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Thymol is a plant-derived natural phenolic compound abundantly present in Thymus vulgaris species. In the present study, we developed a chitosan-based drug delivery system to deliver thymol to A549 cells. The physicochemical properties of thymol-loaded chitosan nanoparticles (thymol-NP) were characterized using polyphasic techniques viz., FTIR, XRD, DLS, and SEM. Thymol-NP exhibited a size of 282.5 nm and encapsulation efficiency of 74.08 ± 0.73%. The IC

Currently, the world is facing a pandemic of the new coronavirus SARS-CoV-2 that causes COVID-19. Identifying key targets in the viral infection lifecycle is urgently needed for designing therapeutic strategies to combat the virus. Furin is a subtilisin-like proprotein convertase with diverse cellular functions. Emerging evidence suggests that furin plays a critical role in the activation and/or infectivity of SARS-CoV-2. In this perspective, we discuss the potential role of furin in the entry SARS-CoV-2 into host cells. Furthermore, we evaluate available peptide and non-peptide furin inhibitors and potential outcomes, including immune responses.

The human oral cavity is comprised of dynamic and polynomial microbes which uniquely reside in the microenvironments of oral cavities. The cumulative functions of the symbiotic microbial communities maintain normal homeostasis; however, a shifted microbiota yields a dysbiosis state, which produces local and systemic diseases including dental caries, periodontitis, cancer, obesity and diabetes. Recent research reports claim that an association occurs between oral dysbiosis and the progression of different types of cancers including oral, gastric and pancreatic ones. Different mechanisms are proposed for the development of cancer, such as induction of inflammatory reactions, production of carcinogenic materials and alteration of the immune system. Medications are available to treat these associated diseases; however, the current strategies may further worsen the disease by unwanted side effects. Natural-derived polyphenol molecules significantly inhibit a wide range of systemic diseases with fewer side effects. In this review, we have displayed the functions of the oral microbes and we have extended the report regarding the role of polyphenols in oral microbiota to maintain healthy conditions and prevention of diseases with emphasis on the treatment of oral microbiota-associated cancer.

Alzheimer's disease (AD) etiology has been studied for a long time and it is found to be multifaceted involving the accumulation of amyloid β and tau protein. Oxidative stress is an early event in AD associated neurodegeneration provoking neuronal death through mitochondrial dysfunction and activation of caspase-3. Therefore we tested the efficacy of dihydroactinidiolide (DHAc), a monoterpene lactone against the oxidative load involved in AD like pathological conditions induced by sodium dithionite, glutamate, amyloid β and colchicine in SH-SY5Y cells. Some of the indicators of neurotoxicity like acetylcholinesterase activity, intracellular reactive oxygen species (ROS), nitrite content, lipid peroxidation, protein carbonylation, nuclear and membrane damage were found to be significantly high in the toxicant treated cells when compared to the control cells while DHAc pretreatment significantly restored the toxicant induced neuronal damage signatures. Caspase-3 activity was found to be increased in the toxicant treated cells while DHAc significantly reduced it. Western blotting and RT-PCR revealed that DHAc significantly increased anti-apoptotic Bcl-2 expression and mRNA levels of Nrf2 and HO-1. Therefore DHAc was found to protect SH-SY5Y cells from neurotoxicant induced oxidative stress and apoptosis by regulating cellular antioxidant defenses and apoptosis related genes.

Thymol is a monoterpene phenol found in thyme species plants. The present study was carried out to investigate the effect of thymol and its molecular mechanism on non-small lung cancer (A549) cells. The cytotoxic effect of thymol on A549 cells was assessed via MTT assay. ROS production, macromolecular damage, apoptosis were determined using DCF-DA, PI, AO/EtBr stains, respectively. ROS-dependent effect of thymol was confirmed using NAC. The expression of caspase-9, Bcl-2, Bax and cell cycle profile was analyzed via western blot and FACS, respectively. The antiproliferative effect of thymol on A549 cells was found to be both dose and time dependent with IC50 values of 112 μg/ml (745 μM) at 24 h. Thymol treatment favored apoptotic cell death and caused G0/G1 cell cycle arrest. It mediated cellular and nuclear morphological changes, phosphatidylserine translocation, and mitochondrial membrane depolarization. Additionally, upregulation of Bax, downregulation of Bcl-2, and apoptotic fragmented DNA were also observed. Thymol induced ROS by reducing the SOD level which was confirmed via in vitro and in silico analysis. Furthermore, the levels of lipid peroxides and protein carbonyl content were elevated in thymol-treated groups. Notably, N-acetyl cysteine pretreatment reversed the efficacy of thymol on A549 cells. Moreover, thymol-treated human PBMC cells did not show any significant cytotoxicity. Overall, our results confirmed that thymol can act as a safe and potent therapeutic agent to treat NSCLC.

Alzheimer's disease (AD) is an acquired neurological disorder of cognitive and behavioral impairments, with a long and progressive route. Currently, efforts are being made to develop potent drugs that target multiple pathological mechanisms that drive the successful treatment of AD in human beings. The development of nano-drug delivery systems has recently emerged as an effective strategy to treat AD.In the present study, the protective effect of Phytol and Phytol loaded Poly Lactic-co-Glycolic Acid nanoparticles (Phytol-PLGANPs) were evaluated in Wistar rat scopolamine model of AD.The consumption of Phytol and Phytol-PLGANPs significantly ameliorated the cognitive deficits caused by scopolamine on spatial and short term memory. Phytol and Phytol-PLGANPs significantly enhanced the cholinergic effect by inhibiting both acetylcholinesterase and butyrylcholinesterase (AChEBuChE), β-secretase 1 (BACE1) activity, attenuating macromolecular damage, reducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) level by activating antioxidative defense system (Superoxide dismutase and catalase) and restoring glutathione metabolizing enzyme systems (Glutathione S-transferase) and also regulating the apoptotic mediated cell death. Moreover,Overall, the outcome of the study suggests that Phytol and Phytol-PLGANPs act as a potent candidate with better anti-amnesic effects and multi-faceted neuroprotective potential against scopolamine-induced memory dysfunction in Wistar rats.

Vascular diseases arise due to vascular endothelium dysfunction in response to several pro-inflammatory stimuli and invading pathogens. Thickening of the vessel wall, formation of atherosclerotic plaques consisting of proliferating smooth muscle cells, macrophages and lymphocytes are the major consequences of impaired endothelium resulting in atherosclerosis, hypercholesterolemia, hypertension, type 2 diabetes mellitus, chronic renal failure and many others. Decreased nitric oxide (NO) bioavailability was found to be associated with anomalous endothelial function because of either its reduced production level by endothelial NO synthase (eNOS) which synthesize this potent endogenous vasodilator from L-arginine or its enhanced breakdown due to severe oxidative stress and eNOS uncoupling. Polyphenols are a group of bioactive compounds having more than 7000 chemical entities present in different cereals, fruits and vegetables. These natural compounds possess many OH groups which are largely responsible for their strong antioxidative, anti-inflammatory antithrombotic and anti-hypersensitive properties. Several flavonoid-derived polyphenols like flavones, isoflavones, flavanones, flavonols and anthocyanidins and non-flavonoid polyphenols like tannins, curcumins and resveratrol have attracted scientific interest for their beneficial effects in preventing endothelial dysfunction. This article will focus on in vitro as well as in vivo and clinical studies evidences of the polyphenols with eNOS modulating activity against vascular disease condition while their molecular mechanism will also be discussed.

The inhibition of Aβ peptide development and aggregation is a hopeful curative approach for the discovery of disease modifying drugs for Alzheimer's disease (AD) treatment. Recent research mainly focuses on the discovery of drugs from marine setting due to their immense therapeutic potential. The present study aims to evaluate the brown macroalga Padina gymnospora and its active constituent α-bisabolol against Aβ25-35 induced neurotoxicity in Neuro2a cells and transgenic Caenorhabditis elegans (CL2006 and CL4176). The results of the in vitro study revealed that the acetone extract of P. gymnospora (ACTPG) and its active constituent α-bisabolol restores the Aβ25-35 induced alteration in the oxidation of intracellular protein and lipids. In addition, ACTPG and α-bisabolol inhibited cholinesterase and β-secretase activity in Neuro2a cells. Moreover, the intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) production was reduced by ACTPG and α-bisabolol in Neuro2a cells. The decrease in the expression level of apoptotic proteins such as Bax and caspase-3 in ACTPG and α-bisabolol treated group indicates that the seaweed and its bioactive compound have anti-apoptotic property. Further, the in vivo study revealed that the ACTPG and α-bisabolol exerts neuroprotective effect against Aβ induced proteotoxicity in transgenic C. elegans strains of AD. Moreover it altered the Aβ mediated pathways, lifespan, macromolecular damage and down regulated the AD related gene expression of ace-1, hsp-4 and Aβ, thereby preventing Aβ synthesis. Overall, the outcome of the study signifies the neuroprotective effect of ACTPG and α-bisabolol against Aβ mediated AD pathology.

