Biji Thomas George, M. Jhancy, R. Dube, Subhranshu Sekhar Kar, L. Annamma
The rising incidence of obesity has coincided with rising levels of poor reproductive outcomes. The molecular basis for the association of infertility in obese males is now being explained through various mechanisms. Insulin resistance, hyperglycemia, and changes in serum and gonadal concentrations of adipokines, like leptin, adiponectin, resistin, and ghrelin have been implicated as causes of male infertility in obese males. The effects of obesity and hypogonadism form a vicious cycle whereby dysregulation of the hypothalamic–pituitary–testicular axis—due to the effect of the release of multiple mediators, thus decreasing GnRH release from the hypothalamus—causes decreases in LH and FSH levels. This leads to lower levels of testosterone, which further increases adiposity because of increased lipogenesis. Cytokines such as TNF-α and interleukins, sirtuins, and other inflammatory mediators like reactive oxygen species are known to affect fertility in obese male adults. There is evidence that parental obesity can be transferred through subsequent generations to offspring through epigenetic marks. Thus, negative expressions like obesity and infertility have been linked to epigenetic marks being altered in previous generations. The interesting aspect is that these epigenetic expressions can be reverted by removing the triggering factors. These positive modifications are also transmitted to subsequent generations.
{"title":"The Molecular Basis of Male Infertility in Obesity: A Literature Review","authors":"Biji Thomas George, M. Jhancy, R. Dube, Subhranshu Sekhar Kar, L. Annamma","doi":"10.3390/ijms25010179","DOIUrl":"https://doi.org/10.3390/ijms25010179","url":null,"abstract":"The rising incidence of obesity has coincided with rising levels of poor reproductive outcomes. The molecular basis for the association of infertility in obese males is now being explained through various mechanisms. Insulin resistance, hyperglycemia, and changes in serum and gonadal concentrations of adipokines, like leptin, adiponectin, resistin, and ghrelin have been implicated as causes of male infertility in obese males. The effects of obesity and hypogonadism form a vicious cycle whereby dysregulation of the hypothalamic–pituitary–testicular axis—due to the effect of the release of multiple mediators, thus decreasing GnRH release from the hypothalamus—causes decreases in LH and FSH levels. This leads to lower levels of testosterone, which further increases adiposity because of increased lipogenesis. Cytokines such as TNF-α and interleukins, sirtuins, and other inflammatory mediators like reactive oxygen species are known to affect fertility in obese male adults. There is evidence that parental obesity can be transferred through subsequent generations to offspring through epigenetic marks. Thus, negative expressions like obesity and infertility have been linked to epigenetic marks being altered in previous generations. The interesting aspect is that these epigenetic expressions can be reverted by removing the triggering factors. These positive modifications are also transmitted to subsequent generations.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138944481","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}
Yan Lin, Qiao Li, Guangyu Liang, Nanyin Xiao, Jiankun Yang, Xiao Yang, Heng Zhang, Cuntai Zhang, Anding Liu
Aging is a biological process with a gradual decline in functional capacity, and this process often enhances the risk of chronic disease morbidity and mortality. With advanced age, the immune system undergoes a process of remodeling that can lead to a chronic inflammatory state, termed immunosenescence and inflammaging, respectively. Immunosenescence is accompanied by changes in the number, proportion, and functional capacity of the innate immune cells. The accumulation of dysfunctional immune cells and the presence of low-grade inflammation can lead to organ damage and expedite the aging process. The liver, crucial in regulating the body’s metabolism and immune function, is not exempt from these effects. Age-related modifications affect its immune function and regenerative abilities, potentially increasing the prevalence of age-related liver diseases. While aging’s impact on the liver is relatively less severe compared to other organ systems, it still experiences an infiltration of innate immune cells and heightened inflammation levels. This review will elaborate on how aging affects the liver’s innate immune cells, such as neutrophils, macrophages, dendritic cells, mast cells, and innate lymphoid cells. It will also explore potential strategies for delaying immunosenescence to alleviate these age-related changes.
{"title":"Overview of Innate Immune Cell Landscape in Liver Aging","authors":"Yan Lin, Qiao Li, Guangyu Liang, Nanyin Xiao, Jiankun Yang, Xiao Yang, Heng Zhang, Cuntai Zhang, Anding Liu","doi":"10.3390/ijms25010181","DOIUrl":"https://doi.org/10.3390/ijms25010181","url":null,"abstract":"Aging is a biological process with a gradual decline in functional capacity, and this process often enhances the risk of chronic disease morbidity and mortality. With advanced age, the immune system undergoes a process of remodeling that can lead to a chronic inflammatory state, termed immunosenescence and inflammaging, respectively. Immunosenescence is accompanied by changes in the number, proportion, and functional capacity of the innate immune cells. The accumulation of dysfunctional immune cells and the presence of low-grade inflammation can lead to organ damage and expedite the aging process. The liver, crucial in regulating the body’s metabolism and immune function, is not exempt from these effects. Age-related modifications affect its immune function and regenerative abilities, potentially increasing the prevalence of age-related liver diseases. While aging’s impact on the liver is relatively less severe compared to other organ systems, it still experiences an infiltration of innate immune cells and heightened inflammation levels. This review will elaborate on how aging affects the liver’s innate immune cells, such as neutrophils, macrophages, dendritic cells, mast cells, and innate lymphoid cells. It will also explore potential strategies for delaying immunosenescence to alleviate these age-related changes.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"28 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138945954","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}
Due to its complement of diverse proteins, such as actin filaments, intermediate filaments, and microtubules, the cytoskeleton is essential not only for structural stability but also for regulating cellular signaling, intracellular transportation, and cell division [...]
{"title":"The Cytoskeleton and Its Binding Proteins as Mechanosensors, Transducers, and Functional Regulators of Cells","authors":"W. Lee","doi":"10.3390/ijms25010172","DOIUrl":"https://doi.org/10.3390/ijms25010172","url":null,"abstract":"Due to its complement of diverse proteins, such as actin filaments, intermediate filaments, and microtubules, the cytoskeleton is essential not only for structural stability but also for regulating cellular signaling, intracellular transportation, and cell division [...]","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"28 24","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138947100","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. Arabkari, D. Barua, Muhammad Mosaraf Hossain, Mark Webber, Terry Smith, Ananya Gupta, Sanjeev Gupta
X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer.
{"title":"miRNA-378 Is Downregulated by XBP1 and Inhibits Growth and Migration of Luminal Breast Cancer Cells","authors":"V. Arabkari, D. Barua, Muhammad Mosaraf Hossain, Mark Webber, Terry Smith, Ananya Gupta, Sanjeev Gupta","doi":"10.3390/ijms25010186","DOIUrl":"https://doi.org/10.3390/ijms25010186","url":null,"abstract":"X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"20 21","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138947184","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}
Angraecum, commonly known as Darwin’s orchid, is the largest genus of Angraecinae (Orchidaceae). This genus exhibits a high morphological diversity, making it as a good candidate for macroevolutionary studies. In this study, four complete plastomes of Angraecum were firstly reported and the potential variability hotspots were explored. The plastomes possessed the typical quadripartite structure and ranged from 150,743 to 151,818 base pair (bp), with a guanine–cytosine (GC) content of 36.6–36.9%. The plastomes all contained 120 genes, consisting of 74 protein-coding genes (CDS), 38 transfer RNA (tRNA) genes and 8 ribosomal RNA (rRNA) genes; all ndh genes were pseudogenized or lost. A total of 30 to 46 long repeats and 55 to 63 SSRs were identified. Relative synonymous codon usage (RSCU) analysis indicated a high degree of conservation in codon usage bias. The Ka/Ks ratios of most genes were lower than 1, indicating that they have undergone purifying selection. Based on the ranking of Pi (nucleotide diversity) values, five regions (trnSGCU-trnGGCC, ycf1-trnNGGU, trnNGUU-rpl32, psaC-ndhE and trnSGCU-trnGGCC) and five protein-coding genes (rpl32, rps16, psbK, rps8, and ycf1) were identified. The consistent and robust phylogenetic relationships of Angraecum were established based on a total of 40 plastomes from the Epidendroideae subfamily. The genus Angraecum was strongly supported as a monophyletic group and sister to Aeridinae. Our study provides an ideal system for investigating molecular identification, plastome evolution and DNA barcoding for Angraecum.
{"title":"Characterization of Angraecum (Angraecinae, Orchidaceae) Plastomes and Utility of Sequence Variability Hotspots","authors":"Cheng-Yuan Zhou, Wen-Jun Lin, Ruyi Li, YU-HAN Wu, Zhong-Jian Liu, Ming-He Li","doi":"10.3390/ijms25010184","DOIUrl":"https://doi.org/10.3390/ijms25010184","url":null,"abstract":"Angraecum, commonly known as Darwin’s orchid, is the largest genus of Angraecinae (Orchidaceae). This genus exhibits a high morphological diversity, making it as a good candidate for macroevolutionary studies. In this study, four complete plastomes of Angraecum were firstly reported and the potential variability hotspots were explored. The plastomes possessed the typical quadripartite structure and ranged from 150,743 to 151,818 base pair (bp), with a guanine–cytosine (GC) content of 36.6–36.9%. The plastomes all contained 120 genes, consisting of 74 protein-coding genes (CDS), 38 transfer RNA (tRNA) genes and 8 ribosomal RNA (rRNA) genes; all ndh genes were pseudogenized or lost. A total of 30 to 46 long repeats and 55 to 63 SSRs were identified. Relative synonymous codon usage (RSCU) analysis indicated a high degree of conservation in codon usage bias. The Ka/Ks ratios of most genes were lower than 1, indicating that they have undergone purifying selection. Based on the ranking of Pi (nucleotide diversity) values, five regions (trnSGCU-trnGGCC, ycf1-trnNGGU, trnNGUU-rpl32, psaC-ndhE and trnSGCU-trnGGCC) and five protein-coding genes (rpl32, rps16, psbK, rps8, and ycf1) were identified. The consistent and robust phylogenetic relationships of Angraecum were established based on a total of 40 plastomes from the Epidendroideae subfamily. The genus Angraecum was strongly supported as a monophyletic group and sister to Aeridinae. Our study provides an ideal system for investigating molecular identification, plastome evolution and DNA barcoding for Angraecum.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"6 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138947474","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}
Gibberellin (GA) is an important plant hormone that is involved in various physiological processes during plant development. Sweet cherries planted in southern China have always encountered difficulty in bearing fruit. In recent years, gibberellin has successfully solved this problem, but there has also been an increase in malformed fruits. This study mainly explores the mechanism of malformed fruit formation in sweet cherries. By analyzing the synthesis pathway of gibberellin using metabolomics and transcriptomics, the relationship between gibberellin and the formation mechanism of deformed fruit was preliminarily determined. The results showed that the content of GA3 in malformed fruits was significantly higher than in normal fruits. The differentially expressed genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were mainly enriched in pathways such as “plant hormone signal transduction”, “diterpenoid biosynthesis”, and “carotenoid biosynthesis”. Using Quantitative Real-Time Reverse Transcription PCR (qRT-PCR) analysis, the gibberellin hydrolase gene GA2ox and gibberellin synthase genes GA20ox and GA3ox were found to be significantly up-regulated. Therefore, we speculate that the formation of malformed fruits in sweet cherries may be related to the accumulation of GA3. This lays the foundation for further research on the mechanism of malformed sweet cherry fruits.
{"title":"Preliminary Study on the Formation Mechanism of Malformed Sweet Cherry (Prunus avium L.) Fruits in Southern China Using Transcriptome and Metabolome Data","authors":"Wangshu Zhang, Yue Xu, Luyang Jing, Baoxin Jiang, Qinghao Wang, Yuxi Wang","doi":"10.3390/ijms25010153","DOIUrl":"https://doi.org/10.3390/ijms25010153","url":null,"abstract":"Gibberellin (GA) is an important plant hormone that is involved in various physiological processes during plant development. Sweet cherries planted in southern China have always encountered difficulty in bearing fruit. In recent years, gibberellin has successfully solved this problem, but there has also been an increase in malformed fruits. This study mainly explores the mechanism of malformed fruit formation in sweet cherries. By analyzing the synthesis pathway of gibberellin using metabolomics and transcriptomics, the relationship between gibberellin and the formation mechanism of deformed fruit was preliminarily determined. The results showed that the content of GA3 in malformed fruits was significantly higher than in normal fruits. The differentially expressed genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were mainly enriched in pathways such as “plant hormone signal transduction”, “diterpenoid biosynthesis”, and “carotenoid biosynthesis”. Using Quantitative Real-Time Reverse Transcription PCR (qRT-PCR) analysis, the gibberellin hydrolase gene GA2ox and gibberellin synthase genes GA20ox and GA3ox were found to be significantly up-regulated. Therefore, we speculate that the formation of malformed fruits in sweet cherries may be related to the accumulation of GA3. This lays the foundation for further research on the mechanism of malformed sweet cherry fruits.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"42 20","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138948925","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}
M. Krasnova, A. Efremova, A. Bukhonin, E. Zhekaite, T. Bukharova, Y. Melyanovskaya, Dmitry Goldshtein, E. Kondratyeva
The authors of this article analyzed the available literature with the results of studying the prevalence of complex alleles of the CFTR gene among patients with cystic fibrosis, and their pathogenicity and influence on targeted therapy with CFTR modulators. Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of the CFTR protein, and more than 2000 genetic variants are known. Clinically significant variants are divided into seven classes. Information about the frequency of complex alleles appears in a number of registers, along with the traditional presentation of data on genetic variants. Complex alleles (those with the presence of more than two nucleotide variants on one allele) can complicate the diagnosis of the disease, and change the clinical manifestations of cystic fibrosis and the response to treatment, since each variant in the complex allele can contribute to the functional activity of the CFTR protein, changing it both in terms of increasing and decreasing function. The role of complex alleles is often underestimated, and their frequency has not been studied. At the moment, characteristic frequently encountered complex alleles have been found for several populations of patients with cystic fibrosis, but the prevalence and pathogenicity of newly detected complex alleles require additional research. In this review, more than 35 complex alleles of the CFTR gene from existing research studies were analyzed, and an analysis of their influence on the manifestations of the disease and the effectiveness of CFTR modulators was also described.
{"title":"The Effect of Complex Alleles of the CFTR Gene on the Clinical Manifestations of Cystic Fibrosis and the Effectiveness of Targeted Therapy","authors":"M. Krasnova, A. Efremova, A. Bukhonin, E. Zhekaite, T. Bukharova, Y. Melyanovskaya, Dmitry Goldshtein, E. Kondratyeva","doi":"10.3390/ijms25010114","DOIUrl":"https://doi.org/10.3390/ijms25010114","url":null,"abstract":"The authors of this article analyzed the available literature with the results of studying the prevalence of complex alleles of the CFTR gene among patients with cystic fibrosis, and their pathogenicity and influence on targeted therapy with CFTR modulators. Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of the CFTR protein, and more than 2000 genetic variants are known. Clinically significant variants are divided into seven classes. Information about the frequency of complex alleles appears in a number of registers, along with the traditional presentation of data on genetic variants. Complex alleles (those with the presence of more than two nucleotide variants on one allele) can complicate the diagnosis of the disease, and change the clinical manifestations of cystic fibrosis and the response to treatment, since each variant in the complex allele can contribute to the functional activity of the CFTR protein, changing it both in terms of increasing and decreasing function. The role of complex alleles is often underestimated, and their frequency has not been studied. At the moment, characteristic frequently encountered complex alleles have been found for several populations of patients with cystic fibrosis, but the prevalence and pathogenicity of newly detected complex alleles require additional research. In this review, more than 35 complex alleles of the CFTR gene from existing research studies were analyzed, and an analysis of their influence on the manifestations of the disease and the effectiveness of CFTR modulators was also described.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"39 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138949792","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}
R. Dube, Subhranshu Sekhar Kar, M. Jhancy, Biji Thomas George
Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the nondevelopment of the uterus. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and the 46 XX Karyotype. With advancements in reproductive techniques, women with MA having biological offspring is possible. The exact etiology of MA is unknown, although several genes and mechanisms affect the development of Müllerian ducts. Through this systematic review of the available literature, we searched for the genetic basis of MA. The aims included identification of the genes, chromosomal locations, changes responsible for MA, and fertility options, in order to offer proper management and counseling to these women with MA. A total of 85 studies were identified through searches. Most of the studies identified multiple genes at various locations, although the commonest involved chromosomes 1, 17, and 22. There is also conflicting evidence of the involvement of various candidate genes in the studies. The etiology of MA seems to be multifactorial and complex, involving multiple genes and mechanisms including various mutations and mosaicism.
全世界约有五分之一的夫妇患有不孕症。先天性无子宫会导致女性绝对不孕。穆勒氏无子宫症是指子宫不发育。Mayer-Rokitansky-Küster-Hauser（MRKH）综合征是一种卵巢正常且核型为 46 XX 的子宫阴道缺失症。随着生殖技术的发展，患有 MA 的妇女有可能生育后代。尽管有多种基因和机制会影响缪勒管的发育，但缪勒管缺失症的确切病因尚不清楚。通过对现有文献的系统回顾，我们寻找了MA的遗传基础。目的包括确定导致MA的基因、染色体位置、变化以及生育选择，以便为这些患有MA的女性提供适当的管理和咨询。通过检索，共确定了 85 项研究。大多数研究确定了不同位置的多个基因，但最常见的涉及 1、17 和 22 号染色体。此外，关于各种候选基因参与研究的证据也相互矛盾。马氏综合征的病因似乎是多因素和复杂的，涉及多个基因和机制，包括各种突变和嵌合。
{"title":"Molecular Basis of Müllerian Agenesis Causing Congenital Uterine Factor Infertility—A Systematic Review","authors":"R. Dube, Subhranshu Sekhar Kar, M. Jhancy, Biji Thomas George","doi":"10.3390/ijms25010120","DOIUrl":"https://doi.org/10.3390/ijms25010120","url":null,"abstract":"Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the nondevelopment of the uterus. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and the 46 XX Karyotype. With advancements in reproductive techniques, women with MA having biological offspring is possible. The exact etiology of MA is unknown, although several genes and mechanisms affect the development of Müllerian ducts. Through this systematic review of the available literature, we searched for the genetic basis of MA. The aims included identification of the genes, chromosomal locations, changes responsible for MA, and fertility options, in order to offer proper management and counseling to these women with MA. A total of 85 studies were identified through searches. Most of the studies identified multiple genes at various locations, although the commonest involved chromosomes 1, 17, and 22. There is also conflicting evidence of the involvement of various candidate genes in the studies. The etiology of MA seems to be multifactorial and complex, involving multiple genes and mechanisms including various mutations and mosaicism.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"63 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138950653","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}
S. Žunec, Donna Vadlja, A. Ramić, A. Zandona, N. Maraković, Iva Brekalo, I. Primožič, M. Katalinić
The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system’s activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (Ki = 0.26 − 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1′-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1′-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7–200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12–C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells’ mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds’ scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders.
{"title":"Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability","authors":"S. Žunec, Donna Vadlja, A. Ramić, A. Zandona, N. Maraković, Iva Brekalo, I. Primožič, M. Katalinić","doi":"10.3390/ijms25010155","DOIUrl":"https://doi.org/10.3390/ijms25010155","url":null,"abstract":"The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system’s activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (Ki = 0.26 − 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1′-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1′-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7–200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12–C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells’ mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds’ scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"35 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138951621","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}
L. Gaetani, G. Bellomo, Elena Di Sabatino, S. Sperandei, Andrea Mancini, K. Blennow, Henrik Zetterberg, L. Parnetti, M. Di Filippo
Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune activation biomarkers in the CSF of individuals with MS and explore distinct signatures between MS with and without oligoclonal bands (OCB). A total of 118 subjects, including relapsing–remitting MS with OCB (MS OCB+) (n = 58), without OCB (MS OCB−) (n = 24), and controls with other neurological diseases (OND) (n = 36), were included. CSF samples were analyzed by means of proximity extension assay (PEA) for quantifying 92 immune-related proteins. Neurofilament light chain (NfL), a marker of axonal damage, was also measured. Machine learning techniques were employed to identify biomarker panels differentiating MS with and without OCB from controls. Analyses were performed by splitting the cohort into a training and a validation set. CSF CD5 and IL-12B exhibited the highest discriminatory power in differentiating MS from controls. CSF MIP-1-alpha, CD5, CXCL10, CCL23 and CXCL9 were positively correlated with NfL. Multivariate models were developed to distinguish MS OCB+ and MS OCB− from controls. The model for MS OCB+ included IL-12B, CD5, CX3CL1, FGF-19, CST5, MCP-1 (91% sensitivity and 94% specificity in the training set, 81% sensitivity, and 94% specificity in the validation set). The model for MS OCB− included CX3CL1, CD5, NfL, CCL4 and OPG (87% sensitivity and 80% specificity in the training set, 56% sensitivity and 48% specificity in the validation set). Comprehensive immune profiling of CSF biomarkers in MS revealed distinct pathophysiological signatures associated with OCB status. The identified biomarker panels, enriched in T cell activation markers and immune mediators, hold promise for improved diagnostic accuracy and insights into MS pathogenesis.
{"title":"The Immune Signature of CSF in Multiple Sclerosis with and without Oligoclonal Bands: A Machine Learning Approach to Proximity Extension Assay Analysis","authors":"L. Gaetani, G. Bellomo, Elena Di Sabatino, S. Sperandei, Andrea Mancini, K. Blennow, Henrik Zetterberg, L. Parnetti, M. Di Filippo","doi":"10.3390/ijms25010139","DOIUrl":"https://doi.org/10.3390/ijms25010139","url":null,"abstract":"Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune activation biomarkers in the CSF of individuals with MS and explore distinct signatures between MS with and without oligoclonal bands (OCB). A total of 118 subjects, including relapsing–remitting MS with OCB (MS OCB+) (n = 58), without OCB (MS OCB−) (n = 24), and controls with other neurological diseases (OND) (n = 36), were included. CSF samples were analyzed by means of proximity extension assay (PEA) for quantifying 92 immune-related proteins. Neurofilament light chain (NfL), a marker of axonal damage, was also measured. Machine learning techniques were employed to identify biomarker panels differentiating MS with and without OCB from controls. Analyses were performed by splitting the cohort into a training and a validation set. CSF CD5 and IL-12B exhibited the highest discriminatory power in differentiating MS from controls. CSF MIP-1-alpha, CD5, CXCL10, CCL23 and CXCL9 were positively correlated with NfL. Multivariate models were developed to distinguish MS OCB+ and MS OCB− from controls. The model for MS OCB+ included IL-12B, CD5, CX3CL1, FGF-19, CST5, MCP-1 (91% sensitivity and 94% specificity in the training set, 81% sensitivity, and 94% specificity in the validation set). The model for MS OCB− included CX3CL1, CD5, NfL, CCL4 and OPG (87% sensitivity and 80% specificity in the training set, 56% sensitivity and 48% specificity in the validation set). Comprehensive immune profiling of CSF biomarkers in MS revealed distinct pathophysiological signatures associated with OCB status. The identified biomarker panels, enriched in T cell activation markers and immune mediators, hold promise for improved diagnostic accuracy and insights into MS pathogenesis.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":"9 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138951875","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：