Inhibition Of Systemic Inflammation Research Articles

Biological gene therapy for psoriasis: more than just skin clearance

Psoriasis is recognized as a systemic inflammatory disease, significantly affecting all major aspects of patients’ health, requiring a timely comprehensive approach to treatment. This approach should improve the overall well-being of patients and consider the psychosocial aspects of their lives. Special attention in modern research is given to psoriatic arthritis (PsA), which affects up to 30% of patients with psoriasis. There is growing interest in the possibility of stopping the progression of the psoriatic process and preventing the manifestation of PsA. Recent studies have shown that timely treatment with genetically engineered biological agents (biologics) can halt disease progression and prevent the development of disabling complications. The article discusses key clinical and immunological markers that can predict the development of PsA, opening pathways for earlier and targeted therapy. Special attention is given to the role of guselkumab, a monoclonal antibody targeting interleukin-23, in preventing the development of PsA in high-risk patients. Clinical observations of three patients with psoriasis treated with guselkumab showed not only complete skin clearance (PASI 0) but also positive changes in all major parameters of psoriasis severity, sustained remission of the skin process, and positive dynamics of manifestations of psoriatic onychodystrophy, which is currently considered the main predictor of PsA. These results indicate suppression of systemic inflammation and control of disease progression risk. The significant overall improvement in patient condition, along with the key indicator of therapy effectiveness – improved quality of life emphasizes the importance and efficacy of timely initiation of targeted therapy in patients with psoriasis with certain aggravating factors.

Revealing the biological mechanism of acupuncture in alleviating excessive inflammatory responses and organ damage in sepsis: a systematic review.

Sepsis is a systemic inflammation caused by a maladjusted host response to infection. In severe cases, it can cause multiple organ dysfunction syndrome (MODS) and even endanger life. Acupuncture is widely accepted and applied in the treatment of sepsis, and breakthroughs have been made regarding its mechanism of action in recent years. In this review, we systematically discuss the current clinical applications of acupuncture in the treatment of sepsis and focus on the mechanisms of acupuncture in animal models of systemic inflammation. In clinical research, acupuncture can not only effectively inhibit excessive inflammatory reactions but also improve the immunosuppressive state of patients with sepsis, thus maintaining immune homeostasis. Mechanistically, a change in the acupoint microenvironment is the initial response link for acupuncture to take effect, whereas PROKR2 neurons, high-threshold thin nerve fibres, cannabinoid CB2 receptor (CB2R) activation, and Ca2+ influx are the key material bases. The cholinergic anti-inflammatory pathway of the vagus nervous system, the adrenal dopamine anti-inflammatory pathway, and the sympathetic nervous system are key to the transmission of acupuncture information and the inhibition of systemic inflammation. In MODS, acupuncture protects against septic organ damage by inhibiting excessive inflammatory reactions, resisting oxidative stress, protecting mitochondrial function, and reducing apoptosis and tissue or organ damage.

Hydroethanolic Extract of Morus nigra L. Leaves: A Dual PPAR-α/γ Agonist with Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated RAW 264.7

Inhibition of systemic inflammation has been a beneficial strategy in treating several non-communicable diseases, which represent one of the major causes of mortality in the world. The Peroxisome Proliferator-Activated Receptors (PPAR) are interesting pharmacological targets, since they can act both through the metabolic and anti-inflammatory pathways. Morus nigra L. has flavonoids in its chemical composition with recognized anti-oxidant activity and often associated with anti-inflammatory activity. Therefore, this study aimed to evaluate the hydroethanolic extract of M. nigra leaves' ability to activate PPAR and promote anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated murine macrophage cells. The leaf extract was prepared by cold maceration, and the chemical profile was obtained by HPLC-DAD. Activation of PPAR α and γ was evaluated by the luciferase reporter assay. The anti-inflammatory activity was assessed by measuring the reactive oxygen species (ROS), nitric oxide (NO), and Tumor Necrosis Factor-α (TNF-α) in RAW 264.7 cells after stimulation with LPS from Escherichia coli. The HPLC-DAD analysis identified two major compounds: rutin and isoquercitrin. The extract showed agonist activity for the two types of PPAR, α and γ, although its major compounds, rutin and isoquercitrin, did not significantly activate the receptors. In addition, the extract significantly reduced the production of ROS, NO, and TNF-α. Treatment with the specific PPAR-α antagonist, GW 6471, was able to partially block the anti-inflammatory effect caused by the extract.

Effects of Colchicine on Measures of Lipolysis in Adults With Obesity

Background: Obesity-associated inflammation promotes adipose tissue (AT) dysfunction and contributes to the progression of type 2 diabetes and cardiovascular disease. Recent clinical studies have demonstrated that colchicine may improve metabolic and cardiovascular outcomes; however, colchicine’s effects on metabolic and inflammatory measures within AT remain unclear. Methods: The aim of this study was to examine if colchicine’s anti-inflammatory effects would improve measures of lipolysis and immune cell populations in subcutaneous AT (SAT). This is a secondary analysis of a double-blind, randomized, placebo-controlled pilot study in which 40 nondiabetic adults with obesity and metabolic syndrome (MetS) were randomized to colchicine 0.6mg or placebo twice daily for 3 months. Blood samples for insulin, glucose, and free fatty acids were collected in the fasted state and during a frequently-sampled intravenous glucose tolerance test. Noninsulin-suppressible (l0), insulin-suppressible (l2), and maximal (l0+l2) lipolysis rates were calculated by minimal model analysis. Body composition was determined by DXA. SAT immune cell populations were characterized by flow cytometry fluorescence-activated single cell sorting of the stromovascular fractions obtained after collagenase digestion of SAT samples obtained using a mini-liposuction technique pre- and post-intervention. Results: Data from 18 subjects in the colchicine group (Mean ± SD: age 48.4 ± 13.5 y; BMI 39.3 ± 6.3 kg/m2; sex: female 72.2%) and 18 subjects in the placebo group (age 44.7 ± 10.2 y; BMI 41.8 ± 8.2 kg/m2; sex: female 77.8%) were available for this study. Colchicine treatment significantly reduced l2 (p = 0.04) and l0+l2 (p = 0.04) versus placebo. These changes were significantly associated with reductions in systemic inflammation, including the changes in high-sensitivity C-reactive protein concentrations, white blood cell count, circulating monocyte and neutrophil populations, and the neutrophil-lymphocyte ratio (p’s < 0.015). Colchicine did not significantly alter SAT immune cell population distributions (p’s > 0.05). Conclusions: In adults with obesity and MetS, colchicine may improve insulin action at the level of AT. These improvements were positively associated with the suppression of systemic inflammation. However, no local AT inflammatory cell populations were significantly affected by colchicine use in our study, suggesting that colchicine’s systemic, rather than local, anti-inflammatory effects may be more consequential in ameliorating AT metabolic pathways in MetS. Further studies are warranted to elucidate the biological mechanisms underlying colchicine’s effects in AT, as these investigations could potentially shed light on treatments to improve metabolic outcomes in human obesity.

Suppression of systemic inflammation and signs of acute and chronic cholangitis by multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione.

An aberrant activity of growth factor receptors followed by excessive cell proliferation plays a significant role in pathogenesis of cholangitis. Therefore, inhibition of these processes could be a fruitful therapeutic strategy. The effects of multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione (MI-1) on the hepatic and systemic manifestations of acute and chronic cholangitis in rats were addressed. MI-1 (2.7mg/kg per day) was applied to male rats that experienced α-naphthylisothiocyanate-induced acute (3days) or chronic (28days) cholangitis. Liver autopsy samples, blood serum markers, and leukograms were studied. MI-1 localization in liver cells and its impact on viability of HepG2 (human hepatoma), HL60 (human leukemia), and NIH3T3 (normal murine fibroblasts) cell lines and lymphocytes of human peripheral blood (MTT, DNA fragmentation, DNA comet assays, Propidium Iodide staining) were assessed. Under both acute and chronic cholangitis, MI-1 substantially reduced liver injury, fibrosis, and inflammatory scores (by 46-86%) and normalized blood serum markers and leukograms. Moreover, these effects were preserved after a 28-day recovery period (without any treatment). MI-1 inhibited the HL60, HepG2 cells, and human lymphocytes viability (IC50 0.6, 9.5 and 8.3µg/ml, respectively), while NIH3T3 cells were resistant to that. Additionally, HepG2 cells and lymphocytes being incubated with MI-1 demonstrated insignificant pro-apoptotic and pro-necrotic changes and DNA single-strand breaks, suggesting that MI-1 effects in liver might be partly caused by its cytotoxic action towards liver cells and lymphocytes. In conclusion, MI-1 attenuated the systemic inflammation and signs of acute and chronic cholangitis partly through cytotoxicity towards cells of hepatic and leukocytic origin.

