Periodic and Intermittent Fasting in Diabetes and Cardiovascular Disease.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is one of the leading causes of death globally. Nutrition plays a central role in CVD risk by affecting aging, adiposity, glycemia, blood pressure, cholesterol, inflammation, and other risk factors and can affect CVD risk not only based on calorie intake and dietary composition but also the timing and range of meals. This review evaluates the effects of fasting, fasting-mimicking diets, and time-restricted eating on the reduction of CVD risk factors and provides initial data on their potential to serve as CVD prevention and treatment therapies. RECENT FINDINGS: Intermittent fasting (IF), time-restricted eating (TRE), prolonged fasting (PF), and fasting-mimicking diets (FMD) show promise in the reduction of CVD risk factors. Results on IF, TRE, PF, and FMD on CVD risk factors are significant and often independent of weight loss, yet long-term studies on their effect on CVD are still lacking. Coupling periodic and prolonged, or intermittent and more frequent cycles of fasting or fasting-mimicking diets, designed to maximize compliance and minimize side effects, has the potential to play a central role in the prevention and treatment of CVD and metabolic syndrome.

Myocardial hypothermia increases autophagic flux, mitochondrial mass and myocardial function after ischemia-reperfusion injury.

Animal studies have demonstrated beneficial effects of therapeutic hypothermia on myocardial function, yet exact mechanisms remain unclear. Impaired autophagy leads to heart failure and mitophagy is important for mitigating ischemia/reperfusion injury. This study aims to investigate whether the beneficial effects of therapeutic hypothermia are due to preserved autophagy and mitophagy. Under general anesthesia, the left anterior descending coronary artery of 19 female farm pigs was occluded for 90 minutes with consecutive reperfusion. 30 minutes after reperfusion, we performed pericardial irrigation with warm or cold saline for 60 minutes. Myocardial tissue analysis was performed one and four weeks after infarction. Therapeutic hypothermia induced a significant increase in autophagic flux, mitophagy, mitochondrial mass and function in the myocardium after infarction. Cell stress, apoptosis, inflammation as well as fibrosis were reduced, with significant preservation of systolic and diastolic function four weeks post infarction. We found similar biochemical changes in human samples undergoing open chest surgery under hypothermic conditions when compared to the warm. These results suggest that autophagic flux and mitophagy are important mechanisms implicated in cardiomyocyte recovery after myocardial infarction under hypothermic conditions. New therapeutic strategies targeting these pathways directly could lead to improvements in prevention of heart failure.

Exploring the roles of MSCs in infections: focus on bacterial diseases.

Despite human healthcare advances, some microorganisms continuously react evolving new survival strategies, choosing between a commensal fitness and a pathogenic attitude. Many opportunistic microbes are becoming an increasing cause of clinically evident infections while several renowned infectious diseases sustain a considerable number of deaths. Besides the primary and extensively investigated role of immune cells, other cell types are involved in the microbe-host interaction during infection. Interestingly, mesenchymal stem cells (MSCs), the current leading players in cell therapy approaches, have been suggested to contribute to tackling pathogens and modulating the host immune response. In this context, this review critically explores MSCs' role in E. coli, S. aureus, and polymicrobial infections. Summarizing from various studies, in vitro and in vivo results support the mechanistic involvement of MSCs and their derivatives in fighting infection and in contributing to microbial spreading. Our work outlines the double face of MSCs during infection, disease, and sepsis, highlighting potential pitfalls in MSC-based therapy due to the MSCs' susceptibility to pathogens' weapons. We also identify potential targets to improve infection treatments, and propose the potential applications of MSCs for vaccine research.

Oxidative muscles have better mitochondrial homeostasis than glycolytic muscles throughout life and maintain mitochondrial function during aging.

Preservation of mitochondrial function, which is dependent on mitochondrial homeostasis (biogenesis, dynamics, disposal/recycling), is critical for maintenance of skeletal muscle function. Skeletal muscle performance declines upon aging (sarcopenia) and is accompanied by decreased mitochondrial function in fast-glycolytic muscles. Oxidative metabolism promotes mitochondrial homeostasis, so we investigated whether mitochondrial function is preserved in oxidative muscles. We compared tibialis anterior (predominantly glycolytic) and soleus (oxidative) muscles from young (3 mo) and old (28-29 mo) C57BL/6J mice. Throughout life, the soleus remained more oxidative than the tibialis anterior and expressed higher levels of markers of mitochondrial biogenesis, fission/fusion and autophagy. The respiratory capacity of mitochondria isolated from the tibialis anterior, but not the soleus, declined upon aging. The soleus and tibialis anterior exhibited similar aging-associated changes in mitochondrial biogenesis, fission/fusion, disposal and autophagy marker expression, but opposite changes in fiber composition: the most oxidative fibers declined in the tibialis anterior, while the more glycolytic fibers declined in the soleus. In conclusion, oxidative muscles are protected from mitochondrial aging, probably due to better mitochondrial homeostasis ab initio and aging-associated changes in fiber composition. Exercise training aimed at enriching oxidative fibers may be valuable in preventing mitochondria-related aging and its contribution to sarcopenia.

Three-dimensional imaging technologies: a priority for the advancement of tissue engineering and a challenge for the imaging community.

Tissue engineering/regenerative medicine (TERM) is an interdisciplinary field that applies the principle of engineering and life sciences to restore/replace damaged tissues/organs with in vitro artificially-created ones. Research on TERM quickly moves forward. Today newest technologies and discoveries, such as 3D-/bio-printing, allow in vitro fabrication of ex-novo made tissues/organs, opening the door to wide and probably never-ending application possibilities, from organ transplant to drug discovery, high content screening and replacement of laboratory animals. Imaging techniques are fundamental tools for the characterization of tissue engineering (TE) products at any stage, from biomaterial/scaffold to construct/organ analysis. Indeed, tissue engineers need versatile imaging methods capable of monitoring not only morphological but also functional and molecular features, allowing three-dimensional (3D) and time-lapse in vivo analysis, in a non-destructive, quantitative, multidimensional analysis of TE constructs, to analyze their pre-implantation quality assessment and their fate after implantation. This review focuses on the newest developments in imaging technologies and applications in the context of requirements of the different steps of the TERM field, describing strengths and weaknesses of the current imaging approaches.

Inflammation in tissue engineering: The Janus between engraftment and rejection.

Tissue engineering (TE) for tissue and organ regeneration or replacement is generally performed with scaffold implants, which provide structural and molecular support to in vitro seeded or in vivo recruited cells. TE implants elicit the host immune response, often resulting in engraftment impediment or rejection. Besides this negative effect, however, the immune system components also yield a positive influence on stem cell recruitment and differentiation, allowing tissue regeneration and healing. Thus, a balanced cooperation between proinflammatory and proresolution players of the immune response is an essential element of implant success. In this context, macrophage plasticity plays a fundamental role. Therefore modulating the immune response, instead of immune suppressing the host, might be the best way to successfully implant TE tissues or organs. In particular, it is becoming evident that the scaffold, immune, and stem cells are linked by a three-way interaction, and many efforts are being made for scaffold-appropriate design and functionalization in order to drive the inflammation process toward regeneration, vascularization, and implant success. This review discusses current and potential strategies for inflammation modulation to aid engraftment and regeneration, supporting the concept that quality, and not quantity, of inflammation might influence implant success.

Targeting PKCθ in skeletal muscle and muscle diseases: good or bad?

Protein kinase Cθ (PKCθ) is a member of the novel calcium-independent PKC family, with a relatively selective tissue distribution. Most studies have focused on its unique role in T-lymphocyte activation and suggest that inhibition of PKCθ could represent a novel therapeutic approach in the treatment of chronic inflammation, autoimmunity and allograft rejection. However, considering that PKCθ is also expressed in other cell types, including skeletal muscle cells, it is important to understand its function in different tissues before proposing it as a molecular target for the treatment of immune-mediated diseases. A number of studies have highlighted the role of PKCθ in mediating several intracellular pathways, regulating muscle cell development, homoeostasis and remodelling, although a comprehensive picture is still lacking. Moreover, we recently showed that lack of PKCθ in a mouse model of Duchenne muscular dystrophy (DMD) ameliorates the progression of the disease. In the present article, we review new developments in our understanding of the involvement of PKCθ in intracellular mechanisms regulating skeletal muscle development, growth and maintenance under physiological conditions and recent advances showing a hitherto unrecognized role of PKCθ in promoting muscular dystrophy.

PKC theta ablation improves healing in a mouse model of muscular dystrophy.

Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C θ (PKCθ) is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKCθ could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/θ(-/-), where PKCθ expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/θ(-/-) mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKCθ expression in hematopoietic cells.These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKCθ activity in the development of DMD. Although the immune cell population(s) involved remain unidentified, our findings reveal that PKCθ can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches.