Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models. APPROACH AND RESULTS: Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations. CONCLUSIONS: Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.

Emerging PD-1/PD-L1 antagonists for the treatment of malignant melanoma.

INTRODUCTION: Increased understanding of the interactive mechanisms between tumors and the immune system led to the development of immune checkpoint inhibitors, which have revolutioned the treatment of metastatic melanoma and subsequently many other tumors. In 2014, nivolumab and pembrolizumab, two checkpoint inhibitors binding to PD-1, were approved for the treatment of metastatic melanoma. Since then, a plethora of new molecules have enriched the armamentarium against melanoma. AREAS COVERED: This review summarizes the last updates about treatment with nivolumab and pembrolizumab, data on other PD-1/PDL-1 agents such as spartalizumab and atezolizumab and emerging compounds, new combinations with NKTR-214, anti LAG-3, anti IDO-1 and TVEC, new checkpoint inhibitors (e.g. TIM-3 or TIGIT) and other new molecules for the treatment of metastatic melanoma. EXPERT OPINION: Currently, several ongoing clinical trials are investigating novel molecules, or immunotherapy combinations, in order to achieve even better survival outcomes for patients, overcoming resistance mechanisms and improving toxicity profiles. The challenge in the near future will be to select the most appropriate treatments according to the specific characteristics of the patients.