Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.

Influence of pancreaticoduodenectomy for periampullary carcinoma on intestinal microbiome and metabolites.

Recent growing evidence suggests a role for intestinal microbiome and metabolites in patients' postoperative recovery. Therefore, there is a need to gain insight into the impact of pancreaticoduodenectomy for periampullary carcinoma on microbiome and metabolites and the potential impact of their changes on patients' condition. Based on 16S rDNA gene sequencing and untargeted metabolomic analysis, we found that the diversity and abundance of intestinal microbiome were significantly higher in patients preoperatively than postoperatively, and the level of intestinal probiotics was significantly lower after surgery compared with preoperatively. In addition, the choline metabolism level was increased and the amino acid metabolism level was decreased after surgery. A total of 53 differential microbiome and 52 differential metabolites were detected, and the differential metabolites were mapped to approximately 60 different KEGG metabolic pathways, of which 13 KEGG metabolic pathways had a differential metabolite number greater than 5. A total of 88 colony-metabolite pairs with significant positive correlation and 69 colony-metabolite pairs with significant negative correlation were identified. Our results reveal alterations in intestinal microbiome after pancreaticoduodenectomy, suggesting its association with postoperative complications. Moreover, the elevated choline metabolism level in postoperative patients may predict their poorer prognosis. At the same time, the decreased abundance of such probiotic bacteria as Prevotella spp. in the postoperative intestine of patients will affect the amino acid metabolism of the organism to some extent.

Sertraline-Induced Acute Pancreatitis: A Case Report and Literature Review.

Objective: Acute pancreatitis (AP) is a process of acute inflammation and cell damage of the pancreas. Gallstones and alcohol abuse are the most common cause for AP. Drug-induced pancreatitis (DIP), accounting for less than 3% of the AP, has become increasingly recognized as an additional and vitally important etiology of acute pancreatitis. Sertraline is an antidepressant of the selective serotonin reuptake inhibitor (SSRI)class that has a range of side effects even when used at the recommended dose. A recognized but rare association in teenagers is acute pancreatitis. The report is of a 15-year-old male teenager with a history of depression who developed acute pancreatitis following self-overdose of his sertraline prescription. Case Report: A 15-year-old teenager with an overdose of sertraline, which was the only medication he took, presented abdominal pain, nausea, and vomiting. The common causes of alcohol consumption, gallstones, biliary duct obstruction, malignancy, trauma, hypertriglyceridemia, and hypercalcemia were eliminated. The increased level of amylase and parenchymal edema of the pancreas revealed in computed tomography supported the diagnosis of acute pancreatitis. After discontinuation of the drug and conventional acute pancreatitis treatment, he recovered evenly. Conclusion: With the increasing use of antidepressant medications in patients of teenagers, this report is a reminder that clinicians should be aware of the association between SSRIs such as sertraline, particularly in cases of overdose, and the development of acute pancreatitis.

Small-molecule agonist AdipoRon alleviates diabetic retinopathy through the AdipoR1/AMPK/EGR4 pathway.

BACKGROUND: Diabetes mellitus (DM) is a progressive disease that involves multiple organs due to increased blood glucose, and diabetic retinopathy (DR) is the main complication of DM in the eyes and causes irreversible vision loss. In the pathogenesis of diabetic vascular disease, oxidative stress caused by hyperglycemia plays an important role in Müller cell impairment. In recent years, AdipoRon, an adiponectin analog that demonstrated important physiological functions in obesity, diabetes, inflammation, and cardiovascular diseases, demonstrated cellular protection from apoptosis and reduced inflammatory damage through a receptor-dependent mechanism. Here, we investigated how AdipoRon reduced oxidative stress and apoptosis in Müller glia in a high glucose environment. RESULTS: By binding to adiponectin receptor 1 on Müller glia, AdipoRon activated 5' adenosine monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase phosphorylation downstream, thereby alleviating oxidative stress and eventual apoptosis of cells and tissues. Transcriptome sequencing revealed that AdipoRon promoted the synthesis and expression of early growth response factor 4 (EGR4) and inhibited the cellular protective effects of AdipoRon in a high-glucose environment by reducing the expression of EGR4. This indicated that AdipoRon played a protective role through the EGR4 and classical AMPK pathways. CONCLUSIONS: This provides a new target for the early treatment of DR.

