Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination.

BACKGROUND: Lactate is an important metabolite derived from glycolysis under physiological and pathological conditions. The Warburg effect reveals the vital role of lactate in cancer progression. Numerous studies have reported crucial roles for lactate in cancer progression and cell fate determination. Lactylation, a novel posttranslational modification (PTM), has provided a new opportunity to investigate metabolic epigenetic regulation, and studies of this process have been initiated in a wide range of cancer cells, cancer-associated immune cells, and embryonic stem cells. CONCLUSION: Lactylation is a novel and interesting mechanism of lactate metabolism linked to metabolic rewiring and epigenetic remodeling. It is a potential and hopeful target for cancer therapy. Here, we summarize the discovery of lactylation, the mechanisms of site modification, and progress in research on nonhistone lactylation. We focus on the potential roles of lactylation in cancer progression and cell fate determination and the possible therapeutic strategies for targeting lysine lactylation. Finally, we suggest some future research topics on lactylation to inspire some interesting ideas.

Short-Chain Fatty Acids Ameliorate Depressive-like Behaviors of High Fructose-Fed Mice by Rescuing Hippocampal Neurogenesis Decline and Blood-Brain Barrier Damage.

Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood-brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.

Identification of Two Mutations in PCDHGA4 and SLFN14 Genes in an Atrial Septal Defect Family.

Atrial septal defect (ASD) is a common acyanotic congenital cardiac disorder associated with genetic mutations. The objective of this study was to identify the genetic factors in a Chinese family with ASD patients by a whole exome sequencing approach. Causative ASD gene mutations were examined in 16 members from a three-generation family, among which 6 individuals were diagnosed as having ASD. One hundred and eighty-three unrelated healthy Chinese were recruited as a normal control group. Peripheral venous blood was collected from every subject for genetic analysis. Exome sequencing was performed in the ASD patients. Potential causal mutations were detected in non-ASD family members and normal controls by polymerase chain reaction and sequencing analysis. The results showed that all affected family members carried two novel compound mutations, c.1187delT of PCDHGA4 and c.2557insC of SLFN14, and these two mutations were considered to have synergetic function on ASD. In conclusion, the mutations of c.1187delT of PCDHGA4 and c.2557insC of SLFN14 may be pathogenic factors contributing to the development of ASD.

[Assessment of injuries caused by diethyl sulfate poisoning].

OBJECTIVE: To develop criteria to assess injuries due to diethyl sulfate poisoning. METHODS: Patients were evaluated with respect to their toxic status and outcomes, in comparison to typical cases. RESULTS: Among 44 poisoned patients, 4 patients were classified as major injuries, 4 person as minor injuries, and the rest of 36 patients were classified as not poisoned according to poisoning diagnostic criteria by No.GBZ40-2002 "Diagnostic Criteria of Occupational Acute Diethyl Sulfate Poisoning". CONCLUSION: In assessment of the injuries caused by diethyl sulfate poisoning, one should follow diagnostic criteria set by National Occupational Acute Poisoning due to Chemicals and Drugs and "Criteria for Assessment of Human Body Injury."

[Purification and characterization of weak-acid antibacterial peptide MD7095 from Musca domestica larvae].

Musca domestica,which belongs to insecta, diptera, cyclorrhapha, muscidae, is the most common muscae and the richest resource. It is very significant and valuable to isolate antibacterial peptides from Musca domestica and to develop these peptides into antibacterial medicine. Due to purify a pure peptide from the natural materials (animal, plant and microorganism tissue) is very difficult and complex, few research is going on. It had been reported that the most antibacterial peptides from Musca domestica were alkaline, no weak-acid antibacterial peptides had been reported so far. Based on a high sensitivity detection method, using dilute acetic acid extraction, alginic acid absorption, NaCl salting-out, Sephadex G-25 gel filtration, CMC23 ion-exchange chromatography, electrophoresis, a group of weak-acid antibacterial peptides had been purified from Musca domestica larvae and partial characterized. The peptides had characters of broad antibacterial spectrum and low minimum bactericidal concentration against Gram-positive bacterium such as Bacillus thuringiensis, Bacillus subtilis, Staphylococcus aureus and Gram-negative bacterium such as Pseudomonas aeruginosa, Escherichia coli. The peptides were very stable to keep the antibacterial activity even kept in 95 degrees C for 120 min and frozen-thawed for 10 times. A weak-acid antibacterial peptide MD7095 had been purified in high degree of purity by electro-elution,and was determined Mr 7095Da with MALDI-TOF-MS and pl 5.59 with IEF-PAGE. Peptide mass fingerprinting (PMF) analysis showed MD7095 was a novel bioactive peptide. Few peptides with antibacterial activity against Bacillus thuringiensis had been reported. Observation by scanning electron microscopy (SEM), it was suggested that the bioactivity mechanism of antibacterial peptides from Musca domestica larvae against Bacillus thuringiensis was to perforate cell membrane and lead to bacterium lysis and die. It is hopeful to develop the antibacterial peptides from Musca domestica to candidate medicine.

