3' Uridylation Confers miRNAs with Non-canonical Target Repertoires.

Many microRNAs (miRNAs) exist alongside abundant miRNA isoforms (isomiRs), most of which arise from post-maturation sequence modifications such as 3' uridylation. However, the ways in which these sequence modifications affect miRNA function remain poorly understood. Here, using human miR-27a in cell lines as a model, we discovered that a nonfunctional target site unable to base-pair extensively with the miRNA seed sequence can regain function when an upstream adenosine is able to base-pair with a post-transcriptionally added uridine in the miR-27a tail. This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. We provide evidence that TUMR expands the targets of other endogenous miRNAs. Our study reveals a function of uridylated isomiRs in regulating non-canonical miRNA targets.

Determination of rosmarinic acid and its N-substituted analog A1 in rat plasma using high-performance liquid chromatography-tandem mass spectrometry and its application in pharmacokinetics.

BACKGROUND: The aim of this study was to determine the concentration of rosmarinic acid (RA) and its analog (E)-3-(3,4-dihydroxyphenyl)-2-(3-(3,4-dihydroxyphenyl)acrylamido)propanoic acid (A1) in rat plasma following oral administration. The significance of this study lies in the development of a rapid, sensitive, and alternative method using liquid chromatography-tandem mass spectrometry for the accurate quantification and identification of RA and A1 in vivo. METHODS: Liquid chromatography-tandem mass spectrometry was employed to analyze RA and A1 in rat plasma. A C18 column (1.9 µm, 2.1 × 100 mm) with a C18 guard column (5 µm, 2.1 × 10 mm) and a triple-quadrupole mass spectrometer combined with an electrospray ionization source were utilized. Sample pretreatment involved a one-step protein precipitation using isopropanol:ethyl acetate (20:80, v/v) as the solvent. Pseudoephedrine hydrochloride served as a standard. RESULTS: The developed method exhibited a linear relationship within the concentration ranges of 5-750 ng/ml for both RA and A1. Relative standard deviations in daily courses were less than 15%, and the relative errors recorded were within 15%. This is the first study to concentrate on determining A1 and RA in rat plasma through oral administration. CONCLUSIONS: The liquid chromatography-tandem mass spectrometry method developed in this study offers a rapid, sensitive, and alternative approach for the accurate quantification and identification of RA and A1 in vivo. The findings serve as a significant foundation for evaluating the clinical applications of the medicine.

Predictive value of elevated alanine aminotransferase for in-hospital mortality in patients with acute myocardial infarction.

BACKGROUND AND AIMS: Liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are markers of hepatic dysfunction and fatty liver disease. Although ALT and AST have been suggested as risk factors for cardiovascular disease, their role as predictors of mortality after acute myocardial infarction (AMI) has not been established. The objective of this study was to investigate the predictive value of ALT and AST for mortality in patients with AMI. METHODS: We analyzed records of 712 patients with AMI and no known liver disease treated at the Department of Cardiovascular Center in the First Hospital of Jilin University. The primary outcome was all-cause in-hospital mortality. Relationships between primary outcome and various risk factors, including serum transaminase levels, were assessed using multivariate logistic regression analysis. RESULTS: Age (P < 0.001), hypertension (P = 0.034), prior myocardial infarction (P < 0.001), AST (P < 0.001), ALT (P < 0.001), creatinine (P = 0.007), blood urea nitrogen (P = 0.006), and troponin I (P < 0.001) differed significantly between ST-segment elevation myocardial infarction (STEMI) and non-STEMI. The following factors were associated with an increased risk of in-hospital all-cause mortality in patients with AMI: ALT ≥ 2ULN (adjusted odds ratio [AOR] 2.240 [95% confidence interval (CI), 1.331-3.771]; P = 0.002); age ≥ 65 year (AOR 4.320 [95% CI 2.687-6.947]; P < 0.001); increased fasting plasma glucose (FPG) (AOR 2.319 [95% CI 1.564-3.438]; P < 0.001); elevated D-dimer (AOR 2.117 [95% CI 1.407-3.184]; P < 0.001); elevated fibrinogen (AOR 1.601 [95% CI 1.077-2.380]; P = 0.20); and reduced estimated glomerular filtration rate (eGFR) (AOR 2.279 [95% CI 1.519-3.419]; P < 0.001). CONCLUSIONS: Our findings demonstrated that elevated ALT was independently associated with increased in-hospital all-cause mortality in patients with AMI. Other risk factors were increased age, FPG, D-dimer, and fibrinogen and decreased eGFR.

QuagmiR: a cloud-based application for isomiR big data analytics.

SUMMARY: MicroRNAs (miRNAs) function as master regulators of gene expression. Recent studies demonstrate that miRNA isoforms (isomiRs) play a unique role in cancer development. Here, we present QuagmiR, the first cloud-based tool to analyze isomiRs from next generation sequencing data. Using a novel and flexible searching algorithm designed for the detection and annotation of heterogeneous isomiRs, it permits extensive customization of the query process and reference databases to meet the user 's diverse research needs. AVAILABILITY AND IMPLEMENTATION: QuagmiR is written in Python and can be obtained freely from GitHub (https://github.com/Gu-Lab-RBL-NCI/QuagmiR). QuagmiR can be run from the command line on local machines, as well as on high-performance servers. A web-accessible version of the tool has also been made available for use by academic researchers through the National Cancer Institute-funded Seven Bridges Cancer Genomics Cloud (https://cancergenomicscloud.org). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Estimating the ploidy of Gracilariopsis lemaneiformis at both the cellular and genomic level1.

The determination of the ploidy level of an organism is a prerequisite for studies of evolution, cellular function, and genomic construction. Identification of the ploidy of the economically important red alga Gracilariopsis lemaneiformis has been hindered by its small genome and large number of chromosomes. Therefore, in the current study, PloidyNGS, a tool that calculates the number of reads supporting different alleles at each position along the genome sequence, and fluorescence in situ hybridization coupled with tyramide signal amplification (TSA-FISH) were used to clarify the ploidy of G. lemaneiformis. In addition, flow cytometry (FCM) was used to estimate the ploidy of different somatic cells. The PloidyNGS results showed that most of the alleles in the gametophyte were monomorphic, whereas the TSA-FISH results showed that one hybridization signal was observed in gametophytic nuclei and two in tetrasporophytic nuclei when the nuclei were hybridized by single copy gene probes. These results confirmed that G. lemaneiformis is a haploid in the gametophytic generation and diploid in the sporophytic generation. Moreover, the FCM result suggested that G. lemaneiformis was not an endopolyploid. Based on previous studies, we hypothesize that the nuclear number is important for the cellular differentiation and function of this species. We also suggest that G. lemaneiformis evolved from a paleopolyploid, the genome of which has been diploidized, and that traces of genomic doubling are no longer apparent. Thus, this study provides important evidence for further studies on the evolution and genomes of red algae.

Molecular Cloning of cpcU and Heterodimeric Bilin Lyase Activity Analysis of CpcU and CpcS for Attachment of Phycocyanobilin to Cys-82 on the ß-Subunit of Phycocyanin in Arthrospira platensis FACHB314.

A new bilin lyase gene cpcU was cloned from Arthrospira platensis FACHB314 to study the assembly of the phycocyanin ß-Subunit. Two recombinant plasmids, one contained the phycocyanobilin (PCB) producing genes (hoxI and pcyA), while the other contained the gene of the ß-Subunit of phycobiliprotein (cpcB) and the lyase gene (cpcU, cpcS, or cpcU/S) were constructed and separately transferred into Escherichia coli in order to test the activities of relevant lyases for catalyzing PCB addition to CpcB during synthesizing fluorescent ß-PC of A. platensis FACHB314. The fluorescence intensity examination showed that Cys-82 maybe the active site for the ß-Subunit binding to PCBs and the attachment could be carried out by CpcU, CpcS, or co-expressed cpcU/S in A. platensis FACHB314.

