Diet impact on Mitochondrial Bioenergetics and Dynamics

Diet induced obesity is associated with impaired mitochondrial function and dynamic behavior. Mitochondria are highly dynamic organelles and the balance in fusion/fission is strictly associated with their bioenergetics. Fusion processes are associated with the optimization of mitochondrial function, whereas fission processes are associated with the removal of damaged mitochondria. In diet-induced obesity, impaired mitochondrial function and increased fission processes were found in liver and skeletal muscle. Diverse dietary fat sources differently affect mitochondrial dynamics and bioenergetics. In contrast to saturated fatty acids, omega 3 polyunsaturated fatty acids induce fusion processes and improve mitochondrial function. Moreover, the pro-longevity effect of caloric restriction has been correlated with changes in mitochondrial dynamics leading to decreased cell oxidative injury. Noteworthy, emerging findings revealed an important role for mitochondrial dynamics within neuronal populations involved in central regulation of body energy balance. In conclusion, mitochondrial dynamic processes with their strict interconnection with mitochondrial bioenergetics are involved in energy balance and diet impact on metabolic tissues

Interaction of NF-κB and NFAT with the Interferon-γ Promoter

Interferon-gamma (IFN-gamma) is a pleiotropic lymphokine whose production is restricted to activated T cells and NK cells. Along with other cytokines, IFN-gamma gene expression is inhibited by the immunosuppressant cyclosporin A. We have previously identified an intronic enhancer region (C3) of the IFN-gamma gene that binds the NF-kappaB protein c-Rel and that shows partial DNA sequence homology with the cyclosporin A-sensitive NFAT binding site and the 3'-half of the NF-kappaB consensus site. Sequence analysis of the IFN-gamma promoter revealed the presence of two additional C3-related elements (C3-1P and C3-3P). In addition, an NF-kappaB site (IFN-gamma kappaB) was identified within the promoter region. Based on this observation, we have analyzed the potential role of NF-kappaB and NFAT family members in regulating IFN-gamma transcription. Electrophoretic mobility shift assay analysis demonstrated that after T cell activation, the p50 and p65 NF-kappaB subunits bind specifically to the newly identified IFN-gamma kappaB and C3-related sites. In addition, we identified the NFAT proteins as a component of the inducible complexes that bind to the C3-3P site. Site-directed mutagenesis and transfection studies demonstrate that calcineurin-inducible transcriptional factors enhance the transcriptional activity of the IFN-gamma promoter through the cyclosporin-sensitive C3-3P site, whereas NF-kappaB proteins functionally interact with the C3-related sites. In addition, when located downstream to the beta-galactosidase gene driven by the IFN-gamma promoter, the intronic C3 site worked in concert with both the IFN-gamma kappaB and the C3-3P site to enhance gene transcription. These results demonstrate that the coordinate activities of NFAT and NF-kappaB proteins are involved in the molecular mechanisms controlling IFN-gamma gene transcription

Retinoic acid-induced transcriptional modulation of the human interferon-γ promoter

Disregulation of vitamin A metabolism is able to generate different immunological effects, including altered response to infection, reduced IgG production, and differential regulation of cytokine gene expression (including interleukin-2 and -4 and interferon-gamma (IFN-gamma)). In particular, IFN-gamma gene expression is significantly affected by vitamin A and/or its derivatives (e.g. retinoic acid (RA)). Here, we analyze the effect of retinoic acid on IFN-gamma transcription. Transient transfection assays in the human T lymphoblastoid cell line Jurkat demonstrated that the activation of the IFN-gamma promoter was significantly down-regulated in the presence of RA. Surprisingly, two different AP-1/CREB-ATF-binding elements situated in the initial 108 base pairs of the IFN-gamma promoter and previously shown to be critical for transcriptional activity were unaffected by RA. Utilizing promoter deletions and electrophoretic mobility shift analysis, we identified a USF/EGR-1-binding element cooperating in the modulation of IFN-gamma promoter activity by RA. This element was found to be situated in a position of the IFN-gamma promoter close to a silencer element previously identified in our laboratory. These results suggest that direct modulation of IFN-gamma promoter activity is one of the possible mechanisms involved in the inhibitory effect of retinoids on IFN-gamma gene expression

Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards

Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research

Endoscopic management of patients with post-surgical leaks involving the gastrointestinal tract: a large case series

Background: Post-surgical anastomotic leaks often require a re-intervention, are associated with a definite morbidity and mortality, and with relevant costs. We described a large series of patients with different post-surgical leaks involving the gastrointestinal tract managed with endoscopy as initial approach. Methods: This was a retrospective analysis of prospectively collected cases with anastomotic leaks managed with different endoscopic approaches (with surgical or radiological drainage when needed) in two endoscopic centres during 5 years. Interventions included: (1) over-the-scope clip (OTSC) positioning; (2) placement of a covered self-expanding metal stent (SEMS); (3) fibrin glue injection (Tissucol); and (4) endo-sponge application, according to both the endoscopic feature and patient’s status. Results: A total of 76 patients underwent endoscopic treatment for a leak either in the upper (47 cases) or lower (29 cases) gastrointestinal tract, and the approach was successful in 39 (83%) and 22 (75.9%) patients, respectively, accounting for an overall 80.3% success rate. Leak closure was achieved in 84.9% and 78.3% of patients managed by using a single or a combination of endoscopic devices. Overall, leak closure failed in 15 (19.7%) patients, and the surgical approach was successful in all 14 patients who underwent re-intervention, whilst one patient died due to sepsis at 7 days. Conclusions: Our data suggest that an endoscopic approach, with surgical or radiological drainage when needed, is successful and safe in the majority of patients with anastomotic gastrointestinal leaks. Therefore, an endoscopic treatment could be attempted before resorting to more invasive, costly and risky re-intervention

Endoscopic management of patients with post-surgical leaks involving the gastrointestinal tract: a large case series

Background: Post-surgical anastomotic leaks often require a re-intervention, are associated with a definite morbidity and mortality, and with relevant costs. We described a large series of patients with different post-surgical leaks involving the gastrointestinal tract managed with endoscopy as initial approach. Methods: This was a retrospective analysis of prospectively collected cases with anastomotic leaks managed with different endoscopic approaches (with surgical or radiological drainage when needed) in two endoscopic centres during 5 years. Interventions included: (1) over-the-scope clip (OTSC) positioning; (2) placement of a covered self-expanding metal stent (SEMS); (3) fibrin glue injection (Tissucol); and (4) endo-sponge application, according to both the endoscopic feature and patient’s status. Results: A total of 76 patients underwent endoscopic treatment for a leak either in the upper (47 cases) or lower (29 cases) gastrointestinal tract, and the approach was successful in 39 (83%) and 22 (75.9%) patients, respectively, accounting for an overall 80.3% success rate. Leak closure was achieved in 84.9% and 78.3% of patients managed by using a single or a combination of endoscopic devices. Overall, leak closure failed in 15 (19.7%) patients, and the surgical approach was successful in all 14 patients who underwent re-intervention, whilst one patient died due to sepsis at 7 days. Conclusions: Our data suggest that an endoscopic approach, with surgical or radiological drainage when needed, is successful and safe in the majority of patients with anastomotic gastrointestinal leaks. Therefore, an endoscopic treatment could be attempted before resorting to more invasive, costly and risky re-intervention

Total neoadjuvant therapy for the treatment of locally advanced rectal cancer: a systematic minireview

Colorectal carcinoma is the second leading cause of cancer-related deaths, and indeed, rectal cancer accounting for approximately one third of newly diagnosed patients. Gold standard in the treatment of rectal cancer is a multimodality approach, aiming at a good control of the local disease. Distant recurrences are the major cause of mortality. Currently, Locally Advanced Rectal Cancer (LARC) patients undergo a combined treatment of chemotherapy and radiotherapy, followed by surgery. Eventually, more chemotherapy, namely adjuvant chemotherapy (aCT), may be necessary. Total Neoadjuvant Therapy (TNT) is an emerging approach aimed to reduce distant metastases and improve local control. Several ongoing studies are analyzing whether this new approach could improve oncological outcomes. Published results were encouraging, but the heterogeneity of protocols in use, makes the comparison and interpretation of data rather complex. One of the major concerns regarding TNT administration is related to its effect on larger and more advanced cancers that might not undergo similar down-staging as smaller, early-stage tumors. This minireview, based on a systematic literature search of randomized clinical trials and meta-analysis, summarizes current knowledge on TNT. The aim was to confirm or refute whether or not current practice of TNT is based on relevant evidence, to establish the quality of that evidence, and to address any uncertainty or variation in practice that may be occurring. A tentative grouping of general study characteristics, clinical features and treatments characteristics has been undertaken to evaluate if the reported studies are sufficiently homogeneous in terms of subjects involved, interventions, and outcomes to provide a meaningful idea of which patients are more likely to gain from this treatment

Gastroenterological complications in kidney transplant patients

Kidney transplantation is the surgical operation by which one of the two original kidneys is replaced with another healthy one donated by a compatible individual. In most cases, donors are recently deceased. There is the possibility of withdrawing a kidney from a consenting living subject. Usually, living donors are direct family members, but they could be volunteers completely unrelated to the recipient. A much-feared complication in case of kidney transplantation is the appearance of infections. These tend to arise due to immune-suppressor drugs administered as anti-rejection therapy. In this review, we describe the gastrointestinal complications that can occur in subjects undergoing renal transplantation associated with secondary pathogenic microorganisms or due to mechanical injury during surgery or to metabolic or organic toxicity correlated to anti-rejection therapy. Some of these complications may compromise the quality of life or pose a significant risk of mortality; fortunately, many of them can be prevented and treated without the stopping the immunosuppression, thus avoiding the patient being exposed to the risk of rejection episodes