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.

Energy conversion and storage via photoinduced polarization change in non-ferroelectric molecular [CoGa] crystals.

To alleviate the energy and environmental crisis, in the last decades, energy harvesting by utilizing optical control has emerged as a promising solution. Here we report a polar crystal that exhibits photoenergy conversion and energy storage upon light irradiation. The polar crystal consists of dinuclear [CoGa] molecules, which are oriented in a uniform direction inside the crystal lattice. Irradiation with green light induces a directional intramolecular electron transfer from the ligand to a low-spin CoIII centre, and the resultant light-induced high-spin CoII excited state is trapped at low temperature, realizing energy storage. Additionally, electric current release is observed during relaxation from the trapped light-induced metastable state to the ground state, because the intramolecular electron transfer in the relaxation process is accompanied with macroscopic polarization switching at the single-crystal level. It demonstrates that energy storage and conversion to electrical energy is realized in the [CoGa] crystals, which is different from typical polar pyroelectric compounds that exhibit the conversion of thermal energy into electricity.

The role of macrophages in the tumor microenvironment and tumor metabolism.

The complexity and plasticity of the tumor microenvironment (TME) make it difficult to fully understand the intratumoral regulation of different cell types and their activities. Macrophages play a crucial role in the signaling dynamics of the TME. Among the different subtypes of macrophages, tumor-associated macrophages (TAMs) are often associated with poor prognosis, although some subtypes of TAMs can at the same time improve treatment responsiveness and lead to favorable clinical outcomes. TAMs are key regulators of cancer cell proliferation, metastasis, angiogenesis, extracellular matrix remodeling, tumor metabolism, and importantly immunosuppression in the TME by modulating various chemokines, cytokines, and growth factors. TAMs have been identified as a key contributor to resistance to chemotherapy and cancer immunotherapy. In this review article, we aim to discuss the mechanisms by which TAMs regulate innate and adaptive immune signaling in the TME and summarize recent preclinical research on the development of therapeutics targeting TAMs and tumor metabolism.

Macroscopic Polarization Change of Mononuclear Valence Tautomeric Cobalt Complexes Through the Use of Enantiopure Ligand.

The crystallization of a complex having electron transfer properties in a polar space group can induce the polarization switching of a crystal in a specific direction, which is attractive for the development of sensors, memory devices, and capacitors. Unfortunately, the probability of crystallization in a polar space group is usually low. Noticing that enantiopure compounds crystallize in Sohncke space groups, this paper reports a strategy for the molecular design of non-ferroelectric polarization switching crystals based on the use of intramolecular electron transfer and chirality. In addition, this paper describes the synthesis of a mononuclear valence tautomeric (VT) cobalt complex bearing an enantiopure ligand. The introduction of enantiomer enables the crystallization of the complex in the polar space group (P21 ). The polarization of the crystals along the b-axis direction is not canceled out and the VT transition is accompanied by a change in the macroscopic polarization of the polar crystal. Polarization switching via electron transfer is realized at around room temperature.

Therapeutic Targeting of Cancer Stem Cells in Lung, Head and Neck, and Bladder Cancers.

Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)-a subpopulation of tumor cells with capacities for self-renewal and multi-lineage differentiation-represent a pool of therapeutically resistant cells. CSCs often share physical and molecular characteristics with the stem cell population of the human body. It remains challenging to selectively target CSCs in therapeutically resistant tumors. The generation of CSCs and induction of therapeutic resistance can be attributed to several deregulated critical growth regulatory signaling pathways such as WNT/ß-catenin, Notch, Hippo, and Hedgehog. Beyond growth regulatory pathways, CSCs also change the tumor microenvironment and resist endogenous immune attack. Thus, CSCs can interfere with each stage of carcinogenesis from malignant transformation to the onset of metastasis to tumor recurrence. A thorough review of novel targeted agents to act against CSCs is fundamental for advancing cancer treatment in the setting of both intrinsic and acquired resistance.

Manipulating electron redistribution to achieve electronic pyroelectricity in molecular [FeCo] crystals.

Pyroelectricity plays a crucial role in modern sensors and energy conversion devices. However, obtaining materials with large and nearly constant pyroelectric coefficients over a wide temperature range for practical uses remains a formidable challenge. Attempting to discover a solution to this obstacle, we combined molecular design of labile electronic structure with the crystal engineering of the molecular orientation in lattice. This combination results in electronic pyroelectricity of purely molecular origin. Here, we report a polar crystal of an [FeCo] dinuclear complex exhibiting a peculiar pyroelectric behavior (a substantial sharp pyroelectric current peak and an unusual continuous pyroelectric current at higher temperatures) which is caused by a combination of Fe spin crossover (SCO) and electron transfer between the high-spin Fe ion and redox-active ligand, namely valence tautomerism (VT). As a result, temperature dependence of the pyroelectric behavior reported here is opposite from conventional ferroelectrics and originates from a transition between three distinct electronic structures. The obtained pyroelectric coefficient is comparable to that of polyvinylidene difluoride at room temperature.

In vivo therapeutic evaluation of a novel bis-lawsone derivative against tumor following delivery using mesoporous silica nanoparticle based redox-responsive drug delivery system.

Herein, we have evaluated the in vivo therapeutic efficacy and systemic toxicity profile of a synthetic anticancer compound [3,3'-((4-(trifluoromethyl)phenyl)methylene)bis(2-hydroxynaphthalene-1,4-dione)]. A multifunctional mesoporous silica nanoparticle (MSN) based drug delivery network was also fabricated which specifically showed targeting nature towards the cancer cell. The mesopores of silica nanoparticles were tagged with phenyl boronic acid (PBA) for targeted drug delivery into tumor tissue. 1j was then loaded inside the nanocarriers followed by pore blocking with gold nanoparticles (GN) to attain a redox-responsive controlled drug delivery pattern. The synthesized nanocarriers (1j@-MSN-PBA-GN) having mean diameter of ~86 nm exhibited a moderate 1j loading content of 13.68% with overall negative surface charge. Both the targeted and non-targeted nanoformulations were tested for their anticancer activities both in vitro and in vivo models, and found more effective as compared with free 1j treatment. However, the targeted nanoformulations showed higher therapeutic effect due to increased cellular internalization and caused mitochondria-dependent apoptosis in MCF-7 cells via oxidative stress. Besides, the targeted nanoformulation significantly inhibited in the development of solid tumor in comparison to non-targeted nanoformulations and free 1j as a consequence of increased internalization of the drug-candidate in tumor tissue. Therefore, this study proposes that 1j can be considered as a potent anti-carcinogenic compound in vivo and its therapeutic potential is further increased by using PBA functionalized and GN gated MSN-based controlled drug delivery system without showing any significant systemic toxicity.

Effect of COVID-19 on Lungs: Focusing on Prospective Malignant Phenotypes.

Currently, the healthcare management systems are shattered throughout the world, even in the developed nations due to the COVID-19 viral outbreak. A substantial number of patients infected with SARS-CoV2 develop acute respiratory distress syndrome (ARDS) and need advanced healthcare facilities, including invasive mechanical ventilation. Intracellular infiltration of the SARS-CoV2 virus particles into the epithelial cells in lungs are facilitated by the spike glycoprotein (S Protein) on the outer side of the virus envelope, a membrane protein ACE2 (angiotensin-converting enzyme 2) and two proteases (TMPRSS2 and Furin) in the host cell. This virus has unprecedented effects on the immune system and induces a sudden upregulation of the levels of different pro-inflammatory cytokines. This can be a cause for the onset of pulmonary fibrosis in the lungs. Existence of a high concentration of inflammatory cytokines and viral load can also lead to numerous pathophysiological conditions. Although it is well established that cancer patients are among the high-risk population due to COVID-19-associated mortality, it is still unknown whether survivors of COVID-19-infected subjects are at high-risk population for developing cancer and whether any biologic and clinical features exist in post-COVID-19 individuals that might be related to carcinogenesis.

Concurrent Targeting of Potential Cancer Stem Cells Regulating Pathways Sensitizes Lung Adenocarcinoma to Standard Chemotherapy.

Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined with chemotherapy in lung adenocarcinoma. Here, we showed that YAP1 contributes to CSC regulation and enhances tumor formation while suppressing apoptosis. Mechanistically, YAP1 promotes phosphorylation of STAT3 by upregulating IL6. In lung adenocarcinoma clinical specimens, YAP1 expression correlated with that of IL6 (P < 0.01). More importantly, YAP1 and phosphorylated STAT3 (pSTAT3) protein expressions were significantly correlated (P < 0.0001) in primary lung adenocarcinoma as determined by IHC. Immunoblotting of 13 lung adenocarcinoma patient-derived xenografts (PDX) showed that all YAP1-expressing PDXs also exhibited pSTAT3. Additional investigations revealed that chemotherapy resistance and malignant stemness were influenced by upregulating NANOG, OCT4, and SOX2, and the expression of these targets significantly attenuated by genetically and pharmacologically hindering the activities of YAP1 and STAT3 in vivo and in vitro Therapeutically, the dual inhibition of YAP1 and STAT3 elicits a long-lasting therapeutic response by limiting CSC expansion following chemotherapy in cell line xenograft and PDX models of lung adenocarcinoma. Collectively, these findings provide a conceptual framework to target the YAP1 and STAT3 pathways concurrently with systemic chemotherapy to improve the clinical management of lung adenocarcinoma, based on evidence that these two pathways expand CSC populations that mediate resistance to chemotherapy.

GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma.

Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urothelial carcinoma of the bladder (UCB), silencing of GULP1 facilitated the nuclear accumulation of NRF2, led to constitutive activation of NRF2 signaling, and conferred resistance to the platinum drug cisplatin. Knockdown of GULP1 in UCB cells promoted tumor cell proliferation in vitro and enhanced tumor growth in vivo. In primary UCB, GULP1 silencing was more prevalent in muscle-invasive UCB compared to nonmuscle-invasive UCB. GULP1 knockdown cells showed resistance to cisplatin treatment. In parallel with decreased GULP1 expression, we observed increased expression of NRF2, HMOX1, and other candidate antioxidant genes in cisplatin-resistant cells. Furthermore, low or no expression of GULP1 was observed in most cisplatin nonresponder cases. Silencing of GULP1 was associated with GULP1 promoter hypermethylation in cell lines and primary tumors, and a high frequency of GULP1 promoter methylation was observed in multiple sets of primary clinical UCB samples. Together, our findings demonstrate that GULP1 is a KEAP1-binding protein that regulates KEAP1-NRF2 signaling in UCB and that promoter hypermethylation of GULP1 is a potential mechanism of GULP1 silencing.

Assessment of cytotoxic and genotoxic potentials of a mononuclear Fe(II) Schiff base complex with photocatalytic activity in Trigonella.

BACKGROUND: In recent times, coordination complexes of iron in various oxidation states along with variety of ligand systems have been designed and developed for effective treatment of cancer cells without adversely affecting the normal cell and tissues of various organs. METHODS: In this study, we have evaluated the mechanism of action of a Fe(II) Schiff base complex in the crop plant Trigonella foenum-graecum L. (Fenugreek) as the screening system by using morphological, cytological, biochemical and molecular approaches. Further functional characterization was performed using MCF-7 cell line and solid tumour model for the assessment of anti-tumour activity of the complex. RESULTS: Our results indicate efficiency of the Fe(II) Schiff base complex in the induction of double strand breaks in DNA. Complex treatment clearly induced cytotoxic and genotoxic damage in Trigonella seedlings. The Fe-complex treatment caused cell cycle arrest via the activation of ATM-ATR kinase mediated DNA damage response pathway with the compromised expression of CDK1, CDK2 and CyclinB1 protein in Trigonella seedlings. In cultured MCF-7 cells, the complex induces cytotoxicity and DNA fragmentation through intracellular ROS generation. Fe-complex treatment inhibited tumour growth in solid tumour model with no additional side effects. CONCLUSION: The growth inhibitory and cytotoxic effects of the complex result from activation of DNA damage response along with oxidative stress and cell cycle arrest. GENERAL SIGNIFICANCE: Overall, our results have provided comprehensive information on the mechanism of action and efficacy of a Fe(II) Schiff base complex in higher eukaryotic genomes and indicated its future implications as potential therapeutic agent.

New mononuclear and binuclear oxomolybdenum(V) complexes containing NN chelator: Syntheses, DFT calculations, interaction with BSA protein and in vitro cytotoxic activity.

A neutral bidentate ligand 2-(3-methyl-5-phenyl pyrazol-1-yl) benzthiazole (L) has been synthesized by refluxing equimolar proportions of 2-hydrazino benzthiazole and benzoyl acetone in ethanol. The ligand acts in a NN donor fashion and forms stable mononuclear, MoOX3L [L = Ligand, X = Cl (1), Br (2)] and binuclear Mo2O4X2L2 [L = Ligand, X = Cl (3), Br (4)] complexes with molybdenum(V). The ligand and complexes are thoroughly characterized by elemental analyses, IR, UV-Vis spectroscopy, EPR study, magnetic susceptibility, thermogravimetry and cyclic voltammetry. Magnetic moment measurements reveal that the mononuclear complexes are paramagnetic while the binuclear complexes are diamagnetic in nature. EPR studies also confirm the presence of a mononuclear Mo(V) moiety in the complexes. Relevant Density Functional Theory (DFT) calculations have been carried out to determine the structures of the synthesized compounds. The binding mode and mechanism of interaction of the synthesized compounds with bovine serum albumin (BSA) were studied by concentration dependent absorption and fluorescence titration experiments. The ligand and complexes 1-4 are screened for their potential in vitro anticancer activities against three different human cancer cell lines, namely, cervix adenocarcinoma epithelial cells (HeLa), renal carcinoma cells (SK-RC-45) and breast adenocarcinoma cells (MCF-7). The oxomolybdenum(V) complexes are found to exhibit higher anticancer potency towards the cancer cells than the free ligand. Also, structure activity relationship (SAR) studies of this new series of oxomolybdenum(V) complexes indicate that the anticancer activity is to some extent dependent on the electronic effects of the halogen atom coordinated to the molybdenum centre.

Targeted delivery of quercetin via pH-responsive zinc oxide nanoparticles for breast cancer therapy.

Naturally occurring bioactive compounds are gaining much importance as anti-tumor agents in recent times due to their high therapeutic potential and less systemic toxicity. However, different preclinical and clinical studies have noted significant shortcomings, such as nonspecific tumor targeting and low bioavailability which limit their usage in therapeutics. Therefore, a safe and compatible nanoparticle mediated controlled drug delivery system is in high demand to enable effective transport of the drug candidates in the tumor tissue. Herein, we have synthesized phenylboronic acid (PBA) conjugated Zinc oxide nanoparticles (PBA-ZnO), loaded with quercetin (a bioflavonoid widely found in plants), with zeta potential around -10.2 mV and diameter below 40 nm. Presence of PBA moieties over the nanoparticle surface facilitates targeted delivery of quercetin to the sialic acid over-expressed cancer cells. Moreover, Quercetin loaded PBA-ZnO nanoparticles (denoted as PBA-ZnO-Q) showed pH responsive drug release behavior. Results suggested that PBA-ZnO-Q induced apoptotic cell death in human breast cancer cells (MCF-7) via enhanced oxidative stress and mitochondrial damage. In line with the in vitro results, PBA-ZnO-Q was found to be effective in reducing tumor growth in EAC tumor bearing mice. Most interestingly, PBA-ZnO-Q is found to reduce tumor associated toxicity in liver, kidney and spleen. The cytotoxic potential of the nanohybrid is attributed to the combinatorial cytotoxic effects of quercetin and ZnO in the cancer cells. Overall, the presented data highlighted the chemotherapeutic potential of the novel nanohybrid, PBA-ZnO-Q which can be considered for clinical cancer treatment.

pH-responsive and targeted delivery of curcumin via phenylboronic acid-functionalized ZnO nanoparticles for breast cancer therapy.

Nanoparticle-mediated targeted delivery of bioactive natural compounds has recently been gaining much interest for breast cancer therapy. Herein, phenyl boronic acid (PBA)-conjugated and pH-responsive ZnO nanoparticles (diameter ∼40 nm) were synthesized for the tumor tissue-specific delivery of curcumin. PBA conjugation facilitates the targeted delivery of curcumin to the sialic acid overexpressed in breast cancer cell membranes. Curcumin-loaded ZnO nanoparticles (ZnO-PBA-Curcumin) caused apoptotic cell death in MCF-7 human breast cancer cells by inducing oxidative stress and mitochondrial damage. Further, in vivo intravenous (i.v.) administration of ZnO-PBA-Curcumin was found to effectively decrease tumor growth in Ehrlich ascites carcinoma (EAC) tumor-bearing mice via the enhanced accumulation of curcumin. Interestingly, ZnO-PBA-Curcumin did not show any signs of systemic toxicity. The cytotoxic potential of the nanohybrid ZnO-PBA-Curcumin is attributed to the combinatorial cytotoxic effects of curcumin and ZnO in cancer cells. Collectively, ZnO-PBA-Curcumin may represent a potential treatment modality for breast cancer therapy. This study provides insight into the tumor cell targeting mechanism using PBA functionalization, and the anticancer efficacy of curcumin-loaded pH-sensitive nanohybrids can be attributed to the differential oxidative stress-inducing properties of curcumin and Zn+2 ions.

Microwave induced synthesis of ZnO nanorods and their efficacy as a drug carrier with profound anticancer and antibacterial properties.

In the present study, we report the microwave-induced synthesis of fluorescent zinc oxide nanorods (ZnO) and their usage as a cargo material to carry hydrophobic drug, quercetin. TEM and SEM showed the rod-shape morphology of our synthesized ZnO. XRD showed several diffraction peaks correspond to a hexagonal wurtzite structure. The optical and chemical natures of these nanorods were also confirmed from the UV-vis (showed a distinct absorption bands from 361 to 395 nm) and FTIR spectrum (showed absorption band specific to Zn-O stretching). The synthesized ZnO also showed fluorescence emission at around 550 nm when excited under UV irradiation. Quercetin was loaded onto ZnO surface via employing a metal ion-ligand coordination bond, (ZnO/QR), which exhibit pH-sensitive release behavior. ZnO/QR displayed superior drug loading content (42%) and loading efficiency (72.4%). in vitro assays showed that ZnO/QR exhibited higher anticancer, as well as antibacterial activities compared with free quercetin and ZnO. All these results highlight the synthesis of ZnO nanorods under microwave irradiation, which can be used as a plausible therapeutic option for bioimaging and drug delivery purpose.

Mangiferin Ameliorates Cisplatin Induced Acute Kidney Injury by Upregulating Nrf-2 via the Activation of PI3K and Exhibits Synergistic Anticancer Activity With Cisplatin.

Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-κB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro-survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin.

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.