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Highlights: [•] Mitochondrial fission/fusion and mitophagy regulators modulate RLR responses. [•] NLRP3 activation is dependent on mitochondrial localization and mROS. [•] Cyclic AMP activates the NLRP3 inflammasome via the calcium-sensing receptor. [•] LPS increases succinate to stabilize HIF-1α-mediated regulation of IL-1β. [•] ECSIT interacts with TRIM59 negatively regulating TLR signaling. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is associated with the manifestation and origin of a plethora of diseases and disorders. Whilst classically the role of these archetypical ‘powerhouses’ in many disease phenotypes has been attributed to their ability to regulate cell metabolism and cell death pathways, emerging data posit that mitochondria may also act as powerful initiators and masters of the innate immune response. This new paradigm complements the current mitochondrial dogma, whereby molecules endogenously present on or inside the mitochondria may act as immune regulators in response to stress or pathogens and may also be responsible for the initiation and/or manifestation of chronic inflammation observed in many diseases and disorders. [Copyright &y& Elsevier]

Abstract: Structural derivatives of 4-MTA, an illegal amphetamine analogue have been previously shown to have anticancer effects in vitro. In this study we report the synthesis of a series of novel 1,3-bis(aryl)-2-nitro-1-propene derivatives related in structure to 4-MTA. A number of these compounds containing a classic nitrostyrene structure are shown to have antiproliferative activities in vitro in a range of malignant cell lines, particularly against Burkitt’s lymphoma derived cell lines, whilst having no effect on ‘normal’ peripheral blood mononuclear cells. Such effects appear to be independent of the serotonin transporter, a high affinity target for amphetamines and independent of protein tyrosine phosphatases and tubulin dynamics both of which have been previously associated with nitrostyrene-induced cell death. We demonstrate that a number of these compounds induce caspase activation, PARP cleavage, chromatin condensation and membrane blebbing in a Burkitt’s lymphoma derived cell line, consistent with these compounds inducing apoptosis in vitro. Although no specific target has yet been identified for the action of these compounds, the cell death elicited is potent, selective and worthy of further investigation. [Copyright &y& Elsevier]

Abstract: 4-Methylthioamphetamine (4-MTA) is recognised as a 3,4-methylenedioxymethamphetamine (MDMA)-like drug of abuse. Such amphetamine-type drugs often contain byproducts of uncontrolled, illegal clandestine synthetic processes. We report the isolation and structural identification of a number of novel pyridines, dihydropyridone and N,N-di(1-aryl-2-propyl) amines as route-specific byproducts associated with clandestine synthesis of 4-MTA and related amphetamines. We report the in vitro cytotoxicity of 4-MTA, its synthesis byproducts together with some structurally related sulfur substituted α-alkyl phenethylamines in cell lines overexpressing human monoamine transporters as well as in a primary neuronal cell line model and a dopaminergic neuroblastoma cell line. 4-MTA along with a number of other structurally related amphetamine derivatives and synthetic impurities were found to be cytotoxic to these cells within pharmacologically defined concentrations implying that 4-MTA is a cytotoxic agent in vitro and therefore might have the potential to be a neurotoxic agent in vivo. [Copyright &y& Elsevier]

Abstract: The discovery that some serotonin reuptake transporter (SERT) ligands have the potential to act as pro-apoptotic agents in the treatment of cancer adds greatly to their diverse pharmacological application. 4-Methylthioamphetamine (MTA) is a selective ligand for SERT over other monoamine transporters. In this study, a novel library of structurally diverse 4-MTA analogues were synthesised with or without N-alkyl and/or C-α methyl or ethyl groups so that their potential SERT-dependent antiproliferative activity could be assessed. Many of the compounds displayed SERT-binding activity as well as cytotoxic activity. While there was no direct correlation between these two effects, a number of derivatives displayed anti-tumour effects in lymphoma, leukaemia and breast cancer cell lines, showing further potential to be developed as possible chemotherapeutic agents. [Copyright &y& Elsevier]

Abstract Iron is one of the most abundant transition elements and is indispensable for almost all organisms. While the ability of iron to participate in redox chemistry is an essential requirement for participation in a range of vital enzymatic reactions, this same feature of iron also makes it dangerous in the generation of hydroxyl radicals and superoxide anions. Given the high local oxygen tensions in the lung, the regulation of iron acquisition, utilization, and storage therefore becomes vitally important, perhaps more so than in any other biological system. Iron plays a critical role in the biology of essentially every cell type in the lung, and in particular, changes in iron levels have important ramifications on immune function and the local lung microenvironment. There is substantial evidence that cigarette smoke causes iron dysregulation, with the implication that iron may be the link between smoking and smoking-related lung diseases. A better understanding of the connection between cigarette smoke, iron, and respiratory diseases will help to elucidate pathogenic mechanisms and aid in the identification of novel therapeutic targets. Graphical abstract fx1 Highlights • Cigarette smoke induces significant dysregulation of iron homeostasis in the lung. • Iron dysregulation is observed in a number of smoking-related lung diseases. • Iron is an intriguing target for novel therapies in smoking-related lung diseases. [ABSTRACT FROM AUTHOR]

Activated macrophages undergo metabolic reprogramming, which not only supports their energetic demands but also allows for the production of specific metabolites that function as signaling molecules. Several Krebs cycles, or Krebs-cycle-derived metabolites, including succinate, α-ketoglutarate, and itaconate, have recently been shown to modulate macrophage function. The accumulation of 2-hydroxyglutarate (2HG) has also been well documented in transformed cells and more recently shown to play a role in T cell and dendritic cell function. Here we have found that the abundance of both enantiomers of 2HG is increased in LPS-activated macrophages. We show that L-2HG, but not D-2HG, can promote the expression of the proinflammatory cytokine IL-1β and the adoption of an inflammatory, highly glycolytic metabolic state. These changes are likely mediated through activation of the transcription factor hypoxia-inducible factor-1α (HIF-1α) by L-2HG, a known inhibitor of the HIF prolyl hydroxylases. Expression of the enzyme responsible for L-2HG degradation, L-2HG dehydrogenase (L-2HGDH), was also found to be decreased in LPS-stimulated macrophages and may therefore also contribute to L-2HG accumulation. Finally, overexpression of L-2HGDH in HEK293 TLR4/MD2/CD14 cells inhibited HIF-1α activation by LPS, while knockdown of L-2HGDH in macrophages boosted the induction of HIF-1α-dependent genes, as well as increasing LPS-induced HIF-1α activity. Taken together, this study therefore identifies L-2HG as a metabolite that can regulate HIF-1α in macrophages. [ABSTRACT FROM AUTHOR]