bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2024‒06‒23
fifteen papers selected by
Irene Sambri, TIGEM
  1. RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD): a review on the clinical manifestations and therapeutic options.
  2. Unsupervised Cluster Analysis in Patients with Cardiorenal Syndromes: Identifying Vascular Aspects.
  3. Cardiac Metabolism.
  4. Deciphering Congenital Heart Disease Using Human Induced Pluripotent Stem Cells.
  5. Cardiac Development and Animal Models of Congenital Heart Defects.
  6. Zebrafish Congenital Heart Disease Models: Opportunities and Challenges.
  7. Research progress of autophagy in heart failure.
  8. YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFβ uptake in human pluripotent stem cell-derived cardiomyocytes.
  9. Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
  10. IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease.
  11. TGF‑β/Smad signaling in chronic kidney disease: Exploring post‑translational regulatory perspectives (Review).
  12. Transcription factor EB (TFEB) interaction with RagC is disrupted during enterovirus D68 infection.
  13. The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease.
  14. Astragaloside IV Protects Against Podocyte Injury by Upregulating Mitophagy via the Mfn2/Pink1/Parkin Axis.
  15. Polarization of organoids by bioengineered symmetry breaking.
  1. Kidney Blood Press Res. 2024 Jun 20.
    RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD): a review on the clinical manifestations and therapeutic options.
    Francesco Trepiccione, Irene Sambri, Barbara Ruggiero, Francesco Emma, Andrea Ballabio, Giulia Florio, Ines Vanderheyden, Anna Iervolino, François Jouret.
      BACKGROUND: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated Autosomal Dominant Kidney Hypomagnesemia with Cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mTORC1 pathway. This disruption hinders the the nuclear translocation and transcriptional activity of the transcription factor EB (TFEB) a crucial regulator of lysosomal and autophagic function.SUMMARY: All identified RRAGD variants compromise kidney function, leading to hypomagnesemia and hypokalemia of various severity. The renal phenotype for most of the variants (i.e. S76L, I221K, P119R, P119L), typically manifests in the second decade of life occasionally preceded by childhood symptoms of dilated cardiomyopathy. In contrast, the P88L variant is associated to dilated cardiomyopathy manifesting in adulthood. To date, the T97P variant has not been linked to cardiac involvement. The most severe manifestations of ADKH-RRAGD, particularly concerning electrolyte imbalance and heart dysfunction requiring transplantation in childhood appear to be associated with the S76L, I221K, P119R variants.
    KEY MESSAGES: This review aims to provide an overview of the clinical presentation for ADKH-RRAGD, aiming to enhance o awareness, promote early diagnosis and facilitate proper treatment. It also reports on the limited experience in patient management with diuretics, magnesium and potassium supplements, metformin, or calcineurin- and SGLT2-inhibitors.
    DOI:  https://doi.org/10.1159/000539889
  2. J Clin Med. 2024 May 28. pii: 3159. [Epub ahead of print]13(11):
    Unsupervised Cluster Analysis in Patients with Cardiorenal Syndromes: Identifying Vascular Aspects.
    Jean-Baptiste de Freminville, Jean-Michel Halimi, Valentin Maisons, Guillaume Goudot, Arnaud Bisson, Denis Angoulvant, Laurent Fauchier.
      Background/Objectives: Cardiorenal syndrome (CRS) is a disorder of the heart and kidneys, with one type of organ dysfunction affecting the other. The pathophysiology is complex, and its actual description has been questioned. We used clustering analysis to identify clinically relevant phenogroups among patients with CRS. Methods: Data for patients admitted from 1 January 2012 to 31 December 2012 were collected from the French national medico-administrative database. Patients with a diagnosis of heart failure and chronic kidney disease and at least 5 years of follow-up were included. Results: In total, 13,665 patients were included and four clusters were identified. Cluster 1 could be described as the vascular-diabetes cluster. It comprised 1930 patients (14.1%), among which 60% had diabetes, 94% had coronary artery disease (CAD), and 80% had peripheral artery disease (PAD). Cluster 2 could be described as the vascular cluster. It comprised 2487 patients (18.2%), among which 33% had diabetes, 85% had CAD, and 78% had PAD. Cluster 3 could be described as the metabolic cluster. It comprised 2163 patients (15.8%), among which 87% had diabetes, 67% dyslipidemia, and 62% obesity. Cluster 4 comprised 7085 patients (51.8%) and could be described as the low-vascular cluster. The vascular cluster was the only one associated with a higher risk of cardiovascular death (HR: 1.48 [1.32-1.66]). The metabolic cluster was associated with a higher risk of kidney replacement therapy (HR: 1.33 [1.17-1.51]). Conclusions: Our study supports a new classification of CRS based on the vascular aspect of pathophysiology differentiating microvascular or macrovascular lesions. These results could have an impact on patients' medical treatment.
