Pubblicazioni recenti - cardiac stem
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RNA Binding Properties of SOX Family Members.
Cells2024 Jul;13(14):. doi: 1202.
Ghafoori Seyed Mohammad, Sethi Ashish, Petersen Gayle F, Tanipour Mohammad Hossein, Gooley Paul R, Forwood Jade K,
Abstract
SOX proteins are a family of transcription factors (TFs) that play critical functions in sex determination, neurogenesis, and chondrocyte differentiation, as well as cardiac, vascular, and lymphatic development. There are 20 SOX family members in humans, each sharing a 79-residue L-shaped high mobility group (HMG)-box domain that is responsible for DNA binding. SOX2 was recently shown to interact with long non-coding RNA and large-intergenic non-coding RNA to regulate embryonic stem cell and neuronal differentiation. The RNA binding region was shown to reside within the HMG-box domain; however, the structural details of this binding remain unclear. Here, we show that all SOX family members, except group H, interact with RNA. Our mutational experiments demonstrate that the disordered C-terminal region of the HMG-box domain plays an important role in RNA binding. Further, by determining a high-resolution structure of the HMG-box domain of the group H family member SOX30, we show that despite differences in RNA binding ability, SOX30 shares a very similar secondary structure with other SOX protein HMG-box domains. Together, our study provides insight into the interaction of SOX TFs with RNA.
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RNA Helicase DDX5 Maintains Cardiac Function by Regulating Alternative Splicing.
Circulation2024 Jul;():. doi: 10.1161/CIRCULATIONAHA.123.064774.
Jia Kangni, Cheng Haomai, Ma Wenqi, Zhuang Lingfang, Li Hao, Li Zhigang, Wang Ziyang, Sun Hang, Cui Yuke, Zhang Hang, Xie Hongyang, Yi Lei, Chen Zhiyong, Sano Motoaki, Fukuda Keiichi, Lu Lin, Pu Jun, Zhang Yan, Gao Ling, Zhang Ruiyan, Yan Xiaoxiang,
Abstract
BACKGROUND:
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear.
METHODS:
We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing.
RESULTS:
We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca/calmodulin-dependent protein kinase II? (), thus preventing the production of CaMKII?A, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca homeostasis. In line with this, we found increased intracellular Ca transients and increased sarcoplasmic reticulum Ca content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKII?A partially rescued the cardiac dysfunction and HF in knockout mice.
CONCLUSIONS:
These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF.
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Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic ?-cells.
iScience2024 Jul;27(7):110291. doi: 10.1016/j.isci.2024.110291.
Zhou Zhimin, Gong Maolian, Pande Amit, Margineanu Anca, Lisewski Ulrike, Purfürst Bettina, Zhu Han, Liang Lei, Jia Shiqi, Froehler Sebastian, Zeng Chun, Kühnen Peter, Khodaverdi Semik, Krill Winfried, Röpke Torsten, Chen Wei, Raile Klemens, Sander Maike, Izsvák Zsuzsanna,
Abstract
KCNQ1/Kv7, a low-voltage-gated K channel, regulates cardiac rhythm and glucose homeostasis. While mutations are associated with long-QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet-like organoids (SC-islets) using CRISPR-mediated homology-repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage-activated Ca channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and ?-cell survival in hereditary diabetes pathology.
© 2024 The Authors.
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Cardiovascular and metabolic risk incidence among adult allogeneic stem cell transplant recipients: a narrative review.
Transplant Cell Ther2024 Jul;():. doi: S2666-6367(24)00545-1.
