Nitric Oxide as a Determinant of Human Longevity and Health Span.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage-L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

Tryptophan in Nutrition and Health 2.0.

This editorial summarizes the eight articles that have been collected for the Special Issue entitled "Tryptophan in Nutrition and Health 2 [...].

Functions of Astrocytes under Normal Conditions and after a Brain Disease.

In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural origin (astrocytes, radial glia, and oligodendroglia) and differentiated blood monocytes (microglia). During ontogeny, neurons develop earlier (at fetal day 15 in the rat) and astrocytes develop later (at fetal day 21 in the rat), which could indicate their important and crucial role in the CNS. Analysis of the phylogeny reveals that reptiles have a lower number of astrocytes compared to neurons and in humans this is reversed, as there have a greater number of astrocytes compared to neurons. These data perhaps imply that astrocytes are important and special cells, involved in many vital functions, including memory, and learning processes. In addition, astrocytes are involved in different mechanisms that protect the CNS through the production of antioxidant and anti-inflammatory proteins and they clean the extracellular environment and help neurons to communicate correctly with each other. The production of inflammatory mediators is important to prevent changes in brain homeostasis. On the contrary, excessive, or continued production appears as a characteristic element in many diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and in neurodevelopmental diseases, such as bipolar disorder, schizophrenia, and autism. Furthermore, different drugs and techniques have been developed to reverse oxidative stress and/or excess of inflammation that occurs in many CNS diseases, but much remains to be investigated. This review attempts to highlight the functional relevance of astrocytes in normal and neuropathological conditions by showing the molecular and cellular mechanisms of their role in the CNS.

Study of the effectiveness of wavelet genetic programming model for water quality analysis in the Uttar Pradesh region.

Water constitutes an essential part of the earth as it helps in making the environment greener and support life. But water quality and availability are drastically affected by rising water pollution and its poor sanitation. Water gets contaminated due to the excessive use of chemicals by the industries, fertilizers, and pesticides by the farmers. Not only the surface water, groundwater and river water are also getting contaminated. Several published work in Indian context have used different models for the prediction of water quality. Some of them performed poorly due to the presence of irrelevant and missing data in the training samples. Moreover, these studies have assessed water quality on the basis of biochemical oxygen demand (BOD) and coliform and chemical oxygen demand (COD), whereas dissolved oxygen(DO) is one of the most important parameters in terms of water quality assessment as it is considered a key determinant of pollution. Thus, there is a strong need to categorically identify and visualize the DO as one of the key components responsible for deteriorating the quality of water in Indian context. The main objective of this work is to build a wavelet genetic programming (WGP)-based workflow model for the assessment of water quality in 13 rivers of Uttar Pradesh region. WGP model has a unique feature of discarding the redundant and irrelevant data values from the source data. The proposed WGP model has given promising results which can be attributed to two factors: firstly, the novel use of Morlet wavelet in place of the widely popular Db wavelet, as the mother wavelet, and secondly, the use of MICE technique for missing value imputation in the pre-processing stage. The proposed model not only cleans the data but also demonstrates the feasibility of using DO values as one of the prime factors to assess the water quality.

The Ethnopharmacological Properties of Green-Engineered Metallic Nanoparticles against Metabolic Disorders.

Metabolic syndrome is a multifaceted pathophysiologic condition that is largely caused by an imbalance between caloric intake and energy expenditure. The pathogenesis of metabolic syndrome is determined by an individual's genetic/epigenetics and acquired factors. Natural compounds, notably plant extracts, have antioxidant, anti-inflammatory, and insulin-sensitizing properties and are considered to be a viable option for metabolic disorder treatment due to their low risk of side effects. However, the limited solubility, low bioavailability, and instability of these botanicals hinder their performance. These specific limitations have prompted the need for an efficient system that reduces drug degradation and loss, eliminates unwanted side effects, and boosts drug bioavailability, as well as the percentage of the drug deposited in the target areas. The quest for an enhanced (effective) drug delivery system has led to the formation of green-engineered nanoparticles, which has increased the bioavailability, biodistribution, solubility, and stability of plant-based products. The unification of plant extracts and metallic nanoparticles has helped in the development of new therapeutics against metabolic disorders such as obesity, diabetes mellitus, neurodegenerative disorders, non-alcoholic fatty liver, and cancer. The present review outlines the pathophysiology of metabolic diseases and their cures with plant-based nanomedicine.