Expression of a chimeric human/salmon calcitonin gene integrated into the Saccharomyces cerevisiae genome using rDNA sequences as recombination sites.

Calcitonin participates in controlling homeostasis of calcium and phosphorus and plays an important role in bone metabolism. The aim of this study was to endow an industrial strain of Saccharomyces cerevisiae with the ability to express chimeric human/salmon calcitonin (hsCT) without the use of antibiotics. To do so, a homologous recombination plasmid pUC18-rDNA2-ura3-P pgk -5hsCT-rDNA1 was constructed, which contains two segments of ribosomal DNA of 1.1 kb (rDNA1) and 1.4 kb (rDNA2), to integrate the heterologous gene into host rDNA. A DNA fragment containing five copies of a chimeric human/salmon calcitonin gene (5hsCT) under the control of the promoter for phosphoglycerate kinase (P pgk ) was constructed to express 5hsCT in S. cerevisiae using ura3 as a selectable auxotrophic marker gene. After digestion by restriction endonuclease HpaI, a linear fragment, rDNA2-ura3-P pgk -5hsCT-rDNA1, was obtained and transformed into the △ura3 mutant of S. cerevisiae by the lithium acetate method. The ura3-P pgk -5hsCT sequence was introduced into the genome at rDNA sites by homologous recombination, and the recombinant strain YS-5hsCT was obtained. Southern blot analysis revealed that the 5hsCT had been integrated successfully into the genome of S. cerevisiae. The results of Western blot and ELISA confirmed that the 5hsCT protein had been expressed in the recombinant strain YS-5hsCT. The expression level reached 2.04 % of total proteins. S. cerevisiae YS-5hsCT decreased serum calcium in mice by oral administration and even 0.01 g lyophilized S. cerevisiae YS-5hsCT/kg decreased serum calcium by 0.498 mM. This work has produced a commercial yeast strain potentially useful for the treatment of osteoporosis.

Synthesis of a temperature-sensitive matrine-imprinted polymer and its potential application for the selective extraction of matrine from radix Sophorae tonkinensis.

A temperature-sensitive matrine-imprinted polymer was prepared in chloroform by free-radical cross-linking copolymerization of methacrylic acid at 60 °C in the presence of ethylene glycol dimethacrylate as the cross-linker, N-isopropyl acrylamide as the temperature-responsive monomer and matrine as the template molecule. Binding experiments and Scatchard analyses revealed that two classes of binding sites were formed on molecular imprinted polymer (MIP) at 50 °C. Additionally, the thermoresponsive MIP was tested for its application as a sorbent material for the selective separation of matrine from Chinese medicinal plant radix Sophorae tonkinensis. It was shown that the thermoresponsive MIP displayed different efficiency in clean-up and enrichments using the SPE protocol at different temperatures.

Pharmacokinetic Analysis of Two N-Substituted Rosmarinic Acid Analogs in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry.

This study reports the development of an effective high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantification of two analogs of rosmarinic acid (RA) in rat plasma, namely methyl (E)-2-(3-(3,4-difluorophenyl)acrylamido)-3-(3,4-dihydroxyphenyl)propanoate (A11) and methyl (E)-3-(3,4-dihydroxyphenyl)-2-(3-(3,4-dihydroxyphenyl)acrylamido)propanoate (A2). These analogs, featuring N atoms instead of O atoms, exhibit enhanced bioavailability and distinct pharmacological activities compared with RA. The HPLC separation was carried out on a C18 column (1.9 µm, 2.1 mm × 100 mm) coupled with a security guard C18 column (5 µm, 2.1 mm × 10 mm). A triple-quadrupole mass spectrometer equipped with an electrospray ionization ion source was utilized for ion generation. Pseudoephedrine hydrochloride was utilized as a standard, and a single-step protein precipitation method using isopropanol:ethyl acetate (v/v, 20:80) was employed for sample pretreatment. The developed method demonstrated excellent linearity over the concentration range of 5-750 ng/ml for both A11 and A2, with relative standard deviations of <15% and relative errors within 15% during daily course analysis. The method allowed for the unambiguous quantification and identification of A11 and A2 in vivo. The results of this study provide a meaningful foundation for evaluating the clinical applications of these analogs.

LONP1 ameliorates liver injury and improves gluconeogenesis dysfunction in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown. METHODS: In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. RESULTS: We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders. CONCLUSION: We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

Longitudinal changes in sarcopenia was associated with survival among cirrhotic patients.

Background: Sarcopenia is common in patients with liver cirrhosis and is an independent predictor of multiple clinical outcomes. Most studies to date have used a static assessment of sarcopenia. However, there is very limited data evaluating the temporal course of muscle area in cirrhosis. To bridge this gap in clinical studies, we performed a longitudinal analysis to evaluate the impact of changes in sarcopenia for cirrhotic patients. Methods: Adult patients with clinically diagnosed liver cirrhosis who underwent at least 2 abdominal computed tomography (CT) scans in the hospital were enrolled. The interval between the two abdominal scans was 6 ± 1 months. Patients were categorized into persistent non-sarcopenia, new-onset sarcopenia, sarcopenia to non-sarcopenia, and persistent sarcopenia based on changes in sarcopenia. Kaplan-Meier method and Log-rank tests were used to separately compare unadjusted survival curves by different statuses of sarcopenia. Cox regression analysis was performed to assess the associations between different states of sarcopenia and overall mortality. The association between persistent non-sarcopenia and new-onset sarcopenia was analyzed by multivariate logistic regression analysis. Results: A total of 307 patients were included for analysis. At the second assessment, 10.10% (31/307) patients were new-onset sarcopenia, 27.69% (85/307) with persistent sarcopenia status, while 13.03% (40/307) patients with sarcopenia developed non-sarcopenia and 49.19% (151/307) with persistent non-sarcopenia status. The overall survival rate was significantly lower in the persistent sarcopenia and new-onset sarcopenia than in the non-sarcopenia group and sarcopenia to non-sarcopenia group (p < 0.001). Persistent sarcopenia (HR 5.799, 95%CI 1.563-21.521, p = 0.009) and new onset sarcopenia (HR 5.205, 95%CI 1.482-18.282, p = 0.010) were identified as poor prognostic factors for cirrhotic patients. The etiology of cirrhosis and the initial skeletal muscle mass were independent risk factors for new-onset sarcopenia. Conclusion: Sarcopenia is a dynamically changing process in patients with cirrhosis. Persistent and new-onset sarcopenia were independently and robustly associated with overall survival.

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

Application of Global Leadership Initiative on Malnutrition criteria in patients with liver cirrhosis.

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) criteria were published to build a global consensus on nutritional diagnosis. Reduced muscle mass is a phenotypic criterion with strong evidence to support its inclusion in the GLIM consensus criteria. However, there is no consensus regarding how to accurately measure and define reduced muscle mass in clinical settings. This study aimed to investigate the optimal reference values of skeletal muscle mass index for diagnosing sarcopenia and GLIM-defined malnutrition, as well as the prevalence of GLIM-defined malnutrition in hospitalized cirrhotic patients. METHODS: This retrospective study was conducted on 1002 adult patients with liver cirrhosis between January 1, 2018, and February 28, 2022, at Beijing You-An Hospital, Capital Medical University. Adult patients with a clinical diagnosis of liver cirrhosis and who underwent an abdominal computed tomography (CT) examination during hospitalization were included in the study. These patients were randomly divided into a modeling group (cohort 1, 667 patients) and a validation group (cohort 2, 335 patients). In cohort 1, optimal cut-off values of skeletal muscle index at the third lumbar skeletal muscle index (L3-SMI) were determined using receiver operating characteristic analyses against in-hospital mortality in different gender groups. Next, patients in cohort 2 were screened for nutritional risk using the Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. Additionally, the reference values of reduced muscle mass in GLIM criteria were derived from the L3-SMI values from cohort 1. Multivariate logistic regression analysis was used to analyze the association between GLIM-defined malnutrition and clinical outcomes. RESULTS: The optimal cut-off values of L3-SMI were 39.50 cm 2 /m 2 for male patients and 33.06 cm 2 /m 2 for female patients. Based on the cut-off values, 31.63% (68/215) of the male patients and 23.3% (28/120) of the female patients had CT-determined sarcopenia in cohort 2. The prevalence of GLIM-defined malnutrition in cirrhotic patients was 34.3% (115/335) and GLIM-defined malnutrition was an independent risk factor for in-hospital mortality in patients with liver cirrhosis ( Wald = 6.347, P  = 0.012). CONCLUSIONS: This study provided reference values for skeletal muscle mass index and the prevalence of GLIM-defined malnutrition in hospitalized patients with liver cirrhosis. These reference values will contribute to applying the GLIM criteria in cirrhotic patients.

