Hyunseong Kim, C. Yeo, Jin Young Hong, Wanjin Jeon, Hyun Kim, Junseong Lee, Yoon Jae Lee, Seung Ho Baek, I. Ha
Intervertebral disc degeneration (IDD) progresses owing to damage and depletion of nucleus pulposus (NP) cells. Cytoprotection mitigates oxidative stress, nutrient deprivation, and mechanical stress, which lead to cell damage and necrosis. We aimed to examine the protective effect of Raphanus sativus Linne (RSL), common radish, against oxidative stress by H2O2 in human NP cells and whether the RSL extracts can inhibit triggering receptor expressed on myeloid cells 2 (TREM2), an inducer of apoptosis and degeneration in NP cells. We administered hydrogen peroxide (H2O2) to cultured human NP cells treated with RSL extracts. We used immunoblotting and quantitative PCR to investigate expression of the apoptosis-associated proteins in cultured cells. RSL significantly enhanced cell survival by suppressing the activation of cleaved caspase-3 and Bax. In contrast, RSL extract increased Bcl2 concentration to downregulate apoptosis. Additionally, RSL treatment notably enhanced the mRNA levels of ACAN and Col2a1 while significantly reducing those of ADAMTS-4, ADAMTS-5, MMP3, and MMP13, key genes involved in NP degeneration. While H2O2 elevated TREM2 expression, causing disc degeneration, RSL downregulated TREM2 expression. Thus, our findings imply that RSL supports human NP cells under oxidative stress and regulates the pathways underlying disc degeneration, particularly TREM2, and that RSL extracts may potentially prevent IDD.
{"title":"Raphanus sativus Linne Protects Human Nucleus Pulposus Cells against H2O2-Induced Damage by Inhibiting TREM2","authors":"Hyunseong Kim, C. Yeo, Jin Young Hong, Wanjin Jeon, Hyun Kim, Junseong Lee, Yoon Jae Lee, Seung Ho Baek, I. Ha","doi":"10.3390/biology13080602","DOIUrl":"https://doi.org/10.3390/biology13080602","url":null,"abstract":"Intervertebral disc degeneration (IDD) progresses owing to damage and depletion of nucleus pulposus (NP) cells. Cytoprotection mitigates oxidative stress, nutrient deprivation, and mechanical stress, which lead to cell damage and necrosis. We aimed to examine the protective effect of Raphanus sativus Linne (RSL), common radish, against oxidative stress by H2O2 in human NP cells and whether the RSL extracts can inhibit triggering receptor expressed on myeloid cells 2 (TREM2), an inducer of apoptosis and degeneration in NP cells. We administered hydrogen peroxide (H2O2) to cultured human NP cells treated with RSL extracts. We used immunoblotting and quantitative PCR to investigate expression of the apoptosis-associated proteins in cultured cells. RSL significantly enhanced cell survival by suppressing the activation of cleaved caspase-3 and Bax. In contrast, RSL extract increased Bcl2 concentration to downregulate apoptosis. Additionally, RSL treatment notably enhanced the mRNA levels of ACAN and Col2a1 while significantly reducing those of ADAMTS-4, ADAMTS-5, MMP3, and MMP13, key genes involved in NP degeneration. While H2O2 elevated TREM2 expression, causing disc degeneration, RSL downregulated TREM2 expression. Thus, our findings imply that RSL supports human NP cells under oxidative stress and regulates the pathways underlying disc degeneration, particularly TREM2, and that RSL extracts may potentially prevent IDD.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"61 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiaming Zhu, Peng Guo, Yuting Zheng, Shiqing Xiang, Yang Zhao, Xinyu Liu, Chengzhang Fu, Youming Zhang, Hai Xu, Ling Li, Wenjia Wang, Mingyu Wang
Bacterial resistance to antibiotics can lead to long-lasting, hard-to-cure infections that pose significant threats to human health. One key mechanism of antimicrobial resistance (AMR) is to reduce the antibiotic permeation of cellular membranes. For instance, the lack of outer membrane porins (OMPs) can lead to elevated AMR levels. However, knowledge on whether mutations of OMPs can also influence antibiotic susceptibility is limited. This work aims to address this question and identified an A226D mutation in OmpC, a trimeric OMP, in Escherichia coli. Surveillance studies found that this mutation is present in 50 E. coli strains for which whole genomic sequences are available. Measurement of minimum inhibition concentrations (MICs) found that this mutation leads to a 2-fold decrease in MICs for β-lactams ampicillin and piperacillin. Further survival assays confirmed the role this mutation plays in β-lactam susceptibility. With molecular dynamics, we found that the A226D mutation led to increased overall flexibility of the protein, thus facilitating antibiotic uptake, and that binding with piperacillin was weakened, leading to easier antibiotic penetration. This work reports a novel mutation that plays a role in antibiotic susceptibility, along with mechanistic studies, and further confirms the role of OMPs in bacterial tolerance to antibiotics.
