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Δ1‐pyrroline‐5‐carboxylate reductase isoform 1 (PYCR1) is the last enzyme of proline biosynthesis and catalyzes the NAD(P)H‐dependent reduction of Δ1‐pyrroline‐5‐carboxylate to L‐proline. High PYCR1 gene expression is observed in many cancers and linked to poor patient outcomes and tumor aggressiveness. The knockdown of the PYCR1 gene or the inhibition of PYCR1 enzyme has been shown to inhibit tumorigenesis in cancer cells and animal models of cancer, motivating inhibitor discovery. We screened a library of 71 low molecular weight compounds (average MW of 131 Da) against PYCR1 using an enzyme activity assay. Hit compounds were validated with X‐ray crystallography and kinetic assays to determine affinity parameters. The library was counter‐screened against human Δ1‐pyrroline‐5‐carboxylate reductase isoform 3 and proline dehydrogenase (PRODH) to assess specificity/promiscuity. Twelve PYCR1 and one PRODH inhibitor crystal structures were determined. Three compounds inhibit PYCR1 with competitive inhibition parameter of 100 μM or lower. Among these, (S)‐tetrahydro‐2H‐pyran‐2‐carboxylic acid (70 μM) has higher affinity than the current best tool compound N‐formyl‐l‐proline, is 30 times more specific for PYCR1 over human Δ1‐pyrroline‐5‐carboxylate reductase isoform 3, and negligibly inhibits PRODH. Structure‐affinity relationships suggest that hydrogen bonding of the heteroatom of this compound is important for binding to PYCR1. The structures of PYCR1 and PRODH complexed with 1‐hydroxyethane‐1‐sulfonate demonstrate that the sulfonate group is a suitable replacement for the carboxylate anchor. This result suggests that the exploration of carboxylic acid isosteres may be a promising strategy for discovering new classes of PYCR1 and PRODH inhibitors. The structure of PYCR1 complexed with l‐pipecolate and NADH supports the hypothesis that PYCR1 has an alternative function in lysine metabolism. [ABSTRACT FROM AUTHOR]

Simple Summary: The recently identified lysine methyltransferase (KMT) 9 regulates the growth of different types of cancer. While KMT9 was shown to be overexpressed in muscle-invasive bladder cancer (MIBC) tissue samples of patients, a potential functional role of the enzyme in MIBC remains to be clarified. In this study, we show that KMT9 regulates the proliferation, migration, and invasion of various MIBC cell lines as well as the growth of BC tumor organoids and xenografts in mice. Our data provide evidence that tumor cell growth relies on the enzymatic function of KMT9 and that a small-molecule inhibitor of KMT9 impairs BC cell proliferation. These results suggest that KMT9 is a potential novel therapeutic target for MIBC treatment. Novel treatment modalities are imperative for the challenging management of muscle-invasive and metastatic BC to improve patient survival rates. The recently identified KMT9, an obligate heterodimer composed of KMT9α and KMT9β, regulates the growth of various types of tumors such as prostate, lung, and colon cancer. While the overexpression of KMT9α was previously observed to be associated with aggressive basal-like MIBC in an analysis of patients' tissue samples, a potential functional role of KMT9 in this type of cancer has not been investigated to date. In this study, we show that KMT9 regulates proliferation, migration, and invasion of various MIBC cell lines with different genetic mutations. KMT9α depletion results in the differential expression of genes regulating the cell cycle, cell adhesion, and migration. Differentially expressed genes include oncogenes such as EGFR and AKT1 as well as mediators of cell adhesion or migration such as DAG1 and ITGA6. Reduced cell proliferation upon KMT9α depletion is also observed in Pten/Trp53 knockout bladder tumor organoids, which cannot be rescued with an enzymatically inactive KMT9α mutant. In accordance with the idea that the catalytic activity of KMT9 is required for the control of cellular processes in MIBC, a recently developed small-molecule inhibitor of KMT9 (KMI169) also impairs cancer cell proliferation. Since KMT9α depletion also restricts the growth of xenografts in mice, our data suggest that KMT9 is an actionable novel therapeutic target for the treatment of MIBC. [ABSTRACT FROM AUTHOR]

Objective: Preoperative chronic stress (CS) is associated with postoperative brain injury in patients undergoing open heart cardiac surgery. This research is to explore the potential molecular biological mechanisms of brain damage following cardiac surgery in preoperative CS rats by the analyses combining proteomics and metabolomics. Methods: We constructed the chronic unpredictable stress (CUS) and cardiac surgery models in adult rats. We proved the brain injury in CUS cardiac surgery rats by Hematoxylin–Eosin (H&E) staining, followed by separating the hippocampal tissue and investigating the potential mechanisms of brain injury by the methods of data-independent acquisition proteomics and untargeted metabolomics. Results: The signaling pathways of glycoproteins and metabolism of amino acids were the main possible mechanisms of brain injury in CUS rats following cardiac surgery according to the proteomics and metabolomics. In addition, the pathways of animo acids metabolism such as the pathways of lysine degradation and β-alanine metabolism may be the main mechanism of cardiac surgery related brain injury in preoperative CUS rats. Conclusions: The pathways of animo acids metabolism such as lysine degradation and β-alanine metabolism may be the potential mechanisms of brain injury in CUS rats following cardiac surgery. We should focus on the varieties of bioproteins and metabolites in these pathways, and related changes in other signaling pathways induced by the two pathways. [ABSTRACT FROM AUTHOR]

Lysine and its pathway metabolites have been identified as novel biomarkers for metabolic and vascular diseases. The role of them in the identification of moyamoya disease (MMD) has not been elucidated. This study aimed to determine the association between lysine pathway metabolites and the presence of MMD. We prospectively enrolled 360 MMD patients and 89 healthy controls from September 2020 to December 2021 in Beijing Tiantan Hospital. Serum levels of lysine, pipecolic acid and 2-aminoadipic acid were measured by liquid chromatography-mass spectrometry. We employed logistic regression and restricted cubic spline to explore the association between these metabolites and the presence of MMD. Stratified analyses were also conducted to test the robustness of results. We observed that lysine levels in MMD patients were significantly higher and pipecolic acid levels were significantly lower compared to HCs (both p < 0.001), while no difference was found in the level of 2-AAA between both groups. When comparing metabolites by quartiles, elevated lysine levels were linked to increased odds for MMD (the fourth quartile [Q4] vs the first quartile [Q1]: odds ratio, 3.48, 95%CI [1.39–8.75]), while reduced pipecolic acid levels correlated with higher odds (Q4 vs Q1: odds ratio, 0.08; 95 % CI [0.03–0.20]). The restricted cubic spline found a L-shaped relationship between pipecolic acid level and the presence of MMD, with a cutoff point at 2.52 μmol/L. Robust results were also observed across subgroups. Elevated lysine levels were correlated with increased odds of MMD presence, while lower pipecolic acid levels were associated with higher odds of the condition. These results suggest potential new biomarkers for the identification of MMD. URL: https://www.chictr.org.cn/. Unique identifier: ChiCTR2200061889. [ABSTRACT FROM AUTHOR]

Abstract Background Bladder cancer (BLCA) research in Koreans is still lacking, especially in focusing on the prediction of BLCA. The current study aimed to discover metabolic signatures related to BLCA onset and confirm its potential as a biomarker. Methods We designed two nested case-control studies using Korean Cancer Prevention Study (KCPS)-II. Only males aged 35–69 were randomly selected and divided into two sets by recruitment organizations [set 1, BLCA (n = 35) vs. control (n = 35); set 2, BLCA (n = 31) vs. control (n = 31)]. Baseline serum samples were analyzed by non-targeted metabolomics profiling, and OPLS-DA and network analysis were performed. Calculated genetic risk score (GRS) for BLCA from all KCPS participants was utilized for interpreting metabolomics data. Results Critical metabolic signatures shown in the BLCA group were dysregulation of lysine metabolism and tryptophan-indole metabolism. Furthermore, the prediction model consisting of metabolites (lysine, tryptophan, indole, indoleacrylic acid, and indoleacetaldehyde) reflecting these metabolic signatures showed mighty BLCA predictive power (AUC: 0.959 [0.929–0.989]). The results of metabolic differences between GRS-high and GRS-low groups in BLCA indicated that the pathogenesis of BLCA is associated with a genetic predisposition. Besides, the predictive ability for BLCA on the model using GRS and five significant metabolites was powerful (AUC: 0.990 [0.980–1.000]). Conclusion Metabolic signatures shown in the present research may be closely associated with BLCA pathogenesis. Metabolites involved in these could be predictive biomarkers for BLCA. It could be utilized for early diagnosis, prognostic diagnosis, and therapeutic targets for BLCA.

