Recent Patents, Regulatory Issues, and Toxicity of Nanoparticles in Neuronal Disorders.

BACKGROUND: Form last few decades, nanoparticles have witnessed breakthroughs in the treatment of neurological disorders due to their unique physiochemical properties, which make them an effective drug delivery system. However, there is not much information available on the toxicity of nanoparticles in neuronal disorders. The toxic effect of nanoparticles on brain disorders and their regulatory issues are the primary concerns of the healthcare industry. METHODS: A strategical literature search was performed on various bibliographic databases such as Scopus, PubMed, SciFinder, Google Scholar, Medline, Google Patent, Derwent Innovation, and Orbit Intelligence for retrieval of peer-reviewed articles and patents on regulatory issues and toxicity of nanoparticles in neuronal disorders for last decade. The relevant hits of articles and patents were analyzed, and citation search for the relevant documents was carried out. RESULTS: The literature documents have been summarized regarding the existing regulatory issues and toxicity of nanoparticles on neuronal disorders with a focus on the detailed mechanism of the developmental toxicity of nanoparticles. The focus of this report is to emphasize the negative effects of nanoparticle on neuronal disorders, which may partially contribute to the management of toxicity of nanoparticles. CONCLUSION: Although nanoparticles have unique physical and chemical properties that explain the broad range of application for the central nervous system, they can also manifest neurotoxic effects due to cell necrosis, generation of free radicals, immune responses and neuroinflammation. Thus, this review highlights risk assessment, safety regulations and regulatory guidelines of nanoparticles, which may reduce adverse reactions in humans and animals.

In vitro enzyme inhibitory and cytotoxic studies with Evolvulus alsinoides (Linn.) Linn. Leaf extract: a plant from Ayurveda recognized as Dasapushpam for the management of Alzheimer's disease and diabetes mellitus.

BACKGROUND: Evolvulus alsinoides (Linn.) Linn. (Convolvulaceae) is a therapeutic herb alleviating brain patterns associated with three categories of regulatory principles of the body, mind, and behaviour. In the current research, enzyme inhibition and cytotoxic potentials of E. alsinoides (L.) L. leaf extract has been studied validating its potential application. METHODS: The plant phenolics in the leaf extracts obtained via cold-maceration with solvents viz.: n-hexane, chloroform, ethyl acetate, methanol, and water were quantitatively analyzed. The antioxidant potency was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Ability of Plasma (FRAP) assays at five concentrations (100-500 µg). The enzyme inhibition potential was performed with α-amylase, α-glucosidase, and acetylcholinesterase at seven concentrations (25-500 µg). The experiments were done in triplicates and statistically validated using Minitab-17 and SPSS 22. RESULTS: Water extract contain 45.08 ± 0.02 mg GAE/g, 49.30 ± 0.07 mg GAE/g, 211.21 ± 0.02 mg QE/g tannins, phenolics, flavonoids respectively. Its antioxidant activity was supported by IC50 52.43 ± 0.2 µg/mL (DPPH assay) and 41.58 ± 0.03 (FRAP assay). Methanolic extract inhibits α-amylase with IC50 1.33 ± 0.05 µg/mL. Water extract inhibits α-glucosidase and acetylcholinesterase with IC50 3.58 ± 0.02 µg/mL and 4.46 ± 0.03 µg/mL. Cytotoxicity studies with SH-SY5Y cell-line substantiate the inhibition potential of water extract with IC50 103.0035 µg/mL. DISCUSSION AND CONCLUSIONS: The extracts with potent antioxidant and enzyme-inhibiting activity were determined. The findings of the research are the first report about the inhibition effects of Evolvulus alsinoides (Linn.) Linn extracts against α-amylase, α-glucosidase and acetylcholinesterase. The extracts shall be examined in future studies to evaluate its pharmaceutical potential.

Novel roles of Drosophila FUS and Aub responsible for piRNA biogenesis in neuronal disorders.

piRNAs, small non-coding RNAs, were considered to be restricted to germline cells. Although they have recently been detected in somatic cells including neurons, it remains unclear how piRNA biogenesis is involved in neuronal diseases. We herein examined the possible roles of Aubergine (Aub), a Piwi-family protein (PIWI) responsible for piRNA biogenesis, in the neuronal disorders, using the Cabeza (Caz) knockdown Drosophila. Caz is a Drosophila homologue of FUS, which is one of the genes causing amyotrophic lateral sclerosis (ALS). Aub overexpression enhanced the mobility defects accompanied by anatomical defects in motoneurons at neuromuscular junctions induced by the neuron-specific knockdown of Caz. In order to elucidate the underlying mechanisms, we examined pre-piRNA and mature-size piRNA levels under these conditions. qRT-PCR and RNA-seq analyses revealed that the Caz knockdown increased pre-piRNA levels, but reduced mature-size piRNA levels in the central nervous system (CNS), suggesting a role in the pre-piRNAs production. Aub overexpression did not increase mature-size piRNA levels. These results suggest that the accumulated pre-piRNAs are abnormal abortive pre-piRNAs that cannot be further processed by slicers, including Aub. We also demonstrated a relationship between Caz and pre-piRNAs in the CNS by RNA immunoprecipitation. Aub overexpression induced the abnormal cytoplasmic localization of Caz. Based on these results, we propose a model in which Caz knockdown-induced abnormal pre-piRNAs associate with Caz, then translocate and accumulate in the cytoplasm, a process that may be mediated by Aub. The novel roles for Caz and Aub demonstrated herein using the Caz-knockdown fly will contribute to a deeper understanding of the pathogenesis of ALS.

Coordination of AMPA receptor trafficking by Rab GTPases.

Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPA-type glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity-induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD). We highlight the importance of the tight spatio-temporal control of Rab activity and suggest that this is critical for proper neuronal functions. We also discuss how abnormal AMPA receptor trafficking and malfunctioning of Rabs can lead to neurologic disorders or memory problems.

Clinical implications and electrochemical biosensing of monoamine neurotransmitters in body fluids, in vitro, in vivo, and ex vivo models.

Monoamine neurotransmitters (MNTs) belong to one of the most important groups of neurotransmitters in the central nervous system. They play crucial role in functioning of cardiovascular, renal, and hormonal systems along with establishing human brain-body integration. Abnormal level of MNT is associated with numerous psychotic (schizophrenia, depression, dementia, etc.) and neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease, etc.), therefore their sensitive and robust detection is of great clinical significance. Electrochemical detection (ECD) techniques have been paving the path in this direction, for more than four decades now. Keeping the immense importance of MNTs in mind, this review has been formulated to describe fundamentals of MNTs followed by their clinical significance in neuroscience. Herein, we have emphasized on the ECD of MNTs, in various matrices reported till date. In order to provide information on ECD of MNTs in clinically comparable systems, we have included a comprehensive discussion on sensor design and its analytical performance towards analyzing MNTs in the in vitro, in vivo, and ex vivo models. An extensive table is also incorporated to provide better understanding of the role of MNTs in various clinical conditions. Furthermore, this review briefly discusses the challenges faced with EC sensing techniques and loopholes present in current research works. Apart from this, three extended tables are also included in this review, to provide an insight into the amount of work done in ECD of MNTs in last ten years (2008-2018). These tables comprehensively discuss sensor fabrication strategies for determining MNTs in various matrices and models along with their mode of detection and analytical performance.

RETREG1 (FAM134B): A new player in human diseases: 15 years after the discovery in cancer.

FAM134B (family with sequence similarity 134, member B)/RETREG1 and its functional roles are relatively new in human diseases. This review aimed to summarize various functions of FAM134B since our first discovery of the gene in 2001. The protein encoded by FAM134B is a reticulophagy receptor that regulates turnover of the endoplasmic reticulum (ER) by selective phagocytosis. Absence or non-functional expression of FAM134B protein impairs ER-turnover and thereby is involved in the pathogenesis of some human diseases. FAM134B inhibition contributes to impair proteostasis in the ER due to the accumulation of misfolded or aggregated proteins, which in turn leads to compromised neuronal survival and progressive neuronal degenerative diseases. Mutations in FAM134B associated with hereditary sensory and autonomic neuropathy type IIB (HSAN IIB). Selective cleavage of FAM134B by Dengue, Zika, and West Nile virus encoded protease NS2B3 leads to the increased production of infection units, whereas upregulation of FAM134B inhibits viral replication. In cancer, FAM134B acts as a tumor suppressor and inhibit cancer growth both in-vitro and in-vivo. Pharmacological upregulation of FAM134B resulted in reduced cancer cell growth and proliferation. In addition, FAM134B mutations are common in patients with colorectal adenocarcinoma, and oesophageal squamous cell carcinoma. These mutations and expression changes of FAM134B were associated with the biological aggressiveness of these cancers. FAM134B also plays a role in allergic rhinitis, vascular dementia, and identification of stem cells. Taken together, information available in the literature suggests that FAM134B plays critical roles in human diseases, by interacting with different biological and chemical mediators, which are primarily regulated by ER turnover.

An Overview of the Protective Effects of Chitosan and Acetylated Chitosan Oligosaccharides against Neuronal Disorders.

Chitin is the second most abundant biopolymer on Earth and is mainly comprised of a marine invertebrate, consisting of repeating ß-1,4 linked N-acetylated glucosamine units, whereas its N-deacetylated product, chitosan, has broad medical applications. Interestingly, chitosan oligosaccharides have therapeutic effects on different types of neuronal disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, and nerve crush injury. A common link among neuronal disorders is observed at a sub-cellular level, such as atypical protein assemblies and induced neuronal death. Chronic activation of innate immune responses that lead to neuronal injury is also common in these diseases. Thus, the common mechanisms of neuronal disorders might explain the general therapeutic effects of chitosan oligosaccharides and their derivatives in these diseases. This review provides an update on the pathogenesis and therapy for neuronal disorders and will be mainly focused on the recent progress made towards the neuroprotective properties of chitosan and acetylated chitosan oligosaccharides. Their structural features and the underlying molecular mechanisms will also be discussed.

Zika virus and Zika fever.

An emerging mosquito-borne arbovirus named Zika virus (ZIKV), of the family Flaviviridae and genus Flavivirus, is becoming a global health threat. ZIKV infection was long neglected due to its sporadic nature and mild symptoms. However, recently, with its rapid spread from Asia to the Americas, affecting more than 30 countries, accumulating evidences have demonstrated a close association between infant microcephaly and Zika infection in pregnant women. Here, we reviewed the virological, epidemiological, and clinical essentials of ZIKV infection.

The cell- and tissue-specific transcription mechanism of the TATA-less syntaxin 1A gene.

Syntaxin 1A (Stx1a) plays an important role in regulation of neuronal synaptic function. To clarify the mechanism of basic transcriptional regulation and neuron-specific transcription of Stx1a we cloned the Stx1a gene from rat, in which knowledge of the expression profile was accumulated, and elucidated that Stx1a consisting of 10 exons, possesses multiple transcription initiation sites and a 204-bp core promoter region (CPR) essential for transcription in PC12 cells. The TATA-less, conserved, GC-rich CPR has 2 specific protein (SP) sites that bind SP1 and are responsible for 65% of promoter activity. The endogenous CPR, including 23 CpG sites, is not methylated in PC12 cells, which express Stx1a and fetal rat skin keratinocyte (FRSK) cells, which do not, although an exogenous methylated CPR suppresses reporter activity in both lines. Trichostatin A (TSA) and class I histone deacetylase (HDAC) inhibitors, but not 5-azacytidine, induce Stx1a in FRSK cells. Acetylated histone H3 only associates to the CPR in FRSK cells after TSA addition, whereas the high acetylated histone H3-CPR association in PC12 cells was unchanged following treatment. HDAC inhibitor induction of Stx1a was negated by mithramycin A and deletion/mutation of 2 SP sites. HDAC1, HDAC2, and HDAC8 detach from the CPR when treated with TSA in FRSK cells and are associated with the CPR in lungs, and acetylated histone H3 associates to this region in the brain. In the first study characterizing a syntaxin promoter, we show that association of SP1 and acetylated histone H3 to CPR is important for Stx1a transcription and that HDAC1, HDAC2, and HDAC8 decide cell/tissue specificity in a suppressive manner.