Aging alters antiviral signaling pathways resulting in functional impairment in innate immunity in response to pattern recognition receptor agonists

The progressive impairment of immunity to pathogens and vaccines with aging is a significant public health problem as the world population shifts to an increased percentage of older adults (>?65). We have previously demonstrated that cells obtained from older volunteers have delayed and defective induction of type I interferons and T cell and B cell helper cytokines in response to TLR ligands when compared to those from adult subjects. However, the underlying intracellular mechanisms are not well described. Herein, we studied two critical pathways important in the production of type I interferon (IFN), the interferon response factor 7 (pIRF7), and TANK-binding kinase (pTBK-1). We show a decrease in pIRF7 and pTBK-1 in cross-priming dendritic cells (cDC1s), CD4⁺ T cell priming DCs (cDC2s), and CD14^dimCD16⁺ vascular patrolling monocytes from older adults (n?=?11) following stimulation with pathway-specific agonists in comparison with young individuals (n?=?11). The decrease in these key antiviral pathway proteins correlates with decreased phagocytosis, suggesting impaired function in Overall, our findings describe molecular mechanisms which explain the innate functional impairment in older adults and thus could inform us of novel approaches to restore these defects.

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Targeting inflammation: a potential approach for the treatment of depression

Major depressive disorder (MDD) or Depression is one of the serious neuropsychiatric disorders affecting over 280 million people worldwide. It is 4th important cause of disability, poor quality of life, and economic burden. Women are more affected with the depression as compared to men and severe depression can lead to suicide. Most of the antidepressants predominantly work through the modulation on the availability of monoaminergic neurotransmitter (NTs) levels in the synapse. Current antidepressants have limited efficacy and tolerability. Moreover, treatment resistant depression (TRD) is one of the main causes for failure of standard marketed antidepressants. Recently, inflammation has also emerged as a crucial factor in pathological progression of depression. Proinflammatory cytokine levels are increased in depressive patients. Antidepressant treatment may attenuate depression via modulation of pathways of inflammation, transformation in structure of brain, and synaptic plasticity. Hence, targeting inflammation may be emerged as an effective approach for the treatment of depression. The present review article will focus on the preclinical and clinical studies that targets inflammation. In addition, it also concentrates on the therapeutic approaches’ that targets depression via influence on the inflammatory signaling pathways.

Graphical abstract

Graphical abstract demonstrate the role of various factors in the progression and neuroinflammation, oxidative stress. It also exhibits the association of neuroinflammation, oxidative stress with depression.

     

Anti-inflammatory Properties of the Alpha-Melanocyte-Stimulating Hormone in Models of Granulomatous Inflammation

Purpose

Alpha-melanocyte stimulating hormone (α-MSH) is known to have anti-inflammatory effects. However, the anti-inflammatory properties of α-MSH on normal bronchial epithelial cells are largely unknown, especially in the context of in vitro sarcoidosis models.

Methods

We evaluated the anti-inflammatory effects of α-MSH on two different in vitro sarcoidosis models (lung-on-membrane model; LOMM and three-dimensional biochip pulmonary sarcoidosis model; 3D-BSGM) generated from NBECs and an in vivo sarcoidosis mouse model.

Results

Treatment with α-MSH decreased inflammatory cytokine levels and downregulated type I interferon pathway genes and related proteins in LOMM and 3D-BSGM models. Treatment with α-MSH also significantly decreased macrophages and cytotoxic T-cells counts in a sarcoidosis mice model.

Conclusion

Our results confirm the direct role of type I IFNs in the pathogenesis of sarcoid lung granulomas and highlight α-MSH as a potential novel therapeutic agent for treating pulmonary sarcoidosis.