Background: Bladder cancer (BLCA) research in Koreans is still lacking, especially in focusing on the prediction of BLCA. The current study aimed to discover metabolic signatures related to BLCA onset and confirm its potential as a biomarker. Methods: We designed two nested case-control studies using Korean Cancer Prevention Study (KCPS)-II. Only males aged 35–69 were randomly selected and divided into two sets by recruitment organizations [set 1, BLCA (n = 35) vs. control (n = 35); set 2, BLCA (n = 31) vs. control (n = 31)]. Baseline serum samples were analyzed by non-targeted metabolomics profiling, and OPLS-DA and network analysis were performed. Calculated genetic risk score (GRS) for BLCA from all KCPS participants was utilized for interpreting metabolomics data. Results: Critical metabolic signatures shown in the BLCA group were dysregulation of lysine metabolism and tryptophan-indole metabolism. Furthermore, the prediction model consisting of metabolites (lysine, tryptophan, indole, indoleacrylic acid, and indoleacetaldehyde) reflecting these metabolic signatures showed mighty BLCA predictive power (AUC: 0.959 [0.929–0.989]). The results of metabolic differences between GRS-high and GRS-low groups in BLCA indicated that the pathogenesis of BLCA is associated with a genetic predisposition. Besides, the predictive ability for BLCA on the model using GRS and five significant metabolites was powerful (AUC: 0.990 [0.980–1.000]). Conclusion: Metabolic signatures shown in the present research may be closely associated with BLCA pathogenesis. Metabolites involved in these could be predictive biomarkers for BLCA. It could be utilized for early diagnosis, prognostic diagnosis, and therapeutic targets for BLCA. [ABSTRACT FROM AUTHOR]

Objective: Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH) production, report pain in joints. We undertook this study to characterize the joint pathology of mice with overexpression of bovine GH (bGH) or a GH receptor antagonist (GHa) and to investigate the effect of GH on regulation of chondrocyte cellular metabolism. Methods: Knee joints from mice overexpressing bGH or GHa and wild‐type (WT) control mice were examined using histology and micro–computed tomography for osteoarthritic (OA) pathologies. Additionally, cartilage from bGH mice was used for metabolomics analysis. Mouse primary chondrocytes from bGH and WT mice, with or without pegvisomant treatment, were used for quantitative polymerase chain reaction and Seahorse respirometry analyses. Results: Both male and female bGH mice at ~13 months of age had increased knee joint degeneration, which was characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher Osteoarthritis Research Society International and Mankin scores in bGH mice compared to WT control mice. Metabolomics analysis revealed changes in a wide range of metabolic pathways in bGH mice, including beta‐alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes up‐regulated fatty acid oxidation and increased expression of Col10a. Joints of GHa mice were remarkably protected from developing age‐associated joint degeneration, with smooth articular joint surface. Conclusion: This study showed that an excessive amount of GH promotes joint degeneration in mice, which was associated with chondrocyte metabolic dysfunction and hypertrophic changes, whereas antagonizing GH action through a GHa protects mice from OA development. [ABSTRACT FROM AUTHOR]

Background: DNA damage repair is a crucial mechanism highly related to therapy resistance for various therapeutic strategies. Our previous results have shown that the degree of drug resistance in small‐cell lung cancer (SCLC) cell lines was proportional to both the transcription and expression levels of Wee1, indicating that Wee1, an evolutionarily highly conserved kinase, plays a vital role in the therapeutic resistance of SCLC. In the present study, we aim to determine the nonclassical mechanism of Wee1 on DNA repair regulation. Methods: Western blot was conducted to determine the mono‐ubiquitination level of H2Bub. Comet assay was used to evaluate the degree of DNA damage. Immunofluorescence was conducted to determine the DNA repair markers. Co‐immunoprecipitation was utilized to assess the potential interactions with H2BY37ph. MTT assays were used to evaluate the survival rates of SCLC cells. Results: Overexpression of Wee1 increases the level of H2BK120ub and alleviates ionizing radiation (IR)‐induced DNA damage in SCLC cells. Moreover, H2BK120ub is a crucial molecule in Wee1‐mediated double‐strain break (DSB) repair in SCLC cells. Mechanisms study indicated that H2BY37ph is involved in Wee1‐mediated H2BK120ub through interaction with the E3 ubiquitin ligase RNF20–RNF40 complex and upregulates its phosphorylation, mutation of H2BY37 phosphorylation sites attenuated DSB repair and enhanced the sensitivity of IR‐induced SCLC cell death. Conclusion: H2BY37ph produces crosstalk with H2BK120ub in an E3 ubiquitin ligase‐dependent manner, promoting Wee1‐mediated DSB repair in SCLC cells. This study clarifies the nonclassical mechanism of Wee1 regulation of DSB repair, which provides a theoretical basis for the clinical understanding of the regulatory network of Wee1 and its use as a target for overcoming multiple types of therapeutic resistance. [ABSTRACT FROM AUTHOR]

Post-translational modifications on histones are well known to regulate chromatin structure and function, but much less information is available on modifications of the centromeric histone H3 variant and their effect at the kinetochore. Here, we report two modifications on the centromeric histone H3 variant CENP-A/Cse4 in the yeast Saccharomyces cerevisiae, methylation at arginine 143 (R143me) and lysine 131 (K131me), that affect centromere stability and kinetochore function. Both R143me and K131me lie in the core region of the centromeric nucleosome, near the entry/exit sites of the DNA from the nucleosome. Unexpectedly, mutation of Cse4-R143 (cse4-R143A) exacerbated the kinetochore defect of mutations in components of the NDC80 complex of the outer kinetochore (spc25-1) and the MIND complex (dsn1-7). The analysis of suppressor mutations of the spc25-1 cse4-R143A growth defect highlighted residues in Spc24, Ndc80, and Spc25 that localize to the tetramerization domain of the NDC80 complex and the Spc24-Spc25 stalk, suggesting that the mutations enhance interactions among NDC80 complex components and thus stabilize the complex. Furthermore, the Set2 histone methyltransferase inhibited kinetochore function in spc25-1 cse4-R143A cells, possibly by methylating Cse4-K131. Taken together, our data suggest that Cse4-R143 methylation and Cse4-K131 methylation affect the stability of the centromeric nucleosome, which is detrimental in the context of defective NDC80 tetramerization and can be compensated for by strengthening interactions among NDC80 complex components. [ABSTRACT FROM AUTHOR]

In higher fungi, lysine is biosynthesized via the α-aminoadipate (AAA) pathway, which differs from plants, bacteria, and lower fungi. The differences offer a unique opportunity to develop a molecular regulatory strategy for the biological control of plant parasitic nematodes, based on nematode-trapping fungi. In this study, in the nematode-trapping fungus model Arthrobotrys oligospora, we characterized the core gene in the AAA pathway, encoding α-aminoadipate reductase (Aoaar), via sequence analyses and through comparing the growth, and biochemical and global metabolic profiles of the wild-type and Aoaar knockout strains. Aoaar not only has α-aminoadipic acid reductase activity, which serves fungal L-lysine biosynthesis, but it also is a core gene of the non-ribosomal peptides biosynthetic gene cluster. Compared with WT, the growth rate, conidial production, number of predation rings formed, and nematode feeding rate of the ΔAoaar strain were decreased by 40–60%, 36%, 32%, and 52%, respectively. Amino acid metabolism, the biosynthesis of peptides and analogues, phenylpropanoid and polyketide biosynthesis, and lipid metabolism and carbon metabolism were metabolically reprogrammed in the ΔAoaar strains. The disruption of Aoaar perturbed the biosynthesis of intermediates in the lysine metabolism pathway, then reprogrammed amino acid and amino acid-related secondary metabolism, and finally, it impeded the growth and nematocidal ability of A. oligospora. This study provides an important reference for uncovering the role of amino acid-related primary and secondary metabolism in nematode capture by nematode-trapping fungi, and confirms the feasibility of Aoarr as a molecular target to regulate nematode-trapping fungi to biocontrol nematodes. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is a common neurological complication of diabetes mellitus without efficient interventions. Both lysine demethylase 5B (KDM5B) and sirtuin‐3 (SIRT3) have been found to regulate islet function and glucose homeostasis. KDM5B was predicted to bind to the SIRT3 promoter by bioinformatics. Here, we investigated whether KDM5B affected DPN development via modulating SIRT3. Methods: The db/db mice and high glucose‐stimulated Schwann cells (RSC96) were used as in vivo and in vitro models of DPN, respectively. Glucose level, glucose and insulin tolerance of mice were measured. Neurological function was evaluated by motor nerve conduction velocity (MNCV), tactile allodynia assay and thermal sensitivity assay. Adenosine triphosphate level, oxygen consumption rate, extracellular acidification rate, β‐oxidation rate, acetyl‐CoA level, acetylation levels and activities of long‐chain acyl CoA dehydrogenase (LCAD) and pyruvate dehydrogenase (PDH) were detected. Methyl thiazolyl tetrazolium assay was adopted to determine cell viability. Reactive oxygen species (ROS) production was detected by MitoSox staining. Western blotting for measuring target protein levels. Molecular mechanisms were investigated by co‐immunoprecipitine (Co‐IP), chromatin immunoprecipitation (ChIP) and luciferase reporter assay. Results: KDM5B was up‐regulated, while SIRT3 was down‐regulated in DPN models. SIRT3 overexpression or AMPK activation ameliorated mitochondrial metabolism dysfunction and ROS overproduction during DPN. KDM5B overexpression triggered mitochondrial metabolism disorder and oxidative stress via directly transcriptional inhibiting SIRT3 expression by demethylating H3K4me3 or indirectly repressing AMPK pathway‐regulated SIRT3 expression. Conclusion: KDM5B contributes to DPN via regulating SIRT3‐mediated mitochondrial glucose and lipid metabolism. KDM5B inhibition may be an effective intervention for DPN. [ABSTRACT FROM AUTHOR]

