Pub Date : 2025-01-12DOI: 10.1016/j.jare.2025.01.017
Zhongnan Lin, Yining Xu, Hongyi Jiang, Wen Zeng, Yuhan Wang, Liang Zhu, Chihao Lin, Chao Lou, Hanting Shen, Han Ye, Yean Gu, Huachen Yu, Xiaoyun Pan, Lin Zheng
Introduction
Cyclin-Dependent Kinase 8 (CDK8), a CDK family member, regulates the development of inflammatory processes through transcriptional activation. The involvement of CDK8 in osteoarthritis (OA) progression is not yet understood.
Objectives
This study aims to investigate whether CDK8, through its transcriptional regulatory functions, collaborates with NF-κB in chondrocytes to regulate the transcription of senescence-associated secretory phenotype (SASP) genes, thereby exacerbating the inflammatory microenvironment in the progression of osteoarthritis (OA), and to explore the specific mechanisms involved.
Methods
The effects of CDK8 silencing or overexpression will be assessed by measuring OA pathological markers through H&E staining, immunoblotting, Western blot, qRT-PCR, immunofluorescence and ELISA. The DMM surgery mouse model will be used as the OA model, and the PAM and Von Frey tests will be employed to measure the pain threshold in mice. Luciferase and ChIP assays will be conducted to explore the transcriptional regulation and elongation mechanisms of CDK8.
Result
CDK8 influences OA advancement by being recruited to the SASP promoter region in cooperation with NF-κB, leading to the elongation phosphorylation of Rpb1 CTD within the context of NF-κB-induced gene specificity, thereby regulating SASP transcription. The SASP secreted by chondrocytes during this process promotes the inflammatory microenvironment in the joint and drives macrophage differentiation into osteoclasts, further worsening the severity of osteoarthritis.
Conclusion
The SASP secreted by chondrocytes during the OA process plays a crucial role in worsening the severity of the disease. Inhibiting CDK8 expression can decrease its secretion by downregulating the transcription levels of SASP, which are co-regulated by CDK8 and NF-κB. This could offer a new target for osteoarthritis treatment.
{"title":"CDK8 mediated inflammatory microenvironment aggravates osteoarthritis progression","authors":"Zhongnan Lin, Yining Xu, Hongyi Jiang, Wen Zeng, Yuhan Wang, Liang Zhu, Chihao Lin, Chao Lou, Hanting Shen, Han Ye, Yean Gu, Huachen Yu, Xiaoyun Pan, Lin Zheng","doi":"10.1016/j.jare.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.017","url":null,"abstract":"<h3>Introduction</h3>Cyclin-Dependent Kinase 8 (CDK8), a CDK family member, regulates the development of inflammatory processes through transcriptional activation. The involvement of CDK8 in osteoarthritis (OA) progression is not yet understood.<h3>Objectives</h3>This study aims to investigate whether CDK8, through its transcriptional regulatory functions, collaborates with NF-κB in chondrocytes to regulate the transcription of senescence-associated secretory phenotype (SASP) genes, thereby exacerbating the inflammatory microenvironment in the progression of osteoarthritis (OA), and to explore the specific mechanisms involved.<h3>Methods</h3>The effects of CDK8 silencing or overexpression will be assessed by measuring OA pathological markers through H&E staining, immunoblotting, Western blot, qRT-PCR, immunofluorescence and ELISA. The DMM surgery mouse model will be used as the OA model, and the PAM and Von Frey tests will be employed to measure the pain threshold in mice. Luciferase and ChIP assays will be conducted to explore the transcriptional regulation and elongation mechanisms of CDK8.<h3>Result</h3>CDK8 influences OA advancement by being recruited to the SASP promoter region in cooperation with NF-κB, leading to the elongation phosphorylation of Rpb1 CTD within the context of NF-κB-induced gene specificity, thereby regulating SASP transcription. The SASP secreted by chondrocytes during this process promotes the inflammatory microenvironment in the joint and drives macrophage differentiation into osteoclasts, further worsening the severity of osteoarthritis.<h3>Conclusion</h3>The SASP secreted by chondrocytes during the OA process plays a crucial role in worsening the severity of the disease. Inhibiting CDK8 expression can decrease its secretion by downregulating the transcription levels of SASP, which are co-regulated by CDK8 and NF-κB. This could offer a new target for osteoarthritis treatment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"13 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-12DOI: 10.1016/j.jare.2025.01.018
Haobo Xu, Xinxing He, Juan Chen, Xiaozhou Huang, Yazhen Chen, Yichen Xu, Yu Xiao, Tao Liu, Hanjie He, Yingping Wang, Xiaodong Yang, Leilei Shi, Hongzhi Zhang, Wende Yan
Introduction
Soil nutrient supply drives the ecological functions of soil micro-food webs through bottom-up and top-down mechanisms in degraded agroecosystems. Nutrient limitation responds sensitively to variations in degraded agroecosystems through restoration practices, such as legume intercropping.
Objectives
This study examined the effects of legume intercropping on trophic cascade dynamics through resource supply in degraded purple soil ecosystems.
Methods
A field experiment was conducted with three plantation types: Camellia oleifera monoculture (CK), C. oleifera–Arachis hypogaea (peanut) intercropping (CP), and C. oleifera–Senna tora intercropping (CS). Using soil nutrient limitation as a premise, modified by legume intercropping, we assessed the biodiversity of soil biotic taxa, analysed their community composition, and applied partial least squares path modelling (PLS-PM) to link trophic cascade with ecological functions.
