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1.
Ferroptosis and cuproptposis in kidney Diseases: dysfunction of cell metabolism.
Chen, T, Liang, L, Wang, Y, Li, X, Yang, C
Apoptosis : an international journal on programmed cell death. 2024;(3-4):289-302
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Abstract
Metal ions play an important role in living organisms and are involved in essential physiological activities. However, the overload state of ions can cause excess free radicals, cell damage, and even cell death. Ferroptosis and cuproptosis are specific forms of cell death that are distinct from apoptosis, necroptosis, and other regulated cell death. These unique modalities of cell death, dependent on iron and copper, are regulated by multiple cellular metabolic pathways, including steady-state metal redox treatment mitochondrial activity of lipid, amino acid and glucose metabolism, and various signaling pathways associated with disease. Although the mechanisms of ferroptosis and cuproptosis are not yet fully understood, there is no doubt that ion overload plays a crucial act in these metal-dependent cell deaths. In this review, we discussed the core roles of ion overload in ferroptosis and cuproptosis, the association between metabolism imbalance and ferroptosis and cuproptosis, the extract the diseases caused by ion overload and current treatment modalities.
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Identification and characterization of the TetR family transcriptional regulator NffT in Rhizobium johnstonii.
Li, X, Li, Z, Wei, Y, Chen, Z, Xie, S
Applied and environmental microbiology. 2024;(3):e0185123
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Abstract
Symbiotic nitrogen fixation (SNF) by rhizobia is not only the main natural bionitrogen-source for organisms but also a green process leveraged to increase the fertility of soil for agricultural production. However, an insufficient understanding of the regulatory mechanism of SNF hinders its practical application. During SNF, nifA-fixA signaling is essential for the biosynthesis of nitrogenases and electron transfer chain proteins. In the present study, the TetR regulator NffT, whose mutation increased fixA expression, was discovered through a fixA-promoter-β-glucuronidase fusion assay performed with Rhizobium johnstonii. Real-time quantitative PCR analysis showed that nffT deletion increased the expression of symbiotic genes including nifA and fixA in nifA-fixA signaling, and fixL, fixK, fnrN, and fixN9 in fixL-fixN signaling. nffT overexpression resulted in disordered nodules and reduced nitrogen-fixing efficiency. Electrophoretic mobility shift assays revealed that NffT directly regulated the transcription of RL0091-93, which encode an ATP-binding ABC transporter predicted to be involved in carbohydrate transport. Purified His-tagged NffT bound to a 68 bp DNA sequence located -32 to -99 bp upstream of RL0091-93 and NffT deletion significantly increased the expression of RL0091-93. nffT-promoter-β-glucuronidase fusion assay indicated that nffT expression was regulated by the cobNTS genes and cobalamin. Mutations in cobNTS significantly decreased the expression of nffT, and cobalamin restored its expression. These results revealed that NffT affects nodule development and nitrogen-fixing reaction by participating in a complex regulatory network of symbiotic and carbohydrate metabolic genes and, thus, plays a pivotal regulatory role during symbiosis of R. johnstonii-Pisum sativum.IMPORTANCESymbiotic nitrogen fixation (SNF) by rhizobia is a green way to maintain soil fertility without causing environmental pollution or consuming chemical energy. A detailed understanding of the regulatory mechanism of this complex process is essential for promoting sustainable agriculture. In this study, we discovered the TetR-type regulator NffT, which suppressed the expression of fixA in Rhizobium johnstonii. Furthermore, NffT was confirmed to play pleiotropic roles in R. johnstonii-Pisum sativum symbiosis; specifically, it inhibited rhizobial growth, nodule differentiation, and nitrogen-fixing reactions. We revealed that NffT indirectly affected R. johnstonii-P. sativum symbiosis by participating in a complex regulatory network of symbiotic and carbohydrate metabolic genes. Furthermore, cobalamin, a chemical molecule, was reported for the first time to be involved in TetR-type protein transcription during symbiosis. Thus, NffT identification connects SNF regulation with genetic, metabolic, and chemical signals and provides new insights into the complex regulation of SNF, laying an experimental basis for the targeted construction of rhizobial strains with highly efficient nitrogen-fixing capacity.
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Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities.
Yuan, S, Xu, F, Zhang, H, Chen, J, Ruan, X, Li, Y, Burgess, S, Åkesson, A, Li, X, Gill, D, et al
Journal of thrombosis and haemostasis : JTH. 2024;(3):738-748
Abstract
BACKGROUND Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. OBJECTIVES We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. METHODS A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. RESULTS The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Low-density lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%-49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. Five proteins (interleukin-6 receptor subunit alpha, LRP12, prothrombin, angiopoietin-1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. CONCLUSION This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.
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Potassium levels and the risk of all-cause and cardiovascular mortality among patients with cardiovascular diseases: a meta-analysis of cohort studies.
