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1.
Bioact Mater ; 23: 206-222, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36439082

RESUMO

Recent evidence highlights multifaceted biological needs to recapitulate the bone microenvironment for bone regeneration. Neurotization has great potential for realizing multi-system modulations in bone tissue engineering (BTE). However, a neural strategy involving all the key bone repair steps temporally has not yet been reported. In this study, we reported the neural tissue engineering hydrogel-encapsulated Schwann cell-derived exosomes (SC Exo). This sustained-release SC Exo system prominently enhanced bone regeneration by promoting innervation, immunoregulation, vascularization, and osteogenesis in vivo. Moreover, the in vitro results further confirmed that this system significantly induced M2 polarization of macrophages, tube formation of HUVECs, and BMSCs osteogenic differentiation. Furthermore, BMSCs osteogenesis was promoted by upregulating the TGF-ß1/SMAD2/3 signaling pathway. In summary, a novel cell-free and easily prepared SC Exo neural engineering was successfully developed to promote bone regeneration by orchestrating the entire bone healing microenvironment, which may provide a new strategy for tissue engineering and clinical treatment of bone defects.

2.
Anal Chem ; 94(46): 16132-16141, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36346692

RESUMO

The construction of isothermal nucleic acid amplification systems with extremely high signal amplification abilities is of great importance for biomarker detection and disease diagnosis. Herein, for the first time, we proposed an intermolecular and intramolecular priming co-directed synergistic multi-strand displacement amplification (SM-SDA) system for microRNA (miRNA) detection. Strategically, the SM-SDA system is made of a single multi-functionalized hairpin probe (MF-HP) that is engineered with a long stem and endowed with target complementation, configuration transformation, enzyme recognition, and signal reporting abilities. The presence of a specific target, the model of miRNA-21, to react with MF-HP would cause an intermolecular priming-directed strand replication in parallel with an intramolecular priming-directed strand replication. The co-directed priming pattern results in the occurrence of SM-SDA containing a target-induced cyclical strand displacement amplification (T-CSDA), a target analogue primer (TAP)-induced CSDA (TAP-CSDA), and a nicked trigger primer (NTP)-induced CSDA (NTP-CSDA). The resulting multiple circuits with a synergetic signal amplification capacity remarkably enhance the target miRNA response, which has not only improved the sensitivity for qualitative and quantitative detection of miRNA but also realized the analysis of target miRNA from real clinical samples. As a proof-of-concept study, this simple but attractive isothermal signal amplification system holds a great potential for molecular diagnosis of diseases and will stimulate interest, new ideas, and discoveries in this fascinating field.


Assuntos
Técnicas Biossensoriais , MicroRNAs , MicroRNAs/análise , Técnicas de Amplificação de Ácido Nucleico/métodos
3.
Hepatol Res ; 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36317959

RESUMO

BACKGROUND: The clinical features have been well described in obese chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD). However, little is known about the clinical features of lean CHB-NAFLD patients. METHODS: The study retrospectively included treatment-naïve CHB patients who underwent ultrasound between 2015 and 2021. Liver fibrosis was assessed by aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrosis-4 score (FIB-4), NAFLD fibrosis score (NFS), and transient elastography. RESULTS: Among 1226 CHB-NAFLD patients, 25.0% patients were lean. The age, gender, and platelet, alanine aminotransferase, AST, and albumin levels were comparable between lean CHB-NAFLD and nonlean patients. The levels of plasma glucose, triglycerides, total cholesterol, and uric acid, as well as proportions of concurrent hypertension and diabetes, were lower in lean patients. Lean patients presented higher hepatitis B surface antigen (HBsAg) levels (3.4 log10 IU/ml vs. 3.2 log10 IU/ml, p = 0.006), hepatitis B virus (HBV) DNA levels (4.1 log10 IU/ml vs. 3.2 log10 IU/ml, p < 0.001), and hepatitis B e antigen (HBeAg) positive proportions (40.4% vs. 30.2%, p = 0.002) than nonlean patients. The values of APRI, FIB-4, and liver stiffness were comparable between two groups. However, lean patients had lower NFS values (-3.0 vs. -2.6, p < 0.001) and lower proportions (12.6% vs. 21.1%, p = 0.003) of advanced fibrosis (NFS ≥ -1.5) than nonlean patients. Similar results were observed in HBeAg-positive and HBeAg-negative subgroups. CONCLUSIONS: Nearly a quarter of CHB-NAFLD patients were lean. Lean patients had lower proportions of metabolic abnormalities and advanced liver fibrosis than nonlean patients. However, lean CHB-NAFLD patients had higher HBsAg levels, HBV DNA levels, and HBeAg-positive proportions. Registry and registration no. of the study/trial: Clinicaltrials.gov, Identifier: NCT03097952.

5.
Front Genet ; 13: 1065320, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36437918

RESUMO

Retinoids, natural and synthetic derivatives of vitamin A, have many regulatory functions in human body, including regulating cellular proliferation, differentiation, apoptosis. Moreover, retinoids have been used successfully for the treatment of certain malignancies, especially acute promyelocytic leukemia (APL) in adults and neuroblastoma in children. However, retinoids have not yet been translated into effective systemic treatments for most solid cancers. Some recent studies have shown that retinoids promote tumorigenesis. Therefore, we performed this meta-analysis to systematically evaluate the efficacy of retinoids in the chemoprevention and treatment of cancers. We performed literature search of several electronic databases, including PubMed, Embase and Cochrane Library from 2000 January to 2021 November. Various outcomes were applied to investigate the potential of retinoids for prevention and treatment of cancers. The primary outcomes in this study were disease recurrence and clinical response. The secondary outcomes included overall survival (OS), cancer development, disease progression and event-free survival. We identified 39 randomized controlled trials with 15,627 patients in this study. Our results showed that lower recurrence rate and better clinical response were obtained in retinoids treated patients with cancer or premalignancy as compared with control. The differences were statistically significant (RR = 0.85, 95% CI = 0.74-0.96, p = 0.01; RR = 1.24, 95% CI = 1.03-1.49, p = 0.02, respectively). Retinoids treatment was not associated with improvement in overall survival, cancer development, disease progression or event-free survival. Subgroup analysis conducted based on cancer type showed that patients benefited from retinoids treatment in APL, renal cell carcinoma, hepatocellular carcinoma, lung cancer, Kaposi sarcoma, and complete hydatidiform mole. No significant therapeutic effect was noted in head and neck cancer, acute myeloid leukemia (AML), melanoma, breast cancer, bladder cancer, cervical intraepithelial neoplasia (CIN) or cervical carcinoma. Subgroup analysis based on tumor classification demonstrated that retinoids group obtained a lower recurrence rate and better clinical response than control group in solid cancers. In conclusion, clinical application of retinoids was associated with reduction in disease recurrence and improvement in clinical response, illustrating that retinoids play a key role in cancer prevention and therapy. Further research is needed to broaden the utility of retinoids in other types of cancers. Systematic Review Registration: PROSPERO, identifier CRD42022296706.

6.
Artigo em Inglês | MEDLINE | ID: mdl-36324235

RESUMO

BACKGROUND: Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). AIMS: To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. METHODS: This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg-positive, normal ALT and HBV DNA ≤106  IU/ml (GZ-A); HBeAg-positive, elevated ALT and HBV DNA ≤2 × 104  IU/ml (GZ-B); HBeAg-negative, normal ALT and HBV DNA ≥2 × 103  IU/ml (GZ-C) and HBeAg-negative, elevated ALT and HBV DNA ≤2 × 103  IU/ml (GZ-D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. RESULTS: Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg-positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg-negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ-D (42.6%) was the dominant category, followed by GZ-C (38.8%), GZ-A (10.3%) and GZ-B (8.3%). The highest proportion of significant histological disease was observed patients in GZ-B (100.0%), followed by GZ-A (84.0%), GZ-D (69.9%) and GZ-C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg-negative GZ. CONCLUSIONS: Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg-positive and HBeAg-negative GZ CHB patients with high PT.

7.
Nutrients ; 14(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36296905

RESUMO

BACKGROUND: Mental illness places as a distant first in global burdens, exceeding both cardiovascular and circulatory diseases, in terms of the years lived with the disability. The emergence of the new and burgeoning area of "Nutrition Psychiatry" offers promise in improving mental health with diet. Mental health and well-being are critical to commuters but rarely recieve the attention they need. This study aimed to examine the bidirectional relationship between the frequency of eating out and depression, anxiety, and stress symptoms in a sample of Beijing commuters. METHODS: A total of 3337 commuters (mean (SD) age, 38.78 (10.41); 74.74% males) from the cohort study CHCN-BTH were included. The psychiatric symptoms were evaluated using a 21-item self-reported depression-anxiety-stress scale (DASS-21). A Cochran-Armitage trend chi-square test, restricted cubic spline, multiple logistic regression, multinomial logit models, and E-values were performed to estimate the associations between eating out and psychiatric symptoms in both directions. RESULTS: A daily rate of eating out more than 50% had a higher risk for depression (OR, 95% CI: 1.68, 1.184-2.393), anxiety (1.73, 1.259-2.369), and stress (1.99, 1.191-3.329) than the individuals eating at home. A higher frequency of eating out for lunch was significantly associated with an increased risk of depression (1.78, 1.28-2.46), anxiety (1.67, 1.26-2.23), and stress (2.05, 1.31-3.22). Similar results were found when eating out for dinner with increased risks for depression 2.20 (1.59, 3.06), anxiety 1.91 (1.42, 2.59), and stress 2.61 (1.68, 4.05). There is limited evidence supporting the effects of psychiatric symptoms on the frequency of eating out in the reverse analyses. CONCLUSIONS: The frequency of eating out is positively associated with an increased risk of psychiatric symptoms, especially when eating out for lunch and dinner. People eating at home have the lowest risk of suffering psychiatric symptoms, followed by those eating in the workplace canteen. Eating at home should be considered for future recommendations for the prevention of psychiatric symptoms.


Assuntos
Depressão , Transtornos Mentais , Masculino , Humanos , Adulto , Feminino , Depressão/etiologia , Pequim/epidemiologia , Estudos de Coortes , Ansiedade/psicologia
8.
Cancer Chemother Pharmacol ; 90(6): 499-510, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36283983

RESUMO

INTRODUCTION: Mefuparib (CVL218) is a novel second-generation poly-ADP-ribose polymerase (PARP) inhibitor for cancer treatment. CVL218 can easily enter the brain. However, the transport mechanism by which CVL218 crosses the blood-brain barrier (BBB) is unknown. METHODS: (1) [14C] CVL218 metabolism in rats was traced by a liquid scintillation counter and oxidative combustion. (2) Metabolic profiles and metabolites were identified by UHPLC-ß-RAM/UHPLC-Fraction Collector and UHPLC-Q Exactive Plus MS. (3) The partition coefficient Kp,uu,brain value was simulated by two strategies. One strategy was using ACD and GastroPlus Software based on the results of intravenous administration pharmacokinetics and plasma protein-binding studies. The reliability was confirmed by comparison with another strategy (brain/plasma distribution study). RESULTS: (1) Rapid drug elimination was observed 24 h after intragastric administration. The total cumulative excretion in urine and feces within 168 h accounted for 97.15% of the dose. The cumulative radioactive dose recovery in bile was 41.87% within 72 h. The drug-related substances were extensively distributed to the tissues within 48 h. (2) M8 was the major metabolite in plasma, urine, feces and bile. (3) CVL218 exhibited high brain protein-binding rate (88.16%). The Kp,uu,brain value (8.42) simulated by the simple software strategy was similar to that of the brain/plasma distribution study (7.01). CONCLUSIONS: CVL218 is a fast-metabolizing drug and is mainly excreted in feces. The B/P ratio prediction and observation data for CVL218 were consistent. Furthermore, the Kp,uu,brain value indicated that penetration through the BBB might be mediated by uptake transporters.


Assuntos
Bile , Animais , Ratos , Bile/metabolismo , Fezes/química , Taxa de Depuração Metabólica , Preparações Farmacêuticas/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Reprodutibilidade dos Testes , Distribuição Tecidual , Radioisótopos de Carbono
9.
Front Pharmacol ; 13: 1040504, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36313368