Graphical Abstract

     

MicroRNA-32-5p attenuates cerebral ischemia/reperfusion injuries by modulating the phosphatase and tensin homologous protein

Non-coding RNAs have recently attracted much attention with the potential in the treatment of cerebral ischemia/reperfusion (I/R) injuries. In this study, we investigated the role of miR-32-5p in cerebral I/R injuries by using oxygen–glucose deprivation/reperfusion (OGD/R) PC12 cells and middle cerebral artery occlusion/reperfusion (MCAO/R) rats. The expression of genes and proteins were detected by RT-qPCR and Western blot, respectively. The function of OGD/R PC12 cells was detected using MTT assay and flow cytometry analysis. The influences of MCAO/R on rats was evaluated by measuring the infarct volume and brain water content. Bioinformatics analysis and luciferase gene reporter assay were used to identify the relationship between miR-32-5p and PTEN. The results showed that miR-32-5p had neuroprotective effects on OGD/R induced PC12 cells and MCAO/R injured rats’ brain. The level of miR-32-5p was significantly reduced after OGD/R. Overexpression of miR-32-5p significantly reduced MCAO/R-induced brain damages in rats. Moreover, PTEN was found to be a target of miR-32-5p, and overexpression of PTEN attenuated the effects of miR-32-5p overexpression on cerebral I/R injuries. In addition, miR-32-5p was able to activate PI3K/AKT signaling by inhibiting PTEN. In conclusion, miR-32-5p prevents brain I/R injuries through modulating PTEN/PI3K/AKT signaling pathway.

Graphic Abstract

     

Identification of hub genes correlated with sleep deprivation using co-expression analysis

Background

Sleep deprivation (SD) has become a serious concern worldwide. This study aimed to identify key modules and candidate hub genes correlated with diseases caused by SD, using co-expression analysis.

Methods

The weighted gene co-expression network analysis was performed to construct a co-expression network of hub genes correlated with SD. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to search for signaling pathways. The protein–protein interaction network analysis of central genes was performed to recognize the interactions among central genes. Molecular Complex Detection, a plugin in Cytoscape, was used to discover the hub gene clusters involved in SD.

Results

A total of 564 genes in the yellow module were identified based on the results of topological overlap measure–based clustering. The yellow module showed a pivotal correlation with SD. Six hub gene clusters prominently associated with SD were identified. Heat shock protein family and circadian clock genes among them may be the hub genes involved in SD.

Conclusions

These genes and pathways might become therapeutic targets with clinical usefulness in the future.

Graphical abstract

     

Antiparkinsonian activity of Cucurbita pepo seeds along with possible underlying mechanism

Cucurbita pepo is used as a vegetable in Pakistan and its seeds are also rich in tocopherol. Data showed the pivotal role of tocopherol in the treatment of Parkinson’s disease (PD). The current study was designed to probe into the antiparkinson activity of methanolic extract of C. pepo (MECP) seeds in the haloperidol-induced Parkinson rat model. Behavioral studies showed improvement in motor functions. The increase in catalase, superoxide dismutase, glutathione levels whereas the decreases in the malondialdehyde and nitrite levels were noted in a dose-dependent manner. Acetylcholine-esterase (AchE) activity was increased. Molecular docking results revealed significant binding interaction of selected phytoconstituents within an active site of target protein AchE (PDB ID: 4EY7). Furthermore, α-synuclein was up regulated with down regulation of TNF-α and IL-1β in the qRT-PCR study. Subsequently, ADMET results on the basis of structure to activity predictions in terms of pharmacokinetics and toxicity estimations show that selected phytochemicals exhibited moderately acceptable properties. These properties add knowledge towards the structural features which could improve the bioavailability of selected phytochemicals before moving towards the initial phase of the drug development. Our integrated drug discovery scheme concluded that C. pepo seeds could ameliorate symptoms of PD and may prove a lead remedy for the treatment of PD.

Graphical abstract

     

Computational exploration of vicine – an alkaloid glycoside mediated pathological hallmark of adenosine kinase to promote neurological disorder

Epilepsy disease is characterized by the neuronal dysfunction or abnormal neuronal activity of the brain which is regulated by astrocytes. These are glial cells and found to be the major regulators of the brain which are guided by the occurrence of adenosine kinase (ADK) enzyme in the central nervous system (CNS). During the normal physiological environment, ADK maintains the level of adenosine in the CNS. Dysfunction of ADK levels results in accumulation of adenosine levels in the CNS that leads to the pathophysiology of the brain such as astrogliosis which is a pathological hallmark of epileptic seizures. Vicine, an alkaloid glycoside in bitter gourd juice (Momordica charantia) is found to be toxic to the human system if the bitter gourd juice is consumed more. This compound inhibits ADK enzyme activity to lead epilepsy and seizure. Here, the toxic effect of vicine targeting ADK using computational predictions was investigated. The 3-dimensional structure of ADK has been constructed using I-Tasser, which has been refined by ModRefiner, GalaxyRefine, and 3D refine and it was endorsed using PROCHECK, ERRAT, and VADAR. 3D structure of the ligand molecule has been obtained from PubChem. Molecular docking has been achieved using AutoDock 4.2 software, from which the outcome showed the effective interaction between vicine and ADK, which attains binding free energy (?G) of ??4.13 kcal/mol. Vicine molecule interacts with the active region ARG 149 of ADK and inhibits the functions of ADK that may cause imbalance in energy homeostasis. Also, pre-ADMET results robustly propose in which vicine possesses toxicity, and meanwhile, from the Ames test, it was shown as mutagenic. Hence, the results from our study suggest that vicine was shown to be toxic that suppresses the ADK activity to undergo pathological conditions in the neuronal junctions to lead epilepsy.

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Associations of Pretreatment Physical Status Parameters with Tolerance of Concurrent Chemoradiation and Survival in Patients with Non-small Cell Lung Cancer

Objective

The aim of this study was to evaluate associations between pretreatment physical status parameters and tolerance of concurrent chemoradiation (cCHRT) and survival among patients with stage III non-small cell lung cancer (NSCLC).

Methods

A retrospective cohort study was conducted among patients with stage III NSCLC who had received cCHRT between 2006 and 2015. Multivariate independent associations were analysed between the pretreatment parameters age, Charlson comorbidity index, World Health Organization performance status (WHO performance status), body mass index (BMI), fat-free mass index (FFMI), maximal handgrip strength, forced expiratory volume in one second and carbon monoxide lung diffusion capacity on the one hand with tolerance of cCHRT (defined as a received radiation dose at least equal to the prescribed radiation dose) and survival on the other hand.

Results

527 of 577 patients (91.3%) tolerated cCHRT. A WHO performance status ≥ 2 (odds ratio (OR) 0.43) and BMI < 18.5 kg/m² (OR 0.36) were associated with poorer tolerance of cCHRT. In the total group, a WHO performance status ≥ 2 (hazard ratio (HR) 1.73), low FFMI (HR 1.23) and intolerance of cCHRT (HR 1.55) were associated with poorer survival.

Conclusion

In patients with stage III NSCLC receiving cCHRT, poor WHO performance status and BMI < 18.5 kg/m² were independently associated with tolerance of cCHRT. Physical status parameters and intolerance of cCHRT were independently associated with poorer survival. Besides using this information for treatment decisions, optimizing physical status in patients at risk for intolerance of cCHRT might be a next step for improving treatment outcomes.

Graphic Abstract

     

Selenium prevents interferon-gamma induced activation of TRPM2 channel and inhibits inflammation,mitochondrial oxidative stress,and apoptosis in microglia

Microglia as the primary immune cells of brain act protective effects against injuries and infections in the central nervous system. Inflammation via excessive Ca²⁺ influx and oxygen radical species (ROS) generation is a known factor in many neurodegenerative disorders. Importantly, the Ca²⁺ permeable TRPM2 channel is activated by oxidative stress. Thus, TRPM2 could provide the excessive Ca²⁺ influx in the microglia. Although TRPM2 expression level is high in inflammatory cells, the interplay between mouse microglia and TRPM2 channel during inflammation is not fully identified. Thus, it is important to understand the mechanisms and factors involved in order to enhance neuronal regeneration and repair. The data presented here indicate that TRPM2 channels were activated in microglia cells by interferon-gamma (IFNγ). The IFNγ treatment further increased apoptosis (early and late) and cytokine productions (TNF-α, IL-1β, and IL-6) which were due to increased lipid peroxidation and ROS generations as well as increased activations of caspase −3 (Casp-3) and − 9 (Casp-9). However, selenium treatment diminished activations of TRPM2, cytokine, Casp-3, and Casp-9, and levels of lipid peroxidation and mitochondrial ROS production in the microglia that were treated with IFNγ. Moreover, addition of either PARP1 inhibitors (PJ34 or DPQ) or TRPM2 blockers (2-APB or ACA) potentiated the modulator effects of selenium. These results clearly suggest that IFNγ leads to TRPM2 activation in microglia cells; whereas, selenium prevents IFNγ-mediated TRPM2 activation and cytokine generation. Together the interplay between IFNγ released from microglia cells is importance in brain inflammation and may affect oxidative cytotoxicity in the microglia.

Summary of pathways involved in IFNγ-induced TRPM2 activation and microglia death through excessive reactive oxygen species (ROS): Modulator role of selenium (Se). The IFNγ causes the microglia activation. Nudix box domain of TRPM2 is sensitive to ROS. The ROS induces DNA damage and ADPR-ribose (ADPR) production in the nucleus via PARP1 enzyme activation. ADPR and ROS-induced TRPM2 activation stimulates excessive Ca²⁺ influx. ROS are produced in the mitochondria through the increase of free cytosolic Ca²⁺ (via TRPM2 activation) by the IFNγ treatment, although they are diminished by the TRPM2 channel blocker (ACA and 2-APB) and PARP1 inhibitor treatments. The main mechanism in the cell death and inflammatory effects of IFNγ is mediated by stimulation of ROS-mediated caspase (caspase −3 and − 9) activations and cytokine production (TNF-α, IL-1β, and IL-6) via TRPM2 activation, respectively. The apoptotic, inflammatory, and oxidant actions of IFNγ are modulated through TRPM2 inhibition by the Se treatment

     

The Renin-Angiotensin System in Hypertension,a Constantly Renewing Classic: Focus on the Angiotensin AT2-Receptor

It is common knowledge that the renin-angiotensin system (RAS), in particular angiotensin II acting through the angiotensin AT₁-receptor (AT₁R), is pivotal for the regulation of blood pressure (BP) and extracellular volume. More recent findings have revealed that the RAS is far more complex than initially thought and that it harbours additional mediators and receptors, which are able to counteract and thereby fine-tune AT₁R-mediated actions. This review will focus on the angiotensin AT₂-receptor (AT₂R), which is one of the “counter-regulatory” receptors within the RAS. It will review and discuss data related to the role of the AT₂R in regulation of BP and focus on the following 3 questions: Do peripheral AT₂R have an impact on BP regulation, and, if so, does this effect become apparent only under certain conditions? Are central nervous system AT₂R involved in regulation of BP, and, if so, which brain areas are involved and what are the mechanisms? Does dysfunction of AT₂R contribute to the pathogenesis of hypertension in preeclampsia?     

Effect of angiotensin II type 2 receptor on stroke,cognitive impairment and neurodegenerative diseases

Here, we briefly review the role of the renin–angiotensin system (RAS) in cognitive impairment and neurodegenerative disease, mainly discussing our experimental studies on the angiotensin II type 2 (AT₂) receptor. Ischemic brain damage is enhanced in mice with overexpression of angiotensin II, with reduced cerebral blood flow in the penumbra and an increase in oxidative stress in the ischemic area. Angiotensin II binds two types of receptors, type 1 (AT₁) and type 2 (AT₂). Our previous experiments showed that AT₁ receptor signaling has a harmful effect, and AT₂ receptor signaling has a protective effect on the brain after stroke. AT₂ receptor signaling in bone marrow stromal cells or hematopoietic cells was shown to prevent ischemic brain damage after middle cerebral artery occlusion. In contrast, AT₂ receptor signaling also affects cognitive function. We showed that direct stimulation of the AT₂ receptor by a newly generated direct AT₂ receptor agonist, Compound 21 (C21), enhanced cognitive function in wild‐type (C57BL6) mice and an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid β (1–40). Finally, we carried out clinical research by investigating the levels of RAS components in patients with neurodegenerative diseases. We observed a reduction of angiotensin II and angiotensin converting enzyme (ACE) 2 levels, and an increase in ACE level in cerebrospinal fluid from patients with multiple sclerosis. These results suggest that RAS is also involved in neurodegenerative disease. Therefore, regulation of RAS might be a new therapeutic target to protect neurons from neural diseases. Geriatr Gerontol Int 2012; ••: ••–•• .     

