Beta-adrenergic stimulation promotes an endoplasmic reticulum stress-dependent inflammatory program in salivary gland epithelial cells.

The effect of beta-adrenergic stimulation on human labial minor salivary gland epithelial cells (LMSGEC) on IL-6 production, and its dependency to endoplasmic reticulum (ER) stress were investigated. Primary LMSGEC from Sjögren's syndrome (SS) patients and controls in culture were stimulated with epinephrine and IL-6 expression was evaluated by qPCR and ELISA. The expression of ß-ARs in cultured LMSGEC was tested by qPCR, while adrenoceptors and cAMP levels were examined in LMSGs by immunofluorescence. ER evaluation was performed by Transmission electron microscopy (TEM) and ER stress by Western blot. Adrenergic induced IL-6 production by cultured LMSGEC was evaluated after alleviation of the ER stress by applying Tauroursodeoxycholic acid (TUDCA) and silencing of PKR-like ER kinase (PERK) and activating transcription factor 4 (ATF4) RNAs. Expression of IL-6 by LMSGEC was upregulated after ß-adrenergic stimulation, while the silencing of adrenoreceptors downregulated IL-6. The amelioration of ER stress, as well as the silencing of PERK/ATF4, prevented epinephrine-induced upregulation of IL-6. Adrenergic stimulation led to higher and sustained IL-6 levels secreted by LMSGEC of SS patients compared to controls. Adrenergic signaling was endogenously enhanced in LMSGEC of SS patients (expression of ß-ARs in situ, intracellular cAMP in cultured LMSGEC). In parallel, SS-LMSGEC expressed dilated ER (TEM) and higher levels of GRP78/BiP. PERK/ATF4 pathway of the ER stress emerged a considerable mediator of adrenergic stimulation for IL-6 production by the LMSGEC. An enhanced endogenous adrenergic activation and a stressed ER observed in SS-LMSGEC may contribute to a sustained IL-6 production by these cells after adrenergic stimulation.

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives.

Resveratrol, a naturally occurring stilbene, exhibits numerous beneficial health effects. Various studies have demonstrated its diverse biological actions, including anti-oxidant, anti-inflammatory, and anti-platelet properties, thereby supporting its potential for cardio protection, neuroprotection, and anti-cancer activity. However, a significant limitation of resveratrol is its weak bioavailability. To overcome this challenge, multiple research groups have investigated the synthesis of new resveratrol derivatives to enhance bioavailability and pharmacological activities. Nevertheless, there are limited data on the effects of resveratrol derivatives on platelet function. Therefore, the objective of this study was to synthesize resveratrol methoxy derivatives and evaluate their anti-platelet and anti-proliferative activity. Platelet-rich plasma (PRP) obtained from healthy volunteers was utilized to assess the derivatives' ability to inhibit platelet aggregation induced by platelet activating factor (PAF), adenosine diphosphate (ADP), and thrombin receptor activating peptide (TRAP). Additionally, the derivatives' anti-tumor activity was evaluated against the proliferation of PC-3 and HCT116 cells. The results revealed that some methoxy derivatives of resveratrol exhibited comparable or even superior anti-platelet activity compared to the original compound. The most potent derivative was the 4'-methoxy derivative, which demonstrated approximately 2.5 orders of magnitude higher anti-platelet activity against TRAP-induced platelet aggregation, indicating its potential as an anti-platelet agent. Concerning in silico studies, the 4'-methyl group of 4'-methoxy derivative is oriented similarly to the fluorophenyl-pyridyl group of Vorapaxar, buried in a hydrophobic cavity. In terms of their anti-tumor activity, 3-MRESV exhibited the highest potency in PC-3 cells, while 3,4'-DMRESV and TMRESV showed the greatest efficacy in HCT116 cells. In conclusion, methoxy derivatives of resveratrol possess similar or improved anti-platelet and anti-cancer effects, thereby holding potential as bioactive compounds in various pathological conditions.

Acute and delayed hormonal and blood cell count responses to high-intensity exercise before and after short-term high-intensity interval training.

The acute and delayed hormonal and blood cell responses to a high-intensity interval training (HIIT) session, were examined before and after a 3-week intervention (9 HIIT sessions of 4-6 × 30 s high-intensity cycling bouts) in eight recreationally active male volunteers (age: 24.3 ± 1.4 y, VO2max: 41.2 ± 3.2 ml/kg/min). Blood samples were collected before and 0.5, 24, 48 h following the first and last training session. Before training, the HIIT session induced acute increases in cortisol, prolactin and TSH concentration, while free-T4 peaked 24 h later (p < 0.001) and testosterone remained unchanged. White blood cell count was increased 0.5 h after exercise (p < 0.001), while lymphocyte percentage decreased 24 h post exercise (p < 0.01). After three weeks of HIIT, cortisol, WBC and lymphocyte responses were decreased by ~42% (p = 0.002), 8.6% (p = 0.032) and 9.6% (p = 0.039), respectively, despite an increase in total work. These findings show that short-term HIIT may induce rapid adaptations of the hypothalamic-pituitary-adrenal axis and may blunt exercise-induced immune responses.

Myostatin in combination with creatine phosphokinase or albumin may differentiate patients with cirrhosis and sarcopenia.

In patients with liver cirrhosis (LC), sarcopenia is correlated with frequent complications and increased mortality. Myostatin, a myokine, is a potential biomarker of skeletal mass and/or sarcopenia. The aim of this study was to examine the association between myostatin and muscle mass and evaluate myostatin as a biomarker of sarcopenia in LC. Skeletal muscle index (SMI) and myosteatosis were evaluated by computed tomography scan. Muscle quantity and quality along with muscle strength and function were used to diagnose sarcopenia. Serum myostatin was measured by ELISA. One hundred and fifteen consecutive patients with LC [72.2% male, median age 59 yr (IQR 52-67), MELD 12 (8-16), 28.7% with compensated LC] were included. Low SMI was diagnosed in 49.6% and sarcopenia in 34.8% (21.7% severe). Myostatin levels were lower in low (P < 0.001) compared with patients with normal SMI and were strongly correlated with SMI in MELD score ≥ 15 (r = 0.571, P < 0.001). Myostatin was also lower in patients with sarcopenia compared with those without (P < 0.001) and even lower in severe sarcopenia (P < 0.001). In multivariate analysis, myostatin, age, and albumin remained significant predictors of low SMI after adjustment for sex, MELD, and creatine phosphokinase (CPK). Similarly, myostatin and age predicted sarcopenia after adjustment for sex, MELD, CPK, and albumin. The ratios log10myostatin-to-CPK or albumin-to-myostatin were found to have acceptable diagnostic accuracy in ruling out sarcopenia in total patients. However, the best diagnostic performance was shown in MELD ≥ 15 (AUROC 0.829 or 0.801, respectively). Myostatin is independently associated with both skeletal muscle mass and sarcopenia. Myostatin in combination with CPK or albumin are good surrogate markers in excluding sarcopenia.NEW & NOTEWORTHY Serum levels of myostatin were significantly lower in cirrhotic patients with impaired skeletal mass index (SMI) and sarcopenia than those without. Serum levels of myostatin have a positive correlation with SMI. Myostatin levels are independently associated with sarcopenia, diagnosed according to the latest criteria, in patients with cirrhosis. Myostatin in combination with creatine phosphokinase or albumin have good accuracy excluding sarcopenia in patients with cirrhosis.

A weight-loss Mediterranean diet/lifestyle intervention ameliorates inflammation and oxidative stress in patients with obstructive sleep apnea: results of the "MIMOSA" randomized clinical trial.

