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2.
Elife ; 122024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38994733

RESUMO

Asymmetric cell divisions (ACDs) generate two daughter cells with identical genetic information but distinct cell fates through epigenetic mechanisms. However, the process of partitioning different epigenetic information into daughter cells remains unclear. Here, we demonstrate that the nucleosome remodeling and deacetylase (NuRD) complex is asymmetrically segregated into the surviving daughter cell rather than the apoptotic one during ACDs in Caenorhabditis elegans. The absence of NuRD triggers apoptosis via the EGL-1-CED-9-CED-4-CED-3 pathway, while an ectopic gain of NuRD enables apoptotic daughter cells to survive. We identify the vacuolar H+-adenosine triphosphatase (V-ATPase) complex as a crucial regulator of NuRD's asymmetric segregation. V-ATPase interacts with NuRD and is asymmetrically segregated into the surviving daughter cell. Inhibition of V-ATPase disrupts cytosolic pH asymmetry and NuRD asymmetry. We suggest that asymmetric segregation of V-ATPase may cause distinct acidification levels in the two daughter cells, enabling asymmetric epigenetic inheritance that specifies their respective life-versus-death fates.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , ATPases Vacuolares Próton-Translocadoras , Caenorhabditis elegans/genética , Animais , ATPases Vacuolares Próton-Translocadoras/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Divisão Celular Assimétrica , Apoptose , Epigênese Genética , Nucleossomos/metabolismo
3.
Mol Med Rep ; 30(3)2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38994757

RESUMO

Cancer incidence is increasing globally, presenting a growing public health challenge. While anticancer drugs are crucial in treatment, their limitations, including poor targeting ability and high toxicity, hinder effectiveness and patient safety, requiring relentless scientific research and technological advancements to develop safer and more effective therapeutics. Cinnamaldehyde (CA), an active compound derived from the natural plant cinnamon, has garnered attention in pharmacological research due to its diverse therapeutic applications. CA has potential in treating a wide array of conditions, including cardiovascular diseases, diabetes, inflammatory disorders and various forms of cancer. The present review comprehensively summarizes the physicochemical and pharmacokinetic profiles of CA, and delves into the latest advancements in elucidating its potential mechanisms and targets across various cancer types. CA and its derivatives have antitumor effects, which encompass inhibiting cell proliferation, arresting the cell cycle, inducing apoptosis, limiting cell migration and invasion, and suppressing angiogenesis. Additionally, the present review explores targeted formulations of CA, laying a scientific foundation for further exploration of its implications in cancer prevention and treatment strategies.


Assuntos
Acroleína , Antineoplásicos , Neoplasias , Acroleína/análogos & derivados , Acroleína/química , Acroleína/farmacologia , Acroleína/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos
4.
Int J Mol Med ; 54(3)2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38994762

RESUMO

Age­related macular degeneration (AMD) is an ocular disease that threatens the visual function of older adults worldwide. Key pathological processes involved in AMD include oxidative stress, inflammation and choroidal vascular dysfunction. Retinal pigment epithelial cells and Müller cells are most susceptible to oxidative stress. Traditional herbal medicines are increasingly being investigated in the field of personalized medicine in ophthalmology. Triptonide (Tn) is a diterpene tricyclic oxide, the main active ingredient in the extract from the Chinese herbal medicinal plant Tripterygium wilfordii, and is considered an effective immunosuppressant and anti­inflammatory drug. The present study investigated the potential beneficial role of Tn in retinal oxidative damage in order to achieve personalized treatment for early AMD. An oxidative stress model of retinal cells induced by H2O2 and a retinal injury model of mice induced by light and N­Methyl­D­aspartic acid were constructed. In vitro, JC­1 staining, flow cytometry and apoptosis assay confirmed that low concentrations of Tn effectively protected retinal cells from oxidative damage, and reverse transcription­quantitative PCR and western blotting analyses revealed that Tn reduced the expression of retinal oxidative stress­related genes and inflammatory factors, which may depend on the PI3K/AKT/mTOR­induced Nrf2 signaling pathway. In vivo, by retinal immunohistochemistry, hematoxylin and eosin staining and electroretinogram assay, it was found that retinal function and structure improved and choroidal neovascularization was significantly inhibited after Tn pretreatment. These results suggested that Tn is an efficient Nrf2 activator, which can be expected to become a new intervention for diseases such as AMD, to inhibit retinal oxidative stress damage and pathological neovascularization.


Assuntos
Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Retina , Transdução de Sinais , Estresse Oxidativo/efeitos dos fármacos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Triterpenos/farmacologia , Masculino , Apoptose/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Linhagem Celular , Peróxido de Hidrogênio
5.
Int J Mol Med ; 54(3)2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38994756

RESUMO

Drug resistance is a key factor underlying the failure of tumor chemotherapy. It enhances the stem­like cell properties of cancer cells, tumor metastasis and relapse. Luteolin is a natural flavonoid with strong anti­tumor effects. However, the mechanism(s) by which luteolin protects against paclitaxel (PTX)­resistant cancer cell remains to be elucidated. The inhibitory effect of luteolin on the proliferation of EC1/PTX and EC1 cells was detected by cell counting kit­8 assay. Colony formation and flow cytometry assays were used to assess clonogenic capacity, cell cycle and apoptosis. Wound healing and Transwell invasion tests were used to investigate the effects of luteolin on the migration and invasion of EC1/PTX cells. Western blotting was used to detect the protein levels of EMT­related proteins and stem cell markers after sphere formation. Parental cells and drug­resistant cells were screened by high­throughput sequencing to detect the differential expression of RNA and differential genes. ELISA and western blotting were used to verify the screened PI3K/Akt signaling pathway, key proteins of which were explored by molecular docking. Hematoxylin and eosin staining and TUNEL staining were used to observe tumor xenografts on morphology and apoptosis in nude mice. The present study found that luteolin inhibited tumor resistance (inhibited proliferation, induced cell cycle arrest and apoptosis and hindered migration invasion, EMT and stem cell spherification) in vitro in PTX­resistant esophageal squamous cell carcinoma (ESCC) cells. In addition, luteolin enhanced drug sensitivity and promoted the apoptosis of drug­resistant ESCC cells in combination with PTX. Mechanistically, luteolin may inhibit the PI3K/AKT signaling pathway by binding to the active sites of focal adhesion kinase (FAK), Src and AKT. Notably, luteolin lowered the tumorigenic potential of PTX­resistant ESCC cells but did not show significant toxicity in vivo. Luteolin enhanced drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in PTX­resistant ESCC and could be a promising agent for the treatment of PTX­resistant ESCC cancers.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Luteolina , Paclitaxel , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Luteolina/farmacologia , Paclitaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Linhagem Celular Tumoral , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Camundongos Nus , Movimento Celular/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto , Antineoplásicos Fitogênicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Masculino
6.
Sci Rep ; 14(1): 15870, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982153

RESUMO

Recent studies indicate that Glypican 1 (GPC-1) is aberrantly expressed and plays a key role in certain cancers, but little is known in the hepatocellular carcinoma. Raw data from TCGA, GTEx and TIMER databases were utilized to comprehensively analyze GPC-1 expression landscape in pan-cancer, and the biological function of GPC-1 was investigated in liver cancer cells. The results revealed that GPC-1 is highly expressed in HCC, negatively correlated with survival, and also positively correlated with immune infiltration and clinical stage. Furthermore, GPC-1 promoted cell proliferation and inhibited apoptosis in the HCC cell lines. WGCNA analysis and HCCDB database revealed that Akt acted as a key molecule related to GPC-1, influencing biological functions and regulating cell malignant behaviors via the AKT signaling pathway. In conclusion, our findings provide a relatively comprehensive understanding of the oncogenic role of GPC-1 in HCC, implying that GPC-1 could serve as an innovative therapeutic target.


Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glipicanas , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Glipicanas/metabolismo , Glipicanas/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Linhagem Celular Tumoral , Apoptose/genética , Transdução de Sinais , Proteínas Proto-Oncogênicas c-akt/metabolismo
7.
Sci Rep ; 14(1): 15831, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982188

RESUMO

2-Hydroxyoleic acid (2-OHOA) has gained attention as a membrane lipid therapy (MLT) anti-cancer drug. However, in the viewpoint of anti-cancer drug, 2-OHOA shows poor water solubility and its effectiveness still has space for improvement. Thus, this study aimed to overcome the problems by formulating 2-OHOA into liposome dosage form. Furthermore, in the context of MLT reagents, the influence of 2-OHOA on the biophysical properties of the cytoplasmic membrane remains largely unexplored. To bridge this gap, our study specifically focused the alterations in cancer cell membrane fluidity and lipid packing characteristics before and after treatment. By using a two-photon microscope and the Laurdan fluorescence probe, we noted that liposomes incorporating 2-OHOA induced a more significant reduction in cancer cell membrane fluidity, accompanied by a heightened rate of cellular apoptosis when compared to the non-formulated 2-OHOA. Importantly, the enhanced efficacy of 2-OHOA within the liposomal formulation demonstrated a correlation with its endocytic uptake mechanism. In conclusion, our findings underscore the significant influence of 2-OHOA on the biophysical properties of cancer plasma membranes, emphasizing the potential of liposomes as an optimized delivery system for 2-OHOA in anti-cancer therapy.


Assuntos
Membrana Celular , Lipossomos , Fluidez de Membrana , Lipossomos/química , Humanos , Membrana Celular/metabolismo , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Fluidez de Membrana/efeitos dos fármacos , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Apoptose/efeitos dos fármacos , Lauratos/química , Microscopia de Fluorescência por Excitação Multifotônica , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Ácidos Oleicos/química , Corantes Fluorescentes/química
8.
PLoS One ; 19(7): e0306926, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38990890

RESUMO

The primary objective of this work was to delve into the potential therapeutic advantages and dissect the molecular mechanisms of salidroside in enhancing erectile function in rats afflicted with diabetic microvascular erectile dysfunction (DMED), addressing both the whole-animal and cellular dimensions.We established a DMED model in Sprague‒Dawley (SD) rats and conducted in vivo experiments. The DMED rats were administered varying doses of salidroside, the effects of which on DMED were compared. Erectile function was evaluated by applying electrical stimulation to the cavernous nerves and measuring intracavernous pressure in real time. The penile tissue underwent histological examination and Western blotting. Hydrogen peroxide (H2O2) was employed in the in vitro trial to induce an oxidative stress for the purpose of identifying alterations in cell viability. The CCK-8 assay was used to measure the viability of corpus cavernous smooth muscle cells (CCSMCs) treated with vs. without salidroside. Flow cytometry was utilized to detect alterations in intracellular reactive oxygen species (ROS). Apoptosis was assessed through Western blotting and TdT-mediated dUTP nick-end labelling (TUNEL). Animal and cellular experiments indicate that the Nrf2/HO-1 signalling pathway may be upregulated by salidroside, leading to the improvement of erectile function in diabetic male rats by alleviating oxidative stress and reducing apoptosis in corpus cavernosum tissue.


Assuntos
Apoptose , Disfunção Erétil , Glucosídeos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Fenóis , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Transdução de Sinais , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Disfunção Erétil/etiologia , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fenóis/farmacologia , Fenóis/uso terapêutico , Glucosídeos/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Pênis/efeitos dos fármacos , Pênis/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Sobrevivência Celular/efeitos dos fármacos
9.
Proc Natl Acad Sci U S A ; 121(29): e2405231121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38990952

RESUMO

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.


