C-reactive protein as an effector molecule in Covid-19 pathogenesis.

The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.

Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation.

Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.

A pilot study of the effects of chromium picolinate supplementation on serum fetuin-A, metabolic and inflammatory factors in patients with nonalcoholic fatty liver disease: A double-blind, placebo-controlled trial.

BACKGROUND: Evaluating the impact of chromium picolinate supplementation on glycemic status, lipid profile, inflammatory markers and fetuin-A in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: In present research, participants (N = 46) were randomized to (400 mcg/day, n = 23) chromium picolinate and placebo (n = 23) for 3 months. RESULTS: Glucose indices, and lipid profiles, inflammatory biomarker and fetuin-A were measured before and after the intervention. Chromium reduced triglyceride (TG), atherogenic index of plasma (AIP), very-low-density lipoprotein (VLDL), insulin, homeostatic model assessment for insulin resistance (HOMA-IR), high-sensitivity C-reactive protein (hs-CRP), interleukin (IL) -6, tumor necrosis factor-alpha (TNF-α) and fetuin-A significantly compared to placebo group (p < 0.05). Furthermore, chromium significantly increased the quantitative insulin sensitivity check index (QUICKI). There were no significant differences in total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), fasting blood sugar (FBS), Hemoglobin A1c (HbA1C), interleukin (IL)-17 between the two groups (p < 0.05). CONCLUSION: Chromium picolinate significantly decreased TG, insulin, HOMA-IR, fetuin-A, the number of inflammatory factors, and increased QUICKI without changing FBS, HbA1C, TC, LDL, HDL, IL-17 levels and liver steatosis intensity in patients with NAFLD. Further studies by examining the effect of different doses of chromium and mechanisms of cellular action, would help further clarify the subject.

Long non coding RNA SLC26A4-AS1 exerts antiangiogenic effects in human glioma by upregulating NPTX1 via NFKB1 transcriptional factor.

Malignant gliomas are a heterogeneous group of brain tumors with a poor prognosis, which is largely due to its aggressive invasiveness and angiogenesis. In recent years, it has been found that multiple long noncoding RNAs (lncRNAs) participate in a wide range of biological functions including angiogenesis through the regulation of gene expression in cancers. In this study, we investigate and report the novel role of lncRNA SLC26A4-AS1 in gliomas, with a novel mechanism involving transcription factors NFKB1 and NPTX1. We determined that SLC26A4-AS1 was downregulated in human glioma tissues and cells. Furthermore, overexpression of SLC26A4-AS1 or NPTX1 restrained the aggressiveness of glioma cells and their pro-angiogenic ability. SLC26A4-AS1 was also found to upregulate NPTX1 by recruiting NFKB1 into the NPTX1 promoter. Moreover, silencing of either NPTX1 or NFKB1 restored the aggressive and pro-angiogenic properties of glioma cells in the presence of SLC26A4-AS1. Taken together, we demonstrate that SLC26A4-AS1 promotes NPTX1 transcriptional activity by recruiting NFKB1 and thus exerting antiangiogenic effects on glioma cells. This study provides an experimental basis for the intervention of SLC26A4-AS1 in the treatment of gliomas.

Biphasic roles of pentraxin 3 in cerebrovascular function after white matter stroke.

Recent clinical studies suggest that pentraxin 3 (PTX3), which is known as an acute-phase protein that is produced rapidly at local sites of inflammation, may be a new biomarker of disease risk for central nervous system disorders, including stroke. However, the effects of PTX3 on cerebrovascular function in the neurovascular unit (NVU) after stroke are mostly unknown, and the basic research regarding the roles of PTX3 in NVU function is still limited. In this reverse translational study, we prepared mouse models of white matter stroke by vasoconstrictor (ET-1 or L-Nio) injection into the corpus callosum region to examine the roles of PTX3 in the pathology of cerebral white matter stroke. PTX3 expression was upregulated in GFAP-positive astrocytes around the affected region in white matter for at least 21 days after vasoconstrictor injection. When PTX3 expression was reduced by PTX3 siRNA, blood-brain barrier (BBB) damage at day 3 after white matter stroke was exacerbated. In contrast, when PTX3 siRNA was administered at day 7 after white matter stroke, compensatory angiogenesis at day 21 was promoted. In vitro cell culture experiments confirmed the inhibitory effect of PTX3 in angiogenesis, that is, recombinant PTX3 suppressed the tube formation of cultured endothelial cells in a Matrigel-based in vitro angiogenesis assay. Taken together, our findings may support a novel concept that astrocyte-derived PTX3 plays biphasic roles in cerebrovascular function after white matter stroke; additionally, it may also provide a proof-of-concept that PTX3 could be a therapeutic target for white matter-related diseases, including stroke.

Potent repression of C-reactive protein (CRP) expression by the JAK1/2 inhibitor ruxolitinib in inflammatory human hepatocytes.

OBJECTIVE AND DESIGN: To determine whether inflammatory hepatocytes may constitute primary targets for ruxolitinib, a Janus kinase (JAK) inhibitor, its effects towards expression of hepatic acute-phase proteins, especially C-reactive protein (CRP), were assessed. MATERIALS: Ruxolitinib effects were analysed in primary human hepatocytes and human hepatoma HepaRG cells exposed to various inflammatory stimuli. RESULTS: Ruxolitinib was found to fully inhibit lipopolysaccharide (LPS)-induced CRP secretion and mRNA expression, at concentrations (IC50 = 12.9 nM) achievable in human blood. It similarly repressed CRP up-regulation due to several Toll-like receptor agonists or pro-inflammatory cytokines [interleukin (IL) 1ß, IL6 and tumour necrosis factor α] and counteracted LPS-mediated induction of serum amyloid A, fibrinogen, haptoglobin and serpin. Ruxolitinib was additionally found to block the activation of the IL6/JAK/signal transducer and activator of transcription (STAT) pathway triggered by LPS and whose inhibition by the neutralizing anti-IL6 receptor antibody tocilizumab prevented CRP induction. CONCLUSION: Ruxolitinib can potently repress induction of CRP in inflammatory human hepatocytes, most likely through targeting the IL6/JAK/STAT signalling cascade. Hepatic production of acute-phase proteins during liver inflammation may, therefore, constitute a target for ruxolitinib.

Hsa_circ_0070269 inhibits hepatocellular carcinoma progression through modulating miR-182/NPTX1 axis.

Circular RNAs (circRNAs) have recently been shown to play critical roles in tumorigenesis. However, the roles of circRNAs in hepatocellular carcinoma (HCC) remain largely unknown. In the present study, we identified a novel circRNA (hsa_circ_0070269) was significantly decreased in HCC tissues and cell lines, low hsa_circ_0070269 expression was positively associated with advanced tumor stage, lymph node metastasis, and poor overall survival. Hsa_circ_0070269 overexpression suppressed proliferation and invasion of HCC cells in vitro and reduced tumor growth in vivo. Mechanistically, hsa_circ_0070269 increased NPTX1 expression via sponging miR-182 in HCC cells, which inhibited aggressive tumor behavior. Taken together, our findings suggest that hsa_circ_0070269 might play an important role in HCC development via miR-182/NPTX1 axis, therefore could serve as a potential therapeutic target for HCC treatment.

Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting specific IL (interleukin) signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF [tumor necrosis factor]) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) has shown that specific targeting of IL-1ß can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine-targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1ß, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 contemporary trials provide proof of principle that focused cytokine inhibition, not broad-spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.

A simple and rapid-acting approach for the reduction of C-reactive protein.

