The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called
) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis ...controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers.
In preference to synthetic or petroleum-based materials, current research in food and pharmaceutical industries has focused on the development of biodegradable and sustainable materials due to their ...low toxicity, and biocompatibility. In particular, the natural water-soluble polysaccharide tara gum (Caesalpinia spinosa) has been widely used as a food-grade and drug-delivery agent due to its biodegradability, and biocompatibility. Moreover, owing to its easily modifiable hydroxy groups, tara gum, and its derivatives have been employed as food packaging films and pharmaceutical materials. In the present critical review, facile grafting methods of tara gum are reviewed, and an up-to-date comprehensive application of tara gum polysaccharides revealed their uses in pH-sensitive food packaging. In addition, modified tara gum materials exhibited improved drug delivery applications with biocompatible properties. The non-toxic nature and non-Newtonian, pseudoplastic rheological properties as well as the synergistic behavior of tara gum with other polysaccharides explore its further industrial applications in several fields. Additionally, several approaches for improving tara gum for use as a stabilizer and thickener for food items, and monitoring food spoilage, have provided notable customized characteristics. In brief, its many advantages make tara gum polysaccharide a promising material for applications in the food and pharmaceutical industries.
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•Modified tara gum polysaccharides exhibit improved physicochemical properties.•Tara gum polysaccharide shows smart pH-sensitive food packaging biomaterial.•Modified tara gum polysaccharides display improved drug delivery applications.•The future directions in the utilization and modification of tara gum are outlined.
The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification. However, the mechanism and physiological significance by which ...post-translational modifications lead to PTEN suppression remain unclear. Here we demonstrate that PTEN destabilization is induced by EGFR- or oncogenic PI3K mutation-mediated AKT activation in cervical cancer. EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase. These processes require the stabilization of MKRN1 via AKT-mediated phosphorylation. In cervical cancer patients with high levels of pAKT and MKRN1 expression, PTEN protein levels are low and correlate with a low 5-year survival rate. Taken together, our results demonstrate that PI3K/AKT signals enforce positive-feedback regulation by suppressing PTEN function.
Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. ...miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ADR cells. In this study, we found that primary and mature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment.
Melanoma is a highly aggressive and treatment-resistant cancer, and the incidence and mortality rates are increasing worldwide. Thymoquinone (TQ) is the active component of Nigella sativa seed ...extracts and exerts anticancer effects in various cancer cells. However, the anticancer effects of TQ on melanoma and the underlying molecular mechanisms remain elusive.
In this study, TQ treatment induced apoptosis in SK-MEL-28 cells. Interestingly, constitutive phosphorylation of Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) was markedly decreased following TQ treatment. Furthermore, TQ treatment downregulated STAT3-dependent genes including cyclin D1, D2, and D3 and survivin. Moreover, inhibition of Jak2/STAT3 using AG490, an inhibitor of Jak2 or genetic ablation of STAT3, abrogated the expression of target genes. TQ increased the levels of reactive oxygen species (ROS), whereas pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, prevented the suppressive effect of TQ on Jak2/STAT3 activation and protected SK-MEL-28 cells from TQ-induced apoptosis. TQ administration further attenuated the growth of SK-MEL-28 tumor xenografts. Taken together, TQ induced apoptosis of SK-MEL-28 by hindering the Jak2/STAT3 signaling pathway through ROS generation. Our results support further development of TQ as a potential anticancer therapeutic agent for treating melanoma.
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•Thymoquinone (TQ) induces apoptosis via accumulation of ROS.•TQ decreases expression of Bcl-2, Bcl-xl, D cyclins, and survivin via suppression of Jak2/STAT3 signaling pathway.•Jak2 is involved in STAT3 activation through phosphorylation of STAT3 at serine residue in melanoma cells.•Treatment with a ROS scavenger N-acetyl cysteine significantly prevents TQ-induced apoptosis.•TQ suppresses tumor growth in xenograft mouse model.
Megalin has been proposed as an endocytic receptor for aminoglycosides as well as estrogen and androgen. We aimed to investigate the otoprotective effects of antiandrogens (flutamide, FM) on ...kanamycin (KM)-induced hearing loss in rats. Rats were divided into four groups. The KM group was administered KM (20 mg/kg/day) for 5 days, while the FM group received FM (15 mg/kg/day) for 10 days. In the KM + FM group, KM and FM (15 mg/kg/day) were simultaneously injected for 5 days and then FM was injected for 5 days. Auditory brainstem responses were measured. Western blotting and/or quantitative reverse transcriptase-polymerase chain reaction were performed for megalin, cytochrome P450 1A1 (Cyp1a1), Cyp1b1, metallothionein 1A (MT1A), MT2A, tumor necrosis factor (TNF)-α, caspase 3, and cleaved caspase 3. The FM + KM group showed attenuated auditory thresholds when compared with the KM group at 4, 8, 16, and 32 kHz (all p < 0.05). The KM + FM group showed lower megalin and Cyp1b1 levels than the KM group (all p < 0.05). The KM + FM group revealed lower MT1A, TNFα, and caspase 3 protein levels, compared with those in the KM group (all p < 0.05). Androgen receptor inhibition protects against cochlear injuries in KM-induced hearing loss rats by attenuating megalin expression, revealing anti-inflammatory and anti-apoptotic effects.
This article investigates robust stabilizing control of biological systems modeled by Boolean networks (BNs). A population of BNs is considered where a majority of BNs have the same BN dynamics, but ...some BNs are inflicted by mutations damaging particular nodes, leading to perturbed dynamics that prohibit global stabilization to the desired attractor. The proposed control strategy consists of two steps. First, the nominal BN is transformed and curtailed into a sub-BN via a simple coordinate transformation and network reduction associated with the desired attractor. The feedback vertex set (FVS) control is then applied to the reduced BN to determine the control inputs for the nominal BN. Next, the control inputs derived in the first step and mutated nodes are applied to the nominal BN so as to identify residual dynamics of perturbed BNs, and additional control inputs are selected according to the canalization effect of each node. The overall control inputs are applied to the BN population, so that the nominal BN converges to the desired attractor and perturbed BNs to their own attractors that are the closest possible to the desired attractor. The performance of the proposed robust control scheme is validated through numerical experiments on random BNs and a complex biological network.
Fault diagnosis for rotating machinery is important for reliability and safety, and shaft misalignment is one of the most common causes of mechanical vibration or shaft failure. In this study, we ...detected defects caused by misalignment of the shaft axis in rotating machinery using an artificial intelligence machine learning technique for fault recognition. Unlike other methods that focus on the time domain, we changed vibration data in the time domain to the power spectrum component value in the frequency domain. Then, the power spectrum values were classified using principle component analysis (PCA). Based on the results, defects are determined using a machine learning technique that uses a support vector machine (SVM). The results show that defects can be quickly determined from only vibration data about normal and abnormal states. By using the proposed pre-processing method, the machine learning framework based on vibration data can be effectively applied to diagnosis not only shaft defects but also faults of other rotating machines such as motors and engines
Recurrence and drug resistance of breast cancer are still the main reasons for breast cancer-associated deaths. Cancer stem cell (CSC) model has been proposed as a hypothesis for the lethality of ...breast cancer. Molecular mechanisms underlying CSC maintenance are still unclear. In this study, we generated mammospheres derived from breast cancer MDA-MB231 cells and MCF7 cells to enrich CSCs and performed DNA microarray analysis. We found that the expression of carboxy terminus of HSP70-interacting protein (CHIP) E3 ubiquitin ligase was significantly downregulated in breast CSCs. CHIP depletion increased mammosphere formation, whereas CHIP overexpression reversed this effect. We identified interactomes by mass spectrometry and detected CHIP directly interacted with OCT4, a stemness factor. CHIP overexpression decreased OCT4 stability through proteasomal degradation. CHIP induced OCT4 ubiquitination, whereas H260Q, a catalytic CHIP mutant, did not. Interestingly, we determined that OCT4 was ubiquitinated at lysine 284, and CHIP overexpression did not degrade K284R mutant OCT4. CHIP overexpression decreased the proliferation and side population of breast cancer cells, but these were not occurred in K284R mutant OCT4 overexpressed cells. Only 1000 cells showing CHIP depletion or OCT4 overexpression sufficiently generated breast tumors and lung metastases in xenografted mice. Ubiquitination-defective mutant of OCT4(K284R) overexpressed cells drastically generated tumor burdens in mice. Patients with breast cancer who showed low CHIP expression had poor survival probability. Taken together, we suggest that CHIP-induced OCT4 ubiquitination is important in breast CSCs. Regulation of CHIP expression and OCT4 protein stability is a considerable approach for breast cancer therapy.
It is well-known that microbiota dysbiosis is closely associated with numerous diseases in the human body. The oral cavity and gut are the two largest microbial habitats, playing a major role in ...microbiome-associated diseases. Even though the oral cavity and gut are continuous regions connected through the gastrointestinal tract, the oral and gut microbiome profiles are well-segregated due to the oral-gut barrier. However, the oral microbiota can translocate to the intestinal mucosa in conditions of the oral-gut barrier dysfunction. Inversely, the gut-to-oral microbial transmission occurs as well in inter- and intrapersonal manners. Recently, it has been reported that oral and gut microbiomes interdependently regulate physiological functions and pathological processes. Oral-to-gut and gut-to-oral microbial transmissions can shape and/or reshape the microbial ecosystem in both habitats, eventually modulating pathogenesis of disease. However, the oral-gut microbial interaction in pathogenesis has been underappreciated to date. Here, we will highlight the oral-gut microbiome crosstalk and its implications in the pathogenesis of the gastrointestinal disease and cancer. Better understanding the role of the oral-gut microbiome axis in pathogenesis will be advantageous for precise diagnosis/prognosis and effective treatment.
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