An in vitro model mimicking the complement system to favor directed phagocytosis of unwanted cells

BACKGROUND: Opsonization, is the molecular mechanism by which target molecules promote interactions with phagocyte cell surface receptors to remove unwanted cells by induced phagocytosis. We designed an in vitro system to demonstrate that this procedure could be driven to eliminate adipocytes, using peptides mimicking regions of the complement protein C3b to promote opsonization and enhance phagocytosis. Two cell lines were used: (1) THP-1 monocytes differentiated to macrophages, expressing the C3b opsonin receptor CR1 in charge of the removal of unwanted coated complexes; (2) 3T3-L1 fibroblasts differentiated to adipocytes, expressing AQP7, to evaluate the potential of peptides to stimulate opsonization. (3) A co-culture of the two cell lines to demonstrate that phagocytosis could be driven to cell withdrawal with high efficiency and specificity. RESULTS: An array of peptides were designed and chemically synthesized p3691 and p3931 joined bound to the CR1 receptor activating phagocytosis (p < 0.033) while p3727 joined the AQP7 protein (p < 0.001) suggesting that opsonization of adipocytes could occur. In the co-culture system p3980 and p3981 increased lipid uptake to 91.2% and 89.0%, respectively, as an indicator of potential adipocyte phagocytosis. CONCLUSIONS: This in vitro model could help understand the receptor­ligand interaction in the withdrawal of unwanted macromolecules in vivo. The adipocyte-phagocytosis discussed may help to control obesity, since peptides of C3b stimulated the CR1 receptor, promoting opsonisation and phagocytosis of lipidcontaining structures, and recognition of AQP7 in the differentiated adipocytes, favored the phagocytic activity of macrophages, robustly supported by the co-culture strategy.

Expression of autophagy related gene 5 and cyclin E in coronary heart disease and its clinical significance / 中南大学学报(医学版)

OBJECTIVES@#To explore the expression of autophagy related genes 5 (ATG5) and cyclin E in coronary heart disease (CHD) and its clinical significance.@*METHODS@#From April 2018 to August 2018, 80 patients diagnosed with CHD in the Second Xiangya Hospital, Central South University were selected as an observation group, and another 80 healthy subjects were selected as a control group. The expression of ATG5 and cyclin E mRNA in nucleate cells and the plasma protein in the 2 groups were detected and analyzed. The model of macrophage-derived foam cells induced by oxidized low density lipoprotein (ox-LDL) was used to simulate atherosclerosis. The proliferation of macrophage- derived foam cells and the protein levels of ATG5 and cyclin E induced by ox-LDL at different concentrations were examined.@*RESULTS@#Compared with the control group, the levels of ATG5 mRNA and protein in the blood in the observation group were decreased, and the cyclin E mRNA and protein levels were increased, there were statistically difference (both <0.05). Receiver operating characteristic (ROC) curve showed that the area under curve (AUC) of ATG5 mRNA, cyclin E mRNA, ATG5 protein and cyclin E protein were 0.739, 0.780, 0.671 and 0.807, respectively. Pearson analysis showed that the ATG5 mRNA was negatively correlated with the cyclin E mRNA (=-0.734, <0.05),while the plasma ATG5 protein was negatively correlated with the plasma cyclin E protein (=-0.746, <0.05). Macrophage-derived foam cell model induced by ox-LDL showed that the proliferation of foam cells and the expression levels of cyclin E protein were increased in a concentration and time-dependent manner, and the expression levels of ATG5 protein were decreased in a concentration-dependent manner.@*CONCLUSIONS@#The levels of ATG5 mRNA and protein are lowly expressed while the levels of cyclin E mRNA and protein are highly expressed in the patients with CHD.The ATG5 protein levels are lowly expressed in ox-LDL-treated macrophage-derived foam cells while the cyclin E protein levels are highly expressed in ox-LDL-treated macrophage-derived foam cells. Based on these observations, we conclude that ATG5 inhibits the degradation of the cyclin E and promotes the proliferation of macrophages, involving in the occurrence and development of CHD.