C-reactive protein (CRP) is an acute-phase protein which can bind to and aggregate oxidized low-density lipoprotein (ox-LDL) particles, thereby enhancing the uptake of oxLDL by macrophages. This finally leads to the formation of foam cells that are a typical characteristic of atherosclerotic plaques. Serum CRP has been shown to bind to phospholipids such as phophatidylcholine (PC), phosphatidylglycerol (PG) and phosphatidylserine (PS). Owing to the rapid and efficient clearance of nanoliposomes from the circulation by the liver, we hypothesized that nanoliposomes composed of the mentioned phospholipids can serve as a potential tool to lower elevated serum CRP levels following acute inflammation. To evaluate this hypothesis, nanoliposomal formulations containing hydrogenated soy phosphatidylcholine (HSPC), a combination of HSPC and 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG), and a combination of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS) were prepared using lipid film hydration method followed by extrusion at the final concentration of 20 mM. To elevate circulating CRP levels in mice, 0.1 ml of Freund's complete adjuvant (CFA) containing 5 mg/ml heat-killed Mycobacterium tuberculosis was subcutaneously injected into the hind paw of the mice. CFA-challenged mice were intravenously treated with nanoliposomal formulations at the dose of 250 µmol/kg 16 h after CFA challenge that is coincided with peak serum CRP level. After 2 h, the blood was collected and serum level of CRP was measured using a quantitative sandwich enzyme-linked immunosorbent assay. All nanoliposomal formulations showed a size range from 100 to 150 nm in diameter and a polydispersity index of < 0.1. Results showed that all nanoliposomal formulations including DOPC/DOPS, HSPC and HSPC/DSPG could significantly decrease serum levels of CRP by 82.76% (74.44-86.92%, p = 0.0001), 44.41% (35.79-50.21%, p = 0.0001) and 38.47% (17.21-43.52%, p=0.0002) [Median (interquartile range)], respectively, when compared with the control group. Dexamethasone as a standard could decrease serum CRP level by 27.47% (16.32-31.63%, p = 0.0025) which was a smaller effect compared with the nanoliposomal preparations. In conclusion, negatively charged nanoliposomes could efficiently reduce the elevated serum levels of CRP in CFA-challenged mice.

Identification of the C-Reactive Protein Interaction Network Using a Bioinformatics Approach Provides Insights into the Molecular Pathogenesis of Hepatocellular Carcinoma.

BACKGROUND/AIMS: C reactive protein (CRP) levels are elevated in many diseases, including malignant tumors and cardiovascular disorders. In this study, the protein interaction network for CRP was evaluated to determine the importance of CRP and its interacting proteins in the molecular pathogenesis of hepatocellular carcinoma (HCC). METHODS: Isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometry were used to identify CRP interacting proteins in SMMC7721 cells. Moreover, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to evaluate enriched genes and pathways for differentially expressed genes using DAVID and WebGestalt. Co-immunoprecipitation and western blot analyses were employed to assess interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1. RESULTS: In total, 52 proteins that interact with CRP were identified. A GO analysis suggested that most of the interacting proteins were involved in CRP complexes and regulated metabolic processes. A KEGG pathway analysis suggested that most CRP-interacting proteins contribute to the TRAIL signaling pathway, Class I PI3K/Akt signaling pathway, plasma membrane estrogen receptor signaling, Nectin adhesion pathway, and S1P1 pathway. Immunoprecipitation and western blot analyses revealed interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1. CONCLUSIONS: iTRAQ based proteomic profiling revealed the network of CRP interacting proteins. This network may activate the PI3K/Akt signaling pathway, thereby contributing to the pathogenesis of HCC.

Antibodies against monomeric C-reactive protein - a promising biomarker of lupus nephritis?

OBJECTIVE AND AIM: A significant incidence of systemic lupus erythematosus (SLE), the severity of lupus nephritis and varying responses to treatment rationalize the search for novel biomarkers of disease activity. The aim of the study was to assess whether antibodies against monomeric C reactive protein (anti-mCRP) are associated with the presence of lupus nephritis, correlate with disease activity, and whether they can serve to evaluate a response to treatment. METHODS: The study involved 74 patients with lupus nephritis, 29 patients with systemic lupus without renal involvement and 31 patients with primary glomerulonephritis; the control group included 31 healthy volunteers. Interleukin-6 and tumor necrosis factor alpha were measured using commercially available ELISA tests. The presence of anti-mCRP in the serum was tested with the use of in-house ELISA. RESULTS: The highest prevalence and concentrations of antibodies against monomeric C-reactive protein were observed among patients with lupus nephritis, as compared to other groups. The elevated level of anti-mCRP was associated with standard clinical and laboratory indicators of SLE activity. Moreover, the highest concentrations of both Il-6 and TNF-α were observed for patients with the most severe nephropathy. A significant decrease in anti-mCRP and cytokines' levels in the course of treatment was observed. CONCLUSION: The study gives further evidence that antibodies against monomeric C-reactive protein may be considered an indicator of renal involvement in patients with SLE. Assessment of anti-mCRP supports monitoring of disease activity and can be used in evaluating the treatment effectiveness.

