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1.
Semin Cancer Biol ; 100: 1-16, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38503384

RESUMO

Transcription factors (TFs) are essential in controlling gene regulatory networks that determine cellular fate during embryogenesis and tumor development. TFs are the major players in promoting cancer stemness by regulating the function of cancer stem cells (CSCs). Understanding how TFs interact with their downstream targets for determining cell fate during embryogenesis and tumor development is a critical area of research. CSCs are increasingly recognized for their significance in tumorigenesis and patient prognosis, as they play a significant role in cancer initiation, progression, metastasis, and treatment resistance. However, traditional therapies have limited effectiveness in eliminating this subset of cells, allowing CSCs to persist and potentially form secondary tumors. Recent studies have revealed that cancer cells and tumors with CSC-like features also exhibit genes related to the epithelial-to-mesenchymal transition (EMT). EMT-associated transcription factors (EMT-TFs) like TWIST and Snail/Slug can upregulate EMT-related genes and reprogram cancer cells into a stem-like phenotype. Importantly, the regulation of EMT-TFs, particularly through post-translational modifications (PTMs), plays a significant role in cancer metastasis and the acquisition of stem cell-like features. PTMs, including phosphorylation, ubiquitination, and SUMOylation, can alter the stability, localization, and activity of EMT-TFs, thereby modulating their ability to drive EMT and stemness properties in cancer cells. Although targeting EMT-TFs holds potential in tackling CSCs, current pharmacological approaches to do so directly are unavailable. Therefore, this review aims to explore the role of EMT- and CSC-TFs, their connection and impact in cellular development and cancer, emphasizing the potential of TF networks as targets for therapeutic intervention.


Assuntos
Neoplasias , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Neoplasias/genética , Neoplasias/terapia , Transição Epitelial-Mesenquimal/genética , Diferenciação Celular , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral
2.
Clin Cancer Res ; 29(16): 3130-3141, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37195712

RESUMO

PURPOSE: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL DESIGN: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. RESULTS: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation. CONCLUSIONS: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.


Assuntos
Antineoplásicos , Carcinoma Ductal Pancreático , Interferon Tipo I , Neoplasias Pancreáticas , Humanos , Antineoplásicos/farmacologia , Transdução de Sinais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo
3.
Semin Cancer Biol ; 92: 102-127, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37054904

RESUMO

Cerebral ischemic stroke and glioma are the two leading causes of patient mortality globally. Despite physiological variations, 1 in 10 people who have an ischemic stroke go on to develop brain cancer, most notably gliomas. In addition, glioma treatments have also been shown to increase the risk of ischemic strokes. Stroke occurs more frequently in cancer patients than in the general population, according to traditional literature. Unbelievably, these events share multiple pathways, but the precise mechanism underlying their co-occurrence remains unknown. Transcription factors (TFs), the main components of gene expression programmes, finally determine the fate of cells and homeostasis. Both ischemic stroke and glioma exhibit aberrant expression of a large number of TFs, which are strongly linked to the pathophysiology and progression of both diseases. The precise genomic binding locations of TFs and how TF binding ultimately relates to transcriptional regulation remain elusive despite a strong interest in understanding how TFs regulate gene expression in both stroke and glioma. As a result, the importance of continuing efforts to understand TF-mediated gene regulation is highlighted in this review, along with some of the primary shared events in stroke and glioma.


Assuntos
Neoplasias Encefálicas , Glioma , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Glioma/complicações , Glioma/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Acidente Vascular Cerebral/genética
4.
Biochimie ; 212: 1-11, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37011805

RESUMO

Although the mechanisms as well as pathways associated with cancer stem cell (CSC) maintenance, expansion, and tumorigenicity have been extensively studied and the role of tumor cell (TC)-derived exosomes in this process is well understood, there is a paucity of research focusing specifically on the functional mechanisms of CSC-derived exosomes (CSC-Exo)/-exosomal-ncRNAs and their impact on malignancy. This shortcoming needs to be addressed, given that these vesicular and molecular components of CSCs could have a great impact on the cancer initiation, progression, and recurrence through their interaction with other key tumor microenvironment (TME) components, such as MSCs/MSC-Exo and CAFs/CAF-Exo. In particular, understanding CSCs/CSC-Exo and its crosstalk with MSCs/MSC-Exo or CAFs/CAF-Exo that are associated with the proliferation, migration, differentiation, angiogenesis, and metastasis through an enhanced process of self-renewal, chemotherapy as well as radiotherapy resistance may aid cancer treatment. This review contributes to this endeavor by summarizing the characteristic features and functional mechanisms of CSC-Exo/MSC-Exo/CAF-Exo and their mutual impact on cancer progression and therapy resistance.


Assuntos
Exossomos , MicroRNAs , Neoplasias , Humanos , Exossomos/metabolismo , Microambiente Tumoral , Neoplasias/metabolismo , Diferenciação Celular , Células-Tronco Neoplásicas/patologia , MicroRNAs/metabolismo
5.
Membranes (Basel) ; 13(3)2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-36984744

RESUMO

In this work, MXene as a hydrophilic 2D nanosheet has been suggested to tailor the polyphenylsulfone (PPSU) flat sheet membrane characteristics via bulk modification. The amount of MXene varied in the PPSU casting solution from 0-1.5 wt.%, while a series of characterization tools have been employed to detect the surface characteristics changes. This included atomic force microscopy (AFM), scanning electron microscopy (SEM), contact angle, pore size and porosity, and Fourier-transform infrared spectroscopy (FTIR). Results disclosed that the MXene content could significantly influence some of the membranes' surface characteristics while no effect was seen on others. The optimal MXene content was found to be 0.6 wt.%, as revealed by the experimental work. The roughness parameters of the 0.6 wt.% nanocomposite membrane were notably enhanced, while greater hydrophilicity has been imparted compared to the nascent PPSU membrane. This witnessed enhancement in the surface characteristics of the nanocomposite was indeed reflected in their performance. A triple enhancement in the pure water flux was witnessed without compromising the retention of the membranes against the Cu2+, Cd2+ and Pd2+ feed. In parallel, high, and comparable separation rates (>92%) were achieved by all membranes regardless of the MXene content. In addition, promising antifouling features were observed with the nanocomposite membranes, disclosing that these nanocomposite membranes could offer a promising potential to treat heavy metals-containing wastewater for various applications.

6.
STAR Protoc ; 4(2): 102163, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36930646

RESUMO

Here, we present a protocol to generate a murine model of liver metastasis by directly injecting tumor cells into the portal vein under ultrasound guidance. We describe steps for animal and cell preparation and two techniques for injecting tumor cells. One technique is freehand, while the other technique is device-assisted using a 3D-printed prototype device. Finally, we describe tumor surveillance with bioluminescent imaging.

7.
J Nucl Med ; 64(1): 117-123, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35738905

RESUMO

Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with 18F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. 18F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on 18F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased 18F-FDG uptake in the spleen. The average spleen SUVmax in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in STING agonist-treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased 18F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that 18F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development.


Assuntos
Fluordesoxiglucose F18 , Ativação Linfocitária , Masculino , Animais , Camundongos , Fluordesoxiglucose F18/metabolismo , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons , Transdução de Sinais
8.
Semin Cancer Biol ; 88: 18-31, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36410636

RESUMO

Signal transducer and activator of transcription (STAT) proteins compose a family of transcription factors critical for cancer stem cells (CSCs), and they are involved in maintaining stemness properties, enhancing cell proliferation, and promoting metastasis. Recent studies suggest that STAT proteins engage in reciprocal communication between CSCs and infiltrate immune cell populations in the tumor microenvironment (TME). Emerging evidence has substantiated the influence of immune cells, including macrophages, myeloid-derived suppressor cells, and T cells, on CSC survival through the regulation of STAT signaling. Conversely, dysregulation of STATs in CSCs or immune cells contributes to the establishment of an immunosuppressive TME. Thus, STAT proteins are promising therapeutic targets for cancer treatment, especially when used in combination with immunotherapy. From this perspective, we discuss the complex roles of STATs in CSCs and highlight their functions in the crosstalk between CSCs and the immune microenvironment. Finally, cutting-edge clinical trial progress with STAT signaling inhibitors is summarized.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Fatores de Transcrição/metabolismo , Microambiente Tumoral , Antineoplásicos/uso terapêutico , Neoplasias/genética , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo
9.
Cureus ; 15(12): e50027, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38186472

RESUMO

INTRODUCTION: The COVID-19 pandemic triggered the unprecedented 'long COVID' crisis, with persistent symptoms beyond two months post-infection. This study explores the nexus between long COVID symptoms, patient demographics such as age, gender, and smoking, and clinical factors like vaccination, disease severity, and comorbidities. METHODS: A retrospective analysis of records was conducted between September 2021 and December 2022. The analysis covered adults with confirmed COVID-19 diagnoses. Data encompassed demographics, medical history, vaccination, disease severity, hospitalization, treatments, and post-COVID symptoms, analyzed using logistic regression. RESULTS: Among 289 participants, the average age was 51.51 years. Around 62.6% were females, and 93% received the COVID-19 vaccination, i.e., primarily the mRNA vaccine (48.4%) and the adenovirus vector-based vaccine (34.8%). Reinfections occurred in 11.76% of cases. Disease severity varied, with 75% having mild, 15% having moderate, and 10% having severe infections. Hospitalization rates were significant (25.6%), including 10.7% requiring intensive care. Thirteen distinct post-COVID symptoms were reported. Fatigue, shortness of breath upon exertion, and brain fog emerged as the most prevalent symptoms. Notably, females exhibited higher symptom prevalence. Significant correlations were established between higher BMI and smoking with augmented symptomatology. Conversely, a link between booster doses and symptom reduction was discerned. Using multinomial regression analysis, gender and smoking were identified as predictors of post-COVID-19 symptoms. CONCLUSION: The study underscores obesity, smoking, and the female gender's impact on long COVID symptoms; boosters show promise in alleviation. Respiratory pathology might underlie persistent symptoms in cases with radiological abnormalities and abnormal spirometry. Findings contribute to risk stratification, intervention strategies, and further research.

10.
Cell Rep ; 38(2): 110236, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35021095

RESUMO

We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Interferon Tipo I/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Interferon Tipo I/farmacologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Nucleotídeos/antagonistas & inibidores , Nucleotídeos/biossíntese , Nucleotídeos/metabolismo , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias Pancreáticas
11.
Semin Cancer Biol ; 83: 208-226, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-32717336

RESUMO

Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.


Assuntos
Doenças Autoimunes , MicroRNAs , RNA Longo não Codificante , Neoplasias Cutâneas , Doenças Autoimunes/genética , Humanos , RNA Longo não Codificante/genética , RNA Nucleolar Pequeno/genética , RNA não Traduzido/genética , Neoplasias Cutâneas/genética
12.
Cancers (Basel) ; 13(21)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34771621

RESUMO

Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, yet the specific impact of the CD95/CD95L system in this crosstalk has not been well studied. In this study, we show that gemcitabine stimulates the expression of pro-inflammatory cytokines, such as IL6 and IL8, under the influence of the CD95/CD95L system and the pharmacological inhibitor, sCD95Fc, substantially reduced the expression in two PDAC cell lines, PancTuI-luc and A818-4. The stem cell phenotype was reduced when induced upon gemcitabine as well by sCD95Fc. Moreover, TNF-α as well as TRAIL up-regulate the expression of CD95 and CD95L in both cell lines. Conversely, we detected a significant inhibitory effect of sCD95Fc on the expression of both IL8 and IL6 induced upon TNF-α and TRAIL stimulation. In vivo, CD95L inhibition reduced xeno-transplanted recurrent PDAC growth. Thus, our findings indicate that inhibition of CD95 signaling altered the chemotherapeutic effects of gemcitabine, not only by suppressing the pro-inflammatory responses that arose from the CD95L-positive tumor cells but also from the TNF-α and TRAIL signaling in a bi-lateral crosstalk manner.

13.
Cureus ; 13(8): e17336, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34557372

RESUMO

Introduction Adverse events related to Drug-Drug Interactions (DDIs) are among the few common reasons for hospitalization worldwide; however, they can be prevented with an efficient patient-centered system. Different mechanisms have successfully limited the prevalence of DDIs in developed countries. There are limited data regarding DDIs from limited-resource settings. Furthermore, there is no cost-effective system that has shown promising results in preventing them in this setting. This study aims to assess the frequency of potential DDIs in a low-resource setting and to check its association with different factors such as poly-pharmacy and demographics. Methods Through this cross-sectional study, drug charts of patients admitted to a medical unit in November 2019 were analyzed using a structured questionnaire. A list of drugs co-prescribed to each patient was entered into the Medscape Drug Interaction checker to calculate the frequency and severity of potential DDIs. Results The mean age of patients was 49 years, and on average, seven drugs were prescribed to each patient. Among 100 analyzed prescriptions, 400 potential DDIs were identified with a mean of 4±5.42 per patient. According to Medscape interaction checker classification, 2 DDIs were contraindicated, 28 were serious, 246 required close monitoring, and 124 were minor. The most frequently encountered drug interaction was "spironolactone with furosemide." There was a significant correlation of the occurrence of potential DDIs with increased numbers of prescribed drugs. Conclusion Our patient population was prescribed more drugs per patient than calculated in other settings. Poly-pharmacy is an independent risk factor for DDIs. Lastly, advancing age exposes patients to poly-pharmacy, and therefore, they are at a higher risk of developing DDIs.

14.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34480004

RESUMO

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.


Assuntos
Didesoxinucleosídeos/administração & dosagem , Radioisótopos de Flúor/administração & dosagem , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Biomed Pharmacother ; 143: 112142, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536761

RESUMO

Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.


Assuntos
Antineoplásicos/uso terapêutico , Benzofenantridinas/uso terapêutico , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Oxidantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais
16.
Membranes (Basel) ; 11(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34357192

RESUMO

In the current work, a Gum, Arabic-modified Graphene (GGA), has been synthesized via a facile green method and employed for the first time as an additive for enhancement of the PPSU ultrafiltration membrane properties. A series of PPSU membranes containing very low (0-0.25) wt.% GGA were prepared, and their chemical structure and morphology were comprehensively investigated through atomic force microscopy (AFM), Fourier transforms infrared spectroscopy (FTIR), X-ray diffraction (XRD), and field emission scanning electron microscopy (FESEM). Besides, thermogravimetric analysis (TGA) was harnessed to measure thermal characteristics, while surface hydrophilicity was determined by the contact angle. The PPSU-GGA membrane performance was assessed through volumetric flux, solute flux, and retention of sodium alginate solution as an organic polysaccharide model. Results demonstrated that GGA structure had been successfully synthesized as confirmed XRD patterns. Besides, all membranes prepared using low GGA content could impart enhanced hydrophilic nature and permeation characteristics compared to pristine PPSU membranes. Moreover, greater thermal stability, surface roughness, and a noticeable decline in the mean pore size of the membrane were obtained.

17.
BMJ Case Rep ; 14(7)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233865

RESUMO

Ticagrelor is a part of dual antiplatelet therapy (DAPT) which has proven benefits in patients with acute coronary syndrome especially in those undergoing percutaneous coronary intervention (PCI). However, like most other drugs, it can lead to undesired and adverse effects such as dyspnoea, easy bruising and gastrointestinal bleeding. We present a case of 70-year-old woman who developed diarrhoea following initiation of DAPT comprising of aspirin and ticagrelor following PCI. After excluding more common causes, it was attributed to ticagrelor administration and completely resolved after it was replaced with another oral antiplatelet agent. On follow-up, the patient reported complete resolution of symptoms.


Assuntos
Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/tratamento farmacológico , Idoso , Diarreia/induzido quimicamente , Feminino , Hemorragia , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Ticagrelor/efeitos adversos
18.
Drug Discov Today ; 26(7): 1689-1701, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33737072

RESUMO

Solute carrier (SLC) transporters are primarily known for their function in the transportation of various exogenous/endogenous substances via influx/efflux mechanisms. In addition to their diverse role in several tumor-modulating functions, such as proliferation, migration, angiogenesis, epithelial-mesenchymal transition (EMT), epigenetic modification, chemoresistance, immunoregulation, and oncometabolism, influx/efflux-independent contributions of SLCs in the activation of various signaling network cascades that might drive metastatic tumor formation have also been uncovered. Disappointingly, even after two decades and the discovery of >450 SLCs, many of their members remain orphans in terms of cancer pathogenesis. In this review, we summarize the current understanding of the tumor-modulating functions, mechanisms, and complexity of SLCs, as well as their potential as targets for cancer therapy.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Animais , Carcinogênese , Resistencia a Medicamentos Antineoplásicos , Humanos , Proteínas de Membrana Transportadoras/imunologia , Invasividade Neoplásica , Neoplasias/patologia , Neovascularização Patológica/patologia , Proteínas Supressoras de Tumor/metabolismo
19.
Membranes (Basel) ; 11(3)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673720

RESUMO

Among many contaminants in wastewater, organic phenol compounds presented a major concern to endanger the water resources safety. In the present study, blend nanofiltration (NF) membranes comprising polyphenylsulfone (PPSU) and polyethersulfone (PES) were prepared via the non-induced phase separation and their performance was examined against 4-Nitrophenol (4-NP). The PES ratio in the dope solution was varied from 6 to 9 wt.% to probe the impact of PES on the retention and permeation characteristics of the final membranes. A series of experimental tools were employed to estimate the characteristics of the membranes, including surface and cross-section, hydrophilicity, pore size and pore size distribution. Performance evaluation of the NF membranes was conducted considering two operational variables; pH and initial feed solution. About 99% removal of 4-NP along with 6.2 L/m2.h.bar was achieved at the optimum operating conditions as revealed by optimization and mathematical modelling.

20.
Cancer Cell Int ; 21(1): 135, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632198

RESUMO

BACKGROUND: The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration. METHODS: A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples. RESULTS: We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4+ T cell, CD8+ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression. CONCLUSIONS: SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.

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