Reprogramming of urea cycle in cancer: Mechanism, regulation and prospective therapeutic scopes.

Hepatic urea cycle, previously known as ornithine cycle, is the chief biochemical pathway that deals with the disposal of excessive nitrogen in form of urea, resulted from protein breakdown and concomitant condensation of ammonia. Enzymes involved in urea cycle are expressed differentially outside hepatic tissue and are mostly involved in production of arginine from citrulline in arginine-depleted condition. Inline, cancer cells frequently adapt metabolic rewiring to support sufficient biomass production in order to sustain tumor cell survival, multiplication and subsequent growth. For the accomplishment of this aim, metabolic reprogramming in cancer cells is set in way so that cellular nitrogen and carbon repertoire can be utilized and channelized maximally towards anabolic reactions. A strategy to meet such outcome is to cut down unnecessary catabolic reactions and nitrogen elimination. Thus, transfigured urea cycle is a hallmark of neoplasia. During oncogenesis, altered expression and regulation of enzymes involved in urea cycle is a revolutionary approach meet to maximum incorporation of nitrogen for sustaining tumor specific biogenesis. Currently, we have reviewed neoplasm-specific deregulations of urea cycle-enzymes in different types and stages of cancers suggesting its context-oriented dynamic nature. Considering such insight to be valuable in terms of prospective cancer diagnosis and therapeutics adaptive evolution of deregulated urea cycle has been enlightened.

Correction: Mangiferin ameliorates collateral neuropathy in tBHP induced apoptotic nephropathy by inflammation mediated kidney to brain crosstalk.

Correction for 'Mangiferin ameliorates collateral neuropathy in tBHP induced apoptotic nephropathy by inflammation mediated kidney to brain crosstalk' by Sukanya Saha et al., Food Funct., 2019, 10, 5981-5999, https://doi.org/10.1039/C9FO00329K.

Genetic Underpinnings of Pulmonary Fibrosis: An Overview.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disorder, in which genetic and environmental factors are involved in disease onset. Although, by definition, the disease is considered idiopathic in nature, evidence-based studies have indicated familial cases of pulmonary fibrosis, in which genetic factors contribute to IPF pathogenesis. METHODS: Both common as well as rare genetic variants are associated with sporadic as well as familial forms of IPF. Although clinical inferences of the genetic association have still not been explored properly, observation-based studies have found a genotypic influence on disease development and outcome. RESULTS: Based on genetic studies, individuals with a risk of IPF can be easily identified and can be classified more precisely. Identification of genetic variants also helps to develop more effective therapeutic approaches. CONCLUSION: Further comprehensive research is needed to get a blueprint of IPF pathogenesis. The rapidly evolving field of genetic engineering and molecular biology, along with the bioinformatics approach, will possibly explore a new horizon very soon to achieve this goal.

Biological evaluation of the novel 3,3'-((4-nitrophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) derivative as potential anticancer agents via the selective induction of reactive oxygen species-mediated apoptosis.

Selective initiation of programmed cell death in cancer cells than normal cells is reflected as an attractive chemotherapeutic strategy. In the current study, a series of synthetic bis-coumarin derivatives were synthesized possessing reactive oxygen species (ROS) modulating functional groups and examined in four cancerous and two normal cell lines for their cytotoxic ability using MTT assay. Among these compounds, 3 l emerged as the most promising derivative in persuading apoptosis in human renal carcinoma cells (SKRC-45) among diverse cancer cell lines. 3 l causes significantly less cytotoxicity to normal kidney cells compared to cisplatin. This compound was able to induce apoptosis and cell-cycle arrest by modulating the p53 mediated apoptotic pathways via the generation of ROS, decreasing mitochondrial membrane potential, and causing DNA fragmentation. Unlike cisplatin, the 3 l derivative was found to inhibit the nuclear localisation of NF-κB in SKRC-45 cells. It was also found to reduce the proliferation, survival and migration ability of SKRC-45 cells by downregulating COX-2/ PTGES2 cascade and MMP-2. In an in vivo tumor model, 3 l showed an anticancer effect by reducing the mean tumor mass, volume and inducing caspase-3 activation, without affecting kidney function. Further studies are needed to establish 3 l as a promising anti-cancer drug candidate.

Fabrication of phenyl boronic acid modified pH-responsive zinc oxide nanoparticles as targeted delivery of chrysin on human A549 cells.