The occurence and development of tumors is a complicated process, which not only depends on the mutation or deletion of genes, but also is affected by epigenetic regulation. Accumulating evidences have shown that epigenetic modifications play fundamental roles in transcriptional regulation, heterochromatin formation, X chromosome inactivation, DNA damage response and tumor development. SET domain containing lysine methyltransferase 7 (SETD7) was initially identified as an important lysine methyltransferase, which methylated histone and non-histone proteins. These modifications play fundamental roles. Once this modification disorders, it can directly lead to cell abnormalities and cause many diseases. Studies have shown that SETD7 is related to the occurence and development of various tumors, but the methylation sites of SETD7 and its regulatory mechanism have not been fully elucidated. Tis article summarizes the research progress of the role of SETD7 on histone and non-histone methylation modification in tumors and the molecular mechanism, in order to provide new therapeutic targets for tumor pathogenesis and diagnosis. [ABSTRACT FROM AUTHOR]

The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates nonalcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting that LSD1 has a context-dependent role in promoting maladaptive changes in obesity. In analysis of insulin target tissues we identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD. [ABSTRACT FROM AUTHOR]

Background: Although eradication therapy for chronic Helicobacter pylori (H. pylori) reduces the risk of gastric cancer (GC), its effectiveness is not complete. Therefore, it is also critically important to identifying those patients who remain at high risk after H. pylori eradication therapy. Accumulation of protein methylation is strongly implicated in cancer, and recent study showed that dimethylation of eEF1A lysine 55 (eEF1AK55me2) promotes carcinogenesis in vivo. We aimed to investigate the relationship between eEF1A dimethylation and H. pylori status, efficacy of eradication therapy, and GC risk in H. pylori-eradicated mucosa, and to reveal the potential downstream molecules of eEF1A dimethylation.Methods: Records of 115 patients (11 H. pylori-negative, 29 H. pylori-positive, 75 post-eradication patients) who underwent upper gastrointestinal endoscopy were retrospectively reviewed. The eEF1A dimethyl level was evaluated in each functional cell type of gastric mucosa by immunofluorescent staining. We also investigated the relationship between eEF1AK55me2 downregulation by CRISPR/Cas9 mediated deletion of Mettl13, which is known as a dimethyltransferase of eEF1AK55me2.Results: The level of eEF1A dimethylation significantly increased in the surface and basal areas of H. pylori-positive mucosa compared with the negative mucosa (surface, p = 0.0031; basal, p = 0.0036, respectively). The eEF1A dimethyl-levels in the surface area were significantly reduced by eradication therapy (p = 0.005), but those in the basal area were maintained even after eradication therapy. Multivariate analysis revealed that high dimethylation of eEF1A in the basal area of the mucosa was the independent factor related to GC incidence (odds ratio = 3.6611, 95% confidence interval = 1.0350-12.949, p = 0.0441). We also showed the relationship between eEF1A dimethylation and expressions of reprogramming factors, Oct4 and Nanog, by immunohistochemistry and in vitro genome editing experiments.Conclusions: The results indicated that H. pylori infection induced eEF1A dimethylation in gastric mucosa. The accumulation of dimethyl-eEF1A in the basal area of the mucosa might contribute to GC risk via regulation of reprograming factors in H. pylori eradicated-gastric mucosa. [ABSTRACT FROM AUTHOR]

Simple Summary: The histone methyltransferase SET domain-containing protein 8 (SETD8) methylates histone H4 lysine 20 and non-histone proteins such as p53. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation. The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetic events, which comprise post-translational modifications of histone tails or DNA methylation, control gene expression by altering chromatin structure without change in the DNA sequence. Histone tails modifications are driven by specific cellular enzymes such as histone methyltransferases or histone acetylases, which play a key role in regulating diverse biological processes. Their alteration may have consequences on growth and tumorigenesis. Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers. [ABSTRACT FROM AUTHOR]

In humans, a single enzyme 2-aminoadipic semialdehyde synthase (AASS) catalyses the initial two critical reactions in the lysine degradation pathway. This enzyme evolved to be a bifunctional enzyme with both lysine-2-oxoglutarate reductase (LOR) and saccharopine dehydrogenase domains (SDH). Moreover, AASS is a unique drug target for inborn errors of metabolism such as glutaric aciduria type 1 that arise from deficiencies downstream in the lysine degradation pathway. While work has been done to elucidate the SDH domain structurally and to develop inhibitors, neither has been done for the LOR domain. Here, we purify and characterize LOR and show that it is activated by alkylation of cysteine 414 by N-ethylmaleimide. We also provide evidence that AASS is rate-limiting upon high lysine exposure of mice. Finally, we present the crystal structure of the human LOR domain. Our combined work should enable future efforts to identify inhibitors of this novel drug target.

Background: Parenteral nutrition (PN) is often a necessity for preterm infants; however, prolonged PN leads to gut atrophy, weakened gut barrier function, and a higher risk of intestinal infections. Peptide transporter-1 (PepT1) is a di- or tripeptide transporter in the gut and, unlike other nutrient transporters, its activity is preserved with the onset of intestinal atrophy from PN. As such, enteral amino acids in the form of dipeptides may be more bioavailable than free amino acids when atrophy is present.Objectives: In Yucatan miniature piglets with PN-induced intestinal atrophy, we sought to determine the structural and functional effects of enteral refeeding with lysine as a dipeptide, compared to free L-lysine.Methods: Piglets aged 7-8 days were PN-fed for 4 days to induce intestinal atrophy, then were refed with enteral diets with equimolar lysine supplied as lysyl-lysine (Lys-Lys; n = 7), free lysine (n = 7), or Lys-Lys with glycyl-sarcosine (n = 6; to determine whether competitive inhibition of Lys-Lys uptake would abolish PepT1-mediated effects). The diets provided lysine at 75% of the requirement and were gastrically delivered for a total of 18 hours. Whole-body and tissue-specific protein synthesis, as well as indices for gut structure and barrier function, were measured.Results: The villus height, mucosal weight, and free lysine concentration were higher in the Lys-Lys group compared to the other 2 groups (P < 0.05). Lysyl-lysine led to greater whole-body protein synthesis compared to free lysine (P < 0.05). Mucosal myeloperoxidase activity was lower in the Lys-Lys group (P < 0.05), suggesting less inflammation. The inclusion of glycyl-sarcosine with Lys-Lys abolished the dipeptide effects on whole-body and tissue-specific protein synthesis (P < 0.05), suggesting that improved lysine availability was mediated by PepT1.Conclusions: Improved intestinal structure and whole-body protein synthesis suggests that feeding strategies designed to exploit PepT1 may help to avoid adverse effects when enteral nutrition is reintroduced into the compromised guts of neonatal piglets. [ABSTRACT FROM AUTHOR]

Acetyl-CoA Carboxylase 1 catalyzes the conversion of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis. As a master regulator of lipid synthesis, acetyl-CoA carboxylase 1 has been proposed to be a therapeutic target for numerous metabolic diseases. We have shown that acetyl-CoA carboxylase 1 activity is reduced in the absence of the lysine acetyltransferase NuA4 in Saccharomyces cerevisiae. This change in acetyl-CoA carboxylase 1 activity is correlated with a change in localization. In wild-type cells, acetyl-CoA carboxylase 1 is localized throughout the cytoplasm in small punctate and rod-like structures. However, in NuA4 mutants, acetyl-CoA carboxylase 1 localization becomes diffuse. To uncover mechanisms regulating acetyl-CoA carboxylase 1 localization, we performed a microscopy screen to identify other deletion mutants that impact acetyl-CoA carboxylase 1 localization and then measured acetyl-CoA carboxylase 1 activity in these mutants through chemical genetics and biochemical assays. Three phenotypes were identified. Mutants with hyper-active acetyl-CoA carboxylase 1 form 1 or 2 rod-like structures centrally within the cytoplasm, mutants with mid-low acetyl-CoA carboxylase 1 activity displayed diffuse acetyl-CoA carboxylase 1, while the mutants with the lowest acetyl-CoA carboxylase 1 activity (hypomorphs) formed thick rod-like acetyl-CoA carboxylase 1 structures at the periphery of the cell. All the acetyl-CoA carboxylase 1 hypomorphic mutants were implicated in sphingolipid metabolism or very long-chain fatty acid elongation and in common, their deletion causes an accumulation of palmitoyl-CoA. Through exogenous lipid treatments, enzyme inhibitors, and genetics, we determined that increasing palmitoyl-CoA levels inhibits acetyl-CoA carboxylase 1 activity and remodels acetyl-CoA carboxylase 1 localization. Together this study suggests yeast cells have developed a dynamic feed-back mechanism in which downstream products of acetyl-CoA carboxylase 1 can fine-tune the rate of fatty acid synthesis. [ABSTRACT FROM AUTHOR]

Haloarchaea with the capacity to degrade alkanes is promising to deal with petroleum pollution in hypersaline environments. However, only a limited number of haloarchaeal species are investigated, and their pathway and mechanism for alkane degradation remain unclear. In this study, Halogranum rubrum RO2-11, a haloarchaeal strain, verified the ability to degrade kerosene and hexadecane in 184 g/L NaCl, with 53% and 52% degradation rates after 9 and 4 days, respectively. Genome sequencing and gene annotation indicated that strain RO2-11 possesses a complete potential alkane-degrading pathway, of which alkane hydroxylases may include CYP450, AlmA, and LadA. Transcriptome and metabolome analyses revealed that the upregulation of related genes in TCA cycle, lysine biosynthesis, and acetylation may help improve hexadecane degradation. Additionally, an alternative degrading pathway of hexadecane based on dual-terminal β -oxidation may occur in strain RO2-11. It is likely to be the first report of alkane degradation by the genus Halogranum , which may be helpful for applications of oil-pollution bioremediation under high-salt conditions. [Display omitted] • Halogranum rubrum RO2-11 possesses a complete potential alkane-degrading pathway. • Hexadecane-degrading enzymes keep high activities even in the absence of alkane. • The degradation pathway involves alkane oxygenation and dual-terminal β -oxidation. • Upregulation of TCA cycle, lysine synthesis & acetylation may help for degradation. [ABSTRACT FROM AUTHOR]

Objective: Regular exercise is a powerful tool that enhances skeletal muscle mass and strength. Lysine acetylation is an important post-translational modification (PTM) involved in a broad array of cellular functions. Skeletal muscle protein contains a considerable number of lysine-acetylated (Kac) sites, so we aimed to investigate the effects of exercise-induced lysine acetylation on skeletal muscle proteins. Methods: We randomly divided 20 male C57BL/6 mice into exercise and control groups. After 6 weeks of treadmill exercise, a lysine acetylation proteomics analysis of the gastrocnemius muscles of mice was performed. Results: A total of 2,254 lysine acetylation sites in 693 protein groups were identified, among which 1,916 sites in 528 proteins were quantified. The enrichment analysis suggested that protein acetylation could influence both structural and functional muscle protein properties. Moreover, molecular docking revealed that mimicking protein deacetylation primarily influenced the interaction between substrates and enzymes. Conclusion: Exercise-induced lysine acetylation appears to be a crucial contributor to the alteration of skeletal muscle protein binding free energy, suggesting that its modulation is a potential approach for improving exercise performance. [ABSTRACT FROM AUTHOR]

Background: Sunflower is a promising protein source but data on amino acid (AA) digestibility are lacking in humans. Classically, the determination of AA digestibility requires ileal digesta sampling. The dual isotope method is minimally invasive but has not been compared to the conventional approach.Objectives: This study aimed to determine the true ileal digestibility of sunflower AAs in healthy volunteers who ate biscuits containing 15nitrogen (N) protein isolate, in comparison with the dual isotope method.Methods: Twelve healthy volunteers (men and women; 40.4 ± 10.5 years old; BMI, 23.7 ± 2.9 kg/m2) were equipped with a naso-ileal tube. For 4 hours, they consumed 9 repeated meals comprising 15N-sunflower protein biscuits together with 13carbon (C)-AAs, carried either in chocolate (SUN + Ch; n = 7) or apple puree (SUN + P; n = 5). Ileal digesta and blood were sampled throughout 8 hours after ingestion of the first meal. The 15N and 13C AA enrichments were measured in digesta to determine ileal digestibility directly and in plasma to determine lysine and threonine digestibility using the dual isotope method. Differences between methods and between vector groups were analyzed using paired and unpaired t-tests, respectively.Results: The ileal digestibility of sunflower indispensable AAs (IAA) was 89% ± 5.3%, with threonine and lysine having the lowest digestibility. In the SUN + Ch meal, IAA digestibility was 3% below that of SUN + P (P < 0.05). The mean free 13C-AA ileal digestibility was 98.1% ± 0.9%. No matter which matrix was used to carry 13C-AAs, plasma 15N and 13C-AA kinetics displayed a 1-hour offset. Digestibility obtained with the dual isotope method (70.4% ± 6.0% for threonine and 75.9% ± 22.3% for lysine) was below the target values.Conclusions: The ileal digestibility of IAAs from a sunflower isolate incorporated in a biscuit was close to 90% in healthy adults. Under our experimental conditions, the dual isotope method provided lower values than the usual method. Further protocol developments are needed to validate the equivalence between both methods. This trial was registered at clinicaltrials.gov as NCT04024605. [ABSTRACT FROM AUTHOR]

Background: Sorghum is the fifth most consumed cereal grain but limiting in the indispensable amino acid lysine. Complementing sorghum with lentils can improve the quality of sorghum-based diets. However, knowledge of lysine bioavailability in sorghum is lacking.Objectives: The study objectives were to determine the bioavailability of lysine in sorghum and to assess the effect of complementation of sorghum and lentils in a mixed-meal format.Methods: We studied 5 healthy young men (≤30 years; BMI <25 kg/m2) in a repeated-measure design using the indicator amino acid oxidation (IAAO) method, with L-[1-13C] phenylalanine as the indicator. Each subject participated in 8 determinations in random order. On the reference diet, subjects received 4 amounts of L-lysine (5, 8, 12, and 15 mg. kg-1 . d-1) from a crystalline amino acid mixture patterned after egg protein. On the test diet, they received 3 levels of lysine (8.2, 12.5, and 15.7 mg. kg-1 . d-1) from sorghum, and on the complementation diet they received 1 level of lysine from a mixed meal of sorghum and lentils. The bioavailability of lysine in sorghum was estimated by comparing the IAAO response to the test diet with the IAAO response to the reference diet using the slope-ratio method. Effectiveness of complementation was assessed by comparing the IAAO response to the mixed meal to the IAAO response to the test protein.Results: The bioavailability of lysine from sorghum was 94%. Upon complementation with lentils, there was a decline in the oxidation of L-[1-13C] phenylalanine by 19% (P < 0.0495), reflecting an improvement in available lysine in the mixed meal due to increased lysine intake.Conclusions: Although the bioavailability of lysine in sorghum is high, its lysine content is limiting. Complementation with lentils in a 1:1 ratio is recommended to achieve the lysine requirement for adult men consuming a sorghum-based diet. This trial was registered at clinicaltrials.gov as NCT03411005. [ABSTRACT FROM AUTHOR]

Summary: Background. Over the past few years, dramatic breakthroughs in the field of tumor immunotherapy with immune checkpoint inhibitors (ICIs) have made a therapeutic revolution for non-small cell lung cancer (NSCLC). While only some patients present a favorable response to this treatment. It is urgent to explore the potential molecular mechanisms underlying the regulation of tumor immune microenvironment in the process of immunotherapy. Lysine acetyltransferase 2B (KAT2B) plays a crucial role in the regulation of gene expression at the post-transcriptional level by acetylation, and is associated with many types of cancer. Methods. RNA-sequencing data, genetic mutation data, and corresponding clinical information were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, then subjected to immune characteristics, gene expression, survival, genetic alteration, enrichment analyses. Results. KAT2B expression correlated positively with infiltrating levels of multiple immune cells and mRNA expression levels of immune checkpoint genes in NSCLC. Furthermore, KAT2B expression was downregulated in tumor tissues, and low KAT2B expression was associated with unsatisfactory efficacy of immune checkpoint blockade (ICB) and poor prognosis of patients with lung adenocarcinoma. Moreover, there were higher somatic genes mutation frequency in patients with low expression of KAT2B. Finally, functional enrichment analysis suggested that KAT2B was mainly linked to the regulation of immune cells and interferon − gamma (IFN-γ) mediated signaling pathways, response to IFN-γ, antigen processing and presentation. Conclusion. This is the first comprehensive study to disclose that KAT2B is correlated with immune infiltrates and may serve as a novel biomarker predicting prognosis and response to immunotherapy in NSCLC. [ABSTRACT FROM AUTHOR]

In higher fungi, lysine is biosynthesized via the α-aminoadipate (AAA) pathway, which differs from plants, bacteria, and lower fungi. The differences offer a unique opportunity to develop a molecular regulatory strategy for the biological control of plant parasitic nematodes, based on nematode-trapping fungi. In this study, in the nematode-trapping fungus model Arthrobotrys oligospora, we characterized the core gene in the AAA pathway, encoding α-aminoadipate reductase (Aoaar), via sequence analyses and through comparing the growth, and biochemical and global metabolic profiles of the wild-type and Aoaar knockout strains. Aoaar not only has α-aminoadipic acid reductase activity, which serves fungal L-lysine biosynthesis, but it also is a core gene of the non-ribosomal peptides biosynthetic gene cluster. Compared with WT, the growth rate, conidial production, number of predation rings formed, and nematode feeding rate of the ΔAoaar strain were decreased by 40–60%, 36%, 32%, and 52%, respectively. Amino acid metabolism, the biosynthesis of peptides and analogues, phenylpropanoid and polyketide biosynthesis, and lipid metabolism and carbon metabolism were metabolically reprogrammed in the ΔAoaar strains. The disruption of Aoaar perturbed the biosynthesis of intermediates in the lysine metabolism pathway, then reprogrammed amino acid and amino acid-related secondary metabolism, and finally, it impeded the growth and nematocidal ability of A. oligospora. This study provides an important reference for uncovering the role of amino acid-related primary and secondary metabolism in nematode capture by nematode-trapping fungi, and confirms the feasibility of Aoarr as a molecular target to regulate nematode-trapping fungi to biocontrol nematodes.

Background: Cardiomyocyte metabolism changes before cardiac remodeling, but its role in early cardiac hypertrophy detection remains unclear. This study investigated early changes in plasma metabolomics in a pressure-overload cardiac hypertrophy model induced by transverse aortic constriction (TAC).Methods: The TAC model was constructed by partly ligating the aortic arch. Twelve Sprague-Dawley rats were randomly divided into the TAC group (n = 6) and sham group (n = 6). Three weeks after surgery, cardiac echocardiography was performed to assess cardiac remodeling and function. Hematoxylin/eosin (HE), Masson, and wheat germ agglutinin (WGA) stains were used to observe pathological changes. Plasma metabolites were detected by UPLC-QTOFMS and Q-TOFMS. Specific metabolites were screened by orthogonal partial least squares discriminant analysis (OPLS-DA). Metabolic pathways were characterized by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the predictive value of the screened metabolites was analyzed by receiver operating characteristic (ROC) curve analysis.Results: Three weeks after surgery, the TAC and sham groups had similar left heart function and interventricular septum and diastolic left ventricular posterior wall thicknesses. However, on pathological examination, the cross-sectional area of cardiomyocytes and myocardial fibrosis severity were significantly elevated in TAC rats. OPLS-DA showed different metabolic patterns between the TAC and sham groups. Based on the criteria VIP > 1 and P < 0.05, 13 metabolites were screened out. KEGG analysis identified disrupted lysine degradation through the related metabolites 5-aminopentanoic acid, N6-acetyl-L-lysine, and L-lysine, with areas under the ROC curve (AUCs) of 0.917, 0.889, and 0.806, respectively, for predicting compensated cardiomyocyte hypertrophy.Conclusion: Disruption of lysine degradation might be involved in early cardiac hypertrophy development, and related metabolites might be potential predictive and interventional targets for subclinical cardiomyocyte hypertrophy. [ABSTRACT FROM AUTHOR]

Histone posttranslational modifications (HPTMs) are crucial epigenetic mechanisms regulating various biological events. Different types of HPTMs characterize and shape functional chromatin states alone or in combination, and dedicated effector proteins selectively recognize these modifications for gene expression. The dysregulation of HPTM recognition events takes part in human diseases. With the application of mass spectrometry- (MS-) based proteomics, novel histone lysine acylation has been successively discovered, e.g., propionylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, malonylation, succinylation, crotonylation, glutarylation, and lactylation. These nine types of modifications expand the repertoire of HPTMs and regulate chromatin remodeling, gene expression, cell cycle, and cellular metabolism. Recent researches show that HPTMs have a close connection with the pathogenesis of cancer, metabolic diseases, neuropsychiatric disorders, infertility, kidney diseases, and acquired immunodeficiency syndrome (AIDS). This review focuses on the chemical structure, sites, functions of these novel HPTMs, and underlying mechanism in gene expression, providing a glimpse into their complex regulation in health and disease. [ABSTRACT FROM AUTHOR]

Summary: Lysine is the main limiting essential amino acid (EAA) in the rice seeds, which is a major energy and nutrition source for humans and livestock. In higher plants, the rate‐limiting steps in lysine biosynthesis pathway are catalysed by two key enzymes, aspartate kinase (AK) and dihydrodipicolinate synthase (DHDPS), and both are extremely sensitive to feedback inhibition by lysine. In this study, two rice AK mutants (AK1 and AK2) and five DHDPS mutants (DHDPS1–DHDPS5), all single amino acid substitution, were constructed. Their protein sequences passed an allergic sequence‐based homology alignment. Mutant proteins were recombinantly expressed in Escherichia coli, and all were insensitive to the lysine analog S‐(2‐aminoethyl)‐l‐cysteine (AEC) at concentrations up to 12 mm. The AK and DHDPS mutants were transformed into rice, and free lysine was elevated in mature seeds of transgenic plants, especially those expressing AK2 or DHDPS1, 6.6‐fold and 21.7‐fold higher than the wild‐type (WT) rice, respectively. We then engineered 35A2D1L plants by simultaneously expressing modified AK2 and DHDPS1, and inhibiting rice LKR/SDH (lysine ketoglutaric acid reductase/saccharopine dehydropine dehydrogenase). Free lysine levels in two 35A2D1L transgenic lines were 58.5‐fold and 39.2‐fold higher than in WT and transgenic rice containing native AK and DHDPS, respectively. Total free amino acid and total protein content were also elevated in 35A2D1L transgenic rice. Additionally, agronomic performance analysis indicated that transgenic lines exhibited normal plant growth, development and seed appearance comparable to WT plants. Thus, AK and DHDPS mutants may be used to improve the nutritional quality of rice and other cereal grains. [ABSTRACT FROM AUTHOR]

Lysine (Lys) is indispensable nutritionally, and its levels in plants are modulated by both transcriptional and post-transcriptional control during plant ontogeny. Animal glutamate receptor homologs have been detected in plants, which may participate in several plant processes through the Lys catabolic products. Interestingly, a connection between Lys and serotonin metabolism has been established recently in rice. 2-Aminoadipate, a catabolic product of Lys appears to play a critical role between serotonin accumulation and the color of rice endosperm/grain. It has also been shown that expression of some lysine-methylated proteins and genes encoding lysine-methyltransferases (KMTs) are regulated by cadmium even as it is known that Lys biosynthesis and its degradation are modulated by novel mechanisms. Three complex pathways co-exist in plants for serine (Ser) biosynthesis, and the relative preponderance of each pathway in relation to plant development or abiotic stress tolerance are being unfolded slowly. But the phosphorylated pathway of L-Ser biosynthesis (PPSB) appears to play critical roles and is essential in plant metabolism and development. Ser, which participates indirectly in purine and pyrimidine biosynthesis and plays a pivotal role in plant metabolism and signaling. Also, L-Ser has been implicated in plant responses to both biotic and abiotic stresses. A large body of information implicates Lys-rich and serine/arginine-rich (SR) proteins in a very wide array of abiotic stresses. Interestingly, a link exists between Lys-rich K-segment and stress tolerance levels. It is of interest to note that abiotic stresses largely influence the expression patterns of SR proteins and also the alternative splicing (AS) patterns. We have checked if any lncRNAs form a cohort of differentially expressed genes from the publicly available PPSB, sequence read archives of NCBI GenBank. Finally, we discuss the link between Lys and Ser synthesis, catabolism, Lys-proteins, and SR proteins during plant development and their myriad roles in response to abiotic stresses.

Lysine (Lys) is indispensable nutritionally, and its levels in plants are modulated by both transcriptional and post-transcriptional control during plant ontogeny. Animal glutamate receptor homologs have been detected in plants, which may participate in several plant processes through the Lys catabolic products. Interestingly, a connection between Lys and serotonin metabolism has been established recently in rice. 2-Aminoadipate, a catabolic product of Lys appears to play a critical role between serotonin accumulation and the color of rice endosperm/grain. It has also been shown that expression of some lysine-methylated proteins and genes encoding lysine-methyltransferases (KMTs) are regulated by cadmium even as it is known that Lys biosynthesis and its degradation are modulated by novel mechanisms. Three complex pathways co-exist in plants for serine (Ser) biosynthesis, and the relative preponderance of each pathway in relation to plant development or abiotic stress tolerance are being unfolded slowly. But the phosphorylated pathway of L-Ser biosynthesis (PPSB) appears to play critical roles and is essential in plant metabolism and development. Ser, which participates indirectly in purine and pyrimidine biosynthesis and plays a pivotal role in plant metabolism and signaling. Also, L-Ser has been implicated in plant responses to both biotic and abiotic stresses. A large body of information implicates Lys-rich and serine/arginine-rich (SR) proteins in a very wide array of abiotic stresses. Interestingly, a link exists between Lys-rich K-segment and stress tolerance levels. It is of interest to note that abiotic stresses largely influence the expression patterns of SR proteins and also the alternative splicing (AS) patterns. We have checked if any lncRNAs form a cohort of differentially expressed genes from the publicly available PPSB, sequence read archives of NCBI GenBank. Finally, we discuss the link between Lys and Ser synthesis, catabolism, Lys-proteins, and SR proteins during plant development and their myriad roles in response to abiotic stresses. [ABSTRACT FROM AUTHOR]

Extensive efforts have been made to fortify essential amino acids and boost nutrition in plants, but unintended effects on growth and physiology are also observed. Understanding how different amino acid metabolisms are connected with other biological pathways is therefore important. In addition to protein synthesis, amino acid metabolism is also tightly linked to energy and carbohydrate metabolism, the carbon-nitrogen budget, hormone and secondary metabolism, stress responses, and so on. Here, we update the currently available information on the connections between amino acid metabolisms, which tend to be overlooked in higher plants. Particular emphasis was placed on the connections between lysine metabolism and other pathways, such as tryptophan metabolism, the tricarboxylic acid cycle, abiotic and biotic stress responses, starch metabolism, and the unfolded protein response. Interestingly, regulation of lysine metabolism was found to differ between plant species, as is the case between dicots and monocots. Determining the metabolic connection between amino acid metabolisms will help improve our understanding of the metabolic flux, supporting studies on crop nutrition.

