Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

Platelet changes in patients with hepatitis C virus-related liver cirrhosis after directly acting antiviral therapy

Background and Purpose of the study:Thrombocytopenia is the most common haematological abnormality in patients with Liver Cirrhosis and it is caused by multiple factors. This study evaluated platelets (PLT) count changes in patients with HCV related LC after DAAs therapy. Materials and Methods: We enrolled 83 patients with LC. In all patients were evaluated liver function tests and PLT count at baseline (BL), at end of therapy (ET) and three months post treatment (PostT), Elastography and ultrasound (US) at BL, and US at PostT. LC diagnosis was histological in 13 patients, in 71 with liver stiffness >12 kPa. All patients were SVR (58 patients had DAAs therapy without, 25 with Ribavirin). 79% were genotype 1b. US diameter of spleen (DS) was measured. The paired t Student\u2019s test was used. Results: PLT at BL were significantly lower compared to both ET and PostT, P <0.0001, while in ET were higher than in PostT, P<0.0001. In group without Ribavirin PLT at BL were significantly lower compared to both ET and PostT (respectively P <0.001). PLT at PostT were higher than at ET but not significantly (P=ns). In Ribavirin group PLT at BL were significantly lower compared to both ET and PostT, P <0.001, while in ET were significantly higher than in PostT, P<0.0001. DS at enrollment vs PostT didn\u2019t show any statistical difference. Conclusions: PLT increase after antiviral treatment in absence of any difference between spleen dimensions before and after therapy confirm that thrombocytopenia in cirrhotic patients is not only due to portal hypertension but also to a direct effect of HCV

EFFETTI DELLA TERAPIA CON DIRECT ACTING ANTIVIRALS (DAAS) SUI PARAMETRI ECOGRAFICI DI IPERTENSIONE PORTALE

Obiettivi dello studio: Tra gli end point della terapia antivirale con DAAs nella cirrosi HCV (LCHCV) oltre all' eradicazione del virus vi sono: la regressione della fibrosi e dell’ipertensione portale. Abbiamo valutato in pazienti LCHCV e risposta sostenuta (SVR) alla terapia con DAAs il comportamento dell’AST to Platelet Ratio Index (APRI) (marker indiretto di fibrosi) e di due segni ecografici di ipertensione portale: calibro della vena porta (cVP) e diametro longitudinale della milza (DLM). Materiali: 98 pazienti con LCHCV,al Baseline (BL) a fine terapia (FT) e tre mesi (PostT3) e 9 mesi dopo la fine della terapia (PostT9) eseguivano i test di funzionalità epatica e la conta piastrinica, l’ecografia al BL, a PostT3 e a PostT9, la misurazione della liver stiffness (LS) con il Fibroscan al BL. La diagnosi di LC era istologica in 13 pazienti, in 85 con LS, ecografica e endoscopica. Il 79% era genotipo 1b. Al momento dell’analisi 45 erano al PostT9. Statistica: t di Student per dati appaiati, r Pearson, test del chiquadro. Risultati: Il cVP al BL era significativamente più elevato vs PostT3 (P<0.003) e PostT9 (P<0.004), nessuna differenza era rilevata tra PostT3 e PostT9. Il DLM presentava un trend in diminuzione non significativo nei tre tempi. L’APRI al BL era significativamente più elevato vs PostT3 e PostT9 (P<0001), nessuna differenza tra PostT3 e PostT9 (P=ns). Le correlazioni tra i tempi di valutazione BL, PostT3 e PostT9 (indicati come 0,1,2) e i parametri studiati erano: APRI=- 0.5 (P<0.0001), cVP = -0.21 (P<0.005), DLM= -0.12 (P<0.05). I pazienti che al BL avevano LS < 20 kPa, presentavano al PostT3 una riduzione più frequente del cVP (P<0.05), differenza che scompariva al PostT9 (P=ns). Conclusioni: I nostri dati suggeriscono che la terapia con DAAs eradica l’HCV e determina un miglioramento dell’ipertensione portale, evidenziato dalla riduzione del cVP. Le cause di ciò potrebbero essere diverse. La precoce riduzione del cVP, e dell’APRI, la correlazione inversa ritrovata per APRI e cVP e DLM nei tre tempi di valutazione e infine la maggiore frequenza di riduzione del cVP al PostT3 nei pazienti con LS < 20 KPa ci fanno supporre che all’inizio la diminuzione della necroinfiammazione sia il fattore predominante. Più tardivamente agirebbe la riduzione della fibrosi come suggerito dall’assenza di differenza al T9 tra i pazienti con LS <20 kPa e dal trend di riduzione del DLM che potrebbe essere tardivo in quanto correlato alla fibrosi

