Melatonin abrogates liver, ovarian, and uterine toxicities induced by tamoxifen in a breast cancer mouse model

33-43Melatonin is known for its efficacy in breast cancer treatment. However, the safety profile of melatonin, particularly its effect on liver, uterus and ovaries is largely unknown. Here, we explored the safety profile of melatonin using virgin female mice of the Swiss albino strain. Further, we investigated whether melatonin can overcome liver, ovaries and uterine toxicities which are induced by tamoxifen using N,N-dimethylbenzylamine (DMBA) induced breast cancer mouse model? Treatment of tamoxifen after breast cancer induction in mice resulted in reduction of breast masses but severe pathological abnormalities like liver steatosis, hyper ovulation, ovarian cysts, uterine glands dilatations and endometriosis were observed in treated animals. Whereas, melatonin when used in combination with tamoxifen helped to reduce the mouse mammary tumor volume and significantly decreases liver enzymes, steroid hormones and oxidative stress. Melatonin also reverted the liver, ovarian and uterus toxicity induced by tamoxifen. The results have demonstrated that tamoxifen when used as combination therapy with melatonin serve as an effective anti-breast cancer molecule with minimum liver, ovarian and uterus toxicities

Melatonin abrogates liver, ovarian, and uterine toxicities induced by tamoxifen in a breast cancer mouse model

Melatonin is known for its efficacy in breast cancer treatment. However, the safety profile of melatonin, particularly its effect on liver, uterus and ovaries is largely unknown. Here, we explored the safety profile of melatonin using virgin female mice of the Swiss albino strain. Further, we investigated whether melatonin can overcome liver, ovaries and uterine toxicities which are induced by tamoxifen using N,N-dimethylbenzylamine (DMBA) induced breast cancer mouse model? Treatment of tamoxifen after breast cancer induction in mice resulted in reduction of breast masses but severe pathological abnormalities like liver steatosis, hyper ovulation, ovarian cysts, uterine glands dilatations and endometriosis were observed in treated animals. Whereas, melatonin when used in combination with tamoxifen helped to reduce the mouse mammary tumor volume and significantly decreases liver enzymes, steroid hormones and oxidative stress. Melatonin also reverted the liver, ovarian and uterus toxicity induced by tamoxifen. The results have demonstrated that tamoxifen when used as combination therapy with melatonin serve as an effective anti-breast cancer molecule with minimum liver, ovarian and uterus toxicities

Genome-wide identification of NAC transcription factors and regulation of monoterpenoid indole alkaloid biosynthesis in Catharanthus roseus

NAC transcription factors (TFs) are crucial to growth and defense responses in plants. Though NACs have been characterized for their role in several plants, comprehensive information regarding their role in Catharanthus roseus, a perennial ornamental plant, is lacking. Homology modelling was employed to identify and characterize NACs in C. roseus. In-vitro propagation of C. roseus plants was carried out using cell suspension and nodal culture and were elicited with two auxin-antagonists, 5-fluoro Indole Acetic Acid (5-F-IAA) and α-(phenyl ethyl-2-oxo)-Indole-Acetic-Acid (PEO-IAA) for the enhanced production of monoterpenoid indole alkaloids (MIAs) namely catharanthine, vindoline, and vinblastine. Analyses revealed the presence of 47 putative CrNAC genes in the C. roseus genome, primarily localized in the nucleus. Phylogenetic analysis categorized these CrNACs into eight clusters, demonstrating the highest synteny with corresponding genes in Camptotheca acuminata. Additionally, at least one defense or hormone-responsive cis-acting element was identified in the promoter region of all the putative CrNACs. Of the two elicitors, 5-F-IAA was effective at 200 µM to elicit a 3.07-fold increase in catharanthine, 2.76-fold in vindoline, and 2.4-fold in vinblastine production in nodal culture. While a relatively lower increase in MIAs was recorded in suspension culture. Validation of RNA-Seq by qRT-PCR showed upregulated expression of stress-related genes (CrNAC-07 and CrNAC-24), and downregulated expression of growth-related gene (CrNAC-25) in elicited nodal culture of C. roseus. Additionally, the expression of genes involved in the biosynthesis of MIAs was significantly upregulated upon elicitation. The current study provides the first report on the role of CrNACs in regulating the biosynthesis of MIAs

The Impact of Industrialization, Trade Openness, Financial Development, and Energy Consumption on Economic Growth in Indonesia

This study aimed to scrutinize the impact of financial development, energy consumption, industrialization, and trade openness on economic growth in Indonesia over the period 1984–2018. To do so, the study employed the autoregressive distributed lag (ARDL) model to estimate the long-run and short-run nexus among the variables. Furthermore, fully modified ordinary least squares (FMOLS), dynamic least squares (DOLS), and canonical cointegrating regression (CCR) were used for a more robust examination of the empirical findings. The result of cointegration confirms the presence of cointegration among the variables. Findings from the ARDL indicate that industrialization, energy consumption, and financial development (measured by domestic credit) positively influence economic growth in the long run. However, financial development (measured by money supply) and trade openness demonstrate a negative effect on economic growth. The positive nexus among industrialization, financial development, energy consumption, and economic growth explains that these variables were stimulating growth in Indonesia. The error correction term indicates a 68% annual adjustment from any deviation in the previous period’s long-run equilibrium economic growth. These findings provide a strong testimony that industrialization and financial development are key to sustained long-run economic growth in Indonesia

The Impact of Industrialization, Trade Openness, Financial Development, and Energy Consumption on Economic Growth in Indonesia

This study aimed to scrutinize the impact of financial development, energy consumption, industrialization, and trade openness on economic growth in Indonesia over the period 1984–2018. To do so, the study employed the autoregressive distributed lag (ARDL) model to estimate the long-run and short-run nexus among the variables. Furthermore, fully modified ordinary least squares (FMOLS), dynamic least squares (DOLS), and canonical cointegrating regression (CCR) were used for a more robust examination of the empirical findings. The result of cointegration confirms the presence of cointegration among the variables. Findings from the ARDL indicate that industrialization, energy consumption, and financial development (measured by domestic credit) positively influence economic growth in the long run. However, financial development (measured by money supply) and trade openness demonstrate a negative effect on economic growth. The positive nexus among industrialization, financial development, energy consumption, and economic growth explains that these variables were stimulating growth in Indonesia. The error correction term indicates a 68% annual adjustment from any deviation in the previous period’s long-run equilibrium economic growth. These findings provide a strong testimony that industrialization and financial development are key to sustained long-run economic growth in Indonesia

Histopathology of the Liver, Kidney, and Spleen of Mice Exposed to Gold Nanoparticles

Gold nanoparticles (GNPs) are biocompatible nanomaterials that are currently researched for biomedical applications such as imaging and targeted drug delivery. In this investigation, we studied the effects of a single dose (injected on day 1) as well as a priming dose (two injections with a gap of one week) of 5 nm, 20 nm, and 50 nm diameter GNPs on the structural and biochemical changes in the liver, kidney, and spleen of mice. The results showed that small sized GNPs (5 nm) produced significant pathological changes in the liver on day 2 that gradually reduced on day 8. The medium (20 nm) and large (50 nm) sized GNPs preferentially targeted the spleen and caused significant pathological changes to the spleen architecture on day 2 that persisted on day 8 as well. There were minimal and insignificant pathological changes to the kidneys irrespective of the GNPs size. The animals that were primed with the pre-exposure of GNPs did not show any aggravation of histological changes after the second dose of the same GNPs. None of the dose regimens of the GNPs were able to significantly affect the markers of oxidative stress including glutathione (GSH) and malondialdehyde (MDA) in all of the organs that were studied. In conclusion, the size of GNPs plays an important role in their pathological effects on different organs of mice. Moreover, the primed animals become refractory to further pathological changes after the second dose of GNPs, suggesting the importance of a priming dose in medical applications of GNPs

In Silico Investigation of AKT2 Gene and Protein Abnormalities Reveals Potential Association with Insulin Resistance and Type 2 Diabetes

Type 2 diabetes (T2D) develops from insulin resistance (IR) and the dysfunction of pancreatic beta cells. The AKT2 protein is very important for the protein signaling pathway, and the non-synonymous SNP (nsSNPs) in AKT2 gene may be associated with T2D. nsSNPs can result in alterations in protein stability, enzymatic activity, or binding specificity. The objective of this study was to investigate the effect of nsSNPs on the AKT2 protein structure and function that may result in the induction of IR and T2D. The study identified 20 variants that were considered to be the most deleterious based on a range of analytical tools included (SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, and I-Mut). Two mutations, p.A179T and p.L183Q, were selected for further investigation based on their location within the protein as determined by PyMol. The results indicated that mutations, p.A179T and p.L183Q alter the protein stability and functional characteristics, which could potentially affect its function. In order to conduct a more in-depth analysis of these effects, a molecular dynamics simulation was performed for wildtype AKT2 and the two mutants (p.A179T and p.L183Q). The simulation evaluated various parameters, including temperature, pressure, density, RMSD, RMSF, SASA, and Region, over a period of 100 ps. According to the simulation results, the wildtype AKT2 protein demonstrated higher stability in comparison to the mutant variants. The mutations p.A179T and p.L183Q were found to cause a reduction in both protein stability and functionality. These findings underscore the significance of the effects of nsSNPs (mutations p.A179T and p.L183Q) on the structure and function of AKT2 that may lead to IR and T2D. Nevertheless, they require further verifications in future protein functional, protein–protein interaction, and large-scale case–control studies. When verified, these results will help in the identification and stratification of individuals who are at risk of IR and T2D for the purpose of prevention and treatment