RESUMEN
The design of novel agrochemicals starting from bioactive natural products is one of the most effective ways in the discovery and development of new pesticidal agents. In this paper, a series of novel butenolide-containing methylxanthine derivatives (Ia-Ir) were designed based on natural methylxanthine caffeine and stemofoline, and the derivatized insecticide flupyradifurone of the latter. The structures of the synthesized compounds were confirmed via 1H-NMR, 13C NMR, HRMS and X-ray single crystal diffraction analyses. The biological activities of the compounds were evaluated against a variety of agricultural pests including oriental armyworm, bean aphid, diamondback moth, fall armyworm, cotton bollworm, and corn borer; the results indicated that some of them have favorable insecticidal potentials, particularly toward diamondback moth. Among others, Ic and Iq against diamondback moth possessed LC50 values of 6.187â mg â L-1 and 3.269â mg â L-1, respectively, - 2.5- and 4.8-fold of relative insecticidal activity respectively to that of flupyradifurone (LC50=15.743â mg â L-1). Additionally, both the DFT theoretical calculation and molecular docking with acetylcholine binding protein were conducted for the highly bioactive compoundâ (Ic). Ic and Iq derived from the integration of caffeine (natural methylxanthine) and butenolide motifs can serve as novel leading insecticidal compounds for further optimization.
Asunto(s)
4-Butirolactona , Teoría Funcional de la Densidad , Insecticidas , Simulación del Acoplamiento Molecular , Mariposas Nocturnas , Insecticidas/química , Insecticidas/farmacología , Insecticidas/síntesis química , Animales , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacología , 4-Butirolactona/síntesis química , Mariposas Nocturnas/efectos de los fármacos , Cristalografía por Rayos X , Estructura Molecular , Xantinas/farmacología , Xantinas/química , Xantinas/síntesis química , Áfidos/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Three polysaccharides, PTC, PTH, and PTB, were extracted from Pinellia ternata using three different extraction conditions: room temperature water, hot water, and 2 % Na2CO3 solution. PTC and PTH were composed of rhamnose, glucose, galactose, mannose, glucuronic acid, galacturonic acid, and arabinose, which combine to form complex structures. PTB was composed solely of glucose and rhamnose. Further analysis indicated that PTC and PTB exhibited triple-helix structures. PTC showed the highest scavenging capacity against DPPH, superoxide anion, and hydroxyl radicals, with half maximal inhibitory concentrations (IC50) of 1004.1, 1584.1, and 1584.1â µg/mL, respectively. Additionally, PTC, PTH, and PTB were subjected to sulfation, phosphorylation, and selenization, resulting in the production of nine derivates. The distinctive absorptive bands of these derivates were determined through infrared spectroscopy. Selenized and sulfated derivates have shown significant antitumor and immunoenhancing properties. Our findings revealed that at 400â µg/mL, the inhibition rate of selenated PTB on HeLa cells was 54.2 % and that on HepG2 cells was 43.1 %. Additionally, selenized PTC displayed significant immunoenhancing activity, with a proliferation rate of 63.7 % at 400â µg/mL in RAW264.7 cells. These results provide valuable evidence supporting the consideration of polysaccharides from Pinellia ternata as a potential candidate for the development of antineoplastic drugs.
Asunto(s)
Pinellia , Polisacáridos , Polisacáridos/química , Polisacáridos/farmacología , Polisacáridos/aislamiento & purificación , Humanos , Pinellia/química , Células Hep G2 , Células HeLa , Proliferación Celular/efectos de los fármacos , Ratones , Animales , Supervivencia Celular/efectos de los fármacos , Picratos/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Compuestos de Bifenilo/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificaciónRESUMEN
YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), an m6A reader, has a role in the development and progression of breast cancer as well as the immunological microenvironment. The networks of competing endogenous RNA in cancer have received much attention in research. In tumor gene therapy, the regulatory networks of m6A and competing endogenous RNA are increasingly emerging as a new route. We evaluated the relationship between the YTHDF1 expression, overall survival, and clinicopathology of breast cancer using TCGA, PrognoScan, and other datasets. We used Western blot to demonstrate that YTHDF1 is substantially expressed in breast cancer tissues. Furthermore, we explored YTHDF1's functions in the tumor mutational burden, microsatellite instability, and tumor microenvironment. Our findings indicate that YTHDF1 is a critical component of the m6A regulatory proteins in breast cancer and may have a particular function in the immunological microenvironment. Crucially, we investigated the relationship between YTHDF1 and the associated competitive endogenous RNA regulatory networks, innovatively creating three such networks (Dehydrogenase/Reductase 4-Antisense RNA 1-miR-378g-YTHDF1, HLA Complex Group 9-miR-378g-YTHDF1, Taurine Up-regulated 1-miR-378g-YTHDF1). Furthermore, we showed that miR-378g could inhibit the expression of YTHDF1, and that miR-378g/YTHDF1 could impact MDA-MB-231 proliferation. We speculate that YTHDF1 may serve as a biomarker for poor prognosis and differential diagnosis, impact the growth of breast cancer cells via the ceRNA network axis, and be a target for immunotherapy against breast cancer.
Asunto(s)
Neoplasias de la Mama , MicroARNs , Proteínas de Unión al ARN , Humanos , Western Blotting , MicroARNs/genética , Neoplasias , ARN sin Sentido , ARN Endógeno Competitivo/genética , ARN Endógeno Competitivo/metabolismo , Proteínas de Unión al ARN/genética , Microambiente Tumoral/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismoRESUMEN
To discover new agrochemicals with prominent pesticidal properties, a series of novel ß-naphthol derivatives containing benzothiazolylamino and various heteroaryl groups (8a-q) were efficiently synthesised via Betti reaction. The bioassay results showed that most of the synthesised compounds exhibited favourable insecticidal potentials, particularly towards oriental armyworm (50-100% at 200 mg·L-1) and diamondback moth (50-95% at 10 mg·L-1). Compounds 8 b, 8f, 8 g, 8j, 8k, 8n, and 8o possessed LC50 values of 0.0988-5.8864 mg·L-1 against diamondback moth. Compounds 8i, 8 l, and 8 m also displayed lethality rates of 30-90% against spider mite at the concentration of 100 mg·L-1. Overall, some compounds could be considered as new insecticidal/acaricidal leading structures for further investigation. The calcium imaging experiments revealed that 8 h, 8i, and viii could activate the release of calcium ions in insect (M. separata) central neurons at a higher concentration (50 mg·L-1). The SAR analysis provided valuable information for further structural modifications.
Asunto(s)
Benzotiazoles/farmacología , Mariposas Nocturnas/efectos de los fármacos , Naftalenos/farmacología , Plaguicidas/farmacología , Animales , Benzotiazoles/síntesis química , Benzotiazoles/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Plaguicidas/síntesis química , Plaguicidas/química , Relación Estructura-ActividadRESUMEN
Cancer-associated fibroblasts (CAFs) represent one of the main components in the tumor stroma and play a key role in breast cancer progression. Transforming growth factor-ß (TGF-ß) has been established to mediate breast cancer metastasis by regulating the epithelial-mesenchymal transition (EMT) and stemness of cancer cells. Caveolin-1 (CAV-1) is a scaffold protein of caveolae that is related to the proliferation and metabolism of cancer cells. It is now well demonstrated that CAV-1 deficiency in the tumor stroma is positively correlated with distant metastasis, but the mechanism remains unclear. Here, we explore whether CAV-1-deficient fibroblasts play an essential role in the EMT and stemness of breast cancer cells (BCCs) through TGF-ß signaling. We establish a specific small interfering RNA (siRNA) to inhibit CAV-1 expression in fibroblasts and coculture them with BCCs to investigate the effect of CAV1-deficient fibroblasts and the tumor microenvironment on breast cancer progression. This study refreshingly points out that CAV-1 deficiency in fibroblasts enhances TGF-ß1 secretion and then activates the TGF-ß1/Smad signaling pathway of BCCs, thus promoting the metastasis and stemness of BCCs. Collectively, our findings indicate an unexpected role of CAV-1 deficiency in fibroblasts and the tumor microenvironment as a permissive factor, which is regulated by the TGF-ß1 signaling pathway in BCCs.
Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal/genética , Fibroblastos/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Microambiente TumoralRESUMEN
Breast cancer (BC) is one of the most devastating cancers, with high morbidity and mortality, among the female population worldwide. In BC, mesenchymal stem cells (MSCs), as pluripotent stromal stem cells, play a significant role in TME formation and tumor progression. Recently, an increasing number of studies have demonstrated that extracellular vesicles (EVs) are essential for the crosstalk between MSCs and BC cells. MSC-derived EVs (MSC-EVs) can deliver a diversity of molecules, including lipids, proteins, and nucleic acids, etc., to target cells, and produce corresponding effects. Studies have demonstrated that MSC-EVs exert both inhibitory and promotive effects in different situations and different stages of BC. Meanwhile, MSC-EVs provide novel therapeutic options for BC, such as EVs as carriers for drug delivery. Therefore, in this review, we summarize the role of MSC-EVs in BC progression and application in clinical treatment, in the hope of providing a basis for further research.
Asunto(s)
Neoplasias de la Mama , Vesículas Extracelulares , Células Madre Mesenquimatosas , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Sistemas de Liberación de Medicamentos , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Células Madre Mesenquimatosas/metabolismoRESUMEN
In recent years, malignant breast cancer metastasis has caused a great increase in mortality. Research on the genetic and molecular mechanisms of malignant breast cancer has continued to deepen, and targeted therapy has become the general trend. Among them, competing endogenous RNA (ceRNA)-related molecules have received much attention. Homeobox transcript antisense RNA (HOTAIR) has been reported to function extensively as a ceRNA in breast cancer. Notably, miR-203 and Caveolin 1 (CAV1) have also been found to play a role in breast cancer. However, the relationship between the three remains unclear. In this study, we present a new mechanic through bioinformatics tool and basic experiments: the HOTAIR/miR-203/CAV1 axis, which complemented the role network of HOTAIR as a ceRNA, thus, it will provide a novel potential idea for breast cancer research and therapy.
Asunto(s)
Neoplasias de la Mama , Caveolina 1 , MicroARNs , ARN Largo no Codificante , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Caveolina 1/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , ARN Largo no Codificante/genéticaRESUMEN
Referring to the structural information of the "hit" compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl- and thioether/sulfoxide/sulfone-containing acetamide derivatives have been designed and synthesized. The structures of new compounds were confirmed by 1H NMR, 13C NMR and HRMS. The single-crystal structure of A was firstly reported. All the new synthesized compounds were evaluated for insecticidal activities on Mythimna separata Walker and Plutella xylostella L. Through a step-by-step structural optimization, the high insecticidal agents, especially towards Plutella xylostella L., have been found, and thienylpyridyl- and sulfone/thioether-containing acetamides Iq, Io, Ib and A, which are comparable with the control insecticides cartap, triflumuron and chlorantraniliprole in the present study, can be used as novel lead structures for new insecticides innovation research. In addition, some of the compounds, e.g., A, Ih, Id, Io and Iq, also exhibited favourable fungicidal activities against Physalospora piricola, Rhizoctonia cerealis and Sclerotinia sclerotiorum and would provide useful guidance for the design and development of new fungicides.
Asunto(s)
Acetamidas , Plaguicidas , Animales , Ascomicetos , Basidiomycota , Insecticidas/química , Mariposas Nocturnas/efectos de los fármacos , Relación Estructura-Actividad , SulfurosRESUMEN
In order to search for the new ryanodine receptor (RyR) regulator, a series of 35 novel fluoro-substituted compounds introduced 1-(2-chloro-4,5-difluorophenyl)-1H-pyrazole moiety containing modified pyrazole heterocycle were designed and synthesized. Then, they were tested for the insecticidal activities against Mythimna separata and Plutella xylostella in our greenhouse. After a systematic biological screening, it was found out that IVc showed 50% larvicidal activities against Mythimna separata at 0.1 mg L-1, equivalent to that of chlorantraniliprole (36%, 0.1 mg L-1). The activity of IVc against Plutella xylostella was 90% at 10-5 mg L-1, whereas the chlorantraniliprole was 70% at the same concentration. Then, insect electrophysiology experiments were conducted to study the pattern of action of IVc and IVe. It was confirmed by the experimental results that both compounds could lead to the release of calcium from the endoplasmic reticulum of neurons as classical anthranilic diamide insecticides.
Asunto(s)
Insecticidas/farmacología , Mariposas Nocturnas/efectos de los fármacos , Pirazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Insecticidas/síntesis química , Insecticidas/química , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
Lung cancer is one of the most malignant cancers around the world, with high morbidity and mortality. Metastasis is the leading cause of lung cancer deaths and treatment failure. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs), two groups of small non-coding RNAs (nc-RNAs), are confirmed to be lung cancer oncogenes or suppressors. Transforming growth factor-ß (TGF-ß) critically regulates lung cancer metastasis. In this review, we summarize the dual roles of miRNAs and lncRNAs in TGF-ß signaling-regulated lung cancer epithelial-mesenchymal transition (EMT), invasion, migration, stemness, and metastasis. In addition, lncRNAs, competing endogenous RNAs (ceRNAs), and circular RNAs (circRNAs) can act as miRNA sponges to suppress miRNAs, thereby mediating TGF-ß signaling-regulated lung cancer invasion, migration, and metastasis. Through this review, we hope to cast light on the regulatory mechanisms of miRNAs and lncRNAs in TGF-ß signaling-regulated lung cancer metastasis and provide new insights for lung cancer treatment.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , Invasividad Neoplásica/genética , ARN Largo no Codificante/genética , Factor de Crecimiento Transformador beta/metabolismo , Animales , Transición Epitelial-Mesenquimal , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Invasividad Neoplásica/patología , ARN Largo no Codificante/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Ubiquitin-specific protease 18 (USP18) is an important inhibitor of interferon (IFN) antiviral activity, and the aim of this study was to investigate the association between the USP18 mRNA level change in peripheral blood mononuclear cells (PBMCs) when stimulated with IFN in vitro before initiating treatment and the treatment outcomes in HBeAg-positive chronic hepatitis B (CHB) patients treated with IFN. A total of 44 patients who received standard IFN-based anti-HBV therapy and follow-up were enrolled in the study. The in vitro IFN-induced USP18 mRNA change (USP18IFN-N ) was measured via comparison of quantitative PCR-determined USP18 transcription levels of BPMCs cultured with and without IFN stimulation. Either for virological (VR) or serological response (SR), the baseline USP18IFN-N was significantly higher (P = 0.018 for VR, P = 0.008 for SR) among nonresponders (n = 23 for VR, n = 33 for SR) than that of responders (n = 21 for VR, n = 11 for SR). Multivariate analyses revealed baseline USP18IFN-N was a novel independent predictor for either VR (OR = 0.292, 95% CI = 0.102-0.835, P = 0.022) or SR (OR = 0.173, 95% CI = 0.035-0.849, P = 0.031) in our cohort. In addition, baseline USP18IFN-N in combination with HBV DNA loads or HBeAg levels showed improved accuracy of pretreatment prediction for VR or SR responders, respectively. Baseline USP18IFN-N levels are associated with both virological and serological response, and have the potential to become a clinical predictor for treatment outcomes in HBeAg-positive CHB patients before initiating IFN-α therapy.
