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INTRODUCTION: Endometriosis, a common and distressing gynecological condition, affects fertility and causes pain, is often managed with medications such as Elagolix. The present study aimed to construct a physiologically based pharmacokinetic (PBPK) model for elagolix to predict its pharmacokinetics in different populations, including those with special conditions, to enhance treatment strategies for endometriosis. METHODS: The PBPK model was optimized using observational data based on the oral administration of elagolix in a healthy Chinese population under fasting conditions. Model accuracy was further verified by comparing the predicted postprandial elagolix concentration data for healthy Chinese individuals with observed data and by comparing these values with the predicted values in a US population model with renal injury or following multiple-dose administration. RESULTS: Elagolix pharmacokinetic (PK) profiles in the Chinese and American populations exhibited no differences that were attributable to ethnicity. The model predicted in vivo PK in adolescents aged 14-18 years, revealing no clinically significant differences in the effects of elagolix between adolescents and adults. In addition, no predicted PK differences in individuals with overweight were observed. However, notable variations emerged in those classified as obesity class 2 and above compared to healthy individuals. CONCLUSION: Our study presents a novel PBPK model for elagolix in healthy Chinese women, addressing a clinical data gap for its use in adolescents and obese patients. By validating the model with real-world factors, including diet and renal impairment, we provide initial pharmacokinetic predictions for these populations, contributing to a more informed clinical approach.
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Resistant hypertension (RH) poses a significant health challenge, yet its underlying pathogenesis remains unclear. This study employs untargeted proteomic techniques to analyze the plasma of patients with RH and controlled hypertension (CH), identifying 157 differentially expressed proteins, with TGFB1 emerging as a key candidate. Through gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Protein-Protein Interaction Networks (PPI) topological analysis, TGFB1's differential regulation in RH is established. ELISA verification solidifies TGFB1's role, marking it as a potential biological target for early RH diagnosis and treatment. The study underscores the importance of proteomic approaches in enhancing our understanding of RH and improving therapeutic strategies. These findings carry implications for advancing RH diagnostics and treatment modalities, addressing a critical gap in current knowledge.
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Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/ß-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process.
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Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular , MicroRNAs , Animais , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Valva Aórtica/patologia , Valva Aórtica/metabolismo , Camundongos , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Via de Sinalização Wnt , Modelos Animais de Doenças , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Humanos , Metiltransferases/metabolismo , Metiltransferases/genética , RNA Circular/genética , RNA Circular/metabolismo , MasculinoRESUMO
Nitazoxanide (NTZ) is an effective antiparasitic drug with potent antiviral and antimicrobial activity. This randomized, open-label, 2-sequence, 2-period crossover trial was designed to evaluate the bioequivalence (BE) of the NTZ dry suspension in healthy subjects and investigated the effect of food intake on the pharmacokinetic (PK) properties of tizoxanide (an active metabolite of NTZ, TIZ). Sixty healthy Chinese subjects were enrolled and received a single dose of 500 mg/25 mL of preparations on days 1 and 4 under overnight fasting or fed conditions, respectively. The plasma concentration of TIZ was determined using high-performance liquid chromatography/tandem mass spectrometry. PK parameters were calculated using WinNonlin 8.2 and BE was evaluated using SAS 9.4. The 90% confidence intervals for the geometric mean ratio (test/reference) of maximum concentration (Cmax), the area under the curve from time 0 to the time of the last quantifiable concentration (AUC0-t), and the area under the curve from time 0 to extrapolation to infinity (AUC0-∞) were all within the equivalent interval of 80%-125%, compliant with BE requirements. In comparison with fasting, on taking the reference and test preparations of the NTZ dry suspension after a meal, the AUC0-t increased by 48.9% and 47.3%, respectively, the AUC0-∞ increased by 48.4% and 48.3%, respectively, and the post-meal Tmax was prolonged by 1.8-2 hours. Our results demonstrate that the test and reference preparations were bioequivalent. High-fat meals significantly improve the degree of drug absorption and delay the rate of drug absorption.
