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1.
Signal Transduct Target Ther ; 6(1): 340, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504054

RESUMO

As COVID-19 continues to spread rapidly worldwide and variants continue to emerge, the development and deployment of safe and effective vaccines are urgently needed. Here, we developed an mRNA vaccine based on the trimeric receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein fused to ferritin-formed nanoparticles (TF-RBD). Compared to the trimeric form of the RBD mRNA vaccine (T-RBD), TF-RBD delivered intramuscularly elicited robust and durable humoral immunity as well as a Th1-biased cellular response. After further challenge with live SARS-CoV-2, immunization with a two-shot low-dose regimen of TF-RBD provided adequate protection in hACE2-transduced mice. In addition, the mRNA template of TF-RBD was easily and quickly engineered into a variant vaccine to address SARS-CoV-2 mutations. The TF-RBD multivalent vaccine produced broad-spectrum neutralizing antibodies against Alpha (B.1.1.7) and Beta (B.1.351) variants. This mRNA vaccine based on the encoded self-assembled nanoparticle-based trimer RBD provides a reference for the design of mRNA vaccines targeting SARS-CoV-2.


Assuntos
Vacinas contra COVID-19 , COVID-19/prevenção & controle , Nanopartículas , SARS-CoV-2/imunologia , Vacinas Sintéticas , Animais , COVID-19/imunologia , COVID-19/patologia , Vacinas contra COVID-19/química , Vacinas contra COVID-19/farmacologia , Chlorocebus aethiops , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/uso terapêutico , Células Th1/imunologia , Células Th1/patologia , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia , Células Vero
2.
Neuro Oncol ; 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34232318

RESUMO

BACKGROUND: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts. METHODS: Mice bearing intracranial tumors received lisavanbulin +/- RT +/- TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis. RESULTS: Lisavanbulin monotherapy showed significant benefit (p<0.01) in 9 of 14 PDXs tested (median survival extension 9-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours post-dose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, p=0.0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, p=0.06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, p=0.0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, p=0.04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (p=0.01). CONCLUSIONS: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.

3.
PLoS One ; 16(6): e0252818, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34111164

RESUMO

Most deaths from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection occur in older subjects. We assessed the utility of serum inflammatory markers interleukin-6 (IL-6), C reactive protein (CRP), and ferritin (Roche, Indianapolis, IN), and SARS-CoV-2 immunoglobulin G (IgG), immunoglobulin M (IgM), and neutralizing antibodies (Diazyme, Poway, CA). In controls, non-hospitalized subjects, and hospitalized subjects assessed for SARS-CoV-2 RNA (n = 278), median IgG levels in arbitrary units (AU)/mL were 0.05 in negative subjects, 14.83 in positive outpatients, and 30.61 in positive hospitalized patients (P<0.0001). Neutralizing antibody levels correlated significantly with IgG (r = 0.875; P<0.0001). Having combined values of IL-6 ≥10 pg/mL and CRP ≥10 mg/L occurred in 97.7% of inpatients versus 1.8% of outpatients (odds ratio 3,861, C statistic 0.976, P = 1.00 x 10-12). Antibody or ferritin levels did not add significantly to predicting hospitalization. Antibody testing in family members and contacts of SARS-CoV-2 RNA positive cases (n = 759) was invaluable for case finding. Persistent IgM levels were associated with chronic COVID-19 symptoms. In 81,624 screened subjects, IgG levels were positive (≥1.0 AU/mL) in 5.21%, while IgM levels were positive in 2.96% of subjects. In positive subjects median IgG levels in AU/mL were 3.14 if <30 years of age, 4.38 if 30-44 years of age, 7.89 if 45-54 years of age, 9.52 if 55-64 years of age, and 10.64 if ≥65 years of age (P = 2.96 x 10-38). Our data indicate that: 1) combined IL-6 ≥10 pg/mL and CRP ≥10 mg/L identify SARS-CoV-2 positive subjects requiring hospitalization; 2) IgG levels were significantly correlated with neutralizing antibody levels with a wide range of responses; 3) IgG levels have significant utility for case finding in exposed subjects; 4) persistently elevated IgM levels are associated with chronic symptoms; and 5) IgG levels are significantly higher in positive older subjects than their younger counterparts.


Assuntos
COVID-19/sangue , Inflamação/sangue , Adulto , Fatores Etários , Idoso , Envelhecimento , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Hospitalização , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Inflamação/diagnóstico , Inflamação/epidemiologia , Inflamação/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação
4.
Neuro Oncol ; 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34050676

RESUMO

BACKGROUND: Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important. METHODS: PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH and phosphoproteomics. RESULTS: Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment. CONCLUSIONS: Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.

5.
ACS Appl Mater Interfaces ; 13(22): 25611-25623, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34038086

RESUMO

Hydrogel-based three-dimensional (3D) bioprinting has been illustrated as promising to fabricate tissue scaffolds for regenerative medicine. Notably, bioprinting of hydrated and soft 3D hydrogel scaffolds with desired structural properties has not been fully achieved so far. Moreover, due to the limitations of current imaging techniques, assessment of bioprinted hydrogel scaffolds is still challenging, yet still essential for scaffold design, fabrication, and longitudinal studies. This paper presents our study on the bioprinting of hydrogel scaffolds and on the development of a novel noninvasive imaging method, based on synchrotron propagation-based imaging with computed tomography (SR-PBI-CT), to study the structural properties of hydrogel scaffolds and their responses to environmental stimuli both in situ and in vivo. Hydrogel scaffolds designed with varying structural patterns were successfully bioprinted through rigorous printing process regulations and then imaged by SR-PBI-CT within physiological environments. Subjective to controllable compressive loadings, the structural responses of scaffolds were visualized and characterized in terms of the structural deformation caused by the compressive loadings. Hydrogel scaffolds were later implanted in rats as nerve conduits for SR-PBI-CT imaging, and the obtained images illustrated their high phase contrast and were further processed for the 3D structure reconstruction and quantitative characterization. Our results show that the scaffold design and printing conditions play important roles in the printed scaffold structure and mechanical properties. More importantly, our obtained images from SR-PBI-CT allow us to visualize the details of hydrogel 3D structures with high imaging resolution. It demonstrates unique capability of this imaging technique for noninvasive, in situ characterization of 3D hydrogel structures pre- and post-implantation in diverse physiological milieus. The established imaging platform can therefore be utilized as a robust, high-precision tool for the design and longitudinal studies of hydrogel scaffold in tissue engineering.


Assuntos
Bioimpressão/métodos , Hidrogéis/química , Regeneração Nervosa , Condução Nervosa , Impressão Tridimensional/instrumentação , Tecidos Suporte/química , Tomografia Computadorizada por Raios X/métodos , Animais , Processamento de Imagem Assistida por Computador , Masculino , Ratos , Ratos Sprague-Dawley , Engenharia Tecidual , Raios X
6.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786619

RESUMO

Breast cancer is the most common cancer in women and is one of the three most common malignancies worldwide. Serum microRNAs (miRNAs/miRs) are ideal biomarkers for tumor diagnosis and prognosis due to their specific biological characteristics. In several different types of cancer, miRNAs are associated with cell migration and invasion. In the present study, miR­25­3p expression levels were detected in tissue and serum samples derived from patients with breast cancer, and the diagnostic and prognostic value of miR­25­3p in breast cancer was evaluated. Cellular function assays were performed to evaluate the role of miR­25­3p in breast cancer. Moreover, dual­luciferase reporter assays and western blotting were performed to investigate the target of miR­25­3p. miR­25­3p expression was upregulated in breast cancer tissue and serum samples compared with normal breast tissue and serum samples. Patients with breast cancer with high serum miR­25­3p levels were more likely to have lymph node metastasis compared with those with low serum miR­25­3p levels. The area under the curve for miR­25­3p in the diagnosis of breast cancer was 0.748, with 57.1% sensitivity and 95.0% specificity. Moreover, the Kaplan­Meier survival curves demonstrated that patients with breast cancer with a low expression of serum miR­25­3p had a higher overall survival rate compared with patients with a high serum miR­25­3p expression. miR­25­3p knockdown suppressed breast cancer cell proliferation and invasion, and transducer of ERBB2, 1 (TOB1) was identified as a potential target gene regulated by miR­25­3p. Therefore, the present study suggested that miR­25­3p regulated cellular functions via TOB1 in breast cancer; therefore, miR­25­3p may serve as a breast cancer biomarker.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metástase Linfática , Células MCF-7 , MicroRNAs/sangue , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
7.
Int J Mol Med ; 47(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537835

