLRP3 inflammasome were detected using western blots. High HDAC3 expression was detected only in the late DR mice (4 months of diabetes duration) but not early DR mice (2 months of diabetes duration). The immunohistochemical assay showed that HDAC3 expression was correlated with both retinal thickness and RCG contents. HDAC3 inhibitor significantly protected the HG-treated RGCs from damaged cell viability, severe apoptosis, and oxidative stress. Advanced pathway analyses showed that HDAC3 inhibition inactivated NLRP3 inflammasome and thus alleviated retinal inflammation. Conclusion. In conclusion, HDAC3 was involved in RGC loss and thus promoted the progression of neurodegeneration of DR. Besides, HDAC3 inhibitor demonstrated protective effects in neurodegeneration in DR through downregulation of NLRP3 activity. The effects of HDAC3 inhibitor in DR management should be confirmed in clinical trials.

WWOX inhibition by Zfra1-31 restores mitochondrial homeostasis and viability of neuronal cells exposed to high glucose.

Diabetes has been associated with an increased risk of cognitive decline and dementia. However, the mechanisms underlying this association remain unclear and no effective therapeutic interventions exist. Accumulating evidence demonstrates that mitochondrial defects are a key feature of diabetes contributing to neurodegenerative events. It has also been demonstrated that the putative tumor suppressor WW domain-containing oxidoreductase 1 (WWOX) can interact with mitochondria in several pathological conditions. However, its role in diabetes-associated neurodegeneration remains unknown. So, this study aimed to evaluate the role of WWOX activation in high glucose-induced neuronal damage and death. Our experiments were mainly performed in differentiated SH-SY5Y neuroblastoma cells exposed to high glucose and treated (or not) with Zfra1-31, the specific inhibitor of WWOX. Several parameters were analyzed namely cell viability, WWOX activation (tyrosine 33 residue phosphorylation), mitochondrial function, reactive oxygen species (ROS) production, biogenesis, and dynamics, autophagy and oxidative stress/damage. The levels of the neurotoxic proteins amyloid β (Aβ) and phosphorylated Tau (pTau) and of synaptic integrity markers were also evaluated. We observed that high glucose increased the levels of activated WWOX. Interestingly, brain cortical and hippocampal homogenates from young (6-month old) diabetic GK rats showed increased levels of activated WWOX compared to older GK rats (12-month old) suggesting that WWOX plays an early role in the diabetic brain. In neuronal cells, high glucose impaired mitochondrial respiration, dynamics and biogenesis, increased mitochondrial ROS production and decreased mitochondrial membrane potential and ATP production. More, high glucose augmented oxidative stress/damage and the levels of Aβ and pTau proteins and affected autophagy, contributing to the loss of synaptic integrity and cell death. Of note, the activation of WWOX preceded mitochondrial dysfunction and cell death. Importantly, the inhibition of WWOX with Zfra1-31 reversed, totally or partially, the alterations promoted by high glucose. Altogether our observations demonstrate that under high glucose conditions WWOX activation contributes to mitochondrial anomalies and neuronal damage and death, which suggests that WWOX is a potential therapeutic target for early interventions. Our findings also support the efficacy of Zfra1-31 in treating hyperglycemia/diabetes-associated neurodegeneration.

Nigella sativa oil ingestion mitigates aluminum chloride induced cerebella oxidative, neurogenic damages and impaired motor functions in rats

Varying neurological effects, and impairments to motor functions, neurochemistry and neuromorphology have been associated with Aluminium chloride (AlCl3) induced neurotoxicity. This study aims to investigate the efficacy of Nigella sativa oil (NSO) in AlCl3 induced cerebellar toxicity in rats. Thirty-two male Wistar rats were randomly divided into four groups and received: normal saline; 100 mg/kg.bw of AlCl3; 100 mg/kg.bw AlCl3 and 1 ml/kg.bw of NSO; and 1 ml/kg.bw, orally and daily for fourteen days. On the 13th day of the experiment, the rats were each exposed to a single trial of the Open Field Test (OFT), of which line crossing frequency, rearing frequency, and freezing period were recorded as measures of exploratory and locomotive behaviours of the animals. By day 15, the rats were euthanized, their brains were excised, the cerebellum dissected from five brains of each group, and homogenized for iochemical evaluations of nitric oxide (NO) metabolites and total reactive oxygen species (ROS) levels. The remaining three brains in each group were processed for histology and Ki67 immunohistochemistry investigations. The results of this study shows that AlCl3 impaired motor related behaviours in the AlCl3 exposed animals, by significantly reducing the line crossing and rearing frequencies, and increasing the freezing period. This effect was observed to be mitigated in the animal group that received NSO following AlCl3 administration, as the animals showed improved motor behaviours. AlCl3 also caused an increase in the cerebellar activities of NO and ROS, while it depleted Ki67 expressions and caused neurodegenerative-like effects in the cerebellar histoarchitecture of the exposed animals. Intervention with NSO depleted ROS/NO levels and protected the cerebellum from the nitrosative and oxidative stress induced by AlCl3. NSO was also observed to preserve the cerebellar cortex histoarchitecture and neurogenic morphology against the neurodegenerative effect of AlCl3. It can be concluded that NSO, with its high efficacy against oxidative stress and neuroinflammation, is a potent natural therapeutic agent in aluminum and heavy metal neurotoxicity.

Chemistry, Biosynthesis and Pharmacology of Viniferin: Potential Resveratrol-Derived Molecules for New Drug Discovery, Development and Therapy.

Viniferin is a resveratrol derivative. Resveratrol is the most prominent stilbenoid synthesized by plants as a defense mechanism in response to microbial attack, toxins, infections or UV radiation. Different forms of viniferin exist, including alpha-viniferin (α-viniferin), beta-viniferin (β-viniferin), delta-viniferin (δ-viniferin), epsilon-viniferin (ε-viniferin), gamma-viniferin (γ-viniferin), R-viniferin (vitisin A), and R2-viniferin (vitisin B). All of these forms exhibit a range of important biological activities and, therefore, have several possible applications in clinical research and future drug development. In this review, we present a comprehensive literature search on the chemistry and biosynthesis of and the diverse studies conducted on viniferin, especially with regards to its anti-inflammatory, antipsoriasis, antidiabetic, antiplasmodic, anticancer, anti-angiogenic, antioxidant, anti-melanogenic, neurodegenerative effects, antiviral, antimicrobial, antifungal, antidiarrhea, anti-obesity and anthelminthic activities. In addition to highlighting its important chemical and biological activities, coherent and environmentally acceptable methods for establishing vinferin on a large scale are highlighted to allow the development of further research that can help to exploit its properties and develop new phyto-pharmaceuticals. Overall, viniferin and its derivatives have the potential to be the most effective nutritional supplement and supplementary medication, especially as a therapeutic approach. More researchers will be aware of viniferin as a pharmaceutical drug as a consequence of this review, and they will be encouraged to investigate viniferin and its derivatives as pharmaceutical drugs to prevent future health catastrophes caused by a variety of serious illnesses.