PURPOSE: Inflammation and oxidative stress are implicated in obstructive sleep apnea (OSA) pathophysiology. We aimed at exploring whether the combination of a weight-loss Mediterranean diet/lifestyle intervention with OSA standard care, i.e., continuous positive airway pressure (CPAP) prescription, can lead to greater improvements in inflammation and oxidative stress, compared to standard care alone. METHODS: This was a randomized controlled clinical trial in 187 adult, overweight patients with moderate-to-severe OSA. Participants were randomized to a standard care (SCG, n = 65), a Mediterranean diet (MDG, n = 62) or a Mediterranean lifestyle group (MLG, n = 60). All groups received OSA standard care. Intervention arms participated in a 6-month behavioral weight-loss intervention based on the Mediterranean diet, while the MLG also received counselling on physical activity and sleep habits. RESULTS: Seven patients were excluded and 53/180 were lost to follow-up. In intention to treat analysis (n = 180), the SCG did not exhibit changes in any of the markers assessed. Post-intervention age-, sex-, baseline- and CPAP use-adjusted plasma high sensitivity C-reactive protein levels (mg/L) were lower in the MDG and the MLG compared to the SCG (mean difference - 1.33, P = 0.039 and - 1.68, P = 0.007, respectively). The MLG also exhibited lower urinary 8-iso prostaglandin F2a levels (ng/mg creatinine) compared to the SCG and the MDG (mean difference - 1.10, P < 0.0001 and - 0.80, P = 0.001, respectively). Adiponectin and oxidized guanine levels were not altered in any of the study groups. Results were similar in per protocol analysis (n = 127). CONCLUSION: A weight-loss Mediterranean diet/lifestyle intervention on top of CPAP has anti-inflammatory and antioxidant benefits in OSA. REGISTRATION: The trial was prospectively registered at ClinicalTrials.gov (NCT02515357) on August 4, 2015.

Novel Substituted Purine Isosteres: Synthesis, Structure-Activity Relationships and Cytotoxic Activity Evaluation.

A number of pyrrolo[2,3-c]pyridines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold that allowed the extraction of interesting SARs. The cytotoxic activity of the new derivatives was evaluated against prostatic (PC-3) and colon (HCT116) cell lines, and the most potent analogues showed IC50 values in the nM to low µM range, while they were found to be non-toxic against normal human fibroblasts (WI-38). Flow cytometric analysis of DNA content revealed that the most promising derivative 14b caused a statistically significant accumulation of PC-3 cells at G2/M phase and induced apoptosis in PC-3 cells.

Glycyrrhiza glabra-Enhanced Extract and Adriamycin Antiproliferative Effect on PC-3 Prostate Cancer Cells.

Prostate cancer is the second most commonly diagnosed cancer in men worldwide, which is almost incurable, once it progresses into the metastatic stage. Adriamycin (ADR) is a known chemotherapeutic agent that causes severe side effects. In recent years, studies in natural plant products have revealed their anticancer activities. In particular, Glycyrrhiza glabra enhanced extract (GGE), commonly known as licorice, has been reported to exert antiproliferative properties against cancer cells. In this study, the cytotoxic potential of GGE was assessed in PC-3 cells, when it is administrated alone or in combination with Adriamycin. PC-3 cells were treated with GGE and/or ADR, and the inhibition of cell proliferation was evaluated by the MTT assay. Cell cycle alterations and apoptosis rate were measured through flow cytometry. Expression levels of autophagy-related genes were evaluated with specific ELISA kits, Western blotting, and real-time PCR, while NMR spectrometry was used to identify the implication of specific metabolites. Our results demonstrated that GGE alone or in co-treatment with ADR shows antiproliferative properties against PC-3 cells, which are mediated by both apoptosis and autophagy mechanisms.

Autoimmune epithelitis (Sjögren's syndrome); the impact of metabolic status of glandular epithelial cells on auto-immunogenicity.

It is well established that distinct cell metabolic alterations strongly contribute to the modulation of innate and adaptive immune responses. In the past decade the term immunometabolism has been introduced to describe the intracellular metabolic shifts of immune cells that lead to alterations of their functions. The pathogenesis of Sjögren's syndrome (SS), also referred to as autoimmune epithelitis, is not completely understood, but strong evidence supports the central role of the salivary glandular epithelial cells which are the target cells in the initiation of the autoimmune responses. Moreover, the altered epithelial functional phenotype, observed in the salivary gland lesion, may explain their disturbed secretory as well as immunoregulatory functions. From an immunometabolic perspective we have focused our studies on the endoplasmic reticulum (ER) of the salivary gland epithelial cells (SGEC) and the implication of its altered functions in the immunogenicity of these cells in SS. We showed that ER of SGEC in SS patients in situ is stressed and extensively dilated. Using salivary gland cell cultures, we studied in vitro the effect of ER stress on the metabolic behavior and viability of the cells. ER stress induced by thapsigargin increased spliced X-box binding protein-1 (XBP-1, transcription factor that increases the transcription of UPR target genes) levels in a time-dependent manner followed by autophagy and resulted to cell apoptosis. In apoptotic cells, we observed that the autoantigens Ro52 and La were redistributed in apoptotic blebs. During the induction of ER stress autophagy rescued the cells from apoptosis acting as a protective mechanism. We have also shown that adiponectin, a multifunctional hormone, is upregulated in the SGEC of SS patients acting in an autocrine or paracrine manner in the same cells. Adiponectin through activation of AMPK, the major sensor for cell energy demands, protected SGEC from apoptosis. Our results in combination with the work of others indicate that any effort of cell adaptation to ER stress may up regulate a proinflammatory milieu. This enhances the notion that metabolic alterations of the targeted epithelial cells in SS, independently of the cause, may induce an immunogenic phenotype. Therefore, SGEC have the potential to directly regulate susceptibility to and/or severity of autoimmune responses. Since adiponectin plays a vital role in the viability of SGEC through phosphorylation of AMPK, therapeutic interventions using PPAR agonists that upregulate adiponectin and concomitantly modify the energy metabolism, may be promising candidates for therapeutic intervention in SS.

Silymarin Enriched Extract (Silybum marianum) Additive Effect on Doxorubicin-Mediated Cytotoxicity in PC-3 Prostate Cancer Cells.

Silymarin-enriched extract (SEE) is obtained from Silybum marianum (Asteraceae). Doxorubicin (DXR) is a widely used chemotherapeutical yet with severe side effects. The goal of the present study was to assess the pharmacologic effect of SEE and its bioactive components silibinin and silychristine when administrated alone or in combination with DXR in the human prostate cancer cells (PC-3). PC-3 cells were treated with SEE, silibinin (silybins A and B), silychristine, alone, and in combination with DXR, and cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis, and autophagy rate were assessed by flow cytometry. Expression levels of autophagy-related genes were quantified by qRT-PCR, ELISA and western blot while transmission electron microscopy was performed to reveal autophagic structures. Finally, NMR spectrometry was used to identify specific metabolites related to autophagy. SEE inhibited PC-3 cell proliferation in a dose-dependent manner while the co-treatment (DXR-SEE) revealed an additive cytotoxic effect. Cell cycle, apoptosis, and autophagy variations were observed in addition to altered expression levels of autophagy related genes (LC3, p62, NBR1, Beclin1, ULK1, AMBRA1), while several modifications in autophagic structures were identified after DXR-SEE co-treatment. Furthermore, treated cells showed a different metabolic profile, with significant alterations in autophagy-related metabolites such as branched-chain amino acids. In conclusion, the DXR-SEE co-treatment provokes perturbations in the autophagic mechanism of prostate cancer cells (PC-3) compared to DXR treatment alone, causing an excessive cell death. These findings propose the putative use of SEE as an adjuvant cytotoxic agent.

Association between male Infertility and seminal plasma levels of growth hormone and insulin-like growth factor-1.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been proposed to play a pivotal role in male infertility due to their anabolic effects. The aim of this study was to investigate possible associations between seminal plasma levels of GH and IGF-1 and sperm parameters. Fifty men participated in this study. Semen analysis was performed, while cell-free seminal plasma was collected following sperm centrifugation. Seminal plasma concentrations of IGF-1 and GH were determined by enzyme-linked immunosorbent assay (ELISA). Due to the presence of asthenozoospermia in all participants who presented with abnormal sperm parameters, the participants were further subdivided into normal (group A), asthenozoospermic (group B) and asthenozoospermic plus at least one additional abnormal parameter (group C). A marginally nonsignificant statistical difference (p = 0.063) was revealed between the GH levels corresponding to the asthenozoospermic and the normal group with the latter presenting with higher GH levels. A statistically significant positive correlation (p < 0.05) was noted between levels of GH and IGF-1 in group C. The above relationship has also been observed in men with low sperm concentration, vitality, volume and abnormal morphology. These novel findings require further investigation in order for the biological significance of those associations to be clarified.

Antiproliferative Effects of Red and White Wine Extracts in PC-3 Prostate Cancer Cells.

