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AUXIN/INDOLE-3-ACETIC ACIDs are transcriptional repressors for auxin signalling. Aux/IAAs of Arabidopsis thaliana display some functional redundancy. The IAA3/SHY2 clade (IAA1, IAA2, IAA3 and IAA4) show strong sequence similarity, but no higher-order mutants have been reported. Here, through CRISPR/Cas9 genome editing, we generated loss-of-function iaa1/2/3/4 mutants. The quadruple mutants only exhibited a weak phenotype. Thus, we additionally knocked out IAA7/AXR2 and IAA16, which are coexpressed with IAA1/2/3/4. Remarkably, under white light control conditions, the iaa1/2/3/4/7/16 mutants exhibited a shade avoidance-like phenotype with over-elongated hypocotyls and petioles and hyponastic leaves. The sextuple mutants were highly sensitive to low light intensity, and the hypocotyl cells of the mutants were excessively elongated. Transcriptome profiling and qRT-PCR analyses revealed that the sextuple mutation upregulated IAA19/MSG2 and IAA29, two shared shade/auxin signalling targets. Besides, genes encoding cell wall-remodelling proteins and shade-responsive transcription regulators were upregulated. Using dual-luciferase reporter assays, we verified that IAA2/IAA7 targeted the promoters of cell wall-remodelling genes to inhibit their transcription. Our work indicates that the IAA1/2/3/4/7/16 gene set is required for the optimal integration of auxin and shade signalling. The mutants generated here should be valuable for exploring the complex interactions among signal sensors, transcription activators and transcription repressors during hormone/environmental responses.
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Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.
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Apoptose , Sinalização do Cálcio , Cálcio , Receptores de Inositol 1,4,5-Trifosfato , Neoplasias Meníngeas , Meningioma , Animais , Humanos , Camundongos , Cálcio/metabolismo , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/genética , Meningioma/metabolismo , Meningioma/patologia , Meningioma/genética , Neurofibromina 2RESUMO
OBJECTIVE: To retrospectively analyze the clinical characteristics of 193 Chinese patients with McCune-Albright syndrome (MAS). METHODS: By using keywords "McCune-Albright syndrome", "Albright syndrome", or " fibrous dysplasia " as the search terms, 193 cases of MAS reported in China from January 1990 to November 2022 from the Wanfang data, CNKI, VIP, PubMed, and Embase databases were obtained, and their clinical data was retrospectively analyzed. Intergroup comparisons were carried out by using t test, Mann-Whitney U test, and X2 test. RESULTS: The 193 MAS patients had included 42 males and 151 females, with the median first-visit age of females being younger than males. The typical triad group had accounted for 46.1% of patients, and the middle first-visit and diagnosis age was younger than the atypical group. The primary reason for first-visit in males of MAS was fibrous dysplasia (FD), whilst that in females of MAS was peripheral precocious puberty (PPP). FD has occurred in 84.5% of the patients, with an average age of onset age being 6.1 years old, and 90% was ≤ 16 years of age. Endocrine hyperfunction was found in 79.3% of the patients, with a higher proportion in females compared with males (P < 0.05). Pituitary involvement was seen in 21.8% of the patients, and the incidence of craniofacial FD and cranial nerve compression was significantly higher in those with elevated growth hormone (GH) than without (P < 0.05). Café-au-Lait Spots were noted in 86.5% of the patients, and 28.3% (28/99) had located on the different side of FD. CONCLUSION: Most MAS patients had atypical manifestations and multi-systemic involvement. It is more common and occurs earlier in females. The most common reasons for initial diagnosis in male and female patients were FD and PPP, respectively. Patients with elevated GH should be examined for cranial nerve compression.
