Production Of Pro-inflammatory Mediators Research Articles

Extrato de tarântula cubensis (Theranekron®) inibe a inflamação no edema induzido por algas vermelhas na pata de ratos

ABSTRACT The aim of this study was to investigate the anti-inflammatory effect of alcoholic extract of Tarantula cubensis alcoholic extract (TCAE) in experimentally induced inflammation in rats. Fifty-four adult Sprague-Dawley male rats were randomly divided into nine groups. Paw edema was induced by 0.2mL subplantar (s.p.) injection of 1% carrageenan (CAR) into the right hind paw. Rats were treated with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (INDO) (10mg/kg, p.o.) or TCAE at different doses (1, 10 or 100µg/kg) injected s.c. for systemic or s.p. for local anti-inflammatory effect. Saline was used as control. Changes in paw thickness, volume, and weight were calculated as percentages. Formalin-fixed paws were used for histopathological examination. We detected that TCAE applied s.c. at 10µg/kg and 100µg/kg doses resulted in thinner paw thickness, lower paw volume, and lower paw weights four hours after the induction of inflammation when compared with the INDO group (p<0.05). The paw edema inhibitory effect of TCAE applied at a dose of 10µg/kg, s.c. was 68% when compared with the INDO which had an inhibitory effect of 56%. These results were verified with similar histopathological findings. The anti-inflammatory feature of 10µg/kg of TCAE given systematically was similar to the effects of INDO. Our results suggest that TCAE has anti-inflammatory effects by reducing edema and decreasing inflammatory reaction. These results may be attributed to the inhibition of the production of proinflammatory mediators. Thus, TCAE may be considered as a potential anti-inflammatory agent for treating acute inflammatory conditions.

YES-10 Improves Stress, Tension, and Fatigue by Reducing Cortisol and IL-6 Levels.

The extract of Clematis mandshurica Rupr. (CMR) inhibits the production of proinflammatory mediators from lipopolysaccharide-stimulated peritoneal macrophages and concanavalin A-stimulated splenocytes. Erigeron annuus Pers. (EAP) extract suppresses the production of reactive oxygen species (ROS) from preadipocytes. Furthermore, the mixture of the leaf extracts of CMR and EAP, YES-10®, protected against nerve injuries induced by ischemia/reperfusion, suggesting a ROS-scavenging action. These observations show the anti-inflammatory action of YES-10. Inflammatory cytokines can cause alterations in mental function, including depression, by influencing the neurotransmitter system. Thus, it was hypothesized that YES-10 could improve mental health, such as depression, anxiety, and sense of well-being. Seventy-two subjects were recruited and randomly divided into YES-10 or placebo groups (n = 36 per group). Each group was daily administered two capsules orally, containing 200 mg of YES-10 or placebo, for 4 weeks in a double-blinded manner and tested for levels of depression, anxiety, well-being, and mental fitness using the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Psychosocial Well-being Index (PWI), and Mental Fitness Scale (MFS). In addition, the levels of cortisol (a stress hormone), interleukin-6 (IL-6) (an inflammatory cytokine), and 8-hydroxydeoxyguanosine (8-OHdG; a marker of oxidative stress) in the serum were measured. The BDI, BAI, PWI, and MFS scores decreased significantly, and the serum levels of cortisol, IL-6, and 8-OHdG were lowered significantly (P < .05), suggesting that YES-10 has the ability to improve mental health by relieving stress and by decreasing inflammation and oxidative stress.

Contribution of senescent and reactive astrocytes on central nervous system inflammaging.

Astrocytes, the most predominant cells in the central nervous system (CNS), have well-recognized neuroprotective functions. However, during the CNS aging, astrocytes can become neurotoxic and contribute to chronic inflammation in age-associated brain deterioration and disease. Astrocytes are known to become senescent or reactive due to the exposure to stressful stimuli, in both cases they contribute to an impaired cognitive function through the production of pro-inflammatory mediators. Although both scenarios (senescence and reactive gliosis) have been studied independently, there are no direct studies comparing their secretomes simultaneously in the aging-brain. In this review we discuss the most recent studies in that respect, in order to analyze their simultaneous participation in brain aging.

