Dietary carotenoids, connexins and cancer: what is the connection?

2004 ◽  
Vol 32 (6) ◽  
pp. 985-989 ◽  
Author(s):  
J.S. Bertram
Keyword(s):  
Epidemiological Studies ◽  
Experimental Models ◽  
Genetically Engineered ◽  
Gap Junctional Intercellular Communication ◽  
Independent Manner ◽  
Waste Products ◽  
Initiation Phase ◽  
Experimental Systems ◽  
Junctional Communication ◽  
Wide Scale

Carotenoids and retinoids are chemically related; indeed a major source of vitamin A in humans occurs through enzymic cleavage of β-carotene. However, most dietary carotenoids cannot be converted into retinoids. Retinoids have demonstrated cancer-preventive activities in humans and experimental models; however, their toxicity has precluded wide-scale clinical use. In contrast, carotenoids are essentially non-toxic and their cancer-preventive activities, although strongly supported by epidemiological studies, have only been satisfactorily demonstrated in experimental systems. We have shown that in an experimental cell culture system consisting of carcinogen-treated 10T1/2 cells, both retinoids and all dietary carotenoids examined can reversibly inhibit neoplastic transformation in the post-initiation phase of carcinogenesis. This activity strongly correlates with their ability to increase gap junctional intercellular communication by up-regulating the expression of the gene CX43 (connexin43). Connexins comprise the structural unit of gap junctions, organelles which allow direct transfer of signals, nutrients and waste products between contacting cells. CX43 is the most widely expressed member of the gap junction family of genes, and we have demonstrated that its expression is strongly down-regulated in human cancers and in several premalignant conditions. When several human tumour cell lines were genetically engineered to conditionally express CX43 under the influence of a tetracycline promoter, their neoplastic phenotype was strongly attenuated. Specifically, induced cells were inhibited from growing in an anchorage-independent manner and, additionally, growth as xenografts in immunocompromised animals was also strongly attenuated. Growth inhibition in suspension was associated both with increased G1 cell-cycle arrest and with increased apoptosis. We propose a model whereby junctional communication allows the transfer of growth inhibitory signals from normal to neoplastic cells and that retinoids and carotenoids, by increasing signal transfer, act to prevent cancer.

scholarly journals PI3k and Stat3: Oncogenes that are Required for Gap Junctional, Intercellular Communication

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 167 ◽  
Author(s):  
Mulu Geletu ◽  
Zaid Taha ◽  
Patrick T. Gunning ◽  
Leda Raptis
Keyword(s):  
Intercellular Communication ◽  
Single Cells ◽  
Survival Function ◽  
Phosphatidyl Inositol ◽  
Transformed Cells ◽  
Gap Junctional Intercellular Communication ◽  
Junctional Communication ◽  
Human Lung Carcinoma ◽  
Mutational Activation ◽  
Gap Junctional

Gap junctional, intercellular communication (GJIC) is interrupted in cells transformed by oncogenes such as activated Src. The Src effector, Ras, is required for this effect, so that Ras inhibition restores GJIC in Src-transformed cells. Interestingly, the inhibition of the Src effector phosphatidyl-inositol-3 kinase (PI3k) or Signal Transducer and Activator of Transcription-3 (Stat3) pathways does not restore GJIC. In the contrary, inhibition of PI3k or Stat3 in non-transformed rodent fibroblasts or epithelial cells or certain human lung carcinoma lines with extensive GJIC inhibits communication, while mutational activation of PI3k or Stat3 increases GJIC. Therefore, it appears that oncogenes such as activated Src have a dual role upon GJIC; acting as inhibitors of communication through the Ras pathway, and as activators through activation of PI3k or Stat3. In the presence of high Src activity the inhibitory functions prevail so that the net effect is gap junction closure. PI3k and Stat3 constitute potent survival signals, so that their inhibition in non-transformed cells triggers apoptosis which, in turn, has been independently demonstrated to suppress GJIC. The interruption of gap junctional communication would confine the apoptotic event to single cells and this might be essential for the maintenance of tissue integrity. We hypothesize that the GJIC activation by PI3k or Stat3 may be linked to their survival function.

