Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts

Bone and immune system are functionally interconnected. Immune and bone cells derive from same progenitors in the bone marrow, they share a common microenvironment and are being influenced by similar mediators. The evidence on increased bone resorption associated with inappropriate activation of T cells such as during inflammation, is well established. However, the molecular mechanisms beyond this clinical observation have begun to be intensively studied with the advancement of osteoimmunology. Now days, we have firm evidence on the influence of numerous pro-inflammatory cytokines on bone cells, with the majority of data focused on osteoclasts, the bone resorbing cells. It has been shown that some pro-inflammatory cytokines could possess osteoclastogenic and/or anti-osteoclastogenic properties and can target osteoclasts directly or via receptor activator of nuclear factor κB (RANK)/RANK ligand(RANKL)/osteoprotegerin (OPG) system. Several studies have reported opposing data regarding (anti)osteoclastogenic properties of these cytokines. Therefore, the first part of this review is summarizing current evidence on the influence of pro-inflammatory cytokines on osteoclasts and thus on bone resorption. In the second part, the evidence on the role of pro-inflammatory cytokines in osteoporosis and osteoarthritis is reviewed to show that unravelling the mechanisms beyond such complex bone diseases, is almost impossible without considering skeletal and immune systems as an indivisible integrated system

The many faces of estrogen signaling

Estrogens have long been known as important regulators of the female reproductive functions; however, our understanding of the role estrogens play in the human body has changed significantly over the past years. It is now commonly accepted that estrogens and androgens have important functions in both female and male physiology and pathology. This is in part due to the local synthesis and action of estrogens that broadens the role of estrogen signaling beyond that of the endocrine system. Furthermore, there are several different mechanisms through which the three estrogen receptors (ERs), ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER1) are able to regulate target gene transcription. ERα and ERβ are mostly associated with the direct and indirect genomic signaling pathways that result in target gene expression. Membrane-bound GPER1 is on the other hand responsible for the rapid non-genomic actions of estrogens that activate various protein-kinase cascades. Estrogen signaling is also tightly connected with another important regulatory entity, i.e. epigenetic mechanisms. Posttranslational histone modifications, microRNAs (miRNAs) and DNA methylation have been shown to influence gene expression of ERs as well as being regulated by estrogen signaling. Moreover, several coregulators of estrogen signaling also exhibit chromatin-modifying activities further underlining the importance of epigenetic mechanisms in estrogen signaling. This review wishes to highlight the newer aspects of estrogen signaling that exceed its classical endocrine regulatory role, especially emphasizing its tight intertwinement with epigenetic mechanisms

Molecular Mechanisms of Insulin Resistance, Obesity and Metabolic Syndrome

Inzulinska rezistencija je stanje poremećene sposobnosti odgovora na djelovanje inzulina. Najčešći osnovni uzrok je središnja pretilost, iako je primarna inzulinska rezistencija moguća i u osoba s normalnom težinom. Suvišno abdo-minalno masno tkivo otpušta povećane količine faktora tumorske nekroze α i slobodnih masnih kiselina, što izravno utječe na inzulinsko signaliziranje, smanjuje preuzimanje glukoze u mišićima, dovodi do pretjerane sinteze trigliceri-da i izaziva glukoneogenezu u jetri. Ostali čimbenici za koje se pretpostavlja da igraju ulogu u inzulinskoj rezistenciji su adiponektin (sniženje), leptin, IL-6 i neki drugi adipokini. Smatra se da je obična pretilost poligenog podrijetla uz utjecaj "pretilogene" okoline - povećan unos hrane i nedostatak tjelesne aktivnosti. Današnja visoka učestalost pretilosti mogla bi se objasniti evolucijskim pritiskom za odabir gena koji promiču pohranu masti za preživljenje u vrijeme gladovanja. Inzulinska rezistencija je prisutna zajedno sa središnjom pretilosti, hipertenzijom i dislipidemijom, koje se skupno označavaju kao metabolički sindrom. Ove pojavnosti predstavljaju snažne čimbenike rizika za šećernu bolest tipa 2 i kardiovaskularnu bolest.Insulin resistance is a state of impaired responsiveness to insulin action. The most common underlying cause is central obesity although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of tumor necrosis factor α and free fatty acids, which directly affect insulin signaling, diminish glucose uptake in the muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play a role in insulin resistance are adiponectin (a decrease), leptin, IL-6 and some other adipokines. Common obesity is thought to be of polygenic origin with influence of "obesogenic" environment, i.e. increased food intake and the lack of physical activity. Today\u27s high prevalence of obesity could be explained by evolutionary pressure for selection of genes promoting fat storage to survive in starvation. Insulin resistance frequently coexists with central obesity, hypertension and dyslipidemia, which have collectively been denoted as metabolic syndrome. These manifestations represent strong risk factors for diabetes mellitus type 2 and cardiovascular disease

