Elevated Levels Of Inflammatory Mediators Research Articles

Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID.

A persistent state of inflammation has been reported during the COVID-19 pandemic. This study aimed to assess short-term heart rate variability (HRV), peripheral body temperature, and serum cytokine levels in patients with long COVID. We evaluated 202 patients with long COVID symptoms categorized them according to the duration of their COVID symptoms (≤120 days, n = 81; >120 days, n = 121), in addition to 95 healthy individuals selected as controls. All HRV variables differed significantly between the control group and patients with long COVID in the ≤120 days group (p < 0.05), and participants in the long COVID ≤120 days group had higher temperatures than those in the long COVID >120 days group in all regions analysed (p < 0.05). Cytokine analysis showed higher levels of interleukin 17 (IL-17) and interleukin 2 (IL-2), and lower levels of interleukin 4 (IL-4) (p < 0.05). Our results suggest a reduction in parasympathetic activation during long COVID and an increase in body temperature due to possible endothelial damage caused by the maintenance of elevated levels of inflammatory mediators. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 appear to constitute a long-term profile of COVID-19 cytokines, and these markers are potential targets for long COVID-treatment and prevention strategies.

Iron accumulation in ferroptosis and the role of lipid peroxidation in osteoarthritis

Ferroptosis is a recently discovered mode of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, which can reach lethal levels, but this process was found to be inhibited by ferroptosis inhibitor-specific reverse. Osteoarthritis (OA) is the most common degenerative joint disease characterized by complex pathogenesis including mechanical overload, elevated levels of inflammatory mediators, metabolic alterations, and cellular senescence and death. Since iron accumulation and oxidative stress are common pathological features of OA, the role of ferroptosis in OA has been extensively explored. Accumulating evidence indicates that iron homeostasis and lipid peroxidation are closely related to the pathogenesis of OA. This article will focus on the mechanisms of ferroptosis and the role of iron homeostasis and lipid peroxidation in the pathogenesis of OA, summarizing recent evidence.

Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model.

Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.

Plant Bioactives in the Treatment of Inflammation of Skeletal Muscles: A Molecular Perspective.

Skeletal muscle mass responds rapidly to growth stimuli, precipitating hypertrophies (increased protein synthesis) and hyperplasia (activation of the myogenic program). For ages, muscle degeneration has been attributed to changes in the intracellular myofiber pathways. These pathways are tightly regulated by hormones and lymphokines that ultimately pave the way to decreased anabolism and accelerated protein breakdown. Despite the lacunae in our understanding of specific pathways, growing bodies of evidence suggest that the changes in the myogenic/regenerative program are the major contributing factor in the development and progression of muscle wasting. In addition, inflammation plays a key role in the pathophysiology of diseases linked to the failure of skeletal muscles. Chronic inflammation with elevated levels of inflammatory mediators has been observed in a spectrum of diseases, such as inflammatory myopathies and chronic obstructive pulmonary disease (COPD). Although the pathophysiology of these diseases varies greatly, they all demonstrate sarcopenia and dysregulated skeletal muscle physiology as common symptoms. Medicinal plants harbor potential novel chemical moieties for a plenitude of illnesses, and inflammation is no exception. However, despite the vast number of potential antiinflammatory compounds found in plant extracts and isolated components, the research on medicinal plants is highly daunting. This review aims to explore the various phytoconstituents employed in the treatment of inflammatory responses in skeletal muscles, while providing an in-depth molecular insight into the latter.

Nucleic Acid-Based COVID-19 Therapy Targeting Cytokine Storms: Strategies to Quell the Storm.

Coronavirus disease 2019 (COVID-19) has shaken the world and triggered drastic changes in our lifestyle to control it. Despite the non-typical efforts, COVID-19 still thrives and plagues humanity worldwide. The unparalleled degree of infection has been met with an exceptional degree of research to counteract it. Many drugs and therapeutic technologies have been repurposed and discovered, but no groundbreaking antiviral agent has been introduced yet to eradicate COVID-19 and restore normalcy. As lethality is directly correlated with the severity of disease, hospitalized severe cases are of the greatest importance to reduce, especially the cytokine storm phenomenon. This severe inflammatory phenomenon characterized by elevated levels of inflammatory mediators can be targeted to relieve symptoms and save the infected patients. One of the promising therapeutic strategies to combat COVID-19 is nucleic acid-based therapeutic approaches, including microRNAs (miRNAs). This work is an up-to-date review aimed to comprehensively discuss the current nucleic acid-based therapeutics against COVID-19 and their mechanisms of action, taking into consideration the emerging SARS-CoV-2 variants of concern, as well as providing potential future directions. miRNAs can be used to run interference with the expression of viral proteins, while endogenous miRNAs can be targeted as well, offering a versatile platform to control SARS-CoV-2 infection. By targeting these miRNAs, the COVID-19-induced cytokine storm can be suppressed. Therefore, nucleic acid-based therapeutics (miRNAs included) have a latent ability to break the COVID-19 infection in general and quell the cytokine storm in particular.