Tan Jlc, Barmanray R D, Cirone B, Klarica D, Russell A, Spencer A, Wright T,
Abstract
Advances in allogeneic hematopoietic stem cell transplantation (alloHSCT) and supportive care over the past decade have reduced transplant and relapse-related mortality, leading to a greater number of long-term survivors. However, transplant-related late effects, such as cardiovascular (CVD) and metabolic diseases, are becoming significant concerns for this group. This review aims to address several key questions regarding cardiovascular late effects in alloHSCT recipients, including the long-term incidence of CVD-related events, the prevalence of risk factors, screening and management recommendations, and evidence for screening and prevention strategies. A literature search was conducted in PubMed Central using the National Library of Medicine search engine, covering all relevant research from inception to 2023. The initial search identified 751 research records, of which 41 were shortlisted based on specific criteria (?18 years of age at the time of transplant, allogeneic transplant, and inclusion of more than 30 patients). Our review highlights published evidence confirming the increased CVD risk among alloHSCT recipients. This risk is especially pronounced among individuals who have developed traditional and modifiable risk factors or have been exposed to transplant-specific risk factors. Evidence of the use of traditional cardiac risk factor calculators in the alloHSCT population is limited, in addition, there is emerging evidence that general population calculators potentially underestimate CVD risk given the increased risk of CVD in the allogeneic group as a whole. Studies that develop and validate transplant recipient-specific CVD risk stratification tools appear to be severely lacking and the field's focus needs to be shifted here in the coming years. To improve patient engagement and adherence to CVD risk factor measures, we recommend that a multidisciplinary model involving both specialists and primary care physicians is crucial in ensuring regular follow-up in the community and to potentially improve adherence.
Copyright © 2024. Published by Elsevier Inc.
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Generation of human induced pluripotent stem cell (hiPSC) lines derived from three patients carrying the pathogenic CRYAB (A527G) mutation and one non-carrier family member.
Stem Cell Res2024 Jul;80():103497. doi: 10.1016/j.scr.2024.103497.
Kelters Ilse R, Verbueken Devin, Beekink Tess, Van Laake Linda W, Sluijter Joost P G, Maas Renee G C, Buikema Jan W,
Abstract
A newly identified pathogenic variant (A527G) in alpha B-crystallin (?B-crystallin) has been linked to congenital cataract and young-onset dilated cardiomyopathy (DCM) within a Dutch family, although the disease mechanism remains unclear. Four human induced pluripotent stem cell (hiPSC) clones were generated from three symptomatic patients carrying the A527G variant, and one healthy proband. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using integration-free Sendai viral pluripotency vectors. The established hiPSCs clones exhibited regular ESC-like morphology, expression of pluripotency markers, and normal karyotyping. These hiPSC lines can facilitate future studies to understand the chaperone function and its role in DCM disease progression.
Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.
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State of the art in Purkinje bioengineering.
Tissue Cell2024 Jul;90():102467. doi: 10.1016/j.tice.2024.102467.
Birla Ravi K,
Abstract
This review article will cover the recent developments in the new evolving field of Purkinje bioengineering and the development of human Purkinje networks. Recent work has progressed to the point of a methodological and systematic process to bioengineer Purkinje networks. This involves the development of 3D models based on human anatomy, followed by the development of tunable biomaterials, and strategies to reprogram stem cells to Purkinje cells. Subsequently, the reprogrammed cells and the biomaterials are coupled to bioengineer Purkinje networks, which are then tested using a small animal injury model. In this article, we discuss this process as a whole and then each step separately. We then describe potential applications of bioengineered Purkinje networks and challenges in the field that need to be overcome to move this field forward. Although the field of Purkinje bioengineering is new and in a state of infancy, it holds tremendous potential, both for therapeutic applications and to develop tools that can be used for disease modeling.
Copyright © 2024 Elsevier Ltd. All rights reserved.
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Resistin Regulates Inflammation and Insulin Resistance in Humans via the Endocannabinoid System.
Research (Wash D C)2024 ;7():0326. doi: 0326.