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Área Sob a Curva , Estudos Cross-Over , Interações Alimento-Droga , Voluntários Saudáveis , Nitrocompostos , Suspensões , Equivalência Terapêutica , Tiazóis , Humanos , Masculino , Adulto , Adulto Jovem , Administração Oral , Tiazóis/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/sangue , Feminino , Nitrocompostos/farmacocinética , Nitrocompostos/administração & dosagem , Jejum , Antiparasitários/farmacocinética , Antiparasitários/administração & dosagem , Antiparasitários/sangue , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND: Among those with heart failure (HF), women are more likely to develop depression than men. Few studies have focused on the outcomes of female patients with HF with depressive symptoms. METHODS AND RESULTS: A total of 506 female patients with HF with preserved ejection fraction were included in this secondary analysis from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) cohort, and 439 female patients with HF with reduced ejection fraction were included from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) cohort. Depressive symptoms were measured using the Patient Health Questionnaire-9 and Beck Depression Inventory-II. The depression class was categorized by severity, and the change in clinical depression class was defined as aggravated (1-grade increase) or improved (1-grade decrease). The prognostic value of depressive symptoms was determined by using multivariable Cox proportional hazards models. Female patients with improved depressive symptoms had worse depressive status at baseline and lower baseline Kansas City Cardiomyopathy Questionnaire scores. Depression class at the 12-month visit and depression class change were the dominant prognostic factors for cardiovascular death in female patients with HF with preserved ejection fraction (hazard ratio [HR], 1.43 [95% CI, 1.02-2.01], P=0.036; HR, 1.71 [95% CI, 1.14-2.55], P=0.009). Among the patients with HF with reduced ejection fraction, both the depression class at baseline and depression class change had significant prognostic effects on cardiovascular death (HR, 3.30 [95% CI, 1.70-6.39], P<0.001; HR, 2.21 [95% CI, 1.28-3.80], P=0.004). However, the prognostic value of depressive assessments for hospitalization in patients with HF is unclear. CONCLUSIONS: In female patients with HF with reduced ejection fraction, the depression class at baseline was most strongly associated with cardiovascular death, whereas in female patients with HF with preserved ejection fraction, the change in depression class exhibited a more significant prognostic trend.
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Depressão , Insuficiência Cardíaca , Volume Sistólico , Humanos , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/psicologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/complicações , Volume Sistólico/fisiologia , Depressão/diagnóstico , Depressão/psicologia , Depressão/epidemiologia , Idoso , Pessoa de Meia-Idade , Prognóstico , Função Ventricular Esquerda , Fatores de Risco , Fatores Sexuais , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Modelos de Riscos Proporcionais , Fatores de TempoRESUMO
In this study, an ultra-performance liquid chromatography-tandem mass spectrometry method was established for the development and validation of baloxavir acid (BXA) concentrations and the active ingredients of the antiviral drug baloxavir marboxil (BXM). Further, the method was applied to study the pharmacokinetics of BXA. BXA was determined by the electrospray ionization multiple reaction monitoring positive ion mode, and the mass-to-charge ratios (m/z) of BXA and internal standard baloxavir-d4 were 484.2 â 247.2 and 488.1 â 247.2. An Oasis max online column (2.1 × 20 mm, 30 µm) was used with 1% formic acid in water (A) and 2% formic acid in acetonitrile (B) as mobile phases at a flow rate of 0.5 mL·min-1 for chromatographic separation. The linearity was good in the range of 3-200 ng·mL-1 (r = 0.9994), with 3.00 ng·mL-1 lower limit of quantification. The relative standard deviation of the inter-assay precision was less than or equal to 6.51%, and the accuracy was in the range of 91.28%-104.29%. This method is suitable for the determination of BXA and for performing pharmacokinetic studies in clinical research.
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BACKGROUND: Janagliflozin is a novel sodium-glucose cotransport-2 inhibitor. Despite its remarkable effect in glycemic control, no systematic research has evaluated the effect of renal impairment (RI) on its pharmacokinetics and pharmacodynamics. METHODS: Here, patients with T2DM (n = 30) were divided into normal renal function (eGFR ≥ 90 mL/min/1.73 m2), mild RI (eGFR between 60 and 89 mL/min/1.73 m2), moderate RI-I (eGFR between 45 and 59 mL/min/1.73 m2), and moderate RI-II (eGFR between 30 and 44 mL/min/1.73 m2) groups. They were administered 50 mg janagliflozin orally, and plasma and urine samples were collected for the determination of janagliflozin concentration. RESULTS: Following oral administration, janagliflozin was rapidly absorbed, with the time to Cmax of 2-6 h for janagliflozin and 3-6 h for its metabolite XZP-5185. Plasma exposure levels were similar for janagliflozin in T2DM patients with or without RI but decreased for the metabolite XZP-5185 in T2DM patients with eGFR between 45 and 89 mL/min/1.73 m2. Janagliflozin significantly promoted the excretion of urinary glucose, even in patients with reduced eGFR. Janagliflozin was well tolerated in patients with T2DM with or without RI, and no serious adverse events (SAEs) occurred during this trial. CONCLUSIONS: The exposure levels of janagliflozin in T2DM patients were slightly increased with worsening of RI (i.e., 11% increase in the AUC in patients with moderate RI compared with the normal renal function group). Despite worsening of renal function, janagliflozin exerted a significant pharmacologic effect and was well tolerated, even in patients with moderate RI, implying a promising role in the treatment of patients with in T2DM. REGISTRATION: China Drug Trial register ( http://www.chinadrugtrials.org.cn/I ) identifier no.: CTR20192721.
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Diabetes Mellitus Tipo 2 , Insuficiência Renal , Xilitol , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , População do Leste Asiático , Glucose/metabolismo , Insuficiência Renal/complicações , Xilitol/análogos & derivados , Xilitol/farmacocinéticaRESUMO
Hemodynamic overload and dysregulation of cellular metabolism are involved in development of calcific aortic valve disease (CAVD). However, how mechanical stress relates to metabolic changes in CAVD remains unclear. Here, we show that Piezo1, a mechanosensitive ion channel, regulated glutaminase 1 (GLS1)-mediated glutaminolysis to promote osteogenic differentiation of valve interstitial cells (VICs). In vivo, two models of aortic valve stenosis were constructed by ascending aortic constriction (AAC) and direct wire injury (DWI). Inhibition of Piezo1 and GLS1 in these models respectively mitigated aortic valve lesion. In vitro, Piezo1 activation induced by Yoda1 and oscillatory stress triggered osteogenic responses in VICs, which were prevented by Piezo1 inhibition or knockdown. Mechanistically, Piezo1 activation promoted calcium-dependent Yes-associated protein (YAP) activation. YAP modulated GLS1-mediated glutaminolysis, which enhanced osteogenic differentiation through histone acetylation of runt-related transcription factor 2 (RUNX2) promoters. Together, our work provided a cross-talk between mechanotransduction and metabolism in the context of CAVD.
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Valva Aórtica , Osteogênese , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Osteogênese/genética , Mecanotransdução Celular , Células Cultivadas , Diferenciação Celular/genéticaRESUMO
Macrophages are important effector cells in tumor progression and immune regulation. Previously, we demonstrated that the transcription suppressor homeobox containing 1(HMBOX1) exhibits immunosuppressive activity in LPS-induced acute liver injury by impeding macrophage infiltration and activation. We also observed a lower proliferation in HMBOX1-overexpressed RAW264.7 cells. However, the specific mechanism was unclear. Here, a work was performed to characterize HMBOX1 function related to cell proliferation from a metabolomics standpoint by comparing the metabolic profiles of HMBOX1-overexpressed RAW264.7 cells to those of the controls. Firstly, we assessed HMBOX1 anti-proliferation activity in RAW264.7 cells with CCK8 assay and clone formation. Then, we performed metabolomic analyses by ultra-liquid chromatography coupled with mass spectrometry to explore the potential mechanisms. Our results indicated that HMBOX1 inhibited the macrophage growth curve and clone formation ability. Metabolomic analyses showed significant changes in HMBOX1-overexpressed RAW264.7 metabolites. A total of 1312 metabolites were detected, and 185 differential metabolites were identified based on the criterion of OPLS-DA VIP > 1 and p value < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the elevated HMBOX1 in RAW264.7 inhibited the pathways of amino acid and nucleotide metabolism. Glutamine concentrations decreased significantly in HMBOX1-overexpressed macrophages, and glutamine-related transporter SLC1A5 was also downregulated. Furthermore, SLC1A5 overexpression reversed HMBOX1 inhibition of macrophage proliferation. This study demonstrated the potential mechanism of the HMBOX1/SLC1A5 pathway in cell proliferation by regulating glutamine transportation. The results may help provide a new direction for therapeutic interventions in macrophage-related inflammatory diseases.
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Glutamina , Proteínas de Homeodomínio , Camundongos , Animais , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Células RAW 264.7 , MetabolômicaRESUMO
INTRODUCTION: Lanqin Oral Liquid (LQL) is a traditional Chinese medicine preparation (TCMP) containing five herbal medicines and has been commonly used for the treatment of pharyngitis and hand-foot-and-mouth disease in clinic. The material basis of LQL has been reported in our previous study, but the contents of the major components and the features of saccharide in LQL are still unclear. OBJECTIVES: This study aimed to establish accurate and rapid methods for the quantification of the major components and profiling of saccharide in LQL. The quantitative results combined with similarity evaluation were applied to improve the quality control of LQL. METHODOLOGY: An ultra-high performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UPLC-QQQ-MS) method was utilised to determine 44 major components. Cosine similarity was used to evaluate the similarities among 20 batches of LQL based on the quantitative results of 44 major components. The physicochemical properties, structure, composition, and contents of saccharide in LQL were detected by a combination of chemical and instrumental analysis. RESULTS: A total of 44 compounds, including flavonoids, iridoid glycosides, alkaloids, and nucleosides, were accurately determined. The 20 batches of LQL were remarkably similar (> 0.95). In addition, d-glucose, galactose, d-glucuronic acid, arabinose, and d-mannose were detected in saccharide of LQL. The contents of saccharide in LQL were 13.52-21.09 mg/ml. CONCLUSIONS: The established methods can be applied for the comprehensive quality control of LQL, including characterisation of saccharide and quantification of representative components. Our study will provide a robust chemical foundation for disclosing the quality markers of its therapeutic effect.
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Medicamentos de Ervas Chinesas , Medicamentos de Ervas Chinesas/química , Medicina Tradicional Chinesa , Espectrometria de Massas em Tandem/métodos , Flavonoides/análise , Controle de Qualidade , Cromatografia Líquida de Alta Pressão/métodosRESUMO
Homeobox containing 1 (HMBOX1) is a transcription factor that was identified in 2006 from a cDNA library of the human pancreas. It belongs to the HNF gene class of the homeobox family. HMBOX1 is widely expressed in normal human tissues; however, its expression level is rather uneven. Homeobox members have been widely reported to participate in embryonic development and differentiation as well as in pathological and physiological processes. Although research on the role of HMBOX1 is still in its infancy, many reports have revealed its regulatory role in cell differentiation, immune regulation, inflammation, and tumor progression. HMBOX1 plays an important role in promoting the differentiation of bone marrow stromal stem cells (BMSCs) into endothelial cells and contributes to their physiological functions. As an immunoregulatory factor, HMBOX1 can significantly inhibit the inflammatory response in hepatocytes and NK cells and impede the infiltration of peripheral immune cells to the liver. In tumor development, HMBOX1 exerts diametrically opposite biological functions, inhibiting or promoting the process. HMBOX1 possesses complex and diverse biological functions. In this review, we provide a brief overview of the research on HMBOX1.
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Recent breakthrough experiments revealed the iso-reticular Zr-MOFs, MIL-140B and MIL-140C, as promising sorbents for the separation of C6 isomers. Interestingly while the ultra-small pore MIL-140B exhibited hexane isomer sorption hierarchy according to the normal boiling point order (n-C6 > 3MP (3-methyl pentane)), an uncommon shift in the elution order was observed in the larger pore MIL-140C. It was only speculated that the flexibility of the MOFs might be the origin of this intriguing behavior. Herein, flexible force field hybrid osmotic Monte Carlo combined with molecular dynamics simulations were carried out to unravel the microscopic mechanism of the adsorption and dynamics of both C6 isomers in MIL140B and MIL140C. Thermodynamically preferred adsorption of n-C6 over 3MP was predicted for MIL-140B and to a slightly less extent for MIL-140C. Interestingly while the mobility of n-C6 was found to remain higher than that of 3MP in the whole range of loading for MIL-140B, 3MP becomes more mobile than n-C6 at saturation in MIL-140C. This suggests that this kinetics order is most probably the origin of the inversion of the elution order observed experimentally for MIL-140C. The translational and rotational dynamics of the two guests in MIL-140B and MIL-140C was further understood in-depth.
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Famitinib is a tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. Here, a 3-period crossover trial investigated the effect of high-fat or low-fat food intake on the single-dose pharmacokinetic properties of oral famitinib. Twenty-four healthy Chinese participants were enrolled and received a single 25-mg dose of famitinib malate capsule following a high-fat or low-fat breakfast before dosing. Blood samples were collected before dosing (0 hour) to 192 hours after dosing, and famitinib concentrations in plasma were determined with validated liquid chromatography-tandem mass spectrometry. Compared with the fasting condition, the geometric mean ratios for low-fat/fasting were 98.6%, 107.7%, and 107.5% for maximum plasma concentration, area under the plasma concentration-time curve (AUC) over the dosing interval, and AUC from time 0 to infinity, respectively. Those for high-fat/fasting were 84.4%, 105.0%, and 105.1% for maximum plasma concentration, AUC over the dosing interval, and AUC from time 0 to infinity, respectively. There was no significant difference in adverse events between fasting and fed conditions, and no serious adverse events occurred during the trial. In conclusion, oral famitinib bioavailability is not affected by food intake, implying that patients with cancer do not need to consider dietary status when using famitinib. This is considered important for convenience and treatment compliance.
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Neoplasias , Humanos , População do Leste Asiático , Ingestão de Alimentos , Indóis/farmacocinética , Neoplasias/tratamento farmacológico , Receptores Proteína Tirosina Quinases , /farmacocinéticaRESUMO
Piezo1 is a mechanically-gated calcium channel. Recent studies have shown that Piezo1, a mechanically-gated calcium channel, can attenuate both psychosine- and lipopolysaccharide-induced demyelination. Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage, in this study, we investigated the role of Piezo1 in intracerebral hemorrhage. We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon (within 48 hours) after intracerebral hemorrhage, primarily in oligodendrocytes. Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema, myelin sheath loss, and degeneration in injured tissue, a substantial reduction in oligodendrocyte apoptosis, and a significant improvement in neurological function. In addition, we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway. These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage, as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath, thereby improving neuronal function after intracerebral hemorrhage.
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The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.
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Metal-organic frameworks are a class of porous solids that exhibit intriguing flexibility under stimuli, leading often to reversible giant structural changes upon guest adsorption. DUT-49(Cu) and MIL-53(Cr) are fascinating flexible MOFs owing to their guest-induced breathing and negative gas adsorption behaviors respectively. Molecular simulation is one of the most relevant tools to examine these phenomena at the atomistic scale and gain a unique understanding of the physics behind them. Although molecular dynamics and Monte Carlo simulations are widely used in the field of porous materials, these methods hardly consider the structural deformation of a soft material upon guest adsorption. In this work, a cutting-edge osmotic molecular dynamics approach is developed to consider simultaneously the fluid adsorption process and material flexibility. We demonstrate that this newly developed computational strategy offers a unique opportunity to gain unprecedented molecular insights into the flexibility of this class of materials.
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Objective: Heart failure with mildly reduced ejection fraction (HFmrEF) has been recently recognized as a unique phenotype of heart failure (HF) in current practical guideline. However, risk stratification models for mortality and HF re-hospitalization are still lacking. This study aimed to develop and validate a novel machine learning (ML)-derived model to predict the risk of mortality and re-hospitalization for HFmrEF patients. Methods: We assessed the risks of mortality and HF re-hospitalization in HFmrEF (45-49%) patients enrolled in the TOPCAT trial. Eight ML-based models were constructed, including 72 candidate variables. The Harrell concordance index (C-index) and DeLong test were used to assess discrimination and the improvement in discrimination between models, respectively. Calibration of the HF risk prediction model was plotted to obtain bias-corrected estimates of predicted versus observed values. Results: Least absolute shrinkage and selection operator (LASSO) Cox regression was the best-performing model for 1- and 6-year mortality, with a highest C-indices at 0.83 (95% CI: 0.68-0.94) over a maximum of 6 years of follow-up and 0.77 (95% CI: 0.64-0.89) for the 1-year follow-up. The random forest (RF) showed the best discrimination for HF re-hospitalization, scoring 0.80 (95% CI: 0.66-0.94) and 0.85 (95% CI: 0.71-0.99) at the 6- and 1-year follow-ups, respectively. For risk assessment analysis, Kansas City Cardiomyopathy Questionnaire (KCCQ) subscale scores were the most important predictor of readmission outcome in the HFmrEF patients. Conclusion: ML-based models outperformed traditional models at predicting mortality and re-hospitalization in patients with HFmrEF. The results of the risk assessment showed that KCCQ score should be paid increasing attention to in the management of HFmrEF patients.
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BACKGROUND: No effective therapeutic agents for calcific aortic valve disease (CAVD) are available currently. Dietary supplementation has been proposed as a novel treatment modality for various diseases. As a flavanone, hesperetin is widely abundant in citrus fruits and has been proven to exert protective effects in multiple diseases. However, the role of hesperetin in CAVD remains unclear. METHODS: Human aortic valve interstitial cells (VICs) were isolated from aortic valve leaflets. A mouse model of aortic valve stenosis was constructed by direct wire injury (DWI). Immunoblotting, immunofluorescence staining, and flow cytometry were used to investigate the roles of sirtuin 7 (Sirt7) and nuclear factor erythroid 2-related factor 2 (Nrf2) in hesperetin-mediated protective effects in VICs. RESULTS: Hesperetin supplementation protected the mice from wire-injury-induced aortic valve stenosis; in vitro, hesperetin inhibited the lipopolysaccharide (LPS)-induced activation of NF-κB inflammatory cytokine secretion and osteogenic factors expression, reduced ROS production and apoptosis, and abrogated LPS-mediated injury to the mitochondrial membrane potential and the decline in the antioxidant levels in VICs. These benefits of hesperetin may have been obtained by activating Nrf2-ARE signaling, which corrected the dysfunctional mitochondria. Furthermore, we found that hesperetin could directly bind to Sirt7 and that the silencing of Sirt7 decreased the effects of hesperetin in VICs and potently abolished the ability of hesperetin to increase Nrf2 transcriptional activation. CONCLUSIONS: Our work demonstrates that hesperetin plays protective roles in the aortic valve through the Sirt7-Nrf2-ARE axis; thus, hesperetin might be a potential dietary supplement that could prevent the development of CAVD.
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Janagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes mellitus (T2DM). The janagliflozin pharmacokinetics (PK) in T2DM patients with cirrhosis or renal impairment (RI) are unknown. To predict the janagliflozin PK in these patients, we constructed a physiologically based PK (PBPK) model that predicted the janagliflozin PK in normal animals. The model was extrapolated to healthy humans and optimized with the measured data. A PBPK model for T2DM patients was developed and optimized with the measured data. Based on the physiological alterations in cirrhosis or RI patients, the T2DM model was applied to predict the janagliflozin PK in these patients. Results were validated using fold error values. The predicted AUC values were 21,880, 24,881, 26,996, and 28,419 ng/ml·h in T2DM patients with no cirrhosis, Child-Pugh-A, B, and C, respectively, and those in T2DM patients with RI-mild, RI-moderate, and RI-severe were 21,810, 21,840, and 22,845 ng/ml·h, respectively. Janagliflozin exposure increased with increasing cirrhosis severity, whereas it remained stable regardless of the RI severity. The PBPK model predicted the janagliflozin PK in patients with T2DM and liver cirrhosis or RI. Dose adjustment is less critical for these patients. Risk benefit assessment in janagliflozin dosing for T2DM patients with liver disease is recommended.