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1.
Drug Des Devel Ther ; 16: 3-12, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35018094

RESUMO

Purpose: Abiraterone acetate tablets (I)(N-AbA) is a novel tablet co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). This study aimed to compare the pharmacokinetics, bioequivalence, safety, and food effects of N-AbA with the reference ZYTIGA® (R-AbA) in healthy Chinese male subjects. Patients and Methods: This study was conducted in three parts. Part I was an open, dose-escalation trial conducted in 16 Chinese healthy males; Part II was a randomized, open-label, 2 × 4 crossover, single-dose bioequivalence trial conducted in 36 subjects; Part III was a randomized, 3 × 3 crossover trial conducted on 24 volunteers to investigate the effect of food on the pharmacokinetics of N-AbA. Results: The exposure (AUC0-∞) and maximum concentration (Cmax) of abiraterone and excipient SNAC were linear in the range of 75-450 mg dose. The bioavailability of N-AbA 300 mg was equivalent to that of R-AbA 1000 mg. The drug exposure of prednisone and prednisolone was not affected by SNAC co-administration. The Cmax of orally administered abiraterone as R-AbA in a modified fed state was 5.9 times and AUC0-∞ was 4.3 times, respectively, higher than those in of orally administered abiraterone as N-AbA in a high-fat diet. The Cmax and AUC0-∞ of orally administered abiraterone as N-AbA on a high-fat diet were 2.2 times and 2 times, respectively, higher than those on a fasting state. All adverse events reported in the three parts of the study were grade 1 or 2, and no serious adverse events were reported. Conclusion: These three Phase I trials showed that N-AbA and excipient SNAC had excellent linear pharmacokinetic characteristics. A single dose of N-AbA 300 mg was bioequivalent to R-AbA 1000 mg in healthy subjects under fasting conditions. Meanwhile, SNAC had no effect on the pharmacokinetics of prednisone and prednisolone. The effect of food on N-AbA was significantly lower than that on R-AbA.

2.
Cell Commun Signal ; 20(1): 7, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022057

RESUMO

BACKGROUND: Glioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Extensive changes in the tumor microenvironment is a key reason for resistance to chemo- or radio-therapy and frequent tumor recurrences. Understanding the tumor-nontumor cell interaction in TME is critical for developing new therapy. Glioblastomas are known to recruit normal cells in their environs to sustain growth and encroachment into other regions. Neural progenitor cells (NPCs) have been noted to migrate towards the site of glioblastomas, however, the detailed mechanisms underlying glioblastoma-mediated NPCs' alteration remain unkown. METHODS: We collected EVs in the culture medium of three classic glioblastoma cell lines, U87 and A172 (male cell lines), and LN229 (female cell line). U87, A172, and LN229 were co-cultured with their corresponding EVs, respectively. Mouse NPCs (mNPCs) were co-cultured with glioblastoma-derived EVs. The proliferation and migration of tumor cells and mNPCs after EVs treatment were examined. Proteomic analysis and western blotting were utilized to identify the underlying mechanisms of glioblastoma-derived EVs-induced alterations in mNPCs. RESULTS: We first show that glioblastoma cell lines U87-, A172-, and LN229-derived EVs were essential for glioblastoma cell prolifeartion and migration. We then demonstrated that glioblastoma-derived EVs dramatically promoted NPC proliferation and migration. Mechanistic studies identify that glioblastoma-derived EVs achieve their functions via activating PI3K-Akt-mTOR pathway in mNPCs. Inhibiting PI3K-Akt pathway reversed the elevated prolfieration and migration of glioblastoma-derived EVs-treated mNPCs. CONCLUSION: Our findings demonstrate that EVs play a key role in intercellular communication in tumor microenvironment. Inhibition of the tumorgenic EVs-mediated PI3K-Akt-mTOR pathway activation might be a novel strategy to shed light on glioblastoma therapy. Video Abstract.

