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1.
Med Oncol ; 41(8): 191, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954116

RESUMO

Zinc-finger proteins are involved in many biological processes. However, the role of Zinc-finger protein 334 (ZNF334) in cervical cancer remains unidentified. This study showed that promoter methylation of ZNF334 was responsible for its reduced expression. ZNF334 suppressed malignant biological behaviors in cervical cancer. Notably, ZNF334 reversed the EMT process both in vitro and in vivo. RNA-seq coupled with bioinformatics analysis caught P3H3 which is upregulated by ZNF334. Dual-luciferase reporter and Chromatin immunoprecipitation assays illustrated that ZNF334 directly regulate P3H3. Knockdown of P3H3 attenuated the reversal of EMT induced by ZNF334. Additionally, ZNF334 overexpression sensitized cervical cancer cells to the cytotoxic effects of paclitaxel, cyclosporine and sunitinib. In conclusions, this study illustrated that DNA methylation-based silencing ZNF334 played a vital role in cervical cancer, by regulating P3H3 in turn affects EMT. ZNF334 has the potential to become a novel diagnostic biomarker and a potential treatment target for cervical cancer.


Assuntos
Metilação de DNA , Transição Epitelial-Mesenquimal , Neoplasias do Colo do Útero , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Humanos , Feminino , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Animais , Camundongos , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Camundongos Nus , Regiões Promotoras Genéticas/genética , Histonas/metabolismo , Histonas/genética , Camundongos Endogâmicos BALB C
2.
Am J Pathol ; 194(5): 796-809, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38395146

RESUMO

α-Synuclein (α-Syn) is a key determinator of Parkinson disease (PD) pathology, but synapse and microcircuit pathologies in the retina underlying visual dysfunction are poorly understood. Herein, histochemical and ultrastructural analyses and ophthalmologic measurements in old transgenic M83 PD model (mice aged 16 to 18 months) indicated that abnormal α-Syn aggregation in the outer plexiform layer (OPL) was associated with degeneration in the C-terminal binding protein 2 (CtBP2)+ ribbon synapses of photoreceptor terminals and protein kinase C alpha (PKCα)+ rod bipolar cell terminals, whereas α-Syn aggregates in the inner retina correlated with the reduction and degeneration of tyrosine hydroxylase- and parvalbumin-positive amacrine cells. Phosphorylated Ser129 α-synuclein expression was strikingly restricted in the OPL, with the most severe degenerations in the entire retina, including mitochondrial degeneration and loss of ribbon synapses in 16- to 18-month-old mice. These synapse- and microcircuit-specific deficits of the rod pathway at the CtBP2+ rod terminals and PKCα+ rod bipolar and amacrine cells were associated with attenuated a- and b-wave amplitudes and oscillatory potentials on the electroretinogram. They were also associated with the impairment of visual functions, including reduced contrast sensitivity and impairment of the middle range of spatial frequencies. Collectively, these findings demonstrate that α-Syn aggregates cause the synapse- and microcircuit-specific deficits of the rod pathway and the most severe damage to the OPL, providing the retinal synaptic and microcircuit basis for visual dysfunctions in PD.


Assuntos
Proteína Quinase C-alfa , alfa-Sinucleína , Animais , Camundongos , alfa-Sinucleína/metabolismo , Células Amácrinas/metabolismo , Proteína Quinase C-alfa/metabolismo , Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/ultraestrutura , Sinapses/metabolismo , Fatores de Transcrição/metabolismo
3.
Front Immunol ; 14: 1249731, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37928544

RESUMO

Introduction: OAS1(2'-5'-oligoadenylate synthetase 1) is a member of the Interferon-Stimulated Genes which plays an important role in the antiviral process. In recent years, the role of OAS1 in tumors has attracted attention, and it was found to be associated with prognosis in several tumors. However, the mechanism by which OAS1 affects tumors is unclear and pan-cancer study of OAS1 is necessary to better understand its implication in cancers. Methods: The expression, prognostic value, genetic alteration, alternative splicing events of OAS1 in pan-cancers were analyzed using TCGA, GTEx, HPA, GEPIA and OncoSplicing databases. OAS1 associated immune cell infiltration was evaluated using the ESTIMATE, xCell, CIBERSORT and QUANTISEQ algorithm. Single cell transcriptome data download using TISH database. Finally, the roles of the OAS1 on apoptosis, migration and invasion were investigated in two pancreatic cancer cells. Results: Our results revealed significant differences in OAS1 expression among various tumors, which had prognostic implications. In addition, we investigated the impact of OAS1 on genomic stability, methylation status, and other factors across different types of cancer, and the effects of these factors on prognosis. Notably, our study also demonstrated that OAS1 overexpression can contribute to CTL dysfunction and macrophage M2 polarization. In addition, cell experiments showed that the knockdown of OAS1 could reduce the invasive ability and increased the apoptosis rate of PAAD cells. Discussion: These results confirmed that OAS1 could be a prognostic biomarker and therapeutic target for its potential role in CTL dysfunction and macrophage M2 polarization.


