Microglia lactylation in relation to central nervous system diseases

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

Acid tolerance of lactate-utilizing bacteria of the order Bacteroidales contributes to prevention of ruminal acidosis in goats adapted to a high-concentrate diet

The rapid accumulation of organic acids,particularly lactate,has been suggested as the main cause of ruminal acidosis(RA)for ruminants fed high-concentrate diets.Previous research has shown that a gradual shift from low-to high-concentrate diets within 4 to 5 weeks effectively reduces the risk for RA.However,the mechanisms remain unknown.In this study,20 goats were randomly allocated into four groups(n=5)and fed with a diet containing a weekly increasing concentrate portion of 20%,40%,60%,and 80%over 28 d.At d 7,14,21,and 28,one group(named C20,C40,C60,and C80 according to the last concentrate level that they received)was killed and the ruminal microbiome was collected.Ruminal acidosis was not detected in any of the goats during the experiment.Nonetheless,ruminal pH dropped sharply from 6.2 to 5.7(P<0.05)when dietary concentrate increased from 40%to 60%.A combined metagenome and metatranscriptome sequencing approach identified that this was linked to a sharp decrease in the abundance and expression of genes encoding nicotinamide adenine dinucleotide(NAD)-dependent lactate dehydrogenase(nLDH),catalyzing the enzymatic conversion of pyruvate to lactate(P<0.01),whereas the expression of two genes encoding NAD-independent lactate dehydrogenase(iLDH),catalyzing lactate oxidation to pyruvate,showed no significant concomitant change.Abundance and expression alterations for nLDH-and iLDH-encoding genes were attributable to bacteria from Clostridiales and Bacteroidales,respectively.By analyzing the gene profiles of 9 metagenome bins(MAG)with nLDH-encoding genes and 5 MAG with iLDH-encoding genes,we identified primary and secondary active transporters as being the major types of sugar transporter for lactate-producing bacteria(LPB)and lactate-utilizing bacteria(LUB),respectively.Furthermore,more adenosine triphosphate was required for the phosphorylation of sugars to initiate their catabolic pathways in LPB compared to LUB.Thus,the low dependence of sugar transport systems and catabolic pathways on primary energy sources supports the acid tolerance of LUB from Bacteroidales.It favors ruminal lactate utilization during the adaptation of goats to a high-concentrate diet.This finding has valuable implications for the development of measures to prevent RA.

Increased maternal consumption of methionine as its hydroxyl analog promoted neonatal intestinal growth without compromising maternal energy homeostasis

Background： To determine responses of neonatal intestine to maternal increased consumption of DL-methionine（DLM） or DL-2-hydroxy-4-methylthiobutanoic acid（HMTBA）, eighteen primiparous sows（Landrace × Yorkshire） were allocated based on body weight and backfat thickness to the control, DLM and HMTBA groups（n = 6）, with the nutritional treatments introduced from postpartum d0 to d14.Results： The DLM-fed sows showed negative energy balance manifested by lost bodyweight, lower plasma glucose, subdued tricarboxylic acid cycle, and increased plasma lipid metabolites levels. Both villus height and ratio of villus height to crypt depth averaged across the small intestine of piglets were higher in the DLM and HMTBA groups than in the control group. Piglet jejunal oxidized glutathione concentration and ratio of oxidized to reduced glutathione were lower in the HMTBA group than in the DLM and control groups. However, piglet jejunal aminopeptidase A, carnitine transporter 2 and IGF-II precursor m RNA abundances were higher in the DLM group than in the HMTBA and control groups.Conclusion： Increasing maternal consumption of methionine as DLM and HMTBA promoted neonatal intestinal growth by increasing morphological development or up-regulating expression of genes responsible for nutrient metabolism. And increasing maternal consumption of HMTBA promoted neonatal intestinal antioxidant capacity without compromising maternal energy homeostasis during early lactation.

Differential expression and function of the endogenous lactate receptor, GPR81, in ERα-positive/HER2-positive epithelial vs. post-EMT triple-negative mesenchymal breast cancer cells

Aim:Lactate can signal through the endogenous lactate receptor,GPR81,which is expressed in some cancers.Lactate metabolism is altered by the metastasis-promoting process of epithelial-mesenchymal transition(EMT).This study examined the expression and function of GPR81 in breast cancer samples,and in receptor-positive epithelial vs.triple-negative post-EMT mesenchymal breast cancer cells.Methods:GPR81 mRNA expression was examined by breast cancer microarray,and by a Kaplan-Meier survival curve.Using 3-dimensional culture conditions,GPR81 mRNA expression in epithelial and mesenchymal breast cancer cell lines was measured by qRT-PCR.GPR81 siRNA was used to assess the role of GPR81,alone or in conjunction with tamoxifen,in the regulation of MCT1 and MCT4 lactate transporters,intracellular lactate,and cell proliferation and survival.Results:GPR81 mRNA levels were elevated in receptor-positive breast cancer,relative to non-tumor and triple-negative samples,and correlated with increased survival.GPR81 expression was elevated in the two epithelial breast cancer cell lines vs.the corresponding post-EMT mesenchymal cell lines.GPR81 knock-down in epithelial MCF7 cells caused:1,selectively lower mRNA and protein expression of the MCT1 transporter,but not MCT2 or MCT4 ;transporters;2,lower levels of intracellular lactate;and 3,decreased proliferation and survival in lactate only-containing conditions.GPR81 siRNA plus tamoxifen displayed additive suppressive effects on MCT1 expression and cell viability.Conclusion:GPR81 promotes the ability of epithelial breast cancer cells to import lactate for energy use.As such,GPR81 represents a potential target for treatment of hormone-positive breast cancer cells,and may be prognostic for higher grade breast cancer.

Recent advances on the circadian gene PER2 and metabolic rhythm of lactation of mammary gland

Due to regulation by circadian rhythm, the lactation of the mammary gland has rhythmicity. As one of prominent members of period protein family which regulates biological rhythms, PER2 plays an important role in developing the milk duct and maintaining the polarity and the morphology of the mammary epithelium; at the same time, it is also closely related with the metabolism of milk protein and milk fat. This paper summarized recent researches on PER2 gene and related researches on mammary gland development and metabolism to provide some information for the studies of the theory and technology on physiological functions of the mammary gland and milk quality control.