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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.

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 mortality rate due to malaria has increased tremendously in the last decade. Even though the causative agent of this disease is known, the preventive measures are not potent enough to control the spread of this disease. Malarial infection involves a strong interrelationship between oxidative stress and pathogenesis. This review addresses the various oxidative stress-related mechanisms associated with vector defense, host immunity, plasmodial pathogenesis, and corresponding therapeutic strategies. The mechanisms involving host and vector defense show both similarity and contradiction to the processes involving plasmodial pathogenesis under different circumstances. Therefore, corresponding ameliorative peculiarities are observed in the therapeutic mechanisms adopted by the anti-malarial drugs. The malarial parasite augments oxidative stress to weaken the host and exerts antioxidant effects against host defense mechanisms. However, the anti-malarial drugs induce oxidative insult to reduce parasitic load and exert antioxidant effects against parasite infection-induced oxidative stress in host. Thus, the anti-malarial drugs exhibit antioxidant activity in hosts and/or pro-oxidant activity in parasites.

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.

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.

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.

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.

Heat shock proteins (HSP) also referred to as stress proteins are a family of proteins produced by cells in response to exposure to stressful conditions like heat, cold, different kinds of environmental stress, such as infection, inflammation, exercise, exposure of the cell to toxins (ethanol, arsenic, trace metals, and UV light, among many others), starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants), water deprivation and during wound healing or tissue remodeling. In this review, the authors have elucidated the role of heat shock proteins in stress tolerance both in eukaryotes and prokaryotes. Here, the role of heat shock proteins in survival during more extreme conditions and maintenance of normal cellular homeostasis have also been briefly discussed.

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.

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.

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).