ABSTRACT
Abnormal epigenetics has been recognised as an early event in tumour progression and aberrant acetylation of lysine in particular has been understood in tumorigenesis. Therefore, it has become an attractive target for anticancer drug development. However, HDAC inhibitors have limited success due to toxicity and drug resistance concerns. Present study deals with design and synthesis of bivalent indanone based HDAC6 and antitubulin ligands as anticancer agents. Two of the analogues 9 and 21 exhibited potent antiproliferative activities (IC50, 0.36-3.27 µM) and high potency against HDAC 6 enzyme. Compound 21 showed high selectivity against HDAC 6 while 9 exhibited low selectivity. Both the compounds also showed microtubule stabilization effects and moderate anti-inflammatory effect. Dual targeted anticancer agents with concomitant anti-inflammatory effects will be more attractive clinical candidates in future.
Subject(s)
Antineoplastic Agents , Tubulin , Hydroxamic Acids/pharmacology , Histone Deacetylases , Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Anti-Inflammatory Agents/pharmacology , Histone Deacetylase 6 , Cell Line, Tumor , Cell ProliferationABSTRACT
A series of cationic lipo-benzamide compounds with varying lengths of hydrocarbon chains (C2M-C18M) were evaluated for anti-Candida activity. Four compounds harbouring 8-11 hydrocarbon chains demonstrated concentration-dependent inhibition of fungal cell growth with Minimum Inhibitory Concentration (MIC) of ≤6.2⯵gâ¯ml-1. The most active compound (C9M) inhibited growth of both Candida albicans and non-albicans strains and is equally active against pairs of azole sensitive and resistant clinical isolates of C. albicans. Compound C9M also inhibited different stages of Candida biofilms. Scanning Electron Microscopy (SEM) of Candida cells after C9M treatment was also done and no significant cell lysis was observed. Hemolysis assay was performed and only 2.5% haemolysis was observed at MIC concentration.
Subject(s)
Alkanes/pharmacology , Antifungal Agents/pharmacology , Biofilms/drug effects , Candida albicans/drug effects , Alkanes/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Candida albicans/cytology , Cations/chemical synthesis , Cations/chemistry , Cations/pharmacology , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and eukaryotes encode one or more DNA ligases. DNA ligases are indispensable in various DNA repair and replication processes and a deficiency or an inhibition of their activity can lead to accumulation of DNA damage and strand breaks. DNA damage, specially strand breaks at unsustainable levels can lead to replication block and/or cell death. DNA ligases as potential anticancer targets have been realized only recently. There is enough rationale to suggest that ligases have a tremendous potential for novel therapeutics including anticancer and antibacterial therapy, specially when the world is facing acute problems of drug resistance and chemotherapy failure, with an immediate need for new therapeutic targets. Here, we review the current state of the art in the development of human ligase inhibitors, their structures, molecular mechanisms, physiological effects, and their potential in future cancer therapy. Citing examples, we focus on strategies for improving the activity and specificity of existing and novel inhibitors by using structure-based rational approaches. In the end, we describe potential new sites on the ligase I protein that can be targeted for the development of novel inhibitors. This is the first comprehensive review to compile all known human ligase inhibitors and to provide a rationale for the further development of ligase inhibitors for cancer therapy.
Subject(s)
DNA Ligases/metabolism , Neoplasms/enzymology , Neoplasms/therapy , Amino Acid Sequence , DNA Ligases/antagonists & inhibitors , DNA Ligases/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/classification , Enzyme Inhibitors/pharmacology , Humans , Molecular Sequence Data , Molecular Targeted TherapyABSTRACT
Human DNA ligases are enzymes that are indispensable for DNA replication and repair processes. Among the three human ligases, ligase I is attributed to the ligation of thousands of Okazaki fragments that are formed during lagging strand synthesis during DNA replication. Blocking ligation therefore can lead to the accumulation of thousands of single strands and subsequently double strand breaks in the DNA, which is lethal for the cells. The reports of the high expression level of ligase I protein in several cancer cells (versus the low ligase expression level and the low rate of division of most normal cells in the adult body) support the belief that ligase I inhibitors can target cancer cells specifically with minimum side effects to normal cells. Recent publications showing exciting data for a ligase IV inhibitor exhibiting antitumor activity in mouse models also strengthens the argument for ligases as valid antitumor targets. Keeping this in view, we performed a pharmacophore-based screening for potential ligase inhibitors in the Maybridge small molecule library and procured some of the top-ranking compounds for enzyme-based and cell-based in vitro screening. We report here the identification of novel ligase I inhibitors with potential anticancer activity against a colon cancer cell line.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA Ligases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , DNA/metabolism , DNA Ligase ATP , DNA Ligases/metabolism , Humans , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/enzymologyABSTRACT
Results from studies involving exposure to road traffic noise and risk of hypertension are diverse and have seldom reached statistical significance. This study was designed with the aim of investigating whether there is any association between road traffic noise and prevalence of hypertension in an urban adult population. Similar studies have never been reported from India. A cross-sectional study was performed on 909 adults (533 female and 376 male) aged 18-80 years residing in close proximity to roadways in Asansol City. Time-weighted equivalent noise level (L den) was estimated using a standard modeling platform. Odds for hypertension in relation to traffic noise exposure were estimated by univariate and multifactorial logistic regression. The adjusted odds ratio (OR) for self-reported hypertension was 1.99 (95 % confidence interval (CI) 1.66-2.39) per 5 dB(A) increase of L den (range 55.1-77.9). A gender-related risk difference was observed among the male (OR 1.81 (1.42-2.31)) and female (OR 2.18 (1.66-2.88)) respondents. For increase in 9 years of age, the odds of hypertension risk increased by 60 % (OR 1.66 (1.43-1.91) among those exposed above L den 60 dB(A). Vulnerable subgroups were female aged 35-54 years and male aged 45-54 years. The study suggests that a threshold exposure to road traffic noise at L den > 65 dB(A) for men and L den > 60 dB(A) in women may be associated with the occurrence of hypertension.
Subject(s)
Hypertension/epidemiology , Motor Vehicles , Noise, Transportation/adverse effects , Urban Health , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Hypertension/etiology , India/epidemiology , Male , Middle Aged , Risk Assessment , Sex Factors , Urban Population , Young AdultABSTRACT
There is an established evidence that exposure to high levels of road traffic noise is associated with elevated risk of coronary heart disease (CHD). The results however have been heterogeneous and mostly inconclusive. The present investigation aimed to examine this association in adult subjects, with a secondary aim of identifying potentially vulnerable sub-populations. Similar studies have never been reported from Indian population. For exposure assessment, the time-weighted road traffic noise indicator, L den, was used as a continuous and categorical predictor. A cross-sectional study was designed, and sociodemographic and lifestyle- and health-related characteristics were recorded for 909 (533 females and 376 males) subjects aged 18-80 years. The respondents living in areas with L den < 60 dB(A) were designated as the reference group. Odds for self-reported CHD in relation to traffic noise exposure were estimated by univariate and multifactorial logistic regression with adjustments for potential confounders and effect modifiers. The adjusted odds ratio (OR) for self-reported CHD was 1.72 (95 % CI 1.36-2.19) per 5 dB(A) increase of L den (range 55-80 dB(A)). A gender-related risk difference was observed among male (OR 1.47 (1.07-2.02)) and female (OR 1.83 (1.27-2.65)) respondents. A stronger effect for subjects in the age group 55-64 years old was found, with age, residence period, body mass index, and self-reported stress being significant confounders. This study suggests epidemiological evidence that exposure to road traffic noise of L den > 65 dB(A) may be associated with occurrence of CHD in adult subjects. A trend was observed indicating increasing risk with higher exposure levels. The study results are also suggestive of higher risk of outcome among those with other chronic ailments (diabetes, pulmonary, or renal issues) and residing in the same location in excess of 15 years. Orientation of bedroom windows was identified as a significant effect modifier.
Subject(s)
Coronary Disease/epidemiology , Noise, Transportation , Adolescent , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Environmental Exposure/analysis , Environmental Exposure/statistics & numerical data , Environmental Monitoring , Female , Humans , Logistic Models , Male , Middle Aged , Prevalence , Risk , Self Report , Young AdultABSTRACT
BACKGROUND: It is hypothesized that exposure to transportation noise is associated with an increased risk of cardiovascular disease among adult population. The present study further explores this association in the light of new findings. The objective of this study was to perform a meta-analysis of studies reported during the last 3 decades on the association of transportation noise exposure with cardiovascular disease endpoints among adult population in cross-sectional studies. MATERIALS AND METHODS: Relative risks were pooled from 12 studies by using an inverse-variance weighted fixed-effects model. The cardiovascular health outcomes included ischemic heart disease, myocardial infraction, angina pectoris, electrocardiogram-ischemia and cardiovascular medication. RESULTS: The pooled risk estimate (95% confidence interval) of 1.04 (0.96-1.12), shows a positive but nonsignificant association. The sensitivity analysis, conducted by excluding studies one by one, resulted in a positive and significant risk estimate. Contrary to the earlier meta-analysis, this study observed heterogeneity among subgroups and produced significant positive results to show that there exists an association between air traffic noise exposure and cardiovascular disease. It was also observed that the risk of cardiovascular disease due to exposure to transportation noise has increase to significant levels over the last 30 years. CONCLUSION: It can be concluded that though the association between transportation noise exposure and cardiovascular disease is evident, but not at a significant level. This study although provides evidence that air traffic noise is a serious cause of concern.
Subject(s)
Cardiovascular Diseases/etiology , Noise, Transportation/adverse effects , Humans , RiskABSTRACT
Abnormal uterine bleeding (AUB) is an acute/chronic variation in the normal menstrual cycle that affects adolescents, women of reproductive age and perimenopausal women. AUB affects approximately 3-30% of reproductive-aged women worldwide, and reduces their quality of life and productivity whilst increasing the overall healthcare burden. Its management requires thorough medical evaluation and individualized treatment. Depending on the severity and cause of AUB, its treatment ranges from lifestyle modifications and hormonal therapies to more invasive procedures or surgery. Although hormonal therapy is the preferred first-line measure in AUB, the available pharmacological options have various adverse effects. There exists a need for safer and more efficient treatment regimens with high patient compliance to effectively treat AUB. Norethisterone, also known as norethindrone, is a widely used synthetic analogue of progestogen. Controlled release formulations of norethisterone/ norethisterone acetate help maintain constant drug levels in the blood and exert minimal side-effects; therefore, they are promising therapeutic agents for effective AUB management. The present review summarizes the epidemiology and diagnosis of AUB, with a focus on the safety, efficacy and tolerability of norethisterone/ norethisterone acetate in AUB management. We also report a case of AUB in a 40-year-old woman, who was treated with NETA tablets. The treatment resulted in favourable outcomes, and patient satisfaction.
ABSTRACT
DNA topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention. Human DNA Ligase 1 (hLig I), recognized primarily for its role in DNA replication and repair of DNA breaks, intriguingly exhibits a DNA relaxation activity akin to Topo 1. This raised the hypothesis that hLig I might compensate for Topo 1 inhibition, contributing to resistance against Topo 1 inhibitors. To explore this hypothesis, we assessed the efficacy of hLig I inhibition alone and in combination with Topo 1 in cancer cells. As anticipated, the overexpression of hLig I was observed after Topo 1 inhibition in colorectal cancer cells, affirming our hypothesis. Previously identified as an inhibitor of hLig I's DNA relaxation activity, compound 27 (C 27), when combined with Topotecan, demonstrated a synergistic antiproliferative effect on colorectal cancer cells. Notably, cells with downregulated hLig I (via siRNA, inhibitors, or genetic manipulation) exhibited significantly heightened sensitivity to Topotecan. This observation strongly supports the concept that hLig I contribute to resistance against clinically relevant Topo 1 inhibitors in colorectal cancers. In conclusion, our findings offer evidence for the synergistic impact of combining hLig I inhibitors with Topotecan in the treatment of colorectal cancers, providing a promising strategy to overcome resistance to Topo 1 inhibitors.Communicated by Ramaswamy H. Sarma.
ABSTRACT
Ataxia telangiectasia (A-T) is a pleiotropic disease, with a characteristic hypersensitivity to ionizing radiation that is caused by biallelic mutations in A-T mutated (ATM), a gene encoding a protein kinase critical for the induction of cellular responses to DNA damage, particularly to DNA double strand breaks. A long known characteristic of A-T cells is their ability to synthesize DNA even in the presence of ionizing radiation-induced DNA damage, a phenomenon termed radioresistant DNA synthesis. We previously reported that ATM kinase inhibition, but not ATM protein disruption, blocks sister chromatid exchange following DNA damage. We now show that ATM kinase inhibition, but not ATM protein disruption, also inhibits DNA synthesis. Investigating a potential physical interaction of ATM with the DNA replication machinery, we found that ATM co-precipitates with proliferating cell nuclear antigen (PCNA) from cellular extracts. Using bacterially purified ATM truncation mutants and in vitro translated PCNA, we showed that the interaction is direct and mediated by the C terminus of ATM. Indeed, a 20-amino acid region close to the kinase domain is sufficient for strong binding to PCNA. This binding is specific to ATM, because the homologous regions of other PIKK members, including the closely related kinase A-T and Rad3-related (ATR), did not bind PCNA. ATM was found to bind two regions in PCNA. To examine the functional significance of the interaction between ATM and PCNA, we tested the ability of ATM to stimulate DNA synthesis by DNA polymerase δ, which is implicated in both DNA replication and DNA repair processes. ATM was observed to stimulate DNA polymerase activity in a PCNA-dependent manner.
Subject(s)
Cell Cycle Proteins/metabolism , DNA Polymerase III/metabolism , DNA-Binding Proteins/metabolism , DNA/biosynthesis , Proliferating Cell Nuclear Antigen/metabolism , Protein Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/metabolism , 3' Untranslated Regions , Amino Acid Motifs , Amino Acid Sequence , Ataxia Telangiectasia Mutated Proteins , Base Sequence , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/genetics , Cell Line , DNA Repair , DNA Replication , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Gene Knockdown Techniques , Humans , Models, Molecular , Molecular Sequence Data , Morpholines/pharmacology , Peptide Fragments/chemistry , Proliferating Cell Nuclear Antigen/chemistry , Protein Binding , Protein Interaction Domains and Motifs , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , RNA Interference , Thioxanthenes/pharmacology , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/geneticsABSTRACT
The repair of reactive oxygen species-induced base lesions and single strand breaks (SSBs) in the nuclear genome via the base excision (BER) and SSB repair (SSBR) pathways, respectively, is well characterize, and important for maintaining genomic integrity. However, the role of mitochondrial (mt) BER and SSBR proteins in mt genome maintenance is not completely clear. Here we show the presence of the oxidized base-specific DNA glycosylase Nei-like 2 (NEIL2) and the DNA end-processing enzyme polynucleotide kinase 3'-phosphatase (PNKP) in purified human mitochondrial extracts (MEs). Confocal microscopy revealed co-localization of PNKP and NEIL2 with the mitochondrion-specific protein cytochrome c oxidase subunit 2 (MT-CO2). Further, chromatin immunoprecipitation analysis showed association of NEIL2 and PNKP with the mitochondrial genes MT-CO2 and MT-CO3 (cytochrome c oxidase subunit 3); importantly, both enzymes also associated with the mitochondrion-specific DNA polymerase γ. In cell association of NEIL2 and PNKP with polymerase γ was further confirmed by proximity ligation assays. PNKP-depleted ME showed a significant decrease in both BER and SSBR activities, and PNKP was found to be the major 3'-phosphatase in human ME. Furthermore, individual depletion of NEIL2 and PNKP in human HEK293 cells caused increased levels of oxidized bases and SSBs in the mt genome, respectively. Taken together, these studies demonstrate the critical role of NEIL2 and PNKP in maintenance of the mammalian mitochondrial genome.
Subject(s)
DNA Breaks, Single-Stranded , DNA Glycosylases/metabolism , DNA Repair Enzymes/metabolism , DNA Repair/physiology , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , Genome, Mitochondrial/physiology , Mitochondria/enzymology , Mitochondrial Proteins/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Cytochromes c/genetics , Cytochromes c/metabolism , DNA Glycosylases/genetics , DNA Polymerase gamma , DNA Repair Enzymes/genetics , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , DNA-Directed DNA Polymerase/genetics , DNA-Directed DNA Polymerase/metabolism , HEK293 Cells , Humans , Mitochondria/genetics , Mitochondrial Proteins/genetics , Phosphotransferases (Alcohol Group Acceptor)/geneticsABSTRACT
Preceding research has linked noise exposure, road traffic bring the dominant community source, with annoyance, which is an indicator of more serious, chronic health conditions. This study aimed to explore the association between residential road traffic noise and self-reported annoyance from an adult Indian population, residing close to roadways. The cross-sectional study used a questionnaire survey in an urban Indian municipality along roadways, where faηade noise assessment was made manually. The survey included randomly selected subjects aged 19-59 years, residing minimum of 10 years in the area and residing within 50 m of the roadways. Association of self-reported annoyance and noise exposure was examined by binary and multiple logistic regressions. The noise exposure was classified in units of 5 dB (A) from <65 dB (A) to 80 dB (A). Self-reported annoyance was marked at levels above 65-70 dB (A). A 67.5 dB (AA) is suggested as a threshold level. The association was statistically significant for female subjects with the adjusted odds ratio being 2.35 (95% confidence intervals: 0.99-5.58). Prevalence of annoyance was more for male subjects. Both age and period of residence were significant predictors of annoyance. Vulnerable age sub-groups were 34-40 years, followed by 50-60 years. The results of this study further suggest the association residential noise exposure near roadways and self-reported annoyance, among the study subjects.
Subject(s)
Emotions , Noise, Transportation/statistics & numerical data , Adult , Age Factors , Cross-Sectional Studies , Environmental Exposure/statistics & numerical data , Female , Humans , India , Logistic Models , Male , Middle Aged , Motor Vehicles , Noise, Transportation/adverse effects , Pilot Projects , Risk Factors , Sex Factors , Surveys and Questionnaires , Urban Population , Young AdultABSTRACT
The up-regulation of ABC transporters Cdr1p and Cdr2p that efflux antifungal azole drugs are a leading cause of Multi-Drug Resistance (MDR) in the white fungus Candida albicans. C. albicans was reported to infect patients following the recent Covid-19 pandemic after they were given steroids for recovery. Previously, the TAC1 gene was identified as the transcriptional activator of Candida drug resistance genes (CDR1 and CDR2) and has no known human homologs. This makes it a good target for the development of novel antifungals. We, therefore, carried out the molecular dissection study of TAC1 to understand the functional regulation of the ABC transporter genes (CDR1 and CDR2) under its control. The N-terminal DNA Binding Domain (DBD) of Tac1p interacts with the Drug Responsive Element (DRE) present in the upstream promoter region of CDR1 and CDR2 genes of C. albicans. The interaction between DBD and DRE recruits Tac1p to the promoter of CDR genes. The C-terminal Acidic Activation Domain (AAD) of Tac1p interacts with the TATA box Binding Protein (TBP) and thus recruits TBP to the TATA box of CDR1 and CDR2 genes. Taking a cue from a previous study involving a TAC1 deletion strain that suggested that Tac1p acts as a xenobiotic receptor, in this study, we identified that the Middle Homology Region (MHR) of Tac1p acts as a probable xenobiotic binding domain (XBD) which plays an important role in Candida drug resistance. In addition, we studied the role of Tac1p in the regulation of some lipid profiling genes and stress response genes since they also contain the DRE consensus sequence and found that some of them can respond to xenobiotic stimuli.
ABSTRACT
MMP-9, also known as gelatinase B, is a zinc-metalloproteinase family protein that plays a key role in the degradation of the extracellular matrix (ECM). The normal function of MMP-9 includes the breakdown of ECM, a process that aids in normal physiological processes such as embryonic development, angiogenesis, etc. Interruptions in these processes due to the over-expression or downregulation of MMP-9 are reported to cause some pathological conditions like neurodegenerative diseases and cancer. In the present study, an integrated approach for ML-based virtual screening of the Maybridge library was carried out and their biological activity was tested in an attempt to identify novel small molecule scaffolds that can inhibit the activity of MMP-9. The top hits were identified and selected for target-based activity against MMP-9 protein using the kit (Biovision K844). Further, MTT assay was performed in various cancer cell lines such as breast (MCF-7, MDA-MB-231), colorectal (HCT119, DL-D-1), cervical (HeLa), lung (A549) and ovarian cancer (SKOV3). Interestingly, one compound viz., RJF02215 exhibited anti-cancer activity selectively in SKOV3. Wound healing assay and colony formation assay performed on SKOV3 cell line in the presence of RJF02215 confirmed that the compound had a significant inhibitory effect on this cell line. Thus, we have identified a novel molecule that can inhibit MMP-9 activity in vitro and inhibits the proliferation of SKOV3 cells. Novel molecules based on the structure of RJF02215 may become a good value addition for the treatment of ovarian cancer by exhibiting selective MMP-9 activity.Communicated by Ramaswamy H. Sarma.
ABSTRACT
A series of organometallic Re(I)(L)(CO)3Br complexes with 4'-substituted terpyridine ligands (L) has been synthesised as electrocatalysts for CO2 reduction. The complexes' spectroscopic characterisation and computationally optimised geometry demonstrate a facial geometry around Re(I) with three cis COs and the terpyridine ligand coordinating in a bidentate mode. The effect of substitution on the 4'-position of terpyridine (Re1-5) on CO2 electroreduction was investigated and compared with a known Lehn-type catalyst, Re(I)(bpy)(CO)3Br (Re7). All complexes catalyse CO evolution in homogeneous organic media at moderate overpotentials (0.75-0.95 V) with faradaic yields of 62-98%. The electrochemical catalytic activity was further evaluated in the presence of three Brønsted acids to demonstrate the influence of the pKa of the proton sources. The TDDFT and ultrafast transient absorption spectroscopy (TAS) studies showed combined charge transfer bands of ILCT and MLCT. Amongst the series, the Re-complex containing a ferrocenyl-substituted terpyridine ligand (Re5) shows an additional intra-ligand charge transfer band and was probed using UV-Vis spectroelectrochemistry.
ABSTRACT
Preferential repair of bulky DNA adducts from the transcribed genes via nucleotide excision repair is well characterized in mammalian cells. However, definitive evidence is lacking for similar repair of oxidized bases, the major endogenous DNA lesions. Here we show that the oxidized base-specific human DNA glycosylase NEIL2 associates with RNA polymerase II and the transcriptional regulator heterogeneous nuclear ribonucleoprotein-U (hnRNP-U), both in vitro and in cells. NEIL2 immunocomplexes from cell extracts preferentially repaired the mutagenic cytosine oxidation product 5-hydroxyuracil in the transcribed strand. In a reconstituted system, we also observed NEIL2-initiated transcription-dependent base excision repair of 5-hydroxyuracil in the transcribed strand, with hnRNP-U playing a critical role. Chromatin immunoprecipitation/reimmunoprecipitation studies showed association of NEIL2, RNA polymerase II, and hnRNP-U on transcribed but not on transcriptionally silent genes. Furthermore, NEIL2-depleted cells accumulated more DNA damage in active than in silent genes. These results strongly support the preferential role of NEIL2 in repairing oxidized bases in the transcribed genes of mammalian cells.
Subject(s)
DNA Adducts/metabolism , DNA Damage , DNA Glycosylases/metabolism , DNA Repair , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , RNA Polymerase II/metabolism , Cell-Free System , Cytosine/metabolism , DNA Adducts/genetics , DNA Glycosylases/genetics , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , HEK293 Cells , Heterogeneous-Nuclear Ribonucleoprotein U/genetics , Heterogeneous-Nuclear Ribonucleoprotein U/metabolism , Humans , Oxidation-Reduction , RNA Polymerase II/genetics , Transcription, Genetic/geneticsABSTRACT
This article reviews the literature on research conducted during the last two decades on traffic noise impacts in India. Road traffic noise studies in India are fewer and restricted only to the metropolitan areas. The studies over the years have also focused on the monitoring, recording, analysis, modeling, and to some extent mapping related themes. Negligible studies are observed in areas of physiological and sleep research exposure-effect context. Most impact studies have been associated with annoyance and attitudinal surveys only. Little scientific literature exists related to effects of traffic noise on human physiology in the Indian context. The findings of this review search and analysis observe that very little studies are available relating to traffic noise and health impacts. All of them are subjective response studies and only a small portion of them quantify the exposure-effect chain and model the noise index with annoyance. The review of papers showed that road traffic noise is a cause for annoyance to a variety of degree among the respondents. A generalization of impacts and meta-analysis was not possible due to variability of the study designs and outputs preferred.
Subject(s)
Environmental Exposure/adverse effects , Noise, Transportation/adverse effects , Environmental Exposure/statistics & numerical data , Humans , India , Noise, Transportation/statistics & numerical dataABSTRACT
BACKGROUND: Anthrax is a life-threatening infectious disease that normally affects animals, especially ruminants. It is caused by the bacteria Bacillus anthracis. The most common mode of infection is through the skin, which causes a painless sore that usually heals without treatment. If left untreated, cutaneous anthrax may progress in up to 20% of cases to septicaemia with potentially lethal outcome. METHODOLOGY: We visited a small tribal village of the state of West Bengal, where an outbreak of cutaneous anthrax was suspected following slaughtering a dead bullock. The population at risk were subjected to detailed interrogation, thorough clinical examination and relevant investigations. RESULTS: The mean age of our study population was 32.1 years, and 100% were male. The mean incubation period was three days. Most cases (81.8%) were exposed to the bacteria during butchering. The predominantly affected sites were fingers (54.5%), followed by forearms (18.2%), around elbows (18.2%) and arm (9.1%). All cases initially had painless papules, ulcers with vesicles; dissemination of the lesion was seen in 27.3% of patients. 9 patients (who were alive) underwent complete blood count, baseline biochemistry and chest X-ray. Smears were made from the cutaneous lesions for gram's stain in 5 patients. Wound swabs were also inoculated in nutrient broth and subcultured in blood agar media. FNAC from the enlarged axillary lymph node was done in 1 patient and blood was sent for aerobic culture in 2 individuals. Both the blood cultures were sterile. Smears made from the culture obtained from cutaneous lesion of one of the affected person revealed gram positive aerobic spore bearing non-motile bacilli in long chain with capsular halo suggesting Bacillus anthracis. In this outbreak, the attack rate was 7% and case fatality rate was 18%. CONCLUSION: Cutaneous anthrax should be considered as a differential diagnosis in cases presenting with painless ulcers, vesicles or eschars with a recent history of exposure to animals or animal products. It is important to recognise the clinical aspects of this disease in routine practice since any delay in treatment may have fatal consequences, as observed in this study.
Subject(s)
Anthrax/epidemiology , Bacillus anthracis/isolation & purification , Disease Outbreaks , Skin Diseases, Bacterial/epidemiology , Adolescent , Adult , Animals , Anthrax/diagnosis , Anthrax/drug therapy , Anthrax/microbiology , Anti-Bacterial Agents/therapeutic use , Contact Tracing , Epidemiologic Studies , Humans , Incidence , India/epidemiology , Male , Middle Aged , Population Surveillance , Risk Factors , Rural Population , Severity of Illness Index , Skin Diseases, Bacterial/diagnosis , Skin Diseases, Bacterial/drug therapy , Skin Diseases, Bacterial/microbiology , Treatment Outcome , Upper Extremity/microbiology , Young AdultABSTRACT
Cathepsin S (CatS) is one of the cysteinyl cathepsins widely studied for its clinical significance and found to be a promising therapeutic target for several diseases; to name a few is arthritis, allergic inflammation, cancer, diabetes, obesity, and cystic fibrosis. Elevated CatS level is a contributing factor for related disorders, and therefore among different strategies to regulate the activity of CatS, one is to design a quality inhibitor. Earlier, we have demonstrated a highly selective CatS inhibitor, RO5444101 interacts primarily with the S2 pocket of the protein which is structurally unique in contrast to other variants of cathepsin. However, the molecular properties of RO5444101 can question its efficacy at the clinical level. In the present study, we have implemented a series of molecular modeling methods to screen the Maybridge library considering the pharmacophoric features of RO5444101 and other relevant inhibitors of CatS. Based on the priority list, eight hits were subjected to biological evaluation. Subsequently, KM07987 was found to be most potent, with the IC50 of <5 µM. Molecular dynamics simulations also relate to our experimental findings and propose the importance of CatS's S2 pocket, which primarily interacts with the inhibitors. Based on the S2 pocket interactions, structural modifications of the promising hits can further be translated into novel scaffolds for improved inhibition of CatS.
Subject(s)
Cathepsins , Molecular Dynamics Simulation , Cathepsins/metabolism , HumansABSTRACT
Lysosome has been long understood as a vital digestive organelle. Increasing reports indicate that the lysosome also plays a crucial role in the pathogenesis of a variety of neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Abnormal protein degradation and deposition stimulated by lysosomal dysfunction may cause age-related neurodegeneration. Enormous efforts have been devoted to the development of effective therapeutics against Alzheimer's disease, the most debilitating neurodegenerative disease. Endopeptidase activity of the Cathepsin-B is associated with the pathological processes. Work presented here focuses on identification of new inhibitors against Cathepsin-B protein using diverse computational approaches together. The inhibitors identified were further tested for in-vitro activity using enzyme based assay method. The identified inhibitors provided interesting understanding on how the water thermodynamic properties along with hydrophobic, steric, electronic, and structural requirements contribute to cathepsin-B inhibitory activity. These water thermodynamic studies, may further be used in computer aided drug discovery pipeline to design and predict more potent derivatives of various scaffolds as cathepsin-B inhibitors.