A review on structure-function mechanism and signaling pathway of serine/threonine protein PIM kinases as a therapeutic target.

The proviral integration for the Moloney murine leukemia virus (PIM) kinases, belonging to serine/threonine kinase family, have been found to be overexpressed in various types of cancers, such as prostate, breast, colon, endometrial, gastric, and pancreatic cancer. The three isoforms PIM kinases i.e., PIM1, PIM2, and PIM3 share a high degree of sequence and structural similarity and phosphorylate substrates controlling tumorigenic phenotypes like proliferation and cell survival. Targeting short-lived PIM kinases presents an intriguing strategy as in vivo knock-down studies result in non-lethal phenotypes, indicating that clinical inhibition of PIM might have fewer adverse effects. The ATP binding site (hinge region) possesses distinctive attributes, which led to the development of novel small molecule scaffolds that target either one or all three PIM isoforms. Machine learning and structure-based approaches have been at the forefront of developing novel and effective chemical therapeutics against PIM in preclinical and clinical settings, and none have yet received approval for cancer treatment. The stability of PIM isoforms is maintained by PIM kinase activity, which leads to resistance against PIM inhibitors and chemotherapy; thus, to overcome such effects, PIM proteolysis targeting chimeras (PROTACs) are now being developed that specifically degrade PIM proteins. In this review, we recapitulate an overview of the oncogenic functions of PIM kinases, their structure, function, and crucial signaling network in different types of cancer, and the potential of pharmacological small-molecule inhibitors. Further, our comprehensive review also provides valuable insights for developing novel antitumor drugs that specifically target PIM kinases in the future. In conclusion, we provide insights into the benefits of degrading PIM kinases as opposed to blocking their catalytic activity to address the oncogenic potential of PIM kinases.

Metagenomic landscape of sediments of river Ganga reveals microbial diversity, potential plastic and xenobiotic degradation enzymes.

The Ganga is the largest river in India, serves as a lifeline for agriculture, drinking water, and religious rites. However, it became highly polluted due to the influx of industrial wastes and untreated sewages, leading to the decline of aquatic biodiversity. This study investigated the microbial diversity and plastic-xenobiotic degrading enzymes of six sediment metagenomes of river Ganga at Prayagraj (RDG, TSG, SDG) and Devprayag (KRG, BNG, BRG). The water quality parameters, higher values of BOD (1.8-3.7 ppm), COD (23-29.2 ppm) and organic carbon (0.18-0.51%) were recorded at Prayagraj. Comparative analysis of microbial community structure between Prayagraj and Devprayag revealed significant differences between Bacteroidetes and Firmicutes, which emerging as the predominant bacterial phyla across six sediment samples. Notably, their prevalence was highest in the BRG samples. Furthermore, 25 OTUs at genus level were consistent across all six samples. Alpha diversity exhibited minimal variation among samples, while beta diversity indicated an inverse relationship between species richness and diversity. Co-occurrence network analysis established that genera from the same and different groups of phyla show positive co-relations with each other. Thirteen plastic degrading enzymes, including Laccase, Alkane-1 monooxygenase and Alkane monooxygenase, were identified from six sediment metagenomes of river Ganga, which can degrade non-biodegradable plastic viz. Polyethylene, Polystyrene and Low-density Polyethelene. Further, 18 xenobiotic degradation enzymes were identified for the degradation of Bisphenol, Xylene, Toluene, Polycyclic aromatic hydrocarbon, Styrene, Atrazene and Dioxin etc. This is the first report on the identification of non-biodegradable plastic degrading enzymes from sediment metagenomes of river Ganga, India. The findings of this study would help in pollution abatement and sustainable management of riverine ecosystem.

Deciphering the impact of endoparasitic infection on immune response and gut microbial composition of Channa punctata.