Особенности комплексной терапии иммуновоспалительных ревматических заболеваний в условиях пандемии COVID-19

The rapid spread of a new coronavirus infection (COVID-19) requires innovative solutions, including tactics optimization in using genetically engineered and targeted drugs in patients with immuno-inflammatory rheumatic diseases (RD). The authors studied the characteristics of the complex therapy of immuno-inflammatory RD in the COVID-19 pandemic conditions, analyzed the COVID-19 course in patients with RD who received combined therapy with genetically engineered and basic synthetic anti-rheumatic drugs and were under follow-up from March 2020 to March 2021. The researchers found that synthetic basic (methotrexate, leflunomide, etc.), targeted synthetic (tofacitinib, baricitinib, apremilast) and biologic disease-modifying antirheumatic drugs used in the RD treatment, except high-dose glucocorticoids and anti-B cell drugs (rituximab), do not have a negative effect and are not associated with a severe COVID-19 course. The use of interleukin-6 (IL-6) inhibitors is the standard pathogenetic therapy for cytokine release syndrome in COVID-19. Proactive therapy with IL-6 inhibitors provides inhibition of systemic inflammation and contributes to the suppression of cytokine storm syndrome, preventing the development of multiple organ failure and fatal outcome. KEYWORDS: rheumatic diseases, cytokine storm, multiple organ failure, genetically engineered biological drugs, interleukin-6, COVID-19. FOR CITATION: Samigullina R.R., Mazurov V.I., Trofimov E.A. Characteristics of complex therapy of immuno-inflammatory rheumatic diseases in COVID-19 pandemic conditions. Russian Medical Inquiry. 2021;5(5):260–267 (in Russ.). DOI: 10.32364/2587-6821-2021- 5-5-260-267.

Effects of Lonicera confusa and Astragali Radix extracts supplementation on egg production performance, egg quality, sensory evaluation, and antioxidative parameters of laying hens during the late laying period

Lonicera confusa (LC) and Astragali Radix (AR) extracts have been shown to have antioxidant and anti-inflammatory activities in human. To determine whether LC or/and AR extracts had similar functions to improve the egg production and egg quality, 1,440 (52-wk-old) Lohmann pink-shell hens were randomly distributed into 4 treatments with nine replicates of 40 hens. The hens were fed a basal diet (CON) or the basal diet supplemented with 0.1% LC extracts, 0.1% AR extracts, or 0.1% LC extracts plus 0.1% AR extracts (LC-AR) for 12 wk. The eggs were collected on week 6 and 12 for analysis, and the plasma and ovaries were collected at end of trial. Dietary treatment did not influence (P < 0.05) egg production, egg weight, and feed conversion ratio. However, LC-AR addition increased (P < 0.02) yolk color and sensory quality of hard-boiled eggs compared to other groups. The LC-AR supplementation increased (P = 0.02), and LC addition tended to increase (P = 0.08) Haugh unit of eggs on week 12 compared to CON. The LC-AR supplementation decreased (P < 0.001), and LC or AR individual addition tended to decrease (P < 0.10) plasma malondialdehyde concentration compared to CON. Conversely, LC supplementation increased (P = 0.02) total superoxide dismutase activity, and LC or/and AR supplementation increased the activities of manganese-containing superoxide dismutase (MnSOD) (P < 0.08) and glutathione peroxidase (GSH-Px) (P < 0.01) in plasma, and the mRNA abundance of MnSOD, GSH-Px1, and catalase in ovaries (P < 0.05) compared to CON. The LC or/and AR supplementation decreased the concentrations of interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) in plasma (P < 0.05), and the mRNA abundance of IL-6 and TNF-α in ovaries (P < 0.04) compared to CON. These results suggested dietary inclusion of LC or/and AR improved the albumen quality, and a blend of LC and AR improved yolk color, which were associated with the enhancement of antioxidant capacity and the suppression of systemic inflammation in hens.

Antioxidant and anti-inflammatory effects of dexrazoxane on dopaminergic neuron degeneration in rodent models of Parkinson's disease

