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Pharmacotherapy Feb 2024Acid-suppressive drugs (ASDs) are widely used in many gastric acid-associated diseases. Nocturnal acid breakthrough has been a common problem of many ASDs, such as... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Acid-suppressive drugs (ASDs) are widely used in many gastric acid-associated diseases. Nocturnal acid breakthrough has been a common problem of many ASDs, such as proton-pump inhibitors (PPIs) and H -receptor antagonists (H2RAs). Potassium-competitive acid blockers (P-CABs) are expected to solve this continuing conundrum. This article examined major ASDs and compared them with placebo in terms of nocturnal acid-inhibitory effects, using a network meta-analysis of randomized controlled trials (RCTs).
METHODS
To compare the effectiveness of major ASDs, a Bayesian network meta-analysis (NMA) was applied to process data extracted from RCTs. The plausible ranking for each regimen and some subgroups were assessed by surface under the cumulative ranking curves (SUCRA).
RESULTS
Fifty-five RCTs were conducted with 2015 participants. In terms of nocturnal acid-inhibitory effects, the overall results showed that tegoprazan (SUCRA 91.8%) and vonoprazan (SUCRA 91.0%) had the best performance, followed by new PPIs (including tenatoprazole and ilaprazole) (SUCRA 76.6%), additional H2RAs once at bedtime (AHB) (SUCRA 61.3%), isomer PPIs (including esomeprazole and dexlansoprazole) (SUCRA 38.6%), revaprazan (SUCRA 34.7%), traditional PPIs (including omeprazole, rabeprazole, pantoprazole, lansoprazole) (SUCRA 32.6%), H2RAs (SUCRA 23.1%), and placebo (SUCRA 0.3%). In some subgroups, the nocturnal acid-inhibitory effect of vonoprazan or tegoprazan was better than most of the other regimens, even new PPIs and AHB.
CONCLUSIONS
This is the first study to compare the effect of ASDs on inhibiting nocturnal acid breakthrough. Overall, in terms of nocturnal acid-inhibitory effect, vonoprazan and tegoprazan had an advantage against other regimens including H2RAs, isomer PPIs, traditional PPIs, AHB, and new PPIs. Even in some subgroups, such as language classification (English), types of study design (crossover-RCT), age (≤40 years), BMI (18.5-24.9 kg/m ), continent (Asia and North America), disease status (health), the duration of therapy (2 weeks), and time of administration (at daytime or at night-time), the nocturnal acid-inhibitory effect of vonoprazan or tegoprazan were better than most regimens, even AHB and new PPIs.
Topics: Humans; Adult; Pharmaceutical Preparations; Network Meta-Analysis; Proton Pump Inhibitors; Rabeprazole; Histamine H2 Antagonists; Benzene Derivatives; Imidazoles; Pyrroles; Sulfonamides
PubMed: 38049205
DOI: 10.1002/phar.2899 -
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue Sep 2023To investigate the effect of hyperoxia on intestinal metabolomics in mice.
OBJECTIVE
To investigate the effect of hyperoxia on intestinal metabolomics in mice.
METHODS
Sixteen 8-week-old male C57BL/6 mice were randomly divided into hyperoxia group and control group, with 8 mice in each group. The hyperoxia group was exposed to 80% oxygen for 14 days. Mice were anesthetized and euthanized, and cecal contents were collected for untargeted metabolomics analysis by liquid chromatography-mass spectrometry (LC-MS) combined detection. Orthogonal partial least square discriminant analysis (OPLS-DA), volcano plot analysis, heat map analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the effects of hyperoxia on metabolism.
RESULTS
(1) OPLS-DA analysis showed that RY was 0.967 and Q was 0.796, indicating that the model was reliable. (2) Volcano plot and heat map analysis showed significant statistical differences in the expression levels of metabolites between the two groups, with 541 up-regulated metabolites, 64 down-regulated metabolites, and 907 no differences, while the elevated 5-hydroxy-L-lysine was the most significant differential metabolite induced by high oxygen. (3) KEGG pathway enrichment analysis showed that porphyrin and chlorophyll metabolism (P = 0.005), lysine degradation (P = 0.047), and aromatic compound degradation (P = 0.024) were the targets affected by hyperoxia. (4) Differential analysis of metabolic products through KEGG enrichment pathway showed that hyperoxia had a significant impact on the metabolism of porphyrin and chlorophyll, lysine, and aromatic compounds such as benzene and o-cresol.
CONCLUSIONS
Hyperoxia significantly induces intestinal metabolic disorders. Hyperoxia enhances the metabolism of porphyrins and chlorophyll, inhibits the degradation of lysine, and delays the degradation of aromatic compounds such as benzene and o-cresol.
Topics: Mice; Male; Animals; Lysine; Hyperoxia; Benzene; Mice, Inbred C57BL; Metabolic Diseases; Oxygen; Chlorophyll; Porphyrins; Biomarkers
PubMed: 37803959
DOI: 10.3760/cma.j.cn121430-20230607-00427 -
ACS Applied Bio Materials Jul 2023The low endogenous regenerative capacity of the heart, added to the prevalence of cardiovascular diseases, triggered the advent of cardiac tissue engineering in the last...
The low endogenous regenerative capacity of the heart, added to the prevalence of cardiovascular diseases, triggered the advent of cardiac tissue engineering in the last decades. The myocardial niche plays a critical role in directing the function and fate of cardiomyocytes; therefore, engineering a biomimetic scaffold holds excellent promise. We produced an electroconductive cardiac patch of bacterial nanocellulose (BC) with polypyrrole nanoparticles (Ppy NPs) to mimic the natural myocardial microenvironment. BC offers a 3D interconnected fiber structure with high flexibility, which is ideal for hosting Ppy nanoparticles. BC-Ppy composites were produced by decorating the network of BC fibers (65 ± 12 nm) with conductive Ppy nanoparticles (83 ± 8 nm). Ppy NPs effectively augment the conductivity, surface roughness, and thickness of BC composites despite reducing scaffolds' transparency. BC-Ppy composites were flexible (up to 10 mM Ppy), maintained their intricate 3D extracellular matrix-like mesh structure in all Ppy concentrations tested, and displayed electrical conductivities in the range of native cardiac tissue. Furthermore, these materials exhibit tensile strength, surface roughness, and wettability values appropriate for their final use as cardiac patches. experiments with cardiac fibroblasts and H9c2 cells confirmed the exceptional biocompatibility of BC-Ppy composites. BC-Ppy scaffolds improved cell viability and attachment, promoting a desirable cardiomyoblast morphology. Biochemical analyses revealed that H9c2 cells showed different cardiomyocyte phenotypes and distinct levels of maturity depending on the amount of Ppy in the substrate used. Specifically, the employment of BC-Ppy composites drives partial H9c2 differentiation toward a cardiomyocyte-like phenotype. The scaffolds increase the expression of functional cardiac markers in H9c2 cells, indicative of a higher differentiation efficiency, which is not observed with plain BC. Our results highlight the remarkable potential use of BC-Ppy scaffolds as a cardiac patch in tissue regenerative therapies.
Topics: Polymers; Myocytes, Cardiac; Pyrroles; Cell Differentiation
PubMed: 37342003
DOI: 10.1021/acsabm.3c00303 -
Digestive Diseases and Sciences Mar 2024Low-dose aspirin (LDA) administration is associated with an elevated risk of recurring peptic ulcer (PU) and gastrointestinal (GI) hemorrhage. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Low-dose aspirin (LDA) administration is associated with an elevated risk of recurring peptic ulcer (PU) and gastrointestinal (GI) hemorrhage.
AIMS
This systematic review and Bayesian network meta-analysis aimed to comprehensively assess the effectiveness of diverse medications in preventing the recurrence of PU and GI hemorrhage in patients with a history of PU receiving long-term LDA therapy.
METHODS
This systematic review and network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered on PROSPERO (CRD42023406550). We searched relevant studies in main databases from inception to March 2023. All statistical analyses were performed using R (version 4.1.3), with the "Gemtc" (version 1.0-1) package. The pooled risk ratio (RR), corresponding 95% credible interval (95% CrI), and the surface under the cumulative ranking curve (SUCRA) were calculated.
RESULTS
11 Randomized clinical trials (RCTs) were included. The analysis underscored pantoprazole was the most efficacious for reducing the risk of PU recurrence (RR [95% CrI] = 0.02 [0, 0.28]; SUCRA: 90.76%), followed by vonoprazan (RR [95% CrI] = 0.03 [0, 0.19]; SUCRA: 86.47%), comparing with the placebo group. Pantoprazole also performed well in preventing GI hemorrhage (RR [95% CrI] = 0.01[0, 0.42]; SUCRA: 87.12%) compared with Teprenone.
CONCLUSIONS
For patients with a history of PU receiving LDA, pantoprazole and vonoprazan might be the optimal choices to prevent PU recurrence and GI hemorrhage.
Topics: Humans; Pantoprazole; Peptic Ulcer; Aspirin; Gastrointestinal Hemorrhage; Pyrroles; Sulfonamides
PubMed: 38252210
DOI: 10.1007/s10620-023-08233-4 -
Breast Cancer Research and Treatment Sep 2023In a phase II trial in patients with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In a phase II trial in patients with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb) enhanced T-cell activation and improved overall survival versus GCb alone. The survival benefit was more pronounced in patients with higher immune-related gene expression. We assessed immune cell subsets and used molecular profiling to further elucidate effects on antitumor immunity.
METHODS
Patients with mTNBC and ≤ 2 prior chemotherapy regimens for locally recurrent TNBC or mTNBC were randomized 1:1:1 to GCb on days 1 and 8, trilaciclib prior to GCb on days 1 and 8, or trilaciclib alone on days 1 and 8, and prior to GCb on days 2 and 9. Gene expression, immune cell populations, and Tumor Inflammation Signature (TIS) scores were assessed in baseline tumor samples, with flow cytometric analysis and intracellular and surface cytokine staining used to assess immune cell populations and function.
RESULTS
After two cycles, the trilaciclib plus GCb group (n = 68) had fewer total T cells and significantly fewer CD8+ T cells and myeloid-derived suppressor cells compared with baseline, with enhanced T-cell effector function versus GCb alone. No significant differences were observed in patients who received GCb alone (n = 34). Of 58 patients in the trilaciclib plus GCb group with antitumor response data, 27 had an objective response. RNA sequencing revealed a trend toward higher baseline TIS scores among responders versus non‑responders.
CONCLUSION
The results suggest that administering trilaciclib prior to GCb may modulate the composition and response of immune cell subsets to TNBC.
Topics: Humans; Carboplatin; Triple Negative Breast Neoplasms; Pyrimidines; Pyrroles; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37418031
DOI: 10.1007/s10549-023-07009-8 -
Virulence Dec 2023Candidiasis caused by infection has long been a serious human health problem. The pathogenicity of is mainly due to its virulence factors, which are novel targets of...
Candidiasis caused by infection has long been a serious human health problem. The pathogenicity of is mainly due to its virulence factors, which are novel targets of antifungal drugs for low risk of resistance development. In this study, we identified a maleimide compound [1-(4-methoxyphenyl)-1hydro-pyrrole-2,5-dione, MPD] that exerts effective anti-virulence activity. It could inhibit the process of adhesion, filamentation, and biofilm formation in . In addition, it exhibited low cytotoxicity, hemolytic activity, and drug resistance development. Moreover, in () infection model, the survival time of infected larvae was significantly prolonged under the treatment of MPD. Further, mechanism research revealed that MPD increased farnesol secretion by upregulating the expression of Dpp3. The increased farnesol inhibited the activity of Cdc35, which then decreased the intracellular cAMP content resulting in the inhibition of virulence factors via the Ras1-cAMP-Efg1 pathway. In all, this study evaluated the inhibitory effect of MPD on various virulence factors of and identified the underlying mechanisms. This suggests a potential application of MPD to overcome fungal infections in clinics.
Topics: Animals; Humans; Candida albicans; Virulence Factors; Farnesol; Candidiasis; Antifungal Agents; Maleimides; Biofilms; Hyphae
PubMed: 37367101
DOI: 10.1080/21505594.2023.2230009 -
Acta Dermato-venereologica Nov 2023Several non-randomized clinical trials and retrospective studies have demonstrated encouraging efficacy and well-tolerated safety of tofacitinib in the treatment of... (Observational Study)
Observational Study
Several non-randomized clinical trials and retrospective studies have demonstrated encouraging efficacy and well-tolerated safety of tofacitinib in the treatment of alopecia areata. However, there are scarce data on a large cohort of patients with alopecia areata in long-term real-world practice. This single-centre, retrospective, observational cohort study included 126 patients with alopecia areata treated with tofacitinib between February 2021 and December 2022. The aims of this study are to evaluate drug survival, effectiveness and safety of tofacitinib for treatment of alopecia areata, and to identify potential factors influencing long-term outcomes. Median duration of treatment was 23.00 (interquartile range (IQR) 15.00, 47.25) weeks. Median all-cause survival time of 126 patients treated with tofacitinib was 44 weeks (95% confidence interval (95% CI) 36.3, 51.7), and the all-cause drug retention rate at 12 weeks, 24 weeks and 48 weeks were 90.0%, 66.4% and 42.3%, respectively. The most common reason for discontinuation was complete remission/satisfaction. A total of 80 patients treated with tofacitinib for over 6 months were included in the efficacy analysis, the overall complete response rate at 24 weeks was 33.8% (27/80). No life-threatening serious adverse events occurred. Sex is an independent risk factor in predicting patient outcomes. This real-world study confirmed the high effectiveness and acceptable safety profile of tofacitinib in alopecia areata, with a satisfactory drug survival rate, and provides supporting data for the clinical application of tofacitinib in Chinese patients with alopecia areata.
Topics: Humans; Alopecia Areata; Retrospective Studies; Protein Kinase Inhibitors; Pyrroles
PubMed: 37955531
DOI: 10.2340/actadv.v103.13475 -
Cell Communication and Signaling : CCS Feb 2024Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1...
BACKGROUND
Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells.
METHOD
We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo.
RESULT
PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model.
CONCLUSION
Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.
Topics: Humans; Male; Animals; T-Lymphocytes; Prostate; Tumor Microenvironment; Prostatic Neoplasms; Cell Proliferation; Glycolysis; Cell Line, Tumor; Pyrroles
PubMed: 38326896
DOI: 10.1186/s12964-024-01493-1 -
Hepatology Communications Oct 2023Bile, which contains bile acids, the natural ligands for farnesoid x receptor (FXR), moves from the liver to the intestine through bile ducts. Ductular reaction often...
BACKGROUND
Bile, which contains bile acids, the natural ligands for farnesoid x receptor (FXR), moves from the liver to the intestine through bile ducts. Ductular reaction often occurs during biliary obstruction. A subset of patients with erythropoietic protoporphyria, an inherited genetic mutation in heme biosynthetic enzyme ferrochelatase, accumulate porphyrin-containing bile plugs, leading to cholestasis. Here, we examined the link between FXR, bile plug formation, and how heme biosynthesis relates to this connection.
METHODS
We treated female and male wild-type and global and tissue-specific Fxr knockout mice with a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine, an inhibitor of ferrochelatase, and examined the expression of heme biosynthetic genes. We mined FXR mouse ChIP-Seq data, performed biochemical and histological analysis, and tested HepG2 and primary human hepatocytes after treatment with obeticholic acid, an FXR agonist.
RESULTS
We observed that hepatic but not intestinal Fxr loss resulted in reduced bile plugs and ductular reaction in the liver. Then, we examined if FXR plays a regulatory role in heme biosynthesis and found significantly lower porphyrin accumulation in 3,5-diethoxycarbonyl-1, 4-dihydrocollidine-fed Fxr knockout mice. Gene expression and FXR mouse ChIP-Seq atlas analysis revealed that FXR orchestrates the expression of multiple heme biosynthetic enzymes. Finally, human HepG2 cells and primary human hepatocytes treated with obeticholic acid, showed increased expression of several heme biosynthetic genes.
CONCLUSIONS
Overall, our data show that hepatic Fxr is necessary to maintain ductular reaction and accumulation of bile plugs. FXR can direct the expression of multiple heme biosynthetic genes. Thus, modulating FXR activity in EPP patients may help alleviate its associated liver disease.
Topics: Animals; Female; Humans; Male; Mice; Cholestasis; Ferrochelatase; Heme; Liver; Porphyrins
PubMed: 37695073
DOI: 10.1097/HC9.0000000000000213 -
Bioorganic & Medicinal Chemistry Feb 2024A structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity...
A structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspin was determined by X-ray crystallography.
Topics: Protein Kinase Inhibitors; Pyrroles; Structure-Activity Relationship; Protein Serine-Threonine Kinases; Isoquinolines
PubMed: 38320389
DOI: 10.1016/j.bmc.2024.117619