DN4 questionnaire as a useful tool for evaluating the pharmacotherapeutic response to opioid pharmacotherapy in malignant neuropathy.

Objective: Tapentadol is a drug of choice for neuropathic cancer pain. DN4 questionnaire quickly determines neuropathic pain component. The aim of this study is to determine the correlation between neuropathic malignant pain component by applying tapentadol antidolorose pharmacotherapy in combination with palliative radiotherapy of osseous neuropathic metastatic changes in breast cancer patients before and after palliative radiotherapy. Methods: The first patients group comprised 30 patients with primary breast cancer and proved painful bone secondary deposits with neuropathy for which tapentadol was prescribed, and they underwent palliative radiotherapy. The second group comprised 30 patients with primary breast cancer and proved painful bone metastases with neuropathy treated only with palliative antidolorose radiotherapy. Key findings : After two-months-follow up, tapentadol group patients had lower DN4 score values (Z=2,021; p=0.043). Significantly lower number of tapentadol group patients was without neuropathic pain after a three-month-follow up (χ ²=5,711; p=0.017). Significantly greater number of tapentadol group patients had best ECOG score 0 ( χ² =7,486; p=0.023). There was statistically significant positive correlation between tapentadol dose and DN4 score in patients after a month (ρ=0,471; p=0.009) and three months after the radiotherapy completion (ρ=0,610; p<0.001). Tapentadol is an opioid analgesic efficient for neuropathy relief in these patients and DN4 questionnaire is an efficient pharmacotherapy tool.

Randomised clinical trial to test the phenolization in sacrococcygeal pilonidal disease.

To test the efficacy and safety of phenolization in uncomplicated Sacrococcygeal pilonidal disease (SPD) the phenolization in uncomplicated SPD is feasible and secure in selected patients in observational studies. The greatest benefits are obtained to reduce the length of sick leave (LSL) and complications. Single-center randomised controlled clinical trial. Patients were recruited at University Hospital of Tarragona Joan XXIII of Spain. Patients were randomised into two treatment groups. All patients with uncomplicated sacrococcygeal disease, localised in the midline and with only 1 fistulous orifice. The patients were randomly assigned to the phenolization group (PhG) or conventional-surgery group (CsG). Both groups were managed without admission. The main endpoint was the recurrence of sacrococcygeal disease. Secondary endpoints included time of sick leave, complications, and readmission. 124 patients were included in the study. No disease recurrence was observed in either group. Clinical follow-up was carried out with a mean of 493.8 days (SD 6.59). The LSL was shorter in the PhG (mean 19.63 days, SD 28.15) than in the CSG (43.95 days, SD 38.60). The LSL reduction was -24.31 days (P .002). The phenolization in selected SPD is a safe and feasible procedure in selected patients. This approach could become the standard of care for patients with selected Sacrococcygeal pilonidal.

Salidroside attenuates cardiac dysfunction in a rat model of diabetes.

AIM: This study aimed to investigate the therapeutic effects of salidroside on diabetes-induced cardiovascular disease. METHODS: Sprague-Dawley rats treated with 65 mg/kg of streptozotocin (STZ) on a daily basis were used to establish the diabetic rat model (blood glucose levels >13.9 mmol/L). Cardiac functions of diabetic rats were evaluated by their haemodynamic alterations. Western blot assay was performed to evaluate the protein levels of multiple signalling pathway factors. Quantitative real-time PCR assay was performed to investigate the inflammation and oxidative stress of diabetic rats. RESULTS: Salidroside treatment improved the cardiac functions of diabetic rats. In addition, salidroside therapy attenuated the cardiac oxidative stress induced by diabetes. Salidroside inhibited the diabetes-induced inflammation in diabetic rat hearts. The apoptosis of cardiomyocytes was also alleviated by the treatment of salidroside. Salidroside also upregulated the phosphorylation levels of AMPK, ACC, TSC2 and RAPTOR. CONCLUSION: Salidroside exerts protective effects against diabetes-induced cardiac dysfunction by modulating the mTOR and AMPK signalling pathways.

Chronic bisphenol A exposure triggers visual perception dysfunction through impoverished neuronal coding ability in the primary visual cortex.

Contrast perception is a fundamental visual ability that allows us to distinguish objects from the background. However, whether it is perturbed by chronic exposure to environmental xenoestrogen, bisphenol A (BPA), is still elusive. Here, we used adult cats to explore BPA-induced changes in contrast sensitivity (CS) and its underlying neuronal coding mechanism. Behavioral results showed that 14 days of BPA exposure (0.4 mg/kg/day) was sufficient to induce CS declines at the tested spatial frequencies (0.05-2 cycles/deg) in all four cats. Furthermore, based on multi-channel electrophysiological recording and interneuronal correlation analysis, we found that the BPA-exposed cats exhibited an obvious up-regulation in noise correlation in the primary visual cortex (area 17, A17), thus providing a population neuronal coding basis for their perceptual dysfunction. Moreover, single neuron responses in A17 of BPA-exposed cats revealed a slight but marked decrease in CS compared to that of control cats. Additionally, these neuronal responses presented an overt decrease in signal-to-noise ratio, accompanied by increased trial-to-trial response variability (i.e., noise). To some extent, these neuron population and unit dysfunctions in A17 of BPA-exposed cats were attributable to decreased response activity of fast-spiking neurons. Together, our findings demonstrate that chronic BPA exposure restricts contrast perception, in response to impoverished neuronal coding ability in A17.

Inhibitory activity of acteoside in melanoma via regulation of the ERß-Ras/Raf1-STAT3 pathway.

BACKGROUND: Melanoma is an aggressive cancer with a rapidly increasing incidence rate worldwide. Acteoside has been shown to have antitumor effects in multiple human cancers; however, the underlying function and mechanisms of acteoside in melanoma remain unclear. PURPOSE: This study explored the inhibitory effect of acteoside on melanoma and the possible mechanisms. METHODS: Acteoside (15 mg/kg, 30 mg/kg) was administered to mice daily for 21 days. ICI182,780 (0.5 mg/kg) was intraperitoneally injected 30 min before acteoside administration three times a week to evaluate whether the effects elicited by acteoside were mediated via the estrogen receptor. Tumor growth and metabolism, cardiac function, ROS and apoptosis levels in the spleen, serum inflammatory factors, and immune cells in the spleen were monitored. STAT3, p-STAT3, CD31, and survivin levels in tumor tissues were measured via immunofluorescence. Ras, Raf1, STAT3, p-STAT3, Bcl-2, Bax, cleaved caspase-3, and cleaved caspase-9 levels in tumor tissues were determined via Western Blotting. RESULTS: The results showed that acteoside inhibited melanoma growth, alleviated inflammation levels in mice, attenuated ROS and apoptosis levels in the spleen, downregulated the levels of CD31, survivin, Ras, Raf1, p-STAT3, and Bcl-2, and upregulated the levels of ERß, Bax, cleaved caspase-3, and cleaved caspase-9. Moreover, the effect of acteoside was blocked by ICI182,780. CONCLUSION: Acteoside may promote the apoptosis of tumor cells by regulating the ERß-Ras/Raf1-STAT3 signaling axis, thus inhibiting the occurrence and development of melanoma.

Human Metabolism and Urinary Excretion Kinetics of Nonylphenol in Three Volunteers after a Single Oral Dose.

Nonylphenol (NP) is an endocrine-disrupting anthropogenic chemical that is ubiquitous in the environment. Human biomonitoring data and knowledge on internal NP exposure are still sparse, and its human metabolism is largely unknown. Therefore, in this study, we investigated human metabolism and urinary excretion of NP. Three male volunteers received a single oral dose of 1 mg 13C6-labeled NP (10.6-11.7 µg/kg body weight). Consecutive full urine voids were collected for 48 h. A metabolite screening identified nine ring- and/or side chain-oxidized metabolites. We chose the most promising hits, the alkyl chain-oxidized metabolites hydroxy-NP (OH-NP) and oxo-NP, for quantitative investigation next to the parent NP. For this purpose, we newly synthesized specific n - 1-oxidized monoisomeric analytical standards. Quantification of the polyisomeric metabolites was performed via online-solid phase extraction-LC-MS/MS with stable isotope dilution using a previously published consensus method. Alkyl chain hydroxylation (OH-NP) constituted the major metabolism pathway representing 43.7 or 62.2% (depending on the mass transition used for quantification) of the NP dose excreted in urine. The urinary excretion fraction (FUE) for oxo-NP was 6.0 or 9.3%. The parent NP, quantified via an analogous isomeric 13C6-NP standard, represented 6.6%. All target analytes were excreted predominately as glucuronic acid conjugates. Excretion was rather quick, with concentration maxima in urine 2.3-3.4 h after dosing and biphasic elimination kinetics (elimination half-times first phase: 1.0-1.5 h and second phase: 5.2-6.8 h). Due to its high FUE and insusceptibility to external contamination (contrary to parent NP), OH-NP represents a robust and sensitive novel exposure biomarker for NP. The novel FUEs enable to robustly back-calculate the overall NP intakes from urinary metabolite levels in population samples for a well-informed cumulative exposure and risk assessment.

Effects of Bisphenol A and Bisphenol S Exposure at Low Doses on the Metabolome of Adolescent Male Sprague-Dawley Rats.

Toxic effects induced upon exposure to low-dose bisphenol A (BPA) or bisphenol S (BPS) remains controversial. In this study, metabolomics was used to examine the metabolomic perturbation arising from 28 days of exposure to BPA or BPS at 50 µg/kg bw/day in Sprague-Dawley (SD) rats. Endogenous metabolite profiling revealed a clear discrimination of metabolome in the rat plasma among BPA-treatment, BPS-treatment, and control groups. BPA exposure induced the up-regulation of 19 metabolites and down-regulation of 32 metabolites in plasma of SD rats, compared with the control. BPS exposure induced the up-regulation of 15 metabolites and the down-regulation of 33 metabolites in the plasma of SD rats, compared with the control. Joint pathway analysis suggested marked perturbations in the citrate cycle, butanoate metabolism, and alanine, aspartate, and glutamate metabolism for BPA-exposed rats as well as glycerophospholipid metabolism for BPS-exposed rats. These findings provide novel insights into associations between the metabolomic perturbation and phenotypic changes arising from BPA and BPS exposure.

Synchronizing In Silico, In Vitro, and In Vivo Studies for the Successful Nose to Brain Delivery of an Anticancer Molecule.

Sesamol is a sesame seed constituent with reported activity against many types of cancer. In this work, two types of nanocarriers, solid lipid nanoparticles (SLNs) and polymeric nanoparticles (PNs), were exploited to improve sesamol efficiency against the glioma cancer cell line. The ability of the proposed systems for efficient brain targeting intranasally was also inspected. By the aid of two docking programs, the virtual loading pattern inside these nanocarriers was matched to the real experimental results. Interactions involved in sesamol-carrier binding were also assessed, followed by a discussion of how different scoring functions account for these interactions. The study is an extension of the computer-assisted drug formulation design series, which represents a promising initiative for an upcoming industrial innovation. The results proved the power of combined in silico tools in predicting members with the highest sesamol payload suitable for delivering a sufficient dose to the brain. Among nine carriers, glyceryl monostearate (GMS) and polycaprolactone (PCL) scored the highest sesamol payload practically and computationally. The EE % was 66.09 ± 0.92 and 61.73 ± 0.47 corresponding to a ΔG (binding energy) of -8.85 ± 0.16 and -5.04 ± 0.11, respectively. Dynamic light scattering evidenced the formation of 215.1 ± 7.2 nm and 414.25 ± 1.6 nm nanoparticles, respectively. Both formulations demonstrated an efficient cytotoxic effect and brain-targeting ability compared to the sesamol solution. This was evidenced by low IC50 (38.50 ± 10.37 µM and 27.81 ± 2.76 µM) and high drug targeting efficiency (7.64 ± 1.89-fold and 13.72 ± 4.1-fold) and direct transport percentages (86.12 ± 3.89 and 92.198 ± 2.09) for GMS-SLNs and PCL-PNs, respectively. The results also showed how different formulations, having different compositions and characteristics, could affect the cytotoxic and targeting ability.

Rhodiola crenulata reduces ventricular arrhythmia through mitigating the activation of IL-17 and inhibiting the MAPK signaling pathway.

PURPOSE: Ventricular arrhythmia (VA) is related to inflammatory activity. Rhodiola crenulate (RC) and its main active component, salidroside, have been reported as anti-inflammatory agents. The aim of this study was to demonstrate the effect of RC and salidroside in preventing VA via the inhibition of IL-17 in an ischemic heart failure (HF) model. METHODS: Rabbit HF models were established by coronary artery ligation for 4 weeks. These rabbits were treated with RC (125, 250, 500 mg/kg) and salidroside (9.5 mg/kg) once every 2 days for 4 weeks. WBC, serum biochemistry, ECG, and the expression of CD4+ T cells were measured every 2 weeks. The mRNA and protein expressions of IL-17 were measured by real time-PCR, ELISA, and Western blotting after RC and salidroside treatment for 4 weeks. Open-chest epicardial catheter stimulation was performed for VA provocation. RESULTS: After RC and salidroside treatment in HF left ventricle, (1) the levels of WBC and CD4+ T cells decreased, (2) the expression of IL-17 and its downstream target genes, IL-6, TNF-α, IL-1ß, IL-8, and CCL20, reduced, (3) the level of NLRP3 inflammasome was decreased, (4) fibrosis and collagen production were significantly downregulated, (5) p38 MAPK and ERK1/2 phosphorylation were attenuated, (6) the inducibility of VA was decreased, and (7) the levels of Kir2.1, Nav1.5, NCX, PLB, SERCA2a and RyR were up-regulated. CONCLUSIONS: RC inhibited the expression of IL-17 and its downstream target genes that were mediated by activation of several MAPKs, which decreased the levels of fibrosis and apoptosis and suppressed VA.

Anti-neuroinflammatory effects of a food-grade phenolic-enriched maple syrup extract in a mouse model of Alzheimer's disease.

Objectives: Alzheimer's disease (AD) is a growing global health crisis exacerbated by increasing life span and an aging demographic. Convergent lines of evidence, including genome-wide association studies, strongly implicate neuroinflammation in the pathogenesis of AD. Several dietary agents, including phenolic-rich foods, show promise for the prevention and/or management of AD, which in large part, has been attributed to their anti-inflammatory effects. We previously reported that a food-grade phenolic-enriched maple syrup extract (MSX) inhibited neuroinflammation in vitro but whether these effects are translatable in vivo remain unknown. Herein, we assessed MSX's ability to attenuate early neuroinflammation in a transgenic mouse model of AD.Methods: The effects of MSX on AD-related neuroinflammation was evaluated by orally administering MSX (100 and 200 mg/kg/day for 30 days) to the 3xTg-AD mouse model of AD. The expression of inflammatory markers in mouse brains were analyzed with LC-MS/MS with SWATH acquisition.Results: 3xTg-AD mice dosed orally with MSX have decreased expression of several inflammatory proteins, including, most notably, the AD risk-associated protein 'triggering receptor expressed on myeloid cells-2' (TREM2), and stimulator of interferon genes TMEM173, and suppressor of cytokine signaling-6 (SOCS6). However, this decrease in inflammation did not coincide with a decrease in pathogenic amyloid generation or lipid peroxidation.Discussion: These data demonstrate that oral administration of this maple syrup derived natural product reduces key neuroinflammatory indices of AD in the 3xTg-AD model of AD. Therefore, further studies to investigate MSX's potential as a dietary intervention strategy for AD prevention and/or management are warranted.