Targeting Immunity in End-Stage Renal Disease.

BACKGROUND: Despite the stable incidence of end-stage renal disease (ESRD), it continues to be associated with an unacceptably high cardiovascular risk. SUMMARY: ESRD is characterized by enhanced oxidative stress and severe inflammation, which boost cardiovascular risk, thus increasing cardiovascular-associated mortality rate. While substantial effort has been made in the technological innovation of dialytic techniques, few significant advances have been made to reduce inflammation in patients with ESRD. Indeed, this contrasts with the extensive scientific breakthroughs made in the basic field of science in targeting inflammation. There is thus a pressing need for clinical trials to test the effect of reducing inflammation in patients with ESRD. Here, we will revisit the negative effect of ESRD on inflammation and explore the impact of enhanced inflammation on cardiovascular outcomes and survival in patients with ESRD. Finally, we will discuss the need for clinical trials that target inflammation in ESRD, as well as weigh potential disadvantages and offer novel innovative approaches. Key Message: We will try to understand why the issue of inflammation has not been successfully addressed thus far in patients with ESRD, while at the same time weighing the potential disadvantages and offering novel innovative approaches for targeting inflammation in patients with ESRD.

Presynaptic Neuronal Pentraxin Receptor Organizes Excitatory and Inhibitory Synapses.

Three neuronal pentraxins are expressed in brain, the membrane-bound "neuronal pentraxin receptor" (NPR) and the secreted proteins NP1 and NARP (i.e., NP2). Neuronal pentraxins bind to AMPARs at excitatory synapses and play important, well-documented roles in the activity-dependent regulation of neural circuits via this binding activity. However, it is unknown whether neuronal pentraxins perform roles in synapses beyond modulating postsynaptic AMPAR-dependent plasticity, and whether they may even act in inhibitory synapses. Here, we show that NPR expressed in non-neuronal cells potently induces formation of both excitatory and inhibitory postsynaptic specializations in cocultured hippocampal neurons. Knockdown of NPR in hippocampal neurons, conversely, dramatically decreased assembly and function of both excitatory and inhibitory postsynaptic specializations. Overexpression of NPR rescued the NPR knockdown phenotype but did not in itself change synapse numbers or properties. However, the NPR knockdown decreased the levels of NARP, whereas NPR overexpression produced a dramatic increase in the levels of NP1 and NARP, suggesting that NPR recruits and stabilizes NP1 and NARP on the presynaptic plasma membrane. Mechanistically, NPR acted in excitatory synapse assembly by binding to the N-terminal domain of AMPARs; antagonists of AMPA and GABA receptors selectively inhibited NPR-induced heterologous excitatory and inhibitory synapse assembly, respectively, but did not affect neurexin-1ß-induced synapse assembly as a control. Our data suggest that neuronal pentraxins act as signaling complexes that function as general trans-synaptic organizers of both excitatory and inhibitory synapses by a mechanism that depends, at least in part, on the activity of the neurotransmitter receptors at these synapses. SIGNIFICANCE STATEMENT: Neuronal pentraxins comprise three neuronal proteins, neuronal pentraxin receptor (NPR) which is a type-II transmembrane protein on the neuronal surface, and secreted neuronal pentraxin-1 and NARP. The general functions of neuronal pentraxins at synapses have not been explored, except for their basic AMPAR binding properties. Here, we examined the functional role of NPR at synapses because it is the only neuronal pentraxin that is anchored to the neuronal cell-surface membrane. We find that NPR is a potent inducer of both excitatory and inhibitory heterologous synapses, and that knockdown of NPR in cultured neurons decreases the density of both excitatory and inhibitory synapses. Our data suggest that NPR performs a general, previously unrecognized function as a universal organizer of synapses.

Impact of a Proprietary Standardized Olive Fruit Extract (SOFE) on Cardio-Ankle Vascular Index, Visual Analog Scale and C-Reactive Protein Assessments in Subjects with Arterial Stiffness Risk.

INTRODUCTION: The chemical components of olive fruit provide a wide range of cardiovascular benefits. Arterial stiffness is an important cardiovascular risk factor and can be assessed using the Cardio-Ankle Vascular Index (CAVI). OBJECTIVE: The objective of this study was to assess the impact of a proprietary standardized olive fruit extract (SOFE) in subjects at risk for arterial stiffness. METHODS: Twelve of 36 subjects were assigned to each of the following groups for this 11-day, double-blind, placebo-controlled study: Group 1: 250 mg SOFE-50 mg active ingredient, hydroxytyrosol (dosage achieved with two capsules per day); Group 2: 500 mg SOFE-100 mg active ingredient, hydroxytyrosol (dosage achieved with two capsules per day); and Group 3: placebo. RESULTS: All three groups showed a decrease in CAVI scores, although no significant between-group differences were observed. Group 2 had the largest reduction, with mean CAVI scores decreasing from 11.02 to 8.91. Group 2 showed the strongest response in visual analog scale (VAS) energy intensity (11.71% increase). Results for C-reactive protein (CRP) blood levels showed no changes of statistical significance between groups. Mean triglyceride levels from Group 2 decreased by 21.64%, the most significant change among all three groups. CONCLUSIONS: SOFE, an olive fruit extract containing many of the phytochemicals shown to provide cardiovascular benefits, was safe and well-tolerated. SOFE 500 mg had a greater effect on CAVI scores, suggesting improved arterial elasticity, and a clear reduction in triglycerides compared with placebo and SOFE 250 mg. The decreased CAVI scores suggest that increasing high-density lipoprotein cholesterol and lowering triglycerides with SOFE could potentially reduce patients' risk of developing atherosclerosis. Although more studies are needed, positive cardiovascular health trends, including improved vessel elasticity and positive triglyceride effects, were evident with SOFE.

Long-term effect of antiepileptic drug switch on serum lipids and C-reactive protein.

BACKGROUND: Prior studies have shown that switching patients from inducing antiepileptic drugs (AEDs) to lamotrigine, levetiracetam, or topiramate reduces serum lipids and C-reactive protein (CRP). These studies were all of short duration, and some drugs, such as zonisamide, have not been investigated. METHODS: We recruited 41 patients taking phenytoin or carbamazepine who were being switched to zonisamide, lamotrigine, or levetiracetam. We measured serum lipids and CRP before the switch, >6weeks after, and >6months after. An untreated control group (n=14) underwent similar measurement. We combined these data with those of our previous investigation (n=34 patients and 16 controls) of a very similar design. RESULTS: There were no differences in outcome measures between the two inducing AEDs nor among the three noninducing AEDs. Total cholesterol (TC), atherogenic lipids, and CRP were higher under inducer treatment than in controls. All measures were elevated under inducer treatment relative to noninducer treatment, including TC (24mg/dL higher, 95% CI: 17.5-29.9, p<0.001) and CRP (72% higher, 95% CI: 41%-111%, p<0.001). The difference between drug treatments was clinically meaningful for atherogenic lipids (16%, 95% CI: 11%-20%, p<0.001) but small for high-density lipoprotein cholesterol (5%, 95% CI: 1%-9%, p<0.05). All measures were stable between 6weeks and 6months after drug switch. CONCLUSIONS: We demonstrate that switching from inducing to noninducing AEDs produces an enduring reduction in serum lipids and CRP. These results provide further evidence that inducing AEDs may be associated with elevated vascular disease risk. These are the first vascular risk marker data in patients taking zonisamide, which shows a profile similar to that of other noninducing AEDs.

From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection.

Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1ß-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1ß activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1ß, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.

Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp.

One of the cardinal features of neural development and adult plasticity is the contribution of activity-dependent signaling pathways. However, the interrelationships between different activity-dependent genes are not well understood. The immediate early gene neuronal-activity-regulated pentraxin (NPTX2 or Narp) encodes a protein that has been associated with excitatory synaptogenesis, AMPA receptor aggregation, and the onset of critical periods. Here, we show that Narp is a direct transcriptional target of brain-derived neurotrophic factor (BDNF), another highly regulated activity-dependent gene involved in synaptic plasticity. Unexpectedly, Narp is bidirectionally regulated by BDNF. Acute BDNF withdrawal results in downregulation of Narp, whereas transcription of Narp is greatly enhanced by BDNF. Furthermore, our results show that BDNF directly regulates Narp to mediate glutamatergic transmission and mossy fiber plasticity. Hence, Narp serves as a significant epistatic target of BDNF to regulate synaptic plasticity during periods of dynamic activity.

The association of antidepressant medications and diabetic retinopathy among people with diabetes.

OBJECTIVE: To determine if the use of antidepressants was associated with lower odds of diabetic retinopathy and if so, to determine if this association was mediated by decreased inflammation as measured by C-reactive protein (CRP). DESIGN: This was a cross sectional study of 1,041 participants with type 2 diabetes 40-85years old from the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression was used to examine the association between the outcome of diabetic retinopathy and the primary exposure of antidepressant medication usage. We also determined whether CRP meets standard criteria as a mediator between antidepressant use and diabetic retinopathy. RESULTS: Participants using antidepressants were less likely to have diabetic retinopathy (OR 0.50, 95% CI: 0.31-0.82). CRP did not meet one of the criteria for mediation. However, CRP was an effect modifier such that the association of antidepressant use and diabetic retinopathy was only present among participants with CRP ≥0.3mg/dl. Among the antidepressant drug classes, selective serotonin reuptake inhibitor (SSRI) users had significantly lower odds of developing diabetic retinopathy compared to non-users of antidepressants. CONCLUSIONS: Using representative survey data of US adults with type-2 diabetes, this study found that antidepressant use was associated with lower odds of diabetic retinopathy. Further longitudinal and experimental studies are necessary to confirm this finding and to determine if there is a role for antidepressants in preventing diabetic retinopathy in select patient populations.

Emodin Inhibits Homocysteine-Induced C-Reactive Protein Generation in Vascular Smooth Muscle Cells by Regulating PPARγ Expression and ROS-ERK1/2/p38 Signal Pathway.

Atherosclerosis is an inflammatory disease. As an inflammatory molecule, C-reactive protein (CRP) plays a direct role in atherogenesis. It is known that the elevated plasma homocysteine (Hcy) level is an independent risk factor for atherosclerosis. We previously reported that Hcy produces a pro-inflammatory effect by inducing CRP expression in vascular smooth muscle cells (VSMCs). In the present study, we observed effect of emodin on Hcy-induced CRP expression in rat VSMCs and molecular mechanisms. The in vitro results showed that pretreatment of VSMCs with emodin inhibited Hcy-induced mRNA and protein expression of CRP in a concentration-dependent manner. The in vivo experiments displayed that emodin not only inhibited CRP expression in the vessel walls in mRNA and protein levels, but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further study revealed that emodin diminished Hcy-stimulated generation of reactive oxygen species (ROS), attenuated Hcy-activated phosphorylation of ERK1/2 and p38, and upregulated Hcy-inhibited expression of peroxisome proliferator-activated receptor gamma (PPARγ) in VSMCs. These demonstrate that emodin is able to inhibit Hcy-induced CRP generation in VSMCs, which is related to interfering with ROS-ERK1/2/p38 signal pathway and upregulating PPARγ expression. The present study provides new evidence for the anti-inflammatory and anti-atherosclerotic effects of emodin.

Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers.

The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers.