Neuron Disease Research Articles

Gut-Brain Axis a Key Player to Control Gut Dysbiosis in Neurological Diseases.

Parkinson's disease is a chronic neuropathy characterised by the formation of Lewy bodies (misfolded alpha-synuclein) in dopaminergic neurons of the substantia nigra and other parts of the brain. Dopaminergic neurons play a vital role in generating both motor and non-motor symptoms. Finding therapeutic targets for Parkinson's disease (PD) is hindered due to an incomplete understanding of the disease's pathophysiology. Existing evidence suggests that the gut microbiota participates in the pathogenesis of PD via immunological, neuroendocrine, and direct neural mechanisms. Gut microbial dysbiosis triggers the loss of dopaminergic neurons via mitochondrial dysfunction. Gut dysbiosis triggers bacterial overgrowth in the small intestine, which increases the permeability barrier and induces systemic inflammation. It results in excessive stimulation of the innate immune system. In addition to that, activation of enteric neurons and enteric glial cells initiates the aggregation of alpha-synuclein. This alpha-synucleinopathy thus affects all levels of the brain-gut axis, including the central, autonomic, and enteric nervous systems. Though the neurobiological signaling cascade between the gut microbiome and the central nervous system is poorly understood, gut microbial metabolites may serve as a promising therapeutic strategy for PD. This article summarises all the known possible ways of bidirectional signal communication, i.e., the "gut-brain axis," where microbes from the middle gut interact with the brain and vice versa, and highlights a unique way to treat neurodegenerative diseases by maintaining homeostasis. The tenth cranial nerve (vagus nerve) plays a significant part in this signal communication. However, the leading regulatory factor for this axis is a diet that helps with microbial colonisation and brain function. Short-chain fatty acids (SCFAs), derived from microbially fermented dietary fibres, link host nutrition to maintain intestinal homeostasis. In addition to that, probiotics modulate cognitive function and the metabolic and behavioural conditions of the body. As technology advances, new techniques will emerge to study the tie-up between gut microbes and neuronal diseases.

Modeling the motion of disease-associated KIF1A heterodimers

KIF1A is a member of the kinesin-3 motor protein family that transports synaptic vesicle precursors in axons. Mutations in the Kif1a gene cause neuronal diseases. Most patients are heterozygous and have both mutated and intact KIF1A alleles, suggesting that heterodimers composed of wild-type KIF1A and mutant KIF1A are likely involved in pathogenesis. In this study, we propose mathematical models to describe the motility of KIF1A heterodimers composed of wild-type KIF1A and mutant KIF1A. Our models precisely describe run length, run time, and velocity of KIF1A heterodimers using a few parameters obtained from two homodimers. The first model is a simple hand-over-hand model in which stepping and detachment rates from a microtubule of each head are identical to those in the respective homodimers. Although the velocities of heterodimers expected from this model were in good agreement with the experimental results, this model underestimated the run lengths and run times of some heterodimeric motors. To address this discrepancy, we propose the tethered-head affinity model, in which we hypothesize a tethered head, in addition to a microtubule-binding head, contributes to microtubule binding in a vulnerable one-head-bound state. The run lengths and run times of the KIF1A heterodimers predicted by the tethered-head affinity model matched well with experimental results, suggesting a possibility that the tethered head affects the microtubule binding of KIF1A. Our models provide insights into how each head contributes to the processive movement of KIF1A and can be used to estimate motile parameters of KIF1A heterodimers.

