Adipose tissue metabolism may be impaired in patients with cancer. In particular, increased lipolysis was described in cancer-promoting adipose tissue atrophy. For this reason, we assessed the ...expression of the lipolysis-associated genes and proteins in subcutaneous adipose tissue (SAT) of gastrointestinal (GI) cancer patients compared to controls to verify their involvement in cancer, among different types of GI cancers, and in cachexia.
We considered patients with GI cancer (gastric, pancreatic, and colorectal) at their first diagnosis, with/without cachexia, and controls with benign diseases. We collected SAT and total RNA was extracted and ATGL, HSL, PPARα, and MCP1 were analyzed by qRT-PCR. Western blot was performed to evaluate CGI-58, PLIN1 and PLIN5.
We found higher expression of ATGL and HSL in GI cancer patients with respect to controls (p ≤ 0.008) and a trend of increase for PPARα (p = 0.055). We found an upregulation of ATGL in GI cancer patients with cachexia (p = 0.033) and without cachexia (p = 0.017) vs controls. HSL was higher in patients with cachexia (p = 0.020) and without cachexia (p = 0.021), compared to controls. ATGL was upregulated in gastric cancer vs controls (p = 0.014) and higher HSL was found in gastric (p = 0.008) and in pancreatic cancer (p = 0.033) vs controls. At the protein level, we found higher CGI-58 in cancer vs controls (p = 0.019) and in cachectic vs controls (p = 0.029), as well as in gastric cancer vs controls (p = 0.027).
In our cohort of GI cancer patients, we found a modulation in the expression of genes and proteins involved in lipolysis, and differences were interestingly detected according to cancer type.
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of spinal motor neurons as well as corticospinal (CSN) large pyramidal neurons within cortex layer V. An intense ...microglia immune response has been associated with both upper and lower motor neuron degeneration in ALS patients, whereas microgliosis occurrence in the motor cortex of hSOD1G93A mice—the best characterized model of this disease—is not clear and remains under debate. Since the impact of microglia cells in the neuronal environment seems to be crucial for both the initiation and the progression of the disease, here we analyzed the motor cortex of hSOD1G93A mice at the onset of symptoms by the immunolabeling of Iba1/TMEM119 double positive cells and confocal microscopy. By means of Sholl analysis, we were able to identify and quantify the presence of presumably activated Iba1/TMEM119-positive microglia cells with shorter and thicker processes as compared to the normal surveilling and more ramified microglia present in WT cortices. We strongly believe that being able to analyze microglia activation in the motor cortex of hSOD1G93A mice is of great importance for defining the timing and the extent of microglia involvement in CSN degeneration and for the identification of the initiation stages of this disease.
Cancer cachexia is a debilitating syndrome mainly characterized by muscle and fat wasting, leading to the progressive loss of body weight and complicating the management of cancer patient. In ...particular, the loss of muscle weight is a negative prognostic factor, being associated with chemotherapy toxicity and reduced survival. Increased inflammation and protein dysmetabolism are some of the impairments that lead to muscle wasting in cancer patients. Together with these alterations, tumor growth and chemotherapy administration may affect mitochondrial function, impinging on the muscle energy metabolism. Indeed, therapeutic approaches poised to correct both hypercatabolism and mitochondrial alterations could be effective in preventing cancer-induced muscle wasting. Among the non-pharmacological approaches, exercise training is one of the best modulator of muscle physiology able to impinge on both protein and energy metabolism. However, the wasting phenotype that characterizes cancer patients could be not compatible with physical training, prompting the development of different strategies to improve muscle metabolism. The aim of this mini-review is to discuss both the beneficial effects and the limitations of exercise training in cancer cachexia and the adoption of drugs able to modulate exercise-induced pathways.
