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1.
Bull Environ Contam Toxicol ; 109(3): 534-541, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35876846

RESUMEN

This study aims to investigate methylmercury (MeHg) demethylation processes in human gut. Here, we determined the compositions and MeHg demethylation rates of gut microbiota in residents from different Hg exposure levels (Wanshan (WS) town and Yangtou (YT) town) and different Hg exposure sources (Zhuchang (ZC) town and YT town) regions. MeHg and inorganic Hg exposure levels in residents of WS town were significantly higher than those of YT and ZC town. Desulfovibrio and Methanogens, which related to Hg methylation/demethylation, showed significantly higher abundance in WS and ZC, comparing with YT. In vitro experiments demonstrated that human intestinal microbiota could degrade MeHg directly. Besides, gut microbiota in WS and ZC exhibited significantly higher demethylation rates than YT, suggesting Desulfovibrio and Methanogens may play important roles in intestinal MeHg demethylation. This study highlights Hg exposure levels and sources may affect demethylation efficiency of gut microbiota, which provides new insights for MeHg demethylation processes in human body.


Asunto(s)
Microbioma Gastrointestinal , Mercurio , Compuestos de Metilmercurio , Desmetilación , Humanos , Mercurio/metabolismo , Mercurio/toxicidad , Metilación , Compuestos de Metilmercurio/metabolismo , Compuestos de Metilmercurio/toxicidad
2.
Inorg Chem ; 60(2): 1007-1015, 2021 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-33410671

RESUMEN

Density functional theory (DFT) and ab initio calculations were performed to probe the origin of the magnetic relaxation barriers for two finite single-chain magnets (SCMs) featuring a one-dimension chain, Co(hfac)2(R-NapNIT) (R-NapNIT = 2-(2'-(R-)naphthyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, R = MeO (1) or EtO (2)). Our calculations show that the strong intrachain CoII-CoII exchange coupling interactions transmitted by radicals can contribute much more than ionic anisotropy to the height of the reversal barrier of magnetization for the single-chain magnets (SCMs) with |2E| < |4J/3|. In addition, the anisotropic energy barrier ΔA decreases with the decrease of |2E/J| ratio and finally vanishes in the limit of broad domain walls (|2E| < < |4 J/3|). Therefore, the total magnetic relaxation energy barriers of two SCMs mostly originate from the correlation energy barrier Δξ deriving from the indirect ferromagnetic interaction between CoII-CoII transmitted by the strong CoII-radical antiferromagnetic interactions.

3.
J Nat Prod ; 84(7): 1954-1966, 2021 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-34170694

RESUMEN

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 µM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 µM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Chaperoninas/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Triterpenos Pentacíclicos/farmacología , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones Desnudos , Simulación del Acoplamiento Molecular , Estructura Molecular , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra
4.
Langenbecks Arch Surg ; 406(2): 437-447, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33025078

RESUMEN

PURPOSE: Laparoscopy-assisted gastrectomy (LAG) is proven by considerable studies as a safe procedure for early gastric cancer (EGC), but its long-term oncologic outcomes in advanced gastric cancer (AGC) have not been well-described. This study aimed at verifying the non-inferiority of LAG in the treatment of EGC and comparing the oncological feasibility of LAG and open gastrectomy (OG) for AGC. METHODS: A total of 209 consecutive patients who underwent LAG or OG with D2 lymph node dissection between December 2008 and November 2012 were included. The survival rate was estimated with the Kaplan-Meier method and the risk factors affecting the survival and recurrence were evaluated with Cox regression models. Subgroup analysis was performed in AGC patients receiving both distal and total gastrectomy. RESULTS: Of 209 patients, 194 (92.8%; mean age, 62.7 years; 56 [28.9%] women) eligible patients were finally enrolled in this study. No significant differences in the number of lymph nodes retrieved and postoperative complications were observed between patients receiving LAG and OG. During a mean follow-up of 58.3 ± 38.1 months (range 0-121 months), the 5-year overall survival and disease-free survival rates were 56.1% and 53.0% for LAG, and 57.7% and 50.9% for OG. In the subgroup analysis for AGC, laparoscopy-assisted distal gastrectomy and total gastrectomy did not result in inferior long-term outcomes, and recurrence was found in 49 patients (31.2%). Age more than 65 years and the advanced tumor stage were independent risk factors of survival. CONCLUSION: LAG is a feasible and safe treatment for gastric cancer, with good oncologic results.