Yang Han-Mo, Kim Joonoh, Kim Baek-Kyung, Seo Hyun Ju, Kim Ju-Young, Lee Joo-Eun, Lee Jaewon, You Jihye, Jin Sooryeonhwa, Kwon Yoo-Wook, Jang Hyun-Duk, Kim Hyo-Soo,
Abstract
Resistin plays an important role in the pathophysiology of obesity-mediated insulin resistance in mice. However, the biology of resistin in humans is quite different from that in rodents. Therefore, the association between resistin and insulin resistance remains unclear in humans. Here, we tested whether and how the endocannabinoid system (ECS) control circulating peripheral blood mononuclear cells (PBMCs) that produce resistin and infiltrate into the adipose tissue, heart, skeletal muscle, and liver, resulting in inflammation and insulin resistance. Using human PBMCs, we investigate whether the ECS is connected to human resistin. To test whether the ECS regulates inflammation and insulin resistance in vivo, we used 2 animal models such as "humanized" nonobese diabetic/Shi-severe combined immunodeficient interleukin-2R? (null) (NOG) mice and "humanized" resistin mouse models, which mimic human body. In human atheromatous plaques, cannabinoid 1 receptor (CB1R)-positive macrophage was colocalized with the resistin expression. In addition, resistin was exclusively expressed in the sorted CB1R-positive cells from human PBMCs. In CB1R-positive cells, endocannabinoid ligands induced resistin expression via the p38-Sp1 pathway. In both mouse models, a high-fat diet increased the accumulation of endocannabinoid ligands in adipose tissue, which recruited the CB1R-positive cells that secrete resistin, leading to adipose tissue inflammation and insulin resistance. This phenomenon was suppressed by CB1R blockade or in resistin knockout mice. Interestingly, this process was accompanied by mitochondrial change that was induced by resistin treatment. These results provide important insights into the ECS-resistin axis, leading to the development of metabolic diseases. Therefore, the regulation of resistin via the CB1R could be a potential therapeutic strategy for cardiometabolic diseases.
Copyright © 2024 Han-Mo Yang et al.
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Unveiling impaired vascular function and cellular heterogeneity in diabetic donor-derived vascular organoids.
Stem Cells2024 Jul;():. doi: sxae043.
Naderi-Meshkin Hojjat, Wahyu Setyaningsih Wiwit A, Yacoub Andrew, Carney Garrett, Cornelius Victoria A, Nelson Clare-Ann, Kelaini Sophia, Donaghy Clare, Dunne Philip D, Amirkhah Raheleh, Zampetaki Anna, Zeng Lingfang, Stitt Alan W, Lois Noemi, Grieve David J, Margariti Andriana,
Abstract
Vascular organoids (VOs), derived from induced pluripotent stem cells (iPSCs), hold promise as in vitro disease models and drug screening platforms. However, their ability to faithfully recapitulate human vascular disease and cellular composition remains unclear. In this study, we demonstrate that VOs derived from iPSCs of donors with diabetes (DB-VOs) exhibit impaired vascular function compared to non-diabetic VOs (ND-VOs). DB-VOs display elevated levels of reactive oxygen species (ROS), heightened mitochondrial content and activity, increased proinflammatory cytokines, and reduced blood perfusion recovery in vivo. Through comprehensive single-cell RNA sequencing, we uncover molecular and functional differences, as well as signaling networks, between vascular cell types and clusters within DB-VOs. Our analysis identifies major vascular cell types (endothelial cells [ECs], pericytes, and vascular smooth muscle cells) within VOs, highlighting the dichotomy between ECs and mural cells. We also demonstrate the potential need for additional inductions using organ-specific differentiation factors to promote organ-specific identity in VOs. Furthermore, we observe basal heterogeneity within VOs and significant differences between DB-VOs and ND-VOs. Notably, we identify a subpopulation of ECs specific to DB-VOs, showing overrepresentation in the ROS pathway and underrepresentation in the angiogenesis hallmark, indicating signs of aberrant angiogenesis in diabetes. Our findings underscore the potential of VOs for modeling diabetic vasculopathy, emphasize the importance of investigating cellular heterogeneity within VOs for disease modeling and drug discovery, and provide evidence of GAP43 (neuromodulin) expression in ECs, particularly in DB-VOs, with implications for vascular development and disease.
© The Author(s) 2024. Published by Oxford University Press.
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Informing Hazard Identification and Risk Characterization of Environmental Chemicals by Combining Transcriptomic and Functional Data from Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes.
Chem Res Toxicol2024 Jul;():. doi: 10.1021/acs.chemrestox.4c00193.
Tsai Han-Hsuan D, Ford Lucie C, Burnett Sarah D, Dickey Allison N, Wright Fred A, Chiu Weihsueh A, Rusyn Ivan,
Abstract
Environmental chemicals may contribute to the global burden of cardiovascular disease, but experimental data are lacking to determine which substances pose the greatest risk. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a high-throughput cardiotoxicity model that is widely used to test drugs and chemicals; however, most studies focus on exploring electro-physiological readouts. Gene expression data may provide additional molecular insights to be used for both mechanistic interpretation and dose-response analyses. Therefore, we hypothesized that both transcriptomic and functional data in human iPSC-derived cardiomyocytes may be used as a comprehensive screening tool to identify potential cardiotoxicity hazards and risks of the chemicals. To test this hypothesis, we performed concentration-response analysis of 464 chemicals from 12 classes, including both pharmaceuticals and nonpharmaceutical substances. Functional effects (beat frequency, QT prolongation, and asystole), cytotoxicity, and whole transcriptome response were evaluated. Points of departure were derived from phenotypic and transcriptomic data, and risk characterization was performed. Overall, 244 (53%) substances were active in at least one phenotype; as expected, pharmaceuticals with known cardiac liabilities were the most active. Positive chronotropy was the functional phenotype activated by the largest number of tested chemicals. No chemical class was particularly prone to pose a potential hazard to cardiomyocytes; a varying proportion (10-44%) of substances in each class had effects on cardiomyocytes. Transcriptomic data showed that 69 (15%) substances elicited significant gene expression changes; most perturbed pathways were highly relevant to known key characteristics of human cardiotoxicants. The bioactivity-to-exposure ratios showed that phenotypic- and transcriptomic-based POD led to similar results for risk characterization. Overall, our findings demonstrate how the integrative use of in vitro transcriptomic and phenotypic data from iPSC-derived cardiomyocytes not only offers a complementary approach for hazard and risk prioritization, but also enables mechanistic interpretation of the in vitro test results to increase confidence in decision-making.
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Development and disease-specific regulation of RNA splicing in cardiovascular system.
Front Cell Dev Biol2024 ;12():1423553. doi: 1423553.
Jiang Jinxiu, Wu Hongchun, Ji Yabo, Han Kunjun, Tang Jun-Ming, Hu Shijun, Lei Wei,
Abstract
Alternative splicing is a complex gene regulatory process that distinguishes itself from canonical splicing by rearranging the introns and exons of an immature pre-mRNA transcript. This process plays a vital role in enhancing transcriptomic and proteomic diversity from the genome. Alternative splicing has emerged as a pivotal mechanism governing complex biological processes during both heart development and the development of cardiovascular diseases. Multiple alternative splicing factors are involved in a synergistic or antagonistic manner in the regulation of important genes in relevant physiological processes. Notably, circular RNAs have only recently garnered attention for their tissue-specific expression patterns and regulatory functions. This resurgence of interest has prompted a reevaluation of the topic. Here, we provide an overview of our current understanding of alternative splicing mechanisms and the regulatory roles of alternative splicing factors in cardiovascular development and pathological process of different cardiovascular diseases, including cardiomyopathy, myocardial infarction, heart failure and atherosclerosis.
Copyright © 2024 Jiang, Wu, Ji, Han, Tang, Hu and Lei.
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Stem cell-derived cardiomyocytes expressing a dominant negative pacemaker HCN4 channel do not reduce the risk of graft-related arrhythmias.
Front Cardiovasc Med2024 ;11():1374881. doi: 1374881.
Wulkan Fanny, Romagnuolo Rocco, Qiang Beiping, Valdman Sadikov Tamilla, Kim Kyung-Phil, Quesnel Elya, Jiang Wenlei, Andharia Naaz, Weyers Jill J, Ghugre Nilesh R, Ozcan Bilgehan, Alibhai Faisal J, Laflamme Michael A,
Abstract
BACKGROUND:
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) show tremendous promise for cardiac regeneration following myocardial infarction (MI), but their transplantation gives rise to transient ventricular tachycardia (VT) in large-animal MI models, representing a major hurdle to translation. Our group previously reported that these arrhythmias arise from a focal mechanism whereby graft tissue functions as an ectopic pacemaker; therefore, we hypothesized that hPSC-CMs engineered with a dominant negative form of the pacemaker ion channel HCN4 (dnHCN4) would exhibit reduced automaticity and arrhythmogenic risk following transplantation.
METHODS:
We used CRISPR/Cas9-mediated gene-editing to create transgenic dnHCN4 hPSC-CMs, and their electrophysiological behavior was evaluated by patch-clamp recordings and optical mapping. Next, we transplanted WT and homozygous dnHCN4 hPSC-CMs in a pig MI model and compared post-transplantation outcomes including the incidence of spontaneous arrhythmias and graft structure by immunohistochemistry.
