Effects of resveratrol on the proliferation and osteogenic differentiation of deciduous dental pulp stem cells from neurofibromatosis type 1 patient.

PURPOSE: We aimed at verifying whether resveratrol can decrease cell proliferation and change osteogenic differentiation of cells obtained from patients with type 1 neurofibromatosis (NF1). METHODS: Deciduous dental pulp derived stem cells were isolated from NF1 patient and healthy volunteer. These cells were subjected to increasing concentrations of resveratrol and evaluated for proliferation and mineralization of osteogenic differentiation. RESULTS: The results showed that resveratrol reduced the difference in proliferation between CNT and NF1 cells in a dose-dependent manner and this property was more prominent in affected cells than in healthy cells. Resveratrol showed no statistically significant changes in mineralization in osteogenic differentiation of NF1 cells, at low doses tested. CONCLUSIONS: In conclusion, in a dose-dependent manner, resveratrol displays interesting properties that could be applied in a possible treatment aimed at decreasing cellular proliferation in neurofibromatosis. Furthermore, it is selective concerning healthy cells and not affecting cell differentiation. Further research to cell selectivity, differentiation to other tissue types, and cell cytotoxicity are needed.

Antidepressant-like effect of rosmarinic acid during LPS-induced neuroinflammatory model: The potential role of cannabinoid receptors/PPAR-γ signaling pathway.

Rosmarinic acid (RA), an ester of caffeic acid and 3, 4-dihydroxyphenyllactic acid, has anti-inflammatory and neuroprotective activities. Herein, this study investigated in silico the drug-likeness and the potential molecular targets to RA. Moreover, it tested the antidepressant-like potential of RA in the lipopolysaccharide (LPS)-induced depression model. RA (MW = 360.31 g/mol) meets the criteria of both Lipinski's rule of five and the Ghose filter. It also attends to relevant pharmacokinetic parameters. Target prediction analysis identified RA's potential targets and biological activities, including the peroxisome proliferator-activated receptor (PPAR) and the cannabinoid receptors CB1 and CB2 . In vivo, RA's acute, repetitive, and therapeutic administration showed antidepressant-like effect since it significantly reduced the immobility time in the tail suspension test and increased grooming time in the splash test. Further, the pretreatment with antagonists of CB1 , CB2 , and PPAR-γ receptors significantly blocked the antidepressant-like effect of RA. Altogether, our findings suggest that cannabinoid receptors/PPAR-γ signaling pathways are involved with the antidepressant-like effect of RA. Moreover, this molecule meets important physicochemical and pharmacokinetic parameters that favor its bioavailability. RA constitutes a promising, innovative, and safe molecule for the pharmacotherapy of major depressive disorder.

(-)-ß-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis.

(-)-ß-caryophyllene (BCP), a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid, has already been shown in precedent literature to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain. Herein, we endeavored to investigate the therapeutic potential of BCP on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Furthermore, we sought to demonstrate some of the mechanisms that underlie the modulation BCP exerts on autoimmune activated T cells, the pro-inflammatory scenery of the central nervous system (CNS), and demyelination. Our findings demonstrate that BCP significantly ameliorates both the clinical and pathological parameters of EAE. In addition, data hereby presented indicates that mechanisms underlying BCP immunomodulatory effect seems to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes, as well as protein expression of pro-inflammatory cytokines. Furthermore, it diminished axonal demyelination and modulated Th1/Treg immune balance through the activation of CB2 receptor. Altogether, our study represents significant implications for clinical research and strongly supports the effectiveness of BCP as a novel molecule to target in the development of effective therapeutic agents for MS.

Technological Device for Manufacturing Transdermal Films: Possible Applications to the Individualized Treatment for Erectile Dysfunction.

Pharmacological advances in erectile dysfunction (ED) treatment have aroused growing interest among health professionals towards sexual dysfunction, generating an increasing demand for dosage forms and drug delivery systems, including tadalafil. This study aimed to develop a device to generate patches that would enable drug dosage individualization and transdermal administration. To create such a mechanical device, technical drawings were made using the CAD software. A functional prototype was built, and a pharmaceutical formulation containing tadalafil (10 mg cm-2) was prepared. An analytical method (HPLC) was developed and validated. The average weight of adhesives (n = 10) was 241.01 mg; the content uniformity for preparations in unit doses (n = 10) was 108.93%, and a CV <2% for intraadhesive tadalafil content (n = 40) was observed. The ex vivo permeation of patches containing tadalafil was determined in Franz cells (n = 6), equipped with human skin and kept for 12 h in contact with the patch, by using the tape stripping method. The optimized method showed acceptable confidence limits within the range recommended by regulatory agencies, being validated for use in this ex vivo permeation study. Tadalafil could permeate to the viable epidermis and dermis (5.7%). The created device produced homogeneous patches of tadalafil, showing such technological innovation as to be feasible in individualized therapy for the treatment of ED.

Lower phosphorylated glycogen synthase kinase-3B levels in platelets of patients with schizophrenia: increment by olanzapine treatment.

Glycogen synthase kinase-3B (GSK-3B) is involved with important neuronal processes such as cell survival, gene regulation, mood and cognitive performance. This enzyme is inactivated by phosphorylation at the phospho-Ser9 site. We compared GSK-3B levels in patients with schizophrenia to a health control group. The levels of phosphorylated and total GSK-3B in platelets of ten drug-free patients, ten long-term olanzapine treated patients and 20 healthy controls were determined by means of an enzyme immunoassay kit. In drug-free patients, GSK-3B levels were accessed again after 8 weeks on treatment with olanzapine. At baseline, drug-free patients presented lower phosphorylated and total GSK-3B levels than healthy controls (p < 0.05). After 8 weeks on olanzapine treatment, phosphorylated and total GSK-3B levels were significantly increased (p < 0.01). Reduced phospho-Ser9-GSK-3B in schizophrenia may disrupt signal-transduction pathways and influence crucial cellular processes, such as transcription, apoptosis, stress response and cell proliferation. Further studies should clarify whether the increment of GSK-3B phosphorylation by olanzapine is related to its antipsychotic effects.

An effective and biocompatible antibiofilm coating for central venous catheter.

The aim of this study was to investigate the in vitro and in vivo efficacy and the tissue reaction of an antibiofilm coating composed of xylitol, triclosan, and polyhexamethylene biguanide. The antimicrobial activity was analyzed by a turbidimetric method. Scanning electron microscopy was used to evaluate the antiadherent property of central venous catheter (CVC) fragments impregnated with an antibiofilm coating (I-CVC) in comparison with noncoated CVC (NC-CVC) fragments. Two in vivo assays using subcutaneous implantation of NC-CVC and I-CVC fragments in the dorsal area of rats were performed. The first assay comprised hematological and microbiological analysis. The second assay evaluated tissue response by examining the inflammatory reactions after 7 and 21 days. The formulation displayed antimicrobial activity against all tested strains. A biofilm disaggregation with significant reduction of microorganism's adherence in I-CVC fragments was observed. In vivo antiadherence results demonstrated a reduction of early biofilm formation of Staphylococcus aureus ATCC 25923, mainly in an external surface of the I-CVC, in comparison with the NC-CVC. All animals displayed negative hemoculture. No significant tissue reaction was observed, indicating that the antibiofilm formulation could be considered biocompatible. The use of I-CVC could decrease the probability of development of localized or systemic infections.

Association of frailty with endothelial dysfunction and its possible impact on negative outcomes in Brazilian predialysis patients with chronic kidney disease.

BACKGROUND: Frailty is a state of physiological vulnerability common in the elderly. It is more predominant in patients with Chronic Kidney Disease in comparison to healthy subjects, which can also be diagnosed in non-elderly individuals and be associated with innumerous causes such as muscle strength, body composition and inflammation. The association between frailty and endothelial function, as well as the association between frailty and the combined outcome of mortality multiple cause and start of renal replace therapy were assessed. METHODS: In the initial analysis, sixty-one predialysis patients with Chronic Kidney Disease stages were evaluated and included in this study. Due to patient drop-out during follow-up, fifty-seven patients were subsequently re-evaluated 12 months later. The diagnosis of frailty was based on the Johansen et al. (J Am Soc Nephrol 18(11):2960-67, 2007) criteria. The groups were divided into Non-frail and Frail. Sociodemographic, inflammatory markers (IL-6, TNF-?, CRP-us), endothelial dysfunction (flow-mediated vasodilatation - FMD), body composition (DXA) and the 25-hidroxi-vitamin D parameters were analyzed. RESULTS: The average age of the patients used in the study was 64.9 ± 10.3 years old. The predominance of frailty was 42.6%, of which 46% were non-elderly. After some adjustments, frailty was associated with gender (OR = 11.32; IC 95% = 2.30 to 55.67), advanced age (OR = 4.07; IC 95% = 1.02 to 16.20), obesity (OR = 6.63; IC 95% = 0.82 to 11.44) and endothelial dysfunction (OR = 3.86; IC 95% = 1.00 to 14.88). The ratio of the incidence of frail subjects to the variable outcome was 2.5 (CI 95%, 1.04 to 6.50). CONCLUSIONS: Although an observational study does not allow one to determine the casual relation between frailty and endothelial dysfunction, we conclude that frailty was predominant in our sample of Brazilian patients with chronic kidney disease on predialysis, even in elderly individuals. This was linked to either worse endothelial function or mortality.

