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Cell & Bioscience Jun 2024Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4...
BACKGROUND
Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4 in gastrointestinal stromal tumors (GISTs).
RESULTS
We found that ZSWIM4 expression is inhibited by the predominantly mutated protein KIT in GISTs, while conversely, ZSWIM4 inhibits KIT expression and downstream signaling. Consistent with the observation, ZSWIM4 inhibited GIST cell survival and proliferation in vitro. RNA sequencing of GISTs from KIT mice and KIT/ZSWIM4 mice showed that loss of ZSWIM4 expression increases the expression of circadian clock pathway member BMAL1 which contributes to GIST cell survival and proliferation. In addition, we found that KIT signaling increases the distribution of ZSWIM4 in the nucleus of GIST cells, and which is important for its inhibition of KIT and BMAL1. In agreement with the results in vitro, the in vivo studies showed that ZSWIM4 deficiency increases the tumorigenesis of GISTs in KIT mice.
CONCLUSIONS
Taken together, our results revealed that the entry of ZSWIM4 to the nucleus is important for its inhibition of KIT and BMAL1, ultimately attenuating GIST tumorigenesis. The results provide a novel insight in the understanding of signal transduction in GISTs and lay strong theoretical basis for the advancement of GIST treatment.
PubMed: 38951864
DOI: 10.1186/s13578-024-01271-z -
The EMBO Journal Jul 2024Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA...
Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identify RNA-binding proteins and modifiers that participate in the p53 response. Among the top hits, we find the mA reader YTHDC1 as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites of TP53 and other genes involved in the DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency also causes the retention of introns and therefore aberrant protein production of key DNA damage factors. While YTHDC1-mediated intron retention requires mA, TP53 transcriptional pause-release is promoted by YTHDC1 independently of mA. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation.
PubMed: 38951610
DOI: 10.1038/s44318-024-00153-x -
Scientific Reports Jul 2024To assess malnutrition contribution to the functional status and health related quality of life after hospitalization due to COVID-19 pneumonia, 66 selected adults...
To assess malnutrition contribution to the functional status and health related quality of life after hospitalization due to COVID-19 pneumonia, 66 selected adults referred for physical rehabilitation accepted to participate in the study; none of them required oxygen supply or had history of lung/musculoskeletal/neurological/immune/rheumatic disease or trauma, or contraindication for respiratory-function tests. At three evaluations, with 3 months in-between, assessments included: self-report of functional status, the St. George's Respiratory Questionnaire, spirometry, the 6-min-walk-test, the MRC-scale, the 30-s sit-to-stand-test, the timed-up-and-go-test, nutritional status, and ultrasound imaging (vastus medialis and diaphragm). At referral, patients had nutritional deficits with protein deficiency, which gradually improved; while muscle thickness (of both vastus medialis and diaphragm) increased, along with muscle strength and mobility (ANOVA, p < 0.05). Contrarywise, the distance covered during the 6-min-walk-test decreased (ANOVA, p < 0.05), with a negative influence from excess body mass. During rehabilitation, health-related quality of life and functional status improved, with negative influence from a history of tobacco use and referral delay, respectively. After hospitalization due to COVID-19, early diagnosis of both protein deficiency and decrease of skeletal muscle thickness could be relevant for rehabilitation, while pondering the negative impact of excess body mass on submaximal exercise performance.
Topics: Humans; COVID-19; Quality of Life; Male; Female; Malnutrition; Middle Aged; Aged; Follow-Up Studies; Functional Status; Nutritional Status; SARS-CoV-2; Adult; Hospitalization; Muscle Strength; Surveys and Questionnaires
PubMed: 38951534
DOI: 10.1038/s41598-024-65698-7 -
Stem Cell Reviews and Reports Jun 2024Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by...
Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc. Previous biochemical investigations and loss-of-function studies in mice have provided insights into the mechanism of STAMBP, however, it remains controversial how STAMBP deficiency leads to malformation of those affected tissues in patients. In this study, we investigated the function and underlying mechanism of STAMBP during neural differentiation of human embryonic stem cells (hESCs). We found that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STAMBP-deficiency. Our study not only provides novel insight into the mechanism of neural defects in STAMBP mutant patients, it also indicates that the death receptor mediated apoptosis is an obstacle for long-term maintenance/expansion of NPCs in vitro thus counteracting this cell death pathway could be beneficial to the generation of NPCs in vitro.
PubMed: 38951308
DOI: 10.1007/s12015-024-10751-1 -
Naunyn-Schmiedeberg's Archives of... Jun 2024A previous study has confirmed the upregulation of circ_0007142 expression in CC. Here, we aimed to investigate the effect and mechanism of circ_0007142 in CC...
