Markers for obese and non-obese Type 2 diabetes identified using whole blood metabolomics

Definitive differences in blood metabolite profiles between obese and non-obese Type 2 diabetes (T2D) have not been established. We performed an LC–MS-based non-targeted metabolomic analysis of whole blood samples collected from subjects classified into 4 types, based on the presence or absence of obesity and T2D. Of the 125 compounds identified, 20, comprising mainly nucleobases and glucose metabolites, showed significant increases or decreases in the T2D group. These included cytidine, UDP-glucuronate, UMP, 6-phosphogluconate, and pentose-phosphate. Among those 20 compounds, 11 enriched in red blood cells (RBCs) have rarely been studied in the context of diabetes, indicating that RBC metabolism is more extensively disrupted than previously known. Correlation analysis revealed that these T2D markers include 15 HbA1c-associated and 5 irrelevant compounds that may reflect diabetic conditions by a different mechanism than that of HbA1c. In the obese group, enhanced protein and fatty acid catabolism causes increases in 13 compounds, including methylated or acetylated amino acids and short-chain carnitines. Our study, which may be considered a pilot investigation, suggests that changes in blood metabolism due to obesity and diabetes are large, but essentially independent.journal articl

The astrocytic TRPA1 channel mediates an intrinsic protective response to vascular cognitive impairment via LIF production

認知症に対する新たな生体防御機構の発見 --アストロサイトのTRPA1活性化が、LIF産生を介して白質傷害や認知機能障害を防ぐ--. 京都大学プレスリリース. 2023-07-24.Vascular cognitive impairment (VCI) refers to cognitive alterations caused by vascular disease, which is associated with various types of dementia. Because chronic cerebral hypoperfusion (CCH) induces VCI, we used bilateral common carotid artery stenosis (BCAS) mice as a CCH-induced VCI model. Transient receptor potential ankyrin 1 (TRPA1), the most redox-sensitive TRP channel, is functionally expressed in the brain. Here, we investigated the pathophysiological role of TRPA1 in CCH-induced VCI. During early-stage CCH, cognitive impairment and white matter injury were induced by BCAS in TRPA1-knockout but not wild-type mice. TRPA1 stimulation with cinnamaldehyde ameliorated BCAS-induced outcomes. RNA sequencing analysis revealed that BCAS increased leukemia inhibitory factor (LIF) in astrocytes. Moreover, hydrogen peroxide-treated TRPA1-stimulated primary astrocyte cultures expressed LIF, and culture medium derived from these cells promoted oligodendrocyte precursor cell myelination. Overall, TRPA1 in astrocytes prevents CCH-induced VCI through LIF production. Therefore, TRPA1 stimulation may be a promising therapeutic approach for VCI

Chronic Orofacial Pain in Dental Patients: Retrospective Investigation over 12 years

Orofacial pain is often difficult to diagnose and treat. However, there have been few reports on the clinical observation of dental patients with orofacial pain. We retrospectively investigated the characteristics of 221 dental patients who had suffered from persistent orofacial pain. Data were collected from the outpatient medical records in our clinic over the past 12 years. More than half of the patients (53.8%) had suffered with pain for more than 6 months from pain onset until the first visit to our clinic. The main diagnoses were neuropathic pain (30.3%), myofascial pain (23.5%), psychogenic pain (20.4%), odontogenic toothache (17.2%), and others (7.7%) such as temporomandibular disorders and glossitis. The treatments included pharmacotherapy, splint therapy, and others such as nerve block, dental treatment, physiotherapy, and/or psychotherapy. Excluding the patients (52 of 221 initially enrolled patients) with unknown responses to treatment, 65.7% showed remission or a significant improvement in pain in response to treatment. Although only a small group of patients had odontogenic toothache, the rate of improvement was highest for this disorder. In conclusion, early consultation with a dentist is useful to prevent chronicity of odontogenic pain and to make a differential diagnosis in patients with orofacial pain

Multiple nutritional phenotypes of fission yeast mutants defective in genes encoding essential mitochondrial proteins