Research progress on anti-atherosclerosis effect and mechanism of flavonoids compounds mediated by macrophages / 中国中药杂志

Flavonoids are important active ingredients of traditional Chinese medicine, mainly with cardiovascular, anti-liver injury, antioxidant, antispasmodic, and estrogen-like effects. These compounds have obvious effects on the cardiovascular and cerebrovascular diseases. Macrophage-derived foam cells are the key medium in the process of atherosclerosis(AS). In plaque, allserum lipids, serum lipoproteins, and various pro-or anti-inflammatory stimulating factors, chemokines, and small bioactive molecules can significantly affect the macrophage phenotype and induce stronger pro-inflammatory or anti-inflammatory properties. Studies have shown that some flavonoids can be used for macrophages through different pathways and mechanisms, playing an anti-atherosclerosis effect to different degrees, including promotion of cholesterol efflux from macrophages, anti-foaming of macrophages, inhibition of secretion of inflammatory factors, and antioxidant modified low density lipoprotein(ox-LDL)-induced apoptosis of macrophages. Related gene regulation inclu-ded ATP-binding cassette transporter A1(ABCA1), ATP-binding cassette transporter G1(ABCG1), Toll-like receptor(TLR), and scavenger receptor(SR). In this article, we would review the recent research progress of flavonoids on anti-atherosclerosis effect me-diated by macrophage. It is expected to provide new treatment strategies for AS-related cardiovascular and cerebrovascular diseases, and provide research ideas and development directions for the use of related natural medicines and design of new products.

Células gigantes en lepra lepromatosa: dermatitis difusa con células gigantes exuberantes de tipo cuerpo extraño en lepra lepromatosa tratada / Giant cells lepromatous leprosy: Diffuse dermatitis with exuberant foreign body giant cells in treated lepromatous leprosy

Resumen Los pacientes con lepra lepromatosa que han recibido tratamiento durante años, usualmente requieren seguimiento con biopsias de piel para detectar lesiones persistentes o si la baciloscopia es positiva, incluso si los valores son menores que los iniciales. Se presenta el caso de una mujer de 48 años de edad con lepra lepromatosa de 15 años de evolución, índice bacilar de 4 en el extendido directo y en la biopsia, que recibió tratamiento con múltiples medicamentos durante 32 meses, aunque lo recomendado por la Organización Mundial de la Salud (OMS) es una duración de 12 meses. Se tomó una biopsia de piel para determinar si la enfermedad estaba activa. Se observó inflamación dérmica difusa con numerosas células gigantes de tipo cuerpo extraño y macrófagos vacuolados (células de Virchow). Estas células, CD68 positivas, contenían material granular ácido-alcohol resistente positivo con inmunohistoquímica para BCG. Se encontraron bacilos fragmentados y el índice bacilar fue de 2. Se interpretó como una forma residual de lepra lepromatosa y se concluyó que la paciente no requería prolongar el tratamiento con múltiples medicamentos. Este perfil histológico se ha observado en casos similares, pero sin datos clínicos estas biopsias representan un reto diagnóstico. La acumulación de lípidos en estas células gigantes se debe a la destrucción bacilar y a la fusión de macrófagos vacuolados. Se revisó el papel de los lípidos del bacilo y del huésped en la patogenia de la lepra lepromatosa. En estos casos, no es necesario extender los 12 meses de tratamiento con múltiples medicamentos recomendados por la OMS. En el seguimiento de los pacientes, se recomienda contar con los hallazgos clínicos, la baciloscopia, la biopsia anual de piel y los títulos IgM antiglucolípido fenólico.

Abstract Patients with lepromatous leprosy that have received treatment for many years usually get follow up biopsies for persistent skin lesions or positive bacilloscopy even if the values are lower than in the initial bacilloscopy. We report the case of a 48-year old woman with long-standing lepromatous leprosy of 15 years of evolution, with a bacterial index of 4 in the direct smear and the initial skin biopsy. The patient was treated with multidrug therapy for 32 months although the treatment recommended by the World Health Organization (WHO) is only for 12 months. A skin biopsy was taken to determine if there was an active disease. We observed a diffuse dermal inflammation with numerous foreign body giant cells and vacuolated macrophages (Virchow´s cells). These cells contained granular acid-fast material that was also positive with immunohistochemistry for BCG. There were fragmented bacilli and the BI was 2. These cells were also strongly positive for CD68. The biopsy was interpreted as a residual form of lepromatous leprosy that did not require further multidrug therapy. We have observed similar histological profiles in several cases. The lack of clinical data makes it a histological challenge. The accumulation of lipids in these giant cells is due to bacillary destruction and fusion of vacuolated macrophages. We discuss here the role of bacillary and host lipids in the pathogenesis of lepromatous leprosy. We concluded that there was no need to extend the 12-month multidrug therapy recommended by WHO. Clinical findings, bacilloscopy, annual skin biopsy, and anti-phenolic glycolipid-I IgM titers are recommended procedures for the follow-up of these patients.

