Interleukin-6 and its considerable role in the pathogenesis of thyrotoxicosis-related disturbances of bone turnover in postmenopausal women

Background: Thyrotoxicosis is more frequent in postmenopausal women than in the general population, effectively accelerating bone turnover. Interleukin-6 has been shown to be involved in the pathogenesis of bone disorders. Thus, the aim of the present study was to assess the role of IL-6 and its soluble receptor in the pathogenesis of thyrotoxicosis-related disturbances of bone turnover in oestrogen-deficient women. Material and methods: The study was carried out in 40 subjects with toxic nodular goitre in three groups: Group 1 &#8212; 13 premenopausal females, mean age 36 &#177; 15 years (PremTx&#8594;PremEu); Group 2 &#8212; 12 postmenopausal females, mean age 66 &#177; 14 years (PostTx&#8594;PostEu); and Group 3 &#8212; 15 males, mean age 45 &#177; 21 years (MTx&#8594;MEu). Overt thyrotoxicosis and euthyreosis after treatment with thyrostatics were confirmed by thyrotropin, free thyroxine and free triiodothyronin concentrations. Serum levels of bone turnover markers: TRACP5b and osteocalcin as well as serum IL-6 and IL-6sR were determined using ELISA kits. Results: TRACP5b/osteocalcin quotient was significantly elevated in the PostTx females compared to the PremTx women (p < 0.02). There was a positive correlation between serum TRACP5b and osteocalcin in the studied patients (R = 0.45, p < 0.001). Levels of serum IL-6 values were significantly elevated in PostTx: 3.0 (2.14&#8211;6.40) and MTx: 2.24 (1.60&#8211;5.10), compared to PremTx females: 1.39 (0.96&#8211;2.14) (p < 0.01 and p < 0.05 respectively). There were significant positive correlations between IL-6 and IL-6sR concentrations (R = 0.22, p < 0.05) and between IL-6sR and TRACP5b serum levels (R = 0.23, p < 0.05). Conclusions: The results of our study suggest that interleukin-6 plays a considerable role in the pathogenesis of thyrotoxicosis-related disturbances of bone turnover in oestrogen-deficient women. (Pol J Endocrinol 2011; 62 (4): 299&#8211;302)Wstęp: Nadczynność tarczycy występuje częściej u kobiet po menopauzie w porównaniu z populacją ogólną, skutecznie przyspieszając obrót kostny. Wykazano, że interleukina 6 (IL-6) odgrywa istotną rolę w regulacji obrotu kostnego. Uwzględniając ten fakt, celem obecnej pracy była próba oceny roli IL-6 i jej rozpuszczalnego receptora w patogenezie zaburzeń obrotu kostnego w przebiegu tyreotoksykozy u kobiet po menopauzie. Materiał i metody: Badanie przeprowadzono u 40 osób z nadczynnym wolem guzkowym w 3 grupach: 1 &#8212; 13 kobiet przed menopauzą w wieku 36 &#177; 15 lat (PremTx&#198;PremEu), 2 &#8212; 12 kobiet po menopauzie w wieku 66 &#177; 14 lat (PostTx&#198;PostEu) i 3 &#8212; 15 mężczyzn w wieku 45 &#177; 21 lat (MTx&#198;MEu). Stan czynnościowy tarczycy potwierdzono oznaczeniem TSH, fT3 i fT4 w surowicy. Markery obrotu kostnego: TRACP5b i osteokalcyna oraz IL-6 i IL-6sR w surowicy, oznaczono zestawami ELISA. Wyniki: Iloraz TRACP5b/osteokalcyna był istotnie zwiększony u kobiet PostTx w porównaniu z grupą PremTx (p < 0,02). Stwierdzono dodatnią korelację między TRACP5b i osteokalcyną (R = 0,45, p < 0,001). Stężenie IL-6 było istotnie zwiększone w grupie PostTx: 3,0 (2,14&#8211;6,40) i MTx: 2,24 (1,60&#8211;5,10) w porównaniu z odnotowanym u kobiet z grupy PremTx: 1,39 (0,96&#8211;2,14) (odpowiednio: p < 0,01 i p < 0,05). Wykazano istotną dodatnią korelację pomiędzy IL-6 i IL-6sR (R = 0,22, p < 0,05) oraz pomiędzy IL-6sR i TRACP5b (R = 0,23, p < 0,05). Wnioski: Podsumowując, wyniki obecnej pracy wskazują, że IL-6 odgrywa ważną rolę w patogenezie zaburzeń obrotu kostnego w przebiegu tyreotoksykozy u kobiet po menopauzie. (Endokrynol Pol 2011; 62 (4): 299&#8211;302

Plasma levels of soluble tumor necrosis factor-α receptors are related to total and LDL-cholesterol in lean, but not in obese subjects

