Eisenia fetida-driven vermitechnology for the eco-friendly transformation of steel waste slag into organic amendment: An insight through microbial diversity and multi-model approach.

The processing of steel waste slag from the black metallurgical sector seriously threatened the ecology. To counter these dangers, appropriate detoxification methods were required. Vermitechnology was one such strategy that could successfully convert this industrial waste into nutrient-rich products suitable for use in agriculture. This research primarily focuses on employing vermitechnology for the transformation of waste steel slag into vermicompost and to determine changes in microbial composition, nutrient cycling, and metal detoxification facilitated by earthworms (Eisenia fetida). Earthworm populations in steel waste vermibeds (sw-vermibeds) increased by 2.87-3.07 folds. T1(SW + CD-1:1) comparatively showed increased levels of nutrients such as nitrogen, phosphorus, and potassium. Microbial and enzymatic parameters were more pronounced in treatment T1. The findings of phospholipid fatty acid (PLFA) diversity demonstrate microbial diversity and fatty acid composition. Based on PLFA Sobol Sensitivity Analysis (SSA), PUFA and cyclo were the most sensitive inputs to the presence of heavy metal (HMs) concentrations in SW. In accordance with Taylor-based modelling, R-tree, and Mars were the most trusted regression models for predicting HMs toxicity on microbes. The bioavailable metal fractions of HMs (Fe, Ni, Cd, Cu, Pb, and Cr) decreased by 61-83%. The correlation was performed for 0 and 90 days for metal microbial interactions r (0 days), [BSR vs Fe, Cd, Cu, Ni = -0.99, -0.82, -0.43, -0.99] and r (90 days), [FDA vs Fe, Cu, Ni = -0.97, -0.47, -0.95]. Overall, the results indicated that T1(1:1 SW + CD) provided more favorable conditions for the development of microbes and Eisenia fetida. This research presents a new perspective to the world community on the transformation of harmful steel waste slag into advantageous biological resources by introducing a novel method of employing Eisenia fetida to remediate hazardous steel waste slag.

Design, synthesis, and biological evaluation of HDAC6 inhibitors targeting L1 loop and serine 531 residue.

Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones, leading to the silencing of genes. Targeting specific isoforms of HDACs has emerged as a promising approach for cancer therapy, as it can overcome drawbacks associated with pan-HDAC inhibitors. HDAC6 is a unique HDAC isoform that deacetylates non-histone proteins and is primarily located in the cytoplasm. It also has two catalytic domains and a zinc-finger ubiquitin binding domain (Zf-UBD) unlike other HDACs. HDAC6 plays a critical role in various cellular processes, including cell motility, protein degradation, cell proliferation, and transcription. Hence, the deregulation of HDAC6 is associated with various malignancies. In this study, we report the design and synthesis of a series of HDAC6 inhibitors. We evaluated the synthesized compounds by HDAC enzyme assay and identified that compound 8g exhibited an IC50 value of 21 nM and 40-fold selective activity towards HDAC6. We also assessed the effect of compound 8g on various cell lines and determined its ability to increase protein acetylation levels by Western blotting. Furthermore, the increased acetylation of α-tubulin resulted in microtubule polymerization and changes in cell morphology. Our molecular docking study supported these findings by demonstrating that compound 8g binds well to the catalytic pocket via L1 loop of HDAC6 enzyme. Altogether, compound 8g represents a preferential HDAC6 inhibitor that could serve as a lead for the development of more potent and specific inhibitors.

Assessing pollution and health risks from chromite mine tailings contaminated soils in India by employing synergistic statistical approaches.

Potentially toxic elements (PTEs) contamination in the agricultural soil can generate a detrimental effect on the ecosystem and poses a threat to human health. The present work evaluates the PTEs concentration, source identification, probabilistic assessment of health hazards, and dietary risk analysis due to PTEs pollution in the region of the chromite-asbestos mine, India. To evaluate the health risks associated with PTEs in soil, soil tailings and rice grains were collected and studied. The results revealed that the PTEs concentration (mainly Cr and Ni) of total, DTPA-bioavailable, and rice grain was significantly above the permissible limit in site 1 (tailings) and site 2 (contaminated) as compared with site 3 (uncontaminated). The Free ion activity model (FIAM) was applied to detect the solubility of PTEs in polluted soil and their probable transfer from soil to rice grain. The hazard quotient values were significantly higher than the safe (FIAM-HQ < 0.5) for Cr (1.50E+00), Ni (1.32E+00), and, Pb (5.55E+00) except for Cd (1.43E-03), Cu (5.82E-02). Severity adjustment margin of exposure (SAMOE) results denote that the PTEs contaminated raw rice grain has high health risk [CrSAMOE: 0.001; NiSAMOE: 0.002; CdSAMOE: 0.007; PbSAMOE: 0.008] for humans except for Cu. The Positive matrix factorization (PMF) along with correlation used to apportion the source. Self-organizing map (SOM) and PMF analysis identified the source of pollution mainly from mines in this region. Monte Carlo simulation (MCS) revealed that TCR (total carcinogenic risk) cannot be insignificant and children were the maximum sufferers relative to adults via ingestion-pathway. In the spatial distribution map, the region nearer to mine is highly prone to ecological risk with respect to PTEs pollution. Based on appropriate and reasonable evaluation methods, this work will help environmental scientists and policymakers' control PTEs pollution in agricultural soils near the vicinity of mines.

Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay.

HDAC6 and Hsp90, existing as a cytosolic complex play an important role in maintaining the protein homeostasis. The interplay of HDAC6 and Hsp90 has attracted wide attention due to their important role and promise as therapeutic targets in malignant cancers. Therefore, the discovery of dual inhibitors targeting HDAC6 and Hsp90 is of high importance. In the present study, we describe the design, synthesis, and biological evaluation of bifunctional inhibitors against HDAC6 and Hsp90 interplay. In particular, compound 6e shows a significant inhibitory activity against both HDAC6 and Hsp90 with IC50 values of 106 nM and 61 nM, respectively. Compound 6e promotes the acetylation of HDAC6 substrate proteins such as α-tubulin and Hsp90 via HDAC6 inhibition, and also induces the degradation of Hsp90 clients such as Her2, EGFR, Met, Akt, and HDAC6 via Hsp90 inhibition. Compound 6e consequently furnishes potent antiproliferative effect on gefitinib-resistant H1975 non-small cell lung cancer (NSCLC) with a GI50 value of 1.7 µM. In addition, compound 6e successfully achieved significant tumor growth inhibition in H1975 NSCLC xenograft model without noticeable abnormal behavior, body weight changes, and apparent ocular toxicity. We conclude that compound 6e constitutes an excellent tool as well as a valuable lead for assessment of Hsp90 and HDAC6 dual inhibition with a single molecule.

MeBib Suppressed Methamphetamine Self-Administration Response via Inhibition of BDNF/ERK/CREB Signal Pathway in the Hippocampus.

Methamphetamine (MA) is one of the most commonly abused drugs in the world by illegal drug users. Addiction to MA is a serious public health problem and effective therapies do not exist to date. It has also been reported that behavior induced by psychostimulants such as MA is related to histone deacetylase (HDAC). MeBib is an HDAC6 inhibitor derived from a benzimidazole scaffold. Many benzimidazole-containing compounds exhibit a wide range of pharmacological activity. In this study, we investigated whether HDAC6 inhibitor MeBib modulates the behavioral response in MA self-administered rats. Our results demonstrated that the number of active lever presses in MA self-administered rats was reduced by pretreatment with MeBib. In the hippocampus of rats, we also found MA administration promotes GluN2B, an NMDA receptor subunit, expression, which results in sequential activation of ERK/CREB/BDNF pathway, however, MeBib abrogated it. Collectively, we suggest that MeBib prevents the MA seeking response induced by MA administration and therefore, represents a potent candidate as an MA addiction inhibitor.

Microbial Beta Glucosidase Enzymes: Recent Advances in Biomass Conversation for Biofuels Application.

The biomass to biofuels production process is green, sustainable, and an advanced technique to resolve the current environmental issues generated from fossil fuels. The production of biofuels from biomass is an enzyme mediated process, wherein ß-glucosidase (BGL) enzymes play a key role in biomass hydrolysis by producing monomeric sugars from cellulose-based oligosaccharides. However, the production and availability of these enzymes realize their major role to increase the overall production cost of biomass to biofuels production technology. Therefore, the present review is focused on evaluating the production and efficiency of ß-glucosidase enzymes in the bioconversion of cellulosic biomass for biofuel production at an industrial scale, providing its mechanism and classification. The application of BGL enzymes in the biomass conversion process has been discussed along with the recent developments and existing issues. Moreover, the production and development of microbial BGL enzymes have been explained in detail, along with the recent advancements made in the field. Finally, current hurdles and future suggestions have been provided for the future developments. This review is likely to set a benchmark in the area of cost effective BGL enzyme production, specifically in the biorefinery area.