Intestinal parasitic infections caused by helminths are globally distributed and are a major cause of morbidity worldwide. Parasites may modulate the virulence, gut microbiota diversity and host responses during infection. Despite numerous works, little is known about the complex interaction between parasites and the gut microbiota. In the present study, the complex interplay between parasites and the gut microbiota was investigated. A total of 12 bacterial strains across four major families, including Enterobacteriaceae, Morganellaceae, Flavobacteriaceae, and Pseudomonadaceae, were isolated from Channa punctata, infected with the nematode species Aporcella sp., Axonchium sp., Tylencholaimus mirabilis, and Dioctophyme renale. The findings revealed that nematode infection shaped the fish gut bacterial microbiota and significantly affected their virulence levels. Nematode-infected fish bacterial isolates are more likely to be pathogenic, with elevated hemolytic activity and biofilm formation, causing high fish mortality. In contrast, isolates recovered further from non-parasitised C. punctata were observed to be non-pathogenic and had negligible hemolytic activity and biofilm formation. Antibiogram analysis of the bacterial isolates revealed a disproportionately high percentage of bacteria that were either marginally or multidrug resistant, suggesting that parasitic infection-induced stress modulates the gut microenvironment and enables colonization by antibiotic-resistant strains. This isolation-based study provides an avenue to unravel the influence of parasitic infection on gut bacterial characteristics, which is valuable for understanding the infection mechanism and designing further studies aimed at optimizing treatment strategies. In addition, the cultured isolates can supplement future gut microbiome studies by providing wet lab specimens to compare (meta)genomic information discovered within the gut microenvironment of fish.

Effects of Di-(2-Ethylhexyl) Phthalate (DEHP) on Gamete Quality Parameters of Male Koi Carp (Cyprinus carpio).

In this study, we evaluated gamete quality parameters of mature male koi carp (Cyprinus carpio) exposed to three different concentrations (1, 10, and 100 µg/L) of di-(2-ethylhexyl) phthalate (DEHP). After 60 days of exposure, there was a significant decrease in the gonadosomatic index (GSI) of males exposed to 10 and 100 µg/L of DEHP. Histological analysis of the testes revealed impaired histoarchitecture, including inflammatory cells, intratubular vacuoles, and swollen seminiferous tubules in treatment groups. Gamete quality parameters like sperm production, motility, spermatocrit, and sperm density values were significantly decreased at the 10 and 100 µg/L concentrations. Biochemical compositions, including glucose, cholesterol, and total protein levels, were significantly changed in the treatment groups. Similarly, the ionic compositions of seminal fluid (Na, K, Ca, and Mg) also varied in the treatment groups. Furthermore, the 11-ketotestosterone levels were decreased, and the 17-ß estradiol levels were increased in the DEHP-treated groups. The mRNA expression levels of reproduction-related genes, including Fshr, Lhr, Ar, Erα, and Erß, were significantly changed in the DEHP-treated males in a dose-dependent manner. In conclusion, the findings of this study confirmed that environmentally relevant exposure to DEHP may contribute to a decline in the gamete quality of male fishes.

Aeromonas veronii Is a Lethal Pathogen Isolated from Gut of Infected Labeo rohita: Molecular Insight to Understand the Bacterial Virulence and Its Induced Host Immunity.

A case of severe mortality in farmed Labeo rohita was investigated to characterize the causative agent. We identified the bacterial strain as Aeromonas veronii isolated from the gut of infected L. rohita by biochemical assay, scanning electron microscopy and 16S rRNA gene sequence analysis. The in vivo challenge experiment showed that the LD50 of A. veronii was 2.2 × 104 CFU/fish. Virulence gene investigation revealed that the isolated A. veronii possesses Aerolysin, Cytotoxic enterotoxin, Serine protease, Dnase and Type III secretion system genes. The isolated strain was resistant to two antibiotics (ampicillin and dicloxacillin) while susceptible to 22 other antibiotics. The study further revealed that A. veronii induced both stresses along with non-specific and specific immune responses marked by elevated cortisol HSP70, HSP90 and IgM levels in the treated L. rohita fingerlings. Although the bacterial pathogen enhances the immune response, the negative effect on fish, including stress, and high mortality, create concern and a need for A. veronii management in L. rohita farms. The knowledge gained from this study would facilitate future research aimed at assessing the pathogenicity of A. veronii, with an emphasis on microbial disease management in other farmed fish species.