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Background The pathogenesis of pityriasis rubra pilaris (PRP) is not completely understood, but interleukin (IL)-17 has been shown to play a critical role. There are no reliable immunomodulatory agents to treat PRP. We conducted an open-label, single-arm clinical trial of secukinumab, a monoclonal antibody that inhibits IL-17A, for the treatment of PRP. Objectives To evaluate the clinical efficacy of secukinumab and define the transcriptomic landscape of PRP and its response to IL-17A blockade. Methods Twelve patients with PRP were recruited for an open-label trial of secukinumab. Patients received a 24-week course of secukinumab. The primary endpoint was a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) from baseline to week 28. Secondary endpoints included PASI 90, change in Physician’s Global Assessment (PGA), and change in Dermatology Life Quality Index (DLQI). RNA sequencing was performed on lesional and nonlesional skin biopsies obtained at baseline and week 2. Sample groups were compared to identify differential gene expression and pathway enrichment. This trial was registered with ClinicalTrials.gov: ‘Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris’ – NCT03342573. Results At week 28, six of 11 patients (55%) achieved PASI 75, and three patients (27%) achieved PASI 90. PGA (P = 0.008) and DLQI scores (P = 0.010) showed significant improvement with treatment. No serious treatment-related adverse events were encountered. Treatment with secukinumab normalized transcriptional differences between lesional and nonlesional skin. Transcriptomic data from nonresponsive patients suggest that overactivity of innate immune pathways may be driving resistance to secukinumab. Conclusions Secukinumab appears to be an effective treatment for PRP and warrants further investigation. PRP is a transcriptionally heterogeneous disease, reflecting its variable response to therapy. Agents targeting other IL-17 isoforms and innate immune mediators should be considered for future clinical trials. What is already known about this topic? The pathogenesis of pityriasis rubra pilaris is incompletely understood. Successful treatment has been reported with a variety of immunomodulatory agents, but disease is often refractory to therapy.Interleukin (IL)-17 is thought to drive keratinocyte proliferation and vascular dysfunction in this disease.A previous trial demonstrated efficacy of the anti-IL-17A drug ixekizumab for pityriasis rubra pilaris. What does this study add? Herein we describe the findings of a clinical trial of secukinumab, an anti-IL-17A monoclonal antibody, for the treatment of pityriasis rubra pilaris.Secukinumab was effective in treating pityriasis rubra pilaris.Our transcriptomic data give new insight into the expressional changes that occur in response to secukinumab and suggest mechanisms of treatment resistance.

Hidradenitis suppurativa (HS) is an inflammatory skin condition that is often considered a systemic disease due to its association with metabolic comorbidity.In this study, we aimed to identify differences in plasma lipidomic profiles between HS patients and control subjects.HS patients were recruited from a tertiary dermatological centre and demographic and comorbidity matched controls from the general population. A targeted lipidomic approach was performed to characterize over 700 lipid species representing 35 lipid classes/sub-classes. Linear regression models adjusted for confounding factors were used to compare the plasma lipidomic profiles of HS patients to controls. Ordinal regression models were used to study the association of lipids with disease activity and severity scores.60 HS patients and 73 control subjects were recruited. Differential levels (p 0.05) of 32 lipid species in HS patients compared to controls were observed, including a decrease in the long chain base d19:1 containing ceramides, and elevation of hydroxyeicosatetraenoic acid (HETE) and dihydroxyeicosatrienoic acid (DHET) oxylipins. These lipids along with several other molecules showed associations with Hurley, HS-PGA and disease activity scores.This study found mild changes in plasma lipidomic profiles, consistent with previous studies showing attenuated metabolomic changes in plasma as opposed to lesional skin. However, a number of lipid species were associated with increasing activity and severity of the disease. Further, the significant lipid species within the same class showed consistent trends of increase or decrease in HS as compared to controls.

This study aimed to assess the content validity and reliability of the Physician's Global Assessment of Fingernail Psoriasis (PGA-F) by rheumatologists treating patients with psoriatic arthritis.There were 3 stages of analyses with 3 clinician cohort groups. Stage 1 (concept confirmation) included rheumatologist qualitative data (cohort 1) to establish content validity, acceptability, utility, and feasibility of the PGA-F in assessing nail severity. Quantitative information regarding the response category utilization in nail abnormalities was assessed by photographs. Stage 2 (inter-rater reliability) involved quantitative analysis of PGA-F data from study investigators, including rheumatologists, involved in a phase III clinical study (cohort 2) and a cohort of newly recruited rheumatologists (cohort 3). Stage 3 included known-groups validity.Qualitative analyses identified consensus that the PGA-F severity levels are comprehensive of real-world patient symptoms and the instrument is simple to use and understand. Psychometric analyses support the PGA-F as a clinical outcome assessment tool. Inter-rater reliability showed rheumatologist agreement across the fingernail psoriasis severity spectrum. They were monotonically ordered by the hypothesized severity structure with excellent fit to the clinicians who evaluated them. Agreement on the rank order of the severity of the photographs in this target rheumatologist population was consistent with previous reports by dermatologists.The PGA-F was shown to be usable by rheumatologists to measure patients along the full range of the fingernail psoriasis severity spectrum, have a strong relationship with a conceptually similar reference measure, differentiate among patients based on fingernail psoriasis severity, and detect category severity change over a 24-week period.

This study aimed to compare the differences between oral administration and intravenous injection of polygalacturonic acid (PGA) in the regulation of immune and intestinal microflora in ulcerative colitis (UC) mice. PGA was administered orally or intravenously. PGA in the high-dose ig group was the most effective in treating UC by increasing colon length and downregulating disease activity index, histopathological score and proinflammatory cytokine levels. In spleen, the efficacy of PGA on restoring Th17/Treg balance in the high-dose iv group was better than that in the high-dose ig group, the opposite was observed in the lamina propria. The level of colonic IL-17A in the high-dose ig group was lower than that in the high-dose iv group, the opposite was observed for that of colonic IL-10. Western blot and immunohistochemistry analysis revealed that PGA in the high-dose ig group decreased the protein expression of RORγt, and increased that of FOXP3. Furthermore, PGA in the high-dose ig group was more effective than that in the high-dose iv group in improving the intestinal microflora structure. Our results suggest that in immune regulation, oral PGA is more effective in the lamina propria and gut microbiota while intravenous PGA is more effective in the spleen.

This study aimed to prepare alcohol-free curcumin-loaded zein-propylene glycol alginate (zein-PGA-Cur) nanoparticles using the pH-driven method to enhance the bioavailability and physicochemical stability of curcumin. The prepared zein-PGA-Cur nanoparticles exhibited a small size (360 nm) and negative zeta-potential (-5.8 mV), as well as excellent physical stability, under storage conditions of pH 4.0 and temperature at 4 °C for 30 days. In addition, the Fourier transform infrared spectroscopy results demonstrated that the main interactions of pH-driven for the formation of zein-PGA-Cur nanoparticles were hydrogen bonding, hydrophobic, and electrostatic interactions. Fluorescence spectroscopy revealed that the curcumin-induced fluorescence quenching of zein was static. Circular Dichroism spectroscopy demonstrated that the pH-driven method mainly decreased the β-sheet structure of zein from 3.9 % to 1.4 %. Furthermore, the HT-29 colorectal adenocarcinoma cells viability experiments revealed that the prepared zein-PGA-Cur nanoparticles exhibited excellent biocompatibility. In vivo rat experiments also demonstrated that the prepared nanoparticles resulted in a higher plasma concentration of curcumin, representing a 7.2-fold enhancement in bioavailability compared with pure curcumin crystals. The findings of this study will provide a green and energy-saving method for the development of insoluble drug self-assembly systems and promote their wider applications in drug delivery.

