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1.
Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids.
Li, J, Wiesinger, A, Fokkert, L, Bakker, P, de Vries, DK, Tijsen, AJ, Pinto, YM, Verkerk, AO, Christoffels, VM, Boink, GJJ, et al
Cell stem cell. 2024
Abstract
The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The "nodal" cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with in vivo-like gene expression and electrophysiological profiles. We created the so-called "assembloids" composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the "fast-slow-fast" activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of LMNA-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.
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Molecular Mechanisms of Plant Responses to Copper: From Deficiency to Excess.
Xu, E, Liu, Y, Gu, D, Zhan, X, Li, J, Zhou, K, Zhang, P, Zou, Y
International journal of molecular sciences. 2024;(13)
Abstract
Copper (Cu) is an essential nutrient for plant growth and development. This metal serves as a constituent element or enzyme cofactor that participates in many biochemical pathways and plays a key role in photosynthesis, respiration, ethylene sensing, and antioxidant systems. The physiological significance of Cu uptake and compartmentalization in plants has been underestimated, despite the importance of Cu in cellular metabolic processes. As a micronutrient, Cu has low cellular requirements in plants. However, its bioavailability may be significantly reduced in alkaline or organic matter-rich soils. Cu deficiency is a severe and widespread nutritional disorder that affects plants. In contrast, excessive levels of available Cu in soil can inhibit plant photosynthesis and induce cellular oxidative stress. This can affect plant productivity and potentially pose serious health risks to humans via bioaccumulation in the food chain. Plants have evolved mechanisms to strictly regulate Cu uptake, transport, and cellular homeostasis during long-term environmental adaptation. This review provides a comprehensive overview of the diverse functions of Cu chelators, chaperones, and transporters involved in Cu homeostasis and their regulatory mechanisms in plant responses to varying Cu availability conditions. Finally, we identified that future research needs to enhance our understanding of the mechanisms regulating Cu deficiency or stress in plants. This will pave the way for improving the Cu utilization efficiency and/or Cu tolerance of crops grown in alkaline or Cu-contaminated soils.
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Natural Products-Based Inhaled Formulations for Treating Pulmonary Diseases.
Yong, J, Shu, H, Zhang, X, Yang, K, Luo, G, Yu, L, Li, J, Huang, H
International journal of nanomedicine. 2024;:1723-1748
Abstract
Given the unique physiological and pathological characteristics of the lung, the direct, inhalable route is more conducive to pulmonary drug delivery and disease control than traditional systemic drug delivery, significantly circumventing drug loss, off-target effects, systemic and organ toxicity, etc., and is widely regarded as the preferred regimen for pulmonary drug delivery. However, very few lung diseases are currently treated with the preferred inhaled formulations, such as asthma, chronic obstructive pulmonary disease and pulmonary hypertension. And there is a lack of appropriate inhaled formulations for other critical lung diseases, such as lung cancer and pulmonary fibrosis, due to the fact that the physicochemical properties of the drugs and their pharmacokinetic profiles do not match the physiology of the lung, and conventional inhalation devices are unable to deliver them to the specific parts of the lung. Phytochemicals of natural origin, due to their wide availability and clear safety profile, hold great promise for the preparation of inhalable formulations to improve the current dilemma in the treatment of lung diseases. In particular, the preparation of inhalable formulations based on nano- and microparticulate carriers for drug delivery to deep lung tissues, which overcome the shortcomings of conventional inhalation therapies while targeting the drug activity directly to a specific part of the lung, may be the best approach to change the current dilemma of lung disease treatment. In this review, we discuss recent advances in nano- and micron-carrier-based inhalation formulations for the delivery of natural products for the treatment of pulmonary diseases, which may represent an opportunity for practical clinical translation of natural products.
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NAD metabolism-related genes provide prognostic value and potential therapeutic insights for acute myeloid leukemia.
Cao, Y, Shu, W, Jin, P, Li, J, Zhu, H, Chen, X, Zhu, Y, Huang, X, Cheng, W, Shen, Y
Frontiers in immunology. 2024;:1417398
Abstract
INTRODUCTION Acute myeloid leukemia (AML) is an aggressive blood cancer with high heterogeneity and poor prognosis. Although the metabolic reprogramming of nicotinamide adenine dinucleotide (NAD) has been reported to play a pivotal role in the pathogenesis of acute myeloid leukemia (AML), the prognostic value of NAD metabolism and its correlation with the immune microenvironment in AML remains unclear. METHODS We utilized our large-scale RNA-seq data on 655 patients with AML and the NAD metabolism-related genes to establish a prognostic NAD metabolism score based on the sparse regression analysis. The signature was validated across three independent datasets including a total of 1,215 AML patients. ssGSEA and ESTIMATE algorithms were employed to dissect the tumor immune microenvironment. Ex vivo drug screening and in vitro experimental validation were performed to identify potential therapeutic approaches for the high-risk patients. In vitro knockdown and functional experiments were employed to investigate the role of SLC25A51, a mitochondrial NAD+ transporter gene implicated in the signature. RESULTS An 8-gene NAD metabolism signature (NADM8) was generated and demonstrated a robust prognostic value in more than 1,800 patients with AML. High NADM8 score could efficiently discriminate AML patients with adverse clinical characteristics and genetic lesions and serve as an independent factor predicting a poor prognosis. Immune microenvironment analysis revealed significant enrichment of distinct tumor-infiltrating immune cells and activation of immune checkpoints in patients with high NADM8 scores, acting as a potential biomarker for immune response evaluation in AML. Furthermore, ex vivo drug screening and in vitro experimental validation in a panel of 9 AML cell lines demonstrated that the patients with high NADM8 scores were more sensitive to the PI3K inhibitor, GDC-0914. Finally, functional experiments also substantiated the critical pathogenic role of the SLC25A51 in AML, which could be a promising therapeutic target. CONCLUSION Our study demonstrated that NAD metabolism-related signature can facilitate risk stratification and prognosis prediction in AML and guide therapeutic decisions including both immunotherapy and targeted therapies.
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Towards a major methodological shift in depression research by assessing continuous scores of recurrence of illness, lifetime and current suicidal behaviors and phenome features.
Maes, M, Zhou, B, Jirakran, K, Vasupanrajit, A, Boonchaya-Anant, P, Tunvirachaisakul, C, Tang, X, Li, J, Almulla, AF
Journal of affective disorders. 2024;:728-740
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Abstract
BACKGROUND The binary major depressive disorder (MDD) diagnosis is inadequate and should never be used in research. AIMS The study's objective is to explicate our novel precision nomothetic strategy for constructing depression models based on adverse childhood experiences (ACEs), lifetime and current phenome, and biomarker (atherogenicity indices) scores. METHODS This study assessed recurrence of illness (ROI: namely recurrence of depressive episodes and suicidal behaviors, SBs), lifetime and current SBs and the phenome of depression, neuroticism, dysthymia, anxiety disorders, and lipid biomarkers including apolipoprotein (Apo)A, ApoB, free cholesterol and cholesteryl esters, triglycerides, high density lipoprotein cholesterol in 67 normal controls and 66 MDD patients. We computed atherogenic and reverse cholesterol transport indices. RESULTS We were able to extract one factor from a) the lifetime phenome of depression comprising ROI, and traits such as neuroticism, dysthymia and anxiety disorders, and b) the phenome of the acute phase (based on depression, anxiety and quality of life scores). PLS analysis showed that 55.7 % of the variance in the lifetime + current phenome factor was explained by increased atherogenicity, neglect and sexual abuse, while atherogenicity partially mediated the effects of neglect. Cluster analysis generated a cluster of patients with major dysmood disorder, which was externally validated by increased atherogenicity and characterized by increased scores of all clinical features. CONCLUSIONS The outcome of depression should not be represented as a binary variable (MDD or not), but rather as multiple dimensional scores based on biomarkers, ROI, subclinical depression traits, and lifetime and current phenome scores including SBs.
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The association between raw garlic consumption and the risk of depressive symptoms: the TCLSIH cohort study.
Wang, Y, Li, J, Li, L, Quan, S, Meng, G, Gu, Y, Zhang, Q, Liu, L, Wu, H, Lai, S, et al
Food & function. 2024;(8):4436-4445
Abstract
Background: Garlic has antioxidant, anti-inflammatory, cardiovascular improvement and other beneficial effects on human health. However, few studies have evaluated the association of garlic intake with the risk of depressive symptoms. The aim of this prospective cohort was to examine the association between the frequency of raw garlic consumption and depressive symptoms in the general adult population. Methods: A total of 7427 participants (mean ± standard deviation: 39.7 ± 10.5 years) without baseline depressive symptoms were included in the cohort study. Garlic consumption was assessed using a validated food frequency questionnaire, and depressive symptoms were assessed by a Chinese version of the Self-rating Depression Scale score (SDS score ≥ 45). Multivariable Cox proportional hazards models were used to determine the association between garlic consumption and the risk of depressive symptoms. Results: This study identified 1070 cases of depressive symptoms during a median follow-up of 2.0 years, with a depression prevalence of 73.4 cases per 1000 person-years. After multivariate adjustment, the hazard ratios (95% confidence intervals) for depressive symptoms in males were 1.00 (reference) for almost never, 1.05 (0.84, 1.32) for ≤1 time per week, 1.16 (0.90, 1.49) for 2-3 times per week, and 1.31 (0.97, 1.78) for ≥4 times per week, and in females, they were 1.00 (reference) for almost never, 0.85 (0.69, 1.06) for ≤1 time per week, 0.72 (0.54, 0.97) for 2-3 times per week, and 0.78 (0.53, 1.13) for ≥4 times per week. Conclusion: In a large general population, we demonstrate for the first time that moderate raw garlic consumption is associated with a reduced risk of depressive symptoms in females, but not in males. Additional prospective studies with long-term follow-up and randomized controlled trials are necessary to confirm the preliminary results of the current study.
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Effects of complex probiotics on intestinal function and its regulatory mechanism in patients with constipation.
Zhang, X, Jia, Y, Li, X, Wang, X, Li, L, Zhang, P, Dong, X, Ze, X, An, Y, Li, J
Beneficial microbes. 2024;:1-15
Abstract
Chronic constipation is a multi-symptomatic, multifactorial, and heterogeneous gastrointestinal disorder. Current pharmacological treatments for chronic constipation are limited and might negatively impact the patients' quality of life. Although probiotics have been shown to improve constipation symptoms, their specific regulatory mechanisms remain unclear. This study sought to explore how probiotic complexes may affect chronic constipation by improving patients' defecation habits. Furthermore, microbial profiles and non-targeted metabolites were assessed to explore the metabolic pathways involved in the improvement of constipation by probiotics. Patients with chronic constipation were treated using a single-blind, randomised, placebo-controlled trial design. The experimental group was administered Lactobacillus powder prepared from 15 probiotic products, and maltodextrin was used as a placebo. Samples were collected twice daily for 4 weeks, and faecal samples were analysed using 16S rRNA sequencing and untargeted metabolic histology. Probiotic treatment changed the makeup of the gut microbiota, enhanced the quantity of Bifidobacterium and Lactobacillus, and markedly reduced clinical symptoms. The 16S rRNA analysis revealed that the abundance of Bifidobacterium and Prevotella increased while that of Thickettsia declined. Moreover, there was a decrease in the abundance of Faecalibacterium and Roseburia. Non-targeted metabolomics analysis identified several differential metabolites, including succinic acid, fumaric acid, cholesterol, xanthurenic acid, 3-alpha,7-alpha-trihydroxy-5beta-cholestan-26-oic, and N-methyltryptamine. KEGG analysis showed that these metabolites were mainly associated with metabolic pathways such as primary bile acid biosynthesis, tryptophan metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, cholesterol metabolism, and propanoate metabolism. In this study, gut microbiome and non-targeted metabolome analyses were performed on collected faecal samples to compare characteristic microorganisms and differential metabolites to provide new insights and references for probiotic intervention in constipation. Trial registered at chictr.org.cn under number: ChiCTR2200056274.
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Understanding Sorafenib-Induced Cardiovascular Toxicity: Mechanisms and Treatment Implications.
Li, J, Zhang, L, Ge, T, Liu, J, Wang, C, Yu, Q
Drug design, development and therapy. 2024;:829-843
Abstract
Tyrosine kinase inhibitors (TKIs) have been recognized as crucial agents for treating various tumors, and one of their key targets is the intracellular site of the vascular endothelial growth factor receptor (VEGFR). While TKIs have demonstrated their effectiveness in solid tumor patients and increased life expectancy, they can also lead to adverse cardiovascular effects including hypertension, thromboembolism, cardiac ischemia, and left ventricular dysfunction. Among the TKIs, sorafenib was the first approved agent and it exerts anti-tumor effects on hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) by inhibiting angiogenesis and tumor cell proliferation through targeting VEGFR and RAF. Unfortunately, the adverse cardiovascular effects caused by sorafenib not only affect solid tumor patients but also limit its application in curing other diseases. This review explores the mechanisms underlying sorafenib-induced cardiovascular adverse effects, including endothelial dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, dysregulated autophagy, and ferroptosis. It also discusses potential treatment strategies, such as antioxidants and renin-angiotensin system inhibitors, and highlights the association between sorafenib-induced hypertension and treatment efficacy in cancer patients. Furthermore, emerging research suggests a link between sorafenib-induced glycolysis, drug resistance, and cardiovascular toxicity, necessitating further investigation. Overall, understanding these mechanisms is crucial for optimizing sorafenib therapy and minimizing cardiovascular risks in cancer patients.
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Efficacy of telemedicine intervention in the self-management of patients with type 2 diabetes: a systematic review and meta-analysis.
Liu, F, Li, J, Li, X, Yang, Z, Wang, W, Zhao, L, Wu, T, Huang, C, Xu, Y
Frontiers in public health. 2024;:1405770
Abstract
PURPOSE We aimed to report the latest and largest pooled analyses and evidence updates to assess the effectiveness of telemedicine interventions for self-management (DSM) in patients with type 2 diabetes mellitus (T2DM). METHODS A systematic literature search was conducted using PubMed, Cochrane, Embase, and Web of Science in December 2023. We included randomized controlled trials (RCTs) of adults (≥18 years of age) diagnosed with T2DM where the intervention was the application of telemedicine. The Cochrane Risk of Bias Assessment was used to evaluate quality. The study's main outcome indicators were glycosylated hemoglobin (HbA1c) and diabetes self-management (DSM) capacity. RESULTS A total of 17 eligible articles, comprising 20 studies and 1,456 patients (734 in the intervention group and 722 in the control group), were included in the evidence synthesis. The baseline characteristics of both groups were similar in all outcomes. Comprehensive analyses showed post-intervention decreases in HbA1c, 2-h postprandial glucose, systolic and diastolic blood pressure, increases in Diabetes Self- Care activities, DSM competencies based on dietary and medication adherence, and improvements in overall DSM scores, all of which were statistically significant. While no statistically significant differences were observed in body mass index, lipids, and other DSM dimensions. Based on subgroup analyses, app-based experimental interventions targeting under 60 years old populations in Asia and North America were found to be more effective and less heterogeneity in the short term (<6 months of intervention). CONCLUSION Telemedicine interventions may assist patients with T2DM in enhancing their DSM and improving their HbA1c levels. Clinician can use various telemedicine interventions to enhance DSM in T2DM patients, considering local circumstances. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/, CRD42024508522.
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Curcumin hybrid molecules for the treatment of Alzheimer's disease: Structure and pharmacological activities.
Zang, WB, Wei, HL, Zhang, WW, Ma, W, Li, J, Yao, Y
European journal of medicinal chemistry. 2024;:116070
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly. Contemporary treatments can only relieve symptoms but fail to delay disease progression. Curcumin is a naturally derived compound that has demonstrated significant therapeutic effects in AD treatment. Recently, molecular hybridization has been utilized to combine the pharmacophoric groups present in curcumin with those of other AD drugs, resulting in a series of novel compounds that enhance the therapeutic efficacy through multiple mechanisms. In this review, we firstly provide a concise summary of various pathogenetic hypotheses of AD and the mechanism of action of curcumin in AD, as well as the concept of molecular hybridization. Subsequently, we focus on the recent development of hybrid molecules derived from curcumin, summarizing their structures and pharmacological activities, including cholinesterase inhibitory activity, Aβ aggregation inhibitory activity, antioxidant activity, and other activities. The structure-activity relationships were further discussed.