Inhibitory effect of BF523 from Ilex hainanensis on ox LDL-induced foam cells formation / 中国中药杂志

Cardio-cerebral vascular disease induced by atherosclerosis is a serious cause of human health. The pathogenesis of AS is very complex,and the oxidized low-density lipoprotein( ox LDL) induced foam cells formation is considered to be the most important cytological change in AS. Based on the definition of " TCM chemical biology",we clarified the chemical composition of Ilex hainanensis,the effective substances of I. hainanensis on the activity of anti-AS were screened. Then we found that saponin BF523 had the good inhibitory effect on foam cell formation. In this research,we studied the BF523 as the research object to clarify the molecular target of the active compound of I. hainanensis by foam cell formation model. The results showed that BF523 significantly inhibited the oxidation of ox LDL-induced macrophage foaming and decreased the lipid content in macrophages. BF523 had inhibited the phagocytosis of ox LDL in macrophages by reducing the mRNA and protein levels of scavenger receptor CD36,thereby inhibiting the occurrence and development of AS. These findings not only clarified the mechanism of the inhibition of foam cell formation by saponin BF523,but also provided a useful exploration for the enrichment of the theory of " TCM chemical biology".

Porphyromonas gingivalis accelerates atherosclerosis through oxidation of high-density lipoprotein

PURPOSE: The aim of this study was to evaluate the ability of Porphyromonas gingivalis (P. gingivalis) to induce oxidation of high-density lipoprotein (HDL) and to determine whether the oxidized HDL induced by P. gingivalis exhibited altered antiatherogenic function or became proatherogenic. METHODS: P. gingivalis and THP-1 monocytes were cultured, and the extent of HDL oxidation induced by P. gingivalis was evaluated by a thiobarbituric acid-reactive substances (TBARS) assay. To evaluate the altered antiatherogenic and proatherogenic properties of P. gingivalis-treated HDL, lipid oxidation was quantified by the TBARS assay, and tumor necrosis factor alpha (TNF-α) levels and the gelatinolytic activity of matrix metalloproteinase (MMP)-9 were also measured. After incubating macrophages with HDL and P. gingivalis, Oil Red O staining was performed to examine foam cells. RESULTS: P. gingivalis induced HDL oxidation. The HDL treated by P. gingivalis did not reduce lipid oxidation and may have enhanced the formation of MMP-9 and TNF-α. P. gingivalis-treated macrophages exhibited more lipid aggregates than untreated macrophages. CONCLUSIONS: P. gingivalis induced HDL oxidation, impairing the atheroprotective function of HDL and making it proatherogenic by eliciting a proinflammatory response through its interaction with monocytes/macrophages.

Recombinant Human Thioredoxin-1 Protects Macrophages from Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation and Cell Apoptosis

Oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and apoptosis play critical roles in the pathogenesis of atherosclerosis. Thioredoxin-1 (Trx) is an antioxidant that potently protects various cells from oxidative stress-induced cell death. However, the protective effect of Trx on ox-LDL-induced macrophage foam cell formation and apoptosis has not been studied. This study aims to investigate the effect of recombinant human Trx (rhTrx) on ox-LDL-stimulated RAW264.7 macrophages and elucidate the possible mechanisms. RhTrx significantly inhibited ox-LDL-induced cholesterol accumulation and apoptosis in RAW264.7 macrophages. RhTrx also suppressed the ox-LDL-induced overproduction of lectin-like oxidized LDL receptor (LOX-1), Bax and activated caspase-3, but it increased the expression of Bcl-2. In addition, rhTrx markedly inhibited the ox-LDL-induced production of intracellular reactive oxygen species (ROS) and phosphorylation of p38 mitogen-activated protein kinases (MAPK). Furthermore, anisomycin (a p38 MAPK activator) abolished the protective effect of rhTrx on ox-LDL-stimulated RAW264.7 cells, and SB203580 (a p38 MAPK inhibitor) exerted a similar effect as rhTrx. Collectively, these findings indicate that rhTrx suppresses ox-LDL-stimulated foam cell formation and macrophage apoptosis by inhibiting ROS generation, p38 MAPK activation and LOX-1 expression. Therefore, we propose that rhTrx has therapeutic potential in the prevention and treatment of atherosclerosis.