Assuntos
Sinalização do Cálcio , Reparo do DNA , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Mesotelioma , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Humanos , Reparo do DNA/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Mesotelioma/genética , Sinalização do Cálcio/genética , Feminino , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Apoptose/genética , Fibroblastos/metabolismo , Amianto/toxicidade , Instabilidade Genômica
10.
Cancer Med ; 13(13): e7424, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38988047

RESUMO

BACKGROUND: Gastric cancer (GC) is the fourth leading cause of cancer-related death worldwide. Minichromsome maintenance proteins family member 8 (MCM8) assists DNA repair and DNA replication. MCM8 exerts tumor promotor function in multiple digestive system tumors. MCM8 is also considered as a potential cancer therapeutic target. METHODS: Bioinformatics methods were used to analyze MCM8 expression and clinicopathological significance. MCM8 expression was detected by immunohistochemistry (IHC) staining and qRT-PCR. MCM8 functions in GC cell were explored by Celigo cell counting, colony formation, wound-healing, transwell, and annexin V-APC staining assays. The target of MCM8 was determined by human gene expression profile microarray. Human phospho-kinase array kit evaluated changes in key proteins after ribosomal protein S15A (RPS15A) knockdown. MCM8 functions were reassessed in xenograft mouse model. IHC detected related proteins expression in mouse tumor sections. RESULTS: MCM8 was significantly upregulated and predicted poor prognosis in GC. High expression of MCM8 was positively correlated with lymph node positive (p < 0.001), grade (p < 0.05), AJCC Stage (p < 0.001), pathologic T (p < 0.01), and pathologic N (p < 0.001). MCM8 knockdown inhibited proliferation, migration, and invasion while promoting apoptosis. RPS15A expression decreased significantly after MCM8 knockdown. It was also the only candidate target, which ranked among the top 10 downregulated differentially expressed genes (DEGs) in sh-MCM8 group. RPS15A was identified as the target of MCM8 in GC. MCM8/RPS15A promoted phosphorylation of P38α, LYN, and p70S6K. Moreover, MCM8 knockdown inhibited tumor growth, RPS15A expression, and phosphorylation of P38α, LYN, and p70S6K in vivo. CONCLUSIONS: MCM8 is an oncogene and predicts poor prognosis in GC. MCM8/RPS15A facilitates GC progression.


Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas Ribossômicas , Neoplasias Gástricas , Humanos , Proteínas Ribossômicas/metabolismo , Proteínas Ribossômicas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Animais , Camundongos , Prognóstico , Feminino , Masculino , Linhagem Celular Tumoral , Progressão da Doença , Pessoa de Meia-Idade , Proteínas de Manutenção de Minicromossomo/metabolismo , Proteínas de Manutenção de Minicromossomo/genética , Apoptose , Camundongos Nus , Movimento Celular , Ensaios Antitumorais Modelo de Xenoenxerto , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética
11.
Gen Physiol Biophys ; 43(4): 321-333, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38953574

RESUMO

Vitiligo is featured by manifestation of white maculae and primarily results from oxidative stress. Sphingosine kinase-1 (SPHK1) participates in oxidative stress. This paper was devised to explore the role of SPHK1 in vitiligo and to disclose the mechanism. PIG1 cell viability was appraised utilizing cell counting kit-8 assay while Western blot detected SPHK1 and four and a half LIM domains 2 (FHL2). The transduction efficacy of small interfering RNA (siRNA)-SPHK1, siRNA-FHL2 and pcDNA3.1 plasmid overexpressing FHL2 (Ov-FHL2) was checked using Western blot. Flow cytometry detected cell apoptotisis. Western blot detected mitochondrial cytochrome c (Mit-Cyt-c) and cytosolic cytochrome c (Cyto-Cyt-c). Dichloro-dihydro-fluorescein diacetate (DCFH-DA) detected reactive oxygen species (ROS) activity while oxidative stress markers were evaluated using corresponding assay kits. SPHK1 expression was discovered to be increased in hydrogen peroxide (H2O2)-challenged PIG1 cells and SPHK1 interference alleviated H2O2-challenged viability damage, apoptosis, oxidative stress and FHL2 expression in PIG1 cells. FHL2 depletion could suppress viability damage, apoptosis and oxidative stress in H2O2-challenged PIG1 cells. Rescue experiments demonstrated that the suppressive impacts of SPHK1 deficiency on PIG1 cell viability, apoptosis and oxidative stress induced by H2O2 were offset by FHL2 overexpression. Collectively, SPHK1 knockdown protected against vitiligo via the regulation of FHL2.


Assuntos
Sobrevivência Celular , Peróxido de Hidrogênio , Proteínas com Homeodomínio LIM , Melanócitos , Estresse Oxidativo , Fosfotransferases (Aceptor do Grupo Álcool) , Estresse Oxidativo/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Peróxido de Hidrogênio/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Proteínas com Homeodomínio LIM/genética , Humanos , Melanócitos/metabolismo , Melanócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Linhagem Celular
12.
FASEB J ; 38(13): e23737, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38953724

RESUMO

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.


Assuntos
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 2
13.
Eur J Med Chem ; 275: 116617, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38959729

RESUMO

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7-109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G2/M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development.


Assuntos
Antineoplásicos , Apoptose , Benzenossulfonamidas , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Indóis , Sulfonamidas , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Apoptose/efeitos dos fármacos , Estrutura Molecular , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Relação Dose-Resposta a Droga , Nitrogênio/química , Linhagem Celular Tumoral , Células HeLa , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/síntese química
14.
J Nanobiotechnology ; 22(1): 394, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965594

RESUMO

DNA nanostructures have long been developed for biomedical purposes, but their controlled delivery in vivo proposes a major challenge for disease theranostics. We previously reported that DNA nanostructures on the scales of tens and hundreds nanometers showed preferential renal excretion or kidney retention, allowing for sensitive evaluation and effective protection of kidney function, in response to events such as unilateral ureter obstruction or acute kidney injury. Encouraged by the positive results, we redirected our focus to the liver, specifically targeting organs noticeably lacking DNA materials, to explore the interaction between DNA nanostructures and the liver. Through PET imaging, we identified SDF and M13 as DNA nanostructures exhibiting significant accumulation in the liver among numerous candidates. Initially, we investigated and assessed their biodistribution, toxicity, and immunogenicity in healthy mice, establishing the structure-function relationship of DNA nanostructures in the normal murine. Subsequently, we employed a mouse model of liver ischemia-reperfusion injury (IRI) to validate the nano-bio interactions of SDF and M13 under more challenging pathological conditions. M13 not only exacerbated hepatic oxidative injury but also elevated local apoptosis levels. In contrast, SDF demonstrated remarkable ability to scavenge oxidative responses in the liver, thereby mitigating hepatocyte injury. These compelling results underscore the potential of SDF as a promising therapeutic agent for liver-related conditions. This aimed to elucidate their roles and mechanisms in liver injury, providing a new perspective for the biomedical applications of DNA nanostructures.


Assuntos
DNA , Fígado , Nanoestruturas , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/tratamento farmacológico , Camundongos , Fígado/metabolismo , DNA/química , Nanoestruturas/química , Masculino , Distribuição Tecidual , Camundongos Endogâmicos C57BL , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
15.
Mol Cancer ; 23(1): 144, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39004737

