PubMed

Cancer Commun (Lond). 2023 Jan 5. doi: 10.1002/cac2.12403. Online ahead of print.ABSTRACTBACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6-adenosine (METTL5) controls the development of HCC and the Warburg effect.METHODS: In the current study, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione-S-transferase pulldown, coimmunoprecipitation, RNA sequencing, non-targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.RESULTS: We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A (LDHA), enolase 1 (ENO1), triosephosphate isomerase 1 (TPI1), solute carrier family 2 member 1 (SLC2A1), and pyruvate kinase M2 (PKM2). The c-Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c-Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient-derived tumor xenograft (PDX) models, adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.CONCLUSIONS: These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.PMID:36602428 | DOI:10.1002/cac2.12403

J Agric Food Chem. 2023 Jan 5. doi: 10.1021/acs.jafc.2c07043. Online ahead of print.ABSTRACTThe beef quality significantly varies between breeds. Pingliang Red Cattle resembles Wagyu in fat deposition and flavor. To screen key factors affecting beef quality, we performed meat quality trait testing, RNA-seq, and metabolomics on the longissimus dorsi of Pingliang Red Cattle, Wagyu cross F1 generation, and Simmental cattle. The gene and metabolite expression profiles were similar between Pingliang Red Cattle and Wagyu cross F1 generation. Genes such as FASN, ACACA, PLIN1, and FABP4 were significantly upregulated in the Pingliang Red Cattle and Wagyu cross F1 generation (P < 0.05). Similarly, numerous metabolites, such as 3-iodo-l-tyrosine, arachidonic acid, and cis-aconitate, which may improve the beef quality such as fat deposition and tenderness, were found in higher levels in the Pingliang Red Cattle and Wagyu cross F1 generation. This study revealed differences in the transcriptional and metabolic levels between Pingliang Red Cattle and premium beef breeds, suggesting that Pingliang Red Cattle harbors the genetic potential for breeding high-grade beef cattle.PMID:36601774 | DOI:10.1021/acs.jafc.2c07043

Biomed Chromatogr. 2023 Jan 5:e5578. doi: 10.1002/bmc.5578. Online ahead of print.ABSTRACTIn this study, we utilized a serum metabolomics methodology based on gas chromatography coupled with mass spectrometry (GC/MS) to investigate the liver-protective effects of raw and stir-fried semens of Hovenia dulcis in rats models of carbon tetrachloride-induced liver injury. Multivariate statistical analysis, such as principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), were conducted to examine changes in the metabolic state of rats with carbon tetrachloride-induced liver injury, as well as the recovery pattern of rats pretreated with the raw and stir-fried semens of Hovenia dulcis. Liver tissues were subjected to histopathological examination. A total of 47 biomarkers were predicted to contribute to the dynamic pathological processes in the liver injury, such as phenylalanine, glutamic acid, glycine, arachidonic acid and linoleic acid. Further analysis revealed that pathways associated with phenylalanine, tyrosine and tryptophan biosynthesis, and linoleic acid metabolism were altered in the injured liver, and that pretreatment with raw and stir-fried semens of Hovenia dulcis abolished the changes in the aforementioned metabolic pathways.PMID:36601730 | DOI:10.1002/bmc.5578

