Genetic Instability and Disease Progression of Indian Rett Syndrome Patients.

Rett syndrome (RTT) is the rare neurodevelopmental disorder caused by mutations in methyl CpG binding protein 2 (MECP2) gene with a prevalence of 1:10,000 worldwide. The hallmark clinical features of RTT are developmental delay, microcephaly, repetitive behaviours, gait abnormalities, respiratory abnormalities and seizures. Still, the understanding on the diagnosis of RTT among clinicians are less. The aim of our work was to study various clinical manifestations and a spectrum of MECP2 genetic heterogeneity in RTT patients from South Indian population. We screened 208 autistic patients and diagnosed 20 RTT patients, who were further divided into classical RTT (group I; N = 11) and variant RTT (group II; N = 9). The clinical severity of RTT was measured using RSSS, RSBQ, SSI, SSS and RTT gross motor scale. The biochemical analysis showed that thyroid-stimulating hormone (TSH), plasma dopamine and cholesterol levels were higher in group I when compared to group II, whereas the level of blood pressure, calcium, ferritin and high-density lipoprotein levels were significantly decreased in both RTT groups, when compared to the control group. The genetic mutational spectrum of MECP2 mutations were found in 12/20 of RTT patients, which revealed the occurrence of 60% pathogenic mutation and 20% unknown mutation and it was correlated with the clinical finding of respiratory dysfunction, scoliosis and sleeping problems. The significant results of this study provided clinical and genetic aspects of RTT diagnosis and proposed the clinicians to screen abnormal cholesterol, calcium and TSH levels tailed with MECP2 gene mutations for early prognosis of disease severity.

Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4’-Dihydroxyflavone, U0126, and N-Acetyl Cysteine

Background and Objectives@#Flavonoids form the largest group of plant phenols and have various biological and pharma-cological activities. In this study, we investigated the effect of a flavonoid, 3, 4’-dihydroxyflavone (3, 4’-DHF) on osteogenic differentiation of equine adipose-derived stromal cells (eADSCs). @*Methods@#and Results: Treatment of 3, 4’-DHF led to increased osteogenic differentiation of eADSCs by increasing phosphorylation of ERK and modulating Reactive Oxygen Species (ROS) generation. Although PD98059, an ERK inhibitor, suppressed osteogenic differentiation, another ERK inhibitor, U0126, apparently increased osteogenic differentiation of the 3, 4’-DHF-treated eADSCs, which may indicate that the effect of U0126 on bone morphogenetic protein signaling is involved in the regulation of 3, 4’-DHF in osteogenic differentiation of eADSCs. We revealed that 3, 4’-DHF could induce osteogenic differentiation of eADSCs by suppressing ROS generation and co-treatment of 3, 4’-DHF, U0126, and/or N-acetyl cysteine (NAC) resulted in the additive enhancement of osteogenic differentiation of eADSCs. @*Conclusions@#Our results showed that co-treatment of 3, 4’-DHF, U0126, and/or NAC cumulatively regulated osteo-genesis in eADSCs, suggesting that 3, 4’-DHF, a flavonoid, can provide a novel approach to the treatment of osteoporosis and can provide potential therapeutic applications in therapeutics and regenerative medicine for human and companion animals.

Leber's hereditary optic neuropathy: Current approaches and future perspectives on Mesenchymal stem cell-mediated rescue.

Leber's Hereditary Optic Neuropathy (LHON) is an inherited optic nerve disorder. It is a mitochondrially inherited disease due to point mutation in the MT-ND1, MT-ND4, and MT-ND6 genes of mitochondrial DNA (mtDNA) coding for complex I subunit proteins. These mutations affect the assembly of the mitochondrial complex I and hence the electron transport chain leading to mitochondrial dysfunction and oxidative damage. Optic nerve cells like retinal ganglion cells (RGCs) are more sensitive to mitochondrial loss and oxidative damage which results in the progressive degeneration of RGCs at the axonal region of the optic nerve leading to bilateral vision loss. Currently, gene therapy using Adeno-associated viral vector (AAV) is widely studied for the therapeutics application in LHON. Our review highlights the application of cell-based therapy for LHON. Mesenchymal stem cells (MSCs) are known to rescue cells from the pre-apoptotic stage by transferring healthy mitochondria through tunneling nanotubes (TNT) for cellular oxidative function. Empowering the transfer of healthy mitochondria using MSCs may replace the mitochondria with pathogenic mutation and possibly benefit the cells from progressive damage. This review discusses the ongoing research in LHON and mitochondrial transfer mechanisms to explore its scope in inherited optic neuropathy.