scholarly journals rG4-seeker enables high-confidence identification of novel and non-canonical rG4 motifs from rG4-seq experiments

2020 ◽  
Author(s):  
Eugene Yui-Ching Chow ◽  
Kaixin Lyu ◽  
Chun Kit Kwok ◽  
Ting-Fung Chan
Keyword(s):  
False Positive ◽  
Sampling Errors ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Independent Manner ◽  
G Quadruplex ◽  
Positive Discrimination ◽  
Wide Scale ◽  
Noise Models

ABSTRACTWe recently developed the rG4-seq method to detect and map in vitro RNA G-quadruplex (rG4s) structures on a transcriptome-wide scale. rG4-seq of purified human HeLa RNA has revealed many non-canonical rG4s and the effects adjacent sequences have on rG4 formation. In this study, we aimed to improve the outcomes and false-positive discrimination in rG4-seq experiments using a bioinformatic approach. By establishing connections between rG4-seq library preparation chemistry and the underlying properties of sequencing data, we identified how to mitigate indigenous sampling errors and background noise in rG4-seq. We applied these findings to develop a novel bioinformatics pipeline named rG4-seeker(https://github.com/TF-Chan-Lab/rG4-seeker), which uses tailored noise models to autonomously assess and optimize rG4 detections in a replicate-independent manner. Compared with previous methods, rG4-seeker exhibited better false-positive discrimination and improved sensitivity for non-canonical rG4s. Using rG4-seeker, we identified novel features in rG4 formation that were missed previously. rG4-seeker provides a reliable and sensitive approach for rG4-seq investigations, laying the foundations for further elucidation of rG4 biology.

scholarly journals Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

2019 ◽  
Vol 12 (4) ◽  
pp. 147 ◽  
Author(s):  
Sonja C. J. H. Chua ◽  
Hui Qing Tan ◽  
David Engelberg ◽  
Lina H. K. Lim
Keyword(s):  
Protein Function ◽  
Viral Infections ◽  
Experimental Models ◽  
Host Proteins ◽  
Physiological Basis ◽  
Host Interactions ◽  
Experimental Systems ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Unique Potential

Ninety years after the discovery of the virus causing the influenza disease, this malady remains one of the biggest public health threats to mankind. Currently available drugs and vaccines only partially reduce deaths and hospitalizations. Some of the reasons for this disturbing situation stem from the sophistication of the viral machinery, but another reason is the lack of a complete understanding of the molecular and physiological basis of viral infections and host–pathogen interactions. Even the functions of the influenza proteins, their mechanisms of action and interaction with host proteins have not been fully revealed. These questions have traditionally been studied in mammalian animal models, mainly ferrets and mice (as well as pigs and non-human primates) and in cell lines. Although obviously relevant as models to humans, these experimental systems are very complex and are not conveniently accessible to various genetic, molecular and biochemical approaches. The fact that influenza remains an unsolved problem, in combination with the limitations of the conventional experimental models, motivated increasing attempts to use the power of other models, such as low eukaryotes, including invertebrate, and primary cell cultures. In this review, we summarized the efforts to study influenza in yeast, Drosophila, zebrafish and primary human tissue cultures and the major contributions these studies have made toward a better understanding of the disease. We feel that these models are still under-utilized and we highlight the unique potential each model has for better comprehending virus–host interactions and viral protein function.

scholarly journals Natural Born Killers: NK Cells in Cancer Therapy

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2131 ◽  
Author(s):  
S. Elizabeth Franks ◽  
Benjamin Wolfson ◽  
James W. Hodge
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Adoptive Transfer ◽  
Cellular Therapy ◽  
Nk Cell ◽  
Hematologic Malignancy ◽  
Adoptive Cell Therapy ◽  
Genetically Engineered ◽  
Surface Proteins ◽  
Independent Manner

Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor (CAR) expressing T cells has gained FDA approval in hematologic malignancy. However, limited efficacy was observed using CAR-T therapy in solid tumors. Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner. Adoptive transfer of unmodified allogeneic or autologous NK cells has shown limited clinical benefit due to factors including low cell number, low cytotoxicity and failure to migrate to tumor sites. To address these problems, immortalized and autologous NK cells have been genetically engineered to express high affinity receptors (CD16), CARs directed against surface proteins (PD-L1, CD19, Her2, etc.) and endogenous cytokines (IL-2 and IL-15) that are crucial for NK cell survival and cytotoxicity, with positive outcomes reported by several groups both preclinically and clinically. With a multitude of NK cell-based therapies currently in clinic trials, it is likely they will play a crucial role in next-generation cell therapy-based treatment. In this review, we will highlight the recent advances and limitations of allogeneic, autologous and genetically enhanced NK cells used in adoptive cell therapy.

Discovery of steroidal lactam conjugates of POPAM-NH2 with potent anticancer activity

2020 ◽  
Vol 12 (1) ◽  
pp. 19-35 ◽  
Author(s):  
Dimitrios Trafalis ◽  
Panagiotis Dalezis ◽  
Elena Geromichalou ◽  
Sofia Sagredou ◽  
Eleni Sflakidou ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Alkylating Agents ◽  
Experimental Models ◽  
The Novel ◽  
Nitrogen Mustards ◽  
Experimental Systems ◽  
High Antitumor Activity

Aim: Steroidal prodrugs of nitrogen mustards such as estramustine and prednimustine have proven effective anticancer agents in clinical use since the 1970s. In this work, we aimed to develop steroidal prodrugs of the novel nitrogen mustard POPAM-NH2. POPAM-NH2 is a melphalan analogue that was coupled with three different steroidal lactams. Methodology: The new conjugates were preclinically tested for anticancer activity against nine human and one rodent cancer experimental models, in vitro and in vivo. Results & conclusion: All the steroidal alkylators showed high antitumor activity, in vitro and in vivo, in the experimental systems tested. Moreover, these hybrid compounds showed by far superior anticancer activity compared with the alkylating agents, melphalan and POPAM-NH2.

scholarly journals Basophils trigger emphysema development in a murine model of COPD through IL-4–mediated generation of MMP-12–producing macrophages

2018 ◽  
Vol 115 (51) ◽  
pp. 13057-13062 ◽  
Author(s):  
Sho Shibata ◽  
Kensuke Miyake ◽  
Tomoya Tateishi ◽  
Soichiro Yoshikawa ◽  
Yoshinori Yamanishi ◽  
...  
Keyword(s):  
Murine Model ◽  
Genetically Engineered ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Initiation Phase ◽  
Th2 Cytokine ◽  
Reversible Airway Obstruction ◽  
Genetically Engineered Mice ◽  
Matrix Metalloproteinase 12

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has generally been considered a non-Th2-type lung disorder, characterized by progressive airflow limitation with inflammation and emphysema, but its cellular and molecular mechanism remains ill defined, compared with that of asthma characterized by reversible airway obstruction. Here we show a previously unappreciated role for basophils at the initiation phase of emphysema formation in an elastase-induced murine model of COPD in that basophils represent less than 1% of lung-infiltrating cells. Intranasal elastase instillation elicited the recruitment of monocytes to the lung, followed by differentiation into interstitial macrophages (IMs) but rarely alveolar macrophages (AMs). Matrix metalloproteinase-12 (MMP-12) contributing to emphysema formation was highly expressed by IMs rather than AMs, in contrast to the prevailing assumption. Experiments using a series of genetically engineered mice suggested that basophil-derived IL-4, a Th2 cytokine, acted on lung-infiltrating monocytes to promote their differentiation into MMP-12–producing IMs that resulted in the destruction of alveolar walls and led to emphysema development. Indeed, mice deficient for IL-4 only in basophils failed to generate pathogenic MMP-12–producing IMs and hence develop emphysema. Thus, the basophil-derived IL-4/monocyte–derived IM/MMP-12 axis plays a crucial role in emphysema formation and therefore may be a potential target to slow down emphysema progression at the initiation phase of COPD.