Antioxid Redox Signal. 2023 Jan 5. doi: 10.1089/ars.2022.0141. Online ahead of print.ABSTRACTAIMS: This study aimed to explore the mechanism of ferroptosis (an iron-dependent form of nonapoptotic cell death) resistance in senescent chondrocytes.RESULTS: In this study, by utilizing metabolomics and single-cell RNA sequencing, we found that hyperactivation of ferroptosis metabolism was one of the most prominent metabolic features in Senescent chondrocytes (SenChos). Interestingly, however, SenChos were able to survive in this state and were resistant to ferroptosis induced cell death. Next, we elucidated that this survival mechanism of SenChos could be primarily attributed to overexpression of the membrane protein excitatory amino acid transporter protein 1 (EAAT1), which can increase intracellular glutamate levels and activate the glutathione system to counteract ferroptosis. In addition, UCPH-101 (a specific inhibitor of EAAT1) and siRNA-EAAT1 were able to substantially increase the sensitivity of SenChos to ferroptosis and to induce cell death, with no apparent effects on the normal cells. Administration of intra-articular injection of UCPH-101, caused inhibition of EAAT1 selectively, cleared SenChos from cartilage, improved the cartilage homeostasis and significantly delayed the progression of OA.INNOVATION: This work supports a relevant role for EAAT1 in ferroptosis resistance mechanism for SenChos, revealing a potential OA therapeutic target.CONCLUSIONS: EAAT1-glutamate-GPX4 anti-ferroptosis axis is a key survival mechanism for SenChos and EAAT1 is an effective and specific target for anti-senescence therapy in OA.PMID:36601724 | DOI:10.1089/ars.2022.0141

Front Oncol. 2022 Dec 19;12:1095800. doi: 10.3389/fonc.2022.1095800. eCollection 2022.NO ABSTRACTPMID:36601470 | PMC:PMC9807074 | DOI:10.3389/fonc.2022.1095800

Front Nutr. 2022 Dec 19;9:1045805. doi: 10.3389/fnut.2022.1045805. eCollection 2022.ABSTRACTBACKGROUND: Fructose consumption is a potential risk factor for hyperuricemia because uric acid (UA) is a byproduct of fructose metabolism caused by the rapid consumption of adenosine triphosphate and accumulation of adenosine monophosphate (AMP) and other purine nucleotides. Additionally, a clinical experiment with four gout patients demonstrated that intravenous infusion of fructose increased the purine de novo synthesis rate, which implied fructose-induced hyperuricemia might be related to purine nucleotide synthesis. Moreover, the mechanistic (mammalian) target of rapamycin (mTOR) is a key protein both involved in fructose metabolism and purine de novo synthesis. The present study was conducted to elucidate how fructose influences mTOR and purine de novo synthesis in a hepatic cell line and livers of mice.MATERIALS AND METHODS: RNA-sequencing in NCTC 1469 cells treated with 0- and 25-mM fructose for 24 h and metabolomics analysis on the livers of mice fed with 0- and 30-g/kg fructose for 2 weeks were assessed. Gene and protein expression of phosphoribosyl pyrophosphate synthase (PRPSAP1), Glutamine PRPP aminotransferase (PPAT), adenyl succinate lyase (ADSL), adenyl succinate synthetase isozyme-1 (Adss1), inosine-5'-monophosphate dehydrogenase (IMPDH), and guanine monophosphate synthetase (GMPS) was measured. The location of PRPSAP1 and PPAT in the liver was assessed by an immunofluorescence assay.RESULTS: Metabolite profiling showed that the level of AMP, adenine, adenosine, hypoxanthine, and guanine was increased significantly. RNA-sequencing showed that gene expression of phosphoribosyl pyrophosphate synthase (PRPS2), phosphoribosyl glycinamide formyl transferase (GART), AICAR transformylase (ATIC), ADSL, Adss1, and IMPDH were raised, and gene expression of adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), 5',3'-nucleotidase, cytosolic (NT5C), and xanthine oxidoreductase (XOR) was also increased significantly. Fructose increased the gene expression, protein expression, and fluorescence intensity of PRPSAP1 and PPAT in mice livers by increasing mTOR expression. Fructose increased the expression and activity of XOR, decreased the expression of uricase, and increased the serum level of UA.CONCLUSION: This study demonstrated that the increased purine de novo synthesis may be a crucial mechanism for fructose-induced hyperuricemia.PMID:36601078 | PMC:PMC9807165 | DOI:10.3389/fnut.2022.1045805