Recently, different natural bioactive compounds have been used as anticancer agents for their various therapeutic benefits and non-toxic nature to other organs. However, they have various restrictions in preclinical and clinical studies due to their non-targeting nature and insufficient bioavailability. As a result, a zinc oxide nanoparticle (ZnO) based drug delivery medium was constructed which has good bio-compatibility and bio-degradability. It also displays cancer cell-specific drug delivery in a targeted and controlled way. In the present study, phenylboronic acid (PBA) tagged ZnO nanoparticles (ZnO-PBA) was fabricated and in the next step, chrysin (a natural bio-active molecule) was loaded to it to form the nanoconjugate (ZnO-PBA-Chry). Different characterization techniques were used to confirm the successful fabrication of ZnO-PBA-Chry. PBA-tagging to the nanoparticle helps in targeted delivery of chrysin in lung cancer cells (A549) as PBA binds with sialic acid receptors which are over-expressed on the surface of A549 cells. As ZnO dissociates in acidic pH, it shows stimuli-responsive release of chrysin in tumor microenvironment. Application of ZnO-PBA-Chry nanohybrid in lung cancer cell line A549 caused oxidative stress mediated intrinsic cell death and cell cycle arrest. ZnO-PBA-Chry downregulated MMP-2 and VE-Cadherin, thereby inhibiting metastasis and the invasive property of A549 cells.

Melatonin counteracts necroptosis and pulmonary edema in cadmium-induced chronic lung injury through the inhibition of angiotensin II.

The renin-angiotensin system (RAS) is an important regulator in pulmonary physiology. In our study, we identified the efficacy of melatonin to control the RAS in cadmium (Cd) induced chronic lung injury in a mouse model. Swiss albino mice exposed to CdCl2 intraperitoneally (I.P.) (1 mg/kg b.w.; 12 weeks) showed increased release of lactate dehydrogenase in bronchoalveolar lavage fluid, generating reactive oxygen species, impaired antioxidant enzymes function, and disrupted alveolar structure along with increased expression of Angiotensin-II (Ang-II) in lung tissue. Cd-induced angiotensin-converting enzyme-2-Ang-II axis imbalance triggered the onset of Ang-II induced tumour necrosis factor alpha  (TNF-α) mediated necroptosis by upregulating the signalling molecules RIP-1, RIP-3, and p-mixed lineage kinase domain-like. In an in vitro study, colocalization of Ang-II-RIP-3 molecule in Cd intoxicated L-132 cells (human alveolar epithelial cell line), as well as pretreatment of Cd exposed cells with the inhibitor's captopril (10 µM), necrostatin-1 (50 µM), and etanercept (5 µg/ml) indicated TNF-α induced necroptotic cell death via activation of the key molecule, Ang-II. Moreover, Ang-II disrupted the alveolar-capillary barrier by decreasing tight junctional proteins (zonula occludens-1 and occludin) and endothelial VE-cadherin expression. The use of human umbilical vein endothelial cells as a model of junctional protein-expressing cells showed that captopril pretreatment (25 µM) restored VE-cadherin expression in Cd-treated human umbilical vein endothelial cells. In CdCl2 intoxicated mice, melatonin pretreatment (10 mg/kg b.w.; 12 weeks, I.P.) inhibited inflammatory mediators (TNF-α, interleukin [IL]-1ß, and IL-6) release and effectively suppressed (Cd-induced) Ang-II mediated necroptotic cell death and alveolar-capillary breaching due to Cd toxicity.

Enhancement of anti-neoplastic effects of cuminaldehyde against breast cancer via mesoporous silica nanoparticle based targeted drug delivery system.

AIMS: Synthesis of novel drug delivery system for targeted delivery of cuminaldehyde to breast cancer cells and the subsequent analyses of anti-neoplastic potential of the drug. MAIN METHODS: 3-carboxy-phenyl boronic acid (PBA) conjugated and polyacrylic acid (PAA) gated mesoporous silica nanoparticles (MSNs) were synthesized for the targeted delivery of cuminaldehyde (CUM) to breast cancer cells. Enhancement of anti-neoplastic effects of cuminaldehyde (4-isopropylbenzaldehyde) by the nanoconjugates was assessed. KEY FINDINGS: The anti-cancer effects of non-targeted and targeted drug-nanoconjugates were examined in vitro and in vivo. The targeted drug-nanoconjugates caused cell cycle arrest and induced the intrinsic pathway of apoptosis in MCF-7 cells through mitochondrial damage. In vivo intravenous injection of the targeted drug-nanoconjugates led to effective reduction in growth of 4 T1 induced mammary pad tumor in female BALB/c mice via augmented accumulation of cuminaldehyde. The drug-nanoconjugates did not exhibit any systemic toxicity. SIGNIFICANCE: Therefore, MSN-PBA-CUM-PAA represents a potent therapeutic model for breast cancer treatment.