scholarly journals Production of Sustainable Construction Materials Using Agro-Wastes

Materials ◽  
2020 ◽  
Vol 13 (2) ◽  
pp. 262 ◽  
Author(s):  
Chrysanthos Maraveas
Keyword(s):  
Construction Materials ◽  
Sustainable Construction ◽  
Waste Products ◽  
Modern Times ◽  
Bamboo Leaves ◽  
Long Run ◽  
Wide Scale ◽  
Sugarcane Bagasse Ash ◽  
Alternative Approaches ◽  
Building Standards

The construction sector, in modern times, is faced by a myriad of challenges primarily due to the increase in the urban population and dwindling natural resources that facilitate the production of construction materials. Furthermore, higher awareness on climate change is forcing companies to rethink their strategies in developing more sustainable construction materials. Diverse types of agro-waste ranging from rice husk ash (RHA), sugarcane bagasse ash (SCBA), and bamboo leaves ash (BLA) among others have been identified as potent solutions in the development of sustainable construction materials. In this review paper, six different construction materials, made using agro-waste products, are examined. The materials include brick/masonry elements, green concrete, insulation materials for buildings, reinforcement materials for buildings, particleboards, and bio-based plastics. The main criterion adopted in selecting the materials regards their popularity and wide-scale use in modern construction applications. Additionally, as this research emphasizes identifying alternative approaches to develop sustainable construction materials, the focus is directed toward mainstream materials whose continued use has an adverse impact on the environment. The findings obtained from the review showed that the use of agro-waste to develop sustainable construction materials was effective, as the developed materials adhered to established building standards. Therefore, this indicates that agro-waste materials have the potential to replace conventional construction materials and hence achieve economic, environmental, and social sustainability in the long run.

scholarly journals Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations

2007 ◽  
Vol 97 (3) ◽  
pp. 435-439 ◽  
Author(s):  
Graham C. Burdge ◽  
Jo Slater-Jefferies ◽  
Christopher Torrens ◽  
Emma S. Phillips ◽  
Mark A. Hanson ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Epidemiological Studies ◽  
Experimental Models ◽  
Protein Restriction ◽  
Metabolic Phenotype ◽  
Specific Gene ◽  
Gene Promoters ◽  
Pregnant Rats ◽  
Pregnancy And Lactation ◽  
First Time

Epidemiological studies and experimental models show that maternal nutritional constraint during pregnancy alters the metabolic phenotype of the offspring and that this can be passed to subsequent generations. In the rat, induction of an altered metabolic phenotype in the liver of the F1 generation by feeding a protein-restricted diet (PRD) during pregnancy involves the altered methylation of specific gene promoters. We therefore investigated whether the altered methylation of PPARα and glucocorticoid receptor (GR) promoters was passed to the F2 generation. Females rats (F0) were fed a reference diet (180 g/kg protein) or PRD (90 g/kg protein) throughout gestation, and AIN-76A during lactation. The F1 offspring were weaned onto AIN-76A. F1 females were mated and fed AIN-76A throughout pregnancy and lactation. F1 and F2 males were killed on postnatal day 80. Hepatic PPARα and GR promoter methylation was significantly (P < 0·05) lower in the PRD group in the F1 (PPARα 8 %, GR 10 %) and F2 (PPARα 11 %, GR 8 %) generations. There were trends (P < 0·1) towards a higher expression of PPARα, GR, acyl-CoA oxidase and phosphoenolpyruvate carboxykinase (PEPCK) in the F1 and F2 males, although this was significant only for PEPCK. These data show for the first time that the altered methylation of gene promoters induced in the F1 generation by maternal protein restriction during pregnancy is transmitted to the F2 generation. This may represent a mechanism for the transmission of induced phenotypes between generations.

scholarly journals Blastocystis ratti Induces Contact-Independent Apoptosis, F-Actin Rearrangement, and Barrier Function Disruption in IEC-6 Cells

2006 ◽  
Vol 74 (7) ◽  
pp. 4114-4123 ◽  
Author(s):  
Manoj K. Puthia ◽  
Selena W. S. Sio ◽  
Jia Lu ◽  
Kevin S. W. Tan
Keyword(s):  
Barrier Function ◽  
Cell Biology ◽  
Therapeutic Potential ◽  
Gastrointestinal Symptoms ◽  
Epidemiological Studies ◽  
Host Cells ◽  
Epithelial Cell Line ◽  
Epithelial Permeability ◽  
Independent Manner ◽  
Pathogenic Potential

ABSTRACT Blastocystis is an enteric protozoan purportedly associated with numerous clinical cases of diarrhea, flatulence, vomiting, and other gastrointestinal symptoms. Despite new knowledge of Blastocystis cell biology, genetic diversity, and epidemiology, its pathogenic potential remains controversial. Numerous clinical and epidemiological studies either implicate or exonerate the parasite as a cause of intestinal disease. Therefore, the aim of this study was to investigate the pathogenic potential of Blastocystis by studying the interactions of Blastocystis ratti WR1, an isolate of zoonotic potential, with a nontransformed rat intestinal epithelial cell line, IEC-6. Here, we report that B. ratti WR1 induces apoptosis in IEC-6 cells in a contact-independent manner. Furthermore, we found that B. ratti WR1 rearranges F-actin distribution, decreases transepithelial resistance, and increases epithelial permeability in IEC-6 cell monolayers. In addition, we found that the effects of B. ratti on transepithelial electrical resistance and epithelial permeability were significantly abrogated by treatment with metronidazole, an antiprotozoal drug. Our results suggest for the first time that Blastocystis-induced apoptosis in host cells and altered epithelial barrier function might play an important role in the pathogenesis of Blastocystis infections and that metronidazole has therapeutic potential in alleviating symptoms associated with Blastocystis.

Invertebrate Models of Nociception

2020 ◽  
pp. 60-100
Author(s):  
Daniel Hesselson ◽  
Denise S. Walker ◽  
Joshua Neil Massingham ◽  
William R. Schafer ◽  
G. Gregory Neely ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Emotional Experience ◽  
Public Health Problem ◽  
Experimental Models ◽  
Model Organisms ◽  
Experimental Systems ◽  
Significant Public Health ◽  
Noxious Stimuli ◽  
Underlying Mechanisms ◽  
High Level

Chronic pain is a significant public health problem, affecting 20–25% of the global population, and there is a clear need for more specific and effective therapeutics. To achieve this, a comprehensive understanding of the underlying mechanisms and molecular machinery driving pain-related diseases is required. The definition of pain as an “unpleasant sensory and emotional experience” associated with tissue injury is innately anthropomorphic, the emotional element being difficult to reconcile in nonhuman organisms. Even simple invertebrates are nevertheless capable of nociception, the neural processing of noxious stimuli. With the significant advantages of simpler nervous systems, experimental tractability, and a high level of conservation, they have a major role to play in advancing our understanding. This chapter reviews our current molecular- and circuit-level understanding of nociception in two of the most widely used invertebrate experimental models, the nematode Caenorhabditis elegans and the fly Drosophila melanogaster. In particular, it summarizes the molecules, cells, and circuits that contribute to nociception in response to diverse noxious stimuli in these model organisms and the behavioral paradigms that we can harness to study them. The chapter discusses how mechanistic insights gained from these experimental systems can improve our understanding of pain in humans.

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