Front Nutr. 2022 Dec 19;9:1049106. doi: 10.3389/fnut.2022.1049106. eCollection 2022.ABSTRACTINTRODUCTION: Sepsis, an infection with multiorgan dysfunction, is a serious burden on human health. Berberine (BBR), a bioactive component, has a protective effect on sepsis and the effect may be related to gut microbiota. However, studies on the role of BBR with gut microbiota in sepsis are lacking. Therefore, this study investigated the ameliorative effects and the underlying mechanisms of BBR on cecal ligature and puncture (CLP) rats.METHODS: This study has observed the effect of BBR on pathological injury, Inflammation, intestinal barrier function, gut microbiota, and metabolite change in CLP rats by Hematoxylin-eosin staining, enzyme-linked immunosorbent assays, flow cytometry, 16S rDNA, and metabolomics analyses.RESULTS: The inhibition effects of BBR treatment on the histological damage of the lung, kidney, and ileum, the interleukin (IL)-1b, IL-6, IL-17A, and monocyte chemokine-1 levels in serum in CLP rats were proved. Also, the BBR inhibited the diamine-oxidase and fluorescein isothiocyanate-dextran 40 levels, suggesting it can improve intestinal barrier function disorders. The cluster of differentiation (CD) 4+, CD8+, and CD25+ Forkhead box protein P3 (Foxp3) + T lymphocytes in splenocytes were up-regulated by BBR, while the IL-17A+CD4+ cell level was decreased. The abundance of gut microbiota in CLP rats was significantly different from that of the sham and BBR treatment rats. The significantly changed metabolites in the serum mainly included carbohydrates, phenols, benzoic acids, alcohols, vitamins et al. Additionally, this study predicted that the biological mechanism of BBR to ameliorate sepsis involves glycolysis-, nucleotide-, and amino acid-related metabolic pathways.DISCUSSION: This study proved the strong correlation between the improvement effect of BBR on sepsis and gut microbiota and analyzed by metabolomics that gut microbiota may improve CLP rats through metabolites, providing a scientific basis for BBR to improve sepsis and a new direction for the study of the biological mechanism.PMID:36601077 | PMC:PMC9806126 | DOI:10.3389/fnut.2022.1049106

Front Endocrinol (Lausanne). 2022 Dec 19;13:1000650. doi: 10.3389/fendo.2022.1000650. eCollection 2022.ABSTRACTINTRODUCTION: The role of endogenous androgens in kidney function and disease has not been extensively explored in men and women.RESEARCH DESIGN AND METHODS: We analyzed data from the observational KORA F4 study and its follow-up examination KORA FF4 (median follow-up time 6.5 years) including 1293 men and 650 peri- and postmenopausal women, not using exogenous sex hormones. We examined the associations between endogenous androgens (testosterone [T], dihydrotestosterone [DHT], free T [fT], free DHT [fDHT], and T/DHT), with estimated glomerular filtration rate (eGFR) at baseline and follow-up, prevalent, and incident chronic kidney disease (CKD) adjusting for common CKD risk factors.RESULTS: At baseline, 73 men (5.7%) and 54 women (8.4%) had prevalent CKD. Cross-sectionally, no significant associations between androgens and kidney function were observed among men. In women, elevated T (β=-1.305, [95% CI -2.290; -0.320]) and fT (β=-1.423, [95% CI -2.449; -0.397]) were associated with lower eGFR. Prospectively, 81 men (8.8%) and 60 women (15.2%) developed incident CKD. In women, a reverse J-shaped associations was observed between DHT and incident CKD (Pnon-linear=0.029), while higher fDHT was associated with lower incident CKD risk (odds ratio per 1 standard deviation=0.613, [95% CI 0.369; 0.971]. Among men, T/DHT (β=-0.819, [95% CI -1.413; -0.226]) and SHBG (Pnon-linear=0.011) were associated with eGFR at follow-up but not with incident CKD. Some associations appeared to be modified by type 2 diabetes (T2D).CONCLUSION: Suggestive associations are observed of androgens and SHBG with kidney impairment among men and women. However, larger well-phenotyped prospective studies are required to further elucidate the potential of androgens, SHBG, and T2D as modifiable risk factors for kidney function and CKD.PMID:36601008 | PMC:PMC9807167 | DOI:10.3389/fendo.2022.1000650

Front Endocrinol (Lausanne). 2022 Dec 19;13:964389. doi: 10.3389/fendo.2022.964389. eCollection 2022.ABSTRACTOBJECTIVE: Diabetic kidney disease (DKD) is one of the most prevalent complications of diabetes mellitus (DM) and is associated with gut microbial dysbiosis. We aim to build a diagnostic model to aid clinical practice and uncover a crucial harmful microbial community that contributes to DKD pathogenesis and exacerbation.DESIGN: A total of 528 fecal samples from 180 DKD patients and 348 non-DKD populations (138 DM and 210 healthy volunteers) from the First Affiliated Hospital of Zhengzhou University were recruited and randomly divided into a discovery phase and a validation phase. The gut microbial composition was compared using 16S rRNA sequencing. Then, the 180 DKD patients were stratified into four groups based on clinical stages and underwent gut microbiota analysis. We established DKD mouse models and a healthy fecal microbiota transplantation (FMT) model to validate the effects of gut microbiota on DKD and select the potential harmful microbial community. Untargeted metabolome-microbiome combined analysis of mouse models helps decipher the pathogenetic mechanism from a metabolic perspective.RESULTS: The diversity of the gut microbiome was significantly decreased in DKD patients when compared with that of the non-DKD population and was increased in the patients with more advanced DKD stages. The DKD severity in mice was relieved after healthy gut microbiota reconstruction. The common harmful microbial community was accumulated in the subjects with more severe DKD phenotypes (i.e., DKD and DKD5 patients and DKD mice). The harmful microbial community was positively associated with the serum injurious metabolites (e.g., cholic acid and hippuric acid).CONCLUSION: The fecal microbial community was altered markedly in DKD. Combining the fecal analysis of both human and animal models selected the accumulated harmful pathogens. Partially recovering healthy gut microbiota can relieve DKD phenotypes via influencing pathogens' effect on DKD mice's metabolism.PMID:36601003 | PMC:PMC9806430 | DOI:10.3389/fendo.2022.964389

Front Plant Sci. 2022 Dec 19;13:1051165. doi: 10.3389/fpls.2022.1051165. eCollection 2022.ABSTRACTDrought is one of the most common abiotic stressors in plants. Melatonin (MT) is a high-efficiency and low-toxicity growth regulator that plays an important role in plant responses to drought stress. As a wild relative of wheat, Agropyron mongolicum has become an important species for the improvement of degraded grasslands and the replanting of sandy grasslands. However, the physiological and molecular mechanisms by which exogenous MT regulates drought stress in A. mongolicum remain unclear. To assess the effectiveness of MT intervention (100 mg·L-1), polyethylene glycol 6000 was used to simulate drought stress, and its ameliorating effects on drought stress in A. mongolicum seedlings were investigated through physiology, transcriptomics, and metabolomics. Physiological analysis indicated that MT treatment increased the relative water content and chlorophyll content and decreased the relative conductivity of A. mongolicum seedlings. Additionally, MT decreased malondialdehyde (MDA) and reactive oxygen species (ROS) accumulation by enhancing antioxidant enzyme activities. The transcriptome and metabolite profiling analysis of A. mongolicum seedlings treated with and without MT under drought stress identified the presence of 13,466 differentially expressed genes (DEGs) and 271 differentially expressed metabolites (DEMs). The integrated analysis of transcriptomics and metabolomics showed that DEGs and DEMs participated in diverse biological processes, such as flavonoid biosynthesis and carbohydrate metabolism. Moreover, MT may be involved in regulating the correlation of DEGs and DEMs in flavonoid biosynthesis and carbohydrate metabolism during drought stress. In summary, this study revealed the physiological and molecular regulatory mechanisms of exogenous MT in alleviating drought stress in A. mongolicum seedlings, and it provides a reference for the development and utilization of MT and the genetic improvement of drought tolerance in plants from arid habitats.PMID:36600908 | PMC:PMC9806343 | DOI:10.3389/fpls.2022.1051165

J Ovarian Res. 2023 Jan 5;16(1):2. doi: 10.1186/s13048-022-01085-y.ABSTRACTBACKGROUND: Premature ovarian insufficiency (POI) patients are predisposed to metabolic disturbances, including in lipid metabolism and glucose metabolism, and metabolic disorders appear to be a prerequisite of the typical long-term complications of POI, such as cardiovascular diseases or osteoporosis. However, the metabolic changes underlying the development of POI and its subsequent complications are incompletely understood, and there are few studies characterizing the disturbed metabolome in POI patients. The aim of this study was to characterize the plasma metabolome in POI by using ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) metabolomics and to evaluate whether these disturbances identified in the plasma metabolome relate to ovarian reserve and have diagnostic value in POI.METHODS: This observational study recruited 30 POI patients and 30 age- and body mass index (BMI)-matched controls in the Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, from January 2018 to October 2020. Fasting venous blood was collected at 9:00 am on days 2-4 of the menstrual cycle and centrifuged for analysis. An untargeted quantitative metabolomic analysis was performed using UHPLC-MS/MS.RESULTS: Our study identified 48 upregulated and 21 downregulated positive metabolites, and 13 upregulated and 48 downregulated negative metabolites in the plasma of POI patients. The differentially regulated metabolites were involved in pathways such as caffeine metabolism and ubiquinone and other terpenoid-quinone biosynthesis. Six metabolites with an AUC value > 0.8, including arachidonoyl amide, 3-hydroxy-3-methylbutanoic acid, dihexyl nonanedioate, 18-HETE, cystine, and PG (16:0/18:1), were correlated with ovarian reserve and thus have the potential to be diagnostic biomarkers of POI.CONCLUSION: This UHPLC-MS/MS untargeted metabolomics study revealed differentially expressed metabolites in the plasma of patients with POI. The differential metabolites may not only be involved in the aetiology of POI but also contribute to its major complications. These findings offer a panoramic view of the plasma metabolite changes caused by POI, which may provide useful diagnostic and therapeutic clues for POI disease.PMID:36600288 | DOI:10.1186/s13048-022-01085-y

BMC Plant Biol. 2023 Jan 5;23(1):8. doi: 10.1186/s12870-022-04016-7.ABSTRACTBACKGROUND: To reveal the key genes involved in the phenylpropanoid pathway, which ultimately governs the fragrance of Rhododendron fortunei, we performed a comprehensive transcriptome and metabolomic analysis of the petals of two different varieties of two alpine rhododendrons: the scented R. fortunei and the unscented Rhododendron 'Nova Zembla'.RESULTS: Our transcriptomic and qRT-PCR data showed that nine candidate genes were highly expressed in R. fortunei but were downregulated in Rhododendron 'Nova Zembla'. Among these genes, EGS expression was significantly positively correlated with various volatile benzene/phenylpropanoid compounds and significantly negatively correlated with the contents of various nonvolatile compounds, whereas CCoAOMT, PAL, C4H, and BALDH expression was significantly negatively correlated with the contents of various volatile benzene/phenylpropanoid compounds and significantly positively correlated with the contents of various nonvolatile compounds. CCR, CAD, 4CL, and SAMT expression was significantly negatively correlated with the contents of various benzene/phenylpropanoid compounds. The validation of RfSAMT showed that the RfSAMT gene regulates the synthesis of aromatic metabolites in R. fortunei.CONCLUSION: The findings of this study indicated that key candidate genes and metabolites involved in the phenylpropanoid biosynthesis pathway may govern the fragrance of R. fortunei. This lays a foundation for further research on the molecular mechanism underlying fragrance in the genus Rhododendron.PMID:36600207 | DOI:10.1186/s12870-022-04016-7