Asunto(s)
Laparoscopía , Neoplasias Gástricas , Femenino , Gastrectomía , Humanos , Recién Nacido , Escisión del Ganglio Linfático , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Neoplasias Gástricas/cirugía , Resultado del Tratamiento
5.
Inorg Chem ; 58(2): 1301-1308, 2019 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-30592214

RESUMEN

A family of dinuclear dysprosium cores bridged by different ligands within a polyoxometalates (POMs) framework, (TBA)8.5H1.5[(PW11O39)2Dy2X2(H2O)2]·6H2O (X = OH (1), F (2), OAc (3); TBA = tetra- n-butylammonium), was successfully synthesized and structurally characterized. Magnetic studies indicate that the bridging ligands can significantly affect the magnetic behaviors, with 1 and 3 showing antiferromagnetic coupling and 2 bridged by fluoride ions showing ferromagnetic interaction. 1 and 2 behaved as single-molecule magnets (SMMs) with the thermally activated energy barrier of 98(5) and 74(6) cm-1 under zero dc filed, respectively, whereas no SMM behavior was observed for 3 bridged by two µ-η1:η2-acetato ligands. Notably, the low-temperature fluorescence spectra of 1-3 provide valuable information on the energy levels, which are consistent with the anisotropic barriers determined by magnetic measurements. These results offer an insight into the magneto-optical correlation. Furthermore, the effective energy barrier of 1 reaches a breakthrough among all POM-based SMMs.

6.
Inorg Chem ; 57(3): 1408-1416, 2018 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-29314838

RESUMEN

A new type of dinuclear dysprosium(III) complex based on phthalocyanine and salicylaldehyde derivatives (HL-R), [Dy2(Pc)2(L-R)2(H2O)]·2THF (R = OCH3 (1), OC2H5 (2); H2Pc = phthalocyanine; HL-OCH3 = 2-hydroxy-3-methoxybenzaldehyde; HL-OC2H5 = 3-ethoxy-2-hydroxybenzaldehyde), was successfully synthesized and structurally characterized. Complex 1 features a sandwich-type triple-decker structure, where two coplanar L-OCH3 ligands lie in the middle layer shared by two eight-coordinated DyIII ions and two Pc ligands are located in the outer layer. In 2, the introduction of an ethoxy group generates a noncoordination mode for the Oalkoxy atom. Magnetic studies indicate that complex 1 behaves as a zero-field single-molecule magnet with a higher energy barrier, while 2 exhibits a fast tunneling relaxation process. Theoretical calculations revealed that changes in the ligand field environment around DyIII ions can significantly affect the arrangement of the main magnetic axes and further result in distinct magnetic interactions as well as different relaxation behaviors.

7.
Org Biomol Chem ; 16(44): 8513-8524, 2018 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-30357224

RESUMEN

Baefrutones A-F (1-6), six new meroterpenoids with rare triketone-phloroglucinol-monoterpene/sesquiterpene frameworks, together with their biosynthetically related intermediate (±)-baeckenon B (7), were isolated from the aerial part of Baeckea frutescens under the guidance of HPLC-Q/TOF-MS2 investigation. Compounds 1-4 represent the first examples of natural meroterpenoids existing as four pairs of inseparable diastereomeric atropisomers (2 : 1, 1H NMR integration) caused by the restricted rotation around the C-6-C-7-C-1' bonds arising from the intramolecular hydrogen bond between C-1 carbonyl and 2'-OH. The discovery of these architectures not only largely enriched the chemodiversity of the meroterpenoid and atropisomer library, but also might be exciting and challenging for asymmetric organic synthesis. Their structures and absolute configurations were established by extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Compounds 5 and 6 were biomimetically synthesized from 7 and ß-caryophyllene via a regioselective oxidative hetero-Diels-Alder reaction, thus providing access to the construction of the 6/6/9/4 tetracyclic ring system. The anti-inflammatory activities of these meroterpenoids were also discussed.

8.
Zhongguo Zhong Yao Za Zhi ; 42(20): 3847-3859, 2017 Oct.
Artículo en Zh | MEDLINE | ID: mdl-29243417

RESUMEN

Andrographolide is one of the major natural active constituents in Andrographis panniculata of Acanthaceae family. Andrographolide and its derivatives are proved to posses a wide range of biological activities, such as anti-inflammatory, antiviral, anti-tumor, anti-human immunodeficiency virus(HIV), hepatoprotective and α-glucosidase inhibition activity. In this paper, the development of synthesis of rographolide derivatives and their related pharmacological activities were reviewed.


Asunto(s)
Andrographis/química , Diterpenos/síntesis química , Diterpenos/farmacología
9.
Apoptosis ; 20(3): 348-57, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25576195

RESUMEN

In our previous study, 17ß-estradiol was proved to protect rat annulus fibrosus cells against apoptosis induced by interleukin-1ß (IL-1ß). However, whether 17ß-estradiol has protective effect on rat nucleus pulposus cells remains unclear. The purpose of this study was to further explore the effects of 17ß-estradiol on rat nucleus pulposus cells based on IL-1ß-induced apoptosis. TUNEL assay and Annexin V/PI double staining were used to detect apoptosis and revealed that IL-1ß induced notable apoptosis, which was reversed by 17ß-estradiol. Meanwhile, cell viability and binding ability were decreased by IL-1ß, but activated caspase-3 was increased. However, all of the detected effects of IL-1ß were eliminated by 17ß-estradiol. Furthermore, real-time quantitative RT-PCR was used to further find that IL-1ß downregulated expression level of type II collagen, aggrecan, tissue inhibitor of matrix metalloproteinase (TIMP)-1, while upregulated matrix metalloproteinase (MMP)-3, MMP-13 and Bcl-2, which was further confirmed by western blot. Finally, 17ß-estradiol was proved to abolish the above negative effects of IL-1ß. In summary, this work presented that IL-1ß maybe induced apoptosis of rat nucleus pulposus cells, which was resisted by 17ß-estradiol by down-regulating MMP-3 and MMP-13 via a mitochondrial pathway. This research provides a novel insight into the anti-apoptotic effect of 17ß-estradiol on IL-1ß-induced cytotoxicity, and may potentially lead to a better understanding of the clinical effects of 17ß-estradiol, especially in terms of intervertebral disc degeneration.


Asunto(s)
Estradiol/farmacología , Interleucina-1beta/antagonistas & inhibidores , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/genética , Sustancias Protectoras/farmacología , Agrecanos/genética , Agrecanos/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Condrocitos/citología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Regulación de la Expresión Génica , Interleucina-1beta/farmacología , Disco Intervertebral/citología , Disco Intervertebral/efectos de los fármacos , Disco Intervertebral/metabolismo , Masculino , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo
11.
Huan Jing Ke Xue ; 44(8): 4220-4230, 2023 Aug 08.
Artículo en Zh | MEDLINE | ID: mdl-37694617

RESUMEN

The surface ozone (O3) spatiotemporal distribution, variations, and its causes in Ji'nan from 2015 to 2020 were revealed based on the air quality monitoring network data and satellite retrievals from the Ozone Monitoring Instrument (OMI). The results showed that the ozone concentration in Ji'nan gradually increased from 2015 to 2020. The annual 90th percentile of the daily maximum 8-h average (MDA8) O3(namely the annual evaluation value) and the MDA8 O3(April-September) increased by 4.8 µg·(m3·a)-1 and 3.8 µg·(m3·a)-1, respectively. The trend of the ozone levels in the high-concentration range increased faster than that in the low-concentration range. The MDA8 in June increased by 7.4 µg·(m3·a)-1, and the rate range of increases was 2.6-3.9 µg·(m3·a)-1 in the cool seasons (December-February); thus, the O3 control in winter cannot be ignored. It is apparent from the diurnal variations in ozone from 2015 to 2020 in April-September that the average ozone levels have risen in recent years. The growth rate in the daytime was higher than that at night. The capacity of photochemical production has been increasing, especially in recent years. Additionally, it is noteworthy that the peak time for ozone levels occurred approximately 1-2 h earlier. The disparity of ozone concentrations among different stations gradually decreased in recent years. Compared with that in 2015, the range of areas with high O3 concentrations in 2019-2020 was further expanded. The significant positive trends in MDA8-90th and MDA8 (April-September) were observed in 16.1% and 22.6% of the monitoring sites in Ji'nan (P<0.05), most of which were located in urban areas and the suburbs close to urban areas. The temporal and spatial changes in ozone in Jinan had been affected by the changes in VOCs and NOx emissions since 2015. Satellite remote sensing data from 2015 to 2020 revealed that the NO2 tropospheric columns (April-September) showed reductions of 20.6%, with a decreasing rate of 0.3×1015 mole·(cm2·a)-1, especially in the urban areas and suburbs. The detected variation trends of tropospheric HCHO were weak and insignificant, which suggested that the decrease in NOx emissions was much greater than the decrease in VOCs emissions, and the gap had become more obvious in the urban areas. With responses to precursor emissions, the chemical sensitivity of O3 formation had been changing. The VOCs-limited regimes continuously decreased, and the mixed NOx/VOCs-sensitive regimes and NOx-limited regimes increased. In general, such an extremely inappropriate control ratio of ozone precursor NOx/VOCs led to an overall trend of slow increasing fluctuations of O3 in Ji'nan. The findings clearly indicate that the reduction of VOCs in Ji'nan was far from sufficient, and strengthening the current control of VOCs emissions is an effective measure to control the growth trend of O3 pollution in Ji'nan in the near future, especially in urban and surrounding suburban areas.

12.
Chemosphere ; 311(Pt 2): 137135, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36343738

RESUMEN

There is currently no consensus about the impact of prenatal phthalate exposure on blood pressure and glycolipids in children. Few studies consider the health effects as an integrated indicator. The combined effect of multiple phthalate exposures is often ignored. Based on the Ma'anshan Birth Cohort, 2298 woman-child pairs were included in this study. Maternal urine was collected in each trimester to analyze 6 phthalate metabolites. The overall cardiometabolic risk (CMR) score was calculated based on serum glycolipids and blood pressure for children aged 4-7 years. A higher score represents a less favorable CMR profile. The restricted cubic spline model was used to explore the relationship between prenatal phthalate exposure and childhood CMR score. In addition, the quantile g-computation and the Bayesian kernel machine regression were used to evaluate the combined effect. The MBP exposure in the 1st trimester (MBP-1st) and the MEP-2nd were non-linearly associated with the CMR score (Fnonlinear = 3.28 and 5.60, Pnonlinear = 0.0378 and 0.0038, respectively). The MBP-3rd (Flinear = 5.31, Plinear = 0.0012) and the ∑LMWP-3rd (Flinear = 4.37, Plinear = 0.0045) were negatively associated with the score in a linear manner. The phthalate mixture in the 2nd trimester increased the score (psil = 0.1747, 95% CI = 0.0077-0.3416), with the MEP being the most common [weights = 0.5290; posterior inclusion probability (PIP) = 0.40]. The phthalate mixture in the 3rd trimester decreased the score (psil = -0.2024, 95% CI = -0.4097-0.0048), with the MEHP (weights = -0.5101; PIP = 0.14) and the MBP (weights = -0.3993, PIP = 1.00) being the greatest contributors. In conclusion, the MBP-1st and the MEP-2nd are non-linearly associated with the cardiometabolic risk in children. The MBP-3rd and the ∑LMWP-3rd decrease the childhood risk. The combined exposure to phthalate mixture in the second and third trimester elevates and decreases the risk of childhood cardiometabolism, respectively.


