Safety, Tolerability, and Pharmacokinetic of HY0721 in Chinese Healthy Subjects: a First-in-human randomized, double-blind, placebo-controlled dose escalation Phase I study.

BACKGROUND: HY0721 is a novel inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. METHODS: The study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. RESULTS: The administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. CONCLUSION: This study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. TRIAL REGISTRATION: ChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020.

Effects of different addition levels of CHM-JM113 on growth performance, antioxidant capacity, organ index, and intestinal health of AA broilers.

The purpose of the present study was to investigate the effects of different levels of a Chinese herbal medicine formulation combined with JM113 (CHM-JM113) on growth performance, antioxidant capacity, organ index, and intestinal health of AA broilers. The AA broiler chicks were randomly allocated to 5 treatments as follows: a basic diet for the control group, the basic diet supplemented with 0.25% CHM-JM113, 0.5% CHM-JM113, 1% CHM-JM113 and 2% CHM-JM113 for the treatment group, respectively. The results showed that the addition of CHM-JM113 to the diet significantly reduced the mortality (p < 0.01) and improved the European Broiler Index (EBI) (p < 0.05), whereas it had no significance on growth performance of AA broilers (p > 0.05). Comparing the control group, 0.5 and 1% CHM-JM113 group significantly improved the organ index of liver, spleen and bursa (p < 0.05). In terms of intestinal morphology and structure, the addition of different levels of CHM-JM113 increased VH and VH/CD ratio, decreased CD in the small intestine compared to the control group, with 1 and 2% of the additive dose being more effective (p < 0.05). Chinese herbal medicine and probiotics as natural antioxidants also significantly increased the content of SOD in serum of 21-day-old broilers (p < 0.01), and significantly decreased the content of MDA in serum (p < 0.01). At 42 days of age, the addition of 1 and 2% CHM-JM113 significantly increased the content of SOD (p < 0.01) and significantly decreased the content of MDA in the organism (p < 0.01), accompanied by a significant increase in T-AOC and CAT content. In the study of the effect of CHM-JM113 on intestinal immunity, compared with the control group, we found that 1% or 2% CHM-JM113 had a better effect on the expression of occludin and claudin-1 in the intestinal segments of broilers (p < 0.05). For the expression of GATA-3, 0.5% CHM-JM113 may have a better effect (p < 0.05). CHM-JM113 may be used as an antibiotic alternative in broiler production.

Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Effects of swine manure and straw biochars on fluorine adsorption-desorption in soils.

With increasing global awareness of soil health, attention must be paid to fluorine exposure in soils, which poses a threat to human health. Therefore, this study aimed to study the fluorine adsorption characteristics of swine manure and straw biochars and their impact on fluorine adsorption-desorption in soil with batch experiments. The biochar samples originated from high-temperature anaerobic cracking of swine manure (350°C, 500°C, and 650°C) and straw (500°C). Results indicated that the adsorption of soil fluorine reached adsorption equilibrium at around 4 h after the mixing of swine manure and straw biochar. Fluorine adsorption kinetics using these biochars conformed to the quasi-two-stage kinetic model. The fluorine adsorption kinetics for biochar-treated soils conformed to the double-constant equation and the Elovich equation, and the soil treated with straw biochar showed the fastest fluorine adsorption rate. The adsorption isotherms of fluorine for biochars and biochar-treated soils could be fitted by the isothermal adsorption model of Langmuir and Freundlich. The maximal equilibrium quantity of fluorine was 73.66 mg/g for swine manure biochar. The soil, adding with 2% of swine manure biochar achieved with showed at 650°C had the smallest adsorption. This study also shows that the adsorption of fluorine by biochar gradually decreased with the increase of pH. Comparing with other factors, the mixture pH with biochars added had a significant effect on fluorine adsorption. The decreased fluorine adsorption capacities for soils treated with swine manure and straw biochars were closely related to the increased pH in soils after adding biochars. Considering the fluorine threat in soil, this study provides a theoretical basis for the application of biochars on soil fluorine adsorption.

Cholecystohepatic shunt pathway reduces secondary bile acid accumulation to enhance natural killer T cell-mediated anti-hepatocellular carcinoma immunity.

BACKGROUND AND AIM: The impact of cholecystectomy, which blocks the cholecystohepatic shunt pathway (CHSP), on the prognosis of patients with hepatocellular carcinoma (HCC) is unclear. Hepatic secondary bile acids (BAs) inhibit natural killer T (NKT) cell-mediated immunity against HCC, and the regulation of homeostasis of hepatic secondary BAs is controlled by the CHSP. However, the influence of CHSP on NKT cell-mediated immunity against HCC remains unclear. METHODS: The clinical data of hospitalized patients undergoing HCC resection were collected. Meanwhile, an in situ HCC mouse model was established, and the CHSP was augmented using oleanolic acid (OA). RESULTS: After 1:1 propensity score matching, Cox regression analysis revealed that cholecystectomy was an independent risk factor for HCC recurrence after hepatectomy (P = 0.027, hazard ratio: 1.599, 95% confidence interval: 1.055-2.422). Experimentally, when OA enhanced CHSP, a significant decrease was observed in the accumulation of secondary BAs in the livers of mice. Additionally, a significant increase was observed in the levels of C-X-C ligand 16 and interferon γ in the serum and tumor tissues. Further, the percentage of C-X-C receptor 6 (+) NKT cells in the tumor tissues increased significantly, and the growth of liver tumors was inhibited. CONCLUSIONS: This clinical study revealed that cholecystectomy promoted the recurrence after radical hepatectomy in patients with HCC. Preserving the normal-functioning gallbladder as much as possible during surgery may be beneficial to the patient's prognosis. Further investigation into the mechanism revealed that CHSP enhanced NKT cell-mediated immunity against HCC by reducing the hepatic accumulation of secondary BAs.

PCV2 Induced Endothelial Derived IL-8 Affects MoDCs Maturation Mainly via NF-κB Signaling Pathway.

Porcine circovirus type 2 (PCV2) infection can cause immunosuppressive diseases in pigs. Vascular endothelial cells (VECs), as the target cells for PCV2, play an important role in the immune response and inflammatory regulation. Endothelial IL-8, which is produced by porcine hip artery endothelial cells (PIECs) infected with PCV2, can inhibit the maturation of monocyte-derived dendritic cells (MoDCs). Here, we established a co-culture system of MoDCs and different groups of PIECs to further investigate the PCV2-induced endothelial IL-8 signaling pathway that drives the inhibition of MoDC maturation. The differentially expressed genes related to MoDC maturation were mainly enriched in the NF-κB and JAK2-STAT3 signaling pathways. Both the NF-κB related factor RELA and JAK2-STAT3 signaling pathway related factors (IL2RA, JAK, STAT2, STAT5, IL23A, IL7, etc.) decreased significantly in the IL-8 up-regulated group, and increased significantly in the down-regulated group. The expression of NF-κB p65 in the IL-8 up-regulated group was reduced significantly, and the expression of IκBα was increased significantly. Nuclear translocation of NF-κB p65 was inhibited, while the nuclear translocation of p-STAT3 was increased in MoDCs in the PCV2-induced endothelial IL-8 group. The results of treatment with NF-κB signaling pathway inhibitors showed that the maturation of MoDCs was inhibited and the expression of IL-12 and GM-CSF at mRNA level were lower. Inhibition of the JAK2-STAT3 signaling pathway had no significant effect on maturation, and the expression of IL-12 and GM-CSF at mRNA level produced no significant change. In summary, the NF-κB signaling pathway is the main signaling pathway of MoDC maturation, and is inhibited by the PCV2-induced up-regulation of endothelial-derived IL-8.

Inverted loading strategy regulates the Mn-OV-Ce sites for efficient fenton-like catalysis.

Regulating interfacial active sites to improve peroxymonosulfate (PMS) activation efficiency is a hot topic in the heterogeneous catalysis field. In this study, we develop an inverted loading strategy to engineer asymmetric Mn-OV-Ce sites for PMS activation. Mn3O4@CeO2 prepared by loading CeO2 nanoparticles onto Mn3O4 nanorods exhibits the highest catalytic activity and stability, which is due to the formation of more oxygen vacancies (OV) at the Mn-OV-Ce sites, and the surface CeO2 layer effectively inhibits corrosion by preventing the loss of manganese ion active species into the solution. In situ characterizations and density functional theory (DFT) studies have revealed effective bimetallic redox cycles at asymmetric Mn-OV-Ce active sites, which promote surface charge transfer, enhance the adsorption reaction activity of active species toward pollutants, and favor PMS activation to generate (•OH, SO4•-, O2•- and 1O2) active species. This study provides a brand-new perspective for engineering the interfacial behavior of PMS activation.

Factors associated with health behaviours among stroke survivors: A mixed-methods study using COM-B model.

AIMS: To identify factors associated with health behaviours among stroke survivors, through a multi-centre study. DESIGN: A sequential mixed methods design. METHODS: In the quantitative research phase, a total of 350 participants were recruited through multi-stage sampling from December 2022 to June 2023. General information questionnaires, The Stroke Prevention Knowledge Questionnaire (SPKQ), Short Form Health Belief Model Scale (SF-HBMS), Health Promoting Lifestyle Profile (HPLPII), and the WHOQOL-BREF (World Health Organization Quality of Life Questionnaire, Brief Version) were distributed across five tertiary hospitals in Henan province, China. For the qualitative research component, semi-structured interviews were conducted to explore the barriers and facilitators of health behaviour. This study adheres to the GRAMMS guidelines. RESULTS: A total of 315 participants (90.0%) completed the survey. Identified barriers to health behaviour included residing in rural areas, higher scores on the Charlson Comorbidity Index (CCI) and mRS, as well as lower scores on SPKQ, SF-HBMS and WHOQOL-BREF. Twenty-four individuals participated in qualitative interviews. Twenty-eight themes were identified and categorised by frequency, covering areas such as knowledge, skills, intentions, social influences, social/professional role and identity, environmental context and resources, beliefs about capabilities, beliefs about consequences and behavioural regulation. Both quantitative and qualitative data suggested that health behaviour among stroke survivors is at a moderate level, and the identified barrier factors can be mapped into the COM-B model (Capability, Opportunity, Motivation and Behaviour). CONCLUSION: The study indicates that key barriers to health behaviour among stroke survivors align with the COM-B model. These identified factors should be carefully considered in the planning of future systematic interventions aimed at improving health behaviours among stroke survivors. PATIENT OR PUBLIC CONTRIBUTION: Patients were invited to completed questionnaires in the study and semi-structured interviews. The investigators provided explanation of this study' content, purpose and addressed issues during the data collection.

Regulating Mo-based alloy-oxide active interfaces for efficient alkaline hydrogen evolution assisted by hydrazine oxidation.

Improving the efficiency of overall water splitting (OWS) is crucial due to the slow four-electron transfer process in the oxygen evolution reaction (OER). The coupling of the thermodynamically favorable hydrazine oxidation reaction (HzOR) with the hydrogen evolution reaction (HER) significantly boosts hydrogen production. A Ru-decorated MoNi/MoO2 micropillar (Ru-MoNi/MoO2) has been synthesized using a hydrothermal followed by reduction annealing. Benefiting from Ru moderating the active interface of Mo-based alloys/oxides and the unique one-dimensional micropillar morphology. The synthesized Ru-MoNi/MoO2 exhibits outstanding bifunctional activity for HER and HzOR, achieving 10 mA cm-2 at merely -13 mV and -34 mV in 1 M KOH and 1 M KOH + 0.5 M N2H4, respectively. Notably, with Ru-MoNi/MoO2 in a dual-electrode setup, only 0.57 V is needed to achieve 50 mA cm-2, demonstrating good stability and facilitating hydrazine-assisted water splitting (OHzS). This work offers insights into the modulation of alloy/metal oxide active interfaces, contributing to the development of efficient bifunctional catalysts for HER and HzOR.

A potential virulence factor: Brucella flagellin FliK does not affect the main biological properties but inhibits the inflammatory response in RAW264.7 cells.