Assuntos
Interferons , Neoplasias Pancreáticas , Humanos , Prognóstico , Multiômica , Biomarcadores , 2',5'-Oligoadenilato Sintetase/genética
4.
Biochem Biophys Res Commun ; 664: 108-116, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37141638

RESUMO

Pancreatic cancer is an extremely aggressive malignancy with a very disappointing prognosis. Neuroglobin (NGB), a member of the globin family, has been demonstrated to have a significant role in a variety of tumor forms. The possible role of NGB as a tumor suppressor gene in pancreatic cancer was investigated in this work. Information from the public dataset TCGA combined with GTEx was used to analyze the finding that NGB was commonly downregulated in pancreatic cancer cell lines and tissues, correlating with patient age and prognosis. The expression of NGB in pancreatic cancer was investigated via RT-PCR, qRT-PCR, and Western blot experiments. In-vitro and in-vivo assays, NGB elicited cell cycle arrest in the S phase and apoptosis, hindered migration and invasion, reversed the EMT process, and suppressed cell proliferation and development. The mechanism of action of NGB was predicted via bioinformatics analysis and validated using Western blot and co-IP experiments revealed that NGB inhibited the EGFR/AKT/ERK pathway by binding to and reducing expression of GNAI1 and p-EGFR. In addition, pancreatic cancer cells overexpressing NGB showed increased drug sensitivity to gefitinib (EGFR-TKI). In conclusion, NGB inhibits pancreatic cancer progression by specifically targeting the GNAI1/EGFR/AKT/ERK signaling axis.


Assuntos
Neuroglobina , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-akt , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroglobina/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
5.
J Comp Neurol ; 531(10): 1057-1079, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37002599

RESUMO

α-Synuclein (α-Syn) is enriched in presynaptic terminals of the central nervous system including the retina and plays a role in the synaptic vesicle cycle and synaptic transmission. Abnormal aggregation of α-Syn is considered to be the main component of the Lewy bodies that are the pathological hallmarks of Parkinson's disease. Although expression pattern of α-Syn has been described in the retinas, its precise cellular and subcellular locations are poorly understood. We investigated the precise expression of α-Syn using light microscopy (LM) and electron microscopy (EM) with antibodies against α-Syn in the mouse retina. We found that the majority of α-Syn immunoreactivity (IR) is located in GABAergic, glycinergic, and dopaminergic amacrine cells, and their processes often make a direct synapse to other labeled or unlabeled amacrine profiles, bipolar cell terminals, or ganglion cell dendrites. Further, our LM and immuno-EM results confirm the absence of α-Syn in excitatory photoreceptors, bipolar cell bodies, and their ribbon synapses, providing evidence, for the first time, that ribbon synapses do not express α-Syn. Additionally, α-Syn IR is located in the ganglion cells, some of which are intrinsically photosensitive retinal ganglion cells. These results reveal a previously unappreciated inhibitory synapse-specific expression pattern of α-Syn in the retina, suggesting that α-Syn may play a distinct role in the modulation and integration of inhibitory synaptic transmission in the retina.


Assuntos
Retina , alfa-Sinucleína , Animais , Camundongos , Retina/fisiologia , Células Ganglionares da Retina/metabolismo , Terminações Pré-Sinápticas/metabolismo , Sinapses/ultraestrutura
6.
Int J Med Sci ; 20(4): 542-550, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37057214

RESUMO

This study aimed to investigate the capsule-epithelium-fibre unit ultrastructure of the human lens, particularly the interfaces of the epithelium with the capsule and the epithelium with the fibre cell. A total of 12 lenses from donor humans who died of trauma without systemic and ocular diseases were investigated by transmission electron microscopy (TEM), combined with immunofluorescence staining for localising certain specific proteins. Some of the results were further studied in the anterior lens capsules of cataract patients. Our results revealed capsule protrusion into the epithelium in some areas and potential processing of capsule components. The young elongating fibre cells directly adjacent to the epithelium with a high stain density strongly expressed CD24. Numerous extracellular vesicles could be seen in the space between human lens epithelial cells (HLECs) and between HLECs and the capsule. Mitophagy and autophagy were also observed in the HLECs. Our research may be beneficial in better understanding the function of the human lens.


Assuntos
Catarata , Cristalino , Humanos , Cristalino/ultraestrutura , Epitélio/ultraestrutura , Células Epiteliais , Microscopia Eletrônica de Transmissão
7.
J Comp Neurol ; 531(11): 1184-1197, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37073449

RESUMO

The light pathways are segregated into rod and cone pathways in which rods synapse with rod bipolar cells (RBCs), while cones contact cone bipolar cells (CBCs). However, previous studies found that cones can make synapse with RBCs (cone-RBC synapses) and rods can contact OFF CBC in primate and rabbit retinas. Recently, such cone-RBC synapses have been reported physiologically and morphologically in the mouse retina. Nevertheless, the precise subcellular evidence to determine whether it is the invaginating synapse or the flat contact remains absent. This is due to a lack of immunochemically verified ultrastructural data. Here, we investigated the precise expression of protein kinase C alpha (PKCα) using pre-embedding immunoelectron microscopy (immuno-EM) with a monoclonal antibody against PKCα, a biomarker for the RBCs. We determined the nanoscale localization of PKCα in the outer plexiform layer of the mouse and guinea pig retinas. Our results demonstrate the existence of both the direct invaginating synapse and the basal/flat contact of the cone-RBCs, providing for the first time immunochemically verified ultrastructural evidence for the cone-RBC synapse in the mouse and guinea pig retinas. These results suggest that the cross talk between cone and rod pathways is much more extensive than previously assumed.