LPS-stimulated Macrophage Activation Affects Endothelial Dysfunction

Intestinal microbiota is involved in the atherosclerotic process by development of an atheromatous core with foam cells in carotid arteries. It has reported that lipopolysaccharide (LPS) from Escherichia coli localizes in human atherosclerotic plaque and causes inflammation via interaction with toll like receptor 4. However, there is no evidence that whether LPS-activated macrophages regulate endothelial cell (EC) function. We evaluated whether LPS-activated macrophage acts as one of the stimulants activating EC and its underlying signaling pathways. Using Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we confirmed that intraperitoneal injection with LPS increases iNOS protein and inflammatory cytokine, TNF-α and IL-6 mRNA expressions. To determine whether LPS-mediated macrophage inflammatory condition affects EC activation and inflammation, human umbilical vein endothelial cells (HUVECs) were incubated with isolated peritoneal macrophages from LPS-injected mice. Interestingly, p90RSK Serine 380 phosphorylation and protein expression were significantly increased by macrophage treatment in EC. Messenger RNA levels of vascular cell adhesion molecule 1 and p90RSK was increased, but endothelial nitric oxide synthase was decreased. In addition, NF-κB promoter activity, which plays an important role in the pathogenesis of inflammation, was strongly enhanced by the macrophage treatment in EC. We further evaluated the effects of LPS on EC function in the mouse aorta using en face staining. In agreement with in vitro result, p90RSK expression was strongly increased in the steady laminar flow region of the mouse aorta in mice injected with LPS. Together, our study demonstrates that p90RSK might be a one of the major therapeutic candidates for the prevention of vascular diseases mediated by LPS.

IL-33 promotes IL-10 production in macrophages: a role for IL-33 in macrophage foam cell formation

We evaluated the role of IL-10- in IL-33-mediated cholesterol reduction in macrophage-derived foam cells (MFCs) and the mechanism by which IL-33 upregulates IL-10. Serum IL-33 and IL-10 levels in coronary artery disease patients were measured. The effects of IL-33 on intra-MFC cholesterol level, IL-10, ABCA1 and CD36 expression, ERK 1/2, Sp1, STAT3 and STAT4 activation, and IL-10 promoter activity were determined. Core sequences were identified using bioinformatic analysis and site-specific mutagenesis. The serum IL-33 levels positively correlated with those of IL-10. IL-33 decreased cellular cholesterol level and upregulated IL-10 and ABCA1 but had no effect on CD36 expression. siRNA-IL-10 partially abolished cellular cholesterol reduction and ABCA1 elevation by IL-33 but did not reverse the decreased CD36 levels. IL-33 increased IL-10 mRNA production but had little effect on its stability. IL-33 induced ERK 1/2 phosphorylation and increased the luciferase expression driven by the IL-10 promoter, with the highest extent within the −2000 to −1752 bp segment of the 5′-flank of the transcription start site; these effects were counteracted by U0126. IL-33 activated Sp1, STAT3 and STAT4, but only the STAT3 binding site was predicted in the above segment. Site-directed mutagenesis of the predicted STAT3-binding sites (CTGCTTCCTGGCAGCAGAA→CTGCCTGGCAGCAGAA) reduced luciferase activity, and a STAT3 inhibitor blocked the regulatory effects of IL-33 on IL-10 expression. Chromatin immunoprecipitation (CHIP) confirmed the STAT3-binding sequences within the −1997 to −1700 and −1091 to −811 bp locus regions. IL-33 increased IL-10 expression in MFCs via activating ERK 1/2 and STAT3, which subsequently promoted IL-10 transcription and thus contributed to the beneficial effects of IL-33 on MFCs.

Tuberculosis of the thyroid

OBJECTIVE: To present a case of thyroid tuberculosis and to discuss its clinical presentation, differential diagnoses and management.METHODS:Design: Case ReportSetting: Tertiary Government HospitalPatient: OneRESULTS: A 55-year-old farmer presented with an 8-month progressively enlarging anterior neck mass, and fine needle aspiration biopsy yielded grossly turbid straw-colored aspirate admixed with blood with microscopy showing scattered inflammatory cells and macrophages set against a colloid background. After total thyroidectomy, hispathology revealed parenchymal infiltration by multiple aggregates of plump spindled to epitheloid cells forming granulomas with interspersed multinucleated giant cells, central caseation necrosis and surrounding fibrosis with chronic inflammatory infiltrates. The nodal masses also showed prominent germinal centers with interspersed epitheloid cells and foamy macrophages. Final diagnosis was chronic granulomatous inflammation consistent with tuberculosis.CONCLUSION: Tuberculosis (TB) of the thyroid is a rare occurrence that can present as inflammation, infection or tumor formation of the thyroid gland. Diagnosis depends on identification of the tubercle from tissues and aspirates by acid fast staining and TB culture. Treatment consists of multiple drug therapy for tuberculosis but thyroidectomy may be an option if the thyroid gland is severely diseased.

Tuberculosis of the thyroid

@#<p style="text-align: justify;"><strong>OBJECTIVE:</strong> To present a case of thyroid tuberculosis and to discuss its clinical presentation, differential diagnoses and management.<br /><strong>METHODS:</strong><br /><strong>Design:</strong> Case Report<br /><strong>Setting:</strong> Tertiary Government Hospital<br /><strong>Patient:</strong> One<br /><strong>RESULTS:</strong> A 55-year-old farmer presented with an 8-month progressively enlarging anterior neck mass, and fine needle aspiration biopsy yielded grossly turbid straw-colored aspirate admixed with blood with microscopy showing scattered inflammatory cells and macrophages set against a colloid background. After total thyroidectomy, hispathology revealed parenchymal infiltration by multiple aggregates of plump spindled to epitheloid cells forming granulomas with interspersed multinucleated giant cells, central caseation necrosis and surrounding fibrosis with chronic inflammatory infiltrates. The nodal masses also showed prominent germinal centers with interspersed epitheloid cells and foamy macrophages. Final diagnosis was chronic granulomatous inflammation consistent with tuberculosis.<br /><strong>CONCLUSION:</strong> Tuberculosis (TB) of the thyroid is a rare occurrence that can present as inflammation, infection or tumor formation of the thyroid gland. Diagnosis depends on identification of the tubercle from tissues and aspirates by acid fast staining and TB culture. Treatment consists of multiple drug therapy for tuberculosis but thyroidectomy may be an option if the thyroid gland is severely diseased.</p>

Linking resistin, inflammation, and cardiometabolic diseases

Adipose tissue secretes a variety of bioactive substances that are associated with chronic inflammation, insulin resistance, and an increased risk of type 2 diabetes mellitus. While resistin was first known as an adipocyte-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents, it is predominantly expressed and secreted by macrophages in humans. Epidemiological and genetic studies indicate that increased resistin levels are associated with the development of insulin resistance, diabetes, and cardiovascular disease. Resistin also appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and the formation of foam cells. Thus, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with cardiovascular disease and heart failure. Furthermore, recent evidence suggests that resistin is associated with atherogenic dyslipidemia and hypertension. The present review will focus on the role of human resistin in the pathogeneses of inflammation and obesity-related diseases.

The Role of Macrophage Lipophagy in Reverse Cholesterol Transport

Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from lipid droplets of macrophages via autophagy and lysosomes. In this review, we briefly discuss recent advances regarding the mechanisms of the cholesterol efflux pathway in macrophage foam cells, and present lipophagy as a therapeutic target in the treatment of atherosclerosis.