The bacterial flagellum is an elongated filament that protrudes from the cell and is responsible for bacterial motility. It can also be a pathogen-associated molecular pattern (PAMP) that regulates the host immune response and is involved in bacterial pathogenicity. In contrast to motile bacteria, the Brucella flagellum does not serve a motile purpose. Instead, it plays a role in regulating Brucella virulence and the host's immune response, similar to other non-motile bacteria. The flagellin protein, FliK, plays a key role in assembly of the flagellum and also as a potential virulence factor involved in the regulation of bacterial virulence and pathogenicity. In this study, we generated a Brucella suis S2 flik gene deletion strain and its complemented strain and found that deletion of the flik gene has no significant effect on the main biological properties of Brucella, but significantly enhanced the inflammatory response induced by Brucella infection of RAW264.7 macrophages. Further experiments demonstrated that the FliK protein was able to inhibit LPS-induced cellular inflammatory responses by down-regulating the expression of MyD88 and NF-κB, and by decreasing p65 phosphorylation in the NF-κB pathway; it also inhibited the expression of NLRP3 and caspase-1 in the NLRP3 inflammasome pathway. In conclusion, our study suggests that Brucella FliK may act as a virulence factor involved in the regulation of Brucella pathogenicity and modulation of the host immune response.

Disrupted gut microecology after high-dose 131I therapy and radioprotective effects of arachidonic acid supplementation.

BACKGROUND: Despite the potential radiotoxicity in differentiated thyroid cancer (DTC) patients with high-dose 131I therapy, the alterations and regulatory mechanisms dependent on intestinal microecology remain poorly understood. We aimed to identify the characteristics of the gut microbiota and metabolites in DTC patients suffering from high-dose 131I therapy and explore the radioprotective mechanisms underlying arachidonic acid (ARA) treatment. METHODS: A total of 102 patients with DTC were recruited, with fecal samples collected before and after 131I therapy for microbiome and untargeted and targeted metabolomic analyses. Mice were exposed to total body irradiation with ARA replenishment and antibiotic pretreatment and were subjected to metagenomic, metabolomic, and proteomic analyses. RESULTS: 131I therapy significantly changed the structure of gut microbiota and metabolite composition in patients with DTC. Lachnospiraceae were the most dominant bacteria after 131I treatment, and metabolites with decreased levels and pathways related to ARA and linoleic acid were observed. In an irradiation mouse model, ARA supplementation not only improved quality of life and recovered hematopoietic and gastrointestinal systems but also ameliorated oxidative stress and inflammation and preserved enteric microecology composition. Additionally, antibiotic intervention eliminated the radioprotective effects of ARA. Proteomic analysis and ursolic acid pretreatment showed that ARA therapy greatly influenced intestinal lipid metabolism in mice subjected to irradiation by upregulating the expression of hydroxy-3-methylglutaryl-coenzyme A synthase 1. CONCLUSION: These findings highlight that ARA, as a key metabolite, substantially contributes to radioprotection. Our study provides novel insights into the pivotal role that the microbiota-metabolite axis plays in radionuclide protection and offers effective biological targets for treating radiation-induced adverse effects.

Identification and affinity enhancement of T-cell receptor targeting a KRASG12V cancer neoantigen.

Neoantigens derived from somatic mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), the most frequently mutated oncogene, represent promising targets for cancer immunotherapy. Recent research highlights the potential role of human leukocyte antigen (HLA) allele A*11:01 in presenting these altered KRAS variants to the immune system. In this study, we successfully generate and identify murine T-cell receptors (TCRs) that specifically recognize KRAS8-16G12V from three predicted high affinity peptides. By determining the structure of the tumor-specific 4TCR2 bound to KRASG12V-HLA-A*11:01, we conduct structure-based design to create and evaluate TCR variants with markedly enhanced affinity, up to 15.8-fold. This high-affinity TCR mutant, which involved only two amino acid substitutions, display minimal conformational alterations while maintaining a high degree of specificity for the KRASG12V peptide. Our research unveils the molecular mechanisms governing TCR recognition towards KRASG12V neoantigen and yields a range of affinity-enhanced TCR mutants with significant potential for immunotherapy strategies targeting tumors harboring the KRASG12V mutation.

Resourcefulness Among Initial Ischemic Stroke Patients: A Longitudinal Study of 12 Months.

