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1.
J Virol ; 97(10): e0083223, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37796128

RESUMO

IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of several B cell malignancies and Kaposi's sarcoma. We analyzed the function of K8.1, the major antigenic component of the KSHV virion in the infection of different cells. To do this, we deleted K8.1 from the viral genome. It was found that K8.1 is critical for the infection of certain epithelial cells, e.g., a skin model cell line but not for infection of many other cells. K8.1 was found to mediate attachment of the virus to cells where it plays a role in infection. In contrast, we did not find K8.1 or a related protein from a closely related monkey virus to activate fusion of the viral and cellular membranes, at least not under the conditions tested. These findings suggest that K8.1 functions in a highly cell-specific manner during KSHV entry, playing a crucial role in the attachment of KSHV to, e.g., skin epithelial cells.


Assuntos
Glicoproteínas , Herpesvirus Humano 8 , Queratinócitos , Proteínas Virais , Ligação Viral , Internalização do Vírus , Humanos , Glicoproteínas/deficiência , Glicoproteínas/genética , Glicoproteínas/metabolismo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/fisiologia , Queratinócitos/metabolismo , Queratinócitos/virologia , Sarcoma de Kaposi/virologia , Proteínas Virais/genética , Proteínas Virais/metabolismo , Fusão de Membrana , Pele/citologia
2.
J Orthop Sci ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39054230

RESUMO

BACKGROUND: This study aimed to introduce a potential alternative percutaneous treatment for AO types C1, C2, and C3 distal radius fractures using dual-external fixator (a no-bridging cemented-pin frame and a conventional wrist-bridging external fixator). MATERIALS AND METHODS: From January 2018 to January 2021, 52 patients (52 distal radius fractures) were treated with dual-external fixator. For comparison, 61 patients (61 distal radius fractures) were treated with a plate and screw system. Wrist function was assessed using the Mayo Wrist Score. Patient satisfaction was assessed using the Short Assessment of Patient Satisfaction. A P < 0.05 was considered statistically significant. RESULTS: Fracture healing was achieved in all patients. At the final follow-up of 29 months (range, 24-34 months) vs 36 months (range, 26-39 months) (P > 0.05), the patients treated with dual-external fixator and a plate and screw system achieved mean ulnar deviations of 31° vs 29° (P < 0.05), mean Mayo Wrist Scores of 91.12 ± 5.98 vs 88.12 ± 7.54 (P < 0.05), and mean patient satisfaction scores of 23.42 ± 2.47 vs 23.04 ± 2.32 (P > 0.05). CONCLUSIONS: AO types C1, C2, and C3 distal radius fractures can be treated successfully using dual-external fixator. The technique is a potential alternative in addition to the conventional treatments. LEVEL OF EVIDENCE: Level IIa.

3.
Molecules ; 29(2)2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38257288

RESUMO

Cabotegravir is an integrase strand transfer inhibitor (INSTI) for HIV treatment and prevention. Cabotegravir-based long-acting pre-exposure prophylaxis (PrEP) presents an emerging paradigm for infectious disease control. In this scheme, a combination of a high efficacy and low solubility of anti-infection drugs permits the establishment of a pharmaceutical firewall in HIV-vulnerable groups over a long period. Although the structure-activity-relationship (SAR) of cabotegravir as an INSTI is known, the structural determinants of its low solubility have not been identified. In this work, we have integrated multiple experimental and computational methods, namely X-ray diffraction, solid-state NMR (SSNMR) spectroscopy, solution NMR spectroscopy, automated fragmentation (AF)-QM/MM and density functional theory (DFT) calculations, to address this question. The molecular organization of cabotegravir in crystal lattice has been determined. The combination of very-fast magic-angle-sample-spinning (VF MAS) SSNMR and solution NMR, as supported by AF-QM/MM and DFT calculations, permits the identification of structural factors that contribute to the low aqueous solubility of cabotegravir. Our study reveals the multitasking nature of pharmacophores in cabotegravir, which controls the drug solubility and, meanwhile, the biological activity. By unraveling these function-defining molecular features, our work could inspire further development of long-acting HIV PrEP drugs.


Assuntos
Infecções por HIV , Profilaxia Pré-Exposição , Piridonas , Humanos , Farmacóforo , Dicetopiperazinas , Infecções por HIV/prevenção & controle
4.
Molecules ; 29(10)2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38792134

RESUMO

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future.

5.
Cancer ; 129(19): 2999-3009, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37449788

RESUMO

BACKGROUND: The role of carbohydrate antigen 19-9 (CA 19-9) in response assessment among patients with intrahepatic cholangiocarcinoma (iCCA) remains unknown. The authors studied the association of the CA 19-9 response (defined as a reduction >50% from baseline) with the radiologic response and the outcome in patients with unresectable iCCA. METHODS: A prospective cohort of 422 patients who were initially diagnosed with unresectable iCCA, had baseline CA 19-9 levels ≥100 U/mL, and received treatment with systemic therapies at the authors' institution between January 2017 and December 2021 were enrolled in this study. The radiologic response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A landmark assessment of the CA 19-9 response and the radiologic response was performed. The associations between CA 19-9 response and imaging response, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Two hundred sixty-seven patients (63.3%) had a CA 19-9 response. A CA 19-9 response was observed in 123 of 132 (93.2%) radiologic responders and in 144 of 290 (49.7%) radiologic nonresponders (p < .001). CA 19-9 responders outperformed nonresponders in median PFS (10.6 vs. 3.6 months; hazard ratio [HR], 4.8 months; 95% confidence interval [CI], 3.8-6.0 months; p < .001) and OS (21.4 vs. 6.3 months; HR, 5.3 months; 95% CI, 4.2-6.7 months; p < .001). The common independent predictors of both OS and PFS included metastasis, CA 19-9 nonresponder status, and radiologic nonresponder status in multivariable analysis. CONCLUSIONS: CA 19-9 response is a valuable addition to assess tumor response and is associated with improved outcomes in patients with iCCA. Achieving a CA 19-9 response should be one of the therapeutic objectives of patients with iCCA after systemic therapies. PLAIN LANGUAGE SUMMARY: A decline in carbohydrate antigen 19-9 levels from elevated baseline levels should be one of the therapeutic aims of patients with intrahepatic cholangiocarcinoma who are managed with systemic therapies.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Estudos Prospectivos , Colangiocarcinoma/tratamento farmacológico , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos/patologia , Carboidratos/uso terapêutico , Estudos Retrospectivos
6.
Inorg Chem ; 62(12): 4747-4751, 2023 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-36920034

RESUMO

1ReH•Cl, a highly robust and antiaromatic rhenium(I) complex of triarylrosarin, is synthesized. The 1H NMR spectrum of 1ReH•Cl shows upfield-shifted pyrrole protons and highly downfield-shifted inner protons that confirm its antiaromatic nature, with density functional theory calculations strongly supporting this interpretation. Antiaromatic 1ReH•Cl absorbs from the UV to near-IR region of the optical spectrum; cyclic voltammetry, thin-layer UV-vis spectroelectrochemistry, and spin-density distributions clearly reveal that the rosarin backbone of 1ReH•Cl undergoes redox chemistry. The X-ray structure of 1ReH•Cl shows a fully coordinated and protonated inner cavity that effectively prevents proton-coupled electron transfer when treated with an acid. A remarkably negative NICS(0) value, clockwise anisotropy of the induced current density ring current, and the aromatic shielded inner cavity in the 2D ICSS(0) map reveal that the T1 state of 1ReH•Cl is aromatic based on Baird's rule.

7.
BMC Med Imaging ; 23(1): 207, 2023 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-38082242

RESUMO

PURPOSE: The purpose of this study was to investigate the clinical utility of three-dimension (3D) high-resolution inversion recovery (IR)-prepared fast spoiled gradient-recalled (SPGR) magnetic resonance imaging (MRI) in the diagnosis of cranial nerve meningeal carcinomatosis (MC). METHODS: A total of 114 patients with MC from January 2015 to March 2020 were enrolled and their MRIs were analyzed retrospectively. All patients underwent MRIs before being administered a contrast agent. Both a 2D conventional MRI sequence and a 3D IR-prepared fast SPGR high-resolution T1-weighted (BRAVO) scan sequence were measured after contrast agent administration. The characteristics of MC and the involved cranial nerves were then examined. RESULTS: Among the 114 MC patients, 81 (71.05%) had cranial nerve enhancement on contrast-enhanced 3D-BRAVO imaging, while only 41 (35.96%) had image enhancement on conventional MRI. The contrast-enhanced 3D-BRAVO displayed stronger image contrast enhancement of the cranial nerves than the conventional MRI (P < 0.001). Furthermore, detection rates for the facial and auditory nerves, trigeminal nerve, oculomotor nerve, sublingual nerve, optic nerve, glossopharyngeal/vagal/accessory nerve, and abductor nerve on contrast-enhanced 3D-BRAVO imaging were 58.77%, 47.37%, 9.65%, 8.77%, 5.26%, 3.51%, and 0.88%, respectively. We found a statistically significant difference between the affected facial and auditory nerves, as well as the trigeminal nerve, oculomotor nerve, sublingual nerve, and optic nerve. CONCLUSION: In MC, contrast-enhanced 3D-BRAVO imaging displayed the cranial nerves more effectively than 2D conventional enhanced MRI. The facial, auditory, and trigeminal nerves are the primary nerves involved in MC, and improved scanning of these nerves would aid in the early detection and treatment of MC.


Assuntos
Meios de Contraste , Carcinomatose Meníngea , Humanos , Estudos Retrospectivos , Carcinomatose Meníngea/diagnóstico por imagem , Carcinomatose Meníngea/patologia , Nervos Cranianos/diagnóstico por imagem , Nervos Cranianos/patologia , Imageamento por Ressonância Magnética/métodos , Imageamento Tridimensional/métodos
8.
Molecules ; 28(15)2023 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-37570790

RESUMO

The objectives of this study were (1) to investigate the effect of extracts from some plants in the families Nelumbonaceae and Nymphaeaceae on phosphodiesterase 5 (PDE5) and arginase, which have been used in erectile dysfunction treatment, and (2) to isolate and identify the compounds responsible for such activities. The characterization and quantitative analysis of flavonoid constituents in the active extracts were performed by HPLC. Thirty-seven ethanolic extracts from different parts of plants in the genus Nymphaea and Victoria of Nymphaeaceae and genus Nelumbo of Nelumbonaceae were screened for PDE5 and arginase inhibitory activities. The ethanolic extracts of the receptacles and pollens of Nelumbo nucifera Gaertn., petals of Nymphaea cyanea Roxb. ex G.Don, Nymphaea stellata Willd., and Victoria amazonica (Poepp.) Sowerby and the petals and receptacles of Nymphaea pubescens Willd. showed IC50 values on PDE5 of less than 25 µg/mL while none of the extracts showed effects on arginase. The most active extract, N. pubescens petal extract, was fractionated to isolate and identify the PDE5 inhibitors. The results showed that six flavonoid constituents including quercetin 3'-O-ß-xylopyranoside (1), quercetin 3-methyl ether 3'-O-ß-xylopyranoside (2), quercetin (3), 3-O-methylquercetin (4), kaempferol (5) and 3-O-methylkaempferol (6) inhibited PDE5 with IC50 values at the micromolar level.


Assuntos
Nelumbo , Nelumbonaceae , Nymphaea , Nymphaeaceae , Humanos , Masculino , Quercetina , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Arginase , Extratos Vegetais/farmacologia , Flavonoides/análise
9.
Angew Chem Int Ed Engl ; 62(44): e202313122, 2023 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-37707123

RESUMO

The regioselectivity of C-H functionalization is commonly achieved by directing groups, electronic factors, or steric hindrance, which facilitate the identification of reaction sites. However, such strategies are less effective for reactants such as simple monofluoroarenes due to their relatively low reactivity and the modest steric demands of the fluorine atom. Herein, we present an undirected gold-catalyzed para-C-H arylation of a wide array of monofluoroarenes using air-stable aryl silanes and germanes at room temperature. A high para-regioselectivity (up to 98 : 2) can be realized by utilizing a dinuclear dppm(AuOTs)2 (dppm=bis(diphenylphosphino)methane) as the catalyst and hexafluorobenzene as the solvent. This provides a general and practical protocol for the concise construction of structurally diverse para-arylated monofluoroarenes through C-H activation manner. It features excellent functional group tolerance and a broad substrate scope (>80 examples). Besides, this strategy is also robust for other simple monosubstituted arenes and heteroarenes. Our mechanistic studies and theoretical calculations suggest that para-C-H selectivity arises from highly electrophilic and structurally flexible dinuclear Ar-Au(III)-Au(I) species, coupled with noncovalent interaction induced by hexafluorobenzene.

10.
Angew Chem Int Ed Engl ; 62(26): e202218148, 2023 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-37103924

RESUMO

The frequent mutation of KRAS oncogene in some of the most lethal human cancers has spurred incredible efforts to develop KRAS inhibitors, yet only one covalent inhibitor for the KRASG12C mutant has been approved to date. New venues to interfere with KRAS signaling are desperately needed. Here, we report a "localized oxidation-coupling" strategy to achieve protein-specific glycan editing on living cells for disrupting KRAS signaling. This glycan remodeling method exhibits excellent protein and sugar specificity and is applicable to different donor sugars and cell types. Attachment of mannotriose to the terminal galactose/N-acetyl-D-galactosamine epitopes of integrin αv ß3 , a membrane receptor upstream of KRAS, blocks its binding to galectin-3, suppresses the activation of KRAS and downstream effectors, and mitigates KRAS-driven malignant phenotypes. Our work represents the first successful attempt to interfere with KRAS activity by manipulating membrane receptor glycosylation.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias Pulmonares/patologia , Mutação , Polissacarídeos , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais
11.
J Org Chem ; 87(13): 8685-8696, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35699523

RESUMO

A unified route for the total synthesis of three tetracyclic diquinane Lycopodium alkaloids (+)-paniculatine, (-)-magellanine, and (+)-magellaninone has been accomplished in 13-14 overall steps based on late-stage diverse transformations from an advanced tetracyclic common intermediate. In the established synthesis, quick formation of the two five-membered rings was efficiently achieved by an intramolecular reductive coupling of ketone-carbonyl and ester-carbonyl and an organocatalytic intramolecular Michael addition of aldehyde-derived enamine to an internal enone functionality with satisfactory redox and step economies and excellent stereoselectivities, providing the requisite tricyclic carbo-framework possessing multiple dense stereogenic centers, and an intramolecular reductive amination finally furnished the essential piperidine ring.


Assuntos
Alcaloides , Lycopodium , Compostos Heterocíclicos de 4 ou mais Anéis , Estrutura Molecular , Estereoisomerismo
12.
J Integr Plant Biol ; 64(10): 1856-1859, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35962717

RESUMO

A CRISPR/LbCas12a-based nucleic acid detection method that uses crude leaf extracts as samples and is rapid (≤40 min for a full run) and highly sensitive (0.01%) can be used to monitor genetically modified organisms in the field.


Assuntos
Sistemas CRISPR-Cas , Ácidos Nucleicos , Sistemas CRISPR-Cas/genética , Produtos Agrícolas/genética , Plantas Geneticamente Modificadas/genética , Extratos Vegetais , Técnicas de Amplificação de Ácido Nucleico/métodos
13.
Biochem Genet ; 59(6): 1599-1616, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34009493

RESUMO

Plant 14-3-3 proteins play key roles in regulating growth, development, and stress responses. However, little is known about this gene family in papaya (Carica papaya L.). We characterized eight 14-3-3 genes from the papaya genome and designed them as CpGRF1-8. Based on phylogenetic, conserved motif, and gene structure analyses, papaya CpGRFs were divided into ε and non-ε groups. Expression analysis showed differential and class-specific transcription patterns in different organs. Quantitative real-time polymerase chain reaction analysis showed that most CpGRFs had large changes in expression during fruit development and ripening. This indicated that the CpGRFs were involved in regulating fruit development and ripening. Significant expression changes occurred after cold, salt, and drought treatments in papaya seedlings, indicating that CpGRFs were also involved in signaling responses to abiotic stress. These results provide a transcription profile of 14-3-3 genes in organs, during fruit development and ripening and in response to stress. Some highly expressed, fruit-specific, and stress-responsive candidate CpGRFs will be identified for further genetic improvement of papayas.


