Inhibition Of Pro-inflammatory Pathways Research Articles

Microbial-Based Bioactive Compounds to Alleviate Inflammation in Obesity.

The increased prevalence of obesity with several other metabolic disorders, including diabetes and non-alcoholic fatty liver disease, has reached global pandemic proportions. Lifestyle changes may result in a persistent positive energy balance, hastening the onset of these age-related disorders and consequently leading to a diminished lifespan. Although suggestions have been raised on the possible link between obesity and the gut microbiota, progress has been hampered due to the extensive diversity and complexities of the gut microbiota. Being recognized as a potential biomarker owing to its pivotal role in metabolic activities, the dysregulation of the gut microbiota can give rise to a persistent low-grade inflammatory state associated with chronic diseases during aging. This chronic inflammatory state, also known as inflammaging, induced by the chronic activation of the innate immune system via the macrophage, is controlled by the gut microbiota, which links nutrition, metabolism, and the innate immune response. Here, we present the functional roles of prebiotics, probiotics, synbiotics, and postbiotics as bioactive compounds by underscoring their putative contributions to (1) the reduction in gut hyperpermeability due to lipopolysaccharide (LPS) inactivation, (2) increased intestinal barrier function as a consequence of the upregulation of tight junction proteins, and (3) inhibition of proinflammatory pathways, overall leading to the alleviation of chronic inflammation in the management of obesity.

Stem cell secretome-mediated alleviation of scalp psoriasis: A case report

Scalp psoriasis, a skin condition characterized by red, thickened (erythematous), well-demarcated patches or plaques with overlying silvery-white scales, affecting part or all of the scalp, is an autoimmune disease accompanied by itchy skin. The disease is associated with faulty functioning of adaptive and innate components of immune systems. The key proinflammatory cytokines mediating immunopathology of psoriasis are IL-17 and IL-23 which promote proliferation of Th 17 cells which in turn induce proliferation of keratinocytes leading to the disease. Standard management of psoriasis primarily targets the disease by suppression of inflammation using steroid based drugs. However, these are not enough to cure the disease. In recent years researchers have demonstrated the use of mesenchymal stem cells (MSCs) in treating autoimmune disorders and skin disorders. MSCs mediate skin regeneration by a plethora of mechanisms including immune modulation, angiogenesis, proliferation of mediator cells like fibroblasts, and by inhibition of proinflammatory pathways. The paracrine factors secreted by MSCs in surrounding environment like growth factors, cytokines, chemokines, and other signaling and regulatory molecules, act as key molecules in mediating anti-inflammatory responses. Here we describe a case report following the treatment of a patient suffering from scalp psoriasis using MSC- secreted molecules in the conditioned media. Both silvery scales and plaques on the scalp were significantly reduced within 4 weeks of topical application of the conditioned media. The patient remained disease free for 3 years of follow up. Our current results are in good agreement with those of our previous report where we reported complete amelioration of scalp psoriasis following the topical application of the conditioned media.

Transcriptomic Analysis of Ovine Hepatic Lymph Node Following Fasciola hepatica Infection - Inhibition of NK Cell and IgE-Mediated Signaling.

Fasciola hepatica is a trematode parasite responsible for major economic losses in livestock production, and is also a food-borne zoonotic agent in developing rural regions. For years, the immunoregulatory mechanisms employed by the parasite have hampered efforts to develop a successful vaccine candidate. Given that a comprehensive understanding of the immune response to infection is needed, we investigated the gene expression changes in ovine hepatic lymph nodes after experimental infection with F. hepatica. Lymph nodes from uninfected and infected animals were processed for RNA sequencing (RNA-seq) at 16 weeks post-infection. Comparison of groups revealed 5,132 differentially-expressed genes (DEGs). An inhibition of pro-inflammatory pathways, which has previously been described during fasciolosis, was evident in our data. However, other signals previously identified in ruminant peripheral blood mononuclear cells (PBMC) or liver tissue, such as activation of TGF-β or apoptosis-related pathways were not detected. We found inhibition of some key immunological pathways, including natural killer (NK) cell activity and IgE-mediated signaling. These may point to additional some as yet unrecognized mechanisms employed by the parasite to evade the host immune response. Understanding these, and leveraging information from this and other omics studies, will be important for the development of future vaccine prototypes against this parasite.

Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro.

Respiratory syncytial virus (RSV) is a leading cause of hospitalization of infants and young children, causing considerable respiratory disease and repeat infections that may lead to chronic respiratory conditions such as asthma, wheezing, and bronchitis. RSV causes ∼34 million new episodes of lower respiratory tract illness (LRTI) in children younger than 5 years of age, with >3 million hospitalizations due to severe RSV-associated LRTI. The standard of care is limited to symptomatic relief as there are no approved vaccines and few effective antiviral drugs; thus, a safe and efficacious RSV therapeutic is needed. Therapeutic targeting of host proteins hijacked by RSV to facilitate replication is a promising antiviral strategy as targeting the host reduces the likelihood of developing drug resistance. The nuclear export of the RSV M protein, mediated by the nuclear export protein exportin 1 (XPO1), is crucial for RSV assembly and budding. Inhibition of RSV M protein export by leptomycin B correlated with reduced RSV replication in vitro In this study, we evaluated the anti-RSV efficacy of Verdinexor (KPT-335), a small molecule designed to reversibly inhibit XPO1-mediated nuclear export. KPT-335 inhibited XPO1-mediated transport and reduced RSV replication in vitro KPT-335 was effective against RSV A and B strains and reduced viral replication following prophylactic or therapeutic administration. Inhibition of RSV replication by KPT-335 was due to a combined effect of reduced XPO1 expression, disruption of the nuclear export of RSV M protein, and inactivation of the NF-κB signaling pathway.IMPORTANCE RSV is an important cause of LRTI in infants and young children for which there are no suitable antiviral drugs offered. We evaluated the efficacy of KPT-335 as an anti-RSV drug and show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and reduction in RSV levels. KPT-335 treatment also resulted in inhibition of proinflammatory pathways, which has important implications for its effectiveness in vivo.

Cell and molecular mechanisms behind diet-induced hypothalamic inflammation and obesity.

Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus, a key regulator of energy homeostasis. Current studies have revealed the involvement of different cell types, as well as cell and molecular mechanisms, that contribute to diet-induced hypothalamic inflammation (DIHI) and DIO. Subsequent to the discovery that high-fat diet and saturated fatty acids increase the expression of hypothalamic cytokines prior to weight gain, research has focused on understanding the cellular and molecular mechanisms underlying these changes, in addition to the role of inflammation in the pathogenesis of obesity. Recent studies have proposed that the inhibition of pro-inflammatory pathways in microglia and astrocytes is sufficient to protect against DIHI and prevent obesity. In addition, impairment of intracellular and epigenetic mechanisms, such as hypothalamic autophagy and changes in the methylation pattern of certain genes, have been implicated in susceptibility to DIHI and DIO. Interestingly, a sexual dimorphism has been found during DIO in hypothalamic inflammation, glial activation and metabolic diseases, and recent data support an important role of sex steroids in DIHI. These new exciting findings uncover novel obesity pathogenic mechanisms and provide targets to develop therapeutic approaches.

Antimutagenic and cancer preventive potential of culinary spices and their bioactive compounds

Spices significantly contribute to human health through their bioactives. They exert multiple health-beneficial influences including anti-cancer potential. Among natural chemopreventive bioactives capable of inhibiting, retarding, or reversing the multi-stage carcinogenesis, considerable attention has been focused in recent decades on spice derived phytochmicals. Spices with proven anticarcinogenic effects in animal models of cancer include turmeric, garlic, ginger, and black cumin. These spices showed chemopreventive effects against cancers of the skin, forestomach, pancreas, liver, colon, and oral cancer in experimental models. Bioactives of these spices reduce oxidative stress by decreasing free radicals concentration, impede cell division and promote apoptosis in cancerous cells. Additionally, they regulate inflammation and immunocompetence, contributing to cancer prevention. The anticancer potential of curcumin has also been evidenced in clinical studies. Curcumin of turmeric is understood to impede carcinogenesis at all three stages. Curcumin’s anticarcinogenic effect is partly mediated through its inhibition of the transcription factor NFkB and inhibition of proinflammatory pathways. Curcumin induces apoptosis, suppress proliferation and angiogenesis. Use of spices as food adjuncts is a promising approach to reduce the risk of cancer. Although the cancer preventive effects have not been conclusively proven in humans, these spices deserve to be considered as nutraceuticals for deriving anticancer influences.

Inhibition of proinflammatory pathways by bioactive fraction of Tinospora cordifolia.

Tinospora cordifolia (Willd.) Miers ex Hook. f. & Thomson, a known immunomodulatory agent extensively used in ayurveda, has not been effectively validated for the mechanisms involved in immunomodulation and the identification of the active principles. The bioactive fraction of T. cordifolia (TBF) in methanol was used for nitric oxide (NO) radical scavenging activity, lipoxygenase (LOX) and cyclooxygenase (COX) dual inhibition and cytotoxicity studies. Production of the proinflammatory cytokines, tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in dendritic cell (DC) suspensions treated with lipopolysaccharide (LPS) was also studied. The bioactive principles involved were identified with ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometric (UPLC-Q-ToF MS/MS) system. The results indicate significantly higher potency of TBF as compared to positive standards for LOX/COX inhibition with moderate NO radical scavenging activity and the fraction was also found to be non-cytotoxic to monocyte cells. A significant inhibition was also observed in TNF-α and IL-1β production in LPS-treated DC suspensions as compared to standards, rolipram and dexamethasone, respectively. 11 compounds were identified from TBF by MS/MS system. The potent inhibition of LOX and COX enzymes with moderate NO scavenging was indicative of a free radical scavenging-independent mechanism of immunomodulation. Further investigations into the active principles identified would result in the development of lead candidates with potent therapeutic implications.

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

Microglia is the resident innate immune cells that sense pathogens and tissue injury in the central nervous system. Microglia becomes activated in response to injury, infection, and other stimuli that threaten neuronal survival. Microglia activation plays an important role in neurodegenerative diseases. Neochlorogenic acid (NCA) is a natural polyphenolic compound found in dried fruits and other plants. Although previous studies have shown that phenolic acids including NCA have outstanding antioxidant, antibacterial, antiviral, and antipyretic activities, there has not yet been investigated for anti-inflammatory effects. Therefore, for the first time we have examined the potential of NCA to inhibit microglial activation and pro-inflammatory responses in the brain. We found that lipopolysaccharide-induced inducible nitric oxide synthase, and cyclooxygenase-2 expression, and nitric oxide formation was suppressed by NCA in a dose-dependent manner in BV2 microglia. NCA also inhibited the production of pro-inflammatory mediators, tumor necrosis factor-α and interleukin-1 beta. Furthermore, phosphorylated nuclear factor-kappa B p65 and p38 mitogen-activated protein kinase activation were blocked by NCA. Taken together, these results suggest that NCA exerts neuroprotective effects through the inhibition of pro-inflammatory pathways in activated microglia.

Rheumatoid arthritis--a neuroendocrine immune disorder: glucocorticoid resistance, relative glucocorticoid deficiency, low-dose glucocorticoid therapy, and insulin resistance.

Neuroendocrine immunology owes much to the foresighted work of Philip S Hench, who together withEdward C Kendall and Tadeus Reichstein introduced glucocorticoids (GCs) into clinical medicine. Since the 1990s, more than 40 years after adding GC to the therapeutic armamentarium, important work has been carriedout to understand GC action. There were three major pathways of discoveries between 1990 and today. Firstly, the groups of George Chrousos and of Steven Lamberts defined hereditary GC resistance due to abnormalities of the GC receptor (first reviewed in [1,2]). While genetically determined alterations of the GCreceptor were rare in the population, inflammation induced local GC receptor resistance became an important concept of inflammation research [3]. Th e concept gained momentum, particularly in asthma research. Indeed, the local proinflammatory load negatively influences anti-inflammatory GC action [3], but a workable therapeutic approach was not yet introduced into the rheumatology hospital. Secondly, several groups recognized inadequate secretion of GC in relation to inflammation (reviewed by Maurizio Cutolo and colleagues in this supplement). While an acute inflammatory trigger can increase GCserum levels, this response did not appear after repeated administration of the same trigger [4]. Several studies demonstrated that proinflammatory cytokines such asinterleukin-6, interferon alpha, interferon gamma, and others can stimulate the hypothalamic-pituitary-adrenal axis, but responses to repeated stimuli were much less pronounced. While inadequacy of GC secretion is typical for most active inflammatory diseases, the phenomenon can exist for a long time beyond acute inflammation control (that is, imprinting). In such a situation, long-term therapy with low-dose GC must be recognized as a supplementary therapy for the adrenal glands. Indeed, between 1990 and today the outstanding role of low-dose GC (approximately 5 mg/day) was discoveredin rheumatoid arthritis (RA) patients using placebo-controlled randomized clinical trials, as summarized in this supplement by Marlies van der Goes and colleagues. In an unstressed individual, the usual daily production of endogenous cortisol mounts to 5.7 mg/m2 (depending on body surface, ≈10 to 14 mg/day) [5], which equals 2.5 to 3.5 mg prednisolone/day. Thus, under real-life conditions, doses of prednisolone between 2 and 5 mg/day represent an adrenocortical substitution therapy. Importantly, low-dose GC has disease-modifying antirheumatic drug effects as demonstrated in this supplement. Thirdly, timing of daily GC administration reached a new level of precision with a clear pathophysiological concept (reviewed by Cornelia Spies and colleagues). In the early days of GC therapy, doctors and patientsexperienced that GC administration in the evening can sometimes have beneficial effects the following morning. However, these positive effects were accompanied by GC-induced sleep disturbances during the early night. Driven by RA patients' experiences, Arvidson and colleagues overcame this problem by administering GCat 2:00 a.m., and observed a highly beneficial effect in the morning [6]. A more sophisticated method of GC administration was developed during the 2000s - modified GC release, which makes use of GC-loaded pills taken at bedtime and showing abrupt GC release at 2:00 a.m. Under these conditions, GC release occurs at a time when endogenous inflammatory pathways are switched on in a circadian manner [7]. Th e positive effects of nightly GC therapy, as demonstrated in RA[8,9], are due to immediate inhibition of proinflammatory pathways in the increasing flank of nightly inflammation induction [7]. Finally, this supplement presents an article on insulin resistance in chronic inflammatory systemic diseases. While it seems, at first glance, that GCs are not related toinsulin resistance, it turns out that the hypothalamic-pituitary-adrenal axis and thus endogenous GC play an important role in inducing insulin resistance. Pleaserecall that GC can induce elevated levels of glucose, freefatty acids, and glucogenic amino acids in a physiological setting. Insulin resistance is a common phenomenon of physiological states, disease states, and diseases. Th is resistance typically appears in patients with diabetes mellitus, obesity, infection, sepsis, arthritis of different types (including RA), systemic lupus erythematosus, ankylosing spondylitis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, and mental stress. By presenting an integrated theory on insulin resistance, Straub puts forward the concept that insulin resistance is an evolutionarily positively selected program of an activated selfish brain or a stimulated selfish immune system. Long-term use of this adaptive program during chronic activation of the brain or the immune system turns out to be a misguided program that perpetuates the disease process.

233 ERYTHROPOIETIN ATTENUATES CARDIAC DYSFUNCTION IN EXPERIMENTAL SEPSIS VIA ACTIVATION OF THE Β-COMMON RECEPTOR

Rationale There is limited evidence that the tissue-protective effects of erythropoietin are mediated by a heterocomplex of the erythropoietin-receptor and the β-common receptor (‘tissue-protective receptor9), which is pharmacologically distinct from the ‘classical9 erythropoietin-receptor homodimer responsible for erythropoiesis. However, the role of the β-common receptor and/or erythropoietin in sepsis-induced cardiac dysfunction (a well known, serious complication of sepsis) is unknown. Here we report for the first time that β-common receptor is essential for the improvements in the impaired systolic contractility afforded by erythropoietin in experimental sepsis. Methods and Results Cardiac function was assessed in vivo (echocardiography) and ex vivo (Langendorff-perfused heart) in wild-type and β-common receptor knock-out mice, that were subjected to lipopolysaccharide (9 mg/kg; young mice) for 16–18 h or cecal ligation and puncture (aged mice) for 24 h. Mice received erythropoietin (1000 IU/kg) 1 h after lipopolysaccahride or cecal ligation and puncture. Erythropoietin reduced the impaired systolic contractility ( in vivo and ex vivo ) caused by endotoxemia/sepsis in young as well as old wild-type mice in a β-common receptor-dependent fashion. Activation by erythropoietin of the β-common receptor also resulted in the activation of well-known survival pathways (Akt and endothelial nitric oxide synthase) and inhibition of pro-inflammatory pathways (glycogen synthase kinase-3β, nuclear factor-κB and interleukin-1β). All the above pleitropic effects of erythropoietin were lost inβ-common receptor knock-out mice. Conclusions Erythropoietin attenuates the impaired systolic contractility associated with sepsis by activation of the β-common receptor, which in turn, results in activation of survival pathways and inhibition of inflammation. Thus, targeting the 9tissue protective receptor9 with specific agonists devoid of the erythropoietic effects of erythropoietin may represent a novel approach for the treatment of sepsis-associated cardiac dysfunction. *AIK and SMC contributed equally to this study.

Erythropoietin attenuates cardiac dysfunction in experimental sepsis in mice via activation of the β-common receptor

SUMMARYThere is limited evidence that the tissue-protective effects of erythropoietin are mediated by a heterocomplex of the erythropoietin receptor and the β-common receptor (‘tissue-protective receptor’), which is pharmacologically distinct from the ‘classical’ erythropoietin receptor homodimer that is responsible for erythropoiesis. However, the role of the β-common receptor and/or erythropoietin in sepsis-induced cardiac dysfunction (a well known, serious complication of sepsis) is unknown. Here we report for the first time that the β-common receptor is essential for the improvements in the impaired systolic contractility afforded by erythropoietin in experimental sepsis. Cardiac function was assessed in vivo (echocardiography) and ex vivo (Langendorff-perfused heart) in wild-type and β-common receptor knockout mice, that were subjected to lipopolysaccharide (9 mg/kg body weight; young mice) for 16–18 hours or cecal ligation and puncture (aged mice) for 24 hours. Mice received erythropoietin (1000 IU/kg body weight) 1 hour after lipopolysaccharide or cecal ligation and puncture. Erythropoietin reduced the impaired systolic contractility (in vivo and ex vivo) caused by endotoxemia or sepsis in young as well as old wild-type mice in a β-common-receptor-dependent fashion. Activation by erythropoietin of the β-common receptor also resulted in the activation of well-known survival pathways (Akt and endothelial nitric oxide synthase) and inhibition of pro-inflammatory pathways (glycogen synthase kinase-3β, nuclear factor-κB and interleukin-1β). All the above pleiotropic effects of erythropoietin were lost in β-common receptor knockout mice. Erythropoietin attenuates the impaired systolic contractility associated with sepsis by activation of the β-common receptor, which, in turn, results in activation of survival pathways and inhibition of inflammation.

Inflammatory Pathways Are Activated during Cardiomyocyte Hypertrophy and Attenuated by Peroxisome Proliferator-activated Receptors PPARα and PPARδ

Accumulating evidence indicates an important role for inflammation in cardiac hypertrophy and failure. Peroxisome proliferator-activated receptors (PPARs) have been reported to attenuate inflammatory signaling pathways and, as such, may interfere with cardiac remodeling. Accordingly, the objectives of the present study were to explore the relationship between cardiomyocyte hypertrophy and inflammation and to investigate whether PPARalpha and PPARdelta are able to inhibit NF-kappaB activation and, consequently, the hypertrophic growth response of neonatal rat cardiomyocytes (NCM). mRNA levels of markers of both hypertrophy and inflammation were increased following treatment with the pro-hypertrophic factor phenylephrine (PE) or the chemokine TNF-alpha. Induction of inflammatory genes was found to be fast (within 2 h after stimulation) and transient, while induction of hypertrophic marker genes was more gradual (peaking at 24-48 h). Inflammatory and hypertrophic pathways appeared to converge on NF-kappaB as both PE and TNF-alpha increased NF-kappaB binding activity as measured by electrophoretic mobility shift assay. Following transient transfection, the p65-induced transcriptional activation of a NF-kappaB reporter construct was significantly blunted after co-transfection of PPARalpha or PPARdelta in the presence of their respective ligands. Finally, adenoviral overexpression of PPARalpha and PPARdelta markedly attenuated cell enlargement and the expression of hypertrophic marker genes in PE-stimulated NCM. The collective findings reveal a close relationship between hypertrophic and inflammatory signaling pathways in the cardiomyocyte. It was shown that both PPARalpha and PPARdelta are able to mitigate cardiomyocyte hypertrophy in vitro by inhibiting NF-kappaB activation.