RESUMO

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) represents a prevalent malignant tumor, with approximately 40% of patients encountering treatment challenges or relapse attributed to rituximab resistance, primarily due to diminished or absent CD20 expression. Our prior research identified PDK4 as a key driver of rituximab resistance through its negative regulation of CD20 expression. Further investigation into PDK4's resistance mechanism and the development of advanced exosome nanoparticle complexes may unveil novel resistance targets and pave the way for innovative, effective treatment modalities for DLBCL. METHODS: We utilized a DLBCL-resistant cell line with high PDK4 expression (SU-DHL-2/R). We infected it with short hairpin RNA (shRNA) lentivirus for RNA sequencing, aiming to identify significantly downregulated mRNA in resistant cells. Techniques including immunofluorescence, immunohistochemistry, and Western blotting were employed to determine PDK4's localization and expression in resistant cells and its regulatory role in phosphorylation of Histone deacetylase 8 (HDAC8). Furthermore, we engineered advanced exosome nanoparticle complexes, aCD20@ExoCTX/siPDK4, through cellular, genetic, and chemical engineering methods. These nanoparticles underwent characterization via Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM), and their cellular uptake was assessed through flow cytometry. We evaluated the nanoparticles' effects on apoptosis in DLBCL-resistant cells and immune cells using CCK-8 assays and flow cytometry. Additionally, their capacity to counteract resistance and exert anti-tumor effects was tested in a resistant DLBCL mouse model. RESULTS: We found that PDK4 initiates HDAC8 activation by phosphorylating the Ser-39 site, suppressing CD20 protein expression through deacetylation. The aCD20@ExoCTX/siPDK4 nanoparticles served as effective intracellular delivery mechanisms for gene therapy and monoclonal antibodies, simultaneously inducing apoptosis in resistant DLBCL cells and triggering immunogenic cell death in tumor cells. This dual action effectively reversed the immunosuppressive tumor microenvironment, showcasing a synergistic therapeutic effect in a subcutaneous mouse tumor resistance model. CONCLUSIONS: This study demonstrates that PDK4 contributes to rituximab resistance in DLBCL by modulating CD20 expression via HDAC8 phosphorylation. The designed exosome nanoparticles effectively overcome this resistance by targeting the PDK4/HDAC8/CD20 pathway, representing a promising approach for drug delivery and treating patients with Rituximab-resistant DLBCL.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Exossomos , Linfoma Difuso de Grandes Células B , Nanopartículas , Rituximab , Humanos , Exossomos/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Rituximab/farmacologia , Rituximab/uso terapêutico , Animais , Camundongos , Nanopartículas/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
16.
Int J Nanomedicine ; 19: 6811-6828, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39005959

RESUMO

Purpose: Angiogenesis is a tightly controlled process that initiates the formation of new vessels and its dysfunction can lead to life-threatening diseases. Apoptotic extracellular vesicles (ApoEVs) have emerged as a proangiogenic agent with high safety and isolation efficiency profile, and ApoEVs from supernumerary tooth-derived pulp stem cells (SNTSC-ApoEVs) have their unique advantages with an easily accessible parental cell source and non-invasive cell harvesting. However, the detailed characteristics of SNTSC-ApoEVs are largely unknown. This study aimed to investigate the proangiogenic capacity and function molecule of SNTSC-ApoEVs. Methods: SNTSC-ApoEVs were isolated and characterized. In vitro effects of SNTSC-ApoEVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) were evaluated by CCK-8, wound healing, transwell, and tube formation assays. The mRNA and protein levels of proangiogenic genes were quantified by qRT-PCR, Western blot, and immunofluorescence analysis. A Matrigel plug model was established in 6-week-old male nu/nu mice for one week, and the in vivo impact of SNTSC-ApoEVs on micro-vessel formation was assessed by histological analysis. Proteomic analysis and RNA sequencing were performed to explore the active ingredients and underlying mechanisms. Results: SNTSC-ApoEVs enhanced the proliferation, migration, and angiogenesis of HUVECs in vitro. In the Matrigel plug model in vivo, SNTSC-ApoEVs promoted CD31-positive luminal structure formation. Apart from expressing general ApoEV markers, SNTSC-ApoEVs were enriched with multiple proteins related to extracellular matrix-cell interactions. Mechanistically, SNTSC-ApoEVs transferred COL1A1 to HUVECs and promoted endothelial functions by activating the PI3K/Akt/VEGF cascade. Conclusion: SNTSC-ApoEVs can promote angiogenesis by transferring the functional molecule COL1A1 and activating the PI3K/Akt/VEGF pathway, making SNTSC-ApoEVs a promising strategy for the treatment of angiogenesis-related diseases.