The apoptotic protease activating factor 1 (Apaf1) is the main component of the apoptosome, and a crucial factor in the mitochondria-dependent death pathway. Here we show that Apaf1 plays a role in ...regulating centrosome maturation. By analyzing Apaf1-depleted cells, we have found that Apaf1 loss induces centrosome defects that impair centrosomal microtubule nucleation and cytoskeleton organization. This, in turn, affects several cellular processes such as mitotic spindle formation, cell migration and mitochondrial network regulation. As a consequence, Apaf1-depleted cells are more fragile and have a lower threshold to stress than wild-type cells. In fact, we found that they exhibit low Bcl-2 and Bcl-X(L) expression and, under apoptotic treatment, rapidly release cytochrome c. We also show that Apaf1 acts by regulating the recruitment of HCA66, with which it interacts, to the centrosome. This function of Apaf1 is carried out during the cell life and is not related to its apoptotic role. Therefore, Apaf1 might also be considered a pro-survival molecule, whose absence impairs cell performance and causes a higher responsiveness to stressful conditions.
Foregut division—the separation of dorsal (oesophageal) from ventral (tracheal) foregut components—is a crucial event in gastro-respiratory development, and frequently disturbed in clinical birth ...defects. Here, we examined three outstanding questions of foregut morphogenesis. The origin of the trachea is suggested to result either from respiratory outgrowth or progressive septation of the foregut tube. We found normal foregut lengthening despite failure of tracheo-oesophageal separation in Adriamycin-treated embryos, whereas active septation was observed only in normal foregut morphogenesis, indicating a primary role for septation. Dorso-ventral patterning of Nkx2.1 (ventral) and Sox2 (dorsal) expression is proposed to be critical for tracheo-oesophageal separation. However, normal dorso-ventral patterning of Nkx2.1 and Sox2 expression occurred in Adriamycin-treated embryos with defective foregut separation. In contrast, Shh expression shifts dynamically, ventral-to-dorsal, solely during normal morphogenesis, particularly implicating Shh in foregut morphogenesis. Dying cells localise to the fusing foregut epithelial ridges, with disturbance of this apoptotic pattern in Adriamycin, Shh and Nkx2.1 models. Strikingly, however, genetic suppression of apoptosis in the Apaf1 mutant did not prevent foregut separation, indicating that apoptosis is not required for tracheo-oesophageal morphogenesis. Epithelial remodelling during septation may cause loss of cell-cell or cell-matrix interactions, resulting in apoptosis (anoikis) as a secondary consequence.
Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS ...by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS.
The level of One Health (OH), or “One Health-ness,” of health interventions has been defined as the capacity to operate according to six dimensions concerning OH operations and OH infrastructures, ...respectively (thinking, planning, and working; and information sharing, reciprocal learning, and systemic organization). Although health initiatives and research increasingly claim their orientation toward OH, such a capacity is rarely assessed. The objective of this study is to evaluate the One Health-ness of the academic team of the University of Bologna (UNIBO Team) working in the “ELEPHANT” project (Empowering universities' Learning and rEsearch caPacities in the one Health Approach for the maNagement of animals at the wildlife, livestock and human interface in SouTh Africa). This project involves universities, six from South Africa and two from Europe, and aims at embedding OH in research and learning to enable the control of diseases at the human, animal, and environmental interface, and to emphasize the interests of local African communities with wildlife conservation. The methodology adopts the NEOH method, developed in 2018 by the EU-COST Action, “Network for the Evaluation of One Health.” The approach is based on questionnaires delivered to participants, which focus on the six OH dimensions, and then translate answers into quantitative metrics through the OH Index (OHI) and the OH Ratio (OHR). The following two evaluation levels are foreseen: the whole project and the single partner institutions. The evaluations are carried on in parallel, with preliminary, mid-term, and final assessments, to monitor the efficacy of the project actions. The preliminary evaluation of the UNIBO Team resulted in the OHI of 0.23 and the OHR of 1.69 which indicate a low degree of OH-ness and an imbalance between OH operation and OH infrastructure. The UNIBO case study will be the baseline for the evaluation of the other partner institutions involved in the ELEPHANT project. This type of evaluation can support the implementation of OH practices inside a project and underpin the strategies that allow to achieving more effective results. Any improvement in the OH-ness of each single academic team can be also considered as a result of the ELEPHANT project, thus showing its multiplier effect in the context.
Apaf1 (apoptotic protease activating factor 1) is the central component of the apoptosome, a multiprotein complex that activates procaspase-9 after cytochrome c release from the mitochondria in the ...intrinsic pathway of apoptosis. Other cellular roles, including a pro-survival role, have also been described for Apaf1, while the relative contribution of each function to cell death, but also to cell homeostatic conditions, remain to be clarified.
Here we examined the response to apoptosis induction of available embryonic fibroblasts from Apaf1 knockout mice (MEFS KO Apaf1). In the absence of Apaf1, cells showed mitochondria with an altered morphology that affects cytochrome c release and basal metabolic status.
We analysed mitochondrial features and cell death response to etoposide and ABT-737 in two different Apaf1-deficient MEFS, which differ in the immortalisation protocol. Unexpectedly, MEFS KO Apaf1 immortalised with the SV40 antigen (SV40IM-MEFS Apaf1) and those which spontaneously immortalised (SIM-MEFS Apaf1) respond differently to apoptotic stimuli, but both presented relevant differences at the mitochondria when compared to MEFS WT, indicating a role for Apaf1 at the mitochondria.
Cytochrome c is a key molecule in mitochondria-mediated apoptosis. It also plays a pivotal role in cell respiration. The switch between these two functions occurs at the moment of its release from ...mitochondria. This process is therefore extremely relevant for the fate of the cell. Since cytochrome c mediates respiration, we studied the changes in respiratory chain activity during the early stages of apoptosis in order to contribute to unravel the mechanisms of cytochrome c release. We found that, during staurosporine (STS)- induced apoptosis in PC12 cells, respiration is affected before the release of cytochrome c, as shown by a decrease in the endogenous uncoupled respiration and an uncoupling event, both occurring independently of cytochrome c release. The decline in the uncoupled respiration occurs also upon Bcl-2 overexpression (which inhibits cytochrome c release), while the uncoupling event is inhibited by Bcl-2. We also observed that the first stage of nuclear condensation during STS-induced apoptosis does not depend on the release of cytochrome c into the cytosol and is a reversibile event. These findings may contribute to understand the mechanisms affecting mitochondria during the early stages of apoptosis and priming them for the release of apoptogenic factors.
Abstract Inflammation and immune response play an important role in the pathogenesis of atherosclerosis. In this prospective study we tested the hypothesis of whether polymorphic variations in the ...NOD2/CARD15 gene may influence the risk of developing clinically evident coronary artery disease (CAD). ARG702TRP, GLY908ARG, and Leu1007fsinsC NOD2/CARD15 polymorphisms were analyzed in 109 consecutive patients with angiographically documented CAD and in 109 age- and sex-matched healthy controls. The ARG702TRP, GLY908ARG, and Leu1007fsinsC polymorphisms were analyzed by polymerase chain reaction followed by restriction digestion. The prevalence of the Leu1007fsinsC polymorphism was significantly increased in CAD patients compared with controls (11.9% vs 1.8%; odds ratios (OR) 7.2, 95% confidence interval (95% CI) 1.5–32.9; p = 0.01), especially in those presenting with an acute coronary syndrome (OR 5.7; 95% CI 1.1–39.7; p = 0.034 vs stable angina). In CAD patients the frequency of GLY908ARG polymorphism was significantly lower (1.8% vs 6.4% in controls; OR 0.05, 95% CI 0.01–0.69; p = 0.031, at multivariable analysis) and the prevalence of the ARG702TRP polymorphism was higher compared with controls (10.1% vs 3.7%; OR 2.9, 95% CI 0.91–9.6; p = 0.07). We report in a Caucasian population that NOD2/CARD15 polymorphisms influence the development of clinically evident and angiographically documented coronary artery disease. In particular, the Leu1007fsinsC polymorphism was associated with an increased risk of clinically evident and angiographically documented coronary atherosclerosis and clinical destabilization of coronary plaques, whereas the GLY908ARG polymorphism demonstrated a protective effect on coronary atherogenesis. These correlations were independent of cardiovascular risk factors at multivariable analysis. These findings may contribute to the identification of a novel genetic approach for the stratification of cardiovascular risk profile.
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