3.
Hereditas ; 159(1): 3, 2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-34998434

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are involved in the prognosis of nasopharyngeal carcinoma (NPC). This study used clinical data and expression data of miRNAs to develop a prognostic survival signature for NPC patients to detect high-risk subject. RESULTS: We identified 160 differentially expressed miRNAs using RNA-Seq data from the GEO database. Cox regression model consisting of hsa-miR-26a, hsa-let-7e, hsa-miR-647, hsa-miR-30e, and hsa-miR-93 was constructed by the least absolute contraction and selection operator (LASSO) in the training set. All the patients were classified into high-risk or low-risk groups by the optimal cutoff value of the 5-miRNA signature risk score, and the two risk groups demonstrated significant different survival. The 5-miRNA signature showed high predictive and prognostic accuracies. The results were further confirmed in validation and external validation set. Results from multivariate Cox regression analysis validated 5-miRNA signature as an independent prognostic factor. A total of 13 target genes were predicted to be the target genes of miRNA target genes. Both PPI analysis and KEGG analysis networks were closely related to tumor signaling pathways. The prognostic model of mRNAs constructed using data from the dataset GSE102349 had higher AUCs of the target genes and higher immune infiltration scores of the low-risk groups. The mRNA prognostic model also performed well on the independent immunotherapy dataset Imvigor210. CONCLUSIONS: This study constructed a novel 5-miRNA signature for prognostic prediction of the survival of NPC patients and may be useful for individualized treatment of NPC patients.


Assuntos
MicroRNAs , Neoplasias Nasofaríngeas , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Prognóstico
4.
Toxicol Appl Pharmacol ; 435: 115848, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34958783

RESUMO

Organic anion transporting polypeptide 1B1 (OATP1B1), which is specifically expressed at the basolateral membrane of human hepatocytes, is well recognized as the key determinant in the pharmacokinetics of a wide variety of drugs and considered as an important drug-drug interaction (DDI) site. Triptergium wilfordii Hook. f. (TWHF) is a traditional Chinese medicine that has a long history in treating diseases and more pharmacological effects were demonstrated recently. Components of TWHF mainly belong to the groups of alkaloids, diterpenoids, and triterpenoids. However, whether TWHF constituents are involved in herb-drug interaction (HDI) remains largely unknown. In the present study, we investigated the effect of four major components of TWHF, i.e. Triptolide (TPL), Celastrol (CL), and two alkaloids Wilforine (WFR) and Wilforgine (WFG) on the function of OATP1B1. It was found that co-incubation of these compounds greatly inhibited the uptake function of OATP1B1, with WFG (IC50 = 3.63 ± 0.61 µM) and WFR (IC50 = 3.91 ± 0.30 µM) showing higher inhibitory potency than TPL (IC50 = 184 ± 36 µM) and CL (IC50 = 448 ± 81 µM). Kinetic analysis revealed that co-incubation of WFG or WFR led to the reduction of both Km and Vmax of the DCF uptake. On the other hand, pre-incubation of WFG or WFR increased Km value of OATP1B1; while CL affected both Km and Vmax. In conclusion, co- and pre-incubation of the tested TWHF components inhibited OATP1B1 activity in different manners. Although co-incubation of WFG and WFR did not seem to directly compete with the substrates, pre-incubation of these alkaloids may alter the substrate-transporter interaction.

5.
Med Res Rev ; 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34877672

RESUMO

Andrographolide, a well-known natural lactone having a range of pharmacological actions in traditional Chinese medicine. It has long been used to cure a variety of ailments. In this review, we cover the pharmacokinetics and pharmacological activity of andrographolide which supports its further clinical application in cancers and inflammatory diseases. Growing evidence shows a good therapeutic effect in inflammatory diseases, including liver diseases, joint diseases, respiratory system diseases, nervous system diseases, heart diseases, inflammatory bowel diseases, and inflammatory skin diseases. As a result, the effects of andrographolide on immune cells and the processes that underpin them are discussed. The preclinical use of andrographolide to different organs in response to malignancies such as colorectal, liver, gastric, breast, prostate, lung, and oral cancers has also been reviewed. In addition, several clinical trials of andrographolide in inflammatory diseases and cancers have been summarized. This review highlights recent advances in ameliorating inflammatory diseases as well as cancers by andrographolide and its analogs, providing a new perspective for subsequent research of this traditional natural product.

6.
Front Cell Dev Biol ; 9: 771336, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34881243

RESUMO

The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation; however, the inhibitory effect of the Wnt pathway in osteoclastogenesis is largely unknown. Here, we demonstrate that Wnt7b, a potent Wnt ligand that enhances bone formation and increases bone mass, also abolishes osteoclastogenesis in vitro. Importantly, enforced expression of Wnt in bone marrow macrophage lineage cells significantly disrupts osteoclast formation and activity, which leads to a dramatic increase in bone mass. Mechanistically, Wnt7b impacts the glucose metabolic process and AKT activation during osteoclastogenesis. Thus, we demonstrate that Wnt7b diminishes osteoclast formation, which will be beneficial for osteoporosis therapy in the future.

7.
Int J Ophthalmol ; 14(12): 1903-1908, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34926206

RESUMO

AIM: To investigate the safety and efficacy of sticky silicone oil (SSO) removal using a 22-gauge vein detained needle and inner limiting membrane (ILM) wrap-and-peel technique. METHODS: This retrospective consecutive case series reviewed the records of patients with a history of retinal detachment who had received silicone oil and perfluorocarbon liquid (PFCL) as intraocular tamponades. Patients were included in the analysis if they exhibited SSO remnants during silicone oil removal. The aspiration of most of the SSO remnants was performed by a 22-gauge vein detained needle. The small amounts of droplets adhered to the macula and epi-macular membrane were subsequently removed by the ILM warp-and-peel technique. The anatomical and functional outcomes, and postoperative complications were recorded. In vitro experiments were performed to simulate the formation of SSO remnants in four groups. RESULTS: Of 711 patients who underwent silicone oil removal during the study period, 9 patients exhibited SSO remnants and underwent follow-up for at least 3mo. Seven eyes (78%) underwent the ILM wrap-and-peel technique to completely remove small droplets of SSO that were glued to the macula and epi-macular membrane. No obvious complications occurred. Postoperative optical coherence tomography revealed normal retinal structure in all patients. In vitro analyses showed that balanced salt solution and prolonged vibration (for 1wk) had the strongest effects on silicone oil and PFCL compound opacities. CONCLUSION: SSO remnants could be removed in an intact manner and without complications, using a vein detained needle-assisted and ILM wrap-and-peel technique. The findings suggest that PFCL and infusion fluid should be completely removed before silicone oil injection to prevent SSO formation.

9.
Adv Mater ; : e2107922, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34837252

RESUMO

Rebuilding mineralized tissues in skeletal and dental systems remains costly and challenging. Despite of numerous demands and heave clinical burden over the world, sources of autografts, allografts, and xenografts are far limited, along with massive risks including viral infections, ethic crisis, and so on. Per such dilemma artificial scaffolds have emerged to provide efficient alternatives. Up to date, cell-free biomimetic mineralization (BM) and cell-dependent scaffolds both demonstrated promising capabilities of regenerating mineralized tissues. However, BM and cell-dependent scaffolds own distinctive mechanisms for mineral genesis, which makes them methodically, synthetically, and functional disparate. In this review, we systematically summarized these two strategies in regenerative dentistry and orthopedics at the level of mechanisms. For BM, we focused on methodological and theoretical advances; and meanwhile for cell-dependent scaffolds we demonstrated how scaffolds orchestrated osteogenic cell fate. Our summaries of experimental advances and clinical progresses will endow researchers with mechanistic understandings of artificial scaffolds in rebuilding hard tissues, by which better clinical choices and research directions may be approached. This article is protected by copyright. All rights reserved.