Assuntos
Proteína Quinase C-alfa , Células Fotorreceptoras Retinianas Cones , Cobaias , Camundongos , Animais , Coelhos , Células Fotorreceptoras Retinianas Cones/fisiologia , Retina/fisiologia , Células Bipolares da Retina , Sinapses/ultraestrutura , Células Fotorreceptoras
8.
BMC Psychol ; 10(1): 87, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379355

RESUMO

BACKGROUND: The sudden outbreak of COVID-19 had a great impact on the physical and mental health of people all over the world, especially for students whose physical and mental development was not yet mature. In order to understand the physical and mental conditions of students during the epidemic period and provide a theoretical basis for coping with psychological problems in public health emergencies, this study explored the mediating role of sleep disorders in the effect of the psychological stress response (PSR) on non-suicidal self-injury (NSSI), along with the moderating role of emotional management ability (EMA). METHODS: The SRQ-20, Pittsburgh Sleep Quality Index, NSSI Behavior Questionnaire, and Emotional Management Questionnaire were used to investigate the mental health of Chinese students in April 10-20 (Time point 1, T1) and May 20-30 (Time point 2, T2), 2020. A total of 1,955 students (Mage = 19.64 years, 51.4% male) were examined at T1 and 342 students (Mage = 20.06 years, 48.2% male) were reassessed at T2. RESULTS: Overall, the detection rate of PSR and NSSI were 17.60% (n = 344) and 24.90% (n = 486) respectively in the T1 sample, and were 16.37% (n = 56) and 25.44% (n = 87), in the T2 sample. We also found that sleep disorders played a mediating role in the effect of PSR on NSSI in the T1 and T2 samples. In addition, EMA was shown to regulate the effect of PSR on sleep disorders and the effect of sleep disorders on NSSI in the T1 samples. CONCLUSION: We found that PSR resulting from public health emergency might lead to NSSI behaviors in individuals. PSR may also cause sleep disorders, which can bring about NSSI. However, these effects were also moderated by the EMA. This research expands our understanding of PSR and NSSI in students during the pandemic.


Assuntos
COVID-19 , Comportamento Autodestrutivo , Transtornos do Sono-Vigília , COVID-19/epidemiologia , China/epidemiologia , Feminino , Humanos , Masculino , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/etiologia , Comportamento Autodestrutivo/psicologia , Transtornos do Sono-Vigília/epidemiologia , Estresse Psicológico/epidemiologia , Estudantes/psicologia
9.
Int J Clin Exp Pathol ; 8(10): 12357-67, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26722422

RESUMO

CXCL12 is positively associated with the metastasis and prognosis of various human malignancies. Cancer-associated fibroblasts (CAFs), the main cells secreting CXCL12, are capable of inducing epithelial to mesenchymal transition (EMT) of breast cancer cells. However, it has not been completely understood whether CXCL12 is involved in EMT of breast cancer cells and the underlying mechanisms. The present study aimed to investigate the effects of CXCL12 on the EMT and cancer stem cell (CSC)-like phenotypes formation by transfecting pEGFP-N1-CXCL12 plasmid into MCF-7 cells. Real time-PCR and Western blot analysis demonstrated the successful over expression of CXCL12 in MCF-7 cells. Cell counting kit-8 assay, wound healing assay and Transwell invasion analysis confirmed that over expression of CXCL12 significantly promoted the proliferation, migration and invasion in MCF-7 cells (P<0.05). In addition, ALDH activity was dramatically enhanced compared with parental (P<0.001), accompanied by the notably elevated mRNA and protein levels of OCT-4, Nanog, and SOX2 in CXCL12 overexpressed-MCF-7 cells (P<0.001). Furthermore, we observed the down regulation of E-cadherin and up regulation of vimentin, N-cadherin, and α-SMA in CXCL12 overexpressed-MCF-7 cells (P<0.01). Meanwhile, western blot and immunofluorescence assay showed that over expression of CXCL12 activated Wnt/ß-catenin pathway to induce EMT of MCF-7 cells, as evidenced by the increased expression of E-cadherin after silencing ß-catenin by siRNA interference (P<0.001). Collectively, our findings suggested that over expression of CXCL12 could trigger EMT by activating Wnt/ß-catenin pathway and induce CSC-like phenotypes formation to promote the proliferation and metastasis in MCF-7. Hence, CXCL12 may become a promising candidate for breast cancer therapy.


Assuntos
Neoplasias da Mama/patologia , Quimiocina CXCL12/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Células-Tronco Neoplásicas/metabolismo , Via de Sinalização Wnt/fisiologia , Western Blotting , Neoplasias da Mama/metabolismo , Feminino , Imunofluorescência , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
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