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Background:Retinal ganglion cells (RGCs) are highly energy dependent due to their continuous action potential firing requirements and long unmyelinated axons hence highly susceptible to mitochondrial dysfunctions, observed in glaucoma. Dr. Das’s lab recently had identified Tank-binding kinase 1 (TBK1) inhibition by BX795 drug activates mitochondrial biogenesis and promotes RGC protection with glaucomatous Optineurin (OPTN-E50K) mutation. OPTN is a critical player for mitophagy. It is still not clear if activation of mito-biogenesis improved mitochondrial homeostasis which I investigated in this project.MethodsTo investigate mitochondrial homeostasis in human RGCs, I have used a robust well-characterized human stem cell differentiated RGC (hRGC) model with wild-type (WT) and E50K mutation background which Dr. Das’s lab routinely uses. To investigate mitochondrial homeostasis, I used JC1 live cell mitochondrial dye which fluoresces red when bound to healthy mitochondria and green when bound to damaged mitochondria. I used this assay on hRGCs treated with BX795 and mitochondrial stressor CCCP and measured red to green mitochondria ratio on confocal z-stacks using ImageJ.ResultsUnder basal level, we found hRGCsWT had a significantly increased healthy (red:green) mitochondria compared to hRGCsE50K. This suggests E50K mutation disrupts mitochondrial homeostasis. To gain mitochondrial homeostasis, it is possible that hRGCsE50K will produce more mitochondria over time than the WT. Indeed, we observed significant increase in healthy mitochondria for hRGCsE50K at 3h and 24h of DMSO and BX795 treatment, but not for hRGCsWT. We also observed under CCCP damage for 3h, hRGCsE50K had significantly higher amount of damaged mitochondria (p=0.051) while hRGCsWT maintained homeostasis.Conclusion and Potential ImpactMy study suggests glaucomatous OPTN-E50K mutation disrupts mitochondrial homeostasis and activation of mito-biogenesis by BX enriches healthy mitochondria leading to hRGCE50K protection. This study has high impact as further avenues for promoting mito-biogenesis could lead to glaucoma neuroprotection therapy.

Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding on how to improve mitochondrial homeostasis to promote neuroprotection. Here we used human stem cell differentiated retinal ganglion cells (hRGCs) of the CNS, which are highly sensitive towards mitochondrial dysfunctions due to their unique structure and function, to identify mechanisms for improving mitochondrial quality control (MQC). We found that hRGCs are efficient in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria under acute damage. Using a glaucomatous Optineurin mutant (E50K) stem cell lines, we saw that at basal level mutant hRGCs possess less mitochondrial mass and suffer mitochondrial swelling due to excess ATP production load. Activation of mitochondrial biogenesis through pharmacological inhibition of the Tank binding kinase 1 (TBK1) restored energy homeostasis, mitigated mitochondrial swelling with neuroprotection against acute mitochondrial damage for glaucomatousE50KhRGCs, revealing a novel neuroprotection mechanism.

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 CdCl

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.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.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.Therefore, MSN-PBA-CUM-PAA represents a potent therapeutic model for breast cancer treatment.

The nonconventional purely aliphatic scalable and reusable fluorescent guar gum (GRGM)

The nonconventional purely aliphatic scalable and reusable fluorescent guar gum (GRGM)-grafted-acrylic acid-co-3-(N-isopropylacrylamido)propanoic acid (NIPAPA)-co-N-isopropylacrylamide (GRGM-grafte...

Asiatic acid (AA), an aglycone of pentacyclic triterpene glycoside, obtained from the leaves of Centella asiatica exerts anticancer effects by inhibiting cellular proliferation and inducing apoptosis in a wide range of carcinogenic distresses. However, its chemotherapeutic efficacy is dampened by its low bioavailability. Polymeric nanoparticles (NPs) exhibit therapeutic efficacy and compliance by improving tissue penetration and lowering toxicity. Thus, to increase the therapeutic effectiveness of AA in the treatment of breast cancer, AA-loaded poly lactic-co-glycolic acid (PLGA) NPs (AA-PLGA NPs) have been formulated. The AA-PLGA NPs were characterized on the basis of their average particle size, zeta potential, electron microscopic imaging, drug loading, and entrapment efficiency. The NPs exhibited sustained drug release profile in vitro. Developed NPs exerted dose-dependent cytotoxicity to MCF-7 and MDA-MB-231 cells without damaging normal cells. The pro-oxidant and pro-apoptotic properties of AA-PLGA NPs were determined by the study of the cellular levels of SOD, CAT, GSH-GSSG, MDA, protein carbonylation, ROS, mitochondrial membrane potential, and FACS analyses on MCF-7 cells. Immunoblotting showed that AA-PLGA NPs elicited an intrinsic pathway of apoptosis in MCF-7 cells. In vivo studies on female BALB/c mice exhibited reduced volume of mammary pad tumor tissues and augmented expression of caspase-3 when administered with AA-PLGA NPs. No systemic adverse effect of AA-PLGA NPs was observed in our studies. Thus, AA-PLGA NPs can act as an efficient drug delivery system against breast cancer.