Photoprotective activity of resveratrol analogues.

Resveratrol is a promising agent for protecting human skin from UV radiation and to reduce the occurrence of cutaneous malignancies. We describe the photoprotective activity of six resveratrol analogues using the diffuse transmittance technique to determine the SPF and the protection against UVA radiation. The analogues presented a varied profile of photoprotection, the SPF ranging from 2 to 10 and the UVAPF from 0 to 9. Among the six compounds tested, the protection against UVB sunrays provided by compound B was more significant than the protection provided by resveratrol; compounds C, D, E and F show photoprotection similar to resveratrol.

Azastilbene analogs as tyrosinase inhibitors: new molecules with depigmenting potential.

This research has been an effort to develop synthetic resveratrol analogs in order to improve the depigmenting potential of natural resveratrol. Six resveratrol analogs were synthesized and tested for tyrosinase inhibitory activity in vitro, by qualitative and quantitative steps. The results showed the analog C as being the most powerful tyrosinase inhibitor (IA50=65.67±0.60 µg/mL), followed by the analogs B, E, F, A, and D, respectively. The analog C presented a tyrosinase inhibition potential better than natural resveratrol (P<0.001). The best depigmenting activity was provided by the presence of hydroxyl in the orthoposition on the second phenolic ring.

Three-Dimensionally Printed Vaginal Rings: Perceptions of Women and Gynecologists in a Cross-Sectional Survey.

Three-dimensional printing technologies can be implemented for the fabrication of personalized vaginal rings (VRs) as an alternative approach to traditional manufacturing. Although several studies have demonstrated the potential of additive manufacturing, there is a lack of knowledge concerning the opinions of patients and clinicians. This study aimed to investigate the perception of women and gynecologists regarding VRs with personalized shapes. The devices were printed with different designs (traditional, "Y", "M", and flat circle) by Fused Deposition Modeling for a cross-sectional survey with 155 participants. Their anticipated opinion was assessed through a questionnaire after a visual/tactile analysis of the VRs. The findings revealed that most women would feel comfortable using some of the 3D-printed VR designs and demonstrated good acceptability for the traditional and two innovative designs. However, women presented multiple preferences when the actual geometry was assessed, which directly related to their age, previous use of the vaginal route, and perception of comfort. In turn, gynecologists favored prescribing traditional and flat circle designs. Overall, although there was a difference in the perception between women and gynecologists, they had a positive opinion of the 3D-printed VRs. Finally, the personalized VRs could lead to an increase in therapeutic adherence, by meeting women's preferences.

Protocol of HOTFy: randomised clinical trial to hyperbaric oxygen therapy in fibromyalgia.

INTRODUCTION: Fibromyalgia is a polysymptomatic syndrome with a prevalence between 0.2% and 13% of the population and causes work disabilities in approximately half of affected patients. Several treatments to fibromyalgia have been proposed with partial improvement. This study aims to evaluate the efficacy of hyperbaric oxygen therapy and when it should be introduced to fibromyalgia. METHODS AND ANALYSIS: This is a protocol for an open-label, crossover, randomised clinical trial comparing treatment with hyperbaric oxygen therapy and standardised treatment to fibromyalgia. In the proposed study, 56 individuals with fibromyalgia will be randomised in a 1:1 ratio into a single, fixed, random block, in which one group will receive hyperbaric oxygen therapy and another will receive standard treatment. Subsequently, the groups will be crossed. Participants will be evaluated at baseline, eight and 16 weeks based on functional impairment assessed with the Fibromyalgia Impact Questionnaire-Brazilian Portuguese version, psychopathological symptoms questionnaire and short-form quality of life questionnaire. The improvement of symptoms concerning the moment of therapy used will be compared between groups. For sample size calculation, a moderate effect size, 80% power and 95% CI will be estimated, in a total of 46 patients. Considering a dropout of 20%, 56 patients should be recruited. ETHICS AND DISSEMINATION: The study was approved by the Universidade Federal de Juiz de Fora Teaching Hospital ethics committee and assigned the number 53058421.9.0000.5133 (version 3). The results will be disseminated via publications in peer-reviewed journals and presentations in medical meetings. TRIAL REGISTRATION NUMBER: RBR-6prps8g)/UTN U1111-1278-3224.

Inhibitory effects of resveratrol analogs on mushroom tyrosinase activity.

Skin pigmentation disorders typically involve an overproduction or uneven distribution of melanin, which results in skin spots. Resveratrol can inhibit tyrosinase, the active enzyme in the synthesis of melanin, but it does not inhibit the synthesis of melanin to an extent that enables its use alone as a skin whitening agent in pharmaceutical formulations, so its use as a coadjuvant in treatment of hyperpigmentation is suggested. Six resveratrol analogs were tested for tyrosinase inhibitory activity in vitro. Among the analogs tested, compound D was the most powerful tyrosinase inhibitor (IC(50) = 28.66 µg/mL), two times more active than resveratrol (IC(50) = 57.05 µg/mL), followed by the analogs A, E, B, F and C, respectively. This demonstrated that the hydroxylation at C4' on the phenolic ring was the molecular modification with most importance for the observed activity.

Is vitamin D status relevant to psoriasis and psoriatic arthritis? A retrospective cross-sectional study.

BACKGROUND: Psoriasis is a systemic, immune-mediated disease characterized by inflammatory manifestations in the skin and joints. Vitamin D deficiency is currently considered a pandemic and is associated with comorbidities including psoriasis and psoriatic arthritis (PsA). OBJECTIVES: To determine the prevalence of hypovitaminosis D [25(OH)D] in patients with plaque psoriasis, with and without PsA, and of independent predictors of serum 25(OH)D levels. DESIGN AND SETTING: Retrospective cross-sectional study conducted among 300 patients at an outpatient clinic in a university center in Juiz de Fora, Minas Gerais, Brazil. METHODS: Demographic and clinical data (psoriasis area and severity index [PASI], family history, age at onset, disease duration, and the presence of PsA according to Classification Criteria for Psoriatic Arthritis), skin phototype, and season of the year were reviewed. RESULTS: Hypovitaminosis D (< 30 ng/mL) was highly prevalent in patients with psoriasis with and without PsA (82.2% and 74.9%, respectively). An inverse correlation between PASI and vitamin D was found (without PsA r = -0.59 and, PsA r = -0.52, P < 0.001), and multivariate regression revealed that hypovitaminosis D was associated with disease severity, season, and phototype. It was confirmed by binary logistic regression between PASI and vitamin D deficiency (< 30 ng/mL), (odds ratio, OR 1.78 CI: -0.20-0.53, P < 0.001). CONCLUSION: Hypovitaminosis D (< 30 ng/mL) was highly prevalent in psoriatic patients with and without PsA. Season and skin phototype were associated with 25(OH)D levels. An inverse association between PASI and serum 25(OH)D levels was established.

25-Hydroxyvitamin D as a biomarker of vitamin D status in plaque psoriasis and other dermatological diseases: a cross-sectional study.

BACKGROUND: Hypovitaminosis D is a public health problem associated with several chronic inflammatory and immunological diseases, including psoriasis. OBJECTIVES: This study aimed to determine the prevalence of hypovitaminosis D in patients with plaque psoriasis. A comparison was made between vitamin D levels in patients with psoriasis and those with other non-inflammatory dermatoses without photosensitivity. In addition, it evaluated the effects of the patients' Fitzpatrick skin phototype and the season of the year on the serum levels of vitamin D. DESIGN AND SETTINGS: A retrospective cross-sectional study was conducted at an outpatient clinic in a university center in Juiz de Fora (MG), Brazil. METHODS: A review of dermatology patients' demographic data, including skin phototype and serum levels of 25-hydroxyvitamin D [25(OH)D], over 12 months in 2016. RESULTS: This study included 554 patients: 300 patients allocated to the plaque psoriasis group and 254 control patients with other dermatological diseases. Regarding the season of the year, 229, 132, 62, and 131 participants were evaluated in summer, autumn, winter, and spring, respectively. As for the skin phototype, 397, 139, and 18 patients had phototypes III, IV, and V, respectively. The serum levels of 25(OH)D were significantly lower in the psoriasis group (24.91 ± 7.16 ng/mL) than in the control group (30.37 ± 8.14 ng/mL). CONCLUSIONS: Hypovitaminosis D (< 30 ng/mL) was present in 76.66% of patients with psoriasis versus 53.94% of control patients. Vitamin D deficiency (< 20 ng/mL) was observed in 25% of the patients with psoriasis versus 8.66% in the control group (P < 0.001). The season and patient's skin phototype were independent predictors of serum vitamin D levels.

Systemic, Intrathecal, and Intracerebroventricular Antihyperalgesic Effects of the Calcium Channel Blocker CTK 01512-2 Toxin in Persistent Pain Models.

CTK 01512-2 toxin is a recombinant peptide of the Phα1ß version derived from the venom of the Phoneutria nigriventer spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512-2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512-2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1-4 h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512-2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512-2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.

Coupling of Fused Deposition Modeling and Inkjet Printing to Produce Drug Loaded 3D Printed Tablets.

In the current study, we have coupled Fused Deposition Modelling (FDM) for the fabrication of plain polyvinyl alcohol (PVA) tablets followed by dispensing of minoxidil ethanolic solutions using inkjet printing. The use of a drop-on-solid printing approach facilitates an accurate and reproducible process while it controls the deposition of the drug amounts. For the purpose of the study, the effect of the solvent was investigated and minoxidil ink solutions of ethanol 70% v/v (P70) or absolute ethanol (P100) were applied on the plain PVA tablets. Physicochemical characterization showed that solvent miscibility with the polymer substrate plays a key role and can lead to the formation of drug crystals on the surface or drug absorption in the polymer matrix. The produced minoxidil tablets showed sustained release profiles or initial bursts strongly affected by the solvent grade used for dispensing the required dose on drug loaded 3D printed tablets. This paradigm demonstrates that the coupling of FDM and inkjet printing technologies could be used for rapid development of personalized dosage forms.

Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.

Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM. Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mg/kg; injected subcutaneously (s.c.) once daily for three consecutive days) administration. Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mg/kg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mg/kg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration. Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine. In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.

Salivary alpha-amylase activity: a possible indicator of pain-induced stress in orthodontic patients.

INTRODUCTION: Pain, a common experience reported by orthodontic patients, has its intensity assessed with the help of subjective scales, which have a limited and disputable value. Such unpleasant experience, which may raise stress levels, is reflected by an increase in the salivary concentration of alpha-amylase. OBJECTIVE: Assess the correlation between the salivary levels of alpha-amylase and pain intensity reported by patients during orthodontic treatment. PATIENTS: Twenty male patients (11-37 years of age) were assessed daily, before treatment, after bracket bonding, and after initial arch wire insertion. DESIGN: Saliva was sampled for alpha-amylase analysis, and pain intensity was measured with the visual analog scale. RESULTS: There was no correlation between alpha-amylase concentrations in the saliva and pain intensity, although the patients had a significant and progressive increase of alpha-amylase levels during the assessment period. CONCLUSIONS: The findings may reflect the psychological stress caused by the presence and activation of the fixed appliance.

Prevalence of psoriatic arthritis among patients with plaque psoriasis: a Brazilian retrospective study.

BACKGROUND: Psoriatic arthritis is the most frequent and impactful comorbidity among psoriatic patients and appears in most cases after skin disease. Dermatologists play a key role in its early diagnosis and treatment. OBJECTIVE: To determine the prevalence of psoriatic arthritis and associated variables among patients with plaque psoriasis seen at a reference center for treating psoriasis. DESIGN AND SETTING: Retrospective cross-sectional study conducted among 300 patients at an outpatient clinic in a university center in Juiz de Fora, MG, Brazil. METHODS: Standardized records of 300 patients with plaque psoriasis were examined. Demographic data and medical variables relating to psoriasis (Psoriasis Area and Severity Index (PASI), family history, age at onset and disease progression) and psoriasis arthritis (CASPAR criteria) were evaluated. Laboratory and radiographic tests in the medical records were reviewed. RESULTS: Seventy-three (24.3%) of these 300 patients with plaque psoriasis had psoriatic arthritis. Asymmetric oligoarthritis (58.9%) was the most common clinical form, followed by polyarthritis (20.5%), distal interphalangeal arthritis (15.2%) and spondyloarthritis (5.4%). Dactylitis was present in 21.9% and enthesitis in 35.6% of patients. Compared with patients without arthritis, patients with arthritis had higher average age, higher frequency of positive family history of psoriasis, longer duration of evolution and higher PASI rates. CONCLUSION: Psoriatic arthritis is often underdiagnosed. Since dermatologists perform the initial approach, these professionals need to be trained to diagnose this comorbidity and treat it, together with rheumatologists.