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1.
Int J Biol Macromol ; 271(Pt 1): 132617, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38795891

RESUMEN

Platycodon grandiflorum (P. grandiflorum) has long been used as a food and traditional herbal medicine. As a food, P. grandiflorum is often transformed into pickles for consumption, and as a traditional Chinese medicine, P. grandiflorum clears the lung, nourishes the pharynx, dispels phlegm, and discharges pus. Polysaccharides are among the main active components of P. grandiflorum. Recent literature has described the preparation, identification, and pharmacological activity of these polysaccharides. Studies have shown that these polysaccharides exhibit a variety of significant biological effects in vitro and in vivo, such as immune stimulation and antioxidant, anti-liver injury, anti-apoptosis and antitumour effects. However, there is no systematic summary of the related research articles on P. grandiflorum polysaccharide, which undoubtedly brings some difficulties to the future research. The purpose of this review is to comprehensively describe research progress on the extraction, purification, structural characterization, modification, and biological activity of P. grandiflorum polysaccharides. The shortcomings of recent research are summarized, further research on their biological activity is proposed to provide new reference value for the application of P. grandiflorum polysaccharides in drugs and health products in the future.

2.
Adv Mater ; 36(23): e2313273, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38533901

RESUMEN

The rapid growth of electric vehicle use is expected to cause a significant environmental problem in the next few years due to the large number of spent lithium-ion batteries (LIBs). Recycling spent LIBs will not only alleviate the environmental problems but also address the challenge of limited natural resources shortages. While several hydro- and pyrometallurgical processes are developed for recycling different components of spent batteries, direct regeneration presents clear environmental, and economic advantages. The principle of the direct regeneration approach is restoring the electrochemical performance by healing the defective structure of the spent materials. Thus, the development of direct regeneration technology largely depends on the formation mechanism of defects in spent LIBs. This review systematically details the degradation mechanisms and types of defects found in diverse cathode materials, graphite anodes, and current collectors during the battery's lifecycle. Building on this understanding, principles and methodologies for directly rejuvenating materials within spent LIBs are outlined. Also the main challenges and solutions for the large-scale direct regeneration of spent LIBs are proposed. Furthermore, this review aims to pave the way for the direct regeneration of materials in discarded lithium-ion batteries by offering a theoretical foundation and practical guidance.

3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 46(1): 82-87, 2024 Feb.
Artículo en Chino | MEDLINE | ID: mdl-38433636

RESUMEN

The purpose of this paper is to systematically summarize the gene polymorphisms associated with osteoporosis(OP)susceptibility in Zhuang ethnic group in Guangxi.These genes mainly encode vitamin D receptor,estrogen receptor,calcitonin receptor,and adiponectin.The genotype and allele distribution frequency were compared between Zhuang ethnic group and other ethnic groups,which can clarify the existing genes and the potential gene polymorphism associated with OP in Zhuang ethnic group.The findings provide a representative solution for the subsequent research on the genes associated with OP susceptibility in ethnic minorities.


Asunto(s)
Etnicidad , Osteoporosis , Humanos , Etnicidad/genética , China , Polimorfismo Genético , Frecuencia de los Genes , Osteoporosis/genética
4.
J Colloid Interface Sci ; 661: 409-435, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38306750

RESUMEN

Water-splitting electrocatalysis has gained increasing attention as a promising strategy for developing renewable energy in recent years, but its high overpotential caused by the unfavorable thermodynamics has limited its widespread implementation. Therefore, there is an urgent need to design catalytic materials with outstanding activity and stability that can overcome the high overpotential and thus improve the electrocatalytic efficiency. Metal-organic frameworks (MOFs) based and/or derived materials are widely used as water-splitting catalysts because of their easily controlled structures, abundant heterointerfaces and increased specific surface area. Herein, some recent research findings on MOFs-based/derived materials are summarized and presented. First, the mechanism and evaluation parameters of electrochemical water splitting are described. Subsequently, advanced modulation strategies for designing MOFs-based/derived catalysts and their catalytic performance toward water splitting are summarized. In particular, the correlation between chemical composition/structural functionalization and catalytic performance is highlighted. Finally, the future outlook and challenges for MOFs materials are also addressed.

5.
Vet Sci ; 10(12)2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-38133236

RESUMEN

The most important pathogenic Mycoplasma species in bovines are Mycoplasma bovis (M. bovis) and Mycoplasma mycoides subsp. mycoides (Mmm). Mmm causes contagious bovine pleuropneumonia (CBPP), which is a severe respiratory disease widespread in sub-Saharan Africa but eradicated in several countries, including China. M. bovis is an important cause of the bovine respiratory disease complex (BRD), characterized worldwide by pneumonia, arthritis, and mastitis. Secreted proteins of bacteria are generally considered virulence factors because they can act as toxins, adhesins, and virulent enzymes in infection. Therefore, this study performed a comparative proteomic analysis of the secreted proteins of M. bovis and Mmm in order to find some virulence-related factors as well as discover differential diagnostic biomarkers for these bovine mycoplasmas. The secretome was extracted from both species, and liquid chromatography-tandem mass spectrometry was used, which revealed 55 unique secreted proteins of M. bovis, 44 unique secreted proteins of Mmm, and 4 homologous proteins. In the M. bovis secretome, 19 proteins were predicted to be virulence factors, while 4 putative virulence factors were identified in the Mmm secretome. In addition, five unique secreted proteins of Mmm were expressed and purified, and their antigenicity was confirmed by Western blotting assay and indirect ELISA. Among them, Ts1133 and Ts0085 were verified as potential candidates for distinguishing Mmm infection from M. bovis infection.

6.
PLoS Pathog ; 19(4): e1011324, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37023208

RESUMEN

Post-translational modifications (PTMs) are essential for host antiviral immune response and viral immune evasion. Among a set of novel acylations, lysine propionylation (Kpr) has been detected in both histone and non-histone proteins. However, whether protein propionylation occurs in any viral proteins and whether such modifications regulate viral immune evasion remain elusive. Here, we show that Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral interferon regulatory factor 1 (vIRF1) can be propionylated in lysine residues, which is required for effective inhibition of IFN-ß production and antiviral signaling. Mechanistically, vIRF1 promotes its own propionylation by blocking SIRT6's interaction with ubiquitin-specific peptidase 10 (USP10) leading to its degradation via a ubiquitin-proteasome pathway. Furthermore, vIRF1 propionylation is required for its function to block IRF3-CBP/p300 recruitment and repress the STING DNA sensing pathway. A SIRT6-specific activator, UBCS039, rescues propionylated vIRF1-mediated repression of IFN-ß signaling. These results reveal a novel mechanism of viral evasion of innate immunity through propionylation of a viral protein. The findings suggest that enzymes involved in viral propionylation could be potential targets for preventing viral infections.


Asunto(s)
Herpesvirus Humano 8 , Sirtuinas , Antivirales/metabolismo , Herpesvirus Humano 8/genética , Evasión Inmune , Factor 1 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Lisina/metabolismo , Sirtuinas/metabolismo , Proteínas Virales/metabolismo , Humanos
7.
Molecules ; 27(21)2022 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-36364307

RESUMEN

Natural products have multifarious bioactivities against bacteria, fungi, viruses, cancers and other diseases due to their diverse structures. Nearly 65% of anticancer drugs are natural products or their derivatives. Thus, natural products play significant roles in clinical cancer therapy. With the development of biosynthetic technologies, an increasing number of natural products have been discovered and developed as candidates for clinical cancer therapy. Here, we aim to summarize the anticancer natural products approved from 1950 to 2021 and discuss their molecular mechanisms. We also describe the available synthetic biology tools and highlight their applications in the development of natural products.


