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
.
was reported to infect patients ...following the recent Covid-19 pandemic after they were given steroids for recovery. Previously, the
gene was identified as the transcriptional activator of
drug resistance genes (
and
) 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
to understand the functional regulation of the ABC transporter genes (
and
) 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
and
genes of
. The interaction between DBD and DRE recruits Tac1p to the promoter of
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
and
genes. Taking a cue from a previous study involving a
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
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.
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.
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.
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.
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.
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.
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.
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.
Human Flap endonuclease1 (FEN1) is an enzyme that is indispensable for DNA replication and repair processes and inhibition of its Flap cleavage activity results in increased cellular sensitivity to ...DNA damaging agents (cisplatin, temozolomide, MMS, etc.), with the potential to improve cancer prognosis. Reports of the high expression levels of FEN1 in several cancer cells support the idea that FEN1 inhibitors may target cancer cells with minimum side effects to normal cells. In this study, we used large publicly available, high-throughput screening data of small molecule compounds targeted against FEN1. Two machine learning algorithms, Support Vector Machine (SVM) and Random Forest (RF), were utilized to generate four classification models from huge PubChem bioassay data containing probable FEN1 inhibitors and non-inhibitors. We also investigated the influence of randomly selected Zinc-database compounds as negative data on the outcome of classification modelling. The results show that the SVM model with inactive compounds was superior to RF with Matthews's correlation coefficient (MCC) of 0.67 for the test set. A Maybridge database containing approximately 53 000 compounds was screened and top ranking 5 compounds were selected for enzyme and cell-based in vitro screening. The compound JFD00950 was identified as a novel FEN1 inhibitor with in vitro inhibition of flap cleavage activity as well as cytotoxic activity against a colon cancer cell line, DLD-1.
Human DNA ligase I (hLigI) plays an important role in the process of DNA replication and repair mechanisms, making it an important target for cancer. This article reports the design, synthesis, and ...biological activity of a series of 59 curcumin-monocarbonyl-dithiocarbamate hybrid molecules. Many of the synthetic compounds tested in this study showed a significant inhibitory effect on hLig1 activity (>90% inhibition) and demonstrated significant antiproliferative activity against colon cancer cells (DLD-1) at the 10 µM concentrations, with certain compounds showing selective activity against DLD-1 as compared to the normal HEK-293 and VERO cell line. The activity of curcuminoids were compared against Doxorubicin and Bleomycin which were used as positive control compounds with activity towards hLigI. Further, we checked the cytotoxicity of two compounds (
27
and
49
) along with positive control Doxorubicin in a concentration-dependent manner against DLD-1, HEK293, and VERO cell lines. Overall, our studies demonstrated that compounds
27
and
49
have significantly better hLigI inhibition and targeted cytotoxic activities than the previously reported monocarbonyl-curcumin hybrid compound
23
*. This study brings us a step closer towards our quest to explore the molecular space for novel hLig1 inhibitors that will be suitable for clinical trials in cancer patients.
Graphical abstract
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.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.
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.
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