Daucosterol (DS) is a plant phytosterol which is shown to induce oxidative stress mediated apoptosis in various cancer cell lines. However, the molecular mechanism underlying its cellular action has not been documented against Non- Small Cell Lung Cancer (NSCLC). Therefore, we attempted to decipher the mechanisms responsible for DS-induced anti-proliferation on human NSCLC cells. The present study showed, DS strongly inhibits the growth of A549 cells after 72 h time point with an IC50 value of ∼20.9 μM. Further DS elicits increased reactive oxygen species level and promote intrinsic apoptotic cell death on A549 cells as evidenced by increased expression of caspase-3, caspase-9, Bax, PARP inactivation, cytochrome-c release, and diminished expression of bcl-2 protein. DS failed to display its apoptotic actions upon pretreatment with the reactive oxygen species inhibitor NAC (N-acetyl cysteine). Indeed, apoptotic signal which was enhanced through p53/p21 activation and knockdown of p53 expression also moderately affected the DS induced apoptosis. In addition, DS preferentially inhibited the cell growth of p53 wild-type NSCLC cell lines than the mutant p53 models. Further, we show that inhibition of Thioredoxin (TrxR) redox system is principally associated with DS induced oxidative stress mediated apoptotic cell death on A549 cells. Moreover, we also demonstrated that DS stably interacted with serine residues in TrxR active sites. The obtained results confirmed that the anti-proliferative mechanism and increased reactive oxygen species level of DS was associated with down-regulation of TrxR1 pathway which triggers the p53 mediated intrinsic apoptotic mode of cell death in NSCLC cells.

The initiation of human cancer is primarily driven by carcinogenic substances including chemicals, radiations, viruses, and parasites. The carcinogenesis mechanism is a complex process in which cellular DNA mutations contribute to the initiation, which is the first step, and seems to be irreversible. The second stage is promoted over a long period and is largely reversible in initial stages. The key events for the carcinogenesis process tend to be epigenetic. Cancer genes are classified by their ability to regulate oncogenesis as the dominant oncogenes and recessive tumor suppressors. Activation of oncogenes may be due to the occurrence of mutations in these genes. Besides, a single sufficiently activated oncogene will initiate the entire process of the cancerous transition of a normal cell. Their function in cancer growth has been widely demonstrated in experimental studies involving viruses and chromosome translocations. Furthermore, micro-RNAs (miRNAs) are preserved throughout development and regulate gene expression during cell proliferation, growth, and even in cancer progression by an unidentified control mechanism. miRNAs also play a crucial function in malignancy. The discovery and elucidation of the carcinogenic molecular pathways of carcinogens provide a deeper understanding of how genetic manipulation influences the mechanism of neoplastic development. The current chapter explains the different mechanisms involved in the carcinogenesis process.

This chapter describes the hepatotoxicity activity of plant extracts. The major physiological functions of the liver are the secretion, storage, and metabolism of bile. The diseases that affect this vital organ, called hepatic diseases, are among the major worldwide health problems. They are caused by different factors including hepatotoxins, which are the chemical compounds that cause liver injury. In addition, herbal drugs used to treat various diseases, when used for the long term, result in hepatotoxicity ranging from mild liver enzyme changes to chronic liver disease, leading to liver failure. In traditional and modern medicine, some herbal drugs from medicinal plants cause herb-induced liver injury (HILI). The objective of this chapter is to summarize the effects of plant extract-induced hepatotoxicity, the mechanisms of toxicity, and the identification of plants that cause liver damage.

Obesity is a major health concern for a growing fraction of the population, with the prevalence of obesity and its related metabolic disorders not being fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue, leads to the pathogenesis of obesity related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. In the whole, the collected data show that there are both natural and synthetic compounds that show beneficial promising activity as PPAR agonists in chronic diseases related to obesity.

Nowadays due to the concern with the environmental impact of analytical techniques and in order to reduce the ecological footprint there is a tendency to use more efficient and faster procedures that use a smaller amount of organic solvents. Polyphenols have been widely studied in plant-based matrices due to their wide and potent biological properties ; however there are no standardized procedures both for sample preparation and analysis of these compounds. The second of a two-part review will carry out a critical review of the extraction procedures and analytical methods applied to polyphenols and their selection criteria over a wide range of factors in relation to commerce- associated, environmental, and economic factors. It is foreseen that in the future the analysis of polyphenols in plant-based matrices includes the use of techniques that allow the simultaneous determination of different subclasses of polyphenols using fast, sophisticated, and automated techniques that allow the minimal consumption of solvents