Emerging evidence has demonstrated that the integrity and the function of blood-brain barrier (BBB) are gradually impaired in the processes of aging and nervous system disorders, including neurodegenerative diseases (e.g. Parkinson's disease, PD). The leakage of BBB contributes to the infiltration of peripheral immune cells and harmful mediators into brain parenchyma, even the drugs that can not cross BBB under physiological conditions. Therefore, PD has been regarded as not only a neurodegenerative disease, but also a systemic disorder. In the present study, we demonstrate for the first time that Dexrazoxane (Dex), a drug clinically used to reduce doxorubicin-induced cardiotoxicity in chemotherapy, can enter into midbrain and striatum through broken BBB in 6-hydroxydopamine (6-OHDA)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rodent models of PD. Unexpectedly, Dex (1.5, 5, 15 mg/kg, i.p.) administration for 3-week significantly ameliorates apomorphine-induced contralateral rotation behavior in 6-OHDA-treated rats and Dex (10 mg/kg, i.p.) treatment for 5-week improves MPTP-induced mouse motor dysfunctions. We find that Dex administration protects dopaminergic neurons against neurotoxin-induced degeneration in SNc, accompanied by the attenuated glial cell activation. Further study indicates that suppression of oxidative stress and endoplasmic reticulum stress, as well as the inhibition of systemic inflammation in both peripheral tissues and brain, contribute to the neuroprotective effects of Dex in PD models. Our study implies that Dex may serve as an effective neuroprotectant to treat neurodegeneration and has potential clinical value in term of PD therapeutics.

A randomized, subject and rater-blinded, placebo-controlled trial of dimethyl fumarate for obstructive sleep apnea.

To investigate the therapeutic effect of dimethyl fumarate (DMF, an immunomodulatory agent) on obstructive sleep apnea (OSA), and potential influence of any such effect by selected proinflammatory molecules. Patients with OSA who deferred positive airway pressure therapy were randomized (2:1) to receive DMF or placebo for 4 months. Participants underwent polysomnography before randomization and at 4 months. Blood was collected monthly. The primary outcome was the mean group change in respiratory disturbance index (δ-RDI). Secondary analyses focused on the association between treatment effect of DMF (on RDI) and expression of plasma cytokines and chemokines, or nuclear factor κ-B (NFκB) signaling molecules in peripheral blood mononuclear cells. N = 65 participants were randomized. N = 50 participants (DMF = 35, placebo = 15) had complete data for final analyses. The mean difference in δ-RDI between groups was 13.3 respiratory events/hour of sleep: -3.1+/-12.9 vs. 10.2+/-13.1 in DMF and placebo groups, respectively (mixed-effects model treatment effect: β = -0.14, SE = 0.062, p = 0.033). Plasma levels of TNF-α showed only nonsignificant decreases, and IL-10 and IL-13 only nonsignificant increases, in DMF-treated participants compared with placebo. No significant interaction or main effect on RDI for selected cytokines and chemokines was found. Participants with a therapeutic response to DMF did experience significant reductions in intracellular NFκB signaling molecules at 4 months. Overall, DMF was well-tolerated. The immunomodulatory drug DMF partially ameliorates OSA severity. Suppression of systemic inflammation through reduction of NFκB signaling may mediate this effect. ClinicalTrials.gov, NCT02438137, https://clinicaltrials.gov/ct2/show/NCT02438137?term=NCT02438137&rank=1.

Induction of ET‐1‐ and non‐ET‐1‐mediated endothelium‐dependent vasoconstriction in endotoxemic hypotensive shock

Effective managements of refractory hypotension to vasoconstrictors in severe sepsis are limited. A new strategy to ameliorate endotoxemic hypotension by inducing endothelium‐dependent constriction of endotoxemic large arteries was examined. In lipopolysaccharide (LPS)‐induced endotoxemic rats, oroxylin‐A (OroA, 15 mg/kg, iv) administered 6 hours after LPS‐challenge promptly reversed/normalized diminished mean arterial pressure and heart rate. OroA (1–10 μM), which did not constrict isolated normal arteries, repeatedly induced exclusive endothelium‐dependent sustained‐constriction without tachyphylaxis of isolated endotoxemic aortic and tail arteries. OroA‐induced constriction of mesenteric arteries with intact‐endothelium (EC+) was blocked by endothelin‐1 (ET‐1)‐receptor antagonists which, did not affect that of tail or aortic arteries, suggesting ET‐1‐mediated and non‐ET‐1‐substance(s)‐mediated vasoconstrictions, respectively. In parallel, repeated applications of ET‐1 to mesenteric arteries lead to significant tachyphylaxis, OroA, however, induced repeated constriction of tail arteries without tachyphylaxis, Moreover, OroA significantly decreased LPS‐induced expression of ET‐1 mRNA and proteins in tail arteries, while OroA increased those in the mesenteric arteries, suggesting the heterogeneities of the endothelial cells. OroA‐induced ET‐1‐mediated and non‐ET‐1‐substance(s)‐mediated constrictions of all isolated arteries (EC+) were blocked exclusively by ROCK inhibitors. OroA reversed LPS‐induced suppression of RhoA‐activities and enhanced ROCK‐phosphorylation only in arteries with endothelium. Activated muscle ROCK‐activities in mesenteric arteries (EC+) but not those in tail or aortic arteries (EC+) were blocked by ET‐1‐receptor antagonists. Moreover, OroA‐post‐treatment suppressed, via inhibiting NF‐κB, inducible‐NOS expression and circulating NO. LPS induces region‐dependent expression of endothelial ET‐1‐ and/or non‐ET‐1‐vasoconstrictors. Both ET‐1 and non‐ET‐1 were released specifically by OroA‐activated muscle RhoA/ROCK‐pathway, causing prompt‐and‐sustained vasoconstriction that partly is due to OroA‐induced decrease of circulating NO. Simultaneous preservation of endothelial functions, induction of endothelium‐dependent constriction of large arteries, and suppression of systemic inflammation, as shown by OroA, offer new strategies for acute management of endotoxemic‐hypotensive shock.Support or Funding Informationsupported by MOST &amp; Tzu Chi FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Low-Dose Sodium Nitrite Fluid Resuscitation Prevents Lethality From Crush Syndrome by Improving Nitric Oxide Consumption and Preventing Myoglobin Cytotoxicity in Kidney in A Rat Model.