{"title":"The A226D Mutation of OmpC Leads to Increased Susceptibility to β-Lactam Antibiotics in Escherichia coli","authors":"Jiaming Zhu, Peng Guo, Yuting Zheng, Shiqing Xiang, Yang Zhao, Xinyu Liu, Chengzhang Fu, Youming Zhang, Hai Xu, Ling Li, Wenjia Wang, Mingyu Wang","doi":"10.3390/biology13080600","DOIUrl":"https://doi.org/10.3390/biology13080600","url":null,"abstract":"Bacterial resistance to antibiotics can lead to long-lasting, hard-to-cure infections that pose significant threats to human health. One key mechanism of antimicrobial resistance (AMR) is to reduce the antibiotic permeation of cellular membranes. For instance, the lack of outer membrane porins (OMPs) can lead to elevated AMR levels. However, knowledge on whether mutations of OMPs can also influence antibiotic susceptibility is limited. This work aims to address this question and identified an A226D mutation in OmpC, a trimeric OMP, in Escherichia coli. Surveillance studies found that this mutation is present in 50 E. coli strains for which whole genomic sequences are available. Measurement of minimum inhibition concentrations (MICs) found that this mutation leads to a 2-fold decrease in MICs for β-lactams ampicillin and piperacillin. Further survival assays confirmed the role this mutation plays in β-lactam susceptibility. With molecular dynamics, we found that the A226D mutation led to increased overall flexibility of the protein, thus facilitating antibiotic uptake, and that binding with piperacillin was weakened, leading to easier antibiotic penetration. This work reports a novel mutation that plays a role in antibiotic susceptibility, along with mechanistic studies, and further confirms the role of OMPs in bacterial tolerance to antibiotics.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"56 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olesja D. Bogomaz, V. D. Bemova, Nikita A. Mirgorodskii, T. Matveeva
Naturally transgenic plants are plants that have undergone Agrobacterium-mediated transformation under natural conditions without human involvement. Among Arachis hypogaea L., A. duranensis Krapov. & W.C. Greg, A. ipaensis Krapov. & W.C. Greg, A. monticola Krapov. & Rigoni, and A. stenosperma Krapov. & W.C. Greg are known to contain sequences derived from the T-DNA of “Agrobacterium”. In the present study, using molecular genetics and bioinformatic methods, we characterized natural transgenes in 18 new species from six sections of the genus Arachis. We found that small fragments of genes for enzymes of the agropine synthesis pathway were preserved only in some of the studied samples and were lost in the majority of the species during evolution. At the same time, genes, similar to cucumopine synthases (cus-like), remained intact in almost all of the investigated species. In cultivated peanuts, they are expressed in a tissue-specific manner. We demonstrated the intraspecific variability of the structure and expression of the cus-like gene in cultivated peanuts. The described diversity of gene sequences horizontally transferred from Agrobacterium to plants helps to shed light on the phylogeny of species of the genus Arachis and track possible hybridization events. Data on the ability of certain species to hybridize are useful for planning breeding schemes aimed at transferring valuable traits from wild species into cultivated peanuts.