Results
Legume intercropping altered the abundance of biotic taxa, leading to changes in biotic diversity and microbial life strategies. The PLS-PM results indicated that legume intercropping enhanced bacterial diversity by aggravating soil P limitation, which subsequently increased protist consumer diversity and omnivore-predator nematode abundance through a bottom-up effect. Omnivore-predator nematodes and protist consumers indirectly influenced soil P metabolism, down-regulated through bacteria in the top-down effect. We observed high consistency between the untargeted metabolomic analysis and soil nutrient limitations. These findings indicate that soil micro-food web structure and function responded sensitively to legume intercropping in degraded ecosystems.
Conclusion
The results highlight the role of soil nutrient limitation in shaping micro-food webs and suggest that soil P limitation controls the down-regulation of soil P-related ecological functions through bottom-up and top-down effects.
{"title":"Soil nutrient limitation controls trophic cascade effects of micro-food web-derived ecological functions in degraded agroecosystems","authors":"Haobo Xu, Xinxing He, Juan Chen, Xiaozhou Huang, Yazhen Chen, Yichen Xu, Yu Xiao, Tao Liu, Hanjie He, Yingping Wang, Xiaodong Yang, Leilei Shi, Hongzhi Zhang, Wende Yan","doi":"10.1016/j.jare.2025.01.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.018","url":null,"abstract":"<h3>Introduction</h3>Soil nutrient supply drives the ecological functions of soil micro-food webs through bottom-up and top-down mechanisms in degraded agroecosystems. Nutrient limitation responds sensitively to variations in degraded agroecosystems through restoration practices, such as legume intercropping.<h3>Objectives</h3>This study examined the effects of legume intercropping on trophic cascade dynamics through resource supply in degraded purple soil ecosystems.<h3>Methods</h3>A field experiment was conducted with three plantation types: <em>Camellia oleifera</em> monoculture (CK), <em>C. oleifera</em>–<em>Arachis hypogaea</em> (<em>peanut</em>) intercropping (CP), and <em>C. oleifera</em>–<em>Senna tora</em> intercropping (CS). Using soil nutrient limitation as a premise, modified by legume intercropping, we assessed the biodiversity of soil biotic taxa, analysed their community composition, and applied partial least squares path modelling (PLS-PM) to link trophic cascade with ecological functions.<h3>Results</h3>Legume intercropping altered the abundance of biotic taxa, leading to changes in biotic diversity and microbial life strategies. The PLS-PM results indicated that legume intercropping enhanced bacterial diversity by aggravating soil P limitation, which subsequently increased protist consumer diversity and omnivore-predator nematode abundance through a bottom-up effect. Omnivore-predator nematodes and protist consumers indirectly influenced soil P metabolism, down-regulated through bacteria in the top-down effect. We observed high consistency between the untargeted metabolomic analysis and soil nutrient limitations. These findings indicate that soil micro-food web structure and function responded sensitively to legume intercropping in degraded ecosystems.<h3>Conclusion</h3>The results highlight the role of soil nutrient limitation in shaping micro-food webs and suggest that soil P limitation controls the down-regulation of soil P-related ecological functions through bottom-up and top-down effects.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"10 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-11DOI: 10.1016/j.jare.2025.01.012
Shiyi Zhang, Na Wang, Zhichao Gao, Jia Gao, Xiaohui Wang, Hao Xie, Cong-Yi Wang, Shu Zhang
Background
The balance of redox states is crucial for maintaining physiological homeostasis. For decades, the focus has been mainly on the concept of oxidative stress, which is involved in the mechanism of almost all diseases. However, robust evidence has highlighted that reductive stress, the other side of the redox spectrum, plays a pivotal role in the development of various diseases, particularly those related to metabolism and cardiovascular health.
Aim of Review
In this review, we present an extensive array of evidence for the occurrence of reductive stress and its significant implications mainly in metabolic and cardiovascular diseases.
Key Scientific Concepts of Review
Reductive stress is defined as a shift in the cellular redox balance towards a more reduced state, characterized by an excess of endogenous reductants (such as NADH, NADPH, and GSH) over their oxidized counterparts (NAD+, NADP+, and GSSG). While oxidative stress has been the predominant mechanism studied in obesity, metabolic disorders, and cardiovascular diseases, growing evidence underscores the critical role of reductive stress. This review discusses how reductive stress contributes to metabolic and cardiovascular pathologies, emphasizing its effects on key cellular processes. For example, excessive NADH accumulation can disrupt mitochondrial function by impairing the electron transport chain, leading to decreased ATP production and increased production of reactive oxygen species. In the endoplasmic reticulum (ER), an excess of reductive equivalents hampers protein folding, triggering ER stress and activating the unfolded protein response, which can lead to insulin resistance and compromised cellular homeostasis. Furthermore, we explore how excessive antioxidant supplementation can exacerbate reductive stress by further shifting the redox balance, potentially undermining the beneficial effects of exercise, impairing cardiovascular health, and aggravating metabolic disorders, particularly in obese individuals. This growing body of evidence calls for a reevaluation of the role of reductive stress in disease pathogenesis and therapeutic interventions.