Asunto(s)
Enfermedades Cardiovasculares , Contaminantes Ambientales , Ácidos Ftálicos , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Humanos , Preescolar , Niño , Teorema de Bayes , Estudios de Cohortes , Ácidos Ftálicos/metabolismo , Factores de Riesgo , Glucolípidos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Exposición a Riesgos Ambientales , Efectos Tardíos de la Exposición Prenatal/inducido químicamente
13.
World J Clin Cases ; 10(26): 9264-9275, 2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-36159417

RESUMEN

BACKGROUND: Alpha-fetoprotein (AFP) is one of the diagnostic standards for primary liver cancer (PLC); however, AFP exhibits insufficient sensitivity and specificity for diagnosing PLC. AIM: To evaluate the effects of high-risk factors and the diagnostic value of AFP in stratified PLC. METHODS: In total, 289 PLC cases from 2013 to 2019 were selected for analysis. First, the contributions of high-risk factors in stratifying PLC were compared according to the following criteria: Child-Pugh score, clinical stage of liver cirrhosis, tumor size, and Barcelona Clinic Liver Cancer (BCLC) stage. Then, the diagnostic value of AFP was evaluated in different stratifications of PLC by receiver operating characteristic curves. For PLC cases in which AFP played little role, the diagnostic values of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), gamma-glutamyl transferase (GGT), and AFP were analyzed. RESULTS: The roles of high-risk factors differed in stratified PLC. The incidence of smoking and drinking history was higher in PLC with Child-Pugh scores of C (P < 0.0167). The hepatitis B virus (HBV) infection rate in PLC with cirrhosis was more than in PLC without cirrhosis (P < 0.0167). Small tumors were more prone to cirrhosis than large tumors (P < 0.005). BCLC stage D PLC was more likely to be associated with HBV infection and cirrhosis (P < 0.0083). AFP levels were higher in PLC with cirrhosis, diffuse tumors, and BCLC stage D disease. In diagnosing PLC defined as Child-Pugh A, B, and C, massive hepatoma, diffuse hepatoma, BCLC stage B, C, and D, and AFP showed significant diagnostic value [all area under the curve (AUC) > 0.700]. However, these measures were meaningless (AUC < 0.600) in small hepatomas and BCLC A stage PLC, but could be replaced by the combined detection of CEA, CA 19-9, GGT, and AFP (AUC = 0.810 and 0.846, respectively). CONCLUSION: Stratification of PLC was essential for precise diagnoses and benefited from evaluating AFP levels.

14.
J Hepatobiliary Pancreat Sci ; 29(6): 629-640, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35224875

RESUMEN

BACKGROUND/PURPOSE: This over 7-year case study is the first to compare the results of laparoscopic Glissonian pedicle approach hemihepatectomy (LGAH) and laparoscopic hilar dissection approach hemihepatectomy (LHAH) in a randomized controlled trial (RCT). METHODS: Patients who had undergone laparoscopic hemihepatectomy, either LGAH or LHAH, between March 2012 and December 2019 at our center were prospectively enrolled and assigned to the LGAH or LHAH group. Both groups were stratified and compared, and the preoperative and follow-up outcomes were analyzed. The primary endpoint was total operative time. RESULTS: The groups were equally matched for age, sex, HBsAg, Child-Pugh class, benign disease, malignancy, liver cirrhosis, tumor diameter and type of resection. Ninety-six patients had undergone LGAH and 94 had undergone LHAH. No preoperative death occurred in the two groups. LGAH did not enhance the postoperative overall complication rates (P = .465) or intraoperative blood loss (P = .535) compared with LHAH. However, the overall operative time (P = .014) and hilar dissection time (P = .000) were significantly shorter in the LGAH group than in the LHAH group. No significant differences were found between the groups regarding the 1-year (P = .384), 3-year (P = .332), and 5-year overall survival rates (P = .662) or 1-year (P = .856), 3-year (P = .348), and 5-year disease-free survival rates (P = .573). CONCLUSIONS: LGAH and LHAH are both effective procedures for treating the hilar structures in selected patients. LGAH has advantages over LHAH in reducing total operation time under the condition where both procedures can be used. LGAH for selected patients is worthy of promotion owing to its simplicity and convenience. REGISTRATION NUMBER: NCT01567631 (http://www. CLINICALTRIALS: gov).


Asunto(s)
Laparoscopía , Neoplasias Hepáticas , Disección , Hepatectomía/métodos , Humanos , Laparoscopía/métodos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Tempo Operativo , Complicaciones Posoperatorias/cirugía , Resultado del Tratamiento
15.
Cancer Invest ; 29(3): 208-13, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21314329

RESUMEN

Biological therapies can be beneficial in cancer patients. The present study aims to examine the inhibitory mechanism of curcumin on cancer cells in patients with colorectal cancer. The results showed that curcumin administration increased body weight, decreased serum TNF-alpha levels, increased apoptotic tumor cells, enhanced expression of p53 molecule in tumor tissue, and modulated tumor cell apoptotic pathway. We conclude that the curcumin treatment improves the general health of patients with colorectal cancer via the mechanism of increased p53 molecule expression in tumor cells and consequently speeds up tumor cell apoptosis.


Asunto(s)
Antineoplásicos/uso terapéutico , Peso Corporal/efectos de los fármacos , Caquexia/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Curcumina/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Caquexia/etiología , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/metabolismo , Terapia Combinada , Procedimientos Quirúrgicos del Sistema Digestivo , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Masculino , Estadificación de Neoplasias , Radioterapia , Factor de Necrosis Tumoral alfa/sangre , Proteína p53 Supresora de Tumor/efectos de los fármacos , Regulación hacia Arriba
16.
Cell Death Discov ; 7(1): 298, 2021 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-34663798

RESUMEN

The increasing incidence of hepatocellular carcinoma (HCC) is of great concern globally, but the molecular pathogenesis of these tumors remains unclear. Sorafenib is a first-line drug for the treatment of advanced HCC. However, the efficacy of sorafenib in improving patient survival is limited, and most patients inevitably develop resistance to this drug. Recent studies have demonstrated that the activation of the IRE1α-XBP1s pathway might play a protective role in the response to sorafenib and contribute to malignancy in HCC. Here, we found that RCN1, an endoplasmic reticulum resident protein, is significantly upregulated in sorafenib-resistant HCC cells and promotes tumor progression. Our analysis showed that RCN1 may be an independent predictor of tumor recurrence and overall survival. Mechanistically, RCN1 promotes the dissociation of GRP78 from IRE1α in sorafenib-resistant cells by interacting with GRP78 through its EFh1/2 domain. Subsequently, the IRE1α-XBP1s pathway, a branch of the unfolded protein response, is sustainably activated. Interestingly, IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in HCC. These results suggest that RCN1-targeted therapy might be a feasible strategy for the treatment of HCC.

17.
J Med Chem ; 64(11): 7760-7777, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34019417

RESUMEN

N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood-brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1-20). Compound 18, with the most potent activity (IC50 = 74 nM), high BBB permeability (Pe = 19.1 × 10-6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.


Asunto(s)
Aminoácidos/química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Propanoles/química , Aminoácidos/metabolismo , Aminoácidos/farmacología , Animales , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Diseño de Fármacos , Semivida , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/patología , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Simulación del Acoplamiento Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Relación Estructura-Actividad
18.
Dalton Trans ; 49(41): 14576-14583, 2020 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-33107526

RESUMEN

Complete active space self-consistent field (CASSCF) combined with restricted active space spin interaction with spin-orbit coupling (RASSI-SO) was used to probe why single-ion magnets (SIMs) composed of the "prolate" lanthanide ion ErIII cannot possess huge energy barriers. According to the proposal by Long et al., equatorially coordinated ligand environments are preferable for "prolate" lanthanide ions to have large energy barriers. However, our calculations show that the larger gx,y values in the first excited Kramers' doublets (KDs) induced by the surrounding equatorially coordinated ligands lead to their larger transversal magnetic moments which result in fast quantum tunneling of magnetizations (QTMs) in their first excited states. Therefore, the spin-phonon transitions can only proceed from the ground to the first excited KDs for our studied three compounds and all models. However, the effective energy barriers Ueff of the three compounds are smaller than the calculated energy gaps between the lowest two KDs due to their more flexible molecular structures. For the above reason, the energy barriers did not increase continuously as we expected when we decreased the Er-L bond lengths. We deduced that mononuclear ErIII compounds cannot easily possess huge energy barriers through enhancing the surrounding equatorially coordinated ligand field.

19.
Chem Asian J ; 14(15): 2620-2628, 2019 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-31066179

RESUMEN

The employment of a new rigid N-tridentate ligand, bis(1-chloroimidazo[1,5-a]pyridin-3-yl)pyridine (bcpp), in the construction of cobalt(II) single-ion magnets is reported. Two cobalt(II) complexes, [Co(bcpp)Cl2 ] (1) and [Co(bcpp)Br2 ] (2), have been prepared and characterized. Single-crystal XRD analyses reveal that complexes 1 and 2 are isostructural. They are pentacoordinated mononuclear cobalt(II) compounds with expected trigonal bipyramidal geometry. Both analysis of the magnetic data and ab initio calculations reveal easy-plane magnetic anisotropy (D>0) for 1 and 2. Detailed alternating current magnetic susceptibility measurements reveal the occurrence of slow magnetic relaxation behavior for the cobalt(II) centers of 1 and 2; thus indicating that both complexes are field-induced single-ion magnets.

20.
Chem Asian J ; 14(7): 986-994, 2019 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-30628179

RESUMEN

To explore the influences of the subtle structural variations in the ligand backbones on the single-molecule magnetic properties of dinuclear dysprosium(III) complexes, three ligands-H2 L1 (H2 L1 =N1 ,N3 -bis(salicylaldehyde)diethylenetriamine), H2 L2 (H2 L2 =N1 ,N3 -bis(3-methoxysalicylidene)diethylenetriamine), and H2 L3 (H2 L3 =N1 ,N3 -bis(5-chlorosalicyladehyde)diethylenetriamine)-were synthesized and employed to prepare the expected dinuclear dysprosium(III) complexes. The three ligands differ in terms of the substituents at the benzene rings of the salicylaldehyde moieties. The reactions of Dy(NO3 )3 ⋅6 H2 O, pivalic acid, and the ligands H2 L1 , H2 L2 , and H2 L3 generated complexes with the formulae [Dy2 (L1 )2 (piv)2 ] (1), [Dy2 (L2 )2 (piv)2 ] (2), and [Dy2 (L3 )2 (piv)2 ]⋅ 2 MeCN (3), respectively. The purposeful attachment of the functional groups with varied sizes at the benzene rings of the salicylaldehyde backbones resulted in slight differences in the Dy-O-Dy bond angles and the Dy⋅⋅⋅Dy bond lengths in 1-3; consequently, the three complexes exhibited distinct magnetic properties. They all showed slow magnetization relaxation with energy barriers of 40.32 (1), 31.67 (2), and 33.53 K (3). Complete active space self-consistent field (CASSCF) calculations were performed on complexes 1-3 to rationalize the slight discrepancy observed in the magnetic behavior. The calculated results satisfactorily explained the experimental outcomes.

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