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1.
Bioact Mater ; 21: 69-85, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36017070

RESUMO

Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration (IDD). Current limitations of stem cells include with their insufficient cell source, poor proliferation capacity, low nucleus pulposus (NP)-specific differentiation potential, and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation. To address these challenges, embryo-derived long-term expandable nucleus pulposus progenitor cells (NPPCs) and esterase-responsive ibuprofen nano-micelles (PEG-PIB) were prepared for synergistic transplantation. In this study, we propose a biomaterial pre-modification cell strategy; the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis. The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro; their further synergistic transplantation yielded effective functional recovery, histological regeneration, and inhibition of pyroptosis during IDD regeneration. Herein, we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.

2.
J Colloid Interface Sci ; 629(Pt A): 399-408, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36088689

RESUMO

In vitro or in vivo fluorescence imaging based on quantum dots (QDs) has shown promise for the noninvasive diagnosis of atherosclerosis. However, simultaneous in vitro and in vivo imaging remains challenging due to the limitation of the current synthesis method of dual-emission QDs (dual-emitting hybrid QDs, and broad-spectrum emitting QDs). Herein, we fabricate a dual-emission (visible region and near-infrared region emission) QDs (ZAISe/ZnS) via the "bottom to up" method of a quaternary inorganic compound for the foam cells and atherosclerosis plaque imaging simultaneously without the intricate size modulation and the strict optical filter requirements. The oil-soluble ZAISe/ZnS is further encapsulated with bovine serum albumin (BSA) to realize phase transfer and ultimately possess the inflammation-targeting properties via biomimetic treatment with MMV (macrophage-derived micro-vesicle). The results first indicate that the as-constructed ZAISe/ZnS@BSA@MMV could accurately locate the foam cells and conduct long-term imaging of the atherosclerotic plaque, which provides a new strategy for the early and noninvasive diagnosis of atherosclerosis.


Assuntos
Aterosclerose , Placa Aterosclerótica , Pontos Quânticos , Humanos , Soroalbumina Bovina , Células Espumosas , Placa Aterosclerótica/diagnóstico por imagem , Compostos de Zinco , Sulfetos , Aterosclerose/diagnóstico por imagem
3.
Front Pharmacol ; 13: 807651, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370667

RESUMO

Overview: The treatment of chronic renal failure (CRF) with traditional Chinese medicine has attracted much attention, but its mechanism is not clear. Network pharmacology is an effective strategy for exploring the interaction mechanisms between Chinese herbs and diseases, however, it still needs to be validated in cell and/or animal experiments due to its virtual screening characteristics. Herein, the anti-CRF mechanism of the Fushengong decoction (FSGD) was investigated using a dual-dimension network pharmacological strategy combined with in vivo experiment. Methods: The traditional Chinese medicine systems pharmacology (TCMSP) database (https://tcmspw.com) and UHPLC-MS/MS technology were used to identify the effective compounds of FSGD in theory and practice, such as quercetin, formononetin, and pachymic acid. The putative targets of FSGD and CRF were obtained from the Swisstarget prediction platform and the Genecards database, respectively. The common target pathways between FSGD and CRF were got from the dual-dimension network pharmacology analysis, which integrated the cross-common targets from the TCMSP components-Swisstarget-Genecards-Venn platform analysis in theory, and the UHPLC-MS/MS identified effective ingredients-Swisstarget screening, such as TNF and PI3K/AKT. Furthermore, system molecular determinations were used to prove the dual-dimension network pharmacology study through CRF rat models, which were constructed using adenine and treated with FSGD for 4 weeks. Results: A total of 121 and 9 effective compounds were obtained from the TCMSP database and UHPLC-MS/MS, respectively. After dual-dimension network pharmacology analysis, the possible mechanism of PTEN/PI3K/AKT/NF-κB pathway was found for FSGD in CRF. In vivo experiments indicated that FSGD can play a role in protecting renal function and reducing fibrosis by regulating the PTEN/PI3K/AKT/NF-κB pathway. These findings provide a reference for FSGD in CRF. Conclusion: Based on the theoretical and practical dual-dimension network pharmacology analysis for FSGD in CRF, the possible molecular mechanism of PTEN/PI3K/AKT/NF-κB was successfully predicted, and these results were verified by in vivo experiments. In this study, the dual-dimension network pharmacology was used to interpret the key signal pathway for FSGD in CRF, which also proved to be a smart strategy for the study of effective substances and pharmacology in FSGD.