Objective: To explore distinct longitudinal trajectories of resourcefulness among initial ischemic stroke patients from diagnosis to 12 months, and to identify whether sociodemographic factors, disease-related factors, self-efficacy, family function, and social support can predict patterns in the trajectories of resourcefulness. Methods: A prospective longitudinal study was conducted. Initial ischemic stroke patients who met inclusion and exclusion criteria were followed up when still in hospital (Preparing for discharge, Baseline, T1), at 1 month (T2), at 3 months (T3), at 6 months (T4), at 9 months (T5) and 12 months (T6) (±1 week) after discharge. General information, National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), General Self-Efficacy Scale (GSES), General Family Functioning Subscale (FAD-GF), and Social Support Rate Scale (SSRS) were used in T1. The Resourcefulness Scale© was evaluated at 6 time points. Growth mixture modeling was used to identify trajectory patterns of resourcefulness. Logistic regression was used to identify predictors of resourcefulness trajectories. Results: Three longitudinal trajectories of resourcefulness were identified and named as the high-stable class (38.9%, n=71), fluctuation class (41.2%, n=75), and low-stable class (19.9%, n=36), respectively. Dwelling areas (x2=6.805, P=0.009), education (x2=44.865, P=0.000), monthly income (x2=13.063, P=0.001), NIHSS scores (x2=44.730, P=0.000), mRS scores (x2=51.788, P=0.000), Hcy (x2=9.345, P=0.002), GSES (x2=56.933, P=0.000), FAD-GF (x2=41.305, P=0.000) and SSRS (x2=52.373, P=0.000) were found to be statistically significant for distinguishing between different resourcefulness trajectory patterns. Lower education (OR=0.404), higher NIHSS(OR=6.672) scores, and higher mRS(OR=21.418) scores were found to be risk factors for lower resourcefulness, whereas higher education(OR=0.404), GSES(OR=0.276), FAD-GF(OR=0.344), and SSRS(OR=0.358) scores were identified as protective factors enhancing resourcefulness. Conclusion: This study obtained three patterns of trajectories and identified their predictive factors in initial ischemic stroke. The findings will assist health care professionals in identifying subgroups of patients and when they may be at risk of low resourcefulness and provide timely targeted intervention to promote resourcefulness.

Design and biological evaluation of dual tubulin/HDAC inhibitors based on millepachine for treatment of prostate cancer.

In this work, a novel of dual tubulin/HDAC inhibitors were designed and synthesized based on the structure of natural product millepachine, which has been identified as a tubulin polymerization inhibitor. Biological evaluation revealed that compound 9n exhibited an impressive potency against PC-3 cells with the IC50 value of 16 nM and effectively inhibited both microtubule polymerization and HDAC activity. Furthermore, compound 9n not only induced cell cycle arrest at G2/M phase, but also induced PC- 3 cells apoptosis. Further study revealed that the induction of cell apoptosis by 9n was accompanied by a decrease in mitochondrial membrane potential and an elevation in reactive oxygen species levels in PC-3 cells. Additionally, 9n exhibited inhibitory effects on tumor cell migration and angiogenesis. In PC-3 xenograft model, 9n achieved a remarkable tumor inhibition rate of 90.07%@20 mg/kg, significantly surpassing to that of CA-4 (55.62%@20 mg/kg). Meanwhile, 9n exhibited the favorable drug metabolism characteristics in vivo. All the results indicate that 9n is a promising dual tubulin/HDAC inhibitor for chemotherapy of prostate cancer, deserving the further investigation.

Persistent effects of swine manure biochar and biogas slurry application on soil nitrogen content and quality of lotus root.

Using swine manure biochar and biogas slurry in agriculture proves to be an effective strategy for soil improvement and fertilization. In this study, a pot trial on the growth of lotus root was conducted to investigate the persistent effects of applying 350°C swine manure biochar (1% and 2%) and biogas slurry (50% and 100%) on soil nitrogen nutrient and lotus root quality. The results showed that compared to chemical fertilizer alone (A0B0), swine manure biochar significantly increased soil nitrogen content after one year of application. The contents of total nitrogen (TN), alkali-hydrolyzed nitrogen (AHN), ammonium nitrogen (NH4 +-N), and nitrate nitrogen (NO3- -N) increased by 17.96% to 20.73%, 14.05% to 64.71%, 17.76% to 48.68% and 2.22% to 8.47%, respectively, during the rooting period. When swine manure biochar was present, the application of biogas slurry further elevated soil nitrogen content. The co-application of swine manure biochar and biogas slurry significantly increased soil nitrogen content, and the 100% nitrogen replacement with biogas slurry combined with 2% swine manure biochar (A2B2) treatment exhibited the most significant enhancement effect during whole plant growth periods. Soil enzyme activities, including soil protease (NPT), leucine aminopeptidase (LAP), b-glucosidase (ß-GC) and dehydrogenase (DHA), showed a tendency to increase and then decrease with the prolongation of lotus root fertility period, reaching the maximum value during the rooting period. Compared to A0B0, the treatment with 2% swine manure biochar had the most significant effect on enzyme activities and increased the lotus root's protein, soluble sugar, and starch contents. Nitrate content decreased with the application of 2% swine manure biochar as the amount of biogas slurry increased. In conclusion, swine manure biochar effectively improved soil nitrogen content, enzyme activity, and lotus root quality. Even after one year of application, 2% swine manure biochar had the best enhancement effect.

Targeting HOXA11-AS to mitigate prostate cancer via the glycolytic metabolism: In vitro and in vivo.

As oncogenes or oncogene suppressors, long-stranded non-coding RNAs are essential for the formation and progression of human tumours. However, the mechanisms behind the regulatory role of RNA HOXA11-AS in prostate cancer (PCa) are unclear. PCa is a common malignant tumour worldwide, and an increasing number of studies have focused on its metabolic profile. Studies have shown that the long non-coding RNA (lncRNA) HOXA11-AS is aberrantly expressed in many tumours. However, the role of HOXA11-AS in PCa is unclear. This work aimed to determine how HOXA11-AS regulated PCa in vitro and in vivo. We first explored the clinical role of HOXA11-AS in PCa using bioinformatics methods, including single sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO)-logistics systematically. In this study, PCa cell lines were selected to assess the PCa regulatory role of HOXA11-AS overexpression versus silencing in vitro, and tumour xenografts were performed in nude mice to assess tumour suppression by HOXA11-AS silencing in vivo. HOXA11-AS expression was significantly correlated with clinicopathological factors, epithelial-mesenchymal transition (EMT) and glycolysis. Moreover, key genes downstream of HOXA11-AS exhibited good clinical diagnostic properties for PCa. Furthermore, we studied both in vitro and in vivo effects of HOXA11-AS expression on PCa. Overexpression of HOXA11-AS increased PCa cell proliferation, migration and EMT, while silencing HOXA11-AS had the opposite effect on PCa cells. In addition, multiple metabolites were downregulated by silencing HOXA11-AS via the glycolytic pathway. HOXA11-AS silencing significantly inhibited tumour development in vivo. In summary, silencing HOXA11-AS can inhibit PCa by regulating glucose metabolism and may provide a future guidance for the treatment of PCa.

A new methodology to reveal potential nucleic acid modifications associated with the risk of endometrial cancer through dispersive solid-phase extraction coupled with UHPLC-QE-Orbitrap-MS/MS and HPLC-UV.

Nucleic acid modifications have attracted increasing attention in recent years since they have been found to be related to a number of diseases including cancer. Previous studies have shown that the early development of endometrial cancer (EC) is often accompanied by changes in methylation levels of related genes, and the expression of related proteins that regulate reactive oxygen species (ROS) shows significant differences in EC cells and tissues. However, it has not been reported whether nucleic acid modifications related to methylation or ROS can serve as biomarkers for EC. Accurate quantification of these nucleic acid modifications still has challenges because their amounts in urine are very low and the interferences in urine are complicated. In this study, a novel dispersive solid-phase extraction (DSPE) method based on chitosan-carbon nanotube-Al2O3 (CS-CNT-Al2O3) has been established for the analysis of 5-hydroxymethyluracil (5 mU), 5-methyl-2'-deoxycytidine (5-mdC), 5-hydroxymethyl-2'-deoxycytidine (5-hmdC), 5-formyl-2'-deoxycytidine (5-fdC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in EC patient urine samples coupled with UHPLC-QE-Orbitrap-MS/MS and HPLC-UV. Firstly, the synthesis of the CS-CNT-Al2O3 nanocomposite was conducted by a sono-coprecipitation method and was characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDS), and Fourier transform infrared (FTIR). Under the optimal extraction conditions of DSPE, we successfully quantified 5 mU, 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG in urine samples from 37 EC patients and 39 healthy controls. The results showed that there were significant differences in the levels of 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG in EC patients compared to the healthy control group. The receiver operator characteristic (ROC) curve analysis was carried out to evaluate the potential of 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG to distinguish EC patients from healthy volunteers. The area under the curve (AUC) for 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG was 0.7412, 0.667, 0.8438, and 0.7981, respectively. It indicated that 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG had certain potential in distinguishing between EC patients and healthy volunteers and they could act as potential non-invasive biomarkers for early diagnosis of EC. Moreover, the present study would stimulate investigations of the effects of nucleic acid modifications on the initiation and progression of EC.

Comparative Efficacy of P-CAB vs Proton Pump Inhibitors for Grade C/D Esophagitis: A Systematic Review and Network Meta-analysis.

INTRODUCTION: Los Angeles grade C/D esophagitis is a severe manifestation of gastroesophageal reflux disease that require active treatment and close follow-up. Potassium competitive acid blockers (P-CAB) are promising alternatives to proton pump inhibitors (PPI). We aimed to compare the efficacy and safety of P-CAB and PPI in healing grade C/D esophagitis to aid clinical decision-making. METHODS: A systematic literature search was performed using PubMed, MEDLINE, and Cochrane Central Register of Controlled Trials. Randomized controlled trials were eligible for inclusion if efficacy of P-CAB and PPI in healing grade C/D esophagitis was reported. Pooled risk ratios and risk difference with 95% credible intervals were used to summarize estimated effect of each comparison. The benefit of treatments was ranked using the surface under the cumulative probability ranking score. RESULTS: Of 5,876 articles identified in the database, 24 studies were eligible. Studies included incorporated 3 P-CAB (vonoprazan, tegoprazan, and keverprazan) and 6 PPI (lansoprazole, esomeprazole, omeprazole, rabeprazole extended-release (ER), pantoprazole, and dexlansoprazole). Based on the failure to achieve mucosal healing, 20 mg of vonoprazan q.d. ranked the first among PPI in initial and maintained healing of grade C/D esophagitis (surface under the cumulative probability ranking score = 0.89 and 0.87, respectively). Vonoprazan had similar risk of incurring adverse events, severe adverse events, and withdrawal to drug when compared with PPI. For those who attempted lower maintenance treatment dose, 10 mg of vonoprazan q.d. was a reasonable choice, considering its moderate efficacy and safety. DISCUSSION: Vonoprazan has considerable efficacy in initial and maintained healing of grade C/D esophagitis compared with PPI, with moderate short-term and long-term safety.

MicroRNA-145-5p Regulates the Epithelial-Mesenchymal Transition in Nasal Polyps by Targeting Smad3.

OBJECTIVES: The annual prevalence of chronic rhinosinusitis (CRS) is increasing, and the lack of effective treatments imposes a substantial burden on both patients and society. The formation of nasal polyps in patients with CRS is closely related to tissue remodeling, which is largely driven by the epithelial-mesenchymal transition (EMT). MicroRNA (miRNA) plays a pivotal role in the pathogenesis of numerous diseases through the miRNA-mRNA regulatory network; however, the specific mechanism of the miRNAs involved in the formation of nasal polyps remains unclear. METHODS: The expression of EMT markers and Smad3 were detected using western blots, quantitative real-time polymerase chain reaction, and immunohistochemical and immunofluorescence staining. Differentially expressed genes in nasal polyps and normal tissues were screened through the Gene Expression Omnibus database. To predict the target genes of miR-145-5p, three different miRNA target prediction databases were used. The migratory ability of cells was evaluated using cell migration assay and wound healing assays. RESULTS: miR-145-5p was associated with the EMT process and was significantly downregulated in nasal polyp tissues. In vitro experiments revealed that the downregulation of miR-145-5p promoted EMT. Conversely, increasing miR-145-5p levels reversed the EMT induced by transforming growth factor-ß1. Bioinformatics analysis suggested that miR-145-5p targets Smad3. Subsequent experiments confirmed that miR-145-5p inhibits Smad3 expression. CONCLUSION: Overall, miR-145-5p is a promising target to inhibit nasal polyp formation, and the findings of this study provide a theoretical basis for nanoparticle-mediated miR-145-5p delivery for the treatment of nasal polyps.