Crush syndrome (CS) is a serious medical condition characterized by muscle cell damage resulting from pressure. CS has a high mortality, even when patients receive fluid therapy. We examined whether administration of NaNO2-containing fluid can improve survival in a rat model of CS. The CS model was generated by subjecting anesthetized rats to bilateral hind limb compression with a rubber tourniquet for 5 h. Rats were then randomly divided into six groups: sham; CS with no treatment; CS with normal saline treatment; CS with normal saline + 25 mEq/L bicarbonate treatment; and CS with normal saline + 200 or 500 μmol/kg NaNO2. Blood and tissue samples were collected for histological and biochemical analyses at predetermined time points before and after reperfusion. Ischemic compression of rat hind limbs reduced nitrite content in the crushed muscle, and subsequent reperfusion resulted in reactive oxygen species-induced circulatory dysfunction and systemic inflammation. Rats treated with 200 μmol/kg NaNO2 showed increased nitric oxide (NO) levels, blood circulation, and neoangiogenesis, decreased generation of reactive oxygen species, and suppression of the inflammatory response, leading to complete recovery. Treatment with 200 μmol/kg NaNO2 prevents muscle damage induced by ischemia reperfusion via the protective effects of NO and suppression of systemic inflammation, thereby increasing survival rates in CS.

Dietary Fiber and the Human Gastrointestinal Microbiota as Predictors of Bone Health

BackgroundIncreasingly, the gastrointestinal (GI) microbiota is emerging as a factor relevant to bone health. Proposed mechanisms of the inter‐relationships among dietary fiber, the GI microbiota, and bone health include increased availability of absorbable calcium because of lowered gut pH related to bacterial fermentation of fiber; short‐chain fatty acid (SCFA) signaling from bacterial metabolism of dietary fibers that regulates mineral absorption and cell proliferation, thereby increasing surface area for absorption; and suppression of systemic inflammation, a risk factor for osteoporosis, by the microbiota. However, these relationships are under‐investigated in human populations.ObjectiveWe aimed to determine the relationships among bone health, dietary fiber consumption, and the GI microbiota and their metabolites (i.e., SCFAs) in adults.MethodsCross‐sectional analyses were conducted on 25–46‐year‐old adults (n=64, 36 females). Dietary fiber, calcium, and vitamin D intake were assessed using a 7‐day diet record. Body composition and bone density were assessed using dual‐energy X‐ray absorptiometry (DXA). Fecal samples were utilized to assess bacterial composition, SCFA concentrations, and pH. Barcoded amplicon pools of bacterial sequences were generated using high‐throughput sequencing followed by analysis using QIIME 1.9.0. SCFAs were quantified on a dry matter basis using gas chromatography. Fecal pH was measured using a pH meter. Relationships between bacterial relative abundances, SCFA concentrations, and pH were first assessed using Pearson (for normally distributed variables) and Spearman (for non‐normally distributed variables) correlations, with partial correlation for normalized dietary fiber intake (fiber/kcal). Then, a regression model was conducted to assess the relationship between fiber and bone density after adjusting for covariates including age, sex, and BMI.ResultsBivariate analyses revealed that greater bone mineral density was correlated with higher intakes of fiber (r=0.24, p=0.03). Bone mineral density was inversely related to Blautia (r=−0.28, p=0.03) and Clostridiaceae (rho= −0.31, p=0.01). Greater bone mineral density tended to be related to higher fecal butyrate concentration (r=0.31, p=0.08) and lower fecal pH (r=−0.30, p=0.06). Similar to bone mineral density, bone mineral content was inversely related to Blautia (r=−0.26, p=0.04) and Clostridiaceae (rho=−0.27, p=0.03); and greater bone mineral content tended to be positively related to fecal butyrate concentration (r=.30, p=0.09) and negatively related to fecal pH (r=−0.30, p=0.06). Interestingly, Blautia and Clostridiaceae were not related to fecal pH or butyrate. The linear regression model revealed a positive relationship between greater bone mineral density and dietary fiber intake (p=0.02)ConclusionsIn summary, bone mineral density was associated with greater intakes of fiber, lower fecal pH, and higher fecal concentrations of butyrate, which supports proposed mechanisms. Additional study is necessary to determine the role of specific microbes in this relationship.Support or Funding InformationPartial funding for this study was provided by the Hass Avocado Board and the USDA National Institute of Food and Agriculture, Hatch project ILLU 538 384.

JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer

ABSTRACTHuman pancreatic cancer does not respond to immune check point blockade immunotherapy. One key feature of pancreatic cancer is the association between its progression and chronic inflammation. Emerging evidence supports a key role for the JAK-STAT pathway in pancreatic cancer inflammation. We aimed at testing the hypothesis that sustained JAK-STAT signaling suppresses cytotoxic T lymphocyte (CTL) activation to counteract anti-PD-1 immunotherapy-induced CTL activity in pancreatic cancer. We show that human pancreatic carcinomas express high level of PD-L1 and exhibit low level of CTL infiltration. JAK-STAT inhibitor Ruxolitinib selectively inhibits STAT1 and STAT3 activation and increases CTL infiltration to induce a Tc1/Th1 immune response in the tumor microenvironment in an orthotopic pancreatic cancer mouse model. Ruxilitinib-mediated tumor suppressive efficacy diminishes in T-cell-deficient mice. Pancreatic tumor grows significantly faster in IFNγ-deficient mice. However, neutralizing IFNγ does not alter tumor growth but diminishes Ruxolitinib-induced tumor suppression in vivo, indicating that lymphocytes and IFNγ are essential for Ruxolitinib-induced host antitumor immune response. Both type I and type II interferons upregulate PD-L1 expression through the JAK-STAT signaling pathway in mouse pancreatic tumor cells. Tumor cells respond to activated T cells by activating STAT3. The inhibition of STAT3 downregulates immune suppressive cytokines production by tumor cells, resulting in increased T cell activation and effector function. Consequently, Ruxolitinib significantly improves the efficacy of anti-PD-1 immunotherapy. Our data demonstrate that Ruxolitinib is effective in the inhibition of systemic inflammation in the tumor microenvironment and therefore upregulates CTL infiltration and activation to overcome pancreatic cancer resistance to anti-PD-1 immunotherapy.

Reduced Klotho expression contributes to poor survival rates in human patients with ovarian cancer, and overexpression of Klotho inhibits the progression of ovarian cancer partly via the inhibition of systemic inflammation in nude mice.

Klotho is a recently discovered anti‑aging gene, which has been reported as a tumor suppressor in numerous human malignancies; however, the role of Klotho in human ovarian cancer remains to be elucidated. The aim of the present study was to detect the expression of Klotho and evaluate its association with the progression of human ovarian cancer. A clinical follow‑up study of 120patients with ovarian cancer and 78normal controls was conducted. The expression levels of Klotho were determined by western blotting and immunohistochemistry. The results demonstrated that high Klotho expression levels were detected in all normal controls, whereas the positive rate of Klotho was 61.6% in the ovarian cancer group, which was significantly decreased compared with in the control group (P<0.01). Furthermore, reduced Klotho expression was significantly correlated with decreased survival rates in patients with ovarian cancer (P=0.025). Subsequently, Klotho levels were detected in seven human ovarian cancer cell lines by western blotting. The results demonstrated that the highest levels of Klotho were detected in CaOV3 cells, medium levels of Klotho were detected in CaOV4 and SKOV‑3 cells, and almost no Klotho was detected in the other four cell lines: OVCA432, OVCAR‑5, OVCAR‑8 and A2780 cells. The association between Klotho levels and cell proliferation was determined by MTT assay, and the results indicated that higher levels of Klotho inhibited the proliferation of A2780 and OVCAR‑5 cells, whereas reduced Klotho expression promoted cell growth of CaOV3 and SKOV‑3 cells. In addition, the plasma levels of inflammatory cytokines in tumor‑bearing mice and normal control mice were detected by enzyme‑linked immunosorbent assay, and plasma interleukin (IL)‑6 and IL‑1β levels were elevated in all tumor‑bearing mice. Notably, the mRNA expression levels of IL‑6 were significantly higher in the liver, ovaries and kidneys of Klotho‑/‑ mice compared with in wild type mice (P<0.01), thus indicating that aberrant Klotho expression may contribute to systemic inflammation in Klotho‑/‑ mice. Finally, the invivo antitumor role of aberrant Klotho expression was determined in a nude mice model. A2780 cells were transfected with pCMV6‑Klotho and the stably transfected cells were screened; the mice were injected with the stably transfected cells. The results indicated that tumor volume and tumor weight were significantly decreased in the pCMV6‑Klotho group compared with in the pCMV6 vector group (P<0.01). These findings suggest that overexpression of Klotho may suppress tumor growth in animal models. In conclusion, Klotho was demonstrated to act as a potent tumor suppressor in human ovarian cancer cells. Reduced Klotho expression was detected in the specimens of patients with ovarian cancer, and overexpression of Klotho significantly inhibited cell proliferation of human ovarian cancer cells. Therefore, Klotho may be considered a useful key target for the molecular therapy of human ovarian cancer.

Plasma Transfusion: History, Current Realities, and Novel Improvements.

Traumatic hemorrhage is the leading cause of preventable death after trauma. Early transfusion of plasma and balanced transfusion have been shown to optimize survival, mitigate the acute coagulopathy of trauma, and restore the endothelial glycocalyx. There are a myriad of plasma formulations available worldwide, including fresh frozen plasma, thawed plasma, liquid plasma, plasma frozen within 24 h, and lyophilized plasma (LP). Significant equipoise exists in the literature regarding the optimal plasma formulation. LP is a freeze-dried formulation that was originally developed in the 1930s and used by the American and British military in World War II. It was subsequently discontinued due to risk of disease transmission from pooled donors. Recently, there has been a significant amount of research focusing on optimizing reconstitution of LP. Findings show that sterile water buffered with ascorbic acid results in decreased blood loss with suppression of systemic inflammation. We are now beginning to realize the creation of a plasma-derived formulation that rapidly produces the associated benefits without logistical or safety constraints. This review will highlight the history of plasma, detail the various types of plasma formulations currently available, their pathophysiological effects, impacts of storage on coagulation factors in vitro and in vivo, novel concepts, and future directions.

Inhibition of platelet function with clopidogrel is associated with a reduction of inflammation in patients with peripheral artery disease.

The reactivity of platelets is increased in patients with peripheral artery disease (PAD). RANTES and sCD40L are chemokines which are stored in the alpha-granules of platelets. Clopidogrel inhibits and thus reduces platelet reactivity. Whether a treatment with clopidogrel is associated with an inhibition of systemic inflammation in patients with PAD has not been thoroughly explored. This study examined the effect of clopidogrel on platelet reactivation and the release of inflammatory chemokines in patients with PAD. 40 patients with PAD were randomized into two groups. In the first group A the patients were treated with 100mg acetylsalicylic acid (ASA) and additional placebo for 4weeks. The patients in group B received 75mg/d clopidogrel in addition to ASA 100mg for 4weeks. After obtaining blood at days 0, 7 and 28 the platelet activation was determined by measuring the surface protein expression of CD63, CD62p and thrombospondin (TSP) after stimulation with TRAP and ADP. The release of the chemokines RANTES and sCD40L from platelets was analyzed by ELISA. Platelet activation markers (CD62p and CD63) and chemokine RANTES were significantly reduced in patients with PAD after 7 and 28days after treatment with clopidogrel. No alterations were found in TSP expression and sCD40L during the treatment. The treatment with clopidogrel leads to a reduction of platelet reactivity and release of RANTES from the platelets of patients with PAD.

Abstract 3435: Notch signaling and inflammation in a murine model of sarcoma-associated cachexia

Abstract Introduction Cachexia is characterized by progressive muscle loss. Cancer-associated cachexia (CAC) affects over 50% of oncology patients, correlates with advanced disease stage, and shorter progression-free survival. TNF-α is implicated in CAC. TNF-α and klotho are antagonistic: decreased klotho causes susceptibility to inflammation. Notch receptors regulate muscle stem cell (MSC) function. Active Notch signaling inhibits differentiation and maintains MSC quiescence. Notch upregulates Pax7 expression, inhibiting MSC differentiation. Hes1 expression indicates active Notch signaling. Sarcomas are malignancies of the connective tissues. Sarcoma patients experience musculoskeletal impairment and are uniquely susceptible to cachexia. The mechanisms of sarcoma-associated cachexia (SAC) are unknown. Here we describe SAC in a mouse model of osteosarcoma (OS). Methods 1. Mouse Model of OS: 2 × 105 K7M2 OS cells were injected into right hindlimb tibias of 4-week old SCID/Beige mice. After 4 weeks, the right hindlimb was amputated to render mice free of primary but not metastatic disease. Mice were sacrificed 10 weeks post-injection. 2. Histology: Muscle tissues from the contralateral hindlimbs of tumor-bearing animals and the hindlimbs of control animals were harvested for histology. 3. Immunohistochemistry (IHC): Immunostains for Notch3 and Pax7 were performed on tumors, contralateral hindlimbs from tumor-bearing animals, and control hindlimbs. 4. RT-PCR: The expressions of TNF-α, klotho, and Hes1 were compared in tumor tissue, muscle from tumor-bearing animals, and control muscle. 5. Co-Culture:Muscle stem cells (MSCs) were co-cultured with other MSCs or OS cells in a transwell system. MSC differentiation was assessed with IHC for fast-type myosin heavy chain. Results 1. Atrophy was appreciated in uninjected hindlimbs of sarcoma-bearing animals compared with controls. 2. Muscle from sarcoma-bearing animals displayed smaller myofibers and greater fibrosis than controls, indicating atrophy and systemic inflammation. 3. IHC for Notch3 showed intratumoral positivity. Greater Notch3 positivity, Pax7 positivity, and colocalization were appreciated in atrophic muscle from experimental animals compared with control muscle. 4. There was greater TNF-α and less klotho expression in both tumors and skeletal muscle of sarcoma-bearing animals compared with normal muscle. Hes1 expression was greater in tumor and atrophic muscle than normal muscle. 5. Co-culture with OS cells resulted in decreased MSC differentiation. Co-culture in the presence of a Notch inhibitor rescued myogenic differentiation. Conclusion These data suggest that sarcoma may cause SAC via two mechanisms: (1)-TNF-α-mediated inflammation, and (2)-the dysregulation of MSC homeostatsis by aberrant Notch signaling. The inhibition of systemic inflammation and Notch signaling may represent novel strategies to combat SAC. Citation Format: Kurt R. Weiss, Xiaodong Mu, Rashmi Agarwal. Notch signaling and inflammation in a murine model of sarcoma-associated cachexia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3435. doi:10.1158/1538-7445.AM2015-3435

Cardiovascular effects of methotrexate in rheumatoid arthritis revisited.

Cardiovascular events such as myocardial infarction (MI) and stroke due to enhanced inflammatory atherosclerosis account for increased premature mortality in rheumatoid arthritis (RA). Accumulated evidence suggests that accelerated atherosclerosis and related cardiovascular comorbidities in RA are confounded not only by traditional risk factors (TRF) but also by a number of immune and inflammatory pathways. Since chronic inflammation and autoimmune disorders play a key role in atherosclerosis and related cardiovascular complications in RA, effective suppression of systemic inflammation can be viewed as a strategy for cardiovascular therapy and prevention in this disease. This article overviews some mechanisms of action of methotrexate on TRF, clinical and subclinical manifestations of RA-induced atherosclerosis, and related cardiovascular morbidity and mortality.

Psoriasis is a systemic disease with multiple cardiovascular and metabolic comorbidities.

There is evidence that patients with moderate to severe psoriasis have an increased risk of conditions such as cardiovascular disease, obesity, diabetes mellitus, and metabolic syndrome. The precise mechanisms underlying the observed increase in cardiovascular disease in psoriasis remain to be defined but inflammatory pathways mutual to both conditions are probably involved. Suppression of systemic inflammation in psoriasis could help reduce cardiovascular inflammation but robust evidence is still lacking evidence is lacking. This article summarizes the current literature on cardiovascular and metabolic comorbidities in psoriasis, identifies research gaps, and suggests management strategies to reduce cardiovascular risk in patients with moderate to severe psoriasis.

AB0578 Tocilizumab influence on the serum lipid profiles and rapid progression of intima media-thickness in patients with rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is characterized by a high risk of cardiovascular events (CVE) associated with atherosclerosis (AS). A key role in the development of AS belongs to rheumatoid inflammation. Influence...