RESUMO

Background: Epimedii Folium, as a natural botanical medicine, has been reported to have protective effects on intestinal diseases by modulating multiple signaling pathways. This study aimed to explore the potential targets and molecular mechanisms of Epimedii Folium extract (EFE) against cisplatin-induced intestinal injury through network pharmacology, molecular docking, and animal experiments. Methods: Network pharmacology was used to predict potential candidate targets and related signaling pathways. Molecular docking was used to simulate the interactions between significant potential candidate targets and active components. For experimental validation, mice were intraperitoneally injected with cisplatin 20 mg/kg to establish an intestinal injury model. EFE (100, 200 mg/kg) was administered to mice by gavage for 10 days. The protective effect of EFE on intestinal injury was analyzed through biochemical index detection, histopathological staining, and western blotting. Results: Network pharmacology analysis revealed that PI3K-Akt and apoptosis signaling pathways were thought to play critical roles in EFE treatment of the intestinal injury. Molecular docking results showed that the active constituents of Epimedii Folium, including Icariin, Epimedin A, Epimedin B, and Epimedin C, stably docked with the core AKT1, p53, TNF-α, and NF-κB. In verified experiments, EFE could protect the antioxidant defense system by increasing the levels of glutathione peroxidase (GSH-Px) and catalase (CAT) while reducing the content of malondialdehyde (MDA). EFE could also inhibit the expression of NF-κB and the secretion of inflammatory factors, including TNF-α, IL-1ß, and IL-6, thereby relieving the inflammatory damage. Further mechanism studies confirmed that EFE had an excellent protective effect on cisplatin-induced intestinal injury by regulating PI3K-Akt, caspase, and NF-κB signaling pathways. Conclusion: In summary, EFE could mitigate cisplatin-induced intestinal damage by modulating oxidative stress, inflammation, and apoptosis.

10.
J Clin Ultrasound ; 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36063031

RESUMO

We describe a rare case of unruptured right SOVA in a 52-year-old man who was successfully treated with right SOVA repair and right coronary artery reconstruction. Our case demonstrates the usefulness of transthoracic echocardiography, contrastive echocardiography, and transesophageal echocardiography in diagnosing SOVA.

11.
Front Cell Infect Microbiol ; 12: 953027, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36061868

RESUMO

Quick differentiation of the circulating variants and the emerging recombinant variants of SARS-CoV-2 is essential to monitor their transmission. However, the widely used gene sequencing method is time-consuming and costly when facing the viral recombinant variants, because partial or whole genome sequencing is required. Allele-specific real time RT-PCR (qRT-PCR) represents a quick and cost-effective method in SNP genotyping and has been successfully applied for SARS-CoV-2 variant screening. In the present study, we developed a panel of 3 multiplex allele-specific qRT-PCR assays targeting 12 key differential mutations for quick differentiation of SARS-CoV-2 recombinant variants (XD and XE) and Omicron subvariants (BA.1 and BA.2). Two parallel multiplex qRT-PCR reactions were designed to separately target the protype allele and the mutated allele of the four mutations in each allele-specific qRT-PCR assay. The variation of Cp values (ΔCp) between the two multiplex qRT-PCR reactions was applied for mutation determination. The developed multiplex allele-specific qRT-PCR assays exhibited outstanding analytical sensitivities (with limits of detection [LoDs] of 2.97-27.43 copies per reaction), wide linear detection ranges (107-100 copies per reaction), good amplification efficiencies (82% to 95%), good reproducibility (Coefficient of Variations (CVs) < 5% in both intra-assay and inter-assay tests) and clinical performances (99.5%-100% consistency with Sanger sequencing). The developed multiplex allele-specific qRT-PCR assays in this study provide an alternative tool for quick differentiation of SARS-CoV-2 recombinant variants (XD and XE) and Omicron subvariants (BA.1 and BA.2).


Assuntos
COVID-19 , SARS-CoV-2 , Alelos , COVID-19/diagnóstico , Teste para COVID-19 , Humanos , RNA Viral/genética , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2/genética
12.
Mol Metab ; 65: 101600, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36113774

RESUMO

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is characterized by high recurrence and metastasis and places a heavy burden on societies worldwide. Cancer cells thrive in a changing microenvironment by reprogramming lipidomic metabolic processes to provide nutrients and energy, activate oncogenic signaling pathways, and manage redox homeostasis to avoid lipotoxicity. The mechanism by which OSCC cells maintain lipid homeostasis during malignant progression is unclear. METHODS: The altered expression of fatty acid (FA) metabolism genes in OSCC, compared with that in normal tissues, and in OSCC patients with or without recurrence or metastasis were determined using public data from the TCGA and GEO databases. Immunohistochemistry was performed to examine the carboxylesterase 2 (CES2) protein level in our own cohort. CCK-8 and Transwell assays and an in vivo xenograft model were used to evaluate the biological functions of CES2. Mass spectrometry and RNA sequencing were performed to determine the lipidome and transcriptome alterations induced by CES2. Mitochondrial mass, mtDNA content, mitochondrial membrane potential, ROS levels, and oxygen consumption and apoptosis rates were evaluated to determine the effects of CES2 on mitochondrial function in OSCC. RESULTS: CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis. CES2high OSCC patients showed better overall survival than CES2low OSCC patients. Restoring CES2 expression reduced OSCC cell viability and suppressed their migration and invasion in vitro, and it inhibited OSCC tumor growth in vivo. CES2 reprogrammed lipid metabolism in OSCC cells by hydrolyzing neutral lipid diacylglycerols (DGs) to release free fatty acids and reduce the membrane structure lipid phospholipids (PLs) synthesis. Free FAs were converted to acyl-carnitines (CARs) and transferred to mitochondria for oxidation, which induced reactive oxygen species (ROS) accumulation, mitochondrial damage, and apoptosis activation. Furthermore, the reduction in signaling lipids, e.g., DGs, PLs and substrates, suppressed PI3K/AKT/MYC signaling pathways. Restoring MYC rescued the diminished cell viability, suppressed migratory and invasive abilities, damaged mitochondria and reduced apoptosis rate induced by CES2. CONCLUSIONS: We demonstrated that CES2 downregulation plays an important role in OSCC by maintaining lipid homeostasis and reducing lipotoxicity during tumor progression and may provide a potential therapeutic target for OSCC.


Assuntos
Carboxilesterase/metabolismo , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Hidrolases de Éster Carboxílico/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , DNA Mitocondrial/metabolismo , DNA Mitocondrial/farmacologia , DNA Mitocondrial/uso terapêutico , Diglicerídeos/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Homeostase , Humanos , Mitocôndrias/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/farmacologia , Proteínas Proto-Oncogênicas c-myc/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sincalida/metabolismo , Sincalida/farmacologia , Sincalida/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
13.
J Clin Ultrasound ; 50(9): 1401-1402, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36069422

RESUMO

This article described a rare case of atypical aortic dissection in a 7-year-old boy with Loeys-Dietz syndrome, and emergency procedure was performed successfully. The imaging appearance of echocardiography and CT in atypical dissection was described.


Assuntos
Aneurisma Dissecante , Síndrome de Loeys-Dietz , Masculino , Humanos , Criança , Síndrome de Loeys-Dietz/complicações , Síndrome de Loeys-Dietz/diagnóstico por imagem , Aneurisma Dissecante/complicações , Aneurisma Dissecante/diagnóstico por imagem , Aneurisma Dissecante/cirurgia , Ecocardiografia
14.
Acta Biomater ; 153: 1-12, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36116724

RESUMO

Numerous tissue regeneration paradigms show evident neurological dependence, including mammalian fingertip, skin, and bone regeneration. The mature skeleton is innervated by an abundant nervous system that infiltrates the developing axial and appendicular bones and maintains the stability of the systemic skeletal system by controlling blood flow, regulating bone metabolism, secreting neurotransmitters, and regulating stem cell behavior. In recent years, neurotization in tissue-engineered bone has been considered as a promising strategy to effectively overcome the challenge of vascularization and innervation regeneration in the central zone of "critical-sized bone defects" that conventional tissue-engineered scaffolds are unable to handle, however, further validation is needed in relevant clinical applications. Therefore, this study reviews the mechanisms by which the nervous system regulates bone metabolism and regeneration through a variety of neurogenic or non-neurogenic factors, as well as the recent progress and design strategies of neuralized tissue-engineered bone, to provide new ideas for further studies on subsequent neural bone tissue engineering. STATEMENT OF SIGNIFICANCE: The interaction of nerve and bone tissue during skeletal development and repair has attracted widespread attention, with emerging evidences highlighting the regulation of bone metabolism and regeneration by the nervous system, but the underlying mechanisms have not been elucidated. Thus, further applications of neuro-bone tissue engineering still needs careful consideration. In this review, we summarize the numerous neurogenic and non-neurogenic factors which are involved in bone repair and regeneration, and further explore the current status of their application and biomaterial design in neuro-bone tissue engineering, and finally discuss the challenge and prospective for neuro-bone tissue engineering to facilitate its further development.


Assuntos
Osso e Ossos , Engenharia Tecidual , Animais , Estudos Prospectivos , Tecidos Suporte , Regeneração Óssea , Mamíferos
16.
ACS Nano ; 16(8): 11498-11503, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35943159

RESUMO

Due to their layered nature, two-dimensional nanomaterials can stack into artificial material systems, with van der Waals interaction between the adjacent constituent layers. In such heterostructures, the physical properties are largely affected by the interlayer coupling and can thus be effectively tuned by a number of means. In this Perspective, we highlight four such experimental approaches: stacking order, electric field, intercalation, and pressure, and we discuss challenges and opportunities in future studies for van der Waals heterostructures.

17.
J Dent Res ; 101(13): 1628-1636, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35918888

RESUMO

TLR9 is a critical nucleic acid sensing receptor in mediating periodontitis and periodontitis-associated comorbidities. Emerging evidence implicates TLR9 as a key sensor during aging, although its participation in periodontal aging is unexplored. Here, we investigated whether TLR9-mediated host responses can promote key hallmarks of aging, inflammaging, and senescence, in the course of periodontitis using a multipronged approach comprising clinical and preclinical studies. In a case-control model, we found increased TLR9 gene expression in gingival tissues of older (≥55 y) subjects with periodontitis compared to older healthy subjects as well as those who are younger (<55 y old) with and without the disease. Mechanistically, this finding was supported by an in vivo model in which wild-type (WT) and TLR9-/- mice were followed for 8 to 10 wk (young) and 18 to 22 mo (aged). In this longitudinal model, aged WT mice developed severe alveolar bone resorption when compared to their younger counterpart, whereas aged TLR9-/- animals presented insignificant bone loss when compared to the younger groups. In parallel, a boosted inflammaging milieu exhibiting higher expression of inflammatory/osteoclast mediators (Il-6, Rankl, Cxcl8) and danger signals (S100A8, S100A9) was noted in gingival tissues of aged WT mice compared to the those of aged TLR9-/- mice. Consistently, WT aged mice displayed an increase in prosenescence balance as measured by p16INK4a/p19ARF ratio compared to the younger groups and aged TLR9-/- animals. Ex vivo experiments with bone marrow-derived macrophages primed by TLR9 ligand (ODN 1668) further corroborated in vivo and clinical data and showed enhanced inflammatory-senescence circuit followed by increased osteoclast differentiation. Together, these findings reveal first systematic evidence implicating TLR9 as one of the drivers of periodontitis during aging and functioning by boosting a deleterious inflammaging/senescence environment. This finding calls for further investigations to determine whether targeting TLR9 will improve periodontal health in an aging population.


Assuntos
Perda do Osso Alveolar , Periodontite , Camundongos , Animais , Receptor Toll-Like 9/metabolismo , Perda do Osso Alveolar/metabolismo , Periodontite/metabolismo , Osteoclastos/metabolismo , Envelhecimento
19.
Mol Cancer Res ; 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36001806

RESUMO

Inhibitors targeting bromodomain and extra-terminal (BET) proteins are promising anticancer drugs. Emergence of drug resistance during treatments will impair their therapeutic effectiveness. To investigate the mechanisms of acquired resistance to BET inhibitor (BETi)s, we generated a series of drug resistant sublines by exposing non-small cell lung cancer (NSCLC) NCI-H1975 cells to the BETi ABBV-075. These sublines displayed cross-resistance to other tested BETis, increased migration abilities, reduced growth rates accompanied by an increased proportion of cells in G1 phase and decreased apoptotic responses to BETis. The changes in RNA expression and gene mutation profiles in the resistant variants indicate that emergence of BETi resistance is multifactorial. Importantly, all the tested ABBV-075-resistant variants showed loss of vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) and increase in the antiapoptotic BCL-2 protein. By knockdown, knockout and reconstitution of VOPP1 in resistant cells, their parental cells and other NSCLC cells, we confirmed that the loss of VOPP1 contributed to BETi resistance. Moreover, knockout of VOPP1 in the parental cells caused the increased expression of BCL-2, and the latter directly mediated BETi resistance. Through combined treatments with BETis and BCL-2 inhibitors (BCL-2is), we demonstrated that BCL-2is synergistically sensitized the resistant cells to BETis. Implications: Based on these results, for the first time, we establish a causal link from VOPP1 loss to BCL-2 gain and then to BETi resistance, which provides new insights into BETi resistance and paves the way for further testing to circumvent BETi resistance.

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