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Displasia Fibrosa Poliostótica , Humanos , Displasia Fibrosa Poliostótica/genética , Masculino , Feminino , Criança , Adolescente , China , Pré-Escolar , Adulto , Estudos Retrospectivos , Adulto Jovem , Lactente , Povo Asiático/genética , Pessoa de Meia-Idade , População do Leste AsiáticoRESUMO
Quasi-one-dimensional (quasi-1D) van der Waals crystal fibrous red phosphorus (RP) exhibits pronounced in-plane optical anisotropy, positioning it as a potential candidate for polarization-related micro-nano devices. Unfortunately, a comprehensive investigation into the complex refractive index of fibrous RP and the structure-activity relationship connecting the distinctive quasi-1D structure with optical anisotropy is currently deficient. Herein, we have collectively determined the complex refractive index of the fibrous RP flakes within the ab-plane through Kramers-Kronig (KK) analysis and theoretical calculation. Notably, the maximum birefringence of fibrous RP reaches 0.642@475â nm with an absolute extinction coefficient of only 0.08, superior to the reported traditional optical crystals and the emerging low-dimensional materials as well. The remarkable birefringence can be attributed to the synergistic influence of the large electronic dipole polarizability, anisotropic electron density distribution and the distortion of stereochemically active lone pair (SCALP). This work demonstrates the potential of fibrous RP for polarization-sensitive devices, illuminating possibilities to exploit novel giant birefringent crystals based on the structure-activity relationship.
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Chiral hybrid perovskites have aroused great interest due to their unique versatile properties. However, designing chiral perovskites with narrow bandgaps is challenging, with their electronic properties such as the Rashba-Dresselhaus effect and piezoelectricity remaining unclear. Herein, single crystals of zero-dimensional (0D) tellurium-based chiral hybrid perovskite, (R-/S-α-PEA)2TeI6 and (R-/S-α-PEA)2TeBr6 (PEA = phenylethylammonium), with sizes of over 5 mm are grown by seed-crystal-assisted solution-temperature-lowering. The optical bandgaps are about 1.60 and 2.18 eV for the iodide and bromide analogues, respectively, which are the lowest among various chiral lead-free hybrid perovskites with the same halide ions in the X-site to the best of our knowledge. First-principles calculations reveal that (R-/S-α-PEA)2TeBr6 shows a larger Rashba-Dresselhaus spin-splitting than (R-/S-α-PEA)2TeI6, probably thanks to the greater distortion of [TeBr6] octahedra. Moreover, the piezoelectric coefficients d33 of (R-/S-α-PEA)2TeI6 and (R-/S-α-PEA)2TeBr6 are about 2.6 and 1.8 pC N-1, respectively. This work deepens the understanding of physical properties of 0D tellurium-based chiral perovskites with potential multifunctionality, including spintronic and piezoelectric performances.
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Aim: To investigate the current status of experience and support of nurses as second victims and explore its related factors in nurses. Design: A sequential, explanatory, mixed-method study was applied. Methods: A total of 406 nurses from seven tertiary hospitals in China were chosen as participants between September to October 2023. The Chinese version of the Second Victim Experience and Support Questionnaire (SVEST), Somatic Complaints of Sub-health Status Questionnaire (SCSSQ) and Generalized Anxiety Disorder (GAD-7) were applied to collect quantitative data. Eight nurses were selected for a qualitative study through in-depth interviews. Through interpretive phenomenological analysis, the interview data were analysed to explore the experience and support of nurses as second victims. Results: Practice distress (15.74 ± 4.97) and psychological distress (15.48 ± 3.74) were the highest dimensions, indicating Chinese nurses experienced second victim-related practice and psychological distress. Nurses with different gender, age, education, marital status, income, working hours, professional titles, and unit types have different levels of second victim-related experience and support (p < 0.05). In addition, the score of SVEST was positively associated with SCSSQ (r = 0.444) and GAD-7 (r = 0.490) (p < 0.05). This qualitative study found that the experience and support of nurses as second victims included nurses' perceptions and needs for patient safety events; psychological, physical and practice distress of nurses; and nurses and hospitals coping style after patient safety events. Discussion: Our findings suggest that nurses who are second victims of patient safety events experience severe practice and psychological distress, indicating that nursing managers should pay attention to psychological and practice distress of nurses after patient safety events and provide effective preventive measures.
