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Doxorubicin is a chemotherapeutic medication commonly used to treat many types of cancers, but it has side effects including vomiting, rash, hair loss, and bone marrow suppression. The most dangerous side effects are cardiomyopathy, cardiofibrosis, and heart failure, as doxorubicin generates cytotoxicity and stops DNA replication. There is no treatment to block these side effects. We have developed a transgenic mouse line overexpressing the circular RNA circNlgn and shown that circNlgn is a mediator of doxorubicin-induced cardiofibrosis. Increased expression of circNlgn decreased cardiac function and induced cardiofibrosis by upregulating Gadd45b, Sema4C, and RAD50 and activating p38 and pJNK in circNlgn transgenic heart. Silencing circNlgn decreased the effects of doxorubicin on cardiac cell activities and prevented doxorubicin-induced expression of fibrosis-associated molecules. The protein (Nlgn173) translated by circNlgn could bind and activate H2AX, producing γH2AX, resulting in upregulation of IL-1b, IL-2Rb, IL-6, EGR1, and EGR3. We showed that silencing these molecules in the signaling pathway prevented doxorubicin-induced cardiomyocyte apoptosis, increased cardiomyocyte viability, decreased cardiac fibroblast proliferation, and inhibited collagen production. This mechanism may hold therapeutic implications for mitigating the side effects of doxorubicin therapy in cancer patients.

In recent years, significant attention has focused on circular RNA (circRNA) translation to determine its clinical significance. Cap-independent translation of circRNAs driven by an internal ribosome entry site (IRES) or an N6-methyladenosine (m

Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of the chemotherapeutic agents in cancer. Chronic inflammation provides a favorable environment for tumorigenesis by inducing immunosuppression, whereas acute inflammation prompts tumor suppression by generating anti-tumor immune responses. Inflammatory factors derived from interstitial cells or tumor cells can stimulate cell proliferation and survival by modulating oncogenes and/or tumor suppressors. Recently, a new class of RNAs i.e., circular RNAs (circRNAs) has been implicated in inflammatory diseases. Although there are reports on circRNAs imparting functions in inflammatory insults, whether these circularized transcripts hold the potential to regulate inflammation induced cancer or tumor related inflammation, and modulate the interactions between tumor microenvironment (TME) and the inflammatory stromal/immune cells awaits further elucidation. Contextually, the current review describes the molecular association between inflammation and cancer, and spotlights the regulatory mechanisms by which circRNAs can moderate TME in response to inflammatory signals/ triggers. We also present comprehensive information about the immune cell(s)-specific expression and functions of the circRNAs in TME, modulation of inflammatory signaling pathways to drive tumorigenesis, and their plausible roles in inflammasomes and tumor development. Moreover, the diagnostic/prognostic and therapeutic potential of these circRNAs in harnessing inflammatory responses in cancer is also discussed.

Circular RNAs (circRNAs) are a large class of noncoding RNAs, generated from a process called back-splicing, that possess critical regulatory functions in many cellular events. A large body of literature has reported various circRNA functions and their underlying mechanisms, including sponging miRNA, exerting transcriptional and translational regulation, interacting with proteins, and translating into peptides and proteins. CircRNA dysregulation has been implicated in many cancers, including lung, breast, liver, gastric, colorectal, and ovarian cancer. They are detectable in bodily fluids and relatively stable, making them potential cancer biomarker candidates. Furthermore, targeting circRNA expression levels is a potential therapeutic approach for treating cancers. In this review, we describe the functional mechanisms of circRNAs and discuss limitations of current mechanism studies. Following this, we outline the potential of circRNAs to be effective biomarkers in various cancers and present circRNA-based therapeutic approaches. Finally, we discuss challenges in using circRNAs as diagnostic and therapeutic tools and propose future research directions.

Circular RNAs (circRNAs) represent a large group of non-coding RNAs that are widely detected in mammalian cells. Although most circRNAs are generated in a sense orientation, there is a group of circRNAs that are synthesized in an antisense orientation. High-throughput analysis of breast cancer specimens revealed a significant enrichment of 209 antisense circRNAs. The tumor suppressor SCRIB was shown to potentially produce thirteen circRNAs, three of which are in an antisense orientation. Among these three circRNAs, circSCRIB (hsa_circ_0001831) was the most enriched in the breast cancer panel. This antisense SCRIB circRNA was shown to span one intron and two exons. We hypothesized that this circRNA could decrease pre-mRNA splicing and mRNA translation. To test this, we generated a hsa_circ_0001831 expression construct. We found that there was decreased SCRIB mRNA production but increased cancer cell proliferation, migration, and invasion. In comparison, an exonic sequence construct did not affect mRNA splicing but decreased protein translation, leading to increased E-cadherin expression and decreased expression of N-cadherin and vimentin. Thus, there was increased cell migration, invasion, proliferation, colony formation, and tumorigenesis. Our study suggests a novel modulatory role of antisense circRNAs on their parental transcripts. This may represent a promising approach for developing circRNA-directed therapy.

Circular RNAs (circRNAs) are a group of non-coding RNAs with a unique circular structure generated by back-splicing. It is acknowledged that circRNAs play critical roles in cardiovascular diseases. However, functional studies of circRNAs were impeded due to lack of effective in vivo silencing approaches. Since most circRNAs are produced by protein-coding transcripts, gene editing typically affects the coding activity of the parental genes. In this study, we developed a circular antisense RNA (cA-circSlc8a1) that could silence the highly expressed circRNA circSlc8a1 in the mouse heart but not its parental Slc8a1 linear mRNA. Transgenic cA-circSlc8a1 mice developed congestive heart failure resulting in a significant increase in the body weight secondary to peripheral edema and congestive hepatopathy. To further test the role of circSlc8a1, we generated transgenic mice overexpressing circSlc8a1 and observed a protective effect of circSlc8a1 in a pressure overload model. Mechanistically, we found that circSlc8a1 translocated into mitochondria to drive ATP synthesis. While establishing a transgenic murine model for antisense-mediated circRNA silencing without interfering with the parental linear RNA, our finding revealed the essential role of circSlc8a1 in maintaining heart function and may lay the groundwork of using the circular antisense RNA as a potential gene therapy approach for cardiovascular diseases.

Circular RNAs (circRNAs) are circularized, single-stranded RNAs that are covalently linked. With their abundance in tissues and developmental stage-specific expression, circRNAs participate in a variety of physiological and pathological processes. In this review, we discuss the development of circRNAs used as biomarkers and therapeutic targets for cardiovascular diseases (CVDs), focusing on recent discoveries and applications of exosomal circRNAs that highlight opportunities and challenges. Some studies have identified a spectrum of circRNAs that are differentially expressed in CVDs, while other studies further manipulated specific circRNA expression and showed an ameliorated pathogenic state such as ischemic injury, hypertrophy, and cardiac fibrosis. Studies and applications of circRNAs are being rapidly developed. We expect to see clinical use of circRNAs as biomarkers and targets for disease treatment in the near future., Graphical Abstract, Large numbers of differentially expressed circRNAs have been identified in pathogenic heart tissues and cells. Gain-of-function and loss-of-function approaches are being developed to manipulate specific circRNA expression in order to modulate heart conditions. circRNAs may be used as potential biomarkers for early diagnosis and may be targets for therapeutic strategies.

BACKGROUND: Dietary polyphenols including anthocyanins target multiple organs. OBJECTIVE: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G). METHODS: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2). RESULTS: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P 3-fold, P

Metastatic cancer cells invade surrounding tissues by forming dynamic actin-based invadopodia, which degrade the surrounding extracellular matrix and allow cancer cell invasion. Regulatory RNAs, including circular RNA, have been implicated in this process. By microarray, we found that the circular RNA circSKA3 was highly expressed in breast cancer cells and human breast cancer tissues. We further found that the invasive capacity of breast cancer cells was positively correlated with circSKA3 expression, through the formation of invadopodia. Mechanistically, we identified Tks5 and integrin β1 as circSKA3 binding partners in these tumor-derived invadopodia. Ectopic circSKA3 expression conferred increased tumor invasiveness in vitro and in vivo. We further identified the RNA-protein binding sites between circSKA3, Tks5 and integrin β1. In tumor formation assays, we found that circSKA3 expression promoted tumor progression and invadopodium formation. Mutation of the circSKA3 binding sites or transfection with blocking oligos abrogated the observed effects. Thus, we provide evidence that the circular RNA circSKA3 promotes tumor progression by complexing with Tks5 and integrin β1, inducing invadopodium formation.

The mast cell-nerve unit classically has represented a fundamental neuroimmune axis in the development of itch because of the traditional prominence of histamine as a pruritogen. However, it is appreciated increasingly that most chronic itch disorders are likely nonhistaminergic in nature, provoking the hypothesis that other novel effector itch mechanisms derived from mast cells are important. In this review, we present an overview of classical mast cell biology and put these concepts into the context of recent advances in our understanding of the regulation and function of the mast cell-nerve unit in itch biology.

Summary Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31−/− mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-β1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-β-IL-31 axis with implications for treatment of wound itching., Graphical Abstract, Highlights • IL-31 expression is increased in skin wounds during the peak of itch response • Il31 −/− mice have less itch behavior during wound healing • IL-31 increases calcium influx and Il31ra, Trpv1 expression in itch sensory neurons • TGF-β1 induces expression of IL-31 in dermal conventional type 2 dendritic cells, Xu et al. find that TGF-β, produced as part of the wound healing process, induces expression of interleukin-31 by dermal conventional type 2 DCs, which, in turn, increases neuron sensitivity and provokes itching.

Pullorum disease caused by Salmonella Pullorum is one of the most important infectious diseases in the poultry industry worldwide, which leads to serious economic losses in many developing countries because of its high mortality rate in young chicks. The traditional slide agglutination test with low cost, fast reaction, and on-site detection has been widely used in the diagnosis of Pullorum disease. However, in practice, the test performance is with the disadvantages of false positive results and unstable detection results. In this paper, we developed self-made agglutination antigens prepared by local isolates in the poultry farm and compare the detection performance with commercial agglutination antigens (China Institute of Veterinary Drug Control) and Group D Salmonella ELISA kit (BioChek UK Ltd). The results of detecting 200 serum samples indicated that the consistency of commercial agglutination antigen detecting in 2 times was only 79.5%. Using the ELISA kit as the reference method, the commercial agglutination antigen detecting results of the Kappa test were only moderately consistent (0.58 ∼ 0.59). Meanwhile, positive and total coincidence rates of the self-made agglutination antigen test with more reliable repeat could reach 97.4 and 88%, respectively, and the result of Kappa test was highly consistent (0.75). The Receiver Operating Characteristic curve analysis clarified that the area under the receiver-operating-characteristic curve values of self-made and commercial agglutination antigen tests could reach 0.861 and 0.804, respectively. These results were coincident when detecting known positive serum from the infected chickens. It's worth mentioning that the visible positive reaction of self-made agglutination antigen test appeared faster and stronger than commercial antigen test. In conclusion, self-made Salmonella Pullorum agglutination antigen developed in this study was much better than commercial agglutination antigen and is expected to be a valuable tool in the diagnosis of the epidemiology of Salmonella Pullorum.

In the present work, thermo-physical properties of aqueous Graphene Nanoplatelet (GNP) at various mass concentrations of GNPs was experimentally measured. An experimental investigation was conducted to quantify the heat transfer coefficient, friction factor, pressure drop value, pumping power and thermo-hydraulic performance index of the nanofluid within a microchannel at various heat flux and Reynolds number. Results showed that GNP/water nanofluid can plausibly enhance the heat transfer coefficient and the Nusselt number by ~80%. In addition, a small increase in the friction factor and the pressure drop value was seen, which was attributed to the augmentation in the friction forces. The maximum increase in the pressure drop was 18.3% recorded at the highest Reynolds number and the highest mass concentration of the nanofluid. Also, despite the augmentation in the pressure drop value, the thermal performance of the system increased by 76% showing the great potential of the GNP/water nanofluid cooling and/or heating applications despite ~20% augmentation in the pumping power at Reynolds number > 1376. The enhancement in the thermal performance of the system was attributed to the thermophoresis effect, Brownian motion and the enhancement in the thermal conductivity of the nanofluid due to the presence of the GNP nanoplatelets.

Circular RNAs represent a large class of non-coding RNAs that are extensively expressed in mammals. However, the functions of circular RNAs are largely unknown. We recently reported that the circular RNA circ-Ccnb1 could bind with H2AX in p53 mutant cells and suppressed mutant p53 in tumor progression. Here we found that circ-Ccnb1 could interact with both Ccnb1 and Cdk1 proteins. Normally, Ccnb1 and Cdk1 proteins form a complex, allowing Ccnb1 to function as an all-or-none switch for cell mitosis. The interaction of circ-Ccnb1 with Ccnb1 and Cdk1 proteins dissociated the formation of Ccnb1-Cdk1 complex, by forming a large complex containing circ-Ccnb1, Ccnb1 and Cdk1. Formation of this large complex may occur in cytosol and nuclei, and Ccnb1 loses its roles in enhancing cell migration, invasion, proliferation and survival. In vivo, ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. These results have added another layer of mechanisms for circ-Ccnb1 to regulate tumor progression in vitro and in vivo.