4.
J Adv Res ; 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36396044

RESUMO

INTRODUCTION: The R-loop is a naturally formed three-strand nucleic acid structure that recently has been reported to participate in multiple biological processes and helped answer some previously unexplained scientific questions. Meiosis process involves multiple chromatin-related events such as DNA double-stranded breaks (DSB) formation, repairing and transcriptional dynamics. OBJECTIVES: Explore the regulatory roles and physiological functions of R-loops in the mammalian meiosis process. METHODS: In our study, using genome-wide S9.6 CUT & Tag seq, we first mapped the genomic distribution and dynamic changes of R-loop during the meiotic process in mice, from spermatogonia to secondary spermatocytes. And we further explore the role of R-loop in physiological conditions by constructing conditional knockout mice of Rnaseh1, which deleted the R-loop endonuclease before meiosis entry. RESULTS: R-loop predominantly distributes at promoter-related regions and varies across different meiotic stages. By joint analysis with the corresponding transcriptome, we found that the R-loop was closely related to transcription during the meiotic process. The high frequency of promoter-related R-loop in meiotic cells is usually accompanied by high transcription activity, and we further verified this in the leptotene/zygotene to the pachytene transition process. Moreover, the lack of RNase H1 caused sterility in male mice with R-loop accumulation and abnormal DSB repair in spermatocytes. Further analysis showed that abnormal R-loop accumulation in the leptotene/zygotene stages influenced transcriptional regulation in the pachytene stage. CONCLUSION: The mutual regulation of the R-loop and transcription plays an essential role in spermatogenesis. And R-loop is also important for the normal repair process of DSB during meiosis.

5.
J Transl Med ; 20(1): 528, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371204

RESUMO

BACKGROUND: MICAL1 is involved in the malignant processes of several types of cancer; however, the role of MICAL1 in pancreatic cancer (PC) has not been well-characterized. This study aimed to investigate the expression and function of MICAL1 in PC. METHODS: RT-qPCR and immunohistochemistry were used to detect MICAL1 expression in PC and adjacent nontumor tissues. Cell Counting Kit-8, EdU, clone formation, wound healing, and Transwell assays as well as animal models were used to investigate the effects of overexpression or inhibition of MICAL1 expression on the proliferation, invasion, and metastasis of PC cells. RNA-seq was used to explore the main pathway underlying the functions of MICAL1. Proteomics, mass spectrometry, and co-immunoprecipitation assays were used to investigate the interaction of proteins with MICAL1. Rescue experiments were conducted to validate these findings. RESULTS: Both MICAL1 mRNA and protein levels were upregulated in PC tissues compared with matched adjacent nontumor tissues. The expression level of MICAL1 was associated with the proliferative and metastatic status of PC. Repression of MICAL1 significantly inhibited PC cell growth, migration, and invasion in vitro and in vivo. RNA sequencing analysis indicated that MICAL1 was closely correlated with the WNT pathway. Overexpression of MICAL1 (1) promoted the phosphorylation of TBC1D1 at the Ser660 site, (2) facilitated the distribution of FZD7 on the cytomembrane, (3) inhibited the degradation of FZD7 in the lysosome, and (4) activated the WNT pathway. CONCLUSIONS: MICAL1 was upregulated in PC and involved in stimulating the progression of PC cells by activating the WNT/ß-catenin signaling pathway. Therefore, MICAL1 is a potential therapeutic target for PC.