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Pathological scarring resulting from traumas and wounds, such as hypertrophic scars and keloids, pose significant aesthetic, functional and psychological challenges. This study provides a comprehensive transcriptomic analysis of these conditions, aiming to illuminate underlying molecular mechanisms and potential therapeutic targets. We employed a co-expression and module analysis tool to identify significant gene clusters associated with distinct pathophysiological processes and mechanisms, notably lipid metabolism, sebum production, cellular energy metabolism and skin barrier function. This examination yielded critical insights into several skin conditions including folliculitis, skin fibrosis, fibrosarcoma and congenital ichthyosis. Particular attention was paid to Module Cluster (MCluster) 3, encompassing genes like BLK, TRPV1 and GABRD, all displaying high expression and potential implications in immune modulation. Preliminary immunohistochemistry validation supported these findings, showing elevated expression of these genes in non-fibrotic samples rich in immune activity. The complex interplay of different cell types in scar formation, such as fibroblasts, myofibroblasts, keratinocytes and mast cells, was also explored, revealing promising therapeutic strategies. This study underscores the promise of targeted gene therapy for pathological scars, paving the way for more personalised therapeutic approaches. The results necessitate further research to fully ascertain the roles of these identified genes and pathways in skin disease pathogenesis and potential therapeutics. Nonetheless, our work forms a strong foundation for a new era of personalised medicine for patients suffering from pathological scarring.
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Cicatriz Hipertrófica , Queloide , Humanos , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/terapia , Cicatriz Hipertrófica/metabolismo , Queloide/genética , Queloide/terapia , Queratinócitos/metabolismo , Fibroblastos/metabolismo , Miofibroblastos/metabolismoRESUMO
Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment involving disruptions to inner hair cells (IHCs), ribbon synapses, spiral ganglion neurons (SGNs), and/or the auditory nerve itself. The outcomes of cochlear implants (CI) for ANSD are variable and dependent on the location of lesion sites. Discovering a potential therapeutic agent for ANSD remains an urgent requirement. Here, 293T stable transfection cell lines and patient induced pluripotent stem cells (iPSCs)-derived auditory neurons carrying the apoptosis inducing factor (AIF) p.R422Q variant were used to pursue a therapeutic regent for ANSD. Nicotinamide adenine dinucleotide (NADH) is a main electron donor in the electron transport chain (ETC). In 293T stable transfection cells with the p.R422Q variant, NADH treatment improved AIF dimerization, rescued mitochondrial dysfunctions, and decreased cell apoptosis. The effects of NADH were further confirmed in patient iPSCs-derived neurons. The relative level of AIF dimers was increased to 150.7 % (P = 0.026) from 59.2 % in patient-neurons upon NADH treatment. Such increased AIF dimerization promoted the mitochondrial import of coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4), which further restored mitochondrial functions. Similarly, the content of mitochondrial calcium (mCa2+) was downregulated from 136.7 % to 102.3 % (P = 0.0024) in patient-neurons upon NADH treatment. Such decreased mCa2+ levels inhibited calpain activity, ultimately reducing the percentage of apoptotic cells from 30.5 % to 21.1 % (P = 0.021). We also compared the therapeutic effects of gene correction and NADH treatment on hereditary ANSD. NADH treatment had comparable restorative effects on functions of ANSD patient-specific cells to that of gene correction. Our findings offer evidence of the molecular mechanisms of ANSD and introduce NADH as a potential therapeutic agent for ANSD therapy.
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Fator de Indução de Apoptose , Apoptose , Perda Auditiva Central , NAD , Células Receptoras Sensoriais , Perda Auditiva Central/genética , Perda Auditiva Central/metabolismo , Perda Auditiva Central/fisiopatologia , Apoptose/efeitos dos fármacos , NAD/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Dimerização , Mitocôndrias/efeitos dos fármacos , Células HEK293 , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/metabolismo , Cálcio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Calpaína/metabolismo , Ativação Enzimática/efeitos dos fármacos , Genótipo , Humanos , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismoRESUMO
Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA (lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer (TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1 (PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.