Synthesis of natural products has speeded up drug discovery process by minimizing the time for their purification from natural source. Several diseases like Alzheimer's disease (AD) demand exploring multi targeted drug candidates, and for the first time we report the multi AD target inhibitory potential of synthesized dihydroactinidiolide (DA). Though the activity of DA in several solvent extracts have been proved to possess free radical scavenging, anti bacterial and anti cancer activities, its neuroprotective efficacy has not been evidenced yet. Hence DA was successfully synthesized from β-ionone using facile two-step oxidation method. It showed potent acetylcholinesterase (AChE) inhibition with half maximal inhibitory concentration (IC50) 34.03 nM, which was further supported by molecular docking results showing strong H bonding with some of the active site residues such as GLY117, GLY119 and SER200 of AChE. Further it displayed DPPH and (.NO) scavenging activity with IC50 value 50 nM and metal chelating activity with IC50 >270 nM. Besides, it significantly prevented amyloid β25-35 self-aggregation and promoted its disaggregation at 270 nM. It did not show cytotoxic effect towards Neuro2a (N2a) cells up to 24 h at 50 and 270 nM while it significantly increased viability of amyloid β25-35 treated N2a cells through ROS generation at both the concentrations. Cytotoxicity profile of DA against human PBMC was quite impressive. Hemolysis studies also revealed very low hemolysis i.e. minimum 2.35 to maximum 5.61%. It also had suitable ADME properties which proved its druglikeness. The current findings demand for further in vitro and in vivo studies to develop DA as a multi target lead against AD.

p300/CBP Associated Factor (PCAF), a GNAT family member protein, represent a valid target for therapeutic interventions since its dysfunction has implicated in variety of diseases like cancer, diabetes, inflammatory diseases, etc. Despite its potential for therapeutics, only a small number of PCAF inhibitors were reported. Hence, in this study, the catalytic domain of PCAF was explored to screen novel, potent and cell permeable inhibitor from three small molecule databases like Life Chemical, Maybridge and Chembridge by using Structure Based Virtual Screening (SBVS) method. Further, Induced Fit Docking, Binding Free Energy calculation, Single Point Energy calculation and Molecular Dynamics Simulation were performed on selected hits. In silico results revealed that F2209-0381 has higher binding energy of −109.722 and have greater cell permeability (QPPCaco = 1456.764; QPPMDCK = 742.941) than rest of hits. Cytotoxicity effect and protein expression analysis of F2209-0381 on A549 cells reveals that it exhibited strong inhibition with IC50 value of 58.31 μg/ml and significantly reduced the expression of PCAF after 72 h time point. Thus, this study warrants that F2209-0381 could become a novel, potent and cell permeable drug of PCAF thereby it could combat its mediated diseases.

In the present study, the antiproliferative activity of phytol and its mechanism of action against human lung adenocarcinoma cell line A549 were studied in detail. Results showed that phytol exhibited potent antiproliferative activity against A549 cells in a dose and time-dependent manner with an IC50 value of 70.81 ± 0.32 μM and 60.7 ± 0.47 μM at 24 and 48 h, respectively. Phytol showed no adverse toxic effect in normal human lung cells (L-132), but mild toxic effect was observed when treated with maximum dose (67 and 84 μM). No membrane-damaging effect was evidenced by PI staining and SEM analysis. The results of mitochondrial membrane potential analysis, cell cycle analysis, FT-IR and Western blotting analysis clearly demonstrated the molecular mechanism of phytol as induction of apoptosis in A549 cells, as evidenced by formation of shrinked cell morphology with membrane blebbing, depolarization of mitochondrial membrane potential, increased cell population in the sub-G0 phase, band variation in the DNA and lipid region, downregulation of Bcl-2, upregulation of Bax and the activation of caspase-9 and -3. In addition, phytol inhibited the CAM vascular growth as evidenced by CAM assay, which positively suggests that phytol has anti-angiogenic potential. Taken together, these findings clearly demonstrate the mode of action by which phytol induces cell death in A549 lung adenocarcinoma cells.