BACKGROUND: Tumor necrosis factor-α (TNFα) is a mediator of insulin resistance. Plasma levels of soluble TNFα receptors (sTNFR1 and sTNFR2) probably reflect paracrine action of the cytokine. TNFα is also a regulator of lipid metabolism, however, data about impact of obesity on the relationships between TNFα and plasma lipids remain controversial. AIM: The purpose of the present study was to examine the associations of TNFα system with plasma lipids in lean and obese subjects with normal glucose metabolism. METHODS: We examined 63 subjects, 33 lean (BMI<25 kg × m(-2)) and 30 with marked overweight or obesity (BMI>27.8 kg × m(-2)). Anthropometric and biochemical parameters were measured. Oral glucose tolerance test and euglycemic hyperinsulinemic clamp were also performed. RESULTS: Obese subjects were markedly more insulin resistant and had higher levels of both TNFα receptors. Total (TC) and LDL-cholesterol (LDL-C), triglycerides (TG) and non-esterified fatty acids (NEFA) were also higher in the obese group. In obese subjects, both receptors were significantly related to TG and HDL-cholesterol (HDL-C), while sTNFR2 was also associated with NEFA. All those correlations disappeared after controlling for insulin sensitivity. In lean subjects, both receptors were related to TC, HDL-C and LDL-C. In that group, sTNFR1 predicted values of all those parameters independently of BMI, plasma glucose and insulin, and insulin sensitivity. CONCLUSION: We conclude that TNFα receptors are associated with plasma lipids in different way in lean and in obese subjects. TNFα system is probably important in determining cholesterol levels in lean subjects, while in obese this effect might be masked by other metabolic abnormalities

Serum interleukin-16 and RANTES during treatment of Graves&prime; orbitopathy with corticosteroids and teleradiotherapy

Introduction: To assess the usefulness of circulating IL-16 and RANTES measurements as markers of Graves&prime; orbitopathy (GO) activity and to estimate the role of these cytokines in GO pathogenesis. Material and methods: 42 individuals were divided into four groups: Group 1 comprised 15 euthyroid patients with clinical symptoms of GO who underwent corticosteroid therapy consisting of intravenous infusions of methylprednisolone (MP) and teleradiotherapy (TR); Group 2 comprised ten patients with hyperthyroid GD (Gtx); Group 3 comprised ten patients with GD in euthyreosis (Geu); and Group 4 comprised seven healthy volunteers age- and sex-matched to Groups 1&#8211;3. Serum samples were collected 24 hours before the first dose of MP, 24 hours after the first dose of MP, before TR, and at the end of therapy. Serum IL-16 and RANTES were determined by ELISA and TSH-Rab by RIA. Results: Serum IL-16 levels in patients with GO were significantly elevated at the end of therapy: 346 pg/mL (257&#8211;538) compared to IL-16 values before treatment: 250 ng/mL (211&#8211;337) and to the control group. RANTES serum concentrations did not significantly differ between studied groups, and immunosuppressive treatment did not influence its level. A negative correlation between TSH-Rab and RANTES was found in all studied groups (R = &#8211;0.32, p < 0.01). Conclusions: Our data suggests that IL-16 may exert an immunoregulatory effect in Graves&prime; orbitopathy. Serum measurements of both IL-16 and RANTES may be clinically useful; however, establishing their place in the diagnostics and treatment monitoring of GO needs further research. (Pol J Endocrinol 2012; 63 (2): 92&#8211;96)Wstęp: Ocena przydatności oznaczania krążącej IL-16 i RANTES jako wskaźników aktywności GO oraz określenie roli tych cytokin w patogenezie GO. Materiał i metody: 42 osoby w 4 grupach: 1 &#8212; 15 pacjentów z klinicznymi objawami orbitopatii w eutyreozie (GO), którzy poddali się leczeniu kortykosteroidami przy zastosowaniu podawanego dożylnie metylprednizolonu (MP) i teleradioterapii (TR); 2 &#8212; 10 pacjentów z chorobą Gravesa w nadczynności (Gtx); 3 &#8212; 10 pacjentów z chorobą Gravesa w eutyreozie (Geu); 4 &#8212; 7 zdrowych ochotników dobranych pod względem płci i wieku do grup 1.&#8211;3. Próbki krwi pobrano 24 h przed MP, 24 h po 1. dawce MP, przed TR i po zakończeniu leczenia. Stężenia IL-16 i RANTES w surowicy oznaczono metodą ELISA, a TSH-Rab &#8212; metodą RIA. Wyniki: Stężenie IL-16 w surowicy u pacjentów z GO było istotnie wyższe po zakończeniu terapii &#8212; 346 pg/ml (257&#8211;538) w porównaniu z wartością IL-16 przed leczeniem &#8212; 250 ng/ml (211&#8211;337) i w odniesieniu do grupy kontrolnej. Stężenie RANTES w surowicy nie różniło się istotnie między badanymi grupami i leczenie immunosupresyjne nie wpłynęło na jej wartość. Wykazano ujemną korelację między TSH-Rab i RANTES we wszystkich badanych grupach (R = &#8211;0,32; p < 0,01). Wnioski: Uzyskane dane wskazują, że IL-16 może wywierać immunomodulujący wpływ na przebieg orbitopatii. Zarówno oznaczenia IL-16, jak i RANTES w surowicy mogą być przydatne klinicznie, jednak ustalenie ich miejsca w diagnostyce i monitorowaniu leczenia GO wymaga dalszych badań. (Endokrynol Pol 2012; 63 (2): 92&#8211;96

