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Cinnamon is a natural spice with a wide range of pharmacological functions, including anti-microbial, antioxidant, and anti-tumor activities. The aim of this study is to investigate the effects of cinnamaldehyde-rich cinnamon extract (CRCE) on the colorectal cancer cell lines HCT 116 and HT-29. The gas chromatography mass spectrometry analysis of a lipophilic extract of cinnamon revealed the dominance of trans-cinnamaldehyde. Cells treated with CRCE (10-60 µg/mL) showed significantly decreased cell viability in a time- and dose-dependent manner. We also observed that cell proliferation and migration capacity were inhibited in CRCE-treated cells. In addition, a remarkable increase in the number of sub-G1-phase cells was observed with arrest at the G2 phase by CRCE treatment. CRCE also induced mitochondrial stress, and finally, CRCE treatment resulted in activation of apoptotic proteins Caspase-3, -9, and PARP and decreased levels of mu-2-related death-inducing gene protein expression with BH3-interacting domain death agonist (BID) activation.
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Cinnamomum zeylanicum , Neoplasias del Colon , Humanos , Cinnamomum zeylanicum/química , Apoptosis , Neoplasias del Colon/tratamiento farmacológico , Células HT29 , Muerte Celular , Proliferación Celular , Extractos Vegetales/farmacología , Extractos Vegetales/química , Supervivencia CelularRESUMEN
After decades of research and development concerning cancer treatment, cancer is still at large and very much a threat to the global human population. Cancer remedies have been sought from all possible directions, including chemicals, irradiation, nanomaterials, natural compounds, and the like. In this current review, we surveyed the milestones achieved by green tea catechins and what has been accomplished in cancer therapy. Specifically, we have assessed the synergistic anticarcinogenic effects when green tea catechins (GTCs) are combined with other antioxidant-rich natural compounds. Living in an age of inadequacies, combinatorial approaches are gaining momentum, and GTCs have progressed much, yet there are insufficiencies that can be improvised when combined with natural antioxidant compounds. This review highlights that there are not many reports in this specific area and encourages and recommends research attention in this direction. The antioxidant/prooxidant mechanisms of GTCs have also been highlighted. The current scenario and the future of such combinatorial approaches have been addressed, and the lacunae in this aspect have been discussed.
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Anticarcinógenos , Catequina , Neoplasias , Humanos , Té/química , Antioxidantes , Catequina/química , Neoplasias/tratamiento farmacológico , Anticarcinógenos/farmacologíaRESUMEN
MALDI-TOF-MS has essentially delivered more than expected with respect to clinical pathogens. Viruses are the most versatile entities of clinical pathogens that have challenged well-established microbiological methodologies. This review evaluates the existing scenario with respect to MALDI TOF-MS analytical technique in the successful analysis of viral pathogens. The milestones achieved with respect to detection and identification of COVID-19 has been presented. The fact that only a handful of scattered applications for COVID-19 exist has been pointed out in the review. Further, the lapses in the utilization of the available state-of-the art MALDI-TOF-MS variants/benchmark sophistications for COVID-19 analysis, are highlighted. When the world is seeking for rapid solutions for early, sensitive, rapid COVID-19 diagnosis, maybe MALDI-TOF-MS, may be the actual 'gold standard'. Reverting to the title, this review emphasizes that there is a need for extrapolating MALDI-TOF-MS for COVID-19 analysis and this calls for urgent scientific attention.
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Of the biologically active components, polysaccharides play a crucial role of high medical and pharmaceutical significance. Mushrooms have existed for a long time, dating back to the time of the Ancient Egypt and continue to be well explored globally and experimented with in research as well as in national and international cuisines. Mushroom polysaccharides have slowly become valuable sources of nutraceuticals which have been able to treat various diseases and disorders in humans. The application of mushroom polysaccharides for anticancer mycotherapy is what is being reviewed herein. The widespread health benefits of mushroom polysaccharides have been highlighted and the significant inputs of mushroom-based polysaccharides in anticancer clinical trials have been presented. The challenges and limitation of mushroom polysaccharides into this application and the gaps in the current application areas that could be the future direction have been discussed.
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Agaricales/química , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Polisacáridos/uso terapéutico , Antineoplásicos/farmacología , Suplementos Dietéticos , Humanos , Polisacáridos/farmacologíaRESUMEN
Cervical cancer is a life-threatening disease and the fourth most common cancer among women worldwide. Apple pomace is a multifunctional phenolic compound possessing effective biological activity against cervical cancer cells. This study aimed to investigate the anticancer effects of quercetin-3-glucoside (Q3G) extracted from apple pomace in HeLa cell lines and analyze its molecular mechanisms. High-performance liquid chromatography revealed that Q3G, coumaric acid, phloridzin, quercetin, and phloretin are the major polyphenolic compounds constituting apple pomace. Among them, Q3G possessed the greatest antioxidant and anti-inflammatory effects in vitro and exhibited significant cytotoxic effects in HeLa cells in a dose-and time-dependent manner. Flow cytometric analysis indicated that Q3G induced cell cycle arrest at the S phase in a time-dependent manner by altering cyclin-dependent kinase 2. Moreover, it induced apoptosis via chromosomal DNA degradation and increased reactive oxygen species generation. Furthermore, Q3G treatment altered the apoptosis-associated protein expression in the cells by activating caspase-9/-3, downregulating anti-apoptosis protein B-cell lymphoma (Bcl)-2 expressions and up regulating the pro-apoptotic Bcl-2-associated X protein. BH3-interacting domain death agonist cleavage occurred prior to the degradation of an anti-apoptotic Mu-2-related death-inducing gene involved in cell death signaling. Consequently, apple pomace Q3G holds promise as an anti-inflammatory and anticancer agent for treating cervical cancer.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Malus/química , Quercetina/análogos & derivados , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Apoptosis , Proliferación Celular , Femenino , Humanos , Quercetina/farmacología , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/patologíaRESUMEN
The clinical sampling of urine is noninvasive and unrestricted, whereby huge volumes can be easily obtained. This makes urine a valuable resource for the diagnoses of diseases. Urinary and renal proteomics have resulted in considerable progress in kidney-based disease diagnosis through biomarker discovery and treatment. This review summarizes the bioinformatics tools available for this area of proteomics and the milestones reached using these tools in clinical research. The scant research publications and the even more limited bioinformatic tool options available for urinary and renal proteomics are highlighted in this review. The need for more attention and input from bioinformaticians is highlighted, so that progressive achievements and releases can be made. With just a handful of existing tools for renal and urinary proteomic research available, this review identifies a gap worth targeting by protein chemists and bioinformaticians. The probable causes for the lack of enthusiasm in this area are also speculated upon in this review. This is the first review that consolidates the bioinformatics applications specifically for renal and urinary proteomics.
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Biología Computacional/métodos , Riñón/metabolismo , Orina/química , Biomarcadores/orina , Humanos , Proteómica , Enfermedades Urológicas/diagnóstico , Enfermedades Urológicas/metabolismo , Enfermedades Urológicas/orinaRESUMEN
Glycosylation plays a crucial role in various diseases and their etiology. This has led to a clear understanding on the functions of carbohydrates in cell communication, which eventually will result in novel therapeutic approaches for treatment of various disease. Glycomics has now become one among the top ten technologies that will change the future. The direct implication of glycosylation as a hallmark of cancer and for cancer therapy is well established. As in proteomics, where bioinformatics tools have led to revolutionary achievements, bioinformatics resources for glycosylation have improved its practical implication. Bioinformatics tools, algorithms and databases are a mandatory requirement to manage and successfully analyze large amount of glycobiological data generated from glycosylation studies. This review consolidates all the available tools and their applications in glycosylation research. The achievements made through the use of bioinformatics into glycosylation studies are also presented. The importance of glycosylation in cancer diagnosis and therapy is discussed and the gap in the application of widely available glyco-informatic tools for cancer research is highlighted. This review is expected to bring an awakening amongst glyco-informaticians as well as cancer biologists to bridge this gap, to exploit the available glyco-informatic tools for cancer.
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Biomarcadores de Tumor/metabolismo , Glicómica/métodos , Glicoproteínas/metabolismo , Neoplasias/metabolismo , Animales , Glicosilación , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Procesamiento Proteico-PostraduccionalRESUMEN
Despite multitudes of reports on cancer remedies available, we are far from being able to declare that we have arrived at that defining anti-cancer therapy. In recent decades, researchers have been looking into the possibility of enhancing cell death-related signaling pathways in cancer cells using pro-apoptotic proteins. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Mu-2/AP1M2 domain containing, death-inducing (MUDENG, MuD) have been established for their ability to bring about cell death specifically in cancer cells. Targeted cell death is a very attractive term when it comes to cancer, since most therapies also affect normal cells. In this direction TRAIL has made noteworthy progress. This review briefly sums up what has been done using TRAIL in cancer therapeutics. The importance of MuD and what has been achieved thus far through MuD and the need to widen and concentrate on applicational aspects of MuD has been highlighted. This has been suggested as the future perspective of MuD towards prospective progress in cancer research.
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Complejo 1 de Proteína Adaptadora/genética , Subunidades mu de Complejo de Proteína Adaptadora/genética , Proteínas Reguladoras de la Apoptosis/genética , Neoplasias/tratamiento farmacológico , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Complejo 1 de Proteína Adaptadora/antagonistas & inhibidores , Subunidades mu de Complejo de Proteína Adaptadora/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias/genética , Neoplasias/patología , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF/antagonistas & inhibidoresRESUMEN
OBJECTIVE: Gamma-aminobutyric acid (GABA) and piperine (PIP) are both nutritional supplements with potential use in animal diets. The purpose of this study is to investigate the effect of GABA and/or PIP treatment on the gene expression pattern of a pig kidney epithelial cell line. METHODS: LLCPK1 cells were treated with GABA, PIP, or both, and then the gene expression pattern was analyzed using microarray. Gene ontology analysis was done using GeneOntology (Geneontology.org), and validation was performed using quantitative real-time polymerase chain reaction. RESULTS: Gene ontology enrichment analysis was used to identify key pathway(s) of genes whose expression levels were regulated by these treatments. Microarray results showed that GABA had a positive effect on the transcription of genes related to regulation of erythrocyte differentiation and that GABA and PIP in combination had a synergistic effect on genes related to immune systems and processes. Furthermore, we found that effects of GABA and/or PIP on these selected genes were controlled by JNK/p38 MAPK pathway. CONCLUSION: These results can improve our understanding of mechanisms involved in the effect of GABA and/or PIP treatment on pig kidney epithelial cells. They can also help us evaluate their potential as a clinical diagnosis and treatment.
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Context: Methyl lucidone (ML) from the dried fruit of Lindera erythrocarpa Makino (Lauraceae) exhibits cytotoxic effects in various cancer cell lines. However, its effects on ovarian cancer cells remain unknown.Objective: This study evaluates the mechanism of ML-induced apoptosis, cell cycle distribution in ovarian cells.Materials and methods: The cytotoxic effect of ML (2.5-80 µM) on OVCAR-8 and SKOV-3 cells was evaluated by MTS assay for 24 and 48 h. Apoptosis and cell cycle arrest were analysed by flow cytometry. PCR, western blot analyses were performed to examine the related signalling pathways.Results: ML induced significant cellular morphological changes and apoptosis in ovarian cancer cells, leading to an antiproliferative effect (IC50 = 33.3-54.7 µM for OVCAR-8 and 48.8-60.7 µM for SKOV-3 cells). Treatment with ML induced cleavage of caspase-3/9 and PARP and release of cytochrome c from the mitochondria. Moreover, ML downregulated the expression of Bcl-2 and Bcl-xL and induced cell cycle arrest in the G2/M phase. Additionally, ML suppressed the expression of cyclin-A/B and promoted that of the cyclin-dependent kinase inhibitors p21 and p27. The expression of death receptors was not altered. Interestingly, ML also inhibited the activity of PI3K/Akt and NF-κB.Discussion and conclusions: ML caused G2/M phase arrest and apoptosis in ovarian cancer cells by activating intrinsic apoptotic pathways and suppressing the PI3K/Akt survival pathway. ML may be a potential anticancer agent to suppress ovarian cancer proliferation; thus, to improve the survival rate of cancer patients.
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Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Ciclopentanos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclopentanos/administración & dosificación , Ciclopentanos/aislamiento & purificación , Femenino , Frutas , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Lindera/química , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , FN-kappa B/metabolismo , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: Tumor-associated macrophages can promote breast cancer metastasis by secreting cytokines and growth factors. Interleukin (IL)-32θ, a newly identified IL-32 isoform, was previously shown to down-regulate various proinflammatory factors of macrophages. Here, we report the presence of IL-32θ in breast cancer tissues and evaluate its effects on macrophage-regulated breast cancer metastasis. METHODS: RT-qPCR was used to analyze the mRNA expression of IL-32θ, Chemokine (C-C motif) ligand 18 (CCL18) in breast cancer tissues. In vitro cell-based experiments using IL-32θ-expressing MDA-MB-231 cells were conducted to examine the effects of IL-32θ on metastasis and its molecular signaling. In vivo xenograft, immunohistochemistry, and optical imaging models were generated to support in vitro and clinical findings. RESULTS: The clinical data displayed opposite expression patterns of CCL18 and IL-32θ mRNA in macrophage-infiltrated breast tumor tissues compared with those in the other tissues tested. In MDA-MB-231 cells, IL-32θ overexpression attenuated migration, invasion, tumor-promoting factors, and increased epithelial markers levels upon treatment with conditioned media from THP-1-derived macrophages. Additionally, IL-32θ expression in a xenograft model led to a remarkable decrease in tumor size and macrophage-stimulated tumor promotion. This inhibition was mediated through a direct interaction with protein kinase C-δ (PKCδ), subsequently eliminating the downstream factors STAT3 and NF-κB. Blocking CCL18 during co-culture of macrophages and breast cancer cells reduced the levels of breast cancer progression-related factors and PKCδ downstream signaling suggesting CCL18 as the main macrophage-secreted factors triggering the signaling pathway inhibited by IL-32θ. CONCLUSIONS: Our findings demonstrate a novel role of IL-32θ as an intracellular modulator to suppress macrophage-promoted breast cancer progression by targeting CCL18-dependent signaling.
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Neoplasias de la Mama/metabolismo , Quimiocina CCL18/metabolismo , Interleucinas/metabolismo , Macrófagos/metabolismo , Transducción de Señal , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Quimiocina CCL18/genética , Femenino , Humanos , Interleucinas/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones SCID , Persona de Mediana Edad , FN-kappa B/metabolismo , Metástasis de la Neoplasia , Factor de Transcripción STAT3/metabolismoRESUMEN
Mu-2-related death-inducing (MuD) gene is involved in apoptosis in tumor cells. Although we have previously produced mouse monoclonal antibodies (MAbs) that specifically recognize human MuD, the application scope of MuD MAbs was restricted due to their mouse origin. Therefore, we attempted the generation of single-chain variable fragment (scFv) against MuD. The heavy- and light-chain variable region genes from two MuD hybridomas were isolated by PCR and joined by DNA encoding a (Gly4Ser1)3 linker. These scFv fragments were cloned into a phagemid vector and expressed as E-tagged fusion proteins in Escherichia coli HB2151. The reactivity of selected Abs was evaluated using ELISA. Selected MuDscFv Abs specifically recognized human MuD, retaining ~ 50% potency of the parent MAbs. MuDscFv-M3H9 recognized the middle region of MuD, while MuDscFv-C22B3 recognized a broad region. Intracellular expression of MuDscFvs-C22B3 protected cells from TRAIL-induced apoptosis. These MuDscFv Abs may help in the study of intracellular signaling pathway centered on MuD and of drug use target and points.
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Proteínas Reguladoras de la Apoptosis/inmunología , Clonación Molecular/métodos , Anticuerpos de Cadena Única/biosíntesis , Anticuerpos de Cadena Única/metabolismo , Secuencia de Aminoácidos/genética , Animales , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos/inmunología , Proteínas Reguladoras de la Apoptosis/genética , Ensayo de Inmunoadsorción Enzimática , Escherichia coli/genética , Expresión Génica/genética , Ingeniería Genética/métodos , Humanos , Hibridomas/inmunología , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes/genética , Anticuerpos de Cadena Única/inmunologíaRESUMEN
Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.
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Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Interleucina-13/metabolismo , Interleucinas/farmacología , Monocitos/metabolismo , Proteína Quinasa C-delta/metabolismo , Factor de Transcripción STAT3/metabolismo , Sitios de Unión , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Humanos , Subunidad alfa2 del Receptor de Interleucina-13/genética , Interleucinas/metabolismo , Modelos Biológicos , Monocitos/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Factor de Transcripción STAT6/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
We investigated the role of peroxisome proliferator-activated receptor (PPAR) δ on angiotensin (Ang) II-induced activation of matrix metalloproteinase (MMP)-2 in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, attenuated Ang II-induced activation of MMP-2 in a concentration-dependent manner. GW501516 also inhibited the generation of reactive oxygen species in VSMCs treated with Ang II. A marked increase in the mRNA levels of tissue inhibitor of metalloproteinase (TIMP)-2 and -3, endogenous antagonists of MMPs, was also observed in GW501516-treated VSMCs. These effects were markedly reduced in the presence of siRNAs against PPARδ, indicating that the effects of GW501516 are PPARδ dependent. Among the protein kinases inhibited by GW501516, suppression of phosphatidylinositol 3-kinase/Akt signaling was shown to have the greatest effect on activation of MMP-2 in VSMCs treated with Ang II. Concomitantly, GW501516-mediated inhibition of MMP-2 activation in VSMCs treated with Ang II was associated with the suppression of cell migration to levels approaching those in cells not exposed to Ang II. Thus, activation of PPARδ confers resistance to Ang II-induced degradation of the extracellular matrix by upregulating expression of its endogenous inhibitor TIMP and thereby modulating cellular responses to Ang II in vascular cells.
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Metaloproteinasa 2 de la Matriz/metabolismo , Miocitos del Músculo Liso/metabolismo , PPAR delta/metabolismo , Angiotensina II/farmacología , Animales , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Masculino , Músculo Liso Vascular/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Ratas , Transducción de Señal/efectos de los fármacos , TiazolesRESUMEN
[This corrects the article DOI: 10.1016/j.jgr.2019.05.003.].
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Osterix (Osx), a zinc-finger transcription factor, is required for osteoblast differentiation and new bone formation during embryonic development. Calmodulin-dependent kinase II (CaMKII) acts as a key regulator of osteoblast differentiation. However, the precise molecular signaling mechanisms between Osterix and CaMKII are not known. In this study, we focused on the relationship between Osterix and CaMKII during osteoblast differentiation. We examined the role of the CaMKII pathway in the regulation of protein levels and its transcriptional activity on Osterix. We showed that CaMKII interacts with Osterix by increasing the protein levels and enhancing the transcriptional activity of Osterix. Conversely, CaMKII inhibitor KN-93 decreases the protein levels and increases the stability of Osterix. The siRNA-mediated knockdown of CaMKII decreased the protein levels and transcriptional activity of Osterix. These results suggest that Osterix is a novel target of CaMKII and the activity of Osterix can be modulated by a novel mechanism involving CaMKII during osteoblast differentiation.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Diferenciación Celular , Osteoblastos/citología , Osteogénesis/fisiología , Factores de Transcripción/metabolismo , Animales , Bencilaminas/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Línea Celular , Células HEK293 , Humanos , Ratones , Osteoblastos/metabolismo , Osteogénesis/genética , Inhibidores de Proteínas Quinasas/farmacología , Factor de Transcripción Sp7 , Sulfonamidas/farmacología , Factores de Transcripción/genética , Transcripción GenéticaRESUMEN
MUDENG, also known as AP5M1, was originally identified as an adaptin domain-containing gene that induced cell death in lymphoma cell lines. However, little is known of the mechanism responsible for MUDENG-mediated cell death. In this study, we investigated MUDENG changes during TRAIL-induced cell death. We found that MUDENG is rapidly processed in response to TRAIL in Jurkat and BJAB cells with time line similar to that of caspase activation. Caspase-3-mediated MUDENG cleavage was confirmed by an in vitro cleavage assay using recombinant active caspase proteins. Caspase cleavage sites (D276 and D290) were located in the adaptin domain of MUDENG, and cleaved MUDENG showed the reduced killing activity. These results suggest that the adaptin domain plays a key role in MUDENG-mediated cell death.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Activación Enzimática , Células HeLa , Humanos , Células Jurkat , Neoplasias Experimentales , Unión ProteicaRESUMEN
UV radiation-mediated photodamage to the skin has been implicated in premature aging and photoaging-related skin cancer and melanoma. Little is known about the cellular events that underlie premature senescence, or how to impede these events. In the present study we demonstrate that PPARδ (peroxisome-proliferator-activated receptor δ) regulates UVB-induced premature senescence of normal keratinocytes. Activation of PPARδ by GW501516, a specific ligand of PPARδ, significantly attenuated UVB-mediated generation of ROS (reactive oxygen species) and suppressed senescence of human keratinocytes. Ligand-activated PPARδ up-regulated the expression of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and suppressed the PI3K (phosphatidylinositol 3-kinase)/Akt pathway. Concomitantly, translocation of Rac1 to the plasma membrane, which leads to the activation of NADPH oxidases and generation of ROS, was significantly attenuated. siRNA (small interfering RNA)-mediated knockdown of PTEN abrogated the effects of PPARδ on cellular senescence, on PI3K/Akt/Rac1 signalling and on generation of ROS in keratinocytes exposed to UVB. Finally, when HR-1 hairless mice were treated with GW501516 before exposure to UVB, the number of senescent cells in the skin was significantly reduced. Thus ligand-activated PPARδ confers resistance to UVB-induced cellular senescence by up-regulating PTEN and thereby modulating PI3K/Akt/Rac1 signalling to reduce ROS generation in keratinocytes.
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Queratinocitos/efectos de la radiación , Fosfohidrolasa PTEN/fisiología , Superóxidos/antagonistas & inhibidores , Animales , Membrana Celular/metabolismo , Células Cultivadas , Senescencia Celular , Niño , Activación Enzimática , Humanos , Queratinocitos/fisiología , Ligandos , Ratones , Ratones Pelados , PPAR delta/agonistas , PPAR delta/fisiología , Fosfohidrolasa PTEN/biosíntesis , Fosfatidilinositol 3-Quinasas/fisiología , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Piel/citología , Piel/metabolismo , Piel/efectos de la radiación , Superóxidos/metabolismo , Tiazoles/farmacología , Rayos Ultravioleta , Regulación hacia Arriba , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Extensive growth of microscopic algae and cyanobacteria results in harmful algal blooms (HABs) in marine, brackish, and freshwater environments. HABs can harm humans and animals through their toxicity or by producing ecological conditions such as oxygen depletion, which can kill fish and other economically or ecologically important organisms. This review summarizes the reports on various HABs that are able to bring about marine fish kills. The predominant HABs, their toxins, and their effects on fishes spread across various parts of the globe are discussed. The mechanism of HAB-driven fish kills is discussed based on the available reports, and existing mitigation methods are presented. Lapses in the large-scale implementation of mitigation methods demonstrated under laboratory conditions are projected. Clay-related technologies and nano-sorption-based nanotechnologies, although proven to make significant contributions, have not been put to use in real-world conditions. The gaps in the technology transfer of the accomplished mitigation prototypes are highlighted. Further uses of remote sensing and machine learning state-of-the-art techniques for the detection and identification of HABs are recommended.
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Aminoglycosides (AGs) are broad-spectrum antibiotics used to treat bacterial infections. Over the last two decades, studies have reported the potential of AGs in the treatment of genetic disorders caused by nonsense mutations, owing to their ability to induce the ribosomes to read through these mutations and produce a full-length protein. However, the principal limitation in the clinical application of AGs arises from their high toxicity, including nephrotoxicity and ototoxicity. In this study, five novel pseudo-trisaccharide analogs were synthesized by chemo-enzymatic synthesis by acid hydrolysis of commercially available AGs, followed by an enzymatic reaction using recombinant substrate-flexible KanM2 glycosyltransferase. The relationships between their structures and biological activities, including the antibacterial, nephrotoxic, and nonsense readthrough inducer (NRI) activities, were investigated. The absence of 1-N-acylation, 3',4'-dideoxygenation, and post-glycosyl transfer modifications on the third sugar moiety of AGs diminishes their antibacterial activities. The 3',4'-dihydroxy and 6'-hydroxy moieties regulate the inâ vitro nephrotoxicity of AGs in mammalian cell lines. The 3',4'-dihydroxy and 6'-methyl scaffolds are indispensable for the ex vivo NRI activity of AGs. Based on the alleviated inâ vitro antibacterial properties and nephrotoxicity, and the highest ex vivo NRI activity among the five compounds, a kanamycin analog (6'-methyl-3''-deamino-3''-hydroxykanamycin C) was selected as a novel AG hit for further studies on human genetic disorders caused by premature transcriptional termination.