The association between CD4+ CD25+ regulatory T cells and non-small cell lung carcinoma

Lung cancer is the second most common malignancy in the USA, and it is the leading cause of cancer-related deaths among men and women. Regulatory T cells (Tregs) in peripheral blood play crucial roles in suppressing antitumor immune responses in cancer patients. A defect in the immune response may contribute to tumor growth. This study was conducted to test the hypothesis that regulatory T cell lymphocytes might contribute to immune dysfunction in non-small cell lung carcinoma (NSCLC) patients, with a specific aim of determining its role in the development and progression of NSCLC. CD4+ CD25+ Treg cell enumeration by flow cytometry was performed for 30 NSCLC patients both preoperatively and postoperatively, together with 20 controls. Higher percentages of CD4+ CD25+ Treg cells were found in NSCLC patients both pre- (11.24?±?5.34) and postoperatively (8.75?±?4.66) in comparison to the control group (2.16?±?0.97); this difference was statistically significant (p?NSCLC patients: healthy donor < stage I < stage II < stage III whether preoperatively (r?=?0.5, p?=?0.005) or postoperatively (r?=?0.4, p?=?0.008). Treg cells decreased significantly after surgical removal of the tumors, from 11.24?±?5.34 to 8.75?±?4.66; the difference was statistically significant (p?NSCLC patients; their percentage correlates with tumor staging, and it decreases following surgical removal of the tumor. Thus, manipulation of these regulatory T cells could lead to new strategies for the treatment of cancer.     

The utility of IgG,IgM, and CD138 immunohistochemistry in the evaluation of autoimmune liver diseases

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) present with distinct clinical features. The term “PBC–AIH overlap syndrome (OS)” has been adopted to describe the condition characterized by occurrence of both PBC and AIH, although this clinical entity is difficult to define. This study aimed to assess the utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of AIH, PBC, and OS. Immunohistochemistry was performed with anti-human IgG, IgM, and CD138 to detect specific plasma cells in the liver. Predominant IgG staining was observed in AIH (85.7 %), while equivocal (46.1 %) or predominant (38.5 %) IgM staining was observed in PBC. In OS, equivocal (20 %) or predominant (80 %) IgG staining was observed. The IgM/IgG ratio was significantly higher in PBC than in AIH or OS (P < 0.005). Histological findings revealed significantly higher IgM expression in PBC at cholangitis activity grades 2–3 compared to those at cholangitis activity grades 0–1. In contrast, a significantly higher IgG expression was observed in PBC at hepatitis activity and fibrosis grades 2–3 compared to those at hepatitis activity and fibrosis grades 0–1. Taken together, periportal plasmacytic infiltrates with variable immunohistochemistry patterns of IgG and IgM expression characterized different autoimmune liver diseases.     

Analytical issues possibly affecting the performance of commercial human cytomegalovirus IgG avidity assays

In the majority of cytomegalovirus (CMV) immunoglobulin G (IgG) avidity assays, avidity determination can be performed on the entire CMV IgG measurable positive concentration range. However, in some exceptional samples with very low IgG levels, inappropriately low avidity indexes have been described. In this study, we addressed some possible causes and the clinical importance of these inappropriately low avidity indexes. We compared VIDAS (bioMérieux), Liaison (DiaSorin), and Architect (Abbott) CMV IgG avidity assays on 129 samples from patients with past CMV infections, focusing on samples with low IgG levels. Inappropriately low avidity samples were further evaluated using seven different urea-based IgG avidity assays. We confirmed that inappropriately low avidity indexes in samples with very low IgG levels occur, but are rare. We could show that this phenomenon is not confined to a single assay and that assays employing chaotropic agents are affected more frequently and profoundly. In situations where the CMV IgG avidity is performed on CMV immunoglobulin M (IgM)-negative samples, the avidity index should be interpreted cautiously in cases of very low CMV IgG levels, whatever the technique used.     

