Haplotype-resolved genomes of octoploid species in Phyllanthaceae family reveal a critical role for polyploidization and hybridization in speciation.

The Phyllanthaceae family comprises a diverse range of plants with medicinal, edible, and ornamental value, extensively cultivated worldwide. Polyploid species commonly occur in Phyllanthaceae. Due to the rather complex genomes and evolutionary histories, their speciation process has been still lacking in research. In this study, we generated chromosome-scale haplotype-resolved genomes of two octoploid species (Phyllanthus emblica and Sauropus spatulifolius) in Phyllanthaceae family. Combined with our previously reported one tetraploid (Sauropus androgynus) and one diploid species (Phyllanthus cochinchinensis) from the same family, we explored their speciation history. The three polyploid species were all identified as allopolyploids with subgenome A/B. Each of their two distinct subgenome groups from various species was uncovered to independently share a common diploid ancestor (Ancestor-AA and Ancestor-BB). Via different evolutionary routes, comprising various scenarios of bifurcating divergence, allopolyploidization (hybrid polyploidization), and autopolyploidization, they finally evolved to the current tetraploid S. androgynus, and octoploid S. spatulifolius and P. emblica, respectively. We further discuss the variations in copy number of alleles and the potential impacts within the two octoploids. In addition, we also investigated the fluctuation of metabolites with medical values and identified the key factor in its biosynthesis process in octoploids species. Our study reconstructed the evolutionary history of these Phyllanthaceae species, highlighting the critical roles of polyploidization and hybridization in their speciation processes. The high-quality genomes of the two octoploid species provide valuable genomic resources for further research of evolution and functional genomics.

Risk factors and the nomogram model for malnutrition in patients with nasopharyngeal carcinoma.

BACKGROUND: For patients with nasopharyngeal carcinoma (NPC), the incidence of malnutrition is quite high, and malnutrition has severe effects on NPC patients. However, there is currently no recognized gold standard or specific nutritional assessment tool available to assess malnutrition in NPC patients. Our objective was to develop and verify a new nomogram model for NPC patients. METHODS: Data were collected from NPC patients. To evaluate risk factors for malnutrition, univariate and multivariate logistic regression analyses were used. Based on the risk factors, a new nomogram model was developed. The efficacy of the model was evaluated and validated. RESULTS: Logistic regression analysis showed that age ≥ 65 years, the number of chemotherapy cycles completed ≥ 1, a high total radiation dose received, low body mass index (BMI), low albumin, and low chloride were the risk factors. The assessment effect of the new model was good by evaluation and validation; it can be used as an assessment tool for malnutrition in NPC patients. CONCLUSIONS: Age ≥ 65 years, completing ≥ 1 chemotherapy cycles, a high total radiation dose received, low BMI, low albumin, and low chloride levels are risk factors for malnutrition in NPC patients. The assessment effect of the new model, developed based on these risk factors, is good, and it can be used as an assessment tool for malnutrition in NPC patients.

Scaling of MoS2 Transistors and Inverters to Sub-10 nm Channel Length with High Performance.

Two-dimensional (2D) semiconductors such as monolayer molybdenum disulfide (MoS2) are promising building blocks for ultrascaled field effect transistors (FETs), benefiting from their atomic thickness, dangling-bond-free flat surface, and excellent gate controllability. However, despite great prospects, the fabrication of 2D ultrashort channel FETs with high performance and uniformity remains a challenge. Here, we report a self-encapsulated heterostructure undercut technique for the fabrication of sub-10 nm channel length MoS2 FETs. The fabricated 9 nm channel MoS2 FETs exhibit superior performances compared with sub-15 nm channel length including the competitive on-state current density of 734/433 µA/µm at VDS = 2/1 V, record-low DIBL of ∼50 mV/V, and superior on/off ratio of 3 × 107 and low subthreshold swing of ∼100 mV/dec. Furthermore, the ultrashort channel MoS2 FETs fabricated by this new technique show excellent homogeneity. Thanks to this, we scale the monolayer inverter down to sub-10 nm channel length.

Giant Correlated Gap and Possible Room-Temperature Correlated States in Twisted Bilayer MoS_{2}.

Moiré superlattices have emerged as an exciting condensed-matter quantum simulator for exploring the exotic physics of strong electronic correlations. Notable progress has been witnessed, but such correlated states are achievable usually at low temperatures. Here, we report evidence of possible room-temperature correlated electronic states and layer-hybridized SU(4) model simulator in AB-stacked MoS_{2} homobilayer moiré superlattices. Correlated insulating states at moiré band filling factors v=1, 2, 3 are unambiguously established in twisted bilayer MoS_{2}. Remarkably, the correlated electronic state at v=1 shows a giant correlated gap of ∼126 meV and may persist up to a record-high critical temperature over 285 K. The realization of a possible room-temperature correlated state with a large correlated gap in twisted bilayer MoS_{2} can be understood as the cooperation effects of the stacking-specific atomic reconstruction and the resonantly enhanced interlayer hybridization, which largely amplify the moiré superlattice effects on electronic correlations. Furthermore, extreme large nonlinear Hall responses up to room temperature are uncovered near correlated electronic states, demonstrating the quantum geometry of moiré flat conduction band.

The application of the PDCA cycle in the nutritional management of patients with nasopharyngeal carcinoma.

OBJECTIVE: This study is to explore the effect of the Plan-Do-Check-Act (PDCA) cycle on the nutritional management of patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 100 NPC patients were randomly divided into a control group and a PDCA group, with 50 patients in each group. The control group adopted a routine nutritional management strategy, and the PDCA group adopted a PDCA cycle management strategy. The body weight, body mass index (BMI), hemoglobin, serum prealbumin, serum albumin, the Patient-Generated Subjective Global Assessment (PG-SGA) score, the Nutrition Risk Screening 2002 (NRS-2002) score, the incidence rate of nutritional risk, the grade of malnutrition, and the grade of oral mucositis were compared between the two groups. RESULTS: The body weight, BMI, and serum prealbumin in the PDCA group were higher than those in the control group, and the difference was statistically significant (p < 0.05). The NRS2002 score and PG-SGA score in the PDCA group were lower than those in the control group, and the differences were statistically significant (p < 0.05). The incidence of nutritional risk, the grade of malnutrition, and the grade of oral mucositis were less in the PDCA group than those in the control group (p < 0.05). There was no significant difference in hemoglobin and serum albumin between the two groups (p > 0.05). CONCLUSION: The PDCA cycle can improve body weight, BMI, and serum prealbumin in NPC patients. It can reduce the NRS2002 score, the PG-SGA score, the incidence of nutritional risk, the severity of malnutrition, and the severity of oral mucositis in NPC patients.

Nontargeted metabolomics reveals the potential mechanism underlying the association between birthweight and metabolic disturbances.

AIMS: The aim of this study was to characterize the metabolites associated with small- and large-gestational-age newborns in maternal and cord blood, and to investigate potential mechanisms underlying the association between birthweight and metabolic disturbances. RESEARCH DESIGN AND METHODS: We recorded detailed anthropometric data of mother-offspring dyads. Untargeted metabolomic assays were performed on 67 pairs of cord blood and maternal fasting plasma samples including 16 pairs of small-for-gestational (SGA, < 10th percentile) dyads, 28 pairs of appropriate-for-gestational (AGA, approximate 50 percentile) dyads, and 23 pairs of large-for-gestational (LGA, > 90th percentile) dyads. The association of metabolites with newborn birthweight was conducted to screen for metabolites with U-shaped and line-shaped distributions. The association of metabolites with maternal and fetal phenotypes was also performed. RESULTS: We found 2 types of metabolites that changed in different patterns according to newborn birthweight. One type of metabolite exhibited a "U-shaped" trend of abundance fluctuation in the SGA-AGA-LGA groups. The results demonstrated that cuminaldehyde level was lower in the SGA and LGA groups, and its abundance in cord blood was negatively correlated with maternal BMI (r = -0.352 p = 0.009) and weight gain (r = -0.267 p = 0.043). 2-Methoxy-estradiol-17b 3-glucuronide, which showed enrichment in the SGA and LGA groups, was positively correlated with homocysteine (r = 0.44, p < 0.001) and free fatty acid (r = 0.42, p < 0.001) in maternal blood. Serotonin and 13(S)-HODE were the second type of metabolites, denoted as "line-shaped", which both showed increasing trends in the SGA-AGA-LGA groups in both maternal and cord blood and were both significantly positively correlated with maternal BMI before pregnancy. Moreover, cuminaldehyde, serotonin, 13(S)-HODE and some lipid metabolites showed a strong correlation between maternal and cord blood. CONCLUSIONS: These investigations demonstrate broad-scale metabolomic differences associated with newborn birthweight in both pregnant women and their newborns. The U-shaped metabolites associated with both the SGA and LGA groups might explain the U-shaped association between birthweight and metabolic dysregulation. The line-shaped metabolites might participate in intrauterine growth regulation. These observations might help to provide new insights into the insulin resistance and the risk of metabolic disturbance of SGA and LGA babies in adulthood and might identify potential new markers for adverse newborn outcomes in pregnant women.

Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD.

O-linked b-N-acetyl-glucosaminylation (O-GlcNAcylation) is one of the most common post-translational modifications of proteins, and is established by modifying the serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc signaling is considered a critical nutrient sensor, and affects numerous proteins involved in cellular metabolic processes. O-GlcNAcylation modulates protein functions in different patterns, including protein stabilization, enzymatic activity, transcriptional activity, and protein interactions. Disrupted O-GlcNAcylation is associated with an abnormal metabolic state, and may result in metabolic disorders. As the liver is the center of nutrient metabolism, this review provides a brief description of the features of the O-GlcNAc signaling pathway, and summarizes the regulatory functions and underlying molecular mechanisms of O-GlcNAcylation in liver metabolism. Finally, this review highlights the role of O-GlcNAcylation in liver-associated diseases, such as diabetes and nonalcoholic fatty liver disease (NAFLD). We hope this review not only benefits the understanding of O-GlcNAc biology, but also provides new insights for treatments against liver-associated metabolic disorders.

Glucokinase Inactivation Ameliorates Lipid Accumulation and Exerts Favorable Effects on Lipid Metabolism in Hepatocytes.

Glucokinase-maturity onset diabetes of the young (GCK-MODY) is a kind of rare diabetes with low incidence of vascular complications caused by GCK gene inactivation. This study aimed to investigate the effects of GCK inactivation on hepatic lipid metabolism and inflammation, providing evidence for the cardioprotective mechanism in GCK-MODY. We enrolled GCK-MODY, type 1 and 2 diabetes patients to analyze their lipid profiles, and found that GCK-MODY individuals exhibited cardioprotective lipid profile with lower triacylglycerol and elevated HDL-c. To further explore the effects of GCK inactivation on hepatic lipid metabolism, GCK knockdown HepG2 and AML-12 cell models were established, and in vitro studies showed that GCK knockdown alleviated lipid accumulation and decreased the expression of inflammation-related genes under fatty acid treatment. Lipidomic analysis indicated that the partial inhibition of GCK altered the levels of several lipid species with decreased saturated fatty acids and glycerolipids including triacylglycerol and diacylglycerol, and increased phosphatidylcholine in HepG2 cells. The hepatic lipid metabolism altered by GCK inactivation was regulated by the enzymes involved in de novo lipogenesis, lipolysis, fatty acid ß-oxidation and the Kennedy pathway. Finally, we concluded that partial inactivation of GCK exhibited beneficial effects in hepatic lipid metabolism and inflammation, which potentially underlies the protective lipid profile and low cardiovascular risks in GCK-MODY patients.

Advances in lipodystrophy syndrome caused by LMNA gene mutation.

Lipodystrophy syndrome caused by LMNA gene mutation is a group of autosomal dominant monogenic diseases, characterized by selective fat loss and metabolic abnormalities with insulin resistance. In this review, we summarize the clinical manifestations caused by multiple pathogenic LMNA mutations reported so far, including metabolic complications, cardiovascular abnormalities, gonadal axis disorders, myopathy, and renal abnormalities. Meanwhile, we also clarify the possible pathogenic mechanism, diagnosis, and treatment, in order to improve the understanding of the disease and to provide a reference for basic research and clinical diagnosis and treatment of this disease.

A Clinical Prediction Model to Distinguish Maturity-Onset Diabetes of the Young From Type 1 and Type 2 Diabetes in the Chinese Population.

OBJECTIVE: Genetic detection for the diagnosis of maturity-onset diabetes of the young (MODY) in China has low sensitivity and specificity. Better gene detection is urgently needed to distinguish testing subjects. We proposed to use numerous and weighted clinical traits as key indicators for reasonable genetic testing to predict the probability of MODY in the Chinese population. METHODS: We created a prediction model based on data from 306 patients, including 140 patients with MODY, 84 patients with type 1 diabetes (T1D), and 82 patients with type 2 diabetes (T2D). This model was evaluated using receiver operating characteristic curves. RESULTS: Compared with patients with T1D, patients with MODY had higher C-peptide levels and negative antibodies, and most patients with MODY had a family history of diabetes. Different from T2D, MODY was characterized by lower body mass index and younger diagnostic age. A clinical prediction model was established to define the comprehensive probability of MODY by a weighted consolidation of the most distinguishing features, and the model showed excellent discrimination (areas under the curve of 0.916 in MODY vs T1D and 0.942 in MODY vs T2D). Further, high-sensitivity C-reactive protein, glycated hemoglobin A1c, 2-h postprandial glucose, and triglyceride were used as indicators for glucokinase-MODY, while triglyceride, high-sensitivity C-reactive protein, and hepatocellular adenoma were used as indicators for hepatocyte nuclear factor 1-α MODY. CONCLUSION: We developed a practical prediction model that could predict the probability of MODY and provide information to identify glucokinase-MODY and hepatocyte nuclear factor 1-α MODY. These results provide an advanced and more reasonable process to identify the most appropriate patients for genetic testing.

Bone mesenchymal stem cells stimulation by magnetic nanoparticles and a static magnetic field: release of exosomal miR-1260a improves osteogenesis and angiogenesis.

BACKGROUND: The therapeutic potential of exosomes derived from stem cells has attracted increasing interest recently, because they can exert similar paracrine functions of stem cells and overcome the limitations of stem cells transplantation. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been confirmed to promote osteogenesis and angiogenesis. The magnetic nanoparticles (eg. Fe3O4, γ-Fe2O3) combined with a static magnetic field (SMF) has been commonly used to increase wound healing and bone regeneration. Hence, this study aims to evaluate whether exosomes derived from BMSCs preconditioned with a low dose of Fe3O4 nanoparticles with or without the SMF, exert superior pro-osteogenic and pro-angiogenic activities in bone regeneration and the underlying mechanisms involved. METHODS: Two novel types of exosomes derived from preconditioned BMSCs that fabricated by regulating the contents with the stimulation of magnetic nanoparticles and/or a SMF. Then, the new exosomes were isolated by ultracentrifugation and characterized. Afterwards, we conducted in vitro experiments in which we measured osteogenic differentiation, cell proliferation, cell migration, and tube formation, then established an in vivo critical-sized calvarial defect rat model. The miRNA expression profiles were compared among the exosomes to detect the potential mechanism of improving osteogenesis and angiogenesis. At last, the function of exosomal miRNA during bone regeneration was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro. RESULTS: 50 µg/mL Fe3O4 nanoparticles and a 100 mT SMF were chosen as the optimum magnetic conditions to fabricate two new exosomes, named BMSC-Fe3O4-Exos and BMSC-Fe3O4-SMF-Exos. They were both confirmed to enhance osteogenesis and angiogenesis in vitro and in vivo compared with BMSC-Exos, and BMSC-Fe3O4-SMF-Exos had the most marked effect. The promotion effect was found to be related to the highly riched miR-1260a in BMSC-Fe3O4-SMF-Exos. Furthermore, miR-1260a was verified to enhance osteogenesis and angiogenesis through inhibition of HDAC7 and COL4A2, respectively. CONCLUSION: These results suggest that low doses of Fe3O4 nanoparticles combined with a SMF trigger exosomes to exert enhanced osteogenesis and angiogenesis and that targeting of HDAC7 and COL4A2 by exosomal miR-1260a plays a crucial role in this process. This work could provide a new protocol to promote bone regeneration for tissue engineering in the future.

In Situ Oxygen Doping of Monolayer MoS2 for Novel Electronics.

In 2D semiconductors, doping offers an effective approach to modulate their optical and electronic properties. Here, an in situ doping of oxygen atoms in monolayer molybdenum disulfide (MoS2 ) is reported during the chemical vapor deposition process. Oxygen concentrations up to 20-25% can be reliable achieved in these doped monolayers, MoS2- x Ox . These oxygen dopants are in a form of substitution of sulfur atoms in the MoS2 lattice and can reduce the bandgap of intrinsic MoS2 without introducing in-gap states as confirmed by photoluminescence spectroscopy and scanning tunneling spectroscopy. Field effect transistors made of monolayer MoS2- x Ox show enhanced electrical performances, such as high field-effect mobility (≈100 cm2 V-1 s-1 ) and inverter gain, ultrahigh devices' on/off ratio (>109 ) and small subthreshold swing value (≈80 mV dec-1 ). This in situ oxygen doping technique holds great promise on developing advanced electronics based on 2D semiconductors.

Enhanced osteogenic differentiation of human bone-derived mesenchymal stem cells in 3-dimensional printed porous titanium scaffolds by static magnetic field through up-regulating Smad4.

The reconstruction of large bone defects remains a significant challenge for orthopedists. Three-dimensional-printed (3DP) scaffold is considered a promising repair material. Static magnetic field (SMF) treatment is an effective and noninvasive therapeutic method to improve bone regeneration. However, the osteogenic effect of SMF on human bone-derived mesenchymal stem cells (hBMSCs) in 3DP scaffolds, as well as its potential mechanism, are unclear. In this study, the osteogenic effect of SMF on hBMSCs in a 3DP scaffold was investigated in vitro and in vivo. In addition, the potential mechanism for promoting osteogenesis was investigated by proteomic analysis. The results showed that SMF promoted osteogenic differentiation of hBMSCs in vitro. A total of 185 differential proteins were identified under SMF conditions by proteomic analysis. The osteogenic effect might be associated with bone morphogenetic protein-Smad1/5/8-signaling pathway and increased transport of phosphorylated Smad1/5/8 and phosphorylated Smad2/3 to the nucleus by up-regulating Smad4 under SMF conditions. The in vivo experiment showed that bone regeneration and osseointegration was enhanced by SMF in the rat model of bone defect. In conclusion, moderate SMF was a safe and effective method for enhancing osteogenesis in 3DP scaffolds in vitro and in vivo.-He, Y., Yu, L., Liu, J., Li, Y., Wu, Y., Huang, Z., Wu, D., Wang, H., Wu, Z., Qiu, G. Enhanced osteogenic differentiation of human bone-derived mesenchymal stem cells in 3-dimensional printed porous titanium scaffolds by static magnetic field through up-regulating Smad4.

Long noncoding RNA LOXL1-AS1 regulates prostate cancer cell proliferation and cell cycle progression through miR-541-3p and CCND1.

Prostate cancer is one of the most frequent malignancies affecting men. Long non-coding RNAs (lncRNAs) are involved in the pathogenesis of prostate cancer. LncRNA LOXL1-AS1 participates in the pathogenesis of the exfoliation syndrome. However, the role of LOXL1-AS1 in cancer remains largely unknown. Here, we found that LOXL1-AS1 down-regulation inhibited prostate cancer cell proliferation and cell cycle progression. RNA sequencing analysis revealed that it regulates the expression of cell cycle-related genes. LOXL1-AS1 is predominantly distributed in the cytoplasm, where it interacts with miR-541-3p. In addition, miR-541-3p targets the cell cycle regulator CCND1 in prostate cancer cells. LOXL1-AS1 down-regulation inhibits the expression of CCND1 and cell cycle progression, whereas these effects are abolished upon miR-541-3p suppression. In summary, our study revealed that LOXL1-AS1 regulates prostate cancer cell proliferation and cell cycle progression through miR-541-3p and CCND1. Modulation of their levels may be used to treat prostate cancer.

Association between the CYP1B1 polymorphisms and risk of cancer: a meta-analysis.

The previous, published data on the association between CYP1B1 polymorphisms and cancer risk remained controversial. To derive a more precise estimation of the association between the CYP1B1 polymorphisms and cancer risk, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP1B1 Leu432Val, Asn453Ser, Arg48Gly, and Ala119Ser polymorphisms. For Asn453Ser and Arg48Gly polymorphisms, significantly decreased endometrial cancer was observed among Caucasians. For Ala119Ser polymorphism, we found that individuals with the minor variant genotypes had a high risk of prostate cancer. For Leu432Val polymorphism, we found that individuals with the minor variant genotypes had a higher risk of endometrial cancer and lung cancer and had a lower risk of ovarian cancer. In summary, this meta-analysis suggests that Leu432Val polymorphism is associated with ovarian cancer, lung cancer, and endometrial cancer risk; Asn453Ser and Arg48Gly polymorphisms are associated with endometrial cancer risk among Caucasians, Ala119Ser polymorphism is associated with prostate cancer risk, and Ala119Ser polymorphism is associated with breast cancer risk in Caucasians. In addition, our work also points out the importance of new studies for Ala119Ser polymorphism in endometrial cancer, because high heterogeneity was observed (I (2) > 75 %).

Nitinol stents loaded with a high dose of antitumor 5-fluorouracil or paclitaxel: esophageal tissue responses in a porcine model.

BACKGROUND: A poor prognosis associated with esophageal cancer leads to surgical resection not suitable for most patients. Nitinol stents loaded with 50% 5-fluorouracil (5-FU) or paclitaxel (PTX), functioning both as a stent and local chemotherapy, could provide a new therapy modality for these patients. OBJECTIVE: To investigate esophageal tissue responses to nitinol stents loaded with 50% 5-FU or PTX implanted in the esophagus of healthy pigs. DESIGN: Twenty-three healthy Bama mini-pigs were randomly divided into 4 groups for stent implantation: group A (PTX stent, n = 13), group B (5-FU stent, n = 8), group C (blank film-covered stent, n = 1), and group D (bare stent, n = 1). Tissue responses were observed by endoscopy or pathologic analyses, and 5-FU or PTX concentrations were measured in the esophagus at the stent implantation site at different time points. SETTING: Animal laboratory. INTERVENTIONS: Endoscopic placement of esophagus stent. MAIN OUTCOME MEASUREMENTS: Endoscopic examination, histology, and drug concentration analysis. RESULTS: In general, the esophageal tissue responses varied according to different parts of 5-FU or PTX stent (middle part [drug-containing part] and bare ends [drug-free part]). Severe tissue responses at the bare ends of the stent included inflammation, ulceration, and granulation. However, the tissue responses were greatly reduced in the middle part of the stent. The drug concentrations in the esophagus that had contact with the 5-FU stent or PTX stent were very high, especially for the first period after implantation, which did not cause obvious tissue damage. LIMITATION: Some subjects had incomplete follow-up because of unexpected deaths and stent migration. CONCLUSION: The nitinol stents loaded with 50% 5-FU or PTX did not cause severe esophageal tissue responses, although there was a large concentration of the drug in these tissues.

SGLT2 inhibitor improves kidney function and morphology by regulating renal metabolism in mice with diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease. AIM: To investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism. METHODS: DKD model was established using high-fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low-dose of canagliflozin, 4) high-dose of canagliflozin and 5) ß-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed. RESULTS: Canagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. ß-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice. CONCLUSION: Canagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.