Asunto(s)
Antineoplásicos , Productos Biológicos , Neoplasias , Humanos , Biología Sintética , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Productos Biológicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Hongos , Neoplasias/tratamiento farmacológico
8.
Redox Biol ; 53: 102339, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35636017

RESUMEN

Cervical cancer is one of the most common gynecological malignancies with poor prognosis due to constant chemoresistance and repeated relapse. Ciclopirox olamine (CPX), a synthetic antifungal agent, has recently been identified to be a promising anti-cancer candidate. However, the detailed mechanisms related to its anti-cancer effects remain unclear and need to be further elucidated. In this study, we found that CPX could induce proliferation inhibition in cervical cancer cells by targeting PARK7. Further results demonstrated that CPX could induce cytoprotective autophagy by downregulating the expression of PARK7 to activate PRKAA1 or by PARK7-independent accumulation of ROS to inhibit mTOR signaling. Meanwhile, CPX treatment increased the glycogen clustering and glycophagy in cervical cancer cells. The presence of N-acetyl-l-cysteine (NAC), a ROS scavenger, led to further clustering of glycogen in cells by reducing autophagy and enhancing glycophagy, which promoted CPX-induced inhibition of cervical cancer cell proliferation. Together, our study provides new insights into the molecular mechanisms of CPX in the anti-cancer therapy and opens new avenues for the glycophagy in cancer therapeutics.


Asunto(s)
Neoplasias del Cuello Uterino , Apoptosis , Autofagia , Ciclopirox/farmacología , Femenino , Glucógeno/farmacología , Humanos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología
9.
Mol Imaging ; 2022: 2679260, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35330799

RESUMEN

[18F]tetrafluoroborate (TFB) has been introduced as the 18F-labeled PET imaging probe for the human sodium iodide symporter (NIS). Noninvasive NIS imaging using [18F]TFB has received much interest in recent years for evaluating various NIS-expressing tumors. Cancers are a global concern with enormous implications; therefore, improving diagnostic methods for accurate detection of cancer is extremely important. Our aim was to investigate the PET imaging capabilities of [18F]TFB in NIS-transfected lung cell line A549 and endogenous NIS-expressing tumor cells, such as thyroid cancer K1 and gastric cancer MKN45, and broaden its application in the medical field. Western blot and flow cytometry were used to assess the NIS expression level. Radioactivity counts of [18F]TFB, in vitro, in the three tumor cells were substantially higher than those in the KI inhibition group in the uptake experiment. In vivo PET imaging clearly delineated the three tumors based on the specific accumulation of [18F]TFB in a mouse model. Ex vivo biodistribution investigation showed high [18F]TFB absorption in the tumor location, which was consistent with the PET imaging results. These results support the use of NIS-transfected lung cell line A549 and NIS-expressing tumor cells MKN45 and K1, to investigate probing capabilities of [18F]TFB. We also demonstrate, for the first time, the feasibility of [18F]TFB in diagnosing stomach cancer. In conclusion, this study illustrates the promising future of [18F]TFB for tumor diagnosis and NIS reporter imaging.


Asunto(s)
Neoplasias , Simportadores , Animales , Línea Celular , Línea Celular Tumoral , Ratones , Tomografía de Emisión de Positrones/métodos , Simportadores/genética , Simportadores/metabolismo , Distribución Tisular
10.
J Med Virol ; 94(6): 2766-2775, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35149992

RESUMEN

Kaposi's sarcoma-associated herpesvirus (KSHV) causes life-long latent infection and malignancies, including KS commonly found in AIDS patients. Lytic replication can be induced to kill tumor cells harboring latent KSHV, through viral cytopathic effects and the subsequent antiviral immune responses. Viral FLICE-inhibitory protein (vFLIP), encoded by KSHV ORF K13, inhibits KSHV lytic reactivation, implying that the competing endogenous RNA (ceRNA) networks regulated by vFLIP can be modulated to induce the lytic reactivation of latent KSHV, a promising strategy for KSHV-associated malignancies. Here, we performed whole-transcriptome sequencing to reveal the global landscape of noncoding RNAs and messenger RNAs (mRNAs) in iSLK-RGB-BAC16 cells and iSLK-RGB-K13 mutant cells. It showed that vFLIP regulated 227 differentially expressed (DE) long non-coding RNAs (lncRNAs), 57 DE circular RNAs (circRNAs), 20 DE microRNAs (miRNAs), and 1371 DE mRNAs. Enrichment analysis verified that riboflavin metabolism was simultaneously enriched in DE genes related to miRNAs, lncRNAs, and circRNAs. The upregulated hsa-miR-378i and hsa-miR-3654, and downregulated miR-4467, miR-3163, miR-4451, and miR-4257 were significantly enriched in the ceRNA complex network, which contained 9 upregulated and 7 downregulated circRNAs, 5 upregulated and 85 downregulated lncRNAs, 5 upregulated and 35 downregulated mRNAs. Finally, we constructed and validated two vFLIP-regulated ceRNA networks: circRNA hsa_circ_0070049/hsa-miR-378i/SPEG/FOXQ1 and lncRNA AL031123.1/hsa-miR-378i/SPEG/FOXQ1. Taken together, the two ceRNA networks may mediate KSHV reactivation. These novel findings refreshed the present understanding of ceRNA network in KSHV lytic induction and provided potential therapeutic targets for KSHV-associated malignancies.


Asunto(s)
Herpesvirus Humano 8 , MicroARNs , Neoplasias , ARN Largo no Codificante , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Factores de Transcripción Forkhead , Herpesvirus Humano 8/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Virales/metabolismo
11.
J Affect Disord ; 297: 486-494, 2022 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-34715194

RESUMEN

BACKGROUND: Sudden and unpredictable changes caused by the COVID-19 pandemic have profoundly threatened the psychological well-being and increased insecurity among adolescents worldwide. At a critical developmental stage, the well-being of the youth is more vulnerable to adverse environments. This study constructed a moderated mediation model to explore the buffering factors between insecurity and subjective well-being of the youth during the pandemic. METHODS: During the COVID-19 outbreak in June 2020, data of 5,503 Chinese youth (15-29 years old) were collected via an online questionnaire. Subjective well-being, insecurity, self-control, and hope were measured, and the moderated mediation model was analyzed. RESULTS: Findings from this study showed that with the mediating effect of self-control, insecurity negatively predicted subjective well-being, and hope moderated the association between insecurity and self-control. Specifically, the link between insecurity and self-control was stronger when hope was low but weaker when hope was high. LIMITATIONS: Since this study was mainly conducted in China, and considering the continuous change of the pandemic on a global scale, it is of great significance to conduct cross-cultural and cross-time studies in the future. CONCLUSIONS: The results demonstrate that self-control and hope play important roles in buffering the negative effects of insecurity on the subjective well-being of adolescents and young adults. The findings provide implications for reducing the negative impact of insecurity from a positive psychology perspective and for youth mental health interventions during public health crises.


Asunto(s)
COVID-19 , Pandemias , Adolescente , Adulto , Brotes de Enfermedades , Humanos , Salud Mental , SARS-CoV-2 , Adulto Joven
12.
Food Chem ; 346: 128976, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33476948

RESUMEN

This study was aimed to investigate the effect of incubation temperature on the binding of hexanal, octanal and 3-methylbutyraldehyde to myosin. Fluorescence quenching, Fourier transform infrared spectroscopy, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and gas chromatography-mass spectrometry (GC-MS) were employed. An increase in aldehyde concentration led to a reduction in fluorescence intensity in myosin. SPR revealed that the interactions were involved in a rapid combination and dissociation, and the dissociation constants significantly decreased from 25 to 37 °C. ITC showed that the values of entropy, enthalpy and Gibbs free energy were negative. The interactions were driven by hydrogen bonds and van der Waals forces. GC-MS further demonstrated that the highest binding capacity occurred at 37 °C between myosin and aldehydes. The findings provide a new insight into the mechanism on controlling or maintaining meat flavor.


Asunto(s)
Aromatizantes/química , Miosinas/química , Calorimetría , Aromatizantes/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Enlace de Hidrógeno , Miosinas/metabolismo , Unión Proteica , Espectrometría de Fluorescencia , Electricidad Estática , Temperatura , Termodinámica
13.
Mol Divers ; 25(1): 525-533, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32410113

RESUMEN

Cerebral amyloid angiopathy (CAA) commonly found in the aged is pathologically characterized by ß-amyloid (Aß) deposition in the walls of arteries and capillaries of brain. In this study, four flexible multidentate benzyldiamine derivatives as potential probes for cerebrovascular Aß deposition were designed and synthesized. In in vitro inhibition assays, the ligands 18-21 displayed high affinities for Aß aggregates with Ki values of 1.45 ± 0.53 nM, 1.68 ± 0.35 nM, 1.16 ± 0.23 nM and 1.72 ± 0.19 nM, respectively. A significant improvement in the binding affinity over the monomer, compounds 9-12 or benzyldiamine derivatives, demonstrated the applicability of the multidentate approach. The underlying mechanism of these novel Aß agents was explored by molecular docking technique, which theoretically verified the high affinities of the multidentate benzyldiamine derivatives for Aß aggregates. Moreover, the molecular masses of the ligands 18-21 are more than 700 Dalton, which are believed to be hardly capable of penetrating blood brain barrier. In this regard, these ligands could be used to distinguish CAA from Alzheimer's disease which is another Aß-related disorder disease. To convert these ligands to positron emission tomography imaging agents, we attempted to radiosynthesize [18F]18. Though the radiolabeling was not very successful, the preliminary results suggested that these newly proposed multidentate benzyldiamine derivatives may be used as potential Aß imaging agents in cerebral amyloid angiopathy.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Bencilaminas/uso terapéutico , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Bencilaminas/química , Bencilaminas/farmacología , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Simulación del Acoplamiento Molecular , Agregado de Proteínas
14.
Bioorg Med Chem Lett ; 30(11): 127160, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32247732

RESUMEN

The objective of the study was to prepare and evaluate a 18F-radiolabled tracer (Al18F-5), derivated from the antitumor agent 2-(4-aminophenyl)benzothiazole, as a PET probe for tumor imaging. Al18F-5 was successfully prepared with approx. 40% radiochemical yield in aqueous phase. In in vitro cell uptake experiments and competition assay, Al18F-5 displayed good tumor-binding ability and specificity in HeLa cells (24.7 ± 0.9% ID/106 cells, IC50 = 63.8 ± 13.6 nM) and MCF-7 cells (6.8 ± 0.3% ID/106 cells, IC50 = 331.1 ± 33.7 nM). The nonradioactive compound, Al19F-5, visibly marked HeLa cells and MCF-7 cells but did not stain HEB cells in florescent staining, which further indicated the tumor-binding ability of Al18F-5. In in vivo PET imaging, HeLa and MCF-7 tumors were clearly delineated by specific accumulation of Al18F-5 in model mice. In biodistribution study, Al18F-5 exhibited good tumor uptake (4.66 ± 0.13% ID/g and 3.69 ± 0.56% ID/g, respectively), moderate tumor-to-muscle ratio (3.38 and 2.48, respectively) at 1 h post injection, which were in a good consistency with the results of PET imaging. In conclusion, Al18F-5 might be developed as a candidate PET probe for tumor imaging, though additional optimizations are still needed to improve pharmacokinetics in vivo.


Asunto(s)
Benzotiazoles/química , Medios de Contraste/química , Radiofármacos/síntesis química , Animales , Benzotiazoles/metabolismo , Línea Celular Tumoral , Medios de Contraste/metabolismo , Radioisótopos de Flúor/química , Humanos , Ratones , Microscopía Fluorescente , Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos/química , Radiofármacos/metabolismo , Distribución Tisular , Trasplante Heterólogo
15.
Poult Sci ; 98(12): 6378-6387, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31406997

RESUMEN

The aim of this study was to investigate the effect of dietary resveratrol supplementation on innate immunity and inflammatory responses in the spleen of yellow-feather broilers under heat stress. A total of 288 yellow-feather broilers of 28-day-old were randomly assigned to 3 treatment groups with 6 replicates. A thermo-neutral group (TN) (24 ± 2°C) received a basal diet and another 2 heat-stressed groups (37 ± 2°C for 8 h/D and 24 ± 2°C for the remaining time) were fed the basal diet (HT) or basal diet with 500 mg/kg resveratrol (HT+Res) for 14 consecutive days. The results showed that heat stress decreased (P < 0.05) the growth index of thymus, spleen, and bursa of Fabricius, reduced (P < 0.05) the levels of complement C3 and C4 in serum. Heat stress also caused activation of inflammatory immune responses evidenced by increased (P < 0.05) the mRNA abundance of HSP (heat shock protein) 70, toll-like receptor (TLR)1, TLR4, TLR5, myeloid differentiation factor-88 (MyD88), nucleotide-binding oligomerization domain 1 (NOD1), Dectin-1, transforming growth factor-ß-activated kinase 1 (TAK1), interleukin (IL)-1, IL-4, IL-6, and tumor necrosis factor (TNF)-α, but decreased the mRNA abundance of interferon (IFN)-γ, activated nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), and phosphoinositide-3 kinases-protein kinase B (PI3K/AKT) signaling pathways. Dietary supplementation with resveratrol improved (P < 0.05) the growth index of thymus, spleen and bursa Fabricius, and increased (P < 0.05) the serum level of complement C3 under heat stress. In addition, resveratrol reduced (P < 0.05) the mRNA abundance of HSP70, TLR4, TLR5, NOD1, Dectin-1, and TAK1, and inhibited the NF-κB, MAPK and PI3K/AKT signaling pathway via down-regulated the phosphorylation of p65, extracellular signal-regulated kinases 1/2, c-Jun N-terminal protein kinase and AKT, as well as decreased the inflammatory cytokines expression, including IL-1, IL-4, IL-6, and TNF-α in the spleen under heat stress. Collectively, dietary resveratrol could have beneficial effects to regulate innate immunity and inflammatory response, via inhibiting the activation of NF-κB, MAPK, and PI3K/AKT signaling pathways induced by heat stress in the spleen.


Asunto(s)
Pollos/inmunología , Calor/efectos adversos , Inmunidad Innata/efectos de los fármacos , Inflamación/veterinaria , Enfermedades de las Aves de Corral/tratamiento farmacológico , Resveratrol/metabolismo , Alimentación Animal/análisis , Animales , Dieta/veterinaria , Suplementos Dietéticos/análisis , Inmunidad Innata/inmunología , Inflamación/tratamiento farmacológico , Distribución Aleatoria , Resveratrol/administración & dosificación , Estrés Fisiológico
16.
Theranostics ; 9(17): 4878-4892, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31410188

RESUMEN

Rationale: The sustained and severe endoplasmic reticulum (ER) stress in cancer cells may contribute to apoptotic cell death, thus representing a potential target for cancer therapy. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small-cell lung cancer (NSCLC). However, it remains unclear if brigatinib has alternative model of action to exert antitumor effect in ALK-negative cancers. Methods: ALK-positive NSCLC cells and various human ALK-negative cancer cells, especially human colorectal cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells. Results: Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo, supporting the repurposing of brigatinib in CRC, independently of ALK. Conclusion: The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers.


Asunto(s)
Antineoplásicos/farmacología , Autofagia , Neoplasias Colorrectales/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Compuestos Organofosforados/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Células A549 , Animales , Antineoplásicos/uso terapéutico , Apoptosis , Neoplasias Colorrectales/metabolismo , Endopeptidasas/metabolismo , Femenino , Células HCT116 , Células HT29 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Compuestos Organofosforados/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Esteroides/metabolismo , Ubiquitinación
17.
Cancer Chemother Pharmacol ; 84(4): 719-728, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31281953

RESUMEN

PURPOSE: Glioblastoma is the most common, malignant and devastating type of primary brain tumor. Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is characterized by its lethality to precancerous and cancerous cells. However, many kinds of tumor cells, including most glioma cells, tend to evade TRAIL-induced apoptosis. Celastrol is a pleiotropic compound from a traditional Chinese medicine that has proven to be useful as a sensitizer for TRAIL treatment. However, the underlying mechanism and role of celastrol in the sensitization of glioma cells remain to be elucidated. METHODS: The viability of glioma cell lines was examined by the CCK-8 assay. The expression of DR5 was detected by reverse transcriptase quantitative real-time PCR. The protein expression of DR5, cleaved caspase-8, cleaved caspase-3 and PARP were measured by western blot. The apoptosis rates and the sub-G1 population were detected by flow cytometry. The cellular morphological changes were assessed by TUNEL apoptosis and Hoechst 33258 staining assays. The knockdown of DR5 expression was conducted by siRNA. RESULTS: In this study, we observed that celastrol treatment inhibited cell viability in a dose-dependent manner, while glioma and normal human astroglial cell lines were resistant to TRAIL treatment. We also observed that the antiproliferative effects of TRAIL in combination with a noncytotoxic concentration of celastrol were significantly greater than those of celastrol or TRAIL alone. In addition, cell death induced by the combination treatment was apoptotic and occurred through the death receptor pathway via activation of caspase-8, caspase-3, and PARP. Furthermore, celastrol upregulated death receptor 5 (DR5) at the mRNA and protein levels, and siRNA-mediated DR5 knockdown reduced the killing effect of the combination drug treatment on glioma cells and reduced the activation of caspase-3, caspase-8 and PARP. CONCLUSIONS: Taken together, the results of our study demonstrate that celastrol sensitizes glioma cells to TRAIL via the death receptor pathway and that DR5 plays an important role in the effects of this cotreatment. The results indicate that this cotreatment is a promising tumor-killing therapeutic strategy with high efficacy and low toxicity.


Asunto(s)
Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF , Triterpenos/farmacocinética , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Medicamentos Herbarios Chinos/farmacocinética , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Triterpenos Pentacíclicos , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Tripterygium , Regulación hacia Arriba
18.
Clin Chim Acta ; 495: 611-624, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31176645

RESUMEN

Oncoproteomics is the systematic study of cancer samples using omics technologies to detect changes implicated in tumorigenesis. Recent progress in oncoproteomics is already opening new avenues for the identification of novel biomarkers for early clinical stage cancer detection, targeted molecular therapies, disease monitoring, and drug development. Such information will lead to new understandings of cancer biology and impact dramatically on the future care of cancer patients. In this review, we will summarize the advantages and limitations of the key technologies used in (onco)proteogenomics, (the Omics Pipeline), explain how they can assist us in understanding the biology behind the overarching "Hallmarks of Cancer", discuss how they can advance the development of precision/personalised medicine and the future directions in the field.


Asunto(s)
Neoplasias/metabolismo , Proteómica/métodos , Macrodatos , Descubrimiento de Drogas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina de Precisión , Proteómica/instrumentación
19.
Antioxidants (Basel) ; 8(3)2019 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-30889815

RESUMEN

Heat stress is a non-specific physiological response of the body when exposed to high ambient temperatures, which can break the balance of body redox and result in oxidative stress that affects growth performance as well as the health of poultry species. Polyphenols have attracted much attention in recent years due to their antioxidant ability and thus, can be an effective attenuator of heat stress. In this paper, the potential mechanisms underlying the inhibitory effect of polyphenols on heat stress in poultry has been reviewed to provide a reference and ideas for future studies related to polyphenols and poultry production.

20.
Chem Commun (Camb) ; 55(12): 1797-1800, 2019 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-30667425

RESUMEN

Amorphous transition-metal (hydr)oxides have proven to be the most promising oxygen evolution reaction (OER) electrocatalysts. Here, a facile and novel strategy for the generation of porous amorphous cobalt oxide through one-step treatment of the cobalt carbonate hydroxide precursor with concentrated sulfuric acid has been reported. Benefiting from the optimized amorphous structure, the prepared catalyst exhibits an excellent water-oxidation activity in an alkaline electrolyte with the demand of 50 mV less overpotential at 10 mA cm-2 compared to that of highly-crystallized Co3O4. Compared with the 400 °C annealing process for Co3O4, the ultrafast acid treatment process within 10 seconds at room-temperature for achieving such amorphous cobalt oxide demonstrates tremendous convenience. More impressively, after continuous testing for 60 h at an overpotential of 370 mV, it still maintains a porous configuration as well as ∼92% of the original current density. Our findings not only present a high-efficiency OER electrocatalyst, but also provide a methodology with broad applicability toward the systematic study of other non-crystal oxides for green energy applications.

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