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Ferroptose , Neoplasias Mamárias Animais , RNA Longo não Codificante , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Ferroptose/genética , Separação de Fases , RNA Longo não Codificante/genética , Peroxidases , Peroxirredoxinas/genéticaRESUMO
High-fat diet (HFD)-induced obesity is a crucial risk factor for metabolic syndrome, mainly due to adipose tissue dysfunctions associated with it. However, the underlying mechanism remains unclear. This study has used genetic screening to identify an obesity-associated human lncRNA LINK-A as a critical molecule bridging the metabolic microenvironment and energy expenditure in vivo by establishing the HFD-induced obesity knock-in (KI) mouse model. Mechanistically, HFD LINK-A KI mice induce the infiltration of inflammatory factors, including IL-1ß and CXCL16, through the LINK-A/HB-EGF/HIF1α feedback loop axis in a self-amplified manner, thereby promoting the adipose tissue microenvironment remodeling and adaptive thermogenesis disorder, ultimately leading to obesity and insulin resistance. Notably, LINK-A expression is positively correlated with inflammatory factor expression in individuals who are overweight. Of note, targeting LINK-A via nucleic acid drug antisense oligonucleotides (ASO) attenuate HFD-induced obesity and metabolic syndrome, pointing out LINK-A as a valuable and effective therapeutic target for treating HFD-induced obesity. Briefly, the results reveale the roles of lncRNAs (such as LINK-A) in remodeling tissue inflammatory microenvironments to promote HFD-induced obesity.
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Resistência à Insulina , Síndrome Metabólica , RNA Longo não Codificante , Humanos , Animais , Camundongos , RNA Longo não Codificante/metabolismo , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Dieta HiperlipídicaRESUMO
The growth of high-quality halide perovskite single crystals is imperative to study their intrinsic physical properties and to realize high-performance optoelectronic devices. Here, a room-temperature solvent evaporation-induced crystallization (RTSEIC) method is reported based on Le Chatelier's principle, which provides a general strategy to grow halide perovskite single crystals including 3D, 2D, 1D, and 0D, and either hybrid or all-inorganic halide perovskites. Taking 2D n-BA2 PbBr4 (n-BA = butylammonium) as an example, the room-temperature crystallization kinetics is demonstrated. The centimeter-sized n-BA2 PbBr4 single crystals exhibit an extremely small full width at half maximum (FWHM) of 0.024° in (0 0 2) plane rocking curve and a small trap density of 2.74 × 1010 cm-3 . The superior crystalline quality endows the n-BA2 PbBr4 single crystal ultraviolet photodetectors with recorded performance among reported n-BA2 PbBr4 ultraviolet photodetectors, demonstrating a detectivity reaching 1.8 × 1013 Jones, a fast response time of 55 µs and a high on-off ratio of 104 . The low-cost, simple, general, and efficient RTSEIC method is anticipated to promote the blossoming of halide perovskites single crystals.
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Mitochondrial DNA (mtDNA) mutations result in a variety of genetic diseases. As an emerging therapeutic method, mtDNA editing technology recognizes targets more based on the protein and less on the nucleic acid. Although the protein recognition type mtDNA editing technology represented by zinc finger nuclease technology, transcription activator like effector nuclease technology and base editing technology has made some progress, the disadvantages of complex recognition sequence design hinder further popularization. Gene editing based on nucleic acid recognition by the CRISPR system shows superiority due to the simple structure, easy design and modification. However, the lack of effective means to deliver nucleic acids into mitochondria limits application in the field of mtDNA editing. With the advances in the study of endogenous and exogenous import pathways and the deepening understanding of DNA repair mechanisms, growing evidence shows the feasibility of nucleic acid delivery and the broad application prospects of nucleic acid recognition type mtDNA editing technology. Based on the classification of recognition elements, this article summarizes the current principles and development of mitochondrial gene editing technology, and discusses its application prospects.
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Genes Mitocondriais , Ácidos Nucleicos , Edição de Genes , Mitocôndrias/genética , DNA Mitocondrial/genética , TecnologiaRESUMO
Fibrous red phosphorus (RP) has triggered growing attention as an emerging quasi-one-dimensional (quasi-1D) van der Waals crystal recently. Unfortunately, it is difficult to achieve substrate growth of high-quality fibrous RP flakes due to their inherent quasi-1D structure, which impedes their fundamental property exploration and device integration. Herein, we demonstrate a bottom-up approach for the growth of fibrous RP flakes with (001)-preferred orientation via a chemical vapor transport (CVT) reaction in the P/Sn/I2 system. The formation of fibrous RP flakes can be attributed to the synergistic effect of Sn-mediated P4 partial pressure and the SnI2 capping layer-directed growth. Moreover, we investigate the optical anisotropy of the as-grown flakes, demonstrating their potential application as micro phase retarders in polarization conversion. Our developed bottom-up approach lays the foundation for studying the anisotropy and device integration of fibrous red phosphorus, opening up possibilities for the two-dimensional growth of quasi-1D van der Waals materials.
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Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment caused by dysfunction of inner hair cells, ribbon synapses, spiral ganglion neurons and/or the auditory nerve itself. Approximately 1/7000 newborns have abnormal auditory nerve function, accounting for 10%-14% of cases of permanent hearing loss in children. Although we previously identified the AIFM1 c.1265 G > A variant to be associated with ANSD, the mechanism by which ANSD is associated with AIFM1 is poorly understood. We generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) via nucleofection with episomal plasmids. The patient-specific iPSCs were edited via CRISPR/Cas9 technology to generate gene-corrected isogenic iPSCs. These iPSCs were further differentiated into neurons via neural stem cells (NSCs). The pathogenic mechanism was explored in these neurons. In patient cells (PBMCs, iPSCs, and neurons), the AIFM1 c.1265 G > A variant caused a novel splicing variant (c.1267-1305del), resulting in AIF p.R422Q and p.423-435del proteins, which impaired AIF dimerization. Such impaired AIF dimerization then weakened the interaction between AIF and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4). On the one hand, the mitochondrial import of ETC complex subunits was inhibited, subsequently leading to an increased ADP/ATP ratio and elevated ROS levels. On the other hand, MICU1-MICU2 heterodimerization was impaired, leading to mCa2+ overload. Calpain was activated by mCa2+ and subsequently cleaved AIF for its translocation into the nucleus, ultimately resulting in caspase-independent apoptosis. Interestingly, correction of the AIFM1 variant significantly restored the structure and function of AIF, further improving the physiological state of patient-specific iPSC-derived neurons. This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD. Mitochondrial dysfunction, especially mCa2+ overload, plays a prominent role in ANSD associated with AIFM1. Our findings help elucidate the mechanism of ANSD and may lead to the provision of novel therapies.
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Fator de Indução de Apoptose , Cálcio , Células-Tronco Pluripotentes Induzidas , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Criança , Humanos , Recém-Nascido , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Cálcio/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/metabolismoRESUMO
Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction. Here, we screened a mitochondria-associated compound library by quantifying the mitochondrial membrane potential of HCM cybrids and the survival rate of HCM-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in galactose media. 1-Deoxynojirimycin (DNJ) was identified to rescue mitochondrial function by targeting optic atrophy protein 1 (OPA1) to promote its oligomerization, leading to reconstruction of the mitochondrial cristae. DNJ treatment further recovered the physiological properties of HCM iPSC-CMs by improving Ca2+ homeostasis and electrophysiological properties. An angiotensin II-induced cardiac hypertrophy mouse model further verified the efficacy of DNJ in promoting cardiac mitochondrial function and alleviating cardiac hypertrophy in vivo. These results demonstrated that DNJ could be a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy. Our findings will help elucidate the mechanism of HCM and provide a potential therapeutic strategy.
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1-Desoxinojirimicina , Cardiomiopatia Hipertrófica , Animais , Camundongos , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/genética , Cardiomegalia/metabolismoRESUMO
Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM-NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM-NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development.
