1,354,990 research outputs found
The polarity of entry and release of Canine Coronavirus from epithelial cells
No full textCanine coronavirus (CCoV) is an enveloped, single-strand RNA virus belonging to the Alphacoronavirus genus in the Coronaviridae family Pratelli [1,2] Despite their labile nature, RNA viruses are able to rapidly adjust to negative pressures of immune system, generating novel strains that might have selective advantages over parental genomes.
Epithelial cells in the gastrointestinal tracts are the target of CCoVs infection. The apical face, exposed towards the intestinal lumen, and the basolateral face have different composition and the tight junctions with neighbouring cells separate the two faces preventing mixing of membrane components. The epithelial cell surface from which viruses are released conditions the development of virus pathogenesis. Entry and release of viruses from epithelial cells can occur through either domains as a result of the distribution of viral receptors. Polarized virus release influence viral spread: basolateral release allows the infection of underlying tissues leading to a systemic infection, and apical release can limit viral spread by preventing the infection of cells other than epithelial ones.
Recent study has highlighted a new pathogenetic characteristic of CCoV in vitro, which is able to infect epithelial cells from both apical and basolateral compartments, and even if with different titres, CCoV was released both in the apical and in the basolateral medium after infection. Consequently, the current view that CCoV infection is restricted to the intestine should be modified, arguing that the direction of release may be toward the blood stream inducing systemic infection
ZnCl2 sustains the adriamycin-induced cell death inhibited by high glucose
No full textHyperglycemia, the condition of high blood glucose, is typical of diabetes and obesity and represents a significant clinical problem. The relationship between hyperglycemia and cancer risk has been established by several studies. Moreover, hyperglycemia has been shown to reduce cancer cell response to therapies, conferring resistance to drug-induced cell death. Therefore, counteracting the negative effects of hyperglycemia may positively improve the cancer cell death induced by chemotherapies. Recent studies showed that zinc supplementation may have beneficial effects on glycemic control. Here we aimed at evaluating whether ZnCl2 could counteract the high-glucose (HG) effects and consequently restore the drug-induced cancer cell death. At the molecular level we found that the HG-induced expression of genes known to be involved in chemoresistance (such as HIF-1α, GLUT1, and HK2 glycolytic genes, as well as NF-ΚB activity) was reduced by ZnCl2 treatment. In agreement, the adryamicin (ADR)-induced apoptotic cancer cell death was significantly impaired by HG and efficiently re-established by ZnCl2 cotreatment. Mechanistically, the ADR-induced c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) phosphorylation, inhibited by HG, was efficiently restored by ZnCl2. The JNK involvement in apoptotic cell death was assessed by the use of JNK dominant-negative expression vector that indeed impaired the ZnCl2 ability to restore drug-induced cell death in HG condition. Altogether, these findings indicate that ZnCl2 supplementation efficiently restored the drug-induced cancer cell death, inhibited by HG, by both sustaining JNK activation and counteracting the glycolytic pathway. © The Author(s) 2016
EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis
No full textAutophagy is a catabolic process strongly involved in the immune response, and its dysregulation contributes to the onset of several diseases including cancer. The human oncogenic gammaherpesviruses, Epstein—Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), manipulate autophagy, either during the de novo infection or during the lytic reactivation, in naturally latently-infected lymphoma cells. In particular, the gammaherpesvirus infection reduces autophagy in immune cells, such as monocytes, resulting in the impairment of cell survival and cell differentiation into dendritic cells (DCs), which are essential for initiating and regulating the immune response. In the case of EBV, the reduction of autophagy in these cells, leading to p62 accumulation, activated the p62-NRF2-antioxidant response, reducing ROS, and further inhibiting autophagy. KSHV inhibits autophagy in monocytes by de-phosphorylating JNK2, altering the calpains⁻calpastatin balance and increasing the calpain activity responsible for the cleavage of ATG5. To further impair the immune response, KSHV also inhibits autophagy in differentiated DCs by hyper-phosphorylating STAT3. Conversely, when the lytic cycle is induced in vitro in latently-infected lymphoma B cells, both EBV and KSHV promote autophagy to enhance their replication, although the final autophagic steps are blocked through the down-regulation of Rab7. This strategy allows viruses to avoid the destructive environment of lysosomes, and to exploit the autophagic machinery for intracellular transportation. EBV and KSHV encode for proteins that may either inhibit or promote autophagy and, in addition, they can modulate the cellular pathways that control this process. In this review we will discuss the findings that indicate that autophagy is dysregulated by gammaherpesvirus to promote immune suppression, facilitate viral replication and contribute to the onset and maintenance of gammaherpesvirus-associated malignancies
ER Stress, UPR Activation and the Inflammatory Response to Viral Infection
No full textThe response to invading pathogens such as viruses is orchestrated by pattern recognition receptor (PRR) and unfolded protein response (UPR) signaling, which intersects and converges in the activation of proinflammatory pathways and the release of cytokines and chemokines that harness the immune system in the attempt to clear microbial infection. Despite this protective intent, the inflammatory response, particularly during viral infection, may be too intense or last for too long, whereby it becomes the cause of organ or systemic diseases itself. This suggests that a better understanding of the mechanisms that regulate this complex process is needed in order to achieve better control of the side effects that inflammation may cause while potentiating its protective role. The use of specific inhibitors of the UPR sensors or PRRs or the downstream pathways activated by their signaling could offer the opportunity to reach this goal and improve the outcome of inflammation-based diseases associated with viral infections
Indagini preliminari sulla Toxoplasmosi suina a mezzo dell’ immunofluorescenza indiretta
No full textResearch Productivity Among Canadian First Year Dermatology Residents: A 15 Year Analysis
No full textA retrospective review was conducted to obtain names of the residents that began training in Canadian dermatology residency programs between 2008 and 2022. Metrics reflective of research productivity (publication count, dermatology publications, authorship position, and H-index) were obtained from Scopus and trends were identified and evaluated using descriptive, univariate, and bivariate statistics. From the 10 Canadian residency programs, 371 dermatology residents producing 828 publications, of which 329 were dermatology-related were identified. Overall, 56% of residents had a minimum of one publication at the time of the match, with a mean of 2.23 + 4.27 publications and H-index of 1.36 + 2.23. A significant increase in all research productivity metrics was observed during the 2018 – 2022 period. Over the past 15 years, the amount of publications authored by incoming dermatology residents has increased significantly which may suggest an increased emphasis placed on medical research by medical students and residency programs
Cancer cells dysregulate PI3K/AKT/mTOR pathway activation to ensure their survival and proliferation: mimicking them is a smart strategy of gammaherpesviruses
No full textThe serine/threonine kinase mammalian target of rapamycin (mTOR) is the catalytic subunit of two complexes, mTORC1 and mTORC2, which have common and distinct subunits that mediate separate and overlapping functions. mTORC1 is activated by plenty of nutrients, and the two complexes can be activated by PI3K signaling. mTORC2 acts as an upstream regulator of AKT, and mTORC1 acts as a downstream effector. mTOR signaling integrates both intracellular and extracellular signals, acting as a key regulator of cellular metabolism, growth, and survival. A dysregulated activation of mTOR, as result of PI3K pathway or mTOR regulatory protein mutations or even due to the presence of cellular or viral oncogenes, is a common finding in cancer and represents a central mechanism in cancerogenesis. In the final part of this review, we will focus on the PI3K/AKT/mTOR activation by the human gammaherpesviruses EBV and KSHV that hijack this pathway to promote their-mediated oncogenic transformation and pathologies
Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 interferes with homeodomain-interacting protein kinase 2/p53 activity to impair solid tumors chemosensitivity
No full textResistance to chemotherapy represents a major hurdle to successful cancer treatment. A key role for efficient response to anticancer therapies is played by TP53 oncosuppressor gene that indeed is mutated in 50% of human cancers or inactivated at protein level in the remaining 50%. Homeodomain-interacting protein kinase 2 (HIPK2) is the wild-type p53 (wtp53) apoptotic activator, and its inhibition by hypoxia or hyperglycemia may contribute to tumor chemoresistance mainly by impairing p53 apoptotic activity. Another important molecule able to induce chemoresistance is nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) transcription factor, whose activation by oxidative and/or electrophilic stress regulates a transcriptional antioxidant program allowing cancer cells to adapt and survive to stresses. NRF2 may shift from cytoprotective to tumor-promoting function, according to tumor phases. NRF2 may crosstalk with both wtp53 and mutant p53 (mutp53), inhibiting the wtp53 apoptotic function and strengthening the mutp53 oncogenic function. NRF2 has also been shown to induce HIPK2 mRNA expression cooperating in inducing cytoprotection. Although HIPK2, p53, and NRF2 have been individually extensively studied, their interplay has not been clearly addressed yet. On the basis of the background and our results, we aim at hypothesizing the unexpected pro-survival activity played by the NRF2/HIPK2/p53 interplay that can be hijacked by cancer cells to bypass drugs cytotoxicity
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