Neointimal hyperplasia is a complex process after vascular interventions, acute platelet deposition and smooth muscle cell proliferation both contributed to this process. There are still no perfect solutions to solve this problem. Rivaroxaban is a novel anticoagulant that has been widely used in clinic, it has a good pharmacological effects both in vivo and in vitro. Chitosan microparticle rapamycin (MP-rapa) was fabricated, interspaces of polyglycolic acid (PGA) scaffold were used as a reservoir of MP-rapa, and the scaffold was coated with hyaluronic acid rivaroxaban (MP-rapa-riva). Scanning electronic microscopy (SEM) photographs were taken and water contact angles were measured, rat inferior vena cava (IVC) patch venoplasty model was used; patches were harvested at day 14 and examined by immunohistochemistry and immunofluorescence. SEM photographs showed the microparticles rapamycin were inside the interspace of the scaffold, hyaluronic acid rivaroxaban was also successfully coated onto the surface of the scaffold. There was a thinner neointima, fewer proliferating cell nuclear antigen (PCNA) positive cells, fewer macrophages in the MP-rapa and MP-rapa-riva grafts compared to the control PGA graft. The result showed that this scaffold with dual anticoagulation and antiproliferation functions can effectively inhibit venous neointimal hyperplasia, although this is an animal experiment, it showed promising potential clinical application in the future.

The aim of this review was to evaluate the most used suture materials with regards to their inflammatory response, their bacterial adhesion, and their physical properties when used to close oral wounds.Four databases (PubMed, Scopus, DentistryOral Sciences, and OVID) were searched to retrieve relevant studies from January 1, 2000, to January 31, 2020.Out of the 269 articles, only 13 studies were selected as they were relevant and met the systematic review's protocol. These studies showed that almost all suture materials studies (catgut, polyglycolic acid [PGA] sutures, nylon, expanded polytetrafluoroethylene, and silk sutures) caused bacterial adherence and tissue reaction. In nylon and chromic catgut, the number of bacteria accumulated was lowest. Silk and nylon were found to be more impacted than catgut and PGA in terms of physical characteristics such as tensile strength. PGA, on the other hand, was said to be the most susceptible to knot unwinding.Following an oral surgical operation, all sutures revealed varied degrees of irritation and microbial accumulation. Nonresorbable monofilament synthetic sutures, however, exhibited less tissue response and less microbial accumulation.

Introduction: Hip involvement in patients with spondyloarthritis is responsible for disability and functional impairment. Its treatment is not codified. Our study aimed to determine the associated factors with moderate and severe hip involvement in spondyloarthritis patients. It also aimed to assess the efficacy of tumour necrosis factor inhibitors (TNFi) on hip disease. Methods: We conducted a cross-sectional study, including 44 spondyloarthritis patients with hip involvement. Hip involvement was diagnosed based on radiographic findings. We assessed the following parameters: Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Radiology Index (BASRI), patient global assessment (PGA), and Lequesne index. We compared these parameters and the mean radiographic joint space width between the time of the study to those right before the use of TNFi. Results: Hip involvement was bilateral in 31 patients. The mean age was 44.56±12.21 years. There were 29 men. Severe and moderate involvement (BASRI-hip>3) was reported in 21 hips from 75 affected. These patients were older and had longer diagnosis delays than patients with BASRI- hip Conclusion : Our study showed that higher body mass and Lequesne indexes are associated with moderate and severe hip involvement. TNFi may improve both the Lequesne index and PGA and stabilize the radiological findings.

Psoriasis is a common chronic and recurrent disease in dermatology, which has a great impact on the physical and mental health of patients. Meta-analysis can evaluate the effectiveness and safety of defubao in the treatment of psoriasis vulgaris. This article observes psoriasis skin lesions treated with topical defubao and the changes in blood vessels under dermoscopy. Considering that the Apriori algorithm and the existing improved algorithm have the problems of ignoring the weight and repeatedly scanning the database, this paper proposes a matrix association rule method based on random forest weighting. This method uses the random forest algorithm to assign weights to each item in the data set, and introduces matrix theory to convert the transaction data set into a matrix form and store it, thereby improving operating efficiency. This article included 11 studies, of which 7 studies used the indicator “Researcher’s Overall Assessment” (IGA) to evaluate the efficacy, 5 studies used the “Patient Overall Assessment” (PGA) as the efficacy evaluation index, and Loss Area and Severity Index (PASI) was used as an observation index to evaluate the efficacy. Seven studies conducted safety comparisons. In this paper, IGA and PGA were used as evaluation indicators. The treatment effect of the defubao group was better than the calcipotriol group and the betamethasone group. The differences were statistically significant. The effect of the Fubao treatment for 8 weeks is significantly better than that of 4 weeks and 2 weeks, and the differences are statistically different. Using PASI as the evaluation index, a descriptive study was carried out, and it was found that after 4 weeks of treatment for psoriasis vulgaris, the average PASI reduction rate of patients was higher than that of the calcipotriol group and the betamethasone group. The safety evaluation found that after 8 weeks of treatment, the incidence of adverse events in the defubao group was significantly lower than that in the calcipotriol group.

Synergistic therapy, especially the combination of photothermal therapy and chemotherapy, has been proposed as an effective therapeutic approach for breast cancer treatment. In this study, a smart platform for synergistic photothermal therapy and chemotherapy was developed by hybridizing doxorubicin-encapsulated thermosensitive liposomes and gold nanorods into porous scaffolds of gelatin and polyglutamic acid (Dox-lipo/AuNR/Gel/PGA). The Dox-lipo/AuNR/Gel/PGA composite scaffolds had good photothermal conversion and temperature-dependent doxorubicin release properties. Under near-infrared laser irradiation, the composite scaffolds increased the local temperature to not only kill the breast cancer cells in the scaffolds but also accelerate the release of doxorubicin to eliminate the breast cancer cells surrounding the scaffolds.

Background: The scientific evidence of methotrexate (MTX) in children with severe plaque psoriasis is scarce. Objectives: To retrospectively evaluate the efficacy and safety of oral MTX in children with severe plaque psoriasis in a single center in China. Methods: We enrolled 42 children with severe plaque psoriasis who were administrated MTX. Efficacy was evaluated by the psoriasis area and severity index (PASI) score, physician global assessment (PGA) score, and body surface area (BSA) score. The Children’s Dermatology Life Quality Index (CDLQI) score and safety data were recorded. Results: Among 42 children (22 males, 20 females), the mean age was 11.2 years old. The initial weight-based dosage of oral MTX ranged from 0.1 to 0.3 mg/kg weekly. Overall, 80.6 and 47.2% of patients achieved PASI75 (at least 75% improvement from baseline in PASI score) and PASI90 (at least 90% improvement from baseline in PASI score) at week 12, respectively. 72.2% of patients achieved PGA 0/1 at week 12. BSA and PGA scores significantly decreased from baseline from week 4, accompanied by CDLQI score improvement from week 8. The steady effect of MTX could be reached at week 16. Elevated liver enzymes (28.6%) and infections (28.6%) were the most common side effects. Relapse was recorded in 9 (30.0%) of 30 patients, and the mean posttherapy disease-free interval was 7.2 months. Conclusions: MTX is an effective and safe option for children with severe plaque psoriasis with adequate monitoring.

Exposure-response modeling is important to optimize dose and dosing regimens in clinical drug development. While primary clinical trial endpoints often have few categories and thus provide only limited information, sometimes there may be additional, more informative endpoints. Benefits of fully incorporating relevant information in longitudinal exposure-response modeling through joint modeling have recently been shown. This manuscript aims to further investigate the benefit of joint modeling of an ordered categorical primary endpoint with a related near-continuous endpoint, through the sharing of model parameters in the latent variable indirect response (IDR) modeling framework. This is illustrated by analyzing the data collected through up to 116 weeks from a phase 3b response-adaptive trial of ustekinumab in patients with psoriasis. The primary endpoint was based on the 6-point physician's global assessment (PGA) score. The Psoriasis area and severity Index (PASI) data, ranging from 0 to 72 with 0.1 increments, were also available. Separate and joint latent variable Type I IDR models of PGA and PASI scores were developed and compared. The results showed that the separate PGA model had a substantial structural bias, which was corrected by the joint modeling of PGA and PASI scores.

BACKGROUND Port-wine stain (PWS) is a congenital capillary malformation that often occurs on the face. Feasible and quantitative evaluation of facial port-wine stain (FPWS) can significantly impact its clinical management and aid in future research. AIM To develop and validate an easy-to-use scoring system for FPWS evaluation. METHODS A facial port-wine stain area and severity index (FSASI) scoring system was proposed. To determine the FSASI score, the face was divided into four regions: forehead, right malar, left malar, and perioral. The severity of FPWS in each region was evaluated by three factors: percentage of the area affected, lesion color, and thickness. To evaluate the intra- and inter-rater reliability of FSASI, two separate FSASI assessments on 111 clinical pictures were conducted by each rater in a one-week interval, and the results from 6 independent raters at different time points were compared. Validity of the FSASI scores was assessed by comparing it with physician global assessment (PGA) and traditional classification data. Validity of the area and color elements of FSASI was also determined. The changes in FSASI scores after vascular-targeted photodynamic therapy (V-PDT) were analyzed to evaluate the treatment effect. RESULTS The FSASI scoring system showed good intra- and inter-rater reliability (ICC >0.75, p

Clinical trials in patients with ulcerative colitis (UC) face the challenge of high and variable placebo response rates. The Mayo Clinical Score (MCS) is used widely as the primary endpoint in clinical trials to describe the clinical status of patients with UC. The MCS is comprised of four subscores, each scored 0, 1, 2 and 3: rectal bleeding (RB), stool frequency (SF), physician’s global assessment (PGA), and endoscopy (ENDO) subscore. Excluding the PGA subscore gives the modified MCS. Quantitative insight on the placebo response, and its impact on the components of the MCS over time, can better inform clinical trial design and interpretation. Longitudinal modeling of the MCS, and the modified MCS, can be challenging due to complex clinical trial design, population heterogeneity, and limited assessments for the ENDO subscore. The current study pooled patient-level placebo/standard of care (SoC) arm data from five clinical trials in the TransCelerate database to develop a longitudinal placebo response model that describes the MCS over time in patients with UC. MCS subscores were modeled using proportional odds models, and the removal of patients from the placebo/SoC arm, or “dropout”, was modeled using logistic regression models. The subscore and dropout models were linked to allow for the prediction of the MCS and the modified MCS. Stepwise covariate modeling identified prior exposure to TNF-α antagonists as a statistically significant predictor on the RB + SF subscore. Patients with prior exposure to TNF-α antagonists had higher post-baseline RB + SF subscores than naive patients.

Objective Achieving targeted disease activity (DA) is the primary therapeutic strategy in RA. Point measurements of DA are done at out-patient visits, however true DA between visits remains unobserved. This study sought to describe and validate a new outcome measure, i.e. time in remission (TIR). Methods Patients were enrolled in the Czech ATTRA-RA registry. TIR was calculated using linear interpolation of the DAS28-ESR determined at outpatient visits. Correlation coefficients were computed between TIR and DAS28-CRP, HAQ, Simple Disease Activity Index (SDAI), patient global assessment (PGA) and physician global assessment (PhGA). Using logistic regression, TIR was used as a predictor of remission (SDAI ≤3.3) and non-disability (HAQ Results Since 2010, 2618 RA patients started anti-TNF therapy and were followed until 2020 or until treatment discontinuation. During the first 6 months of therapy, 56% of patients had no remission (TIR = 0), and 22% of patients reached sustained remission (TIR = 1), while 22% of patients had point remissions with 0 Conclusions TIR is an intuitive way of estimating unobserved DA between scheduled visits; its calculation only requires two consecutive DA values (https://www.medevio.cz/tir-calculator/). TIR is a valid predictor of RA outcomes.

Nanoparticle (NP) drug delivery systems are known to potentially enhance the efficacy of therapeutic agents. As for antimicrobial drugs, therapeutic solutions against drug-resistant microbes are urgently needed due to the worldwide antimicrobial resistance issue. Usnic acid is a widely investigated antimicrobial agent suffering from poor water solubility. In this study, polymer nanoparticles based on polyglycerol adipate (PGA) grafted with polycaprolactone (PCL) were developed as carriers for usnic acid. We demonstrated the potential of the developed systems in ensuring prolonged bactericidal activity against a model bacterial species, Staphylococcus epidermidis. The macromolecular architecture changes produced by PCL grafted from PGA significantly influenced the drug release profile and mechanism. Specifically, by varying the length of PCL arms linked to the PGA backbone, it was possible to tune the drug release from a burst anomalous drug release (high PCL chain length) to a slow diffusion-controlled release (low PCL chain length). The developed nanosystems showed a prolonged antimicrobial activity (up to at least 7 days) which could be used in preventing/treating infections occurring at different body sites, including medical device-related infection and mucosal/skin surface, where Gram-positive bacteria are commonly involved.

Generally, the anchoring of inorganic nanoparticles onto the surface of fibers faces the problem of poor stability, which limits the wide application of nanoparticle functionalized fibers. Herein, nanofibers with shell-core structures were constructed by coaxial electrospinning of two polymers with different melting points (Tm). Polyglycolic acid (PGA, Tm = 225 °C) was employed as the core layer, while polycaprolactone (PCL, Tm = 60 °C) was used as the shell layer. Silver nanoparticles (AgNPs) were electrosprayed on the nanofibers and the shell layer (PCL) was heated and melted to bond the AgNPs, thus realizing a stable AgNP-composited nanofiber for the construction of antibacterial functional surface. By regulating the shell-core flow ratio and the condition for heat treatment, the appropriate thickness of the shell layer was obtained with a flow ratio of 3:1 (PCL:PGA). The optimal composite structure was constructed when the thermal bonding was taken under 80 °C for 5 min. Furthermore, it was found that the composite nanofibers prepared by thermal bonding had better hydrophilicity, mechanical property, and AgNPs bonding stability, and their antibacterial rate against Staphylococcus aureus ( S. aureus) reached over 97%. Overall, a facile and universal method for the preparation of nanoparticle-anchored nanofibers was established in this study. The robust nanoparticle-composited nanofibers are promising for applications in optoelectronic devices, electrode materials, and so on.