Verruciform xanthoma in the hard palate: a case report and literature review

Oral verruciform xanthoma (OVX) is an uncommon lesion that appears on the oral mucosa. The aim of this paper was to discuss the probable etiopathogenesis of OVX in the hard palate, reinforcing the importance of including this lesion in the differential diagnosis of verrucous lesions. A 43-year-old male smoker presented with a painless lesion with a verrucous surface and erythematous spots on the hard palate. Excisional biopsy revealed oral mucosa consisting of hyperkeratosis, acanthosis, and elongated rete pegs. Subjacent connective tissue showed numerous foam cells with clear cytoplasm and pyknotic nucleus, negative on periodic acid-Schiff staining. Immunohistochemical analysis revealed foam cells positive for anti-CD68 antibody, while anti-KI-67 antibody was restricted to the basal layer of the oral epithelium. A final diagnosis of OVX was established. The patient showed no signs of recurrence after seven months of follow-up. Physical trauma and smoking habits can be directly related to the etiology of verruciform xanthoma because the lesion is chronic and inflammatory with slow growth, and sites if high trauma are more often affected by such a lesion. The hard palate is the second most commonly affected site, and local trauma caused by smoking can be a cause of this type of lesion.

Correlation between autophagy and polarization of macrophages in atherosclerosis plaque in arteriosclerosis obliterans amputees / 药学学报

This study was designed to investigate the correlation between autophagy and polarization of macrophages in atherosclerosis (AS) plaque in arteriosclerosis obliterans amputees. Femoral artery specimens from arteriosclerosis obliterans amputees were performed hematoxylin and eosin (HE) staining, oil red O and immunofluorescence staining to observe the morphology of atherosclerotic plaque, phenotype of macrophages and autophagy in plaque; using real-time quantitative RT-PCR technology to detect the mRNA level of M1 and M2 type markers in arterial tissue; to analyze polarized signal pathway and autophagy protein levels in macrophages by Western blotting. Arterial specimens staining showed obvious lipid deposition and obvious infiltration of amount of foam cells and inflammatory cells. Macrophages were mainly expression M1 type in percentage in fibrous plaque. Although both M1 and M2 macrophages were upregulated in atheromatous plaque, the increase was dominant in M2 type in percentage. The level of autophagy was significantly higher in the atheromatous plaque than that of fibrous plaque. The expression of tumor necrosis factor- α (TNF-α), monocyte chemotactic protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and interleukin-12 (IL-12) mRNA was significantly higher in fibrous plaque than that of atheromatous plaque (P < 0.01 or 0.05), and arginase-1 (Arg-1), transforming growth factor-β (TGF-β), CD163 and interleukin-10 (IL-10) mRNA was significantly lower than that in atheromatous plaque (P < 0.01). The levels of p-STAT1 and NF-κB were significantly increased in fibrous plaque (P < 0.01), while p-STAT6 expression was significantly increased in atheromatous plaque (P < 0.01). The level of LC3-II was significantly higher in atheromatous plaque than that in fibrous plaque (P < 0.01). Macrophages in early atherosclerotic plaque were induced to M1 type through p-STAT1/NF-κB pathway and expressed moderate levels of autophagy; while macrophages in advanced plaques were induced to polarization of M2 type through p-STAT6 pathway. M2 macrophages expressed a higher level of autophagy than M1 macrophages.

Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels.

Economic evaluation in the context of rare diseases: is it possible? / Evaluación económica en el contexto de enfermedades raras: ¿es posible? / Avaliação econômica no âmbito das doenças raras: isto é possível?

This study analyzes the available evidence on the adequacy of economic evaluation for decision-making on the incorporation or exclusion of technologies for rare diseases. The authors conducted a structured literature review in MEDLINE via PubMed, CRD, LILACS, SciELO, and Google Scholar (gray literature). Economic evaluation studies had their origins in Welfare Economics, in which individuals maximize their utilities based on allocative efficiency. There is no widely accepted criterion in the literature to weigh the expected utilities, in the sense of assigning more weight to individuals with greater health needs. Thus, economic evaluation studies do not usually weigh utilities asymmetrically (that is, everyone is treated equally, which in Brazil is also a Constitutional principle). Healthcare systems have ratified the use of economic evaluation as the main tool to assist decision-making. However, this approach does not rule out the use of other methodologies to complement cost-effectiveness studies, such as Person Trade-Off and Rule of Rescue.

El objetivo fue sistematizar las evidencias disponibles sobre la pertinencia de utilizar la evaluación económica para la incorporación/exclusión de tecnología en enfermedades raras. Se realizó una revisión sistemática de la literatura en MEDLINE vía PubMed, CRD, LILACS, SciELO y Google Académico (literatura gris). Los estudios de evaluación económica se originan de la Economía del Bienestar, en la que los individuos maximizan sus utilidades, basándose en la eficiencia de asignación. No existe un criterio ampliamente aceptado para examinar las utilidades, a fin de dar más peso a los individuos con mayores necesidades. Generalmente, los estudios no equilibran asimétricamente las utilidades, todas son consideradas iguales, lo que en Brasil es también un principio constitucional. Los sistemas de salud han ratificado el uso de la evaluación económica como la principal herramienta para ayudar en la toma de decisiones. Sin embargo, este abordaje no excluye el uso de otras metodologías complementarias a los estudios de coste-efectividad, como la técnica de compensación personal o la regla del rescate.

O objetivo deste estudo foi analisar as evidências disponíveis sobre a adequação do uso de avaliação econômica sobre incorporação/exclusão de tecnologias para doenças raras. Foi realizada uma revisão estruturada da literatura, nas bases MEDLINE, via PubMed, CRD, LILACS, SciELO e Google Acadêmico (literatura cinzenta). Os estudos de avaliação econômica têm origem na Economia do Bem-Estar, na qual os indivíduos maximizam suas utilidades, fundamentando-se na eficiência alocativa. Não há um critério amplamente aceito para ponderar as utilidades esperadas, no sentido de dar mais peso aos indivíduos com maiores necessidades em saúde. Geralmente não se ponderam assimetricamente as utilidades; todas são tratadas de forma igualitária, que, no caso brasileiro, também é um princípio constitucional. Os sistemas de saúde têm ratificado o uso de avaliação econômica como principal instrumento para auxiliar na tomada de decisão. No entanto, essa postura não exclui o uso de outras metodologias complementares aos estudos de custo-efetividade, como Person Trade-Off e regra de resgate.

The effect of miR-124 on homocysteine-induced atherosclerosis via promoter region DNA methylation in ApoE(-/-) mice / 生理学报

The aim of the present study is to explore the role of miR-124 and its promoter region DNA methylation in homocysteine (Hcy)-induced atherosclerosis. ApoE(-/-) mice were fed with hypermethionine diet for 16 weeks to duplicate hyperhomocysteinemia model. Meanwhile, a normal control group (C57BL/6J mice fed with normal diet, N-control) and a model control group (ApoE(-/-) mice fed with normal diet, A-control) were set. The degree of atherosclerosis was observed by HE and oil red O staining. Automatic biochemical analyzer was used to detect the serum levels of Hcy. Foam cell model was duplicated and oil red O staining was used to confirm whether the model was successfully established. And foam cells were stimulated with 0, 50, 100, 200, 500 μmol/L Hcy and 50 μmol/L Hcy + 10 μmol/L AZC respectively. Real-time quantitative PCR (RT-qPCR) was used to detect the expressions of miR-124 in mice aorta and foam cells; Nested landing methylation specific PCR (nMS-PCR) was used to detect the levels of miR-124 promoter DNA methylation in mice aorta and foam cells. Meanwhile, the effects of DNA methylation inhibitor AZC on miR-124 expression were observed at the cellular level. The effect of miR-124 promoter DNA methylation status on lipid accumulation in foam cells was observed by oil red O staining. The results showed that compared with model control group, the serum levels of Hcy in high methionine group were significantly increased (P < 0.01) and developed aortic atherosclerotic plaque, the expression of miR-124 was markedly decreased (P < 0.01), while the levels of miR-124 promoter DNA methylation were significantly increased (P < 0.01). Given different levels of Hcy, the expression of miR-124 in foam cells was decreased, while the levels of miR-124 promoter DNA methylation were increased in a dose-dependent manner (P < 0.05, P < 0.01). AZC reversed the results of mentioned indices as above markedly (P < 0.05). Downregulation of miR-124 may play a role in Hcy-induced atherosclerosis and its promoter DNA methylation status may be an important mechanism in this process.