Connexin43 inhibition attenuated dopaminergic neuronal loss in the lipopolysaccharide-induced mice model of Parkinson’s disease

Studies using in vitro Parkinson’s disease (PD) models have found that lipopolysaccharide (LPS) induced reduction of connexin 43 (Cx43) gap junction communication and elevation of hemichannel function, which could cause neurotoxicity directly and indirectly via excessive ATP and glutamate release. However, in vivo study about Cx43 expression and function, as well as the efficacy of Cx43 inhibition for neuronal survival in PD is lacking. This study aimed to unravel the role of Cx43 in PD and understand the underlying mechanisms using an in vivo PD model. Male C57BL/6 mice received intranigral injection of LPS (5 μg) and 43Gap27 (4 μg), a Cx43 inhibitor, simultaneously. Results showed that following LPS treatment, total Cx43 expression decreased by about 60%, but the relative level of phosphorylated Cx43 increased to about double that controls (all p < 0.05). The administration of 43Gap27 significantly attenuated the loss of dopaminergic neurons and restored dopamine and its metabolites levels. Moreover, 43Gap27 treatment inhibited intense microgliosis and astrogliosis in nigrostriatal system induced by LPS and also ameliorated elevated levels of inflammatory mediators. Interestingly, Cx43 inhibition also increased nerve growth factors. In conclusion, Cx43 inhibition was able to prevent LPS-mediated dopaminergic neuronal death, possibly via neuroinflammation reaction reduction and neurotrophic factors elevation. Therefore, Cx43 may be a promising therapeutic target for degenerative neurological disorders such as PD.

Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

Major depressive disorder is a debilitating disorder affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention. Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression. However, less is known about potential interaction between BDNF and inflammation, particularly within the central nervous system. Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and anti-depressant response. Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF, and BDNF may play an important negative regulatory role on inflammation within the brain. Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities. Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.

Immune Profiling of COVID-19 in Correlation with SARS and MERS.

Acute respiratory distress syndrome (ARDS) is a major complication of the respiratory illness coronavirus disease 2019, with a death rate reaching up to 40%. The main underlying cause of ARDS is a cytokine storm that results in a dysregulated immune response. This review discusses the role of cytokines and chemokines in SARS-CoV-2 and its predecessors SARS-CoV and MERS-CoV, with particular emphasis on the elevated levels of inflammatory mediators that are shown to be correlated with disease severity. For this purpose, we reviewed and analyzed clinical studies, research articles, and reviews published on PubMed, EMBASE, and Web of Science. This review illustrates the role of the innate and adaptive immune responses in SARS, MERS, and COVID-19 and identifies the general cytokine and chemokine profile in each of the three infections, focusing on the most prominent inflammatory mediators primarily responsible for the COVID-19 pathogenesis. The current treatment protocols or medications in clinical trials were reviewed while focusing on those targeting cytokines and chemokines. Altogether, the identified cytokines and chemokines profiles in SARS-CoV, MERS-CoV, and SARS-CoV-2 provide important information to better understand SARS-CoV-2 pathogenesis and highlight the importance of using prominent inflammatory mediators as markers for disease diagnosis and management. Our findings recommend that the use of immunosuppression cocktails provided to patients should be closely monitored and continuously assessed to maintain the desirable effects of cytokines and chemokines needed to fight the SARS, MERS, and COVID-19. The current gap in evidence is the lack of large clinical trials to determine the optimal and effective dosage and timing for a therapeutic regimen.

Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis.

Epileptic seizure-induced brain injuries include activation of neuroimmune response with activation of microglia, astrocytes cells releasing neurotoxic inflammatory mediators underlies the pathophysiology of epilepsy. A wide spectrum of neuroinflammatory pathways is involved in neurodegeneration along with elevated levels of inflammatory mediators indicating the neuroinflammation in the epileptic brain. Therefore, the neuroimmune response is commonly observed in the epileptic brain, indicating elevated cytokine levels, providing an understanding of the neuroinflammatory mechanism contributing to seizures recurrence. Clinical and experimental-based evidence suggested the elevated levels of cytokines responsible for neuronal excitation and blood-brain barrier (BBB) dysfunctioning causing the drug resistance in epilepsy. Therefore, the understanding of the pathogenesis of neuroinflammation in epilepsy, including migration of microglial cells releasing the inflammatory cytokines indicating the correlation of elevated levels of inflammatory mediators (interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) triggering the generation or recurrence of seizures. The current review summarized the knowledge regarding elevated inflammatory mediators as immunomodulatory response correlating multiple neuroinflammatory NF-kB, RIPK, MAPK, ERK, JNK, JAK-STAT signaling cascades in epileptogenesis. Further selective targeting of inflammatory mediators provides beneficial therapeutic strategies for epilepsy.

Emerging perspectives on mitochondrial dysfunctioning and inflammation in epileptogenesis.

Mitochondrial dysfunction is a common denominator of neuroinflammation recognized by neuronal oxidative stress-mediated apoptosis that is well recognized by common intracellular molecular pathway-interlinked neuroinflammation and mitochondrial oxidative stress, a feature of epileptogenesis. In addition, the neuronal damage in the epileptic brain corroborated the concept of brain injury-mediated neuroinflammation, further providing an interlink between inflammation, mitochondrial dysfunction, and oxidative stress in epilepsy. A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to provide evidence of preclinical and clinically used drugs targeting such nuclear, cytosolic, and mitochondrial proteins suggesting that the correlation of mechanisms linked to neuroinflammation has been elucidated in the current review. Despite that, the evidence of elevated levels of inflammatory mediators and pro-apoptotic protein levels can provide the correlation of inflammatory responses often concerned with hyperexcitability attributing to the fact that mitochondrial redox mechanisms and higher susceptibilities to neuroinflammation result from repetitive recurring epileptic seizures. Therefore, providing an understanding of seizure-induced pathological changes read by activating neuroinflammatory cascades like NF-kB, RIPK, MAPK, ERK, JNK, and JAK-STAT signaling further related to mitochondrial damage promoting hyperexcitability. The current review highlights the further opportunity for establishing therapeutic interventions underlying the apparent correlation of neuroinflammation mediated mitochondrial oxidative stress might contribute to common intracellular mechanisms underlying a future prospective of drug treatment targeting mitochondrial dysfunction linked to the neuroinflammation in epilepsy.

SO023HEPATOCYTE GROWTH FACTOR (HGF) PRECLUDE HIGH-FAT DIET-INDUCED OBESITY AND IMPROVED INSULIN RESISTANCE IN MICE

Abstract Background and Aims Obesity and its associated chronic inflammation in adipose tissue initiate insulin resistance, which is related to several pathologies including hypertension and atherosclerosis. Previous reports demonstrated that circulating hepatocyte growth factor (HGF) level was associated with obesity and type 2 diabetes. However, its precise role in obesity and related-pathology is unclear. Method In this experiment, cardiac-specific over-expression of human HGF in mice (HGF-Tg mice) which showed 4-5 times higher serum HGF levels than wild-type mice were used. We chose cardiac specific HGF overexpression, as other strain of HGF transgenic mice such as liver and kidney specific HGF overexpression mice develop cancer and cystic diseases, which are rare in the heart. In the present study, using HGF-Tg mice and anti-HGF neutralizing antibody (HGF-Ab), we explored the role of HGF in obese and insulin resistance induced by high fat diet (HFD) for 14 weeks (200 or 400ug/week). Results With normal chow diet (ND), there were no significant changes in body weight between WT and HGF-Tg mice. While body weight in wild-type mice fed with HFD for 14 weeks was significantly increased accompanied with insulin resistance, HGF-Tg mice prevented body weight gain and insulin resistance. Insulin resistance in obesity arises from the combination of altered functions of insulin target cells (e.g., liver, skeletal muscle, and adipose tissue) and the accumulation of macrophages that secrete pro-inflammatory mediators in adipose tissue. The accumulation of macrophages and elevated levels of inflammatory mediators in adipose tissue were significantly inhibited in HGF-Tg mice as compared to wild-type mice. In the gWAT, the mRNA levels of the mature macrophage marker F4/80, the chemoattractants, MCP-1 and CXCL2, and the inflammatory cytokines, such as TNF-α and iNOS, were significantly increased in WT mice fed with HFD. However, these levels were markedly reduced in HGF-Tg mice fed with HFD. Additionally, activation of Akt by insulin administration was significantly reduced in the gWAT SM, and liver by HFD; however, this activation was restored in HGF-Tg mice. Moreover, insulin-induced Akt signaling was decreased in HGF-Ab groups as compared to saline group under HFD condition. Importantly, HFD significantly increased the level of HGF mRNA by approximately 2 fold in gWAT, SM, and liver without changing cMet expression. All together, these data indicate that the HGF as one of the systemic gWAT, SM, and liver-derived growth factor plays a role in compensatory mechanism against insulin-resistance through the at least anti-inflammatory effect in adipose tissue. The HFD-induced obesity in wild-type mice treated with HGF-neutralizing antibody showed an exacerbated response to the glucose tolerance test. Conclusion HGF suppresses inflammation in adipose tissue induced by a high-fat diet, and as a result improves systemic insulin resistance. These gain-of-function and loss-of-function studies demonstrated that the elevated HGF level induced by HFD have protective role against obesity and insulin resistance.

Inhibition of CD44 induces apoptosis, inflammation, and matrix metalloproteinase expression in tendinopathy

Apoptosis has emerged as a primary cause of tendinopathy. CD44 signaling pathways exert anti-apoptotic and -inflammatory effects on tumor cells, chondrocytes, and fibroblast-like synoviocytes. The aim of this study was to examine the association among CD44, apoptosis, and inflammation in tendinopathy. Expression of CD44 and apoptotic cell numbers in tendon tissue from patients with long head of biceps (LHB) tendinopathy were determined according to the histological grades of tendinopathy. Primary tenocytes from Achilles tendon of Sprague-Dawley rats 1 week after collagenase injection were cultured with an antagonizing antibody against CD44. Treatment responses were determined by evaluating cell viability and expression of tendon-related proliferation markers, inflammatory mediators, and apoptosis. The expression of CD44 and apoptosis were positively correlated with the severity of tendinopathy in the human LHB tendinopathy. Furthermore, CD44 expression and apoptotic cells were co-stained in tendinopathic tendon. Blocking the CD44 signaling pathways in rat primary tenocytes by OX-50 induced cell apoptosis and the elevated levels of cleaved caspase-3. Furthermore, they had decreased cell viability and expression of collagen type I, type III, tenomodulin, and phosphorylated AKT. In contrast, there were elevated levels of inflammatory mediators, including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cyclooxygenase-2, and phosphorylated NF-κB, as well as matrix metalloproteinase (MMP) family members including MMP-1, -3, -9, and -13 in tenocytes upon OX-50 treatment. This study is the first to demonstrate the association of CD44 and apoptosis in tendinopathy. Our data imply that CD44 may play a role in tendinopathy via regulating apoptosis, inflammation, and extracellular matrix homeostasis.

RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that is associated with significantly high mortality. In spite of advances in IBC diagnoses, the prognosis is still poor compared to non-IBC. Due to the aggressive nature of the disease, we hypothesize that elevated levels of inflammatory mediators may drive tumorigenesis and metastasis in IBC patients. Utilizing IBC cell models and patient tumor samples, we can detect elevated NF-κB activity and hyperactivation of non-canonical drivers of NF-κB (nuclear factor kappaB)-directed inflammation such as tyrosine phosphorylated receptor-interacting protein kinase 2 (pY RIPK2), when compared to non-IBC cells or patients. Interestingly, elevated RIPK2 activity levels were present in a majority of pre-chemotherapy samples from IBC patients at the time of diagnosis to suggest that patients at diagnosis had molecular activation of NF-κB via RIPK2, a phenomenon we define as “molecular inflammation”. Surprisingly, chemotherapy did cause a significant increase in RIPK2 activity and thus molecular inflammation suggesting that chemotherapy does not resolve the molecular activation of NF-κB via RIPK2. This would impact on the metastatic potential of IBC cells. Indeed, we can demonstrate that RIPK2 activity correlated with advanced tumor, metastasis, and group stage as well as body mass index (BMI) to indicate that RIPK2 might be a useful prognostic marker for IBC and advanced stage breast cancer.

Unexpectedly decreased plasma cytokines in patients with chronic back pain

IntroductionChronic back pain is one of the most important socioeconomic problems that affects the global population. Elevated levels of inflammatory mediators, such as cytokines, have been correlated with pain, but their role in chronic back pain remains unclear. The effectiveness of anti-inflammatory drugs seems to be limited for chronic back pain. The authors wanted to investigate the levels of inflammatory mediators in long-term medically treated patients with persistent chronic back pain.MethodsCytokine plasma levels of patients with chronic back pain (n=23), compared to pain-free healthy controls (n=30), were investigated by immunoassay. Patients with chronic back pain were exposed to long-term conservative medical therapy with physiotherapy and anti-inflammatories, also combined with antidepressants and/or muscle-relaxants.ResultsThe patients with chronic back pain expressed lower levels of the chemokines MCP1, CCL5, and CXCL6 compared to pain-free healthy controls. Significantly lower concentrations of the anti-inflammatory cytokines, interleukin (IL)-4 and granulocyte-colony stimulating factor were also found. Interestingly, levels of proinflammatory cytokines (IL-2, IL-6, IL-1β, tumor necrosis factor alpha), IL-10, granulocyte-macrophage colony-stimulating factor, and stromal cell-derived factor 1 alpha showed no significant differences between both groups.ConclusionThis decrease of inflammatory mediators in medically treated patients with chronic back pain is of unclear origin and might be either a long-term side effect of medical therapy or related to chronic pain. Further longitudinal research is necessary to elucidate the underlying cause of these findings.

The Role of Toll-Like Receptor Signaling in the Progression of Heart Failure.

Medical systems worldwide are being faced with a growing need to understand mechanisms behind the pathogenesis of heart failure (HF) that is considered as a leading cause of morbidity and mortality around the world. Elevated levels of inflammatory mediators have been identified in patients with HF, which are primarily manifestations of innate immune responses mediated by pattern recognition receptors (PRRs). Toll-like receptors (TLRs), which belong to PRRs, are subjected to the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to generate innate immune responses. More and more emerging data indicate that TLR signaling pathway molecules are involved in the progression of HF. Herein, we present new data with regard to the activation of TLRs in the failing heart, focusing on TLR2, TLR3, TLR4, and TLR9, and suggest the potential use of TLRs in target therapy.

Neuroinflammation in Amyotrophic Lateral Sclerosis: Role of Redox (dys)Regulation.

Amyotrophic lateral sclerosis (ALS) is due to degeneration of upper and lower motor neurons in the anterior horn of the spinal cord and in the motor cortex. Mechanisms leading to motor neuron death are complex and currently the disease is untreatable. Recent Advances: Work in genetic models of ALS indicates that an imbalance in the cross talk that physiologically exists between motor neurons and the surrounding cells is eventually detrimental to motor neurons. In particular, the cascade of events collectively known as neuroinflammation and mainly characterized by a reactive phenotype of astrocytes and microglia, moderate infiltration of peripheral immune cells, and elevated levels of inflammatory mediators has been consistently observed in motor regions of the central nervous system (CNS) in sporadic and familial ALS, constituting a hallmark of the disease. Resident glial cells and infiltrated immune cells are considered among the major producers of reactive species of oxygen and nitrogen in pathological conditions of the CNS, including motor neuron diseases. The timing and exact role of oxidative stress-mediated neuroinflammation and damage to motor neurons in ALS are still not fully elucidated. It is clear that a major challenge in the next future will be to envisage effective strategies to modulate the neuroinflammatory response in the symptomatic stage of disease, to prevent progression of neurodegeneration through the propagation of oxidative damage. Antioxid. Redox Signal. 29, 15-36.

Emerging role of Interleukins IL-23/IL-17 axis and biochemical markers in the pathogenesis of Type 2 Diabetes: Association with age and gender in human subjects

Chronic hyperglycaemia in type 2 diabetes (T2D) is associated with increased oxidative stress and inflammation. Keeping the above fact into consideration we analyse the effect of age and gender on oxidative stress biomarkers and pro-inflammatory cytokines in T2D patients. The study included 148 diabetic and 110 healthy subjects, grouped on the basis of age and gender. Plasma malondialdehyde, protein carbonyl content and nitric oxide levels were elevated significantly in diabetic patients, with significant decrease in Ferric reducing ability of plasma, vitamin C, reduced glutathione, erythrocyte thiol groups and erythrocyte antioxidant enzyme activity and these changes were even more pronounced as age progressed. Serum IL-1β, IL-6, IL-17A, IL-22 levels and TNF-α mRNA expression was significantly upregulated in all the age groups whereas IL-23 mRNA was upregulated only in the higher age group. Female diabetic patients experienced higher oxidative stress and greater serum IL-6 levels and TNF-α mRNA expression as compared to their male counterparts. This study suggested that diabetes onset is accompanied with increased oxidative stress and elevated levels of inflammatory mediators. The effect was more prominent in aged patients. Female patients experienced greater oxidative stress as compared to males of those age groups with slightly higher levels of inflammatory cytokines.

Hepatocyte Growth Factor Prevented High-Fat Diet-Induced Obesity and Improved Insulin Resistance in Mice

Obesity and its associated chronic inflammation in adipose tissue initiate insulin resistance, which is related to several pathologies including hypertension and atherosclerosis. Previous reports demonstrated that circulating hepatocyte growth factor (HGF) level was associated with obesity and type 2 diabetes. However, its precise role in obesity and related-pathology is unclear. In this experiment, cardiac-specific over-expression of human HGF in mice (HGF-Tg mice) which showed 4–5 times higher serum HGF levels than wild-type mice were used. While body weight in wild-type mice fed with high fat diet (HFD) for 14 weeks was significantly increased accompanied with insulin resistance, HGF-Tg mice prevented body weight gain and insulin resistance. The accumulation of macrophages and elevated levels of inflammatory mediators in adipose tissue were significantly inhibited in HGF-Tg mice as compared to wild-type mice. The HFD-induced obesity in wild-type mice treated with HGF-neutralizing antibody showed an exacerbated response to the glucose tolerance test. These gain-of-function and loss-of-function studies demonstrated that the elevated HGF level induced by HFD have protective role against obesity and insulin resistance.

Salivary and serum inflammatory mediators among pre-conception women with periodontal disease.

BackgroundThere have been inconsistent conclusions regarding the levels of inflammatory mediators in saliva and serum among people with or without periodontal disease. Although pre-conception has been put forward as the optimal time for the periodontal treatment in order to improving pregnancy outcomes, few studies have been conducted to examine inflammatory mediators in saliva and serum among pre-conception women.MethodsPre-conception women were recruited between January 2012 and December 2014. Women were provided with an oral health examination to detect periodontal disease. Salivary and serum samples were collected at the same of examination. Inflammatory mediators includinginterleukin-1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α) and beta-glucuronidase (β–glucuronidase) were tested and analyzed among women with overall periodontal disease (n = 442) or moderate/severe periodontal disease (n = 247). Results were compared to that in women with a healthy periodontium (n = 91).ResultsSignificantly increased concentrations of inflammatory mediators of IL-1β, IL-6, TNF-α and β-glucuronidase in saliva and IL-1β, β-glucuronidase and TNF-α in serum were found among pre-conception women with moderate/severe periodontal disease, compared with women without periodontal disease. Significantly increased levels were also found in all the above saliva inflammatory mediators and in serum IL-1β and TNF-α among women with overall periodontal disease. The levels of all inflammatory mediators in saliva and almost all inflammatory mediators except IL-6 in serum significantly increased with severity of periodontal disease.ConclusionPeriodontal disease is highly associated with the elevated levels of inflammatory mediators in saliva and some mediators in serum among pre-conception women.

Intra-amygdala microinfusion of neuropeptide S attenuates neuropathic pain and suppresses the response of spinal microglia and astrocytes after spinal nerve ligation in rats

The amygdala circuitry and neuropeptide S (NPS) have been shown to play an important role in the pain modulation. However, the alleviative effect of NPS in amygdala on neuropathic pain (NP) is not fully understood. Here, we demonstrate a possibility that the intra-amygdala microinfusion of NPS attenuates NP symptoms and suppresses the response of spinal microglia and astrocytes after spinal nerve injury. Spinal nerve ligation (SNL) in rats resulted in a striking decline in level of NPS and density of NPS-immunopositive cells in amygdala. SNL rats randomly received chronic bilateral microinjections of NPS (1, 10 and 100pmol/side) or saline into the amygdala via cannulas on days 3, 6, 9, 12, 15 and 18 post-surgery. Chronic treatment with NPS increased thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) on day 11–21 post-SNL. The simultaneous treatment with SHA68 as non-peptide NPS receptor antagonist decreased the TWL and MWT, and reversed the inhibitory effects of NPS in SNL rats. NPS also significantly attenuated immunoreactivities of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein for microglia and astrocytes. Furthermore, the elevated levels of inflammatory mediators and expressions of nuclear factor κB p65 and CX3C chemokine receptor 1 due to SNL were significantly attenuated by NPS in amygdala. These effects of NPS were also counteracted by SHA 68. SHA 68 per se deteriorated the symptom of NP and the response of spinal microglia and astrocytes in SNL rats. Our study identified a protective role for NPS in amygdala against the development of NP, possibly attributing to its anti-inflammatory activity and inhibition of spinal microglia and astrocytes.