Low Effect Research Articles

Saffron and its major constituents against neurodegenerative diseases: A mechanistic review

BackgroundNeurodegeneration has been recognized as the main pathophysiological alteration in the majority of brain-related diseases. Despite contemporary attempts to provide acceptable medicinal therapies, the conclusion has not been much beneficial. Besides, the complex pathophysiological mechanisms behind neurodegenerative diseases (NDDs) urge the needs for finding novel multi-target agents. Accordingly, saffron with major active constituents and as multi-targeting agents have shown beneficial effects in modulating NDDs with higher efficacy and lower side effects. PurposeThe present study provides a systematic and comprehensive review of the existing in vitro, in vivo, and clinical data on the effectiveness, and signaling pathways of saffron and its key phytochemical components in the management of NDDs. The need to develop novel saffron delivery systems is also considered. MethodsStudies were identified through systematic and comprehensive searches in Science Direct, PubMed, and Scopus databases through April 30, 2024. The whole saffron major constituents (e.g., saffron, crocin, crocetin, picrocrocin, and safranal) and NDDs (e.g., neuro*, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington*, Parkinson*, Alzheimer*, and brain) were selected as keywords to find related studies. In the systematic analysis, 64 articles were directly included in the current study. Additional reports were added within a comprehensive review. ResultsSaffron and its active metabolites crocin, crocetin, safranal, and picrocrocin have shown acceptable efficacy in managing NDDs like Alzheimer's disease, Parkinson's disease, Attention deficit hyperactivity disorder, depression, and other NDDs via modulating apoptotic (e.g., caspases, Bax/Bcl-2, cytochrome c, and death receptors), inflammatory (e.g., NF-κB, IL-1β, IL-6, TNF-α, and COX-2), and oxidative strass (e.g., Nrf2, GSH, GPx, CAT, SOD, MDA, ROS, and nitrite) signaling pathways. The presented in vitro, in vivo, and clinical evidences showed us a better future of controlling NDDs with higher efficacy, while decreasing associated side effects with no significant toxicity. Additionally, employing novel delivery systems could increase the efficacy of saffron phytoconstituents to resolve the issues pharmacokinetic limitations. ConclusionSaffron and its major constituents employ anti-inflammatory, anti-apoptotic and antioxidant mechanisms in modulating several dysregulated-signaling pathways in NDDs. However, further research is necessary to elucidate the precise underlying mechanisms in exploring the feasibility of using saffron active compounds against NDDs. More studies should focus on dose-response relationships, long-term effects, highlighting key mechanisms, and designing more well-controlled clinical trials. Additionally, developing stable and cost-benefit novel delivery systems in future works helps to remove the pharmacokinetic limitations of saffron major constituents.

Bioactive Natural Leads and Traditional Herbal Plants in the Management of Inflammatory Bowel Diseases: A Brief Review

: Inflammatory bowel disease is a chronic relapsing disorder that causes chronic inflammation and ulcers in the GIT. Depending upon the location, ulcerative colitis and Crohn's disease come under IBD. The exact etiology of IBD is still unknown. Over 8 lakhs of people were affected by inflammatory disease yearly, and the death rate increased daily. Depending upon the severity of the disease, JAK inhibitors, anti-TNF agents, and immunosuppressants can be used to manage ulcerative colitis and Crohn's disease. However, these treatments have been associated with harmful adverse effects, which cannot be ignored. To treat inflammatory diseases safely, various herbal medicines and their bioactive are preferred as game changers. Recently, the effectiveness of herbal plants has been recommended as the treatment against IBD, as shown by various in vivo models and clinical trials. The various herbal plants reported in the literature include gallic acid, lupeol, and curcumin aloe vera. This review focused on medicinal plants' anti-inflammatory, antioxidant, and anti-ulcer properties. Over 1.2 million healthcare practitioners are using herbal bioactive and have the advantages of lower side effects. Therefore, it is estimated that in Europe, the demand for plant-based products/formulations has risen by millions in 2020, showing the current position of herbal-based products in consumer health awareness.

O92 EFFICACY AND SAFETY OF LOW-DOSE ANTIHYPERTENSIVE COMBINATION DRUGS INCLUDING AMLODIPINE, TELMISARTAN, AND CHLORTHALIDONE: A MULTICENTER, RANDOMIZED, DOUBLE-BLINDED, PARALLEL, PHASE II CLINICAL TRIAL

