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The diterpenoid, sugiol, has been reported to exert anticancer effects against a number of human cancers. However, the anticancer effects of sugiol have not been evaluated against the human glioma cells. The present study was designed to examine the effects of sugiol on the proliferation of human U87 glioma cells. The results showed that sugiol significantly (P < 0.05) suppressed the viability of the U87 cells in a concentration dependent manner and exhibited an IC50 value of 15 μM. On the other hand, the growth inhibitory effects of sugiol were minimal on the normal human astrocytes. Acridine orange and ethidium bromide staining (AO/EB) staining revealed that sugiol induces apoptosis which was further confirmed by Western blot analysis, wherein upregulation of Bax and downregulation of Bcl-2 were observed in U87 cells. Flow cytometry showed that sugiol causes cell cycle arrest at the G0/G1 stage. The relative percentage of G1 phase was found to be increased from 26.58% at 0 μM to 70.96% at 30 μM sugiol. Taken together, the results suggest sugiol inhibits the growth of glioma cells and may prove to be a lead molecule in the management of human glioma. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a vector‐borne disease caused by around 20 species of Leishmania. The main clinical forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). VL is caused by Leishmania infantum in Central and South America, Mediterranean Basin, Middle East, and by L. donovani in Asia and Africa. Sterol C‐24 methyltransferase (LdSMT) of L. donovani is a transferase enzyme of the sterol biosynthesis pathway. This pathway is one of the major targets for drug developments in Leishmania. Due to insufficient evidence about the exact function of SMT inside the cell and the uniqueness of the SMT enzyme in the Leishmania parasites made it a significant target for an effective drug development approach. We performed virtual screening of the Food and Drug Administration (FDA)‐approved drug library against LdSMT and found simeprevir, an antiviral drug on top in the binding score. It showed a significant binding affinity with LdSMT. The binding was supported by hydrogen bonds and several other interactions. Simeprevir inhibited L. donovani growth of promastigotes with 50% inhibitory concentration (IC50) of 51.49 ± 5.87 μM. Further studies showed that simeprevir induced ROS generation in 44.7% of parasites at 125‐μM concentration. Here, we for the first time reported simeprevir as an antileishmanial lead molecule using a drug repurposing approach. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality around the world. Early diagnosis of CVD could provide the opportunity for sensible management and better clinical outcome along with the prevention of further progression of the disease. In the current study, we used an untargeted metabolomic approach to identify possible metabolite(s) that associate well with the CVD and could serve either as therapeutic target or disease-associated metabolite. We identified 26 rationally adjusted unique metabolites that were differentially present in the serum of CVD patients compared with healthy individuals, among them 15 were found to be statistically significant. Out of these metabolites, we identified some novel metabolites like UDP-l-rhamnose and N1-acetylspermidine that have not been reported to be linked with CVD directly. Further, we also found that some metabolites like ethanolamide, solanidine, dimethylarginine, N-acetyl-l-tyrosine, can act as a discriminator of CVD. Metabolites integrating pathway enrichment analysis showed enrichment of various important metabolic pathways like histidine metabolism, methyl histidine metabolism, carnitine synthesis, along with arginine and proline metabolism in CVD patients. Our study provides a great opportunity to understand the pathophysiological role and impact of the identified unique metabolites and can be extrapolated as specific CVD specific metabolites. [ABSTRACT FROM AUTHOR]

Cynaroside, a flavonoid, has been shown to have antibacterial, antifungal and anticancer activities. Here, we evaluated its antileishmanial properties and its mechanism of action through different in silico and in vitro assays. Cynaroside exhibited antileishmanial activity in time- and dose-dependent manner with 50% of inhibitory concentration (IC50) value of 49.49 +- 3.515 µM in vitro. It inhibited the growth of parasite significantly at only 20 µM concentration when used in combination with miltefosine, a standard drug which has very high toxicity. It also inhibited the intra-macrophagic parasite significantly at low doses when used in combination with miltefosine. It showed less toxicity than the existing antileishmanial drug, miltefosine at similar doses. Propidium iodide staining showed that cynaroside inhibited the parasites in G0/G1 phase of cell cycle. 2,7-dichloro dihydro fluorescein diacetate (H2DCFDA) staining showed cynaroside induced antileishmanial activity through reactive oxygen species (ROS) generation in parasites. Molecular-docking studies with key drug targets of Leishmania donovani showed significant inhibition. Out of these targets, cynaroside showed strongest affinity with uridine diphosphate (UDP)-galactopyranose mutase with -10.4 kcal/mol which was further validated by molecular dynamics (MD) simulation. The bioactivity, ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, Organisation for Economic Co-operation and Development (OECD) chemical classification and toxicity risk prediction showed cynaroside as an enzyme inhibitor having sufficient solubility and non-toxic properties. In conclusion, cynaroside may be used alone or in combination with existing drug, miltefosine to control leishmaniasis with less cytotoxicity. [ABSTRACT FROM AUTHOR]

Cancer and autoimmune diseases are the two devastating conditions that together constitute a leading health problem worldwide. The rising burden of these disorders in the developing world demands a multifaceted approach to address the challenges it poses. Understanding the root causes and specific molecular mechanisms by which the progression of the diseases takes place is need of the hour. A strong inflammatory background and common developmental pathways, such as activation of immune cells, proliferation, increased cell survival and migration which are controlled by growth factors and inflammatory cytokines have been considered as the critical culprits in the progression and complications of these disorders. Enzymes are the potential immune modulators which regulate various inflammatory events and can break the circulating immune complexes via macrophages production. In the current manuscript, we have uncovered the possible role of proteolytic enzymes in the pathogenesis and progression of cancer and autoimmune diseases. In the light of the available scientific literature, we advocate in-depth comprehensive studies which will shed light towards the role of proteolytic enzymes in the modulation of inflammatory responses in cancer and autoimmune diseases together. [ABSTRACT FROM AUTHOR]

The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer's Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases. [ABSTRACT FROM AUTHOR]

Interleukin-10 (IL-10) is an anti inflammatory cytokine involved in the ongoing coronary inflammation and related patho-physiological processes. The piece of work presented herein is aimed at investigating possible association of polymorphisms in IL-10 promoter with Saudi cardiovascular disease (CVD) patients. The study included 80 confirmed CVD patients with diabetes and 75 healthy control individuals both men and women. Concentration of IL-10 in the serum samples were measured by ELISA method. For single nucleotide polymorphism (SNP) analysis, Sanger method of DNA sequencing was followed. The IL-10 level was found to be significantly elevated in CVD patients ( P < 0.001) and its associated complications viz. ST-elevation myocardial infarction [STEMI] ( P <0.01), non ST-elevation myocardial infarction [NSTEMI] ( P < 0.05), and unstable angina [UA] ( P < 0.001). We also observed a significant association between polymorphisms in IL-10 promoter at −1082 and −819 locus with Saudi CVD patients. Moreover, at −1082 A/G locus, AA haplotype was found to be less frequent in the CVD patients compared with control individuals. On the other hand, highly significant rise in heterozygous (A/G genotype) condition was observed in patient samples compared with control ones ( P < 0.001). Similarly, the genotypic frequencies at −819 C/T locus were also found to be significantly associated ( P < 0.001) with CVD patients compared with control individuals. Our study provides the status of polymorphism in IL-10 promoter and its association with CVD risk in Saudi population. As per our information, ours is the first article that shows the genetic diversity in IL-10 promoters and its level in the Saudi CVD patients. © 2017 IUBMB Life, 69(7):522-527, 2017 [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a well-known cause of memory loss and dementia in elderly people all across the world. It is pathophysiologically characterized by the extracellular deposition of amyloid beta (Aβ) proteins and retention of intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins. Several enzymes, such as lipoxygenases, acetylcholinesterases, secretases, glycogen synthase kinase 3, caspases, sirtuins have been reported to actively participate in the pathogenesis of AD. Due to the limited drug for the management of AD till now (only memantine and four other acetylcholinesterase inhibitors) , there is an urgent need to find out the novel inhibitors that could specifically act against these enzymes or therapeutically important targets, and barricade or decelerate AD progression. In this current review, we aim to unravel various enzymes and their potential inhibitors that could be exploited against AD pathogenesis. We have also covered several other important miscellaneous targets which could be used as AD therapeutics. [ABSTRACT FROM AUTHOR]

Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression. The correct funding information should be as follows: B Original: b Funding: Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia [Grant number IFPRC-146-141-2020]. Reference 1 Tabrez S., Zughaibi T.A., Hoque M., Suhail M., Khan M.I., Khan A.U. Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression. [Extracted from the article]

α-Crystallin, a member of small heat shock proteins, is the major structural protein within the eye lens and is believed to play an exceptional role in the stability of lens proteins and its transparency. In the current manuscript, we have investigated the effect of an organic solvent, trifluoroethanol (TFE), on the structure and function of α-crystallin isolated from camel eye lens. Incubation of this protein with TFE changed the secondary and tertiary structures, which resulted in the aggregation of α-crystallin as evidenced by intrinsic fluorescence, Rayleigh's scattering, Thioflavin T assay, and circular dichroism spectroscopic studies. The treatment with different concentrations of TFE led to increased exposure of hydrophobic domains of α-crystallin, which was observed by 8-anilino 1-napthalene sulfonic acid extrinsic fluorescence assay. These results clearly indicate that TFE induced significant changes in the secondary and tertiary structures of α-crystallin, leading to aggregation and amyloid formation. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay established the cytotoxicity of the aggregated α-crystallin towards HepG2 cell lines through reactive oxygen species production. In conclusion, α-crystallin protein was found to be susceptible to conformational changes by TFE, suggesting that α-crystallin, although basically acting like a heat shock protein and functionally displaying chaperone-like activity, might capitulate to change in lens environment induced by diseased conditions or age-related changes, resulting in cataract formation. [ABSTRACT FROM AUTHOR]

The non-enzymatic reaction between reducing sugars and proteins has received increased attention in nutritional and medical research recently. In the current manuscript, effect of glycation in structural changes of human serum albumin (HSA) by the metabolites of glucose such as glyoxal, methylglyoxal and glyceraldehyde was studied using different spectroscopy techniques. Glycation of HSA was monitored by following advanced glycation end-products (AGEs) fluorescence changes, HSA intrinsic fluorescence measurement, extrinsic fluorescence using 8-analino 1-nephthlene sulfonic acid (ANS) dye, and circular dichroism (CD) studies. AGEs were formed within 7 days of incubation with glyoxal, methylglyoxal and glyceraldehyde. However, methylglyoxal induced significant structural changes in HSA compared with glyoxal and glyceraldehydes. Moreover, ANS binding to native and glycated-HSA showed difference in binding pattern of these metabolites to HSA. The CD spectrum revealed changes in the secondary structure of HSA upon glycation when compared to native HSA. Furthermore, the MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay established the cytotoxicity of the glycated- HSA towards human liver carcinoma (HepG2) cell lines via the production of reactive oxygen species. [ABSTRACT FROM AUTHOR]

There are accumulating evidences suggesting that interaction between advanced glycation end products (AGEs) and their receptors (RAGEs) induces oxidative stress and subsequently encourages inflammatory reactions, thereby resulting in progressive alteration in renal architecture and function. Interventions that reduce the tissue burden of AGEs have yielded significant positive results in inhibiting the progression of diabetic complications such as diabetic nephropathy. Lycopene, a carotenoid, plays an important role in protection against oxidative stress and hence might prove an efficient antiglycating agent. Current study investigates the effect of lycopene in downregulating the menace caused by ribose-induced glycation both in vitro and in vivo. We observed that treatment with lycopene decelerated the ribose induced AGE formation in HK-2 cells and in rat kidneys thereby downregulating the expression RAGE. HK-2 cells with decreased levels of RAGE showed a decline in nuclear factor κB (NFκB) and matrix metalloproteinase 2 (MMP 2) expressions. Administration of ribose not only induced hyperglycemia in Wistar rats but also developed diabetic nephropathy (DN). However, lycopene was found effective in relieving the biochemical symptoms of DN. Thus lycopene provides protection against development of diabetic nephropathy and ameliorates renal function by halting AGE-RAGE axis. © 2015 BioFactors, 41(5):372-381, 2015. [ABSTRACT FROM AUTHOR]

Aims Extremely low frequency electromagnetic fields (ELF-EMFs) are widely employed in electrical appliances and different equipment such as television sets, mobile phones, computers and microwaves. The molecular mechanism through which ELF-EMFs can influence cellular behavior is still unclear. A hypothesis is that ELF-EMFs could interfere with chemical reactions involving free radical production. Under physiologic conditions, cells maintain redox balance through production of ROS/RNS and antioxidant molecules. The altered balance between ROS generation and elimination plays a critical role in a variety of pathologic conditions including neurodegenerative diseases, aging and cancer. Actually, there is a disagreement as to whether there is a causal or coincidental relationship between ELF-EMF exposure and leukemia development. Increased ROS levels have been observed in several hematopoietic malignancies including acute and chronic myeloid leukemias. Main methods In our study, the effect of ELF-EMF exposure on catalase, cytochrome P450 and inducible nitric oxide synthase activity and their expression by Western blot analysis in myelogenous leukemia cell line K562 was evaluated. Key findings A significant modulation of iNOS, CAT and Cyt P450 protein expression was recorded as a result of ELF-EMF exposure in both phorbol 12-myristate 13-acetate (PMA)-stimulated and non-stimulated cell lines. Modulation in kinetic parameters of CAT, CYP-450 and iNOS enzymes in response to ELF-EMF indicates an interaction between the ELF-EMF and the enzymological system. Significance These new insights might be important in establishing a mechanistic framework at the molecular level within which the possible effects of ELF-EMF on health can be understood. [ABSTRACT FROM AUTHOR]

Glyoxal, methylglyoxal and 3-deoxyglucosones are reactive dicarbonyl compounds, which transform free amino groups of proteins and lipoproteins macromolecule into advanced glycation end-products (AGEs). AGEs play a significant role in the pathophysiology of aging and diabetic complications because of their genotoxic effect. Glyoxal also reacts with free amino group of nucleic acids resulting in the formation of DNA–AGEs. The present study reports the genotoxicity and immunogenicity of AGEs formed by Glyoxal–Arginine–Fe 3+ (G–Arg–Fe 3+ ) system as a glycating agent. Immunogenicity of native and G–Arg–Fe 3+ –DNA was probed in female rabbits. Immunofluorescence suggests the presence of immune complex deposition in the kidney section of immunized rabbits. Spectroscopic analysis and melting temperature indicates the structural modification in the human DNA. The modified human DNA is found to be highly immunogenic, whereas unmodified form was simply non-immunogenic. This study shows the presence of auto-antibodies against G–Arg–Fe 3+ modified human DNA in the sera of diabetes type 1 and in few cases type 2 patients due to secondary complications of nephropathy. The glyco-oxidative lesions have also been detected in the lymphocyte DNA isolated from patients having type 1 and type 2 diabetes. The results show structural perturbations generating new epitopes in G–Arg–Fe 3+ –DNA rendering it pretty immunogenic. [ABSTRACT FROM AUTHOR]

Highlights: [•] We have highlighted some well-known genes involved in carcinogenesis. [•] We have covered carcinogenesis because of certain environmental pollutants. [•] We have reported carcinogenesis in response to heavy metals and pesticides. [•] First time exposure of these pollutants has been reported in a single article. [Copyright &y& Elsevier]

Today cancer is a leading cause of death among the developed countries. Its highly complex nature makes it difficult to understand as it entails multiple cellular physiological systems such as cell signaling and apoptosis. The biggest challenges faced by cancer chemoprevention/chemotherapy is maintaining drug circulation and avoiding multidrug resistance. Overall there is modest evidence regarding the protective effects of nutrients from supplements against a number of cancers. Numerous scientific literatures available advocate the use of polyphenols for chemoprevention. Some groups have also suggested use of combination of nutrients in cancer prevention. However, we have yet to obtain the desired results in the line of cancer chemotherapy research. Nanotechnology can play a pivotal role in cancer treatment and prevention. Moreover, nanoparticles can be modified in various ways to prolong circulation, enhance drug localization, increase drug efficacy, and potentially decrease the chances of multidrug resistance. In this communication, we will cover the use of various polyphenols and nutrients in cancer chemoprevention. The application of nanotechnology in this regard will also be included. In view of available reports on the potential of nanoparticles, we suggest their usage along with different combination of nutrients as cancer chemotherapeutic agents. [ABSTRACT FROM PUBLISHER]

Abstract: Trichloroethylene (TCE) is a suspected genotoxic and carcinogenic compound which is usually present in the air, soil and water as pollutant. To estimate the genotoxic potential of TCE in a pure chemical form as well as an ingredient of the complex sample, Ames fluctuation test using TA98 and TA100 strains and Allium cepa genotoxicity assay were performed. For the genotoxicity analysis of TCE in natural milieu, the above mentioned tests were performed on the waste waters collected from two different stations of northern India namely Saharanpur and Aligarh, U.P., and these waste waters were supplemented with 50 and 100mg/l of trichloroethylene. TCE alone was found to be non-genotoxic by both the testing system up to the range of 1000mg/l concentration (data not shown). However, the test water samples supplemented with 100mg/l of TCE, exhibited a significant increase in the genotoxicity compared with control by both the testing systems. In Ames fluctuation test, Mi(f) value was found to be increased by 41% and 53% with 100mg/l of TCE supplemented Saharanpur and Aligarh waste water samples respectively, in the presence of S9 fraction compared with their respective controls. Allium cepa genotoxicity test also showed around 25% increase in total chromosomal aberration frequency following 100mg/l TCE supplementation. However, supplementation of 50mg/l TCE to the test water samples could not enhance the genotoxicity to a significant extent. From these results, we can conclude that TCE itself was non-genotoxic but it may promote mutation and/or DNA damage at a concentration of 100mg/l under certain environmental conditions. We suggest that some chemicals in the test water samples might be interacting with TCE and/or metabolite(s) to cause the enhancement in genotoxicity. The mechanism of these synergistic effects should be explored further. [Copyright &y& Elsevier]

Abstract: Oxidative stress-mediated genotoxicity of wastewaters taken from two different cities, Saharanpur (SWW) and Aligarh (AWW), were compared with a battery of short-term assays namely the Allium cepa genotoxicity test, the plasmid-nicking assay, and the Ames fluctuation test. Both test-water samples – when used undiluted – increased the frequency of chromosomal abnormalities and/or micronuclei and alterations in the mitotic index of root cells of Allium cepa. Bridges and fragmentation of the chromosome were the predominant effects of the Saharanpur water sample while the Aligarh sample induced mainly chromosome fragmentation. Single- and double-strand breaks were also observed in plasmid DNA treated with these test wastewaters. The plasmid-nicking assay performed on SWW resulted in linearization of plasmid DNA when 18μl was tested (in a total reaction volume of 20μl). However, with the same amount of AWW, all three forms of plasmid, viz. supercoiled, open circular and linear were observed. Supplementation with specific scavengers of reactive oxygen species (ROS) caused a significant decline in mutagenicity of test-water samples in all the tests, pointing at oxidative stress as the mediator of the observed genotoxicity. The role of heavy metals in the AWW-induced oxidative stress and that of phenolics in SWW cannot be ruled out. [Copyright &y& Elsevier]

Rapid industrialization, use of modern agriculture practices, and fast urbanization vis-a-vis indiscriminate use of xenobiotics have led to the serious problems of water pollution in India and abroad. The complexicity of the pollutants in environmental samples demands a multitude of genotoxicity testing with increasing simplicity, sensitivity, and affordability. Moreover, various pollutants mutually affect their own toxic behavior, which complicates the problem of risk assessment. An overview, highlighting the genotoxicity testing system, such as Ames plate incorporation test, Ames fluctuation test, E. coli survival assay, Allium cepa toxicity/genotoxicity test, comet assay, and plasmid nicking assay, is presented in this article, and a comparison has been made to estimate the efficacy of these genotoxicity bioassays performed on some surface waters. Some work on toxicity biomarkers vis-a-vis studies on surface waters has also been included in the present review. [ABSTRACT FROM PUBLISHER]

Trichloroethylene (TCE) is a potent hepatocarcinogen (National Cancer Institute, USA) and is widely used as a metal degreasing agent. Concentration-dependent effect of TCE exposure on Allium cepa (onion) bulbs for 48 h was determined on the activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GPx), ascorbate peroxidase (APx), monodehydroascorbate reductase (MDHAR) and dehydroascorbate reductase (DHAR). Levels of hydrogen peroxide (H2O2), ascorbate (ASC), and glutathione (GSH) were also measured in onion homogenates to monitor TCE-induced oxidative stress. At 200 ppm TCE concentration, the activities of GST and GR in exposed onion bulbs exhibited roughly three-fold induction compared with control, whereas reduction in activities at higher levels of TCE concentration was recorded. A two-fold induction of CAT with a simultaneous and significant induction in activities of APx, GPx, and MDHAR at increasing TCE concentrations was observed at 150 ppm of TCE exposure. Minimum level of induction was observed for SOD (79%) and DHAR (63%) at 250 and 300 ppm of TCE, respectively. Results indicate that GST, GR, APx, and CAT in A. cepa system could serve as potential indicators of TCE-induced enzymatic perturbations. [ABSTRACT FROM AUTHOR]

Abstract: In the present study the effect of laboratory exposure to wastewaters from Aligarh (AWW) and Saharanpur (SWW) on the activities of cytochrome P450 (CYP450) isozymes like ethoxyresorufin-o-deethylase (EROD), pentoxyresorufin-o-deethylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) were investigated in the liver and kidney of rats. The industrial wastewater samples from Saharanpur city of northern India resulted 12, 3.5 and 1.5-fold rise in the EROD (CYP1A1), PROD (CYP2B1) and NDMA-d (CYP2E1) activity, respectively, in the liver of treated animals. Renal EROD and PROD activities were found to be enhanced by around 5 and 7-folds, respectively, as a result of SWW treatment. On the other hand, Aligarh samples showed significant inhibition in these test CYP450 enzymes both in hepatic as well as renal tissues. Strong induction of CYP1A1 (>10-fold) suggests that EROD can serve as a potent biomarker of SWW in the liver of treated animal. However, PROD and EROD can also act as fairly good biomarkers in case of renal tissue. Marked elevation of EROD activity in SWW treated animals strongly suggests the overwhelming levels of EROD inducers in the Saharanpur sample while a meagre amount of inducers accompanied with significant levels of inhibitors in the Aligarh sample. [Copyright &y& Elsevier]

Abstract: In the present study, alteration in antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione peroxidase (GPx) and marker enzymes of tissue damage alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) with laboratory exposure to wastewaters from Aligarh (AWW) and Saharanpur (SWW) were investigated in rat liver and kidney. Levels of malondialdehyde (MDA), reduced glutathione (GSH) and hydrogen peroxide (H2O2) were also determined. A profound enhancement of 5 and 2.5-folds in MDA level was recorded in the liver and kidney respectively as a result of oral administration of SWW to the rats. Exposure to both AWW and SWW resulted in 3–4-fold increase in GR activity and 3-fold increase in SOD and ALT activity in the hepatic tissue compared to control values. Ingestion of AWW and SWW resulted in 3.5-fold rise in renal AST levels whereas AWW caused 75% decline in GST activity in kidney of treated rats. Results indicate that wastewater (AWW/SWW) caused severe damage to renal and hepatic tissues and the effect seems in part to be mediated by suppression of antioxidant system with GR and SOD as potential candidates for hepatic toxicity biomarkers of wastewaters. [Copyright &y& Elsevier]

Trichloroethylene (TCE) is a prevalent occupational and environmental contaminant that has been reported to cause a variety of toxic effects. This article reviews toxicity, mutagenicity, and carcinogenicity caused by the exposure of TCE and its metabolites in the living system as well as on their (TCE and its metabolites) toxicity biomarkers. [ABSTRACT FROM AUTHOR]

Superoxide dismutase (SOD) is a crucial enzyme responsible for the redox homeostasis inside the cell. As a part of the antioxidant defense system, it plays a pivotal role in the dismutation of the superoxide radicals (O2−) generated mainly by the oxidative phosphorylation, which would otherwise bring out the redox dysregulation, leading to higher reactive oxygen species (ROS) generation and, ultimately, cell transformation, and malignancy. Several studies have shown the involvement of ROS in a wide range of human cancers. As SOD is the key enzyme in regulating ROS, any change, such as a transcriptional change, epigenetic remodeling, functional alteration, and so forth, either activates the proto‐oncogenes or aberrant signaling cascades, which results in cancer. Interestingly, in some cases, SODs act as tumor promoters instead of suppressors. Furthermore, SODs have also been known to switch their role during tumor progression. In this review, we have tried to give a comprehensive account of SODs multifactorial role in various human cancers so that SODs‐based therapeutic strategies could be made to thwart cancers. [ABSTRACT FROM AUTHOR]

Leishmaniasis is considered a tropical neglected disease, which is caused by an intramacrophagic parasite, Leishmania. It is endemic in 89 different countries. Autophagy‐related protein 8 (Ldatg8) is responsible for the transformation of parasites from promastigote to amastigote differentiation. Ldatg8 is one of the key drug targets of Leishmania donovani (L. donovani) responsible for the defense of parasites during stress conditions. Virtual screening of natural ligand library had been performed against Ldatg8 to identify novel and potent inhibitors. Molecular docking and molecular dynamics simulation studies showed that urolithin A stably blocked Ldatg8. Urolithins are combinations of coumarin and isocoumarin. Further, we evaluated the antileishmanial effects of urolithin A by antileishmanial assays. Urolithin A inhibited the growth and proliferation of L. donovani promastigotes with an IC50 value of 90.3 ± 6.014 μM. It also inhibited the intramacrophagic parasite significantly with an IC50 value of 78.67 ± 4.62 μM. It showed limited cytotoxicity to the human THP‐1 differentiated macrophages with a CC50 value of 190.80 ± 16.89 μM. Further, we assayed reactive oxygen species (ROS) generation and annexin V/PI staining upon urolithin A treatment of parasites to have an insight into the mechanism of its action. It induced ROS significantly in a dose‐dependent manner, which caused apoptosis partially in parasites. The potential inhibitors for Ldatg8, identified in this study, would provide the platform for the development of an effective and affordable antileishmanial drug. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is regarded as the most aggressive form of brain tumor delineated by high cellular heterogeneity; it is resistant to conventional therapeutic regimens. In this study, the anti-cancer potential of garcinol, a naturally derived benzophenone, was assessed against GBM. During the analysis, we observed a reduction in the viability of rat glioblastoma C6 cells at a concentration of 30 µM of the extract (p < 0.001). Exposure to garcinol also induced nuclear fragmentation and condensation, as evidenced by DAPI-stained photomicrographs of C6 cells. The dissipation of mitochondrial membrane potential in a dose-dependent fashion was linked to the activation of caspases. Furthermore, it was observed that garcinol mediated the inhibition of NF-κB (p < 0.001) and decreased the expression of genes associated with cell survival (Bcl-XL, Bcl-2, and survivin) and proliferation (cyclin D1). Moreover, garcinol showed interaction with NF-κB through some important amino acid residues, such as Pro275, Trp258, Glu225, and Gly259 during molecular docking analysis. Comparative analysis with positive control (temozolomide) was also performed. We found that garcinol induced apoptotic cell death via inhibiting NF-κB activity in C6 cells, thus implicating it as a plausible therapeutic agent for GBM. [ABSTRACT FROM AUTHOR]

Curcumin is a natural compound derived from turmeric and can target malignant tumor molecules involved in cancer propagation. It has potent antioxidant activity, but its effectiveness is limited due to poor absorption and rapid elimination from the body. Various curcumin derivatives have also shown anticancer potential in in‐vitro and in‐vivo models. Curcumin can target multiple signaling pathways involved in cancer development/progression or induce cancer cell death through apoptosis. In addition, curcumin and its derivatives could also enhance the effectiveness of conventional chemotherapy, radiation therapy and reduce their associated side effects. Lately, nanoparticle‐based delivery systems are being developed/explored to overcome the challenges associated with curcumin's delivery, increasing its overall efficacy. The use of an imaging system to track these formulations could also give beneficial information about the bioavailability and distribution of the nano‐curcumin complex. In conclusion, curcumin holds significant promise in the fight against cancer, especially in its nanoform, and could provide precise delivery to cancer cells without affecting normal healthy cells. Significance statement: The current article highlights the usage of natural compounds, especifically curcumin, as an anticancer agent. Due to their inherent property, such as poor absorption and solubility, low bioavailability, and rapid elimination, this potent compound has yet to be exploited to its potential. To overcome the above‐mentioned issues, several nanoformulations have been developed that overcome these limitations and enhance the efficacy of this compound in different in‐vitro and in‐vivo cancer models. [ABSTRACT FROM AUTHOR]