{"title":"Reductive stress: The key pathway in metabolic disorders induced by overnutrition","authors":"Shiyi Zhang, Na Wang, Zhichao Gao, Jia Gao, Xiaohui Wang, Hao Xie, Cong-Yi Wang, Shu Zhang","doi":"10.1016/j.jare.2025.01.012","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.012","url":null,"abstract":"<h3>Background</h3>The balance of redox states is crucial for maintaining physiological homeostasis. For decades, the focus has been mainly on the concept of oxidative stress, which is involved in the mechanism of almost all diseases. However, robust evidence has highlighted that reductive stress, the other side of the redox spectrum, plays a pivotal role in the development of various diseases, particularly those related to metabolism and cardiovascular health.<h3>Aim of Review</h3>In this review, we present an extensive array of evidence for the occurrence of reductive stress and its significant implications mainly in metabolic and cardiovascular diseases.<h3>Key Scientific Concepts of Review</h3>Reductive stress is defined as a shift in the cellular redox balance towards a more reduced state, characterized by an excess of endogenous reductants (such as NADH, NADPH, and GSH) over their oxidized counterparts (NAD<sup>+</sup>, NADP<sup>+</sup>, and GSSG). While oxidative stress has been the predominant mechanism studied in obesity, metabolic disorders, and cardiovascular diseases, growing evidence underscores the critical role of reductive stress. This review discusses how reductive stress contributes to metabolic and cardiovascular pathologies, emphasizing its effects on key cellular processes. For example, excessive NADH accumulation can disrupt mitochondrial function by impairing the electron transport chain, leading to decreased ATP production and increased production of reactive oxygen species. In the endoplasmic reticulum (ER), an excess of reductive equivalents hampers protein folding, triggering ER stress and activating the unfolded protein response, which can lead to insulin resistance and compromised cellular homeostasis. Furthermore, we explore how excessive antioxidant supplementation can exacerbate reductive stress by further shifting the redox balance, potentially undermining the beneficial effects of exercise, impairing cardiovascular health, and aggravating metabolic disorders, particularly in obese individuals. This growing body of evidence calls for a reevaluation of the role of reductive stress in disease pathogenesis and therapeutic interventions.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"68 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-11DOI: 10.1016/j.jare.2025.01.019
Chengyu Li, Zhaojun Liu, Chen Fu, Hongmin Li, Tong He, Gang Wu, Yanan Sheng, Ming Shen, Honglin Liu
Introduction
Hypoxia, a condition characterized by inadequate oxygen supply to tissues, triggers various cellular responses, including apoptosis. The RNA demethylase FTO has been shown to exert anti-apoptotic effects, but its functions independent of RNA demethylase—particularly those involving protein–protein interactions—during hypoxia remain unclear.
Objectives
This study aimed to elucidate the cytoprotective mechanism of FTO in preventing apoptosis under hypoxic stress.
Methods
NIH/3T3 cells, MEF cells, and mouse granulosa cells were cultured under hypoxia (1 % O2) and treated with inhibitors (chloroquine, MG132, cycloheximide) to identify FTO degradation pathways. RNA interference was used to knock down atg7, nedd4, and fto. Mass spectrometry identified FTO-associated proteins, and their interactions with FTO were analyzed with immunoprecipitation assays. FTO localization was examined through nuclear and cytoplasmic fractionation and fluorescence microscopy. Apoptosis was evaluated by flow cytometry (annexin V/PI). The role of FTO independent of its m6A demethylase activity was determined by inhibiting FTO function using FB23-2 or an H228A/D230A mutant lacking m6A demethylase activity.
Results
Upon hypoxia exposure, FTO relocated from the nucleus to the cytoplasm and underwent degradation through a regulatory pathway in which the E1-like ubiquitin-activating enzyme ATG7 and the E3 ubiquitin ligase NEDD4 cooperatively activated both the ubiquitin–proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) in NIH/3T3 cells, MEF cells, and mouse granulosa cells. Furthermore, knocking down atg7 resulted in FTO accumulation in the cytoplasm, where FTO exerted its protective effect by binding with RACK1, which impairs the interaction between RACK1 and MTK1, thereby blocking activation of JNK1/2 and subsequently preventing apoptosis in hypoxic cells.
Conclusion
This study reveals a novel function of cytoplasmic FTO in disrupting the RACK1-MTK1-JNK1/2-apoptosis cascade during hypoxia, positioning the functional context of FTO at the layer of protein–protein interactions, which extends its mechanistic role beyond RNA demethylation.
{"title":"Hypoxia-induced degradation of FTO promotes apoptosis by unmasking RACK1-mediated activation of MTK1-JNK1/2 pathway","authors":"Chengyu Li, Zhaojun Liu, Chen Fu, Hongmin Li, Tong He, Gang Wu, Yanan Sheng, Ming Shen, Honglin Liu","doi":"10.1016/j.jare.2025.01.019","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.019","url":null,"abstract":"<h3>Introduction</h3>Hypoxia, a condition characterized by inadequate oxygen supply to tissues, triggers various cellular responses, including apoptosis. The RNA demethylase FTO has been shown to exert anti-apoptotic effects, but its functions independent of RNA demethylase—particularly those involving protein–protein interactions—during hypoxia remain unclear.<h3>Objectives</h3>This study aimed to elucidate the cytoprotective mechanism of FTO in preventing apoptosis under hypoxic stress.<h3>Methods</h3>NIH/3T3 cells, MEF cells, and mouse granulosa cells were cultured under hypoxia (1 % O<sub>2</sub>) and treated with inhibitors (chloroquine, MG132, cycloheximide) to identify FTO degradation pathways. RNA interference was used to knock down <em>atg7</em>, <em>nedd4</em>, and <em>fto</em>. Mass spectrometry identified FTO-associated proteins, and their interactions with FTO were analyzed with immunoprecipitation assays. FTO localization was examined through nuclear and cytoplasmic fractionation and fluorescence microscopy. Apoptosis was evaluated by flow cytometry (annexin V/PI). The role of FTO independent of its m6A demethylase activity was determined by inhibiting FTO function using FB23-2 or an H228A/D230A mutant lacking m6A demethylase activity.<h3>Results</h3>Upon hypoxia exposure, FTO relocated from the nucleus to the cytoplasm and underwent degradation through a regulatory pathway in which the E1-like ubiquitin-activating enzyme ATG7 and the E3 ubiquitin ligase NEDD4 cooperatively activated both the ubiquitin–proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) in NIH/3T3 cells, MEF cells, and mouse granulosa cells. Furthermore, knocking down <em>atg7</em> resulted in FTO accumulation in the cytoplasm, where FTO exerted its protective effect by binding with RACK1, which impairs the interaction between RACK1 and MTK1, thereby blocking activation of JNK1/2 and subsequently preventing apoptosis in hypoxic cells.<h3>Conclusion</h3>This study reveals a novel function of cytoplasmic FTO in disrupting the RACK1-MTK1-JNK1/2-apoptosis cascade during hypoxia, positioning the functional context of FTO at the layer of protein–protein interactions, which extends its mechanistic role beyond RNA demethylation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"29 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Flavonoids are naturally occurring dietary phytochemicals with significant antioxidant effects aside from several health benefits. People often consume them in combination with other food components. Compiling data establishes a link between bioactive flavonoids and prevention of several diseases in animal models, including cardiovascular diseases, diabetes, gut dysbiosis, and metabolic dysfunction-associated steatotic liver disease (MASLD). However, numerous clinical studies have demonstrated the ineffectiveness of flavonoids contradicting rodent models, thereby challenging the validity of using flavonoids as dietary supplements.
Aim of Review
This review provides a clinical perspective to emphasize the effective roles of dietary flavonoids as well as to summarize their specific mechanisms in animals briefly.
Key Scientific Concepts of Review
First, this review offers an in-depth elucidation of the metabolic processes of flavonoids within human, encompassing the small, large intestine, and the liver. Furthermore, the review provides a comprehensive overview of the various functions of flavonoids in the gastrointestinal tract, including hindering the breakdown and assimilation of macronutrients, such as polysaccharides and lipids, regulating gut hormone secretion as well as inhibition of mineral iron absorption. In the large intestine, an unabsorbed major portion of flavonoids interact with the gut flora leading to their biotransformation. Once absorbed and circulated in the bloodstream, bioactive flavonoids or their metabolites exert numerous beneficial systemic effects. Lastly, we examine the protective effects of flavonoids in several metabolic disorders, including endothelial dysfunction, MASLD, cardiovascular disease, obesity, hyperlipidemia, and insulin resistance. In conclusion, this review outlines the safety and future prospects of flavonoids in the field of health, especially in the prevention of metabolic syndrome (MetS).
{"title":"Flavonoids for gastrointestinal tract local and associated systemic effects: A review of clinical trials and future perspectives","authors":"Xiaopeng Li, Enjun Xie, Shumin Sun, Jie Shen, Yujin Ding, Jiaqi Wang, Xiaoyu Peng, Ruting Zheng, Mohamed A. Farag, Jianbo Xiao","doi":"10.1016/j.jare.2025.01.014","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.014","url":null,"abstract":"<h3>Background</h3>Flavonoids are naturally occurring dietary phytochemicals with significant antioxidant effects aside from several health benefits. People often consume them in combination with other food components. Compiling data establishes a link between bioactive flavonoids and prevention of several diseases in animal models, including cardiovascular diseases, diabetes, gut dysbiosis, and metabolic dysfunction-associated steatotic liver disease (MASLD). However, numerous clinical studies have demonstrated the ineffectiveness of flavonoids contradicting rodent models, thereby challenging the validity of using flavonoids as dietary supplements.<h3>Aim of Review</h3>This review provides a clinical perspective to emphasize the effective roles of dietary flavonoids as well as to summarize their specific mechanisms in animals briefly.<h3>Key Scientific Concepts of Review</h3>First, this review offers an in-depth elucidation of the metabolic processes of flavonoids within human, encompassing the small, large intestine, and the liver. Furthermore, the review provides a comprehensive overview of the various functions of flavonoids in the gastrointestinal tract, including hindering the breakdown and assimilation of macronutrients, such as polysaccharides and lipids, regulating gut hormone secretion as well as inhibition of mineral iron absorption. In the large intestine, an unabsorbed major portion of flavonoids interact with the gut flora leading to their biotransformation. Once absorbed and circulated in the bloodstream, bioactive flavonoids or their metabolites exert numerous beneficial systemic effects. Lastly, we examine the protective effects of flavonoids in several metabolic disorders, including endothelial dysfunction, MASLD, cardiovascular disease, obesity, hyperlipidemia, and insulin resistance. In conclusion, this review outlines the safety and future prospects of flavonoids in the field of health, especially in the prevention of metabolic syndrome (MetS).","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"19 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1016/j.jare.2025.01.013
Danil Yu. Pimenov, Leonardo Rosa Ribeiro da Silva, Mustafa Kuntoğlu, Bruno Souza Abrão, Luiz Eduardo dos Santos Paes, Emanoil Linul
Background
Today, in a wide variety of industries, grinding operations are an extremely important finishing process for obtaining precise dimensions and meeting strict requirements for roughness and shape accuracy. However, the constant wear of abrasive tools during grinding negatively affects the dimensional and surface conditions of the workpiece. Therefore, effective monitoring of the wear process during grinding operations helps to predict tool life, plan maintenance and ensure consistent product quality.
