Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity.

Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.

Effects of Timing and Types of Protein Supplementation on Improving Muscle Mass, Strength, and Physical Performance in Adults Undergoing Resistance Training: A Network Meta-Analysis.

Precise protein supplementation strategies for muscle improvement are still lacking. The timing or type of protein supplementation has been debated as a window of opportunity to improve muscle mass, strength, and physical performance. We conducted a network meta-analysis of randomized controlled trials with protein supplements and resistance training. PubMed, Web of Science, Cochrane Library, and SPORTDiscus databases were searched until May 1, 2023. We included 116 eligible trials with 4,711 participants that reported on 11 timing and 14 types of protein supplementation. Compared with placebo, protein supplementation after exercise (mean difference [MD]: 0.54 kg [95% confidence intervals 0.10, 0.99] for fat-free mass, MD: 0.34 kg [95% confidence intervals 0.10, 0.58] for skeletal muscle mass) and at night (MD: 2.85 kg [0.49, 5.22] for handgrip strength, MD: 12.12 kg [3.26, 20.99] for leg press strength) was most effective in improving muscle mass and strength, respectively (moderate certainty). Milk proteins (milk, whey protein, yogurt, casein, and bovine colostrum), red meat, and mixed protein were effective for gains in both muscle mass and strength (moderate certainty). No timing or type of protein showed a significant enhancement in physical performance (timed up-to-go test, 6-min walk test, and gait speed). Pre/postexercise and Night are key recommended times of protein intake to increase muscle mass and strength, respectively. Milk proteins are the preferred types of protein supplements for improving muscle mass and strength. Future randomized controlled trials that directly compare the effects of protein timing or types are needed. This trial was registered at International Prospective Register of Systematic Reviews as CRD42022358766.

Intracellular tacrolimus concentration correlates with impaired renal function through regulation of the IS-AHR-ABC transporter in peripheral blood mononuclear cells.

BACKGROUNDS: Tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMCs) is regarded as a better predictor of its immunosuppressive effect than the TAC concentration in whole blood. However, whether the exposure of TAC in PBMCs or WB was altered in post-transplant recipients with renal impairment remains unclear. METHODS: We investigated the relationship of trough TAC concentration in WB and PBMCs with renal functions in post-transplant recipients. The pharmacokinetic profiles of TAC in PBMCs and WB in the two chronic kidney disease (CKD) rat models were examined using UPLC-MS/MS. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to analyze the expression of proteins and mRNAs related to TAC metabolism and transport, respectively. In addition, the effects of uremic toxins on human PBMCs were investigated using whole-transcriptome sequencing (RNA sequencing [RNA-seq]). RESULTS: We observed a decrease in the trough TAC concentration in PBMCs in the recipients with estimated glomerular filtration rate (eGFR) < 90 mL/min, compared with those of recipients with eGFR > 90 mL/min, but there was no difference in blood based on TAC concentrations (C0Blood). In a 150-patient post-transplant cohort, no significant relationship was observed between PBMCs and WB concentrations of TAC, and the eGFR value was correlated with TAC C0PBMCs but not with TAC C0Blood. In two CKD rat models, the TAC pharmacokinetic profile in the PBMCs was significantly lower than that in the control group; however, the blood TAC pharmacokinetic profiles in the two groups were similar. Transcriptome results showed that co-incubation of human PBMCs with uremic toxins upregulated the expression of AHR, ABCB1, and ABCC2. Compared to control rats, plasma IS increased by 1.93- and 2.26-fold and the expression of AHR, P-gp, and MRP2 in PBMCs was higher in AD and 5/6 nephrectomy (NX) rats, without modifying the expression of other proteins related to TAC exposure. CONCLUSION: The pharmacokinetics of TAC in PBMCs changed with a decline in renal function. Uremic toxins accumulate during renal insufficiency, which activates AHR, upregulates the expression of P-gp and MRP2, and affects their intracellular concentrations. Our findings suggest that monitoring TAC concentrations in PBMCs is more important than monitoring WB concentrations in post-transplant recipients with renal impairment.

Deoxynivalenol Exposure Induced Colon Damage in Mice Independent of the Gut Microbiota.

SCOPE: To investigate whether deoxynivalenol (DON) can induce intestinal damage through gut microbiota in mice. METHODS AND RESULTS: Mice are orally administered DON (1 mg kg-1 bw day-1 ) for 4 weeks, and then recipient mice receive fecal microbiota transplantation (FMT) from DON-exposed mice after antibiotic treatment. Furthermore, the mice are orally treated with DON (1 mg kg-1 bw day-1 ) for 4 weeks after antibiotic treatment. Histological damage, disruption of tight junction protein expression, and increased oxidative stress and apoptosis in the colon as well as higher serum lipopolysaccharides are observed after DON exposure. Moreover, DON exposure changes the composition and diversity of the gut microbiota as well as the contents of fecal metabolites (mainly bile acids). Differential metabolic pathways may be related to mitochondrial metabolism, apoptosis, and inflammation following DON exposure. However, only a decrease in mRNA levels of occludin and claudin-3 is observed in the colon of recipient mice after FMT. After depleting the gut microbiota in mice, DON exposure can also cause histological damage, disorders of tight junction protein expression, and increased oxidative stress and apoptosis in the colon. CONCLUSIONS: DON exposure can induce colon damage in mice independent of the gut microbiota.

Insight into the phenolics and antioxidant activity of Indian jujube (Ziziphus mauritiana Lamk) peel and pulp subjected to the simulated digestion.

To evaluate the release and activity of Indian jujube phenolics in vivo, its peel and pulp were subjected to simulated digestions. The phenolics content and antioxidant activity of the digested samples were determined. The results showed that the total phenolics/flavonoids in the peel were respectively 4.63 and 4.48 times higher than that in the pulp. The release of phenolics and flavonoids respectively increased by 79.75% and 39.98% in the peel and 86.34% and 23.54% in the pulp after the intestinal digestion. The correlation between the total phenolics/flavonoids and antioxidant activity was higher in the peel (r > 0.858, p < 0.01) than that in the pulp. The phenolics profiles of the peel were almost the same after the digestion, and four phenolics including naringenin tri-glycoside, quercetin-3-O-[(2-hexosyl)-6-rhamnosyl] -hexoside, quercetin-3-O-pentosylhexoside and quercetin-3-O-(2-pentosyl -rhamnoside)-4'-O-rhamnoside were found to be the main flavonoids of Indian jujube peel, and they showed high recovery (>89.88%) during the digestion, implying that these phenolics may play a vital role in the function of Indian jujubes.

Vertical Graphene-Supported NiMo Nanoparticles as Efficient Electrocatalysts for Hydrogen Evolution Reaction under Alkaline Conditions.

Water electrolysis as an important and facile strategy to generate hydrogen has attracted great attention, and efficient electrocatalysts play a key role in hydrogen evolution reaction (HER). Herein, vertical graphene (VG)-supported ultrafine NiMo alloy nanoparticles (NiMo@VG@CC) were fabricated successfully via electro-depositing as efficient self-supported electrocatalysts for HER. The introduction of metal Mo optimized the catalytic activity of transition metal Ni. In addition, VG arrays as the three-dimensional (3D) conductive scaffold not only ensured high electron conductivity and robust structural stability, but also endowed the self-supported electrode large specific surface area and exposed more active sites. With the synergistic effect between NiMo alloys and VG, the optimized NiMo@VG@CC electrode exhibited a low overpotential of 70.95 mV at 10 mA cm-2 and a remarkable stable performance over 24 h. This research is anticipated to offer a powerful strategy for the fabrication of high-performance hydrogen evolution catalysts.

Pharmacokinetics and bioequivalence evaluation of omeprazole and sodium bicarbonate dry suspensions in healthy Chinese volunteers.

Omeprazole and sodium bicarbonate dry suspension are effective treatments for acid-related disorders. This study compared the bioequivalence and safety of the two formulations of omeprazole and sodium bicarbonate powder and assessed how CYP2C19 gene polymorphisms affect pharmacokinetics (PK). A single-center, randomized, single-dose, 2-sequence and 2-period crossover method was performed in forty healthy Chinese subjects. Blood samples were collected after a single dose for PK (AUC0-∞, AUC0-t, and Cmax) analysis. The concentrations of Omeprazole in human plasma were determined by HPLC-MS/MS. Besides, the gene polymorphisms of CYP2C19 were assessed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95% CI)] of Test/Reference preparation for Cmax: 95.2% (88.48%, 102.43%), AUC0-t: 97.47% (94.4%, 101.02%), AUC0-∞: 97.68% (94.27%, 101.21%) were within the range of 80.00-125.00%. The non-parametric test showed no statistical difference in Tmax between the two groups (p > 0.05). All drugs were well tolerated, no severe adverse reactions occurred, and no significant differences in adverse events between the two drugs. For CYP2C19 gene polymorphisms, the results showed that of 40 subjects, 12 subjects were extensive metabolizers, 24 were intermediate metabolizers, and 4 were poor metabolizers, the frequency of metabolic genotypes were 30%, 60%, and 10%. And the allele distributions for CYP2C19 were *1, *2, and *3 at 60%, 38.75%, and 1.25%. Both the CYP2C19 alleles and metabolic genotypes were consistent with other studies in Chinese. The results of PK parameters showed that different genotypes of CYP2C19 lead to significant differences in t1/2, AUC0-t, AUC0-∞ and Cmax, but no significant differences in Tmax in each group. At the same time, we confirmed that the PK parameters of the test and reference had no differences between the males and females. This study has shown that the pharmacokinetic parameters of the two formulations are not significantly different, which showed bioequivalence and exemplary safety. CYP2C19 gene polymorphism significantly differed in the PK parameters of omeprazole sodium bicarbonate powder.

Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents.

BACKGROUND: Ischemia of the bile duct is a common feature in liver disease and transplantation, which represents a major cause of morbidity and mortality, especially after liver transplantation. Detailed knowledge of its pathogenesis remains incomplete due to the lack of appropriate in vitro models. METHODS: To recapitulate biliary damage induced by ischemia and reperfusion in vitro, human intrahepatic cholangiocyte organoids (ICOs) were grown at low oxygen levels of 1% up to 72 h, followed by re-oxygenation at normal levels. FINDINGS: ICOs stressed by ischemia and subsequent re-oxygenation represented the dynamic change in biliary cell proliferation, upregulation of epithelial-mesenchymal transition (EMT)-associated markers, and the evocation of phase-dependent cell death programs similar to what is described in patients. Clinical-grade alpha-1 antitrypsin was identified as a potent inhibitor of both ischemia-induced apoptosis and necroptosis. INTERPRETATION: These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies. FUNDING: Dutch Digestive FoundationMLDS D16-26; TKI-LSH (Topconsortium Kennis en Innovatie-Life Sciences & Health) grant RELOAD, EMC-LSH19002; Medical Delta program "Regenerative Medicine 4D"; China Scholarship Council No. 201706230252.

A Pharmacokinetic Drug-Drug Interactions Study between Entecavir and Hydronidone, a Potential Novel Antifibrotic Small Molecule, in Healthy Male Volunteers.