A previous study has confirmed the upregulation of circ_0007142 expression in CC. Here, we aimed to investigate the effect and mechanism of circ_0007142 in CC progression. The expression of circ_0007142, microRNA-128-3p (miR-128-3p), S100 calcium-binding protein A14 (S100A14), and epithelial mesenchymal transition (EMT)-related markers was measured by qRT-PCR and Western blot. Cell proliferative, migratory, and invasion abilities were evaluated using cell counting Kit-8, cell colony formation, 5-ethynyl-2'-deoxyuridine, and transwell assays, respectively. The interaction among circ_0007142, miR-128-3p and S100A14 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. In vivo experiment was implemented to investigate the effect of circ_0007142 on tumor growth. CC tissues and cells displayed high expression of circ_0007142 and S100A14, and low expression of miR-128-3p in comparison to the controls. Knockdown of circ_0007142 resulted in the inhibition of cell proliferation, migration invasion, and EMT in vitro. In support, circ_0007142 deficiency hindered tumor growth and EMT in vivo. In rescue experiments, downregulation of miR-128-3p relieved circ_0007142 absence-mediated anticancer impacts. MiR-128-3p overexpression-induced inhibitory effects on cell growth and metastasis were attenuated by S100A14 overexpression. Importantly, circ_0007142 regulated S100A14 expression by sponging miR-128-3p. Circ_0007142 knockdown suppressed CC cell malignant behaviors by miR-128-3p/S100A14 pathway, providing a possible circRNA-targeted therapy for CC.
PubMed: 38951152
DOI: 10.1007/s00210-024-03250-0 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2024A retrospective analysis was conducted on a MonoMAC syndrome case admitted in October 2022 to the First Affiliated Hospital of Zhejiang University School of Medicine.... (Review)
Review
[Allogeneic hematopoietic stem cell transplantation in a patient with MonoMAC syndrome and hematopoietic dysplasia which was induced by GATA2 deficiency: a case report and literature review].
A retrospective analysis was conducted on a MonoMAC syndrome case admitted in October 2022 to the First Affiliated Hospital of Zhejiang University School of Medicine. The patient, a 16-year-old female with a history of persistent monocytopenia and mild anemia for several years, experienced recurrent symptoms of cough, expectoration, and fever, leading to multiple visits to the hospital. The diagnosis of MonoMAC syndrome was confirmed through comprehensive assessments including routine blood tests, pathogen metagenomic sequencing, lung and bone marrow biopsies, and next-generation sequencing of peripheral blood. The patient underwent haploidentical hematopoietic stem cell transplantation, with a smooth course of transplantation, achieving neutrophil engraftment on + 16 d and platelet engraftment on + 17 d, eventually restoring normal monocyte and NK cell counts. MonoMAC syndrome patients often initially present with infectious symptoms, and the diagnosis can be established based on significant monocytopenia in routine blood tests, history of non-tuberculous mycobacterial infections, and GATA2 germline mutations. Allogeneic hematopoietic stem cell transplantation may be required for some patients to improve their prognosis.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Female; Adolescent; GATA2 Deficiency; GATA2 Transcription Factor; Transplantation, Homologous; Retrospective Studies
PubMed: 38951071
DOI: 10.3760/cma.j.cn121090-20231013-00199 -
International Journal of Gynecological... Jul 2024Although early-detected cervical cancer is associated with good survival, the prognosis for late-stage disease is poor and treatment options are sparse. Mismatch repair...
OBJECTIVE
Although early-detected cervical cancer is associated with good survival, the prognosis for late-stage disease is poor and treatment options are sparse. Mismatch repair deficiency (MMR-D) has surfaced as a predictor of prognosis and response to immune checkpoint inhibitor(s) in several cancer types, but its value in cervical cancer remains unclear. This study aimed to define the prevalence of MMR-D in cervical cancer and assess the prognostic value of MMR protein expression.
METHODS
Expression of the MMR proteins MLH-1, PMS-2, MSH-2, and MSH-6 was investigated by immunohistochemical staining in a prospectively collected cervical cancer cohort (n=508) with corresponding clinicopathological and follow-up data. Sections were scored as either loss or intact expression to define MMR-D, and by a staining index, based on staining intensity and area, evaluating the prognostic potential. RNA and whole exome sequencing data were available for 72 and 75 of the patients and were used for gene set enrichment and mutational analyses, respectively.
RESULTS
Five (1%) tumors were MMR-deficient, three of which were of neuroendocrine histology. MMR status did not predict survival (HR 1.93, p=0.17). MSH-2 low (n=48) was associated with poor survival (HR 1.94, p=0.02), also when adjusting for tumor stage, tumor type, and patient age (HR 2.06, p=0.013). MSH-2 low tumors had higher tumor mutational burden (p=0.003) and higher frequency of (frameshift) mutations in the double-strand break repair gene (p<0.01).
CONCLUSION
MMR-D is rare in cervical cancer, yet low MSH-2 expression is an independent predictor of poor survival.
Topics: Humans; Female; Uterine Cervical Neoplasms; Prognosis; Middle Aged; DNA-Binding Proteins; MutS Homolog 2 Protein; DNA Mismatch Repair; Adult; Aged; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1
PubMed: 38950928
DOI: 10.1136/ijgc-2024-005377 -
Cellular Signalling Jun 2024Diabetes-associated periodontitis (DP) presents severe inflammation and resistance to periodontal conventional treatment, presenting a significant challenge in clinical...
Diabetes-associated periodontitis (DP) presents severe inflammation and resistance to periodontal conventional treatment, presenting a significant challenge in clinical management. In this study, we investigated the underlying mechanism driving the hyperinflammatory response in gingival epithelial cells (GECs) of DP patients. Our findings indicate that lysosomal dysfunction under high glucose conditions leads to the blockage of autophagy flux, exacerbating inflammatory response in GECs. Single-cell RNA sequencing and immunohistochemistry analyses of clinical gingival epithelia revealed dysregulation in the lysosome pathway characterized by reduced levels of lysosome-associated membrane glycoprotein 2 (LAMP2) and V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C) in subjects with DP. In vitro stimulation of human gingival epithelial cells (HGECs) with a hyperglycemic microenvironment showed elevated release of proinflammatory cytokines, compromised lysosomal acidity and blocked autophagy. Moreover, HGECs with deficiency in ATP6V0C demonstrated impaired autophagy and heightened inflammatory response, mirroring the effects of high glucose stimulation. Proteomic analysis of acetylation modifications identified altered acetylation levels in 28 autophagy-lysosome pathway-related proteins and 37 sites in HGECs subjected to high glucose stimulation or siATP6V0C. Overall, our finding highlights the pivotal role of lysosome impairment in autophagy obstruction in DP and suggests a potential impact of altered acetylation of relevant proteins on the interplay between lysosome dysfunction and autophagy blockage. These insights may pave the way for the development of effective therapeutic strategies against DP.
PubMed: 38950874
DOI: 10.1016/j.cellsig.2024.111273 -
Neurobiology of Disease Jun 2024The glymphatic system serves as a perivascular pathway that aids in clearing liquid and solute waste from the brain, thereby enhancing neurological function. Disorders...
OBJECTIVE
The glymphatic system serves as a perivascular pathway that aids in clearing liquid and solute waste from the brain, thereby enhancing neurological function. Disorders in glymphatic drainage contribute to the development of vasogenic edema following cerebral ischemia, although the molecular mechanisms involved remain poorly understood. This study aims to determine whether a deficiency in dystrophin 71 (DP71) leads to aquaporin-4 (AQP4) depolarization, contributing to glymphatic dysfunction in cerebral ischemia and resulting in brain edema.
METHODS
A mice model of middle cerebral artery occlusion and reperfusion was used. A fluorescence tracer was injected into the cortex and evaluated glymphatic clearance. To investigate the role of DP71 in maintaining AQP4 polarization, an adeno-associated virus with the astrocyte promoter was used to overexpress Dp71. The expression and distribution of DP71 and AQP4 were analyzed using immunoblotting, immunofluorescence, and co-immunoprecipitation techniques. The behavior ability of mice was evaluated by open field test. Open-access transcriptome sequencing data were used to analyze the functional changes of astrocytes after cerebral ischemia. MG132 was used to inhibit the ubiquitin-proteasome system. The ubiquitination of DP71 was detected by immunoblotting and co-immunoprecipitation.
RESULTS
During the vasogenic edema stage following cerebral ischemia, a decline in the efflux of interstitial fluid tracer was observed. DP71 and AQP4 were co-localized and interacted with each other in the perivascular astrocyte endfeet. After cerebral ischemia, there was a notable reduction in DP71 protein expression, accompanied by AQP4 depolarization and proliferation of reactive astrocytes. Increased DP71 expression restored glymphatic drainage and reduced brain edema. AQP4 depolarization, reactive astrocyte proliferation, and the behavior of mice were improved. After cerebral ischemia, DP71 was degraded by ubiquitination, and MG132 inhibited the decrease of DP71 protein level.
CONCLUSION
AQP4 depolarization after cerebral ischemia leads to glymphatic clearance disorder and aggravates cerebral edema. DP71 plays a pivotal role in regulating AQP4 polarization and consequently influences glymphatic function. Changes in DP71 expression are associated with the ubiquitin-proteasome system. This study offers a novel perspective on the pathogenesis of brain edema following cerebral ischemia.
PubMed: 38950712
DOI: 10.1016/j.nbd.2024.106586 -
The Journal of Clinical Investigation Jul 2024Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I...
Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
Topics: Humans; Zebrafish; Leigh Disease; Cilia; Animals; Mitochondria; Kidney Diseases, Cystic; Electron Transport Complex I; Armadillo Domain Proteins; Retina; Eye Abnormalities; Mice; Abnormalities, Multiple; Cerebellum; Mitochondrial Proteins; Zebrafish Proteins; Male
PubMed: 38949024
DOI: 10.1172/JCI175560