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2.
Cell Biol Toxicol ; 39(6): 2501-2526, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37755585

RESUMEN

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer that is highly associated with Epstein-Barr virus (EBV) infection. EBV acts as an epigenetic driver in NPC tumorigenesis, reprogramming the viral and host epigenomes to regulate viral latent gene expression, and creating an environment conducive to the malignant transformation of nasopharyngeal epithelial cells. Targeting epigenetic mechanisms in pre-clinical studies has been shown promise in eradicating tumours and overcoming immune resistance in some solid tumours. However, its efficacy in NPC remains inclusive due to the complex nature of this cancer. In this review, we provide an updated understanding of the roles of epigenetic factors in regulating EBV latent gene expression and promoting NPC progression. We also explore the crosstalk between epigenetic mechanisms and immune evasion in NPC. Particularly, we discuss the potential roles of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors in reversing immune suppression and augmenting antitumour immunity. Furthermore, we highlight the advantages of combining epigenetic therapy and immune checkpoint inhibitor to reverse immune resistance and improve clinical outcomes. Epigenetic drugs have the potential to modulate both epigenetic mediators and immune factors involved in NPC. However, further research is needed to fully comprehend the diverse range of epigenetic modifications in NPC. A deeper understanding of the crosstalk between epigenetic mechanisms and immune evasion during NPC progression is crucial for the development of more effective treatments for this challenging disease.


Asunto(s)
Carcinoma , Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Evasión Inmune , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Epigénesis Genética
3.
Nutr Res ; 118: 41-51, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37562156

RESUMEN

Diet is a modifiable risk factor for pancreatic cancer. We hypothesized that specific dietary patterns would increase/decrease pancreatic cancer risk. We evaluated the association of dietary patterns with pancreatic cancer risk in the UK Women's Cohort Study. Dietary patterns were assessed at enrollment using: (1) self-reported practice of vegan/vegetarian dietary habits, (2) diet quality indices (World Health Organization Healthy Diet Indicator and Mediterranean Diet Score), and (3) principal component analysis-derived dietary patterns. The association of dietary patterns with pancreatic cancer incidence was quantified using Cox regression survival analysis. Over a median follow-up of 19 years of 35,365 respondents, there were 136 incident cases of pancreatic cancer. No association between dietary habits/quality and pancreatic cancer incidence was evident after adjustments (hazard ratio (95% confidence interval): self-reported omnivores vs vegan/vegetarian dietary habit: 1.13 (0.73-1.76); per-unit increase in World Health Organization Healthy Diet Indicator scores: 0.99 (0.91-1.09); per-unit increase in Mediterranean Diet Score: 0.92 (0.83-1.02). Similarly, no association of principal component analysis-derived dietary patterns with pancreatic cancer risk was evident ("prudent:" 1.02 [0.94-1.10]; ``meat-based:'' 1.00 [0.92-1.09]; ``fast-food, sugar-sweetened beverages, and carbohydrate-rich snacks:'' 0.96 [0.86-1.07]; ``cereal and dairy-rich:'' 1.04 [0.94-1.16], and ``low-diversity and lowfat:'' 1.00 [0.89-1.13]). In this prospective cohort of women, several major dietary patterns were of poor quality. There was no evidence of a prospective association between any of the dietary patterns explored and pancreatic cancer incidence.


Asunto(s)
Dieta Mediterránea , Neoplasias Pancreáticas , Humanos , Femenino , Estudios de Cohortes , Estudios Prospectivos , Dieta , Factores de Riesgo , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/etiología
4.
World J Gastrointest Oncol ; 15(6): 943-958, 2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37389119

RESUMEN

Pancreatic cancer is the leading cause of cancer mortality worldwide. Research investigating effective management strategies for pancreatic cancer is ongoing. Vitamin E, consisting of both tocopherol and tocotrienol, has demonstrated debatable effects on pancreatic cancer cells. Therefore, this scoping review aims to summarize the effects of vitamin E on pancreatic cancer. In October 2022, a literature search was conducted using PubMed and Scopus since their inception. Original studies on the effects of vitamin E on pancreatic cancer, including cell cultures, animal models and human clinical trials, were considered for this review. The literature search found 75 articles on this topic, but only 24 articles met the inclusion criteria. The available evidence showed that vitamin E modulated proliferation, cell death, angiogenesis, metastasis and inflammation in pancreatic cancer cells. However, the safety and bioavailability concerns remain to be answered with more extensive preclinical and clinical studies. More in-depth analysis is necessary to investigate further the role of vitamin E in the management of pancreatic cancers.

5.
Nutrients ; 15(8)2023 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-37111076

RESUMEN

BACKGROUND: Tocotrienol, a type of vitamin E, is well known for its anti-cancer and other biological activities. This systematic review aims to summarize the involvement of endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) as the underlying molecular mechanisms for the anticancer properties of tocotrienol. METHOD: A comprehensive literature search was performed in March 2023 using the PubMed, Scopus, Web of Science, and EMBASE databases. In vitro, in vivo, and human studies were considered. RESULT: A total of 840 articles were retrieved during the initial search, and 11 articles that fit the selection criteria were included for qualitative analysis. The current mechanistic findings are based solely on in vitro studies. Tocotrienol induces cancer cell growth arrest, autophagy, and cell death primarily through apoptosis but also through paraptosis-like cell death. Tocotrienol-rich fractions, including α-, γ- and δ-tocotrienols, induce ERS, as evidenced by upregulation of UPR markers and/or ERS-related apoptosis markers. Early endoplasmic reticulum calcium ion release, increased ceramide level, proteasomal inhibition, and upregulation of microRNA-190b were suggested to be essential in modulating tocotrienol-mediated ERS/UPR transduction. Nevertheless, the upstream molecular mechanism of tocotrienol-induced ERS is largely unknown. CONCLUSION: ERS and UPR are essential in modulating tocotrienol-mediated anti-cancer effects. Further investigation is needed to elucidate the upstream molecular mechanism of tocotrienol-mediated ERS.


Asunto(s)
Tocotrienoles , Humanos , Tocotrienoles/farmacología , Estrés del Retículo Endoplásmico , Respuesta de Proteína Desplegada , Apoptosis , Muerte Celular
6.
Int J Ophthalmol ; 16(1): 40-46, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36659939

RESUMEN

AIM: To compare the effect of vegetable oils on the uptake of lutein and zeaxanthin by adult retinal pigment epithelial (ARPE)-19 cells in vitro. METHODS: ARPE-19 cells were cultured in Dulbecco's Modified Eagle Medium-F-12 supplemented with 10% foetal bovine serum and 1% penicillin-streptomycin in a humidified 5% CO2 incubator maintained at 37°C. Cells were treated with 247 µmol/L lutein, 49 µmol/L zeaxanthin and 1% (v/v) of either coconut oil, corn oil, peanut oil, olive oil, sunflower oil, soybean oil, castor oil, or linseed oil for 48h. Lutein and zeaxanthin concentration in the cells were quantified by high performance liquid chromatography. RESULTS: Among the oils tested, the highest lutein and zeaxanthin uptake was observed with coconut oil while the lowest was observed with linseed oil. CONCLUSION: ARPE-19 uptake of lutein and zeaxanthin are found to be dependent on the type of oils.

7.
Int J Urol ; 29(9): 1085-1094, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35975690

RESUMEN

OBJECTIVES: TP53 loss-of-function is commonly found in aggressive prostate cancer. However, a highly-efficient therapy for this tumor subtype is still lacking. In this study, we investigated the relationship between TP53 mutation status and autophagy in prostate cancer and assessed the efficacy of autophagy inhibitors on TP53-deficient tumors. METHODS: We first evaluated the expression patterns of p53 and autophagy-related proteins, namely LC3B, ULK1 and BECLIN1, as well as their relationship in treatment-naïve and castration-resistant prostate cancer specimens through immunohistochemistry. Subsequently, we generated a Trp53-deleted genetically-engineered mouse model, established prostate tumor organoid lines from the mice and assessed the efficacy of autophagy inhibitors in overcoming Enzalutamide resistance in the tumor organoid model. We also investigated the impact of TP53 re-expression in modulating responses to autophagy inhibitors using LNCaP cell line, which harbored a TP53 missense mutation. Lastly, we attempted to identify potential autophagy-related genes that were crucial for TP53-deficient tumor maintenance. RESULTS: TP53 loss-of-function was associated with increased levels of autophagy-related proteins in aggressive prostate cancers and Trp53-deleted genetically-engineered mouse-derived tumors. Moreover, the generated androgen receptor-independent tumor organoids were highly vulnerable to autophagy inhibition. Upon TP53 re-expression, not only did the surviving LNCaP cells demonstrate resistance, but they also showed growth advantage in response to autophagy inhibition. Lastly, PEX14, an important peroxisomal regulator was differentially upregulated in aggressive tumors with TP53 loss-of-function mutations, thus implying the importance of peroxisome turnover in this tumor subtype. CONCLUSION: Our results support the potential use of autophagy inhibitors in prostate cancers that contain TP53 loss-of-function mutations.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Proteína p53 Supresora de Tumor , Animales , Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Línea Celular Tumoral , Humanos , Inmunohistoquímica , Mutación con Pérdida de Función , Masculino , Ratones , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteína p53 Supresora de Tumor/genética
8.
Cancers (Basel) ; 14(15)2022 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-35954379

RESUMEN

Despite medical advancements, the prognosis of pancreatic ductal adenocarcinoma (PDAC) has not improved significantly over the past 50 years. By utilising the large-scale genomic datasets available from the Australia Pancreatic Cancer Project (PACA-AU) and The Cancer Genomic Atlas Project (TCGA-PAAD), we studied the immunophenotype of PDAC in silico and identified that tumours with high cytotoxic T lymphocytes (CTL) killing activity were associated with favourable clinical outcomes. Using the STRING protein-protein interaction network analysis, the identified differentially expressed genes with low CTL killing activity were associated with TWIST/IL-6R, HDAC5, and EOMES signalling. Following Connectivity Map analysis, we identified 44 small molecules that could restore CTL sensitivity in the PDAC cells. Further high-throughput chemical library screening identified 133 inhibitors that effectively target both parental and CTL-resistant PDAC cells in vitro. Since CTL-resistant PDAC had a higher expression of histone proteins and its acetylated proteins compared to its parental cells, we further investigated the impact of histone deacetylase inhibitors (HDACi) on CTL-mediated cytotoxicity in PDAC cells in vitro, namely SW1990 and BxPC3. Further analyses revealed that givinostat and dacinostat were the two most potent HDAC inhibitors that restored CTL sensitivity in SW1990 and BxPC3 CTL-resistant cells. Through our in silico and in vitro studies, we demonstrate the novel role of HDAC inhibition in restoring CTL resistance and that combinations of HDACi with CTL may represent a promising therapeutic strategy, warranting its further detailed molecular mechanistic studies and animal studies before embarking on the clinical evaluation of these novel combined PDAC treatments.

9.
Front Pharmacol ; 13: 903210, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35873548

RESUMEN

With less than 10% of 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal types of cancer. Current literature supports that gemcitabine is the first-line treatment of PDAC. However, poor cellular penetration of gemcitabine along with the acquired and intrinsic chemoresistance of tumor against it often reduced its efficacy and hence necessitates the administration of high gemcitabine dose during chemotherapy. Photodynamic therapy (PDT), a more selective and minimally invasive treatment, may be used synergistically with gemcitabine to reduce the doses utilized and dose-related side effects. This study reports the synergistic use of Re(I) bisquinolinyl complex, a transition metal complex photosensitizer with gemcitabine against PDAC. Re(I) bisquinolinyl complex was found to act synergistically with gemcitabine against PDAC in vitro at various ratios. With the aim to enhance cellular uptake and therapeutic efficiency, the Re(I) bisquinolinyl complex and gemcitabine were encapsulated into liquid crystalline nanoparticles (LCNPs) system. The formulations were found to produce homogeneous drug-loaded LCNPs (average size: 159-173 nm, zeta potential +1.06 to -10 mV). Around 70% of gemcitabine and 90% of the Re(I) bisquinolinyl complex were found to be entrapped efficiently in the formulated LCNPs. The release rate of gemcitabine or/and the Re(I) bisquinolinyl complex loaded into LCNPs was evaluated in vitro, and the hydrophilic gemcitabine was released at a faster rate than the lipophilic Re(I) complex. LCNPs loaded with gemcitabine and Re(I) bisquinolinyl complex in a 1:1 ratio illustrated the best anti-cancer activity among the LCNP formulations (IC50 of BxPC3: 0.15 µM; IC50 of SW 1990: 0.76 µM) through apoptosis. The current findings suggest the potential use of transition metal-based photosensitizer as an adjunctive agent for gemcitabine-based chemotherapy against PDAC and the importance of nano-formulation in such application.

10.
World J Gastroenterol ; 28(18): 1934-1945, 2022 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-35664961

RESUMEN

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development. Regardless, it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses, thus allowing continuous tumor growth and development. Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer. Compared with other cancers, pancreatic cancer has a tumor microenvironment that can resist most treatment modalities, including emerging immunotherapy. Sadly, the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients, suggesting that pancreatic cancer has successfully evaded immunomodulation. In this review, we summarize the impact of genetic alteration and epigenetic modification (especially histone deacetylases, HDAC) on immune evasion in pancreatic cancer. HDAC overexpression significantly suppresses tumor suppressor genes, contributing to tumor growth and progression. We review the evidence on HDAC inhibitors in tumor eradication, improving T cells activation, restoring tumor immunogenicity, and modulating programmed death 1 interaction. We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.


Asunto(s)
Histona Desacetilasas , Neoplasias Pancreáticas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/genética , Humanos , Evasión Inmune , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Microambiente Tumoral , Neoplasias Pancreáticas
11.
Cancer Lett ; 543: 215794, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35718268

RESUMEN

Prostate cancer is frequently characterized as a multifocal disease with great intratumoral heterogeneity as well as a high propensity to metastasize to bone. Consequently, modeling prostate tumor has remained a challenging task for researchers in this field. In the past decades, genomic advances have led to the identification of key molecular alterations in prostate cancer. Moreover, resistance towards second-generation androgen-deprivation therapy, namely abiraterone and enzalutamide has unveiled androgen receptor-independent diseases with distinctive histopathological and clinical features. In this review, we have critically evaluated the commonly used preclinical models of prostate cancer with respect to their capability of recapitulating the key genomic alterations, histopathological features and bone metastatic potential of human prostate tumors. In addition, we have also discussed the potential use of the emerging organoid models in prostate cancer research, which possess clear advantages over the commonly used preclinical tumor models. We anticipate that no single model can faithfully recapitulate the complexity of prostate cancer, and thus, propose the use of a cost- and time-efficient integrated tumor modeling approach for future prostate cancer investigations.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Antagonistas de Andrógenos/uso terapéutico , Humanos , Masculino , Nitrilos , Organoides/patología , Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética
12.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-35163030

RESUMEN

c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members integrate signals that affect proliferation, differentiation, survival, and migration in a cell context- and cell type-specific way. JNK and p38 MAPK activities are found upregulated in nasopharyngeal carcinoma (NPC). Studies have shown that activation of JNK and p38 MAPK signaling can promote NPC oncogenesis by mechanisms within the cancer cells and interactions with the tumor microenvironment. They regulate multiple transcription activities and contribute to tumor-promoting processes, ranging from cell proliferation to apoptosis, inflammation, metastasis, and angiogenesis. Current literature suggests that JNK and p38 MAPK activation may exert pro-tumorigenic functions in NPC, though the underlying mechanisms are not well documented and have yet to be fully explored. Here, we aim to provide a narrative review of JNK and p38 MAPK pathways in human cancers with a primary focus on NPC. We also discuss the potential therapeutic agents that could be used to target JNK and p38 MAPK signaling in NPC, along with perspectives for future works. We aim to inspire future studies further delineating JNK and p38 MAPK signaling in NPC oncogenesis which might offer important insights for better strategies in diagnosis, prognosis, and treatment decision-making in NPC patients.


Asunto(s)
Antineoplásicos/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Humanos , Carcinoma Nasofaríngeo/enzimología , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/enzimología , Neoplasias Nasofaríngeas/patología
13.
Phytochemistry ; 193: 112988, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34717280

RESUMEN

Four undescribed cucurbitacins, designated as petiolaticins A-D, and four known cucurbitacins were isolated from the bark and leaves of Elaeocarpus petiolatus (Jack) Wall. Their chemical structures were elucidated based on detailed analyses of the NMR and MS data. The absolute configuration of petiolaticin A was also determined by X-ray diffraction analysis. Petiolaticin A represents a cucurbitacin derivative incorporating a 3,4-epoxyfuranyl-bearing side chain, while petiolaticin B possesses a furopyranyl unit fused to the tetracyclic cucurbitane core structure. Petiolaticins A, B, and D were evaluated in vitro against a panel of human breast, pancreatic, and colorectal cancer cell lines. Petiolaticin A exhibited the greatest cytotoxicity against the MDA-MB-468, MDA-MB-231, MCF-7, and SW48 cell lines (IC50 7.4, 9.2, 9.3, and 4.6 µM, respectively). Additionally, petiolaticin D, 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one, and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside were tested for their ability to inhibit cell entry of a pseudotyped virus bearing the hemagglutinin envelope protein of a highly pathogenic avian influenza virus. Petiolaticin D showed the highest inhibition (44.3%), followed by 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one (21.0%), and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside showed limited inhibition (9.0%). These preliminary biological assays have demonstrated that petiolaticins A and D possess anticancer and antiviral properties, respectively, which warrant for further investigations.


Asunto(s)
Elaeocarpaceae , Triterpenos , Animales , Cucurbitacinas , Estructura Molecular , Extractos Vegetales , Hojas de la Planta , Triterpenos/farmacología , Pseudotipado Viral
14.
Front Mol Biosci ; 8: 748470, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34820423

RESUMEN

Sphingosine kinases (SPHKs) are conserved lipid enzymes that catalyze the formation of sphingosine-1-phosphate (S1P) through ATP-dependent phosphorylation of sphingosine. Two distinct SPHK isoforms, namely SPHK1 and SPHK2, have been identified to date, and the former has been implicated for its oncogenic roles in cancer development and progression. While SPHK1 signaling axis has been extensively studied in non-stem breast cancer cells, recent evidence has emerged to suggest a role of SPHK1 in regulating cancer stem cells (CSCs). With the clinical implications of CSCs in disease relapse and metastasis, it is believed that therapeutic approaches that can eradicate both non-stem cancer cells and CSCs could be a key to cancer cure. In this review, we first explore the oncogenic functions of sphingosine kinase 1 in human cancers and summarize current research findings of SPHK1 signaling with a focus on breast cancer. We also discuss the therapeutic potentials and perspectives of targeting SPHK1 signaling in breast cancer and cancer stem cells. We aim to offer new insights and inspire future studies looking further into the regulatory functions of SPHK1 in CSC-driven tumorigenesis, uncovering novel therapeutic avenues of using SPHK1-targeted therapy in the treatment of CSC-enriched refractory cancers.

15.
J Nat Prod ; 84(8): 2272-2281, 2021 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-34342431

RESUMEN

Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.


Asunto(s)
Alcaloides/farmacología , Antineoplásicos Fitogénicos/farmacología , Músculo Liso/efectos de los fármacos , Rhizophoraceae/química , Tropanos/farmacología , Alcaloides/aislamiento & purificación , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Humanos , Técnicas In Vitro , Malasia , Masculino , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Corteza de la Planta/química , Hojas de la Planta/química , Ratas , Ratas Sprague-Dawley , Tráquea/efectos de los fármacos , Tropanos/aislamiento & purificación
16.
J Cell Mol Med ; 25(17): 8187-8200, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34322995

RESUMEN

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.


Asunto(s)
Azetidinas/farmacología , Docetaxel/farmacología , Janus Quinasa 1/antagonistas & inhibidores , Nitrilos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Purinas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Masculino
17.
BMC Urol ; 21(1): 95, 2021 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-34187440

RESUMEN

BACKGROUND: Nocturia is widely prevalent condition with detrimental effects on quality of life and general health. In Malaysia, there is a lack of up-to-date prevalence study on nocturia. This study aimed to investigate the prevalence of nocturia and awareness pertaining to nocturia among Malaysian adults. METHODS: A cross-sectional population-based study was conducted among Malaysian adults aged ≥ 18 years old. The data was collected by mixed mode self-administered questionnaire from May 2019 to September 2019. Nocturia was defined as one or more voids at night. RESULTS: There were a total of 4616 respondents with 74.5% of response rate. The overall prevalence of nocturia among Malaysian adults was found to be 57.3%. In multivariate analysis, respondents aged 31-40 (1.91 [1.52-2.40]) or > 60 years old (2.03 [1.48-2.71]), and those who presented with hypertension (2.84 [2.28-3.53]), diabetes mellitus (1.78 [1.42-2.25]), renal disease (3.58 [1.93-6.63]) or overactive bladder (1.61 [1.10-2.35]) were associated with higher prevalence of nocturia. A significantly lower disease prevalence (p < 0.05) was noted among those aged 41-50 (0.73 [0.59-0.91]), male (0.78 [0.69-0.88]) and Chinese (0.47 [0.30-0.74]) or Indian (0.34 [0.21-0.54]) ethnicities. A total of 37.3% of respondents with nocturia reported that they faced sleeping difficulty about half the time or more after waking up in the middle of night. Those who had ≥ 2 voids per night experienced significantly higher mean bother score than those who had 1 void per night (p < 0.001). Approximately half (56.7%) of all respondents were not aware that night time urination is a medical condition. Only 25.2% of respondents with nocturia had sought medical attention for their nocturia. CONCLUSIONS: The prevalence of nocturia among Malaysian adults is high and strongly influenced by age, sex, race and comorbidities. However, the general awareness pertaining to nocturia being a health issue remains low among Malaysians. The findings also highlighted the impact of nocturia on sleep and the need for nocturia education to better address this disease.


Asunto(s)
Nocturia/epidemiología , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Vida Independiente , Malasia/epidemiología , Masculino , Persona de Mediana Edad , Nocturia/etiología , Prevalencia , Autoinforme , Adulto Joven
18.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33805207

RESUMEN

Medical devices are indispensable in the healthcare setting, ranging from diagnostic tools to therapeutic instruments, and even supporting equipment. However, these medical devices may be associated with life-threatening complications when exposed to blood. To date, medical device-related infections have been a major drawback causing high mortality. Device-induced hemolysis, albeit often neglected, results in negative impacts, including thrombotic events. Various strategies have been approached to overcome these issues, but the outcomes are yet to be considered as successful. Recently, superhydrophobic materials or coatings have been brought to attention in various fields. Superhydrophobic surfaces are proposed to be ideal blood-compatible biomaterials attributed to their beneficial characteristics. Reports have substantiated the blood repellence of a superhydrophobic surface, which helps to prevent damage on blood cells upon cell-surface interaction, thereby alleviating subsequent complications. The anti-biofouling effect of superhydrophobic surfaces is also desired in medical devices as it resists the adhesion of organic substances, such as blood cells and microorganisms. In this review, we will focus on the discussion about the potential contribution of superhydrophobic surfaces on enhancing the hemocompatibility of blood-contacting medical devices.


Asunto(s)
Materiales Biocompatibles/química , Incrustaciones Biológicas/prevención & control , Sangre , Desinfección/métodos , Contaminación de Equipos/prevención & control , Interacciones Hidrofóbicas e Hidrofílicas , Humectabilidad , Adhesión Bacteriana/efectos de los fármacos , Materiales Biocompatibles/farmacología , Biopelículas/efectos de los fármacos , Biotecnología , Fibrinolíticos/farmacología , Hemólisis , Humanos , Nanopartículas , Propiedades de Superficie
19.
Cancers (Basel) ; 13(5)2021 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-33801191

RESUMEN

(1) Background: We studied the association of both conventional (BMI, waist and hip circumference and waist-hip ratio) and novel (UK clothing sizes) obesity indices with pancreatic cancer risk in the UK women's cohort study (UKWCS). (2) Methods: The UKWCS recruited 35,792 women from England, Wales and Scotland from 1995 to 1998. Cancer diagnosis and death information were obtained from the National Health Service (NHS) Central Register. Cox's proportional hazards regression was used to evaluate the association between baseline obesity indicators and pancreatic cancer risk. (3) Results: This analysis included 35,364 participants with a median follow-up of 19.3 years. During the 654,566 person-years follow up, there were 136 incident pancreatic cancer cases. After adjustments for age, smoking, education and physical activity, each centimetre increase in hip circumference (HR: 1.03, 95% CI: 1.01-1.05, p = 0.009) and each size increase in skirt size (HR: 1.12, 95% CI: 1.02-1.23, p = 0.041) at baseline increased pancreatic cancer risk. Baseline BMI became a significant predictor of pancreatic cancer risk (HR: 1.04, 95% CI: 1.00-1.08, p = 0.050) when latent pancreatic cancer cases were removed. Only baseline hip circumference was associated with pancreatic cancer risk (HR: 1.03, 95% CI: 1.00-1.05, p = 0.017) when participants with diabetes at baseline were excluded to control for reverse causality. (4) Conclusion: Hip circumference and skirt size were significant predictors of pancreatic cancer risk in the primary analysis. Thus, hip circumference is useful to assess body shape relationships. Additionally, standard skirt sizes offer an economical and objective alternative to conventional obesity indices for evaluating pancreatic cancer risk in women.

20.
Cancers (Basel) ; 13(8)2021 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-33918087

RESUMEN

Epstein-Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.

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