Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies.

Inflammaging refers to the age-related low grade, sterile, chronic, systemic, and long-lasting subclinical, proinflammatory status, currently recognized as the main risk factor for development and progression of the most common age-related diseases (ARDs). Extensive investigations were focused on a plethora of proinflammatory stimuli that can fuel inflammaging, underestimating and partly neglecting important endogenous anti-inflammaging mechanisms that could play a crucial role in such age-related proinflammatory state. Studies on autonomic nervous system (ANS) functions during aging highlighted an imbalance toward an overactive sympathetic nervous system (SNS) tone, promoting proinflammatory conditions, and a diminished parasympathetic nervous system (PNS) activity, playing anti-inflammatory effects mediated by the so called cholinergic anti-inflammatory pathway (CAP). At the molecular level, CAP is characterized by signals communicated via the vagus nerve (with the possible involvement of the splenic nerves) through acetylcholine release to downregulate the inflammatory actions of macrophages, key players of inflammaging. Notably, decreased vagal function and increased burden of activated/senescent macrophages (macrophaging) probably precede the development of several age-related risk factors and diseases, while increased vagal function and reduced macrophaging could be associated with relevant reduction of risk profiles. Hypothalamic-pituitary-adrenal axis (HPA axis) is another pathway related to ANS promoting some anti-inflammatory response mainly through increased cortisol levels. In this perspective review, we highlighted that CAP and HPA, representing broadly "anti-inflammaging" mechanisms, have a reduced efficacy and lose effectiveness in aged people, a phenomenon that could contribute to fuel inflammaging. In this framework, strategies aimed to re-balance PNS/SNS activities could be explored to modulate systemic inflammaging especially at an early subclinical stage, thus increasing the chances to reach the extreme limit of human lifespan in healthy status.

The Impact of Abnormal Lipid Metabolism on the Occurrence Risk of Idiopathic Pulmonary Arterial Hypertension.

The aim was to determine whether lipid molecules can be used as potential biomarkers for idiopathic pulmonary arterial hypertension (IPAH), providing important reference value for early diagnosis and treatment. Liquid chromatography-mass spectrometry-based lipidomic assays allow for the simultaneous detection of a large number of lipids. In this study, lipid profiling was performed on plasma samples from 69 IPAH patients and 30 healthy controls to compare the levels of lipid molecules in the 2 groups of patients, and Cox regression analysis was used to identify meaningful metrics, along with receiver operator characteristic curves to assess the ability of the lipid molecules to predict the risk of disease in patients. Among the 14 lipid subclasses tested, 12 lipid levels were significantly higher in IPAH patients than in healthy controls. Free fatty acids (FFA) and monoacylglycerol (MAG) were significantly different between IPAH patients and healthy controls. Logistic regression analysis showed that FFA (OR: 1.239, 95%CI: 1.101, 1.394, p < 0.0001) and MAG (OR: 3.711, 95%CI: 2.214, 6.221, p < 0.001) were independent predictors of IPAH development. Among the lipid subclasses, FFA and MAG have potential as biomarkers for predicting the pathogenesis of IPAH, which may improve the early diagnosis of IPAH.

Integrated models of blood protein and metabolite enhance the diagnostic accuracy for Non-Small Cell Lung Cancer.

BACKGROUND: For early screening and diagnosis of non-small cell lung cancer (NSCLC), a robust model based on plasma proteomics and metabolomics is required for accurate and accessible non-invasive detection. Here we aim to combine TMT-LC-MS/MS and machine-learning algorithms to establish models with high specificity and sensitivity, and summarize a generalized model building scheme. METHODS: TMT-LC-MS/MS was used to discover the differentially expressed proteins (DEPs) in the plasma of NSCLC patients. Plasma proteomics-guided metabolites were selected for clinical evaluation in 110 NSCLC patients who were going to receive therapies, 108 benign pulmonary diseases (BPD) patients, and 100 healthy controls (HC). The data were randomly split into training set and test set in a ratio of 80:20. Three supervised learning algorithms were applied to the training set for models fitting. The best performance models were evaluated with the test data set. RESULTS: Differential plasma proteomics and metabolic pathways analyses revealed that the majority of DEPs in NSCLC were enriched in the pathways of complement and coagulation cascades, cholesterol and bile acids metabolism. Moreover, 10 DEPs, 14 amino acids, 15 bile acids, as well as 6 classic tumor biomarkers in blood were quantified using clinically validated assays. Finally, we obtained a high-performance screening model using logistic regression algorithm with AUC of 0.96, sensitivity of 92%, and specificity of 89%, and a diagnostic model with AUC of 0.871, sensitivity of 86%, and specificity of 78%. In the test set, the screening model achieved accuracy of 90%, sensitivity of 91%, and specificity of 90%, and the diagnostic model achieved accuracy of 82%, sensitivity of 77%, and specificity of 86%. CONCLUSIONS: Integrated analysis of DEPs, amino acid, and bile acid features based on plasma proteomics-guided metabolite profiling, together with classical tumor biomarkers, provided a much more accurate detection model for screening and differential diagnosis of NSCLC. In addition, this new mathematical modeling based on plasma proteomics-guided metabolite profiling will be used for evaluation of therapeutic efficacy and long-term recurrence prediction of NSCLC.

Association between serum manganese and serum klotho in a 40-80-year-old American population from NHANES 2011-2016.

Objectives: Manganese is one of the essential trace elements that are required by the human body. Klotho protein is a classic anti-aging marker. The association between the levels of serum manganese and serum klotho in individuals between the ages of 40-80 in the United States remains unclear. Methods: Data for this cross-sectional study was obtained from the National Health and Nutrition Examination Survey (NHANES 2011-2016) in the United States. We performed multiple linear regression analyses to investigate the association between the levels of serum manganese and serum klotho. Furthermore, we performed a fitted smoothing curve according to a restricted cubic spline (RCS). Stratification and subgroup analyses were performed for further verification of the results. Results: Weighted multivariate linear regression analysis showed that serum manganese levels were independently and positively associated with serum klotho levels (ß = 6.30, 95% confidence interval: 3.30-9.40). Kruskal-Wallis test showed that participants with higher manganese quartiles had higher serum klotho levels (Q1: 808.54 ± 256.39 pg/mL; Q2: 854.56 ± 266.13 pg/mL; Q3: 865.13 ± 300.60 pg/mL; and Q4: 871.72 ± 338.85 pg/mL, p < 0.001). The RCS curve indicated that the association between the levels of serum manganese and serum klotho was non-linear. Furthermore, a significantly positive association was found between serum manganese and serum klotho levels in the majority of subgroups. Conclusion: A non-linear and positive association was found between the levels of serum manganese and serum klotho in individuals aged 40-80 in the United States according to the NHANES (2011-2016).

Balanced basal-levels of ROS (redox-biology), and very-low-levels of pro-inflammatory cytokines (cold-inflammaging), as signaling molecules can prevent or slow-down overt-inflammaging, and the aging-associated decline of adaptive-homeostasis.

Both reactive oxygen species (ROS) from redox-biology and pro-inflammatory cytokines from innate immunity/and other sources, in addition to their role in redox-biology, and in defense and repair, have long been regarded as potentially harmful factors associated with oxidative stress and inflammatory states. However, their important physiological functions as signaling molecules have been demonstrated to be of importance, also in Geroscience, particularly when ROS are at balanced basal levels (redox-biology) and pro-inflammatory cytokines are at very low levels (cold-inflammaging). Under these conditions, both of these components (alone or in combination) may act as signaling/response molecules involved in regulating/maintaining or restoring adaptive homeostasis during aging, particularly in the early phases of even very-mild non-damaging internal or external environmental stimuli that could nevertheless elicit low-grade warnings-signals for homeostatic stability. If signals potentially perturbing homeostasis persist, the levels of ROS and pro-inflammatory mediators increase resulting in a switch from adaptive to maladaptive responses which may lead to oxidative stress and overt-inflammaging (or even to an overt inflammatory state), thus paving the way to the risks of aging-related diseases (ARDs). Conversely, upon adaptive-responses, low-levels of ROS and very-low-levels of pro-inflammatory-cytokines, alone or in combination, can result in an amplified capacity to prevent or slow-down overt-inflammaging (2-fold to 4-fold increase of pro-inflammatory cytokines) thus maintaining or restoring homeostasis. Therefore, these signaling molecules may also have the sequential incremental potential to prevent or slow the subsequent decline of adaptive homeostasis that will occur later in the lifespan. These scenarios may lead us to conceive of, and conceptualize, both these molecules and their basal-low levels, as well as their dynamics and the time-course of responses, as 'potential important pillars of adaptive-homeostasis in aging' since the earliest phases of the occurrence of any even very- mild environmental potential imbalance.

CircGSAP alleviates pulmonary microvascular endothelial cells dysfunction in pulmonary hypertension via regulating miR-27a-3p/BMPR2 axis.

BACKGROUND: Our previous study showed that circular RNA-gamma-secretase-activating protein (circGSAP) was down-regulated in pulmonary microvascular endothelial cells (PMECs) in response to hypoxia, and regulated the cell cycle of PMECs via miR-942-5p sponge in pulmonary hypertension (PH). However, the mechanism whether circGSAP affects the dysfunction of PEMCs through other microRNAs (miRNAs) remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of circGSAP regulating PMECs dysfunction by absorbing other miRNAs to regulate target genes in idiopathic pulmonary arterial hypertension (IPAH). METHODS: Quantitative real-time polymerase chain reaction, immunofluorescence staining, Cell Counting Kit-8, Calcein-AM/PI staining, Transwell assay, dual-luciferase reporter assay, and ELISA were used to elucidate the roles of circGSAP. RESULTS: Here we showed that plasma circGSAP levels were significantly decreased in patients with IPAH and associated with poor outcomes. In vivo, circGSAP overexpression improved survival, and alleviated pulmonary vascular remodeling of monocrotaline-induced PH (MCT-PH) rats. In vitro, circGSAP overexpression inhibited hypoxia-induced PMECs proliferation, migration and increased mortality by absorbing miR-27a-3p. BMPR2 was identified as a miR-27a-3p target gene. BMPR2 silencing ameliorated the effect of the miR-27a-3p inhibitor on PMECs proliferation,migration and mortality. The levels of BMPR2 were upregulated in circGSAP-overexpressed PMECs and lung tissues of MCT-PH rats. CONCLUSION: Our findings demonstrated that circGSAP alleviated the dysfunction of PMECs via the increase of BMPR2 by competitively binding with miR-27a-3p, and mitigated pulmonary vascular remodeling of MCT-PH rats, providing potential therapeutic strategies for IPAH.

CircGSAP regulates the cell cycle of pulmonary microvascular endothelial cells via the miR-942-5p sponge in pulmonary hypertension.

Background We recently demonstrated that circGSAP was diminished in lung tissues from patients with pulmonary arterial hypertension and in hypoxia-induced pulmonary microvascular endothelial cells (PMECs). However, the underlying role of circGSAP in PMECs remains unknown. The study aimed to investigate the contribution of circGSAP to proliferation, apoptosis and cell cycle of PMECs in hypoxic environment and explore the mechanism. Methods The expression of circGSAP was quantified by real-time PCR or immunofluorescence in human lung tissue and PMECs. CircGSAP plasmid, circGSAP small interfering RNA (siRNA), miRNA inhibitor and target gene siRNA were synthesized to verify the role of circGSAP on regulating the proliferation, apoptosis, and cell cycle of PMECs. Results CircGSAP levels were decreased in lungs and plasma of patients with pulmonary hypertension second to chronic obstructive pulmonary disease (COPD-PH) and were associated with poor outcomes of COPD-PH patients. Upregulation of circGSAP inhibited proliferation, apoptosis resistance and G1/S transition of PMECs. Dual luciferase reporter assays showed that circGSAP acted as a competitive endogenous RNA regulating miR-942-5p, and identified SMAD4 as a target gene of miR-942-5p, Then, we verified the functions of miR-942-5p and SMAD4 in PMECs. In addition, the effect of circGSAP siRNA on PMECs was mitigated by transfection of miR-942-5p inhibitor, and the effect of miR-942-5p inhibitor on PMECs was inhibited by SMAD4 siRNA. Conclusion Our findings demonstrated that diminished circGSAP accelerated cell cycle to facilitate cell proliferation and apoptosis resistance through competitively binding miR-942-5p to modulate SMAD4 expressions in hypoxia-induced PMECs, indicating potential therapeutic strategies for PH.

Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies.

As the global aging process continues to lengthen, aging-related diseases (e.g., chronic obstructive pulmonary disease (COPD), heart failure) continue to plague the elderly population. Aging is a complex biological process involving multiple tissues and organs and is involved in the development and progression of multiple aging-related diseases. At the same time, some of these aging-related diseases are often accompanied by hypoxia, chronic inflammation, oxidative stress, and the increased secretion of the senescence-associated secretory phenotype (SASP). Hypoxia seems to play an important role in the process of inflammation and aging, but is often neglected in advanced clinical research studies. Therefore, we have attempted to elucidate the role played by different degrees and types of hypoxia in aging and aging-related diseases and their possible pathways, and propose rational treatment options based on such mechanisms for reference.

Cold-inflammaging: When a state of homeostatic-imbalance associated with aging precedes the low-grade pro-inflammatory-state (inflammaging): Meaning, evolution, inflammaging phenotypes.

The age-related pro-inflammatory state, discovered and called 'inflammaging' by Franceschi et al. (2000) plays an important role in the pathogenesis of age-related chronic diseases. A substantial body of data established that inflammaging is accompanied by a '2-fold to 4-fold' increase in plasma levels of pro-inflammatory mediators in healthy elderly people, when compared to the healthy adult population. This review focuses on the pre-inflammaging phase, here we reported as 'cold-inflammaging', a state where plasma levels of cytokines are slightly increased, but below the lower limit of 2-fold increase established for inflammaging. Slightly altered cytokine levels by innate immunity are known to be associated with homeostasis imbalances, this functional pleiotropy of cytokines as signal transducers, have a physiological counterpart, representing an adaptive process aimed at restoring (or achieving a new) homeostatic stability. If a dyshomeostatic state persists, the cytokine response by innate immunity increases and becomes a driver of inflammaging. A scenario where cytokines are characterised as major players in homeostasis imbalances at the beginning (cold-inflammaging) and then in chronic low-grade pro-inflammatory-state (inflammaging). Other important drivers of inflammaging are cellular senescence with its senescence-associated secretory phenotype, the altered gut microbiota, and the age-related dysregulation in the production of endogenous molecular waste (Garb-aging). The main purpose of this review being to thoroughly investigate each step of the pathway from cold-inflammaging to overt-inflammaging, because aging, cold-inflammaging, overt-inflammaging and the pathogenesis of age-related diseases have been shown to share some established basic pillars of geroscience that largely converge on inflammaging.

Potential role of cellular senescence in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare and chronic lung vasculature disease characterised by pulmonary vasculature remodelling, including abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional endothelial cells (ECs). Remodelling of the pulmonary vasculature occurs from maturity to senescence, and it has become apparent that cellular senescence plays a central role in the pathogenesis of various degenerative vascular diseases and pulmonary pathologies. Cellular senescence represents a state of stable proliferative arrest accompanied by the senescence-associated secretory phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment. Evidence shows that in PAH patients, higher levels of cytokines, chemokines and inflammatory mediators can be detected and correlate with clinical outcome. Moreover, senescent cells accrue with age in epithelial, endothelial, fibroblastic and immunological compartments within human lungs, and evidence has shown that ECs and PASMCs in lungs from patients with chronic obstructive pulmonary disease were characterised by a higher number of senescent cells. However, there is little evidence uncovering the molecular pulmonary vasculature senescence in PAH. Herein, we review the cellular senescence in pulmonary vascular remodelling, and emphasise its importance in PAH. We further introduce some signalling pathways which might be involved in vasculature senescence and PAH, with the intent to discuss the possibility of the PAH therapy via targeting cellular senescence and reduce PAH progression and mortality.

HMGB1 plays an important role in pyroptosis induced blood brain barrier breakdown in diabetes-associated cognitive decline.

Diabetes mellitus increases the risk of dementia, and evidence suggests hyperglycemia is a key contributor to neurodegeneration. However, our understanding of diabetes-associated cognitive decline, an important complication of diabetes mellitus, is lacking and the underlying mechanism is unclear. Blood brain barrier (BBB) breakdown is a possible cause of dementia in diabetes mellitus and Alzheimer's disease. Accumulating evidence shows BBB dysfunction caused by hyperglycemia contributes to cognitive decline. A specific type of inflammatory programmed cell death, called pyroptosis, has potential as a therapeutic target for BBB-associated diseases. Potential inducers of pyroptosis include inflammasomes such as NLRP3, whose activation relies on damage-associated molecular patterns. High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein found in most cell types, and acts as a damage-associated molecular pattern when released from the nucleus. We propose that HMGB1 influences vascular inflammation by activating the NLRP3 inflammasome and thereby initiating pyroptosis in vascular cells. Moreover, HMGB1 plays a pivotal role in the pathogenesis of diabetes mellitus and diabetic complications. Here, we review the role of HMGB1 in BBB dysfunction induced by hyperglycemia and propose that HMGB1 is a promising therapeutic target for countering diabetes-associated cognitive decline.

The circular RNA circTXNRD1 promoted ambient particulate matter-induced inflammation in human bronchial epithelial cells by regulating miR-892a/COX-2 axis.

Particulate matter (PM)-induced airway inflammation contributes to the development and exacerbation of chronic airway diseases. Circular RNA (circRNA) is a new class of non-coding RNA that participates in gene regulation in various respiratory diseases, but the regulatory role of circRNA in PM-induced airway inflammation has not been fully elucidated. In this study, we performed the human circRNA microarray to reveal differentially expressed circRNAs in PM-induced human bronchial epithelial cells (HBECs). A total of 176 upregulated and 15 downregulated circRNAs were identified. Of these, a new circRNA termed circTXNRD1 was upregulated by PM exposure in a dose- and time-dependent manner. Knockdown of circTXNRD1 significantly attenuated PM-induced expression of proinflammatory cytokine interleukin 6 (IL-6). CircRNA pull-down, dual-luciferase reporter assay and fluorescence in situ hybridization showed that circTXNRD1 acted as an endogenous sponge to decrease miR-892a levels in HBECs. Downregulation of miR-892a could increase cyclooxygenase-2 (COX-2) expression and eventually promote IL-6 secretion in PM-induced HBECs. Taken together, our findings reveal circTXNRD1 as a novel inflammatory mediator in PM-induced inflammation in HBECs via regulating miR-892a/COX-2 axis. These results provide new insight into the biological mechanism underlying PM-induced inflammation in chronic airway diseases.

Do inflammaging and coagul-aging play a role as conditions contributing to the co-occurrence of the severe hyper-inflammatory state and deadly coagulopathy during COVID-19 in older people?

The coronavirus disease 2019 (COVID-19) is a new infectious respiratory disease, which has caused a pandemic that has become the world's leading public health emergency, threatening people of all ages worldwide, especially the elderly. Complications of COVID-19 are closely related to an upregulation of the inflammatory response revealed by the pro-inflammatory profile of plasma cytokines (to the point of causing a cytokine storm), which is also a contributing cause of the associated coagulation disorders with venous and arterial thromboembolisms, causing multiple organ dysfunction and failure. In severe fulminant cases of COVID-19, there is an activation of coagulation and consumption of clotting factors leading to a deadly disseminated intravascular coagulation (DIC). It is well established that human immune response changes with age, and also that the pro-inflammatory profile of plasma cytokines is upregulated in both healthy and diseased elderly people. In fact, normal aging is known to be associated with a subclinical, sterile, low-grade, systemic pro-inflammatory state linked to the chronic activation of the innate immune system, a phenomenon known as "inflammaging". Inflammaging may play a role as a condition contributing to the co-occurrence of the severe hyper-inflammatory state (cytokine storm) during COVID-19, and also in other severe infections (sepsis) in older people. Moreover, we must consider the impact of inflammation on coagulation due to the crosstalk between inflammation and coagulation. The systemic inflammatory state and coagulation disorders are closely related, a phenomenon that here we call "coagul-aging" (Giunta S.). In this review, we discuss the various degrees of inflammation in older adults after being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the adverse effects of aging on the inflammatory response and coagulation system. It is important to note that although there is no gender difference in susceptibility to COVID-19 infection, however, due to differences in angiotensin-converting enzyme 2 (ACE2) expression, innate immunity, and comorbidities, older men exhibit more severe disease and higher mortality than older women. There are currently no FDA-approved specific antiviral drugs that can be used against the virus. Therapies used in patients with COVID-19 consist of remdesivir, dexamethasone, low-molecular-weight heparin, in addition to monoclonal antibodies against the spike protein of SARS-CoV-2 in the early phase of the disease. Future pharmacological research should also consider targeting the possible role of the underlying scenario of inflammaging in healthy older people to prevent or mitigate disease complications. It is worth mentioning that some specific cytokine antagonists and traditional Chinese medicine preparations can reduce the elderly's inflammatory state.

Exposure to particulate matter 2.5 and cigarette smoke induces the synthesis of lipid droplets by glycerol kinase 5.

Particulate matter (PM2.5) and cigarette smoke exposure are leading factors contributing to various diseases, especially respiratory diseases. The purpose of this research was to study the effects of PM2.5 and cigarette smoke on glycerol kinase 5 (GK5) expression and the possible mechanisms by which GK5 participates in lipid droplet (LD) synthesis in alveolar epithelial A549 cells. Real-time polymerase chain reaction (RT-PCR) and western blotting have been used for the detection of messenger RNA (mRNA) and protein expression respectively. GK5 overexpressing cells were established by lentivirus transfection, whereby lentiviral vectors deliver the gene into chromosomes, allowing stable expression. Affymetrix microarray analysis, a widely used tool for measuring genome-wide gene expression, has been used to explore differential gene expression profiles. A549 cells stimulated with PM2.5 and cigarette smoke extract (CSE) showed elevated GK5 expression in a dose-dependent manner. Transmission electron microscopy and oil red O staining were used to observe LDs in cells. Further, GK5 overexpressing cells showed increased LDs and upregulation of genes and proteins related to lipogenesis and lipid transportation. Affymetrix microarray analysis revealed that GK5 overexpression resulted in the differential expression of more than 109 genes, which were mainly involved in the regulation of cell death, cell survival, cellular movement and migration, and those involved in cellular growth and proliferation pathways. Overall, this study demonstrates that GK5 is upregulated during PM2.5 and cigarette smoke exposure and induces LD synthesis.

Combined Antioxidant, Anti-inflammaging and Mesenchymal Stem Cell Treatment: A Possible Therapeutic Direction in Elderly Patients with Chronic Obstructive Pulmonary Disease.

Chronic Obstructive Pulmonary Disease (COPD) is a worldwide health problem associated with high morbidity and mortality, especially in elderly patients. Aging functions include mitochondrial dysfunction, cell-to-cell information exchange, protein homeostasis and extracellular matrix dysregulation, which are closely related to chronic inflammatory response and oxidation-antioxidant imbalance in the pathogenesis of COPD. COPD displays distinct inflammaging features, including increased cellular senescence and oxidative stress, stem cell exhaustion, alterations in the extracellular matrix, reduced levels of endogenous anti-inflammaging molecules, and reduced autophagy. Given that COPD and inflammaging share similar general features, it is very important to identify the specific mechanisms of inflammaging, which involve oxidative stress, inflammation and lung mesenchymal stem cell function in the development of COPD, especially in elderly COPD patients. In this review, we highlight the studies relevant to COPD progression, and focus on mechanisms associated with inflammaging.

Chinese Tuina Protects against Neonatal Hypoxia-Ischemia through Inhibiting the Neuroinflammatory Reaction.

Aim. Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of perinatal morbidity and mortality. Chinese Tuina is an effective treatment for HIE, but the molecular mechanisms are yet unknown. This study investigated the effect and mechanisms of Chinese Tuina on the inflammatory response in neonatal HIE rats. Main Methods. 30 male neonatal rats were divided randomly into 3 groups: sham, HIE, and HIE with Chinese Tuina (CHT) groups. The HIE and CHT groups were subjected to left common carotid occlusion and hypoxia at 3 days postnatal (P3). The pups in the CHT group received Chinese Tuina treatment on the next day for 28 days. The weight was measured at P4, P9, P13, P21, and P31. The behavioral functions were determined at P21. The protein expression and the methylation level in promoter regions of TNF-α and IL-10 were determined by Western blotting, immunohistochemistry, and pyrosequencing, respectively, at P33. Key Findings. The weight gain in the HIE group was slow compared with that of the CHT group. The rats in the CHT group performed better both in the balance beam and hang plate experiment. Chinese Tuina inhibited the expression of TNF-α and upregulated the expression of IL-10. Neonatal hypoxic-ischemic injury downregulated the methylation level in promoter regions of TNF-α at all CpG points but not IL-10. However, Chinese Tuina did not change the methylation level in promoter regions of TNF-α and IL-10. Significance. Chinese Tuina protected against HIE through inhibiting the neuroinflammatory reaction. While HIE markedly downregulated the methylation level of TNF-α, the protective effects of Chinese Tuina were independent of the regulation of the methylation level of TNF-α and IL-10.

Pyrroloquinoline quinone delays inflammaging induced by TNF-α through the p16/p21 and Jagged1 signalling pathways.

Previous studies on the longevity effect of pyrroloquinoline quinine (PQQ) on nematode worms have revealed that PQQ can enhance the antioxidant capacity of nematode worms, thus extending the lifespan of the worms. The induction and development of cellular senescence are closely connected with inflammatory reactions. The aim of this study was to determine the effect of PQQ and ageing factors on senescent cells. To this end, we cultivated human embryonic lung fibroblasts in nutrient solution with or without tumour necrosis factor-alpha (TNF-α) to establish an inflammaging model in vitro. The cells were preincubated with or without PQQ to determine if PQQ had any anti-inflammaging effect. More senescent cells were detected with the addition of TNF-α than without (P < .01). The ratio of senescent cells to non-senescent cells in the TNF-α group was greater than that in the control group (P < .01). When cells were preincubated with PQQ prior to TNF-α treatment, there were fewer senescent cells than those in the control group, which was not pretreated with PQQ (P < .05). The same tendency was noted with regard to p21, p16, and Jagged1. In summary, we used TNF-α, a well-known pro-inflammatory cytokine associated with inflammaging, to establish an in vitro inflammaging model and provided evidence that PQQ delays TNF-α -induced cellular senescence and has anti-inflammaging properties.

Characteristics of Long Noncoding RNAs in the Pancreas of Rats With Acute Pancreatitis.

OBJECTIVE: Long noncoding RNAs (lncRNAs) have received increasing attention as potential regulators of several biological processes. However, the precise effects of lncRNAs in acute pancreatitis (AP) have seldom been studied. This study aimed to describe the microarray-based differential expression profile of messenger RNA (mRNAs) and lncRNAs in AP and identify candidate biomarkers for the diagnosis, prognosis, and treatment of AP. METHODS: A rat model of AP was generated with retrograde pancreatic ductal injection of sodium taurocholate, and the pancreas was harvested for microarray detection. The biological functions of differentially expressed mRNAs noted from microarray data were assessed by bioinformatics analysis. A coding-noncoding gene coexpression network was built for the most promising mRNAs, from which 10 lncRNAs were selected for subsequent validation by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: There were 1156 lncRNAs and 3022 mRNAs distinctively dysregulated in rats with AP relative to the controls. The significantly enriched Gene Ontology term associated with upregulated mRNAs was immune system process. Kyoto Encyclopedia of Genes and Genomes functional analysis demonstrated that the upregulated transcripts were highly enriched in natural killer cell-mediated cytotoxicity. CONCLUSIONS: Further research is needed to establish lncRNAs uc.308-, BC158811, BC166549, BC166474, and BC161988 as diagnostic and therapeutic targets.

Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling.

Iron deposition in the brain is an early issue in Alzheimer's disease (AD). However, the pathogenesis of iron-induced pathological changes in AD remains elusive. Insulin resistance in brains is an essential feature of AD. Previous studies determined that insulin resistance is involved in the development of pathologies in AD. Tau pathology is one of most important hallmarks in AD and is associated with the impairment of cognition and clinical grades of the disease. In the present study, we observed that ferrous (Fe2+) chloride led to aberrant phosphorylation of tau, and decreased tyrosine phosphorylation levels of insulin receptor ß (IRß), insulin signal substrate 1 (IRS-1) and phosphoinositide 3-kinase p85α (PI3K p85α), in primary cultured neurons. In the in vivo studies using mice with supplemented dietary iron, learning and memory was impaired. As well, hyperphosphorylation of tau and disrupted insulin signaling in the brain was induced in iron-overloaded mice. Furthermore, in our in vitro work we identified the activation of insulin signaling following exogenous supplementation of insulin. This was further attenuated by iron-induced hyperphosphorylation of tau in primary neurons. Together, these data suggest that dysfunctional insulin signaling participates in iron-induced abnormal phosphorylation of tau in AD. Our study highlights the promising role of insulin signaling in pathological lesions induced by iron overloading.

Circular RNAs: a rising star in respiratory diseases.

Circular RNAs (CircRNAs), as a new class of non-coding RNA molecules that, unlike linear RNAs, have covalently closed loop structures from the ligation of exons, introns, or both. CircRNAs are widely expressed in various organisms in a specie-, tissue-, disease- and developmental stage-specific manner, and have been demonstrated to play a vital role in the pathogenesis and progression of human diseases. An increasing number of recent studies has revealed that circRNAs are intensively associated with different respiratory diseases, including lung cancer, acute respiratory distress syndrome, pulmonary hypertension, pulmonary tuberculosis, and silicosis. However, to the best of our knowledge, there has been no systematic review of studies on the role of circRNAs in respiratory diseases. In this review, we elaborate on the biogenesis, functions, and identification of circRNAs and focus particularly on the potential implications of circRNAs in respiratory diseases.