Expression of human T cell immunoglobulin domain and mucin-3 on kidney tissue from immunoglobulin A nephropathy patients

The aim of this study was to evaluate the expression of human T cell immunoglobulin domain and mucin-3 (Tim-3) in renal tissue from patients with immunoglobulin A nephropathy (IgAN) and without IgAN and to evaluate the difference in Tim-3 expression between them. A total of 71 patients with IgAN as IgA group and 13 patients without IgAN as control group were enrolled in the present study. Patients in IgAN accepted percutaneous renal biopsy. We examined the expression of Tim-3 in renal tissue and the serological parameters in serum from all enrolled cases. The expression of Tim-3 and serological parameters were compared between the different groups. Positive staining of Tim-3 protein was seen in 94.3 % patients with IgAN (67 out of 71), but only 15.4 % (2 out of 13) in the cases without IgAN were positive staining of Tim-3. There were significant differences between two groups in almost all serological markers, which reflect IgAN activity. There was a nearly positive correlation between pathological manifestations and expression degree of Tim-3. High immuno-reactivity of Tim-3 was found to be significantly correlated with serological grade (p < 0.001) in IgA group, but there was no such phenomenon in control group. The results showed that there was the expression of Tim-3 in renal tissue from the patients with IgAN, but rarely expression in cases without IgAN. Expression of Tim-3 was associated with the diseases’ activity.     

Histopathological characterization of ductal carcinoma in situ (DCIS) of the breast according to HER2 amplification status and molecular subtype

This study aimed to characterize ductal carcinoma in situ (DCIS) according to human epidermal growth factor receptor 2 (HER2) amplification status and molecular subtype. In addition, we performed a detailed HER2 and CEP17 copy number analysis and we assessed the impact of recent changes in the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on HER2 immunohistochemical (IHC) scores in DCIS. Nuclear grade, extensive comedonecrosis, stromal architecture, stromal inflammation, and progesterone receptor (PR) expression were significantly associated with HER2 amplification status. In multivariate analysis, stromal inflammation and extensive comedonecrosis were the only two features that remained significantly related to HER2 amplification status. The recent changes in ASCO/CAP guidelines resulted in significant upgrading of HER2 IHC score. Remarkably, about one in five non-amplified DCIS presented a 3+ IHC score, regardless of the scoring method. The biological significance of this phenomenon is presently unknown. After categorization according to molecular subtype, luminal A DCIS mainly presented histopathological features associated with good prognosis, whereas luminal B/HER2+ and HER2+ categories displayed a more aggressive phenotype. Overall, our results demonstrate that HER2-amplified DCIS constitute a clearly distinct subgroup which is characterized by histopathological features associated with poor prognosis. Further studies are required to elucidate the biological significance of a 3+ IHC score in non-amplified DCIS, as well as its mechanism.     

Differential RNAi responses of Nicotiana benthamiana individuals transformed with a hairpin-inducing construct during Plum pox virus challenge

Gene silencing and large-scale small RNA analysis can be used to develop RNA interference (RNAi)-based resistance strategies for Plum pox virus (PPV), a high impact disease of Prunus spp. In this study, a pPPViRNA hairpin-inducing vector harboring two silencing motif-rich regions of the PPV coat protein (CP) gene was evaluated in transgenic Nicotiana benthamiana (NB) plants. Wild-type NB plants infected with a chimeric PPV virus (PPV::GFP) exhibited affected leaves with mosaic chlorosis congruent to GFP fluorescence at 21 day post-inoculation; transgenic lines depicted a range of phenotypes from fully resistant to susceptible. ELISA values and GFP fluorescence intensities were used to select transgenic-resistant (TG-R) and transgenic-susceptible (TG-S) lines for further characterization of small interfering RNAs (siRNAs) by large-scale small RNA sequencing. In infected TG-S and untransformed (WT) plants, the observed siRNAs were nearly exclusively 21- and 22-nt siRNAs that targeted the whole PPV::GFP genome; 24-nt siRNAs were absent in these individuals. Challenged TG-R plants accumulated a full set of 21- to 24-nt siRNAs that were primarily associated with the selected motif-rich regions, indicating that a trans-acting siRNAs process prevented viral multiplication. BLAST analysis identified 13 common siRNA clusters targeting the CP gene. 21-nt siRNA sequences were associated with the 22-nt siRNAs and the scarce 23- and 24-nt molecules in TG-S plants and with most of the observed 22-, 23-, and 24-nt siRNAs in TG-R individuals. These results validate the use of a multi-hot spot silencing vector against PPV and elucidate the molecules by which hairpin-inducing vectors initiate RNAi in vivo.     

The parasitic fauna of the European bison (Bison bonasus) (Linnaeus, 1758) and their impact on the conservation. Part 1 The summarising list of parasites noted

During the current century, 88 species of parasites have been recorded in Bison bonasus. These are 22 species of protozoa (Trypanosoma wrublewskii, T. theileri, Giardia sp., Sarcocystis cruzi, S. hirsuta, S. hominis, S. fusiformis, Neospora caninum, Toxoplasma gondii, Cryptosporidium sp., Eimeria cylindrica, E. subspherica, E. bovis, E. zuernii, E. canadensis, E. ellipsoidalis, E. alabamensis, E. bukidnonensis, E. auburnensis, E. pellita, E. brasiliensis, Babesia divergens), 4 trematodes species (Dicrocoelium dendriticum, Fasciola hepatica, Parafasciolopsis fasciolaemorpha, Paramphistomum cervi), 4 cestodes species (Taenia hydatigena larvae, Moniezia benedeni, M. expansa, Moniezia sp.), 43 nematodes species (Bunostomum trigonocephalum, B. phlebotomum, Chabertia ovina, Oesophagostomum radiatum, O. venulosum, Dictyocaulus filaria, D.viviparus, Nematodirella alcidis, Nematodirus europaeus, N. helvetianus, N. roscidus, N. filicollis, N. spathiger, Cooperia oncophora, C. pectinata, C. punctata, C. surnabada, Haemonchus contortus, Mazamastrongylus dagestanicus, Ostertagia lyrata, O. ostertagi, O. antipini, O. leptospicularis, O. kolchida, O. circumcincta, O. trifurcata, Spiculopteragia boehmi, S. mathevossiani, S. asymmetrica, Trichostrongylus axei, T. askivali, T. capricola, T. vitrinus, Ashworthius sidemi, Onchocerca lienalis, O. gutturosa, Setaria labiatopapillosa, Gongylonema pulchrum, Thelazia gulosa, T. skrjabini, T. rhodesi, Aonchotheca bilobata, Trichuris ovis), 7 mites (Demodex bisonianus, D. bovis, Demodex sp., Chorioptes bovis, Psoroptes equi, P. ovis, Sarcoptes scabiei), 4 Ixodidae ticks (Ixodes ricinus, I. persulcatus, I. hexagonus, Dermacentor reticulatus), 1 Mallophaga species (Bisonicola sedecimdecembrii), 1 Anoplura (Haematopinus eurysternus), and 2 Hippoboscidae flies (Lipoptena cervi, Melophagus ovinus). There are few monoxenous parasites, many typical for cattle and many newly acquired from Cervidae.     

Early Systemic Sclerosis: Serum Profiling of Factors Involved in Endothelial,T-cell,and Fibroblast Interplay is Marked by Elevated Interleukin-33 Levels

Purpose

To assess the serum profile of factors involved in endothelial, T-cell, and fibroblast interplay in patients with Raynaud’s phenomenon (RP) associated with nailfold vodeocapillaroscopy (NVC) scleroderma findings and/or systemic sclerosis (SSc) marker autoantibodies, recently labeled as early SSc patients.

Methods

Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), CCL2, CXCL8, IL-13, IL-33, and transforming growth factor-β (TGF-β) were measured in 24 early SSc patients, 48 definite SSc patients, and 24 osteoarthritis/fibromyalgia controls by multiplex suspension immunoassay. All SSc patients were investigated for the presence/absence of preclinical and clinical organ involvement, SSc marker autoantibodies, and NVC abnormalities.

Results

Serum sICAM-1, CCL2, CXCL8, and IL-13 were increased in all SSc patients as compared to controls, and paralleled the severity of the disease subset (early SSc < limited cutaneous SSc < diffuse cutaneous SSc; p?SSc patients as compared to both controls (p?SSc patients (p?SSc there were no differences in the investigated markers according to the functional and serological features assessed.

Conclusions

Our study suggests that an endothelial, T-cell and fibroblast activation can be present in patients with early SSc and it is associated with a distinct profile of circulating factors involved in the cross-talk of these cells. The marked increase of IL-33 in early SSc patients suggests new routes of investigation of cell-cell dynamics in target tissues predating overt disease manifestations, thus opening to new therapeutic approaches.     

An analysis and decision tool to measure cost benefit of newborn screening for severe combined immunodeficiency (SCID) and related T-cell lymphopenia

Severe combined immunodeficiency (SCID) is a group of syndromes resulting from genetic defects causing absence in T-cell and B-cell function, leading to serious and life-threatening infections. SCID is often fatal in the first 2 years of life if not identified and properly treated. While additional laboratory methods are being developed, the current T-cell receptor excision circle assay has proven to have outstanding specificity and sensitivity to accurately identify infants with SCID and other T-cell lymphopenia. The Jeffrey Modell Foundation (JMF) has a long history of advocacy and continues to promote newborn screening for SCID to be implemented in the United States and worldwide. Based on reports provided by California, New York, Texas, and Wisconsin on the results of their population based newborn screening programs, the overall incidence of SCID averaged 1:33,000 and T-cell lymphopenia averaged 1:6,600. JMF has developed a working algorithm or “decision tree”, validated by peer-reviewed scientific literature, to be used by Public Health Departments and Health Ministries in states, countries, and regions throughout the world. This decision tool allows for local or regional data to be applied to measure the threshold and economic impact of implementing newborn screening for SCID and T-cell lymphopenia.     

SPARC/osteonectin is involved in metastatic process to the lung during melanoma progression

The existence of a “metastasis gene signature” that predisposes primary breast cancer cells to metastasize to the lungs has been recently highlighted by gene expression profiling studies. The combination of genes responsible for this process includes genes encoding several metalloproteinases as well as the gene encoding SPARC (secreted protein acidic and rich in cysteine)/osteonectin. SPARC is involved in normal tissue remodeling as it regulates the deposition of extracellular matrix, but also plays a role in neoplastic transformation. Aberrant SPARC expression has been detected both in stromal cells associated with cancer and in cancer cells. The main aim of this study was to investigate whether or not SPARC might be involved in directing metastasis of other types of cancer to the lung. We constructed a tissue microarray containing lung metastases from a variety of primary tumors in different organs and used immunohistochemistry to assess SPARC expression. We found SPARC overexpressed mainly in lung metastases from melanoma. We then assessed the expression of SPARC mRNA and protein in metastatic melanoma from different anatomic sites and in their corresponding primary tumors, and found that it is overexpressed in lung metastases. Our data strongly support the hypothesis that SPARC is involved in directing melanoma metastases specifically to the lung, which underpins its potential as prognostic marker and novel target for specific therapy.     

An identification key for the five most common species of Metastrongylus

Species of the Metastrongylus genus, the lung nematodes of pigs that require an intermediate host (earthworm) to complete their cycle, pose a potential risk to both livestock and humans. This parasite which can result in lung pathology and mixed infections with other pathogens (e.g. viruses) can be fatal to pigs. Although this genus is distributed worldwide, there are no classification keys for identifying this common parasite species. In this work, we take advantage of parasitological surveys of wild boar (Sus scrofa) in northern and central Spain and southern Poland to develop a morphological identification key for the five most common Metastrongylus species (Metastrongylus apri, Metastrongylus pudendotectus, Metastrongylus salmi, Metastrongylus confusus and Metastrongylus asymetricus). In addition, we provide the first record of M. confusus in Spain, probably unidentified until now due to the lack of appropriate identification keys. We hope that this user-friendly identification key will enable parasitologists and veterinary practitioners to avoid further misclassifications of Metastrongylus species.     

The Chemokine CX3CL1 (Fractalkine) and its Receptor CX3CR1: Occurrence and Potential Role in Osteoarthritis

Chemokines are molecules able to induce chemotaxis of monocytes, neutrophils, eosinophils, lymphocytes and fibroblasts. The complex chemokine acts in many physiological and pathological phenomena, including those occurring in the articular cartilage. To date, chemokine CX3CL1 (fractalkine) is the only member of the CX3C class of chemokines with well-documented roles in endothelial cells. CX3CL1 is a unique chemokine that combines properties of chemoattractant and adhesion molecule. The main roles of CX3CL1 include promotion of leukocyte binding and adhesion as well as activation of the target cells. The soluble chemokine domain of CX3CL1 is chemotactic for T cells and monocytes. CX3CL1 acts via its receptor, CX3CR1, which belongs to a family of G protein-coupled receptors. Stimulation of CX3CR1 activates both CX3CL1-dependent and integrin-dependent migrations of cells with synergistically augmented adhesion. Genetic polymorphisms of CX3CR1 may significantly modify the biological roles of CX3CL1, especially in pathologic conditions. Osteoarthritis (OA) is the most common joint disease, affecting approximately 7–8 % of the general population. Development of OA is largely driven by low-grade local background inflammation involving chemokines. The importance of CX3CL1/CX3CR1 signalling in the pathophysiology of OA is still under investigation. This paper, based on a review of the literature, updates and summarises the current knowledge about CX3CL1/CX3CR1 in OA and indicates possible interactions with a potential for therapeutic targeting.     

Distinct VEGF Functions During Bone Development and Homeostasis

Vascular endothelial growth factor-A (VEGF) is a key regulator of physiological hemangiogenesis during development, postnatal growth, and homeostasis. It is well known that VEGF is required for effective coupling of angiogenesis to endochondral and membranous bone formation during skeletal development. However, less well known are the roles of VEGF in regulating the differentiation and/or functions of skeletal cells such as chondrocytes, osteoblasts, and osteoclasts. In this review, we discuss some of these functions. During early skeletal development, VEGF is important for the survival of chondrocytes in the hypoxic regions of the cartilage models of future bones, the vascularization of developing bones and proliferation and differentiation of osteoblastic cells. Postnatally, osteoblast-derived VEGF is critical for maintaining bone homeostasis by stimulating the differentiation of mesenchymal stem cells to osteoblasts and repressing their differentiation to adipocytes. Recent data indicate that these effects of VEGF on osteogenic/adipogenic stem cell fates are based on an intracellular (intracrine) mechanism. In contrast, osteoblast-derived VEGF is also known to stimulate the differentiation of monocytes to osteoclasts by a paracrine mechanism. Mice with VEGF-deficient osteoblastic lineage cells exhibit age-dependent loss of bone mass and an increase in bone marrow fat. These changes are similar to the changes associated with osteoporosis in humans. Thus, a better understanding of the intracellular mechanisms by which VEGF regulates osteoblastic and adipogenic differentiation may lead to the identification of new targets for therapies to prevent osteoporotic bone loss.     

