Natural Immunosuppressants as a Treatment for Chronic Insomnia Targeting the Inflammatory Response Induced by NLRP3/caspase-1/IL-1ß Axis Activation: A Scooping Review.

Chronic insomnia is an inflammatory-related disease with an important pathological basis for various diseases which is a serious threat to a person's physical and mental health. So far, many hypotheses have been proposed to explain the pathogenesis of insomnia, among which inflammatory mechanisms have become the focus of scientific attention. In this regard, the aim of the present scooping review is to evaluate the potential benefits of natural compounds in treatment of chronic insomnia targeting nucleotide-binding oligomerization domain (NOD)-like receptor-pyrin-containing protein 3 (NLRP3)/caspase-1/IL-1ß axis as one of the most important activators of inflammatory cascades. The data show that compounds that have the potential to cause inflammation induce sleep disorders, and that inflammatory mediators are key molecules in regulating the sleep-related activity of neurons. In the inflammatory process of insomnia, the role of NLRP3 in the pathogenesis of insomnia has been gradually considered by researchers. NLRP3 is an intracellular sensor that recognizes the widest range of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). After identification and binding to damage factors, NLRP3 inflammasome is assembled to activate the caspase-1 and IL-1ß. Increased production and secretion of IL-1ß may be involved in central nervous system dysregulation of physiological sleep. The current scooping review reports the potential benefits of natural compounds that target NLRP3 inflammasome pathway activity and highlights the hypothesis which NLRP3 /caspase-1/IL-1ß may serve as a potential therapeutic target for managing inflammation and improving symptoms in chronic insomnia.

Interleukin-1α and tumor necrosis factor α as an inducer for reactive-oxygen-species-mediated NOD-like receptor protein 1/NOD-like receptor protein 3 inflammasome activation in mononuclear blood cells from individuals with chronic insomnia disorder.

BACKGROUND AND PURPOSE: There is some evidence that cytokines may play an important role in sleep deprivation; however, the underlying mechanisms are still unknown. So, the present study aimed to evaluate the relationship between NOD-like receptor protein 1 (NLRP1) and NOD-like receptor protein 3 (NLRP3) inflammasome activation of blood cells and serum levels of cytokines in individuals with chronic insomnia disorder (CID). METHODS: Blood samples were collected from 24 individuals with CID and 24 healthy volunteers. The inflammasome activation was evaluated using real-time polymerase chain reaction of NLRP1, NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and caspase-1; western blot of NLRP1 and NLRP3; caspase-1 activity assay; and serum levels of interleukin-1ß (IL-1ß), IL-18 and other cytokines using enzyme-linked immunosorbent assay. Reactive oxygen species generation in blood cells were detected by flow cytometry assay. Also, magnetic resonance imaging scans were obtained on a Siemens Magnetom Avanto 1.5 T MRI whole-body scanner using an eight-channel head coil. RESULTS: Increased activity of NLRP1 and NLRP3 inflammasomes in blood cells, increased serum levels of pro-inflammatory cytokines and decreased serum levels of IL-10 and transforming growth factor ß in individuals with CID were found. Significant correlation was observed between increased serum concentration of IL-1ß and the severity of insomnia in individuals with CID. The levels of reactive oxygen species in blood cells were found to be correlated with IL-1α and tumor necrosis factor α concentrations in sera from individuals with CID. Moreover, the individuals with CID demonstrated increased right cerebellum cortex and lateral ventricle mean diffusivity bilaterally compared to controls. CONCLUSIONS: This study provided new insights on the pathogenesis of CID and the effects of cytokines on inflammasome activation.

IgLON5 autoimmunity tested positive in patients with isolated chronic insomnia disease.

In the patients with neurological autoimmune diseases such as anti-IgLON5 disease, insomnia symptoms are very common. Clinical diagnosis of the anti-IgLON5 disease is usually made when neurodegenerative processes have occurred. To find the early signs of anti-IgLON5 disease, we evaluate the presence of IgLON5 autoantibodies in the serum of patients with chronic insomnia disease. Based on video-polysomnography, 22 individuals with isolated chronic insomnia disease were found. A control group of 22 healthy people was chosen using the Pittsburgh Sleep Quality Index (PSQI). An indirect immunofluorescence cell-based test of serum anti-IgLON5 antibodies was used to investigate IgLON5 autoimmunity. Anti-IgLON5 antibodies were detected in the serum of four of these patients with the titer of 1/10. The presence of IgLON5 autoantibodies in some patients with chronic insomnia disease can be considered a causing factor of insomnia which can be effective in more specific treatments of these patients. Moreover, the recognition of anti-IgLON5 disease in the early stages and before the progression of tauopathies can be useful in effective and timely treatment.

Evaluation of Sestrin 2, Adiponectin, AMPK, and mTOR Genes Expression in Acute Myeloid Leukemia Patients.

BACKGROUND: Effective treatment of acute myeloid leukemia (AML) is still controversial, therefore; a comprehensive understanding regarding the impaired cellular signaling pathways in AML can be useful in designing new therapeutic approaches. Among signaling pathways involved in AML, the mammalian target of rapamycin (mTOR) signaling pathway is of particular importance. While dysregulation of mTOR signaling has been reported in a wide range of patients with AML, but most studies have focused on mTOR downstream targets, and mTOR upstream targets have been overlooked. OBJECTIVE: In this study, expression of mTOR genes and three upstream targets (5' adenosine monophosphate-activated protein kinase (AMPK, adiponectin, and sestrin 2) involved in mTOR signaling was investigated. MATERIALS AND METHODS: In this study, expression of mTOR, AMPK, sestrin 2, and adiponectin genes in 60 patients with AML were evaluated compared to those of 30 healthy individuals as controls using the Real-Time polymerase chain reaction (Real-Time RT-PCR) method. RESULTS: According to the results, there was a significant difference in the expression of all the studied genes in patients in comparison to the normal control group (P <0.05). Expression of the mTOR gene was increased, while expression of AMPK, sestrin 2, and adiponectin genes was decreased in the patients with AML. Mean expression of the genes (2-ΔCt) (AMPK, sestrin 2, adiponectin, and mTOR) was equal to 7.9, 3.2, 3.74, and 1.49 for controls and 6, 2.1, 2.83, and 2.64 for patients with AML, respectively. CONCLUSIONS: Given the decreased expression levels of sestrin 2, adiponectin, and AMPK genes as tumor inhibitors and the increased expression level of the mTOR gene as an oncogene in the patients with AML in our study, it is thought that disruption of this pathway may be involved in leukemogenesis and can be considered as an effective factor in the progression of cancer.

Factors Influencing Mitochondrial Function as a Key Mediator of Glucose-Induced Insulin Release: Highlighting Nicotinamide Nucleotide Transhydrogenase.

Pancreatic ß-cells recognize blood glucose changes and release insulin that is a peptide hormone responsible for stable glycemia. Diabetes, a chronic disorder of insulin insufficiency, leads to disturbed glucose homeostasis and multi-organ problems. Glucose and insulin are key markers in the follow-up and control of this disease. Mitochondrial metabolism of pancreatic beta cells is a crucial part of glucose-stimulated cascade of insulin secretion. Effective factors on ß-cells mitochondrial function in production of compounds such as tricarboxylic acid intermediates, glutamate, nicotinamide adenine dinucleotide phosphate, and reactive oxygen species can have great effects on the secretion of insulin under diabetes. This review enhances our knowledge of factors influencing mitochondrial function as a key mediator of glucose-induced insulin release that accordingly will be helpful to further our understanding of the mechanisms implicated in the progressive beta cell failure that results in diabetes.

Partial purification and biochemical characterization of peroxidase from rosemary (Rosmarinus officinalis L.) leaves.

BACKGROUND: In this study, it is aimed to purify POD from leaves of Rosmarinus officinalis L. and determine its some biochemical properties. PODs are a group of oxidoreductase enzymes that catalyze the oxidation of a wide variety of phenolic compounds in the presence of hydrogen peroxide as an electron acceptor. MATERIALS AND METHODS: In this investigation, POD was purified 9.3-fold with a yield of 32.1% from the leaves of Rosemary by ammonium sulfate precipitation and ion-exchange chromatography. The enzyme biochemical properties, including the effect of pH, temperature and ionic strength were investigated with guaiacol as an electron donor. For substrate specificity investigation of the enzyme, Michaelis constant and the maximum velocity of an enzymatic reaction values for substrates guaiacol and 3,3', 5,5'-TetraMethyle-Benzidine were calculated from the Lineweaver-Burk graphs. RESULTS: The POD optimum pH and temperature were 6.0 and 40°C. The POD activity was maximal at 0.3 M of sodium phosphate buffer concentration (pH 6.0). Sodium dodecyl sulphate polyacrylamide gel electrophoresis was performed for molecular weight (Mw) determination and Mw of the enzyme was found to be 33 kDa. To investigate the homogeneity of the POD, native-PAGE was done and a single band was observed. CONCLUSION: The stability against high temperature and extreme pH demonstrated that the enzyme could be a potential POD source for various applications in the medicine, chemical and food industries.