Ethnomedicinal use, phytochemistry, pharmacology, and toxicology of Chamaerops humilis: A review

Chamaerops humilis L. is a widespread species in the western and central Mediterranean region. It is used in traditional medicine to treat numerous diseases, particularly diabetes. Aim of the review: This review was devoted to provide valuable information on C. humilis various aspects including its botanical description, taxonomy, geographical distribution, medicinal use, phytochemistry, pharmacological properties, and toxicity. Materials and methods: We searched various scientific databases, such as Scopus, PubMed, Web of Science, SpringerLink, SciFinder, Wiley Online, and Google Scholar, to collect data on C. humilis. The presented data on C. humilis were organized according to botanical description, ethnomedicinal use, bioactive compounds, pharmacology, and toxicological investigation. Results: In traditional medicine, C. humilis was used to treat diabetes, diarrhea, gastritis, gastralgia, constipation, neuronal diseases, and anemia. The extracts and essential oil derived from C. humilis demonstrated various beneficial properties, such asantibacterial, anticholinesterase, antidiabetic, antilithiasic, anti-inflammatory, antitumoral, antioxidant, antityrosinase, and antihyperlipidemic activities. Phytochemical investigations identified several chemical classes of secondary metabolites in C. humilis essential oil and extracts including phenols, sterols, terpenoids, polysaccharides, and fatty acid. Conclusion: Based on the critical analysis of previous studies, further exploration of C. humilis and its bioactive compounds should be conducted for potential medical applications. This may involve isolating and characterizing specific compounds from C. humilis and evaluating their therapeutic potential through preclinical and clinical studies.

Neuronal Nitric Oxide Synthase and Post-Translational Modifications in the Development of Central Nervous System Diseases: Implications and Regulation.

In the Central Nervous System (CNS), Nitric Oxide (NO) is mainly biosynthesized by neuronal Nitric Oxide Synthase (nNOS). The dysregulated activation of nNOS in neurons is critical in the development of different conditions affecting the CNS. The excessive production of NO by nNOS is responsible for a number of proteins' post-translational modifications (PTMs), which can lead to aberrant biochemical pathways, impairing CNS functions. In this review, we briefly revise the main implications of dysregulated nNOS in the progression of the most prevalent CNS neurodegenerative disorders, i.e., Alzheimer's disease (AD) and Parkinson's disease, as well as in the development of neuronal disorders. Moreover, a specific focus on compounds able to modulate nNOS activity as promising therapeutics to tackle different neuronal diseases is presented.

Short- and Long-Term Regulation of HuD: A Molecular Switch Mediated by Folic Acid?

The RNA-binding protein HuD has been shown to play a crucial role in gene regulation in the nervous system and is involved in various neurological and psychiatric diseases. In this study, through the creation of an interaction network on HuD and its potential targets, we identified a strong association between HuD and several diseases of the nervous system. Specifically, we focused on the relationship between HuD and the brain-derived neurotrophic factor (BDNF), whose protein is implicated in several neuronal diseases and is involved in the regulation of neuronal development, survival, and function. To better investigate this relationship and given that we previously demonstrated that folic acid (FA) is able to directly bind HuD itself, we performed in vitro experiments in neuron-like human SH-SY5Y cells in the presence of FA, also known to be a pivotal environmental factor influencing the nervous system development. Our findings show that FA exposure results in a significant increase in both HuD and BDNF transcripts and proteins after 2 and 4 h of treatment, respectively. Similar data were obtained after 2 h of FA incubation followed by 2 h of washout. This increase was no longer detected upon 24 h of FA exposure, probably due to a signaling shutdown mechanism. Indeed, we observed that following 24 h of FA exposure HuD is methylated. These findings indicate that FA regulates BDNF expression via HuD and suggest that FA can behave as an epigenetic modulator of HuD in the nervous system acting via short- and long-term mechanisms. Finally, the present results also highlight the potential of BDNF as a therapeutic target for specific neurological and psychiatric diseases.

The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease.

The Lipid Invasion Model (LIM) is a new hypothesis for Alzheimer's disease (AD) which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD, all of which are also associated with damage to the BBB. This article summarizes the main arguments of the LIM, and new evidence and arguments in support of it. The LIM incorporates and extends the amyloid hypothesis, the current main explanation of the disease, but argues that the greatest cause of late-onset AD is not amyloid-β (Aβ) but bad cholesterol and free fatty acids, let into the brain by a damaged BBB. It suggests that the focus on Aβ is the reason why we have made so little progress in treating the disease in the last 30 years. As well as offering new perspectives for further research into the diagnosis, prevention, and treatment of AD, based on protecting and repairing the BBB, the LIM provides potential new insights into other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis/motor neuron disease.

A Randomized Controlled Clinical Trial of Lung Volume Recruitment in Adults with Neuromuscular Disease.

Rationale: Clinical care guidelines advise that lung volume recruitment (LVR) be performed routinely by people with neuromuscular disease (NMD) to maintain lung and chest wall flexibility and slow lung function decline. However, the evidence base is limited, and no randomized controlled trials of regular LVR in adults have been published. Objectives: To evaluate the effect of regular LVR on respiratory function and quality of life in adults with NMD. Methods: A randomized controlled trial with assessor blinding was conducted between September 2015 and May 2019. People (>14 years old) with NMD and vital capacity <80% predicted were eligible, stratified by disease subgroup (amyotrophic lateral sclerosis/motor neuron disease or other NMDs), and randomized to 3 months of twice-daily LVR or breathing exercises. The primary outcome was change in maximum insufflation capacity (MIC) from baseline to 3 months, analyzed using a linear mixed model approach. Results: Seventy-six participants (47% woman; median age, 57 [31-68] years; mean baseline vital capacity, 40 ± 18% predicted) were randomized (LVR, n = 37). Seventy-three participants completed the study. There was a statistically significant difference in MIC between groups (linear model interaction effect P = 0.002, observed mean difference, 0.19 [0.00-0.39] L). MIC increased by 0.13 (0.01-0.25) L in the LVR group, predominantly within the first month. No interaction or treatment effects were observed in secondary outcomes of lung volumes, respiratory system compliance, and quality of life. No adverse events were reported. Conclusions: Regular LVR increased MIC in a sample of LVR-naive participants with NMD. We found no direct evidence that regular LVR modifies respiratory mechanics or slows the rate of lung volume decline. The implications of increasing MIC are unclear, and the change in MIC may represent practice. Prospective long-term clinical cohorts with comprehensive follow-up, objective LVR use, and clinically meaningful outcome data are needed. Clinical trial registered with anzctr.org.au (ACTRN12615000565549).

A Ratiometric Fluorescent Probe for Hypochlorite and Lipid Droplets to Monitor Oxidative Stress.

Mitochondria are valuable subcellular organelles and play crucial roles in redox signaling in living cells. Substantial evidence proved that mitochondria are one of the critical sources of reactive oxygen species (ROS), and overproduction of ROS accompanies redox imbalance and cell immunity. Among ROS, hydrogen peroxide (H2O2) is the foremost redox regulator, which reacts with chloride ions in the presence of myeloperoxidase (MPO) to generate another biogenic redox molecule, hypochlorous acid (HOCl). These highly reactive ROS are the primary cause of damage to DNA (deoxyribonucleic acid), RNA (ribonucleic acid), and proteins, leading to various neuronal diseases and cell death. Cellular damage, related cell death, and oxidative stress are also associated with lysosomes which act as recycling units in the cytoplasm. Hence, simultaneous monitoring of multiple organelles using simple molecular probes is an exciting area of research that is yet to be explored. Significant evidence also suggests that oxidative stress induces the accumulation of lipid droplets in cells. Hence, monitoring redox biomolecules in mitochondria and lipid droplets in cells may give a new insight into cell damage, leading to cell death and related disease progressions. Herein, we developed simple hemicyanine-based small molecular probes with a boronic acid trigger. A fluorescent probe AB that could efficiently detect mitochondrial ROS, especially HOCl, and viscosity simultaneously. When the AB probe released phenylboronic acid after reacting with ROS, the product AB-OH exhibited ratiometric emissions depending on excitation. This AB-OH nicely translocates to lysosomes and efficiently monitors the lysosomal lipid droplets. Photoluminescence and confocal fluorescence imaging analysis suggest that AB and corresponding AB-OH molecules are potential chemical probes for studying oxidative stress.