Sesamin and sesamol attenuate H2O2-induced oxidative stress on human neuronal cells via the SIRT1-SIRT3-FOXO3a signaling pathway.

Background: An imbalance of free radicals and antioxidant defense systems in physiological processes can result in protein/DNA damage, inflammation, and cellular apoptosis leading to neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Sesamin and sesamol, compounds derived from sesame seeds and oil, have been reported to exert various pharmacological effects, especially antioxidant activity. However, their molecular mechanisms against the oxidative stress induced by exogenous hydrogen peroxide (H2O2) remain to be elucidated. Aim: In this study, neuroprotective effects of sesamin and sesamol on H2O2-induced human neuroblastoma (SH-SY5Y) cell death and possible signaling pathways in the cells were explored. Methods: MTT assay and flow cytometry were conducted to determine cell viability and apoptotic profiles of neuronal cells treated with sesamin and sesamol. Carboxy-DCFDA assay was used to measure reactive oxygen species (ROS). Moreover, Western blot analysis was performed to investigate protein profiles associated with neuroprotection. Results: Pretreatment of the cells with 1 µM of sesamin and sesamol remarkably reduced the SH-SY5Y cell death induced by 400 µM H2O2 as well as the intracellular ROS production. Moreover, the molecular mechanisms underlying neuroprotection of the compounds were associated with activating SIRT1-SIRT3-FOXO3a expression, inhibiting BAX (proapoptotic protein), and upregulating BCL-2 (anti-apoptotic protein). Conclusion: The findings suggest that sesamin and sesamol are compounds that potentially protect neuronal cells against oxidative stress similar to that of the resveratrol, the reference compound. These antioxidants are thus of interest for further investigation in in vivo models of neuroprotection.

Flavanol-rich lychee fruit extract substantially reduces progressive cognitive and molecular deficits in a triple-transgenic animal model of Alzheimer disease.

Effective treatment to prevent or arrest the advance of Alzheimer disease (AD) has yet to be discovered. We investigated whether OligonolR, an FDA-approved flavanol-rich extract prepared from lychee fruit and green tea, exerted beneficial effects relevant to AD in a triple transgenic male mouse model of AD (3×Tg-AD). At 9 months of age, untreated 3×Tg-AD mice vs. wild-type (WT) controls displayed cognitive deficits in behavioral assays and, at 12 months, elevated levels of hippocampal amyloid beta-protein (Aß), amyloid precursor protein (APP), tau phosphorylation, and pro-inflammatory cytokines. 3×Tg-AD mice given Oligonol showed fewer cognitive deficits and attenuated pathological indices at 12 months. Oligonol treatment of 3×Tg-AD mice modulated expression of some critical brain proteins that involve multiple pathways relevant to mitochondrial dysfunction, proteasomal failure, endoplasmic reticulum (ER) stress and synaptic impairment. Together, these results demonstrate that continuous Oligonol treatment attenuates AD-like pathology and cognitive impairment of 3×Tg-AD mice and set the stage for clinical trials of this flavanol-rich plant extract in patients with early AD.

Effect of extra virgin olive oil consumption on glycemic control: A systematic review and meta-analysis.

AIMS: Several health benefits are contributed to extra virgin olive oil (EVOO). The polyphenol fraction of EVOO may be responsible for its cardioprotective impacts. This systematic review and meta-analysis aimed to investigate the effect of EVOO intake on glycemic parameters. Electronic literature searched through 1 September 2020 across MEDLINE/PubMed, Web of Science, and SCOPUS databases to find all clinical trials that reported the effect of EVOO intake on glycemic parameters [FBS(fasting blood glucose), insulin, HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) and HbA1c (glycated hemoglobin A1c)] vs. control. DATA SYNTHESIS: We pooled standardized mean differences (SMD) and 95% confidence intervals (CIs) from randomized clinical trials (RCTs) using random-effects models. Heterogeneity was assessed by Cochran Q-statistic and quantified (I2). We found 13 related trials comprising a total of 633 subjects. In pooled analysis, EVOO intake had no effect on FBS (SMD: -0.07; 95% CI: -0.20, 0.07; I2 = 0.0%), insulin (SMD: -0.32; 95% CI: -0.70, 0.06; I2 = 38.0%), and HOMA-IR (SMD: -0.32; 95% CI: -0.75, 0.10; I2 = 51.0%). However, a decreasing trend was observed in these effects. Subgroup analysis based on age, health status, dose, and EVOO intake duration also did not significantly change results. CONCLUSION: Although EVOO seems a promising hypoglycemic effects, we did not find any significant evidence that EVOO consumption impacts glucose homeostasis. Furthermore, well-designed RCTs with longer durations are still needed to evaluate the EVOO's efficacy on glycemic parameters.

A Clinical Study Evaluating the Efficacy of Topical Bakuchiol (UP256) Cream on Facial Acne.

Acne vulgaris is a common skin disease that manifests clinically as comedones, papules, nodules, and cysts. In this single center, open-label pilot study (ISRCTN13992386), we aimed to evaluate the effectiveness of UP256 cream, a newly patented topical product containing 0.5% bakuchiol, on facial acne and acne-related post-inflammatory hyperpigmentation (PIH). A series of 13 subjects enriched for Fitzpatrick skin types III–VI with mild or moderate acne received treatment with UP256 twice daily for 12 weeks. Efficacy assessments included changes in inflammatory and non-inflammatory lesions as well as a reduction in Evaluator Global Severity Score (EGSS) assessments of acne severity and PIH. Safety, adverse events, and cutaneous tolerability were evaluated throughout the study. UP256 significantly reduced the number of inflammatory lesions and improved existing PIH. UP256 was also cosmetically acceptable and well tolerated by all study subjects. Overall, our results demonstrate that monotherapy with UP256 improves mild to moderate acne and may be particularly well suited for individuals with skin of color. J Drugs Dermatol. 2021;20(3):307-310. doi:10.36849/JDD.5655.

The antagonistic effect of bisphenol A and nonylphenol on liver and kidney injury in rats.

OBJECTIVE: Bisphenol A (BPA) and nonylphenol (NP) are widely distributed endocrine-disrupting compounds. We aimed to estimate the combined toxicity of BPA and NP at a clinically safe dose (100 µg/kg) in rats. MATERIALS AND METHODS: Liver and kidney functions were evaluated by detecting the relevant indicators. Hematoxylin and Eosin (HE) staining was performed to examine the injury in the tissue. TUNEL assay and Western blot were used to detect cell apoptosis and expressions of target factors, respectively. RESULTS: The body weight of rats in the BPA + NP group was lighter than that in the BPA or NP group. BPA or NP weakened liver function through increasing levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), cholesterol (CHOL), triglyceride TG, globulin (GLOB), treponemiapallidum (TP), and total bilirubin (TBIL). BPA and NP could induce kidney damage by elevating the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). Moreover, the malondialdehyde (MDA) content was increased, whereas the activities of superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-PX), glutathione sulfotransferase (GSH-ST), catalase (CAT), and peroxidase (POD) were reduced in those groups exposed to BPA or NP. HE staining exhibited injuries of the liver and kidney. Furthermore, the apoptosis of liver and kidney cells was enhanced by exposure to BPA or NP. Additionally, the expressions of CYP2D6, CYP1A1, and CYP2E1 were triggered by the treatment of BPA or NP. The combined effect of BPA and NP seemed to be antagonistic at a low dose. CONCLUSION: BPA and NP may have potential interactions.

