Search

Paxlovid is a recent FDA approved specific drug for COVID-19. Extensive prescription of Paxlovid could induce potential synthetic cytotoxicity with drugs. Herein, we aimed to examine pairwise synthetic cytotoxicity between Paxlovid and 100 frequently FDA approved small molecule drugs. Liver cell line HL-7702 or L02 was adopted to evaluate synthetic cytotoxicity between Paxlovid and the 100 small molecule drugs. Inhibitory concentration IC-10 and IC-50 doses for all the 100 small molecule drugs and Paxlovid were experimentally acquired. Then, pairwise synthetic cytotoxicity was examined with the fixed dose IC-10 for each drug. The most 4 significant interactive pairs (2 positively interactive and 2 negatively interactive) were further subjected to molecular docking simulation to reveal the structural modulation with Caspase-8, a key mediator for cell apoptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Given the dire state of global warming, it is critical to investigate the elements that influence carbon emissions intensity and to precisely monitor progress in carbon emissions intensity growth in order to meet the aim of lowering CO2 emissions. This research explores the association among renewable energy and non-renewable energy consumption, the urban population, research and development expenditure, technological innovation, and carbon emissions intensity in China using annual time series data over the period 1990 to 2019. The Dynamic ARDL simulation technique was utilized to investigate the long-run and short-run correlations between renewable and non-renewable energy consumption and CEI. The results suggest that there is strong evidence of a long-run correlation between the variables. The findings indicate that in the long-run, renewable energy and non-renewable energy consumption, and research and development expenditure have a positive influence on CEI by 0.27%, 0.75%, and 0.21%, whereas the urban population has a negative influence by 2.31%, respectively. However, the urban population and technological innovation have positively affected the short-run CEI by 12.17% and 0.23%, respectively. Policies should focus on continuous investment in renewable energy sources, clean energy innovation, improving energy efficiency, forest restoration, and carbon neutrality initiatives to lessen the environmental extreme pressure associated with CO2 emissions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Air quality is a social, economical, and health issue for fast-developing countries such as China. Due to the overuse of nonrenewable energy, industrialization, and the population put pressure on air quality, which seriously threatens public health and economic growth. This study focuses on air quality and also aims to investigate the short-and long-run correlation between foreign direct investment, energy consumption, domestic credit, and financial development. The Autoregressive distributed lag model and the Granger non-causality test were carried out over the period from 1985 to 2018. The main findings of this study show a positive and significant long-run impact of energy consumption on air quality. In addition, domestic credit and financial development similarly show a significant positive short-run association with air quality. Moreover, the unidirectional causality correlation running from foreign direct investment and domestic credit to air quality was concluded by the Granger non-causality test. Considering the empirical analysis, this study suggests that domestic financial institutions should offer credit to industries at a low-interest rate in order to help them to switch from non-renewable to renewable energy consumption towards the promotion of sustainable and healthy air quality., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

China is the world's largest fossil fuel consumer and carbon emitter country. In September 2020, China pledged to reduce carbon emissions, and achieve carbon neutrality by 2060. Therefore, this study aimed to contribute to the literature and show the pictorial nexus of bioenergy and fossil fuel consumption, carbon emission, and agricultural bioeconomic growth, a new pathway towards carbon neutrality. For this study, time-series data from 1971 to 2019 were used to analyze the autoregressive distributed lag (ARDL) bound testing and novel dynamic autoregressive distributed lag (DYNARDL) simulation models. Initially, the unit root tests results showed that all variables were stationarity at the level and first difference. The presence of cointegration between selected variables was confirmed by the results from ARDL bound test. In addition, the results of long-run and short-run nexus show an increase in bioenergy consumption that caused an increase in agricultural bioeconomic growth both in the long and short-run nexus. A decrease in fossil fuel consumption was shown to result in increased agricultural bioeconomic growth with respect to both long- and short-term effects. Furthermore, the results of the novel dynamic ARDL simulation model demonstrated that a 10% positive shock from bioenergy consumption caused an increase in agricultural bioeconomic growth, while at the same time, a 10% negative shock in bioenergy consumption led to a decrease. A 10% negative shock from fossil fuels caused an increase in agricultural bioeconomic growth, whereas a 10% positive shock from fossil fuels led to a decrease. Therefore, this study suggests that China needs to switch from fossil fuel and other non-renewable energy consumption to sources of bioenergy and other renewable energy consumption to achieve carbon neutrality by 2060., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The present study on zebrafish (Danio rerio) is the first attempt to demonstrate the circadian mRNA expression of melatonin biosynthesizing enzyme genes (Tph1a, Aanat1, Aanat2 and Hiomt) and clock associated genes (Bmal1a, Clock1a, Per1b, Per2 and Cry2a) in the ovary with a comparison to whole brain in normal (LD=12h L:12h D) and altered photic conditions (continuous dark, DD; continuous light, LL). Moreover, the present study also confirmed the ability of zebrafish ovary to biosynthesize melatonin both in vivo and in vitro with a significant difference at day and night. qRT-PCR analysis of genes revealed a dark acrophase of Aanat2 in both organs while Tph1 is in whole brain in LD condition. On the contrary, Bmal1a and Clock1a giving their peak in light, thereby showing a negative correlation with Tph1a and Aanat2. In LD-ovary, the acrophase of Tph1a, Bmal1a and Clock1a is in light and thus display a positive correlation. This trend of relationship in respect to Tph1a is not changing in altered photic conditions in both organs (except in DD-ovary). On the other hand this association for Aanat2 is varying in ovary under altered photic conditions but only in DD-whole brain. Both in LD and LL the expression of Aanat2 in brain presenting an opposite acrophase with both Bmal1a and Clock1a of ovary and consequently displaying a strong negative correlation among them. Interestingly, all ovarian clock associated genes become totally arrhythmic in DD, representing a loss of correlation between the melatonin synthesizing genes in brain and clock associated genes in ovary. The result is also indicating the formation of two heterodimers namely Clock1a:Bmal1a and Per2:Cry2a in the functioning of clock genes in both organs, irrespective of photic conditions, as they are exhibiting a strong significant positive correlation. Collectively, our data suggest that ovary of zebrafish is working as peripheral oscillator having its own melatonin biosynthesizing machinery and signifying a possible correlation with central oscillating system in various photic conditions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Obesity and increased free fatty acid (FFA) level are tightly linked, leading to the development of cardiovascular disorders. Curcumin is a natural product from Curcuma longa with multiple bioactivities and is known to have cardioprotective effects in several cellular and animal models. The current study was designed to evaluate the cardioprotective effects of curcumin and demonstrate the underlying mechanism in FFA-induced cardiac injury. Using cell culture studies and high fat in vivo model, we explored the mechanistic basis of anti-inflammatory and antioxidant activities of curcumin. We observed that palmitate (PA) treatment in cardiac derived H9C2 cells induced a marked increase in reactive oxygen species, inflammation, apoptosis and hypertrophy. All of these changes were effectively suppressed by curcumin treatment. In addition, oral administration of curcumin at 50mg/kg completely suppressed high fat diet-induced oxidative stress, inflammation, apoptosis, fibrosis, hypertrophy and tissue remodeling in mice. The beneficial actions of curcumin are closely associated with its ability to increase Nrf2 expression and inhibit NF-κB activation. Thus, both in vitro and in vivo studies showed a promising role of curcumin as a cardioprotective agent against palmitate and high fat diet mediated cardiac dysfunction. We indicated the regulatory roles of Nrf2 and NF-κB in obesity-induced heart injury, and suggested that they may be important therapeutic targets in the treatment of obesity-related disorders., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We report a simple chemical reduction method for the synthesis of different colored silver nanoparticles, AgNP, using tyrosine as a reducing agent. Effects of cetyltrimethylammonium bromide, CTAB, and tyrosine concentrations are analyzed by UV-visible measurements and scanning electron microscopy (SEM) to evaluate the mode of AgNP aggregation. The position and shape of the surface resonance plasmon absorption bands strongly depend on the reaction conditions, i.e., [CTAB], [tyrosine], and reaction time. Sub-, post-, and dilution-micellar effects are accountable for the fast and slow nucleation and growth processes. Spectrophotometric measurement also shows that the average size and the polydispersity of AgNP increase with [CTAB] in the solution. CTAB acted as a shape-directing agent., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Variants of unknown significance (VUS) complicate the assignment of risk to new DNA sequence variants found in at-risk populations. This study focused on the poorly studied linker region of the cancer-associated BRCA2 protein encoded by exons twelve through fourteen of BRCA2. To develop a new method to characterize VUS in this region of BRCA2, we first chose to study 4 reported VUS occurring on evolutionarily conserved residues within the linker region. To determine if these VUS represent neutral changes or if they impact the function of the BRCA2 protein, we stably transfected expression plasmids encoding wild-type or each mutant peptide into T47D breast cancer cells, which are wild-type for BRCA2. Four mutant peptide expressing cell lines and a wild-type linker region expressing cell line next were studied by challenging transfected cell lines with the DNA crosslinking compound cisplatin (10μM) for 5days. Expression of the wild-type linker region and certain mutant linker peptides (N2452D and I2285V) decreased apoptosis (as demonstrated by cell death detection assay) in transfected cell lines, indicating that the linker region peptide directly or indirectly affects the DNA damage repair pathway. By determining the cell survival and assaying the apoptotic index of treated cell lines, one could potentially use this screen to determine that a particular VUS has a functional impact on BRCA2 function, and hence is of functional significance. We conclude that this method is useful for screening the effect of linker region VUS on BRCA2 function, and to identify mutations for further testing. We also conclude that mutations in the linker region may have heretofore unappreciated roles in BRCA2 function., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The micellization of gemini surfactant pentamethylene-1,5-bis(tetradecyldimethylammonium bromide) (14-5-14) has been investigated in water and water-organic solvent mixed media (organic solvents used: 1,4-dioxane (DO), dimethylformamide (DMF), ethylene glycol (EG)). The conductivity in water and in mixed media (water+organic solvent) as a function of surfactant concentration was measured at different temperatures and the data were used to find critical micelle concentration (cmc) and degree of counterion dissociation (alpha) of the micelle. From the study, it is observed that the micellization tendency of the surfactant decreases in the presence of organic solvents and the increase in the cmc values is comparatively less below 20% (v/v) of organic solvents showing the predominance of water character in the bulk phase at lower compositions of the organic solvents. Thermodynamic parameters were also obtained from the temperature dependence of the cmc values. The standard free energy of micellization was found to be negative in all the cases that became less negative with the increase in the cosolvent content., (Copyright 2009 Elsevier Inc. All rights reserved.)

