Exploring the Interactive Role of Parathyroid Hormone and Sodium Intake in Inducing Cardiac Hypertrophy in Rats: A Novel Study.

Background and objectives Previous research has suggested that hyperparathyroidism and excessive salt intake may contribute to the development of cardiac hypertrophy. This study aimed to investigate the relationship and underlying mechanisms between parathyroid hormone (PTH) and salt intake in the development of left ventricular hypertrophy (LVH). Additionally, the study sought to determine whether captopril intervention could reduce the impact of sustained PTH stimulation and excessive salt intake on LVH. Methodology We employed 40 eight-week-old male Sprague-Dawley rats, which were randomly assigned to eight groups: a sham group, a PTH group, a low-salt group (0.6% NaCl), a high-salt group (8% NaCl), a PTH + low-salt group, a PTH + high-salt group, a PTH + low salt + captopril group, and a PTH + high salt + captopril group. The rats were continuously infused with recombinant PTH (1-34) (2 pmol/kg per hour) via an osmotic pump for two weeks and were administered varying concentrations of saline for gavage over two weeks, according to their group. We monitored changes in blood pressure, measured heart weight, left ventricular wall thickness, and myocardial histological morphology, and assessed the relative expression of type III collagen. Results The PTH + high-salt group displayed a significant increase in blood pressure, heart weight, and left ventricular posterior wall thickness (P＜0.05), in addition to myocardial cell hypertrophy and increased Col III expression (P＜0.05), compared to other groups. Captopril intervention significantly reduced blood pressure (P＜0.05), ameliorated myocardial tissue morphology changes, and significantly decreased Col III expression (P＜0.05) but did not entirely reverse the increase in heart weight and left ventricular posterior wall thickness (P＞0.05). Conclusions Our findings suggest that the co-intervention of PTH and high salt can lead to an increase in blood pressure, heart weight, myocardial cell hypertrophy, LVH, and myocardial fibrosis levels in Sprague-Dawley rats. Captopril intervention can lower blood pressure and alleviate pathological myocardial tissue changes and myocardial fibrosis but cannot completely reverse LVH.

Population pharmacokinetics of voriconazole and the role of CYP2C19 genotype on treatment optimization in pediatric patients.

The aim of this study was to evaluate factors that impact on voriconazole (VRC) population pharmacokinetic (PPK) parameters and explore the optimal dosing regimen for different CYP2C19 genotypes in Chinese paediatric patients. PPK analysis was used to identify the factors contributing to the variability in VRC plasma trough concentrations. A total of 210 VRC trough concentrations from 91 paediatric patients were included in the study. The median VRC trough concentration was 1.23 mg/L (range, 0.02 to 8.58 mg/L). At the measurement of all the trough concentrations, the target range (1.0~5.5 mg/L) was achieved in 52.9% of the patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.9% and 6.2% of patients, respectively. VRC trough concentrations were adjusted for dose (Ctrough/D), with normal metabolizers (NMs) and intermediate metabolizers (IMs) having significantly lower levels than poor metabolizers (PMs) (PN-P < 0.001, PI-P = 0.039). A one-compartment model with first-order absorption and elimination was suitable to describe the VRC pharmacokinetic characteristics. The final model of VRC PPK analysis contained CYP2C19 phenotype as a significant covariate for clearance. Dose simulations suggested that a maintenance dose of 9 mg/kg orally or 8 mg/kg intravenously twice daily was appropriate for NMs to achieve the target concentration. A maintenance dose of 9 mg/kg orally or 5 mg/kg intravenously twice daily was appropriate for IMs. Meanwhile, PMs could use lower maintenance dose and an oral dose of 6 mg/kg twice daily or an intravenous dose of 5mg/kg twice daily was appropriate. To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict VRC trough concentrations and guide dose adjustments in Chinese pediatric patients.

Therapeutic drug monitoring of voriconazole and CYP2C19 phenotype for dose optimization in paediatric patients.

PURPOSE: The objective of this study was to evaluate factors influencing voriconazole (VRC) plasma trough concentrations and provide research data for optimizing VRC dosing in Chinese paediatric patients. METHODS: Medical records of inpatients were reviewed retrospectively. Multivariate linear regression analysis was used to identify the factors contributing to the variability of VRC plasma trough concentrations. RESULTS: A total of 250 VRC plasma trough concentrations from 131 paediatric patients were included in the analysis. The median VRC plasma trough concentration was 1.28 mg·L-1 (range, 0.02 to 9.69 mg·L-1). The target range was achieved in 51.6% of patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.4% and 8.0% of paediatric patients, respectively. The most commonly identified cytochrome P450 2C19 (CYP2C19) phenotype was intermediate metabolizers (IMs) (48.9%), followed by normal metabolizers (NMs) (40.5%) and poor metabolizers (PMs) (10.7%), but no ultrarapid metabolizers (UMs) were observed in our study. VRC plasma trough concentrations adjusted for dose (Cmin/D) were significantly lower in both NMs and IMs compared to PMs (PN-P < 0.001 and PI-P = 0.010, respectively). The dosage of VRC required to achieve the therapeutic range was related to age, with children aged < 6 years needing a significantly higher oral dose of VRC. The oral and intravenous maintenance doses needed to reach the therapeutic range were significantly lower than the recommended maintenance dose (P < 0.001, P < 0.001). Factors such as CYP2C19 polymorphisms, the combination of omeprazole, levels of albumin and alanine aminotransferase, were found to affect VRC exposure and explained some of the variability. CONCLUSIONS: The VRC plasma trough concentration is significantly influenced by the CYP2C19 phenotype. The recommended maintenance dose for pediatric patients may not be appropriate for Chinese patients. To increase the probability of achieving the therapeutic range for VRC plasma trough concentration, the administration of VRC should consider the age of paediatric patients and the presence of CYP2C19 polymorphisms.

Pharmacomicrobiomics and type 2 diabetes mellitus: A novel perspective towards possible treatment.

Type 2 diabetes mellitus (T2DM), a major driver of mortality worldwide, is more likely to develop other cardiometabolic risk factors, ultimately leading to diabetes-related mortality. Although a set of measures including lifestyle intervention and antidiabetic drugs have been proposed to manage T2DM, problems associated with potential side-effects and drug resistance are still unresolved. Pharmacomicrobiomics is an emerging field that investigates the interactions between the gut microbiome and drug response variability or drug toxicity. In recent years, increasing evidence supports that the gut microbiome, as the second genome, can serve as an attractive target for improving drug efficacy and safety by manipulating its composition. In this review, we outline the different composition of gut microbiome in T2DM and highlight how these microbiomes actually play a vital role in its development. Furthermore, we also investigate current state-of-the-art knowledge on pharmacomicrobiomics and microbiome's role in modulating the response to antidiabetic drugs, as well as provide innovative potential personalized treatments, including approaches for predicting response to treatment and for modulating the microbiome to improve drug efficacy or reduce drug toxicity.

Attitude and Needs Toward MTM Applications of Chronic Disease in China: A Questionnaire Survey.

Objective: Chronic diseases are characterized by high incidence, long-term medication, and complex types of medication. There are also many corresponding medication therapy management (MTM) applications on the market, such as iCarea, and Medisafe. However, the existing research mainly focuses on how to choose high-quality MTM applications, and few researchers consider the expectations of MTM applications from potential users. The aims of this study were to investigate the demand, attitude, and expectations of the Chinese patients for the MTM applications to support. Methods: From August 2019 to December 2019, we created a questionnaire to have knowledge of user needs, preferences, and expectations for MTM applications among 302 chronic patients in Hunan, Guangdong, and other provinces in China. Logistic regression analysis was performed to analyze the risk factors of affecting patients' attitudes toward MTM applications. Then, respondents' expectations and preferences for MTM applications were statistically analyzed. The survey data were merged to provide information for the design of targeted chronic disease MTM applications. Results: A total of 260 (86.09%) out of 302 patients the respondents were willing to use the MTM applications of chronic disease. The independent influencing factors for using the MTM applications were long-term medication history (OR = 4.45, P < 0.001), willing to learn about medicine knowledge (OR = 3.01, P = 0.04), and wanting to get more professional medication knowledge via Internet (OR = 2.86, P = 0.005). It was worth noting that among those willing to use MTM applications, 55.00% of respondents were willing to use the WeChat applet for MTM, while only 23.46% of respondents preferred other applications. As to the more prevalent WeChat applet for MTM, the majority of participants expected the inclusion of useful modules, such as medication log (62.81%), medication reminder (62.81%), and medication recommendations (57.79%). Conclusion: The participants are willing to use MTM applications of chronic disease, with a preference for the WeChat applet. Patients tended to use MTM applications if they had a long-term medication history or a desire for medical knowledge, especially if they want to get more professional medication knowledge via the Internet. Participants are expected to include in the WeChat applet as medication logs, medication reminders, and medication recommendations which should be taken into serious account for the further development of MTM applications.

tRNA Metabolism and Lung Cancer: Beyond Translation.

Lung cancer, one of the most malignant tumors, has extremely high morbidity and mortality, posing a serious threat to global health. It is an urgent need to fully understand the pathogenesis of lung cancer and provide new ideas for its treatment. Interestingly, accumulating evidence has identified that transfer RNAs (tRNAs) and tRNA metabolism-associated enzymes not only participate in the protein translation but also play an important role in the occurrence and development of lung cancer. In this review, we summarize the different aspects of tRNA metabolism in lung cancer, such as tRNA transcription and mutation, tRNA molecules and derivatives, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases (ARSs), aiming at a better understanding of the pathogenesis of lung cancer and providing new therapeutic strategies for it.

YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS.

Lenvatinib is the latest and promising agent that has demonstrated a significant improvement of progression-free survival in advanced hepatocellular carcinoma (HCC). However, resistance emerges soon after initial treatment, limiting the clinical benefits of lenvatinib. Therefore, understanding the mechanism of resistance is necessary for improving lenvatinib efficacy. YRDC promotes the proliferation of hepatocarcinoma cells via regulating the activity of the RAS/RAF/MEK/ERK pathway, which was the primary pathway of the anticancer effect of lenvatinib. The purpose of this study is to investigate whether YRDC modulates the sensitivity of lenvatinib in hepatocarcinoma cells. Using the CCK-8 cell viability assay, wound-healing assay and clone formation assay in cell models, and xenograft assay in null mouse, we demonstrated that Huh7 cells with YRDC knockdown showed decreased susceptibility to lenvatinib than their control cells. Furthermore, we found that lenvatinib inhibited the expression of YRDC in a time-dependent manner. This effect may aggravate resistance to lenvatinib in hepatocarcinoma cells and may be an underlying cause of resistance, which emerges soon after lenvatinib initial treatment. To investigate how YRDC modulates the sensitivity of lenvatinib, we assessed the effect of tRNA with different t6A levels on the translation of the KRAS gene by in vitro rabbit reticulocyte translation system and measured the expression levels of the KRAS gene by western blot together with qPCR. We found that YRDC regulates the protein translation of KRAS in cell models, and the tRNA with low t6A modification level reduces the translation of the KRAS in the in vitro translation system. These results suggested that YRDC mediates the resistance of lenvatinib in hepatocarcinoma cells via modulating the translation of the KRAS. In this study, YRDC was confirmed to be a potential novel predictive biomarker of lenvatinib sensitivity in HCC.

Risk Factors Affecting Clinical Outcome in Patients with Carbapenem-Resistant K. pneumoniae: A Retrospective Study.