Sci Rep. 2023 Jan 4;13(1):149. doi: 10.1038/s41598-023-27461-2.ABSTRACTOncocytic thyroid cancer is characterized by the aberrant accumulation of abnormal mitochondria in the cytoplasm and a defect in oxidative phosphorylation. We performed metabolomics analysis to compare metabolic reprogramming among the oncocytic and non-oncocytic thyroid cancer cell lines XTC.UC1 and TPC1, respectively, and a normal thyroid cell line Nthy-ori 3-1. We found that although XTC.UC1 cells exhibit higher glucose uptake than TPC1 cells, the glycolytic intermediates are not only utilized to generate end-products of glycolysis, but also diverted to branching pathways such as lipid metabolism and the serine synthesis pathway. Glutamine is preferentially used to produce glutathione to reduce oxidative stress in XTC.UC1 cells, rather than to generate α-ketoglutarate for anaplerotic flux into the TCA cycle. Thus, growth, survival and redox homeostasis of XTC.UC1 cells rely more on both glucose and glutamine than do TPC1 cells. Furthermore, XTC.UC1 cells contained higher amounts of intracellular amino acids which is due to higher expression of the amino acid transporter ASCT2 and enhanced autophagy, thus providing the building blocks for macromolecules and energy production. These metabolic alterations are required for oncocytic cancer cells to compensate their defective mitochondrial function and to alleviate excess oxidative stress.PMID:36599897 | DOI:10.1038/s41598-023-27461-2

Nat Commun. 2023 Jan 4;14(1):48. doi: 10.1038/s41467-022-35696-2.ABSTRACTBiopsy is the recommended standard for pathological diagnosis of liver carcinoma. However, this method usually requires sectioning and staining, and well-trained pathologists to interpret tissue images. Here, we utilize Raman spectroscopy to study human hepatic tissue samples, developing and validating a workflow for in vitro and intraoperative pathological diagnosis of liver cancer. We distinguish carcinoma tissues from adjacent non-tumour tissues in a rapid, non-disruptive, and label-free manner by using Raman spectroscopy combined with deep learning, which is validated by tissue metabolomics. This technique allows for detailed pathological identification of the cancer tissues, including subtype, differentiation grade, and tumour stage. 2D/3D Raman images of unprocessed human tissue slices with submicrometric resolution are also acquired based on visualization of molecular composition, which could assist in tumour boundary recognition and clinicopathologic diagnosis. Lastly, the potential for a portable handheld Raman system is illustrated during surgery for real-time intraoperative human liver cancer diagnosis.PMID:36599851 | DOI:10.1038/s41467-022-35696-2

Neurology. 2023 Jan 4:10.1212/WNL.0000000000206776. doi: 10.1212/WNL.0000000000206776. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVES: Modified Atkins Diet (MAD) has emerged as an adjuvant therapy in drug-resistant epilepsy (DRE). Most studies are in children, there is limited evidence for DRE in in adults. The present study aimed to investigate if MAD along with standard drug therapy (SDT) was indeed more effective than SDT alone in reducing seizure frequency and improving psychological outcomes at 6 months in Adolescents and adults with DRE (non-surgical).METHODS: A prospective randomized controlled trial was conducted at tertiary care referral centre, in India. Persons with DRE aged 10-55 years attending outpatient epilepsy clinics between August 2015 and April 2019, who had more than two seizures/month despite using at least three appropriate anti-seizure medications (ASMs) at their maximum tolerated doses and had not been on any form of diet therapy for the past one year, were enrolled. Patients were assessed for the eligibility and randomly assigned to receive SDT plus MAD (intervention arm) or SDT alone (control arm).The primary outcome was>50% reduction in seizure- frequency, and the secondary outcomes were quality of life (QOL), behaviour, adverse events and rate of withdrawal at six months. Intention to treat analysis was performed.RESULTS: 243 patients were screened for eligibility; 160 patients (80 adults and 80 adolescents) were randomized to either intervention or Control arm. Demographic and clinical characteristics in both groups were comparable at baseline. At six months > 50% seizure reduction was seen in 26.2% in the intervention group versus 2.5 % in the control group (95% CI 13.5-33.9; p<0.001). Improvement in QOL was 52.1±17.6 in the intervention group versus 42.5±16.4 in the control group (mean difference, 9.6; 95%CI 4.3 to 14.9, p<0.001). However, behaviour scores could be performed in 49 patients and improvement was seen in intervention versus control group (65.6±7.9 versus 71.4±8.1, p=0.015) at the end of the study. One patient had weight loss; two patients had Diarrhoea.DISCUSSION: MAD group demonstrated improvement in all aspects (reduction in seizure-frequency, and behavioural problems) compared to control group at the end of the study. MAD is an effective modality in controlling seizures, further research is required to assess its efficacy in terms of biomarkers along with descriptive metabolomics studies.PMID:36599697 | DOI:10.1212/WNL.0000000000206776

Anal Chem. 2023 Jan 4. doi: 10.1021/acs.analchem.2c01795. Online ahead of print.ABSTRACTData-dependent acquisition (DDA) mode in ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) can provide massive amounts of MS1 and MS/MS information of compounds in untargeted metabolomics and can thus facilitate compound identification greatly. In this work, we developed a new platform called AntDAS-DDA for the automatic processing of UHPLC-HRMS data sets acquired under the DDA mode. Several algorithms, including extracted ion chromatogram extraction, feature extraction, MS/MS spectrum construction, fragment ion identification, and MS1 spectrum construction, were developed within the platform. The performance of AntDAS-DDA was investigated comprehensively with a mixture of standard and complex plant data sets. Results suggested that features in complex sample matrices can be extracted effectively, and the constructed MS1 and MS/MS spectra can benefit in compound identification greatly. The efficiency of compound identification can be improved by about 20%. AntDAS-DDA can take full advantage of MS/MS information in multiple sample analyses and provide more MS/MS spectra than single sample analysis. A comparison with advanced data analysis tools indicated that AntDAS-DDA may be used as an alternative for routine UHPLC-HRMS-based untargeted metabolomics. AntDAS-DDA is freely available at http://www.pmdb.org.cn/antdasdda.PMID:36599407 | DOI:10.1021/acs.analchem.2c01795

Cell. 2022 Dec 26:S0092-8674(22)01377-0. doi: 10.1016/j.cell.2022.11.001. Online ahead of print.ABSTRACTAging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.PMID:36599349 | DOI:10.1016/j.cell.2022.11.001

Cell Metab. 2023 Jan 3;35(1):150-165.e4. doi: 10.1016/j.cmet.2022.12.006.ABSTRACTTime-restricted feeding (TRF) is an emerging behavioral nutrition intervention that involves a daily cycle of feeding and fasting. In both animals and humans, TRF has pleiotropic health benefits that arise from multiple organ systems, yet the molecular basis of TRF-mediated benefits is not well understood. Here, we subjected mice to isocaloric ad libitum feeding (ALF) or TRF of a western diet and examined gene expression changes in samples taken from 22 organs and brain regions collected every 2 h over a 24-h period. We discovered that TRF profoundly impacts gene expression. Nearly 80% of all genes show differential expression or rhythmicity under TRF in at least one tissue. Functional annotation of these changes revealed tissue- and pathway-specific impacts of TRF. These findings and resources provide a critical foundation for future mechanistic studies and will help to guide human time-restricted eating (TRE) interventions to treat various disease conditions with or without pharmacotherapies.PMID:36599299 | DOI:10.1016/j.cmet.2022.12.006

Cell Metab. 2023 Jan 3;35(1):12-35. doi: 10.1016/j.cmet.2022.11.001.ABSTRACTBoth aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.PMID:36599298 | DOI:10.1016/j.cmet.2022.11.001

Cell Metab. 2023 Jan 3;35(1):118-133.e7. doi: 10.1016/j.cmet.2022.12.003.ABSTRACTImmunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.PMID:36599297 | DOI:10.1016/j.cmet.2022.12.003