Cases of depression among adolescents are gradually increasing. The study of the physiological basis of cognitive function from a biochemical perspective has therefore been garnering increasing attention. Depression has been hypothesized to be associated with the brain biochemical metabolism of the anterior cingulate gyrus, frontal lobe white matter, and the thalamus.

To explore the application of proton magnetic resonance spectroscopy (1H-MRS) in the metabolic alterations in the prefrontal white matter (PWM) and gray matter (GM) in adolescents with depression.

1H-MRS was performed for semi-quantitative analysis of the biochemical metabolites N-acetylaspartate (NAA), choline (Cho) complexes, creatine (Cr), and myo-inositol (mI) in bilateral PWM, anterior cingulate GM, and thalami of 31 adolescent patients with depression (research group) and 35 healthy adolescents (control group), and the NAA/Cr, Cho/Cr, and mI/Cr ratios were calculated. Meanwhile, Hamilton Depression Scale (HAMD) and Wechsler Memory Scale were used to assess the degree of depression and memory function in all adolescents. The correlation of brain metabolite levels with scale scores was also analyzed.

The research group had markedly higher HAMD-24 scores and lower memory quotient (MQ) compared with the control group (P < 0.05). Adolescents with depression were found to have lower bilateral PWM NAA/Cr and Cho/Cr ratios compared with healthy adolescents (P < 0.05). The mI/Cr ratios were found to be similar in both groups (P > 0.05). The bilateral anterior cingulate GM NAA/Cr, Cho/Cr, and mI/Cr also did not demonstrate marked differences (P > 0.05). No statistical inter-group difference was determined in NAA/Cr of the bilateral thalami (P > 0.05), while bilateral thalamic Cho/Cr and mI/Cr were reduced in teenagers with depression compared with healthy adolescents (P < 0.05). A significant negative correlation was observed between the HAMD-24 scores in adolescents with depression with bilateral PWM NAA/Cr and Cho/Cr and were inversely linked to bilateral thalamic Cho/Cr and mI/Cr (P < 0.05). In adolescents with depressions, MQ positively correlated with right PWH NAA/Cr, left PWH Cho/Cr, and bilateral thalamic Cho/Cr and mI/Cr.

PWM and thalamic metabolic abnormalities might influence teen depression, and the reduction in bilateral PWM NAA/Cr and Cho/Cr could be related to the neuropathology of adolescents with depression suffering from memory impairment. There exists a possibility of dysfunction of nerve cell membrane phospholipids in the thalami of adolescent patients with depression.

Inositol hexakisphosphate kinases (IP6Ks) have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to the pyrophosphate, 5-diphosphoinositol-1,2,3,4,6-pentakisphosphate (5-IP7). Most of the currently known potent IP6K inhibitors contain a critical carboxylic acid which limits blood-brain barrier (BBB) penetration. In this work, the synthesis and testing of a variety of carboxylic acid isosteres resulted in several new compounds with improved BBB penetration. The most promising compound has an IP6K1 IC50 of 16 nM with an improved brain/plasma ratio and a favorable pharmacokinetic profile. This series of brain penetrant compounds may be used to investigate the role of IP6Ks in CNS disorders.

The inositol pyrophosphate pathway, a complex cell signaling network, plays a pivotal role in orchestrating vital cellular processes in the budding yeast, where it regulates cell cycle progression, growth, endocytosis, exocytosis, apoptosis, telomere elongation, ribosome biogenesis, and stress responses. This pathway has gained significant attention in pharmacology and medicine due to its role in generating inositol pyrophosphates, which serve as crucial signaling molecules not only in yeast, but also in higher eukaryotes. As targets for therapeutic development, genetic modifications within this pathway hold promise for disease treatment strategies, offering practical applications in biotechnology. The model organism Saccharomyces cerevisiae, renowned for its genetic tractability, has been instrumental in various studies related to the inositol pyrophosphate pathway. This review is focused on the Kcs1 and Vip1, the two enzymes involved in the biosynthesis of inositol pyrophosphate in S. cerevisiae, highlighting their roles in various cell processes, and providing an up-to-date overview of their relationship with phosphate homeostasis. Moreover, the review underscores the potential applications of these findings in the realms of medicine and biotechnology, highlighting the profound implications of comprehending this intricate signaling network.

The inositol pyrophosphates (PP-IPs) are specialized members of the wider inositol phosphate signaling family that possess functionally significant diphosphate groups. The PP-IPs exhibit remarkable functionally versatility throughout the eukaryotic kingdoms. However, a quantitatively minor PP-IP - 1,5 bisdiphosphoinositol tetrakisphosphate (1,5-IP8) - has received considerably less attention from the cell signalling community. The main purpose of this review is to summarize recently-published data which have now brought 1,5-IP8 into the spotlight, by expanding insight into the molecular mechanisms by which this polyphosphate regulates many fundamental biological processes.

A high-throughput fragment-based screen has been employed to discover a series of quinazolinone inositol hexakisphosphate kinase (IP6K) inhibitors. IP6Ks have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, blood coagulation, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to form pyrophosphate 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7). Molecular docking studies and investigation of structure-activity relationships around the quinazolinone core resulted in compounds with submicromolar potency and interesting selectivity for IP6K1 versus the closely related IP6K2 and IP6K3 isoforms.