Although topical drugs are the mainstay of treatment for patients with mild-to-moderate psoriasis, the developments observed in this field in the last two decades have been limited. The most commonly used drugs are still vitamin D analogues and corticosteroids, both with several limitations. The aryl hydrocarbon receptor (AhR) plays a role in the pathogenesis of psoriasis, and tapinarof, a novel, first-in-class, small molecule topical therapeutic AhR-modulating agent has been recently approved by the FDA for the topical treatment of plaque psoriasis in adults. Two large, 12-week, phase III trials, PSOARING 1 and 2, showed that 35.4%-40.2% of patients in the tapinarof 1% cream arm achieved the primary endpoint (Physician's Global Assessment [PGA] score of 0 or 1 and a decrease of ≥2-5 points at week 12) compared with 6.0%-6.3% for vehicle arm, respectively. The most common adverse effects were folliculitis, contact dermatitis, headache and pruritus. In the open label, 40-week, extension trial, PSOARING 3, the efficacy and safety results were similar, with 40.9% of patients achieving a PGA = 0 at least one time during the trial and 58.2% of patients with PGA≥2 achieved PGA = 0/1 at least once during the trial, without tachyphylaxis. There were no new safety signals, with most frequent adverse events being folliculitis, contact dermatitis, and upper respiratory tract infection. Tapinarof 1% cream has shown to be effective and to have a favorable safety profile in the treatment of psoriatic patients, representing an alternative to the current therapeutic options, increasing our armamentarium in the topical treatment of psoriasis.

Background In accordance with previous reports on the utility of polyethylene glycolic acid (PGA) felt and fibrin glue for postoperative pancreatic fistula (POPF), we usually perform distal pancreatectomy (DP) with a PGA felt reinforcement stapler when dissecting the pancreas and cover the stump with PGA felt and fibrin glue (the PPF method). In this study, we retrospectively analyzed our DP cases to compare the risk factors for POPF and the postoperative course of patients receiving the PPF method of treatment versus that of those receiving conventional treatment. Methods A total of 127 DP procedures performed in our department between January 2008 and June 2021 were retrospectively analysed. Results In the PPF method, grade B/C POPF rate tended to decrease, and POPF rate showed a significant decrease. The duration of drainage and the length of postoperative hospitalisation were also significantly shorter with the PPF method. The risk of grade B/C POPF significantly decreased with the PPF method if the pancreas was thick (> 13.5 mm) or the patients were obese. Conclusions The PPF method is useful for POPF in DP and is particularly effective when a thick pancreas or obese patient is involved. Removing the drainage tube early in the PPF method may lead to early discharge.

Background Walking exercise has been demonstrated to improve health in people with diabetes. However, it is largely unknown the influences of various walking intensities such as walking speeds and durations on dynamic plantar pressure distributions in non-diabetics and diabetics. Traditional methods ignoring time-series changes of plantar pressure patterns may not fully capture the effect of walking intensities on plantar tissues. The purpose of this study was to investigate the effect of various walking intensities on the dynamic plantar pressure distributions. In this study, we introduced the peak pressure gradient (PPG) and its dynamic patterns defined as the pressure gradient angle (PGA) to quantify dynamic changes of plantar pressure distributions during walking at various intensities. Methods Twelve healthy participants (5 males and 7 females) were recruited in this study. The demographic data were: age, 27.1 ± 5.8 years; height, 1.7 ± 0.1 m; and weight, 63.5 ± 13.5 kg (mean ± standard deviation). An insole plantar pressure measurement system was used to measure plantar pressures during walking at three walking speeds (slow walking 1.8 mph, brisk walking 3.6 mph, and slow running 5.4 mph) for two durations (10 and 20 min). The gradient at a location is defined as the unique vector field in the two-dimensional Cartesian coordinate system with a Euclidean metric. PGA was calculated by quantifying the directional variation of the instantaneous peak gradient vector during stance phase of walking. PPG and PGA were calculated in the plantar regions of the first toe, first metatarsal head, second metatarsal head, and heel at higher risk for foot ulcers. Two-way ANOVA with Fisher’s post-hoc analysis was used to examine the speed and duration factors on PPG and PGA. Results The results showed that the walking speeds significantly affect PPG (P P Conclusions Our findings indicate that people may walk at a slow speed at 1.8 mph for reducing PPG and preventing PGA concentrated over a small area compared to brisk walking at 3.6 mph and slow running at 5.4 mph.

Background Soumbala is a highly loved alkaline traditional fermented food condiment in Burkina Faso. It harbors various microbiota dominated by fermentative Bacillus spp. as functional microorganism with little confirmed health-promoting properties. Methods The present study aimed to evaluate six Bacillus strains previously isolated and identified from soumbala. These strains were selected as presumptively safe bacteria for probiotic and technological characteristics. These strains were assessed for in vitro probiotic criteria (tolerance to acidic pH, gastric juice, 0.3% (m/v) bile salts, intestinal juice and 0.4% (w/v) phenol, cell surface hydrophobicity, auto-aggregation capacity, antimicrobial activity against foodborne pathogens, antibiotic susceptibility and biofilm production) and technological properties, including protease, amylase, lipase, and tannase activity, as well as poly-γ-glutamic acid (PGA) production and thermo-tolerance. Results All tested Bacillus strains (B54, F20, F24, F21, F26 and F44) presented variable relevant probiotic properties (good tolerance to pH 2 and pH 4, gastric juice, bile salts, intestinal juice and phenol), with marked differences in hydrophobicity and auto-aggregation capacity ranging from 73.62—94.71% and 49.35—92.30%, respectively. They exhibited a broad spectrum of activity against foodborne pathogens depending on target pathogen, with the highest activity exhibited by strain F20 (29.52 mm) against B. cereus 39 (p < 0.001). They also showed good biofilm production as well as variable hydrolytic enzyme activities, including protease (43.00—60.67 mm), amylase (22.59—49.55 mm), lipase (20.02—24.57 mm), and tannase (0—10.67 mm). All tested Bacillus strains tolerated temperature up to 50 °C, while only strains F26 and F44 showed the best PGA production. Conclusion Overall, the tested cultures exhibiting potential probiotic and technological characteristics; particularly B. cereus F20, B. benzoevorans F21, B. cabrialessi F26, and B. tequilensis F44 could be a source of probiotic-starters of commercial interest in the production of high-quality soumbala.

Oxidative stress and inflammation play a pivotal role in the development of cardiovascular diseases, an ever-growing worldwide problem. As a non-pharmacological approach, diet, especially a flavonoid-rich diet, showed promising results in the reduction of cardiovascular diseases and alleviation of their symptoms. In this study, in vitro systems based on human microvascular endothelial cells (hmvEC) and human umbilical cord endothelial cells (HUVEC) were established to determine the effect of Healthberry 865

Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats. During absorption, all forms are converted to MTHF while some unconverted folate form is transported into the blood, especially PGA. The study confirms the rapid distribution of absorbed folate to the placenta and fetus. FRαAb administered, also accumulates rapidly in the placenta and blocks folate transport to the fetus and high folate concentrations are needed to circumvent or overcome the blocking of FRα. In the presence of FRαAb, both Leucovorin and levofolinate are absorbed and distributed to tissues better than the other forms. However, only 50% of the leucovorin is metabolically active whereas levofolinate is fully active and generates higher tetrahydrofolate (THF). Because levofolinate can readily incorporate into the folate cycle without needing methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) in the first pass and is relatively stable, it should be the folate form of choice during pregnancy, other disorders where large daily doses of folate are needed, and food fortification.

