Microglia-dependent neuroprotective effects of 4-octyl itaconate against rotenone-and MPP+-induced neurotoxicity in Parkinson's disease.

Chronic neuroinflammation is implicated in the pathogenesis of Parkinson's disease (PD), one of the most common neurodegenerative diseases. Itaconate, an endogenous metabolite derived from the tricarboxylic acid cycle via immune-responsive gene 1 activity, may mediate anti-inflammatory responses by activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway. This study investigates the neuroprotective potential of 4-octyl itaconate (OI), a cell-permeable derivative of itaconate, in cellular models of PD. OI not only suppressed lipopolysaccharide-induced proinflammatory cascades of inducible nitric oxide synthase, cyclooxygenase-2, and cytokines release in mouse BV2 microglial cells but also activated the Nrf2 signaling pathway and its downstream targets in these cells. Conditioned medium derived from OI-treated BV2 cells protected against rotenone- and MPP+-induced neurotoxicity in Neuro 2A cells. Overall, our findings support the anti-inflammatory neuroprotective potential of OI in PD.

Direct Comparison of Three Buckling-Based Methods to Measure the Elastic Modulus of Nanobiocomposite Thin Films.

To engineer tunable thin-film materials, the accurate measurement of their mechanical properties is crucial. However, characterizing the elastic modulus with current methods is particularly challenging for sub-micrometer thick films and hygroscopic materials because they are highly sensitive to environmental conditions and most methods require free-standing films which are difficult to prepare. In this work, we directly compared three buckling-based methods to determine the elastic moduli of supported thin films: (1) biaxial thermal shrinking, (2) uniaxial thermal shrinking, and (3) the mechanically compressed, strain-induced elastic buckling instability for mechanical measurements (SIEBIMM) method. Nanobiocomposite model films composed of cellulose nanocrystals (CNCs) and polyethyleneimine (PEI) were assembled using layer-by-layer deposition to control composition and thickness. The three buckling-based methods yielded the same trends and comparable values for the elastic moduli of each CNC-PEI film composition (ranging from 15 to 44 GPa, depending on film composition). This suggests that the methods are similarly effective for the quantification of thin-film mechanical properties. Increasing the CNC content in the films statistically increased the modulus; however, increasing the PEI content did not lead to significant changes. For the CNC-PEI system, the standard deviation of elastic moduli determined from SIEBIMM was 2-4 times larger than that for thermal shrinking, likely due to extensive cracking due to the different stress applied to the film when subjected to compression of a relaxed substrate versus the shrinking of a pre-strained substrate. These results show that biaxial thermal shrinking is a reliable method for the determination of the mechanical properties of thin films with a simple implementation and analysis and low sensitivity to small deviations in the input parameter values, such as film thickness or substrate modulus.

Multi-scale structuring of cell-instructive cellulose nanocrystal composite hydrogel sheets via sequential electrospinning and thermal wrinkling.

Structured hydrogel sheets offer the potential to mimic the mechanics and morphology of native cell environments in vitro; however, controlling the morphology of such sheets across multiple length scales to give cells consistent multi-dimensional cues remains challenging. Here, we demonstrate a simple two-step process based on sequential electrospinning and thermal wrinkling to create nanocomposite poly(oligoethylene glycol methacrylate)/cellulose nanocrystal hydrogel sheets with a highly tunable multi-scale wrinkled (micro) and fibrous (nano) morphology. By varying the time of electrospinning, rotation speed of the collector, and geometry of the thermal wrinkling process, the hydrogel nanofiber density, fiber alignment, and wrinkle geometry (biaxial or uniaxial) can be independently controlled. Adhered C2C12 mouse myoblast muscle cells display a random orientation on biaxially wrinkled sheets but an extended morphology (directed preferentially along the wrinkles) on uniaxially wrinkled sheets. While the nanofiber orientation had a smaller effect on cell alignment, parallel nanofibers promoted improved cell alignment along the wrinkle direction while perpendicular nanofibers disrupted alignment. The highly tunable structures demonstrated are some of the most complex morphologies engineered into hydrogels to-date without requiring intensive micro/nanofabrication approaches and offer the potential to precisely regulate cell-substrate interactions in a "2.5D" environment (i.e. a surface with both micro- and nano-structured topographies) for in vitro cell screening or in vivo tissue regeneration. STATEMENT OF SIGNIFICANCE: While structured hydrogels can mimic the morphology of natural tissues, controlling this morphology over multiple length scales remains challenging. Furthermore, the incorporation of secondary morphologies within individual hydrogels via simple manufacturing techniques would represent a significant advancement in the field of structured biomaterials and an opportunity to study complex cell-biomaterial interactions. Herein, we leverage a two-step process based on electrospinning and thermal wrinkling to prepare structured hydrogels with microscale wrinkles and nanoscale fibers. Fiber orientation/density and wrinkle geometry can be independently controlled during the electrospinning and thermal wrinkling processes respectively, demonstrating the flexibility of this technique for creating well-defined multiscale hydrogel structures. Finally, we show that while wrinkle geometry is the major determinant of cell alignment, nanofiber orientation also plays a role in this process.

Bioinspired Thermoresponsive Xyloglucan-Cellulose Nanocrystal Hydrogels.

Thermoresponsive hydrogels present unique properties, such as tunable mechanical performance or changes in volume, which make them attractive for applications including wound healing dressings, drug delivery vehicles, and implants, among others. This work reports the implementation of bioinspired thermoresponsive hydrogels composed of xyloglucan (XG) and cellulose nanocrystals (CNCs). Starting from tamarind seed XG (XGt), thermoresponsive XG was obtained by enzymatic degalactosylation (DG-XG), which reduced the galactose residue content by ∼50% and imparted a reversible thermal transition. XG with native composition and comparable molar mass to DG-XG was produced by an ultrasonication treatment (XGu) for a direct comparison of behavior. The hydrogels were prepared by simple mixing of DG-XG or XGu with CNCs in water. Phase diagrams were established to identify the ratios of DG-XG or XGu to CNCs that yielded a viscous liquid, a phase-separated mixture, a simple gel, or a thermoresponsive gel. Gelation occurred at a DG-XG or XGu to CNC ratio higher than that needed for the full surface coverage of CNCs and required relatively high overall concentrations of both components (tested concentrations up to 20 g/L XG and 30 g/L CNCs). This is likely a result of the increase in effective hydrodynamic volume of CNCs due to the formation of XG-CNC complexes. Investigation of the adsorption behavior indicated that DG-XG formed a more rigid layer on CNCs compared to XGu. Rheological properties of the hydrogels were characterized, and a reversible thermal transition was found for DG-XG/CNC gels at 35 °C. This thermoresponsive behavior provides opportunities to apply this system widely, especially in the biomedical field, where the mechanical properties could be further tuned by adjusting the CNC content.

Xyloglucan Structure Impacts the Mechanical Properties of Xyloglucan-Cellulose Nanocrystal Layered Films-A Buckling-Based Study.

Interactions between polysaccharides, specifically between cellulose and hemicelluloses like xyloglucan (XG), govern the mechanical properties of the plant cell wall. This work aims to understand how XG molecular weight (MW) and the removal of saccharide residues impact the elastic modulus of XG-cellulose materials. Layered sub-micrometer-thick films of cellulose nanocrystals (CNCs) and XG were employed to mimic the structure of the plant cell wall and contained either (1) unmodified XG, (2) low MW XG produced by ultrasonication (USXG), or (3) XG with a reduced degree of galactosylation (DGXG). Their mechanical properties were characterized through thermal shrinking-induced buckling. Elastic moduli of 19 ± 2, 27 ± 1, and 75 ± 6 GPa were determined for XG-CNC, USXG-CNC, and DGXG-CNC films, respectively. The conformation of XG adsorbed on CNCs is influenced by MW, which impacts mechanical properties. To a greater degree, partial degalactosylation, which is known to increase XG self-association and binding capacity of XG to cellulose, increases the modulus by fourfold for DGXG-CNC films compared to XG-CNC. Films were also buckled while fully hydrated by using the thermal shrinking method but applying the heat using an autoclave; the results implied that hydrated films are thicker and softer, exhibiting a lower elastic modulus compared to dry films. This work contributes to the understanding of structure-function relationships in the plant cell wall and may aid in the design of tunable biobased materials for applications in biosensing, packaging, drug delivery, and tissue engineering.

No impact of acute hyperglycaemia on arterial stiffness in the early and late follicular phases of the menstrual cycle in young females.

NEW FINDINGS: • What is the central question of this study? This is the first study to examine the impact of acute hyperglycaemia on arterial stiffness across the early and late follicular phases of the menstrual cycle. • What is the main finding and its importance? Central and peripheral arterial stiffness were not impacted by acute hyperglycaemia. This indicates that premenopausal women might experience protection against deleterious effects of acute hyperglycaemia, regardless of menstrual cycle phase. This research furthers our understanding of the interaction between nutrient intake, hormonal fluctuation and vascular function in premenopausal women. ABSTRACT: Acute hyperglycaemia may result in transient increases in arterial stiffness. However, research in healthy premenopausal women is lacking, and the impact of menstrual phase [early follicular (EF; low oestrogen) and late follicular (LF; high oestrogen)] on vulnerability to acute hyperglycaemia-induced changes in arterial stiffness is unknown. We hypothesized that an acute hyperglycaemia-induced increase in arterial stiffness in the EF phase would be attenuated in the LF phase. Seventeen healthy, naturally menstruating women [21 ± 1 years of age (mean ± SD)] participated in three experimental visits. During two visits, in the EF and LF phase, arterial stiffness was assessed via central and peripheral (arm and leg) pulse wave velocity (PWV) before and 15, 45, 75 and 105 min after consuming an oral glucose challenge (75 g glucose in 300 ml of solution). Blood samples were taken to assess glucose, insulin, oestrogen and progesterone concentrations. During a third visit in the EF phase, participants ingested 300 ml of water as a time control for PWV. Despite significant increases in blood glucose and insulin (P < 0.001), both central and peripheral arm PWV remained unchanged across time and phase, indicating that neither acute hyperglycaemia nor menstrual phase had an impact on central or peripheral arm arterial stiffness. There was a small effect of phase for peripheral leg PWV, where PWV was lower in the LF phase (P = 0.04, Cohen's d = 0.39); however, and in contrast to recent results in young men, peripheral leg PWV was unaffected by hyperglycaemia. These results suggest that premenopausal women might experience protection from acute hyperglycaemia-induced increases in arterial stiffness.

The influence of acute hyperglycaemia on brachial artery flow-mediated dilatation in the early and late follicular phases of the menstrual cycle.

NEW FINDINGS: What is the central question of the study? This is the first study to examine the impact of acute hyperglycaemia on endothelial function [flow-mediated dilatation (FMD)] in premenopausal women across the early and late follicular (EF and LF) phases of the menstrual cycle. What is the main finding and its importance? Flow-mediated dilatation was impaired 90 min after glucose ingestion, with no significant difference between phases. This indicates that women are susceptible to acute hyperglycaemia-induced endothelial dysfunction in both the EF and LF phases of the menstrual cycle, despite potentially vasoprotective elevations in estradiol levels during the LF phase. ABSTRACT: Acute hyperglycaemia transiently impairs endothelial function in healthy men when assessed via flow-mediated dilatation (FMD). However, research in female participants is lacking, and the impact of menstrual phase [early follicular (EF) and late follicular (LF)] on vulnerability to acute hyperglycaemia-induced endothelial dysfunction is unknown. Seventeen healthy, naturally menstruating women [21 ± 1 years old (mean ± SD)] participated in three visits. During two visits (EFGlucose and LFGlucose ), brachial artery FMD was assessed before and 60, 90 and 120 min after an oral glucose challenge (75 g glucose). During an additional EF visit, participants ingested 300 ml of water (EFTimeControl ). Blood glucose and insulin increased 30 min after glucose ingestion (P < 0.001), with no difference between phases. Flow-mediated dilatation did not change in EFTimeControl (P = 0.748) but was reduced 90 min after glucose ingestion (Pre, 8.5 ± 2.5%; Post90, 6.6 ± 2.4%, P = 0.001; Cohen's d = 0.82), with no difference between phases (main effect of phase, P = 0.506; phase by time interaction, P = 0.391). To account for individual variability in the time course of the impact of hyperglycaemia, the maximal hyperglycaemia-induced impairment in FMD was determined in each participant and compared between phases, revealing no significant phase differences (EFGlucose , -3.1 ± 2.8%; LFGlucose , -2.4 ± 2.1%, P = 0.181; d = 0.34). These results indicate that, similar to findings in men, acute hyperglycaemia results in FMD impairment in young women. We did not detect significant protection from acute hyperglycaemia-induced endothelial dysfunction in the LF 'high-oestrogen' phase in this sample, and further research is needed to examine the potential for a protective effect of oestrogen exposure, including oral contraceptive pills and hormone replacement therapy.

Sitting cross-legged for 30 min alters lower limb shear stress pattern but not flow-mediated dilation or arterial stiffness.

Prolonged sitting decreases lower limb endothelial function via sustained reductions in mean shear rate. We tested whether 30 min of sitting cross-legged differentially impacts superficial femoral artery shear rate pattern, flow-mediated dilation (FMD), and leg pulse-wave velocity (PWV) compared with sitting flat-footed. Sitting cross-legged attenuated the reduction in mean and antegrade shear rate and increased arterial pressure compared with sitting flat-footed. Superficial femoral artery FMD and leg PWV were unaltered following either sitting position.

Dynamically Evolving Surface Patterns through Light-Triggered Wrinkling Erasure.

For many applications, it is imperative that changes in polymer surface topography, especially periodic patterns, can be triggered on command by a well-defined remote signal. In this contribution, we report a light-induced cascade of changes in wrinkling wavelengths on thin polymer layers supported by an elastomeric substrate under tensile stress. Through the applied supramolecular design, the effect of varying the ratio of light-active and light-passive components can be easily assessed, and it is shown that both the cascade type as well as the rate of the progress of the dynamic light-induced changes can be tuned by this ratio as well as by the light intensity. Furthermore, for the reported phenomena to occur, nominally only every 20th polymer repeat unit needs to be occupied by a chromophore, which makes the conversion of the sub-nanometer photoisomerization reaction into 10 µm scale changes of periodic surface patterns extremely efficient.

Evidence of sex differences in the acute impact of oscillatory shear stress on endothelial function.

Acutely imposed oscillatory shear stress (OSS) reduces reactive hyperemia flow-mediated dilation (RH-FMD) in conduit arteries of men; however, whether a similar impairment occurs in women or with FMD in response to a controlled, sustained shear stress stimulus (SS-FMD) is unknown. The purpose of this study was to determine the impact of OSS on RH-FMD and SS-FMD in men and women. OSS was provoked in the brachial artery using a 30-min forearm cuff inflation (70 mmHg). Healthy men [ n = 16, 25 yr (SD 3)] and women [ n = 16, 21 yr (SD 2)] completed the OSS intervention twice (separate days). Brachial artery endothelial function was assessed pre- and postintervention via either RH-FMD or 6 min of handgrip SS-FMD using Duplex ultrasound. The RH-FMD stimulus was calculated as shear rate area under the curve 60 s postdeflation (SRAUC60), whereas SS-FMD shear rate was targeted to produce a similar stimulus pre- and postintervention. The OSS intervention decreased RH-FMD in both sexes [men: 6.2% (SD 3.4) to 5.2% (SD 3.0); women: 5.4% (SD 2.0) to 3.1% (SD 1.8), P < 0.001), although this was accompanied by a reduced SRAUC60. There was no significant effect of the intervention on RH-FMD with SRAUC60 as a covariate ( P = 0.310). Handgrip exercise elicited a similar stimulus before and after the intervention ( P = 0.287) in men and women ( P = 0.873). Men demonstrated blunted SS-FMD [4.8% (SD 1.9) to 3.2% (SD 1.9), P < 0.001], whereas women displayed preserved SS-FMD following the intervention [3.5% (SD 1.9) to 4.0% (SD 1.9), P = 0.061]. The lower SS-FMD in men but not women following OSS provides evidence of sex differences in the effects of OSS on conduit artery endothelial function. NEW & NOTEWORTHY Acute exposure to oscillatory shear stress induces transient endothelial dysfunction in men; however, whether women experience similar impairments is unknown. Following acutely imposed oscillatory shear stress, there was a decrease in flow-mediated dilation stimulated by a physiologically relevant sustained increase in shear stress in men but not in premenopausal women. These findings demonstrate, for the first time in humans that there are sex differences in the impact of oscillatory shear stress on endothelial function.

Hydrazide-Derivatized Microgels Bond to Wet, Oxidized Cellulose Giving Adhesion Without Drying or Curing.

Hydrazide-derivatized poly(N-isopropylacrylamide-co-acrylic acid) microgels gave strong adhesion to wet, TEMPO oxidized, regenerated cellulose membranes without a drying or heating step. Adhesion was attributed to hydrazone covalent bond formation with aldehyde groups present on the cellulose surfaces. This is one of only three chemistries we have found that gives significant never-dried adhesion between wet cellulose surfaces. By contrast, for cellulose joints that have been dried and heated before wet testing, the hydrazide-hydrazone chemistry offers no advantages over standard paper industry wet strength resins. The design rules for the hydrazide-microgel adhesives include: cationic microgels are superior to anionic gels; the lower the microgel cross-link density, the higher the adhesion; longer PEG-based hydrazide tethers offer no advantage over shorter attachments; and, adhesion is independent of microgel diameter. Many of these rules were in agreement with predictions of a simple adhesion model where the microgels were assumed to be ideal springs. We propose that the unexpected, high cohesion between neighboring microgels in multilayer films was a result of bond formation between hydrazide groups and residual NHS-carboxyl esters from the preparation of the hydrazide microgels.