Our previous double-blinded, placebo-controlled cross-over study indicated that a nutritional supplement named lycopene-rich tomato nutrient complex (TNC) can protect from UVA1-induced (340-400 nm) and UVA- (320-400 nm)/UVB-induced (280-320 nm) upregulation of molecular markers associated with oxidative stress, inflammation, and ageing.

Ursodeoxycholic acid (UDCA) is an intestinal bacterial metabolite with hepatoprotective effects. However, molecular mechanisms underlying its effects remain unclear.

The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer.

Endometriosis is an inflammatory disease; the hallmark of inflammation is over-activation of matrix metalloproteinases (MMPs). The regulatory effects of Resveratrol on MMPs were formerly depicted in other cell lines. This study aimed at investigating the effects of Resveratrol on expression of MMP-2 and -9 in endometriosis patients. This trial was carried out on endometriosis patients (n = 34) who were randomly divided into treatment (i = 17) and control (n = 17) groups. Alongside the routine protocol, the control and treatment groups took placebo and Resveratrol (400 mg), respectively, for 12-14 weeks. Endometrial tissue and fluid as well as blood sampling from both groups were done before and after the intervention. The level of mRNA and protein of both MMP-2 and -9 reduced in the endometrium of treatment group following intervention. Also, the serum and the endometrial fluid concentration of them lowered within the treatment group. Moreover, the serum and endometrial fluid levels of MMP-2 as well as MMP-9 were also diminished following the surgical removal of endometritic lesions. We showed that Resveratrol can modify the inflammation process in the endometrium of women with endometriosis at least in the level of MMP-2 and -9 expressions. The therapeutic potency of Resveratrol in endometriosis needs more clinical studies.

Lifestyle interventions, including exercise and dietary supplementation, can modify DNA methylation and exert health benefits; however, the underlying mechanisms are poorly understood. Here we investigated the impact of acute aerobic exercise and the supplementation of omega-3 polyunsaturated fatty acids (n-3 PUFA) and extra virgin olive oil (EVOO) on global and gene-specific (PPARGC1A, IL6 and TNF) DNA methylation, and DNMT mRNA expression in leukocytes of disease-free individuals. Eight trained male cyclists completed an exercise test before and after a four-week supplementation of n-3 PUFA and EVOO in a double-blind, randomised, repeated measures design. Exercise triggered global hypomethylation (Pre 79.2%; Post 78.7%; p = 0.008), alongside, hypomethylation (Pre 6.9%; Post 6.3%; p < 0.001) and increased mRNA expression of PPARGC1A (p < 0.001). Associations between PPARGC1A methylation and exercise performance were also detected. An interaction between supplement and trial was detected for a single CpG of IL6 indicating increased DNA methylation following n-3 PUFA and decreased methylation following EVOO (p = 0.038). Global and gene-specific DNA methylation associated with markers of inflammation and oxidative stress. The supplementation of EVOO reduced DNMT1 mRNA expression compared to n-3 PUFA supplementation (p = 0.048), whereas, DNMT3a (p = 0.018) and DNMT3b (p = 0.046) mRNA expression were decreased following exercise. In conclusion, we demonstrate that acute exercise and dietary supplementation of n-3 PUFAs and EVOO induce DNA methylation changes in leukocytes, potentially via the modulation of DNMT mRNA expression. Future studies are required to further elucidate the impact of lifestyle interventions on DNA methylation.

Gut appetite hormone responses may be influenced by meal macronutrients and obesity. The primary aim of this study was to examine in adolescents with obesity and of healthy weight the effect of a high-protein and a high-carbohydrate meal on postprandial gut appetite hormones. A postprandial cross-over study with adolescents 11⁻19 years old was undertaken. Participants consumed, in random order, a high 79% carbohydrate (HCHO) and a high 55% protein (HP) meal. Ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and self-reported appetite were assessed for four hours postprandial. Total energy intake from an ad libitum lunch and remaining 24 h was assessed. Eight adolescents with obesity (OB) and 12 with healthy weight (HW) participated. Compared with HW, OB adolescents displayed a smaller ghrelin iAUC (-25,896.5 ± 7943 pg/mL/4 h vs. -60,863.5 ± 13104 pg/mL/4 h) (p = 0.008) with no effect of meal (p > 0.05). The suppression of ghrelin relative to baseline was similar between OB and HW. Ghrelin suppression was greater following the HP vs. HCHO meal (effect of meal, p = 0.018). Glucose and insulin response were greater following HCHO vs. HP, with responses more marked in OB (time × weight × meal interaction, p = 0.003 and p = 0.018, respectively). There were no effects of weight or macronutrient on GLP-1 or PYY, appetite or subsequent energy intake. The present study demonstrates that dietary protein can modulate postprandial ghrelin responses; however, this did not translate to subsequent changes in subjective appetite or energy intake.

GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD).

Children prenatally exposed to maternal depression more often show behavioral and emotional problems compared to unexposed children, possibly through epigenetic alterations. Current evidence is largely based on animal and observational human studies. Therefore, evidence from experimental human studies is needed. In this follow-up of a small randomized controlled trial (RCT), DNA-methylation was compared between children of women who had received cognitive behavioral therapy (CBT) for antenatal depression and children of women who had received treatment as usual (TAU). Originally, 54 women were allocated to CBT or TAU. A beneficial treatment effect was found on women's mood symptoms.

Vitamin D supplementation has been widely promoted to restore 25-hydroxyvitamin D concentrations; however, experimental evidence suggests a nutrient interaction with vitamin K. We assessed the effects of 1200 IU vitamin D₃ per day versus placebo for six months on vitamin K status in a randomized, double-blind, placebo-controlled trial with participants aged 60⁻80 years with depressive symptoms and ≥1 functional limitation for a secondary analysis. Stored baseline and six-month follow-up blood samples were available for 131 participants (n = 65 placebo vs. n = 66 vitamin D supplementation). We measured dephosphorylated uncarboxylated matrix gla protein (MGP) (dp-ucMGP) concentrations-a marker of vitamin K deficiency. Mean age was 68 years, and 89 participants (68%) were women. Vitamin K antagonists were used by 16 participants and multivitamin supplements by 50 participants. No differences in change between intervention and placebo were found (-38.5 ± 389 vs. 4.5 ± 127 (pmol/L), p = 0.562). When excluding vitamin K antagonist users and multivitamin users, dp-ucMGP at follow-up was significantly higher in the vitamin D group (n = 40) compared to placebo (n = 30), with a difference of 92.8 (5.7, 180) pmol/L, adjusting for baseline dp-ucMGP and sex. In conclusion, vitamin D supplementation for six months did not affect vitamin K status; however, among participants without vitamin K antagonist or multivitamin use, vitamin D supplementation influenced dp-ucMGP concentrations.

Inflammation and oxidative stress are important factors in the development of cardiovascular disease and atherosclerosis. The findings of our previous study suggest that 12 weeks consumption of tart cherry juice lowers the levels of systolic blood pressure (BP) and low-density lipoprotein (LDL) cholesterol in older adults. The present study investigated the effects of tart cherry juice on blood biomarkers of inflammation and oxidative stress. In this randomized-controlled clinical trial, a total of 37 men and women between the ages of 65⁻80 were randomly assigned to consume 480 mL of tart cherry juice or control drink daily for 12 weeks. Several blood biomarkers of inflammation and oxidative stress were assessed at baseline and after 12 weeks intervention. After the 12 weeks intervention, tart cherry juice significantly increased the plasma levels of DNA repair activity of 8-oxoguanine glycosylase (p < 0.0001) and lowered (p = 0.03) the mean c-reactive protein (CRP) level compared to the control group. There was a significant group effect observed for plasma CRP (p = 0.03) and malondialdehyde (MDA) (p = 0.03), and a borderline significant group effect observed for plasma oxidized low-density lipoprotein (OxLDL) (p = 0.07). Within group analysis showed that the plasma levels of CRP, MDA, and OxLDL decreased numerically by 25%, 3%, and 11%, respectively after 12 weeks of tart cherry juice consumption compared with corresponding baseline values. The present study suggests that the ability of tart cherry juice to reduce systolic BP and LDL cholesterol, in part, may be due to its anti-oxidative and anti-inflammatory properties. Larger and longer follow-up studies are needed to confirm these findings.

Lycopene (LP), a naturally occurring carotenoid in red-coloured fruits, especially tomatoes, has a pivotal role in counteracting the deleterious effect of oxidative stress on periodontal tissues. The aim of this study is to prepare solid lipid microparticles (SLMs) encapsulating LP and to assess their biochemical and clinical effects in the management of chronic periodontitis. Optimization of SLMs was performed by assessing particle size and LP entrapment efficiency. Clinical study included 16 chronic periodontitis patients allocated into two groups, Group I was managed by scaling and root planing (SRP) and local delivery of LP loaded SLMs, while Group II was managed by SRP only. Protein carbonyl (PC) levels as a biomarker of oxidative stress and drug concentration in gingival crevicular fluid (GCF) were assessed at different time intervals. Results revealed that optimum formula of SLMs had a particle size of 77.28 µm and entrapped 98.03% of LP. SLMs recorded 30 d of drug release with no burst effect. Patients treated with LP SLMs showed significantly lower levels of PC after SRP compared to those treated with SRP only, in addition to improvement in the measured clinical parameters. In conclusion, locally delivered LP SLMs along with SRP could have a protective effect over periodontal tissues and it has the ability to decrease oxidative damage of proteins in diseased periodontium.

Omega-3 (n-3) fatty acid supplementation enhances muscle protein synthesis and muscle size. Whether n-3 fatty acid supplementation attenuates human muscle disuse atrophy is unknown. We determined the influence of n-3 fatty acid supplementation on muscle size, mass, and integrated rates of myofibrillar protein synthesis (MyoPS) following 2 wk of muscle disuse and recovery in women. Twenty women (BMI = 23.0 ± 2.3 kg/m2, age = 22 ± 3 yr) underwent 2 wk of unilateral limb immobilization followed by 2 wk of return to normal activity. Starting 4 wk prior to immobilization, participants consumed either 5 g/d of n-3 fatty acid or an isoenergetic quantity of sunflower oil (control). Muscle size and mass were measured pre- and postimmobilization, and after recovery. Serial muscle biopsies were obtained to measure integrated (daily) MyoPS. Following immobilization, the decline in muscle volume was greater in the control group compared to the n-3 fatty acid group (14 vs. 8%, P < 0.05) and was not different from preimmobilization at recovery in the n-3 fatty acid group; however, it was still lower in the control group ( P < 0.05). Muscle mass was reduced in the control group only ( P < 0.05). MyoPS was higher in the n-3 group compared with the control group at all times ( P < 0.05). We conclude that n-3 fatty acid supplementation attenuates skeletal muscle disuse atrophy in young women, which may be mediated by higher rates of MyoPS.-McGlory, C., Gorissen, S. H. M., Kamal, M., Bahniwal, R., Hector, A. J., Baker, S. K., Chabowski, A., Phillips, S. M. Omega-3 fatty acid supplementation attenuates skeletal muscle disuse atrophy during two weeks of unilateral leg immobilization in healthy young women.

Plazomicin is an aminoglycoside that was engineered to overcome aminoglycoside-modifying enzymes, which are the most common aminoglycoside resistance mechanism in Enterobacteriaceae. Because plazomicin is predominantly eliminated via renal pathways, an in vitro study was conducted to determine whether plazomicin inhibits the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion (MATE1 and MATE2-K) transporters, using metformin as a probe substrate. Plazomicin inhibited OCT2, MATE1, and MATE2-K transporters with half-maximal inhibition of the transporter values of 5120, 1300, and 338 µg/mL, respectively. To determine whether this in vitro inhibition translates in vivo, an open-label, randomized, 2-period, 2-treatment crossover study (NCT03270553) was carried out in healthy subjects (N = 16), who received a single oral dose of metformin 850 mg alone and in combination with a single intravenous infusion of plazomicin 15 mg/kg. Geometric least-squares mean ratios of the test treatment (combination) vs the reference treatment (metformin alone) and 90% confidence intervals were within the equivalence interval of 80% to 125% (peak plasma concentration, 104.5 [95.1-114.9]; area under the plasma concentration-time curve from time zero to time of last quantifiable concentration, 103.7 [93.5-115.0]; area under the plasma concentration-time curve from time zero to infinity, 104.0 [94.2-114.8]). The results demonstrate that there is no clinically significant drug-drug interaction resulting from coadministration of single doses of intravenous plazomicin 15 mg/kg and oral metformin 850 mg in healthy subjects. Coadministration of plazomicin and metformin was well tolerated in healthy subjects.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron (SMN1) gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (SMN2). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating SMN2 levels.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Several studies suggest that the improvement of oxidative stress is suggested as a possible therapeutic strategy for pediatric nonalcoholic steatohepatitis. We performed a randomized, double-blind placebo-controlled trial to test the potential efficacy, assessed by improvement of oxidative stress parameters and liver ultrasound, and tolerability of a mixture of vitamin E and hydroxytyrosol (HXT) in adolescents with biopsy-proven NAFLD. Four hundred forty consecutive patients were screened, 80 of these with biopsy-proven NAFLD were enrolled. Forty patients received an oral dose of HXT and vitamin E and 40 children received the capsules of placebo for 4 months. Seventy patients completed the study. Patients in the treatment arm showed a decrease of insulin resistance (IR), triglyceride levels, oxidative stress parameters, and steatosis grade. Noteworthy, the steatosis improvement correlates with the levels of advanced glycation end products and carbonylated proteins. The HXT and vitamin E treatment improved the main oxidative stress parameters, IR, and steatosis in children with NAFLD. The use of two natural molecules that may have antioxidant effects seems a promising strategy that could be easily diet integrated to improve NAFLD-related liver damage in children.

GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients.

Spinal muscular atrophy (SMA) is a rare genetic and progressively debilitating neuromuscular disease. It is the leading genetic cause of death among infants. In SMA, low levels of survival of motor neuron (SMN) protein lead to motor neuron death and muscle atrophy as the SMN protein is critical to motor neuron survival. SMA is caused by mutations in, or deletion of, the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein due to alternative splicing which excludes exon 7 from most transcripts, generating truncated, rapidly degraded SMN protein. Patients with SMA rely on limited expression of functional SMN full-length protein from the SMN2 gene, but insufficient levels are generated. RG7800 is an oral, selective SMN2 splicing modifier designed to modulate alternative splicing of SMN2 to increase the levels of functional SMN protein. In two trials, oral administration of RG7800 increased in blood full-length SMN2 mRNA expression in healthy adults and SMN protein levels in SMA patients by up to two-fold, which is expected to provide clinical benefit.

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFβ1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFβ1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFβ1 alone, and TGFα relative to TGFβ1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.

Macrophage activation plays a central role in neoatherosclerosis and in-stent restenosis after percutaneous coronary intervention (PCI). Galectin-3, mainly expressed on macrophages, is an important regulator of inflammation. This study aimed to investigate the effects of berberine (BBR) on oxidized low-density lipoprotein (ox-LDL)-induced macrophage activation and galectin-3 expression and their underlying mechanisms. THP-1-derived macrophages were pretreated with BBR prior to stimulation with ox-LDL. Galectin-3 expression was measured by real-time PCR, Western blotting, and confocal microscopy. Macrophage activation was assessed by lipid accumulation, expression of inflammatory cytokines, and CD11b and CD86. Plasma galectin-3 levels were measured in patients undergoing PCI at baseline and after BBR treatment for 3 months. BBR suppressed ox-LDL-induced upregulation of galectin-3 and macrophage activation. Overexpression of galectin-3 intervened the inhibitory effect of BBR on macrophage activation. BBR activated phospho-AMPK and inhibited phospho-NF-κB p65 nuclear translocation. AMPK inhibition and NF-κB activation abolished the inhibitory effects of BBR on galectin-3 expression and macrophage activation. Combination of BBR and rosuvastatin exerted greater effects than BBR or rosuvastatin alone. However, BBR treatment did not further reduce plasma galectin-3 after PCI in patients receiving standard therapy. In conclusion, BBR alleviates ox-LDL-induced macrophage activation by downregulating galectin-3 via the NF-κB and AMPK signaling pathways.