Synthesis, antiprotozoal and antibacterial activity of nitro- and halogeno-substituted benzimidazole derivatives

Two series of benzimidazole derivatives were sythesised. The first one was based on 5,6-dinitrobenzimidazole, the second one comprises 2-thioalkyl- and thioaryl-substituted modified benzimidazoles. Antibacterial and antiprotozoal. activity of the newly obtained compounds was studied. Some thioalkyl derivatives showed remarkable activity against nosocomial strains of Stenotrophomonas malthophilia, and an activity comparable to that of metronidazole against Gram-positive and Gram-negative bacteria. Of the tested compounds, 5,6-dichloro-2-(4-nitrobenzylthio)-benzimidazole showed the most distinct antiprotozoal activity

Circulating monocyte chemoattractant protein-1 in women with gestational diabetes.

Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a key factor in the recruitment and activation of peripheral blood leukocytes in atherosclerotic lesions and adipose tissue. Elevated levels of circulating MCP-1 have been found in patients with type 1 and type 2 diabetes, as well as with coronary artery disease. In this study we compared serum MCP-1 concentrations between pregnant women with normal glucose tolerance (NGT), gestational diabetes mellitus (GDM) and non-pregnant healthy women. The group studied consisted of 62 patients with GDM (mean age 30.1 +/- 5.0 years) at 29.0 +/- 3.5 week of gestation, 64 pregnant women with NGT (mean age 30.0 +/- 4.7 years) at 29.2 +/- 2.9 week of gestation and 34 non-pregnant healthy women (mean age 29.8 +/- 4.7 years). Serum MCP-1 concentration was measured using an enzyme - linked immunosorbent assay. Median MCP-1 concentrations did not differ significantly between women with GDM (median 342.3 [interquartile range 267.9-424.4] pg/ml) and NGT (338.0 [274.7-408.2] pg/ml), but were markedly lower than those found in non-pregnant women (485.2 [409.6-642.4] pg/ml,

Role of interleukin-6 on RANKL-RANK/osteoprotegerin system in hypothyroid ovariectomized mice.

Postmenopausal women frequently develop hypothyroidism. Estrogen depletion is accompanied by an increase of IL-6, accelerating bone turnover. The influence of hypothyroidism on bone metabolism in postmenopausal women is poorly understood. The aim of the study was an attempt to clarify the role of interleukin-6 on RANKL-RANK/osteoprotegerin system in hypothyroid ovariectomized mice. The study was performed on 56, 12-13 weeks old, female mice: C57BL/6J (wild-type; WT) and C57BL/6JIL6-/-Kopf (IL-6 knock-out; IL6KO). The mice were randomly divided into 8 groups with 7 mice in each one: 1/ WT controls, 2/ IL6KO controls, 3/ WT hypothyroid mice, 4/ IL6KO hypothyroid mice, 5/ WT ovariectomized, 6/ IL6KO ovariectomized, 7/ WT ovariectomized hypothyroid mice and 8/ IL6KO ovariectomized hypothyroid mice. Experimental model of menopause was produced by bilateral ovariectomy carried out in 8-9 weeks old mice. Experimental model of hypothyroidism was induced by propylthiouracyl administration in driking water. The serum levels of TRACP 5b, osteocalcin, OPG and RANKL were determined by ELISA. Serum RANKL concentrations were elevated significantly in all groups of ovariectomized mice as compared to respective controls, but in a minor degree in IL6KO hypothyroid mice as compared to wild-type animals. Moreover sRANKL values were significantly lower in IL6KO as compared to WT controls and IL6KO PTU injected mice. Osteoprotegerin serum levels were decreased in all IL-6 deficient mice and in a highest degree in sham-operated hypothyroid mice. To sum up, the results of the present study suggest that estrogens deficit is a strong stimulus for RANKL-RANK/OPG pathway that breaks an inhibitory influence of hypothyroidism even in IL-6 deficient mice

Polysaccharide BAP1 of Bifidobacterium adolescentis CCDM 368 is a biologically active molecule with immunomodulatory properties

Bifidobacteria are among the most common bacteria used for their probiotic properties and their impact on the maturation and function of the immune system has been well-described. Recently, scientific interest is shifting from live bacteria to defined bacteria-derived biologically active molecules. Their greatest advantage over probiotics is the defined structure and the effect independent of the viability status of the bacteria. Here, we aim to characterize Bifidobacterium adolescentis CCDM 368 surface antigens that include polysaccharides (PSs), lip-oteichoic acids (LTAs), and peptidoglycan (PG). Among them, Bad368.1 PS was observed to modulate OVA-induced cytokine production in cells isolated from OVA-sensitized mice by increasing the production of Th1-related IFN-gamma and inhibition of Th2-related IL-5 and IL-13 cytokines (in vitro). Moreover, Bad368.1 PS (BAP1) is efficiently engulfed and transferred between epithelial and dendritic cells. Therefore, we propose that the Bad368.1 PS (BAP1) can be used for the modulation of allergic diseases in humans. Structural studies revealed that Bad368.1 PS has an average molecular mass of approximately 9,99 x 106 Da and it consists of glucose, galactose, and rhamnose residues that are creating the following repeating unit: [-> 2)-beta-D-Glcp-(1 -> 3)-beta-L-Rhap-(1 -> 4)-beta-D-Glcp-(1 -> 3)-alpha-L-Rhap-(1 -> 4)-beta-D-Glcp-(1 -> 3)-alpha-D-Galp-(1 -> ]

Prenyl Ammonium Salts – New Carriers for Gene Delivery: A B16-F10 Mouse Melanoma Model

Purpose Prenyl ammonium iodides (Amino-Prenols, APs), semi-synthetic polyprenol derivatives were studied as prospective novel gene transfer agents. Methods AP-7, -8, -11 and -15 (aminoprenols composed of 7, 8, 11 or 15 isoprene units, respectively)were examined for their capacity to form complexes with pDNA, for cytotoxicity and ability to transfect genes to cells. Results All the carriers were able to complex DNA. The highest, comparable to commercial reagents, transfection efficiency was observed for AP-15. Simultaneously, AP-15 exhibited the lowest negative impact on cell viability and proliferation—considerably lower than that of commercial agents. AP-15/DOPE complexes were also efficient to introduce pDNA to cells, without much effect on cell viability. Transfection with AP-15/DOPE complexes influenced the expression of a very few among 44 tested genes involved in cellular lipid metabolism. Furthermore, complexes containing AP-15 and therapeutic plasmid, encoding the TIMP metallopeptidase inhibitor 2 (TIMP2), introduced the TIMP2 gene with high efficiency to B16-F10 melanoma cells but not to B16-F10 melanoma tumors in C57BL/6 mice, as confirmed by TIMP2 protein level determination. Conclusion Obtained results indicate that APs have a potential as non-viral vectors for cell transfection

The importance of NFκB1 rs4648068 and RUNX2 rs7771980 polymorphisms in bone metabolism of postmenopausal Polish women

Objectives: Osteoporosis is a multifactorial disease that causes a loss of bone density. However, genetic factors play an increasingly important role in its development. To thoroughly understand the molecular mechanisms, polymorphic variants of genes candidate for osteoporosis are still being sought. The aim of our study was to investigate the influence of NFκB1 gene rs4648068 (A&gt;G) and RUNX2 gene rs7771980 (-1025T&gt;C) polymorphisms on the risk of osteoporosis.Material and methods: A group of 675 postmenopausal Caucasian women (109 women with osteopenia, 333 with osteoporosis and 233 with normal T-score) were examined. The bone mineral density (BMD) at the lumbar spine (L1-L4) was measured by dual energy x-ray absorptiometry (DXA). The analysis of NFκB1 and RUNX2 polymorphisms was performed using real-time PCR method.Results: Analysis of NFκB1 gene rs4648068 polymorphism showed that the GG genotype was slightly more frequent in the study groups compared to the control group. In the osteoporosis group, patients with the G allele in the genotype have lower bone mineral density values. For the RUNX2 rs7771980 polymorphism, in women with osteopenia we observed an increased incidence of TC heterozygotes compared to the control group (29.40% vs 24.90%, p &gt; 0.05), and in women with osteoporosis, the TT genotype was more common (78.70% vs 73.80%, p &gt; 0.05). No correlation was observed between the genotypes and the clinical parameters.Conclusions: The analysis showed no significant relationship between the genotypic distribution and the individual clinical parameters. However, it is suggested an association between the rs4648068 polymorphism of the NFκB1 gene and an increased risk of developing osteoporosis

Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies