Rho iso-alpha acids from hops inhibit the GSK-3/NF-κB pathway and reduce inflammatory markers associated with bone and cartilage degradation

<p>Abstract</p> <p>Background</p> <p><it>Rho </it>iso-alpha acids (RIAA) from hops have been shown to have anti-inflammatory properties. To understand the mechanisms, we evaluated the effect of RIAA in cell signaling pathways and inflammatory markers using various in vitro models. We also investigated their therapeutic effect in mice with collagen-induced arthritis.</p> <p>Methods</p> <p>The LPS-stimulated RAW 264.7 macrophages were used to evaluate the effect of RIAA on the NF-κB and MAPK signaling pathways; phosphorylation of ERK1/2, p38 and JNK was assessed by western blotting and NF-κB binding by electrophoretic mobility shift assays. Effect on the NF-κB activity was evaluated by the luciferase reporter assays in LPS-stimulated RAW 264.7 cells. GSK-3α/β kinase activity was measured in cell-free assays. The inhibitory effect of RIAA on inflammatory markers was assessed by measuring nitric oxide in LPS-stimulated RAW 264.7 cells, RANKL-mediated TRAP activity in transformed osteoclasts, and TNF-α/IL-1β-mediated MMP-13 expression in SW1353 cells. Mice with collagen-induced arthritis were fed with RIAA for 2 weeks. Symptoms of joint swelling, arthritic index and joint damage were assessed.</p> <p>Results</p> <p>RIAA selectively inhibited the NF-κB pathway while having no effect on ERK1/2, p38 and JNK phosphorylation in LPS-stimulated RAW 264.7 cells. RIAA also inhibited GSK-3α/β kinase activity and GSK-3β dependent phosphorylation of β-catenin in RAW 264.7 cells. In addition, RIAA inhibited NF-κB-mediated inflammatory markers in various cell models, including nitric oxide in LPS-stimulated RAW 264.7 cells, RANKL-mediated TRAP activity in transformed osteoclasts, and TNF-α/IL-1β-mediated MMP-13 expression in SW1353 human chondrosarcoma cells. Finally, in a mouse model of collagen-induced arthritis, RIAA ameliorated joint damage as evidenced by significant reduction of the arthritis index and histology score; at 250 mg/kg-body weight, RIAA had efficacy similar to that of 20 mg/kg-body weight of celecoxib.</p> <p>Conclusion</p> <p>RIAA may have potential as an anti-inflammatory therapeutic.</p

Sodium-glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review

Aims: To systematically review randomized controlled trials assessing effects of sodium–glucose cotransporter 2 inhibitors (SGLT2is) on hospitalization for heart failure (HHF) and cardiac structure/function and explore randomized controlled trial (RCT)-derived evidence for SGLT2i efficacy mechanisms in heart failure (HF). Methods and results: Systematic searches of Medline and Embase were performed. In seven trials [3730–17 160 patients; low risk of bias (RoB)], SGLT2is significantly reduced the relative risk of HHF by 27–39% vs. placebo, including in two studies in patients with HF with reduced ejection fraction with or without type-2 diabetes mellitus (T2DM). Improvements in conventional cardiovascular risk factors, including glycaemic levels, cannot account for these effects. Five trials (56–105 patients; low RoB) assessed the effects of 6–12 months of SGLT2i treatment on left ventricular structure/function; four reported significant improvements vs. placebo, and one did not. Five trials (low RoB) assessed SGLT2i treatment effects on serum N-terminal pro B-type natriuretic peptide levels; significant reductions vs. placebo were reported after 8–12 months (two studies; 3730–4744 patients) but not ≤12 weeks (three studies; 80–263 patients). Limited available RCT-derived evidence suggests various possible cardioprotective SGLT2i mechanisms, including improved haemodynamics (natriuresis and reduced interstitial fluid without blood volume contraction/neurohormonal activation) and vascular function, enhanced erythropoiesis, reduced tissue sodium and epicardial fat/inflammation, decreased sympathetic tone, and beneficial changes in cellular energetics. Conclusions: Sodium–glucose cotransporter 2 inhibitors reduce HHF regardless of T2DM status, and reversal of adverse left ventricular remodelling likely contributes to this efficacy. Hypothesis-driven mechanistic trials remain sparse, although numerous trials are planned or ongoing

Systematic review of the effects of sodium-glucose cotransporter 2 inhibitors on hospitalization for heart failure and cardiac structure or function, and exploratory assessment of potential mechanisms

In the past 5 years, there has been a profound shift in the therapeutic focus of trials of sodium-glucose cotransporter 2 inhibitors (SGLT2is). Although initially explored and introduced as glucose-lowering agents for patients with type 2 diabetes mellitus (T2DM), 1 clinical investigation of these molecules has evolved towards heart failure (HF) and chronic kidney disease (CKD) outcomes in patients with and without T2DM. We systematically reviewed randomized controlled trial (RCT) data assessing the effects of SGLT2 is compared with placebo on hospitalization for HF (HHF), cardiac structure and cardiac function, in a PRISMA-compliant manner. We also reviewed, in an exploratory manner, mechanistic evidence for how SGLT2 is may exert their benefits

Hop and Acacia Phytochemicals Decreased Lipotoxicity in 3T3-L1 Adipocytes, db/db Mice, and Individuals with Metabolic Syndrome

The plant-based compounds rho-iso-alpha acids (RIAA) from Humulus lupulus (hops) and proanthocyanidins (PAC) from Acacia nilotica have been shown to modulate insulin signaling in vitro. We investigated their effects on triglyceride (TG) deposition in 3T3-L1 adipocytes, glucose and insulin in obese mouse models, and metabolic syndrome markers in adults with metabolic syndrome. The combination of RIAA and PAC synergistically increased TG content and adiponectin secretion in 3T3-L1 adipocytes under hyperinsulinemic conditions and reduced glucose or insulin in obese mice. In a clinical trial, tablets containing 100 mg RIAA and 500 mg PAC or placebo were administered to metabolic syndrome subjects (3 tablets/day, n = 35; 6 tablets/day, n = 34; or placebo, n = 35) for 12 weeks. Compared to placebo, subjects taking 3 tablets daily showed greater reductions in TG, TG : HDL, fasting insulin, and HOMA scores. The combination of RIAA : PAC at 1 : 5 (wt : wt) favorably modulates dysregulated lipids in insulin resistance and metabolic syndrome

Doug Altman: Driving critical appraisal and improvements in the quality of methodological and medical research.

Doug Altman was a visionary leader and one of the most influential medical statisticians of the last 40 years. Based on a presentation in the "Invited session in memory of Doug Altman" at the 40th Annual Conference of the International Society for Clinical Biostatistics (ISCB) in Leuven, Belgium and our long-standing collaborations with Doug, we discuss his contributions to regression modeling, reporting, prognosis research, as well as some more general issues while acknowledging that we cannot cover the whole spectrum of Doug's considerable methodological output. His statement "To maximize the benefit to society, you need to not just do research but do it well" should be a driver for all researchers. To improve current and future research, we aim to summarize Doug's messages for these three topics

The AdS/CFT Correspondence and a New Positive Energy Conjecture for General Relativity

We examine the AdS/CFT correspondence when the gauge theory is considered on a compactified space with supersymmetry breaking boundary conditions. We find that the corresponding supergravity solution has a negative energy, in agreement with the expected negative Casimir energy in the field theory. Stability of the gauge theory would imply that this supergravity solution has minimum energy among all solutions with the same boundary conditions. Hence we are lead to conjecture a new positive energy theorem for asymptotically locally Anti-de Sitter spacetimes. We show that the candidate minimum energy solution is stable against all quadratic fluctuations of the metric.Comment: 25 pages, harvma

S5S^5: Probing the Milky Way and Magellanic Clouds potentials with the 6-D map of the Orphan-Chenab stream

We present a 6-D map of the Orphan-Chenab (OC) stream by combining the data from 5 years of Southern Stellar Stream Spectroscopic Survey $S^5$ observations with Gaia EDR3 data. We reconstruct the proper motion, radial velocity, distance and on-sky track of stream stars with spline models and extract the stellar density along the stream. The stream has a total luminosity of $M_V=-8.2$ and an average metallicity of $[Fe/H]=-1.9$, similar to classical MW satellites like Draco. The stream shows drastic changes in its physical width varying from 200 pc to 1 kpc, a constant line of sight velocity dispersion of 5 km/s, but an increase in the velocity dispersion along the stream near pericenter to $\sim$ 10 km/s. Despite the large apparent variation in the stellar number density along the stream, the flow rate of stars along the stream is remarkably constant. We model the 6-D stream track by a Lagrange-point stripping method with a flexible MW potential in the presence of a moving extended LMC potential. This allows us to constrain the mass profile of the MW within the distance range 15.6 < r < 55.5 kpc, with the best measured enclosed mass of $(2.85\pm 0.1)\times10^{11}\,M_\odot$ within 32.4 kpc. With the OC stream's closest approach distance to the LMC of $\sim 21$ kpc, our stream measurements are highly sensitive to the LMC mass profile with the most precise measurement of the LMC's enclosed mass being at 32.8 kpc with $M=(7.02\pm 0.9)\times10^{10}\, {M}_\odot$. We confidently detect that the LMC DM halo extends to at least 53 kpc. The fitting of the OC stream allows us to constrain the past LMC trajectory and the degree of dynamical friction it experienced. We demonstrate that the stars on the OC stream show large energy and angular momentum spreads caused by the LMC perturbation and revealing the limitations of orbital invariants for substructure identification in the MW halo.Comment: submitted to MNRAS; comments welcome; data released with the paper is available on Zenodo https://zenodo.org/record/722265

The GALAH survey: Properties of the Galactic disc(s) in the solar neighbourhood

Using data from the GALAH pilot survey, we determine properties of the Galactic thin and thick discs near the solar neighbourhood. The data cover a small range of Galactocentric radius (7.9 RGC 9.5 kpc), but extend up to 4 kpc in height from the Galactic plane, and several kpc in the direction of Galactic anti-rotation (at longitude 260◦ ≤ ≤ 280◦). This allows us to reliably measure the vertical density and abundance profiles of the chemically and kinematically defined ‘thick’ and ‘thin’ discs of the Galaxy. The thin disc (low-α population) exhibits a steep negative vertical metallicity gradient, at d[M/H]/dz = −0.18 ± 0.01 dex kpc−1, which is broadly consistent with previous studies. In contrast, its vertical α-abundance profile is almost flat, with a gradient of d[α/M]/dz = 0.008 ± 0.002 dex kpc−1. The steep vertical metallicity gradient of the low-α population is in agreement with models where radial migration has a major role in the evolution of the thin disc. The thick disc (high-α population) has a weaker vertical metallicity gradient d[M/H]/dz = −0.058 ± 0.003 dex kpc−1. The αabundance of the thick disc is nearly constant with height, d[α/M]/dz = 0.007 ± 0.002 dex kpc−1. The negative gradient in metallicity and the small gradient in [α/M] indicate that the high-α population experienced a settling phase, but also formed prior to the onset of major Type Ia supernova enrichment. We explore the implications of the distinct α-enrichments and narrow [α/M] range of the sub-populations in the context of thick disc formation.LD and MA acknowledge funding from the Australian Government through ARC Laureate Fellowship FL110100012. LD, KCF, and RFGW acknowledge support from ARC grant DP160103747. LC gratefully acknowledges support from the Australian Research Council (grants DP150100250, FT160100402). DMN was supported by the Allan C. and Dorothy H. Davis Fellowship. DS is the recipient of an Australian Research Council Future Fellowship (project number FT1400147). TZ acknowledges financial support from the Slovenian Research Agency (research core funding No. P1-0188). Part of this research was supported by the Munich Institute for Astro- and Particle Physics (MIAPP) of the DFG cluster of excellence ‘Origin and Structure of the Universe’

Signature of a massive rotating metal-poor star imprinted in the Phoenix stellar stream*

The Phoenix stellar stream has a low intrinsic dispersion in velocity and metallicity that implies the progenitor was probably a low mass globular cluster. In this work we use Magellan/MIKE high-dispersion spectroscopy of eight Phoenix stream red giants to confirm this scenario. In particular, we find negligible intrinsic scatter in metallicity ($\sigma(\mathrm{[Fe~II/H]}) = 0.04^{+0.11}_{-0.03}$) and a large peak-to-peak range in [Na/Fe] and [Al/Fe] abundance ratios, consistent with the light element abundance patterns seen in the most metal-poor globular clusters. However, unlike any other globular cluster, we also find an intrinsic spread in [Sr II/Fe] spanning $\sim$1 dex, while [Ba II/Fe] shows nearly no intrinsic spread ($\sigma(\mathrm{[Ba~II/H]}) = {0.03}^{+0.10}_{-0.02}$). This abundance signature is best interpreted as slow neutron capture element production from a massive fast-rotating metal-poor star ($15-20 \mathrm{M}_\odot$, $v_\mathrm{ini}/v_\mathrm{crit} = 0.4$, $[\mathrm{Fe/H}] = -3.8$). The low inferred cluster mass suggests the system would have been unable to retain supernovae ejecta, implying that any massive fast-rotating metal-poor star that enriched the interstellar medium must have formed and evolved before the globular cluster formed. Neutron capture element production from asymptotic giant branch stars or magneto-rotational instabilities in core-collapse supernovae provide poor fits to the observations. We also report one Phoenix stream star to be a lithium-rich giant ($A(\mathrm{Li}) = 3.1 \pm 0.1$). At $[\mathrm{Fe/H}] = -2.93$ it is among the most metal-poor lithium-rich giants known.Comment: Accepted to ApJ 2021-07-0

Multiple Populations and a CH Star Found in the 300S Globular Cluster Stellar Stream

Milky Way globular clusters (GCs) display chemical enrichment in a phenomenon called multiple stellar populations (MSPs). While the enrichment mechanism is not fully understood, there is a correlation between a cluster's mass and the fraction of enriched stars found therein. However, present-day GC masses are often smaller than their masses at the time of formation due to dynamical mass loss. In this work, we explore the relationship between mass and MSPs using the stellar stream 300S. We present the chemical abundances of eight red giant branch member stars in 300S with high-resolution spectroscopy from Magellan/MIKE. We identify one enriched star characteristic of MSPs and no detectable metallicity dispersion, confirming that the progenitor of 300S was a globular cluster. The fraction of enriched stars (12.5\%) observed in our 300S stars is less than the 50\% of stars found enriched in Milky Way GCs of comparable present-day mass ($\sim10^{4.5}$\msun). We calculate the mass of 300S's progenitor and compare it to the initial masses of intact GCs, finding that 300S aligns well with the trend between the system mass at formation and enrichment. 300S's progenitor may straddle the critical mass threshold for the formation of MSPs and can therefore serve as a benchmark for the stellar enrichment process. Additionally, we identify a CH star, with high abundances of \textit{s}-process elements, probably accreted from a binary companion. The rarity of such binaries in intact GCs may imply stellar streams permit the survival of binaries that would otherwise be disrupted.Comment: 15 pages, 7 tables, 8 figures. Accepted for publication in MNRA