Evaluation of mRNA markers in differentiating human SH-SY5Y cells for estimation of developmental neurotoxicity

Current guidelines for developmental neurotoxicity (DNT) evaluation are based on animal models. These have limitations so more relevant, efficient and robust approaches for DNT assessment are needed. We have used the human SH-SY5Y neuroblastoma cell model to evaluate a panel of 93 mRNA markers that are frequent in Neuronal diseases and functional annotations and also differentially expressed during retinoic acid-induced differentiation in the cell model. Rotenone, valproic acid (VPA), acrylamide (ACR) and methylmercury chloride (MeHg) were used as DNT positive compounds. Tolbutamide, D-mannitol and clofibrate were used as DNT negative compounds. To determine concentrations for exposure for gene expression analysis, we developed a pipeline for neurite outgrowth assessment by live-cell imaging. In addition, cell viability was measured by the resazurin assay. Gene expression was analyzed by RT-qPCR after 6 days of exposure during differentiation to concentrations of the DNT positive compounds that affected neurite outgrowth, but with no or minimal effect on cell viability. Methylmercury affected cell viability at lower concentrations than neurite outgrowth, hence the cells were exposed with the highest non-cytotoxic concentration. Rotenone (7.3 nM) induced 32 differentially expressed genes (DEGs), ACR (70 µM) 8 DEGs, and VPA (75 µM) 16 DEGs. No individual genes were significantly dysregulated by all 3 DNT positive compounds (p < 0.05), but 9 genes were differentially expressed by 2 of them. Methylmercury (0.8 nM) was used to validate the 9 DEGs. The expression of SEMA5A (encoding semaphorin 5A) and CHRNA7 (encoding nicotinic acetylcholine receptor subunit α7) was downregulated by all 4 DNT positive compounds. None of the DNT negative compounds dysregulated any of the 9 DEGs in common for the DNT positive compounds. We suggest that SEMA5A or CHRNA7 should be further evaluated as biomarkers for DNT studies in vitro since they also are involved in neurodevelopmental adverse outcomes in humans.

Meclofenoxate Inhibits Aggregation of Alpha-synuclein in vitro.

α-Synuclein, a natively disordered protein, is a key component of Lewy bodies, the ubiquitinated protein aggregates which are the pathological hallmark of Parkinson's disease (PD). Meclofenoxate (centrophenoxine) is a nootropic drug which has shown beneficial therapeutic effects in various neuronal diseases. Administration of meclofenoxate enhanced levels of dopamine and improved motor function in animal models of Parkinson's disease (PD). Evidence suggested that dopamine interacts with and modulates α-synuclein aggregation. The aim of this work was to investigate whether the observed positive effect of addition of meclofenoxate, a nootropic agent, on dopamine level, could be correlated with its effect on aggregation of α-synuclein. Purification of recombinant human α-synuclein was performed by anion exchange chromatography. The purified protein was incubated in the absence and presence of meclofenoxate and was analyzed for aggregation by Thioflavin T fluorescence spectroscopy. Conformational changes in α-synuclein were monitored by fluorescence spectroscopy and fluorescence quenching studies using a neutral quencher. Secondary structure analysis of α-synuclein was monitored by circular dichroism spectroscopy. Recombinant human α-synuclein was expressed and purified by anion-exchange chromatography. Incubation of α-synuclein with meclofenoxate led to lowering aggregation in a concentration-dependent manner. Reduction in formation of oligomers was seen which suggested the formation of an off-pathway species which did not give rise to an aggregation-competent entity. Fluorescence quenching studies revealed that the additive distorted the native conformation of α- synuclein, leading to the formation of lower amounts of aggregation-prone species. In the presence of higher concentrations of meclofenoxate, α-synuclein undergoes a change in its conformation. This change is not dependent on the concentration of the additive. This non-native conformer promotes the formation of a species which does not undergo further aggregation. Our study provides a mechanistic explanation of the earlier observation that meclofenoxate has a beneficial effect on progression of PD in animal models.

Mitochondria: It is all about energy.

Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.

Linderone Isolated from Lindera erythrocarpa Exerts Antioxidant and Anti-Neuroinflammatory Effects via NF-κB and Nrf2 Pathways in BV2 and HT22 Cells.

Linderone is a major compound in Lindera erythrocarpa and exhibits anti-inflammatory effects in BV2 cells. This study investigated the neuroprotective effects and mechanisms of linderone action in BV2 and HT22 cells. Linderone suppressed lipopolysaccharide (LPS)-induced inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-6, and prostaglandin E-2) in BV2 cells. Linderone treatment also inhibited the LPS-induced activation of p65 nuclear factor-kappa B, protecting against oxidative stress in glutamate-stimulated HT22 cells. Furthermore, linderone activated the translocation of nuclear factor E2-related factor 2 and induces the expression of heme oxygenase-1. These findings provided a mechanistic explanation of the antioxidant and anti-neuroinflammatory effects of linderone. In conclusion, our study demonstrated the therapeutic potential of linderone in neuronal diseases.

Human Bone Marrow Mesenchymal Stem Cells-Derived Exosomal miRNA-21-5p Inhibits Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells.

Local anesthetic lidocaine is one of the most common pain therapies, but high concentration of lidocaine induced neurotoxicity and its mechanism is unclear. Exosomal microRNAs (miRNAs) is implicated in neuronal diseases, but its role in lidocaine induced neurotoxicity remains to be elucidated. All the experiments were performed at Huzhou Key Laboratory of Molecular Medicine, Huzhou City, Jiangsu Province, China in 2022. Lidocaine was used to induce apoptosis of SH-SY5Y cells. Exosomes isolated from bone marrow mesenchymal stem cells (BMSC-exos) were used to co-treat SH-SY5Y cells with lidocaine. Cell apoptosis was measured using a flow cytometer. PKH-67 Dye was used for exosome uptake assay. miR-21-5p mimics/inhibitors, or negative controls were transfected with Lipo2000 to study its effect on lid-induced injury. Interactions between miR-21-5p and PDCD4 was analyzed by luciferase reporter assay. Administration of BMSC-exo protected SH-SY5Y cells against lidocaine induced apoptosis. Suppressing miR-21-5p dramatically enhanced PDCD4, but miR-21-5p overexpression sharply down-regulated PDCD4. Mechanism study showed that miR-21-5p bound to 3'-UTR of PDCD4 to inhibit it. Suppressing miR-21-5p reversed the effect of BMSC-exo on Lid-induced injury. Results also indicate that miR-21-5p regulated lidocaine-induced injury through targeting PDCD4. BMSC-exos protected SH-SY5Y cells against lidocaine induced apoptosis through miR-21-5p by targeting PDCD4, which may develop new strategy in the management of lidocaine-induced neurotoxicity.

Disease-modifying pharmacological treatments for amyotrophic lateral sclerosis/motor neuron disease: an overview of intervention reviews

Objectives This is a protocol for a Cochrane Review (overview). The objectives are as follows: To summarise the evidence from Cochrane and non‐Cochrane systematic reviews of pharmacological disease‐modifying treatments for amyotrophic lateral sclerosis/motor neuron disease.

Unraveling the Role of Prickly Pear Extract as a Potent Nutraceutical Agent Against Metabolic Syndromes.

Prickly pear (Opuntia) extracts have garnered con-siderable attention in recent years due to their promising medicinal and nutritional properties. This comprehensive review explores the multifaceted potential of prickly pear extracts in mitigating various chronic diseases, including cardiovascular diseases (CVDs), diabetes, obesity, cancer, neuronal diseases, and renal diseases. This review provides a comprehensive overview of the diverse therapeutic applications of Opuntia extracts in managing chronic diseases. The collective evidence underscores the potential of prickly pear as a valuable natural resource for addressing global health challenges. Further research and clinical investigations are warranted to unlock the full potential of Opuntia in the prevention and treatment of chronic diseases. Studies have suggested that the bioactive compounds within prickly pear may influence glucose metabolism by improving insulin sensitivity, reducing insulin resistance, and modulating gut microbiota composition. These pathways exhibit potential in the reduction of hyperglycemia, which is a fundamental aspect of metabolic syndromes. Opuntia extracts demonstrate also antioxidant, anti-inflammatory capabilities that can contribute to improving health in various conditions. Further research and clinical investigations are warranted to unlock the full potential of Opuntia in the prevention and treatment of chronic diseases.

IQM-22110, a new selective inhibitor of KChIP3 and its electrophysiological effects on Kv4.3, Kv4.3/KChIP3 and Kv4.3/KChIP2 currents.

Kv4 channels generate rapidly activating and inactivating outward currents responsible for the repolarization of both cardiac and neuronal action potentials through ITO (transient outward current) and IA (A-type K+ current), respectively. Kv4 dysfunctions have been identified in both cardiac and neuronal diseases (Brugada syndrome, atrial fibrillation, epilepsy or Alzheimer's disease). However, Kv4 channels need to assemble with regulatory subunits to fully reproduce ITO and IA currents. Among them, we will focus on KChIPs (potassium channel interacting proteins), being KChIP3 predominant in the brain and KChIP2 in both brain and heart. The assembly of these regulatory subunits not only modulates the biophysical properties of the channel, but also its pharmacology. For this reason, we have analysed the electrophysiological effects of IQM-22110 (a novel KChIP3 ligand) on the currents generated by Kv4.3, Kv4.3/KChIP3 and Kv4.3/KChIP2 channels. CHO cells were transiently transfected, and the potassium currents were recorded using the whole-cell patch-clamp technique. Our results indicate that IQM-22110 exerts differential effects on these currents, being the concentration-dependence of inhibition modified, exhibiting a biphasic curve when KChIP3 is present, thus suggesting two binding sites for IQM-22110 in this complex. With molecular dynamics and site-directed mutagenesis, we have identified the binding pocket corresponding to the high affinity site. Also, we have demonstrated that IQM-22110 binds to the closed-active state of the channel. In this study: i) IQM-22110 has proven to be a selective inhibitor of Kv4.3/KChIP3 at low concentrations, and ii) a new binding pocket for selective KChIP3/Kv4.3 ligands has been identified.

Chemical Characterization, Antioxidant Capacity and Anti-Oxidative Stress Potential of South American Fabaceae Desmodium tortuosum.

It has been proposed that oxidative stress is a pathogenic mechanism to induce cytotoxicity and to cause cardiovascular and neuronal diseases. At present, natural compounds such as plant extracts have been used to reduce the cytotoxic effects produced by agents that induce oxidative stress. Our study aimed to evaluate the antioxidant and cytoprotective capacity of Desmodium tortuosum (D. tortuosum) extract in the co- and pre-treatment in EA.hy926 and SH-SY5Y cell lines subjected to oxidative stress induced by tert-butylhydroperoxide (t-BOOH). Cell viability, reactive oxygen species (ROS), nitric oxide (NO), caspase 3/7 activity, reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), and molecular expression of oxidative stress biomarkers (SOD2, NRF2 and NFκB1) and cell death (APAF1, BAX, Caspase3) were all evaluated. It was observed that the D. tortuosum extract, in a dose-dependent manner, was able to reduce the oxidative and cytotoxicity effects induced by t-BOOH, even normalized to a dose of 200 µg/mL, which would be due to the high content of phenolic compounds mainly phenolic acids, flavonoids, carotenoids and other antioxidant compounds. Finally, these results are indicators that the extract of D. tortuosum could be a natural alternative against the cytotoxic exposure to stressful and cytotoxic chemical agents.