Assuntos
Neoplasias Pancreáticas , Via de Sinalização Wnt , Animais , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , Proliferação de Células/genética , Neoplasias Pancreáticas/patologia , Movimento Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
6.
Animals (Basel) ; 12(21)2022 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-36359174

RESUMO

Canine mammary tumors (CMTs) are one of the most common tumors in female dogs, and they are associated with a poor prognosis owing to their high rate of recurrence and metastasis rates, which make their diagnosis especially important in clinical veterinary medicine. In this study, the characteristics of tumors were observed in dogs suffering from CMTs, and clinical diagnosis and histopathology were used to identify tumors. Furthermore, the expression levels of tumor markers for CMTs were analyzed by enzyme-linked immunosorbent assay (ELISA) and quantitative PCR (qPCR). Upon clinical examination, dogs with CMTs displayed a distinct and irregular mass in the mammary gland, and X-ray (Latero-lateral and ventro-dorsal views) and ultrasonography of the abdomen revealed a moderately echogenic mass at the mammary gland with slightly stronger density than the surrounding tissue. A total of 30 tumors were identified by histopathology, 11 benign and 19 malignant. Changes in some indicators in dogs suffering from CMTs and healthy dogs suggested that there were multiple direct or paraneoplastic changes associated with tumors that could be detected/suspected by hematological examination, and ELISA revealed the HER-2 serum concentrations were significantly different between healthy animals and those with malignant tumors. qPCR indicated that tumor markers N-cadherin, Vimentin, HER-2, CEA, CA15-3 and SF were higher in dogs with malignant tumors than healthy dogs, with a low level of E-cadherin in malignant tumors. This study verified that serological tests and molecular biological tests were essential to the early diagnosis, treatment and prognosis of dogs with tumors.

7.
Cell Death Dis ; 13(11): 945, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351890

RESUMO

Pancreatic cancer (PC) is one of the most malignant types of cancer, and is characterized by early metastasis, limited response to chemotherapeutics, and poor prognosis. Therefore, there is an urgent need to explore new therapeutic strategies for PC treatment. Human rhomboid-like 2 (RHBDL2) is differentially expressed in cervical and breast cancer. However, the correlation between RHBDL2 and PC remains unclear. We found that RHBDL2 is highly expressed in human PC cells and tissues and is significantly associated with distant metastasis and poor survival of patients with PC. Gain- and loss-of-function assays indicated that RHBDL2 could accelerate PC cell proliferation and mobility in vitro and in vivo. The RNA-Seq results suggest that RHBDL2 may be involved in the activation of Notch signaling pathway. IMR-1 could restore the proliferation and metastatic capacity of PC cells mediated by RHBDL2. RHBDL2 interacted with and cleaved Notch1, resulting in the release of N1ICD. RHBDL2 decreased the ubiquitination level of N1ICD and collaborated with Ovarian tumor domain-containing 7B (OTUD7B) to stabilize N1ICD via the ubiquitin-proteasome pathway. RHBDL2 facilitated PC cell proliferation and mobility by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway. Thus, targeting this novel pathway may be a potential therapeutic strategy for PC.


Assuntos
Neoplasias Pancreáticas , Transdução de Sinais , Humanos , Proliferação de Células , Neoplasias Pancreáticas/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Endopeptidases/metabolismo , Serina Endopeptidases/metabolismo
8.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361830

RESUMO

C-C chemokine receptor type 5 (CCR5) positively contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a common metabolic liver disease associated with chronic inflammation. CCR5 signaling also facilitates the immunosuppressive activity of a group of immature myeloid cells known as granulocytic myeloid-derived suppressor cells (g-MDSCs). While both hepatocyte and g-MDSC express CCR5, how CCR5 coordinates these two distinct cell types in the hepatic microenvironment remains largely unknown. Here, we used in vivo and ex vivo approaches to define the molecular details of how CCR5 mediates the crosstalk between hepatocytes and g-MDSCs in a mouse model of NAFLD. Global CCR5-deficient mice exhibited more severe steatosis, increased hepatic gene expression of lipogenesis, and exacerbated liver damage in diet-induced obesity. Either NAFLD or CCR5-deficiency per se is causative for the increase of g-MDSCs. Purified g-MDSCs have a higher survival rate in the fatty liver microenvironment, and blockade of CCR5 significantly decreases g-MDSCs' expression of anti-inflammatory factors. On the other hand, the null of CCR5 signaling increases hepatocytes' expression of lipogenic genes in the NAFLD microenvironment. Most importantly, inhibiting g-MDSCs' CCR5 signaling in the fatty liver microenvironment dramatically reduces STAT3 signaling, lipogenic, and pro-inflammatory gene expression in primary hepatocytes. Adoptive cell transfer experiments further demonstrate that CCR5-deficient g-MDSCs mitigate hepatic lipogenic gene expression without facilitating pro-inflammatory cytokine production and liver damage in NAFLD mice. These results suggest that targeting g-MDSCs' CCR5 signaling might serve as a potential therapeutic strategy for NAFLD.


Assuntos
Células Supressoras Mieloides , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Células Supressoras Mieloides/metabolismo , Lipogênese/genética , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Inflamação/patologia , Hepatócitos/metabolismo
9.
Water Res ; 227: 119323, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36395565

RESUMO

Nowadays metal-free persulfate-based advanced oxidation processes (AOPs) have been intensively investigated, however, the catalysts are often too complex to fully consider their application potential. Conventional AOPs usually suffer from severe interference in real water matrix, thus, selective oxidation is practically and scientifically challenging as it could avoid unnecessary inputs of energy and possible secondary pollutants. In this study, a remarkably synergistic effect was achieved when conventional amorphous boron/peroxymonosulfate (Boron/PMS, 0.67 × 10-2 min-1) system was combined with electrolysis (E-Boron/PMS, 1.54 × 10-2 min-1) to degrade sulfamethoxazole (SMX). Evidenced by selectively quenching tests with kinetic evaluation, electron paramagnetic resonance (EPR), solvent-exchange experiment and electrochemical analysis, the dominated reactive oxygen species in E-Boron/PMS system tended to be 1O2, instead of the •OH and SO4•-. Mechanistic study unveiled that 1O2 was generated via accelerated PMS self-decomposition, triggered by interface alkalization and hydroxyl radicals transfer at the cathode interface. 1O2 is considered to be selective to the electron-rich organic compounds, thus E-Boron/PMS system was superior to conventional radical-dominated system (Boron/PMS) for SMX removal in the co-presence of common inorganic anions, showing the great merits of selective oxidation in nonradical system. These findings provided new insights into effective and selective oxidation of SMX via E-Boron/PMS system, which shed new light on the development of nonradical system.


Assuntos
Boro , Peróxidos , Peróxidos/química , Metais , Oxirredução , Sulfametoxazol
10.
Int J Mol Sci ; 23(22)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36430638

RESUMO

Canine pyometra frequently occurs in middle-aged to older intact bitches, which seriously affects the life of dogs and brings an economic loss to their owners. Hence, finding a key metabolite is very important for the diagnosis and development of a new safe and effective therapy for the disease. In this study, dogs with pyometra were identified by blood examinations, laboratory analyses and diagnostic imaging, and fifteen endometrium tissues of sick dogs with pyometra and fifteen controls were collected and their metabolites were identified utilizing a UHPLC-qTOF-MS-based untargeted metabolomics approach. The results indicated that the elevated inflammatory cells were observed in dogs with pyometra, suggesting that sick dogs suffered systemic inflammation. In the untargeted metabolic profile, 705 ion features in the positive polarity mode and 414 ion features in the negative polarity mode were obtained in endometrium tissues of sick dogs with pyometra, with a total of 275 differential metabolites (173 in positive and 102 in negative polarity modes). Moreover, the multivariate statistical analyses such as PCA and PLS-DA also showed that the metabolites were significantly different between the two groups. Then, these differential metabolites were subjected to pathway analysis using Metaboanalyst 4.0, and Galactose metabolism, cAMP signaling pathway and Glycerophospholipid metabolism were enriched, proving some insights into the metabolic changes during pyometra. Moreover, the receiver operating characteristic curves further confirmed kynurenic acid was expected to be a candidate biomarker of canine pyometra. In conclusion, this study provided a new idea for exploring early diagnosis methods and a safe and effective therapy for canine pyometra.