Experimental and epidemiological studies have shown that antioxidant polyphenols can act as chemopreventive agents against prostate cancer. Cabernet Sauvignon and Rombola wine were extracted in order to obtain fractions containing different classes of compounds. All extracts inhibited the androgen-insensitive human prostate cancer cells (PC-3) proliferation in a dose-dependent manner. The most potent compounds were selected to be further tested.Treatment of PC-3 cells with the selected wine extracts marginally increased the cell distribution in S phase, while producing a remarkable induction of autophagy. Finally, the levels of glutathione along with the concentration of hydrogen peroxide and nitrogen oxide were modulated in the treated cells. Herein, we show that red and wine extracts have direct effects on the proliferation, survival, oxidative status, and the induction of autophagy of PC-3 cells. Our data may have important implications for the design of a more effective adjuvant treatment for prostate cancer patients.

The discovery of new cytotoxic pyrazolopyridine derivatives.

A number of new 3,7-disubstituted pyrazolo[3,4-c]pyridines have been designed and synthesized from suitable 2-aminopyridines. The antiproliferative activity of the derivatives was determined against the pancreatic MIA PaCa-2 and ovarian SCOV3 cancer cell-lines. IC50 values of the most promising analogue 46 lie in the submicromolar or low micromolar range. Furthermore, compound 46 shows similar inhibitory activities against DU145, A2058 and PC-3 cancer cells, blocks the cell cycle at the G0/G1 phase and induce apoptosis, as determined by the appearance of apoptotic nuclei.

Bioactive natural products against prostate cancer: mechanism of action and autophagic/apoptotic molecular pathways.

Prostate cancer is one of the leading causes of death worldwide for men. There is increasing evidence that diet and lifestyle play a crucial role in prostate cancer biology and tumorigenesis. Due to the fact that conventional chemotherapy is not adequately effective against prostate cancer and has severe side effects, numerous in vitro studies have been conducted in order to identify the potent cytotoxic or chemopreventive activity of naturally occurring compounds and their respective molecular mechanisms of action. In this context, many natural compounds isolated from plants have been found to inhibit cancer growth and to induce cell cycle arrest, suppress angiogenesis, and promote apoptotic or autophagic cell death. Therefore, in this article, the most promising bioactive natural products and their respective mechanisms of action for the prevention or/and treatment of prostate cancer are presented.

Synthesis of new nebularine analogues and their inhibitory activity against adenosine deaminase.

A number of new 2,6-disubstituted-1-deazanebularine analogues as well as two structurally related pyrazole-fused tricyclic nucleosides were prepared. Their synthesis was carried out by the conversion of 6-amino-2-picoline to a suitable 1-deazapurine, followed by a Vorbrüggen type glycosylation and subsequent elaboration of the condensed pyrazole ring. The synthesized nebularine analogues proved to be weak adenosine deaminase inhibitors.

Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism.

Oleuropein, a natural phenolic compound, prevents acute doxorubicin (DXR)-induced cardiotoxicity but there is no evidence regarding its role in chronic DXR-induced cardiomyopathy (DXR-CM). In the present study, we investigated the role of oleuropein in DXR-CM by addressing cardiac geometry and function (transthoracic echocardiography), cardiac histopathology, nitro-oxidative stress (MDA, PCs, NT), inflammatory cytokines (IL-6, Big ET-1), NO homeostasis (iNOS and eNOS expressions), kinases involved in apoptosis and metabolism (Akt, AMPK) and myocardial metabonomics. Rats were randomly divided into 6 groups: Control, OLEU-1 and OLEU-2 [oleuropein at 1000 and 2000 mg/kg in total, respectively, intraperitoneally (i.p.) for 14 days], DXR (18 mg/kg, i.p. divided into 6 equal doses for 2 weeks), DXR-OLEU-1 and DXR-OLEU-2 (both oleuropein and DXR as previously described). Impaired left ventricular contractility and inflammatory and degenerative pathology lesions were encountered only in the DXR group. The DXR group also had higher MDA, PCs, NT, IL-6 and Big ET-1 levels, higher iNOS and lower eNOS, Akt and AMPK activation compared to controls and the oleuropein-treated groups. Metabonomics depicted significant metabolite alterations in the DXR group suggesting perturbed energy metabolism and protein biosynthesis. The effectiveness of DXR in inhibiting cell proliferation is not compromised when oleuropein is present. We documented an imbalance between iNOS and eNOS expressions and a disturbed protein biosynthesis and metabolism in DXR-CM; these newly recognized pathways in DXR cardiotoxicity may help identifying novel therapeutic targets. Activation of AMPK and suppression of iNOS by oleuropein seem to prevent the structural, functional and histopathological cardiac effects of chronic DXR toxicity.