Assuntos
Apoptose , Colágeno Tipo I , Polpa Dentária , Vesículas Extracelulares , Células Endoteliais da Veia Umbilical Humana , Neovascularização Fisiológica , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Dente Supranumerário , Fator A de Crescimento do Endotélio Vascular , Vesículas Extracelulares/química , Humanos , Polpa Dentária/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Neovascularização Fisiológica/fisiologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos , Colágeno Tipo I/metabolismo , Proliferação de Células , Células-Tronco/citologia , Células-Tronco/metabolismo , Transdução de Sinais , Camundongos Nus , Movimento Celular , Angiogênese
17.
PeerJ ; 12: e17690, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006030

RESUMO

Background: Esophageal squamous cell carcinoma (ESCC) is a deadly type of esophageal cancer. Programmed cell death (PCD) is an important pathway of cellular self-extermination and is closely involved in cancer progression. A detailed study of its mechanism may contribute to ESCC treatment. Methods: We obtained expression profiling data of ESCC patients from public databases and genes related to 12 types of PCD from previous studies. Hub genes in ESCC were screened from PCD-related genes applying differential expression analysis, machine learning analysis, linear support vector machine (SVM), random forest and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. In addition, based on the HTFtarget and TargetScan databases, transcription factors (TFs) and miRNAs interacting with the hub genes were selected. The relationship between hub genes and immune cells were analyzed using the CIBERSORT algorithm. Finally, to verify the potential impact of the screened hub genes on ESCC occurrence and development, a series of in vitro cell experiments were conducted. Results: We screened 149 PCD-related DEGs, of which five DEGs (INHBA, LRRK2, HSP90AA1, HSPB8, and EIF2AK2) were identified as the hub genes of ESCC. The area under the curve (AUC) of receiver operating characteristic (ROC) curve of the integrated model developed using the hub genes reached 0.997, showing a noticeably high diagnostic accuracy. The number of TFs and miRNAs regulating hub genes was 105 and 22, respectively. INHBA, HSP90AA1 and EIF2AK2 were overexpressed in cancer tissues and cells of ESCC. Notably, INHBA knockdown suppressed ECSS cell migration and invasion and altered the expression of important apoptotic and survival proteins. Conclusion: This study identified significant molecules with promising accuracy for the diagnosis of ESCC, which may provide a new perspective and experimental basis for ESCC research.


Assuntos
Apoptose , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose/genética , Perfilação da Expressão Gênica , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Linhagem Celular Tumoral , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Movimento Celular/genética , Proliferação de Células/genética
18.
PeerJ ; 12: e17464, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006038

RESUMO

Objective: The mechanisms of intervertebral disc degeneration (IVDD) in low back pain (LBP) patients are multiples. In this study, we attempt to investigate whether melatonergic system plays a potential role in IVDD patients with LBP by analyzing their clinical specimens. The fucus will be given to the correlation between the melatonin receptor expression and intervertebral disc tissue apoptosis. Methods: In this clinical study, 107 lumbar intervertebral disc nucleus pulposus (NP) specimens from patients with LBP were collected with patients' consents. The disc height (DH) discrepancy ratio, range of motion and sagittal parameters of the pathological plane were measured and Pfirrmann grade was used to classified the grades of IVDD level. Discs at grades 1-3 were served as normal control and grades 4-5 were considered as IVDD. The expression levels of melatonin receptor 1A (MT1) and 1B (MT2) were measured by immunohistochemistry. The apoptosis of NP was assessed using TUNEL staining. Their potential associations among MT1/2, DH, apoptosis, sagittal parameters with IVDD and LBP were evaluated with statistical analysis. Results: The incidence of IVDD was positively associated with age and negatively related to VAS scores for LBP (p < 0.001). Patients with higher degree of IVDD also have higher DH discrepancy ratio (p < 0.001), higher prevalence of lumbar instability (p = 0.003) and higher cell apoptosis compared to the control. Nevertheless, no statistically significant correlation was identified between Pfirrmann grade and lumbar sagittal parameters. MT1 and MT2 both were highly expressed in the NP tissues. Importantly, MT1 expression but not MT2 was significantly increased in the intervertebral disc tissue of patients with IVDD and its level correlated well with cell apoptosis level and the severity of IVDD as well as lower VAS scores for LBP. Conclusion: The highly elevated MT1 expression was found in NP tissues of patients with IVDD and LBP compared to the control. This phenomenon probably reflects the compensating response of the body to the pathological alteration of the IVDD and LBP. Therefore, these findings provide the novel information to use selective agonists of MT1 to target IVDD and LBP clinically.


Assuntos
Apoptose , Degeneração do Disco Intervertebral , Dor Lombar , Humanos , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Dor Lombar/patologia , Dor Lombar/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Vértebras Lombares/patologia , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Idoso , Disco Intervertebral/patologia , Disco Intervertebral/metabolismo
19.
Int J Med Sci ; 21(9): 1718-1729, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006833

RESUMO

Isoproterenol (ISO) administration is a well-established model for inducing myocardial injury, replicating key features of human myocardial infarction (MI). The ensuing inflammatory response plays a pivotal role in the progression of adverse cardiac remodeling, characterized by myocardial dysfunction, fibrosis, and hypertrophy. The Mst1/Hippo signaling pathway, a critical regulator of cellular processes, has emerged as a potential therapeutic target in cardiovascular diseases. This study investigates the role of Mst1 in ISO-induced myocardial injury and explores its underlying mechanisms. Our findings demonstrate that Mst1 ablation in cardiomyocytes attenuates ISO-induced cardiac dysfunction, preserving cardiomyocyte viability and function. Mechanistically, Mst1 deletion inhibits cardiomyocyte apoptosis, oxidative stress, and calcium overload, key contributors to myocardial injury. Furthermore, Mst1 ablation mitigates endoplasmic reticulum (ER) stress and mitochondrial fission, both of which are implicated in ISO-mediated cardiac damage. Additionally, Mst1 plays a crucial role in modulating the inflammatory response following ISO treatment, as its deletion suppresses pro-inflammatory cytokine expression and neutrophil infiltration. To further investigate the molecular mechanisms underlying ISO-induced myocardial injury, we conducted a bioinformatics analysis using the GSE207581 dataset. GO and KEGG pathway enrichment analyses revealed significant enrichment of genes associated with DNA damage response, DNA repair, protein ubiquitination, chromatin organization, autophagy, cell cycle, mTOR signaling, FoxO signaling, ubiquitin-mediated proteolysis, and nucleocytoplasmic transport. These findings underscore the significance of Mst1 in ISO-induced myocardial injury and highlight its potential as a therapeutic target for mitigating adverse cardiac remodeling. Further investigation into the intricate mechanisms of Mst1 signaling may pave the way for novel therapeutic interventions for myocardial infarction and heart failure.


Assuntos
Via de Sinalização Hippo , Isoproterenol , Infarto do Miocárdio , Miócitos Cardíacos , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Animais , Isoproterenol/efeitos adversos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Camundongos , Humanos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Remodelação Ventricular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/genética , Inflamação/patologia , Modelos Animais de Doenças , Proteínas Proto-Oncogênicas , Fator de Crescimento de Hepatócito
20.
J Clin Invest ; 134(14)2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39007268

RESUMO

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.


Assuntos
Apoptose , Neoplasias , Transdução de Sinais , Proteína Supressora de Tumor p53 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , Apoptose/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética
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