Severe asthma is a complex and heterogeneous clinical condition presented as chronic inflammation of the airways. Conventional treatments are mainly focused on symptom control; however, there has been a shift towards personalized medicine. Identification of different phenotypes driven by complex pathobiological mechanisms (endotypes), especially those driven by type-2 (T2) inflammation, has led to improved treatment outcomes. Combining biomarkers with T2-targeting monoclonal antibodies is crucial for developing personalized treatment strategies. Several biological agents, including anti-immunoglobulin E, anti-interleukin-5, and anti-thymic stromal lymphopoietin/interleukin-4, have been approved for the treatment of severe asthma. These biological therapies have demonstrated efficacy in reducing asthma exacerbations, lowering eosinophil count, improving lung function, diminishing oral corticosteroid use, and improving the quality of life in selected patients. Severe asthma management is undergoing a profound transformation with the introduction of ongoing and future biological therapies. The availability of novel treatment options has facilitated the adoption of phenotype/endotype-specific approaches and disappearance of generic interventions. The transition towards precision medicine plays a crucial role in meticulously addressing the individual traits of asthma pathobiology. An era of tailored strategies has emerged, allowing for the successful targeting of immune-inflammatory responses that underlie uncontrolled T2-high asthma. These personalized approaches hold great promise for improving the overall efficacy and outcomes in the management of severe asthma. This article comprehensively reviews currently available biological agents and biomarkers for treating severe asthma. With the expanding repertoire of therapeutic options, it is becoming increasingly crucial to comprehend the influencing factors, understand the pathogenesis, and track treatment progress in severe asthma.
{"title":"Personalized Medicine in Severe Asthma: From Biomarkers to Biologics","authors":"Chun-Yu Chen, Kang-Hsi Wu, Bei Guo, Wen-Ya Lin, Yu-Jun Chang, Chih-Wei Wei, Mao-Jen Lin, Han-Ping Wu","doi":"10.3390/ijms25010182","DOIUrl":"https://doi.org/10.3390/ijms25010182","url":null,"abstract":"Severe asthma is a complex and heterogeneous clinical condition presented as chronic inflammation of the airways. Conventional treatments are mainly focused on symptom control; however, there has been a shift towards personalized medicine. Identification of different phenotypes driven by complex pathobiological mechanisms (endotypes), especially those driven by type-2 (T2) inflammation, has led to improved treatment outcomes. Combining biomarkers with T2-targeting monoclonal antibodies is crucial for developing personalized treatment strategies. Several biological agents, including anti-immunoglobulin E, anti-interleukin-5, and anti-thymic stromal lymphopoietin/interleukin-4, have been approved for the treatment of severe asthma. These biological therapies have demonstrated efficacy in reducing asthma exacerbations, lowering eosinophil count, improving lung function, diminishing oral corticosteroid use, and improving the quality of life in selected patients. Severe asthma management is undergoing a profound transformation with the introduction of ongoing and future biological therapies. The availability of novel treatment options has facilitated the adoption of phenotype/endotype-specific approaches and disappearance of generic interventions. The transition towards precision medicine plays a crucial role in meticulously addressing the individual traits of asthma pathobiology. An era of tailored strategies has emerged, allowing for the successful targeting of immune-inflammatory responses that underlie uncontrolled T2-high asthma. These personalized approaches hold great promise for improving the overall efficacy and outcomes in the management of severe asthma. This article comprehensively reviews currently available biological agents and biomarkers for treating severe asthma. With the expanding repertoire of therapeutic options, it is becoming increasingly crucial to comprehend the influencing factors, understand the pathogenesis, and track treatment progress in severe asthma.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"15 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138947634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mia Langbøl, Jens Rovelt, Arevak Saruhanian, Sarkis Saruhanian, Daniel Tiedemann, Thisayini Baskaran, C. Bocca, R. Vohra, B. Cvenkel, G. Lenaers, M. Kolko
Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs.