Mitochondria are essential for regulation of cellular respiration, energy production, small molecule metabolism, anti-oxidation and cell ageing, among other things. While the mitochondrial genome contains a small number of protein-coding genes, the great majority of mitochondrial proteins are encoded by chromosomal genes. In the fission yeast Schizosaccharomyces pombe, 770 proteins encoded by chromosomal genes are located in mitochondria. Of these, 195 proteins, many of which are implicated in translation and transport, are absolutely essential for viability. We isolated and characterized eight temperature-sensitive (ts) strains with mutations in essential mitochondrial proteins. Interestingly, they are also sensitive to limited nutrition (glucose and/or nitrogen), producing low-glucose-sensitive and \u27super-housekeeping\u27 phenotypes. They fail to produce colonies under low-glucose conditions at the permissive temperature or lose cell viability under nitrogen starvation at the restrictive temperature. The majority of these ts mitochondrial mutations may cause defects of gene expression in the mitochondrial genome. mrp4 and mrp17 are defective in mitochondrial ribosomal proteins. ppr3 is defective in rRNA expression, and trz2 and vrs2 are defective in tRNA maturation. This study promises potentially large dividends because mitochondrial quiescent functions are vital for human brain and muscle, and also for longevity

Effect of dietary components on renal inorganic phosphate (Pi) excretion induced by a Pi-depleted diet

Dietary inorganic phosphate (Pi) is the most important factor in the regulation of renal Pi excretion. Recent studies suggest the presence of an enteric-renal signaling axis for dietary Pi as well as the existence of a mechanism by which the intestine detects changes in luminal Pi concentrations. The mechanisms of intestinal Pi sensing, however, are unknown. In the present study, we focused on Pi depletion signals and investigated the effects of dietary components on intestinal Pi sensing. After feeding rats experimental diets for 3 days, we investigated urinary Pi excretion and plasma biochemical parameters. Renal Pi excretion was suppressed in rats fed a low-Pi diet (0.02% Pi). Elimination of dietary calcium (Ca) completely blocked the suppression of Pi excretion, suggesting that the presence of Ca is essential for the Pi depletion signal. Furthermore, a minimum Ca content of more than 0.02% was necessary for the Pi depletion signal. Magnesium, lanthanum, and strontium, which are agonists of calcium sensing receptor, instead of Ca, reduced Pi excretion.Therefore, dietary Ca appears to be important for the Pi depletion-sensing mechanism in the gastrointestinal tract. In addition, the calcium sensing receptor may be involved in the Pi depletion signal

Genetic defects in SAPK signalling, chromatin regulation, vesicle transport and CoA-related lipid metabolism are rescued by rapamycin in fission yeast

Rapamycin inhibits TOR (target of rapamycin) kinase, and is being used clinically to treat various diseases ranging from cancers to fibrodysplasia ossificans progressiva. To understand rapamycin mechanisms of action more comprehensively, 1014 temperature-sensitive (ts) fission yeast (Schizosaccharomyces pombe) mutants were screened in order to isolate strains in which the ts phenotype was rescued by rapamycin. Rapamycin-rescued 45 strains, among which 12 genes responsible for temperature sensitivity were identified. These genes are involved in stress-activated protein kinase (SAPK) signalling, chromatin regulation, vesicle transport, and CoA- and mevalonate-related lipid metabolism. Subsequent metabolome analyses revealed that rapamycin upregulated stress-responsive metabolites, while it downregulated purine biosynthesis intermediates and nucleotide derivatives. Rapamycin alleviated abnormalities in cell growth and cell division caused by sty1 mutants (Δsty1) of SAPK. Notably, in Δsty1, rapamycin reduced greater than 75% of overproduced metabolites (greater than 2× WT), like purine biosynthesis intermediates and nucleotide derivatives, to WT levels. This suggests that these compounds may be the points at which the SAPK/TOR balance regulates continuous cell proliferation. Rapamycin might be therapeutically useful for specific defects of these gene functions