Asunto(s)
Antivirales/farmacología , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Activación Transcripcional , Ubiquitina Tiolesterasa/genética , Adulto , Antivirales/uso terapéutico , Femenino , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Técnicas In Vitro , Interferón-alfa/uso terapéutico , Masculino , Resultado del TratamientoRESUMEN
Cdc42, a member of the Rho GTPases family, is involved in the regulation of several cellular functions including cell cycle progression, survival, transcription, actin cytoskeleton organization and membrane trafficking. Diabetes is a chronic and metabolic disease, characterized as glycometabolism disorder induced by insulin deficiency related to ß cell dysfunction and peripheral insulin resistance (IR). Diabetes could cause many complications including diabetic nephropathy (DN), diabetic retinopathy and diabetic foot. Furthermore, hyperglycemia can promote tumor progression and increase the risk of malignant cancers. In this review, we summarized the regulation of Cdc42 in insulin secretion and diabetes-associated diseases. Organized researches indicate that Cdc42 is a crucial member during the progression of diabetes, and Cdc42 not only participates in the process of insulin synthesis but also regulates the insulin granule mobilization and cell membrane exocytosis via activating a series of downstream factors. Besides, several studies have demonstrated Cdc42 as participating in the pathogenesis of IR and DN and even contributing to promote cancer cell proliferation, survival, invasion, migration, and metastasis under hyperglycemia. Through the current review, we hope to cast light on the mechanism of Cdc42 in diabetes and associated diseases and provide new ideas for clinical diagnosis, treatment, and prevention.
Asunto(s)
Diabetes Mellitus/metabolismo , Secreción de Insulina , Proteína de Unión al GTP cdc42/metabolismo , Animales , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/patología , Resistencia a la Insulina , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine-induced locomotor activity is related to a reduction in cocaine-enhanced phosphorylated Ca2+ /calmodulin-dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine-induced D3R function. This study investigated whether CART peptide inhibited cocaine-induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus-mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc shell, and induced a significant increase in Ca2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus-transfected CaMKIIα-over-expressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine-induced Ca2+ influx and attenuated the cocaine-increased pCaMKIIα expression in lentivirus-transfected CaMKIIα-over-expressing cells. CART peptide decreased the cocaine-enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα-D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus-transfected CaMKIIα-over-expressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine-induced locomotor sensitization. Cover Image for this issue: doi: 10.1111/jnc.14187.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Locomoción/efectos de los fármacos , Proteínas del Tejido Nervioso/farmacología , Núcleo Accumbens/efectos de los fármacos , Animales , Animales Recién Nacidos , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoprecipitación , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Núcleo Accumbens/citología , Fragmentos de Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D3/metabolismo , TransfecciónRESUMEN
A series of novel anthranilic diamides derivatives (7a-s) containing halogen, trifluoromethyl group and cyano group were designed, synthesized, and characterized by melting point, 1H NMR, 13C NMR and elemental analyses. The bioactivity revealed that most of them showed moderate to excellent activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Above all, the larvicidal activity of 7o against oriental armyworm was 100% and 40% at 0.25 and 0.1â¯mgâ¯L-1, comparable to that of the standard chlorantraniliprole (100%, 0.25â¯mgâ¯L-1 and 20%, 0.1â¯mgâ¯L-1). What is more, 7o against diamondback moth displayed 90% insecticidal activity at 0.01â¯mgâ¯L-1, superior to chlorantraniliprole (45%, 0.01â¯mgâ¯L-1). The experiments 7o on the American cockroach (Periplaneta Americana) heart beating rates (Dorsal vessel) and contractile force were compared with chlorantraniliprole. In addition, 7o could affect the calcium homeostasis in the central neurons of the third larvae of oriental armyworm, which revealed that the ryanodine receptor is the potential target of 7o. The density functional theory (DFT) calculation results revealed the amide bridge, the benzene ring of anthraniloyl moiety and pyrazole ring might play an important role in the insecticidal activity through hydrophobic interactions and π-π conjugations.
Asunto(s)
Diamida/química , Insecticidas/síntesis química , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Cucarachas/efectos de los fármacos , Cucarachas/fisiología , Diamida/síntesis química , Diamida/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Insecticidas/química , Insecticidas/toxicidad , Isoxazoles/química , Larva/efectos de los fármacos , Mariposas Nocturnas/crecimiento & desarrollo , Mariposas Nocturnas/metabolismo , Teoría Cuántica , Canal Liberador de Calcio Receptor de Rianodina/química , Relación Estructura-ActividadRESUMEN
Despite great improvements in the diagnosis and treatment of neoplasms, metastatic disease is still the leading cause of death in cancer patients, with mortality rates still rising. Given this background, new ways to treat cancer will be important for development of improved cancer control strategies. Cdc42 is a member of the Rho GTPase family and plays an important role in cell-to-cell adhesion, formation of cytoskeletal structures, and cell cycle regulation. It thus influences cellular proliferation, transformation, and homeostasis, as well as the cellular migration and invasion processes underlying tumor formation. Cdc42 acts as a collection point for signal transduction and regulates multiple signaling pathways. Moreover, recent studies show that in most human cancers Cdc42 is abnormally expressed and promoting neoplastic growth and metastasis. Regarding possible new treatments for cancer, miRNA and small molecules targeting Cdc42 and related pathways have been recently found to be effective on cancer. In this review, we analyze the newly recognized regulation mechanisms for Cdc42 and Cdc42-related signal pathways, and particularly new treatments using small molecules and miRNAs to inhibit the abnormal overexpression of Cdc42 that may slow down the metastasis process, improve cancer therapy and lead to novel strategies for development of antineoplastic drugs.
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Antineoplásicos/uso terapéutico , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , ARN Neoplásico/metabolismo , Proteína de Unión al GTP cdc42/metabolismo , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/genética , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Neoplasias/genética , ARN Neoplásico/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Proteína de Unión al GTP cdc42/genéticaRESUMEN
Allergic diseases, which include asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS), atopic dermatitis (AD), food allergy (FA), allergic keratoconjunctivitis, seriously affect the quality of life of people all over the world. Recently, interleukin-33 (IL-33) has been found to play an important role in these refractory disorders, mainly by inducing T helper (Th) 2 immune responses. This article reviews the mobilization and biological function of IL-33 in allergic disorders, providing novel insights for addressing these hypersensitive conditions.
Asunto(s)
Hipersensibilidad/inmunología , Interleucina-33/metabolismo , Regulación hacia Arriba , Humanos , Hipersensibilidad/psicología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Calidad de Vida , Transducción de Señal , Células Th2/inmunologíaRESUMEN
To investigate the "methyl" impact on bioactivity of sulfiliminyl dicarboxamides, a total of 16 novel N-cyano and N-trifluoroacetyl sulfiliminyl dicarboxamides containing m-heptafluoroisopropylated aromatic amino moiety were studied. Two series of sulfiliminyl substituents were designed, synthesized and evaluated against oriental armyworm (Pseudaletia separata Walker) for their insecticidal activities. Their chemical structures were established by corresponding [Formula: see text] NMR, HRMS and optical polarimetry. Bioassay results revealed that some of the title compounds showed potent insecticidal activities against oriental armyworm. Notably, compounds IIa, IIIa, IVa exhibited 100% activity at [Formula: see text], in particular, IIa showed a comparable control efficacy to that of the commercial product flubendiamide. The SAR of these N-cyano sulfiliminyl isomers can be summarized as follows (Sc, Ss) [Formula: see text] (Sc, Rs), while the N-trifluoroacetyl sulfiliminyl isomers is (Sc, Rs) [Formula: see text] (Sc, Ss). Comparative molecular field analysis indicated that an electropositive substituent, [Formula: see text] group in the benzene ring was very important for the improvement in biological activity. These results could hold promise for novel chiral sulfiliminyl RyR regulators.
Asunto(s)
Iminas/química , Iminas/síntesis química , Insecticidas/química , Insecticidas/síntesis química , Animales , Técnicas de Química Sintética , Lepidópteros , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
RATIONALE: Vascular smooth muscle cell (VSMC) migration and proliferation are the hallmarks of restenosis pathogenesis after angioplasty. Cyclooxygenase (COX)-derived prostaglandin (PG) E2 is implicated in the vascular remodeling response to injury. However, its precise molecular role remains unknown. OBJECTIVE: This study investigates the impact of COX-2-derived PGE2 on neointima formation after injury. METHODS AND RESULTS: Vascular remodeling was induced by wire injury in femoral arteries of mice. Both neointima formation and the restenosis ratio were diminished in COX-2 knockout mice as compared with controls, whereas these parameters were enhanced in COX-1>COX-2 mice, in which COX-1 is governed by COX-2 regulatory elements. PG profile analysis revealed that the reduced PGE2 by COX-2 deficiency, but not PGI2, could be rescued by COX-1 replacement, indicating COX-2-derived PGE2 enhanced neointima formation. Through multiple approaches, the EP3 receptor was identified to mediate the VSMC migration response to various stimuli. Disruption of EP3 impaired VSMC polarity for directional migration by decreasing small GTPase activity and restricted vascular neointimal hyperplasia, whereas overexpression of EP3α and EP3ß aggravated neointima formation. Inhibition or deletion of EP3α/ß, a Gαi protein-coupled receptor, activated the cAMP/protein kinase A pathway and decreased activation of RhoA in VSMCs. PGE2 could stimulate phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase3ß signaling in VSMCs through Gßγ subunits on EP3α/ß activation. Ablation of EP3 suppressed phosphatidylinositol 3-kinase signaling and reduced GTPase activity in VSMCs and altered cell polarity and directional migration. CONCLUSIONS: COX-2-derived PGE2 facilitated the neointimal hyperplasia response to injury through EP3α/ß-mediated cAMP/protein kinase A and phosphatidylinositol 3-kinase pathways, indicating EP3 inhibition may be a promising therapeutic strategy for percutaneous transluminal coronary angioplasty.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Arteria Femoral/lesiones , Arteria Femoral/metabolismo , Neointima/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E/metabolismo , Animales , Movimiento Celular/fisiología , Células Cultivadas , Ciclooxigenasa 2/genética , Dinoprostona/genética , Hiperplasia/genética , Hiperplasia/metabolismo , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/lesiones , Músculo Liso Vascular/metabolismo , Neointima/genética , Subtipo EP3 de Receptores de Prostaglandina E/genéticaRESUMEN
In order to identify novel chlorantraniliprole derivatives as potential insecticides or fungicides, 25 analogues of chlorantraniliprole were synthesized. The insecticidal activities against oriental armyworm and the antifungal activities against five typical fungi of these derivatives were tested. Compounds 2u, 2x and 2y exhibited good activities against oriental armyworm, especially compounds 2u and 2x which showed higher larvicidal activities than indoxacarb. Moreover, all of the tested compounds exhibited activities against five typical fungi. The Ki values of all synthesized compounds were calculated using AutoDock4. The relationship between the Ki values and the results of insecticidal activities against oriental armyworm further indicated that the membrane-spanning domain protein of the ryanodine receptor might contain chlorantraniliprole binding sites.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Insecticidas/química , Insecticidas/farmacología , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Hongos/efectos de los fármacos , Hongos/metabolismo , Larva/efectos de los fármacos , Larva/metabolismo , Lepidópteros/efectos de los fármacosRESUMEN
A series of novel 2,3-dihydro-1,3,4-oxadiazoles containing N-pyridylpyrazole carboxamides moieties were obtained by applying a new synthetic route. Their insecticidal tests against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of the compounds showed moderate to excellent activities at the testing concentrations. In particular, compound 6a showed 40% larvicidal activities against oriental armyworm at 1mg/L, while 7a against diamondback was 100% at 0.01mg/L. Calcium imaging results demonstrated that 6a, 6d and 7a stimulated a transient elevation in [Ca(2+)]i in the absence of external calcium after the central neurons dye loading with fluo-3 AM, implying that these novel compounds were potential activators of the ligand-gated calcium channel on the endoplasmic reticulum.