{"title":"Distinct Metabolic Profiles of Ocular Hypertensives in Response to Hypoxia","authors":"Mia Langbøl, Jens Rovelt, Arevak Saruhanian, Sarkis Saruhanian, Daniel Tiedemann, Thisayini Baskaran, C. Bocca, R. Vohra, B. Cvenkel, G. Lenaers, M. Kolko","doi":"10.3390/ijms25010195","DOIUrl":"https://doi.org/10.3390/ijms25010195","url":null,"abstract":"Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"3 5","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138944210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gerbera (Gerbera hybrida) is a widely cultivated ornamental plant. However, its genetic improvement is limited by the lack of genetic analysis and molecular markers for traits. In this study, we analyzed the phenotypic and genotypic variation of 140 F1 progeny from two gerbera varieties with different flower types and colors. We evaluated the flower’s morphology, color, and pigment content of the F1 population and performed cluster principal component analysis (PCA) and correlation analysis. The results showed that the main ornamental traits of the hybrid progeny varied greatly. The segregation ratios of single and double flowers and ligulate and split ray florets were both 1:1. The flower colors of the F1 progeny were mainly red and purple-red, similar to the male parent’s color. Furthermore, we conducted a genetic analysis of the hybrid progeny using EST-SSR markers and performed association analysis with phenotypic traits. We identified 2, 2, 3, 1, and 2 loci to be associated with peduncle length (PL), ray floret length (RFL), and outer ray floret; the level of apex relative to the top of involucre (LAI); outer corolla lips (OCL); and the b* of ray floret color, respectively. Our results reveal the genetic patterns of important ornamental traits and provide a theoretical basis and practical tools for gerbera genetic breeding.
非洲菊（Gerbera hybrida）是一种广泛栽培的观赏植物。然而，由于缺乏遗传分析和性状分子标记，其遗传改良受到限制。在本研究中，我们分析了两个具有不同花型和花色的非洲菊品种的 140 个 F1 代后代的表型和基因型变异。我们评估了 F1 群体的花朵形态、颜色和色素含量，并进行了聚类主成分分析（PCA）和相关分析。结果表明，杂交后代的主要观赏性状差异很大。单瓣花与重瓣花、舌状小花与分裂射线小花的分离比均为 1:1。F1 代后代的花色主要为红色和紫红色，与雄性亲本的花色相似。此外，我们还利用EST-SSR标记对杂交后代进行了遗传分析，并与表型性状进行了关联分析。我们发现 2、2、3、1 和 2 个位点分别与花序梗长度（PL）、射线小花长度（RFL）和外射线小花、先端相对于总苞顶部的水平（LAI）、外花冠唇（OCL）和射线小花颜色的 b* 相关。我们的研究结果揭示了重要观赏性状的遗传规律，为非洲菊遗传育种提供了理论依据和实用工具。
{"title":"Phenotypic Variation in Flower Color and Morphology in the Gerbera (Gerbera hybrida) F1 Hybrid Population and Their Association with EST-SSR Markers","authors":"Yiwei Zhou, Xinru Zou, F. Yan, Jingjuan He, Sixian Zeng, Yunyi Yu, Xiaoshuang Tang, Xuanguo Liang, Xiuping Cai, Rangcai Yu, Yanping Fan","doi":"10.3390/ijms25010203","DOIUrl":"https://doi.org/10.3390/ijms25010203","url":null,"abstract":"Gerbera (Gerbera hybrida) is a widely cultivated ornamental plant. However, its genetic improvement is limited by the lack of genetic analysis and molecular markers for traits. In this study, we analyzed the phenotypic and genotypic variation of 140 F1 progeny from two gerbera varieties with different flower types and colors. We evaluated the flower’s morphology, color, and pigment content of the F1 population and performed cluster principal component analysis (PCA) and correlation analysis. The results showed that the main ornamental traits of the hybrid progeny varied greatly. The segregation ratios of single and double flowers and ligulate and split ray florets were both 1:1. The flower colors of the F1 progeny were mainly red and purple-red, similar to the male parent’s color. Furthermore, we conducted a genetic analysis of the hybrid progeny using EST-SSR markers and performed association analysis with phenotypic traits. We identified 2, 2, 3, 1, and 2 loci to be associated with peduncle length (PL), ray floret length (RFL), and outer ray floret; the level of apex relative to the top of involucre (LAI); outer corolla lips (OCL); and the b* of ray floret color, respectively. Our results reveal the genetic patterns of important ornamental traits and provide a theoretical basis and practical tools for gerbera genetic breeding.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"59 40","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138945919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Bhadauria, Manyu Zhang, Wendi Ma, Jun Yang, Wensheng Zhao, You-Liang Peng