Microalgal Carotenoids: Therapeutic Application and Latest Approaches to Enhance the Production.

Microalgae are microscopic photosynthetic organisms frequently found in fresh and marine water ecosystems. Various microalgal species have been considered a reservoir of diverse health-value products, including vitamins, proteins, lipids, and polysaccharides, and are broadly utilized as food and for the treatment of human ailments such as cancer, cardiovascular diseases, allergies, and immunodeficiency. Microalgae-derived carotenoids are the type of accessory pigment that possess light-absorbing potential and play a significant role in metabolic functions. To date, nearly a thousand carotenoids have been reported, but a very less number of microalgae have been used for the commercial production of carotenoids. This review article briefly discussed the carotenoids of microalgal origin and their therapeutic application. In addition, we have briefly compiled the optimization of culture parameters used to enhance microalgal carotenoid production. In addition, the latest biotechnological approaches used to improve the yields of carotenoid has also been discussed.

Therapeutic Potential of Quercetin-Loaded Nanoemulsion against Experimental Visceral Leishmaniasis: In Vitro/Ex Vivo Studies and Mechanistic Insights.

Visceral leishmaniasis (VL) is one of the most fatal and neglected tropical diseases caused by Leishmania donovani (L. donovani). The applications of currently available chemotherapy (amphotericin B, miltefosine, and others) in VL treatment have been limited due to their poor bioavailability, unfavorable toxicity profile, and prolonged parenteral dosing. Quercetin (QT), a potent natural antioxidant, is a prominent target when conducting investigations on alternative therapies against L. donovani infections. However, the therapeutic applications of QT have been restricted due to its low solubility and bioavailability. In the present study, we developed and evaluated the antileishmanial activity (ALA) of quercetin-loaded nanoemulsion (QTNE) against L. donovani clinical strains. In vitro anti-promastigote assay results demonstrated that QTNE (IC50 6.6 µM, 48 h) significantly inhibited the growth of parasites more efficiently than the pure QT suspension in a dose- and time-dependent manner. Results of the anti-amastigote assay revealed that the infected macrophages (%) of QTNE were significantly more than those of the pure QT suspension at all concentrations (6.6, 26.4, and 52.8 µM; p < 0.05, p < 0.01 compared to the control). Moreover, the results of in vitro and ex vivo studies assisted in determining the mechanistic insights associated with the ALA of QTNE. The overall findings suggested that QTNE exhibited potential ALA by enhancing the intracellular ROS and nitric oxide levels, inducing distortion of membrane integrity and phosphatidylserine release (AV/PI), rupturing the parasite DNA (late apoptosis/necrosis process), and upregulating the immunomodulatory effects (IFN-γ and IL-10 levels). Additionally, QTNE showed superior biocompatibility against all of the treated healthy cells (PBMCs, PECs, and BMCs) as compared to the control. In conclusion, QTNE acts as a potential antileishmanial agent targeting both promastigote and intracellular amastigote forms of L. donovani, which thus opens a new avenue for the use of QTNE in VL therapy.

Disaccharide trehalose in experimental therapies for neurodegenerative disorders: Molecular targets and translational potential.

Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities.

Tryptophan in Nutrition and Health.

Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...].

Alzheimer's Disease and Tau Self-Assembly: In the Search of the Missing Link.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by progressive cognitive impairment, apathy, and neuropsychiatric disorders. Two main pathological hallmarks have been described: neurofibrillary tangles, consisting of tau oligomers (hyperphosphorylated tau) and Aß plaques. The influence of protein kinases and phosphatases on the hyperphosphorylation of tau is already known. Hyperphosphorylated tau undergoes conformational changes that promote its self-assembly. However, the process involving these mechanisms is yet to be elucidated. In vitro recombinant tau can be aggregated by the action of polyanions, such as heparin, arachidonic acid, and more recently, the action of polyphosphates. However, how that process occurs in vivo is yet to be understood. In this review, searching the most accurate and updated literature on the matter, we focus on the precise molecular events linking tau modifications, its misfolding and the initiation of its pathological self-assembly. Among these, we can identify challenges regarding tau phosphorylation, the link between tau heteroarylations and the onset of its self-assembly, as well as the possible metabolic pathways involving natural polyphosphates, that may play a role in tau self-assembly.

Facilitation of Insulin Effects by Ranolazine in Astrocytes in Primary Culture.

Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels; however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins (10-8 M), Rn (10-6 M), and Ins + Rn (10-8 M and 10-6 M, respectively) were added to astrocytes for 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. Rn increased protein expression of Cu/Zn-SOD and the pro-inflammatory protein COX-2 was upregulated by Ins. On the contrary, no significant changes were found in the protein expression of NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. In addition, Rn + Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone.

A comprehensive review of environmental fate and degradation of fipronil and its toxic metabolites.

The use of pesticides to increase crop production has become one of the inevitable components of modern agriculture. Fipronil, a phenylpyrazoles insecticide, is one of the most widely used, systemic, broad-spectrum insecticides. Owing to its unique mode of action and selective toxicity, it was once regarded as safer alternatives to more toxic and persistent organochlorine insecticides. However, with the increased use, many studies have reported the toxicity of fipronil and its metabolites in various non-target organisms during the last two decades. Currently, it is regarded as one of the most persistent and lipophilic insecticides in the market. In the environment, fipronil can undergo oxidation, reduction, hydrolysis, or photolysis to form fipronil sulfone, fipronil sulfide, fipronil amide, or fipronil desulfinyl respectively. These metabolites except fipronil amide are more or less toxic and persistent than fipronil and have been reported from diverse environmental samples. Recently many studies have focused on the degradation and removal of fipronil residues from the environment. However, a comprehensive review summarizing and combining these recent findings is lacking. In the present review, we evaluate, summarize, and combine important findings from recent degradation studies of fipronil and its metabolites. An attempt has been made to elucidate the possible mechanism and pathways of degradation of fipronil and its toxic metabolites.

An elaborative NMR based plasma metabolomics study revealed metabolic derangements in patients with mild cognitive impairment: a study on north Indian population.

Mild cognitive impairment (MCI) is transition phase between cognitive decline and dementia. The current study aims to investigate altered metabolic pattern in plasma of MCI for potential biomarkers. MCI (N = 50) and healthy controls (HC, N = 50) age group 55-75 years were screened based on Mini Mental State Examination Test (MMSE) and diffusion tensor imaging (DTI imaging). The MMSE score of MCI was significantly lower (25.74 ± 1.83) compared to healthy control subjects (29 ± 1). The MCI patients exhibit significant changes in white matter integrity in the right frontal lobe, right temporal lobe, left frontal lobe, forcep major, fornix, corpus callosum. Further, the plasma samples of twenty seven MCI patients (N = 27) and twenty HC subjects (N = 20; having no significant differences in any demographics) were analyzed using 1H NMR based metabolomics approach. Consistent with many previous reports, the levels of several plasma metabolites were found to be elevated in MCI patients compared to healthy controls. Further univariate and multivariate ROC curve analyses provided three plasma metabolites as a diagnostic panel of biomarker for MCI; which are lysine, glycine, and glutamine. Overall, the results of this study will help to improve the diagnostic and prognostic strategies of MCI in addition to improving our understanding about disease pathogenesis. We believe that the over-nutritional metabolic phenotype of MCI needs to be targeted for developing future dietary interventions so that the progression of MCI can be limited. Metabolic derangements associated with Mild Cognitive Impairment.

miR-302 Attenuates Mutant Huntingtin-Induced Cytotoxicity through Restoration of Autophagy and Insulin Sensitivity.

Huntington's disease (HD) is an autosomal-dominant brain disorder caused by mutant huntingtin (mHtt). Although the detailed mechanisms remain unclear, the mutational expansion of polyglutamine in mHtt is proposed to induce protein aggregates and neuronal toxicity. Previous studies have shown that the decreased insulin sensitivity is closely related to mHtt-associated impairments in HD patients. However, how mHtt interferes with insulin signaling in neurons is still unknown. In the present study, we used a HD cell model to demonstrate that the miR-302 cluster, an embryonic stem cell-specific polycistronic miRNA, is significantly downregulated in mHtt-Q74-overexpressing neuronal cells. On the contrary, restoration of miR-302 cluster was shown to attenuate mHtt-induced cytotoxicity by improving insulin sensitivity, leading to a reduction of mHtt aggregates through the enhancement of autophagy. In addition, miR-302 also promoted mitophagy and stimulated Sirt1/AMPK-PGC1α pathway thereby preserving mitochondrial function. Taken together, these results highlight the potential role of miR-302 cluster in neuronal cells, and provide a novel mechanism for mHtt-impaired insulin signaling in the pathogenesis of HD.

In vivo polymerization and manufacturing of wires and supercapacitors in plants.

Electronic plants, e-Plants, are an organic bioelectronic platform that allows electronic interfacing with plants. Recently we have demonstrated plants with augmented electronic functionality. Using the vascular system and organs of a plant, we manufactured organic electronic devices and circuits in vivo, leveraging the internal structure and physiology of the plant as the template, and an integral part of the devices. However, this electronic functionality was only achieved in localized regions, whereas new electronic materials that could be distributed to every part of the plant would provide versatility in device and circuit fabrication and create possibilities for new device concepts. Here we report the synthesis of such a conjugated oligomer that can be distributed and form longer oligomers and polymer in every part of the xylem vascular tissue of a Rosa floribunda cutting, forming long-range conducting wires. The plant's structure acts as a physical template, whereas the plant's biochemical response mechanism acts as the catalyst for polymerization. In addition, the oligomer can cross through the veins and enter the apoplastic space in the leaves. Finally, using the plant's natural architecture we manufacture supercapacitors along the stem. Our results are preludes to autonomous energy systems integrated within plants and distribute interconnected sensor-actuator systems for plant control and optimization.

Dithiafulvene derivatized donor-acceptor norbornadienes with redshifted absorption.

Photoisomerization of norbornadiene (N) to its metastable isomer quadricyclane (Q) has attracted interest as a strategy for harvesting and storing solar energy. For this strategy to mature the absorption maximum of N has to be moved from the UV to the visible region. Here we show that functionalization of the system with dithiafulvene (DTF) electron donors causes remarkable redshifts of various N derivatives. Thus, some derivatives were found to absorb light with an absorption onset up to 556 nm. The incorporation of DTF units comes, however, with a drawback with regard to achieving reversible N-to-Q and Q-to-N isomerizations. For some derivatives, the photoisomerization was completely quenched. The compounds were subjected to a computational study to shed light on the underlying reason for this reluctance to undergo photoisomerization. The computational study revealed that in these systems, the first excited state (S1) is positioned close to or lower than the transition state for photoconversion, effectively blocking a possible conversion to Q, thus revealing a practical challenge for the future design of N-Q energy storage systems with an improved solar spectrum match.

Evaluation of oral pharmacokinetics, in vitro metabolism, blood partitioning and plasma protein binding of novel antidiabetic agent, S009-0629 in rats.

S009-0629 [methyl-8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate] is a novel antidiabetic agent with PTP1B inhibitory activity. In this study, we have investigated the in vitro metabolic stability, plasma protein binding, blood partitioning, and oral pharmacokinetic study of S009-0629 in rats. The plasma protein binding, blood partitioning, and metabolic stability were determined by HPLC method. The oral pharmacokinetic study was analyzed by liquid chromatography coupled mass spectrometry (LC-MS/MS) method. The plasma protein binding of S009-0629 using modified charcoal adsorption method at 5 and 10 µg/mL was 80.58 ± 1.04% and 81.95 ± 1.15%, respectively. The KRBC/PL of S009-0629 was independent of concentration and time. The in-vitro half-life of S009-0629 at 5 and 10 µM using rat liver microsomes was determined as 273 ± 24.46 and 281.67 ± 26.53 min, respectively. After oral administration, S009-0629 exhibited Cmax 55.51 ± 1.18 ng/mL was observed at 18 hr (tmax ). S009-0629 was found to have the large apparent volume of distribution (1,894.93 ± 363.67 L/kg). Oral in-vivo t1/2 of S009-0629 was found to be 41.23 ± 5.96 hr. A rapid and highly sensitive LC-MS/MS method was validated for S009-0629 in rat plasma. S009-0629 has high plasma protein binding and low hepatic extraction. S009-0629 has no affinity with human P-gp and BCRP in ATPase assay. After oral dosing, S009-0629 has slow absorption and elimination in rats.

Distribution of cyanobacteria and their interactions with pesticides in paddy field: A comprehensive review.

Cyanobacteria, also known as blue green algae are one of the important ubiquitous oxygen evolving photosynthetic prokaryotes and ultimate source of nitrogen for paddy fields since decades. In past two decades, indiscriminated use of pesticides led to biomagnification that intensively harm the structure and soil functions of soil microbes including cyanobacteria. Cyanobacterial abundance biomass, short generation, water holding capacity, mineralizing capacity and more importantly nitrogen fixing have enormous potential to abate the negative effects of pesticides. Therefore, investigation of the ecotoxicological effects of pesticides on the structure and function of the tropical paddy field associated cyanobacteria is urgent and need to estimate the fate of interaction of pesticides over nitrogen fixations and other attributes. In this regard, comprehensive survey over cyanobacterial distribution patterns and their interaction with pesticides in Indian context has been deeply reviewed. In addition, the present paper also deals the molecular docking pattern of pesticides with the nitrogen fixing proteins, which helps in revealing the functional interpretation over nitrogen fixation process.

Preparation, Characterization and Biological Applications of Biosynthesized Silver Nanoparticles with Chitosan-Fucoidan Coating.

Silver nanoparticles (AgNPs) are gaining a great deal of attention in biomedical applications due to their unique physicochemical properties. In this study, green synthesis of AgNPs was developed using seaweed polysaccharide fucoidan. The AgNPs were further coated with chitosan to form an electrolyte complex on the surface. The developed chitosan⁻fucoidan complex-coated AgNPs were characterized using UV-visible spectroscopy, Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM). FT-IR results suggested strong polyelectrolyte complexation between fucoidan and chitosan. The developed chitosan⁻fucoidan complex-coated AgNPs significantly inhibited microbial growth. Moreover, the AgNPs showed efficient anticancer activity in human cervical cancer cells (HeLa). This study demonstrated that chitosan⁻fucoidan complex-coated AgNPs hold high potential for food and cosmeceutical applications.

Healthcare Text Classification System and its Performance Evaluation: A Source of Better Intelligence by Characterizing Healthcare Text.

A machine learning (ML)-based text classification system has several classifiers. The performance evaluation (PE) of the ML system is typically driven by the training data size and the partition protocols used. Such systems lead to low accuracy because the text classification systems lack the ability to model the input text data in terms of noise characteristics. This research study proposes a concept of misrepresentation ratio (MRR) on input healthcare text data and models the PE criteria for validating the hypothesis. Further, such a novel system provides a platform to amalgamate several attributes of the ML system such as: data size, classifier type, partitioning protocol and percentage MRR. Our comprehensive data analysis consisted of five types of text data sets (TwitterA, WebKB4, Disease, Reuters (R8), and SMS); five kinds of classifiers (support vector machine with linear kernel (SVM-L), MLP-based neural network, AdaBoost, stochastic gradient descent and decision tree); and five types of training protocols (K2, K4, K5, K10 and JK). Using the decreasing order of MRR, our ML system demonstrates the mean classification accuracies as: 70.13 ± 0.15%, 87.34 ± 0.06%, 93.73 ± 0.03%, 94.45 ± 0.03% and 97.83 ± 0.01%, respectively, using all the classifiers and protocols. The corresponding AUC is 0.98 for SMS data using Multi-Layer Perceptron (MLP) based neural network. All the classifiers, the best accuracy of 91.84 ± 0.04% is shown to be of MLP-based neural network and this is 6% better over previously published. Further we observed that as MRR decreases, the system robustness increases and validated by standard deviations. The overall text system accuracy using all data types, classifiers, protocols is 89%, thereby showing the entire ML system to be novel, robust and unique. The system is also tested for stability and reliability.