Assuntos
Carica , Carica/genética , Carica/metabolismo , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética
14.
J Craniofac Surg ; 31(2): 404-407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31856137

RESUMO

Bilateral palpebral fissures (PF) are rarely symmetrical. Palpebral plastic surgery is common in the Chinese population. This study aimed to assess the classification of obviously asymmetric palpebral fissures (OAPF). In addition, double eyelid surgery-based correction for the primary subtype was examined. Various clinical signs and etiologies were examined, and OAPF were classified into 3 subtypes: primary, secondary, and aging. For the secondary and aging subtypes, curative surgeries target the relevant underlying conditions. Patients with the primary subtype underwent corrective surgery based on double eyelid operation. After 8 to 12 months of follow-up, the corrective effects of different surgeries were evaluated in patients (n = 48) with primary OAPF. Satisfying look was obtained in all 48 cases, with smooth double eyelid lines and shapes, and no overt asymmetry between the 2 eyes. Thirteen patients developed hypophasis after levator plication, which was resolved within 1 month. Preoperative and postoperative PF were significantly different (1.48 ±â€Š0.24 versus 0.19 ±â€Š0.09 mm; P < 0.05). Overall, patients with OAPF can be classified into the primary, secondary, and aging subtypes. The 48 cases with the primary subtype showed a satisfying look after double eyelid surgery-based correction.


Assuntos
Pálpebras/cirurgia , Adulto , Blefaroplastia , Feminino , Humanos , Pessoa de Meia-Idade , Satisfação Pessoal , Período Pós-Operatório , Procedimentos de Cirurgia Plástica , Adulto Jovem
15.
J Cell Biochem ; 120(4): 6614-6623, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30368887

RESUMO

Infantile hemangioma (IH) is a common benign tumor. Human umbilical vein endothelial cells (HUVECs) have the potential of stem cells, which has been widely used in vascular endothelial cell experiments. Oral propranolol was first reported to treat hemangioma in 2008. However, the role of propranolol in IH remains unclear. Therefore, in this study, we investigated the effects of propranolol on HUVECs in vitro, to explore the underlying mechanism of propranolol in IH. HUVECs were treated with 0.15, 1.5, and 15 µM of propranolol, and transfected with microRNA-4295 (miR-4295) mimic. Cell viability, migration, and apoptosis were examined using Cell Counting Kit-8, transwell assay, and flow cytometry analysis, respectively. In addition, the expressions and concentrations of miR-4295, vascular endothelial growth factor (VEGF), VEGF-A, FLT1, FLT2, and FOXF1 were assessed using real-time polymerase chain reaction, Western blot assay, and enzyme-linked immunosorbent assay. We found that 15 µM of propranolol decreased HUVEC viability the most. Then, cell migration and the concentrations of VEGF and VEGF-A were reduced, and apoptosis was increased when treated with propranolol. Meanwhile, the expressions of VEGF, VEGF-A, FLT1, FLT2, and FOXF1 were downregulated by propranolol exposure. Further study showed that miR-4295 expression was upregulated in IH tissues, and propranolol treatment downregulated miR-4295 expression in HUVECs. MiR-4295 overexpression alleviated the reductions of viability, migration, and factors expression, as well as the increase of apoptosis. Propranolol suppressed HUVEC viability, migration, the expression of VEGF, VEGF-A, FLT1/2, FOXF1, and promoted apoptosis via downregulation of miR-4295. This study lays a foundation for further study of the effect of propranolol on IH.


Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/patologia , MicroRNAs/genética , Propranolol/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Vasodilatadores/farmacologia
16.
J Cell Biochem ; 120(9): 15625-15634, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31081145