AD-16 Protects Against Hypoxic-Ischemic Brain Injury by Inhibiting Neuroinflammation.

Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic (HI) insult in the neonatal brain. AD-16 is a novel anti-inflammatory compound, recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators. In this study, we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation (OGD) in vitro and in mice with neonatal HI brain injury in vivo. We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury. Single dose post-treatment with AD-16 (1 mg/kg) improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h. Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI. The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.

Echinocystic Acid Inhibits Inflammation and Exerts Neuroprotective Effects in MPTP-Induced Parkinson's Disease Model Mice.

Parkinson’s disease (PD), the second primary neurodegenerative disease affecting human health, is mainly characterized by dopaminergic neuron damage in the midbrain and the clinical manifestation of movement disorders. Studies have shown that neuroinflammation plays an important role in the progression of PD. Excessively activated microglia produce several pro-inflammatory mediators, leading to damage to the surrounding neurons and finally inducing neurodegeneration. Echinocystic acid (EA) exhibits an anti-inflammatory effect in peripheral tissues. However, whether it inhibited neuroinflammation remains unclear. Therefore, the current study investigates the effect of EA on neuroinflammation and whether it can improve PD symptoms through inhibiting neuroinflammation. In our experiments, we discovered that EA inhibited the production of pro-inflammatory mediators in LPS-exposed BV2 cells. Further mechanism-related studies revealed that EA inhibited inflammation by activating PI3K/Akt and inhibiting NF-κB and MAPK signal pathways in LPS-induced BV2 cells. Research revealed that EA eases microglia-mediated neuron death in SN4741 and SHSY5Y cells. In in vivo studies, the results demonstrated that EA improves weight loss and behavioral impairment in MPTP-induced mice. Further studies have revealed that EA inhibited dopaminergic neuron damage and inflammation in the mice midbrain. In conclusion, our study demonstrated that EA inhibits neuroinflammation and exerts neuroprotective effects by activating PI3K/Akt and inhibiting NF-κB and MAPK signal pathways in vivo and in vitro.

Hormone-Related Cancer and Autoimmune Diseases: A Complex Interplay to be Discovered.

Neoplasic transformation is a continuous process that occurs in the body. Even before clinical signs, the immune system is capable of recognizing these aberrant cells and reacting to suppress them. However, transformed cells acquire the ability to evade innate and adaptive immune defenses through the secretion of molecules that inhibit immune effector functions, resulting in tumor progression. Hormones have the ability to modulate the immune system and are involved in the pathogenesis of autoimmune diseases, and cancer. Hormones can control both the innate and adaptive immune systems in men and women. For example androgens reduce immunity through modulating the production of pro-inflammatory and anti-inflammatory mediators. Women are more prone than men to suffer from autoimmune diseases such as systemic lupus erythematosus, psoriasis and others. This is linked to female hormones modulating the immune system. Patients with autoimmune diseases consistently have an increased risk of cancer, either as a result of underlying immune system dysregulation or as a side effect of pharmaceutical treatments. Epidemiological data on cancer incidence emphasize the link between the immune system and cancer. We outline and illustrate the occurrence of hormone-related cancer and its relationship to the immune system or autoimmune diseases in this review. It is obvious that some observations are contentious and require explanation of molecular mechanisms and validation. As a result, future research should clarify the molecular pathways involved, including any causal relationships, in order to eventually allocate information that will aid in the treatment of hormone-sensitive cancer and autoimmune illness.

Hydroethanolic Extract of Prunus domestica L.: Metabolite Profiling and In Vitro Modulation of Molecular Mechanisms Associated to Cardiometabolic Diseases.

High consumption of fruit and vegetables has an inverse association with cardiometabolic risk factors. This study aimed to chemically characterize the hydroethanolic extract of P. domestica subsp. syriaca fruit pulp and evaluate its inhibitory activity against metabolic enzymes and production of proinflammatory mediators. Ultra-high-performance liquid chromatography high-resolution mass spectrometry(UHPLC-HRMS) analysis showed the presence of hydroxycinnamic acids, flavanols, and glycoside flavonols, while nuclear magnetic resonance(NMR) analysis showed, among saccharides, an abundant presence of glucose. P. domestica fruit extract inhibited α-amylase, α-glucosidase, pancreatic lipase, and HMG CoA reductase enzyme activities, with IC50 values of 7.01 mg/mL, 6.4 mg/mL, 6.0 mg/mL, and 2.5 mg/mL, respectively. P. domestica fruit extract inhibited lipopolysaccharide-induced production of nitrite, interleukin-1 β and PGE2 in activated J774 macrophages. The findings of the present study indicate that P. domestica fruit extracts positively modulate in vitro a series of molecular mechanisms involved in the pathophysiology of cardiometabolic diseases. Further research is necessary to better characterize these properties and their potential application for human health.

Extracts of Andrographis paniculata (Burm.f.) Nees Leaves Exert Anti-Gout Effects by Lowering Uric Acid Levels and Reducing Monosodium Urate Crystal-Induced Inflammation.

Andrographis paniculata (Burm.f.) Nees has been found to have anti-inflammatory and immunostimulatory effects. This study was to investigate antihyperuricemic and anti-inflammatory effects of A. paniculata leaf extracts. Andrographolide, 14-deoxy-11,12-didehydroandrographolide, and neoandrographolide were quantified in 80% ethanol (EtOH80) and water extracts using High Performance Liquid Chromatography (HPLC) analysis. Antihyperuricemic activity was evaluated using a spectrophotometric in vitro inhibitory xanthine oxidase (XO) assay. The most active extract and andrographolide were further investigated in a hyperuricemic rat model induced by potassium oxonate to determine serum uric acid levels, liver XO activity, followed by Western blot analysis for renal urate transporter URAT1, GLUT9, and OAT1 to investigate the excretion of uric acid via kidney. Anti-inflammatory activity was assessed by in vitro interleukin assay for interleukin (IL-1α, IL-1β, IL-6, IL-8), and tumor necrosis factor (TNF-α) in monosodium urate (MSU) crystal-induced human fibroblast-like synoviocyte (HFLS) cells using ELISA-kits, followed by Western blot analysis for the expression of MyD88, NLRP3, NF-κB p65, and caspase-1 proteins to investigate the inflammation pathway. In vivo assay of the most active extract and andrographolide were performed based on the swelling rate and inhibition of pro-inflammatory mediator release from synovial fluid of a rat knee joint induced by MSU crystals. The results showed that the EtOH80 extract had a greater amount of andrographolide (11.34% w/w) than the water extract (1.38% w/w). In the XO inhibitory activity, none of the samples exhibited greater than 50% inhibition. However, in a rat model, EtOH80 extract (200 mg/kg/day) and andrographolide (30 mg/kg/day) decreased serum uric acid levels and reduced liver XO activity, reduced the protein expression levels of URAT1 and GLUT9, and restored the decrease in OAT1 levels. In the in vitro anti-inflammatory study, EtOH80 extract and andrographolide significantly decreased production of IL-1α, IL-1β, IL-6, and TNF-α, as well as inhibited the synthesis of MyD88, NLRP3, NF-κB p65, and caspase-1 in a concentration-dependent manner, almost comparable to dexamethasone. The EtOH80 extract (200 mg/kg/day) and andrographolide (30 mg/kg) significantly decreased swelling rate and IL-1α, IL-1β, IL-6, and TNF-α in the synovial fluid of rat models in a time-dependent manner, comparable to indomethacin (3 mg/kg/day). In conclusion, the findings show that EtOH80 extract has a substantial anti-gout effect by lowering uric acid levels and suppressing pro-inflammatory mediator production due to the andrographolide content, that might be beneficial in the treatment of gouty-inflammation.

Coadministration of Curcumin and Hydromorphone Hydrochloride Alleviates Postoperative Pain in Rats.

This study aimed to explore the effect of curcumin and hydromorphone hydrochloride (HH) cotreatment on postoperative pain in rats. An incision + formaldehyde-induced pain rat model was established. Rats were treated with vehicle, curcumin, HH, or curcumin + HH. Paw mechanical withdrawal threshold and thermal withdrawal latency were measured at 1 d before surgery as well as 1 , 2 h, 1 , 3 , and 7 d after surgery to assess pain sensitivity. The L4-6 region of the spinal cord was collected from each rat at 2 h, 1 , 3 , and 7 d after surgery. Western blot analysis and immunohistochemical staining were carried out to detect the protein expression of pain-related genes. Quantitative real-time PCR and enzyme-linked immunosorbent assay were conducted to measure the expression and production of proinflammatory mediators. Compared with other groups, Curcumin + HH significantly reduced pain sensitivity in the model rats. Mechanistically, curcumin + HH suppressed protein expression of stromal cell-derived factor-1 (SDF-1), CXC chemokine receptor 4 (CXCR4), p-Akt, and c-fos while enhancing protein expression of nerve growth factor (NGF) in the dorsal root ganglia (DRG) of model rats. Curcumin + HH inhibited the expression and production of interleukin 1β (IL-1β), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and p65 nuclear factor kappa B (NF-κB) in the DRG. Coadministration of curcumin and HH alleviates incision + formaldehyde-induced pain in rats, possibly by suppressing the SDF-1/CXCR4 pathway and the production of proinflammatory mediators. Our results provide curcumin and HH cotreatment as a promising therapeutic strategy in the management of postoperative pain.

In vitro and in vivo Experimental Investigation of Anti-Inflammatory Effects of Peucedanum japonicum Aqueous Extract by Suppressing the LPS-Induced NF-[Formula: see text]B/MAPK JNK Pathways.

Peucedanum japonicum Thunberg has been used to treat cold, cough, and inflammatory diseases in Southern and Eastern Asia. The effects of P. japonicum root aqueous extract (PJ) on lipopolysaccharide (LPS)-induced inflammation were investigated in RAW264.7 macrophages and an animal model of septic shock. Lipopolysaccharides are endotoxins that trigger excessive inflammatory responses, similar to those elicited by gram-negative bacteria. Inflammation is characterized by a primary defense system against pathogens and the onset of sundry diseases or illnesses, and macrophages are important components of the phagocytic system during inflammatory processes. The present study evaluated the effects of PJ on the production of pro-inflammatory mediators, such as nitric oxide and prostaglandin E2, and assessed the expression of enzymes that induce the production of pro-inflammatory mediators using western blotting. We also evaluated the production and mRNA expression of pro-inflammatory cytokines using enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Using western blotting, we determined whether nuclear factor-kappa B (NF-[Formula: see text]B) and c-Jun N-terminal kinase (JNK) are involved in the molecular mechanisms induced by PJ that suppressed LPS-induced inflammatory responses. We also found that PJ inhibited NF-[Formula: see text]B and JNK pathways in macrophages and reduced LPS-induced mortality in the mouse model of septic shock by inhibiting the activation of NF-[Formula: see text]B and JNK pathways that downregulated the expression of inflammatory mediators. These results indicated that PJ is an effective inflammatory suppressor.

Choline and citicoline ameliorate oxidative stress in acute kidney injury in rats.

The purpose of this study is to investigate the effects of cholinergic anti-inflammatory pathway (CAP)-activating drugs, choline and citicoline (Cytidinediphosphate-choline, CDP-choline), on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) parameters and the contribution of NADPH Oxidase4 (NOX4) p22phox. Endotoxemia induces a systemic inflammatory response characterized by the production of pro-inflammatory mediators and reactive oxygen species (ROS), which eventually develops acute kidney injury (AKI). NADPH Oxidase4 (NOX4) p22phox pathway contributes to the development of endotoxemia-induced AKI. Inflammatory response can be controlled by CAP. Expressions levels of KIM-1, TNF-α, NOX4, p22phox and NFκB in the kidney tissues of rats were analyzed via RT-PCR in experimental groups; 1. Control, 2. LPS (10 mg/kg) + saline, 3. LPS + CDP-choline (375 mg/kg) and 4. LPS + choline (90 mg/kg). Choline and ROS levels in kidney tissues were also measured by a spectrofluorometric assay. LPS-induced elevations of ROS levels were decreased by CDP-choline or choline administration (p < 0.001). LPS-elevated KIM-1, TNFα, NOX4, p22 phox, and NFκB expressions were significantly decreased by choline or CDP-choline treatments (p < 0.001). Decreased ROS production in kidney tissues in treatment groups suggests that choline or CDP-choline may have therapeutic potential in endotoxemia-associated AKI via downregulating NOX4 and p22phox expressions (Tab. 1, Fig. 5, Ref. 45). Text in PDF www.elis.sk Keywords: endotoxemia, choline, cytidine diphosphate choline, acute kidney injury, reactive oxygen species.

Probing Inflammasome Activation in Atherosclerosis.

Atherosclerosis is driven by chronic inflammation in all stages of the disease. Inflammation is fueled by elevated levels of pro-inflammatory cytokines. Interleukins (IL) are cytokines of particular importance in atherosclerosis, due to their key involvement in various pro-atherogenic processes, including infiltration of immune cells to the lesion, stimulation of the production of other pro-inflammatory mediators by other sources, and generation of lipid laden foam cells, all of which contribute to plaque development and progression. Various stimuli that are abundant in atherosclerotic plaques, including oxidized low-density lipoprotein, cholesterol crystals and reactive oxygen species can trigger inflammasome activation. Importantly, activation of the nucleotide oligomerization domain leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activates the caspase-1 protease and results in the generation and release of potent pro-inflammatory cytokines, IL-1β and IL-18. Both cytokines are influential in driving chronic inflammation and atherogenesis. This chapter describes the use of enzyme-linked immunosorbent assay (ELISA) and Western blot to quantify these cytokines in cell supernatant and lysate respectively, after stimulating inflammasome activation in cultured cells.

The α-Gal Syndrome and Potential Mechanisms.

The α-Gal syndrome is a complex allergic disease characterized by the development of specific IgE antibodies against the carbohydrate galactose-α-1,3-galactose (α-Gal), an oligosaccharide present in cells and tissues of non-primate mammals. Individuals with IgE antibodies to α-Gal suffer from a delayed form of anaphylaxis following red meat consumption. There are several features that make the α-Gal syndrome such a unique allergic disease and distinguish it from other food allergies: (1) symptoms causing IgE antibodies are directed against a carbohydrate moiety, (2) the unusual delay between the consumption of the food and the onset of the symptoms, and (3) the fact that primary sensitization to α-Gal occurs via tick bites. This review takes a closer look at the immune response against α-Gal, in healthy and in α-Gal allergic individuals. Furthermore, the similarities and differences between immune response against α-Gal and against the other important glycan moieties associated with allergies, namely cross-reactive carbohydrate determinants (CCDs), are discussed. Then different mechanisms are discussed that could contribute to the delayed onset of symptoms after consumption of mammalian meat. Moreover, our current knowledge on the role of tick bites in the sensitization process is summarized. The tick saliva has been shown to contain proteins carrying α-Gal, but also bioactive molecules, such as prostaglandin E2, which is capable of stimulating an increased expression of anti-inflammatory cytokines while promoting a decrease in the production of proinflammatory mediators. Together these components might promote Th2-related immunity and trigger a class switch to IgE antibodies directed against the oligosaccharide α-Gal. The review also points to open research questions that remain to be answered and proposes future research directions, which will help to get a better understanding and lead to a better management of the disease.

Imperatorin alleviated NLR family pyrin domain-containing 3 inflammasome cascade-induced synovial fibrosis and synovitis in rats with knee osteoarthritis

ABSTRACT We aimed to clarify the therapeutic effects of imperatorin (IMP) on knee osteoarthritis (KOA). Thirty 3-month-old SD male rats were randomly divided into Normal, monosodium iodoacetate (MIA) and MIA+IMP groups. Their synovial tissues were subjected to histopathological analysis. Primary synovial fibroblasts obtained from additional normal rats were treated by lipopolysaccharide (LPS) and then IMP. The mRNA and protein expressions of factors related to synovitis and synovial fibrosis were detected by qRT-PCR and Western blotting, respectively. The concentrations of inflammatory factors IL-1β and IL-18 were measured by ELISA. IMP reduced HIF-1α, NLR family pyrin domain-containing 3 inflammasome expression and IL-1β, IL-18 production in synovial fibroblasts induced by LPS. IMP also downregulated synovial fibrosis markers. In vitro study revealed that MIA-induced synovitis and synovial fibrosis were relieved by IMP. IMP relieves the inflammation associated with synovitis and synovial fibrosis. It reduces the production of pro-inflammatory mediators and cytokines and inhibits TGF-β1, TIMP-1 and VEGF expressions that promote synovial fibrosis.

The Anti-Inflammatory Actions and Mechanisms of Acupuncture from Acupoint to Target Organs via Neuro-Immune Regulation.

Inflammation plays a significant role in the occurrence and development of multiple diseases. This study comprehensively reviews and presents literature from the last five years, showing that acupuncture indeed exerts strong anti-inflammatory effects in multiple biological systems, namely, the immune, digestive, respiratory, nervous, locomotory, circulatory, endocrine, and genitourinary systems. It is well known that localized acupuncture-mediated anti-inflammatory effects involve the regulation of multiple populations and functions of immune cells, including macrophages, granulocytes, mast cells, and T cells. In acupuncture stimulation, macrophages transform from the M1 to the M2 phenotype and the negative TLR4 regulator PPARγ is activated to inhibit the intracellular TLR/MyD88 and NOD signaling pathways. The downstream IκBα/NF-κB and P38 MAPK pathways are subsequently inhibited by acupuncture, followed by suppressed production of inflammasome and proinflammatory mediators. Acupuncture also modulates the balance of helper T cell populations. Furthermore, it inhibits oxidative stress by enhancing SOD activity via the Nrf2/HO-1 pathway and eliminates the generation of oxygen free radicals, thereby preventing inflammatory cell infiltration. The anti-inflammatory effects of acupuncture on different biological systems are also specific to individual organ microenvironments. As part of its anti-inflammatory action, acupuncture deforms connective tissue and upregulates the secretion of various molecules in acupoints, further activating the NF-κB, MAPK, and ERK pathways in mast cells, fibroblasts, keratinocytes, and monocytes/macrophages. The somatic afferents present in acupuncture-activated acupoints also convey sensory signals to the spinal cord, brainstem, and hypothalamic neurons. Upon information integration in the brain, acupuncture further stimulates multiple neuro-immune pathways, including the cholinergic anti-inflammatory, vagus-adrenal medulla-dopamine, and sympathetic pathways, as well as the hypothalamus-pituitary-adrenal axis, ultimately acting immune cells via the release of crucial neurotransmitters and hormones. This review provides a scientific and reliable basis and viewpoints for the clinical application of acupuncture in various inflammatory conditions.

Corilagin potential in inhibiting oxidative and inflammatory stress in LPS-induced murine macrophage cell lines (RAW 264.7).

Inflammation is thought to be the common pathophysiological basis for several disorders. Corilagin is one of the major active compounds which showed broad-spectrum biological and therapeutic activities, such as antitumor, hepatoprotective, anti-oxidant, and anti-inflammatory. This study aimed to evaluate the anti-oxidant and anti-inflammatory activities of corilagin in LPS-induced RAW264.7 cells. Anti-oxidant activities were examined by free radical scavenging of H2O2, NO, and *OH. The safe concentrations of corilagin on RAW264.7 were determined by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on RAW264.7 cell lines. The inflammation cells model was induced with LPS. The anti-inflammatory activities measured IL-6, TNF-α, NO, IL-1β, PGE-2, iNOS, and COX-2 levels using ELISA assay. The results showed that corilagin had a significant inhibition activity dose-dependently in scavenging activities toward H2O2, *OH, and NO with IC50 values 76.85 µg/ml, 26.68 µg/ml, and 66.64 µg/ml, respectively. The anti-inflammatory activity of corilagin also showed a significant decrease toward IL-6, TNF-α, NO, IL-1β, PGE-2, iNOS, and COX-2 levels at the highest concentration (75 µM) compared with others concentration (50 and 25 µM) with the highest inhibition activities being 48.09%, 42.37%, 65.69%, 26.47%, 46.88%, 56.22%, 59.99%, respectively (P<0.05). Corilagin has potential as anti-oxidant and anti-inflammatory in LPS-induced RAW 264.7 cell lines by its ability to scavenge free radical NO, *OH, and H2O2 and also suppress the production of proinflammatory mediators including COX-2, IL-6, IL-1β, and TNF-α in RAW 264.7 murine macrophage cell lines.

Causal Links between Hypovitaminosis D and Dysregulation of the T Cell Connection of Immunity Associated with Obesity and Concomitant Pathologies

Subclinical inflammation in morbid obesity is associated with immune activation and the development of concomitant diseases. Impaired immune homeostasis and immune cell dysregulation in adipose tissue are associated with phenotypic and functional changes in the pool of T lymphocytes and the development of chronic hypovitaminosis D. Low vitamin D levels in obesity lead to the activation, proliferation and production of pro-inflammatory mediators by T cells. Hypovitaminosis D is the cause of a decrease in the functional potential of regulatory and anti-inflammatory lymphocytes and the maintenance of the inflammatory response. The exact molecular genetic mechanisms of the effect of vitamin D on T lymphocytes have not been fully elucidated. Therefore, uncovering the functional role of T cells and their relationship to vitamin D homeostasis in the context of obesity development may contribute to the development of new pathogenetic methods for clinical prediction of the risk of metabolic, oncologic, autoimmune and infectious complications. The review presents the molecular genetic mechanisms of the effect of vitamin D on adipose tissue resident T lymphocytes and the characteristics of vitamin D receptor expression, and analyzes the phenotypic and functional characteristics of potentially pathogenic T lymphocytes in relation to the development of obesity and its associated complications.

Therapeutic Potential of a Novel Bifidobacterium Identified Through Microbiome Profiling of RA Patients With Different RF Levels.

The potential therapeutic effects of probiotic bacteria in rheumatoid arthritis (RA) remain controversial. Thus, this study aimed to discover potential therapeutic bacteria based on the relationship between the gut microbiome and rheumatoid factor (RF) in RA. Bacterial genomic DNA was extracted from the fecal samples of 93 RA patients and 16 healthy subjects. Microbiota profiling was conducted through 16S rRNA sequencing and bioinformatics analyses. The effects of Bifidobacterium strains on human peripheral blood mononuclear cells and collagen-induced arthritis (CIA) mice were assessed. Significant differences in gut microbiota composition were observed in patients with different RF levels. The relative abundance of Bifidobacterium and Collinsella was lower in RF-high than in RF-low and RF-negative RA patients, while the relative abundance of Clostridium of Ruminococcaceae family was higher in RF-high than in RF-low and RF-negative patients. Among 10 differentially abundant Bifidobacterium, B. longum RAPO exhibited the strongest ability to inhibit IL-17 secretion. Oral administration of B. longum RAPO in CIA mice, obese CIA, and humanized avatar model significantly reduced RA incidence, arthritis score, inflammation, bone damage, cartilage damage, Th17 cells, and inflammatory cytokine secretion. Additionally, B. longum RAPO significantly inhibited Th17 cells and Th17-related genes—IL-17A, IRF4, RORC, IL-21, and IL-23R—in the PBMCs of rheumatoid arthritis patients. Our findings suggest that B. longum RAPO may alleviate RA by inhibiting the production of IL-17 and other proinflammatory mediators. The safety and efficacy of B. longum RAPO in patients with RA and other autoimmune disorders merit further investigation.

Discovery of Phenolic Glycoside from Hyssopus cuspidatus Attenuates LPS-Induced Inflammatory Responses by Inhibition of iNOS and COX-2 Expression through Suppression of NF-κB Activation.

It seems quite necessary to obtain effective substances from natural products against inflammatory response (IR) as there are presently clinical problems regarding accompanying side effects and lowered quality of life. This work aimed to investigate the abilities of hyssopuside (HY), a novel phenolic glycoside isolated from Hyssopus cuspidatus (H. cuspidatus), against IR in lipopolysaccharide (LPS)-induced RAW 264.7 cells and mouse peritoneal macrophages. The results indicated that HY could reduce nitric oxide (NO) production and inhibit the production and secretion of pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in LPS-stimulated macrophages. Moreover, data from the immunofluorescence study showed that HY suppressed nuclear translocation of nuclear factor-kappa B (NF-κB) upon LPS induction. The Western blot results suggested that HY reversed the LPS-induced degradation of IκB (inhibitor of NF-κB), which is normally required for the activation of NF-κB. Meanwhile, the overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) diminished significantly with the presence of HY in response to LPS stimulation. On the other hand, HY had a negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. Moreover, an in silico study of HY against four essential proteins/enzymes revealed that COX-2 was the most efficient enzyme for the interaction, and binding of residues Phe179, Asn351, and Ser424 with HY played crucial roles in the observed activity. The structure analysis indicated the typical characterizations with phenylethanoid glycoside contributed to the anti-inflammatory effects of HY. These results indicated that HY manipulated its anti-inflammatory effects mainly through blocking the NF-κB signal transduction pathways. Collectively, we believe that HY could be a potential alternative phenolic agent for alleviating excessive inflammation in many inflammation-associated diseases.

The elderly at risk: aldosterone as modulator of the immune response to SARS-CoV-2 infection.

The elderly population is the most susceptible to SARS-CoV-2 infection and develops the worst clinical phenotype with severe pneumonia and cardiac complications. Older COVID-19 patients are also at higher risk of sudden death, mainly attributable to electrolyte disorders and to an uncontrolled inflammatory response. After the identification of ACE 2 as the receptor of SARS-CoV-2 in human cells, several research studies have focused on the role of the activation of Renin Angiotensin System in COVID-19 clinical course. In the present opinion paper, we discuss the role of hyperaldosteronism in the increasing risk of cardiac complications in COVID-19 older patients. In particular, we focus on the immunoregulatory activity of aldosterone, as the last mediator of the Renin Angiotensin System cascade, in activating the innate and adaptive immune response related to SARS-CoV-2 infection in the elderly. Aldosterone may stimulate dendritic cells and the recruitment of monocytes/macrophages in the endothelium of coronary vessels, favoring the production of pro-inflammatory mediators and T-cells response. Higher basal levels of aldosterone together with SARS-CoV-2-induced production may explain the unfavorable course of COVID-19 in the elderly.