Effect of tooth extraction and antibiotics on carotid artery wall and serum interleukin 6 in chronic periodontitis rats with or without atherosclerosis / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the effect of tooth extraction with antibiotics on atherosclerosis, and to examine the expression of serum interleukin 6(IL-6) and the pathological changes of the carotid artery in chronic periodontitis(CP) rats with or without atherosclerosis(As).</p><p><b>METHODS</b>A total of 44 SD rats were randomly divided into four groups, group A(normal control), group B(As), group C(CP), group D(CP+As). After model establishment, group C and group D were randomly divided into group C1/D1 (tooth extraction) and group C2/D2(tooth extraction with antibiotics) according to random number table and received the corresponding oral intervention treatment respectively. Serum IL-6 levels were determined by enzyme linked immunosorbent assay(ELISA) respectively one week before the intervention, one week after the first intervention, one, three, five weeks after the second intervention. The pathological changes of the carotid artery were accessed under light microscope.</p><p><b>RESULTS</b>At all sampling time points, the levels of serum IL-6 in group B, C, D were higher than that of group A, with group D1 being increased most obviously, significantly higher than that of group A(P< 0.001). One week after the second intervention, the content of IL-6 in group C and group D peaked[C1(127.0 ± 29.9) ng/L, C2: (120.6 ± 23.1) ng/L, D1: (175.1 ± 50.8) ng/L, D2: (160.5 ± 37.7) ng/L], and was significantly higher than that of group B[B: (43.4 ± 7.5) ng/L,P<0.001]. Then they all had varying degrees of decline, 5 weeks after the second intervention, group C1 and D1 were still higher than that of group B, but group C2 and D2 were lower than that of group B. At all sampling time points, the levels of serum IL- 6 in group C2/D2 were lower than those in group C1/D1, 5 weeks after the second intervention the difference was most obvious and statistically significant(P<0.001). Pathology showed that the carotid artery wall in group A was normal. The carotid artery wall was thickened in group B, inflammatory cells and foam cells could be seen, and elastic fibers disordered. The carotid artery wall in group C1 was uneven, foam cells and a small amount of inflammatory cells were visible, and elastic fiber disordered. Obvious thickening was not seen in the carotid artery wall of group C2, a small amount of foam cells and inflammatory cells were found, and elastic fiber mildly disordered. The carotid artery wall in group D1 was obviously uneven, calcium salt deposits were visible in the artery wall, a large amount of inflammatory cells and foam cells could be found, and elastic fiber disordered. Obvious thickening was not seen in the carotid artery wall of group D2, a small amount of inflammatory cells and a large amount of foam cells could be seen, and elastic fiber disordered.</p><p><b>CONCLUSIONS</b>Periodontitis and hyperlipidemia could increase the level of serum IL- 6 and the risk of the As. In chronic periodontitis rats with or without atherosclerosis, when periodontal inflammation was not controlled, tooth extraction may increase the risk of the As. At the time of tooth extraction, giving the anti-inflammatory treatment can reduce the risk to a certain extent.</p>

Effect of serum from patients with chronic renal insufficiency and indoxyl sulfate on lipid accumulation in macrophages in vitro / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the pathologies of aortic root atherosclerotic lesion in uremic apoE-/- mice and explore the effect of serum from patients with chronic renal insufficiency (CRI) and the uremic toxin, indoxyl sulfate (IS), on the expression of cholesterol transporting receptors and lipid accumulation in macrophages in vitro.</p><p><b>METHODS</b>The uremic apoE-/- mouse model was established by surgical operation. Frozen sections of the aortic root were collected from uremic apoE-/- mice, sham-operated apoE-/- mice and C57BL/6J mice and stained with oil red O to calculate the relative area of atherosclerotic plaque. Murine macrophage RAW264.7 cell line was treated for 12 h with different concentrations of IS or serum samples from CRI patients and healthy individuals, and the mRNA expressions of cholesterol transporting receptors (SR-A1, CD36, ABCA1, ABCG1 and SR-B1) were detected. After treatment for 24 h, the cells were induced into foam cells to determine lipid contents using oil red O staining.</p><p><b>RESULTS</b>The relative area of the atherosclerotic plaques in the aortic root increased significantly in uremic apoE-/- mice compared with that in sham-operated apoE-/- mice. CRI serum (5%) and IS (250 µmol/L) obviously increased the mRNA expression of CD36 and lipid accumulation in the macrophages, but did not affect the mRNA expression of other cholesterol transporting receptors.</p><p><b>CONCLUSION</b>CRI can accelerate the progression of atherosclerosis through the mechanism that IS in CRI serum promotes lipid accumulation in macrophages by enhancing the mRNA expression of CD36, which contributes to the formation of foam cells.</p>