Targeting Phosphoinositide 3-Kinase – Five Decades of Chemical Space Exploration

Phosphoinositide 3-kinase (PI3K) plays a key role in a plethora of physiologic processes and controls cell growth, metabolism, immunity, cardiovascular and neurological function, and more. The discovery of wort-mannin as the first potent PI3K inhibitor (PI3Ki) in the 1990s provided rapid identification of PI3K-dependent processes, which drove the discovery of the PI3K/protein kinase B (PKB/Akt)/target of rapamycin (mTOR) pathway. Genetic mouse models and first PI3K isoform-specific inhibitors pinpointed putative therapeutic applications. The recognition of PI3K as target for cancer therapy drove subsequently drug development. Here we provide a brief journey through the emerging roles of PI3K to the development of preclinical and clinical PI3Ki candidates.

Genomic basis of fishing-associated selection varies with population density

Fisheries induce one of the strongest anthropogenic selective pressures on natural populations, but the genetic effects of fishing remain unclear. Crucially, we lack knowledge of how capture-associated selection and its interaction with reductions in population density caused by fishing can potentially shift which genes are under selection. Using experimental fish reared at two densities and repeatedly harvested by simulated trawling, we show consistent phenotypic selection on growth, metabolism, and social behavior regardless of density. However, the specific genes under selection—mainly related to brain function and neurogenesis—varied with the population density. This interaction between direct fishing selection and density could fundamentally alter the genomic responses to harvest. The evolutionary consequences of fishing are therefore likely context dependent, possibly varying as exploited populations decline. These results highlight the need to consider environmental factors when predicting effects of human-induced selection and evolution.

Hfq Regulates Efflux Pump Expression and Purine Metabolic Pathway to Increase Trimethoprim Resistance in Aeromonas veronii

Aeromonas veronii (A. veronii) is a zoonotic pathogen. It causes clinically a variety of diseases such as dysentery, bacteremia, and meningitis, and brings huge losses to aquaculture. A. veronii has been documented as a multiple antibiotic resistant bacterium. Hfq (host factor for RNA bacteriophage Qβ replication) participates in the regulations of the virulence, adhesion, and nitrogen fixation, effecting on the growth, metabolism synthesis and stress resistance in bacteria. The deletion of hfq gene in A. veronii showed more sensitivity to trimethoprim, accompanying by the upregulations of purine metabolic genes and downregulations of efflux pump genes by transcriptomic data analysis. Coherently, the complementation of efflux pump-related genes acrA and acrB recovered the trimethoprim resistance in Δhfq. Besides, the accumulations of adenosine and guanosine were increased in Δhfq in metabonomic data. The strain Δhfq conferred more sensitive to trimethoprim after appending 1 mM guanosine to M9 medium, while wild type was not altered. These results demonstrated that Hfq mediated trimethoprim resistance by elevating efflux pump expression and degrading adenosine, and guanosine metabolites. Collectively, Hfq is a potential target to tackle trimethoprim resistance in A. veronii infection.

Hormonal and neuroendocrine control of reproductive function in teleost fish.

Reproduction is one of the important physiological events for the maintenance of the species. Hormonal and neuroendocrine regulation of teleost requires multiple and complex interactions along the hypothalamic-pituitary-gonad (HPG) axis. Within this axis, gonadotropin-releasing hormone (GnRH) regulates the synthesis and release of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Steroidogenesis drives reproduction function in which the development and differentiation of gonads. In recent years, new neuropeptides have become the focus of reproductive physiology research as they are involved in the different regulatory mechanisms of these species' growth, metabolism, and reproduction. However, especially in fish, the role of these neuropeptides in the control of reproductive function is not well studied. The study of hormonal and neuroendocrine events that regulate reproduction is crucial for the development and success of aquaculture.

Sestrins as modulators of aging processes and diseases related to age

Sestrins are highly conserved proteins that regulate cell growth, metabolism, survival and proliferation under oxidative stress, genotoxic stress, hypoxia or endoplasmic reticulum stress. Sestrins affect cell signaling by inhibiting the production of reactive oxygen species, activating the AMP-activated protein kinase (AMPK), inhibiting the mTOR pathway and acting as a positive regulator of autophagy. Therefore, their protective role against cancer, metabolic disorders, cardiovascular diseases and neurodegeneration is increasingly being postulated. The article describes the mechanisms of action of sestrins and their meaning in aging and age-related diseases. The latest studies indicating their physiological significance and role in key signaling pathways controlling the cell metabolism and survival under stress conditions were also discussed.

Mental health, mitochondria, and the battle of the sexes

This paper presents a broad perspective on how mental disease relates to the different evolutionary strategies of men and women and to growth, metabolism, and mitochondria—the enslaved bacteria in our cells that enable it all. Several mental disorders strike one sex more than the other; yet what truly matters, regardless of one’s sex, is how much one’s brain is “female” and how much it is “male”. This appears to be the result of an arms race between the parents over how many resources their child ought to extract from the mother, hence whether it should grow a lot or stay small and undemanding. An uneven battle alters the child’s risk of developing not only insulin resistance, diabetes, or cancer, but a mental disease as well. Maternal supremacy increases the odds of a psychosis-spectrum disorder; paternal supremacy, those of an autism-spectrum one. And a particularly lopsided struggle may invite one or the other of a series of syndromes that come in pairs, with diametrically opposite, excessively “male” or “female” characteristics. By providing the means for this tug of war, mitochondria take center stage in steadying or upsetting the precarious balance on which our mental health is built.