BACKGROUND The increased prevalence of carbapenem-resistant K. pneumoniae (CRKP) poses a great threat worldwide. Early identification of CRKP in patients is paramount. Moreover, fully understanding the risk factors affecting clinical outcome and actively providing targeted treatment can improve the cure rate of patients with CRKP. Therefore, our study aimed to describe the clinical characteristics and identify the risk factors affecting clinical outcomes in patients with CRKP. MATERIAL AND METHODS From January 2016 to September 2017, CRKP strains and clinical data from 97 hospitalized patients were collected. We first performed an antibiotic susceptibility test on CRKP strains using the Kirby-Bauer disc agar diffusion method. Logistic regression analysis was then performed to analyze risk factors. RESULTS According to clinical outcome, among the 97 CRKP patients, 67 were in the effective group and 30 patients were in the noneffective group. Risk factors found to correlate with poor clinical outcome in patients with CRKP included ICU admission, arteriovenous catheterization, indwelling gastric tube, indwelling urethral catheter, tracheal intubation, mechanical ventilation, hypoproteinemia, and exposure to carbapenems. Multivariate analysis showed that hypoproteinemia (OR: 2.83, p=0.042), presence of an indwelling gastric tube (OR: 4.54, p=0.005), and exposure to carbapenems (OR: 2.77, p=0.045) negatively affected clinical outcome in patients with CRKP. CONCLUSIONS Adverse risk factors correlated with poor clinical outcomes in patients with CRKP were determined. This could be of help in identifying high-risk patients with whom clinicians should take extra precautions and adjust therapeutic strategy to supplement conventional basic treatment with additional measures.

Roles of aminoacyl-tRNA synthetase-interacting multi-functional proteins in physiology and cancer.

Aminoacyl-tRNA synthetases (ARSs) are an important class of enzymes with an evolutionarily conserved mechanism for protein synthesis. In higher eukaryotic systems, eight ARSs and three ARS-interacting multi-functional proteins (AIMPs) form a multi-tRNA synthetase complex (MSC), which seems to contribute to cellular homeostasis. Of these, AIMPs are generally considered as non-enzyme factors, playing a scaffolding role during MSC assembly. Although the functions of AIMPs are not fully understood, increasing evidence indicates that these scaffold proteins usually exert tumor-suppressive activities. In addition, endothelial monocyte-activating polypeptide II (EMAP II), as a cleavage product of AIMP1, and AIMP2-DX2, as a splice variant of AIMP2 lacking exon 2, also have a pivotal role in regulating tumorigenesis. In this review, we summarize the biological functions of AIMP1, EMAP II, AIMP2, AIMP2-DX2, and AIMP3. Also, we systematically introduce their emerging roles in cancer, aiming to provide new ideas for the treatment of cancer.

Glycemic variability: adverse clinical outcomes and how to improve it?

Glycemic variability (GV), defined as an integral component of glucose homoeostasis, is emerging as an important metric to consider when assessing glycemic control in clinical practice. Although it remains yet no consensus, accumulating evidence has suggested that GV, representing either short-term (with-day and between-day variability) or long-term GV, was associated with an increased risk of diabetic macrovascular and microvascular complications, hypoglycemia, mortality rates and other adverse clinical outcomes. In this review, we summarize the adverse clinical outcomes of GV and discuss the beneficial measures, including continuous glucose monitoring, drugs, dietary interventions and exercise training, to improve it, aiming at better addressing the challenging aspect of blood glucose management.

Perspectives of Antidiabetic Drugs in Diabetes With Coronavirus Infections.

Diabetes mellitus (DM) increases the risk of viral infections especially during the period of poor glycemic controls. Emerging evidence has reported that DM is one of the most common comorbidities in the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, also referred to as COVID-19. Moreover, the management and therapy are complex for individuals with diabetes who are acutely unwell with suspected or confirmed COVID-19. Here, we review the role of antidiabetic agents, mainly including insulin, metformin, pioglitazone, dipeptidyl peptidase-4 (DPP4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists in DM patients with coronavirus infection, addressing the clinical therapeutic choices for these subjects.

Association of blood cell counts with the risk of olanzapine- or clozapine-induced dyslipidemia in Chinese schizophrenia patients.