RESUMO

Metastasis is the primary cause of the high mortality rates in head and neck squamous cell carcinoma (HNSCC). MicroRNA (miR)­411­5p has been discovered to serve an important role in cancer metastases. However, to the best of our knowledge, the association between miR­411­5p expression levels and HNSCC metastasis has not been thoroughly investigated. The present study aimed to research the function of miR­411­5p in HNSCC metastasis. The results of the present study revealed that miR­411­5p expression levels were upregulated in patients with HNSCC with lymph node metastasis and the upregulated expression levels of miR­411­5p were positively associated with the metastatic potential of HNSCC. Moreover, miR­411­5p promoted HNSCC cell migration, invasion and epithelial­mesenchymal transition (EMT). The results of the dual­luciferase reporter assays identified RING1 and YY1 binding protein (RYBP) as a functional downstream target gene for miR­411­5p. Therefore, whether miR­411­5p downregulated the expression levels of RYBP in HNSCC cells was subsequently investigated. Notably, the silencing of RYBP expression restored the stimulatory effects of miR­411­5p on HNSCC cell migration, invasion and EMT. In addition, the mRNA expression levels of miR­411­5p and RYBP were found to be inversely correlated in HNSCC samples. In conclusion, the results of the present study indicated that the miR­411­5p­mediated downregulation of RYBP expression levels may exert an important role in HNSCC metastasis and may provide a novel target for the treatment of HNSCC.


Assuntos
Metástase Linfática/genética , MicroRNAs/genética , Proteínas Repressoras/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Regulação para Cima/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Metástase Linfática/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Proteínas Repressoras/genética
8.
J Gen Virol ; 102(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33459587

RESUMO

Baculoviruses are large DNA viruses that replicate within the nucleus of infected host cells. Therefore, many viral proteins must gain access to the nucleus for efficient viral genome replication, gene transcription and virion assembly. To date, the global protein localization pattern of baculoviral proteins is unknown. In this study, we systematically analysed the nuclear localization of 154 ORFs encoded by the prototypic baculovirus, Autographa californica multiple nucleopolyhedrovirus (AcMNPV), either during transient expression or with super-infection of the virus. By transient expression of vectors containing egfp-fused ORFs, we found that in the absence of virus infection, 25 viral proteins were localized in the nucleus. Most of these, which we called 'auto-nuclear localization' proteins, are related to virus replication, transcription or virion structure, and 20 of them contain predicted classical nuclear localization signal. Upon virus infection, 11 proteins, which originally localized in the cytoplasm or both cytoplasm and nucleus in the transfection assays, were completely translocated into the nucleus, suggesting that their nuclear import is facilitated by other viral or host proteins. Further co-transfection experiments identified that four of the 11 proteins, including P143, P33, AC73 and AC114, were imported into the nucleus with the assistance of the auto-nuclear localization proteins LEF-3 (for P143), TLP (for P33) and VP80 (for both AC73 and AC114). This study presents the first global nuclear localization profile of AcMNPV proteins and provides useful information for further elucidation of the mechanisms of baculovirus nuclear entry and gene functions.


Assuntos
Núcleo Celular/metabolismo , Nucleopoliedrovírus/metabolismo , Proteínas Virais/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Citoplasma/metabolismo , Membrana Nuclear/metabolismo , Sinais de Localização Nuclear , Nucleopoliedrovírus/fisiologia , Fases de Leitura Aberta , Células Sf9 , Spodoptera , Transcrição Genética , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Estruturais Virais/química , Proteínas Estruturais Virais/genética , Proteínas Estruturais Virais/metabolismo , Replicação Viral
9.
Int J Biol Macromol ; 169: 239-250, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33345972

RESUMO

In this study, SBA-15 was modified by halogen & haloalkanes and later used to immobilize lipases. The hydrolysis activity and the glycerolysis performance of the immobilized lipases was carefully studied. Highest activity of the immobilized Candida antarctica lipase B (CALB), Lipase from Aspergillus oryzae (AOL), Lecitase® Ultra (LU) and lipase from Rhizomucor miehei (RML) was respectively at 5577, 12000, 2822 and 11,577 U/g; in addition, the highest activity was obtained from the lowest or moderate lipase loading, at 25.73, 90.72, 89.52 and 30.56 mg/g respectively. The mechanism of lipase immobilization was studied and it was through interfacial activation. The halogen & haloalkanes modification of SBA-15 afforded considerable glycerolysis activity for diacylglycerols (DAG) preparation. CALB@SBA-15-CH2CH2(CF2)5CF3 and CALB@SBA-15-CH2CH2(CF2)7CF3 were suitable for DAG production, they both exhibited good reusability in glycerolysis reaction, with 117.36% and 93.06% of their initial glycerolysis activity retained respectively after ten cycles of reuse. The relationships between temperature with triacylglycerols (TAG) conversion were lnV0 = 3.13-3.07/T and lnV0 = 7.90-4.64/T respectively for CALB@SBA-15-CH2CH2(CF2)5CF3 and CALB@SBA-15-CH2CH2(CF2)7CF3; in addition, their activation energy (Ea) was respectively at 25.50 and 38.54 kJ/mol.


Assuntos
Halogênios/química , Lipase/isolamento & purificação , Dióxido de Silício/química , Basidiomycota , Biocatálise , Candida , China , Diglicerídeos , Estabilidade Enzimática , Enzimas Imobilizadas/química , Proteínas Fúngicas , Hidrólise , Lipase/química , Rhizomucor , Temperatura , Termodinâmica , Triglicerídeos
10.
Turk J Med Sci ; 51(3): 1080-1091, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-33356028

RESUMO

Background/aim: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the comparison and its timing between mycophenolate mofetil (MMF) and calcineurin inhibitor (CNI) as maintenance immunosuppression for kidney transplant recipients. Materials and methods: The RCTs of MMF versus CNI as maintenance immunosuppression for kidney transplant recipients were searched from PubMed, Embase, Cochrane Central Register of Controlled Trials (CCRCT), and ClinicalTrials.gov. After screening relevant RCTs, two authors independently assessed the quality of included studies and performed a meta-analysis using RevMan5.3. Relative risk (RR) was used to report dichotomous data, while mean difference (MD) with 95% confidence interval (CI) was used to report continuous outcomes. The analysis was conducted using the random-effect model due to the expected heterogeneity among different studies. Four subgroups were allocated to compare MMF with CNI as maintenance immunosuppression: (1) after 3 months of CNI-based therapy, (2) after 6 months of CNI-based therapy, (3) after 12 months of CNI-based therapy, and (4) in recipients with allograft dysfunction. Results: Twelve RCTs with 950 renal transplant recipients were included. This meta-analysis presented the following results upon comparison between MMF and CNI as maintenance immunosuppression for kidney transplant recipients: (1) MMF significantly improved the glomerular filtration rate (GFR) not only in the comparison performed after 3, 6, or 12 months of CNI-based therapy but also in the comparison of recipients with allograft dysfunction, (2) MMF may increase the risk of acute rejection in the comparison performed after 3 months of CNI-based therapy, but no increase was noted in the comparison performed after 6 or 12 months of CNI- based therapy. Conclusion: Our present meta-analysis suggested that MMF followed at least 6 months of CNI-based therapy is an effective maintenance immunosuppressive regimen for kidney transplant recipients to improve renal function but not increase rejection.

11.
Onco Targets Ther ; 13: 11019-11029, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33149616

RESUMO

Background: Oral squamous cell carcinoma (OSCC), the most common epithelial malignant neoplasm in the head and neck, characterizes with local infiltration and metastasis of lymph nodes. The five-year survival rate of OSCC remains low despite the advances in clinical methods. Thus, it is necessary to develop a new effective therapeutic scheme for OSCC. Our previous results showed that metformin and 4SC-202 synergistically promoted the intrinsic apoptosis of OSCC in vitro and in vivo, but the effects on invasion and migration remained unclear. Methods: Human OSCC cell lines HSC6 and CAL33 were cultured with metformin (16 mM) or/and 4SC-202 (0.4 µM) for 72 h. STAT3 inhibitor S31-201 was applied at concentration of 60 µM for 48 h. Wound-healing assays and transwell assays were used to determine the invasion and migration ability of OSCC. qRT-PCR and Western blot were performed to detect mRNA levels and protein levels. Results: Metformin or/and 4SC-202 suppressed the migration and invasion of OSCC cells. Importantly, the expression of TWIST1 was suppressed by metformin and 4SC-202, while the invasion and migration inhibitory effects of metformin and 4SC-202 were countered by the overexpression of TWIST1. In addition, the phosphorylation level of STAT3 decreased after the administration of metformin or/and 4SC-202. Furthermore, inhibition of STAT3 by S31-201 suppressed the expression of TWIST1 and led to a decline in migration and invasion of OSCC, while overexpression of TWIST1 attenuated these effects. Conclusion: Metformin and 4SC-202 suppressed the invasion and migration of OSCC through inhibition of STAT3/TWIST1, and this scheme can serve as a novel therapeutic strategy for OSCC.

12.
Sheng Wu Gong Cheng Xue Bao ; 36(10): 1961-1969, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33169562

RESUMO

Coronaviruses are a type of positive-sense single-stranded RNA virus with envelope and widely exist in nature to cause respiratory infectious diseases. The novel coronavirus is a new outbreak virus that is susceptible to all people. Up to now, the disease has been widely spread in the world and poses a great threat to public health. In this review, the genomic features, key proteins, host infection and replication of coronaviruses and novel coronaviruses are reviewed in order to provide theoretical basis for the study of the pathogenic mechanism of virus infection on host cells and to provide basic support for the development of specific antiviral drugs.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Replicação Viral , COVID-19 , Humanos , Pandemias , SARS-CoV-2
13.
World J Gastroenterol ; 26(36): 5420-5436, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33024394

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. The gut microbiota can help maintain healthy metabolism and immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical factor in promoting health and homeostasis; it promotes intestinal immunity, stimulates bone marrow precursors to generate macrophage colonies, and enhances the antibacterial and antitumor activity of circulating monocytes. As such, GM-CSF may protect against HCC development by regulating immunity as well as intestinal microecology. AIM: To investigate the impact of GM-CSF on the gut microbiome and metabolic characteristics of HCC. METHODS: Thirty-six male BALB/c nude mice were divided into three groups: Control (n = 10), HCC (n = 13), and HCC + GM-CSF (GM-CSF overexpression, n = 13). We utilized HCC cells to establish orthotopic transplantation tumor models of HCC with normal and over-expressing GM-CSF. Liver injury, immune inflammatory function and intestinal barrier function were evaluated. The fecal microbiome and metabolome were studied using 16S rRNA absolute quantification sequencing and gas chromatography-mass spectrometry. RESULTS: GM-CSF overexpression significantly affected the gut microbiome of mice with HCC and resulted in a high abundance of organisms of the genera Roseburia, Blautia and Butyricimonass, along with a significant reduction in Prevotella, Parabacteroides, Anaerotruncus, Streptococcus, Clostridium, and Mucispirillum. Likewise, GM-CSF overexpression resulted in a substantial increase in fecal biotin and oleic acid levels, along with a prominent decrease in the fecal succinic acid, adenosine, fumaric acid, lipoic acid, and maleic acid levels. Correlation analysis revealed that the intestinal microbiota and fecal metabolites induced by GM-CSF were primarily involved in pathways related to reducing the inflammatory response, biotin metabolism, and intestinal barrier dysfunction. CONCLUSION: GM-CSF can protect against HCC development by regulating immunity and modulating the abundance of specific intestinal microorganisms and their metabolites. This study provides new insights into the therapeutic approaches for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/prevenção & controle , Disbiose/prevenção & controle , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Inflamação , Neoplasias Hepáticas/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Ribossômico 16S/genética
14.
Adv Healthc Mater ; 9(22): e2001175, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33000909

RESUMO

Occlusion of coronary artery and subsequent damage or death of myocardium can lead to myocardial infarction (MI) and even heart failure-one of the leading causes of deaths world wide. Notably, myocardium has extremely limited regeneration potential due to the loss or death of cardiomyocytes (i.e., the cells of which the myocardium is comprised) upon MI. A variety of stem cells and stem cell-derived cardiovascular cells, in situ cardiac fibroblasts and endogenous proliferative epicardium, have been exploited to provide renewable cellular sources to treat injured myocardium. Also, different strategies, including direct injection of cell suspensions, bioactive molecules, or cell-incorporated biomaterials, and implantation of artificial cardiac scaffolds (e.g., cell sheets and cardiac patches), have been developed to deliver renewable cells and/or bioactive molecules to the MI site for the myocardium regeneration. This article briefly surveys cell sources and delivery strategies, along with biomaterials and their processing techniques, developed for MI treatment. Key issues and challenges, as well as recommendations for future research, are also discussed.


Assuntos
Infarto do Miocárdio , Miócitos Cardíacos , Humanos , Infarto do Miocárdio/terapia , Miocárdio , Regeneração , Células-Tronco
15.
BMC Ophthalmol ; 20(1): 415, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33076862

RESUMO

BACKGROUND: Congenital orbital teratoma is relatively rare, and few reports of prenatal ultrasound findings in such cases have been published. CASE PRESENTATION: A rare case of congenital orbital teratoma at 24 + 2 weeks of gestation was previously diagnosed as microphthalmia, noting how orbital teratoma without proptosis is different from microphthalmia, retinoblastoma and intracranial teratoma. Ultrasound examination, analysis of gross specimens, and histopathological evaluation confirmed the diagnosis of orbital teratoma. CONCLUSION: Prenatal ultrasound examination is useful for diagnosis and differential diagnosis of congenital orbital teratoma.


Assuntos
Exoftalmia , Neoplasias Orbitárias , Neoplasias da Retina , Teratoma , Exoftalmia/diagnóstico , Exoftalmia/etiologia , Feminino , Feto , Humanos , Neoplasias Orbitárias/diagnóstico , Gravidez , Teratoma/diagnóstico por imagem
16.
Neoplasia ; 22(11): 617-629, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33045527

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we detected PRMT5 expression in HNSCC tissues and performed series of in vivo and in vitro assays to investigate the function and mechanism of PRMT5 in HNSCC. We found that PRMT5 was overexpressed in dysplastic and cancer tissues, and associated with lymph node metastasis and worse patient survival. PRMT5 knockdown repressed the malignant phenotype of HNSCC cells in vitro and in vivo. PRMT5 specific inhibitor blocked the formation of precancerous lesion and HNSCC in 4NQO-induced tongue carcinogenesis model, prevented lymph node metastasis in tongue orthotopic xenograft model and inhibited cancer development in subcutaneous xenograft model and Patient-Derived tumor Xenograft (PDX) model. Mechanistically, PRMT5-catalyzed H3R2me2s promotes the enrichment of H3K4me3 in the Twist1 promoter region by recruiting WDR5, and subsequently activates the transcription of Twist1. The rescue experiments indicated that overexpressed Twist1 abrogated the inhibition of cell invasion induced by PRMT5 inhibitor. In summary, this study elucidates that PRMT5 inhibition could reduce H3K4me3-mediated Twist1 transcription and retard the carcinogenesis and metastasis of HNSCC.

17.
Ann Palliat Med ; 9(5): 3059-3069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32819134

RESUMO

BACKGROUND: The sustained negative pressure created by vacuum sealing drainage (VSD) on exposed vascular wounds can result in blood vessel compression, embolism, or necrosis. The objective of this research was to explore the ability of an experimental vascular protective shield combined with VSD to protect exposed vessels of the lower limbs and accelerate wound repair. METHODS: (I) The vascular protective shield was prepared; (II) the material was subjected to acute toxicity and hemolysis tests; (III) and 30 New Zealand rabbits were divided into three groups: the control, VSD-only, and combined shield-VSD groups (with ten rabbits in each group). The wound-healing rate, myocardial function, wound histopathology, expression of angiogenesis markers, and exposed vascular compression of these three groups were compared on day 7. RESULTS: (I) The internal structure of the material was smooth; and (II) no toxicity or death was observed in mice of any group. The hemolysis rate in the combined shield-VSD group was very low. (III) The combined shield-VSD group showed a higher wound-healing rate, and higher levels of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), than the other groups (P<0.05), along with a better tissue healing rate. (IV) Left ventricular pressure fluctuations in the combined shield-VSD group were smaller than those in the VSD-only group (P<0.05). (V) Blood vessels in the control and combined shield-VSD group were not damaged, but were damaged in the VSD-only group. CONCLUSIONS: The experimental vascular protective shield exhibited exceptional biosafety. The combination of this shield with VSD reduces influences on systolic and diastolic capacities of myocardium and avoids multiple compressions of exposed vessels, thus contributing to early vascularization of wounds and wound repair.


Assuntos
Tratamento de Ferimentos com Pressão Negativa , Animais , Drenagem , Camundongos , Coelhos , Vácuo , Fator A de Crescimento do Endotélio Vascular , Cicatrização
18.
Cancer Manag Res ; 12: 7021-7032, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848461

RESUMO

Background: Neuropilin-1 (NRP-1) participates in cancer cell proliferation and metastasis as a multifunctional co-receptor by interacting with multiple signaling pathways. However, few studies have addressed the precise function and prognosis analysis of NRP1 in intrahepatic cholangiocarcinoma (ICC). We aimed to study the correlations between NRP1 and clinicopathological characteristics and NRP1 effect on ICC cell line functions. Methods: NRP1 mRNA and its protein levels in human ICC tissues and cell lines were detected by IHC, qRT-PCR, and WB method. Transwell, wound healing, and CCK-8 assays were performed to verify the effects of NRP1 knockdown and overexpression on cell migration and proliferation capability. Results: NRP1 proteins and mRNA levels increased in ICC tissues compared to those in paired adjacent non-tumor tissues. High NRP1 expression of ICC tissues was related to poor prognosis. NRP1 expression level was expected to be an independent prognosticator for overall survival and cumulative tumor recurrence, and was closely related to tumor number (P=0.047). Knockdown of NRP1 inhibited cell proliferation and migration capability of RBE cells in vitro, and NRP1 overexpression in 9810 cells accelerated proliferation and migration. Additionally, NRP1 may promote cell proliferation and migration in ICC via the FAK/PI3-K/AKT pathway. Conclusion: As an oncogene, NRP1 may function as a candidate target and prognostic biomarker of value for ICC therapy.

19.
Front Microbiol ; 11: 1388, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32582138

RESUMO

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly worldwide, seriously endangering human health. In addition to the typical symptoms of pulmonary infection, patients with COVID-19 have been reported to have gastrointestinal symptoms and/or intestinal flora dysbiosis. It is known that a healthy intestinal flora is closely related to the maintenance of pulmonary and systemic health by regulating the host immune homeostasis. Role of the "gut-lung axis" has also been well-articulated. This review provides a novel suggestion that intestinal flora may be one of the mediators of the gastrointestinal responses and abnormal immune responses in hosts caused by SARS-CoV-2; improving the composition of intestinal flora and the proportion of its metabolites through probiotics, and personalized diet could be a potential strategy to prevent and treat COVID-19. More clinical and evidence-based medical trials may be initiated to determine the strategy.

20.
J Clin Lab Anal ; 34(9): e23394, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32472711

RESUMO

BACKGROUND: Neuropilin1 (NRP1) participates in cancer cell proliferation, migration, and metastasis as a multifunctional co-receptor by interacting with multiple signal pathways, but few studies have addressed the precise function of NRP1 in pancreatic cancer (PACA) cells. We aimed to study whether NRP1 gene silencing involved in the proliferation and migration of PACA cells in vitro. METHODS: A lentiviral vector expressing NRP1 shRNA was constructed and transfected into human PACA cells (CFPAC-1 and PANC-1). The expression of NRP1 protein and mRNA was detected by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) assay, respectively. CCK-8 assay, wound healing assay, and transwell assay were conducted to examine the effect of NRP1 silencing on cells proliferation and migration capability. RESULTS: Results of qRT-PCR and Western blot showed successfully established, stably transfected shRNA-NRP1 cells in PACA cells. The proliferation capacity of PACA cells in NRP1 shRNA group was lower significantly than that in the negative control (NC) group (P < .05). The invasion and migration capability of PACA cells in NRP1 shRNA group was lower significantly than that in the NC group (P < .01). CONCLUSIONS: NRP1-shRNA lentiviral interference vectors can effectively decrease NRP1 gene expression in PACA cells, thereby inhibiting cells proliferation and migration, which provides a basis for finding a valuable therapeutic target for PACA therapy.

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