Diabetes: discovery of insulin, genetic, epigenetic and viral infection mediated regulation.

Diabetes mellitus, commonly referred to as diabetes, is a combination of many metabolic diseases. Insulin deficiency in our body is the main cause of diabetes. Insulin is one of the most well studied proteins, yet the genesis of its discovery was not getting much attention so far. Nevertheless, the history of the discovery of insulin is an exemplary of solving observational and scientific riddles, drudgery, patience and even professional turmoil. It is an inspiration for all medical personnel and scientists who are practising in the field of molecular medicine. Additionally, the genetic and epigenetic regulation of different types of diabetes needs to be addressed because of the widespread nature of the disease. Diabetes not only involves genetic predisposition but environmental factors, lifestyle etc. can be the major contributor for its inception. Nonetheless, viral infections at an early age are also found to trigger the onset of type I diabetes. In this review article, the history of the discovery of insulin is detailed along with the justification for the genetic and epigenetic regulatory mechanisms of diabetes and explained how viral infections can also trigger the onset of diabetes.

Melatonin induced suppression of ER stress and mitochondrial dysfunction inhibited NLRP3 inflammasome activation in COPD mice.

In recent decades, the occurrence of chronic obstructive pulmonary disease (COPD) has been increased remarkably in the population. Cigarette smoke (Cs) plays one of the key roles for COPD development. In our study, we explored the ameliorative role of melatonin on COPD progression by using a Cs inhaled in vivo COPD and cigarette smoke extract (CSE)-treated in vitro L-132 (alveolar epithelial cell) models. Mice exposed to Cs (4hr/day for 4 weeks) exhibited abrupt increase of lactate dehydrogenase (LDH) level in broncho alveolar lavage fluid (BALF) and disrupted alveolar structure in lung tissue. Additionally, increased reactive oxygen species (ROS), decreased cellular antioxidant status with reduced GSH/GSSG ratio were also found in Cs exposed lung. Besides, Cs induced endoplasmic reticulum (ER) stress and mitochondrial dysfunctions causing the activation of NLRP3 inflammasome. Activated NLRP3 inflammasome caused Caspase-1 mediated release of IL-1ß and IL-18 resulting in inflammatory outburst. Melatonin showed protection against COPD both in vitro and in vivo. Exhibiting its anti-inflammatory potential, melatonin also attenuated the lung inflammation. It activated the intracellular antioxidant Thioredoxin-1 (thereby suppressing the TXNIP/NLRP3 pathway) and inhibited the impaired mitophagy mediated inflammasome activation (upregulating PINK-1, Parkin, LC3B-II expression). Melatonin also improved the overall antioxidant status of the COPD lung via NRF-2-HO-1 axis restoration.

Matrix metalloproteinase: An upcoming therapeutic approach for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that the level of different kinds of matrix metalloproteinases might be downregulated in IPF as it is a matrix degrading collagenase. However, the role of some matrix metalloproteinases (MMPs) is profibrotic where others have anti-fibrotic functions. These profibrotic MMPs effectively promote fibrosis development by stimulating the process of epithelial to mesenchymal transition. These profibrotic groups also induce macrophage polarization and fibrocyte migration. All of these events ultimately disrupt the balance between profibrotic and antifibrotic mediators, resulting aberrant repair process. Therefore, inhibition of these matrix metalloproteinases functions in IPF is a potential therapeutic approach. In addition to the use of synthetic inhibitor, various natural compounds, gene silencing act as potential natural MMP inhibitor to recover IPF.

Fluorescent Terpolymers via In Situ Allocation of Aliphatic Fluorophore Monomers: Fe(III) Sensor, High-Performance Removals, and Bioimaging.

Herein, purely aliphatic intrinsically fluorescent terpolymers, i.e., 1 and 2, are synthesized through one-pot solution polymerization via N-H functionalized and multi C-C/C-N coupled in situ protrusion of fluorescent monomers using two nonemissive monomers. These scalable terpolymers are suitable for highly selective Fe(III) sensing, high-performance exclusion of Fe(III), logic function and the imaging of normal mammalian Madin-Darby canine kidney and human osteosarcoma cancer cell lines. The structures of terpolymers, in situ attachment of fluorescent monomers, clusteroluminescence, adsorption-mechanism, and cell-imaging abilities are understood via unadsorbed and/or adsorbed microstructural analyses using 1 H/13 C NMR, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, UV-vis spectroscopy, atomic absorption spectroscopy, thermogravimetric analysis, high-resolution transmission electron microscopy, dynamic light scattering, fluorescence imaging, and fluorescence lifetime. The geometries, electronic structures, location of fluorophores, and singlet-singlet absorption and emission of terpolymers are examined using density functional theory (DFT) and time-dependent DFT. For the precise identification of fluorophores, transition from occupied natural transition orbitals (NTOs) to unoccupied NTOs is computed. For 1/2, limit of detection (LOD) values and adsorption capacities are 6.0 × 10-7 /8.0 × 10-7 m and 147.82/120.56 mg g-1 at pHi = 7.0 and 303 K, respectively. The overall properties of 1 are more advantageous compared to 2 in sensing, cell imaging, and adsorptive exclusion of Fe(III).

Mangiferin ameliorates collateral neuropathy in tBHP induced apoptotic nephropathy by inflammation mediated kidney to brain crosstalk.

The kidneys and brain share similarities in anatomy and vaso-regulation and exhibit clinical interactions in various diseases. To investigate the probable mechanism of kidney to brain crosstalk, we developed an in vivo model of renal injury in mice through intoxication with the oxidative stress inducer, tBHP. Proteinuria, abnormalities in the renal tubules and KIM1 activation were found in tBHP intoxicated animals. Due to this renal pathophysiology, various pro-inflammatory molecules (TNF-α, IL-1ß, IL-6, ICAM-1, VCAM-1) especially TNF-α, entered into the brain from kidneys, triggering cerebral inflammatory cascades leading to behavioral anomalies in association with membrane lipid peroxidation, BBB disruption and brain morphological alterations. Moreover, increased levels of reactive oxygen species, decreased antioxidant enzyme activity and an altered GSH/GSSG ratio were found in both these organs. Here, we introduced mangiferin as a protective molecule because of its anti-inflammatory and antioxidant properties. Mangiferin via inhibition of apoptosis and activation of the PI3K/Akt pathway protected the kidneys. It restored the deleterious phenomena in the damaged brain by downregulating the JNK and p38MAPK mediated pro-apoptotic cascade and activating the intracellular antioxidant thioredoxin, thereby protecting against tBHP induced nephropathy mediated neuropathophysiology.

Natural products: An upcoming therapeutic approach to cancer.

Cancer is one of the leading causes of death across the world. Different environmental and anthropogenic factors initiate mutations in different functional genes of growth factors and their receptors, anti-apoptotic proteins, self-renewal developmental proteins, tumor suppressors, transcription factors, etc. This phenomenon leads to altered protein homeostasis of the cell which in turn induces cancer initiation, development, progression and survival. From ancient times various natural products have been used as traditional medicine against different diseases. Natural products are readily applicable, inexpensive, accessible and acceptable therapeutic approach with minimum cytotoxicity. As most of the target-specific anticancer drugs failed to achieve the expected result so far, new multi-targeted therapies using natural products have become significant. In this review, we have summarized the efficacy of different natural compounds against cancer. They are capable of modulating cancer microenvironment and diverse cell signaling cascades; thus playing a major role in combating cancer. These compounds are found to be effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway and Hedgehog pathway). This review article is expected to be helpful in understanding the recent progress of natural product research for the development of anticancer drug.

Mangiferin alleviates arsenic induced oxidative lung injury via upregulation of the Nrf2-HO1 axis.

Arsenic contaminated drinking water consumption is a serious health issue around the world. Chronic inorganic arsenic exposure has been associated with respiratory dysfunctions. It exerts various detrimental effects, disrupting normal cellular homeostasis and turning on severe pulmonary complications. This study elucidated the role of mangiferin, a natural xanthone, against arsenic induced lung toxicity. Chronic exposure of sodium arsenite (NaAsO2) at 10 mg/kg bw for 3 months abruptly increased the LDH release in broncho-alveolar lavage fluid, generated reactive oxygen species (ROS), impaired the antioxidant defense and distorted the alveoli architecture. It caused significant inflammatory outburst and promoted the apoptotic mode of cell death via upregulating the expressions of various proapoptotic molecules related to mitochondrial, extra-mitochondrial and ER stress mediated apoptotic pathway. Activation of inflammatory cascade led to disruption of alveolar capillary barrier and impaired Na+/K+-ATPase function that led to detaining of alveolar fluid clearance activity. Mangiferin due to its anti-inflammatory activity suppressed this inflammation and reduced inflammatory cell infiltration in lung tissue. It significantly restored the antioxidant balance and inhibited apoptosis in lung via upregulating Nrf2-HO1 axis.

Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice.

Arsenic is a potent inducer of several acute and chronic nephrotoxic disorders. It promotes deleterious phenomenon like oxidative stress, inflammation, cell death and altered glucose uptake leading to distorted kidney homeostasis that end up in chronic kidney disease. This study investigated the possible protective role of melatonin; a natural antioxidant produced by the pineal gland, against arsenic induced nephrotoxicity. Melatonin successfully ameliorated arsenic induced renal toxicity both in in vitro and in vivo models. Elevated BUN, creatinine, urine glucose and protein levels and altered renal histopathological conditions were observed in arsenic intoxicated mice. Significant oxidative stress induced damage of biomolecules along with downregulation in antioxidant enzymes and thiols were also detected in the kidney tissues of arsenic-intoxicated mice. These alterations along with mitochondrial dysfunction ultimately triggered TNFα mediated inflammatory and cell death cascades. Interestingly arsenic also led to disruption of glucose uptake in the kidney. These findings suggest that melatonin protects the kidney against toxic effect of arsenic, presumably through its antioxidant, anti-inflammatory and antidiabetic properties by inhibiting inflammatory outburst, apoptosis, necroptosis and stimulating glucose uptake. As melatonin is a natural antioxidant molecule, detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as an effective nephro-protective agent in future.

Ameliorative role of genistein against age-dependent chronic arsenic toxicity in murine brains via the regulation of oxidative stress and inflammatory signaling cascades.

Brain is highly prone to oxidative damage due to its huge lipid content and extensive energy requirements. Exogenous insult in brain via oxidative injury can lead to severe pathophysiological conditions. Age-dependent deterioration of normal brain functions is also noteworthy. Genistein, a polyphenolic isoflavonoid, obtained from the soy plant, is well known to protect against several diseased conditions. Here, in this study chronic brain toxicity model was developed using oral administration of arsenic for 90 days in adult and aged murines. We observed that intraperitoneal administration of genistein improved the arsenic induced behavioral abnormalities in the rats. It was also evident from the histopathological studies that the extent of tissue damage due to arsenic exposure was more in aged rats compared to the adults. Evaluation of different stress markers, intracellular ROS level and mitochondrial membrane potential revealed the involvement of oxidative stress and mitochondrial dysfunction in inducing brain damage in arsenic exposed murines. It was observed that genistein can significantly ameliorate the stressed condition in both the animal groups but the protective effect of genistein was more significant in the adult animals. The underlying signalling mechanism behind the cytotoxicity of arsenic was investigated and revealed that genistein exhibited neuroprotection significantly by modulating the JNK3 mediated apoptosis, ERK1/2 mediated autophagy and TNFα associated inflammatory pathways. Overall study infers that genistein has significant ameliorative effect of against age-dependent cytotoxicity of arsenic in murine brains.

Nutraceuticals: An emerging therapeutic approach against the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is regarded as a progressive and devastating neurodegenerative disorder. In aged individuals, it is the most prevalent cause of dementia and is characterized by gradual loss of cognitive functions. In the last decade, numerous research works were undertaken to investigate the pathogenesis of AD. Although the etiology of AD is still not clear, several histopathological studies confirm prominent changes in the AD affected brains. The major changes include the formation of senile plaques and neurofibrillary tangles primarily owing to the deposition of amyloid ß plaques (Aß) and hyper-phosphorylation of tau protein. Disruption of the redox homeostasis in the brain is a major triggering factor for the development of such pathophysiological conditions. Chemical formulations usually act by inhibiting activities of the enzymes responsible for the development of AD. But with time, these pharmacotherapies develop many side effects including toxicity in different organs. Recent researches are henceforth focused on the identification of novel therapeutic molecules from the nature's basket. This review aims to emphasize the therapeutic effects and regulation of molecular targets of different natural products such as curcumin, resveratrol, genistein and others. These prophylactic multipotent natural compounds have the potency to interfere with the formation as well as deposition of the Aß peptides. These natural compounds have also been found in modulating different intracellular signalling molecules and enzymes including ß-secretase and γ-secretase. This review article is expected to be helpful in understanding the recent progress in natural product research as a therapeutic approach in amelioration and/or delaying the detrimental effects of AD.