Involvement of the renin–angiotensin system in the development of vascular damage in a rat model of arthritis: Effect of angiotensin receptor blockers

Objective

To explore the involvement of the renin–angiotensin system (RAS) in the development of vascular damage in adjuvant‐induced arthritis (AIA) in rats.

Methods

Angiotensin II (Ang II; 0.25 or 1.0 mg/kg/day) was infused in control rats and rats with AIA for 21 days, and the impact of systemic inflammation on Ang II–induced hypertension, endothelial dysfunction, and vascular hypertrophy was evaluated. Expression of angiotensin II type 1 receptor (AT₁R) and angiotensin‐converting enzyme (ACE) in the aortas of rats with AIA were examined by real‐time polymerase chain reaction (PCR) and Western blot analyses. Losartan (3 mg/kg/day) or irbesartan (5 mg/kg/day), both of which are AT₁R blockers, was administered orally to rats with AIA for 21 days. In situ superoxide production in aortas was assessed according to the fluorogenic oxidation of dihydroethidium to ethidium. The expression and activity of NAD(P)H oxidases in aortas were examined by real‐time PCR analysis and lucigenin chemiluminescence assay. Endothelial function in rats with AIA treated in vivo or ex vivo with AT₁R blockers was also determined.

Results

The Ang II–induced hypertensive response, endothelial dysfunction, and vascular hypertrophy were exacerbated in rats with AIA. Expression of AT₁R and ACE was increased in the aortas of rats with AIA. Both losartan and irbesartan decreased the levels of superoxide and the expression and activity NAD(P)H oxidases in the aortas of rats with AIA. The endothelial dysfunction in AIA was improved by the in vivo or ex vivo treatment with AT₁R blockers.

Conclusion

The locally activated RAS is involved in the increased vascular oxidative stress and endothelial dysfunction in AIA. Our findings have important implications for clinical approaches to the reduction of cardiovascular risk in patients with rheumatoid arthritis.

     

Assessing the Prognostic Implications of Myocardial Perfusion Studies: Identification of Patients at Risk vs Patients who May Benefit from Intervention?

Angiotensin II (AII), an octapeptide member of the renin-angiotensin system (RAS), is formed by the enzyme angiotensin converting enzyme (ACE) and exerts adverse cellular effects through an interaction with its type 1 receptor (AT₁R). Both ACE inhibitors and angiotensin receptor blockers (ARB) mitigate the vasoconstrictive, proliferative, proinflammatory, proapoptotic, and profibrotic effects of AII and are widely used as effective anti-remodeling agents in clinical practice. Prediction of individual response to these agents, however, remains problematic and is influenced by many factors including race, gender, and genotype. In addition, systemic and tissue RAS activity do not correlate closely. This report summarizes the results of on-going attempts to noninvasively determine tissue ACE activity and AT₁R expression using novel nuclear tracers. It is hoped that the availability of such imaging techniques improve treatment of heart failure through more selective pharmacologic intervention and better dose titration of available drugs.     

The “His and Hers” of the Renin-Angiotensin System

Sex differences exist in the regulation of arterial pressure and renal function by the renin-angiotensin system (RAS). This may in part stem from a differential balance in the pressor and depressor arms of the RAS. In males, the ACE/AngII/AT₁R pathways are enhanced, whereas, in females, the balance is shifted towards the ACE2/Ang(1-7)/MasR and AT₂R pathways. Evidence clearly demonstrates that premenopausal women, as compared to aged-matched men, are protected from renal and cardiovascular disease, and this differential balance of the RAS between the sexes likely contributes. With aging, this cardiovascular protection in women is lost and this may be related to loss of estrogen postmenopause but the possible contribution of other sex hormones needs to be further examined. Restoration of these RAS depressor pathways in older women, or up-regulation of these in males, represents a therapeutic target that is worth pursuing.     

The significance of brain aminopeptidases in the regulation of the actions of angiotensin peptides in the brain

From the outset, the concept of a brain renin-angiotensin system (RAS) has been controversial and this controversy continues to this day. In addition to the unresolved questions as to the means by which, and location(s) where brain Ang II is synthesized, and the uncertainties regarding the functionality of the different subtypes of Ang II receptors in the brain, a new controversy has arisen with respect to the identity of the angiotensin peptide(s) that activate brain AT₁ receptors. While it has been known for some time that Ang III can activate Ang II receptors with equivalent or near-equivalent efficacy to Ang II, it has been proposed that in the brain, only Ang III is active. This proposal, which we have named “The Angiotensin III Hypothesis” states that Ang II must be converted to Ang III in order to activate brain AT₁ receptors. This review examines several aspects of the controversies regarding the brain RAS with a special focus on brain aminopeptidases, studies that either support or refute The Angiotensin III Hypothesis, and the implications of The Angiotensin III Hypothesis for the activity of the brain RAS. It also addresses the need for further research that can test The Angiotensin III Hypothesis and definitively identify the angiotensin peptide(s) that activate brain AT₁ receptor-mediated effects.     

Efeitos cardiovasculares do receptor tipo 2 da angiotensina

The angiotensin type 2 receptor, AT₂R, has been described as having opposite effects to the angiotensin type 1 receptor, AT₁R. Although the quantities of the AT₂R found in the adult are low, its expression rises in pathological situations. The AT₂R has three major signaling pathways: activation of serine/threonine phosphatases (promoting apoptosis and antioxidant effects), activation of the bradykinin/NO/cGMP pathway (promoting vasodilation), and activation of phospholipase A2 (associated with regulation of potassium currents). The AT₂R appears to have effects in vascular remodeling, atherosclerosis prevention and blood pressure lowering (when associated with an AT₁R inhibitor). After myocardial infarction, the AT₂R appears to decrease infarct size, cardiac hypertrophy and fibrosis, and to improve cardiac function. However, its role in the heart is controversial. In the kidney, the AT₂R promotes natriuresis. Until now, treatment directed at the renin‐angiotensin‐aldosterone system has been based on angiotensin‐converting enzyme inhibitors or angiotensin type 1 receptor blockers. The study of the AT₂R has been revolutionized by the discovery of a direct agonist, C21, which promises to become part of the treatment of cardiovascular disease.     

Protective effects of <Emphasis Type="Italic">Scutellaria baicalensis</Emphasis> Georgi extract on D-galactose induced aging rats

Scutellaria baicalensis Georgi (SBG), a traditional Chinese herb, has attracted considerable attention for its wide range of pharmacological activities. This study aimed to investigate the intervention effects of SBG ethanol extract on aging rats induced by D-galactose (D-gal) and to explore potential mechanisms by serum and liver metabolic profiles. The aging rats were induced by the D-gal (100 mg/kg) for 10 weeks continuously with subcutaneous injection, while the control rats received physiological saline. Two other groups of rats were administered with 100 mg/kg/day and 200 mg/kg/day of SBG by oral route following D-gal injections. The abilities of spatial and learning memory were evaluated by open-field test and Morris water maze test. Then, some biochemical indexes related to cognitive ability and aging were measured. Histopathological feature in hippocampal region was observed by Hematoxylin and eosin (HE) staining. The changes of metabolic profiles were evaluated using proton nuclear magnetic resonance (¹H NMR) spectroscopy coupled with multivariate data analysis. Results showed that SBG could significantly improve the learning and memory functions, reducing oxidative damage and histological abnormalities of hippocampus neurons. In addition, significant differences in the metabolic profiles were observed both in serum and liver between the model group and the control group. After the treatment using SBG, the levels of these metabolites are significantly changed back to their similar levels in the control group. These metabolic changes are related to the disturbance in amino acid metabolism, glycometabolism and choline metabolism. Hence, SBG may have the potential to improve neurodegeneration and provide brain protection.

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Graphical abstract A ¹H NMR-based metabonomic study was conducted to provide a global view of metabolites related to D-gal induced aging rats and assess the holistic efficacy of Scutellaria baicalensis Georgi.