{"title":"Evolutionary Fate of the Opine Synthesis Genes in the Arachis L. Genomes","authors":"Olesja D. Bogomaz, V. D. Bemova, Nikita A. Mirgorodskii, T. Matveeva","doi":"10.3390/biology13080601","DOIUrl":"https://doi.org/10.3390/biology13080601","url":null,"abstract":"Naturally transgenic plants are plants that have undergone Agrobacterium-mediated transformation under natural conditions without human involvement. Among Arachis hypogaea L., A. duranensis Krapov. & W.C. Greg, A. ipaensis Krapov. & W.C. Greg, A. monticola Krapov. & Rigoni, and A. stenosperma Krapov. & W.C. Greg are known to contain sequences derived from the T-DNA of “Agrobacterium”. In the present study, using molecular genetics and bioinformatic methods, we characterized natural transgenes in 18 new species from six sections of the genus Arachis. We found that small fragments of genes for enzymes of the agropine synthesis pathway were preserved only in some of the studied samples and were lost in the majority of the species during evolution. At the same time, genes, similar to cucumopine synthases (cus-like), remained intact in almost all of the investigated species. In cultivated peanuts, they are expressed in a tissue-specific manner. We demonstrated the intraspecific variability of the structure and expression of the cus-like gene in cultivated peanuts. The described diversity of gene sequences horizontally transferred from Agrobacterium to plants helps to shed light on the phylogeny of species of the genus Arachis and track possible hybridization events. Data on the ability of certain species to hybridize are useful for planning breeding schemes aimed at transferring valuable traits from wild species into cultivated peanuts.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"80 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Animal embryonic development occurs under hypoxia, which can promote various developmental processes. Embryonic fibroblasts, which can differentiate into bone and cartilage and secrete various members of the collagen protein family, play essential roles in the formation of embryonic connective tissues and basement membranes. However, the adaptations of embryonic fibroblasts under hypoxia remain poorly understood. In this study, we investigated the effects of hypoxia on mouse embryonic fibroblasts (MEFs). We found that hypoxia can induce migration, promote metabolic reprogramming, induce the production of ROS and apoptosis, and trigger the activation of multiple signaling pathways of MEFs. Additionally, we identified several hypoxia-inducible genes, including Proser2, Bean1, Dpf1, Rnf128, and Fam71f1, which are regulated by HIF1α. Furthermore, we demonstrated that CoCl2 partially mimics the effects of low oxygen on MEFs. However, we found that the mechanisms underlying the production of ROS and apoptosis differ between hypoxia and CoCl2 treatment. These findings provide insights into the complex interplay between hypoxia, fibroblasts, and embryonic developmental processes.
{"title":"Hypoxia-Induced Adaptations of Embryonic Fibroblasts: Implications for Developmental Processes","authors":"Zeyu Li, Delong Han, Zhenchi Li, Lingjie Luo","doi":"10.3390/biology13080598","DOIUrl":"https://doi.org/10.3390/biology13080598","url":null,"abstract":"Animal embryonic development occurs under hypoxia, which can promote various developmental processes. Embryonic fibroblasts, which can differentiate into bone and cartilage and secrete various members of the collagen protein family, play essential roles in the formation of embryonic connective tissues and basement membranes. However, the adaptations of embryonic fibroblasts under hypoxia remain poorly understood. In this study, we investigated the effects of hypoxia on mouse embryonic fibroblasts (MEFs). We found that hypoxia can induce migration, promote metabolic reprogramming, induce the production of ROS and apoptosis, and trigger the activation of multiple signaling pathways of MEFs. Additionally, we identified several hypoxia-inducible genes, including Proser2, Bean1, Dpf1, Rnf128, and Fam71f1, which are regulated by HIF1α. Furthermore, we demonstrated that CoCl2 partially mimics the effects of low oxygen on MEFs. However, we found that the mechanisms underlying the production of ROS and apoptosis differ between hypoxia and CoCl2 treatment. These findings provide insights into the complex interplay between hypoxia, fibroblasts, and embryonic developmental processes.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aaron L. Slusher, Nishant P Visavadiya, Brandon G. Fico, Brisamar Estébanez, Edmund O. Acevedo, Chun-Jung Huang
The impact of cardiorespiratory fitness (VO2max) and obesity on indices of oxidative stress in plasma and circulating exosome-like extracellular vesicles (ELVs) were examined following acute exercise. Indices of oxidative stress in plasma and isolated plasma ELVs were examined in aerobically trained (NW-Tr; n = 15) and untrained (NW-UTr; n = 18) normal-weight individuals and aerobically untrained individuals with obesity (Ob-Utr; n = 10) prior to and immediately following acute maximal treadmill running. Following exercise, ELV flotillin-1 expression (p = 0.008) and plasma total antioxidant capacity (TAC; p = 0.010) increased more in NW-UTr compared to NW-Tr and Ob-UTr participants, whereas plasma protein carbonyls (PC) decreased more in Ob-UTr compared to NW-Tr and NW-UTr groups. ELV glutathione (GSH) concentrations decreased more in NW-Tr compared to NW-UTr and Ob-UTr participants (p = 0.009), whereas lipid peroxidase (LPO) concentrations increased more in Ob-UTr compared to NW-Tr and NW-UTr participants (p = 0.003). Body mass index (BMI) was associated negatively with plasma TAC and PC (p < 0.05) and positively with ELV LPO concentration responses (p = 0.009). Finally, plasma-to-total (plasma + ELV) GSH ratios decreased in Ob-UTr compared to NW-Tr and NW-UTr participants (p = 0.006), PC ratios increased in NW-Tr and NW-UTr compared to Ob-UTr subjects (p = 0.008), and reactive oxygen/nitrogen species ratios increased in NW-UTr and decreased in Ob-UTr participants (p < 0.001). BMI, independently of VO2max, differentially regulates indices of oxidative stress within plasma and circulating ELVs prior to and immediately following acute maximal treadmill exercise.
{"title":"Impact of BMI and Cardiorespiratory Fitness on Oxidative Stress in Plasma and Circulating Exosomes Following Acute Exercise","authors":"Aaron L. Slusher, Nishant P Visavadiya, Brandon G. Fico, Brisamar Estébanez, Edmund O. Acevedo, Chun-Jung Huang","doi":"10.3390/biology13080599","DOIUrl":"https://doi.org/10.3390/biology13080599","url":null,"abstract":"The impact of cardiorespiratory fitness (VO2max) and obesity on indices of oxidative stress in plasma and circulating exosome-like extracellular vesicles (ELVs) were examined following acute exercise. Indices of oxidative stress in plasma and isolated plasma ELVs were examined in aerobically trained (NW-Tr; n = 15) and untrained (NW-UTr; n = 18) normal-weight individuals and aerobically untrained individuals with obesity (Ob-Utr; n = 10) prior to and immediately following acute maximal treadmill running. Following exercise, ELV flotillin-1 expression (p = 0.008) and plasma total antioxidant capacity (TAC; p = 0.010) increased more in NW-UTr compared to NW-Tr and Ob-UTr participants, whereas plasma protein carbonyls (PC) decreased more in Ob-UTr compared to NW-Tr and NW-UTr groups. ELV glutathione (GSH) concentrations decreased more in NW-Tr compared to NW-UTr and Ob-UTr participants (p = 0.009), whereas lipid peroxidase (LPO) concentrations increased more in Ob-UTr compared to NW-Tr and NW-UTr participants (p = 0.003). Body mass index (BMI) was associated negatively with plasma TAC and PC (p < 0.05) and positively with ELV LPO concentration responses (p = 0.009). Finally, plasma-to-total (plasma + ELV) GSH ratios decreased in Ob-UTr compared to NW-Tr and NW-UTr participants (p = 0.006), PC ratios increased in NW-Tr and NW-UTr compared to Ob-UTr subjects (p = 0.008), and reactive oxygen/nitrogen species ratios increased in NW-UTr and decreased in Ob-UTr participants (p < 0.001). BMI, independently of VO2max, differentially regulates indices of oxidative stress within plasma and circulating ELVs prior to and immediately following acute maximal treadmill exercise.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"55 36","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141928951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetic nephropathy (DN) is one of the common complications of diabetes and the main cause of end-stage renal disease (ESRD) in clinical practice. Schisandrin A (Sch A) has multiple pharmacological activities, including inhibiting fibrosis, reducing apoptosis and oxidative stress, and regulating immunity, but its pharmacological mechanism for the treatment of DN is still unclear. In vivo, streptozotocin (STZ) and a high-fat diet were used to induce type 2 diabetic rats, and Sch A was administered for 4 weeks. At the same time, protein–protein interaction (PPI) networks were established to analyze the overlapping genes of DN and Sch A. Subsequently, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to determine the hub pathway. In addition, molecular docking was used to preliminarily verify the affinity of hub proteins and Sch A. Further, H&E staining, Sirius red staining, immunohistochemistry, immunofluorescence, and western blot analysis were used to detect the location and expression of related proteins in DN. This study revealed the multi-target and multi-pathway characteristics of Sch A in the treatment of DN. First, Sch A could effectively improve glucose tolerance, reduce urine microprotein and urine creatinine levels, and alleviate renal pathological damage in DN rats. Second, EGFR was the hub gene screened in overlapping genes (43) of Sch A (100) and DN (2524). Finally, it was revealed that Sch A could inhibit the protein expression levels of EGFR and PTRF and reduced the expression of apoptosis-related proteins, and this effect was related to the modulation of the AKT/GSK-3β signaling pathway. In summary, Sch A has a protective effect in DN rats, EGFR may be a potential therapeutic target, throughout modulating AKT/GSK-3β pathway.
糖尿病肾病（DN）是糖尿病的常见并发症之一，也是临床上终末期肾病（ESRD）的主要病因。五味子素 A（Sch A）具有多种药理活性，包括抑制纤维化、减少细胞凋亡和氧化应激、调节免疫等，但其治疗 DN 的药理机制尚不清楚。在体内，使用链脲佐菌素（STZ）和高脂饮食诱导 2 型糖尿病大鼠，并给予 Sch A 4 周。同时，建立了蛋白-蛋白相互作用（PPI）网络，分析了DN和Sch A的重叠基因；随后，进行了京都基因组百科全书（KEGG）和基因本体（GO）分析，确定了枢纽通路。此外，还采用分子对接法初步验证了枢纽蛋白与 Sch A 的亲和性，并通过 H&E 染色、天狼星红染色、免疫组化、免疫荧光和 Western 印迹分析检测了相关蛋白在 DN 中的位置和表达。该研究揭示了 Sch A 治疗 DN 的多靶点、多途径特点。首先，Sch A能有效改善DN大鼠的糖耐量，降低尿微量蛋白和尿肌酐水平，减轻肾脏病理损伤。其次，表皮生长因子受体（EGFR）是筛选出的 Sch A（100）和 DN（2524）重叠基因（43）中的中心基因。最后，研究发现，Sch A能抑制表皮生长因子受体（EGFR）和PTRF的蛋白表达水平，降低凋亡相关蛋白的表达，而这一作用与AKT/GSK-3β信号通路的调节有关。综上所述，Sch A对DN大鼠具有保护作用，表皮生长因子受体可能是一个潜在的治疗靶点，通过调节AKT/GSK-3β通路。
{"title":"Schisandrin A Attenuates Diabetic Nephropathy via EGFR/AKT/GSK3β Signaling Pathway Based on Network Pharmacology and Experimental Validation","authors":"Pengyu Wang, Qing Lan, Qi Huang, Ruyi Zhang, Shuo Zhang, Leiming Yang, Yan Song, Tong Wang, Guandi Ma, Xiufen Liu, Xiying Guo, Youzhi Zhang, Chao Liu","doi":"10.3390/biology13080597","DOIUrl":"https://doi.org/10.3390/biology13080597","url":null,"abstract":"Diabetic nephropathy (DN) is one of the common complications of diabetes and the main cause of end-stage renal disease (ESRD) in clinical practice. Schisandrin A (Sch A) has multiple pharmacological activities, including inhibiting fibrosis, reducing apoptosis and oxidative stress, and regulating immunity, but its pharmacological mechanism for the treatment of DN is still unclear. In vivo, streptozotocin (STZ) and a high-fat diet were used to induce type 2 diabetic rats, and Sch A was administered for 4 weeks. At the same time, protein–protein interaction (PPI) networks were established to analyze the overlapping genes of DN and Sch A. Subsequently, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to determine the hub pathway. In addition, molecular docking was used to preliminarily verify the affinity of hub proteins and Sch A. Further, H&E staining, Sirius red staining, immunohistochemistry, immunofluorescence, and western blot analysis were used to detect the location and expression of related proteins in DN. This study revealed the multi-target and multi-pathway characteristics of Sch A in the treatment of DN. First, Sch A could effectively improve glucose tolerance, reduce urine microprotein and urine creatinine levels, and alleviate renal pathological damage in DN rats. Second, EGFR was the hub gene screened in overlapping genes (43) of Sch A (100) and DN (2524). Finally, it was revealed that Sch A could inhibit the protein expression levels of EGFR and PTRF and reduced the expression of apoptosis-related proteins, and this effect was related to the modulation of the AKT/GSK-3β signaling pathway. In summary, Sch A has a protective effect in DN rats, EGFR may be a potential therapeutic target, throughout modulating AKT/GSK-3β pathway.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breast cancer heterogeneity presents a significant challenge in clinical therapy, such as over-treatment and drug resistance. These challenges are largely due to its obscure normal epithelial origins, evolutionary stability, and transitions on the cancer subtypes. This study aims to elucidate the cellular emergence and maintenance of heterogeneous breast cancer via quantitative bio-process modeling, with potential benefit to therapeutic strategies for the disease. An endogenous molecular–cellular hypothesis posits that both pathological and physiological states are phenotypes evolved from and shaped by interactions among a number of conserved modules and cellular factors within a biological network. We hereby developed a model of core endogenous network for breast cancer in accordance with the theory, quantifying its intrinsic dynamic properties with dynamic modeling. The model spontaneously generates cell states that align with molecular classifications at both the molecular and modular level, replicating four widely recognized molecular subtypes of the cancer and validating against data extracted from the TCGA database. Further analysis shows that topologically, a singular progression gateway from normal breast cells to cancerous states is identified as the Luminal A-type breast cancer. Activated positive feedback loops are found to stabilize cellular states, while negative feedback loops facilitate state transitions. Overall, more routes are revealed on the cellular transition between stable states, and a traceable count explains the origin of breast cancer heterogeneity. Ultimately, the research intended to strength the search for therapeutic targets.
乳腺癌的异质性给临床治疗带来了巨大挑战，如过度治疗和耐药性。这些挑战主要是由于乳腺癌的正常上皮起源、进化稳定性和癌症亚型的转变不明显。本研究旨在通过定量生物过程建模，阐明异质性乳腺癌的细胞出现和维持过程，从而为该疾病的治疗策略带来潜在益处。内源性分子-细胞假说认为，病理和生理状态都是由生物网络中的一些保守模块和细胞因子之间的相互作用进化和形成的表型。在此，我们根据该理论建立了一个乳腺癌核心内源性网络模型，并通过动态建模量化了其内在的动态特性。该模型在分子和模块层面自发生成与分子分类一致的细胞状态，复制了四种广为认可的癌症分子亚型，并与从 TCGA 数据库中提取的数据进行了验证。进一步的分析表明，从拓扑学上看，从正常乳腺细胞到癌症状态的单一进展通道被确定为 A 型乳腺癌。研究发现，激活的正反馈环路能稳定细胞状态，而负反馈环路则能促进状态转换。总之，研究揭示了细胞在稳定状态之间过渡的更多途径，并通过可追溯的计数解释了乳腺癌异质性的起源。最终，这项研究旨在加强对治疗目标的探索。
{"title":"Heterogeneous Evolution of Breast Cancer Cells—An Endogenous Molecular-Cellular Network Study","authors":"Tianqi Li, Yong-Cong Chen, Ping Ao","doi":"10.3390/biology13080564","DOIUrl":"https://doi.org/10.3390/biology13080564","url":null,"abstract":"Breast cancer heterogeneity presents a significant challenge in clinical therapy, such as over-treatment and drug resistance. These challenges are largely due to its obscure normal epithelial origins, evolutionary stability, and transitions on the cancer subtypes. This study aims to elucidate the cellular emergence and maintenance of heterogeneous breast cancer via quantitative bio-process modeling, with potential benefit to therapeutic strategies for the disease. An endogenous molecular–cellular hypothesis posits that both pathological and physiological states are phenotypes evolved from and shaped by interactions among a number of conserved modules and cellular factors within a biological network. We hereby developed a model of core endogenous network for breast cancer in accordance with the theory, quantifying its intrinsic dynamic properties with dynamic modeling. The model spontaneously generates cell states that align with molecular classifications at both the molecular and modular level, replicating four widely recognized molecular subtypes of the cancer and validating against data extracted from the TCGA database. Further analysis shows that topologically, a singular progression gateway from normal breast cells to cancerous states is identified as the Luminal A-type breast cancer. Activated positive feedback loops are found to stabilize cellular states, while negative feedback loops facilitate state transitions. Overall, more routes are revealed on the cellular transition between stable states, and a traceable count explains the origin of breast cancer heterogeneity. Ultimately, the research intended to strength the search for therapeutic targets.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"19 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141801405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physical exercise can significantly impact our bodies, affecting our functional capacity, structure establishment, and molecular makeup. The magnitude of these changes depends on the specific exercise protocols used. For instance, low-to-moderate-intensity exercise can activate important molecular targets in the short term, such as BDNF-mediated signaling, while high-intensity exercise can maintain these signaling molecules in the active state for a longer term. This makes it challenging to recommend specific exercises for obtaining BDNF-induced benefits. Additionally, exercise-induced molecular signaling targets can have positive and negative effects, with some exercises blunting these targets and others activating them. For example, increasing BDNF concentration through exercise can be beneficial for brain health, but it may also have a negative impact on conditions such as bipolar disorder. Therefore, a deeper understanding of a specific exercise-mediated mechanistic approach is required. This review will delve into how the sprint exercise-mediated activation of BDNF could help maintain brain health and explore potential molecular interventions.
{"title":"Sprint Interval Training Improves Brain-Derived Neurotropic Factor-Induced Benefits in Brain Health—A Possible Molecular Signaling Intervention","authors":"Xueqiang Zhu, Wenjia Chen, A. Thirupathi","doi":"10.3390/biology13080562","DOIUrl":"https://doi.org/10.3390/biology13080562","url":null,"abstract":"Physical exercise can significantly impact our bodies, affecting our functional capacity, structure establishment, and molecular makeup. The magnitude of these changes depends on the specific exercise protocols used. For instance, low-to-moderate-intensity exercise can activate important molecular targets in the short term, such as BDNF-mediated signaling, while high-intensity exercise can maintain these signaling molecules in the active state for a longer term. This makes it challenging to recommend specific exercises for obtaining BDNF-induced benefits. Additionally, exercise-induced molecular signaling targets can have positive and negative effects, with some exercises blunting these targets and others activating them. For example, increasing BDNF concentration through exercise can be beneficial for brain health, but it may also have a negative impact on conditions such as bipolar disorder. Therefore, a deeper understanding of a specific exercise-mediated mechanistic approach is required. This review will delve into how the sprint exercise-mediated activation of BDNF could help maintain brain health and explore potential molecular interventions.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"35 24","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141800474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guohua Cai, Yunxiao Zang, Zhongqian Wang, Shuoshuo Liu, Guodong Wang
Drought stress significantly impacts plant growth, productivity, and yield, necessitating a swift fine-tuning of pathways for adaptation to harsh environmental conditions. This study explored the effects of Arabidopsis BTB-A2.1, BTB-A2.2, and BTB-A2.3, distinguished by their exclusive possession of the Broad-complex, Tramtrack, and Bric-à-brac (BTB) domain, on the negative regulation of drought stress mediated by abscisic acid (ABA) signaling. Promoter analysis revealed the presence of numerous ABA-responsive and drought stress-related cis-acting elements within the promoters of AtBTB-A2.1, AtBTB-A2.2, and AtBTB-A2.3. The AtBTB-A2.1, AtBTB-A2.2, and AtBTB-A2.3 transcript abundances increased under drought and ABA induction according to qRT-PCR and GUS staining. Furthermore, the Arabidopsis btb-a2.1/2/3 triple mutant exhibited enhanced drought tolerance, supporting the findings from the overexpression studies. Additionally, we detected a decrease in the stomatal aperture and water loss rate of the Arabidopsis btb-a2.1/2/3 mutant, suggesting the involvement of these genes in repressing stomatal closure. Importantly, the ABA signaling-responsive gene levels within Arabidopsis btb-a2.1/2/3 significantly increased compared with those in the wild type (WT) under drought stress. Based on such findings, Arabidopsis BTB-A2s negatively regulate drought stress via the ABA signaling pathway.
干旱胁迫会严重影响植物的生长、生产力和产量，因此有必要迅速调整适应恶劣环境条件的途径。本研究探讨了拟南芥 BTB-A2.1、BTB-A2.2 和 BTB-A2.3 对脱落酸（ABA）信号介导的干旱胁迫负调控的影响。启动子分析表明，AtBTB-A2.1、AtBTB-A2.2 和 AtBTB-A2.3 的启动子中存在大量 ABA 响应和干旱胁迫相关的顺式作用元件。根据 qRT-PCR 和 GUS 染色，在干旱和 ABA 诱导下，AtBTB-A2.1、AtBTB-A2.2 和 AtBTB-A2.3 的转录本丰度增加。此外，拟南芥 btb-a2.1/2/3 三重突变体表现出更强的耐旱性，支持了过表达研究的结果。此外，我们还检测到拟南芥 btb-a2.1/2/3 突变体的气孔开度和失水率下降，这表明这些基因参与了抑制气孔关闭的过程。重要的是，在干旱胁迫下，拟南芥btb-a2.1/2/3突变体中的ABA信号响应基因水平比野生型（WT）显著增加。基于这些发现，拟南芥 BTB-A2s 可通过 ABA 信号途径负向调节干旱胁迫。
{"title":"Arabidopsis BTB-A2s Play a Key Role in Drought Stress","authors":"Guohua Cai, Yunxiao Zang, Zhongqian Wang, Shuoshuo Liu, Guodong Wang","doi":"10.3390/biology13080561","DOIUrl":"https://doi.org/10.3390/biology13080561","url":null,"abstract":"Drought stress significantly impacts plant growth, productivity, and yield, necessitating a swift fine-tuning of pathways for adaptation to harsh environmental conditions. This study explored the effects of Arabidopsis BTB-A2.1, BTB-A2.2, and BTB-A2.3, distinguished by their exclusive possession of the Broad-complex, Tramtrack, and Bric-à-brac (BTB) domain, on the negative regulation of drought stress mediated by abscisic acid (ABA) signaling. Promoter analysis revealed the presence of numerous ABA-responsive and drought stress-related cis-acting elements within the promoters of AtBTB-A2.1, AtBTB-A2.2, and AtBTB-A2.3. The AtBTB-A2.1, AtBTB-A2.2, and AtBTB-A2.3 transcript abundances increased under drought and ABA induction according to qRT-PCR and GUS staining. Furthermore, the Arabidopsis btb-a2.1/2/3 triple mutant exhibited enhanced drought tolerance, supporting the findings from the overexpression studies. Additionally, we detected a decrease in the stomatal aperture and water loss rate of the Arabidopsis btb-a2.1/2/3 mutant, suggesting the involvement of these genes in repressing stomatal closure. Importantly, the ABA signaling-responsive gene levels within Arabidopsis btb-a2.1/2/3 significantly increased compared with those in the wild type (WT) under drought stress. Based on such findings, Arabidopsis BTB-A2s negatively regulate drought stress via the ABA signaling pathway.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"15 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141801993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nikos Perdikopanis, Antonis Giannakakis, Ioannis Kavakiotis, A. Hatzigeorgiou
Small open reading frames (sORFs; <300 nucleotides or <100 amino acids) are widespread across all genomes, and an increasing variety of them appear to be translating from non-genic regions. Over the past few decades, peptides produced from sORFs have been identified as functional in various organisms, from bacteria to humans. Despite recent advances in next-generation sequencing and proteomics, accurate annotation and classification of sORFs remain a rate-limiting step toward reliable and high-throughput detection of small proteins from non-genic regions. Additionally, the cost of computational methods utilizing machine learning is lower than that of biological experiments, and they can be employed to detect sORFs, laying the groundwork for biological experiments. We present D-sORF, a machine-learning framework that integrates the statistical nucleotide context and motif information around the start codon to predict coding sORFs. D-sORF scores directly for coding identity and requires only the underlying genomic sequence, without incorporating parameters such as the conservation, which, in the case of sORFs, may increase the dispersion of scores within the significantly less conserved non-genic regions. D-sORF achieves 94.74% precision and 92.37% accuracy for small ORFs (using the 99 nt medium length window). When D-sORF is applied to sORFs associated with ribosomes, the identification of transcripts producing peptides (annotated by the Ensembl IDs) is similar to or superior to experimental methodologies based on ribosome-sequencing (Ribo-Seq) profiling. In parallel, the recognition of putative negative data, such as the intron-containing transcripts that associate with ribosomes, remains remarkably low, indicating that D-sORF could be efficiently applied to filter out false-positive sORFs from Ribo-Seq data because of the non-productive ribosomal binding or noise inherent in these protocols.
{"title":"D-sORF: Accurate Ab Initio Classification of Experimentally Detected Small Open Reading Frames (sORFs) Associated with Translational Machinery","authors":"Nikos Perdikopanis, Antonis Giannakakis, Ioannis Kavakiotis, A. Hatzigeorgiou","doi":"10.3390/biology13080563","DOIUrl":"https://doi.org/10.3390/biology13080563","url":null,"abstract":"Small open reading frames (sORFs; <300 nucleotides or <100 amino acids) are widespread across all genomes, and an increasing variety of them appear to be translating from non-genic regions. Over the past few decades, peptides produced from sORFs have been identified as functional in various organisms, from bacteria to humans. Despite recent advances in next-generation sequencing and proteomics, accurate annotation and classification of sORFs remain a rate-limiting step toward reliable and high-throughput detection of small proteins from non-genic regions. Additionally, the cost of computational methods utilizing machine learning is lower than that of biological experiments, and they can be employed to detect sORFs, laying the groundwork for biological experiments. We present D-sORF, a machine-learning framework that integrates the statistical nucleotide context and motif information around the start codon to predict coding sORFs. D-sORF scores directly for coding identity and requires only the underlying genomic sequence, without incorporating parameters such as the conservation, which, in the case of sORFs, may increase the dispersion of scores within the significantly less conserved non-genic regions. D-sORF achieves 94.74% precision and 92.37% accuracy for small ORFs (using the 99 nt medium length window). When D-sORF is applied to sORFs associated with ribosomes, the identification of transcripts producing peptides (annotated by the Ensembl IDs) is similar to or superior to experimental methodologies based on ribosome-sequencing (Ribo-Seq) profiling. In parallel, the recognition of putative negative data, such as the intron-containing transcripts that associate with ribosomes, remains remarkably low, indicating that D-sORF could be efficiently applied to filter out false-positive sORFs from Ribo-Seq data because of the non-productive ribosomal binding or noise inherent in these protocols.","PeriodicalId":504576,"journal":{"name":"Biology","volume":"35 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141800606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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