Fan, Y, Wu, M, Li, X, Zhao, J, Shi, J, Ding, L, Jiang, H, Li, Z, Zhang, W, Ma, T, et al
Nutrition journal. 2024;(1):8
Abstract
BACKGROUND Abnormal blood potassium levels are associated with an increased risk of cardiometabolic diseases and mortality in the general population; however, evidence regarding the association between dyskalemia and mortality among patients with cardiovascular disease (CVD) remains inconclusive. This study aimed to evaluate the association of potassium levels with all-cause and cardiovascular mortality among patients with CVD. METHODS PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to August 2023 to identify relevant cohort studies among patients with CVD, such as myocardial infarction, stroke, and heart failure. Abnormal potassium levels were considered as hypokalemia or hyperkalemia. The primary outcomes were all-cause mortality based on follow-up length (including in-hospital, short-term and long-term mortality) and cardiovascular mortality. The methodological quality of included studies was assessed by using the Newcastle-Ottawa Scale. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. Restricted cubic splines were applied to explore the dose-response relationship. RESULTS Thirty-one cohort studies involving 227,645 participants with an average age of 68.3 years were included in the meta-analysis, all of which achieved moderate to high quality. Hyperkalemia was significantly associated with an approximately 3.0-fold increased risk of all-cause in-hospital mortality (RR:2.78,95CI%:1.92,4.03), 1.8-fold of all-cause short-term mortality (RR:1.80, 95CI%:1.44,2.27), 1.3-fold of all-cause long-term mortality (RR:1.33, 95CI%:1.19,1.48) and 1.2-fold of cardiovascular mortality (RR:1.19, 95CI%:1.04,1.36). Similar positive associations were also observed between hypokalemia and risk of all-cause mortality and cardiovascular mortality. The RRs of all-cause in-hospital, short-term, long-term mortality and cardiovascular mortality with hyperkalemia were attenuated to 2.21 (95CI%:1.60,3.06), 1.46(95CI%:1.25,1.71), 1.23 (95CI%:1.09,1.39) and 1.13 (95CI%:1.00,1.27) when treating hypokalemia together with normokalemia as the reference group. A U-shaped association was observed between potassium levels and mortality, with the lowest risk at around 4.2 mmol/L. CONCLUSIONS Both hypokalemia and hyperkalemia were positively associated with the risk of mortality in patients with CVD. Our results support the importance of potassium homeostasis for improving the CVD management. REGISTRATION PROSPERO, CRD42022324337.
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Current progress in research focused on salt tolerance in Vitis vinifera L.
Han, Y, Li, X
Frontiers in plant science. 2024;:1353436
Abstract
Soil salinization represents an increasingly serious threat to agronomic productivity throughout the world, as rising ion concentrations can interfere with the growth and development of plants, ultimately reducing crop yields and quality. A combination of factors is driving this progressive soil salinization, including natural causes, global climate change, and irrigation practices that are increasing the global saline-alkali land footprint. Salt stress damages plants both by imposing osmotic stress that reduces water availability while also inducing direct sodium- and chlorine-mediated toxicity that harms plant cells. Vitis vinifera L. exhibits relatively high levels of resistance to soil salinization. However, as with other crops, grapevine growth, development, fruit yields, and fruit quality can all be adversely affected by salt stress. Many salt-tolerant grape germplasm resources have been screened in recent years, leading to the identification of many genes associated to salt stress and the characterization of the mechanistic basis for grapevine salt tolerance. These results have also been leveraged to improve grape yields through the growth of more tolerant cultivars and other appropriate cultivation measures. The present review was formulated to provide an overview of recent achievements in the field of research focused on grapevine salt tolerance from the perspectives of germplasm resource identification, the mining of functional genes, the cultivation of salt-tolerant grape varieties, and the selection of appropriate cultivation measures. Together, we hope that this systematic review will offer insight into promising approaches to enhancing grape salt tolerance in the future.
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Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.
Zhu, Y, Jian, X, Chen, S, An, G, Jiang, D, Yang, Q, Zhang, J, Hu, J, Qiu, Y, Feng, X, et al
Cell metabolism. 2024;(1):159-175.e8
Abstract
The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.
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The potential role of glucose metabolism, lipid metabolism, and amino acid metabolism in the treatment of Parkinson's disease.
Li, H, Zeng, F, Huang, C, Pu, Q, Thomas, ER, Chen, Y, Li, X
CNS neuroscience & therapeutics. 2024;(2):e14411
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Abstract
PURPOSE OF REVIEW Parkinson's disease (PD) is a common neurodegenerative disease, which can cause progressive deterioration of motor function causing muscle stiffness, tremor, and bradykinesia. In this review, we hope to describe approaches that can improve the life of PD patients through modifications of energy metabolism. RECENT FINDINGS The main pathological features of PD are the progressive loss of nigrostriatal dopaminergic neurons and the production of Lewy bodies. Abnormal aggregation of α-synuclein (α-Syn) leading to the formation of Lewy bodies is closely associated with neuronal dysfunction and degeneration. The main causes of PD are said to be mitochondrial damage, oxidative stress, inflammation, and abnormal protein aggregation. Presence of abnormal energy metabolism is another cause of PD. Many studies have found significant differences between neurodegenerative diseases and metabolic decompensation, which has become a biological hallmark of neurodegenerative diseases. SUMMARY In this review, we highlight the relationship between abnormal energy metabolism (Glucose metabolism, lipid metabolism, and amino acid metabolism) and PD. Improvement of key molecules in glucose metabolism, fat metabolism, and amino acid metabolism (e.g., glucose-6-phosphate dehydrogenase, triglycerides, and levodopa) might be potentially beneficial in PD. Some of these metabolic indicators may serve well during the diagnosis of PD. In addition, modulation of these metabolic pathways may be a potential target for the treatment and prevention of PD.
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The efficacy of Kinesio taping in patients with post-stroke dysphagia: A meta-analysis.
Li, X, Cai, H, Tang, K, Li, F
Medicine. 2024;(11):e37491
Abstract
BACKGROUND Dysphagia, or swallowing dysfunction, is a commonly observed complication among stroke patients, which has been associated with increased mortality rates. The treatment of post-stroke dysphagia encompasses various therapeutic approaches, and Kinesio taping has recently emerged as a potentially effective intervention. This study aims to evaluate the potential benefits of Kinesio Tape in improving dysphagia symptoms in individuals who have experienced a stroke. METHODS his study searched PubMed, Embase, The Cochrane Library, Web of Science, Wanfang Medical Database, CBM, CNKI, and Wipro VIP databases. Randomised controlled trials on the effect of intraosseous patches on the recovery of swallowing function in stroke patients were collected according to the inclusion and exclusion criteria. The search was conducted from from the date of database construction to June 2, 2023. Included trials were assessed using the Cochrane Risk of Bias tool. Meta-analyses were performed using ReviewerManager 5.4.1, and publication bias tests were performed using stata17. RESULTS A total of 12 randomized controlled trials consisting of 724 patients were included in the analysis. The results showed that the effective rate of Kinesio taping [RR = 1.27, 95% CI (1.16, 1.39), P < .00001], swallowing function score [MD = 0.78, 95% CI (0.45, 1.11), P < .00001], and quality of life score for patients with swallowing disorders [MD = 21.68, 95% CI (8.47, 36.90), P = .001] were all superior to those of the controls. CONCLUSION Kinesio taping have been shown to improve swallowing function and nutritional status in patients with dysphagia in the pharyngeal phase.
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Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy.
Xiang, D, Zhou, L, Yang, R, Yuan, F, Xu, Y, Yang, Y, Qiao, Y, Li, X
International journal of nanomedicine. 2024;:2091-2112
Abstract
Currently, cancer remains one of the most significant threats to human health. Treatment of most cancers remains challenging, despite the implementation of diverse therapies in clinical practice. In recent years, research on the mechanism of ferroptosis has presented novel perspectives for cancer treatment. Ferroptosis is a regulated cell death process caused by lipid peroxidation of membrane unsaturated fatty acids catalyzed by iron ions. The rapid development of bio-nanotechnology has generated considerable interest in exploiting iron-induced cell death as a new therapeutic target against cancer. This article provides a comprehensive overview of recent advancements at the intersection of iron-induced cell death and bionanotechnology. In this respect, the mechanism of iron-induced cell death and its relation to cancer are summarized. Furthermore, the feasibility of a nano-drug delivery system based on iron-induced cell death for cancer treatment is introduced and analyzed. Secondly, strategies for inducing iron-induced cell death using nanodrug delivery technology are discussed, including promoting Fenton reactions, inhibiting glutathione peroxidase 4, reducing low glutathione levels, and inhibiting system Xc-. Additionally, the article explores the potential of combined treatment strategies involving iron-induced cell death and bionanotechnology. Finally, the application prospects and challenges of iron-induced nanoagents for cancer treatment are discussed.
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Emerging Contaminants: An Emerging Risk Factor for Diabetes Mellitus.
Niu, H, Xu, M, Tu, P, Xu, Y, Li, X, Xing, M, Chen, Z, Wang, X, Lou, X, Wu, L, et al
Toxics. 2024;(1)
Abstract
Emerging contaminants have been increasingly recognized as critical determinants in global public health outcomes. However, the intricate relationship between these contaminants and glucose metabolism remains to be fully elucidated. The paucity of comprehensive clinical data, coupled with the need for in-depth mechanistic investigations, underscores the urgency to decipher the precise molecular and cellular pathways through which these contaminants potentially mediate the initiation and progression of diabetes mellitus. A profound understanding of the epidemiological impact of these emerging contaminants, as well as the elucidation of the underlying mechanistic pathways, is indispensable for the formulation of evidence-based policy and preventive interventions. This review systematically aggregates contemporary findings from epidemiological investigations and delves into the mechanistic correlates that tether exposure to emerging contaminants, including endocrine disruptors, perfluorinated compounds, microplastics, and antibiotics, to glycemic dysregulation. A nuanced exploration is undertaken focusing on potential dietary sources and the consequential role of the gut microbiome in their toxic effects. This review endeavors to provide a foundational reference for future investigations into the complex interplay between emerging contaminants and diabetes mellitus.