Colletotrichum spp. are ascomycete fungi and cause anthracnose disease in numerous crops of economic significance. The genomes of these fungi are distributed among ten core chromosomes and two to three minichromosomes. While the core chromosomes regulate fungal growth, development and virulence, the extent to which the minichromosomes are involved in these processes is still uncertain. Here, we discuss the minichromosomes of three hemibiotrophic Colletotrichum pathogens, i.e., C. graminicola, C. higginsianum and C. lentis. These minichromosomes are typically less than one megabase in length, characterized by containing higher repetitive DNA elements, lower GC content, higher frequency of repeat-induced point mutations (RIPMs) and sparse gene distribution. Molecular genetics and functional analyses have revealed that these pathogens harbor one conditionally dispensable minichromosome, which is dispensable for fungal growth and development but indispensable for fungal virulence on hosts. They appear to be strain-specific innovations and are highly compartmentalized into AT-rich and GC-rich blocks, resulting from RIPMs, which may help protect the conditionally dispensable minichromosomes from erosion of already scarce genes, thereby helping the Colletotrichum pathogens maintain adaptability on hosts. Overall, understanding the mechanisms underlying the conditional dispensability of these minichromosomes could lead to new strategies for controlling anthracnose disease in crops.
Colletotrichum spp.是一种子囊真菌，可导致多种经济作物发生炭疽病。这些真菌的基因组分布在十条核心染色体和两到三条小染色体上。核心染色体调控真菌的生长、发育和毒力，而小染色体在这些过程中的参与程度仍不确定。在此，我们讨论了三种半营养型 Colletotrichum 病原体（即 C. graminicola、C. higginsianum 和 C. lentis）的迷你染色体。这些迷你染色体的长度通常小于一百万位碱基，其特点是含有较多的重复 DNA 元素、较低的 GC 含量、较高的重复诱导点突变（RIPM）频率和稀疏的基因分布。分子遗传学和功能分析表明，这些病原体含有一个条件性可有可无的小染色体，它对真菌的生长发育是可有可无的，但对真菌对宿主的毒力却是不可或缺的。它们似乎是菌株特异性的创新，并被高度区隔为富含 AT 和富含 GC 的区块，这是 RIPMs 的结果，这可能有助于保护条件性可有可无的小染色体免受已经稀缺的基因的侵蚀，从而帮助壳针孢属病原体保持对宿主的适应性。总之，了解这些小染色体的条件可丢弃性的内在机制，可以为控制农作物炭疽病提供新的策略。
{"title":"The Hidden Truths of Fungal Virulence and Adaptation on Hosts: Unraveling the Conditional Dispensability of Minichromosomes in the Hemibiotrophic Colletotrichum Pathogens","authors":"V. Bhadauria, Manyu Zhang, Wendi Ma, Jun Yang, Wensheng Zhao, You-Liang Peng","doi":"10.3390/ijms25010198","DOIUrl":"https://doi.org/10.3390/ijms25010198","url":null,"abstract":"Colletotrichum spp. are ascomycete fungi and cause anthracnose disease in numerous crops of economic significance. The genomes of these fungi are distributed among ten core chromosomes and two to three minichromosomes. While the core chromosomes regulate fungal growth, development and virulence, the extent to which the minichromosomes are involved in these processes is still uncertain. Here, we discuss the minichromosomes of three hemibiotrophic Colletotrichum pathogens, i.e., C. graminicola, C. higginsianum and C. lentis. These minichromosomes are typically less than one megabase in length, characterized by containing higher repetitive DNA elements, lower GC content, higher frequency of repeat-induced point mutations (RIPMs) and sparse gene distribution. Molecular genetics and functional analyses have revealed that these pathogens harbor one conditionally dispensable minichromosome, which is dispensable for fungal growth and development but indispensable for fungal virulence on hosts. They appear to be strain-specific innovations and are highly compartmentalized into AT-rich and GC-rich blocks, resulting from RIPMs, which may help protect the conditionally dispensable minichromosomes from erosion of already scarce genes, thereby helping the Colletotrichum pathogens maintain adaptability on hosts. Overall, understanding the mechanisms underlying the conditional dispensability of these minichromosomes could lead to new strategies for controlling anthracnose disease in crops.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"1 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138944084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hereditary cancers mostly affect the adolescent and young adult population (AYA) at reproductive age. Mutations in BReast CAncer (BRCA) genes are responsible for the majority of cases of hereditary breast and ovarian cancer. BRCA1 and BRCA2 act as tumor suppressor genes as they are key regulators of DNA repair through homologous recombination. Evidence of the accumulation of DNA double-strand break has been reported in aging oocytes, while BRCA expression decreases, leading to the hypothesis that BRCA mutation may impact fertility. Moreover, patients exposed to anticancer treatments are at higher risk of fertility-related issues, and BRCA mutations could exacerbate the treatment-induced depletion of the ovarian reserve. In this review, we summarized the functions of both genes and reported the current knowledge on the impact of BRCA mutations on ovarian ageing, premature ovarian insufficiency, female fertility preservation strategies and insights about male infertility. Altogether, this review provides relevant up-to-date information on the impact of BRCA1/2 mutations on fertility. Notably, BRCA-mutated patients should be adequately counselled for fertility preservation strategies, considering their higher sensitivity to chemotherapy gonadotoxic effects.
{"title":"BRCA Mutations and Fertility Preservation","authors":"J. Dias Nunes, Isabelle Demeestere, M. Devos","doi":"10.3390/ijms25010204","DOIUrl":"https://doi.org/10.3390/ijms25010204","url":null,"abstract":"Hereditary cancers mostly affect the adolescent and young adult population (AYA) at reproductive age. Mutations in BReast CAncer (BRCA) genes are responsible for the majority of cases of hereditary breast and ovarian cancer. BRCA1 and BRCA2 act as tumor suppressor genes as they are key regulators of DNA repair through homologous recombination. Evidence of the accumulation of DNA double-strand break has been reported in aging oocytes, while BRCA expression decreases, leading to the hypothesis that BRCA mutation may impact fertility. Moreover, patients exposed to anticancer treatments are at higher risk of fertility-related issues, and BRCA mutations could exacerbate the treatment-induced depletion of the ovarian reserve. In this review, we summarized the functions of both genes and reported the current knowledge on the impact of BRCA mutations on ovarian ageing, premature ovarian insufficiency, female fertility preservation strategies and insights about male infertility. Altogether, this review provides relevant up-to-date information on the impact of BRCA1/2 mutations on fertility. Notably, BRCA-mutated patients should be adequately counselled for fertility preservation strategies, considering their higher sensitivity to chemotherapy gonadotoxic effects.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"6 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138945093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guangchen Xu, Ge Liu, Ziyu Wang, Yunman Li, Weirong Fang
Ischemic stroke is one of the most significant causes of morbidity and mortality worldwide. However, there is a dearth of effective drugs and treatment methods for ischemic stroke. Significant numbers of circular RNAs (circRNAs) exhibit abnormal expression following ischemic stroke and are considered potential therapeutic targets. CircRNAs have emerged as promising biomarkers due to their stable expression in peripheral blood and their potential significance in ischemic stroke diagnosis and prognosis. This review provides a summary of 31 circRNAs involved in the pathophysiological processes of apoptosis, autophagy, inflammation, oxidative stress, and angiogenesis following ischemic stroke. Furthermore, we discuss the mechanisms of action of said circRNAs and their potential clinical applications. Ultimately, circRNAs exhibit promise as both therapeutic targets and biomarkers for ischemic stroke.