SYVN1 Promotes STAT3 Protein Ubiquitination and Exerts Antiangiogenesis Effects in Retinopathy of Prematurity Development.

Purpose: SYVN1, a gene involved in endoplasmic reticulum-associated degradation, has been found to exert a protective effect by inhibiting inflammation in retinopathy. This study aimed to clarify whether SYVN1 is involved in the pathogenesis of retinopathy of prematurity (ROP) and its potential as a candidate for target therapy. Methods: Human retinal microvascular endothelial cells (hRMECs) and a mouse model of oxygen-induced retinopathy (OIR) were used to reveal the retinopathy development-associated protein expression and molecular mechanism. An adenovirus overexpressing SYVN1 or vehicle control was injected intravitreally at postnatal day 12 (P12), and the neovascular lesions were evaluated in retinal flatmounts with immunofluorescence staining, and hematoxylin and eosin staining at P17. Visual function was assessed by using electroretinogram (ERG). Results: Endogenous SYVN1 expression dramatically decreased in hRMECs under hypoxia and in ROP mouse retinas. SYVN1 regulated the signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor (VEGF) axis. SYVN1 overexpression promoted ubiquitination and degradation of STAT3, decreased the levels of phospho-STAT3, secretion of VEGF, and formation of neovascularization in hRMECs, which could be rescued by STAT3 activator treatment. In addition, SYVN1 overexpression prevented neovascularization and extended physiologic retinal vascular development in the retinal tissues of OIR mice without affecting retinal function. Conclusions: SYVN1 has a protective effect against OIR, and the molecular mechanisms are partly through SYVN1-mediated ubiquitination of STAT3 and the subsequent downregulation of VEGF. These findings strongly support our assumption that SYVN1 confers ROP resistance and may be a potentially novel pharmaceutical target against proliferative retinopathy.

Integration of Vitreous Lipidomics and Metabolomics for Comprehensive Understanding of the Pathogenesis of Proliferative Diabetic Retinopathy.

As a vision-threatening complication of diabetes mellitus (DM), proliferative diabetic retinopathy (PDR) is associated with sustained metabolic disorders. Herein, we collected the vitreous cavity fluid of 49 patients with PDR and 23 control subjects without DM for metabolomics and lipidomics analyses. Multivariate statistical methods were performed to explore relationships between samples. For each group of metabolites, gene set variation analysis scores were generated, and we constructed a lipid network by using weighted gene co-expression network analysis. The association between lipid co-expression modules and metabolite set scores was investigated using the two-way orthogonal partial least squares (O2PLS) model. A total of 390 lipids and 314 metabolites were identified. Multivariate statistical analysis revealed significant vitreous metabolic and lipid differences between PDR and controls. Pathway analysis showed that 8 metabolic processes might be associated with the development of PDR, and 14 lipid species were found to be altered in PDR patients. Combining metabolomics and lipidomics, we identified fatty acid desaturase 2 (FADS2) as an important potential contributor to the pathogenesis of PDR. Collectively, this study integrates vitreous metabolomics and lipidomics to comprehensively unravel metabolic dysregulation and identifies genetic variants associated with altered lipid species in the mechanistic pathways for PDR.

Novel insights into the mechanisms of hard exudate in diabetic retinopathy: Findings of serum lipidomic and metabolomics profiling.

Objective: Retinal hard exudates (HEs) result from lipoproteins leaking from capillaries into extracellular retinal space, and are related to decreased visual acuity in diabetic retinopathy (DR). This study aims to identify differential serum lipids and metabolites associated with HEs. Materials and methods: A cross-sectional study was conducted Jul 2017 âˆ¼ Mar 2021. We assessed the amount of HEs using standard ETDRS photographs for comparison. HEs severity was rated as "no or questionable", "moderate" or "severe". Serum samples were processed via high coverage pseudotargeted lipidomics analysis, and untargeted liquid chromatography coupled with time-of-flight mass spectrometry for metabolomics study, respectively. Weighted gene co-expression network analyses, partial least squares-discriminant analysis, and multi-receiver operating characteristic analysis were applied. Results: A total of 167 patients were included. Discovery group: 116 eyes (116 patients). Validation group: 51 eyes (51 patients). 888 lipids were detected and divided into 18 modules (MEs), ME1 âˆ¼ ME18. Lipids in ME1 significantly increased in patients with HEs in DR (NPDR and PDR combined), NPDR, and PDR, respectively. ME1 enriched to triglycerides (29%), ceramides (17%), and N-acylethanolamines (15%). A combined model of 20 lipids was the best to discriminate HEs, area under curve = 0.804, 95% confidence interval = 0.674-0.916. For metabolomics analysis, 19 metabolites and 13 pathways associated with HEs were identified. Taurine and hypotaurine metabolism, cysteine and methionine metabolism were closely related to HEs (P < 0.01). Conclusions: The lipids and metabolites identified may serve as prediction biomarkers in the early stage of HEs in DR.

Serum Ang-1/Ang-2 ratio may be a promising biomarker for evaluating severity of diabetic retinopathy.

PURPOSE: To investigate the predictive role of serum angiopoietin-1 and angiopoietin-2 (Ang-1/Ang-2) in evaluating the severity of diabetic retinopathy (DR). METHODS: A total of 101 outpatients with type 2 diabetes mellitus (T2DM) were recruited and were further divided into the following five groups: T2DM without DR (non-DR), mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR and proliferative DR (PDR) in accordance with the International Clinical Diabetic Retinopathy Guidelines. Furthermore, 101 serum samples were included in the further analysis using enzyme-linked immunosorbent assays. A receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of each index. RESULTS: The expression of Ang-1 in the PDR group was significantly lower than that in the non-DR group, while Ang-2 showed an opposite upward trend (p < 0.05). The Ang-1/Ang-2 ratio of the non-DR group was significantly lower than that of the moderate NPDR, severe NPDR and PDR (p < 0.05, p < 0.01 and p < 0.01, respectively). Differences in the Ang-1/Ang-2 ratio were observed earlier than those in the individual Ang-1 and Ang-2 measurements. The maximal Youden index was 0.512 with a calculated area under the curve (AUC) value of 0.734 (p < 0.01). CONCLUSIONS: The Ang-1/Ang-2 ratio was helpful in assessing the severity of DR and may provide potential clinical benefits as a biomarker and early warning signs for DR diagnosis.

Metabolomics study of treatment response to conbercept of patients with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

Background: Neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) are major causes of blindness in aged people. 30% of the patients show unsatisfactory response to anti-vascular endothelial growth factor (anti-VEGF) drugs. This study aims to investigate the relationship between serum metabolome and treatment response to anti-VEGF therapy. Methods: A prospective longitudinal study was conducted between March 2017 and April 2019 in 13 clinical sites in China. The discovery group were enrolled from Shanghai General Hospital. The validation group consisted of patients from the other 12 sites. Participants received at least one intravitreal injection of 0.5 mg anti-VEGF drug, conbercept, and were divided into two groups - responders and non-responders. Serum samples of both groups were processed for UHPLC-MS/MS analysis. We constructed principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models to investigate the metabolic differences between two groups using SIMCA-P. Area under curve (AUC) was calculated to screen the biomarkers to predict treatment response. Metabolites sub-classes and enriched pathways were obtained using MetaboAnalyst5.0. Results: 219 eyes from 219 patients (nAMD = 126; PCV = 93) were enrolled. A total of 248 metabolites were detected. PCA and PLS-DA models of the discovery group demonstrated that the metabolic profiles of responders and non-responders clearly differed. Eighty-five differential metabolites were identified, including sub-classes of diacylglycerophosphocholines, lysophosphatidylcholine (LPC), fatty acids, phosphocholine, etc. Responders and non-responders differed most significantly in metabolism of LPC (p = 7.16 × 10^-19) and diacylglycerophosphocholine (p = 6.96 × 10^-17). LPC 18:0 exhibited the highest AUC, which is 0.896 with 95% confidence internal between 0.833 and 0.949, to discriminate responders. The predictive accuracy of LPC 18:0 was 72.4% in the validation group. Conclusions: This study suggests that differential metabolites may be useful for guiding treatment options for nAMD and PCV. Metabolism of LPC and diacylglycerophosphocholine were found to affect response to conbercept treatment. LPC 18:0 was a potential biomarker to discriminate responders from non-responders.

SGLT2 inhibitor-empagliflozin treatment ameliorates diabetic retinopathy manifestations and exerts protective effects associated with augmenting branched chain amino acids catabolism and transportation in db/db mice.

Empagliflozin (EMPA) is the first sodium-glucose co-transporter 2 inhibitor to significantly reduce cardiovascular and kidney complications in type 2 diabetes mellitus. Given this, we speculate that EMPA may have the potential to intervene in diabetic retinopathy (DR), which is another diabetes-specific microvascular complication. Db/db mice were treated with EMPA for different periods to observe the retinas and related mechanisms. EMPA effectively balanced body weight and blood glucose levels, mitigated ocular edema and microaneurysm in db/db mice. EMPA significantly inhibited oxidative stress, apoptosis and recovered tight junction in diabetic retinas. MS/MS analyses showed that EMPA suppressed aberrant branched-chain amino acid (BCAAs) accumulation in db/db retinas, which led to the inhibition of the mammalian target of rapamycin activation, downregulation of inflammation, and angiogenic factors, including TNF-ɑ, IL-6, VCAM-1, and VEGF induced by diabetes. Furthermore, branched-chain α-keto acids (BCKAs), which are catabolites of BCAAs, were increased in diabetic retinas and decreased with EMPA application. Moreover, branched-chain ketoacid dehydrogenase kinase (BCKDK) was enhanced, BCKDHA and BCKDHB were decreased in diabetic retinas. This could be reversed by EMPA treatment, thus promoting BCAAs catabolism to decrease BCAAs and BCKAs accumulation in diabetic retinas. The high levels of BCAAs in the plasma and enhanced L-type amino acid transporter 1 (LAT1) were responsible for the high levels of BCAAs in diabetic retinas, which could be inhibited by EMPA. Overall, EMPA could ameliorate DR manifestations. The normalization of BCAAs catabolism and intake may play a role in this process. This study supports EMPA as a protective drug against DR.

High-Definition Survey of Architectural Heritage Fusing Multisensors-The Case of Beamless Hall at Linggu Temple in Nanjing, China.

Following the development of digital measurement technology in recent years, the information contained in the measurement outcomes have become increasingly rich. However, the traditional graphical representation method based on vector graph needs to be updated. In this study, we use the Beamless Hall of Linggu Temple as an example. Measurements are conducted by using digital techniques, including three-dimensional (3D) laser scanning, close-range photogrammetry, and infrared thermal imaging. The pseudocolours that express spatial information and moisture distribution are calculated and generated through point clouds, which are used to express the land subsidence, wall deformation, moisture distribution, and other effects of the Beamless Hall. Furthermore, combining it with two-dimensional (2D) graphical representation, such as the plan, elevation, and section, damage-related information can be expressed intuitively and efficiently. This method can combine the advantages of graphics and images to provide a comprehensive and intuitive representation of the digital measurement results of brick architecture heritage. It can also provide a reference for surveying similar monuments and buildings of our architectural heritage.

Plasma and Vitreous Metabolomics Profiling of Proliferative Diabetic Retinopathy.

Purpose: To determine the differences of metabolites and metabolic pathways between patients with proliferative diabetic retinopathy (PDR) and without diabetes (nondiabetic controls) in plasma and vitreous, respectively, and to characterize the relationship between plasma and vitreous metabolic profiles. Methods: Liquid chromatography/tandem mass spectrometry technology was performed to distinct metabolite profiles of plasma and vitreous. A total of 139 plasma samples from 88 patients with PDR and 51 nondiabetic controls, as well as 74 vitreous samples from 51 patients with PDR and 23 nondiabetic controls, were screened. Pathway analysis was performed using MetaboAnalyst 5.0. Pearson correlation analysis was used to investigate the correlation of metabolites in vitreous and plasma. Results: After adjusting for age, fasting blood glucose, and urea, in vitreous metabolomes, a total of 76 features distinguished patients with PDR from controls. Fifteen differential metabolites were found in plasma metabolites. Pantothenate and CoA biosynthesis was the common metabolic pathway altered in both plasma and vitreous. Aromatic amino acid metabolism pathways were dysregulated in vitreous of PDR. For four metabolic features, there were positive correlations between vitreous and plasma. Conclusions: Despite great differences between the metabolic profiles of plasma and vitreous in PDR cases, there are also similarities in the change of metabolites and metabolic pathways. Exploring the relationship of metabolomics between vitreous and plasma may help provide new understanding of the mechanism of PDR.

Research Progress of High-Temperature Resistant Functional Gel Materials and Their Application in Oil and Gas Drilling.

With the development of oil exploration, the number of complex situations encountered in the drilling process is continuously increasing. During the operation of large displacement and horizontal wells, the safe density window of drilling fluid is narrow in complex formations and the lost circulation problem is becoming increasingly prominent. This can easily cause the drilling fluid to enter the formation from inside the well through lost circulation channels, which will prolong the drilling cycle, increase drilling costs, affect geological logging, and could cause a series of malignant accidents (such as blowout, sticking of a drilling tool, borehole collapse, and well abandoned). According to the severity, common lost circulation can be classified into three types: fractured lost circulation, karst cave lost circulation, and permeability lost circulation. Currently, researchers are developing different types of lost circulation materials (LCMs) for various lost circulation situations. Compared with conventional lost circulation control methods, the polymer gel lost circulation control technique applies a three-dimensional cage-like viscoelastic body formed via the crosslinking reaction of polymer gels. These materials have strong deformability and can enter fractures and holes through extrusion and deformation without being restricted by lost circulation channels. They then settle in the lost circulation formation and form a plugging layer through a curing reaction or swelling effect. Among the polymer gel LCMs, high-temperature resistant polymer gels can either be used alone or in combination with other LCMs, bringing the advantages of adjustable gelation time, strong lost circulation control ability, and strong filtration ability of the plugging slurry. Moreover, they are suitable for the lost circulation control of microporous leaky layer and have limited influence on the performance of drilling fluids. Therefore, the high-temperature resistant polymer gel lost circulation control technique is increasingly becoming a hot spot in the research of LCMs nowadays. This paper summarizes the research progress into high-temperature resistant functional gels for profile control and water shutoff, lost circulation prevention and control, and hydraulic fracturing. Furthermore, the current application status of high-temperature resistant gels and high-temperature resistant gel temporary plugging agents is demonstrated, followed by a detailed overview of the gel-breaking methods. Overall, this research lays the theoretical foundation for the application and promotion of high-temperature resistant gels.

Pathogenesis Study Based on High-Throughput Single-Cell Sequencing Analysis Reveals Novel Transcriptional Landscape and Heterogeneity of Retinal Cells in Type 2 Diabetic Mice.

Diabetic retinopathy (DR) is the leading cause of acquired blindness in middle-aged people. The complex pathology of DR is difficult to dissect, given the convoluted cytoarchitecture of the retina. Here, we performed single-cell RNA sequencing (scRNA-seq) of retina from a model of type 2 diabetes, induced in leptin receptor-deficient (db/db) and control db/m mice, with the aim of elucidating the factors mediating the pathogenesis of DR. We identified 11 cell types and determined cell-type-specific expression of DR-associated loci via genome-wide association study (GWAS)-based enrichment analysis. DR also impacted cell-type-specific genes and altered cell-cell communication. Based on the scRNA-seq results, retinaldehyde-binding protein 1 (RLBP1) was investigated as a promising therapeutic target for DR. Retinal RLBP1 expression was decreased in diabetes, and its overexpression in Müller glia mitigated DR-associated neurovascular degeneration. These data provide a detailed analysis of the retina under diabetic and normal conditions, revealing new insights into pathogenic factors that may be targeted to treat DR and related dysfunctions.

The Anti-Inflammatory Effect of KS23, A Novel Peptide Derived From Globular Adiponectin, on Endotoxin-Induced Uveitis in Rats.

Purpose: Adiponectin has been shown to exert potent anti-inflammatory activities in a range of systemic inflammatory diseases. This study aimed to investigate the potential therapeutic effects of KS23, a globular adiponectin-derived peptide, on endotoxin-induced uveitis (EIU) in rats and lipopolysaccharide (LPS)-stimulated mouse macrophage-like RAW 264.7 cells. Methods: EIU was induced in Lewis rats by subcutaneous injection of LPS into a single footpad. KS23 or phosphate-buffered saline (PBS) was administered immediately after LPS induction via intravitreal injection. Twenty-four hours later, clinical and histopathological scores were evaluated, and the aqueous humor (AqH) was collected to determine the infiltrating cells, protein concentration, and levels of inflammatory cytokines. In vitro, cultured RAW 264.7 cells were stimulated with LPS in the presence or absence of KS23, inflammatory cytokine levels in the supernatant, nuclear translocation of nuclear factor kappa B (NF-κB) subunit p65, and the expression of NF-kB signaling pathway components were analyzed. Results: KS23 treatment significantly ameliorated the clinical and histopathological scores of EIU rats and reduced the levels of infiltration cells, protein, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the aqueous humor. Consistently, KS23 decreased the expression of TNF-α and IL-6 in the supernatant of LPS-stimulated RAW 264.7 cells and inhibited the LPS-induced nuclear translocation of NF-κB p65 and the phosphorylation of IKKα/ß/IκBα/NF-κB. Conclusion: The in vivo and in vitro results demonstrated the anti-inflammatory effects of the peptide KS23 and suggested that KS23 is a compelling, novel therapeutic candidate for the treatment of ocular inflammation.