    Keywords:  cardiorenal syndrome; chronic kidney disease; heart failure
    DOI:  https://doi.org/10.3390/jcm13113159
  3. Adv Exp Med Biol. 2024 ;1441 365-396
    Cardiac Metabolism.
    Silvia Martin-Puig, Ivan Menendez-Montes.
      The heart is composed of a heterogeneous mixture of cellular components perfectly intermingled and able to integrate common environmental signals to ensure proper cardiac function and performance. Metabolism defines a cell context-dependent signature that plays a critical role in survival, proliferation, or differentiation, being a recognized master piece of organ biology, modulating homeostasis, disease progression, and adaptation to tissue damage. The heart is a highly demanding organ, and adult cardiomyocytes require large amount of energy to fulfill adequate contractility. However, functioning under oxidative mitochondrial metabolism is accompanied with a concomitant elevation of harmful reactive oxygen species that indeed contributes to the progression of several cardiovascular pathologies and hampers the regenerative capacity of the mammalian heart. Cardiac metabolism is dynamic along embryonic development and substantially changes as cardiomyocytes mature and differentiate within the first days after birth. During early stages of cardiogenesis, anaerobic glycolysis is the main energetic program, while a progressive switch toward oxidative phosphorylation is a hallmark of myocardium differentiation. In response to cardiac injury, different signaling pathways participate in a metabolic rewiring to reactivate embryonic bioenergetic programs or the utilization of alternative substrates, reflecting the flexibility of heart metabolism and its central role in organ adaptation to external factors. Despite the well-established metabolic pattern of fetal, neonatal, and adult cardiomyocytes, our knowledge about the bioenergetics of other cardiac populations like endothelial cells, cardiac fibroblasts, or immune cells is limited. Considering the close intercellular communication and the influence of nonautonomous cues during heart development and after cardiac damage, it will be fundamental to better understand the metabolic programs in different cardiac cells in order to develop novel interventional opportunities based on metabolic rewiring to prevent heart failure and improve the limited regenerative capacity of the mammalian heart.
    Keywords:  Cardiac development; Cardiac metabolism; Cardiac regeneration; Fatty acid oxidation; Glycolysis; Hypoxia; Oxidative stress; Pentose phosphate pathway
    DOI:  https://doi.org/10.1007/978-3-031-44087-8_19
  4. Adv Exp Med Biol. 2024 ;1441 239-252
    Deciphering Congenital Heart Disease Using Human Induced Pluripotent Stem Cells.
    Hao Zhang, Joseph C Wu.
      Congenital heart disease (CHD) is a leading cause of birth defect-related death. Despite significant advances, the mechanisms underlying the development of CHD are complex and remain elusive due to a lack of efficient, reproducible, and translational model systems. Investigations relied on animal models have inherent limitations due to interspecies differences. Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for disease modeling. iPSCs allow for the production of a limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. With the development of physiologic three-dimensional cardiac organoids, iPSCs represent a powerful platform to mechanistically dissect CHD and serve as a foundation for future translational research.
    Keywords:  Cardiac organoid; Congenital heart disease (CHD); Differentiation; Disease modeling; Heart development; Induced pluripotent stem cells (iPSCs)
    DOI:  https://doi.org/10.1007/978-3-031-44087-8_13
  5. Adv Exp Med Biol. 2024 ;1441 77-85
    Cardiac Development and Animal Models of Congenital Heart Defects.
    Robert G Kelly.
      The major events of cardiac development, including early heart formation, chamber morphogenesis and septation, and conduction system and coronary artery development, are briefly reviewed together with a short introduction to the animal species commonly used to study heart development and model congenital heart defects (CHDs).
    Keywords:  Arterial pole; Atrioventricular canal; Atrioventricular cushionsAtrioventricularcushion; Atrioventricular septal defect; Cardiac conduction system; Cardiac crescent; Cardiac neural crest cells; Cardiac progenitor cells; Chick; Ciona intestinalis; Common arterial trunk; Double outlet right ventricle; Drosophila melanogaster; Endocardial cushions; Endocardium; Epicardium; Heart tube; Left–right axis; Looping; Mouse; N-ethyl-N-nitrosourea; NKX2–5; Outflow tract; Pharyngeal arch arteries; Pharyngeal mesoderm; Purkinje fibers; Second heart field; Septation; T-box 1; Tetralogy of Fallot; Trabeculae; Venous pole; Xenopus; Zebrafish
    DOI:  https://doi.org/10.1007/978-3-031-44087-8_3
  6. Int J Mol Sci. 2024 May 29. pii: 5943. [Epub ahead of print]25(11):
    Zebrafish Congenital Heart Disease Models: Opportunities and Challenges.
    Dixuan Yang, Zhenjie Jian, Changfa Tang, Zhanglin Chen, Zuoqiong Zhou, Lan Zheng, Xiyang Peng.
      Congenital heart defects (CHDs) are common human birth defects. Genetic mutations potentially cause the exhibition of various pathological phenotypes associated with CHDs, occurring alone or as part of certain syndromes. Zebrafish, a model organism with a strong molecular conservation similar to humans, is commonly used in studies on cardiovascular diseases owing to its advantageous features, such as a similarity to human electrophysiology, transparent embryos and larvae for observation, and suitability for forward and reverse genetics technology, to create various economical and easily controlled zebrafish CHD models. In this review, we outline the pros and cons of zebrafish CHD models created by genetic mutations associated with single defects and syndromes and the underlying pathogenic mechanism of CHDs discovered in these models. The challenges of zebrafish CHD models generated through gene editing are also discussed, since the cardiac phenotypes resulting from a single-candidate pathological gene mutation in zebrafish might not mirror the corresponding human phenotypes. The comprehensive review of these zebrafish CHD models will facilitate the understanding of the pathogenic mechanisms of CHDs and offer new opportunities for their treatments and intervention strategies.
    Keywords:  congenital heart defects; heart disease syndrome; single-defect heart disease; zebrafish model
    DOI:  https://doi.org/10.3390/ijms25115943
  7. Am J Transl Res. 2024 ;16(5): 1991-2000
    Research progress of autophagy in heart failure.
    Lingji Li, Ranran Xi, Bing Gao, Yonglei Zeng, Qiang Ma, Tiantian Gong, Jing Wang.
      Heart failure poses a significant threat to global public health within the realm of cardiovascular diseases. Its pathological progression involves various alterations in cardiomyocytes, among which autophagy, a crucial intracellular degradation mechanism, plays a pivotal role. Autophagy facilitates the breakdown of damaged organelles and proteins, thereby maintaining cellular homeostasis. In the context of heart failure, autophagy coexists with apoptosis and necrosis, influencing myocardial hypertrophy and ventricular remodeling. However, its impact on heart failure manifests a dual nature: moderate autophagy aids in cardiac repair, whereas excessive autophagy may exacerbate ventricular remodeling and cell demise. This review delves into the fundamental biology of autophagy, elucidating its involvement in the pathological cascade of heart failure and its correlation with cardiac hypertrophy and ventricular remodeling. Furthermore, an analysis of the interplay between autophagy regulatory factors and heart failure sheds light on the potential therapeutic implications of autophagy in the prevention and management of heart failure. This exploration provides a theoretical foundation for novel treatment strategies in combating heart failure.
    Keywords:  Heart failure; autophagy; cardiomyocyte
    DOI:  https://doi.org/10.62347/OBXQ9477
  8. bioRxiv. 2024 Jun 05. pii: 2024.06.03.597045. [Epub ahead of print]
    YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFβ uptake in human pluripotent stem cell-derived cardiomyocytes.