Modulating and monitoring the functionality of corticostriatal circuits using an electrostimulable microfluidic device

The central nervous system is organized into different neural circuits, each with particular functions and properties. Studying neural circuits is essential to understanding brain function and neuronal diseases. Microfluidic systems are widely used for reconstructing and studying neural circuits but still need improvement to allow modulation and monitoring of the physiological properties of circuits. In this study, we constructed an improved microfluidic device that supports the electrical modulation of neural circuits and proper reassembly. We demonstrated that our microfluidic device provides a platform for electrically modulating and monitoring the physiological function of neural circuits with genetic indicators for synaptic functionality in corticostriatal (CStr) circuits. In particular, our microfluidic device measures activity-driven Ca2+ dynamics using Ca2+ indicators (synaptophysin-GCaMP6f and Fluo5F-AM), as well as activity-driven synaptic transmission and retrieval using vGlut-pHluorin. Overall, our findings indicate that the improved microfluidic platform described here is an invaluable tool for studying the physiological properties of specific neural circuits.

Euphorbia neriifolia (Indian Spurge Tree): A Plant of Multiple Biological and Pharmacological Activities

Although India has a well-established and growing economy surrounding synthetic drug chemistry with an antibiotic base, a large part of the population, especially in forested villages and tribal belts, is relying solely on plant-derived drugs. This is due to a lower number of side effects, low chances of resistance development against pathogenic microorganisms, as well as the diversity and affordability of such drugs. In the Indian subcontinents, Euphorbia neriifolia Linn. (EN) is one of the valuable plants from the big family of Euphorbiaceae, which is usually found in rocky and hilly areas. E. neriifolia was found to be useful in curing tumors, abdominal swelling, bronchial infection, hydrophobia, earache, cough and cold, asthma, leprosy, gonorrhea, spleen enlargement, leucoderma, snake bites, scorpion stings, and causing appetite improvement, etc. Different in vitro and in vivo experimental studies were performed to determine the antioxidant, anti-diabetic, immunomodulatory, anti-inflammatory, anti-arthritic, wound healing, anti-atherosclerosis, radioprotective, anti-anxiety, anti-convulsant, anti-psychotic, anti-thrombotic, dermal irritation, hemolytic, analgesic, anti-fertility, diuretic, anti-microbial, anti-diarrheal, and anti-carcinogenic activities of the various parts of EN. Several bioactive compounds, such as euphol, nerifoliol, taraxerol, euphonerins A–G, lectin, etc., were isolated from E. neriifolia and need to be investigated further for various biological activities (cardiovascular and neuronal diseases). In the pharmaceutical sector, E. neriifolia was selected for the development of new drugs due to its broad pharmacological activities. Therefore, in the present review, distribution, classification, morphological and microscopical description, phytochemical investigation, pharmacological activities, medicinal uses, harmful effects, and their treatment were evaluated, especially against different lifestyle-related diseases.

Surface charge and dynamic mechanoelectrical stimuli improves adhesion, proliferation and differentiation of neuron-like cells.

Neuronal diseases and trauma are among the current major health-care problems. Patients frequently develop an irreversible state of neuronal disfunction that lacks treatment, strongly reducing life quality and expectancy. Novel strategies are thus necessary and tissue engineering research is struggling to provide alternatives to current treatments, making use of biomaterials capable to provide cell supports and active stimuli to develop permissive environments for neural regeneration. As neuronal cells are naturally found in electrical microenvironments, the electrically active materials can pave the way for new and effective neuroregenerative therapies. In this work the influence of piezoelectric poly(vinylidene fluoride) with different surface charges and dynamic mechanoelectrical stimuli on neuron-like cells adhesion, proliferation and differentiation was addressed. It is successfully demonstrated that both surface charge and electrically active dynamic microenvironments can be suitable to improve neuron-like cells adhesion, proliferation, and differentiation. These findings provide new knowledge to develop effective approaches for preclinical applications.