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1.
Surg Endosc ; 37(5): 4104-4110, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37072636

RESUMEN

BACKGROUND: An optimal method for digestive tract reconstruction (DTR) in laparoscopic radical resection of Siewert type II adenocarcinoma of esophagogastric junction (AEG) has not yet been standardized. The aim of this study was to evaluate the safety and feasibility of a hand-sewn esophagojejunostomy (EJ) technique during transthoracic single-port assisted laparoscopic esophagogastrectomy (TSLE) for Siewert type II AEG with esophageal invasion > 3 cm. METHODS: The perioperative clinical data and short-term outcomes for patients who underwent TSLE using hand-sewn EJ for Siewert type II AEG with esophageal invasion > 3 cm between March 2019 and April 2022 have been retrospectively reviewed. RESULTS: A total of 25 patients were eligible. All 25 patients were successfully operated. None was converted to open surgery or mortality. 84.00% of patients were male and 16.00% were female. The mean age, body mass index (BMI), and the American Society of Anesthesiologists (ASA) score were 67.88 ± 8.10 years, 21.30 ± 2.80 kg/m2, and 2.08, respectively. The average incorporated operative and hand-sewn EJ procedural times were 274.92 ± 57.46 and 23.36 ± 3.00 min, respectively. The length of extracorporeal esophageal involvement and proximal margin was 3.31 ± 0.26 cm and 3.12 ± 0.12 cm, respectively. The average time for the first oral feeding and hospital stay were 6 (3-14) and 7 (3-18) days, respectively. Two patients (8.00%) developed postoperative grade IIIa complications according to the Clavien-Dindo classification, including 1 case of pleural effusion and 1 case of anastomotic leakage, both of whom were cured by puncture drainage. CONCLUSION: Hand-sewn EJ in TSLE is safe and feasible for Siewert type II AEG. This method can ensure safe proximal margins and could be a good option with an advanced endoscopic suture technique for type II tumor with esophageal invasion > 3 cm.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Laparoscopía , Neoplasias Gástricas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Unión Esofagogástrica/cirugía , Unión Esofagogástrica/patología , Neoplasias Esofágicas/patología , Neoplasias Gástricas/patología , Adenocarcinoma/patología , Laparoscopía/métodos , Gastrectomía/métodos , Complicaciones Posoperatorias/etiología
2.
Sensors (Basel) ; 23(14)2023 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-37514717

RESUMEN

The most significant technical challenges of current aerial image object-detection tasks are the extremely low accuracy for detecting small objects that are densely distributed within a scene and the lack of semantic information. Moreover, existing detectors with large parameter scales are unsuitable for aerial image object-detection scenarios oriented toward low-end GPUs. To address this technical challenge, we propose efficient-lightweight You Only Look Once (EL-YOLO), an innovative model that overcomes the limitations of existing detectors and low-end GPU orientation. EL-YOLO surpasses the baseline models in three key areas. Firstly, we design and scrutinize three model architectures to intensify the model's focus on small objects and identify the most effective network structure. Secondly, we design efficient spatial pyramid pooling (ESPP) to augment the representation of small-object features in aerial images. Lastly, we introduce the alpha-complete intersection over union (α-CIoU) loss function to tackle the imbalance between positive and negative samples in aerial images. Our proposed EL-YOLO method demonstrates a strong generalization and robustness for the small-object detection problem in aerial images. The experimental results show that, with the model parameters maintained below 10 M while the input image size was unified at 640 × 640 pixels, the APS of the EL-YOLOv5 reached 10.8% and 10.7% and enhanced the APs by 1.9% and 2.2% compared to YOLOv5 on two challenging aerial image datasets, DIOR and VisDrone, respectively.