Our previous studies have demonstrated that Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese herbal decoction, has a renoprotective effect in 5/6 nephrectomy-induced chronic kidney injury. However, the role and potential mechanisms of JPYSF in the treatment of acute kidney injury (AKI) remain unknown. This study was designed to test the beneficial effect of JPYSF in an AKI mouse model and to investigate the underlying mechanism by using metabolomics analysis. The AKI mouse model was induced by a single intraperitoneal injection of cisplatin at a dose of 20 mg/kg. The mice in the treatment group were pretreated orally with JPYSF (18.35 g/kg/d) for 5 days before cisplatin injection. Seventy-two hours after cisplatin injection, serum and kidney samples were collected for biochemical and histological examination. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was applied to analyze metabolic profiling variations in the kidney. The results showed that pretreatment with JPYSF obviously reduced the levels of serum creatinine and blood urea nitrogen and alleviated renal pathological injury in AKI mice. Orthogonal partial least-squares discriminant analysis (OPLS-DA) score plot revealed a clear separation between the AKI and AKI + JPYSF group. A total of 68 and 87 significantly differentially expressed metabolites were identified in the kidney of AKI mice responding to JPYSF treatment in negative and positive ion mode, respectively. The pivotal pathways affected by JPYSF included vitamin B6 metabolism, alanine, aspartate and glutamate metabolism, lysine biosynthesis, and butanoate metabolism. In conclusion, JPYSF can protect the kidney from cisplatin-induced AKI, which may be associated with regulating renal metabolic disorders. [ABSTRACT FROM AUTHOR]

Background: Lysine rich foods such as milk and legumes serve as important food additions to the lysine deficient cereal-based diets of vegetarian populations in low- and middle-income countries (LMICs) to alleviate the risk of quality corrected dietary protein inadequacy. Dietary protein quality can be determined by estimating the metabolic availability (MA) of lysine.Objectives: The study aimed to estimate the MA of lysine in spray-dried cow milk powder (SMP), heat-treated spray-dried cow milk powder (HSMP), and a habitually consumed cereal-legume based vegetarian meal (VM), using the indicator amino acid oxidation (IAAO) slope-ratio method.Methods: The MA of lysine in SMP, HSMP, and VM was estimated in 7 healthy young men aged 19-24 y with BMI of 21.5 ± 0.5 kg/m2 in a repeated measures design. The IAAO response slopes with 2 graded lysine intakes (10.5 and 15.0 mg·kg-1·d-1) from the SMP and VM were compared with the response slope generated with 3 graded crystalline lysine intakes (6.0, 10.5, and 15.0 mg·kg-1·d-1) at the subrequirement level. To produce HSMP, pasteurized cow milk was heat treated and spray dried. The MA of lysine in HSMP was tested at a single level of lysine intake (15 mg·kg-1·d-1). A total of 8 IAAO experiments were conducted on each participant in randomized order. The IAAO slopes were estimated using a linear mixed-effect regression model.Results: The MA of lysine in SMP, HSMP, and VM was 91.9%, 69.9%, and 86.6% respectively.Conclusions: Heat treatment reduced the MA of lysine by 22% in HSMP compared with SMP in healthy Indian adults. The lysine MA estimates can be used to optimize lysine limited cereal-based diets, with the addition of appropriately processed legumes and milk powder, to meet the protein requirement. This trial was registered at Clinical Trials Registry of India (http://ctri.nic.in) as CTRI/2019/08/020568. [ABSTRACT FROM AUTHOR]

Background: Pearl millet is the chief source of energy in the diet in some developing regions, but has a limited amount of indispensable amino acid lysine. Complementation with pulses like lentils can improve the protein quality of millet diets, but the knowledge of lysine bioavailability (BA) in millet and lentils is lacking.Objectives: The study objectives were to determine the BA of lysine in millet and lentils separately and to assess the effect of complementation of millet and lentils in a mixed meal format.Methods: We studied 9 healthy young men (≤30 y; BMI <25) in a repeated-measure design using the indicator amino acid oxidation (IAAO) method, with L-[1-13C] phenylalanine as the indicator. Each subject completed 7 or 8 experiments in random order. On the reference diet, subjects received 4 graded levels of L-lysine (5, 8, 12, and 15 mg·kg-1.d-1) from a crystalline amino acid mixture patterned after egg protein; on the test diets, they received 3 levels of lysine (10, 12, and 15 mg·kg-1.d-1) from either steamed millet or stewed lentils; and on the complementation diet, they received 1 level of lysine from a mixed meal of steamed millet and stewed lentils. The BA of lysine and the effect of complementation were assessed by comparing the IAAO responses to the test diets and the complementation diet with the IAAO response to L-lysine intakes in the reference protein, using the slope ratio method.Results: The BA of lysine was 97% from millet and 80% from lentils. Complementation of steamed millet with stewed lentils decreased the oxidation of L-[1-13C] phenylalanine by 27% (P < 0.05), signifying improved quality of the combined millet and lentil protein.Conclusions: Lysine has high BA but is still limiting in steamed pearl millet. Complementation with lentils in a 2:1 ratio is recommended to meet the lysine and protein requirements for adult men consuming a millet-based diet. This trial was registered at clinicaltrials.gov as NCT03674736 and NCT03339167. [ABSTRACT FROM AUTHOR]

Accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes, and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases, and cardiomyopathy. Studies investigating the effects of AGE/RAGE axis activation on skeletal muscle oxidative stress and metabolism are more limited. We tested whether a high-fat diet (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild-type and RAGE-deficient mice. The physiological significance of AGE/RAGE axis activation in HFD-fed mice was evaluated in terms of exercise tolerance and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution, and oral glucose intolerance. HFD also induced accumulation of Nε-carboxymethyl-l-lysine, increased protein carbonyl levels, and impaired respiratory chain complex activity in soleus muscle. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD-fed mice. Peak aerobic capacity and mitochondrial cytochrome-c oxidase activity were restored in HFD-fed RAGE−/− mice. We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty HFD in mice induces accumulation of AGEs, oxidative stress, and mitochondrial dysfunction in the soleus muscle. RAGE, the multi-ligand receptor for AGEs, modulates oxidative stress and mitochondrial electron transport chain function in the soleus muscle of HFD-fed mice. [ABSTRACT FROM AUTHOR]

Extensive efforts have been made to fortify essential amino acids and boost nutrition in plants, but unintended effects on growth and physiology are also observed. Understanding how different amino acid metabolisms are connected with other biological pathways is therefore important. In addition to protein synthesis, amino acid metabolism is also tightly linked to energy and carbohydrate metabolism, the carbon-nitrogen budget, hormone and secondary metabolism, stress responses, and so on. Here, we update the currently available information on the connections between amino acid metabolisms, which tend to be overlooked in higher plants. Particular emphasis was placed on the connections between lysine metabolism and other pathways, such as tryptophan metabolism, the tricarboxylic acid cycle, abiotic and biotic stress responses, starch metabolism, and the unfolded protein response. Interestingly, regulation of lysine metabolism was found to differ between plant species, as is the case between dicots and monocots. Determining the metabolic connection between amino acid metabolisms will help improve our understanding of the metabolic flux, supporting studies on crop nutrition. [ABSTRACT FROM AUTHOR]