Quinoline yellow (QY) is a synthetic yellow dye widely used as a coloring agent for various foodstuffs. In the current study, we have examined the role of QY on the aggregation propensity of hen egg-white lysozyme (HEWL) under physiological conditions. The dye induced conformational changes in HEWL leading to aggregate formation were identified by circular dichroism (CD), turbidity analysis, fluorescence measurement and microscopic (TEM) imaging. Molecular docking and molecular dynamics simulation studies were also employed to strengthen binding and aggregation results. Our results indicate that 25–100 µM of QY induces aggregation in HEWL, while lower QY concentrations (5 and 10 µM) does not have any effect on the aggregation propensity of HEWL. The kinetics of HEWL aggregation demonstrate nucleation independent aggregation of HEWL without lag phase. On the other hand, far UV-CD analysis illustrated the loss of α-helical structure with the increasing concentration of QY. TEM results also support the formation of aggregate structures in HEWL when exposed to QY. Molecular docking and simulation studies revealed that the HEWL-QY complex is stable as compared to individual entities. In silico analysis also illustrated that QY-induced aggregation of HEWL proceeds through the formation of hydrogen bonds, electrostatic (Pi-Anion) and Pi-Sulfur interactions. The above-mentioned results highlight the possible detrimental effect by food additive dyes, particularly in protein misfolding. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder. Recent reports suggest that it affects more than 36 million people worldwide and accounts 60–80% of all cases of dementia. It is characterised by aberrations of multiple interactive systems and pathways, which ultimately lead to memory loss and cognitive dysfunction. The exact mechanisms and initial triggering factors that underpin the known pathological defects in AD remain to be fully elucidated. In addition, an effective treatment strategy to reduce the progression of AD is yet to be achieved. In the light of above-mentioned facts, our article deals with the exploration of the mitochondrial defect and oxidative stress leading to this devastating disease. In this communication, we have highlighted specific mitochondrial and antioxidant-directed approach to ameliorate and manage AD. Nonetheless, new approaches should also be investigated that could tackle various molecular events involved in AD pathogenicity. [ABSTRACT FROM AUTHOR]

AbstractNK-lysins from chicken, bovine and human are used as antiviral and antibacterial agents. Gram-negative and gram-positive microorganisms, including Streptococcus pyogenes, Streptococcus mutans, Escherichia coli, Pseudomonas aeruginosa, Klebsiella oxytoca, Shigella sonnei, Klebsiella pneumoniae and Salmonella typhimurium, are susceptible to NK-lysin treatment. The presence of dominant TEM-1 gene was noted in all untreated and treated bacteria, while TOHO-1 gene was absent in all bacteria. Importantly, β-lactamase genes CTX-M-1, CTX-M-8, and CTX-M-9 genes were detected in untreated bacterial strains; however, none of these were found in any bacterial strains following treatment with NK-lysin peptides. NK-lysin peptides are also used to test for inhibition of infectivity, which ranged from 50 to 90% depending on NK-lysin species. Chicken, bo vine and human NK-lysin peptides are demonstrated herein to have antibacterial activity and antiviral activity against Rotavirus (strain SA-11). On the basis of the comparison between these peptides, potent antiviral activity of bovine NK-lysin against Rotavirus (strain SA-11) is particularly evident, inhibiting infection by up to 90%. However, growth was also significantly inhibited by chicken and human NK-lysin peptides, restricted by 80 and 50%, respectively. This study provided a novel treatment using NK-lysin peptides to inhibit expression of β-lactamase genes in β-lactam antibiotic-resistant bacterial infections. [ABSTRACT FROM AUTHOR]

Cu4O3 is the least explored copper oxide, and its nanoformulation is anticipated to have important therapeutic potential especially against cancer. The current study aimed to biosynthesize Cu4O3 nanoparticles (NPs) using an aqueous extract of pumpkin seeds and evaluate its antiproliferative efficacy against cervical cells after screening on different cancer cell lines. The obtained NPs were characterized by different spectroscopic analyses, such as UV‐vis, thermogravimetric, energy dispersive X‐ray, and Fourier‐transform infrared spectroscopy (FTIR). In addition, high‐resolution transmission electron microscopes (HR‐TEM) were used to observe the morphology of the biosynthesized NPs. The UV‐vis spectra showed a peak at around 332 nm, confirming the formation of Cu4O3 NPs. Moreover, FTIR and TAG analyses identified the presence of various bioactive phytoconstituents that might have worked as capping and stabilization agents and comparative stable NPs at very high temperatures, respectively. The HR‐TEM data showed the spherical shape of Cu4O3 NPs in the range of 100 nm. The Cu4O3 NPs was screened on three different cancer cell lines viz., Hela, MDA‐MB‐231, and HCT‐116 using cytotoxicity (MTT) reduction assay. In addition, Vero was taken as a normal epithelial (control) cell. The high responsive cell line in terms of least IC50 was further assessed for its anticancer potential using a battery of biological tests, including morphological alterations, induction of apoptosis/ROS generation, regulation of mitochondrial membrane potential (MMP), and suppression of cell adhesion/migration. Vero cells (control) showed a slight decline in % cell viability even at the highest tested Cu4O3 NPs concentration. However, all the studied cancer cells viz., MDA‐MB‐231, HCT 116, and HeLa cells showed a dose‐dependent decline in cell viability after the treatment with Cu4O3 NPs with a calculated IC50 value of 10, 11, and 7.2 µg/mL, respectively. Based on the above data, Hela cells were chosen for further studies, that showed induction of apoptosis from 3.5 to 9‐folds by three different staining techniques acridine orange/ethidium bromide (AO/EB), 4′,6‐diamidino‐2‐phenylindole (DAPI), and propidium iodide (PI). The enhanced production of reactive oxygen species (>3.5‐fold), modulation in MMP, and suppression of cell adhesion/migration were observed in the cells treated with Cu4O3 NPs. The current study obtained the significant antiproliferative potential of Cu4O3 NPs against the cervical cancer cell line, which needs to be confirmed further in a suitable in vivo model. Based on our results, we also recommend the green‐based, eco‐friendly, and cost‐effective alternative method for synthesizing novel nanoformulation. Significance Statement: Cu4O3 NPs was biosynthesized using pumpkin seeds aqueous extract.The biogenic Cu4O3 NPs was found to be spherical and ~100 nm size.A dose‐dependent cytotoxicity with a IC50 value of 7.2 µg/mL was observed against Hela cells.Induction of apoptosis up to 9‐fold was observed using different staining techniques.The enhanced production of reactive oxygen species, modulation in mitochondrial membrane potential, and suppression of cell adhesion/migration were observed in the cells treated with Cu4O3 NPs. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is one of the most hazardous metals to the environment and human health. Neurotoxicity is of the most serious hazards caused by Cd. Mirtazapine (MZP) is a central presynaptic α2 receptor antagonist used effectively in treating several neurological disorders. This study investigated the anti-inflammatory and antioxidant activity of MZP against Cd-induced neurotoxicity. In this study, rats were randomly divided into five groups: control, MZP (30 mg/kg), Cd (6.5 mg/kg/day; i.p), Cd + MZP (15 mg/kg), and Cd + MZP (30 mg/kg). Histopathological examination, oxidative stress biomarkers, inflammatory cytokines, and the impact of Nrf2 and NF-κB/TLR4 signals were assessed in our study. Compared to Cd control rats, MZP attenuated histological abrasions in the cerebral cortex and CA1 and CA3 regions of the hippocampus as well as the dentate gyrus. MZP attenuated oxidative injury by upregulating Nrf2. In addition, MZP suppressed the inflammatory response by decreasing TNF-α, IL-1β, and IL-6 mediated by downregulating TLR4 and NF-κB. It is noteworthy that MZP's neuroprotective actions were dose-dependent. Collectively, MZP is a promising therapeutic strategy for attenuating Cd-induced neurotoxicity by regulating Nrf2, and NF-κB/TLR4 signals, pending further study in clinical settings. [ABSTRACT FROM AUTHOR]

Cancer is a disease that has been the focus of scientific research and discovery and continues to remain so. Polo-like kinases (PLKs) are basically serine/threonine kinase enzymes that control cell cycle from yeast to humans. PLK-1 stands for 'Polo-like kinase-1'. It is the most investigated protein among PLKs. It is crucial for intracellular processes, hence a ' hot ' anticancer drug-target. Accelerating innovations in Enzoinformatics and associated molecular visualization tools have made it possible to literally perform a ' molecular level walk ' traversing through and observing the minutest contours of the active site of relevant enzymes. PLK-1 as a protein consists of a kinase domain at the protein N-terminal and a Polo Box Domain (PBD) at the C-terminal connected by a short inter-domain linking region. PBD has two Polo-Boxes. PBD of PLK-1 gives the impression of "a small clamp sandwiched between two clips", where the two Polo Boxes are the 'clips' and the 'phosphopeptide' is the small 'clamp'. Broadly, two major sites of PLK-1 can be potential targets: one is the adenosine-5′-triphosphate (ATP)–binding site in the kinase domain and the other is PBD (more preferred due to specificity). Targeting PLK-1 RNA and the interaction of PLK-1 with a key binding partner can also be approached. However, the list of potent small molecule inhibitors targeting the PBD site of PLK-1 is still not long enough and needs due input from the scientific community. Recently, eminent scientists have proposed targeting the 'Y'-shaped pocket of PLK-1-PBD and encouraged design of ligands that should be able to concurrently bind to two or more modules of the 'Y' pocket. Hence, it is suggested that during molecular interaction analyses, particular focus should be kept on the moiety in each ligand/drug candidate which directly interacts with the amino acid residue(s) that belong(s) to one of the three binding modules which together create this Y-shaped cavity. This obviously includes (but it is not limited to) the 'shallow cleft'-forming residues i.e. Trp414, H538 and K540, as significance of these binding residues has been consistently highlighted by many studies. The present article attempts to give a concise yet critically updated overview of targeting PLK-1 for cancer therapy. [ABSTRACT FROM AUTHOR]

Introduction: This study was carried out to evaluate the antioxidant potential of crude extract of Solanum nigrum leaves and its active constituents as treatment against restraint stress in rat's liver. Methods: For this purpose, male albino Wistar rats were treated with crude extract of leaves and its alkaloid and flavonoid fractions both before and after 6 h of acute restraint stress. Prooxidant status of rat liver was assessed by determining the levels of thiobarbituric acid reactive substances, reduced glutathione, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, and the activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST). Results: Six hours of restraint stress generated oxidative stress in rat's liver resulted in a significant rise in the level of the aforementioned liver enzymes. On the other hand, SOD, CAT, and GST enzymatic activities showed a significant decline in their level. The administration of crude leaves extract, both before and after stress exposure, significantly prevented the rise in the level of liver enzymes and reverted the activities of studied biochemical parameters toward their normal control values. However, the reversion was found to be more prominent in after-stress group. Conclusion: The aforementioned results highlight the significant antioxidant potential of S. nigrum extracts. On the basis of our study, we suggest the possible use of S. nigrum leaves extract as a nutritional supplement for combating oxidative stress induced damage. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Aloe vera is a widely used medicinal plant for its various biological activities. This study evaluate possible mutagenic and healing effects of the aqueous extract of A. vera (AEAV) in mice and its oxidant/antioxidant potential in different proficient and deficient Saccharomyces cerevisiae strains. Material and methods The AEAV was topically treated on the wounded skin surface of male albino mice at doses of 10 and 50 mg/kg for seven successive days. The control group was similarly treated with 0.9% NaCl solution. For oxidative/anti-oxidative evaluation, both proficient and deficient strains of S. cerevisiae [cytoplasmic and mitochondrial superoxide dismutase mutant (SOD: Sod1Δ and Sod2Δ), cytoplasmic catalase mutant (CAT: Cat1Δ)], two double defective mutants of Sod1 and Sod2 and Sod1 and Cat1 genes along with a wild-type strains were used. Results The healing property of AEAV was observed at the dose of 50 mg/kg but at the same dose it showed mutagenic and cytotoxic effects in peripheral blood. AEAV did not produce the oxidizing effect, except in the mutated CAT strain at highest concentration (50 mg/kg). Conclusion The high concentration of AEAV showed mutagenicity and cytotoxicity. Beside, the healing capacity is believed to be due to its anti-oxidative defense mechanism. Graphical abstract Scared area of skin treated with saline and the aqueous extract of Aloe vera. [(A) saline solution, (B) AEAV at 10 mg/kg and (C) AEAV at 50 mg/kg] fx1 [ABSTRACT FROM AUTHOR]

Cancer and diabetes mellitus (DM) are among the leading causes of mortality and morbidity in the global arena. Lately, several studies demonstrated that DM could promote cancer. However, the exact mechanism(s) highlighting this association are largely untouched and require comprehensive detailing. In the present review, we aimed to explore and decipher the possible mechanism of DM an cancer association. Hyperglycemia could be a subordinate plausible explanation of carcinogenesis in the diabatic patient. It is well known that high glucose levels may help in cancer proliferation. In addition, chronic inflammation, the other well‐known factor of diabetes, could also play a role in carcinogenesis. Moreover, the numerous medicines to treat diabetes either increase or reduce cancer risk. Insulin is one of the potent growth factors that promotes cell propagation and induces cancer directly or via insulin like growth factor‐1. On the other hand, hyperinsulinemia leads to an increased activity of growth factor‐1 by inhibiting growth factor binding protein‐1. To improve cancer prognosis, individuals with diabetes should be screened to discover cancer at an early stage and treated appropriately. Significance statement: The current article highlights the possible linkage between various forms of cancer and diabetes mellitus based on experimental animal models and epidemiological studies.Different factors such as hyperglycemia, inflammation, and antidiabetic medicine have been suggested to play the interlinking role.Hyperinsulinemia could also increase the chances of cancer through hyperactivations of insulin like growth factor‐1. [ABSTRACT FROM AUTHOR]

Summary: Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β‐amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances. Approximately, 60%‐80% of all cases of dementia in the world are patients with AD. In view of the continuous rise of this disease especially in the aged population, there is a dire need to come up with a novel compound and/or mixture that could work against this devastating disease. In this regard, the best is to rely on natural compounds rather than synthetic ones, because natural compounds are easily available, cost‐effective, and comparatively less toxic. To serve this purpose, lately, scientific community has started exploring the possibility of using different polyphenols either solitary or in combination that can serve as therapeutics against AD. In the current article, we have summarized the role of various polyphenols, namely quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, and caffeic acid as an inhibitor of cholinesterase for the treatment of AD. We have also tried to uncover the mechanistic insight on the action of these polyphenols against AD pathogenicity. [ABSTRACT FROM AUTHOR]

Galectins are mammalian lectins characterized by affinity for β-galactosides and the presence of a conserved carbohydrate recognition domain (CRD). Galectins play crucial role in the causation and progression of deadly human diseases like cancer, neurodegenerative disorders and cardiovascular disorders. Available literature reports relevant roles of galectins in innate as well as adaptive immune responses, along with the modulation of acute inflammatory response. In the current study, we purified the goat heart galectin-1 (GHG-1) and carried out its extensive immunological studies. Immunodiffusion studies revealed that anti-GHG-1 antibodies recognize the GHG-1 more readily as compared to the other galectins, suggesting its preferred utilization in various recognition studies. Antigenic cross-reactivity between galectins isolated from different tissues and species suggest their evolutionary preserved fundamental biological roles. A gradual increase in the lysozyme release was evident when the neutrophils were treated with various neutrophil activating agents. The findings of the present study confirm the increase in lysozyme production under the presence of various neutrophil activators, and thus add new information on GHG-1 induced degranulation. [ABSTRACT FROM AUTHOR]

Abstract: Cancer is a complex disease that transforms a normal cell into a malignant cell by disturbing different molecular mechanisms. Lately, plant‐derived bioactive products have gained prominent attention to serve as anti‐cancer agents. These natural anti‐neoplastic agents are believed to act as alternatives for the synthetic drugs or could be used to enhance the prospect of other drugs in reducing their dose, thus limiting their possible toxic effects. They could also counterbalance the other anti‐cancer drug‐induced adverse effects. Among natural plant‐derived products, coffee has been reported for its significant anti‐carcinogenic effects in the scientific literature. This article aims to highlight the anti‐cancer potential of different coffee components viz. caffeic acid, chlorogenic acids, caffeine (1,3,7‐trimethylxanthine), cafestol, ferulic acid, and kahweol together in a single article. Based on our article, it is quite clear that these bioactive components have important therapeutic potentials against cancerous cells. However, the lack of clinical data negates their use in humans. Therefore, more research is recommended to achieve the desired pharmaceutical value. We also implore assessing their safety and possible adverse effects prior to their progress into clinical trials. © 2018 BioFactors, 44(4):315–326, 2018 [ABSTRACT FROM AUTHOR]

Human mortalin is a Hsp70 mitochondrial protein that plays an essential role in the biogenesis of mitochondria. The deregulation of mortalin expression and its functions could lead to several age-associated disorders and some types of cancers. In the present study, we optimized the expression and purification of recombinant human mortalin by the use of two-step chromatography. Low temperature (18 °C) and 0.5 mM (IPTG) was required for optimum mortalin expression. Chaperone activity of mortalin was assessed by the citrate synthase and insulin protection assay, which suggested their protective role in mitochondria. Folding and unfolding assessments of mortalin were carried out in the presence of guanidine hydrochloride (GdnHCl) by intrinsic fluorescence measurement, ANS (8-analino 1-nephthlene sulfonic acid) binding and CD (circular dichroism) analysis. Under denaturing conditions, mortalin showed decrease in tryptophan fluorescence intensity along with a red shift of 11 nm. Moreover, ANS binding studies illustrated decrease in hydrophobicity. CD measurement of mortalin showed a predominant helical structure. However, the secondary structure was lost at low concentration of GdnHCl (1 M). We present a simple and robust method to produce soluble mortalin and warranted that chaperones are also susceptible to unfolding and futile to maintain protein homeostasis. [ABSTRACT FROM AUTHOR]

Background: Cancer is a chronic, heterogeneous illness that progresses through a spectrum of devastating clinical manifestations and remains the 2nd leading contributor to global mortality. Current cancer therapeutics display various drawbacks that result in inefficient management. The present study is intended to evaluate the anticancer potential of Cu-Mn bimetallic NPs (CMBNPs) synthesized from pumpkin seed extract against colon adenocarcinoma cancer cell line (HT-29). Methods: The CMBNPs were biosynthesized by continuously stirring an aqueous solution of pumpkin seed extract with CuSO4 and manganese (II) acetate tetrahydrate until a dark green solution was obtained. The characteristic features of biogenic CMBNPs were assessed by UV-visible spectrophotometry (UV-vis), X-ray powder diffraction (XRD), energy-dispersive X-ray (EDX), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). A battery of biological assays, viz. neutral red uptake (NRU) assay, in vitro scratch assay, and comet assay, were performed for anticancer efficacy evaluation. Results: The formation of spherical monodispersed bimetallic nanoparticles with an average size of 50 nm was recorded using TEM. We observed dose-dependent cytotoxicity of CMBNPs in the HT-29 cell line with an IC50 dose of 115.2 µg/mL. On the other hand, CMBNPs did not show significant cytotoxicity against normal cell lines (Vero cells). Furthermore, the treatment of CMBNPs inhibited the migration of cancer cells and caused DNA damage with a significant increase in comet tail length. Conclusions: The results showed substantial anticancer efficacy of CMBNPs against the studied cancer cell line. However, it is advocated that the current work be expanded to different in vitro cancer models so that an in vivo validation could be carried out in the most appropriate cancer model. [ABSTRACT FROM AUTHOR]

Cancer development is associated with the deregulation of various cell signaling pathways brought on by certain genetic and epigenetic alterations. Therefore, novel therapeutic strategies have been developed to target those pathways. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) pathway is one major deregulated pathway in various types of cancer. Several anticancer drug candidates are currently being investigated in preclinical and/or clinical studies to target this pathway. Natural bioactive compounds provide an excellent source for anticancer drug development. Curcumin and plumbagin are two potential anticancer compounds that have been shown to target the PI3K/Akt/mTOR pathway individually. However, their combinatorial effect on cancer cells is still unknown. This study aims to investigate the synergistic effect of these two compounds on the PI3K/Akt/mTOR pathway by employing a sequential molecular docking and molecular dynamics (MD) analysis. An increase in binding affinity and a decrease in inhibition constant have been observed when curcumin and plumbagin were subjected to sequential docking against the key proteins PI3K, Akt, and mTOR. The MD simulations and molecular mechanics combined with generalized Born surface area (MM-GBSA) analyses validated the target proteins' more stable conformation when interacting with the curcumin and plumbagin combination. This indicates the synergistic role of curcumin and plumbagin against cancer cells and the possible dose advantage when used in combination. The findings of this study pave the way for further investigation of their combinatorial effect on cancer cells in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria. Significant efforts have been therefore invested into finding potent inhibitors for the treatment. In this work, eighteen novel 1,2,3-triazoles appended with l -amino acid (Phe/Pro/Trp) tail were synthesized via azide-alkyne click chemistry with moderate to good yield, and evaluated for their anti-leishmanial activity against promastigote form of Leishmania donovani (Dd8 strain). Among all, compounds 40 , 43 , and 53 were identified with promising anti-leishmanial activity with IC 50 = 88.83 ± 2.93, 96.88 ± 12.88 and 94.45 ± 6.51 μM respectively and displayed no cytotoxicity towards macrophage cells. Moreover, compound 43 showed highest selectivity index (SI = 8.05) among all the tested compounds. Supported by docking studies, the lead inhibitors ( 40 , 43 and 53 ) showed interactions with key residues in the catalytic site of trypanothione reductase. The results of pharmacokinetic parameters suggest that these selected inhibitors can be carried forward for further structural optimization and pharmacological investigation. [ABSTRACT FROM AUTHOR]

α-Crystallin is a member of small heat shock proteins and is believed to play an exceptional role in the stability of eye lens proteins. The disruption or denaturation of the protein arrangement or solubility of the crystallin proteins can lead to vision problems including cataract. In the present study, we have examined the effect of chemical denaturants urea and guanidine hydrochloride (GdnHCl) on α-crystallin aggregation, with special emphasis on protein conformational changes, unfolding, and amyloid fibril formation. GdnHCl (4 M) induced a 16 nm red shift in the intrinsic fluorescence of α-crystallin, compared with 4 nm shift by 8 M urea suggesting a major change in α-crystallin structure. Circular dichroism analysis showed marked increase in the ellipticity of α-crystallin at 216 nm, suggesting gain in β-sheet structure in the presence of GdnHCl (0.5-1 M) followed by unfolding at higher concentration (2-6 M). However, only minor changes in the secondary structure of α-crystallin were observed in the presence of urea. Moreover, 8-anilinonaphthalene-1-sulfonic acid fluorescence measurement in the presence of GdnHCl and urea showed changes in the hydrophobicity of α-crystallin. Amyloid studies using thioflavin T fluorescence and congo red absorbance showed that GdnHCl induced amyloid formation in α-crystallin, whereas urea induced aggregation in this protein. Electron microscopy studies further confirmed amyloid formation of α-crystallin in the presence of GdnHCl, whereas only aggregate-like structures were observed in α-crystallin treated with urea. Our results suggest that α-crystallin is susceptible to unfolding in the presence of chaotropic agents like urea and GdnHCl. The destabilized protein has increased likelihood to fibrillate. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Cancer is a global health concern with a dynamic rise in occurrence and one of the leading causes of mortality worldwide. Among different types of cancer, ovarian cancer (OC) is the seventh most diagnosed malignant tumor, while among the gynecological malignancies, it ranks third after cervical and uterine cancer and sadly bears the highest mortality and worst prognosis. First-line treatments have included a variety of cytotoxic and synthetic chemotherapeutic medicines, but they have not been particularly effective in extending OC patients' lives and are associated with side effects, recurrence risk, and drug resistance. Hence, a shift from synthetic to phytochemical-based agents is gaining popularity, and researchers are looking into alternative, cost-effective, and safer chemotherapeutic strategies. Lately, studies on the effectiveness of phenolic acids in ovarian cancer have sparked the scientific community's interest because of their high bioavailability, safety profile, lesser side effects, and cost-effectiveness. Yet this is a road less explored and critically analyzed and lacks the credibility of the novel findings. Phenolic acids are a significant class of phytochemicals usually considered in the nonflavonoid category. The current review focused on the anticancer potential of phenolic acids with a special emphasis on chemoprevention and treatment of OC. We tried to summarize results from experimental, epidemiological, and clinical studies unraveling the benefits of various phenolic acids (hydroxybenzoic acid and hydroxycinnamic acid) in chemoprevention and as anticancer agents of clinical significance. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) represent one of the most common infections that are frequently encountered in health care facilities. One of the main mechanisms used by bacteria that allows them to survive hostile environments is biofilm formation. Biofilms are closed bacterial communities that offer protection and safe hiding, allowing bacteria to evade host defenses and hide from the reach of antibiotics. Inside biofilm communities, bacteria show an increased rate of horizontal gene transfer and exchange of resistance and virulence genes. Additionally, bacterial communication within the biofilm allows them to orchestrate the expression of virulence genes, which further cements the infestation and increases the invasiveness of the infection. These facts stress the necessity of continuously updating our information and understanding of the etiology, pathogenesis, and eradication methods of this growing public health concern. This review seeks to understand the role of biofilm formation in recurrent urinary tact infections by outlining the mechanisms underlying biofilm formation in different uropathogens, in addition to shedding light on some biofilm eradication strategies. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver with increasing global prevalence. However, no epidemiological data exist for AIH in human immunodeficiency virus (HIV)-infected patients. Aim: To determine the demographics and comorbid conditions associated with AIH among HIV-infected individuals in the United States. Material and methods: The United States National Inpatient Sample database was used to identify HIV hospital encounters in 2012-2014. The encounters were then classified into 2 groups based on a concomitant primary diagnosis of AIH. Primary outcomes included the demographics and comorbid conditions of AIH among HIV-infected patients. Secondary outcomes assessed the independent predictors of AIH. Results: A total of 48,3310 patients with an HIV diagnosis were included. The estimated AIH prevalence was 52.8/100,000 HIV hospital encounters. The female gender was more likely to have AIH with an odds ratio (OR) of 1.82; 95% confidence interval (CI) 1.42-2.32, p < 0.0001. The age intervals of 35-50 and 51-65 years had higher odds of AIH 110 (43.1%) and 115 (45.1%) with OR = 1.30; 95% CI: 1.02-1.67, p = 0.03 and OR = 1.34; 95% CI: 1.05-1.71, p = 0.02, respectively. African American and Hispanic races were more commonly affected. Moreover, HIV-infected patients with AIH had a higher risk of having elevated transaminases, long-term steroid use, rheumatoid arthritis, and ulcerative colitis. Conclusions: This study illustrates that the estimated prevalence of AIH in HIV-infected patients in the United States is 52.8/100,000. AIH in HIV-positive individuals has a predilection for the female gender and African American and Hispanic races, and shows a higher correlation with rheumatoid arthritis and ulcerative colitis. [ABSTRACT FROM AUTHOR]

Cancer has complex pathophysiology and is one of the primary causes of death and morbidity across the world. Chemotherapy, targeted therapy, radiation therapy, and immunotherapy are examples of traditional cancer treatments. However, these conventional treatment regimens have many drawbacks, such as lack of selectivity, non-targeted cytotoxicity, insufficient drug delivery at tumor sites, and multi-drug resistance, leading to less potent/ineffective cancer treatment. Due to its immanent biophysical property and ability to change in numerous ways, nano-technology has completely transformed how cancer is identified and treated in recent years. Furthermore, nanotechnology providing solutions to these restrictions and boosting cancer therapy. Nanoparticles are widely used nanomedicine platform in cancer immunotherapy due to their excellent physicochemical properties that include size, shape, and surface features, resulting into desirable biological interactions and have been categorized into several types. Nanoparticles can also be potentially be up taken by antigen-presenting cells that promote the cytosolic delivery of encapsulated antigens and adjuvants. Furthermore, nanoparticles can be fine-tuned and functionalized with specific moieties to promote their efficacy in targeting and delivering cargo materials to specific locations. In this review, we summarized and discussed nanoparticles and potential features to be used as carriers in cancer immunotherapy, the current status of different types of nanoparticles, and the importance of their functionalization. Furthermore, we have also discussed nanoparticles-based nanomedicine in targeted delivery of encapsulated cancer immunotherapeutic and their involvement in the modulation of the tumor microenvironment, promoting cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer has complex pathophysiology and is one of the primary causes of death and morbidity across the world. Chemotherapy, targeted therapy, radiation therapy, and immunotherapy are examples of traditional cancer treatments. However, these conventional treatment regimens have many drawbacks, such as lack of selectivity, non-targeted cytotoxicity, insufficient drug delivery at tumor sites, and multi-drug resistance, leading to less potent/ineffective cancer treatment. Due to its immanent biophysical property and ability to change in numerous ways, nano-technology has completely transformed how cancer is identified and treated in recent years. Furthermore, nanotechnology providing solutions to these restrictions and boosting cancer therapy. Nanoparticles are widely used nanomedicine platform in cancer immunotherapy due to their excellent physicochemical properties that include size, shape, and surface features, resulting into desirable biological interactions and have been categorized into several types. Nanoparticles can also be potentially be up taken by antigen-presenting cells that promote the cytosolic delivery of encapsulated antigens and adjuvants. Furthermore, nanoparticles can be fine-tuned and functionalized with specific moieties to promote their efficacy in targeting and delivering cargo materials to specific locations. In this review, we summarized and discussed nanoparticles and potential features to be used as carriers in cancer immunotherapy, the current status of different types of nanoparticles, and the importance of their functionalization. Furthermore, we have also discussed nanoparticles-based nanomedicine in targeted delivery of encapsulated cancer immunotherapeutic and their involvement in the modulation of the tumor microenvironment, promoting cancer immunotherapy. [ABSTRACT FROM AUTHOR]