RESUMO

Immoderate proliferation and deposition of collagen generally result in hypertrophic scars and even keloids. microRNA-29 (miR-29) has been proved as a crucial regulator in these pathological processes. Although mounting evidence have proved baicalein (BAI) impairs scar formation, it is still incompletely understood whether miR-29 participated in the underlying mechanism. In the present study, NIH-3T3 cells were stimulated with BAI, and then cell viability was analyzed by cell counting kit-8 (CCK-8) and Western blot. We further analyzed total soluble collagen, collagen 1, and alpha-smooth muscle actin (α-SMA) in NIH-3T3 cells, which were exposed to transforming growth factor beta 1 (TGF-ß1)/BAI, using a Sircol assay kit, quantitative reverse transcription-PCR (qRT-PCR) and Western blot, respectively. Besides, the miR-29 inhibitor was transduced and its transfection efficiency was verified by qRT-PCR. Finally, the phosphorylated p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) were examined by Western blot. BAI effectively retarded NIH-3T3 proliferation in a dose-dependent manner. Besides, TGF-ß1-induced deposition of total soluble collagen and synthesis of collagen 1 and α-SMA were repressed by BAI at mRNA and protein levels. However, miR-29 inhibitor reversed the effects of BAI. Remarkably, BAI promoted phosphorylated expression of p38MAPK and JNK while miR-29 inhibitor reversed its effects on the phosphorylated expression of p38MAPK and JNK. BAI effectively weakened the cell viability and repressed TGF-ß1-induced total soluble collagen as well as collagen 1 and α-SMA by upregulating miR-29. Mechanically, BAI activates the p38MAPK/JNK pathway by promoting miR-29.


Assuntos
Actinas/genética , Cicatriz Hipertrófica/tratamento farmacológico , MicroRNAs/genética , Fator de Crescimento Transformador beta1/genética , Animais , Proliferação de Células , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/metabolismo , Cicatriz Hipertrófica/patologia , Colágeno/metabolismo , Flavanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , MAP Quinase Quinase 4/genética , Camundongos , Células NIH 3T3 , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética
17.
Crit Care ; 23(1): 106, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944018

RESUMO

BACKGROUND: Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis. METHODS: We assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages. RESULTS: Therapeutic administration of flagellin increased bacterial clearance, decreased organ inflammation and injury, and reduced immune cell apoptosis after experimental sepsis, in a Toll-like receptor 5 (TLR5)-dependent manner. Macrophages, but not neutrophils, mediated the beneficial effects of flagellin on experimental sepsis, and flagellin induced macrophage polarization into M1 in septic mice. Flagellin treatment could directly enhance phagocytosis and bacterial killing of macrophages, but not neutrophils. Subsequent studies demonstrated that flagellin could promote phagosome formation and increase reactive oxygen species (ROS) levels in macrophages. Finally, we found that the expression of TLR5 was significantly elevated on the surface of circulating monocytes, but not neutrophils, from patients with sepsis. Higher expression levels of TLR5 on monocytes were associated with increased mortality, documented bacteremia, and higher Sequential Organ Failure Assessment scores of the septic patients. Moreover, flagellin treatment rescued the impaired phagocytosis and bacterial killing ability of monocytes/macrophages from patients who died of sepsis. CONCLUSIONS: These novel findings not only established the potential value of application of flagellin as an immunoadjuvant in treating sepsis, but also provided new insights into targeted therapeutic strategy on the basis of monocyte TLR5 expression in septic patients.


Assuntos
Flagelina/farmacologia , Sepse/tratamento farmacológico , Receptor 5 Toll-Like/análise , Animais , Carga Bacteriana/estatística & dados numéricos , Modelos Animais de Doenças , Flagelina/uso terapêutico , Inflamação/sangue , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Fatores de Proteção , Sepse/fisiopatologia , Análise de Sobrevida , Receptor 5 Toll-Like/sangue
18.
Int J Hyperthermia ; 36(1): 1239-1245, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31818160

RESUMO

Aim: To compare the effects of the liquid-isolating maneuver and the lever-elevating maneuver in protecting cervical structures during microwave ablation for treating high-risk benign thyroid nodules.Methods: This prospectively study was approved by the Medical Ethics Committee of Panzhihua Central Hospital. A total of 174 patients were enrolled and randomly assigned to a liquid-isolating maneuver group (LIM, n = 87) or a lever-elevating maneuver group (LEM, n = 87). Operation time, postoperative voice change, time to recovery of baseline voice, peri-thyroid hematoma, neck tension, and intraoperative vasovagal reaction were assessed.Results: Operation time was greater in the LIM group than in the LEM group (44.75 ± 13.14 vs. 32.87 ± 10.84 min; p = .017).Voice changes were observed in 6 patients in the LIM group and 2 in the LEM group (6.9% vs. 2.3%, p = .278). The time to recovery of baseline voice was significantly greater in the LIM group compared with the LEM group (36.15 ± 10.24 vs. 24.48 ± 11.53 days, p = .014). The incidences of peri-thyroid hematoma and neck tension were higher in the LIM than in the LEM group (11.5% vs. 3.4%, 10.3% vs. 2.3%, p = .044 and p = .029). One patient (1.1%) in the LEM group and none of the patients in the LIM group experienced a vasovagal response (p = 1.000).Conclusion: The lever-elevating method is feasible and effective for the microwave ablation of benign thyroid nodules, with better protection of neck structures than observed with the liquid-isolating method.


Assuntos
Técnicas de Ablação/métodos , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/cirurgia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Nódulo da Glândula Tireoide/patologia , Resultado do Tratamento , Adulto Jovem
19.
PLoS Comput Biol ; 13(4): e1005441, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28406988

RESUMO

A high level of HER2 expression in breast cancer correlates with a higher tumor growth rate, high metastatic potential, and a poor long-term patient survival rate. Pertuzumab, a human monoclonal antibody, can reduce the effect of HER2 overexpression by preventing HER2 dimerization. In this study, a combination protocol of molecular dynamics modeling and MM/GBSA binding free energy calculations was applied to design peptides that interact with HER2 based on the HER2/pertuzumab crystal structure. Based on a ß hairpin in pertuzumab from Glu46 to Lys65-which plays a key role in interacting with HER2-mutations were carried out in silico to improve the binding free energy of the hairpin that interacts with the Phe256-Lys314 of the HER2 protein. Combined the use of one-bead-one-compound library screening, among all the mutations, a peptide (58F63Y) with the lowest binding free energy was confirmed experimentally to have the highest affinity, and it may be used as a new probe in diagnosing and treating HER2-positive breast cancer.


Assuntos
Anticorpos Monoclonais Humanizados/química , Genes erbB-2 , Sondas Moleculares , Neoplasias/diagnóstico por imagem , Peptídeos/química , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Simulação de Dinâmica Molecular , Mutação , Neoplasias/genética , Homologia de Sequência de Aminoácidos , Ressonância de Plasmônio de Superfície
20.
Int Orthop ; 42(8): 1911-1916, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29318360

RESUMO

PURPOSE: The purpose of this study was to introduce a novel method of percutaneous achievement and maintenance of reduction for acute displaced scaphoid fractures and evaluate the feasibility of this method in treating acute displaced scaphoid fractures as well as explore its indications. METHODS: From February 2012 to March 2014, 15 patients with acute displaced scaphoid fractures were treated with our technique. Two Kirschner wires were used to achieve and maintain the reduction of the scaphoid fractures throughout the entire process of the traditional percutaneous screw fixation process. The following parameters including function scores according to modified Mayo wrist scoring system, range of motion (ROM) of the wrist, grip strength, pinch strength, healing time, time to return to work, and final outcomes were recorded. RESULT: All patients were followed up with a mean period of 2.5 years (range, 2-3.5 years). All fractures healed with a mean of 9.3 weeks (range, 7-11.5 weeks). All patients returned to pre-injury level of activity within six weeks. The functional scores averaged 90.3 (range, 80-100). ROM of the wrist was equal to that of the contralateral side at three months postoperatively. Grip strength and pinch strength compared with contralateral were 98% and 92%, respectively. All were satisfied with the final outcomes. CONCLUSIONS: Our technique is successfully performed in acute displaced scaphoid fractures resulting in shortened immobilization and prompt functional recovery. It broadens the indications of the percutaneous method, which means the advantages of the percutaneous method are maximally reserved whilst the drawbacks of open reduction were avoided.


Assuntos
Fratura-Luxação/cirurgia , Fixação Interna de Fraturas/métodos , Redução Aberta/métodos , Osso Escafoide/lesões , Traumatismos do Punho/cirurgia , Adolescente , Adulto , Parafusos Ósseos/efeitos adversos , Fios Ortopédicos/efeitos adversos , Feminino , Seguimentos , Consolidação da Fratura , Força da Mão , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Amplitude de Movimento Articular , Recuperação de Função Fisiológica , Retorno ao Trabalho/estatística & dados numéricos , Osso Escafoide/cirurgia , Articulação do Punho/cirurgia , Adulto Jovem
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