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Via de Sinalização Hippo , RNA Longo não Codificante , Humanos , Linhagem Celular Tumoral , Proliferação de Células , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.
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Neoplasias da Mama , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Feminino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ubiquitinação , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias Pulmonares/genética , Neoplasias da Mama/genética , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMO
Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.|T260A, p.|R422W, and p.|R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%|â|49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%|â|17.9%, which was significantly higher than that (6.9%|â|7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.
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Fator de Indução de Apoptose , NAD , Humanos , Fator de Indução de Apoptose/química , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , NAD/metabolismo , Dimerização , ApoptoseRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a multifactor-driven malignant tumor with rapid progression, which causes the difficulty to substantially improve the prognosis of HCC. Limited understanding of the mechanisms in HCC impedes the development of efficacious therapies. Despite Krüpple-Like factors (KLFs) were reported to be participated in HCC pathogenesis, the function of KLF14 in HCC remains largely unexplored. METHODS: We generated KLF14 overexpressed and silenced liver cancer cells, and nude mouse xenograft models for the in vitro and in vivo study. Luciferase reporter assay, ChIP-qPCR, Co-IP, immunofluorescence were performed for mechanism research. The expression of KLF14 in HCC samples was analyzed by quantitative RT-PCR, Western blotting, and immunohistochemistry (IHC) analysis. RESULTS: KLF14 was significantly downregulated in human HCC tissues, which was highly correlated with poor prognosis. Inhibition of KLF14 promoted liver cancer cells proliferation and overexpression of KLF14 suppressed cells growth. KLF14 exerts its anti-tumor function by inhibiting Iron-responsive element-binding protein 2 (IRP2), which then causes transferrin receptor-1(TfR1) downregulation and ferritin upregulation on the basis of IRP-IREs system. This then leading to cellular iron deficiency and HCC cells growth suppression in vitro and in vivo. Interestingly, KLF14 suppressed the transcription of IRP2 via recruiting SIRT1 to reduce the histone acetylation of the IRP2 promoter, resulting in iron depletion and cell growth suppression. More important, we found fluphenazine is an activator of KLF14, inhibiting HCC cells growth through inducing iron deficiency. CONCLUSION: KLF14 acts as a tumor suppressor which inhibits the proliferation of HCC cells by modulating cellular iron metabolism via the repression of IRP2. We identified Fluphenazine, as an activator of KLF14, could be a potential compound for HCC therapy. Our findings therefore provide an innovative insight into the pathogenesis of HCC and a promising therapeutic target.
Assuntos
Carcinoma Hepatocelular , Proteína 2 Reguladora do Ferro , Ferro , Fatores de Transcrição Kruppel-Like , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Flufenazina , Regulação Neoplásica da Expressão Gênica , Homeostase , Ferro/metabolismo , Proteína 2 Reguladora do Ferro/genética , Proteína 2 Reguladora do Ferro/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismoRESUMO
The lead-free hybrid perovskite piezoelectrics possess advantages of easy processing, light weight, and low-toxicity over inorganic ceramics. However, the lack of understanding in structure-property relationships hinders exploration of new molecular piezoelectric crystals with excellent performances. Herein, by introducing chiral α-phenylethylammonium (α-PEA+ ) cations into bismuth-based hybrid halides, centimeter-sized (R-α-PEA)4 Bi2 I10 and (S-α-PEA)4 Bi2 I10 single crystals with a superior piezoelectric voltage coefficient g22 of 309 mV m N-1 , are obtained. Structural rigidity in crystals leads to a remarkable electrostrictive coefficient Q22 of 25.8 m4 C-2 , nearly 20 times higher than that of poly(vinylidene fluoride) (PVDF), which is beneficial to improve piezoelectricity with the synergistic effect of chirality. Moreover, the as-grown crystals show outstanding phase stability from 173 K to ≈470 K. This work suggests a design strategy based on rigidity and chirality to exploit novel piezoelectrics among hybrid metal halides.