Stimulation of immunity-linked genes by membrane disruption is linked to Golgi function and the ARF-1 GTPase

Immune-linked genes (ILGs) are activated in response to pathogens but can also be activated by lipid imbalance. Why pathogen attack and metabolic changes both impact ILG activation is unclear. Organelles in the secretory pathway have distinct protein and lipid components and genetically separable stress programs. These stress pathways activate restorative transcriptional programs when lipid ratios become unbalanced or during dysregulated protein folding and trafficking. We find that ILGs are specifically activated when membrane phosphatidylcholine ratios change in the secretory pathway. Consistent with this result, disruption of Golgi function in mutations targeting the ADP-ribosylation factor ARF-1 also activates ILG expression. Since increased protein secretion is altered by metabolic changes and pathogen responses, our data argue that ILG upregulation is a conserved, coordinated response to changes in trafficking resulting from intrinsic cues (lipid changes) or extrinsic stimulation (during the immune response). These findings uncover important and previously unexplored links between metabolism and the stress response.

Roles for Lo microdomains and ESCRT in ER stress-induced lipid droplet microautophagy in budding yeast

Microlipophagy (µLP), degradation of lipid droplets (LDs) by microautophagy, occurs by autophagosome-independent direct uptake of LDs at lysosomes/vacuoles in response to nutrient limitations and ER stressors in Saccharomyces cerevisiae. In nutrient-limited yeast, liquid-ordered (Lo) microdomains, sterol-rich raft-like regions in vacuolar membranes, are sites of membrane invagination during LD uptake. The endosome sorting complex required for transport (ESCRT) is required for sterol transport during Lo formation under these conditions. However, ESCRT has been implicated in mediating membrane invagination during µLP induced by ER stressors or the diauxic shift from glycolysis- to respiration-driven growth. Here, we report that ER stress induced by lipid imbalance and other stressors induces Lo microdomain formation. This process is ESCRT-independent and dependent upon Niemann-Pick type C sterol transfer proteins. Inhibition of ESCRT or Lo microdomain formation partially inhibits lipid imbalance-induced µLP, while inhibition of both blocks this µLP. Finally, although the ER stressors dithiothreitol or tunicamycin induce Lo microdomains, µLP in response to these stressors is ESCRT-dependent and Lo microdomain-independent. Our findings reveal that Lo microdomain formation is a yeast stress response, and stress-induced Lo microdomain formation occurs by stressor-specific mechanisms. Moreover, ESCRT and Lo microdomains play functionally distinct roles in LD uptake during stress-induced µLP.

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

A deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) function in CF leads to chronic lung disease. CF is associated with abnormalities in fatty acids, ceramides, and cholesterol, their relationship with CF lung pathology is not completely understood. Therefore, we examined the impact of CFTR deficiency on lipid metabolism and pro-inflammatory signaling in airway epithelium using mass spectrometric, protein array. We observed a striking imbalance in fatty acid and ceramide metabolism, associated with chronic oxidative stress under basal conditions in CF mouse lung and well-differentiated bronchial epithelial cell cultures of CFTR knock out pig and CF patients. Cell-autonomous features of all three CF models included high ratios of ω-6- to ω-3-polyunsaturated fatty acids and of long- to very long-chain ceramide species (LCC/VLCC), reduced levels of total ceramides and ceramide precursors. In addition to the retinoic acid analog fenretinide, the anti-oxidants glutathione (GSH) and deferoxamine partially corrected the lipid profile indicating that oxidative stress may promote the lipid abnormalities. CFTR-targeted modulators reduced the lipid imbalance and oxidative stress, confirming the CFTR dependence of lipid ratios. However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress.Protein array analysis revealed differential expression and shedding of cytokines and growth factors from CF epithelial cells compared to non-CF cells, consistent with sterile inflammation and tissue remodeling under basal conditions, including enhanced secretion of the neutrophil activator CXCL5, and the T-cell activator CCL17. However, treatment with antioxidants or CFTR modulators that mimic the approved combination therapies, ivacaftor/lumacaftor and ivacaftor/tezacaftor/elexacaftor, did not effectively suppress the inflammatory phenotype.We propose that CFTR deficiency causes oxidative stress in CF airway epithelium, affecting multiple bioactive lipid metabolic pathways, which likely play a role in CF lung disease progression. A combination of anti-oxidant, anti-inflammatory and CFTR targeted therapeutics may be required for full correction of the CF phenotype.

Analytical Strategies in Lipidomics for Discovery of Functional Biomarkers from Human Saliva

Human saliva is increasingly being used and validated as a biofluid for diagnosing, monitoring systemic disease status, and predicting disease progression. The discovery of biomarkers in saliva biofluid offers unique opportunities to bypass the invasive procedure of blood sampling by using oral fluids to evaluate the health condition of a patient. Saliva biofluid is clinically relevant since its components can be found in plasma. As salivary lipids are among the most essential cellular components of human saliva, there is great potential for their use as biomarkers. Lipid composition in cells and tissues change in response to physiological changes and normal tissues have a different lipid composition than tissues affected by diseases. Lipid imbalance is closely associated with a number of human lifestyle-related diseases, such as atherosclerosis, diabetes, metabolic syndromes, systemic cancers, neurodegenerative diseases, and infectious diseases. Thus, identification of lipidomic biomarkers or key lipids in different diseases can be used to diagnose diseases and disease state and evaluate response to treatments. However, further research is needed to determine if saliva can be used as a surrogate to serum lipid profiles, given that highly sensitive methods with low limits of detection are needed to discover salivary biomarkers in order to develop reliable diagnostic and disease monitoring salivary tests. Lipidomic methods have greatly advanced in recent years with a constant advance in mass spectrometry (MS) and development of MS detectors with high accuracy and high resolution that are able to determine the elemental composition of many lipids.

The Role of Irisin in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by progressive memory dysfunction, oxidative stress, and presence of senile plaques formed by amyloid beta (A β ) accumulation in the brain. AD is one of the most important causes of morbidity and mortality worldwide. AD has a variety of risk factors, including environmental factors, metabolic dysfunction, and genetic background. Recent research has highlighted the relationship between AD and systemic metabolic changes such as glucose and lipid imbalance and insulin resistance. Irisin, a myokine closely linked to exercise, has been associated with glucose metabolism, insulin sensitivity, and fat browning. Recent studies have suggested that irisin is involved in the process in central nervous system (CNS) such as neurogenesis and has reported the effects of irisin on AD as one of the neurodegenerative disease. Here, we review the roles of irisin with respect to AD and suggest that irisin highlight therapeutic important roles in AD. Thus, we propose that irisin could be a potential future target for ameliorating AD pathology and preventing AD onset.

TOPICAL DELIVERY OF NANOEMULSION FOR ANTIPSORIATIC DRUGS

Psoriasis is an autoimmune disorder of the skin characterized by relapsing episodes of inflammatory lesions and hyperkeratotic plaques with worldwide occurrence of around 2–5%. Psoriasis is a disease known to be caused by multitude of both genetic and environmental factors such as trauma, drugs, infection, alcohol, smoking and stress but its accurate origin is still not known. Further, available treatment options are associated with both inappropriate cosmetic appearance and related toxicities leading to poor patient compliance in long term use. Nanotechnology based drug delivery system has immense potential to enhance the bioavailability and effectiveness of drugs in their dosage forms, especially lipophilic drugs. Lipid based carrier system can overcome the lipid imbalance and normal moisturizing factors. Nanoemulsions, as one of a new carrier apparently have the prospective to conquer numerous problems related with topical antipsoriatic therapy. This delivery system could perhaps offer a good alternative in topical psoriasis treatment. Not only on how nanoemulsions prepared, but it depends on the active ingredients used and the selection of oil could as well enhance the efficiency of topical treatment towards psoriasis. A good combination of both active and suitable oils would result a better treatment and better effect. Keywords: Topical nanoemulsion, Antipsoriatic therapy, Critical quality attributes.

Drosophila DNA/RNA methyltransferase contributes to robust host defense in ageing animals by regulating sphingolipid metabolism

ABSTRACTDrosophila methyltransferase (Mt2) has been implicated in methylation of both DNA and tRNA. In this study, we demonstrate that loss of Mt2 activity leads to an age dependent decline of immune function in the adult fly. A newly eclosed adult has mild immune defects that exacerbate in a fifteen-day old Mt2−/− fly. The age dependent effects appear to be systemic, including disturbances in lipid metabolism, changes in cell shape of hemocytes and significant fold changes in levels of transcripts related to host defense. Lipid imbalance, as measured by quantitative lipidomics, correlates with immune dysfunction with high levels of immunomodulatory lipids, sphingosine-1phosphate (S1P) and ceramides, along with low levels of storage lipids. Activity assays on fly lysates confirm the age dependent increase in S1P and concomitant reduction of S1P lyase activity. We hypothesize that Mt2 functions to regulate genetic loci such as S1P lyase and this regulation is essential for robust host defense as the animal ages. Our study uncovers novel links between age dependent Mt2 function, innate immune response and lipid homeostasis.