Although evolutionarily conserved to expel ectoparasites and aid in the clearance of toxins and noxious environmental stimuli from the host, the type 2 immune response can become pathologic in the setting of a variety of allergic disorders. Itch can be a behavioral extension of type 2 immunity by evoking scratching, and in the setting of disease, can become chronic and thus highly pathologic as well. Classically, our understanding of itch mechanisms has centered around the canonical IgE-mast cell-histamine axis. However, therapies aimed at blocking the histaminergic itch pathway have been largely ineffective, suggesting the existence of non-histaminergic pathways of itch. Indeed, recent advances in itch biology have provided critical new insight into a variety of novel therapeutic avenues for chronic itch in the setting of a number of allergic disorders. Herein, we highlight how these new developments will likely inform the problem of pruritus in a variety of well-established and emerging conditions in the field of allergy.

In the present work, an experimental investigation was conducted to quantify the heat transfer coefficient, thermal resistance and the thermal performance of a thermosyphon heat pipe charged with zirconia-acetone nanofluid. The thermosyphon was designed to operate at high heat fluxes such as 200 kW/m2 (∼200 sun) similar or larger than the evacuated solar tube heat pipes. The zirconia-acetone nanofluid was prepared and stabilized by adding a surfactant, homogenizing with sonication and setting the pH of the nanofluid with a buffer solution. The thermosyphon was fabricated with an oxygen-free copper with the internal and outer diameters of 10.7 mm and 12 mm, respectively and the axial length of 280 mm. The thermal performance of the heat pipe was assessed for various heat fluxes (1 kW/m2-200 kW/m2), filling ratio (20%–75%), tilt angle (5°–70°) and the mass fraction of the nanofluid (0.025%–0.1%). Results showed that the presence of the nanofluid decreases the total thermal resistance of the heat pipe reaching the minimum value at the largest heat flux applied to the evaporator. Also, the heat transfer coefficient of the evaporator was increased. Likewise, the zirconia-acetone nanofluid enhanced the boiling heat transfer mechanism and the geyser boiling, which resulted in the enhancement in the thermal performance of the heat pipe due to the increase in the heat transfer coefficient of the heat pipe by 36.3% at wt. % = 0.1 in comparison with the pure acetone. The optimum tilt angle and filling ratio values were 65° and 60%, respectively, in which the highest heat transfer coefficient was achieved. A correlation was also developed using a dimensionless analysis to predict the Kutateladze number as an index for the thermal performance of the heat pipe.

Cypermethrin contamination was a potential threat to soil organisms. In the present work, reproductive damage in earthworms (Amynthas corticis) exposed to cypermethrin was investigated. It was found that earthworms could absorb and accumulate residual cypermethrin in soil, and also earthworm activities helped accelerate the degradation of cypermethrin in soil. The accumulation of cypermethrin in earthworms induced sperm damage, and cypermethrin not only caused the imbalance of calcium homeostasis in earthworm sperm cells by inhibiting earthworm sperm Ca

Feed efficiency (FE) is a major economic trait of meat duck. This study aimed to evaluate the effects of residual feed intake (RFI) divergence on growth performance, carcass traits, meat quality, and blood biochemical parameters in small-sized meat ducks. A total of 500 healthy 21-day-old male ducks were housed in individual cages until slaughter at 63 d of age. The growth performance was determined for all the ducks. The carcass yield, meat quality, and blood biochemical parameters were determined for the selected 30 high-RFI (HRFI) and 30 low-RFI (LRFI) ducks. In terms of growth performance, the RFI, feed conversion ratio (FCR), and average daily feed intake (ADFI) were found to be significantly lower in the LRFI group (P0.01), whereas no differences were observed in the BW and body weight gain (P0.05). For slaughter performance, no differences were observed in the carcass traits between the LRFI and HRFI groups (P0.05). For meat quality, the shear force of breast muscle was significantly lower in the LRFI group (P0.05), while the other meat quality traits of breast and thigh muscles demonstrated no differences (P0.05). For blood biochemical parameters, the serum concentrations of triglycerides (TG) and glucose (GLU) were significantly lower in the LRFI group (P0.05), while the other parameters showed no differences (P0.05). The correlation analysis demonstrated a high positive correlation between RFI, FCR, and ADFI (P0.01). The RFI demonstrated a negative effect on the breast muscle and lean meat yields, but a positive effect on the shear force of breast muscle (P0.05). Further, the RFI demonstrated a positive effect on the TG and GLU levels (P0.05). These results indicate that the selection for low RFI could improve the FE of small-sized meat ducks without affecting the production performance. This study provides valuable insight into the biological processes underlying the variations in FE in small-sized meat ducks.