Background and purpose
The PARP inhibitor olaparib has recently been approved for human use for the therapy of cancer. Considering the role of PARP in critical illness, we tested the effect of olaparib in a murine model of burn injury, in order to begin exploring the feasibility of repurposing olaparib for the therapy of burn patients.

Experimental approach
Mice were subjected to scald burn injury and randomized into vehicle or olaparib (10 mg/kg/day i.p.) groups. Outcome variables included indices of organ injury, clinical chemistry parameters, plasma levels of inflammatory mediators (at 24 h, 7 days and 21 days) and burn wound size (at 21 days).

Key results
Olaparib reduced myeloperoxidase levels in heart and lung homogenates and reduced malon dialdehyde levels in all tissues 24 h post-burn. Olaparib also reduced circulating alkaline aminotransferase, amylase and blood urea nitrogen and creatinine levels, indicative of protection against hepatic, pancreatic and renal dysfunction. Pro-inflammatory mediator (TNF-α, IL-1β, IFN-γ, GCSF, GM-CSF, eotaxin, KC, MIP-1-α and interleukins 3,6 and 12) levels as well as the levels of several mediators that are generally considered anti-inflammatory (IL-4, 10 and 13) were reduced by olaparib. Plasma troponin-I levels (an indicator of skeletal muscle damage) was also attenuated by olaparib. Finally, olaparib stimulated wound healing.

Conclusions and Implications
The clinically approved PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in murine burn injury. The data raise the potential utility of olaparib for severe burn injury.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13735

The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third-degree burn injury.

Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our understanding of the mechanisms contributing to muscle wasting during cancer has markedly increased. Both inflammation and oxidative stress (OS) alter anabolic and catabolic signaling pathways mostly culminating with muscle depletion. Several preclinical studies have emphasized the beneficial roles of several classes of nutraceuticals and modes of physical exercise, but their efficacy in CC patients remains scant. The route of nutraceutical administration is critical to increase its bioavailability and achieve the desired anti-cachexia effects. Accumulating evidence suggests that a single therapy may not be enough, and a bimodal intervention (nutraceuticals plus exercise) may be a more effective treatment for CC. This review focuses on the current state of the field on the role of inflammation and OS in the pathogenesis of muscle atrophy during CC, and how nutraceuticals and physical activity may act synergistically to limit muscle wasting and dysfunction.

Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia

Metabolismo y terapia nutricional en el paciente quemado crítico: una revisión actualizada

Astrocytes are specialized cells capable of regulating inflammatory responses in neurodegenerative diseases or traumatic brain injury. In addition to playing an important role in neuroinflammation, these cells regulate essential functions for the preservation of brain tissue. Therefore, the search for therapeutic alternatives to preserve these cells and maintain their functions contributes in some way to counteract the progress of the injury and maintain neuronal survival in various brain pathologies. Among these strategies, the conditioned medium from human adipose-derived mesenchymal stem cells (CM-hMSCA) has been reported with a potential beneficial effect against several neuropathologies. In this study, we evaluated the potential effect of CM-hMSCA in a model of human astrocytes (T98G cells) subjected to scratch injury. Our findings demonstrated that CM-hMSCA regulates the cytokines IL-2, IL-6, IL-8, IL-10, GM-CSF, and TNF-α, downregulates calcium at the cytoplasmic level, and regulates mitochondrial dynamics and the respiratory chain. These actions are accompanied by modulation of the expression of different proteins involved in signaling pathways such as AKT/pAKT and ERK1/2/pERK, and may mediate the localization of neuroglobin (Ngb) at the cellular level. We also confirmed that Ngb mediated the protective effects of CM-hMSCA through regulation of proteins involved in survival pathways and oxidative stress. In conclusion, regulation of brain inflammation combined with the recovery of fundamental cellular aspects in the face of injury makes CM-hMSCA a promising candidate for the protection of astrocytes in brain pathologies.

Mitochondrial Neuroglobin Is Necessary for Protection Induced by Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cells in Astrocytic Cells Subjected to Scratch and Metabolic Injury

Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

/pdf/burn-induced-muscle-metabolic-derangements-and-mitochondrial-1a1u63bb9g.pdf

Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation

Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stre...

Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma

Background: Whether older immigrant populations from the Mediterranean region, continue to follow the MD long after they immigrated is not known. Aim: Compare adherence to the MD and successful aging levels between Greeks living in Greece (GG) and Greeks living abroad (GA). Methods: Anthropometrical, clinical, psychological, sociodemographic, dietary and lifestyle parameters were assessed in a cross-sectional manner in a sample of 252 GG and 252 GA. Mediterranean Diet Score (MedDietScore range 0-55) was used to assess adherence to the MD. Successful aging was evaluated with the validated successful aging index (SAI range 0-10). Results: GA presented higher adherence to MD (p < 0.001); they were consuming significantly more cereals, legumes, vegetables, and fruits compared to GG. GG consumed significantly more dairy (3.8 ± 2.9 vs. 1.9 ± 2.2, p < 0.001) and potatoes (2.4 ± 1.6 vs. 1.9 ± 1.5, p < 0.001) compared to GA. Meat (p = 0.27), poultry (p = 0.72), fish (p = 0.68), olive oil (p = 0.16) and alcohol consumption (p = 0.05) were comparable between the two groups (all p’s > 0.05). MedDietScore was positively associated with SAI among both groups after adjusting for possible confounders (0.041 ± 0.014, p = 0.003 GG and 0.153 ± 0.035, p < 0.001 GA). Also, legumes, cereals, fruits and vegetables were found to be beneficial for successful aging. Conclusion: Adherence to the MD is associated with higher levels of successful aging among people of the same genetic background living in different environments. However, traditional dietary habits are gradually abandoned in their native countries, when, at the same time, are considered cultural heritage and preserved accordingly among immigrants.

Adherence to the Mediterranean Diet and Successful aging in Greeks living in Greece and abroad: the epidemiological Mediterranean Islands Study (MEDIS)

Anastasia Papadimitriou

Papers

Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma

Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma

Adherence to the Mediterranean Diet and Successful aging in Greeks living in Greece and abroad: the epidemiological Mediterranean Islands Study (MEDIS)