    Orlando Chirikian, Mohamed A Faynus, Markus Merk, Zachary Singh, Christopher Muray, Jeffrey Pham, Alex Chialastri, Alison Vander Roest, Alex Goldstein, Trevor Pyle, Kerry V Lane, Brock Roberts, Jacqueline E Smith, Ruwanthi N Gunawardane, Nathan J Sniadecki, David L Mack, Jennifer Davis, Daniel Bernstein, Sebastian J Streichan, Dennis O Clegg, Siddharth S Dey, Maxwell Z Wilson, Beth L Pruitt.
      Hypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease - affecting >1:500 individuals. Advanced forms of HCM clinically present with hypercontractility, hypertrophy and fibrosis. Several single-point mutations in b-myosin heavy chain (MYH7) have been associated with HCM and increased contractility at the organ level. Different MYH7 mutations have resulted in increased, decreased, or unchanged force production at the molecular level. Yet, how these molecular kinetics link to cell and tissue pathogenesis remains unclear. The Hippo Pathway, specifically its effector molecule YAP, has been demonstrated to be reactivated in pathological hypertrophic growth. We hypothesized that changes in force production (intrinsically or extrinsically) directly alter the homeostatic mechano-signaling of the Hippo pathway through changes in stresses on the nucleus. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we asked whether homeostatic mechanical signaling through the canonical growth regulator, YAP, is altered 1) by changes in the biomechanics of HCM mutant cardiomyocytes and 2) by alterations in the mechanical environment. We use genetically edited hiPSC-CM with point mutations in MYH7 associated with HCM, and their matched controls, combined with micropatterned traction force microscopy substrates to confirm the hypercontractile phenotype in MYH7 mutants. We next modulate contractility in healthy and disease hiPSC-CMs by treatment with positive and negative inotropic drugs and demonstrate a correlative relationship between contractility and YAP activity. We further demonstrate the activation of YAP in both HCM mutants and healthy hiPSC-CMs treated with contractility modulators is through enhanced nuclear deformation. We conclude that the overactivation of YAP, possibly initiated and driven by hypercontractility, correlates with excessive CCN2 secretion (connective tissue growth factor), enhancing cardiac fibroblast/myofibroblast transition and production of known hypertrophic signaling molecule TGFβ. Our study suggests YAP being an indirect player in the initiation of hypertrophic growth and fibrosis in HCM. Our results provide new insights into HCM progression and bring forth a testbed for therapeutic options in treating HCM.
    DOI:  https://doi.org/10.1101/2024.06.03.597045
  9. Nat Commun. 2024 Jun 17. 15(1): 5144
    Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
    Yahua Zhang, Fabian Bock, Mohammed Ferdaus, Juan Pablo Arroyo, Kristie L Rose, Purvi Patel, Jerod S Denton, Eric Delpire, Alan M Weinstein, Ming-Zhi Zhang, Raymond C Harris, Andrew S Terker.
      The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.
    DOI:  https://doi.org/10.1038/s41467-024-49562-w
  10. Commun Biol. 2024 Jun 21. 7(1): 756
    IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease.
    Nuo Chen, Xiaoyu Wang, Yaxin Guo, Ming Zhao, Baihui Cao, Bing Zhan, Yubin Li, Tian Zhou, Faliang Zhu, Chun Guo, Yongyu Shi, Qun Wang, Lining Zhang, Yan Li.
      Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.
    DOI:  https://doi.org/10.1038/s42003-024-06427-8
  11. Mol Med Rep. 2024 Aug;pii: 143. [Epub ahead of print]30(2):
    TGF‑β/Smad signaling in chronic kidney disease: Exploring post‑translational regulatory perspectives (Review).
    Jianchun Li, Yuanxia Zou, Jiraporn Kantapan, Hongwei Su, Li Wang, Nathupakorn Dechsupa.
      The TGF‑β/Smad signaling pathway plays a pivotal role in the onset of glomerular and tubulointerstitial fibrosis in chronic kidney disease (CKD). The present review delves into the intricate post‑translational modulation of this pathway and its implications in CKD. Specifically, the impact of the TGF‑β/Smad pathway on various biological processes was investigated, encompassing not only renal tubular epithelial cell apoptosis, inflammation, myofibroblast activation and cellular aging, but also its role in autophagy. Various post‑translational modifications (PTMs), including phosphorylation and ubiquitination, play a crucial role in modulating the intensity and persistence of the TGF‑β/Smad signaling pathway. They also dictate the functionality, stability and interactions of the TGF‑β/Smad components. The present review sheds light on recent findings regarding the impact of PTMs on TGF‑β receptors and Smads within the CKD landscape. In summary, a deeper insight into the post‑translational intricacies of TGF‑β/Smad signaling offers avenues for innovative therapeutic interventions to mitigate CKD progression. Ongoing research in this domain holds the potential to unveil powerful antifibrotic treatments, aiming to preserve renal integrity and function in patients with CKD.
    Keywords:  Smads; TGF‑β; chronic kidney disease; fibrosis; post‑translational modification
    DOI:  https://doi.org/10.3892/mmr.2024.13267
  12. J Virol. 2024 Jun 18. e0055624
    Transcription factor EB (TFEB) interaction with RagC is disrupted during enterovirus D68 infection.
    Alagie Jassey, Noah Pollack, Michael A Wagner, Jiapeng Wu, Ashley Benton, William T Jackson.
      Enterovirus D68 (EV-D68) is a picornavirus associated with severe respiratory illness and a paralytic disease called acute flaccid myelitis in infants. Currently, no protective vaccines or antivirals are available to combat this virus. Like other enteroviruses, EV-D68 uses components of the cellular autophagy pathway to rewire membranes for its replication. Here, we show that transcription factor EB (TFEB), the master transcriptional regulator of autophagy and lysosomal biogenesis, is crucial for EV-D68 infection. Knockdown of TFEB attenuated EV-D68 genomic RNA replication but did not impact viral binding or entry into host cells. The 3C protease of EV-D68 cleaves TFEB at the N-terminus at glutamine 60 (Q60) immediately post-peak viral RNA replication, disrupting TFEB-RagC interaction and restricting TFEB transport to the surface of the lysosome. Despite this, TFEB remained mostly cytosolic during EV-D68 infection. Overexpression of a TFEB mutant construct lacking the RagC-binding domain, but not the wild-type construct, blocks autophagy and increases EV-D68 nonlytic release in H1HeLa cells but not in autophagy-defective ATG7 KO H1HeLa cells. Our results identify TFEB as a vital host factor regulating multiple stages of the EV-D68 lifecycle and suggest that TFEB could be a promising target for antiviral development against EV-D68.IMPORTANCE: Enteroviruses are among the most significant causes of human disease. Some enteroviruses are responsible for severe paralytic diseases such as poliomyelitis or acute flaccid myelitis. The latter disease is associated with multiple non-polio enterovirus species, including enterovirus D68 (EV-D68), enterovirus 71, and coxsackievirus B3 (CVB3). Here, we demonstrate that EV-D68 interacts with a host transcription factor, transcription factor EB (TFEB), to promote viral RNA(vRNA) replication and regulate the egress of virions from cells. TFEB was previously implicated in the viral egress of CVB3, and the viral protease 3C cleaves TFEB during infection. Here, we show that EV-D68 3C protease also cleaves TFEB after the peak of vRNA replication. This cleavage disrupts TFEB interaction with the host protein RagC, which changes the localization and regulation of TFEB. TFEB lacking a RagC-binding domain inhibits autophagic flux and promotes virus egress. These mechanistic insights highlight how common host factors affect closely related, medically important viruses differently.
    Keywords:  3C; RagC; TFEB; autophagy; enterovirus; picornavirus
    DOI:  https://doi.org/10.1128/jvi.00556-24
  13. Cells. 2024 May 28. pii: 931. [Epub ahead of print]13(11):
    The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease.
    Alexandra E Giovou, Monika M Gladka, Vincent M Christoffels.
      During mammalian heart development, the clustered genes encoding peptide hormones, Natriuretic Peptide A (NPPA; ANP) and B (NPPB; BNP), are transcriptionally co-regulated and co-expressed predominately in the atrial and ventricular trabecular cardiomyocytes. After birth, expression of NPPA and a natural antisense transcript NPPA-AS1 becomes restricted to the atrial cardiomyocytes. Both NPPA and NPPB are induced by cardiac stress and serve as markers for cardiovascular dysfunction or injury. NPPB gene products are extensively used as diagnostic and prognostic biomarkers for various cardiovascular disorders. Membrane-localized guanylyl cyclase receptors on many cell types throughout the body mediate the signaling of the natriuretic peptide ligands through the generation of intracellular cGMP, which interacts with and modulates the activity of cGMP-activated kinase and other enzymes and ion channels. The natriuretic peptide system plays a fundamental role in cardio-renal homeostasis, and its potent diuretic and vasodilatory effects provide compensatory mechanisms in cardiac pathophysiological conditions and heart failure. In addition, both peptides, but also CNP, have important intracardiac actions during heart development and homeostasis independent of the systemic functions. Exploration of the intracardiac functions may provide new leads for the therapeutic utility of natriuretic peptide-mediated signaling in heart diseases and rhythm disorders. Here, we review recent insights into the regulation of expression and intracardiac functions of NPPA and NPPB during heart development, homeostasis, and disease.
    Keywords:  cardiac disease; cardiac homeostasis; heart development; natriuretic peptides
    DOI:  https://doi.org/10.3390/cells13110931
  14. Curr Mol Med. 2024 Jun 11.
    Astragaloside IV Protects Against Podocyte Injury by Upregulating Mitophagy via the Mfn2/Pink1/Parkin Axis.
    Yuan Yuan, Yufan Wu, Minhui He, Xue Jiang.
      BACKGROUND: Podocyte injury is the most important pathological hallmark of kidney diseases. Autophagy is a critical factor that involves podocyte injury. Here, we sought to determine whether Astragaloside IV (AS-IV) was able to improve renal function and reverse podocyte injury through the regulation of autophagy.METHODS: Using the Adriamycin (ADR) mice model, cultured immortalized mouse podocytes were exposed to AS-IV. Western blotting, immunofluorescence, and histochemistry were used to analyze markers of autophagy, mitochondrial dysfunction, podocyte apoptosis, and glomerulopathy in the progression of focal segmental glomerular sclerosis.
    RESULTS: We observed that AS-IV can inhibit podocyte apoptosis, increased reactive oxygen species (ROS) generation, mitochondrial fragmentation, and dysfunction by inducing the Mfn2/Pink1/Parkin mitophagy pathway both in vivo and in vitro. Overexpression of Mfn2 reduced puromycin aminonucleoside (PAN)-induced podocyte injury, while downregulation of Mfn2 expression limited the renal protective effect of AS-IV by regulating mitophagy.
    CONCLUSION: AS-IV ameliorates renal function and renal pathological changes in ADR mice and inhibits PAN-induced podocyte injury by directly enhancing Mfn2/Pink1/Parkin-associated autophagy.
    Keywords:  Astragaloside IV; FSGS.; mitofusin 2; mitophagy; podocyte
    DOI:  https://doi.org/10.2174/0115665240310818240531080353
  15. IBRO Neurosci Rep. 2024 Dec;17 22-31
    Polarization of organoids by bioengineered symmetry breaking.
    Jae Ryun Ryu, Kahee Ko, Woong Sun.
      Symmetry breaking leading to axis formation and spatial patterning is crucial for achieving more accurate recapitulation of human development in organoids. While these processes can occur spontaneously by self-organizing capabilities of pluripotent stem cells, they can often result in variation in structure and composition of cell types within organoids. To address this limitation, bioengineering techniques that utilize geometric, topological and stiffness factors are increasingly employed to enhance control and consistency. Here, we review how spontaneous manners and engineering tools such as micropattern, microfluidics, biomaterials, etc. can facilitate the process of symmetry breaking leading to germ layer patterning and the formation of anteroposterior and dorsoventral axes in blastoids, gastruloids, neuruloids and neural organoids. Furthermore, brain assembloids, which are composed of multiple brain regions through fusion processes are discussed. The overview of organoid polarization in terms of patterning tools can offer valuable insights for enhancing the physiological relevance of organoid system.
    Keywords:  Bioengineering; Neural organoid; Pluripotent stem cell; Polarization; Symmetry breaking
    DOI:  https://doi.org/10.1016/j.ibneur.2024.05.002
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