Amyloid beta (Aβ) formation is one of the neuropathological hallmarks of Alzheimer's disease (AD), which induces the generation of reactive oxygen species (ROS), further leading to the alteration of several signalling pathways. In the present study, vitexin has been evaluated for its neuroprotective activity against Aβ25-35 induced toxicity in Neuro-2a cells. Results of cell free studies indicated that vitexin significantly inhibited the aggregation of Aβ25-35. Studies in Neuro-2a cells revealed that Aβ25-35 significantly affected the cell viability by inducing ROS mediated toxicity and apoptosis. However, pre-treatment of Neuro-2a cells with vitexin (50 μM) significantly restored the cell viability up to 92.86 ± 5.57%. Vitexin has been found to inhibit the production of free radicals and suppress ROS mediated lipid peroxidation, protein oxidation and loss of membrane potential. Also, vitexin modulated the expression of genes involved in antioxidant response mechanisms (Nrf-2, HO-1), cholesterol metabolism (LXR-α, APOE, ABCA-1, Seladin-1), and endoplasmic reticulum stress (Grp78, Gadd153) to offer neuroprotection. Aβ25-35 induced caspase-3 activation, and Bax protein expression was also found to be significantly inhibited by vitexin. Taken together, our results indicate that vitexin offers neuroprotection to cells in part via augmenting the antioxidant mechanisms, maintaining lipid homeostasis and inhibiting apoptosis induced by Aβ.

Solid lipid nanoparticles (SLNs) are considered as a promising nanocarrier for increasing the oral delivery of hydrophobic drugs. The primary objective of the present study is to formulate α-bisabolol loaded SLNs through hot homogenization method and to evaluate its neuroprotective effect in Neuro-2a cells. The physico-chemical characterization of α-bisabolol-SLNs through DLS analysis displayed relatively small hydrodynamic size and physically stable zeta-potential value which illustrate that α-bisabolol-SLNs will have enhanced ability to deliver the drug at target site. The PXRD and FTIR analysis evidenced that α-bisabolol-SLNs are amorphous in nature and has good stability. α-Bisabolol-SLNs also significantly inhibited AChE and had antioxidant potential. In addition, the α-bisabolol-SLNs protected the Neuro-2a cells from Aβ induced neurotoxicity and inhibited Aβ aggregation which was corroborated through thioflavin T assay, fluorescent microscope and FT-IR analysis. Thus, the results of the present study evidenced an improved therapeutic efficacy and bioavailability of α-bisabolol to combat AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple pathological consequences such as oxidative stress, inflammation, apoptosis, cholinergic deficit, amyloid plaques, and tangles formation. Hence, development of drugs with multiple targets will be effective in the treatment of AD. The present study aims at evaluation of the neuroprotective effect of Gelidiella acerosa against amyloid beta 25-35 (Aβ 25-35) induced toxicity in PC12 cells. The antioxidative effect was evaluated by monitoring levels of antioxidant enzymes. Protection against ROS-induced damage was assessed by the measurement of lipid peroxidation, protein carbonyl content (PCC), 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence, and nitric oxide (NO) production. The cholinesterase (ChE) inhibitory activity was also evaluated. The antiapoptotic activity was verified by caspase-3 activity. The results of antioxidant assays suggest that G. acerosa significantly (P < .05) restores the levels of antioxidant enzymes. Moreover, the seaweed extract was found to prevent the formation of intracellular ROS induced by Aβ 25-35 and thereby protects PC12 cells from macromolecular damage. The study demonstrated that G. acerosa inhibits ChE activity significantly (P < .05) in PC12 cells. The significant decrease (P < .05) in the level of caspase-3 activity indicates that the seaweed has anti-apoptotic activity. Hence, the outcome of this study signifies the neuroprotective effect of G. acerosa targeting multiple pathological consequences of AD.

Alzheimer's disease is one of the most dreadful disorders of 21st century with no effective therapy till date, clinically characterized by loss of cognitive function. β-amyloid peptide (Aβ) is considered as the key pathogenic factor in AD, which on aggregation provokes oxidative stress mediated neuronal damage affecting activities of daily life such as learning and memory. Hence, the present study focuses on the exploration of neuroprotective potential of T. chebula and T. arjuna by evaluating its antioxidant, anticholinesterase and antiamyloidogenic activities. Results of antioxidant assays showed that methanolic extract of T. chebula fruit (TCF) and T. arjuna bark (TAB) exhibited highest reducing capacity, free radical scavenging activity and metal chelating potential. Furthermore, TCF and TAB also exhibited dual cholinergic effect by inhibiting both AChE (IC50 value 81.26 ± 7.79 73.99 ± 2.11 μg/ml, respectively) and BuChE (IC50 value 81.44 ± 1.23; 52.16 ± 3.94 μg/ml respectively). Total polyphenolic content of TCF and TAB was observed to be 479.25 ± 0.5, 597.25 ± 0.5 μg of Gallic acid Equivalent/mg of extract. Molecular docking studies on LC-MS fractions of TCF and TAB revealed 7-MG as target compound with good predicted activities and promising ADMET properties. Enzyme kinetic studies revealed that 7-MG exhibited competitive and partially noncompetitive mode of inhibition for AChE and BuChE. Results of Th-T fluorescence, confocal microscopic and FTIR analysis illustrated that 7-MG blocked nucleation step thereby preventing the aggregation of Aβ peptide and destabilizing the preformed mature fibrils. Over all the results conclude that 7-MG via its multi-targeting ability may be beneficial in the treatment of AD and related neurodegenerative disorders.