Metabolomics analysis of serum and urine in type 1 diabetes patients with different time in range derived from continuous glucose monitoring.

BACKGROUND: Time in range (TIR), as an important glycemic variability (GV) index, is clearly associated with disease complications in type 1 diabetes (T1D). Metabolic dysregulation is also involved in the risks of T1D complications. However, the relationship between metabolites and TIR remains poorly understood. We used metabolomics to investigate metabolic profile changes in T1D patients with different TIR. METHODS: This study included 85 T1D patients and 81 healthy controls. GV indices, including TIR, were collected from continuous glucose monitoring system. The patients were compared within two subgroups: TIR-L (TIR < 50%, n = 21) and TIR-H (TIR > 70%, n = 14). To screen for differentially abundant metabolites and metabolic pathways, serum and urine samples were obtained for untargeted metabolomics by ultra-performance liquid chromatography‒mass spectrometry. Correlation analysis was conducted with GV metrics and screened biomarkers. RESULTS: Metabolites were significantly altered in T1D and subgroups. Compared with healthy controls, T1D patients had higher serum levels of 5-hydroxy-L-tryptophan, 5-methoxyindoleacetate, 4-(2-aminophenyl)-2,4-dioxobutanoate, and 4-pyridoxic acid and higher urine levels of thromboxane B3 but lower urine levels of hypoxanthine. Compared with TIR-H group, The TIR-L subgroup had lower serum levels of 5-hydroxy-L-tryptophan and mevalonolactone and lower urine levels of thromboxane B3 and phenylbutyrylglutamine. Dysregulation of pathways, such as tryptophan, vitamin B6 and purine metabolism, may be involved in the mechanism of diabetic complications related to glycemic homeostasis. Mevalonolactone, hypoxanthine and phenylbutyrylglutamine showed close correlation with TIR. CONCLUSIONS: We identified altered metabolic profiles in T1D individuals with different TIR. These findings provide new insights and merit further exploration of the underlying molecular pathways relating to diabetic complications.

Integration of proteomics and metabolomics reveals energy and metabolic alterations induced by glucokinase (GCK) partial inactivation in hepatocytes.

AIMS: Glucokinase (GCK) acts as the glucose sensor in maintaining glucose homeostasis. The inactivating mutation of the GCK gene leads to glucokinase-maturity onset diabetes of the young (GCK-MODY). This study aims to gain further insights into the molecular alterations triggered by GCK partial inactivation in hepatocytes, potentially underlying the favorable prognosis of GCK-MODY. MAIN METHODS: A GCK knockdown HepG2 cell model was established, and the integration of proteomics and metabolomics was used to gain a comprehensive understanding of the molecular pathway changes caused by GCK inactivation in the liver. KEY FINDINGS: Proteomic analysis identified 257 differential proteins. KEGG pathway enrichment analysis showed that protein expression changes in the GCK knockdown group were significantly enriched in central carbon metabolism, the TCA cycle, amino acid metabolism and the oxidative phosphorylation pathway. Among them, enzymes in the TCA cycle (PC, IDH2, SDH) were significantly downregulated in GCK-knockdown group. Targeted metabolomics revealed that in the GCK knockdown hepatocytes, TCA cycle intermediates were significantly decreased, including pyruvate, oxaloacetate, citrate and succinic acid, and three metabolites increased including glycine, betaine and homocysteine. These metabolic alterations in turn reduced the accumulation of reactive oxygen species in GCK knockdown hepatocytes. Correlation analysis indicated that TCA cycle metabolites were positively correlated with proteins involved in the TCA cycle, carbon metabolism, glycolysis, Ras signaling, fibrosis and inflammation. SIGNIFICANCE: In conclusion, GCK knockdown reduced TCA cycle flux and oxidative stress in hepatocytes by influencing the levels of key transcription factors and enzymes, providing a comprehensive understanding of the effects of GCK partial inactivation on liver metabolism and molecular mechanisms.