Disruption of the intracellular lipid balance leading to cholesterol accumulation is one of the features of cells that participate in the development of atherosclerotic lesions. Evidence form our laboratory indicates that anti-inflammatory cyclopentenone prostaglandins (cyPGs) of A- and J-family deviate lipid metabolism from the synthesis of cholesterol and cholesteryl esters to the synthesis of phospholipids in foam-cell macrophages. cyPGs possessing an α,β-unsaturated cyclopentane ring are highly electrophilic substances able to promptly react with reactive cysteines of intracellular molecules through Michael addition. On the other hand, HMG-CoA reductase (HMGCR), the enzyme responsible for the rate-limiting step in cholesterol biosynthesis, presents critically reactive cysteines at the entry of catalytic domain, particularly Cys561, that could be target of cyPG inhibition. In the present study, we showed that cyPGs (but not other non-α,β-unsaturated PGs) physically interact with HMGCR, in a dithiothreitol- and β-mercaptoethanol-sensitive way, and block the activity of the catalytic subunit of the enzyme (IC50 for PGA2 = 0.17 μM). PGA2 inhibits HMGCR activity in cultured rat and human macrophages/macrophage-foam cells and leads to enhanced expression of HMGCR protein, as observed with statins. In cell culture models, PGA2 effectively inhibits the reductase at non-toxic doses (e.g., 1 μM) that block cell proliferation thus suggesting that part of the well-known antiproliferative effect of PGA2 may be due to its ability of blocking HMGCR activity, as cells cannot proliferate without a robust cholesterogenesis. Therefore, besides the powerfully anti-inflammatory and antiproliferative effects, the anticholesterogenic effects of PGA2 should be exploited in atherosclerosis therapeutics.

Background/aimsTo assess the comparative efficacy of latanoprostene bunod (LBN), a novel prostaglandin analogue (PGA), to other medications for open-angle glaucoma and ocular hypertension on lowering intraocular pressure (IOP).MethodsA systematic literature review adapted from the Li et al (Ophthalmology, 2016) study was conducted. Medline, Embase and PubMed were searched for randomised controlled trials published between 1 January 2014 and 19 March 2020. Studies had to report IOP reduction after 3 months for at least two different treatments among placebo, PGAs (bimatoprost 0.01%, bimatoprost 0.03%, latanoprost, LBN, tafluprost, unoprostone) or apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide, levobunolol, timolol, travoprost. A Bayesian network meta-analysis was performed to provide the relative effect in terms of mean difference (95% credible interval) of IOP reduction and ranking probabilities. Surface under the cumulative ranking curve (SUCRA) was generated.ResultsA total of 106 trials were included with data for 18 523 participants. LBN was significantly more effective than unoprostone (−3.45 (−4.77 to −2.12)). Although relative effect was not significative, compared with other PGAs, LBN numerically outperformed latanoprost (−0.70 (−1.83 to 0.43)) and tafluoprost (−0.41 (−1.87 to 1.07)), was similar to bimatoprost 0.01% (-0.02(−1.59 to 1.55)) and was slightly disadvantaged by bimatoprost 0.03% (−0.17 (−1.42 to 1.07)). LBN was significantly more efficient than the beta-blockers apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide and timolol. According to SUCRA, LBN was ranked second after bimatoprost 0.03%, followed by bimatoprost 0.01%.ConclusionLBN was significantly more effective than the PGA unoprostone and most of the beta-blockers. Compared with the most widely used PGAs, LBN numerically outperformed latanoprost and travoprost and was similar to bimatoprost 0.01%.

Analysis and comparison of country-level data from the VISIONARY study, examining treatment outcomes with the topical fixed-dose combination of preservative-free tafluprost (0.0015%) and timolol (0.5%) (PF tafluprost/timolol FC) in adults with open-angle glaucoma (OAG) and ocular hypertension (OHT) who were insufficiently treated with or unable to tolerate either beta-blocker or prostaglandin analogue (PGA) topical monotherapy.A European, prospective, observational study was conducted in 11 countries. Adults with OAG/OHT were switched to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Statistical analysis examined changes in mean standard deviation (SD) intraocular pressure (IOP) from baseline at Week 4, Week 12 and Month 6. Data were documented for each eye separately at baseline and during follow up visits, with the eye reported to have the higher IOP (mmHg), as measured using Goldmann applanation tonometry, being selected for analysis (study eye). Country-level subanalysis examined outcomes by prior monotherapy, diagnosis and timing of dosing for those countries recruiting ≥20 patients (Country-level Subanalysis Population). Two-sided pairedMean (SD) age among patients recruited to the VISIONARY study ranged between 63.9 (11.8) and 72.4 (10.6) years across all countries. The majority of participants (50%) were female in each country. The Country-level Subanalysis Population included 551 eyes. Mean (SD) IOP was significantly reduced from baseline in each country at Week 4, Week 12 and Month 6 (Subanalysis of VISIONARY study data revealed significant IOP reductions following a switch to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Cross-country variation was likely due to baseline IOP differences. Within country, outcomes were consistent regardless of diagnosis, dosing or prior monotherapy. Treatment was generally well tolerated.

Micelles as nanocarriers not only offer new opportunities for early diagnosis and treatment of malignant cancers but also encounter numerous barriers in the path of efficient delivery of drugs to diseased areas in the body. To address these issues, we developed a pH/GSH responsive nano-prodrug micelle (NLG919/PGA-Cys-PPA@Gd) with a high drug-loading ratio and controlled drug release performance for MRI-guided tumor photodynamic therapy (PDT) and immune synergistic therapy. Under normal conditions, theranostic nanomicelles remained stable and in a photo-quenched state. Upon accumulation in the tumor site, however, the micelles demonstrated tumor microenvironment (TME) triggered photoactive formed-PPA (a photosensitizer) and NLG919 (an indoleamine 2,3-dioxygenase (IDO) inhibitor) release because the amide bonds of PGA-Cys-PPA and the disulfide linkage of Cys were sensitive to pH and GSH, respectively. More importantly, these micelles could avoid the undesired PPA leakage in blood circulation due to the conjugation between PPA and polymers. Furthermore, the obtained micelles could also enhance the contrast of

The objective of this meta-analysis was to evaluate the effect of prostaglandin analogues (PGA) on central corneal thickness (CCT) in patients with glaucoma. Key electronic databases were searched for randomized controlled trials (RCTs) involving the CCT effects of prostaglandin use for glaucoma. Primary outcome measures were the mean difference in the CCT measurement from baseline to the last available assessment. Intraocular pressure and other corneal changes were recorded as secondary. Efficacy estimates were measured by their weighted mean difference (WMD) with 95% confidence intervals (CI's) by using the random-effects model for primary and secondary outcomes Trial sequential analysis was used to determine if the current evidence was sufficient and conclusive. Eight RCTs met our inclusion criteria. A total of 879 patients were included. The overall effect showed that PGA's had a significant CCT lowering effect (WMD = -7.04, 95%CI: -10.07 to -4.00, P0.00001). We pooled results of 5 RCT's on Travoprost (WMD = -10.44, 95%CI: -16.80 to -4.08, P = 0.001), seven trials on Latanoprost (WMD = -4.73, 95% CI: -9.70 to 0.25, P = 0.06), and three trials on Bimatoprost (WMD = -11.88, 95%CI: -21.03 to -2.73, P = 0.01). The WMD across groups in6 months of PGA use was -11.37 (95%CI: -17.17 to -5.58, P = 0.0001), and in6 months of PGAs group was -8.35 (95% CI: -12.01 to -4.69, P0.00001), suggesting a longitudinal effect of PGAs on CCT. In conclusion, Bimatoprost and Travoprost caused a statistically significant reduction in the thickness of central cornea. Though only a few studies were included, the narrow confidence intervals and adequate sample size suggest that these findings are valid.

Prostaglandin (PG) A

This study delivers the first report on a cell-membrane-mimicking polymer system, poly[oxy(4-(13-cholenoatenonyl)-1,2,3-triazoyl-1-methyl)ethylene

Objectives Evaluate relationships between changes in dermatologic assessments and quality of life (QoL) measures; quantify dermatologic symptom severity impacts on QoL in patients with psoriatic arthritis (PsA) treated with tofacitinib. Methods Data were from two phase III studies; patients received tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg every other week, or placebo advancing to tofacitinib 5 or 10 mg BID at Month 3. Repeated measures longitudinal models assessed relationships between dermatologic assessments (predictors) Itch Severity Item (ISI), Physician’s Global Assessment of Psoriasis (PGA-PsO), and Patient’s Global Joint and Skin Assessment-Visual Analog Scale-Psoriasis question (PGJS-VAS-PsO), and QoL measures (outcomes) Dermatology Life Quality Index (DLQI) and Short Form-36 Health Survey Version 2 (SF-36v2). Models included one predictor and one outcome. Results Direct, approximately linear relationships existed between predictors and outcomes. ISI/PGA-PsO/PGJS-VAS-PsO improvements from baseline of ≥3/≥2/≥40-mm VAS corresponded with clinically meaningful DLQI improvements; improvements from baseline of ≥4/≥3/≥40-mm VAS generally corresponded with clinically meaningful improvements across component scores and all SF-36v2 domains. Conclusions Substantial links exist between dermatologic symptoms and QoL in patients with PsA, potentially informing patient-centered care and research. Rheumatologists should be aware of dermatologic manifestations and QoL impacts in patients with PsA. ClinicalTrials.gov NCT01877668; NCT01882439

Tapinarof cream 1% once daily, an aryl hydrocarbon receptor-modulating agent, was significantly more efficacious than vehicle and well tolerated in two 12-week phase 3 trials in adults with mild to severe plaque psoriasis.To assess long-term safety, efficacy, remittive effect, durability of response, and tolerability of tapinarof.Patients completing the 12-week trials were eligible for 40-weeks' open-label treatment and 4-weeks' follow-up. Treatment was based on the Physician Global Assessment (PGA) score. Patients entering with PGA≥1 received tapinarof until PGA = 0. Patients with PGA = 0 discontinued tapinarof and were monitored for remittive effect. Patients with PGA≥2 were re-treated until PGA = 0.Overall, 91.6% (n = 763) of eligible patients enrolled; 40.9% of patients achieved complete disease clearance (PGA = 0), and 58.2% entering with PGA≥2 achieved PGA = 0 or 1. Mean duration of off therapy remittive effect for patients achieving PGA = 0 was 130.1 days. No new safety signals were observed. Most frequent adverse events were folliculitis (22.7%), contact dermatitis (5.5%), and upper respiratory tract infection (4.7%).Open-label; no control; may not be generalizable to all forms of psoriasis; remittive effect/response rate potentially underestimated.Efficacy improved beyond the 12-week trials, with a 40.9% complete disease clearance rate, ∼4-month off therapy remittive effect, durability on therapy, and consistent safety.

Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria and causes inflammatory diseases. We searched MeOH extracts of collected marine organisms for inhibitors of LPS-induced nitric oxide (NO) production in RAW264.7 cells and identified prostaglandin A

Prostaglandin (PG) A1 is a metabolic product of cyclooxygenase 2 (COX-2) that is potentially involved in regulating the development and progression of Alzheimer's disease (AD). PGA1 is a cyclopentenone (cy) PG characterized by the presence of a chemically reactive α,β-unsaturated carbonyl. PGA1 is potentially involved in the regulation of multiple biological processes via Michael addition; however, the specific roles of PGA1 in AD remain unclear. TauP301S transgenic (Tg) mice were used as in vivo AD models, and neuroblastoma (N) 2a cells were used as an in vitro neuronal model. The PGA1-binding proteins were identified by HPLC-MS-MS after intracerebroventricular injection (i.c.v) of PGA1. Western blotting was used to determine tau phosphorylation in PGA1-treated Tg mice in the absence or in the presence of okadaic acid (OA), an inhibitor of protein phosphatase (PP) 2A. A combination of pull-down assay, immunoprecipitation, western blotting, and HPLC-MS-MS was used to determine that the PP2A scaffold subunit A alpha (PPP2R1A) is activated by the direct binding of PGA1 to cysteine 377. The effect of inhibiting tau hyperphosphorylation was tested in the Morris maze to determine the inhibitory effects of PGA1 on cognitive decline in tauP301S Tg mice. Incubation with N2a cells, pull-down assay, and mass spectrometry (MS) analysis revealed and indicated that PGA1 binds to more than 1000 proteins; some of these proteins are associated with AD and especially with tauopathies. Moreover, short-term administration of PGA1 in tauP301S Tg mice significantly decreased tau phosphorylation at Thr181, Ser202, and Ser404 in a dose-dependent manner. This effect was caused by the activation of PPP2R1A in tauP301S Tg mice. Importantly, PGA1 can form a Michael adduct with cysteine 377 of PPP2R1A, which is critical for the enzymatic activity of PP2A. Long-term treatment of tauP301S Tg mice with PGA1 activated PP2A and significantly reduced tau phosphorylation resulting in improvements in cognitive decline in tauP301S Tg mice. Our data provided new insight into the mechanisms of the ameliorating effects of PGA1 on cognitive decline in tauP301S Tg mice by activating PP2A via a mechanism involving the formation of a Michael adduct with cysteine 377 of PPP2R1A.

Purpose: Data are presented from ophthalmology clinics in Spain participating in the VISIONARY study, examining the effectiveness, tolerability, and safety of the preservative-free tafluprost (0.0015%) and timolol (0.5%) fixed-dose combination (PF tafluprost/timolol FC) in the treatment of OAG and OHT. Methods: An observational, multicenter prospective study examined treatment outcomes following a switch to PF tafluprost/timolol FC in adult OAG/OHT patients demonstrating insufficient response to beta-blocker or prostaglandin analog (PGA) monotherapy. Primary end point was mean change in intraocular pressure (IOP) from baseline at month 6. Changes in the severity of ocular signs and symptoms were also assessed. Results: Overall, 92 patients (51.1% female) were included. Mean (standard deviation) age was 68.3 (12.1) years. Mean IOP was reduced from 21.9 mmHg at baseline to 16.7 mmHg at month 6 (22.3% decrease; P