β-Sitosterol (BS), a major bioactive constituent present in plants and vegetables has shown potent anticancer effect against many human cancer cells, but the underlying mechanism remain elusive on NSCLC cancers. We found that BS significantly inhibited the growth of A549 cells without harming normal human lung and PBMC cells. Further, BS treatment triggered apoptosis via ROS mediated mitochondrial dysregulation as evidenced by caspase-3 & 9 activation, Annexin-V/PI positive cells, PARP inactivation, loss of MMP, Bcl-2-Bax ratio alteration and cytochrome c release. Moreover, generation of ROS species and subsequent DNA stand break were found upon BS treatment which was reversed by addition of ROS scavenger (NAC). Indeed BS treatment increased p53 expression and its phosphorylation at Ser15, while silencing the p53 expression by pifithrin-α, BS induced apoptosis was reduced in A549 cells. Furthermore, BS induced apoptosis was also observed in NCI-H460 cells (p53 wild) but not in the NCI-H23 cells (p53 mutant). Down-regulation of Trx/Trx1 reductase contributed to the BS induced ROS accumulation and mitochondrial mediated apoptotic cell death in A549 and NCI-H460 cells. Taken together, our findings provide evidence for the novel anti-cancer mechanism of BS which could be developed as a promising chemotherapeutic drug against NSCLC cancers.

Over the course of the last three decades, a large body of evidence has shown that polyphenols, the secondary metabolites occurring in plant foods and beverages, exert protective effects due to their antioxidant activity mediated through different mechanisms ranging from direct radical scavenging and metal chelating activities, to the capacity to inhibit pro-oxidant enzymes and to target specific cell-signalling pathways. In the last decade, dietary components, and polyphenols in particular have gained considerable attention as chemopreventive agents against different types of cancer. The signal transducers and activators of transcription (STAT) family is a group of cytoplasmic transcription factors which interact with specific sequences of DNA, inducing the expression of specific genes which in turn give rise to adaptive and highly specific biological responses. Growing evidence suggests that, of the seven STAT members identified, STAT3 is over-expressed in many human tumors (i.e. solid tumors and hematological malignancies) promoting the onset and development of cancer in humans by inhibiting apoptosis or by inducing cell proliferation, angiogenesis, invasion, and metastasis. This review article aims to assess the most recent studies on the role of STATs, with focus on STAT3, in oncogenesis, and the promising effects of some polyphenols on STAT expression. Moreover, the mechanisms behind the anti-inflammatory and antioxidant activities of polyphenols which have an influence on STAT expression are discussed, with a focus on their ability to target specific cell-signalling pathways.

Alzheimer's disease (AD) is an unfavourable neurological condition of the brain leading to the loss of behavioural and cognitive skills of the aging population. At present, drugs representing cholinesterase inhibitors provide lateral side effects to AD patients. Hence, there is a need for improved fabrication of drugs without side effects, for which nanoencapsulated bioactive compounds that can cross the blood-brain barrier offer new hope as novel alternative treatment strategy for AD. This study involved synthesis of phytol loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles by solvent evaporation method. Physico-chemical characterization of phytol-PLGA NPs through the field emission scanning electron microscope, dynamic laser scattering (DLS) measurement revealed that the particles were nanosize range with smooth surface and spherical morphology. Furthermore, the biocompatibility of drug/polymer ratio was investigated by power X-ray diffraction (PXRD) and Fourier-transform infrared spectroscopic (FT-IR) analysis. The in vitro drug release study showed that the phytol was released in a sustained manner. Moreover, phytol-PLGA NPs were able to disrupt amyloid aggregates, exhibit anti-cholinesterase and anti-oxidative property and are non-cytotoxic in Neuro2a cells.

Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death.

Nanoparticles based drug delivery system offers an alternative strategy to overcome several therapeutic limitations of various human ailments, particularly in age-linked Alzheimer's disease. Results of our previous cell-free studies indicated that α-bisabolol loaded solid lipid nanoparticles (ABS) significantly inhibited the aggregation of Aβ25-35. The present study intended to evaluate the neuroprotective effect of ABS against Aβ25-35 induced toxicity in Neuro-2a cell lines. The results of in vitro cell line study revealed that pretreatment of Neuro-2a cell lines with ABS (5 & 10 μg/ml) significantly suppressed the production of free radicals such as reactive oxygen species (ROS)/reactive nitrogen species (RNS), and also augmented the ROS mediated macromolecular damages and loss of mitochondrial membrane potential induced by toxic Aβ peptide when compared to the standard drug donepezil (50 μg/ml). Moreover, reduced β-secretase, caspase-3, and cholinesterase activities were observed in the cells pretreated with ABS, which clearly evidenced the neuroprotective effect of ABS. Reduced expression of Bax and induced expression of Bcl-2 proteins observed through western blot analysis and live/dead cell viability analysis of Neuro-2a cells through confocal microscope further validated that ABS protects the cells from Aβ induced apoptosis. Taken together, the outcome of the present study signifies the neuroprotective effect of ABS against the Aβ induced toxicity in in vitro model of Neuro-2a cells.

Amyloid β (Aβ) induced neurotoxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration in Alzheimer's disease (AD). The nanoparticles based drug carrier system is considered as a promising therapeutic strategy to combat this incurable disease. It was also found to inhibit cholinesterase activity and apoptosis mediated cell death in Neuro-2a cells. The in vivo study further revealed that the Phytol and Phytol-PLGA NPs (Poly Lactic-co-Glycolic Acid Nanoparticles) was found to increase the lifespan, chemotaxis behavior and decrease Aβ deposition & ROS (Reactive oxygen species) production in transgenic Caenorhabditis elegans models of AD (CL2006, CL4176). Phytol and Phytol-PLGA NPs treatment downregulated the expression of AD associated genes viz Aβ, ace-1 and hsp-4 and upregulated the gene involved in the longevity to nematodes (dnj-14) and it also reduced the expression of Aβ peptide at the protein level. Our results of in vitro and in vivo studies suggest that Phytol and Phytol-PLGA NPs hold promising neuroprotective efficacy and targets multiple neurotoxic mechanisms involved in the AD progression.

Context: Alzheimer’s disease (AD) is believed to develop due to deposition of β-amyloid (Aβ) peptide. Hence, efforts are being made to develop potent drug that target amyloid hypothesis. Objective: The present study explores the effect of the seaweed Gelidiella acerosa (Forsskål) Feldmann & Hamel (Gelidiellaceae) against Aβ 25–35 peptide in Swiss albino mice. Materials and methods: The animals were administered through intracerebroventricular (ICV) injection with the Aβ 25–35 peptide (10 μg/10 μL/ICV site) on 21st day of the pretreatment of G. acerosa (whole plant) benzene extract (200 and 400 mg/kg bw). On day 30, animals were sacrificed and brain tissue homogenate was prepared. The activities of AChE, BuChE, b-secretase, MAO-B, and caspase-3 were determined, and Bax expression was assessed by Western blotting. Results: Gelidiella acerosa benzene extract restored the level of antioxidant enzymes and prevented lipid and protein oxidation significantly (p

Quercetin, a ubiquitous flavonoid that is widely distributed in plants is classified as a cognitive enhancer in traditional and oriental medicine. The protective effects of quercetin for the treatment of neurodegenerative disorders and cerebrovascular diseases have been demonstrated in both in vitro and in vivo studies. The free radical scavenging activity of quercetin has been well-documented, wherein quercetin has been observed to exhibit protective effects against oxidative stress mediated neuronal damage by modulating the expression of NRF-2 dependent antioxidant responsive elements, and attenuation of neuroinflammation by suppressing NF-κB signal transducer and activator of transcription-1 (STAT-1). Several in vitro and in vivo studies have also shown that quercetin destabilizes and enhances the clearance of abnormal protein such as beta- amyloid peptide and hyperphosphorlyated tau, the key pathological hallmarks of Alzheimer's disease. Quercetin enhances neurogenesis and neuronal longevity by modulating a broad number of kinase signaling cascades such as phophoinositide 3- kinase (P13-kinase), AKT/PKB tyrosine kinase and Protein kinase C (PKC). Quercetin has also been well reported for its ability to reverse cognitive impairment and memory enhancement during aging. The current review focuses on summarizing the recent findings on the neuroprotective effect of quercetin, its mechanism of action and its possible roles in the prevention of neurological disorders.

Alzheimer's disease (AD) is a devastating brain disorder characterized by an increased level of amyloid-beta (Aβ) peptide deposition and neuronal cell death leading to an impairment of learning and thinking skills. The Aβ deposition is a key factor in senile plaques of the AD brain which cause the elevation of intracellular calcium ions and the production of formidable free radicals, both of which greatly contribute to the AD-associated cascade, leading to unstoppable neuronal loss in the hippocampal region of the brain. Natural products are currently considered as an alternative strategy for the discovery of novel multipotent drugs against AD. They include the naturally occurring dietary soy isoflavone genistein which has been recognized to possess several health-promoting effects. Genistein has been mainly focused because of its potential on amelioration of Aβ-induced impairment and its antioxidant capacity to scavenge the free radicals produced in AD. It can also directly interact with the targeted signaling proteins and stabilize their activity to prevent AD. An improved understanding of the direct interactions between genistein and target proteins would contribute to the further development of AD treatment. This review mainly focuses on molecular targets and the therapeutic effects regulated by genistein, which has the ability to directly target the Aβ peptide and to control its activity involved in intracellular signaling pathways, which otherwise would lead to neuronal death in the hippocampal region of the AD brain.

Amyloid hypothesis states that endogenous β-amyloid peptides (Aβ), especially its aggregated oligomers and fibrils are the key pathogenic factors leading to Alzheimer's disease (AD). Therefore, inhibition of Aβ fibrillation rather than blocking its production is considered promising therapeutic intervention. Hence, the present study was carried out to assess the effect of methanolic leaf extract of R. mucronata (MERM) and its bioactive compound catechin on in vitro fibrillation of Aβ (25-35).Antiaggregation and disaggregation effect by MERM and (+)- catechin against Aβ (25-35) were assessed in three different phases by thioflavin T (ThT) fluorescence assay and confocal microscopic analysis. The conformational changes in the aggregated Aβ fibrils in the presence and absence of MERM and catechin were analysed by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and CD spectroscopy.Results of ThT and confocal microscopic studies showed decrease in fluorescence intensity in MERM and catechin-treated groups illustrating that both MERM and catechin effectively inhibited fibril aggregation as well as destabilized preformed Aβ fibril. TEM revealed that MERM incubated samples were virtually devoid of structured fibrils but had an amorphous-like consistency, whereas the control contained structured fibrils of various width and length. FTIR analysis showed decrease in absorbance at 1630 cmResults suggest that MERM and catechin might have direct interaction with Aβ peptide preventing its fibrillation.

The use of cholinesterase inhibitors and antioxidants is currently considered as an effective therapeutic strategy for the treatment of Alzheimer’s disease (AD). There is also a growing trend to use nutraceuticals for cognitive impairment. Since natural product-based drugs offer better hope for the treatment of AD, the present study was aimed at evaluating the nutritional profile of the brown seaweed Padina gymnospora and investigating the antioxidant and inhibitory effect of different solvent extracts of P. gymnospora on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The nutritional profile of P. gymnospora includes large amounts of carbohydrate, protein, lipid, proline, chlorophyll, fibre, minerals, fatty acids and amino acids, along with antioxidants such as vitamins C and E. Antioxidant activities of various solvent extracts of P. gymnospora were assessed by the DPPH scavenging assay, nitric oxide scavenging assay, reducing power assay and FRAP assay. Acetone extracts showed si...

Alzheimer's disease (AD) threatens to become the scourge of the 21st century, hence there is an urgent need for the exploration of multipotent drug in the treatment of AD. Rhizophora mucronata , tropical red mangrove has been widely used in traditional oriental medicine as astringent, antiseptic, antibacterial, anti-ulcerogenic and anti-inflammatory agent. The present study aimed to evaluate the neuroprotective effect of the catechin rich methanolic leaf extract of R. mucronata (MERM), against Aβ-induced neurotoxicity. Exposure of PC12 cells to Aβ (25–35) increased cellular oxidative stress, the number of apoptotic cells and caspase-3 activity ultimately leading to neuronal death. Pre-treatment with MERM (50 μg/ml) significantly attenuated cell death, decreased the level of intracellular reactive oxygen and nitrogen species thereby inhibiting lipid peroxidation and protein oxidation. MERM attenuated Aβ (25–35) induced apoptosis by stabilizing the mitochondrial membrane potential, and inhibiting caspase-3 activity. MERM also restored the antioxidant status of the Aβ (25–35) treated cells by effectively scavenging ROS/RNS species. HPTLC analysis of MERM illustrated the presence of (+)-catechin as major constituent. Results conclude that MERM effectively attenuated the neurotoxicity induced by Aβ-associated oxidative stress, implying that MERM can act as a potent drug for the treatment of AD.