Clouding phenomenon in aqueous micellar solutions of an anionic surfactant tetra-n-butylammonium dodecylsulfate (TBADS) has been observed as a function of surfactant concentration. Small-angle neutron scattering (SANS) experiments in these systems show clustering of micelles as the temperature approaches the cloud point (CP). The individual micelles and the clusters of micelles coexist at CP. The clustering of micelles depends on the surfactant concentration and temperature. It is proposed that clustering is due to depletion of H-bonded water present around the butyl chains at the micellar surface. This is associated with entropy gain which is considered to be the major thermodynamic factor related to micellar aggregation. The structures (clusters) that emerge depend on the relative lengths of the alkyl chains of the counterion and can be tuned by the temperature.

Diabetic cardiomyopathy is responsible for substantial morbidity and mortality in the diabetic population. Increased oxidative stress has been associated with the pathogenesis of chronic diabetic complications including cardiomyopathy. Multiple biochemical mechanisms have been proposed to increase oxidative stress in diabetes. The present study was aimed at elucidating the role of a potent oxidative and cellular stress-responsive system, the heme oxygenase (HO) system, in the heart in diabetes. Streptozotocin-induced diabetic rats were treated with a potent inhibitor of HO system, tin protoporphyrin IX (SnPPIX, 50 micromol/kg/d), and were compared with untreated diabetic and non-diabetic animals. All treatments began at the onset of diabetes, 48 h after injection of streptozotocin along with the confirmation of hyperglycemia. Animals were euthanized after 1 week and 1 month of treatment, and heart tissues were harvested. Frozen tissues were subjected to HO-1 and HO-2 mRNA expression by real-time RT-PCR and HO activity determination. Paraffin-embedded tissue sections were used for immunohistochemical analysis of HO-1 and HO-2. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) stain, a sensitive and specific marker of DNA damage, was preformed to assess damage induced by oxidative stress. In addition, tissue sections were subjected to histochemical analysis for iron. We further examined non-diabetic animals treated with a direct HO agonist, hemin (50 mg/kg/d). A possible relationship between the HO and the nitric oxide (NO) pathways was also considered by studying the mRNA levels of endothelial nitric oxide synthase (NOS) and inducible NOS, and by measuring the amount of NOS products. Our results demonstrate no significant alterations of the HO system following 1 week of diabetes. However, 1 month of diabetes caused increased oxidative stress as demonstrated by higher levels of 8-OHdG-positive cardiomyocytes (80% positive as compared to 11.25% in controls), in association with increased HO isozyme mRNA (2.7-fold increase as compared to controls) and protein expression, and augmented HO activity (759.3 as compared to 312.3 pmol BR/h/mg protein in controls). Diabetic rats further demonstrated increased number of cardiomyocytes with stainable iron. SnPPIX treatment resulted in reduced number of 8-OHdG-positive cardiomyocytes (19.5% as compared to 80% in diabetics) in parallel with reduced HO activity (569.7 as compared to 759.3 pmol BR/h/mg protein in diabetics). Non-diabetic rats treated with HO-agonist hemin exhibited abnormalities similar to diabetic rats. Our results provide the first direct demonstration that diabetes-induced oxidative stress in the heart is, in part, due to upregulated HO expression and activity. These results provide evidence of pro-oxidant activity of HO in the heart in diabetes, which could be mediated by increased redox-active iron.

Iron-regulated transporter protein 1 (IREG1 or ferroportin 1) is a transmembrane iron transporter that has been described in macrophages and hepatocytes. Ferroportin mutations have been described to result in hepatic iron overload in human pedigrees. The role of hepatic ferroportin in the pathogenesis of C282Y-linked hemochromatosis has not been clearly established. The objective was to study the expression of ferroportin mRNA and protein in C282Y-linked hemochromatosis liver and in controls. Human liver biopsies were stained with an anti-ferroportin antibody and quantitation of ferroportin at 62 kDa was done by Western blotting. mRNA was studied by real time RT-PCR. Ferroportin protein expression was increased in C282Y homozygotes (n = 23) compared to wild-type patients (n = 37) (P < 0.003). There was no significant correlation between ferroportin protein or mRNA expression (n = 25) and liver iron concentration or serum ferritin. Immunohistochemical staining demonstrated ferroportin in hepatocytes and macrophages. In conclusion, ferroportin protein is increased in iron-loaded hemochromatosis liver. The increase in ferroportin protein without an increase in mRNA is consistent with iron-mediated translational regulation through the 5'IRE in the mRNA.