Aim of Review
The objective of this review is to examine current tool condition monitoring techniques, both direct and indirect, in various sensor systems and their application in both traditional and AI-driven grinding processes. By examining these techniques, the review provides insight into how different monitoring techniques can improve process efficiency, reduce downtime, and improve finished product quality, as well as the application of intelligent and adaptive processes to traditional grinding operations.Key Scientific Concepts of Review: The review discusses the critical role of sensor systems in monitoring tool condition, including technologies such as imaging, vibration analysis, acoustic emission, and force measurement. These systems are vital for detecting wear and predicting failures, allowing for timely interventions and preventing unplanned downtimes. The integration of artificial intelligence into these monitoring systems greatly enhances their capabilities, as they enable more proactive strategies and adapt to changing conditions during the grinding process.
{"title":"Review of advanced sensor system applications in grinding operations","authors":"Danil Yu. Pimenov, Leonardo Rosa Ribeiro da Silva, Mustafa Kuntoğlu, Bruno Souza Abrão, Luiz Eduardo dos Santos Paes, Emanoil Linul","doi":"10.1016/j.jare.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.013","url":null,"abstract":"<h3>Background</h3>Today, in a wide variety of industries, grinding operations are an extremely important finishing process for obtaining precise dimensions and meeting strict requirements for roughness and shape accuracy. However, the constant wear of abrasive tools during grinding negatively affects the dimensional and surface conditions of the workpiece. Therefore, effective monitoring of the wear process during grinding operations helps to predict tool life, plan maintenance and ensure consistent product quality.<h3>Aim of Review</h3>The objective of this review is to examine current tool condition monitoring techniques, both direct and indirect, in various sensor systems and their application in both traditional and AI-driven grinding processes. By examining these techniques, the review provides insight into how different monitoring techniques can improve process efficiency, reduce downtime, and improve finished product quality, as well as the application of intelligent and adaptive processes to traditional grinding operations.<em>Key Scientific Concepts of Review:</em> The review discusses the critical role of sensor systems in monitoring tool condition, including technologies such as imaging, vibration analysis, acoustic emission, and force measurement. These systems are vital for detecting wear and predicting failures, allowing for timely interventions and preventing unplanned downtimes. The integration of artificial intelligence into these monitoring systems greatly enhances their capabilities, as they enable more proactive strategies and adapt to changing conditions during the grinding process.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"2020 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.jare.2024.12.044
Yang Tang, Chen Yang, Jiamin Zhao, Heng Heng, Mingxiu Peng, Liang Sun, Liang Dai, Edward Wai-Chi Chan, Sheng Chen
Introduction
Infections stemming from multidrug-resistant bacteria present a substantial threat to public health today. Discovering or synthesizing novel compounds is crucial to alleviate this pressing situation.
Objective
The main purpose of this study is to verify the antibacterial activity of LTX-315 and explore its primary action mode.
Methods
Through antibacterial phenotype assay screening, we obtained a potent compound named LTX-315 from diverse drug libraries, 10,926 compounds in total. Then, the bactericidal effect and its action mode were explored through biochemical and chemistry methods such as a time-killing curve, scanning electronic microscopy, isothermal titration calorimetry analysis, and nuclear magnetic resonance. Finally, the efficacy in vivo of LTX-315 against drug-resistant bacteria was proved through a mice infection model.
Results
In this study, LTX-315, an oncolytic peptide, was discovered to effectively eliminate gram-positive and gram-negative pathogens, even for those multidrug-resistant strains. Through strong electrostatic interactions, LTX-315 can bind to the membrane component phosphatidylglycerol (PG) with extremely high affinity (nanomolar level). Strikingly, in contrast to the typical electrostatic interactions of antibacterial peptides, the indole group of LTX-315, situated near the alkyl chain, exhibits significantly enhanced recognition and interaction with PG due to the hydrophobic effect of the alkyl chain. Furthermore, it exerts various impacts on cell membranes, including damaging integrity, increasing permeability, and decreasing membrane fluidity. Additionally, microscopy revealed significant cell disintegration. The influence, in turn, disrupts several physiological activities inside cells, such as increasing the reactive oxygen species level, ultimately leading to cell death. Finally, the efficacy of LTX-315 in vivo against multidrug-resistant and hypervirulent Klebsiella pneumoniae was demonstrated.
Conclusion
The unique mechanism of LTX-315 involves high-affinity binding to PG and subsequent membrane disruption, providing a novel approach against multidrug-resistant bacteria compared to conventional antibiotics. As a potential candidate, it shows promise in effectively treating bacterial infections, particularly those caused by drug-resistant bacteria, thereby addressing the escalating challenge of antibiotic resistance worldwide.
{"title":"LTX-315 is a novel broad-spectrum antimicrobial peptide against clinical multidrug-resistant bacteria","authors":"Yang Tang, Chen Yang, Jiamin Zhao, Heng Heng, Mingxiu Peng, Liang Sun, Liang Dai, Edward Wai-Chi Chan, Sheng Chen","doi":"10.1016/j.jare.2024.12.044","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.044","url":null,"abstract":"<h3>Introduction</h3>Infections stemming from multidrug-resistant bacteria present a substantial threat to public health today. Discovering or synthesizing novel compounds is crucial to alleviate this pressing situation.<h3>Objective</h3>The main purpose of this study is to verify the antibacterial activity of LTX-315 and explore its primary action mode.<h3>Methods</h3>Through antibacterial phenotype assay screening, we obtained a potent compound named LTX-315 from diverse drug libraries, 10,926 compounds in total. Then, the bactericidal effect and its action mode were explored through biochemical and chemistry methods such as a<!-- --> <!-- -->time-killing curve, scanning electronic microscopy, isothermal titration calorimetry analysis, and nuclear magnetic resonance. Finally, the efficacy in vivo of LTX-315 against drug-resistant bacteria was proved through a<!-- --> <!-- -->mice infection model.<h3>Results</h3>In this study, LTX-315, an oncolytic peptide, was discovered to effectively eliminate gram-positive and gram-negative pathogens, even for those multidrug-resistant strains. Through strong electrostatic interactions, LTX-315 can bind to the membrane component phosphatidylglycerol (PG) with extremely high affinity (nanomolar level). Strikingly, in contrast to the typical electrostatic interactions of antibacterial peptides, the indole group of LTX-315, situated near the alkyl chain, exhibits significantly enhanced recognition and interaction with PG due to the hydrophobic effect of the alkyl chain. Furthermore, it exerts various impacts on cell membranes, including damaging integrity, increasing permeability, and decreasing membrane fluidity. Additionally, microscopy revealed significant cell disintegration. The influence, in turn, disrupts several physiological activities inside cells, such as increasing the reactive oxygen species level, ultimately leading to cell death. Finally, the efficacy of LTX-315 in vivo against multidrug-resistant and hypervirulent <em>Klebsiella pneumoniae</em> was demonstrated.<h3>Conclusion</h3>The unique mechanism of LTX-315 involves high-affinity binding to PG and subsequent membrane disruption, providing a novel approach against multidrug-resistant bacteria compared to conventional antibiotics. As a potential candidate, it shows promise in effectively treating bacterial infections, particularly those caused by drug-resistant bacteria, thereby addressing the escalating challenge of antibiotic resistance worldwide.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"74 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1016/j.jare.2025.01.007
Minghui Wang, Hu Zhang, Jiling Liang, Jielun Huang, Tong Wu, Ning Chen
Background
Alzheimer’s disease (AD) presents a significant challenge to global healthcare systems, with an exacerbation by an aging population. Although the plethora of hypotheses are proposed to elucidate the underlying mechanisms of AD, from amyloid-beta (Aβ) accumulation and Tau protein aggregation to neuroinflammation, a comprehensive understanding of its pathogenesis remains elusive. Recent research has highlighted the critical role of calcium (Ca2+) signaling pathway in the progression of AD, indicating a complex interplay between Ca2+ dysregulation and various pathological processes.
Aim of Review
This review aims to consolidate the current understanding of the role of Ca2+ signaling dysregulation in AD, thus emphasizing its central role amidst various pathological hypotheses. We aim to evaluate the potential of the Ca2+ signaling hypothesis to unify existing theories of AD pathogenesis and explore its implications for developing innovative therapeutic strategies through targeting Ca2+ dysregulation.
Key Scientific Concepts of Review
The review focuses on three principal concepts. First, the indispensable role of Ca2+ homeostasis in neuronal function and its disruption in AD. Second, the interaction between Ca2+ signaling dysfunction and established AD hypotheses posited that Ca2+ dysregulation is a unifying pathway. Third, the dual role of Ca2+ in neurodegeneration and neuroprotection, highlighting the nuanced effects of Ca2+ levels on AD pathology.
随着人口老龄化的加剧，阿尔茨海默病（AD）对全球医疗保健系统构成了重大挑战。尽管提出了大量的假设来阐明AD的潜在机制，从淀粉样蛋白- β (a β)积累和Tau蛋白聚集到神经炎症，但对其发病机制的全面理解仍然难以捉摸。最近的研究强调了钙（Ca2+）信号通路在AD进展中的关键作用，表明Ca2+失调与各种病理过程之间存在复杂的相互作用。本综述旨在巩固目前对Ca2+信号失调在AD中的作用的理解，从而强调其在各种病理假设中的核心作用。我们的目的是评估Ca2+信号传导假说的潜力，以统一现有的AD发病机制理论，并探索其通过靶向Ca2+失调来开发创新治疗策略的意义。综述的关键科学概念综述的重点是三个主要概念。首先，Ca2+稳态在神经元功能及其在AD中的破坏中不可或缺的作用。其次，Ca2+信号功能障碍与AD假说之间的相互作用假设Ca2+失调是一个统一的途径。第三，Ca2+在神经退行性变和神经保护中的双重作用，强调Ca2+水平对AD病理的细微影响。
{"title":"Calcium signaling hypothesis: A non-negligible pathogenesis in Alzheimer’s disease","authors":"Minghui Wang, Hu Zhang, Jiling Liang, Jielun Huang, Tong Wu, Ning Chen","doi":"10.1016/j.jare.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.007","url":null,"abstract":"<h3>Background</h3>Alzheimer’s disease (AD) presents a significant challenge to global healthcare systems, with an exacerbation by an aging population. Although the plethora of hypotheses are proposed to elucidate the underlying mechanisms of AD, from amyloid-beta (Aβ) accumulation and Tau protein aggregation to neuroinflammation, a comprehensive understanding of its pathogenesis remains elusive. Recent research has highlighted the critical role of calcium (Ca<sup>2+</sup>) signaling pathway in the progression of AD, indicating a complex interplay between Ca<sup>2+</sup> dysregulation and various pathological processes.<h3>Aim of Review</h3>This review aims to consolidate the current understanding of the role of Ca<sup>2+</sup> signaling dysregulation in AD, thus emphasizing its central role amidst various pathological hypotheses. We aim to evaluate the potential of the Ca<sup>2+</sup> signaling hypothesis to unify existing theories of AD pathogenesis and explore its implications for developing innovative therapeutic strategies through targeting Ca<sup>2+</sup> dysregulation.<h3>Key Scientific Concepts of Review</h3>The review focuses on three principal concepts. First, the indispensable role of Ca<sup>2+</sup> homeostasis in neuronal function and its disruption in AD. Second, the interaction between Ca<sup>2+</sup> signaling dysfunction and established AD hypotheses posited that Ca<sup>2+</sup> dysregulation is a unifying pathway. Third, the dual role of Ca<sup>2+</sup> in neurodegeneration and neuroprotection, highlighting the nuanced effects of Ca<sup>2+</sup> levels on AD pathology.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"6 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-alcoholic fatty liver disease (NAFLD) acts as the primary contributor to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and potentially hepatocellular carcinoma. The flowers of Chrysanthemum indicum, a traditional edible medicinal herb, have been widely used in China for more than 2000 years. However, the function of C. indicum in managing NAFLD has seldom been investigated.
Objectives
To reveal the novel active components and underlying mechanisms of C. indicum in treating NAFLD.
Methods
An MS/MS-based molecular networking-guided strategy was used for the chemical investigation. The structure identification of the new compounds involved high resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D nuclear magnetic resonance (NMR) spectra, electronic circular dichroism (ECD), and X-ray crystallographic analysis. The biological evaluation was performed using Nile Red staining, flow cytometry, commercial kits, western blotting, co-immunoprecipitation, isothermal titration calorimetry, cellular thermal shift assay, drug affinity responsive target stability assay, molecular docking, and confocal immunofluorescence.
Results
A total of 27 new dimeric sesquiterpenoids, chryindicolides A-Z (1-26) and chrysanthemolide C (27), together with seven known compounds, were isolated from the flowers of C. indicum under the guide of MS/MS-based molecular networking. Among them, compounds 1-7 were rare chlorine-containing guaianolide dimers. Chryindicolide O (15) directly bound and activated the deacetylase Sirtuin 1 (SIRT1) to reduce de novo lipogenesis, enhance fatty acid β-oxidation, and inhibit ferroptosis in palmitic acid and oleic acid (P/O)-induced AML12 hepatocytes. In addition, chryindicolide O significantly ameliorated liver steatosis in high-fat diet-fed zebrafish.
Conclusion
Novel guaianolide dimers from C. indicum alleviated hepatic steatosis through mitigating SIRT1-mediated lipid accumulation and ferroptosis, suggesting that they could be further developed as candidates against NAFLD.
{"title":"Dimeric guaianolide sesquiterpenoids from the flowers of Chrysanthemum indicum ameliorate hepatic steatosis through mitigating SIRT1-mediated lipid accumulation and ferroptosis","authors":"Yu Liu, Fei Zhou, Haoyu Zhao, Jianguo Song, Min Song, Jianzhong Zhu, Ying Wang, Maggie Pui Man Hoi, Ligen Lin, Qingwen Zhang","doi":"10.1016/j.jare.2024.12.047","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.047","url":null,"abstract":"<h3>Introduction</h3>Non-alcoholic fatty liver disease (NAFLD) acts as the primary contributor to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and potentially hepatocellular carcinoma. The flowers of <em>Chrysanthemum indicum</em>, a traditional edible medicinal herb, have been widely used in China for more than 2000 years. However, the function of <em>C. indicum</em> in managing NAFLD has seldom been investigated.<h3>Objectives</h3>To reveal the novel active components and underlying mechanisms of <em>C. indicum</em> in treating NAFLD.<h3>Methods</h3>An MS/MS-based molecular networking-guided strategy was used for the chemical investigation. The structure identification of the new compounds involved high resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D nuclear magnetic resonance (NMR) spectra, electronic circular dichroism (ECD), and X-ray crystallographic analysis. The biological evaluation was performed using Nile Red staining, flow cytometry, commercial kits, western blotting, co-immunoprecipitation, isothermal titration calorimetry, cellular thermal shift assay, drug affinity responsive target stability assay, molecular docking, and confocal immunofluorescence.<h3>Results</h3>A total of 27 new dimeric sesquiterpenoids, chryindicolides A-Z (<strong>1</strong>-<strong>26</strong>) and chrysanthemolide C (<strong>27</strong>), together with seven known compounds, were isolated from the flowers of <em>C. indicum</em> under the guide of MS/MS-based molecular networking. Among them, compounds <strong>1</strong>-<strong>7</strong> were rare chlorine-containing guaianolide dimers. Chryindicolide O (15) directly bound and activated the deacetylase Sirtuin 1 (SIRT1) to reduce <em>de novo</em> lipogenesis, enhance fatty acid β-oxidation, and inhibit ferroptosis in palmitic acid and oleic acid (P/O)-induced AML12 hepatocytes. In addition, chryindicolide O significantly ameliorated liver steatosis in high-fat diet-fed zebrafish.<h3>Conclusion</h3>Novel guaianolide dimers from <em>C. indicum</em> alleviated hepatic steatosis through mitigating SIRT1-mediated lipid accumulation and ferroptosis, suggesting that they could be further developed as candidates against NAFLD.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"526 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Salmonella, a foodborne zoonotic pathogen, is a significant cause of morbidity and mortality in animals and humans globally. With the prevalence of multidrug-resistant strains, Salmonellosis has become a formidable challenge. Host-directed therapy (HDT) has recently emerged as a promising anti-infective approach for treating intracellular bacterial infections.
Objectives
Plant-derived natural products, owing to their structural and functional diversity, are increasingly being explored and utilized as encouraging candidates for HDT compounds. This study aims to identify and screen natural compounds with potential as HDT for the treatment of intracellular Salmonella infections.
Methods
A cell-based screening approach was deployed to identify natural compounds capable of mitigating the intracellular replication of S. enterica. Safety and efficacy of the candidate compounds were evaluated using multiple animal models. RNA sequencing, ELISA, and immunoblotting analyses were conducted to elucidate the underlying mechanisms of action.
Results
Our results reveal that fangchinoline (FAN) effectively reduces S. enterica survival both in vitro and in vivo. Meanwhile, FAN also displays anti-infective activity against other intracellular pathogens, including multidrug-resistant isolates. A 14-day safety evaluation in mice showed no significant toxic or adverse effects from FAN administration. RNA sequencing analysis reveals an upregulation of lysosome pathways in S. enterica-infected cells treated with FAN. Mechanistic studies indicate that FAN increases acid lysosomal quantities and fosters autophagic response in Salmonella-infected cells the AMPK-mTORC1-TFEB axis. In addition, FAN alleviates the inflammatory response in Salmonella-infected cells by inactivating the NF-κB pathway.
Conclusion
Our findings suggest that FAN represents a lead HDT compound for tackling recalcitrant infections caused by intracellular bacterial pathogens.
{"title":"Fangchinoline eliminates intracellular Salmonella by enhancing lysosomal function via the AMPK-mTORC1-TFEB axis","authors":"Mengping He, Huihui Wu, Tianqi Xu, Yurong Zhao, Zhiqiang Wang, Yuan Liu","doi":"10.1016/j.jare.2025.01.015","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.015","url":null,"abstract":"<h3>Introduction</h3><em>Salmonella</em>, a foodborne zoonotic pathogen, is a significant cause of morbidity and mortality in animals and humans globally. With the prevalence of multidrug-resistant strains, <em>Salmonellosis</em> has become a formidable challenge. Host-directed therapy (HDT) has recently emerged as a promising anti-infective approach for treating intracellular bacterial infections.<h3>Objectives</h3>Plant-derived natural products, owing to their structural and functional diversity, are increasingly being explored and utilized as encouraging candidates for HDT compounds. This study aims to identify and screen natural compounds with potential as HDT for the treatment of intracellular <em>Salmonella</em> infections.<h3>Methods</h3>A cell-based screening approach was deployed to identify natural compounds capable of mitigating the intracellular replication of <em>S. enterica</em>. Safety and efficacy of the candidate compounds were evaluated using multiple animal models. RNA sequencing, ELISA, and immunoblotting analyses were conducted to elucidate the underlying mechanisms of action.<h3>Results</h3>Our results reveal that fangchinoline (FAN) effectively reduces <em>S. enterica</em> survival both <em>in vitro</em> and <em>in vivo</em>. Meanwhile, FAN also displays anti-infective activity against other intracellular pathogens, including multidrug-resistant isolates. A 14-day safety evaluation in mice showed no significant toxic or adverse effects from FAN administration. RNA sequencing analysis reveals an upregulation of lysosome pathways in <em>S. enterica</em>-infected cells treated with FAN. Mechanistic studies indicate that FAN increases acid lysosomal quantities and fosters autophagic response in <em>Salmonella</em>-infected cells the AMPK-mTORC1-TFEB axis. In addition, FAN alleviates the inflammatory response in <em>Salmonella</em>-infected cells by inactivating the NF-κB pathway.<h3>Conclusion</h3>Our findings suggest that FAN represents a lead HDT compound for tackling recalcitrant infections caused by intracellular bacterial pathogens.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"13 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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