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Stem Cell Research Aug 2024Dilated cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide....
Dilated cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in dozens of cardiac genes have been connected to the development of DCM including the Troponin T2 gene (TNNT2). Here, we generated a human induced pluripotent stem cells (hiPSCs) from a DCM patient with a familial history that carries a missense mutation in TNNT2. The hiPSCs show typical morphology of pluripotent stem cells, expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers.
Topics: Humans; Cardiomyopathy, Dilated; Induced Pluripotent Stem Cells; Troponin T; Cell Differentiation; Cell Line; Male; Karyotype
PubMed: 38861774
DOI: 10.1016/j.scr.2024.103467 -
Journal of the American Heart... Jun 2024
Topics: Humans; Cardiac Myosins; Animals; Myocardial Contraction; Energy Metabolism; Myocardium
PubMed: 38860415
DOI: 10.1161/JAHA.124.035479 -
BMC Cancer Jun 2024Our study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC).
Integrated multi-omics analyses revealed the association between rheumatoid arthritis and colorectal cancer: MYO9A as a shared gene signature and an immune-related therapeutic target.
BACKGROUND
Our study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC).
METHODS
Mendelian randomization (MR) analysis was conducted to assess the causality between RA and CRC. Summary statistic data-based Mendelian randomization (SMR) leveraging eQTL data was employed to identify the CRC-related causal genes. Integrated analyses of single-cell RNA sequencing and bulk RNA sequencing were employed to comprehensively investigate the shared gene signature and potential mechanisms underlying the pathogenesis of both RA and CRC. Predictive analysis of the shared hub gene in CRC immunotherapy response was performed. Pan-cancer analyses were conducted to explore the potential role of MYO9A in 33 types of human tumors.
RESULTS
MR analysis suggested that RA might be associated with a slight increased risk of CRC (Odds Ratio = 1.04, 95% Confidence Interval = 1.01-1.07, P = 0.005). SMR analysis combining transcriptome analyses identified MYO9A as a causal gene in CRC and a shared gene signature in both RA and CRC. MYO9A may contribute to tumor suppression, while downregulation of MYO9A may impact CRC tumorigenesis by disrupting epithelial polarity and architecture, resulting in a worse prognosis in CRC. Additionally, MYO9A shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Pan-cancer analyses demonstrated MYO9A may have a protective role in the occurrence and progression of various human cancers.
CONCLUSION
RA might be associated with a slight increased risk of CRC. MYO9A is a shared gene signature and a potential immune-related therapeutic target for both CRC and RA. Targeting the MYO9A-mediated loss of polarity and epithelial architecture could be a novel therapeutic approach for CRC.
Topics: Humans; Colorectal Neoplasms; Arthritis, Rheumatoid; Mendelian Randomization Analysis; Myosins; Gene Expression Profiling; Transcriptome; Quantitative Trait Loci; Prognosis; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Multiomics
PubMed: 38858644
DOI: 10.1186/s12885-024-12466-5 -
Nature Communications Jun 2024Chlamydia invasion of epithelial cells is a pathogen-driven process involving two functionally distinct effectors - TarP and TmeA. They collaborate to promote robust...
Chlamydia invasion of epithelial cells is a pathogen-driven process involving two functionally distinct effectors - TarP and TmeA. They collaborate to promote robust actin dynamics at sites of entry. Here, we extend studies on the molecular mechanism of invasion by implicating the host GTPase dynamin 2 (Dyn2) in the completion of pathogen uptake. Importantly, Dyn2 function is modulated by TarP and TmeA at the levels of recruitment and activation through oligomerization, respectively. TarP-dependent recruitment requires phosphatidylinositol 3-kinase and the small GTPase Rac1, while TmeA has a post-recruitment role related to Dyn2 oligomerization. This is based on the rescue of invasion duration and efficiency in the absence of TmeA by the Dyn2 oligomer-stabilizing small molecule activator Ryngo 1-23. Notably, Dyn2 also regulated turnover of TarP- and TmeA-associated actin networks, with disrupted Dyn2 function resulting in aberrant turnover dynamics, thus establishing the interdependent functional relationship between Dyn2 and the effectors TarP and TmeA.
Topics: Chlamydia trachomatis; Humans; Dynamin II; HeLa Cells; Actins; rac1 GTP-Binding Protein; Bacterial Proteins; Chlamydia Infections; Host-Pathogen Interactions; Epithelial Cells
PubMed: 38858371
DOI: 10.1038/s41467-024-49350-6 -
Translational Psychiatry Jun 2024Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic...
Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine's effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.
Topics: Humans; Nerve Tissue Proteins; Neurons; Chromosome Deletion; Phenotype; Chromosome Disorders; Synapses; Chromosomes, Human, Pair 22; Male; Female; Cell Differentiation; Microfilament Proteins; Autism Spectrum Disorder; Child
PubMed: 38858349
DOI: 10.1038/s41398-024-02947-3 -
PLoS Genetics Jun 2024The development of ectodermal organs begins with the formation of a stratified epithelial placode that progressively invaginates into the underlying mesenchyme as the...
The development of ectodermal organs begins with the formation of a stratified epithelial placode that progressively invaginates into the underlying mesenchyme as the organ takes its shape. Signaling by secreted molecules is critical for epithelial morphogenesis, but how that information leads to cell rearrangement and tissue shape changes remains an open question. Using the mouse dentition as a model, we first establish that non-muscle myosin II is essential for dental epithelial invagination and show that it functions by promoting cell-cell adhesion and persistent convergent cell movements in the suprabasal layer. Shh signaling controls these processes by inducing myosin II activation via AKT. Pharmacological induction of AKT and myosin II can also rescue defects caused by the inhibition of Shh. Together, our results support a model in which the Shh signal is transmitted through myosin II to power effective cellular rearrangement for proper dental epithelial invagination.
Topics: Animals; Mice; Hedgehog Proteins; Cell Adhesion; Signal Transduction; Myosin Type II; Cell Movement; Epithelium; Morphogenesis; Tooth; Epithelial Cells; Proto-Oncogene Proteins c-akt; Gene Expression Regulation, Developmental
PubMed: 38857279
DOI: 10.1371/journal.pgen.1011326 -
PloS One 2024The present study aims to investigate the specific protective effects and underlying mechanisms of Ganshuang granule (GSG) on dimethylnitrosamine (DMN)-induced hepatic...
OBJECTIVE
The present study aims to investigate the specific protective effects and underlying mechanisms of Ganshuang granule (GSG) on dimethylnitrosamine (DMN)-induced hepatic fibrosis in rat models.
METHODS
Hepatic fibrosis was experimentally evoked in rats by DMN administration, and varying dosages of GSG were employed as an intervention. Hepatocellular damage was assessed by measuring serum levels of aminotransferase and bilirubin, accompanied by histopathological examinations of hepatic tissue. The hepatic concentrations of platelet-derived growth factor (PDGF) and transforming growth factor-β1 (TGF-β1) were quantitated via enzyme-linked immunosorbent assay (ELISA). The expression of α-smooth muscle actin (α-SMA) within hepatic tissue was evaluated using immunohistochemical techniques. The levels of hepatic interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and a spectrum of interleukins (IL-2, IL-4, IL-6, IL-10) were quantified by quantitative real-time PCR (qRT-PCR). Additionally, hepatic stellate cells (HSCs) were cultured in vitro and exposed to TNF-α in the presence of naringin, a principal component of GSG. The gene expression levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metallopeptidase-1 (MMP-1) in these cells were also quantified by qRT-PCR. Proliferative activity of HSCs was evaluated by the Cell Counting Kit-8 assay. Finally, alterations in Smad protein expression were analyzed through Western blotting.
RESULTS
Administration of GSG in rats with fibrosis resulted in reduced levels of serum aminotransferases and bilirubin, along with alleviation of histopathological liver injury. Furthermore, the fibrosis rats treated with GSG exhibited significant downregulation of hepatic TGF-β1, PDGF, and TNF-α levels. Additionally, GSG treatment led to increased mRNA levels of IFN-γ, IL-2, and IL-4, as well as decreased expression of α-SMA in the liver. Furthermore, treatment with naringin, a pivotal extract of GSG, resulted in elevated expression of MMP-1 and decreased levels of TIMP-1 in TNF-α-stimulated HSCs when compared to the control group. Additionally, naringin administration led to a reduction in Smad expression within the HSCs.
CONCLUSION
GSG has the potential to mitigate fibrosis induced by DMN in rat models through the regulation of inflammatory and fibrosis factors. Notably, naringin, the primary extract of GSG, may exert a pivotal role in modulating the TGF-β-Smad signaling pathway.
Topics: Animals; Liver Cirrhosis; Signal Transduction; Flavanones; Male; Rats; Smad Proteins; Hepatic Stellate Cells; Drugs, Chinese Herbal; Rats, Sprague-Dawley; Dimethylnitrosamine; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Platelet-Derived Growth Factor; Liver; Actins
PubMed: 38857261
DOI: 10.1371/journal.pone.0304185 -
Journal of Cellular and Molecular... Jun 2024Troponin T1 (TNNT1) plays a crucial role in muscle contraction but its role in cancer, particularly in kidney renal clear cell carcinoma (KIRC), is not well-understood....
Troponin T1 (TNNT1) plays a crucial role in muscle contraction but its role in cancer, particularly in kidney renal clear cell carcinoma (KIRC), is not well-understood. This study explores the expression, clinical significance and biological functions of TNNT1 in various cancers, with an emphasis on its involvement in KIRC. We analysed TNNT1 expression in cancers using databases like TCGA and GTEx, assessing its prognostic value, mutation patterns, methylation status and functional implications. The study also examined TNNT1's effect on the tumour microenvironment and drug sensitivity in KIRC, complemented by in vitro TNNT1 knockdown experiments in KIRC cells. TNNT1 is overexpressed in several cancers and linked to adverse outcomes, showing frequent upregulation mutations and abnormal methylation. Functionally, TNNT1 connects to muscle and cancer pathways, affects immune infiltration and drug responses, and its overexpression in KIRC is associated with advanced disease and reduced survival. Knocking down TNNT1 curbed KIRC cell growth. TNNT1's aberrant expression plays a significant role in tumorigenesis and immune modulation, highlighting its value as a prognostic biomarker and a potential therapeutic target in KIRC and other cancers. Further studies are essential to understand TNNT1's oncogenic mechanisms in KIRC.
Topics: Humans; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; DNA Methylation; Gene Expression Regulation, Neoplastic; Immunomodulation; Kidney Neoplasms; Mutation; Prognosis; Troponin T; Tumor Microenvironment
PubMed: 38853457
DOI: 10.1111/jcmm.18410 -
Neurobiology of Disease Aug 2024Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the...
Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene - encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flna mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations.
Topics: Animals; Filamins; rac1 GTP-Binding Protein; Mice; Cerebral Cortex; Actin Depolymerizing Factors; Pyramidal Cells; Neurogenesis; GTPase-Activating Proteins; Neurons; Mice, Transgenic; Periventricular Nodular Heterotopia; Neuropeptides
PubMed: 38852754
DOI: 10.1016/j.nbd.2024.106558 -
Communications Biology Jun 2024Robotically assisted proteomics provides insights into the regulation of multiple proteins achieving excellent spatial resolution. However, developing an effective...
Robotically assisted proteomics provides insights into the regulation of multiple proteins achieving excellent spatial resolution. However, developing an effective method for spatially resolved quantitative proteomics of formalin fixed paraffin embedded tissue (FFPE) in an accessible and economical manner remains challenging. We introduce non-robotic In-insert FFPE proteomics approach, combining glass insert FFPE tissue processing with spatial quantitative data-independent mass spectrometry (DIA). In-insert approach identifies 450 proteins from a 5 µm thick breast FFPE tissue voxel with 50 µm lateral dimensions covering several tens of cells. Furthermore, In-insert approach associated a keratin series and moesin (MOES) with prolactin-induced protein (PIP) indicating their prolactin and/or estrogen regulation. Our data suggest that PIP is a spatial biomarker for hormonally triggered cytoskeletal remodeling, potentially useful for screening hormonally affected hotspots in breast tissue. In-insert proteomics represents an alternative FFPE processing method, requiring minimal laboratory equipment and skills to generate spatial proteotype repositories from FFPE tissue.
Topics: Humans; Proteomics; Paraffin Embedding; Cytoskeleton; Female; Biomarkers; Tissue Fixation; Prolactin; Formaldehyde; Intracellular Signaling Peptides and Proteins; Microfilament Proteins; Membrane Transport Proteins
PubMed: 38851810
DOI: 10.1038/s42003-024-06354-8