Decline of IgG pertussis toxin measured in umbilical cord blood,and neonatal and early infant serum

Maternal pertussis-specific antibodies are passively acquired by infants during pregnancy. An IgG pertussis toxin (IgG-PT) concentration of >20 U/ml is considered to protect neonates against pertussis. To evaluate the IgG concentration at birth and during the first two months of life, we examined the IgG-PT concentration in the umbilical cord blood and three times during the neonatal and early infant period. IgG-PT was measured by validated IgG-specific enzyme-linked immunosorbent assays (ELISA) in umbilical cord blood and in Guthrie card blood samples of umbilical cord blood in 2,790 children, born between 1 August 2006 and 1 December 2008. These measurements were comparable. All children with concentrations of IgG-PT >30 U/ml were included. IgG-PT was also measured in Guthrie card blood samples, when the neonates or early infants were 5 days, 1 month and 2 months old. The mean concentrations of IgG-PT were calculated. The mean concentration of IgG-PT in umbilical cord blood was 60.1 U/ml (LN 4.1; 0.6 SD; n?=?103). At the age of 5 days, 1 month and 2 months, the mean concentration of IgG-PT was 40.6 U/ml (LN 3.7; 0.5 SD; n?=?103), 20.7 U/ml (LN 3.0; 0.7 SD; n?=?62) and 16.7 U/ml (LN 2.8; 0.9 SD; n?=?61), respectively. Four percent of the neonates had a concentration of IgG-PT >30 U/ml in umbilical cord blood, which declined to levels around the concentration needed for protection against pertussis (>20 U/ml) in the first two months of life. Hence, it is of great importance to further investigate the safety of maternal immunisation during pregnancy to prevent life-threatening pertussis in newborns.     

Temporal evolution of human autoantibody response to cytoplasmic rods and rings structure during anti-HCV therapy with ribavirin and interferon-α

Autoantibodies to inosine monophosphate dehydrogenase-2 (IMPDH2), an enzyme involved in de novo biosynthesis of guanine nucleotides, are observed in a subset of hepatitis C virus (HCV) patients receiving interferon alpha (IFN-α) plus ribavirin. Anti-IMPDH2 antibodies display a peculiar cytoplasmic “rod/ring” (RR) pattern in IIF-HEp-2. We examined the dynamics of anti-RR autoimmune response with respect to immunoglobulin isotypes, titer, avidity, and protein targets in 80 sequential samples from 15 HCV patients (plus 12 randomly selected anti-RR-positive, totalizing 92 samples) collected over an 18-month period, including samples collected before, during, and after IFN-α + ribavirin treatment. Immunoprecipitation showed reactivity with the 55 kDa IMPDH2 protein in 12/15 patients (80 %) and 11/15 (73 %) reacted with IMPDH2 in a sandwich ELISA. During treatment, anti-IMPDH2 autoantibodies hit their highest levels after 6–12 months of treatment and decreased post-treatment, while anti-HCV antibodies levels were stable over time. Anti-IMPDH2 IgM levels increased up until the sixth month of treatment and remained stable thereafter, while IgG levels increased steadily up to the twelfth month. Both IgG and IgM decreased during the post-treatment period. IgG avidity increased steadily up to the twelfth month of treatment. In conclusion, this study showed that the temporal kinetics of IFN-α + ribavirin-induced humoral autoimmune response to IMPDH2 exhibited a considerably delayed pace of increase in antibody levels and avidity as well as in isotype class switch in comparison with a conventional humoral response to infectious agents. These unique findings uncover intriguing differences between the autoimmune response and the immune response to exogenous agents in humans.     

Acute disseminated encephalomyelitis progressing to multiple sclerosis: Are infectious triggers involved?

Acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) are demyelinating disorders affecting the central nervous system. An autoimmune aetiology has been proposed for both. ADEM principally affects adolescents following acute infection by a variety of pathogens and has also been reported to occur following vaccination. ADEM typically resolves following medical treatment, whereas MS follows a more relapsing and remitting course. The pathogenesis of MS remains unclear, but it is thought that a combination of infectious and non-infectious environmental factors and host genetics act synergistically to cause disease. A variety of viruses, including Epstein Barr virus, cytomegalovirus, herpes simplex virus and varicella zoster virus, have been implicated as possible infectious triggers. The similar clinical and pathological presentation of ADEM and MS presents a diagnostic challenge for distinguishing ADEM from a first episode of MS. Some cases of ADEM progress to MS for reasons that are not currently clear. This review examines the evidence for infectious agents as triggers for ADEM progressing to MS and suggests potential methods that may facilitate identification of infectious agents that may be responsible for the pathogenesis of ADEM to MS.     

Curcumin inhibits monocyte chemoattractant protein-1 expression and enhances cholesterol efflux by suppressing the c-Jun N-terminal kinase pathway in macrophage

Objective

To investigate the effect of curcumin on monocyte chemoattractant protein 1 (MCP-1) production and reverse cholesterol transport (RCT) in macrophage induced by oxidation low-density lipoprotein (ox-LDL), and to identify the signal pathways involved.

Methods

The macrophages were treated with ox-LDL and various concentrations of curcumin simultaneously. The MCP-1 expression was measured by enzyme-linked immunosorbent assay. The apoAI-mediated cholesterol efflux was measured by ³H-cholesterol-labeled counting radioactivity. The activation of intracellular signaling pathways was studied by Western blotting.

Results

Curcumin decreased the production of MCP-1 induced by ox-LDL in macrophages. MCP-1 expression was restrained by the inhibition of c-Jun N-terminal kinase (JNK) pathway (SP600125) and NF-κB pathway (BAY11-7082). Curcumin suppressed the phosphorylation of JNK and activation of NF-κB. Curcumin also enhanced RCT via up-regulating the expression of liver X receptor alpha (LXRα), ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI). Additionally, the inhibition of JNK (SP600125) increased cholesterol efflux and increased the expression of ABCA1 and SR-BI, but had no effect on LXRα.

Conclusion

Curcumin suppresses MCP-1 production induced by ox-LDL via the JNK pathway and NK-κB pathway, while enhances cholesterol efflux in macrophage via suppressing the JNK pathway and activating the LXR–ABCA1/SR-BI pathway, which indicate that the vascular protective effect of curcumin is related to anti-inflammation and anti-atherosclerosis.     

Modeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells

Friedreich ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is due to GAA repeat expansions within the first intron of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron–sulfur cluster biosynthesis. The triplet codon repeats lead to heterochromatin-mediated gene silencing and loss of frataxin. Nevertheless, inadequacy of existing FRDA-cardiac cellular models limited cardiomyopathy studies. We tested the hypothesis that iron homeostasis deregulation accelerates reduction in energy synthesis dynamics which contributes to impaired cardiac calcium homeostasis and contractile force. Silencing of FXN expressions occurred both in somatic FRDA-skin fibroblasts and two of the induced pluripotent stem cells (iPSC) clones; a sign of stress condition was shown in FRDA-iPSC cardiomyocytes with disorganized mitochondrial network and mitochondrial DNA (mtDNA) depletion; hypertrophic cardiac stress responses were observed by an increase in α-actinin-positive cell sizes revealed by FACS analysis as well as elevation in brain natriuretic peptide (BNP) gene expression; the intracellular iron accumulated in FRDA cardiomyocytes might be due to attenuated negative feedback response of transferring receptor (TSFR) expression and positive feedback response of ferritin (FTH1); energy synthesis dynamics, in terms of ATP production rate, was impaired in FRDA-iPSC cardiomyocytes, which were prone to iron overload condition. Energetic insufficiency determined slower Ca²⁺ transients by retarding calcium reuptake to sarcoplasmic reticulum (SR) and impaired the positive inotropic and chronotropic responses to adrenergic stimulation. Our data showed for the first time that FRDA-iPSCs cardiac derivatives represent promising models to study cardiac stress response due to impaired iron homeostasis condition and mitochondrial damages. The cardiomyopathy phenotype was accelerated in an iron-overloaded condition early in calcium homeostasis aspect.