INTRODUCTION: Hepatic fibrosis is an inevitable process of hepatic sclerosis, malignancy, and insufficiency, and hydronidone is an innovative antifibrosis drug. This study focus on the pharmacokinetic interaction of hydronidone and entecavir in healthy Chinese male subjects. METHODS: An open-label, three-period, multiple-dosage, self-controlled clinical trial was executed in 12 healthy male subjects. In period 1, the subjects took hydronidone 60 mg, q8h, for 7 days. In period 2, they were given entecavir 0.5 mg once daily for 9 days. Then, hydronidone and entecavir were given in combination for 6 days (days 20-26). Blood samples were taken up to 24 h post-dosing, while pre-dose blood samples were drawn on days 7, 19, and 26. RESULTS: The area under the curve (AUC)0-t_ss of entecavir slightly increased from 15.56 ± 2.67 to 16.17 ± 2.77 ng h/ml with coadministration with hydronidone, while the other pharmacokinetic parameters of hydronidone and entecavir were comparable between monotherapy and combination therapy. The geometric mean ratios (GMRs) [90% confidence intervals (CIs)] of Cmax_ss, AUC0-t_ss, and AUC0-∞_ss of entecavir after coadministration compared with entecavir alone were 107.21% (97.04-118.45%), 103.85% (100.94-106.83%), and 110.81% (97.19-126.33%), respectively. And the GMRs and 90% CIs of Cmax,ss, AUC0-t_ss, and AUC0-∞_ss for combination therapy compared with the hydronidone monotherapy group were 102.72% (84.21-125.29%), 106.52% (97.06-116.90%), and 108.86% (96.42-122.89%), respectively. CONCLUSIONS: There was no drug-drug interaction between hydronidone and entecavir in healthy male volunteers. However, multiple doses of hydronidone have a risk with increasing exposure to entecavir in vivo, which needs to be further clarified. REGISTRATION NUMBER: ChiCTR2200059683 (retrospectively registered).

Implicit Weight Learning for Multi-View Clustering.

Exploiting different representations, or views, of the same object for better clustering has become very popular these days, which is conventionally called multi-view clustering. In general, it is essential to measure the importance of each individual view, due to some noises, or inherent capacities in the description. Many previous works model the view importance as weight, which is simple but effective empirically. In this article, instead of following the traditional thoughts, we propose a new weight learning paradigm in the context of multi-view clustering in virtue of the idea of the reweighted approach, and we theoretically analyze its working mechanism. Meanwhile, as a carefully achieved example, all of the views are connected by exploring a unified Laplacian rank constrained graph, which will be a representative method to compare with other weight learning approaches in experiments. Furthermore, the proposed weight learning strategy is much suitable for multi-view data, and it can be naturally integrated with many existing clustering learners. According to the numerical experiments, the proposed implicit weight learning approach is proven effective and practical to use in multi-view clustering.

Multi-View Clustering via Nonnegative and Orthogonal Graph Reconstruction.

The goal of multi-view clustering is to partition samples into different subsets according to their diverse features. Previous multi-view clustering methods mainly exist two forms: multi-view spectral clustering and multi-view matrix factorization. Although they have shown excellent performance in many occasions, there are still many disadvantages. For example, multi-view spectral clustering usually needs to perform postprocessing. Multi-view matrix factorization directly decomposes the original data features. When the size of features is large, it encounters the expensive time consumption to decompose these data features thoroughly. Therefore, we proposed a novel multi-view clustering approach. The main advantages include the following three aspects: 1) it searches for a common joint graph across multiple views, which fully explores the hidden structure information by utilizing the compatibility among views; 2) the introduced nonnegative constraint manipulates that the final clustering results can be directly obtained; and 3) straightforwardly decomposing the similarity matrix can transform the eigenvalue factorization in spectral clustering with computational complexity O(n3) into the singular value decomposition (SVD) with O(nc2) time cost, where n and c , respectively, denote the numbers of samples and classes. Thus, the computational efficiency can be improved. Moreover, in order to learn a better clustering model, we set that the constructed similarity graph approximates each view affinity graph as close as possible by adding the constraint as the initial affinity matrices own. Furthermore, substantial experiments are conducted, which verifies the superiority of the proposed two clustering methods comparing with single-view clustering approaches and state-of-the-art multi-view clustering methods.

Effects of intestinal microbiota on pharmacokinetics of cyclosporine a in rats.

Background: Intestinal microbiota has been confirmed to influencing the pharmacokinetic processes of a variety of oral drugs. However, the pharmacokinetic effects of the gut microbiota on cyclosporine A, a drug with a narrow therapeutic window, remain to be studied. Method: Twenty-one rats were randomly divided into three groups: (a) control group (CON), (b) antibiotic treatment group (ABT) and (c) fecal microbe transplantation group (FMT). The ABT group was administrated with water containing multiple antibiotics to deplete microorganisms. FMT was with the same treatment, followed by oral administration of conventional rat fecal microorganisms for normalization. Result: The bioavailability of CSA increased by 155.6% after intestinal microbes were consumed by antibiotics. After intestinal microbiota reconstruction by fecal transplantation, the increased bioavailability was significantly reduced and basically returned to the control group level. Changes in gut microbiota alter the protein expression of CYP3A1, UGT1A1 and P-gp in liver. The expressions of these three proteins in ABT group were significantly lower than those in CON and FMT groups. The relative abundance of Alloprevolleta and Oscillospiraceae UCG 005 was negatively correlated with CSA bioavailability while the relative abundance of Parasutterella and Eubacterium xylanophilum group was negatively correlated with CSA bioavailability. Conclusion: Intestinal microbiota affects the pharmacokinetics of CSA by regulating the expression of CYP3A1, UGT1A1 and P-GP.

A novel, simple and reliable method for the determination of hydronidone and its metabolites M3 and M4 in human plasma and urine by HPLC-MS/MS and its application to a pharmacokinetic study in health Chinese subjects.

In this study, a novel, simple and reliable high-performance liquid chromatography with tandem mass spetrometry method (HPLC-MS/MS) was developed for the determination of hydronidone and its metabolites M3 and M4 in human plasma and urine so as to study the clinical pharmacokinetics of hydronidone. By effectively inhibiting the proliferation of hepatic stellate cells (HSC), hydronidone can reduce collagen synthesis and curbs the process of liver fibrosis, and is currently in the stage of clinical research for anti-liver fibrosis. Hydronidone and its metabolites M3, M4 were extracted from human plasma by protein precipitation, and the urine samples were directly diluted with acetonitrile and analyzed by HPLC-MS/MS. The quantification ranges in plasma were 1.00-1000 ng/mL, 2.00-2000 ng/mL and 4.00-4000 ng/mL, respectively and in urine were 10.0-2000 ng/L, 100-25000 ng/L and 300-75000 ng/L, respectively. Coefficients of variation of less than 15% between intraday and interday accuracy and precision values were observed for hydronidone, M3 and M4. The S/N (signal-to-noise ratio) of the analyte in each Low limit of quantification sample in the analytical batch was greater than 5, indicating good sensitivity. The recovery rates were above 50% for all analytes. The parameters such as linearity, selectivity, lower precision, accuracy, recovery, stability and matrix effects were validated by the methodology and met the requirements specified by the FDA and the European Medicines Agency. The method has been successfully applied to the pharmacokinetics of hydronidone and its metabolites M3 and M4 in healthy Chinese volunteers.

Liver Ischemia and Reperfusion Induce Periportal Expression of Necroptosis Executor pMLKL Which Is Associated With Early Allograft Dysfunction After Transplantation.

Background: Early allograft dysfunction (EAD) following liver transplantation (LT) remains a major threat to the survival of liver grafts and recipients. In animal models, it is shown that hepatic ischemia-reperfusion injury (IRI) triggers phosphorylation of Mixed Lineage Kinase domain-like protein (pMLKL) inducing necroptotic cell death. However, the clinical implication of pMLKL-mediated cell death in human hepatic IRI remains largely unexplored. In this study, we aimed to investigate the expression of pMLKL in human liver grafts and its association with EAD after LT. Methods: The expression of pMLKL was determined by immunohistochemistry in liver biopsies obtained from both human and rat LT. Human liver biopsies were obtained at the end of preservation (T0) and ~1 hour after reperfusion (T1). The positivity of pMLKL was quantified electronically and compared in rat and human livers and post-LT outcomes. Multiplex immunofluorescence staining was performed to characterize the pMLKL-expressing cells. Results: In the rat LT model, significant pMLKL expression was observed in livers after IRI as compared to livers of sham-operation animals. Similarly, the pMLKL score was highest after IRI in human liver grafts (in T1 biopsies). Both in rats and humans, the pMLKL expression is mostly observed in the portal triads. In grafts who developed EAD after LT (n=24), the pMLKL score at T1 was significantly higher as compared to non-EAD grafts (n=40). ROC curve revealed a high predictive value of pMLKL score at T1 (AUC 0.70) and the ratio of pMLKL score at T1 and T0 (pMLKL-index, AUC 0.82) for EAD. Liver grafts with a high pMLKL index (>1.64) had significantly higher levels of serum ALT, AST, and LDH 24 hours after LT compared to grafts with a low pMLKL index. Multivariate logistical regression analysis identified the pMLKL-index (Odds ratio=1.3, 95% CI 1.1-1.7) as a predictor of EAD development. Immunohistochemistry on serial sections and multiplex staining identified the periportal pMLKL-positive cells as portal fibroblasts, fibrocytes, and a minority of cholangiocytes. Conclusion: Periportal pMLKL expression increased significantly after IRI in both rat and human LT. The histological score of pMLKL is predictive of post-transplant EAD and is associated with early liver injury after LT. Periportal non-parenchymal cells (i.e. fibroblasts) appear most susceptible to pMLKL-mediated cell death during hepatic IRI.

Highly efficient OER catalyst enabled by in situ generated manganese spinel on polyaniline with strong coordination.

The oxygen evolution reaction (OER), as the rate-determining step of electrochemical water splitting, is extremely crucial, and thus it is a requisite to engineer feasible and effective electrocatalysts to shrink the reaction energy barrier and accelerate the reaction. Herein, monodisperse Mn3O4 nanoparticles on a PANI substrate were synthesized by polymerization and in situ oxidation. Combining Mn3O4 nanoparticles and PANI fibers can not only maximize the strong coupling effect and synergistic effect but also construct a well-defined three-dimensional structure with extensive exposed active sites, where the permeation and adherence of the electrolyte are made exceedingly feasible, thus displaying excellent OER activity. Benefiting from the outstanding structural stability, the resulting Mn3O4/PANI/NF is able to deliver a low overpotential of 262 mV at a current density of 10 mA cm-2, which outperforms the commercial RuO2 catalyst (275 mV) as well as presently reported representative Mn-based and PANI-based electrocatalysts and state-of-the-art OER electrocatalysts. The synthetic method for Mn3O4/PANI not only provides a brand-new avenue for the rational design of inorganic material/conductive polymer composites but also broadens the understanding of the mechanism of Mn-based catalysts for highly enhanced OER.

Prediction of response and adverse drug reaction of pemetrexed plus platinum-based chemotherapy in lung adenocarcinoma by serum metabolomic profiling.

BACKGROUND: Pemetrexed plus platinum doublet chemotherapy regimen remains to be the standard first-line treatment for lung adenocarcinoma patients. However, few biomarkers can be used to identify potential beneficiaries with maximal efficacy and minimal toxicity. This study aimed to explore potential biomarker models predictive of efficacy and toxicity after pemetrexed plus platinum chemotherapy based on metabolomics profiling. METHODS: A total of 144 patients who received at least two cycles of pemetrexed plus platinum chemotherapy were enroled in the study. Serum samples were collected before initial treatment to perform metabolomics profiling analysis. Logistic regression analysis was performed to establish prediction models. RESULTS: 157 metabolites were found to be differentially expressed between the response group and the nonresponse group. A panel of Phosphatidylserine 20:4/20:1, Sphingomyelin d18:1/18:0, and Phosphatidic Acid 18:1/20:0 could predict pemetrexed and platinum chemotherapy response with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.7968. 76 metabolites were associated with hematological toxicity of pemetrexed plus platinum chemotherapy. A panel incorporating triglyceride 14:0/22:3/22:5, 3-(3-Hydroxyphenyl) Propionate Acid, and Carnitine C18:0 was the best predictive ability of hematological toxicity with an AUROC of 0.7954. 54 differential expressed metabolites were found to be associated with hepatotoxicity of pemetrexed plus platinum chemotherapy. A model incorporating stearidonic acid, Thromboxane B3, l-Homocitrulline, and phosphoinositide 20:3/18:0 showed the best predictive ability of hepatotoxicity with an AUROC of 0.8186. CONCLUSIONS: This study established effective and convenient models that can predict the efficacy and toxicity of pemetrexed plus platinum chemotherapy in lung adenocarcinoma patients before treatment delivery.

The Value of Echocardiography Combined with NT-pro BNP Level in Assessment and Prognosis of Diastolic Heart Failure.

BACKGROUND: To investigate the significance of echocardiography combined with N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels in the evaluation and prognosis of diastolic heart failure (DHF). METHODS: Clinical data were collected from 168 patients with DHF. Serum levels of NT-pro BNP were first measured by ELISA. Meanwhile, the echocardiography was used to examine left ventricular end-diastolic diameter (LVEDD), left ventricular diameter (LVD), and other parameters. Multivariate logistic regression analysis was performed for variables in heart failure assessment grade or poor prognosis. Finally, the predictive ability for New York Heart Association (NYHA) class as well as prognosis was assessed by ROC curves. RESULTS: NT-pro BNP was the overexpression in the serum of patients with DHF. And the degree of elevation was related to NYHA class, while NT-pro BNP levels were significantly higher in the P-MACE group than in the N-MACE group. According to the multivariate logistic regression analysis, the ratio of peak velocity of left atrial early diastolic blood flow to early diastolic peak velocity of mitral annulus (E/Ea) and serum NT-pro BNP level was risk factors for NYHA class and prognosis. However, LVEF, LVEDD, and flow propagation velocity (Vp) can be a benefit condition. In addition, ROC curve showed that echocardiography combined with NT-pro BNP content had higher accuracy in NYHA class and prognostic assessment of DHF than applied separately. CONCLUSIONS: The diagnosis of echocardiography combined with NT-pro BNP levels has the potential to distinguish the NYHA class in heart function of patients with DHF and determine the prognosis of patients.

Recapitulating lipid accumulation and related metabolic dysregulation in human liver-derived organoids.

Fatty liver disease has grown into a major global health burden, attributed to multi-factors including sedentary lifestyle, obesogenic diet and prevalence of metabolic disorders. The lack of robust experimental models is hampering the research and therapeutic development for fatty liver disease. This study aims to develop an organoid-based 3D culture model to recapitulate key features of fatty liver disease focusing on intracellular lipid accumulation and metabolic dysregulation. We used human liver-derived intrahepatic cholangiocyte organoids and hepatocyte differentiated organoids. These organoids were exposed to lactate, pyruvate, and octanoic acid (LPO) for inducing lipid accumulation and mitochondrial impairment. Lipid accumulation resulted in alternations of gene transcription with major effects on metabolic pathways, including triglyceride and glucose level increase, which is consistent with metabolic changes in fatty liver disease patients. Interestingly, lipid accumulation affected mitochondria as shown by morphological transitions, alternations in expression of mitochondrial encoded genes, and reduction of ATP production. Meanwhile, we found treatment with obeticholic acid and metformin can alleviate fat accumulation in organoids. This study demonstrated that LPO exposure can induce lipid accumulation and associated metabolic dysregulation in human liver-derived organoids. This provides an innovative model for studying fatty liver disease and testing potential therapeutics. KEY MESSAGES: Lactate, pyruvate, and octanoic acid induce lipid accumulation in liver organoids. Organoids of human compared to mouse origin are more efficient in lipid accumulation. Lipid accumulation dysregulates metabolic pathway and impairs mitochondrial function. Demonstrating a proof-of-concept for testing medications in organoids.

Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte Organoids.

BACKGROUND & AIMS: Liver and bile duct diseases often are associated with extensive cell death of cholangiocytes. Necroptosis represents a common mode of programmed cell death in cholangiopathy, however, detailed mechanistic knowledge is limited owing to the lack of appropriate in vitro models. To address this void, we investigated whether human intrahepatic cholangiocyte organoids (ICOs) can recapitulate cholangiopathy-associated necroptosis and whether this model can be used for drug screening. METHODS: We evaluated the clinical relevance of necroptosis in end-stage liver diseases and liver transplantation by immunohistochemistry. Cholangiopathy-associated programmed cell death was evoked in ICOs derived from healthy donors or patients with primary sclerosing cholangitis or alcoholic liver diseases by the various stimuli. RESULTS: The expression of key necroptosis mediators, receptor-interacting protein 3 and phosphorylated mixed lineage kinase domain-like, in cholangiocytes during end-stage liver diseases was confirmed. The phosphorylated mixed lineage kinase domain-like expression was etiology-dependent. Gene expression analysis confirmed that primary cholangiocytes are more prone to necroptosis compared with primary hepatocytes. Both apoptosis and necroptosis could be specifically evoked using tumor necrosis factor α and second mitochondrial-derived activator of caspases mimetic, with or without caspase inhibition in healthy and patient-derived ICOs. Necroptosis also was induced by ethanol metabolites or human bile in ICOs from donors and patients. The organoid cultures further uncovered interdonor variable and species-specific drug responses. Dabrafenib was identified as a potent necroptosis inhibitor and showed a protective effect against ethanol metabolite toxicity. CONCLUSIONS: Human ICOs recapitulate cholangiopathy-associated necroptosis and represent a useful in vitro platform for the study of biliary cytotoxicity and preclinical drug evaluation.

Precise pathological classification of non-small cell lung adenocarcinoma and squamous carcinoma based on an integrated platform of targeted metabolome and lipidome.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the most common subtypes of NSCLC. Despite genetic differences between LUAD and LUSC have been clarified in depth, the metabolic differences of these two subtypes are still unclear. METHODS: Totally, 128 plasma samples of NSCLC patients were collected before initial treatments, followed by determination of LC-ESI-Q TRAP-MS/MS. Differentially expressed metabolites were screened based on a strict standard. RESULTS: Based on the integrated platform of targeted metabolome and lipidome, a total of 1141 endogenous metabolites (including 809 lipids) were finally detected in the plasma of NSCLC patients, including 16 increased and 3 decreased endogenous compounds in LUAD group when compared with LUSC group. Thereafter, a logistic regression model integrating four differential metabolites [2-(Methylthio) ethanol, Cortisol, D-Glyceric Acid, and N-Acetylhistamine] was established and could accurately differentiate LUAD and LUSC with an area under the ROC curve of 0.946 (95% CI 0.886-1.000). The cut-off value showed a satisfactory efficacy with 92.0% sensitivity and 92.9% specificity. KEGG functional enrichment analysis showed these differentially expressed metabolites could be further enriched in riboflavin metabolism, steroid hormone biosynthesis, prostate cancer, etc. The endogenous metabolites identified in this study have the potential to be used as novel biomarkers to distinguish LUAD from LUSC. CONCLUSIONS: Our research might provide more evidence for exploring the pathogenesis and differentiation of NSCLC. This research could promote a deeper understanding and precise treatment of lung cancer.