Novel anti-obesity drugs and plasma lipids

Obesity is a health problem of global, epidemic proportions and a major risk factor for chronic diseases resulting in accelerated morbidity and mortality. Dyslipidemia with a predominance of small dense LDL, impaired functionality of HDL particles, and increased serum levels of remnant particles due to impaired clearance of triglyceride-rich lipoproteins significantly heightens cardiovascular events in obese subjects. Pharmacotherapy in combination with lifestyle modification is the primary approach to reduce obesity-related cardiovascular risk. Although there are several potential anti-obesity drugs, orlistat is the only agent that remains available in the market. Lorcaserin and Qsymia®, approved by the US FDA last year, and contrave with potential approval in 2014, are new anti-obesity drugs with promising therapeutic effects. Although these drugs can be associated with adverse side-effects, these agents have favorable effects on lipid profiles. However, the need for safer anti-obesity agents is clear. © 2014 Future Medicine Ltd

Novel anti-obesity drugs and plasma lipids

Obesity is a health problem of global, epidemic proportions and a major risk factor for chronic diseases resulting in accelerated morbidity and mortality. Dyslipidemia with a predominance of small dense LDL, impaired functionality of HDL particles, and increased serum levels of remnant particles due to impaired clearance of triglyceriderich lipoproteins significantly heightens cardiovascular events in obese subjects. Pharmacotherapy in combination with lifestyle modification is the primary approach to reduce obesity-related cardiovascular risk. Although there are several potential anti-obesity drugs, orlistat is the only agent that remains available in the market. Lorcaserin and Qsymia®, approved by the US FDA last year, and contrave with potential approval in 2014, are new anti-obesity drugs with promising therapeutic effects. Although these drugs can be associated with adverse side effects, these agents have favorable effects on lipid profiles. However, the need for safer anti-obesity agents is clear

Effects of Liraglutide on Metabolic Parameters and Carotid Intima-Media Thickness in Patients with The Metabolic Syndrome: A 12-Month Prospective Pilot Study

Recent research indicates that therapy with the GLP-1 agonist liraglutide in patients with type 2 diabetes mellitus (T2DM) seems to have beneficial actions on blood pressure, lipids, and the atherosclerotic process, which may be independent of its effect on glucose metabolism. However, the effects of liraglutide in subjects with the metabolic syndrome (MetS) are largely unknown. Forty-nine subjects with the MetS (24 men and 25 women, age 65±10 yrs) diagnosed by the AHA/NHLBI criteria were included in a 12-month prospective study. All subjects had T2DM, were naïve to incretin-based therapies, and treated with metformin only. Liraglutide was added at a dose of 0.6 mg subcutaneously daily for two weeks, followed by 1.2 mg daily for the rest of the study. Fasting plasma samples were taken at baseline and after 12 months for laboratory analyses. Carotid-intima media thickness (IMT) was assessed by B-mode real-time ultrasound. Statistical analysis was performed by ANOVA. In comparison to baseline, liraglutide therapy led to a significant reduction in plasma fasting glucose (7.1±1.9 vs 9.6±4.6 mmol/l, p<0.0001) and HbA1c (6.5±0.9 vs 8.7±1.7 %, p<0.0001), as well as in plasma total-cholesterol (3.9±0.8 vs 4.6±1.2 mmol/l, p=0.0062) and triglycerides (1.4±0.6 vs 2.1±1.8 mmol/l, p=0.0387), while low- and high- density lipoprotein cholesterol levels did not change significantly. There was no significant change in weight, waist circumference, and body mass index. By contrast, carotid IMT decreased after 12 months of liraglutide therapy (from 1.00±0.29 to 0.80±0.16 mm, p=0.0004). In patients with the MetS and T2DM, a 12-month treatment with liraglutide significantly improved glucose levels and components of the lipid profile, and reduced carotid IMT. Whether these encouraging metabolic and vascular changes will translate into better clinical and cardiovascular outcomes remains to be seen

Keikipukalides, Furanocembrane Diterpenes from the Antarctic Deep Sea Octocoral \u3cem\u3ePlumarella delicatissima\u3c/em\u3e

During a 2013 cruise in the Southern Ocean we collected specimens of the octocoral Plumarella delicatissima between 800 and 950 m depth. Five new furanocembranoid diterpenes, keikipukalides A–E (1–5), the known diterpene pukalide aldehyde (6), and the known norditerpenoid ineleganolide (7) were isolated from the coral. These Plumarella terpenes lack mammalian cytotoxicity, while 2–7 display activity against Leishmania donovani between 1.9 and 12 μM. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy and mass spectrometry, and keikipukalides A and E were confirmed by X-ray crystallography