Prevalence and clinical impact of sarcopenia in liver transplant recipients: A meta-analysis.

BACKGROUND: The prevalence of sarcopenia in patients undergoing liver transplantation (LT) remains to be determined partly because of different diagnostic criteria. Sarcopenia has recently been recognized as a new prognostic factor for predicting outcomes in LT candidates. AIM: To estimate the prevalence of sarcopenia and evaluate its clinical effect on LT candidates. METHODS: This systematic search was conducted in PubMed, Web of Science, Embase, and Cochrane Library for original English-language articles that investigated the prevalence and influence of sarcopenia in patients undergoing LT from database inception to November 30, 2022. Cohort studies of the definition of sarcopenia that estimate sarcopenia prevalence and evaluate its effect on clinical outcomes and the risk of mortality were included. RESULTS: Twenty-five studies involving 7760 patients undergoing LT were included. The pooled prevalence of sarcopenia in patients undergoing LT was 40.7% [95% confidence intervals (95%CI): 32.1-49.6]. The 1-, 3-, and 5-year cumulative probabilities of post-LT survival in patients with preoperative sarcopenia were all lower than those without sarcopenia (P < 0.05). Sarcopenia was associated with an increased risk of post-LT mortality in patients undergoing LT (adjusted hazard ratio: 1.58; 95%CI: 1.21-2.07). Patients with preoperative sarcopenia had a longer intensive care unit stay, a high risk ratio of sepsis, and serious post-LT complications than those without sarcopenia. CONCLUSION: Sarcopenia is prevalent in a substantial proportion of patients undergoing LT and is strongly and independently associated with higher a risk of mortality risk.

The effects and safety of anticoagulation or antiplatelet therapy following TIPS in cirrhotic patients with portal hypertension: A meta-analysis.

Introduction: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective way to improve portal hypertension, however, the role of anticoagulation or antiplatelet therapy following TIPS remains controversial. We conducted this study to evaluate the efficacy and safety of anticoagulation or antiplatelet therapy following TIPS. Methods: A literature search was conducted on anticoagulation or antiplatelet therapy after TIPS using Pubmed, Web of Science, EMBASE, and Cochrane. The retrieval period was from the earliest accessible date in the database to 31 October 2022. We collected information on the incidence of stent dysfunction, bleeding, hepatic encephalopathy, the new occurrence of portal vein thrombosis, and the survival rate. Stata was analyzed in RevMan. Results: 1. Four studies received anticoagulation or antiplatelet therapy after TIPS without control groups. According to the single-group rate meta-analysis, stent dysfunction occurred at 27% [95% CI (0.19, 0.38)], bleeding occurred at 21% [95% CI (0.14, 0.29)], new portal vein thrombosis occurred at 17% [(95%CI(0.04.0.71)], hepatic encephalopathy occurred at 47% [95%CI (0.34, 0.63)], and death occurred at 31% [95% CI (0.22, 0.42)]. 2. Eight studies, including 1025 patients, compared anticoagulation and antiplatelet therapy after TIPS to TIPS alone. In terms of stent dysfunction, bleeding, and hepatic encephalopathy, there were no significant differences between the two groups. The use of anticoagulation or antiplatelet therapy may result in a significant decrease in the incidence of new portal vein thrombosis and mortality over 1 year. Discussion: Anticoagulant or antiplatelet therapy may not improve the patency rate of TIPS, but may effectively prevent new portal vein thrombosis after TIPS. Following TIPS, the use of anticoagulants or antiplatelet drugs does not lead to an increase in bleeding or death.

Peptide ARHGEF9 Inhibits Glioma Progression via PI3K/AKT/mTOR Pathway.

Background: The most prevalent malignant tumor in a human brain nervous system is called glioma. Peptide is a compound formed by the peptide bond of α-amino acids, and the development of polypeptide drugs has been widely used in many fields. We plan to investigate the underlying peptides with clinical value in glioma. Method: Based on public databases, we targeted the common genes between glioma differentially expressed genes (DEGs) and peptide genes related to glioma prognosis. Then, these common genes were analyzed by LASSO-Cox analysis, prognostic risk model, and nomogram to identify key prognostic peptide genes and the target gene in this study. Next, the mechanism of target gene in glioma was explored by bioinformatics analysis and functional experiments. Results: We obtained a total of 26 overlapping genes for the following study. After that, 6 independent prognostic factors (REPIN1, PSD3, RDX, CDK4, FANCI, and ARHGEF9) were obtained and applied to construct the prognostic nomogram, and ARHGEF9 was the target gene in the study. Next, peptide ARHGEF9 was found to inhibit glioma cell development. Through Spearman's correlation analysis, ARHGEF9 had a close relation with PI3K/AKT/mTOR pathway. In functional experiments, peptide ARHGEF9 could suppress the protein expressions of p-PIK3K, p-AKT and p-mTOR, while IGF-1 could reverse this effect. Conclusion: This study identifies 6 new prognostic biomarkers for glioma patients. Among them, peptide ARHGEF9 gene is an inhibitory gene functioning by targeting PI3K/AKT/mTOR pathway.

Pharmacokinetic Analysis of Rosmarinic Acid and its Analog in Rat Plasma Using Liquid Chromatography-Tandem Mass Spectrometry.

The anticancer effects of rosmarinic acid (RA) are a hotspot of current research. In order to enhance its pharmacological activity, N-substituted RA was prepared, and it has been shown to exhibit notable antitumor effects. In order to elucidate the underlying mechanisms of action, pharmacokinetic analysis is necessary. In the present study, liquid chromatography-tandem mass spectrometric method, was used to determine the concentrations of RA and its analog, (E)-3-(3,4-dihydroxyphenyl)-2-(3-(3,4-dihydroxyphenyl)acrylamido)propanoic acid (A2) in plasma from rats. The analyses were divided into a C18 column (1.9 µm, 2.1 mm × 100 mm) with a security guard C18 column (5 µm, 2.1 mm × 10 mm) and a triple-quadrupole mass spectrometry with an electrospray ionization ion-source generates ions. The sample pretreatment is relevant to the one-step protein precipitation with isopropanol:ethyl acetate (v/v, 1:1) This method presented a linear association within ranges at the concentration of 5-2000 ng/mL for A2 and RA. Relative standard deviations in daily courses were <15% and the relative errors registered within 15%. The methods used in the present study make the unambiguous quantification and identification of RA and A2 possible in vivo. The present study is the first to focus on determining A2 and RA in rat plasma following oral administration. The results may provide a meaningful basis for the evaluation of the application of RA and its analog in clinical practice and also provide a reference method for the pharmacokinetic analysis of RA analogs.

The Potential Role of Gut Microbial-Derived Exosomes in Metabolic-Associated Fatty Liver Disease: Implications for Treatment.

The prevalence and incidence of metabolic-associated fatty liver disease (MAFLD), a clinically heterogeneous disease whose primary clinical therapies include dietary control and exercise therapy, is increasing worldwide and constitutes a significant medical burden. Gut microbes influence the physiopathological processes of the liver through different mechanisms based on the gut-liver axis. Exosomes are essential carriers of intercellular communication. Most previous studies have focused on adipocyte- and hepatocyte-derived exosomes, while the critical role of microbial-derived exosomes and the molecular mechanisms behind them in MAFLD have received little attention. Therefore, we searched and screened the latest relevant studies in the PubMeb database to elucidate the link between microbial-derived exosomes and the pathogenesis of MAFLD, mainly in terms of insulin resistance, intestinal barrier, inflammatory response, lipid metabolism, and liver fibrosis. The aim was to provide a theoretical framework and support for clinical protocols and innovative drug development.

Urinary Neutrophil Gelatinase-Associated Lipocalin Can Predict the Efficacy of Volume Expansion Therapy in Patients With Hepatitis B Cirrhosis and AKI.

Backgrounds: Kidney biomarkers in urine appear to be useful in differential diagnosis between acute tubular necrosis and other types of acute kidney injury (AKI) in cirrhosis. In clinical practice, prerenal azotemia (PRA) is often distinguished from other types of AKI by volume expansion therapy. The aim of the current study was to investigate the accuracy of urinary biomarkers in the differential diagnosis between PRA and other types of AKI. Methods: A total of 65 patients with hepatitis B cirrhosis were prospectively included and divided into AKI and non-AKI groups. Patients with hepatitis B cirrhosis and AKI discontinue diuretics, vasodilators, and nephrotoxic drugs and give volume expansion therapy. The efficacy was judged after 48 h of treatment. Urinary biomarkers were measured at the time of diagnosis of AKI and 48 h after volume expansion therapy. Univariate and multivariate analyses were used to identify independent risk factors for nonresponse to volume expansion therapy. Results: Of the 65 patients, 49 patients with newly diagnosed AKI were screened in the study, and 16 hospitalized patients with hepatitis B cirrhosis without AKI at the same period were screened as the control group. In patients with cirrhosis and AKI, 29 (59.18%) patients were in the response group and 20 (40.81%) patients were in the nonresponse group. The mortality rate in the nonresponse group was significantly higher than that in the response group (75% vs. 13.8% p < 0.001). After logistic regression analysis, urinary neutrophil gelatinase-associated lipocalin (NGAL) and serum creatinine (SCr) at diagnosis of AKI showed significant association with nonresponse to volume expansion therapy. The cutoff values for SCr and urinary NGAL were 128.50 µmol/L and 90.75 ng/ml, respectively. The area under the receiver operating curve (AUC) for SCr and urinary NGAL was 0.815 and 0.831. Conclusion: Elevated urinary NGAL can reflect the degree of kidney injury and is an independent risk factor for nonresponse to volume expansion therapy in patients with hepatitis B cirrhosis and AKI.

The Mechanism Underlying the Influence of Indole-3-Propionic Acid: A Relevance to Metabolic Disorders.

The increasing prevalence of metabolic syndrome has become a serious public health problem. Certain bacteria-derived metabolites play a key role in maintaining human health by regulating the host metabolism. Recent evidence shows that indole-3-propionic acid content can be used to predict the occurrence and development of metabolic diseases. Supplementing indole-3-propionic acid can effectively improve metabolic disorders and is considered a promising metabolite. Therefore, this article systematically reviews the latest research on indole-3-propionic acid and elaborates its source of metabolism and its association with metabolic diseases. Indole-3-propionic acid can improve blood glucose and increase insulin sensitivity, inhibit liver lipid synthesis and inflammatory factors, correct intestinal microbial disorders, maintain the intestinal barrier, and suppress the intestinal immune response. The study of the mechanism of the metabolic benefits of indole-3-propionic acid is expected to be a potential compound for treating metabolic syndrome.