{"title":"Circular RNAs: Promising Treatment Targets and Biomarkers of Ischemic Stroke","authors":"Guangchen Xu, Ge Liu, Ziyu Wang, Yunman Li, Weirong Fang","doi":"10.3390/ijms25010178","DOIUrl":"https://doi.org/10.3390/ijms25010178","url":null,"abstract":"Ischemic stroke is one of the most significant causes of morbidity and mortality worldwide. However, there is a dearth of effective drugs and treatment methods for ischemic stroke. Significant numbers of circular RNAs (circRNAs) exhibit abnormal expression following ischemic stroke and are considered potential therapeutic targets. CircRNAs have emerged as promising biomarkers due to their stable expression in peripheral blood and their potential significance in ischemic stroke diagnosis and prognosis. This review provides a summary of 31 circRNAs involved in the pathophysiological processes of apoptosis, autophagy, inflammation, oxidative stress, and angiogenesis following ischemic stroke. Furthermore, we discuss the mechanisms of action of said circRNAs and their potential clinical applications. Ultimately, circRNAs exhibit promise as both therapeutic targets and biomarkers for ischemic stroke.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"29 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138947061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.
阿尔茨海默病（AD）是全球最常见的神经退行性疾病，在老年人中发病率很高。遗憾的是，由于阿尔茨海默病的发病机制复杂，目前尚无有效的治疗方法。然而，降脂抗炎药物的开发预示着阿尔茨海默病治疗进入了一个新时代。近年来的多项研究表明，脂质代谢失调和神经炎症与阿尔茨海默病的发病机制有关。3-Hydroxyl 3-methylglutaryl CoA reductase（HMGCR）是胆固醇合成的限速酶，在胆固醇代谢中起着关键作用。HMGCR 抑制剂，即他汀类药物，由于其对血脂水平和炎症的影响，已从单纯的降脂药物转变为神经保护化合物。在这篇综述中，我们首先总结了影响胆固醇生物合成的 HMGCR 的主要调节机制。我们还讨论了 HMGCR 诱导的 AD 发病机制，包括脂质代谢紊乱、氧化应激、炎症、小胶质细胞增殖和淀粉样蛋白-β（Aβ）沉积。随后，我们解释了HMGCR作为AD治疗潜在靶点的可能性。基于他汀类药物的AD治疗是一个新兴领域，目前争议颇多，因此我们也阐述了他汀类药物目前在AD治疗中的应用前景和局限性。
{"title":"Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease","authors":"Xun Zhou, Xiaolang Wu, Rui Wang, Lu Han, Huilin Li, Wei Zhao","doi":"10.3390/ijms25010170","DOIUrl":"https://doi.org/10.3390/ijms25010170","url":null,"abstract":"Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"7 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138944786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. Pavlović, Nastasija Milošević Sopta, Darko Mitrović, D. Zaklan, Ana Tomas Petrović, N. Stilinović, S. Vukmirović
Despite its beneficial pharmacological effects in the brain, partly by modulating inositol phosphate multikinase (IPMK) activity, the therapeutic use of quercetin is limited due to its poor solubility, low oral bioavailability, and low permeability through the blood–brain barrier (BBB). We aimed to identify quercetin analogues with improved BBB permeability and preserved binding affinities towards IPMK and to identify the molecular characteristics required for them to permeate the BBB. Binding affinities of quercetin analogues towards IPMK were determined by molecular docking. Principal component analysis (PCA) was applied to identify the molecular descriptors contributing to efficient permeation through the BBB. Among 34 quercetin analogues, 19 compounds were found to form more stable complexes with IPMK, and the vast majority were found to be more lipophilic than quercetin. Using two distinct in silico techniques, insufficient BBB permeation was determined for all quercetin analogues. However, using the PCA method, the descriptors related to intrinsic solubility and lipophilicity (logP) were identified as mainly responsible for clustering four quercetin analogues (trihydroxyflavones) with the highest BBB permeability. The application of PCA revealed that quercetin analogues could be classified with respect to their structural characteristics, which may be utilized in further analogue syntheses and lead optimization of BBB-penetrating IPMK modulators as neuroprotective agents.
{"title":"Principal Component Analysis (PCA) of Molecular Descriptors for Improving Permeation through the Blood–Brain Barrier of Quercetin Analogues","authors":"N. Pavlović, Nastasija Milošević Sopta, Darko Mitrović, D. Zaklan, Ana Tomas Petrović, N. Stilinović, S. Vukmirović","doi":"10.3390/ijms25010192","DOIUrl":"https://doi.org/10.3390/ijms25010192","url":null,"abstract":"Despite its beneficial pharmacological effects in the brain, partly by modulating inositol phosphate multikinase (IPMK) activity, the therapeutic use of quercetin is limited due to its poor solubility, low oral bioavailability, and low permeability through the blood–brain barrier (BBB). We aimed to identify quercetin analogues with improved BBB permeability and preserved binding affinities towards IPMK and to identify the molecular characteristics required for them to permeate the BBB. Binding affinities of quercetin analogues towards IPMK were determined by molecular docking. Principal component analysis (PCA) was applied to identify the molecular descriptors contributing to efficient permeation through the BBB. Among 34 quercetin analogues, 19 compounds were found to form more stable complexes with IPMK, and the vast majority were found to be more lipophilic than quercetin. Using two distinct in silico techniques, insufficient BBB permeation was determined for all quercetin analogues. However, using the PCA method, the descriptors related to intrinsic solubility and lipophilicity (logP) were identified as mainly responsible for clustering four quercetin analogues (trihydroxyflavones) with the highest BBB permeability. The application of PCA revealed that quercetin analogues could be classified with respect to their structural characteristics, which may be utilized in further analogue syntheses and lead optimization of BBB-penetrating IPMK modulators as neuroprotective agents.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"52 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138946289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ALKBH proteins, the homologs of Escherichia coli AlkB dioxygenase, constitute a single-protein repair system that safeguards cellular DNA and RNA against the harmful effects of alkylating agents. ALKBH10B, the first discovered N6-methyladenosine (m6A) demethylase in Arabidopsis (Arabidopsis thaliana), has been shown to regulate plant growth, development, and stress responses. However, until now, the functional role of the plant ALKBH10B has solely been reported in arabidopsis, cotton, and poplar, leaving its functional implications in other plant species shrouded in mystery. In this study, we identified the AlkB homolog SlALKBH10B in tomato (Solanum lycopersicum) through phylogenetic and gene expression analyses. SlALKBH10B exhibited a wide range of expression patterns and was induced by exogenous abscisic acid (ABA) and abiotic stresses. By employing CRISPR/Cas9 gene editing techniques to knock out SlALKBH10B, we observed an increased sensitivity of mutants to ABA treatment and upregulation of gene expression related to ABA synthesis and response. Furthermore, the Slalkbh10b mutants displayed an enhanced tolerance to drought and salt stress, characterized by higher water retention, accumulation of photosynthetic products, proline accumulation, and lower levels of reactive oxygen species and cellular damage. Collectively, these findings provide insights into the negative impact of SlALKBH10B on drought and salt tolerance in tomato plant, expanding our understanding of the biological functionality of SlALKBH10B.
ALKBH 蛋白是大肠杆菌 AlkB 二氧化酶的同源物，它构成了一个单蛋白修复系统，可保护细胞 DNA 和 RNA 免受烷化剂的有害影响。ALKBH10B 是拟南芥（Arabidopsis thaliana）中首次发现的 N6-甲基腺苷（m6A）去甲基化酶，已被证明能调节植物的生长、发育和胁迫反应。然而，到目前为止，植物 ALKBH10B 的功能作用仅在拟南芥、棉花和杨树中有所报道，其在其他植物物种中的功能影响仍是个谜。本研究通过系统发育和基因表达分析，鉴定了番茄（Solanum lycopersicum）中的 AlkB 同源物 SlALKBH10B。SlALKBH10B表现出广泛的表达模式，并受到外源脱落酸（ABA）和非生物胁迫的诱导。通过使用 CRISPR/Cas9 基因编辑技术敲除 SlALKBH10B，我们观察到突变体对 ABA 处理的敏感性增加，与 ABA 合成和响应相关的基因表达上调。此外，Slalkbh10b突变体对干旱和盐胁迫的耐受性增强，表现为更高的保水性、光合产物积累、脯氨酸积累以及更低水平的活性氧和细胞损伤。总之，这些研究结果揭示了 SlALKBH10B 对番茄耐旱和耐盐性的负面影响，拓展了我们对 SlALKBH10B 生物功能的认识。
{"title":"The AlkB Homolog SlALKBH10B Negatively Affects Drought and Salt Tolerance in Solanum lycopersicum","authors":"Hui Shen, Ying Zhou, Changguang Liao, Q. Xie, Guoping Chen, Zongli Hu, Ting Wu","doi":"10.3390/ijms25010173","DOIUrl":"https://doi.org/10.3390/ijms25010173","url":null,"abstract":"ALKBH proteins, the homologs of Escherichia coli AlkB dioxygenase, constitute a single-protein repair system that safeguards cellular DNA and RNA against the harmful effects of alkylating agents. ALKBH10B, the first discovered N6-methyladenosine (m6A) demethylase in Arabidopsis (Arabidopsis thaliana), has been shown to regulate plant growth, development, and stress responses. However, until now, the functional role of the plant ALKBH10B has solely been reported in arabidopsis, cotton, and poplar, leaving its functional implications in other plant species shrouded in mystery. In this study, we identified the AlkB homolog SlALKBH10B in tomato (Solanum lycopersicum) through phylogenetic and gene expression analyses. SlALKBH10B exhibited a wide range of expression patterns and was induced by exogenous abscisic acid (ABA) and abiotic stresses. By employing CRISPR/Cas9 gene editing techniques to knock out SlALKBH10B, we observed an increased sensitivity of mutants to ABA treatment and upregulation of gene expression related to ABA synthesis and response. Furthermore, the Slalkbh10b mutants displayed an enhanced tolerance to drought and salt stress, characterized by higher water retention, accumulation of photosynthetic products, proline accumulation, and lower levels of reactive oxygen species and cellular damage. Collectively, these findings provide insights into the negative impact of SlALKBH10B on drought and salt tolerance in tomato plant, expanding our understanding of the biological functionality of SlALKBH10B.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"9 27","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138943934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn−/−) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis were analyzed in cell-type specific neuroplastin mutant mice. Leydig, Sertoli, peritubular myoid, and germ cells express Np, but spermatogenesis and sperm number are not affected in Nptn−/− males. Neuroplastin lack from CNS neurons or restricted to spermatogonia or Sertoli cells permitted reproduction. Normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels in Nptn−/− males support undisturbed hormonal regulation in the brain. However, Nptn−/− males lack mounting behavior accompanied by low testosterone blood levels. Testosterone rise from juvenile to adult blood levels is absent in Nptn−/− males. LH-receptor stimulation raising intracellular Ca2+ in Leydig cells triggers testosterone production. Reduced Plasma Membrane Ca2+ ATPase 1 (PMCA1) in Nptn−/− Leydig cells suggests that Nptn−/− Leydig cells produce sufficient testosterone for testis and sperm development, but a lack of PMCA-Np complexes prevents the increase from reaching adult blood levels. Behavioral immaturity with low testosterone blood levels underlies infertility of Nptn−/− males, revealing that Np is essential for reproduction.
{"title":"Neuroplastin Expression in Male Mice Is Essential for Fertility, Mating, and Adult Testosterone Levels","authors":"Juanjuan Chen, Xiao Lin, Soumee Bhattacharya, Caroline Wiesehoefer, Gunther Wennemuth, Karin Müller, Dirk Montag","doi":"10.3390/ijms25010177","DOIUrl":"https://doi.org/10.3390/ijms25010177","url":null,"abstract":"Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn−/−) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis were analyzed in cell-type specific neuroplastin mutant mice. Leydig, Sertoli, peritubular myoid, and germ cells express Np, but spermatogenesis and sperm number are not affected in Nptn−/− males. Neuroplastin lack from CNS neurons or restricted to spermatogonia or Sertoli cells permitted reproduction. Normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels in Nptn−/− males support undisturbed hormonal regulation in the brain. However, Nptn−/− males lack mounting behavior accompanied by low testosterone blood levels. Testosterone rise from juvenile to adult blood levels is absent in Nptn−/− males. LH-receptor stimulation raising intracellular Ca2+ in Leydig cells triggers testosterone production. Reduced Plasma Membrane Ca2+ ATPase 1 (PMCA1) in Nptn−/− Leydig cells suggests that Nptn−/− Leydig cells produce sufficient testosterone for testis and sperm development, but a lack of PMCA-Np complexes prevents the increase from reaching adult blood levels. Behavioral immaturity with low testosterone blood levels underlies infertility of Nptn−/− males, revealing that Np is essential for reproduction.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"12 5","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138944419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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