The use of Lactobacillus plantarum esterase genes: a biotechnological strategy to increase the bioavailability of dietary phenolic compounds in lactic acid bacteria.

In Lactobacillus plantarum the metabolism of hydroxybenzoic and hydroxycinnamic acid derivatives follows a similar two-step pathway, an esterase action followed by a decarboxylation. The L. plantarum esterase genes involved in these reactions have been cloned into pNZ8048 or pT1NX plasmids and transformed into technologically relevant lactic acid bacteria. None of the strains assayed can hydrolyse methyl gallate, a hydroxybenzoic ester. The presence of the L. plantarum tannase encoding genes (tanALp or tanBLp) on these bacteria conferred their detectable esterase (tannase) activity. Similarly, on hydroxycinnamic compounds, esterase activity for the hydrolysis of ferulic acid was acquired by lactic acid bacteria when L. plantarum esterase (JDM1_1092) was present. This study showed that the heterologous expression of L. plantarum esterase genes involved in the metabolism of phenolic acids allowed the production of healthy compounds which increase the bioavailability of these dietary compounds in food relevant lactic acid bacteria.

Comprehensive dietary evaluation of Italian primary school children: food consumption and intake of energy, nutrients and phenolic compounds.

Information on children's diet including bioactive compounds is quite scarce. This observational study investigated the composition of the diet of children living in Parma (Italy; n = 172, 8-10 years) using 3-day food records completed in winter and spring. Mean daily intakes of food groups, energy and nutrients were obtained using the national food database, while (poly)phenol contents were estimated from Phenol-Explorer or by specific literature searches. Food consumption, energy and nutrient intakes decreased in spring and were partially in line with national data. Adherence to the nutritional recommendations was not satisfied for the majority of nutrients. Main contributors to the phenolic intake were flavonoids (flavan-3-ols) and phenolic acids (hydroxycinnamic acids), while main dietary sources were fruit, chocolate-based products, vegetables, and tea & coffee (decaffeinated). This study provided the first comprehensive analysis of the nutritional composition of children's diet. Future research should look at the health implications of dietary choices in children.

Design and Engineering of "Green" Nanoemulsions for Enhanced Topical Delivery of Bakuchiol Achieved in a Sustainable Manner: A Novel Eco-Friendly Approach to Bioretinol.

In the present work, we establish novel "environmentally-friendly" oil-in-water nanoemulsions to enhance the transdermal delivery of bakuchiol, the so-called "bioretinol" obtained from powdered Psoralea corylifolia seeds via a sustainable process, i.e., using a supercritical fluid extraction approach with pure carbon dioxide (SC-CO2). According to Green Chemistry principles, five novel formulations were stabilized by "green" hybrid ionic surfactants such as coco-betaine-surfactin molecules obtained from coconut and fermented rapeseed meal. Preliminary optimization studies involving three dispersion stability tests, i.e., centrifugation, heating, and cooling cycles, indicated the most promising candidates for further physicochemical analysis. Finally, nanoemulsion colloidal characterization provided by scattering (dynamic and electrophoretic light scattering as well as backscattering), microscopic (transmission electron and confocal laser scanning microscopy), and spectroscopic (UV-Vis spectroscopy) methods revealed the most stable nanocarrier for transdermal biological investigation. In vitro, topical experiments provided on human skin cell line HaCaT keratinocytes and normal dermal NHDF fibroblasts indicated high cell viability upon treatment of the tested formulation with a final 0.02-0.2 mg/mL bakuchiol concentration. This excellent biocompatibility was confirmed by ex vivo and in vivo tests on animal and human skin tissue. The improved permeability and antiaging potential of the bakuchiol-encapsulated rich extract were observed, indicating that the obtained ecological nanoemulsions are competitive with commercial retinol formulations.

NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats.

Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.

DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.