The VISIONARY study demonstrated statistically significant intraocular pressure (IOP) reductions with the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% (PF tafluprost/timolol FC) in open-angle glaucoma (OAG) or ocular hypertension (OHT) patients, sub-optimally controlled with topical prostaglandin analogue (PGA) or beta-blocker monotherapy. Current subanalyses have examined these data according to the baseline monotherapy.A European, prospective, observational study included adults (aged ≥ 18 years) with OAG or OHT, who were switched to the PF tafluprost/timolol FC from PGA or beta-blocker monotherapy. Treatment outcomes were reported according to prior monotherapy subgroup: beta-blocker, preserved latanoprost, PF-latanoprost, bimatoprost, tafluprost, and travoprost. Endpoints included the mean change from baseline regarding IOP, conjunctival hyperemia, and corneal fluorescein staining (CFS) at Week 4 and Week 12, and at Month 6.The subanalysis included 577 patients. All prior monotherapy subgroups demonstrated statistically significant IOP reductions from baseline at Week 4, that were maintained through Month 6 (p 0.001). Mean (SD) IOP change at Month 6 was 6.6 (4.16), 6.3 (4.39), 5.6 (3.67), 4.9 (2.97), 4.6 (4.39), and 4.7 (3.64) mmHg for prior beta-blocker, preserved latanoprost, PF-latanoprost, tafluprost, bimatoprost, and travoprost subgroups, respectively. The largest IOP change was observed in the preserved latanoprost subgroup for each of the ≥ 20%, ≥ 25%, ≥ 30%, and ≥ 35% IOP reduction categories at Month 6, demonstrating respective reductions of 8.06, 9.20, 10.64, and 11.55 mmHg. CFS was significantly reduced at Month 6 in the prior bimatoprost subgroup (p = 0.0013). Conjunctival hyperemia severity was significantly reduced at each study visit for prior preserved latanoprost users (p 0.001).PF tafluprost/timolol FC therapy provided statistically and clinically significant IOP reductions from Week 4 over the total 6-month period, in patients with OAG/OHT, regardless of the type of prior PGA or beta-blocker monotherapy used. Conjunctival hyperemia severity and CFS decreased significantly in prior bimatoprost and preserved latanoprost users, respectively.European Union electronic Register of Post-Authorization Studies (EU PAS) register number: EUPAS22204.

Objective The aim of this study was to analyze the usefulness of myeloid-related protein 8/14 (MRP8/14) in the prediction of disease course in a real-world setting for patients with new-onset juvenile idiopathic arthritis (JIA), to identify the relationship between MRP8/14 and disease activity using the physician’s global assessment of disease activity (PGA), and determine whether the MRP8/14 levels measured in serum and plasma are equally useful. Methods In this prospective follow-up study, 87 new-onset non-systemic JIA patients were studied. Blood and synovial fluid samples were collected prior to any antirheumatic medication use. MRP8/14 was measured from serum (S-MRP8/14), plasma (P-MRP8/14), and synovial fluid samples using ELISA. Results The baseline MRP8/14 blood levels were significantly higher in patients using synthetic antirheumatic drugs than in patients with no systemic medications at 1 year after diagnosis in serum (mean 298 vs. 198 ng/ml, P P = 0.001). MRP8/14 levels at the time of JIA diagnosis were higher in patients who started methotrexate during 1.5-year follow-up compared to those who achieved long-lasting inactive disease status without systemic medications (serum: mean 298 vs. 219 ng/ml, P = 0.006 and plasma: 296 vs. 141 ng/ml, P = 0.001). P-MRP8/14 was the most effective predictive variable for disease activity (by PGA) in linear multivariate regression model (combined to ESR, CRP, leukocytes, and neutrophils), whereas S-MRP8/14 was not significant. Conclusion Blood MRP8/14 levels at baseline seem to predict disease course in new-onset JIA patients. P-MRP8/14 might be better than S-MRP8/14 when assessing disease activity at the time of JIA diagnosis.

To evaluate the imaging findings and transitional changes in spacer materials used in carbon-ion radiation therapy MATERIALS: Medical records were retrospectively reviewed, and the maximum thickness, volume, and CT value of spacers were calculated from CT scans. Procedure-related complications were recorded.A spacer was surgically placed in six patients in retroperitoneal, presacral, or peritoneal sites. The spacer material was polyglycolic acid (PGA) in four patients and expanded polytetrafluoroethylene (ePTFE) in two patients. The thickness of PGA spacers showed no changes in any patients within 4 weeks, but increased within 6 weeks in one patient and was unchanged or decreased in the remaining patients. PGA spacer volume decreased gradually after placement in three of four patients; this was observed at 4 months in two patients and at 6 months in one patient. The mean CT value of PGA spacers was 83 HU just after placement, and decreased gradually thereafter. Air was seen in the PGA spacers of two patients. Neither ePTFE spacer showed volume changes over time, and the mean CT value was low (mean, -53.7 HU) just after placement but increased rapidly to 145 HU at 2 months.Spacer imaging findings may vary according to type and may change over time. Familiarity with these features is beneficial for diagnostic radiologists.

The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models. Ministry of Education (MOE) Ministry of Health (MOH) This work was supported by the Ministry of Education Singapore AcRF Tier 2 Grant (MOE2016-T2-2-055) (YHS) and Ministry of Health NMRC-LCG Singapore Parkinson’s disease Translational Clinical Programme (MOH-000207) (LKL).

To compare effects of latanoprost, a topical prostaglandin analogue (PGA) commonly used to treat glaucoma and lens instability in dogs, and latanoprostene bunod, a novel PGA with a nitric oxide-donating moiety, on intraocular pressure (IOP) and pupil diameter (PD).Ten ophthalmologically normal Beagle dogs.Dogs were treated twice a day for 5 days in a randomly selected eye with either latanoprost or latanoprostene bunod. After a 6-week washout period, dogs were treated with the opposite drug. IOP and PD were measured at treatment times, at midday on days 1 and 5, and for 6 days post-treatment.Both drugs significantly decreased IOP and PD. At midday on day 5 of treatment, mean IOP in eyes treated with latanoprost was 4.5 mmHg lower than the fellow eye and 3.0 mmHg lower than the same eye at baseline, while mean IOP in eyes treated with latanoprostene bunod was 5.5 mmHg lower than the fellow eye and 3.6 mmHg lower than baseline. Mean PD was 0.94 mm in eyes treated with latanoprost and 0.76 mmHg in eyes treated with latanoprostene bunod. There was no significant difference between the two drugs for either parameter at that time point (p = .372 and .619, respectively, for IOP relative to control and to baseline; p = .076 for PD) or when analyzed longitudinally. Significant diurnal variation in PD was noted and may have implications for treatment of lens' instability.Latanoprost and latanoprostene bunod produce similar IOP reduction and miosis in normal canine eyes.

Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy.

Introduction: The VISIONARY study demonstrated statistically significant intraocular pressure (IOP) reductions with the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% (PF tafluprost/timolol FC) in open-angle glaucoma (OAG) or ocular hypertension (OHT) patients, sub-optimally controlled with topical prostaglandin analogue (PGA) or beta-blocker monotherapy. Current subanalyses have examined these data according to the baseline monotherapy. Methods: A European, prospective, observational study included adults (aged ≥ 18 years) with OAG or OHT, who were switched to the PF tafluprost/timolol FC from PGA or beta-blocker monotherapy. Treatment outcomes were reported according to prior monotherapy subgroup: beta-blocker, preserved latanoprost, PF-latanoprost, bimatoprost, tafluprost, and travoprost. Endpoints included the mean change from baseline regarding IOP, conjunctival hyperemia, and corneal fluorescein staining (CFS) at Week 4 and Week 12, and at Month 6. Results: The subanalysis included 577 patients. All prior monotherapy subgroups demonstrated statistically significant IOP reductions from baseline at Week 4, that were maintained through Month 6 (p

Psoriasis is a common, chronic immune-mediated systemic disease that had no effective and durable treatment. Mesenchymal stem cells (MSCs) have immunomodulatory properties. Therefore, we performed a phase 1/2a, single-arm clinical trial to evaluate the safety and efficacy of human umbilical cord-derived MSCs (UMSCs) in the treatment of psoriasis and to preliminarily explore the possible mechanisms. Seventeen patients with psoriasis were enrolled and received UMSC infusions. Adverse events, laboratory parameters, PASI, and PGA were analyzed. We did not observe obvious side effects during the treatment and 6-month follow-up. A total of 47.1% (8/17) of the psoriasis patients had at least 40% improvement in the PASI score, and 17.6% (3/17) had no sign of disease or minimal disease based on the PGA score. And the efficiency was 25% (2/8) for males and 66.7% (6/9) for females. After UMSC transplantation (UMSCT), the frequencies of Tregs and CD4+ memory T cells were significantly increased, and the frequencies of T helper (Th) 17 and CD4+ naive T cells were significantly decreased in peripheral blood (PB) of psoriasis patients. And all responders showed significant increases in Tregs and CD4+ memory T cells, and significant decreases in Th17 cells and serum IL-17 level after UMSCT. And baseline level of Tregs in responders were significantly lower than those in nonresponders. In conclusion, allogeneic UMSCT is safe and partially effective in psoriasis patients, and level of Tregs may be used as a potent biomarker to predict the clinical efficacy of UMSCT. Trial registration Clinical Trials NCT03765957

Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI).Structural and resting-state functional MRI data were acquired from patients with IA, patients with osteoarthritis (OA) and heathy controls (HCs). Two datasets were adopted to derive (51 IA, 56 OA, and 17 HCs) and validate (31 IA) the observations. 33 IA patients in the derivation dataset and all the patients in validation dataset required biological treatment and were clinically evaluated before and after therapy. Via whole-brain pair-wise FC analyses, we analyzed IA-specific FC measures relevant to therapeutic response to biologics.The value of FC between left insular cortex (IC) and anterior cingulate cortex (ACC) was significantly low in IA patients compared with OA patients and HCs. We demonstrated that the FC between left anterior long insular gyrus as a subdivision of IC and ACC was significantly associated with therapeutic response to biologics regarding the improvement of patients' global assessment (PGA) in both derivation and validation datasets.Disease-specific resting-state FC provides a means to assess the therapeutic improvement of PGA and would be a clinical decision-making tool with predictability for treatment response in both RA and SpA.

The study demonstrated the fabrication of new poly(glycerol adipate) (PGA) nanoparticles decorated with folic acid (FOL-PGA) and triphenylphosphonium (TPP-PGA) and the potential on the delivery of acetogenin-enriched Annona muricata Linn leaf extract to ovarian cancer cells. FOL-PGA and TPP-PGA were successfully synthesized and used to fabricate FOL-decorated nanoparticles (FOL-NPs) and FOL-/TPP- decorated nanoparticles (FOL/TPP-NPs) by blending two polymers at a mass ratio of 1:1. All nanoparticles had small size of around 100 nm, narrow size distribution and high negative surface charge about -30 mV. The stable FOL/TPP-NPs showed highest drug loading of 14.9 ± 1.9% at 1:5 ratio of extract to polymer and reached to 35.8 ± 2.1% at higher ratio. Both nanoparticles released the extract in a biphasic sustained release manner over 5 days. The toxicity of the extract to SKOV3 cells was potentiated by FOL-NPs and FOL/TPP-NPs by 2.0 - 2.6 fold through induction of cell apoptosis. FOL/TPP-NPs showed lower IC

Polygalacturonic acid (PGA), being the backbone of pectins, governs their aggregation that is widely applied in industry. The PGA aggregation was studied by dynamic and static light scattering within a limited space of sodium polygalacturonate nanoparticles obtained by nanoprecipitation (drop-wise addition of alkaline solution of PGA to an ethanol bath). With increasing buffer's pH from 4.0 to 9.1, the colloids changed their form from elongated to spherical one, as indicated by decreasing the structure-sensitive ratio R

Penicillin G acylase (PGA) from Escherichia coli was immobilized on vinyl sulfone (VS) agarose. The immobilization of the enzyme failed at all pH values using 50 mM of buffer, while the progressive increase of ionic strength permitted its rapid immobilization under all studied pH values. This suggests that the moderate hydrophobicity of VS groups is enough to transform the VS-agarose in a heterofunctional support, that is, a support bearing hydrophobic features (able to adsorb the proteins) and chemical reactivity (able to give covalent bonds). Once PGA was immobilized on this support, the PGA immobilization on VS-agarose was optimized with the purpose of obtaining a stable and active biocatalyst, optimizing the immobilization, incubation and blocking steps characteristics of this immobilization protocol. Optimal conditions were immobilization in 1 M of sodium sulfate at pH 7.0, incubation at pH 10.0 for 3 h in the presence of glycerol and phenyl acetic acid, and final blocking with glycine or ethanolamine. This produced biocatalysts with stabilities similar to that of the glyoxyl-PGA (the most stable biocatalyst of this enzyme described in literature), although presenting just over 55% of the initially offered enzyme activity versus the 80% that is recovered using the glyoxyl-PGA. This heterofuncionality of agarose VS beads opens new possibilities for enzyme immobilization on this support.

NPC transplantation; Cell priming; Human fetal neural precursor Trasplante de NPC; Cebado celular; Precursor neuronal fetal humano Trasplantament de NPC; Cebament cel·lular; Precursor neuronal fetal humà Neural precursor cell (NPC) transplantation represents a promising therapy for treating spinal cord injuries (SCIs); however, despite successful results obtained in preclinical models, the clinical translation of this approach remains challenging due, in part, to the lack of consensus on an optimal cell source for human neuronal cells. Depending on the cell source, additional limitations to NPC-based therapies include high tumorigenic potential, alongside poor graft survival and engraftment into host spinal tissue. We previously demonstrated that NPCs derived from rat fetal spinal cords primed with a polyglutamate (PGA)-conjugated form of the Rho/Rock inhibitor fasudil (PGA-SS-FAS) displayed enhanced neuronal differentiation and graft survival when compared to non-primed NPCs. We now conducted a similar study of human-fetal-spinal-cord-derived NPCs (hfNPCs) from legal gestational interruptions at the late gestational stage, at 19–21.6 weeks. In vitro, expanded hfNPCs retained neural features, multipotency, and self-renewal, which supported the development of a cell banking strategy. Before transplantation, we established a simple procedure to prime hfNPCs by overnight incubation with PGA-SS-FAS (at 50 μM FAS equiv.), which improved neuronal differentiation and overcame neurite-like retraction after lysophosphatidic-acid-induced Rho/Rock activation. The transplantation of primed hfNPCs into immune-deficient mice (NU(NCr)-Foxn1nu) immediately after the eighth thoracic segment compression prompted enhanced migration of grafted cells from the dorsal to the ventral spinal cord, increased preservation of GABAergic inhibitory Lbx1-expressing and glutamatergic excitatory Tlx3-expressing somatosensory interneurons, and elevated the numbers of preserved, c-Fos-expressing, activated neurons surrounding the injury epicenter, all in a low percentage. Overall, the priming procedure using PGA-SS-FAS could represent an alternative methodology to improve the capabilities of the hfNPC lines for a translational approach for acute SCI treatment. This research was funded by Fundació Marató TV3 2017/refs.20172230, 20172231, Agencia Valenciana de Innovación (AVI) (INNVAL10/19/047 and Grants RTI2018-095872-B-C21 and PDI2021-1243590B-I00/ERDF funded by MCIN/AEI//10.13039/501100011033 and by ERDF A way of making Europe). This project was also funded by Project 964562 (RISEUP), H2020 FetOpen program.