Mono-, di- and tetra-zinc complexes derived from an amino-benzotriazole phenolate ligand containing a bulkier N-alkyl pendant arm: synthesis, structure and catalysis for ring-opening polymerization of cyclic esters.

Zinc complexes constructed from the amino-modified benzotriazole phenol pro-ligand, 2-(2H-benzotriazol-2-yl)-6-((diisopropylamino)methyl)-4-(2,4,4-trimethylpentan-2-yl)phenol ((C8DIA)BTP-H, 1), were synthesized stepwise and structurally characterized. The reaction of (C8DIA)BTP-H (1) with one equivalent of diethyl zinc (ZnEt2) generates a dimeric and four-coordinated zinc complex, [(µ-(C8DIA)BTP)ZnEt]2 (2), which is doubly bridged by two phenolate groups of C8DIABTP ligands. Further reaction of 2 with benzyl alcohol (BnOH) in stoichiometric proportions affords a tetranuclear zinc benzylalkoxide complex [(µ-OBn)((C8DIA)BTP)Zn]4 (3) that possesses a saddle-shaped core with four µ2-bridging benzylalkoxy groups upon four Zn centres. Interestingly, the di-nuclear Zn alkoxide [(µ-OBn)((C8DIA)BTP)Zn(DMAP)]2 (4) could be prepared by treatment of 3 with a stoichiometric amount of 4-(dimethylamino)pyridine (DMAP). ZnEt2 reacts with two equivalents of 1 in the presence of DMAP (1.0 mol equiv.) to yield a five-coordinated mononuclear zinc complex, [((C8DIA)BTP)2Zn(DMAP)] (5). All complexes adopt an N,O-bidentate coordination mode from the phenoxy oxygen atom and benzotriazole nitrogen atom, in which the nitrogen atom of the pendent arm substituent is not coordinated to the zinc centre. Ring-opening polymerization of ε-caprolactone and ß-butyrolactone catalysed by 2 and 3 was investigated.

[Roles of intracellular calcium and monomeric G-proteins in regulating exocytosis of human neutrophils].

Neutrophils play a major role in host defense against microbial infection. There are some clues indicate that neutrophils may also play a role in the pathophysiology of the airway obstruction in chronic asthma. We studied the roles of intracellular calcium and GTP gamma S in the regulation of neutrophils exocytosis using pipette perfusion and membrane capacitance measurement technique in whole cell patch clamp configuration. The results showed that the membrane capacitance increase induced by calcium revealed a biphasic process. The first phase occurred when the calcium level was between 0.2-14 micromol/L with a plateau amplitude of 1.23 pF and a calcium EC50 of 1.1 micromol/L. This phase might correspond to the release of the tertiary granules. The second phase occurred when the calcium concentration was between 20-70 micromol/L with a plateau increment of 6.36 pF, the calcium EC50 being about 33 micromol/L. This phase might represent the release of the primary and secondary granules. Intracellular calcium also simultaneously increased the exocytotic rate and the eventual extent in neutrophils. On the other hand, GTP gamma S can increase the exocytotic rate in a dose-dependent manner but had no effect on the eventual extent of membrane capacitance increment (>6 pF) if the cell was stimulated for a long period (>20 min). GTP gamma S (ranging from 20 to 100 micromol/L) induced the neutrophils to release all four types of the granules at very low intracellular calcium level.