Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs’ proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.
{"title":"Involvement of Embryo-Derived and Monocyte-Derived Intestinal Macrophages in the Pathogenesis of Inflammatory Bowel Disease and Their Prospects as Therapeutic Targets","authors":"Shujun Zuo, Liping Jiang, Luying Chen, Weikang Wang, Jintao Gu, Jiajie Kuai, Xuezhi Yang, Yang Ma, Chen-chen Han, Wei Wei","doi":"10.3390/ijms25020690","DOIUrl":"https://doi.org/10.3390/ijms25020690","url":null,"abstract":"Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs’ proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"44 35","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139382350","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}
Li Ching Ooi, Vincent Ho, Jing Zhou Zhu, S. Lim, Liping Chung, Askar Abubakar, Tristan Rutland, Wei Chua, W. Ng, Mark Lee, Matthew Morgan, Scott Mackenzie, Cheok Soon Lee
The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells’ behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.
{"title":"p21 as a Predictor and Prognostic Indicator of Clinical Outcome in Rectal Cancer Patients","authors":"Li Ching Ooi, Vincent Ho, Jing Zhou Zhu, S. Lim, Liping Chung, Askar Abubakar, Tristan Rutland, Wei Chua, W. Ng, Mark Lee, Matthew Morgan, Scott Mackenzie, Cheok Soon Lee","doi":"10.3390/ijms25020725","DOIUrl":"https://doi.org/10.3390/ijms25020725","url":null,"abstract":"The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells’ behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"6 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381128","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}
A. Oranger, G. Colaianni, G. Ingravallo, Vincenza Sara Scarcella, M. Faienza, M. Grano, S. Colucci, G. Brunetti
LIGHT/TNFSF14 is linked to several signaling pathways as a crucial member of a larger immunoregulatory network. It is primarily expressed in inflammatory effector cells, and high levels of LIGHT have been reported in obesity. Thus, with the aim of deepening the knowledge of the role of LIGHT on adipose tissue phenotype, we studied wild-type (WT), Tnfsf14−/−, Rag−/− and Rag-/Tnfsf14- (DKO) mice fed a normal diet (ND) or high-fat diet (HFD). Our results show that, although there is no significant weight gain between the mice with different genotypes, it is significant within each of them. We also detected an increase in visceral White Adipose Tissue (vWAT) weight in all mice fed HFD, together with the lowest levels of vWAT weight in Tnfsf14−/− and DKO mice fed ND with respect to the other strain. Inguinal WAT (iWAT) weight is significantly affected by genotype and HFD. The least amount of iWAT was detected in DKO mice fed ND. Histological analysis of vWAT showed that both the genotype and the diet significantly affect the adipocyte area, whereas the number is affected only by the genotype. In iWAT, the genotype and the diet significantly affect mean adipocyte area and number; interestingly, the area with the least adipocyte was detected in DKO mice fed ND, suggesting a potential browning effect due to the simultaneous lack of mature lymphocytes and LIGHT. Consistently, Uncoupling Protein 1 (UCP1) staining of iWAT demonstrated that few positive brown adipocytes appeared in DKO mice. Furthermore, LIGHT deficiency is associated with greater levels of UCP1, highlighting the lack of its expression in Rag−/− mice. Liver examination showed that all mice fed HFD had a steatotic liver, but it was particularly evident for DKO mice. In conclusion, our study demonstrates that the adipose tissue phenotype is affected by LIGHT levels but also much more by mature lymphocytes.
{"title":"LIGHT/TNFSF14 Affects Adipose Tissue Phenotype","authors":"A. Oranger, G. Colaianni, G. Ingravallo, Vincenza Sara Scarcella, M. Faienza, M. Grano, S. Colucci, G. Brunetti","doi":"10.3390/ijms25020716","DOIUrl":"https://doi.org/10.3390/ijms25020716","url":null,"abstract":"LIGHT/TNFSF14 is linked to several signaling pathways as a crucial member of a larger immunoregulatory network. It is primarily expressed in inflammatory effector cells, and high levels of LIGHT have been reported in obesity. Thus, with the aim of deepening the knowledge of the role of LIGHT on adipose tissue phenotype, we studied wild-type (WT), Tnfsf14−/−, Rag−/− and Rag-/Tnfsf14- (DKO) mice fed a normal diet (ND) or high-fat diet (HFD). Our results show that, although there is no significant weight gain between the mice with different genotypes, it is significant within each of them. We also detected an increase in visceral White Adipose Tissue (vWAT) weight in all mice fed HFD, together with the lowest levels of vWAT weight in Tnfsf14−/− and DKO mice fed ND with respect to the other strain. Inguinal WAT (iWAT) weight is significantly affected by genotype and HFD. The least amount of iWAT was detected in DKO mice fed ND. Histological analysis of vWAT showed that both the genotype and the diet significantly affect the adipocyte area, whereas the number is affected only by the genotype. In iWAT, the genotype and the diet significantly affect mean adipocyte area and number; interestingly, the area with the least adipocyte was detected in DKO mice fed ND, suggesting a potential browning effect due to the simultaneous lack of mature lymphocytes and LIGHT. Consistently, Uncoupling Protein 1 (UCP1) staining of iWAT demonstrated that few positive brown adipocytes appeared in DKO mice. Furthermore, LIGHT deficiency is associated with greater levels of UCP1, highlighting the lack of its expression in Rag−/− mice. Liver examination showed that all mice fed HFD had a steatotic liver, but it was particularly evident for DKO mice. In conclusion, our study demonstrates that the adipose tissue phenotype is affected by LIGHT levels but also much more by mature lymphocytes.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"19 21","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139382843","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}
Sungeun Chung, Yujong Yi, Irfan Ullah, Kunho Chung, Seongjun Park, Jaeyeoung Lim, Chaeyeon Kim, Seon-Hong Pyun, Minkyung Kim, Dokyoung Kim, Minhyung Lee, Taiyoun Rhim, Sang-Kyung Lee
Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood–brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.
{"title":"Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia","authors":"Sungeun Chung, Yujong Yi, Irfan Ullah, Kunho Chung, Seongjun Park, Jaeyeoung Lim, Chaeyeon Kim, Seon-Hong Pyun, Minkyung Kim, Dokyoung Kim, Minhyung Lee, Taiyoun Rhim, Sang-Kyung Lee","doi":"10.3390/ijms25010661","DOIUrl":"https://doi.org/10.3390/ijms25010661","url":null,"abstract":"Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood–brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"51 47","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139384629","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}
N. Fifere, R. Ardeleanu, F. Doroftei, Marius Dobromir, A. Airinei
The present study explores an environmentally friendly green approach to obtain cerium oxide nanoparticles via a biomediated route using Mellisa officinalis and Hypericum perforatum plant extracts as reducing agents. The as-prepared nanoparticles were studied for their structural and morphological characteristics using XRD diffractometry, scanning electron microscopy, Raman, fluorescence and electronic absorption spectra, and X-ray photoelectron spectroscopy (XPS). The XRD pattern has shown the centered fluorite crystal structure of cerium oxide nanoparticles with average crystallite size below 10 nm. These observations were in agreement with the STEM data. The cubic fluorite structure of the cerium oxide nanoparticles was confirmed by the vibrational mode around 462 cm−1 due to the Ce-08 unit. The optical band gap was estimated from UV-Vis reflectance spectra, which was found to decrease from 3.24 eV to 2.98 eV. A higher specific area was determined for the sample using M. officinalis aqueous extract. The EDX data indicated that only cerium and oxygen are present in the green synthesized nanoparticles.
本研究探索了一种环境友好型的绿色方法，即使用麦丽莎和贯叶连翘植物提取物作为还原剂，通过生物媒介途径获得氧化铈纳米粒子。利用 X 射线衍射仪、扫描电子显微镜、拉曼光谱、荧光光谱、电子吸收光谱和 X 射线光电子能谱（XPS）研究了制备的纳米粒子的结构和形态特征。X 射线衍射图显示了氧化铈纳米粒子的中心萤石晶体结构，平均结晶尺寸低于 10 纳米。这些观察结果与 STEM 数据一致。氧化铈纳米粒子的立方萤石结构通过 Ce-08 单元在 462 cm-1 附近的振动模式得到了证实。根据紫外可见反射光谱估算出的光带隙从 3.24 eV 减小到 2.98 eV。使用 M. officinalis 水提取物的样品的比表面积更高。EDX 数据表明，绿色合成纳米粒子中只存在铈和氧。
{"title":"Tailoring the Structural and Optical Properties of Cerium Oxide Nanoparticles Prepared by an Ecofriendly Green Route Using Plant Extracts","authors":"N. Fifere, R. Ardeleanu, F. Doroftei, Marius Dobromir, A. Airinei","doi":"10.3390/ijms25010681","DOIUrl":"https://doi.org/10.3390/ijms25010681","url":null,"abstract":"The present study explores an environmentally friendly green approach to obtain cerium oxide nanoparticles via a biomediated route using Mellisa officinalis and Hypericum perforatum plant extracts as reducing agents. The as-prepared nanoparticles were studied for their structural and morphological characteristics using XRD diffractometry, scanning electron microscopy, Raman, fluorescence and electronic absorption spectra, and X-ray photoelectron spectroscopy (XPS). The XRD pattern has shown the centered fluorite crystal structure of cerium oxide nanoparticles with average crystallite size below 10 nm. These observations were in agreement with the STEM data. The cubic fluorite structure of the cerium oxide nanoparticles was confirmed by the vibrational mode around 462 cm−1 due to the Ce-08 unit. The optical band gap was estimated from UV-Vis reflectance spectra, which was found to decrease from 3.24 eV to 2.98 eV. A higher specific area was determined for the sample using M. officinalis aqueous extract. The EDX data indicated that only cerium and oxygen are present in the green synthesized nanoparticles.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"31 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385278","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}
Rika Kojima, Wojciech Paslawski, Guochang Lyu, Ernest Arenas, Xiaoqun Zhang, Per Svenningsson
Mutations in the GBA1 gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of GBA1 mutations do not develop PD throughout their lives. The mechanisms of how GBA1 mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying GBA1 mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate GBA1-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons.
{"title":"Secretome Analyses Identify FKBP4 as a GBA1-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with GBA1 Mutations","authors":"Rika Kojima, Wojciech Paslawski, Guochang Lyu, Ernest Arenas, Xiaoqun Zhang, Per Svenningsson","doi":"10.3390/ijms25010683","DOIUrl":"https://doi.org/10.3390/ijms25010683","url":null,"abstract":"Mutations in the GBA1 gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of GBA1 mutations do not develop PD throughout their lives. The mechanisms of how GBA1 mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying GBA1 mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate GBA1-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"12 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139386517","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}
Meishuang Li, Xiyun Guo, Linxin Cheng, Hong Zhang, Meng Zhou, Manling Zhang, Zhibao Yin, Tianxu Guo, Lihua Zhao, Han Liu, Xiubin Liang, Rongfeng Li
The scarcity of donor kidneys greatly impacts the survival of patients with end-stage renal failure. Pigs are increasingly becoming potential organ donors but are limited by immunological rejection. Based on the human kidney organoid already established with the CHIR99021 and FGF9 induction strategy, we generated porcine kidney organoids from porcine naïve-like ESCs (nESCs). The derived porcine organoids had a tubule-like constructure and matrix components. The porcine organoids expressed renal markers including AQP1 (proximal tubule), WT1 and PODO (podocyte), and CD31 (vascular endothelial cells). These results imply that the organoids had developed the majority of the renal cell types and structures, including glomeruli and proximal tubules. The porcine organoids were also identified to have a dextran absorptive function. Importantly, porcine organoids have a certain abundance of vascular endothelial cells, which are the basis for investigating immune rejection. The derived porcine organoids might serve as materials for immunosuppressor screening for xenotransplantation.
{"title":"Porcine Kidney Organoids Derived from Naïve-like Embryonic Stem Cells","authors":"Meishuang Li, Xiyun Guo, Linxin Cheng, Hong Zhang, Meng Zhou, Manling Zhang, Zhibao Yin, Tianxu Guo, Lihua Zhao, Han Liu, Xiubin Liang, Rongfeng Li","doi":"10.3390/ijms25010682","DOIUrl":"https://doi.org/10.3390/ijms25010682","url":null,"abstract":"The scarcity of donor kidneys greatly impacts the survival of patients with end-stage renal failure. Pigs are increasingly becoming potential organ donors but are limited by immunological rejection. Based on the human kidney organoid already established with the CHIR99021 and FGF9 induction strategy, we generated porcine kidney organoids from porcine naïve-like ESCs (nESCs). The derived porcine organoids had a tubule-like constructure and matrix components. The porcine organoids expressed renal markers including AQP1 (proximal tubule), WT1 and PODO (podocyte), and CD31 (vascular endothelial cells). These results imply that the organoids had developed the majority of the renal cell types and structures, including glomeruli and proximal tubules. The porcine organoids were also identified to have a dextran absorptive function. Importantly, porcine organoids have a certain abundance of vascular endothelial cells, which are the basis for investigating immune rejection. The derived porcine organoids might serve as materials for immunosuppressor screening for xenotransplantation.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"48 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139386438","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}
Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes—Radium-223 and Radium-224 (223/224Ra)—in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of 223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of 223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with 223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.
{"title":"Targeted Radium Alpha Therapy in the Era of Nanomedicine: In Vivo Results","authors":"G. Trencsényi, Csaba Csikos, Z. Képes","doi":"10.3390/ijms25010664","DOIUrl":"https://doi.org/10.3390/ijms25010664","url":null,"abstract":"Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes—Radium-223 and Radium-224 (223/224Ra)—in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of 223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of 223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with 223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"35 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385173","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}
A G-quadruplex (G4) is a typical non-B DNA structure and involved in various DNA-templated events in eukaryotic genomes. PEG and PDS chemicals have been widely applied for promoting the folding of in vivo or in vitro G4s. However, how PEG and PDS preferentially affect a subset of G4 formation genome-wide is still largely unknown. We here conducted a BG4-based IP-seq in vitro under K++PEG or K++PDS conditions in the rice genome. We found that PEG-favored IP-G4s+ have distinct sequence features, distinct genomic distributions and distinct associations with TEGs, non-TEGs and subtypes of TEs compared to PDS-favored ones. Strikingly, PEG-specific IP-G4s+ are associated with euchromatin with less enrichment levels of DNA methylation but with more enriched active histone marks, while PDS-specific IP-G4s+ are associated with heterochromatin with higher enrichment levels of DNA methylation and repressive marks. Moreover, we found that genes with PEG-specific IP-G4s+ are more expressed than those with PDS-specific IP-G4s+, suggesting that PEG/PDS-specific IP-G4s+ alone or coordinating with epigenetic marks are involved in the regulation of the differential expression of related genes, therefore functioning in distinct biological processes. Thus, our study provides new insights into differential impacts of PEG and PDS on G4 formation, thereby advancing our understanding of G4 biology.
{"title":"The Epigenomic Features and Potential Functions of PEG- and PDS-Favorable DNA G-Quadruplexes in Rice","authors":"Ranran Huang, Yilong Feng, Zhicheng Gao, Asgar Ahmed, Wenli Zhang","doi":"10.3390/ijms25010634","DOIUrl":"https://doi.org/10.3390/ijms25010634","url":null,"abstract":"A G-quadruplex (G4) is a typical non-B DNA structure and involved in various DNA-templated events in eukaryotic genomes. PEG and PDS chemicals have been widely applied for promoting the folding of in vivo or in vitro G4s. However, how PEG and PDS preferentially affect a subset of G4 formation genome-wide is still largely unknown. We here conducted a BG4-based IP-seq in vitro under K++PEG or K++PDS conditions in the rice genome. We found that PEG-favored IP-G4s+ have distinct sequence features, distinct genomic distributions and distinct associations with TEGs, non-TEGs and subtypes of TEs compared to PDS-favored ones. Strikingly, PEG-specific IP-G4s+ are associated with euchromatin with less enrichment levels of DNA methylation but with more enriched active histone marks, while PDS-specific IP-G4s+ are associated with heterochromatin with higher enrichment levels of DNA methylation and repressive marks. Moreover, we found that genes with PEG-specific IP-G4s+ are more expressed than those with PDS-specific IP-G4s+, suggesting that PEG/PDS-specific IP-G4s+ alone or coordinating with epigenetic marks are involved in the regulation of the differential expression of related genes, therefore functioning in distinct biological processes. Thus, our study provides new insights into differential impacts of PEG and PDS on G4 formation, thereby advancing our understanding of G4 biology.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385999","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}
This study reports the effect of the not-calcining process on the bioresorption and biomineralization of hydroxyapatite through in vitro dissolution assessment. The prepared calcined hydroxyapatite (c-HAp) and uncalcined hydroxyapatite (unc-HAp) have a particle size of 2 μm and 13 μm, surface areas of 4.47 m2/g and 108.08 m2/g, and a Ca/P ratio of 1.66 and 1.52, respectively. In vitro dissolution assessments of c-HAp and unc-HAp were performed for 20 days at 37 °C in a citric acid buffer according to ISO 10993-14. During the dissolution, the c-HAp and unc-HAp confirmed an increase in weight, and the calcium and phosphorous ions were rapidly released. The calcium ions released from c-HAp formed rod-shaped particles with a longer and thinner morphology, while in unc-HAp, they appeared thicker and shorter. In the ICP-OES results, the concentrations of calcium elements were initially increased and then decreased by this formation. The rod-shaped particles identified as calcium citrate (Ca-citrate) through the XRD pattern. The calcium content of Ca-citrate particles from unc-HAp was higher than that from c-HAp. The unc-HAp demonstrated non-toxic properties in a cytotoxicity evaluation. Therefore, due to its higher bioresorption and biomineralization, unc-HAp exhibits enhanced biocompatibility compared to c-HAp.
{"title":"Comparative In Vitro Dissolution Assessment of Calcined and Uncalcined Hydroxyapatite Using Differences in Bioresorbability and Biomineralization","authors":"Woo Young Jang, Jae Chul Pyun, Jeong Ho Chang","doi":"10.3390/ijms25010621","DOIUrl":"https://doi.org/10.3390/ijms25010621","url":null,"abstract":"This study reports the effect of the not-calcining process on the bioresorption and biomineralization of hydroxyapatite through in vitro dissolution assessment. The prepared calcined hydroxyapatite (c-HAp) and uncalcined hydroxyapatite (unc-HAp) have a particle size of 2 μm and 13 μm, surface areas of 4.47 m2/g and 108.08 m2/g, and a Ca/P ratio of 1.66 and 1.52, respectively. In vitro dissolution assessments of c-HAp and unc-HAp were performed for 20 days at 37 °C in a citric acid buffer according to ISO 10993-14. During the dissolution, the c-HAp and unc-HAp confirmed an increase in weight, and the calcium and phosphorous ions were rapidly released. The calcium ions released from c-HAp formed rod-shaped particles with a longer and thinner morphology, while in unc-HAp, they appeared thicker and shorter. In the ICP-OES results, the concentrations of calcium elements were initially increased and then decreased by this formation. The rod-shaped particles identified as calcium citrate (Ca-citrate) through the XRD pattern. The calcium content of Ca-citrate particles from unc-HAp was higher than that from c-HAp. The unc-HAp demonstrated non-toxic properties in a cytotoxicity evaluation. Therefore, due to its higher bioresorption and biomineralization, unc-HAp exhibits enhanced biocompatibility compared to c-HAp.","PeriodicalId":509625,"journal":{"name":"International Journal of Molecular Sciences","volume":"124 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387768","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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