11.
Theriogenology ; 196: 97-105, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36413869

RESUMO

Pyometra is a common and high-incidence reproductive system disease in female dogs, and its development involves both hormonal and bacterial factors. Characterization of the endometrial microbiome in healthy dogs and diseased dogs with pyometra remains unclear at present, however. In this study, dogs with pyometra were identified based on the clinical examinations, hematology examinations, vaginal smears and uterine histopathology. The endometrial samples of healthy dogs (n = 30) and diseased dogs (n = 41) were then collected and sequenced by 16S rRNA high-throughput sequencing technology. Dogs with pyometra suffered from inflammation, and their endometrial microbial diversity (ACE and Chao 1 indices) was significantly lower than that of healthy dogs (P < 0.05). The endometrial samples of both groups were enriched in four phyla (Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria), with a greater abundance of Firmicutes in diseased dogs (P < 0.05). At the genus level, the most prevalent microbes in diseased dogs belonged to Pseudomonas, Escherichia-Shigella, Mycoplasma, Enterococcus, Haemophilus, Vibrio and Ralstonia, with lower levels of Mycoplasma, Enterococcus and Haemophilus in the healthy control. Principal co-ordinates analysis and non-metric multi-dimensional scaling showed that the endometrial microbiome of diseased dogs clustered separately from that of the healthy controls (P < 0.05). In the LDA effect size analysis, 18 members of the endometrial microbiome were screened. Of these, the bacterial species Pseudomonas_aeruginosa and microbes within the genera Mycoplasma, Enterococcus and Haemophilus were found to be enriched in the uteruses of diseased dogs. Furthermore, the Random Forests model further confirmed that Mycoplasma and Haemophilus could be considered as biomarkers of diseased endometrium. In conclusion, this study provided a theoretical basis for the development of probiotic preparation in the future.

12.
Vaccines (Basel) ; 10(11)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36366336

RESUMO

Liver transplant recipients on chronic immunosuppression show an attenuated antibody response after SARS-CoV-2 vaccination. Adjusting immunosuppressants during vaccination remains debated. We enrolled 380 liver transplant recipients receiving 2 doses of a protein subunit, mRNA, or a vector vaccine. The patients were informed to temporarily suspend immunosuppression for 2 weeks for both vaccination doses. We measured anti-live-SARS-CoV-2 spike neutralizing antibody levels at 1-2 months after the second vaccination; 83.9% of patients had humoral responses (SARS-CoV-2 NT50 ≥ 9.62 IU/mL) to 2 doses of vaccines. The mRNA (86.7%) and protein subunit vaccines (85%) yielded higher response rates than the vector vaccines (40.9%). Immunosuppression suspension during the two vaccinations yielded a higher response rate (91.5% vs. 57.7%). Only eight patients (2.1%) experienced transaminase level elevation of thrice the normal value (>110 IU/L) after the second vaccination. Most recovered spontaneously after resuming immunosuppression. Multivariate analysis revealed ABO incompatibility, white blood cell count <4000, lymphocyte count <20%, tacrolimus trough level >6.5 ng/mL, and no immunosuppression adjustment as independent risk factors to nonresponse. The mRNA and protein subunit vaccines yielded a higher response rate. Immunosuppression suspension for 2 weeks enhanced the antibody response. ABO incompatibility, leukopenia, lymphopenia, a high tacrolimus trough level, and no immunosuppression adjustment are associated with nonresponse.