OBJECTIVE: The aim of this study was to investigate correlation of peripheral blood cell counts with the dyslipidemia induced by olanzapine or clozapine in Chinese schizophrenia patients. METHODS: A total of 703 eligible schizophrenia patients were enrolled . The counts of red blood cell (RBC), platelet, white blood cell (WBC) and its subtypes, and serum lipids were determined for all participants before and after 2-4 weeks of olanzapine or clozapine treatment. RESULTS: The two representative second-generation antipsychotics (SGAs), olanzapine and clozapine, markedly caused dyslipidemia in Chinese schizophrenia patients. The tertiles of total RBC counts were positively associated with the odds of having abnormal triglyceride (p < .01) and high-density lipoprotein cholesterol (HDL-C) levels (.05). The tertiles of platelet counts were also positively associated with the odds of having abnormal total cholesterol (.03), low-density lipoprotein cholesterol (p < .01), HDL-C (.01), and non-HDL-C (p < .01). However, the counts of WBC and its some subtypes were negatively correlated with the risk of dyslipidemia in these patients. CONCLUSION: The profile of peripheral blood cells may be an early biomarker for predicting the risk of metabolic disorders and cardiovascular diseases in schizophrenia patients treated with SGAs.

Roles of circular RNAs in immune regulation and autoimmune diseases.

Circular RNAs (circRNAs), as a novel class of endogenously expressed non-coding RNAs (ncRNAs), have a high stability and often present tissue-specific expression and evolutionary conservation. Emerging evidence has suggested that circRNAs play an essential role in complex human pathologies. Notably, circRNAs, important gene modulators in the immune system, are strongly associated with the occurrence and development of autoimmune diseases. Here, we focus on the roles of circRNAs in immune cells and immune regulation, highlighting their potential as biomarkers and biological functions in autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), primary biliary cholangitis (PBC), and psoriasis, aiming at providing new insights into the diagnosis and therapy of these diseases.

Modulation of YrdC promotes hepatocellular carcinoma progression via MEK/ERK signaling pathway.

Accumulating evidence suggested that YrdC involved in growth, telomere homeostasis, translation and the N6-threonylcarbamoylation (t6A) of tRNA was abnormally expressed in the progression of tumor. However, the role of YrdC in hepatocellular carcinoma remained elusive. Our study aimed to investigate the clinical significance and oncogenic phenotypes of YrdC in hepatocellular carcinoma, and to determine its related mechanism of this disease. With the usage of GEO datasets, we analyzed the expression of YrdC in hepatocellular carcinoma (HCC). Kaplan-Meier survival analysis was used to evaluate the prognostic significance of hepatocellular carcinoma patients in TCGA. Gain- and loss-of-function analyses in vitro of YrdC were also performed to evaluate its effects on oncogenic phenotypes and relevant signaling pathways. YrdC expression was not only dysregulated in hepatocellular carcinoma tissue but also related to the prognosis of patients with hepatocellular carcinoma. In addition, YrdC depletion suppressed the capability of proliferation, migration and invasion of huh7 cells, while there was opposite result for YrdC overexpression. Our data also unraveled that YrdC promoted the progression of HCC by activating MEK/ERK signaling pathways. Together, our findings indicated that YrdC was a potential prognosis marker for hepatocellular carcinoma, and therapeutic strategies targeting YrdC might hold promise in improving the treatment of hepatocellular carcinoma.

The tRNA-associated dysregulation in diabetes mellitus.

Diabetes mellitus (DM) is a complex endocrine and metabolic disorder for human health and well-being. Deregulated glucose and lipid metabolism are the primary underlying manifestations associated with this disease. Transfer RNAs (tRNAs) are considered to mainly participate in protein translation and may contribute to complex human pathologies. Although the molecular mechanisms remain, for the most part, unknown, accumulating evidence indicates that tRNAs play a vital role in the pathogenesis of DM. This paper reviews different aspects of tRNA-associated dysregulation in DM, such as tRNA mutations, tRNA modifications, tRNA aminoacylation and tRNA derivatives, aiming at a better understanding of the pathogenesis of DM and providing new ideas for the personalized treatment of this metabolism-associated disease.

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2).

PURPOSE: The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs. METHODS: The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice. RESULTS: The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice. CONCLUSIONS: Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.

The dysregulation of tRNAs and tRNA derivatives in cancer.

Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.