ABSTRACT
Oral mucositis (OM) is a serious and acute side effect in patients with cancer who receive chemotherapy or radiotherapy, often leading to the suspension of therapy and a need for opioid analgesic and enteral/parenteral nutrition, with an effect on patient survival. Among the various interventions proposed in OM management, laser therapy is becoming a recommended treatment option but has limitations due to its heterogeneous laser parameters. Here, we report on our successful clinical experience on the use of class IV laser therapy to treat OM induced by different chemotherapy regimens. To shed light on the mechanisms of action of laser therapy in improving OM resolution, we have developed an animal model of chemotherapy-induced OM, in which we compare the efficacy of the standard low-power laser therapy protocol with an innovative protocol, defined as high-power laser therapy. We show that high-power laser therapy is more effective than low-power laser therapy in improving OM lesion healing, reducing the inflammatory burden, and preserving tissue integrity. In addition, high-power laser therapy has been particularly effective in promoting the formation of new arterioles within the granulation tissue. Our results provide important insights into the mechanism of action of biostimulating laser therapy on OM in vivo and pave a way for clinical experimentation with the use of high-power laser therapy.
Subject(s)
Antineoplastic Agents/adverse effects , Laser Therapy , Neoplasms/drug therapy , Stomatitis , Adult , Aged , Aged, 80 and over , Animals , Antineoplastic Agents/administration & dosage , Disease Models, Animal , Female , Humans , Male , Mice , Middle Aged , Stomatitis/chemically induced , Stomatitis/pathology , Stomatitis/surgeryABSTRACT
Progress in gene therapy has hinted at the potential misuse of gene transfer in sports to achieve better athletic performance, while escaping from traditional doping detection methods. Suitable animal models are therefore required in order to better define the potential effects and risks of gene doping. Here we describe a mouse model of gene doping based on adeno-associated virus (AAV)-mediated delivery of the insulin-like growth factor-I (IGF-I) cDNA to multiple muscles. This treatment determined marked muscle hypertrophy, neovascularization, and fast-to-slow fiber type transition, similar to endurance exercise. In functional terms, treated mice showed impressive endurance gain, as determined by an exhaustive swimming test. The proteomic profile of the transduced muscles at 15 and 30 days after gene delivery revealed induction of key proteins controlling energy metabolism. At the earlier time point, enzymes controlling glycogen mobilization and anaerobic glycolysis were induced, whereas they were later replaced by proteins required for aerobic metabolism, including enzymes related to the Krebs cycle and oxidative phosphorylation. These modifications coincided with the induction of several structural and contractile proteins, in agreement with the observed histological and functional changes. Collectively, these results give important insights into the biological response of muscles to continuous IGF-I expression in vivo and warn against the potential misuse of AAV-IGF1 as a doping agent.
Subject(s)
Contractile Proteins/metabolism , Dependovirus/genetics , Energy Metabolism/genetics , Insulin-Like Growth Factor I/genetics , Muscle, Skeletal/physiology , Proteome/genetics , Animals , Athletic Performance , Contractile Proteins/genetics , DNA, Complementary/genetics , Electrophoresis, Gel, Two-Dimensional , Gene Transfer Techniques , Genetic Vectors , Humans , Insulin-Like Growth Factor I/metabolism , Male , Mice , Mice, Inbred Strains , Physical Conditioning, Animal , Physical Endurance/genetics , Proteomics , Real-Time Polymerase Chain ReactionABSTRACT
BACKGROUND & AIMS: Involvement of insulin in diabetes-associated liver triglyceride deposition and its potential pathways remain incompletely defined. SIRT1 may negatively modulate lipogenesis and liver triglyceride accumulation, involving AMP-activated protein kinase (AMPK) activation. In streptozotocin-diabetic rats, we hypothesized that insulin negatively modulates liver SIRT1 and activates AMPK-inhibited lipogenic mediators leading to triglyceride accumulation. The impact of insulin deprivation (INS-) and replacement (INS+) on liver inflammation and mitochondrial oxidative capacity (also potentially regulating triglyceride deposition) was also measured. METHODS: Streptozotocin-diabetic rats under chronic (8-week) INS- and INS+. RESULTS: Compared to INS- (P < 0.05), INS+ had low liver SIRT1 with low AMPK activating phosphorylation, low inactivating phosphorylation of its lipogenic target acetyl-CoA carboxylase and high tissue triglycerides. INS- (P < 0.05 vs Control) had liver inflammation and high mitochondrial oxidative capacity, but neither was modulated by INS+. Pair-feeding showed no influence of spontaneous overeating on insulin-induced changes. CONCLUSIONS: Insulin replacement downregulates SIRT1 and AMPK activation in vivo in streptozotocin-diabetic rat liver, likely contributing to insulin-induced liver triglyceride accumulation. Under the current experimental conditions, insulin-deprived diabetes is associated with liver inflammation and high mitochondrial oxidative capacity, that are not affected by insulin replacement and are therefore unlikely to contribute to tissue triglyceride changes in this model.