10.
PLoS Negl Trop Dis ; 15(11): e0009869, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34748586

RESUMO

PURPOSE: Vancomycin-resistant enterococci infection is a worrying worldwide clinical problem. To evaluate the accuracy of GeneXpert vanA/vanB in the diagnosis of VRE, we conducted a systematic review in the study. METHODS: Experimental data were extracted from publications until May 03 2021 related to the diagnostic accuracy of GeneXpert vanA/vanB for VRE in PubMed, Embase, Web of Science and the Cochrane Library. The accuracy of GeneXpert vanA/vanB for VRE was evaluated using summary receiver to operate characteristic curve, pooled sensitivity, pooled specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio. RESULTS: 8 publications were divided into 3 groups according to two golden standard references, vanA and vanB group, vanA group, vanB group, including 6 researches, 5 researches and 5 researches, respectively. The pooled sensitivity and specificity of group vanA and vanB were 0.96 (95% CI, 0.93-0.98) and 0.90 (95% CI, 0.88-0.91) respectively. The DOR was 440.77 (95% CI, 37.92-5123.55). The pooled sensitivity and specificity of group vanA were 0.86 (95% CI, 0.81-0.90) and 0.99 (95% CI, 0.99-0.99) respectively, and those of group vanB were 0.85 (95% CI, 0.63-0.97) and 0.82 (95% CI, 0.80-0.83) respectively. CONCLUSION: GeneXpert vanA/vanB can diagnose VRE with high-accuracy and shows greater accuracy in diagnosing vanA.

11.
Clin Transl Med ; 11(11): e579, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34841705

RESUMO

Increasing evidence supports a central role of the immune system in lung diseases. Understanding how immunological alterations between lung diseases provide opportunities for immunotherapy. Exhausted T cells play a key role of immune suppression in lung cancer and chronic obstructive pulmonary disease was proved in our previous study. The present study aims to furthermore define molecular landscapes and heterogeneity of systemic immune cell target proteomic and transcriptomic profiles and interactions between circulating immune cells and lung residential cells in various lung diseases. We firstly measured target proteomic profiles of circulating immune cells from healthy volunteers and patients with stable pneumonia, stable asthma, acute asthma, acute exacerbation of chronic obstructive pulmonary disease, chronic obstructive pulmonary disease and lung cancer, using single-cell analysis by cytometry by time-of-flight with 42 antibodies. The nine immune cells landscape was mapped among those respiratory system diseases, including CD4+ T cells, CD8+ T cells, dendritic cells, B cells, eosinophil, γδT cells, monocytes, neutrophil and natural killer cells. The double-negative T cells and exhausted CD4+ central memory T cells subset were identified in patients with acute pneumonia. This T subset expressed higher levels of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim3) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) in patients with acute pneumonia and stable pneumonia. Biological processes and pathways of immune cells including immune response activation, regulation of cell cycle and pathways in cancer in peripheral blood immune cells were defined by bulk RNA sequencing (RNA-seq). The heterogeneity among immune cells including CD4+ , CD8+ T cells and NK T cells by single immune cell RNA-seq with significant difference was found by single-cell sequencing. The effect of interstitial telocytes on the immune cell types and immune function was finally studied and the expressions of CD8a and chemokine C-C motif receptor 7 (CCR7) were increased significantly in co-cultured groups. Our data indicate that proteomic and transcriptomic profiles and heterogeneity of circulating immune cells provides new insights for understanding new molecular mechanisms of immune cell function, interaction and modulation as a source to identify and develop biomarkers and targets for lung diseases.

12.
Toxicol Res (Camb) ; 10(4): 696-705, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34745557

RESUMO

This study aimed to clarify the mechanism of propofol on proliferation and apoptosis of colorectal cancer (CRC) cell. SW620 and HCT15 cells were exposed to different concentrations of propofol, the proliferation and apoptotic rate, were measured by MTT, colony formation and flow cytometry assays, respectively. The expressions of miR-1-3p and insulin-like growth factors 1 (IGF1) were examined by real-time polymerase chain reaction (RT-qPCR). Western bolt was employed to quantify the protein levels of IGF1 and apoptotic proteins. The molecular interaction between miR-1-3p and IGF1 was validated using dual-luciferase reporter assay. A xenograft tumor model was established to further assess the effects of propofol on CRC in vivo. Propofol dramatically decreased the proliferation and elevated apoptotic rate of CRC cells. RT-qPCR assay demonstrated that miR-1-3p was downregulated in CRC cells, and could be strikingly increased by propofol. Importantly, miR-1-3p inhibited IGF-1 expression through interacting with its 3'-UTR region, thus inactivating AKT/mTOR signals. Gain or loss of functional study revealed that miR-1-3p downregulation remarkedly diminished the anti-tumor roles of propofol by directly inhibiting IGF1. In vivo study showed that propofol inhibited tumor growth by regulating miR-1-3p/IGF1 axis. Our data eventually elucidated that propofol suppressed CRC progression by promoting miR-1-3p which targeted IGF1. These results might provide a scientific basis for the application of propofol on the clinical surgery and the prognosis of patients with CRC.

13.
Bioengineered ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34719313

RESUMO

Lung microbiota plays an important role in many diseases including lower respiratory tract infections (LRTI) and pneumonia. This study aimed to explore the effects of community-acquired pneumonia (CAP) on microbial diversity and identify potential biomarkers of respiratory tract in CAP LRTI patients. In the current study, a comprehensive bioinformatics analysis was performed based on metagenomic next generation sequencing technology, followed by alpha and beta diversity, LEfSe, and co-occurrence network analysis, and random forest model construction. Our results showed that CAP dramatically influenced taxon abundance, and the significant differences in microbiota including Proteobacteria, Bacteroidetes, Euryarchaeota, Firmicutes and Spirochaetes were observed at the phylum level. Co-occurrence network selected out novel modules involved in microbial proliferation-associated pathways. A random forest model screened Klebsiella pneumoniae and Bacillus cereus as potential diagnostic biomarkers with high AUC values. The microbial composition was different between CAP LRTI patients and non-CAP LRTI patients. Klebsiella pneumoniae and Bacillus cereus were strongly associated with increased severity of LRTI with a pneumonia history. Our findings provided an insight for a better understanding of community and structure of lung microbiota for future diagnosis and treatment in LRTI patients with a history of pneumonia. Moreover, these microbes were considered as potential biomarkers for predicting the risks for the treatment strategies of LRTI.

14.
China CDC Wkly ; 3(34): 711-715, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34594974

RESUMO

What is already known on this topic?: Aerosol transmission was one route for the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and usually occurred in confined spaces. What is added by this report?: Aerosol transmission was found to exist between handshake buildings, i.e., buildings with extremely close proximity that formed relatively enclosed spaces. Transmission was mainly affected by the airflow layout caused by switching air conditioners on and off as well as opening and closing doors and windows. What are the implications for public health practice?: Centralized isolation and home isolation in handshake buildings creates a risk of SARS-CoV-2 aerosol transmission under certain conditions. Attention should be paid to the influence of air distribution layout on aerosol diffusion in isolation wards, and disinfection of isolation venues should be strengthened.

15.
J Cell Mol Med ; 25(22): 10454-10465, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34626080

RESUMO

Emerging evidence indicates extensive oxidative stress is a consequence of obesity which impairs bone formation. Glutathione peroxidase 7 (GPX7) is a conserved endoplasmic reticulum (ER) retention protein, lacking of which causes accumulation of reactive oxygen species (ROS) and promotes adipogenesis. Since the imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cell (BMSC) leads to severe bone diseases such as osteoporosis, it is critical to investigate the potential protective role of Gpx7 in osteogenesis. Here, we provide evidence that deficiency of Gpx7 reduces osteogenesis, but increases adipogenesis in both human BMSCs (hBMSCs) and mouse mesenchymal stem cell line. Interestingly, further studies indicate this defect can be alleviated by the ER stress antagonist, but not the ROS inhibitor, unveiling an unexpected finding that, unlike adipogenesis, lacking of Gpx7 inhibits osteogenesis mediating by induced ER stress instead of enhanced ROS. Furthermore, the mTOR signalling pathway is found down-regulation during osteogenic differentiation in Gpx7-deficient condition, which can be rescued by relief of ER stress. Taken together, for the first time we identify a novel function of Gpx7 in BMSCs' osteogenic differentiation and indicate that Gpx7 may protect against osteoporotic deficits in humans through ER stress and mTOR pathway interplay.

16.
J Endod ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34627784

RESUMO

INTRODUCTION: Periapical lesions are inflammatory diseases mainly caused by microbial infection from the root canal system, affecting the integrity of alveolar bone, periapical cementum, and periodontal ligament. The invasion of pathogenic microorganisms activates local inflammation and host immune response, especially the recruitment and differentiation of T cells. Many studies have discussed the fundamental roles of T cell-related immunological regulation and the possible clinical significance of cytokine disorders in periapical lesions. However, oral pathogen-mediated T cell immune response is far more clarified. Therefore, the aim of this study was to discuss the research status of T cell-related immunology involved in the progression of periapical lesions and potential future directions. METHODS: We conducted a literature review focusing on T cell-related immunology in periapical lesions by searching PubMed, Web of Science, Scopus and ScienceDirect online databases. RESULTS: In total 108 articles were involved in this narrative review. During the development of periapical lesions, the infiltrated number of different types of T cells and the secretion of T cell-related cytokines in root apex region reflected the inflammatory status of periapical lesions. In addition, it was also highly correlated with the periapical bone destruction. Future study could attempt to provide a wider and deeper study on the expression profile and regulatory function of T cells in the development of periapical lesions. CONCLUSION: This review would help us understand the essence of the T cell-related pathology of periapical lesions and raise the potential therapeutic targets for the treatment of apical periodontitis.

17.
Toxicol Lett ; 353: 34-42, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34627953

RESUMO

Gelsemine (GA), the principal alkaloid in Gelsemium elegans Benth, exhibits potent and specific antinociception in chronic pain without the induction of apparent tolerance. However, GA also exerts neurotoxicity and hepatotoxicity when overdosed, and potential detoxification pathways are urgently needed. Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the detoxification of xenobiotic compounds. The study aimed to investigate the role of CYPs-mediated metabolism in GA-induced toxicity. Microsomes, chemical special inhibitors and human recombinant CYPs indicated that GA was mainly metabolized by CYP3A4/5. The major metabolite of GA was isolated and identified as 4-N-demethyl-GA by high-resolution mass spectrometry and nuclear magnetic resonance technology. The CYP3A4 inhibitor ketoconazole significantly inhibited the metabolism of GA. This drastically increased GA toxicity which is caused by increasing the level of malondialdehyde and decreasing the level of the superoxide dismutase in mice. In contrast, the CYP3A4 inducer dexamethasone significantly increased GA metabolism and markedly decreased GA toxicity in mice. Notably, in CYP3A4-humanized mice, the toxicity of GA was significantly reduced compared to normal mice. These findings demonstrated that CYP3A4-mediated metabolism is a robust detoxification pathway for GA-induced toxicity.

18.
J Periodontol ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34647317

RESUMO

BACKGROUND: Periodontitis could lead to periodontal destruction such as the loss of alveolar bone. The issue that how to achieve the regeneration of alveolar bone and periodontal tissues under the inflammatory environment needs to be solved urgently. BMP9 is one of the most potent osteo-inductive BMPs and induces osteogenic differentiation of mesenchymal stem cells (MSCs). The aim of this study is to explore the possible effect of BMP9 on the osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs). METHODS: Human PDLSCs were cultured in osteo-inductive medium with 1µg/mL lipopolysaccharide Porphyromonas gingivitis (LPS-PG). Adenoviral vector expressing system was used to overexpress target genes. In vitro expression of osteogenic markers was assessed by quantitative reverse transcription PCR, western blotting, alkaline phosphatase assay, and alizarin red staining. Subcutaneous implantation nude mice models were used to evaluate the effects of BMP9 on PDLSCs in vivo. Micro-CT, H&E staining, and trichrome staining were performed to assess ectopic bone formation. RESULTS: In the LPS-PG induced inflammatory environment, BMP9 promoted osteogenic differentiation of PDLSCs, but upregulated the expression of inflammatory markers (P>0.05); NELL1 downregulated the expression of inflammation genes in PDLSCs induced by BMP9, while augmenting BMP9 induced osteogenesis of the cells both in vitro and in vivo. In the above process, the MAPK/p38/ERK signaling pathway was triggered by NELL1. CONCLUSION: The combination use of BMP9 and NELL1 might have the potential to promote the regeneration of alveolar bone in periodontitis. This article is protected by copyright. All rights reserved.

19.
Proc Natl Acad Sci U S A ; 118(45)2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34670842

RESUMO

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other pathogens with pandemic potential requires safe, protective, inexpensive, and easily accessible vaccines that can be developed and manufactured rapidly at a large scale. DNA vaccines can achieve these criteria, but induction of strong immune responses has often required bulky, expensive electroporation devices. Here, we report an ultra-low-cost (<1 USD), handheld (<50 g) electroporation system utilizing a microneedle electrode array ("ePatch") for DNA vaccination against SARS-CoV-2. The low cost and small size are achieved by combining a thumb-operated piezoelectric pulser derived from a common household stove lighter that emits microsecond, bipolar, oscillatory electric pulses and a microneedle electrode array that targets delivery of high electric field strength pulses to the skin's epidermis. Antibody responses against SARS-CoV-2 induced by this electroporation system in mice were strong and enabled at least 10-fold dose sparing compared to conventional intramuscular or intradermal injection of the DNA vaccine. Vaccination was well tolerated with mild, transient effects on the skin. This ePatch system is easily portable, without any battery or other power source supply, offering an attractive, inexpensive approach for rapid and accessible DNA vaccination to combat COVID-19, as well as other epidemics.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/imunologia , COVID-19/prevenção & controle , Eletroporação/instrumentação , SARS-CoV-2 , Vacinas de DNA/administração & dosagem , Animais , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Custos e Análise de Custo , Eletroporação/economia , Eletroporação/métodos , Desenho de Equipamento , Feminino , Genes Reporter , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microeletrodos , Agulhas , Pandemias/prevenção & controle , Estudo de Prova de Conceito , Ratos , Ratos Wistar , Pele/imunologia , Pele/metabolismo , Transfecção , Vacinação/economia , Vacinação/instrumentação , Vacinação/métodos , Vacinas de DNA/genética , Vacinas de DNA/imunologia
20.
Int J Biol Sci ; 17(14): 3862-3874, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671204

RESUMO

Fibroblast growth factors (FGFs) include a large family of growth factors that play a critical role in maintaining bone homeostasis, but the specific role of its members such as FGF7 does not well understand. Osteoblasts are a kind of major cells essential for bone formation. Osteoblasts interact with one another to create the unique structure of osteons. The well-connected osteons constitute the cortical bone. As an early osteocyte marker that triggers actin cytoskeleton dynamics, E11 is essential for osteoblasts' dendrites formation. However, the upstream which regulates E11 is mainly unknown. The purpose of this study was to examine the influence of FGF7 on the expression and the distribution of E11 in osteoblasts, which mediated osteoblasts' processes formation and gap junctional intercellular communication (GJIC) partly through connexin43 (Cx43). We first demonstrated that FGF7 increased the expression of E11 in osteoblasts. We then showed that FGF7 promoted osteoblasts' dendrites elongation and functional gap junctions formation. Furthermore, E11 interacted directly with Cx43 in primary osteoblasts. MAPK pathway and PI3K-AKT pathway were involved in the effect of FGF7. Our results shed light on the unique role of FGF7 on osteoblasts, which may indicate that FGF7 plays a more significant role in the later stages of bone development and homeostasis.

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