13.
Front Public Health ; 10: 942113, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388373

RESUMO

Background: Data are limited on the impact of combined lifestyle behaviors on mortality in Jiangxi Province, China. Objective: The study examined the association between combined lifestyle behaviors and all-cause and cardiovascular disease (CVD) mortality in Jiangxi province. Methods: The baseline survey was completed in Jiangxi Province from November 2013 to August 2014. We conducted a follow-up on 12,608 participants of 35 years of age or older from July 2019 to October 2020. Four known lifestyle behaviors were evaluated: alcohol consumption, smoking, diet (AHEI scores), and physical activity. Cox regression analysis was performed to determine the association of combined lifestyle behaviors with all-cause and CVD mortality. Results: During 65,083 person-years of follow-up, among the 11,622 participants (mean age 59.1 years; 40.1% men) 794 deaths occurred, including 375 deaths from CVD disease in this study. Compared to the favorable lifestyle group, the adjusted HR of all-cause mortality was 1.25 (95% CI, 1.03-1.53) for the intermediate lifestyle group and 1.37 (95% CI, 1.11-1.71) for the unfavorable lifestyle group. Compared to the favorable lifestyle group, the adjusted HR of CVD mortality was 1.50 (95% CI, 1.11-2.03) for the intermediate lifestyle group and 1.58 (95% CI, 1.14-2.20) for the unfavorable lifestyle group. Significant interactions of lifestyle and BMI (P for interaction <0.05) with the risk of all-cause mortality and CVD mortality were observed. Conclusion: In the current study, we reaffirm the associations of combined lifestyle factors with total and CVD mortality in Jiangxi Province, our data suggest that an unfavorable lifestyle was associated with a substantially increased risk of all-cause and CVD mortality.


Assuntos
Doenças Cardiovasculares , Estilo de Vida , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Estudos de Coortes , Doenças Cardiovasculares/etiologia , Fumar , China/epidemiologia
14.
Nat Commun ; 13(1): 6528, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36319632

RESUMO

Considering that intravascular reactive oxygen species (ROS) and inflammation are two characteristic features of the atherosclerotic microenvironment, developing an appropriate strategy to treat atherosclerosis by synergistically regulating ROS and inflammation has attracted widespread attention. Herein, a special molecule, zoledronic acid, containing imidazole and bisphosphonate groups, was selected for the first time to assist the assembly of cerium ions and produce functionalized ceria-zoledronic acid nanocomposites (CZ NCs). It not only serves as a new carrier for different kinds of drugs (e.g. probucol, PB) but also exerts an efficient multienzyme activity to achieve collaborative therapy. More importantly, platelet membrane-coated biomimetic nanoplatform (PCZ@PB NCs) specifically accumulate at inflammatory atherosclerotic lesions, synergistically regulate ROS levels and inflammation, and efficiently inhibit foam cell formation. This novel assembly method can also be applied in the treatment of many other diseases associated with oxidative stress and inflammation.


Assuntos
Aterosclerose , Nanopartículas , Humanos , Espécies Reativas de Oxigênio , Nanopartículas/uso terapêutico , Ácido Zoledrônico/uso terapêutico , Aterosclerose/patologia , Inflamação/tratamento farmacológico
15.
Cancers (Basel) ; 14(22)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36428612

RESUMO

The purpose of this research was to evaluate the impact and the underlying molecular mechanism of CLEFMA-induced cell death in human OSCC. The anti-tumour properties of CLEFMA in oral cancer were explored using colony formation, flow cytometry, human apoptosis array, Western blot, and immunohistochemistry assays. The in vivo anti-tumour effect of CLEFMA administered by oral gavage was evaluated using SCC-9-derived xenograft-bearing nude mouse models. CLEFMA significantly suppressed colony formation and elicited cellular apoptosis in oral cancer cells. CLEFMA treatment remarkably increased phosphorylated p38 and HO-1 along with cleavage of poly ADP-ribose polymerase and activation of caspase-8, -9, and -3 in HSC-3 and SCC-9 cells. Administration of HO-1 small interfering RNA significantly protected the cells from CLEFMA-induced caspase-3, -8, and -9 activation. Attenuation of p38 activity by the pharmacologic inhibitor SB203580 dramatically reduced CLEFMA-induced caspase-3, -8, and -9 activation and HO-1 expression in OSCC. The subcutaneous murine xenograft models showed that CLEFMA in vivo suppressed tumour growth in implanted SCC-9 cells. All of these findings indicated that CLEFMA induced apoptosis through the p38-dependent rise in HO-1 signal transduction cascades in OSCC.

16.
Environ Toxicol ; 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36413001

RESUMO

Bisphenol A-glycidyl methacrylate (BisGMA) is a methacrylate monomer that is mainly used in three-dimensional structures to reconstruct dental and bony defects. BisGMA has toxic and proinflammatory effects on macrophages. Rutin is a natural flavonol glycoside that is present in various plants and has useful biological effects, such as anti-inflammatory, anticancer, and antioxidative effects. The aim of this study was to investigate the anti-inflammation of rutin in macrophages after exposure to BisGMA. Pretreatment of the RAW264.7 macrophage with rutin at 0, 10, 30, and 100 µM for 30 min before being incubated with BisGMA at 0 or 3 µM. Proinflammatory cytokines and prostaglandin (PG) E2 were detected by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) was detected by the Griess assay. Expression and phosphorylation of proteins were measured by Western blot assay. Pretreatment with rutin inhibited the BisGMA-induced generation of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and PGE2, in macrophages. Rutin also suppressed the BisGMA-induced secretion of NO and expression of inducible nitric oxide synthase (iNOS) in a concentration-dependent manner. Furthermore, rutin suppressed the mitogen-activated protein kinase (MAPK) phosphorylation in a concentration-dependent manner. Finally, rutin suppressed the BisGMA-induced phosphorylation of nuclear factor (NF)-κB p65 and degradation of inhibitor of κB (IκB). These results indicate that the concentration of rutin has an inhibitory effect on proinflammatory mediator generation, MAPK phosphorylation, NF-κB p65 phosphorylation, and IκB degradation. In conclusion, rutin is a potential anti-inflammatory agent for BisGMA-stimulated macrophages through NF-κB p65 phosphorylation and IκB degradation resulting from MAPK phosphorylation.

17.
Asian J Androl ; 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36348577

RESUMO

To report the regional locations of metastases and to estimate the prognostic value of the pattern of regional metastases in men with metastatic hormone-sensitive prostate cancer (mHSPC), we retrospectively analyzed 870 mHSPC patients between November 28, 2009, and February 4, 2021, from West China Hospital in Chengdu, China. The patients were initially classified into 5 subgroups according to metastatic patterns as follows: simple bone metastases (G1), concomitant bone and regional lymph node (LN) metastases (G2), concomitant bone and nonregional LN (NRLN) metastases (G3), lung metastases (G4), and liver metastases (G5). In addition, patients in the G3 group were subclassified as G3a and G3b based on the LN metastatic plane (below or above the diaphragm, respectively). The associations of different metastatic patterns with castration-resistant prostate cancer-free survival (CFS) and overall survival (OS) were analyzed by univariate and multivariate analyses. The results showed that patients in G1 and G2 had relatively favorable clinical outcomes, patients in G3a and G4 had intermediate prognoses, and patients in G3b and G5 had the worst survival outcomes. We observed that patients in G3b had outcomes comparable to those in G5 but had a significantly worse prognosis than patients in G3a (median CFS: 8.2 months vs 14.3 months, P = 0.015; median OS: 38.1 months vs 45.8 months, P = 0.038). In conclusion, metastatic site can predict the prognosis of patients with mHSPC, and the presence of concomitant bone and NRLN metastases is a valuable prognostic factor. Furthermore, our findings indicate that the farther the NRLNs are located, the more aggressive the disease is.