Bone Mineral Content Distribution in Response to Long-term Training of Elite Rowers.

BACKGROUND/AIM: Bone response to exercise depends on the type and size of the mechanical stimulus. In rowing, athletes are exposed to low mechanical but large compression loads mainly on the trunk. Thus, this study aimed to investigate the impact of rowing on total and regional bone quality and bone turnover parameters in elite rowing athletes vs. control subjects. MATERIALS AND METHODS: Twenty world-class rowers and twenty active, but not athletic, men participated in the study. Bone mineral density (BMD) and body mineral content (BMC) were assessed by dual-energy X-ray absorptiometry (DXA). Bone turnover markers (OPG and RANKL) in serum were assessed by Elisa method. RESULTS: The current research revealed no statistical difference in total bone mineral density (TBMD) and total body mineral content (TBMC) between elite-level rowers and control subjects. Nevertheless, Trunk BMC (p=0.02) and Trunk BMC/TBMC ratio (p=0.01) were significantly higher in rowers than those in the control group. In contrast, in the control group, the Lower limbs BMC/TBMC ratio (p=0.007) was statistically higher. Furthermore, RANKL (p=0.011) and OPG (p=0.03) were statistically significantly higher in rowers, whereas the OPG/RANKL ratio (p=0.012) was statistically higher in the control group. CONCLUSION: Rowing, as a non-weight-bearing exercise, did not alter total bone density but induced a remarkable redistribution of bone density from the lower limbs to the trunk. In addition, the current evidence suggests that the underlying molecular mechanism is based on turnover of intermediates, rather than solely bone redistribution.

Adherence to a "Western-type" dietary pattern is positively associated with the Apnea-Hypopnea Index in adults with obstructive sleep apnea.

Dietary habits have been associated with obstructive sleep apnea (OSA); however, the underlying mechanisms remain unclear. We hypothesized that adherence to dietary patterns may be associated with Apnea-Hypopnea Index (AHI) and OSA severity and that insulin resistance, oxidative stress, and inflammation may act as potential mediators of these associations. This was a cross-sectional study among 269 adult participants with polysomnography-diagnosed moderate-to-severe OSA. Dietary and physical activity habits were assessed through validated questionnaires, and biochemical, inflammatory, and oxidative stress markers were measured for all volunteers. Dietary patterns were identified using principal component analysis, and mediation analyses was also performed. A "Western-type" dietary pattern (characterized by high intakes of full-fat dairy, refined grains, potatoes, red meat, sweets, salty snacks, and soft drinks and low intakes of low-fat dairy and whole grains) was positively associated with AHI. Mediation analyses also revealed that insulin resistance partially explained this association. In multivariable models controlling for age, sex, smoking, socioeconomic status, obesity presence, energy intake, and physical activity level, participants in the highest quartile of adherence to the Western-type dietary pattern had ∼3.5 times higher likelihood of suffering from severe OSA, compared with participants in the lowest quartile of adherence (odds ratio [95% confidence interval]: 3.45 [1.21-9.94], P trend across quartiles: 0.024). After further adjustment for Homeostasis Model of Assessment-Insulin Resistance and high-sensitivity C-reactive protein, this association lost significance. Higher adherence to a less healthy, Western-type dietary pattern is positively associated with AHI and OSA severity, which may partially be mediated through insulin resistance.

Associations between serum vitamin D status and the cardiometabolic profile of patients with obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) and the metabolic syndrome (MetS) frequently coexist. Low serum vitamin D has been positively associated with OSA presence and severity; however, data on its link to cardiometabolic features in patients with OSA remain scarce. We aimed to assess serum 25-hydroxyvitamin D [25(OH)D] and explore its association with cardiometabolic parameters in OSA. METHODS: This was a cross-sectional study among 262 patients (49 ± 9 years old, 73% men) with polysomnography-diagnosed OSA. Participants were evaluated in terms of anthropometric indices, lifestyle habits, blood pressure, biochemical, plasma inflammatory and urinary oxidative stress markers, and the presence of MetS. Serum 25(OH)D was assessed by chemiluminescence, and vitamin D deficiency (VDD) was defined as 25(OH)D < 20 ng/mL. RESULTS: Median (1st, 3rd quartile) serum 25(OH)D levels were 17.7 (13.4, 22.9) ng/mL and 63% of participants had VDD. Serum 25(OH)D correlated negatively with body mass index (BMI), homeostasis model of assessment of insulin resistance (HOMA-IR), total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), and urinary oxidized guanine species (oxG), and positively with high-density lipoprotein cholesterol (all P < 0.050). In logistic regression analysis, serum 25(OH)D was associated with lower odds of MetS [odds ratio (95% confidence interval): 0.94 (0.90-0.98)], after adjustment for age, sex, season of blood sampling, Mediterranean diet score, physical activity, smoking, apnea-hypopnea index, HOMA-IR, hsCRP, and oxG. In the same multivariate model, VDD was associated with ~ twofold greater odds of MetS [2.39 (1.15, 4.97)]. CONCLUSION: VDD is highly prevalent and is associated with a detrimental cardiometabolic profile among patients with OSA.

The Presence of Myosteatosis Is Associated with Age, Severity of Liver Disease and Poor Outcome and May Represent a Prodromal Phase of Sarcopenia in Patients with Liver Cirrhosis.

BACKGROUND/AIMS: Myosteatosis implies impaired muscle quality. The aim of the study was to investigate the association of myosteatosis with other muscle abnormalities and its role in the prognosis of liver cirrhosis (LC). METHOD: Skeletal muscle index (SMI) and myosteatosis were measured by computed tomography. Myosteatosis was defined as muscle radiodensity and evaluated according to dry body mass index (BMI). Median values and interquartile range were used for continuous and count (percentage) for categorical variables. RESULTS: A total of 197 consecutive patients were included (age 61 (IQR 52-68); 67% male; MELD score 11 (interquartile range 7.5-16)). Myosteatosis was identified in 73.6% and sarcopenia in 44.6% of patients. Myosteatosis was positively associated with age (p = 0.024) and Child-Pugh (p = 0.017) and inversely associated with SMI (p = 0.026). Patients with myosteatosis exhibited lower 360-day survival (log-rank p = 0.001) compared to those without it. MELD (p < 0.001) and myosteatosis (p = 0.048) emerged as negative prognostic factors of survival in multivariate model. Individuals combining low muscle strength and impaired muscle quality and quantity displayed more advanced LC, impaired muscle performance, lower BMI (p < 0.001 each) and a three times higher mortality rate compared to those with low muscle quality alone. CONCLUSIONS: The presence of myosteatosis was associated with advanced age, low skeletal mass and more severe LC. Myosteatosis was associated with poor prognosis and may represent a prodromal phase of muscle degeneration before the development of sarcopenia.

Discovery of New 1,4,6-Trisubstituted-1H-pyrazolo[3,4-b]pyridines with Anti-Tumor Efficacy in Mouse Model of Breast Cancer.

Purine analogues are important therapeutic tools due to their affinity to enzymes or receptors that are involved in critical biological processes. In this study, new 1,4,6-trisubstituted pyrazolo[3,4-b]pyridines were designed and synthesized, and their cytotoxic potential was been studied. The new derivatives were prepared through suitable arylhydrazines, and upon successive conversion first to aminopyrazoles, they were converted then to 1,6-disubstituted pyrazolo[3,4-b]pyridine-4-ones; this served as the starting point for the synthesis of the target compounds. The cytotoxic activity of the derivatives was evaluated against several human and murine cancer cell lines. Substantial structure activity relationships (SARs) could be extracted, mainly concerning the 4-alkylaminoethyl ethers, which showed potent in vitro antiproliferative activity in the low µM level (0.75-4.15 µΜ) without affecting the proliferation of normal cells. The most potent analogues underwent in vivo evaluation and were found to inhibit tumor growth in vivo in an orthotopic breast cancer mouse model. The novel compounds exhibited no systemic toxicity; they affected only the implanted tumors and did not interfere with the immune system of the animals. Our results revealed a very potent novel compound which could be an ideal lead for the discovery of promising anti-tumor agents, and could also be further explored for combination treatments with immunotherapeutic drugs.