RESULTS:
dnHCN4 hPSC-CMs exhibited significantly reduced automaticity and pacemaker funny current (I ) density relative to wildtype (WT) cardiomyocytes. Following transplantation with either dnHCN4 or WT hPSC-CMs, all recipient hearts showed transmural infarct scar that was partially remuscularized by scattered islands of human myocardium. However, in contrast to our hypothesis, both dnHCN4 and WT hPSC-CM recipients exhibited frequent episodes of ventricular tachycardia (VT).
CONCLUSIONS:
While genetic silencing of the pacemaker ion channel HCN4 suppresses the automaticity of hPSC-CMs , this intervention is insufficient to reduce VT risk post-transplantation in the pig MI model, implying more complex mechanism(s) are operational .
© 2024 Wulkan, Romagnuolo, Qiang, Valdman Sadikov, Kim, Quesnel, Jiang, Andharia, Weyers, Ghugre, Ozcan, Alibhai and Laflamme.
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Cutibacterium acnes invades submicron osteocyte lacuno-canalicular networks following implant-associated osteomyelitis.
J Orthop Res2024 Jul;():. doi: 10.1002/jor.25929.
Botros Mina, de Mesy Bentley Karen L, Schloemann Derek T, Saito Motoo, Constantine Robert, Ricciardi Benjamin F, Muthukrishnan Gowrishankar,
Abstract
Cutibacterium acnes, part of normal skin flora, is increasingly recognized as an opportunistic pathogen capable of causing chronic prosthetic joint infections (PJI) associated with total hip and knee arthroplasty. However, there is a paucity of literature examining the pathogenesis of C. acnes during PJI. To study this, we developed an implant-associated osteomyelitis murine model in which 8-10-week-old C57BL6 mice were subjected to transtibial implantation of titanium or stainless-steel L-shaped pins contaminated with C. acnes. Postsurgery, mice were killed on Days 14 and 28 for terminal assessments of (1) bacterial load in bone, implant, and internal organs (heart, spleen, kidney, and liver), (2) bone osteolysis (micro-CT), (3) abscess formation (histology), and (4) systematic electron microscopy (EM). In vitro scanning EM (SEM) confirmed that C. acnes can form biofilms on stainless-steel and titanium implants. In mice, C. acnes could persist for 28 days in the tibia. Also, we observed C. acnes dissemination to internal organs. C. acnes chronic osteomyelitis revealed markedly reduced bone osteolysis and abscess formation compared to Staphylococcus aureus infections. Importantly, transmission EM (TEM) investigation revealed the presence of C. acnes within canaliculi, demonstrating that C. acnes can invade the osteocyte lacuno-canalicular networks (OLCN) within bone. Our preliminary pilot study, for the first time, revealed that the OLCN in bone can be a reservoir for C. acnes and potentially provides a novel mechanism of why C. acnes chronic implant-associated bone infections are difficult to treat.
© 2024 Orthopaedic Research Society.
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In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury.
Acta Pharmacol Sin2024 Jul;():. doi: 10.1038/s41401-024-01348-y.
Guo Cong-Ting, Jardin Blake D, Lin Jun-Sen, Ambroise Rachelle L, Wang Ze, Yang Lu-Zi, Mazumdar Neil, Lu Fu-Jian, Ma Qing, Cao Yang-Po, Liu Can-Zhao, Li Kai-Long, Liu Xu-Jie, Lan Feng, Zhao Ming-Ming, Xiao Han, Dong Er-Dan, Pu William T, Guo Yu-Xuan,
Abstract
Z-discs are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-disc-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-disc proteome in vivo. We found palmdelphin (PALMD) as a novel Z-disc-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific Palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed the transverse tubule (T-tubule)-sarcoplasmic reticulum (SR) ultrastructures, which formed the Z-disc-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with the reduction of nexilin (NEXN), a crucial Z-disc-associated protein that is essential for both Z-disc and JMC structures and functions. PALMD interacted with NEXN and enhanced its protein stability while the Nexn mRNA level was not affected. AAV-based NEXN addback rescued the exacerbated cardiac injury in isoproterenol-treated PALMD-depleted mice. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.
© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.
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Molecular changes in endometrium origin stromal cells during initiation of cardiomyogenic differentiation induced with Decitabine, Angiotensin II and TGF- ?1.
Sci Rep2024 Jul;14(1):16966. doi: 16966.
Skliut? Giedr?, Staponkut? Giedr?, Skliutas Edvinas, Malinauskas Mangirdas, Navakauskien? R?ta,
Abstract
Stem cells' differentiation toward cardiac lineage is a complex process dependent on various alterations in molecular basis and regulation pathways. The aim of the study is to show that endometrium-derived stromal cells - menstrual, endometrial and endometriotic, could be an attractive source for examination of the mechanisms underlying cardiomyogenesis. After treatment with Decitabine, Angiotensin II and TGF-?1, cells demonstrated morphological dedifferentiation into early cardiomyocyte-like cells and expressed CD36, CD106, CD172a typically used to sort for human pluripotent stem cell-derived cardiomyocytes. RT-qPCR revealed changed cells' genetic profiles, as majority of cardiac lineage differentiation related genes and cardiac ion channels (calcium, sodium, potassium) coding genes were upregulated after 6 and 13 days of exposure. Additionally, analysis of expression of various signaling proteins (FOXO1, PDGFB, TGFBR1, mTOR, VEGFA, WNT4, Notch1) coding genes showed differences between cell cultures as they seem to employ distinct signaling pathways through differentiation initiation. Early stages of differentiation had biggest impact on cardiomyogenesis related proteins (Nkx-2.5, EZH2, FOXO3a, H3K9Ac) levels, as we noticed after conducting Western blot and as expected, early cardiac transcription factor Nkx-2.5 was highly expressed and localized in nucleus of differentiating cells. These findings led us to assess endometrium origin stromal cells' potential to differentiate towards cardiomyogenic lineage and better understand the regulation of complex differentiation processes in ex vivo model systems.
© 2024. The Author(s).
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Cardiovascular Toxicity in Cancer Therapy: Protecting the Heart while Combating Cancer.
Curr Cardiol Rep2024 Jul;():. doi: 10.1007/s11886-024-02099-2.
Manhas Amit, Tripathi Dipti, Thomas Dilip, Sayed Nazish,
Abstract
PURPOSE OF REVIEW:
This review explores the cardiovascular toxicity associated with cancer therapies, emphasizing the significance of the growing field of cardio-oncology. It aims to elucidate the mechanisms of cardiotoxicity due to radiotherapy, chemotherapy, and targeted therapies, and to discuss the advancements in human induced pluripotent stem cell technology (hiPSC) for predictive disease modeling.
RECENT FINDINGS:
Recent studies have identified several chemotherapeutic agents, including anthracyclines and kinase inhibitors, that significantly increase cardiovascular risks. Advances in hiPSC technology have enabled the differentiation of these cells into cardiovascular lineages, facilitating more accurate modeling of drug-induced cardiotoxicity. Moreover, integrating hiPSCs into clinical trials holds promise for personalized cardiotoxicity assessments, potentially enhancing patient-specific therapeutic strategies. Cardio-oncology bridges oncology and cardiology to mitigate the cardiovascular side-effects of cancer treatments. Despite advancements in predictive models using hiPSCs, challenges persist in accurately replicating adult heart tissue and ensuring reproducibility. Ongoing research is essential for developing personalized therapies that balance effective cancer treatment with minimal cardiovascular harm.
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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Apelin Receptor Homodimerisation Inhibits Hippocampal Neuronal Autophagy via G Protein-Dependent Signalling in Vascular Dementia.
Mol Neurobiol2024 Jul;():. doi: 10.1007/s12035-024-04383-2.
Cai Xin, Hu Shujuan, Liu Wenkai, Yin Yue, Jiang Yunlu, Wang Yixiang, Lu Bowen, Wang Yuliang, Wang Dexiu, Chen Jing,
Abstract
Vascular dementia (VD), a progressive vascular cognitive impairment, is characterised by the presence of cerebral hypoperfusion, increased blood-brain barrier permeability, and white matter lesions. Although current treatment strategies primarily focus on risk factors such as hypertension, diabetes, and heart disease, efficient and targeted therapies are lacking and the underlying mechanisms of VD remain unclear. We previously discovered that Apelin receptors (APJ), which are G protein-coupled receptors (GPCRs), can homodimerize and generate signals that are distinct from those of APJ monomers in VD rats. Apelin-13 reduces the level of APJ homodimers and leads to the proliferation of endogenous neural stem cells in the hippocampal dentate gyrus area, suggesting that it has a neuroprotective role. In this study, we established a rat and cellular oxygen-glucose deprivation/reoxygenation VD model to investigate the impact of APJ homodimerisation on autophagy. We found that APJ homodimers protect against VD by inhibiting autophagy through the G?q and PI3K/Akt/mTOR pathways upon G?i signalling, both in vivo and in vitro. This discovery provides a promising therapeutic target for chronic cerebral ischaemia-reperfusion diseases and an experimental foundation for the development of drugs that target APJ homodimers.
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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Biomimetic Supramolecular Assembly with IGF-1C Delivery Ameliorates Inflammatory Bowel Disease (IBD) by Restoring Intestinal Barrier Integrity.
Adv Sci (Weinh)2024 Jul;():e2403075. doi: 10.1002/advs.202403075.
Fu Enze, Qian Meng, He Ningning, Yin Yilun, Liu Yue, Han Zhibo, Han ZhongChao, Zhao Qiang, Cao Xiaocang, Li Zongjin,
Abstract
The management of dysfunctional intestinal epithelium by promoting mucosal healing and modulating the gut microbiota represents a novel therapeutic strategy for inflammatory bowel disease (IBD). As a convenient and well-tolerated method of drug delivery, intrarectal administration may represent a viable alternative to oral administration for the treatment of IBD. Here, a biomimetic supramolecular assembly of hyaluronic acid (HA) and ?-cyclodextrin (HA-?-CD) for the delivery of the C domain peptide of insulin-like growth factor-1 (IGF-1C), which gradually releases IGF-1C, is developed. It is identified that the supramolecular assembly of HA-?-CD enhances the stability and prolongs the release of IGF-1C. Furthermore, this biomimetic supramolecular assembly potently inhibits the inflammatory response, thereby restoring intestinal barrier integrity. Following HA-?-CD-IGF-1C administration, 16S rDNA sequencing reveals a significant increase in the abundance of the probiotic Akkermansia, suggesting enhanced intestinal microbiome homeostasis. In conclusion, the findings demonstrate the promise of the HA-based mimicking peptide delivery platform as a therapeutic approach for IBD. This biomimetic supramolecular assembly effectively ameliorates intestinal barrier function and intestinal microbiome homeostasis, suggesting its potential for treating IBD.
© 2024 The Author(s). Advanced Science published by Wiley?VCH GmbH.
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Graphene and its hybrid nanocomposite: A Metamorphoses elevation in the field of tissue engineering.
Heliyon2024 Jul;10(13):e33542. doi: e33542.
Singh Rajesh, Rawat Hemant, Kumar Ashwani, Gandhi Yashika, Kumar Vijay, Mishra Sujeet K, Narasimhaji Ch Venkata,
Abstract
In this discourse, we delve into the manifold applications of graphene-based nanomaterials (GBNs) in the realm of biomedicine. Graphene, characterized by its two-dimensional planar structure, superconductivity, mechanical robustness, chemical inertness, extensive surface area, and propitious biocompatibility, stands as an exemplary candidate for diverse biomedical utility. Graphene include various distinctive characteristics of its two-dimensional planar structure, enormous surface area, mechanical and chemical stability, high conductivity, and exceptional biocompatibility. We investigate graphene and its diverse derivatives, which include reduced graphene oxides (rGOs), graphene oxides (GOs), and graphene composites, with a focus on elucidating the unique attributes relevant to their biomedical utility. In this review article it highlighted the unique properties of graphene, synthesis methods of graphene and functionalization methods of graphene. In the quest for novel materials to advance regenerative medicine, researchers have increasingly turned their attention to graphene-based materials, which have emerged as a prominent innovation in recent years. Notably, it highlights their applications in the regeneration of various tissues, including nerves, skeletal muscle, bones, skin, cardiac tissue, cartilage, and adipose tissue, as well as their influence on induced pluripotent stem cells, marking significant breakthroughs in the field of regenerative medicine. Additionally, this review article explores future prospects in this evolving area of study.
© 2024 Published by Elsevier Ltd.
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Mesenchymal stromal cells to treat patients with non-ischaemic heart failure: Results from SCIENCE II pilot study.
ESC Heart Fail2024 Jul;():. doi: 10.1002/ehf2.14925.
Qayyum Abbas Ali, Frljak Sabina, Juhl Morten, Poglajen Gregor, Zemlji?l Gregor, Cerar Andraz, Litman Thomas, Ekblond Annette, Haack-Sørensen Mandana, Højgaard Lisbeth Drozd, Kastrup Jens, Vrtovec Bojan,
Abstract
AIMS:
Allogeneic stem cell therapy is more logistically suitable compared with autologous cell therapy for large-scale patient treatment. We aim to investigate the clinical safety and efficacy profile of the allogeneic adipose tissue derived mesenchymal stromal cell product (CSCC_ASC) as an add-on therapy in patients with chronic non-ischaemic heart failure with reduced left ventricular ejection fraction (HFrEF)
METHODS AND RESULTS:
This is a single-centre investigator-initiated randomized phase I/II study with direct intra-myocardial injections of 100 million allogeneic CSCC_ASC. A total of 30 HFrEF patients with New York Heart Association (NYHA) class ?II despite optimal anticongestive heart failure medication and plasma NT-proBNP > 300 pg/mL (>35 pmol/L) were included and randomized 2:1 to CSCC_ASC or standard care. The primary endpoint left ventricular end systolic volume (LVESV) and other echo related parameters were analysed by an investigator blinded for treatment allocation. No difference in serious adverse events was observed between groups. LVESV decreased significantly from baseline to 6 months follow-up in the ASC group (153.7 ± 53.2 mL and 128.7 ± 45.6 mL, P
CONCLUSIONS:
Intramyocardial injections of allogeneic CSCC_ASC in patients with chronic non-ischaemic HFrEF was safe and improved LVESV, LVEF, NYHA class, and self-reported health compared with standard care group.
© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Proteomic signatures improve risk prediction for common and rare diseases.
Nat Med2024 Jul;():. doi: 10.1038/s41591-024-03142-z.
Carrasco-Zanini Julia, Pietzner Maik, Davitte Jonathan, Surendran Praveen, Croteau-Chonka Damien C, Robins Chloe, Torralbo Ana, Tomlinson Christopher, Grünschläger Florian, Fitzpatrick Natalie, Ytsma Cai, Kanno Tokuwa, Gade Stephan, Freitag Daniel, Ziebell Frederik, Haas Simon, Denaxas Spiros, Betts Joanna C, Wareham Nicholas J, Hemingway Harry, Scott Robert A, Langenberg Claudia,
Abstract
For many diseases there are delays in diagnosis due to a lack of objective biomarkers for disease onset. Here, in 41,931 individuals from the United Kingdom Biobank Pharma Proteomics Project, we integrated measurements of ~3,000 plasma proteins with clinical information to derive sparse prediction models for the 10-year incidence of 218 common and rare diseases (81-6,038 cases). We then compared prediction models developed using proteomic data with models developed using either basic clinical information alone or clinical information combined with data from 37 clinical assays. The predictive performance of sparse models including as few as 5 to 20 proteins was superior to the performance of models developed using basic clinical information for 67 pathologically diverse diseases (median delta C-index?=?0.07; range?=?0.02-0.31). Sparse protein models further outperformed models developed using basic information combined with clinical assay data for 52 diseases, including multiple myeloma, non-Hodgkin lymphoma, motor neuron disease, pulmonary fibrosis and dilated cardiomyopathy. For multiple myeloma, single-cell RNA sequencing from bone marrow in newly diagnosed patients showed that four of the five predictor proteins were expressed specifically in plasma cells, consistent with the strong predictive power of these proteins. External replication of sparse protein models in the EPIC-Norfolk study showed good generalizability for prediction of the six diseases tested. These findings show that sparse plasma protein signatures, including both disease-specific proteins and protein predictors shared across several diseases, offer clinically useful prediction of common and rare diseases.
© 2024. The Author(s).
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