Background: Legumes are an excellent plant source of the limiting indispensable amino acid (IAA) lysine in vegetarian, cereal-based diets. However, their digestibility is poor largely because of their antiprotease content. Extrusion can enhance digestibility by inactivating trypsin inhibitors and thus potentially improve the protein quality of legumes.Objective: We measured the digestibility of extruded chickpea and yellow pea protein with use of a dual stable isotope method in moderately stunted South Indian primary school children.Methods: Twenty-eight moderately stunted children (height-for-age z scores <-2.0 SD and >-3.0 SD) aged 6-11 y from low to middle socioeconomic status were randomly assigned to receive a test protein (extruded intrinsically [2H]-labeled chickpea or yellow pea) along with a standard of U-[13C]-spirulina protein to measure amino acid (AA) digestibility with use of a dual stable isotope method. Individual AA digestibility in the test protein was calculated by the ratios of AA enrichments in the test protein to the standard protein in the food and their appearance in blood plasma collected at 6 and 6.5 h during the experiment, representing a plateau state.Results: The mean AA digestibility of extruded chickpea and yellow pea protein in moderately stunted children (HAZ; -2.86 to -1.2) was high and similar in both extruded test proteins (89.0% and 88.0%, respectively, P = 0.83). However, lysine and proline digestibilities were higher in extruded chickpea than yellow pea (79.2% compared with 76.5% and 75.0% compared with 72.0%, respectively, P < 0.02).Conclusion: Extruded chickpea and yellow pea protein had good IAA digestibility in moderately stunted children, which was 20% higher than an earlier report of their digestibility when pressure-cooked, measured by the same method in adults. Higher digestibility of lysine and proline highlights better retention of these AA in chickpea during extrusion-based processing. Extrusion might be useful for developing high-quality protein foods from legumes. This trial was registered at www.ctri.nic.in as CTRI/2018/03/012439. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori is the most highlighted pathogen across the globe especially in developing countries. Severe gastric problems like ulcers, cancers are associated with H. pylori and its prevalence is widespread. Evolution in the genome and cross-resistance with different antibiotics are the major reason of its survival and pandemic resistance against current regimens. Objectives: To prioritize potential drug target against H. pylori by comparing metabolic pathways of its available strains. Methods: We used various computational tools to extract metabolic sets of all available (61) strains of H. pylori and performed pan genomics and subtractive genomics analysis to prioritize potential drug target. Additionally, the protein interaction and detailed structure-based studies were performed for further characterization of protein. Results: We found 41 strains showing similar set of metabolic pathways. However, 19 strains were found with unique set of metabolic pathways. The metabolic set of these 19 strains revealed 83 unique proteins and BLAST against human proteome further funneled them to 38 non-homologous proteins. The druggability and essentiality testing further converged our findings to a single unique protein as a potential drug target against H. pylori. Conclusion: We prioritized one protein-based drug target which upon subject to applied protocol was found as close homolog of the Saccharopine dehydrogenase. Our study has opened further avenues of research regarding the discovery of new drug targets against H. pylori. [ABSTRACT FROM AUTHOR]

The present investigation was carried out to find out the effects of high dose of L-lysine on the fish and also an attempt has been made to predict the impact on human health. L-lysine is an essential amino acid which is used in medical practices as a growth promoter of bones especially in infants. Important work on metabolism and functions of amino acids in human health and major diseases has been reported by many workers and evaluated the key role of various amino acids in response to infections. Lysine is not synthesized by body; therefore, it must be taken either by diet or supplementation. Lysine first of all isolated from casein in 1889 and introduced as Lysine hydrochloride in 1955. The recommended dose of lysine is 12mg/kg body weight. Side effects of Lysine in large doses i.e. 10-30gm/day may cause abdominal cramps and diarrhea but renal and hepatic toxicity is not reported in normal person. Amino acids are used to treat end stage renal failure and also in liver failure. Recently lysine is used to treat herpes and as a supplement for diabetic people. In present study the effect of acute high dose 2mg/100gm body weight of L-lysine in fish shows toxic effects on kidney and liver which is an alarming indication towards use of high dose of Lysine in man. In kidney it caused glomerular dilation of the capillaries, glomerular hemorrhages and cloudy swelling of renal tubules. In liver it leads swelling of hepatocytes, vacuolization, fatty degeneration and central vein dilation. These histopathological changes are supported by marked rise in level of blood urea, serum creatinine, blood sugar and serum cholesterol. [ABSTRACT FROM AUTHOR]

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Objective(s): Isothiocyanates (ITCs) are biologically active plant secondary metabolites capable of mediating various biological effects including modulation of the epigenome. Our aim was to characterize the effect of allyl isothiocyanate (AITC) on lysine acetylation and methylation marks as a potential epigenetic-induced anti-melanoma strategy. Methods: Our malignant melanoma model consisted of (1) human (A375) and murine (B16-F10) malignant melanoma as well as of human; (2) brain (VMM1) and lymph node (Hs 294T) metastatic melanoma; (3) non-melanoma epidermoid carcinoma (A431) and (4) immortalized keratinocyte (HaCaT) cells subjected to AITC. Cell viability, histone deacetylases (HDACs) and acetyltransferases (HATs) activities were evaluated by the Alamar blue, Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively, while their expression levels together with those of lysine acetylation and methylation marks by western immunoblotting. Finally, apoptotic gene expression was assessed by an RT-PCR-based gene expression profiling methodology. Results: AITC reduces cell viability, decreases HDACs and HATs activities and causes changes in protein expression levels of various HDACs, HATs, and histone methyl transferases (HMTs) all of which have a profound effect on specific lysine acetylation and methylation marks. Moreover, AITC regulates the expression of a number of genes participating in various apoptotic cascades thus indicating its involvement in apoptotic induction. Conclusions: AITC exerts a potent epigenetic effect suggesting its potential involvement as a promising epigenetic-induced bioactive for the treatment of malignant melanoma. [ABSTRACT FROM AUTHOR]

Early brain damage (EBI) following subarachnoid hemorrhage (SAH) is a long-lasting condition with a high occurrence. However, treatment options are restricted. Wu-zhu-yu Decoction (WZYD) can treat headaches and vomiting, which are similar to the early symptoms of subarachnoid hemorrhage (SAH). However, it is yet unknown if WZYD can reduce EBI following SAH and its underlying mechanisms. This study aimed to investigate whether WZYD protects against EBI following SAH by inhibiting oxidative stress through activating nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling via Sirtuin 6 (SIRT6)-mediated histone H3 lysine 56 (H3K56) deacetylation. In the current investigation, the principal components of WZYD were identified using high-performance liquid chromatography-diode array detection (HPLC-DAD). The SAH model in rats using the internal carotid artery plug puncture approach and the SAH model in primary neurons using hemoglobin incubation were developed. WZYD with different doses (137 mg kg−1, 274 mg kg−1, 548 mg kg−1) and the positive drug–Nimodipine (40 mg kg−1) were intragastrically administered in SAH model rats, respectively. The PC12 cells were cultured with corresponding medicated for 24h. In our investigation, neurological scores, brain water content, Evans blue leakage, Nissl staining, TUNEL staining, oxidative stress, expression of apoptosis-related proteins, and Nrf2/HO-1 signaling were evaluated. The interaction between SIRT6 and Nrf2 was detected by co-immunoprecipitation. SIRT6 knockdown was used to confirm its role in WZYD's neuroprotection. The WZYD treatment dramatically reduced cerebral hemorrhage and edema, and enhanced neurological results in EBI following SAH rats. WZYD administration inhibited neuronal apoptosis via reducing the expression levels of Cleaved cysteinyl aspartate specific proteinase-3(Cleaved Caspase-3), cysteinyl aspartate specific proteinase-3(caspase-3), and Bcl-2, Associated X Protein (Bax) and increasing the expression of B-cell lymphoma-2(Bal2). It also decreased reactive oxygen species and malondialdehyde levels and increased Nrf2 and HO-1 expression in the rat brain after SAH. In vitro, WZYD attenuated hemoglobin-induced cytotoxicity, oxidative stress and apoptosis in primary neurons. Mechanistically, WZYD enhanced SIRT6 expression and H3K56 deacetylation, activated Nrf2/HO-1 signaling, and promoted the interaction between SIRT6 and Nrf2. Knockdown of SIRT6 abolished WZYD-induced neuroprotection. WZYD attenuates EBI after SAH by activating Nrf2/HO-1 signaling through SIRT6-mediated H3K56 deacetylation, suggesting its therapeutic potential for SAH treatment. The graph created with BioRender (https://biorender.com). The caption for the abstract graphic: WZYD alleviated SAH symptoms by activating SIRT6/Nrf2/HO-1 antioxidant system and reducing pyroptosis in SAH rats. SIRT6 could directly bind to Nrf2, and SIRT6 could deacetylate the H3K56Ac site of the promoter of Nrf2 target genes, thus promoting the expression antioxidant of gene HO-1. [Display omitted] • Wu-zhu-yu Decoction (WZYD) ameliorated EBI after SAH in rats. • WZYD activated the Nrf2 antioxidant system and reduced oxidative stress and cell death. • WZYD activated the Nrf2 antioxidant system via targeting of SIRT6. • The knockdown of SIRT6 reversed the positive effects of activating the antioxidant system in vivo by WZYD. [ABSTRACT FROM AUTHOR]

Pyridoxine (vitamin B6)-responsive epilepsies are severe forms of epilepsy that manifest as seizures immediately after birth, sometimes in utero, sometimes months, or years after birth. Seizures may be treated efficiently by life-long supplementation with pyridoxine or its biologically active form, pyridoxal phosphate, but even so patients may become intellectually disabled, for which there currently is no effective treatment. The condition may be caused by mutations in several genes (TNSALP, PIGV, PIGL, PIGO, PNPO, PROSC, ALDH7A1, MOCS2, or ALDH4A1). Mutations in ALDH7A1, MOCS2, and ALDH4A1 entail build-up of reactive aldehydes (α-aminoadipic semialdehyde, γ-glutamic semialdehyde) that may react non-enzymatically with macromolecules of brain cells. Such reactions may alter the function of macromolecules, and they may produce “advanced glycation end products” (AGEs). AGEs trigger inflammation in the brain. This understanding points to aldehyde-quenching, anti-AGE, or anti-inflammatory therapies as possible strategies to protect cognitive development and prevent intellectual disability in affected children. Studies on how aldehydes traverse cell membranes and how they affect brain function could further the development of therapies for patients with pyridoxine-responsive epilepsies.

Recent studies have made significant progress in identifying distinct populations of peripheral neurons involved in itch transmission, whereas the cellular identity of spinal interneurons that contribute to itch processing is still a debate. Combining genetic and pharmacological ablation of spinal excitatory neuronal subtypes and behavioral assays, we demonstrate that spinal somatostatin-positive (SOM) excitatory interneurons transmit pruritic sensation. We found that the ablation of spinal SOM/Lbx1 (SOM) neurons caused significant attenuation of scratching responses evoked by various chemical pruritogens (chemical itch). In an attempt to identify substrates of spinal itch neural circuit, we observed that spinal SOM neurons partially overlapped with neurons expressing natriuretic peptide receptor A (Npra), the receptor of peripheral itch transmitter B-type natriuretic peptide. Spinal SOM neurons, however, did not show any overlap with itch transmission neurons expressing gastrin-releasing peptide receptor in the dorsal spinal cord, and the gastrin-releasing peptide-triggered scratching responses were intact after ablating spinal SOM neurons. Dual ablation of SOM and Npra neurons in the spinal cord reduced chemical itch responses to a greater extent than ablation of SOM or Npra neurons alone, suggesting the existence of parallel spinal pathways transmitting chemical itch. Furthermore, we showed that SOM peptide modulated itch processing through disinhibition of somatostatin receptor 2A-positive inhibitory interneuron. Together, our findings reveal a novel spinal mechanism for sensory encoding of itch perception. [ABSTRACT FROM AUTHOR]

Background: Bronchiolitis is associated with a greater risk of developing recurrent wheezing, but with currently available tools, it is impossible to know which infants with bronchiolitis will develop this condition. This preliminary prospective study aimed to assess whether urine metabolomic analysis can be used to identify children with bronchiolitis who are at risk of developing recurrent wheezing.Methods: Fifty-two infants <1 year old treated in the emergency department at University Hospital of Padova for acute bronchiolitis were enrolled (77% tested positive for respiratory syncytial virus [RSV]). Follow-up visits were conducted for 2 years after the episode of bronchiolitis. Untargeted metabolomic analyses based on mass spectrometry were performed on urine samples collected from infants with acute bronchiolitis. Data modeling was based on univariate and multivariate data analyses.Results: We distinguished children with and those without postbronchiolitis recurrent wheeze, defined as ≥3 episodes of physician-diagnosed wheezing. Pathway overrepresentation analysis pointed to a major involvement of the citric acid cycle (P < .001) and some amino acids (lysine, cysteine, and methionine; P ≤ .015) in differentiating between these 2 groups of children.Conclusion: This is the first study showing that metabolomic profiling of urine specimens from infants with bronchiolitis can be used to identify children at increased risk of developing recurrent wheezing. [ABSTRACT FROM AUTHOR]

The gram-negative anaerobe Porphyromonas gingivalis is not only a keystone periodontal pathogen but also an emerging systemic pathogen. Although the newly discovered protein post-translational modification (PTM), lysine succinylation (Ksuc), appears to play an important role in modulating metabolic processes in bacteria, this PTM has not been investigated in P gingivalis. In this study, we used a highly sensitive proteomics approach combining affinity enrichment with high-resolution liquid chromatography coupled with tandem mass spectrometry to examine Ksuc in P gingivalis. In total, 345 Ksuc sites in 233 proteins were identified and determined to be involved in a variety of cellular processes. In the region surrounding Ksuc sites, lysine residues were drastically overrepresented and sequence motifs with succinyl-lysine flanked by a lysine at the +3 or +6 positions appear to be unique to this pathogen. Additionally, our results suggest a crosstalk between Ksuc and glycosylation, but the overlap between Ksuc and acetylation in P gingivalis is quite different from that observed in other organisms. Notably, Ksuc was observed in proteins associated with established virulence factors, including gingipains, fimbriae, RagB, and PorR. Moreover, products of the factors necessary for P gingivalis in vitro survival (18.5%) were found to be succinylated at lysine sites and the same was observed in products of fitness factors for P gingivalis survival in both abscess and epithelial cell colonization environments (12%). Collectively, these results suggest that Ksuc may be a new mechanism in modulating the virulence, adaptation, and fitness of P gingivalis. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the nutritional value of pasta enriched with legume or wheat gluten proteins and dried at varying temperature. A total of four isonitrogenous experimental diets were produced using gluten powder/wheat semolina (6/94, g/g) pasta and faba bean flour/wheat semolina (35/65, g/g) pasta dried at either 55°C (GLT and FLT, respectively) or 90°C (FVHT and GVHT, respectively). Experimental diets were fed to ten 1-month-old Wistar rats (body weight=176 (sem 15) g) for 21 d. Growth and nutritional, metabolic and inflammatory markers were measured and compared with an isonitrogenous casein diet (CD). The enrichment with faba bean increased the lysine, threonine and branched amino acids by 97, 23 and 10 %, respectively. Protein utilisation also increased by 75 % (P <0·01) in FLT in comparison to GLT diet, without any effect on the corrected faecal digestibility (P >0·05). Faba bean pasta diets' corrected protein digestibility and utilisation was only 3·5 and 9 %, respectively, lower than the CD. Growth rate, blood composition and muscle weights were not generally different with faba bean pasta diets compared with CD. Corrected protein digestibility was 3 % lower in GVHT than GLT, which may be associated with greater carboxymethyllysine. This study in growing rats clearly indicates improvement in growth performance of rats fed legume-enriched pasta diet compared with rats fed gluten–wheat pasta diet, regardless of pasta drying temperature. This means faba bean flour can be used to improve the protein quality and quantity of pasta. [ABSTRACT FROM AUTHOR]

Pyridoxine (vitamin B6)-responsive epilepsies are severe forms of epilepsy that manifest as seizures immediately after birth, sometimes in utero , sometimes months, or years after birth. Seizures may be treated efficiently by life-long supplementation with pyridoxine or its biologically active form, pyridoxal phosphate, but even so patients may become intellectually disabled, for which there currently is no effective treatment. The condition may be caused by mutations in several genes (TNSALP, PIGV, PIGL, PIGO, PNPO, PROSC, ALDH7A1, MOCS2 , or ALDH4A1). Mutations in ALDH7A1, MOCS2 , and ALDH4A1 entail build-up of reactive aldehydes (α-aminoadipic semialdehyde, γ-glutamic semialdehyde) that may react non-enzymatically with macromolecules of brain cells. Such reactions may alter the function of macromolecules, and they may produce "advanced glycation end products" (AGEs). AGEs trigger inflammation in the brain. This understanding points to aldehyde-quenching, anti-AGE, or anti-inflammatory therapies as possible strategies to protect cognitive development and prevent intellectual disability in affected children. Studies on how aldehydes traverse cell membranes and how they affect brain function could further the development of therapies for patients with pyridoxine-responsive epilepsies. [ABSTRACT FROM AUTHOR]

Background: Histone methylation has been considered as one of the epigenetic mechanisms of carcinogenesis and progression. Researches on the correlation between histone lysine methylation and gastric cancer (GC) will help in finding novel epigenetic biomarkers for monitoring cancers.Aims: The study detected the expression patterns of histone 3 lysine 9 dimethylation (H3K9me2), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3) in GC tissues and evaluated their clinical merit for GC patients.Methods: One hundred thirty-three paraffin-embedded GC samples were examined by immunohistochemistry for the histone markers: H3K9me2, H3K9me3, and H3K27me3. The relationship and clinicopathological significance of the three lysine methylations on histone H3 with GC were assessed by Paired t test, Chi-square test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard analyses.Results: Strong positive immunostaining of H3K9me2, H3K9me3, and H3K27me3 was observed in cancerous tissues than in their counterpart non-cancer tissues. Higher expression patterns of H3K9me2, H3K9me3, and H3K27me3 significantly related to differentiation degree, lymph nodes metastases, and pathological TNM staging in GC. The GC patients with low scoring of the three markers implied long survival period and best prognosis. In contrast, the patients' survival time was significantly shorter if their cancerous tissues presented high expression of the three markers.Conclusions: H3K9me2, H3K9me3, and H3K27me3 expression patterns closely relate to clinicopathological features and may be the independent risk factors for the survival of GC patients. The combined pattern of the three markers rather than an individual marker is considered to more accurately evaluate the outcome of GC patients. [ABSTRACT FROM AUTHOR]