Association between Pro12Ala and His477His polymorphisms in PPARG gene and insulin resistance in patients with polycystic ovary syndrome

Uvod: Inzulinska rezistencija je obilježena oslabljenim tkivnim odgovorom na djelovanje inzulina, a udružena je s pretilošću, šećernom bolesti tipa 2, metaboličkim sindromom, lipodistrofijama, sindromom policističnih jajnika (engl. polycystic ovary syndrome, PCOS) i kroničnom infekcijom. Inzulinska rezistencija je prisutna kod 50-70% bolesnica s PCOS. Peroksizomni proliferatorom aktivirani receptor gama (engl. peroxisome proliferator-activated receptor γ, PPARγ) je jezgreni receptor koji kontrolira transkripciju gena uključenih u metabolizam slobodnih masnih kiselina i lipogenezu, a važan je za diferencijaciju i preživljenje adipocita. Cilj ovoga probnog istraživanja bio je ispitati povezanost polimorfizama Pro12Ala i His477His PPARG gena s inzulinskom rezistencijom kod bolesnica s PCOS. Bolesnice i metode: U istraživanju je sudjelovalo 69 bolesnica s PCOS. Metodom PCR-RFLP analizirane su frekvencije genotipova. Glukoza natašte i glukoza nakon oralnog testa opterećenja glukozom (engl. oral glucose tolerance test, OGTT), inzulin, hsCRP (engl. high sensitivity C-reactive protein), tjelesna masa, visina, opseg struka, sistolični i dijastolični krvni tlak, indeks tjelesne mase (engl. body mass index, BMI) i indeks procjene modela homeostaze (engl. homeostasis model assessment, HOMA) izmjereni su rutinskim metodama ili su izračunati iz podataka. Rezultati: Pronađena je značajna povezanost između alela Ala polimorfizma Pro12Ala i nižeg BMI (P = 0,040) te između alela T polimorfizma His477His i niže koncentracije hsCRP (P = 0,047). Polimorfizmi Pro12Ala i His477His pokazali su značajnu neravnotežu povezanosti (engl. linkage disequilibrium) (D\u27 = 0,727). Analiza diplotipova nije pokazala da postoji povezanost. Zaključak: U ovom preliminarnom istraživanju pronašli smo značajnu povezanost između alela Ala polimorfizma Pro12Ala i nižeg BMI te alela T polimorfizma His477His i nižeg hsCRP. Međutim, niti jedan od ova dva polimorfizma, pojedinačno ili u kombinaciji (diplotip), nije bio povezan s koncentracijama inzulina i glukoze natašte u plazmi, kao ni s indeksom HOMA, koji su znakoviti za inzulinsku rezistenciju. Stoga zaključujemo kako istraživani polimorfizmi nisu povezani s inzulinskom rezistencijom kod bolesnica s PCOS.Background: Insulin resistance is characterized by attenuated response of tissues to insulin action and is associated with obesity, type 2 diabetes mellitus, metabolic syndrome, lipodystrophies, polycystic ovary syndrome (PCOS) and chronic infection. Insulin resistance is present in 50%—70% of PCOS patients. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor which controls transcription of genes involved in free fatty acid uptake and lipogenesis, and is essential for diferentiation and survival of adipo-cytes. The aim of our pilot study was to investigate the association between Pro12Ala and His477His polymorphisms in PPARG gene with insulin resistance in PCOS patients. Patients and methods: The study included 69 PCOS patients. Genotype frequencies were analyzed by PCR-RFLP methods. Fasting glucose and glucose after oral glucose tolerance test, insulin, and high sensitivity C-reactive protein (hsCRP), body mass, height, waist circumference, systolic and diastolic blood pressure, body mass index (BMI) and homeostasis model assessment (HOMA) index were measured by routine methods or calculated from the findings obtained. Results: A signi;cant association was found between the Ala allele of the Pro12Ala polymorphism and lower BMI (P = 0.040) and between the T allele of the His477His polymorphism and lower hsCRP (P = 0.047). The Pro12Ala and the His477His polymorphisms were in considerable linkage disequilibrium (D\u27 = 0.727). Diplotype analysis showed no association. Conclusions: In our preliminary study, we found a significant association between the Ala allele of the Pro12Ala polymorphism and lower BMI, and between the T allele of the His477His polymorphism and lower hsCRP. However, none of the two polymorphisms, individually or in combination (diplotype), was associated with fasting plasma insulin and glucose concentrations and HOMA index that are characteristic of insulin resistance. We therefore conclude that the polymorphisms investigated are not associated with insulin resistance in PCOS patients

Molecular impact of glutathione peroxidases in antioxidant processes

Reaktivni radikali kisika (ROS) stvaraju se tijekom različitih patoloških procesa u povećanim koncentracijama. Oni su uzrok peroksidacije lipida i oksidacije DNA i proteina zbog svoje visoke kemijske reaktivnosti. Međutim, mehanizmi antioksidacijske zaštite, uključujući različite antioksidacijske enzime, sprječavaju oštećenja tkiva i druge komplikacije povezane s ROS. Ovaj je pregled usredotočen na učinke različitih glutation-peroksidaza (GPX) na molekularnu kontrolu toksikološkog djelovanja reaktivnih kisikovih radikala. Nadalje, opisuju se specifična biokemijska svojstva, sinteza i uloga svakog izoenzima glutation-peroksidaze u biološkim procesima. Male molekule koje djeluju kao oponašatelji aktivnog mjesta glutation-peroksidaza mogle bi postati novo sredstvo u liječenju mnogih oboljenja.Reactive oxygen species (ROS) are produced during different pathological processes in increased concentrations. They cause lipid peroxidation and oxidation of DNA and proteins due to their high chemical reactivity. However, antioxidative defense mechanisms, including different antioxidant enzymes, prevent tissue damages and other ROS-related complications. The focus of this review is on effects of different glutathione peroxidases (GPXs) on molecular control of reactive oxygen species toxicology. Furthermore, specific biochemical properties, synthesis and role of each glutathione peroxidase isoenzyme in biological processes are described. Small molecules acting as mimetics of the active site of glutathione peroxidases could become new tools for treatment of many diseases

Increased DAPK1 but decreased CCL2 plasma levels of nucleic acids in patients with stable angina

Introduction: We hypothesized that patients with stable angina have increased plasma levels of mRNA from genes responsible for atherosclerotic plaque development and destabilisation, i.e. from death-associated protein kinase (DAPK1) and monocyte chemotactic protein-1 (CCL2). Materials and methods: Nucleic acids were isolated from plasma of patients with stabile angina and healthy subjects as controls. mRNAs were transcribed to cDNAs, quantified by real-time PCR and standardized to the amount of a reference gene. Reagents for PCR quantification are declared to be mRNA specific, but in our test conditions DNA was found to interfere in both assays. Results: Patients had 5.1-times higher plasma level of DAPK1 nucleic acids (mRNA and DNA) than controls (P < 0.001) and the highest levels were associated with the presence of diabetes. However, plasma levels of CCL2 tended to be lower than in controls, and in statin-treated patients the decre-ment reached significance (-66.3%; P = 0.041). Conclusion: The estimated levels are explicable in terms of current knowledge. Further studies with specific assays for mRNA PCR quantification are reasonable to access whether this approach offers non-invasive in vivo assessment and monitoring of gene expression profile in atherosclerotic vascular beds