A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

Formulation, Characterization and In Vitro Evaluation of Mesalamine and Bifidobacterium bifidum Loaded Hydrogel Beads in Capsule System for Colon Targeted Delivery.

Mesalamine is a first-line drug for the treatment of inflammatory bowel diseases. However, its premature release associated with marketed formulations leads to adverse effects like gastric trouble, vomiting, and diarrhoea. To minimize these side effects, colon-targeted drug delivery is essential. Besides conventional pharmacotherapy, bifidogenic probiotics with anti-inflammatory activity has been reported to elicit a significant impact on the remission of ulcerative colitis. Bifidogenic probiotics being acid-labile necessitate developing a gastro-resistant formulation for enhancing the delivery of viable cells to the colon. The present study was aimed at developing a fixed-dose unit dosage form of mucoadhesive hydrogel beads loaded with mesalamine and Bifidobacterium bifidum further encapsulated in Eudragit® capsules for the targeted drug delivery at colonic pH. The hydrogel beads were prepared by ionotropic gelation, with the effect of single and dual-crosslinking approaches on various formulation characteristics studied. Standard size 00 Eudragit® gastro-resistant capsules were prepared and the dried beads were filled inside the capsule shells. The formulation was then evaluated for various parameters, including physicochemical characterization, in vitro biocompatibility and anti-inflammatory activity. No interaction was observed between the drug and the polymers, as confirmed through FTIR, XRD, and DSC analysis. The mean particle size of the beads was ~ 457-485 µm. The optimized formulation showed a drug entrapment efficiency of 95.4 ± 2.58%. The Eudragit® capsule shells disintegrated in approximately 13 min at pH 7.4. The mucoadhesive hydrogel beads sustained the drug release above 18 h, with 50% of the drug released by the end of 12 h. The optimized formulation demonstrated significant (p < 0.05) gastro-resistance, biocompatibility, sustained drug release, cell viability, and anti-inflammatory activity.

Effect of Root Canal Taper on the Ability of Endodontically Treated Teeth using the TruNatomy and Protaper Next File Systems to Resist Fracture.

Objectives: This research was done to evaluate how the root canal taper affects the Endodontically Treated Teeth (ETT) prepared with the TruNatomy and Protaper Next file systems in terms of fracture resistance. Materials and Method: Forty recently extracted mandibular premolar teeth were used in this research, which was classified into four groups at random. Groups 1a and 1b used TruNatomy 4% and 6%, respectively, while groups 2a and 2b used the Protaper Next 4% and 6% file systems, respectively. The root canals were cleaned, shaped, and sealed using cold lateral compaction. The root canals were then fixed in standardized autopolymerizing acrylic resin blocks and tested for vertical root fracture using a universal testing machine. Newtons were used to measure the forces needed to cause fractures. Data were statistically analyzed. Results: In comparison with other groups, group 1a (TruNatomy 4%) displayed greater fracture resistance (423.322.43 Newtons), and group 2b (Protaper Next 6%) displayed the least fracture resistance (264.512.76 Newtons). Conclusion: Protaper Next file system had lower fracture resistance than TruNatomy file system. With the use of greater taper instruments, a notable decrease in the fracture resistance of ETT was observed.

Assessment of the Apical Transportation and Quantity of Root Canal Dentin Removed Using Different New Rotary File Systems: An Original Study.

Introduction: The rotary systems have found a common application in the clinical practice for the endodontic therapies. Hence, we compared three recent endodontic systems for the comparison of the dentine removal and the apical transportation particularly in the curved canals. Methods: Oneshape, Pro Taper Next, and Edgefile X3 were the three systems that were compared. Thirty maxillary mesio buccal canals of the human permanent teeth were compared due to its curved nature. The volume of dentin removed and apical transportation (mm) were measured using micro-computed tomographic imaging (mm). Both the coronal section and the entire canal length had their dentin removed in accordance with measurements. Total dentine removed, coronal dentine removed, and the canal transportations were compared for the three rotary file systems. The values were compared with appropriate statistical tests for evaluating the significance. Results: There was no statistically significant difference between the three file systems for the dentin removed. The mean canal transportation was 0.33 ± 0.12, 0.21 ± 0.25, and 0.23 ± 0.21 mm, respectively, for Oneshape, Pro Taper Next, and Typhoon CM. In terms of statistics, there were no appreciable variations among the three rotary tools for apical transfer. Conclusions: The three rotary systems were comparable for the apical transportation and the dentine removal. Despite variations in the magnitude of apical enlargements, none of the instrumentation methods detected apical transportation.

Are we moving from symptomatic to asymptomatic syphilis: A retrospective analysis.

Background: Syphilis remains a global health problem with recent reports of resurgence from various parts of the world. We undertook this study to analyze the current epidemiological and clinical trends of syphilis in our part of the country. Aim and Objectives: To analyze the changing trends in clinical presentation of syphilis and the current status of HIV/AIDS-syphilis co-infection in our area. Materials and Methods: This is a hospital-based retrospective analysis of records of sexually transmitted disease (STD) patients enrolled in "Suraksha clinic" in the department of Skin and VD at a Tertiary Care Hospital in North India. Patient records were analyzed from January 2018 to December 2021. The demographic, clinical, and serological profiles of patients were assessed to study the percentage of syphilis patients attending the STD clinic and their clinical presentations. Results: A total of 7153 patients were enrolled in the"Suraksha clinic" from January 2018 to December 2021, these included the venereal disease patients (3137) and nonvenereal disease patients (4016) who were registered for HIV and venereal disease research laboratory (VDRL) screening from the dermatology outpatient department. Out of 3137 sexually transmitted infection (STI) patients, 139 patients tested positive for VDRL. Treponema pallidum hemagglutination was found positive in 137 patients and negative in two patients. Hence, 137 patients were confirmed syphilis cases, constituting 4.36% of total STD cases in our STI clinic in 4 years. Out of 137 patients, 2 (1.45%) presented with primary chancre, 6 (4.37%) with lesions of secondary syphilis and 129 (94.16%) were found serologically reactive without any symptoms or clinical signs, i.e., in latent syphilis. Our records also showed 14 (10.21%) cases of HIV and syphilis co-infection. Conclusion: In our study, a remarkable rise in the number of patients in the latent syphilis stage is observed over primary and secondary syphilis stage. This signifies the persistence of syphilis in subclinical phase in the community and unfortunately, it goes unnoticed. These could be "warning signs" for changing disease pattern of syphilis in India and points toward hidden resurgence of syphilis as being reported in various parts of the world. To actively look for these "hidden cases," there is a need to strengthen "Suraksha clinics." VDRL testing should be mandatory along with routine testing in all patients visiting the hospital irrespective of their disease. We also propose for the central registration of syphilis patients on lines of HIV-infected patients' registry.

A Ribbon Model for Nematic Polymer Networks.

We present a theory of deformation of ribbons made of nematic polymer networks (NPNs). These materials exhibit properties of rubber and nematic liquid crystals, and can be activated by external stimuli of heat and light. A two-dimensional energy for a sheet of such a material has already been derived from the celebrated neo-classical energy of nematic elastomers in three space dimensions. Here, we use a dimension reduction method to obtain the appropriate energy for a ribbon from the aforementioned sheet energy. We also present an illustrative example of a rectangular NPN ribbon that undergoes in-plane serpentine deformations upon activation under an appropriate set of boundary conditions.

A technical guide to TRITEX, a computational pipeline for chromosome-scale sequence assembly of plant genomes.

BACKGROUND: As complete and accurate genome sequences are becoming easier to obtain, more researchers wish to get one or more of them to support their research endeavors. Reliable and well-documented sequence assembly workflows find use in reference or pangenome projects. RESULTS: We describe modifications to the TRITEX genome assembly workflow motivated by the rise of fast and easy long-read contig assembly of inbred plant genomes and the routine deployment of the toolchains in pangenome projects. New features include the use as surrogates of or complements to dense genetic maps and the introduction of user-editable tables to make the curation of contig placements easier and more intuitive. CONCLUSION: Even maximally contiguous sequence assemblies of the telomere-to-telomere sort, and to a yet greater extent, the fragmented kind require validation, correction, and comparison to reference standards. As pangenomics is burgeoning, these tasks are bound to become more widespread and TRITEX is one tool to get them done. This technical guide is supported by a step-by-step computational tutorial accessible under https://tritexassembly.bitbucket.io/ . The TRITEX source code is hosted under this URL: https://bitbucket.org/tritexassembly .

Planar Equilibria of an Elastic Rod Wrapped Around a Circular Capstan.

We present a study on planar equilibria of a terminally loaded elastic rod wrapped around a rigid circular capstan. Both frictionless and frictional contact between the rod and the capstan are considered. We identify three cases of frictionless contact - namely where the rod touches the capstan at one point, along a continuous arc, and at two points. We show that, in contrast to a fully flexible filament, an elastic rod of finite length wrapped around a capstan does not require friction to support unequal loads at its two ends. Furthermore, we classify rod equilibria corresponding to the three aforementioned cases in a limit where the length of the rod is much larger than the radius of the capstan. In the same limit, we incorporate frictional interaction between the rod and the capstan, and compute limiting equilibria of the rod. Our solution to the frictional case fully generalizes the classic capstan problem to include the effects of finite thickness and bending elasticity of a flexible filament wrapped around a circular capstan. Supplementary Information: The online version contains supplementary material available at 10.1007/s10659-022-09939-8.

Assessment of Effect of Fixed Orthodontic Treatment on Gingival Health: An Observational Study.

BACKGROUND: Prime components of fixed orthodontic treatments decrease the self-cleansing ability of the tongue and the cheeks leading to an increase in production of bacterial plaque. Hence, the present study was undertaken for assessing the effect of fixed orthodontic treatment on gingival health. MATERIALS AND METHODS: A total of 120 patients who were scheduled orthodontic treatment were enrolled. Complete data records of all the patients were recorded. Intra- and extraoral radiographs were obtained and photographic records were noted in separate pro forma. Complete intraoral examination of all the patients was carried out for recording visible plaque, any inflammation (visible clinically), and gingival recession. Based on the assessment of gingival texture and capillary transparency, analysis of gingival biotype was done. Follow-up records were assessed. RESULTS: The mean visible plaque value before treatment and after treatment was found to be 3.11 and 5.81, respectively. The mean visible inflammation value before treatment and after treatment was found to be 2.89 and 15.43, respectively. The mean gingival recession score value before treatment and after treatment was found to be 0.19 and 0.383, respectively. A significant increase in the visible plaque value, visible inflammation value, and gingival recession score was observed posttreatment. While comparing the gingival biotype, it was seen that in both the maxillary and mandibular arches, there was an increase in the thick gingival biotype while there was a decrease in thin maxillary biotype. CONCLUSION: There is a significant increase in plaque accumulation, inflammation, and gingival recession following fixed orthodontic treatment. Hence, during the course of orthodontic treatment, regular oral prophylaxis should be done.

Cellulosic Nanowhiskers: Preparation and Drug Delivery Application.

Nanomaterials have applications in almost every field and among them, green nanomaterials have various biological applications. Green nanomaterials are specifically useful for drug and DNA delivery applications. Considering that cellulose is the most abundant and easily available biomolecule, it has been used for preparing greener cellulose nanomaterials. Cellulosic nanowhiskers are a cost-effective and green alternative to chemical non-viral gene delivery systems. Cellulose nanowhiskers are commonly extracted from plant sources, and they are generally prepared by sulfuric and hydrochloric acid hydrolysis of plant cellulose. In this review, the topic of cellulose nanowhiskers as green biocompatible materials for gene and drug delivery is discussed with several practical examples.

Mechanics of two filaments in tight orthogonal contact.

Networks of flexible filaments often involve regions of tight contact. Predictively understanding the equilibrium configurations of these systems is challenging due to intricate couplings between topology, geometry, large nonlinear deformations, and friction. Here, we perform an in-depth study of a simple, yet canonical, problem that captures the essence of contact between filaments. In the orthogonal clasp, two filaments are brought into contact, with each centerline lying in one of a pair of orthogonal planes. Our data from X-ray tomography (µCT) and mechanical testing experiments are in excellent agreement with finite element method (FEM) simulations. Despite the apparent simplicity of the physical system, the data exhibit strikingly unintuitive behavior, even when the contact is frictionless. Specifically, we observe a curvilinear diamond-shaped ridge in the contact-pressure field between the two filaments, sometimes with an inner gap. When a relative displacement is imposed between the filaments, friction is activated, and a highly asymmetric pressure field develops. These findings contrast to the classic capstan analysis of a single filament wrapped around a rigid body. Both the µCT and FEM data indicate that the cross-sections of the filaments can deform significantly. Nonetheless, an idealized geometrical theory assuming undeformable tube cross-sections and neglecting elasticity rationalizes our observations qualitatively and highlights the central role of the small, but nonzero, tube radius of the filaments. We believe that our orthogonal clasp analysis provides a building block for future modeling efforts in frictional contact mechanics of more complex filamentary structures.

Adhesion of a tape loop.

In this work, we revisit experimentally and theoretically the mechanics of a tape loop. Using primarily elastic materials (polydimethylsiloxane, PDMS, or polycarbonate, PC) and confocal microscopy, we monitor the shape as well as the applied forces during an entire cycle of compression and retraction of a half-loop compressed between parallel glass plates. We observe distinct differences in film shape during the cycle; points of equal applied force or equal plate separation differ in shape upon compression or retraction. To model the adhesion cycle in its entirety, we adapt the 'Sticky Elastica' of [T. J. W. Wagner et al., Soft Matter, 2013, 9, 1025-1030] to the tape loop geometry, which allows a complete analytical description of both the force balance and the film shape. We show that under compression the system is generally not sensitive to interfacial interactions, whereas in the limit of large separation of the confining parallel plates during retraction the system is well described by the peel model. Ultimately, we apply this understanding to the measurement of the energy release rate of a wide range of different cross-linker ratio PDMS elastomer half-loops in contact with glass. Finally, we show how the model illuminates an incredibly simple adhesion measurement technique, which only requires a ruler to perform.

Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia.

In preeclampsia, widespread maternal endothelial dysfunction is often secondary to excessive generation of placental-derived anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and activin A, understanding of which offers potential opportunities for the development of novel therapies. The antimalarial hydroxychloroquine is an anti-inflammatory drug improving endothelial homeostasis in lupus. It has not been explored as to whether it can improve placental and endothelial function in preeclampsia. In this in vitro study, term placental explants were used to assess the effects of hydroxychloroquine on placental production of sFlt-1, sEng, TNF-α, activin A, and 8-isoprostane after exposure to hypoxic injury or oxidative stress. Similarly, human umbilical vein endothelial cells (HUVECs) were used to assess the effects of hydroxychloroquine on in vitro markers of endothelial dysfunction. Hydroxychloroquine had no effect on the release of sFlt-1, sEng, TNF-α, activin A, or 8-isoprostane from placental explants exposed to hypoxic injury or oxidative stress. However, hydroxychloroquine mitigated TNF-α-induced HUVEC production of 8-isoprostane and Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase expression. Hydroxychloroquine also mitigated TNF-α and preeclamptic serum-induced HUVEC monolayer permeability and rescued the loss of zona occludens protein zona occludens 1 (ZO-1). Although hydroxychloroquine had no apparent effects on trophoblast function, it may be a useful endothelial protectant in women presenting with preeclampsia.

Fluorescence Quenching of Dipyrenylalkanes by an Electron/Charge Acceptor.

Compounds possessing two fluorophoric moieties may exhibit dual fluorescence, one characterizing the monomeric fluorophore unit and the other characterizing the intramolecular aggregate. Fluorescence quenching of two dipyrenylalkanes, 1,3-bis(1-pyrenyl)propane [1Py(3)1Py] and 1,10-bis(1-pyrenyl)decane [1Py(10)1Py] having different alkyl chains separating the two termini pyrenyl groups that are capable of forming an intramolecular excimer, by an electron/charge-accepting quencher, nitromethane, is investigated in four different solvents-nonpolar (cyclohexane (CH)), polar-aprotic (acetonitrile (ACN)), polar-protic (ethanol (EtOH)), and chlorinated (dichloromethane (DCM))-under ambient conditions. For a given probe in a solvent, fluorescence from the monomer and the intramolecular excimer are quenched with similar efficiencies; the efficiency of quenching is higher for the probe with the longer alkyl chain separating the two fluorophores. Quenching efficiency is significantly higher in chlorinated solvent DCM. The bimolecular quenching rate constants for intramolecular excimer, however, are either comparable or lower for the longer alkyl chain compound. It is suggested that, while the donor electronic excited-state energetics is more favorable for the long alkyl chain compound, the approach of the quencher to the intramolecular excimer appears to be hindered by the presence of a longer alkyl chain.

Effects of incorporation of groundnut oil and hydrogenated fat on pasting and dough rheological properties of flours from wheat varieties.

The effects of incorporation of groundnut oil (GO) and hydrogenated fat (HF) at different levels (1%, 3% and 5%) on pasting, dough rheology and mixing properties of strong wheat flour (SWF) and weak wheat flour (WWF) were evaluated. SWF showed higher paste viscosities as compared to WWF. However, higher setback viscosity for SWF than WWF was observed. Paste viscosity and mixograph peak time of both flours decreased with an increase in level of GO and HF. Pasting temperature of both flours decreased with an increase in GO. Storage modulus (G') was higher than loss modulus (G″) for dough from both SWF and WWF. G' increased while G″ decreased with an increase in levels of GO and HF. Dough prepared from SWF needed longer time for mixing and showed wider peak width, indicating strong and stable dough as compared to WWF. Addition of GO up to 3% level progressively decreased dough consistency and mixing tolerance and further addition led to an increase in both properties. Contrarily, addition of HF showed opposite effect in WWF. Both GO and HF showed variables effects towards mixing in both flour types. Dough tolerance and breakdown during mixing improved with increase in GO while adversely affected with increase in HF.

Humans adjust their grip force when passing an object according to the observed speed of the partner's reaching out movement.

The way an object is released by the passer to a partner is fundamental for the success of the handover and for the experienced fluency and quality of the interaction. Nonetheless, although its apparent simplicity, object handover involves a complex combination of predictive and reactive control mechanisms that were not fully investigated so far. Here, we show that passers use visual-feedback based anticipatory control to trigger the beginning of the release, to launch the appropriate motor program, and adapt such predictions to different speeds of the receiver's reaching out movements. In particular, the passer starts releasing the object in synchrony with the collision with the receiver, regardless of the receiver's speed, but the passer's speed of grip force release is correlated with receiver speed. When visual feedback is removed, the beginning of the passer's release is delayed proportionally with the receiver's reaching out speed; however, the correlation between the passer's peak rate of change of grip force is maintained. In a second study with 11 participants receiving an object from a robotic hand programmed to release following stereotypical biomimetic profiles, we found that handovers are experienced as more fluent when they exhibit more reactive release behaviours, shorter release durations, and shorter handover durations. The outcomes from the two studies contribute understanding of the roles of sensory input in the strategy that empower humans to perform smooth and safe handovers, and they suggest methods for programming controllers that would enable artificial hands to hand over objects with humans in an easy, natural and efficient way.

Formyl peptide receptor-2 is decreased in foetal growth restriction and contributes to placental dysfunction.

STUDY QUESTION: What is the association between placental formyl peptide receptor 2 (FPR2) and trophoblast and endothelial functions in pregnancies affected by foetal growth restriction (FGR)? SUMMARY ANSWER: Reduced FPR2 placental expression in idiopathic FGR results in significantly altered trophoblast differentiation and endothelial function in vitro. WHAT IS KNOWN ALREADY: FGR is associated with placental insufficiency, where defective trophoblast and endothelial functions contribute to reduced feto-placental growth. STUDY DESIGN, SIZE, DURATION: The expression of FPR2 in placental tissues from human pregnancies complicated with FGR was compared to that in gestation-matched uncomplicated control pregnancies (n = 25 from each group). Fpr2 expression was also determined in placental tissues obtained from a murine model of FGR (n = 4). The functional role of FPR2 in primary trophoblasts and endothelial cells in vitro was assessed in diverse assays in a time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placentae from third-trimester pregnancies complicated by idiopathic FGR (n = 25) and those from gestation-matched pregnancies with appropriately grown infants as controls (n = 25) were collected at gestation 27-40 weeks. Placental tissues were also collected from a spontaneous CBA/CaH × DBA/2 J murine model of FGR. Placental FPR2/Fpr2 mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence FPR2 expression in primary trophoblasts and in human umbilical vein endothelial cells (HUVEC), and the quantitation of cytokines, chemokines and apoptosis was performed following a cDNA array analyses. Functional effects of trophoblast differentiation were measured using HCGB/ß-hCG and syncytin-2 expression as well as markers of apoptosis, tumour protein 53 (TP53), caspase 8, B cell lymphoma 2 (BCL2) and BCL associated X (BAX). Endothelial function was assessed by proliferation, network formation and permeability assays. MAIN RESULTS AND THE ROLE OF CHANCE: Placental FPR2/Fpr2 expression was significantly decreased in FGR placentae (n = 25, P < 0.05) as well as in murine FGR placentae compared to controls (n = 4, P < 0.05). FPR2 siRNA (siFPR2) in term trophoblasts significantly increased differentiation markers, HCGB and syncytin-2; cytokines, interleukin (IL)-6, CXCL8; and apoptotic markers, TP53, caspase 8 and BAX, but significantly reduced the expression of the chemokines CXCL12 and its receptors CXCR4 and CXCR7; CXCL16 and its receptor, CXCR6; and cytokine, IL-10, compared with control siRNA (siCONT). Treatment of HUVECs with siFPR2 significantly reduced proliferation and endothelial tube formation, but significantly increased permeability of HUVECs. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Reduced expression of placental FPR2/Fpr2 was observed in the third trimester at delivery after development of FGR, suggesting that FPR2 is associated with FGR pregnancies. However, there is a possibility that the decreased placental FPR2 observed in FGR may be a consequence rather than a cause of FGR, although our in vitro functional analyses using primary trophoblasts and endothelial cells suggest that FPR2 may have a direct or indirect regulatory role on trophoblast differentiation and endothelial function in FGR. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study linking placental FPR2 expression with changes in the trophoblast and endothelial functions that may explain the placental insufficiency observed in FGR. STUDY FUNDING/COMPETING INTERESTS: P.M. and P.R.E. received funding from the Australian Institute of Musculoskeletal Science, Western Health, St. Albans, Victoria 3021, Australia. M.L. is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; Grant no. 1047025). Monash Health is supported by the Victorian Government's Operational Infrastructure Support Programme. The authors declare that there is no conflict of interest in publishing this work.

Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2.

INTRODUCTION: Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation. METHOD: We used in vitro term placental explants to assess the effects of resveratrol on placental oxidative stress and production of sFlt1, sEng and activin A. Using human umbilical vein endothelial cells we investigated the effects of resveratrol on markers of in vitro endothelial dysfunction, including the expression of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin and endothelin-1, and endothelial permeability. To confirm that resveratrol mediated its effects via Nrf2, we examined the impact of resveratrol on the same in vitro markers of endothelial and placental dysfunction following Nrf2 knockdown. RESULTS: Resveratrol significantly decreased placental oxidative stress and the production of sFlt1 and activin A. Resveratrol significantly mitigated tumor necrosis factor-α stimulated endothelial expression of ICAM1, VCAM1, E-selectin and endothelin-1 and prevented an increase in endothelial monolayer permeability. Nrf2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells. CONCLUSION: Features of placental and endothelial dysfunction characteristic of preeclampsia are improved by resveratrol in vitro, partially via the modulation of Nrf2.