3.
Antimicrob Agents Chemother ; 66(1): e0187621, 2022 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-34780263

RESUMEN

HIV-1 maturation inhibitors (MIs) offer a novel mechanism of action and potential for use in HIV-1 treatment. Prior MIs displayed clinical efficacy but were associated with the emergence of resistance and some gastrointestinal tolerability events. Treatment with the potentially safer next-generation MI GSK3640254 (GSK'254) resulted in up to a 2-log10 viral load reduction in a phase IIa proof-of-concept study. In vitro experiments have defined the antiviral and resistance profiles for GSK'254. The compound displayed strong antiviral activity against a library of subtype B and C chimeric viruses containing Gag polymorphisms and site-directed mutants previously shown to affect potency of earlier-generation MIs, with a mean protein-binding adjusted 90% effective concentration (EC90) of 33 nM. Furthermore, GSK'254 exhibited robust antiviral activity against a panel of HIV-1 clinical isolates, with a mean EC50 of 9 nM. Mechanistic studies established that bound GSK'254 dissociated on average 7.1-fold more slowly from wild-type Gag virus-like particles (VLPs) than a previous-generation MI. In resistance studies, the previously identified A364V Gag region mutation was selected under MI pressure in cell culture and during the phase IIa clinical study. As expected, GSK'254 inhibited cleavage of p25 in a range of polymorphic HIV-1 Gag VLPs. Virus-like particles containing the A364V mutation exhibited a p25 cleavage rate 9.3 times higher than wild-type particles, providing a possible mechanism for MI resistance. The findings demonstrate that GSK'254 potently inhibits a broad range of HIV-1 strains expressing Gag polymorphisms.


Asunto(s)
VIH-1 , Triterpenos , Farmacorresistencia Viral/genética , Succinatos/farmacología , Triterpenos/farmacología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo
4.
BMC Cancer ; 22(1): 927, 2022 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-36030215

RESUMEN

BACKGROUND: Transthoracic single-port assisted laparoscopic five-step maneuver inferior mediastinal lymphadenectomy for Siewert type II adenocarcinoma of esophagogastric junction (AEG) has superiority in lower mediastinal lymph nodes dissection and digestive tract reconstruction. However, the right pleura was probably ruptured in this surgical technique. The aim of this study was to explore whether the infracardiac bursa (ICB) exposed could protect right pleura. METHODS: We retrospectively collected and evaluated the clinical and pathological data of patients who underwent five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymphadenectomy for Siewert II AEG at Guangdong Provincial Hospital of Chinese Medicine between May 2017 and February 2022. RESULTS: A total of 49 patients were eligible, including 31 patients in ICB exposed group (group A) and 18 patients in ICB unexposed group (group B). There were no statistically significant differences in baseline characteristics between the two groups. 4 patients (12.9%) had right pleura rupture in group A, while 14 patients (77.8%) in group B, and the difference was statistically significant (p < 0.001). Compared with group B, the extubation time of endotracheal intubation (10.0 (6.0 ~ 12.0) vs. 13.0 (8.0 ~ 15.0) min, p = 0.003) and thoracic drainage tube stay (6.0 (5.0 ~ 7.0) vs. 8.0 (6.0 ~ 10.5) days, p = 0.041) were significantly shorted in the group A. The drainage volume of thorax (351.61 ± 125.00 vs. 418.61 ± 207.86 mL, p = 0.146) was non-significant less and the rate of complications (3.2% vs. 11.1%, p = 0.074) was non-significant lower in group A compared with group B. The postoperative hospital stay (9.0 (8.0,13.0) vs. 9.0 (8.0,12.0) days, p = 0.983) were similar in two groups. No serious adverse event occurred in any patient. CONCLUSIONS: The ICB exposed could protect the right pleura and may promote postoperative recovery, which may be used as an anatomical marker in inferior mediastinal lymphadenectomy.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Laparoscopía , Neoplasias Gástricas , Unión Esofagogástrica , Gastrectomía , Humanos , Escisión del Ganglio Linfático , Pleura , Estudios Retrospectivos
5.
Proc Natl Acad Sci U S A ; 115(13): 3249-3254, 2018 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-29531094

RESUMEN

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Apoproteínas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Células HeLa , Hemo/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Concentración 50 Inhibidora , Mioglobina/química
6.
Bioorg Med Chem Lett ; 30(3): 126784, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31761656

RESUMEN

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.


Asunto(s)
Amidas/química , Inhibidores de Integrasa VIH/química , Integrasa de VIH/química , VIH-1/enzimología , Compuestos Heterocíclicos con 3 Anillos/química , Animales , Sitios de Unión , Dominio Catalítico , Farmacorresistencia Viral/efectos de los fármacos , Integrasa de VIH/genética , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/metabolismo , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Semivida , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Simulación de Dinámica Molecular , Mutación , Ratas , Relación Estructura-Actividad
7.
Bioorg Med Chem ; 28(13): 115541, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32389483

RESUMEN

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir.


Asunto(s)
Antivirales/síntesis química , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/síntesis química , Integrasa de VIH/metabolismo , Imidazoles/síntesis química , Pirrolidinonas/química , Antivirales/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Quimioterapia Combinada , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Humanos , Imidazoles/farmacología , Mutación , Quinolonas/farmacología , Raltegravir Potásico/farmacología , Relación Estructura-Actividad
8.
Ecotoxicol Environ Saf ; 190: 110089, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31896472

RESUMEN

The use of algae to adsorb heavy metals is an efficient and environmentally friendly treatment for contaminated water and has attracted widespread research attention. In this study, a meta-analysis of the heavy metal adsorption capacity of algae from five different phyla and the factors influencing these capacities was conducted. Phaeophyta was found to have a high heavy metal adsorption capacity, whereas Bacillariophyta had a relatively low adsorption capacity; Chlorophyta, Rhodophyta, and Cyanophyta had moderate adsorption capacities. Non-living algae were more effective in practical applications than living algae were. Algal biomass had a relatively high adsorption efficiency of 1-10 g/L, which did not increase significantly when algal concentration increased. The algal adsorption efficiency for initial heavy metal concentrations of 10-100 mg/L was higher than for concentrations of greater than 100 mg/L. The results further show that algal adsorption of heavy metals reached a maximum capacity of 80-90% within 20 min. Heavy metal adsorption by algae was not temperature-dependent, and it was more effective in moderately to weakly acidic environments (pH = 4-7.5). Considering these aspects for practical applications, algae from some phyla can effectively be used for heavy metal biosorption in contaminated water.


Asunto(s)
Chlorophyta/metabolismo , Metales Pesados/metabolismo , Contaminantes Químicos del Agua/metabolismo , Adsorción , Biomasa , Concentración de Iones de Hidrógeno , Phaeophyceae , Rhodophyta , Temperatura
9.
PLoS Pathog ; 12(11): e1005990, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27893830

RESUMEN

HIV-1 maturation inhibitors (MIs) disrupt the final step in the HIV-1 protease-mediated cleavage of the Gag polyprotein between capsid p24 capsid (CA) and spacer peptide 1 (SP1), leading to the production of infectious virus. BMS-955176 is a second generation MI with improved antiviral activity toward polymorphic Gag variants compared to a first generation MI bevirimat (BVM). The underlying mechanistic reasons for the differences in polymorphic coverage were studied using antiviral assays, an LC/MS assay that quantitatively characterizes CA/SP1 cleavage kinetics of virus like particles (VLPs) and a radiolabel binding assay to determine VLP/MI affinities and dissociation kinetics. Antiviral assay data indicates that BVM does not achieve 100% inhibition of certain polymorphs, even at saturating concentrations. This results in the breakthrough of infectious virus (partial antagonism) regardless of BVM concentration. Reduced maximal percent inhibition (MPI) values for BVM correlated with elevated EC50 values, while rates of HIV-1 protease cleavage at CA/SP1 correlated inversely with the ability of BVM to inhibit HIV-1 Gag polymorphic viruses: genotypes with more rapid CA/SP1 cleavage kinetics were less sensitive to BVM. In vitro inhibition of wild type VLP CA/SP1 cleavage by BVM was not maintained at longer cleavage times. BMS-955176 exhibited greatly improved MPI against polymorphic Gag viruses, binds to Gag polymorphs with higher affinity/longer dissociation half-lives and exhibits greater time-independent inhibition of CA/SP1 cleavage compared to BVM. Virological (MPI) and biochemical (CA/SP1 cleavage rates, MI-specific Gag affinities) data were used to create an integrated semi-quantitative model that quantifies CA/SP1 cleavage rates as a function of both MI and Gag polymorph. The model outputs are in accord with in vitro antiviral observations and correlate with observed in vivo MI efficacies. Overall, these findings may be useful to further understand antiviral profiles and clinical responses of MIs at a basic level, potentially facilitating further improvements to MI potency and coverage.


Asunto(s)
Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral/genética , VIH-1/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Línea Celular , VIH-1/genética , Humanos , Pruebas de Sensibilidad Microbiana , Succinatos/farmacología , Triterpenos/farmacología , Ensamble de Virus/efectos de los fármacos
10.
Bioorg Med Chem Lett ; 28(12): 2124-2130, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29779976

RESUMEN

BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.


Asunto(s)
Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinonas/farmacología , Tiazinas/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/química , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/química
11.
Bioorg Med Chem Lett ; 28(9): 1550-1557, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29631960

RESUMEN

The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.


Asunto(s)
Aminas/farmacología , Fármacos Anti-VIH/farmacología , Diseño de Fármacos , VIH-1/efectos de los fármacos , Triterpenos/farmacología , Aminas/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Triterpenos Pentacíclicos , Relación Estructura-Actividad , Triterpenos/síntesis química , Triterpenos/química , Ácido Betulínico
12.
Surg Endosc ; 31(11): 4790-4798, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28389803

RESUMEN

BACKGROUND: Liver re-resection plays a paramount role in treatment of patients with posthepatectomy hepatocellular carcinoma (HCC) recurrence. Laparoscopic liver resection has been a feasible alternative to open surgery. However, whether laparoscopic liver re-resection for posthepatectomy HCC recurrence is better than open liver re-resection remains unknown. METHOD: From January 2008 to December 2015, 30 patients with recurrent HCC after prior liver resection underwent laparoscopic liver re-resection in our center. To minimize any confounding factors, a propensity score matching study using a patient ratio of 1:1 was conducted to compare the short- and long-term outcomes of patients who underwent laparoscopic or open liver re-resection. RESULT: With the open surgery group compared laparoscopic group, operative time was 207.50 versus 200.5 min (p = 0.903), blood loss was 400 versus 100 ml (p = 0.000196), blood transfusion rate was 43.3 versus 0.0% (p = 0.000046), complication rates were 30.0 versus 6.7% (p = 0.01), and hospital stay was 13.5 versus 9.5 days (p = 0.000008). The median follow-up was 35 months. The 1-year, 3-year, 5-year disease-free survival rates were 79.0, 51.0, and 31.9%, versus 78.3, 57.4, and 43.0%, respectively (p = 0.474). The 1-year, 3-year, and 5-year overall survival rates were 89.4, 75, and 67.5%, versus 96.7, 85.0, and 74.4%, respectively (p = 0.413). CONCLUSION: Laparoscopic liver re-resection for patients with posthepatectomy HCC recurrence provided comparable perioperative and oncological outcomes as open liver re-resection and can be a safe alternative to open procedure.


Asunto(s)
Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/cirugía , Adulto , Anciano , Carcinoma Hepatocelular/mortalidad , China , Supervivencia sin Enfermedad , Femenino , Hepatectomía/métodos , Humanos , Laparoscopía/métodos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Puntaje de Propensión , Estudios Retrospectivos , Resultado del Tratamiento
13.
Antimicrob Agents Chemother ; 60(7): 3956-69, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27090171

RESUMEN

BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat.


Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Farmacorresistencia Viral/genética , VIH-1/metabolismo , Humanos , Succinatos/farmacología , Triterpenos/farmacología , Replicación Viral/efectos de los fármacos
14.
Tumour Biol ; 37(3): 3461-8, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26449829

RESUMEN

Chemokine ligand 18 (CCL18) has been associated with hepatocellular carcinoma (HCC) metastasis. Here, we demonstrated a novel mechanism through which CCL18 enhances cell migration, invasion, and epithelial-mesenchymal transition (EMT) in HCC. (1) Using immunohistochemistry, we analyzed the expression of PITPNM3, a molecule that correlated with CCL18 signaling, in 149 HCC tissue specimens. The results showed that PITPNM3 expression is highly associated with tumor metastasis and differentiation; (2) in vitro experiments showed that CCL18 enhances cell migration, invasion, and EMT in PITPNM3((+)) HCC cells but not in PITPNM3((-)) cells. Silencing of PITPNM3 by short interfering RNA (siRNA) inhibited the induction of cell migration, invasion, and EMT by CCL18; (3) Cell migration, invasion, and EMT induced by CCL18 accompanied with the phosphorylation of IKK and IKBα as well as p65 nuclear translocation in PITPNM3((+)) HCC cells, but not in the cells that PITPNM3 is silenced with siRNA, implying that the activation of NF-κB signaling is involved in the action of CCL18/PITPNM3. These results suggest that CCL18 enhances HCC cell migration, invasion, and EMT through the expression of PITPNM3 and the activation of the NF-κB signaling pathway.


Asunto(s)
Proteínas de Unión al Calcio/fisiología , Carcinoma Hepatocelular/patología , Quimiocinas CC/fisiología , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas/patología , Proteínas de la Membrana/fisiología , FN-kappa B/fisiología , Transducción de Señal/fisiología , Adulto , Anciano , Proteínas de Unión al Calcio/análisis , Línea Celular Tumoral , Movimiento Celular , Femenino , Humanos , Masculino , Proteínas de la Membrana/análisis , Persona de Mediana Edad , Invasividad Neoplásica
15.
Bioorg Med Chem ; 24(8): 1757-70, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26968652

RESUMEN

A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.


Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/crecimiento & desarrollo , Triterpenos/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/virología , Estructura Molecular , Ratas , Relación Estructura-Actividad , Triterpenos/síntesis química , Triterpenos/química , Replicación Viral/efectos de los fármacos
16.
Bioorg Med Chem Lett ; 25(3): 717-20, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25529736

RESUMEN

Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process.


Asunto(s)
Amidas/química , Inhibidores de Integrasa VIH/síntesis química , Integrasa de VIH/química , VIH-1/enzimología , Amidas/síntesis química , Amidas/farmacocinética , Animales , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/efectos de los fármacos , Semivida , Compuestos Heterocíclicos/química , Humanos , Masculino , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
17.
Brain Res ; 1825: 148705, 2024 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-38065285

RESUMEN

The mechanism of action of low-density lipoprotein receptor related protein 4 (LRP4) is mediated largely via the Agrin-LRP4-MuSK signalling pathway in the nervous system. LRP4 contributes to the development of synapses in the peripheral nervous system (PNS). It interacts with signalling molecules such as the amyloid beta-protein precursor (APP) and the wingless type protein (Wnt). Its mechanisms of action are complex and mediated via interaction between the pre-synaptic motor neuron and post-synaptic muscle cell in the PNS, which enhances the development of the neuromuscular junction (NMJ). LRP4 may function differently in the central nervous system (CNS) than in the PNS, where it regulates ATP and glutamate release via astrocytes. It mayaffect the growth and development of the CNS by controlling the energy metabolism. LRP4 interacts with Agrin to maintain dendrite growth and density in the CNS. The goal of this article is to review the current studies involving relevant LRP4 signaling pathways in the nervous system. The review also discusses the clinical and etiological roles of LRP4 in neurological illnesses, such as myasthenia gravis, Alzheimer's disease and epilepsy. In this review, we provide a theoretical foundation for the pathogenesis and therapeutic application of LRP4 in neurologic diseases.


Asunto(s)
Agrina , Proteínas Relacionadas con Receptor de LDL , Proteínas Relacionadas con Receptor de LDL/metabolismo , Agrina/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Unión Neuromuscular/metabolismo
18.
J Photochem Photobiol B ; 255: 112923, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38692166

RESUMEN

Accurately visualizing the intracellular trafficking of upconversion nanoparticles (UCNPs) loaded with phthalocyanines and achieving precise photodynamic therapy (PDT) using near-infrared (NIR) laser irradiation still present challenges. In this study, a novel NIR laser-triggered upconversion luminescence (UCL) imaging-guided nanoparticle called FA@TPA-NH-ZnPc@UCNPs (FTU) was developed for PDT. FTU consisted of UCNPs, folic acid (FA), and triphenylamino-phenylaniline zinc phthalocyanine (TPA-NH-ZnPc). Notably, TPA-NH-ZnPc showcases aggregation-induced emission (AIE) characteristic and NIR absorption properties at 741 nm, synthesized initially via molybdenum-catalyzed condensation reaction. The UCL emitted by FTU enable real-time visualization of their subcellular localization and intracellular trafficking within ovarian cancer HO-8910 cells. Fluorescence images revealed that FTU managed to escape from lysosomes due to the "proton sponge" effect of TPA-NH-ZnPc. The FA ligands on the surface of FTU further directed their transport and accumulation within mitochondria. When excited by a 980 nm laser, FTU exhibited UCL and activated TPA-NH-ZnPc, consequently generating cytotoxic singlet oxygen (1O2), disrupted mitochondrial function and induced apoptosis in cancer cells, which demonstrated great potential for tumor ablation.


Asunto(s)
Indoles , Rayos Infrarrojos , Isoindoles , Lisosomas , Mitocondrias , Nanopartículas , Compuestos Organometálicos , Fotoquimioterapia , Compuestos de Zinc , Compuestos de Zinc/química , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Indoles/química , Indoles/farmacología , Lisosomas/metabolismo , Humanos , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Nanopartículas/química , Línea Celular Tumoral , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Oxígeno Singlete/metabolismo , Femenino , Ácido Fólico/química
19.
Nanomicro Lett ; 16(1): 77, 2024 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-38190031

RESUMEN

Metal tellurides (MTes) are highly attractive as promising anodes for high-performance potassium-ion batteries. The capacity attenuation of most reported MTe anodes is attributed to their poor electrical conductivity and large volume variation. The evolution mechanisms, dissolution properties, and corresponding manipulation strategies of intermediates (K-polytellurides, K-pTex) are rarely mentioned. Herein, we propose a novel structural engineering strategy to confine ultrafine CoTe2 nanodots in hierarchical nanogrid-in-nanofiber carbon substrates (CoTe2@NC@NSPCNFs) for smooth immobilization of K-pTex and highly reversible conversion of CoTe2 by manipulating the intense electrochemical reaction process. Various in situ/ex situ techniques and density functional theory calculations have been performed to clarify the formation, transformation, and dissolution of K-pTex (K5Te3 and K2Te), as well as verifying the robust physical barrier and the strong chemisorption of K5Te3 and K2Te on S, N co-doped dual-type carbon substrates. Additionally, the hierarchical nanogrid-in-nanofiber nanostructure increases the chemical anchoring sites for K-pTex, provides sufficient volume buffer space, and constructs highly interconnected conductive microcircuits, further propelling the battery reaction to new heights (3500 cycles at 2.0 A g-1). Furthermore, the full cells further demonstrate the potential for practical applications. This work provides new insights into manipulating K-pTex in the design of ultralong-cycling MTe anodes for advanced PIBs.

20.
J Vis Exp ; (204)2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38407337

RESUMEN

Mid-pancreatectomy combined with end-to-end anastomosis is a surgical procedure used to treat benign pancreatic tumors. It involves removing the tumor from the middle section of the pancreas and connecting the proximal and distal ends through an anastomosis. The traditional surgical approach for resecting the middle segment of the pancreas involves closing the proximal pancreas and creating a Roux-en-Y anastomosis with the jejunum. However, this approach carries a double risk of pancreatic stump fistula and pancreatico enteric anastomotic leak postoperatively. In this paper, a new procedure is described where stent tubes were placed into the proximal and distal sides of the pancreatic ducts after ensuring sufficient freedom from the proximal distal pancreas. The pancreatic parenchyma was then sutured continuously under direct vision to achieve pancreatic end-to-end anastomosis. This procedure helps preserve pancreatic function, reducing the risk of postoperative pancreatic insufficiency. However, due to the complexity and risks involved, thorough evaluation and preparation are necessary before surgery. We carefully assess the patient's history, serology, and imaging results to determine the feasibility and effectiveness of the procedure. During surgery, we consider the use of a suitable pancreatic duct stent to ensure the flow of pancreatic juice into the intestine through physiological pathways. Our goal is to remove the tumor while preserving as much normal pancreatic tissue as possible for the anastomosis. After the operation, it is crucial to monitor the patient's pancreatic function, paying close attention to blood glucose levels, drainage fluid volume, and amylase value of the pancreatic anastomosis. During the postoperative follow-up visit, the patient's pancreatic function was assessed, and there was no significant change in quality of life compared to before the surgery. This indicates that mid-pancreatectomy combined with end-to-end anastomosis is a safe and effective procedure for treating pancreatic benign neoplasms.


Asunto(s)
Pancreatectomía , Neoplasias Pancreáticas , Humanos , Calidad de Vida , Páncreas/cirugía , Neoplasias Pancreáticas/cirugía , Anastomosis Quirúrgica
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