Metabolomic profile of diabetic retinopathy: a GC-TOFMS-based approach using vitreous and aqueous humor.

AIM: To identify the potential metabolite markers in diabetic retinopathy (DR) by using gas chromatography coupled with time-of-flight mass spectrometry (GC-TOFMS). METHODS: GC-TOFMS spectra were acquired from vitreous and aqueous humor (AH) samples of patients with DR and non-diabetic participants. Comparative analysis was used to elucidate the distinct metabolites of DR. Metabolic pathway was employed to explicate the metabolic reprogramming pathways involved in DR. Logistic regression and receiver-operating characteristic analyses were carried out to select and validate the biomarker metabolites and establish a therapeutic model. RESULTS: Comparative analysis showed a clear separation between disease and control groups. Eight differentiating metabolites from AH and 15 differentiating metabolites from vitreous were highlighted. Out of these 23 metabolites, 11 novel metabolites have not been detected previously. Pathway analysis identified nine pathways (three in AH and six in vitreous) as the major disturbed pathways associated with DR. The abnormal of gluconeogenesis, ascorbate-aldarate metabolism, valine-leucine-isoleucine biosynthesis, and arginine-proline metabolism might weigh the most in the development of DR. The AUC of the logistic regression model established by D-2,3-Dihydroxypropanoic acid, isocitric acid, fructose 6-phosphate, and L-Lactic acid in AH was 0.965. The AUC established by pyroglutamic acid and pyruvic acid in vitreous was 0.951. CONCLUSIONS: These findings have expanded our understanding of identified metabolites and revealed for the first time some novel metabolites in DR. These results may provide useful information to explore the mechanism and may eventually allow the development of metabolic biomarkers for prognosis and novel therapeutic strategies for the management of DR.

Serum Metabolomics Reveals Personalized Metabolic Patterns for Macular Neovascular Disease Patient Stratification.

The macular neovascular disease is a group disorder with complex pathogenesis of neovascularization for vision impairment and irreversible blindness, posing great challenges to precise diagnosis and management. We prospectively recruited participants with age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), and pathological myopia (PM) and compared with cataract patients without fundus diseases as a control group. The serum metabolome was profiled by gas chromatography coupled with time-of-flight mass spectrometry (GC-TOFMS) analysis. Multivariate statistical methods as well as data mining were performed for interpretation of macular neovascularization. A total of 446 participants with macular neovascularization and 138 cataract subjects as the control group were enrolled in this study. By employing GC-TOFMS, 131 metabolites were identified and 33 differentiating metabolites were highlighted in patients with macular neovascularization. For differential diagnosis, three panels of specific metabolomics-based biomarkers provided areas under the curve of 0.967, 0.938, and 0.877 in the discovery phase (n = 328) and predictive values of 87.3%, 79%, and 85.7% in the test phase (n = 256). Personalized pathway dysregulation scores measurement using Lilikoi package in R language revealed the pentose phosphate pathway and mitochondrial electron transport chain as the most important pathways in AMD; purine metabolism and glycolysis were identified as the major disturbed pathways in PCV, while the altered thiamine metabolism and purine metabolism may contribute to PM phenotypes. Serum metabolomics are powerful for characterizing metabolic disturbances of the macular neovascular disease. Differences in metabolic pathways may reflect an underlying macular neovascular disease and serve as therapeutic targets for macular neovascular treatment.

Metabolomic Profile of Posner-Schlossman Syndrome: A Gas Chromatography Time-of-Flight Mass Spectrometry-Based Approach Using Aqueous Humor.

The Posner-Schlossman syndrome (PSS) is a disease with clinically recurrent unilateral anterior uveitis with markedly elevated intraocular pressure (IOP) and subsequent progression to optic neuropathy. Retrospective studies have reported increased annual incidence of PSS, especially in China. While currently, the clinical management of PSS is still challenging. Metabolomics is considered to be a sensitive approach for the development of novel targeted therapeutics because of its direct elucidation of pathophysiological mechanisms. Therefore, we adopted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) technology-based non-targeted metabolomics approach to measure comprehensive metabolic profiles of aqueous humor (AH) samples obtained from patients with PSS, with an aim to demonstrate the underlying pathophysiology, identify potential biomarkers specific to PSS, and develop effective treatment strategies. A comparative analysis was used to indicate the distinct metabolites of PSS. Pathway analysis was conducted using MetaboAnalyst 4.0 to explore the metabolic reprogramming pathways involved in PSS. Logistic regression and receiver-operating characteristic (ROC) analyses were employed to evaluate the diagnostic capability of selected metabolites. Comparative analysis revealed a clear separation between PSS and control groups. Fourteen novel differentiating metabolites from AH samples obtained from patients with PSS were highlighted. Pathway analysis identified 11 carbohydrate, amino acid metabolism and energy metabolism pathways as the major disturbed pathways associated with PSS. The abnormal lysine degradation metabolism, valine-leucine-isoleucine biosynthesis, and citrate circle were considered to weigh the most in the development of PSS. The ROC analysis implied that the combination of glycine and homogentisic acid could serve as potential biomarkers for the discrimination of control and PSS groups. In conclusion, these results revealed for the first time the identity of important metabolites and pathways contributing to the development/progression of PSS, enabled the better understanding of the mechanism of PSS, and might lead to the development of metabolic biomarkers and novel therapeutic strategies to restrict the development/progression of PSS.

BCAA Catabolic Defect Alters Glucose Metabolism in Lean Mice.

Recent studies show branched-chain amino acid (BCAA) catabolic pathway is defective in obese animals and humans, contributing to the pathogenesis of insulin resistance and diabetes. However, in the context of obesity, various processes including the dysfunctional lipid metabolism can affect insulin sensitivity and glycemic regulation. It remains unclear how BCAA catabolic defect may exert direct impacts on glucose metabolism without the disturbance of obesity. The current study characterized the glucose metabolism in lean mice in which the genetic deletion of PP2Cm leads to moderate BCAA catabolic defect. Interestingly, compared to the wildtype control, lean PP2Cm deficient mice showed enhanced insulin sensitivity and glucose tolerance, lower body weight, and the preference for carbohydrate over lipids utilization. Metabolomics profiling of plasma and tissues revealed significantly different metabolic patterns in the PP2Cm deficient mice, featured by the marked alterations in glucose metabolic processes, including gluconeogenesis/glycolysis, glycogen metabolism, and tricarboxylic acid cycle. The metabolic changes of glucose were predominantly observed in liver but not skeletal muscle or white adipose tissue. The elevated branched-chain keto acids (BCKAs) resulted from the BCAA catabolic defect may play a critical role in regulating the expression of key regulators of glucose metabolic processes and the activity of respiratory Complex II/succinate dehydrogenase in TCA cycle. Together, these results show BCAA catabolic defect significantly alters glucose metabolism in lean mice with some impacts different or even opposite from those in obese mice, highlighting the critical role of BCAA catabolism in glycemic regulation and the complex interplay between macronutrients in lean and obese animals.

Mass spectrometry-based metabolomics for irritable bowel syndrome biomarkers.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder without obvious structural abnormalities or consistent associated biomarkers, making its diagnosis difficult. In the present study, we used a urine-based metabolomics approach to identify IBS biomarkers. METHODS: We used an ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) on urine samples from patients suffering from IBS and healthy controls. Data were coupled for multivariate statistical analysis methods. RESULTS: We selected 30 differential metabolites associated with IBS and found steroid hormone biosynthesis and histidine metabolism alterations in patients with IBS that may be involved in the pathogenesis of the disease. In addition, we identified a panel of five metabolite markers composed of cortisone, citric acid, tiglylcarnitine, N6,-N6,-N6-trimethyl-L-lysine and L-histidine that could be used to discriminate between patients and healthy controls and may be appropriate as IBS diagnosis biomarkers. CONCLUSION: Our findings indicate that metabolomics combined with pattern recognition can be useful to identify disease diagnostic IBS markers. CLINICAL TRIAL REGISTRATION: ChiCTR1800020072.