18.
Mol Neurobiol ; 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36318443

RESUMO

Synapses are bridges for information transmission in the central nervous system (CNS), and synaptic plasticity is fundamental for the normal function of synapses, contributing substantially to learning and memory. Numerous studies have proven that microglia can participate in the occurrence and progression of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), by regulating synaptic plasticity. In this review, we summarize the main characteristics of synapses and synaptic plasticity under physiological and pathological conditions. We elaborate the origin and development of microglia and the two well-known microglial signaling pathways that regulate synaptic plasticity. We also highlight the unique role of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia-mediated regulation of synaptic plasticity and its relationship with AD. Finally, we propose four possible ways in which TREM2 is involved in regulating synaptic plasticity. This review will help researchers understand how NDDs develop from the perspective of synaptic plasticity.

19.
Artigo em Inglês | MEDLINE | ID: mdl-36374273

RESUMO

Electronically matched nucleophilic 1,6-conjugate addition has been well studied and widely applied in synthetic areas. In contrast, nucleophilic 1,5-conjugate addition represents an electronically forbidden process and is considered unfeasible. Here, we describe modular protocols for 1,5-conjugate addition reactions via palladium hydride catalysis. Both palladium and synergistic Pd/organocatalyst systems are developed to catalyze 1,5-conjugate reaction, followed by inter- or intramolecular [3+2] cyclization. A migratory 1,5-addition protocol is established to corroborate the feasibility of this umpolung concept. The 1,5-addition products are conveniently transformed into a series of privileged enantioenriched motifs, including polysubstituted tetrahydrofuran, dihydrofuran, cyclopropane, cyclobutane, azetidine, oxetane, thietane, spirocycle and bridged rings. Preliminary mechanistic studies corroborate the involvement of palladium hydride catalysis.

20.
J Pathol ; 258(4): 339-352, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36181299

RESUMO

Hepatocellular carcinoma (HCC) is among the most prevalent visceral neoplasms. So far, reliable biomarkers for predicting HCC recurrence in patients undergoing surgery are far from adequate. In the aim of searching for genetic biomarkers involved in HCC development, we performed analyses of cDNA microarrays and found that the DNA repair gene NEIL3 was remarkably overexpressed in tumors. NEIL3 belongs to the Fpg/Nei protein superfamily, which contains DNA glycosylase activity required for the base excision repair for DNA lesions. Notably, the other Fpg/Nei family proteins NEIL1 and NEIL2, which have the same glycosylase activity as NEIL3, were not elevated in HCC; NEIL3 was specifically induced to participate in HCC development independently of its glycosylase activity. Using RNA-seq and invasion/migration assays, we found that NEIL3 elevated the expression of epithelial-mesenchymal transition (EMT) factors, including the E/N-cadherin switch and the transcription of MMP genes, and promoted the invasion, migration, and stemness phenotypes of HCC cells. Moreover, NEIL3 directly interacted with the key EMT player TWIST1 to enhance invasion and migration activities. In mouse orthotopic HCC studies, NEIL3 overexpression also caused a prominent E-cadherin decrease, tumor volume increase, and lung metastasis, indicating that NEIL3 led to EMT and tumor metastasis in mice. We further found that NEIL3 induced the transcription of MDR1 (ABCB1) and BRAF genes through the canonical E-box (CANNTG) promoter region, which the TWIST1 transcription factor recognizes and binds to, leading to the BRAF/MEK/ERK pathway-mediated cell proliferation as well as anti-cancer drug resistance, respectively. In the HCC cohort, the tumor NEIL3 level demonstrated a high positive correlation with disease-free and overall survival after surgery. In conclusion, NEIL3 activated the BRAF/MEK/ERK/TWIST pathway-mediated EMT and therapeutic resistances, leading to HCC progression. Targeted inhibition of NEIL3 in HCC individuals with NEIL3 induction is a promising therapeutic approach. © 2022 The Pathological Society of Great Britain and Ireland.


Assuntos
Carcinoma Hepatocelular , DNA Glicosilases , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , DNA Glicosilases/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Transcrição Twist/metabolismo
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