Mitochondrial dysfunction: A hidden trigger of autism?

Autism is a heterogeneous neurodevelopmental and neuropsychiatric disorder with no precise etiology. Deficits in cognitive functions uncover at early stages and are known to have an environmental and genetic basis. Since autism is multifaceted and also linked with other comorbidities associated with various organs, there is a possibility that there may be a fundamental cellular process responsible for this. These reasons place mitochondria at the point of interest as it is involved in multiple cellular processes predominantly involving metabolism. Mitochondria encoded genes were taken into consideration lately because it is inherited maternally, has its own genome and also functions the time of embryo development. Various researches have linked mitochondrial mishaps like oxidative stress, ROS production and mt-DNA copy number variations to autism. Despite dramatic advances in autism research worldwide, the studies focusing on mitochondrial dysfunction in autism is rather minimal, especially in India. India, owing to its rich diversity, may be able to contribute significantly to autism research. It is vital to urge more studies in this domain as it may help to completely understand the basics of the condition apart from a genetic standpoint. This review focuses on the worldwide and Indian scenario of autism research; mitochondrial abnormalities in autism and possible therapeutic approaches to combat it.

COVID-19 and olfactory dysfunction: A possible associative approach towards neurodegenerative diseases.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent of novel coronavirus 2019 (COVID-19), has kept the globe in disquiets due to its severe life-threatening conditions. The most common symptoms of COVID-19 are fever, sore throat, and shortness of breath. According to the anecdotal reports from the health care workers, it has been suggested that the virus could reach the brain and can cause anosmia, hyposmia, hypogeusia, and hypopsia. Once the SARS-CoV-2 has entered the central nervous system (CNS), it can either exit in an inactive form in the tissues or may lead to neuroinflammation. Here, we aim to discuss the chronic infection of the olfactory bulb region of the brain by SARS-CoV-2 and how this could affect the nearby residing neurons in the host. We further review the probable cellular mechanism and activation of the microglia 1 phenotype possibly leading to various neurodegenerative disorders. In conclusion, SARS-CoV-2 might probably infect the olfactory bulb neuron enervating the nasal epithelium accessing the CNS and might cause neurodegenerative diseases in the future.

An appraisal on molecular and biochemical signalling cascades during arsenic-induced hepatotoxicity.

Arsenic is a ubiquitous metalloid compound commonly found in the environment, and it is usually found in combination with sulphur and metals. Arsenic is considered as a therapeutic as well as poisoning agent since ancient times. It causes toxic effects on different organs, mainly the liver. In this review, we focused on the molecular mechanism of arsenic-induced hepatotoxicity. Here we envisaged the bridge between arsenic and hepatotoxicity with particular focus on the level of hepatic enzymes such as ALT, AST, and ALP. Here, we attempted to elucidate the role of arsenic in redox imbalance on increased oxidative stress (elevated level of ROS, MDA and NO) and decreased antioxidant levels such as reduced GSH, catalase, and SOD. Oxidative stress induces mitochondrial dysfunction via apoptosis (AKT-PKB, MAPK, PI3/AKT, PKCδ-JNK, AKT/ERK, p53 pathways), fibrosis (TGF-ß/Smad pathway), and necrosis and inflammation (TNF-α, NF-ĸB, IL-1, and IL-6). Along with that, arsenic activates caspases and Bax, decreases Bcl2 through mitochondrial dysfunction, and induces apoptosis regulatory mechanism. We believe the alteration of all these pathways leads to arsenic-induced hepatotoxicity.

Enhanced apoptogenesis and oncogene regulatory mechanism of troxerutin in triple negative breast cancer cells.

Triple negative breast carcinoma (TNBC) is an aggressive form of cancer, with high rates of morbidity, mortality, poor prognosis and limited therapeutic options. The objective of the present study was to elaborate the anticancer activity of Troxerutin (TXN) in TNBC/MDA-MB-231 cells. Herein, we demonstrated the inhibitory effects of TXN on the breast cancer cell growth via induction of apoptosis. Mitochondrial membrane potential (∆Ψm), DNA damage and apoptotic nuclear changes were analyzed by flowcytometry, AO/EtBr and Hoechst staining, respectively. Furthermore, apoptotic protein and gene expressions were analyzed by western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively. Our results indicated that TXN induces apoptosis as evidenced by inhibit the cell proliferation, enhanced apoptotic activation, altered mitochondrial membrane potential and elevated level of DNA damage in TNBC cells. Furthermore, the TXN inhibit anti-apoptotic protein expression with the subsequent upregulation of Cytochrome c, Caspase-9 and Caspase-3. Thus, TXN induces apoptosis in TNBC cells through inducing nuclear damage and altered apoptotic marker expressions. Therefore, TXN might be used as a potential therapeutic agent for the treatment of triple negative breast cancer.

Follow-up studies in COVID-19 recovered patients - is it mandatory?

The novel Coronavirus disease 2019 (COVID-19) is an illness caused due to Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) has declared this outbreak a global health emergency and as on April 24, 2020, it has spread to 213 countries, with 25,91,015 confirmed cases and 742,855 cases have been recovered from COVID-19. In this dreadful situation our team has already published an article in the Science of the Total Environment, which elaborates the various aspects of the SARS-CoV-2 infection. In this situation, it is imperative to understand the possible outcome of COVID-19 recovered patients and determine if they have any other detrimental illnesses by longitudinal analysis to safeguard their life in future. It is necessary to follow-up these recovered patients and performs comprehensive assessments for detection and appropriate management towards their psychological, physical, and social realm. This urges us to suggest that it is highly important to provide counselling, moral support as well as a few recommended guidelines to the recovered patients and society to restore to normalcy. Epidemiological, clinical and immunological studies from COVID-19 recovered patients are particularly important to understand the disease and to prepare better for potential outbreaks in the future. Longitudinal studies on a larger cohort would help us to understand the in-depth prognosis as well as the pathogenesis of COVID-19. Also, follow-up studies will help us provide more information for the development of vaccines and drugs for these kinds of pandemics in the future. Hence, we recommend more studies are required to unravel the possible mechanism of COVID-19 infection and the after-effects of it to understand the characteristics of the virus and to develop the necessary precautionary measures to prevent it.

Drug Studies on Rett Syndrome: From Bench to Bedside.

Drug studies on Rett syndrome (RTT) have drastically increased over the past few decades. This review aims to provide master data on bench-to-bedside drug studies involving RTT. A comprehensive literature review was performed by searching in PUBMED, MEDLINE and Google Scholar, international, national and regional clinical trial registries and pharmaceutical companies using the keywords "Rett syndrome treatment and/or drug or compound or molecule". Seventy drugs were investigated in non-clinical (N = 65 animal/cell line-based studies; N = 5 iPSC-based study) and clinical trials (N = 34) for ameliorating the symptoms of RTT. Though there is good progress in both clinical and non-clinical studies, none of these drugs entered phase III/IV for being launched as a therapeutic agent for RTT.

Does retina play a role in Parkinson's Disease?

Visual disorder is one of the non-motor symptoms found in Parkinson's disease (PD). It can be easily identified in the early stages even before the spread of pathological conditions to the brain parts. Studies have revealed that loss of dopamine (DA) cells in retinal layers is a prime cause for both retinal disturbance and pathological conditions of PD. This reduction of DA in retina is due to the aggregation of phosphorylated α-synuclein (aSyn) in the intra-retinal region, which eventually results in visual impairment in PD. Until now, very limited studies have been focused on the mechanism of aSyn influence and DA depletion as a cause for both retinal layer dysfunction and PD. Thus, more research is warranted to provide the missing connection between the exact role of DA and aSyn as a risk factor for visual problems in PD. Hence, the current review's focus is on the function and effects of DA degeneration in retinal cells of PD. Further, we suggest that iron plays a major role in regulating the aggregation of aSyn in the DA cells of retina and brain in PD. The study finds that the unidentified pathophysiological role of retinal degeneration in PD is an essential biomarker that needs further investigation to use it as a novel therapy in treating retinal dysfunctions in PD.

New insight into NANOG: A novel therapeutic target for ovarian cancer (OC).

Cancer incidence, metastasis, drug resistance and recurrence are still the critical issues of oncological diseases especially Ovarian cancer (OC). It has been suggested that drug resistance and disease relapse are the main causes for the aggressive nature of OC. There is an immediate need to develop novel strategies to understand the mechanism to overcome chemoresistance. Nanog has been found to regulate stemness like cells inside the cancer cells that are termed as Cancer Stem Cells (CSCs). These cells show high self-renewal capacity with a peculiar potential in tumour initiation, heterogeneity, progression, metastasis, recurrence, radiotherapy and multi drug resistance. Recent studies have demonstrated that Nanog, a key transcription factor for pluripotency, has been playing a major role in chemoresistance. In this review, we address the functions of Nanog in both normal and cancer cells, how Nanog is involved in OC tumorigenesis and chemoresistance. This review also highlights the methods that are used for targeting Nanog as a remedy for treating OC. Thus, through this review, we predict that these concepts will open new avenues of research in ovarian cancer stem cells, and would propose Nanog as a target to improve the outcome of chemotherapy.

Molecular docking analysis of a secondary metabolite with the glycoprotein receptors of HSV 1 and HSV 2.

Herpes simplex viruses (HSV) are alpha herpes viruses, which causes life-threatening illness. Therefore, it is of interest to design and develop potential drugs to treat HSV infections. We show the optimal molecular docking properties of a secondary metabolite (3, 7, 11, 15 tetra methyl-2-2-hexadecen-'1-ol) with the glycoprotein receptors of HSV1 and HSV 2 for further consideration.

Autism in India: a case-control study to understand the association between socio-economic and environmental risk factors.

Autism spectrum disorder is a neurodevelopmental disorder and the cause of autism is still unclear. The aim of this study was to investigate the association of socioeconomic, environmental, pregnancy and newborn-related risk factors among children with autism spectrum disorders. This was a population-based case-control study. The study included 55 children with autism spectrum disorder and 55 age and sex matched typically developing normal children (TD) between 3 and 12 years. Several socio-economic factors, environmental factors, pregnancy related, natal, post-natal factors and the first noticed signs by the parents were analyzed. Chi-square test was used to compare nominal variables. For multivariate analysis, forward stepwise logistic regression model was employed to examine the association between autism and the chances that the child develops ASD to assess the odds ratios. Male predominance was observed in the study. Logistic regression model showed statistical significance of the following factors: paternal age greater than 40 years, family history of autism, nutrition during pregnancy, mode of labor, fetal hypoxia, NICU stay and history of breast feeding. In this epidemiological study of autism in Coimbatore city, we found correlation between several environmental factors during fetal development and can be transmitted to succeeding generations, causing atypical behavior phenotypes. The exact exposure magnitude, exposure time in relation to vital developmental periods need to be studied to understand the influence of socioeconomic and environmental factors, which can be improved to prevent ASD-related challenges.

Targeting phosphoinositide-3-kinase pathway in biliary tract cancers: A remedial route?

Biliary tract cancers (BTC) are aggressive tumours with a low survival rate. At the advent of the genomic era, various genetic mutations in cell signalling pathways have been incriminated in carcinogenesis. Genomic analysis studies have connected main components of the phosphoinositide-3-kinase (PI3K) signalling pathway to BTC. PI3K pathway playing a central role in cell signalling and being deregulated in various tumours has been studied as a target for chemotherapy. Novel compounds have also been identified in preclinical trials that specifically target the PI3K pathway in BTCs, but these studies have not accelerated to clinical use. These novel compounds can be examined in upcoming studies to validate them as potential therapeutic agents, as further research is required to combat the growing need for adjuvant chemotherapy to successfully battle this tumour type. Furthermore, these molecules could also be used along with gemcitabine, cisplatin and 5-fluorouracil to improve sensitivity of the tumour tissue to chemotherapy. This review focuses on the basics of PI3K signalling, genetic alterations of this pathway in BTCs and current advancement in targeting this pathway in BTCs. It emphasizes the need for gene-based drug screening in BTC. It may reveal various novel targets and drugs for amelioration of survival in patients with BTC and serve as a stepping stone for further research.

Ampullary carcinoma-A genetic perspective.

Ampulla of vater carcinoma (AVC) is a rare gastrointestinal tumour that is associated with a high mortality rate and it's often diagnosed at later stages due to lack of clinical symptoms. Early diagnosis of this condition is essential to effectively treat patients for better prognosis. A significant amount of advancement has been made in understanding the molecular nature of cancer in the past decade. A substantial number of mutations and alterations have been detected in various tumors. Despite the occurrence of AVC across the globe, the number of studies conducted on this tumor type remains low; this is largely due to its rare occurrence. Moreover, AVC tissues are complex and contain mutations in oncogenes, tumour suppressors, apoptotic proteins, cell proliferation proteins, cell signaling proteins, transcription factors, chromosomal abnormalities and cellular adhesion proteins. The frequently mutated genes included KRAS, TP53 and SMAD4 and are associated with prognosis. Several molecules of the PI3K, Wnt signaling, TGF-beta pathway and cell cycle have also been altered in AVCs. This review comprises of all the genetic mutations, associated pathways and related prognosis that are involved in AVCs from the year 1989 to 2017. This report can be used as a stepping-stone to establish biomarkers for early diagnosis of AVC and to discover molecular targets for drug therapy.

Cell replacement therapy is the remedial solution for treating Parkinson's disease.

The selective degeneration of dopaminergic (DA) neurons in Parkinson's disease (PD) has made an idol target for cell replacement therapies and other emerging surgical treatments. Certainly, by transplantation method, the therapeutic regimens such as human fetal ventral midbrain (hfVM) cells, human embryonic stem cells (hESCs), human neural stem/precursor/ progenitor cells (hNSCs/hNPCs), human mesenchymal stem cells (hMSCs), human induced neural stem cells (hiNSCs), and human induced pluripotent stem cells (hiPSCs) have been used into DA deficient striatum. In recent decades, surgical methods such as deep brain stimulation (DBS) and gene therapies have been used with the aim of treating PD. Though the technology has improved and many treating options arise, the permanent source for curing PD has not been identified yet. In this review, we examine how stem cell therapies have made advancement as a therapeutic source for PD when compared with surgical treatments.

Novel therapeutic approaches: Rett syndrome and human induced pluripotent stem cell technology.

Recent advances in induced pluripotent stem cell (iPSC) technology target screening and discovering of therapeutic agents for the possible cure of human diseases. Human induced pluripotent stem cells (hiPSC) are the right kind of platform for testing potency of specific active compounds. Ayurveda, the Indian traditional system of medicine developed between 2,500 and 500 BC, is a science involving the intelligent formulations of herbs and minerals. It can serve as a "goldmine" for novel neuroprotective agents used for centuries to treat neurological disorders. This review discusses limitations in screening drugs for neurological disorders and the advantages offered by hiPSC integrated with Indian traditional system of medicine. We begin by describing the current state of hiPSC technology in research on Rett syndrome (RTT) followed by the current controversies in RTT research combined with the emergence of patient-specific hiPSC that indicate an urgent need for researchers to understand the etiology and drug mechanism. We conclude by offering recommendations to reinforce the screening of active compounds present in the ayurvedic medicines using the human induced pluripotent neural model system for research involving drug discovery for RTT. This integrative approach will fill the current knowledge gap in the traditional medicines and drug discovery.

A review of Rett syndrome (RTT) with induced pluripotent stem cells.