The nonconventional purely aliphatic intrinsically fluorescent multifunctional terpolymers, such as 2-acrylamido-2-methylpropane sulfonic acid-co-2-(3-acrylamidopropylamido)-2-methylpropane sulfoni...

Phytoestrogens (PEs) are natural estrogen-like substances. They are subdivided into four main classes: isoflavones, lignans, stilbenes (polyphenols), and coumestans. PEs are broadly distributed in regular diet and herbs. They have multiple targets within cells, including the epigenome, that could be advantageous to the development of a chemopreventive drug. Breast cancer is one of the most common cancers found in women. It is the second leading cause of cancer-related death after lung cancer. Chemoprevention using PEs against breast cancer may be an effective approach. PEs have shown anticancer activity via mechanisms, including modulation of estrogen receptors (ERs), redox homeostasis, cell signaling pathways, regulation of the cell cycle, and inhibition of enzyme, angiogenesis, and epigenetic alterations. PEs can bind inadequately to ERs and have a special affinity for ER-β that can inhibit the transcriptional activity of ER-α. Genistein, daidzein, and resveratrol are some of the well-studied PEs. There are some critical issues in developing PEs as effective chemopreventive agents for breast cancer. Still, the multiple targets in breast cancer cells and their capability to modulate the cancer cell homeostasis may lead to the development of new, nontoxic, long-acting, and highly specific therapeutic agents.

Neurodegenerative diseases are one of the major health concerns at present in the older age population across the globe. Reports suggest that aberrant production of mutated form of protein aggregates in the brain leads to onset of these diseases. Till date, the well-studied neurodegenerative diseases are Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and Amyotrophic lateral sclerosis (ALS). Mitochondrial dysfunction, reactive oxygen species accumulation, neuroinflammation, and apoptosis are the hallmarks of pathophysiological response of neurodegenerative diseases. The pharmacotherapies available to alleviate the symptoms of these diseases have several side effects. In this scenario, several natural compounds found in edible items, termed as nutraceuticals, are gaining ground on account of their pleiotropic antioxidant and antiinflammatory properties, and their ability to modulate the activities of kinases and phosphatases. Herein, we focus on the mechanism of various neurodegenerative diseases and the mechanisms of well-known natural components enriched in dietary substances.

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-1β 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.

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.

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-1β, 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.

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.

Curcumin (C) is a natural antioxidant which has many beneficial effects. However, poor bioavailability and less water solubility render it unsuitable as an anti-cancer drug. Herein, curcumin was delivered through Mesoporous silica nanoparticle (MSN) based drug delivery system to enhance its anticancer efficacy. Targeted delivery of curcumin in cancer cells was also achieved by conjugating hyaluronic acid (HA) on the surface of MSN. HA showed its targeting ability through the binding with CD-44 receptors in cancer cells. The synthesis of MSN-HA-C was verified by used several characterization techniques like TEM, SEM, XRD and DLS. MSN-HA-C showed diameter of ∼ 75 nm with negatively charged surface and drug loading content of 14.76 %. The synthesized nanohybrid showed MDA-MB-231 cell death by the induction of ROS, cell cycle arrest and modulation of NF-κB and Bax mediated apoptotic pathway. The nanohybrid also effectually decreased tumor volume in tumor-bearing mice compared with free C due to the increased bioavailability and higher cellular uptake of C in tumor tissue. Overall, the study offered that MSN-HA-C has increased anticancer efficacy than that of free curcumin.

Arthritis is a distinguished inflammatory disease whose onset is mostly proportional with increasing age. Its prominent symptoms include joint pain, stiffness, and decreased range of motion of the affected joints, as well as redness, warmth, and swelling in the joint. Among several kinds of arthritis, rheumatoid arthritis is most fatal kind of inflammatory joint disease affecting people worldwide. Rheumatoid arthritis is a painful autoimmune disease that leads to synovial fibroblast hyperproliferation and massive infiltration of inflammatory immune cells, including CD4+ T cells and innate immune cells such as macrophages, into the joints. Various proinflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-10, and IL-18 promote autoimmunity, chronic inflammation, and tissue destruction. Major anti-inflammatory drugs (such as non-steroidal anti-inflammatory drugs and corticosteroids) suppress inflammation-induced pain by inhibiting the activation and production of various enzymes (such as cyclooxygenase [COX]-1 and COX-2), cytokines (such as TNF-α and IL-1β), and transcription factors (such as nuclear factor-κB [NF-κB], c-Jun N-terminal kinases, and p38 kinases). The negative impacts of such anti-inflammatory medications are adverse effects including Cushing habitus, hypertension, hyperglycemia, gastrointestinal ulceration, and bleeding. Alternatives to these drugs are traditional medicines and natural products, which via their ameliorative activity and minimal side effects offer great hope as promising therapeutic candidates. This further spurs the identification of potential bioactive compounds and their development into drugs to treat this inflammatory disease. Several polyphenolic compounds, terpenoids, and alkaloids are well-known to exhibit significant anti-inflammatory activity in vivo as well as in vitro. They induce the apoptosis of activated T cells and effector T cells and inhibit the expression of proinflammatory genes (IL-1β, IL-6, and TNF-α), chemokines (chemokine [C-C motif] ligand [CCL]-2/monocyte chemoattractant protein [MCP]-1, CCL-7/MCP-3), and enzymes (COX-1 and COX-2). They interfere with receptor activator of nuclear factor κ-B ligand–mediated osteoclast differentiation by downregulating mitogen-activated protein kinases and the NF-κB pathway and suppressing nuclear factor of activated T cells, cytoplasmic 1, tartrate-resistant acid phosphatase, and osteoclast-associated immunoglobulin-like receptor messenger RNA expression to prevent the progression of this disease. Some of them also hinder arthritic progression and improve the histology of affected joints by decreasing lipid peroxidation and increasing the level of antioxidants (such as superoxide dismutase, catalase, glutathione, and glutathione peroxidase) as well as Heme oxygenase-1 expression levels.

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.

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.

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 β plaques (Aβ) 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 Aβ peptides. These natural compounds have also been found in modulating different intracellular signalling molecules and enzymes including β-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.

Oxidative stress is a critical factor for the development of cancer via inducing DNA mutations, damage, and genome instability. Different signaling pathways associated with the progression of cancer can modulate the intracellular level of reactive oxygen species (ROS). The level of intracellular ROS is usually high in cancer cells compared to different normal cell types due to abnormal functionality of different genes and perturbed metabolic activity facilitating extensive cellular proliferation. Among a few therapeutic options practiced recently, chemotherapy is the most effective so far. Despite its antitumor efficacy, treatment procedures of chemotherapy have several major side effects and this provokes the scientists for developing novel therapeutic option with minimum toxicity. Different naturally occurring polyphenolic compounds exhibit potential anti-oxidative, anti-inflammatory, and pro-apoptotic effect in several anticancer studies. The use of different polyphenolic compounds to target the redox status of the cell is a very promising strategy. These pleotropic polyphenolic compounds have been widely documented to modulate different signaling pathways in cancer cells either directly or indirectly. In this comprehensive review, we have summarized the anti-proliferative and pro-apoptotic properties of different polyphenolic compounds in various in vitro and in vivo cancer models.

Proteases in normal cells are important in performing essential biological processes in living systems. A balance between proteases and their inhibitors occurs for normal physiological functions and any disturbance of this balance usually leads to many diseases. The neuronal diseases are one of them. In this chapter, we will focus on the role of proteases and some protease inhibitors in various neurological disorders. Here, we would like to discuss about the role of different proteases (serine protease, cysteine protease, aspartic protease, matrix metallo protease, etc.) in neuropathology, like neuropathy, neuroinflammation, and also some neurological diseases, namely, Alzheimer’s disease and Parkinson’s disease. At the end of this chapter, we will also discuss about the involvement of serine proteases and their inhibitors in overall neurological disorder.

Ferulic acid, a natural phytochemical has gained importance as a potential therapeutic agent by virtue of its easy commercial availability, low cost and minimal side-effects. It is a derivative of curcumin and possesses the necessary pharmacokinetic properties to be retained in the general circulation for several hours. The therapeutic effects of ferulic acid are mediated through its antioxidant and anti-inflammatory properties. It exhibits different biological activities such as anti-inflammatory, anti-apoptotic, anti-carcinogenic, anti-diabetic, hepatoprotective, cardioprotective, neuroprotective actions, etc. The current review addresses its therapeutic effects under different pathophysiological conditions (eg. cancer, cardiomyopathy, skin disorders, brain disorders, viral infections, diabetes etc.).