Human induced pluripotent stem cells (hiPSCs) are pluripotent stem cells generated from somatic cells by the introduction of a combination of pluripotency-associated genes such as OCT4, SOX2, along with either KLF4 and c-MYC or NANOG and LIN28 via retroviral or lentiviral vectors. Most importantly, hiPSCs are similar to human embryonic stem cells (hESCs) functionally as they are pluripotent and can potentially differentiate into any desired cell type when provided with the appropriate cues, but do not have the ethical issues surrounding hESCs. For these reasons, hiPSCs have huge potential in translational medicine such as disease modeling, drug screening, and cellular therapy. Indeed, patient-specific hiPSCs have been generated for a multitude of diseases, including many with a neurological basis, in which disease phenotypes have been recapitulated in vitro and proof-of-principle drug screening has been performed. As the techniques for generating hiPSCs are refined and these cells become a more widely used tool for understanding brain development, the insights they produce must be understood in the context of the greater complexity of the human genome and the human brain. Disease models using iPS from Rett syndrome (RTT) patient's fibroblasts have opened up a new avenue of drug discovery for therapeutic treatment of RTT. The analysis of X chromosome inactivation (XCI) upon differentiation of RTT-hiPSCs into neurons will be critical to conclusively demonstrate the isolation of pre-XCI RTT-hiPSCs in comparison to post-XCI RTT-hiPSCs. The current review projects on iPSC studies in RTT as well as XCI in hiPSC were it suggests for screening new potential therapeutic targets for RTT in future for the benefit of RTT patients. In conclusion, patient-specific drug screening might be feasible and would be particularly helpful in disorders where patients frequently have to try multiple drugs before finding a regimen that works.

Bio Fabrication of Silver Nanoparticle from Argemone mexicana for the Control of Aedes albopictus and their Antimicrobial Activity.

BACKGROUND: Plant synthesized silver nanoparticles give rapid control on mosquito larvae of dengue vector, Aedes albopictus. AgNPs synthesized from the plant, Argemone mexicana for the control of larvae and these nanoparticles inhibit the growth of microbes are broad spectrum of nanoparticle activities. METHODS: Nanoparticles were subjected to analysis by UV-vis spectrophotometry, Fourier transform infrared spectroscopy, scanning electron microscopy and transmission electron microscopy. Furthermore, laboratory evaluation of plant mediated nano-particle carried out lethal toxicity on Aedes albopictus. The characterization studies confirmed the spherical shape and size (5-50 nm) of silver nano-particles. RESULTS: The efficacy of AgNPs was tested at concentration of 2 to 10 ppm against L1 to L4 larval instar of A. albopictus. The LC50 followed by LC90 values were (L1) 5.24, 8.66; (L2) 5.56, 8.85; (L3) 6.20, 10.01 and (L4) 7.04, 10.92 at 10 ppm of silver nanoparticle, whereas LC50 (LC90) values of (L1) 7.63, 11.58; (L2) 8.17, 11.88; 8.80, 12.82 and 8.94, 12.26 at 10 ppm of plant extract alone treated larvae, respectively. The mortality rates were positively correlated with the concentration of AgNPs. Significant (P<0.05) high square value changes in the larval mortality were also recorded between the period of exposure against all larval instar of A. albopictus. Silver nanoparticles were also tested for antimicrobial activity and significant toxicity inhibition was observed against the gram positive microbes and it exhibited mild toxicity against P. aeroginosa. CONCLUSION: Plant, A. mexicana synthesized silver nano-particles are rapid and potential mosquito larvicidal as well as antimicrobial agents. Finding of our results support that silver nanoparticles can be prepared in a simple and cost-effective manner and are suitable for bio-formulation against mosquitoes and microbes.

Synthesis of silver and gold nanoparticles using cashew nut shell liquid and its antibacterial activity against fish pathogens.

This study reveals a green process for the production of multi-morphological silver (Ag NPs) and gold (Au NPs) nanoparticles, synthesized using an agro-industrial residue cashew nut shell liquid. Aqueous solutions of Ag(+) ions for silver and chloroaurate ions for gold were treated with cashew nut shell extract for the formation of Ag and Au NPs. The nano metallic dispersions were characterized by measuring the surface plasmon absorbance at 440 and 546 nm for Ag and Au NPs. Transmission electron microscopy showed the formation of nanoparticles in the range of 5-20 nm for silver and gold with assorted morphologies such as round, triangular, spherical and irregular. Scanning electron microscopy with energy dispersive spectroscopy and X-ray diffraction analyses of the freeze-dried powder confirmed the formation of metallic Ag and Au NPs in crystalline form. Further analysis by Fourier transform infrared spectroscopy provided evidence for the presence of various biomolecules, which might be responsible for the reduction of silver and gold ions. The obtained Ag and Au NPs had significant antibacterial activity, minimum inhibitory concentration and minimum bactericidal concentration on bacteria associated with fish diseases.