Background and Objective: Although single pill high-dose triple antihypertensive combinations are already available on South Korea, there are no reports evaluating the efficacy and safety of the low-dose combination of amlodipine, telmisartan, and chlorthalidone. The aim of this clinical trial was to assess the efficacy and safety of low-dose combination drug containing telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (6.25 mg). Methods: This study was a randomized, double-blinded, parallel, multicenter, phase II clinical trial. In total, 221 subjects from 21 clinical trial sites in South Korea were randomly assigned to groups 1 (AD-209; telmisartan 20 mg/amlodipine 2.5 mg/chlorthalidone 6.25 mg), 2 (AD-209-1A; telmisartan 20 mg/amlodipine 2.5 mg), 3 (AD-209-1B; amlodipine 2.5 mg/chlorthalidone 6.25 mg), and 4 (AD-209-1C; telmisartan 20 mg/chlorthalidone 6.25 mg) in a 1:1:1:1 ratio, and the treatments lasted 8 weeks. After the initial drug administration, the subjects visited the clinical trial sites at weeks 4 and 8 to evaluate drug efficacy and safety. Results: In patients with mild-moderate hypertension, the mean change in MSSBP from baseline to week 8 between group 1 and groups 2, 3, and 4 was -5.93, -8.69, and -1.51 mmHg, respectively. The blood pressure of the subjects in group 1 was significantly lower than that of those in groups 2 and 3. It was also lower than that of subjects in group 4 although this difference was not significant. Among the 221 subjects enrolled, 20 (9.05%) experienced 25 treatment-emergent adverse events (TEAEs); of these, 14 (6.33%) experienced 17 adverse drug reactions (ADRs). No significant differences in the TEAE or ADR incidence rates were found between group 1 and groups 2, 3, and 4. Conclusions: AD-209 (telmisartan 20 mg/amlodipine 2.5 mg/chlorthalidone 6.25 mg), a low-dose triple combination drug, demonstrated a higher blood pressure lowering effect than the corresponding a low-dose dual combination drugs in patients with essential hypertension. Its safety was similar to that of the dual-combination drugs.

Abstract 53: Chronic Angiotensin-(1-7) Treatment May Enhance GABAergic Neurotransmission onto Melanocortin-4 Receptor Neurons in The Hypothalamic Paraventricular Nucleus in a Sex-Specific Manner

Angiotensin (Ang)-(1-7) is a protective hormone of the renin-angiotensin system that lowers blood pressure in animal models of cardiovascular disease; however, the precise mechanisms remain incompletely understood. Recent data from our laboratory suggests that blood pressure lowering effects of Ang-(1-7) may involve the arcuate nucleus of the hypothalamus (ARC). We have shown that Ang-(1-7) activates proopiomelanocortin (POMC)-containing neurons in the ARC. While ARC POMC neuron activation canonically increases blood pressure by stimulating melanocortin-4 receptors (MC4R) in the hypothalamic paraventricular nucleus (PVN), these neurons also release the inhibitory neurotransmitter GABA. Selective activation of these GABAergic POMC neurons could serve as a novel mechanism to lower blood pressure. In this study, we hypothesized that Ang-(1-7) treatment inhibits PVN MC4R neuron activity via enhanced GABAergic function. To test this, male and female MC4R-GFP mice were implanted with osmotic mini pumps at 14 weeks of age and treated chronically with either Ang-(1-7) (400 ng/kg/min) or saline. After six weeks of drug administration, action potential firing of PVN MC4R-expressing neurons was examined using cell attached electrophysiology. To assess GABAergic function, changes in action potential firing frequency following bath application of the GABA A receptor antagonist bicuculline (10 μm) were compared between Ang-(1-7) and saline treated animals (n=4-6 mice/group). While Ang-(1-7) did not alter baseline firing frequency of MC4R PVN neurons in male mice (1.5±0.6 vs. 1.1±0.3 Hz saline; p=0.630, unpaired t-test), it enhanced bicuculline responsiveness as indicated by a greater peak increase in action potential firing frequency (156.9±18.0 vs. 106.2±6.8 % saline; p=0.013). In female mice, Ang-(1-7) increased baseline action potential firing frequency of PVN MC4R neurons (1.5±0.4 vs. 0.3±0.1 Hz saline; p=0.026) but did not alter bicuculline responsiveness (111.0±5.3 vs. 143.2±25.3 % saline; p=0.241). Overall, our data suggest that Ang-(1-7) enhances GABAergic neurotransmission onto PVN MC4R neurons in a sex-specific manner. These data provide new insight into the neural mechanisms of Ang-(1-7), which could have implications for understanding the beneficial cardiovascular effects of this hormone. Additional studies are needed to examine this inhibitory neurocircuit in the context of hypertension as well as precise mechanisms underlying the observed sex differences.

Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal angiogenesis

Retinal neovascularization is a leading cause of blindness. While current anti-VEGF drugs effectively inhibit pathological angiogenesis, some patients develop resistance or reduced responsiveness to treatments over time, leading to diminished effectiveness. In this study, we identified high activation of the cGAS-STING signaling pathway, which exacerbated pathological neovascularization and vessel leakage. We developed an injectable thermo-responsive supramolecular hydrogel loaded with an anti-STING drug. The hydrogel, made of Pluronic F127 (PF·127) consisting of poly(ethylene oxide) and poly(propylene oxide) units, demonstrated excellent transparency and biocompatibility. Importantly, the thermo-sensitive property allowed for precise spatial release of the drug, extending the effective treatment duration of C-176, which suppressed STING activation in the retina, reduced inflammation, and protected retinal tissue. HydroC-176 effectively inhibited microglial cell infiltration and the release of inflammatory angiogenic factors, highlighting its enhanced efficacy. While demonstrating slightly lower effectiveness compared to traditional anti-VEGF therapy, HydroC-176 exhibited more robust capabilities in regulating ocular microenvironmental inflammation. This approach may assist in enhancing the sensitivity and effectiveness of anti-VEGF therapy for reducing ocular inflammation, potentially improving patients’ response to traditional treatment. These results have suggested innovative and comprehensive strategies for the management of retinal neovascularization.

Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator.

The AMP-activated protein kinase (AMPK) signalling pathway is a desirable target for various cardiovascular diseases (CVD), while the involvement of AMPK-mediated specific downstream pathways and effective interventions in hyperlipidaemia-induced endothelial dysfunction remain largely unknown. Herein, we aim to identify an effective AMPK activator and to explore its efficacy and mechanism against endothelial dysfunction. Molecular docking technique was adopted to screen for the potent AMPK activator among 11 most common rare ginsenosides. In vivo, poloxamer 407 (P407) was used to induce acute hyperlipidaemia in C57BL/6J mice. In vitro, palmitic acid (PA) was used to induce lipid toxicity in HAEC cells. We discovered the strongest binding of ginsenoside Rh4 to AMPKα1 and confirmed the action of Rh4 on AMPK activation. Rh4 effectively attenuated hyperlipidaemia-related endothelial injury and oxidative stress both in vivo and in vitro and restored cell viability, mitochondrial membrane potential and mitochondrial oxygen consumption rate in HAEC cells. Mechanistically, Rh4 bound to AMPKα1 and simultaneously up-regulated AKT/eNOS-mediated NO release, promoted PGC-1α-mediated mitochondrial biogenesis and inhibited P38 MAPK/NFκB-mediated inflammatory responses in both P407-treated mice and PA-treated HAEC cells. The AMPK inhibitor Compound C treatment completely abrogated the regulation of Rh4 on the above pathways and weakened the lowering effect of Rh4 on endothelial impairment markers, suggesting that the beneficial effects of Rh4 are AMPK dependent. Rh4 may serve as a novel AMPK activator to protect against hyperlipidaemia-induced endothelial dysfunction, providing new insights into the prevention and treatment of endothelial injury-associated CVD.

Correlation of Serum Vitamin D and High-Density Lipoprotein (HDL) Cholesterol Levels With Disease Activity in Rheumatoid Arthritis: A Single-Center Experience From Eastern India.

Background Rheumatoid arthritis (RA) is a progressive, symmetric, and erosive polyarthritis with a variety of extraarticular manifestations such as mononeuritis multiplex, central nervous system vasculitis, Felty's syndrome, dyslipidemia, carditis, and interstitial lung disease. Vitamin D plays a role in both adaptive and innate immunity, and its deficiency leads to the development of many autoimmune disorders. Additionally, RA patients have a lipid paradox consisting particularly of dysfunctional and low levels of high-density lipoprotein (HDL) with reduced low-density lipoprotein lowering effect, which increases cardiovascular morbidity and potentiates widespread systemic inflammation. Both are modifiable risk factors. Although there are numerous studies on vitamin D and HDL cholesterol in disease progression in RA, there is sparse literature from India studying both these factors in combination. In this study, we tried to establish the correlation of serum vitamin D and HDL cholesterol levels, if any, with disease activity using the Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 ESR) score. Methods A descriptive cross-sectional study comprising 80 patients was conducted at a tertiary care center in Eastern India over 12 months. Newly diagnosed RA patients aged >17 years satisfying the diagnostic criteria were included. Serum vitamin D level and HDL cholesterol were measured. Then, the DAS28 ESR score was calculated, and a correlation was looked for between serum vitamin D and HDL cholesterol. Results Patients aged 35-43 years accounted for 32 (42.5%) of participants, of whom 58 (72.5%) were females. Almost half, 38 (47.5%), had vitamin D deficiency. The mean vitamin D level was 22.988 ± 10.01 ng/ml. The mean HDL cholesterol level was 42.3 ± 7.23 mg/dl. The mean DAS28-ESR score was 3.81 ± 1.19. A statistically significant inverse correlation was found between vitamin D levels and DAS28 ESR score (p -0.0003) and HDL (p -0.000349). Conclusions Vitamin D deficiency and low HDL cholesterol levels are more common in RA patients. These factors may contribute to increased disease activity. Both are treatable factors in addition to conventional therapies.

Abstract P442: Impact of arterial stiffness on the blood pressure lowering effect of the dual endothelin antagonist aprocitentan in patients with resistant hypertension

Background: The phase-3 PRECISION study demonstrated the efficacy of aprocitentan to lower both office and ambulatory blood pressure (BP) in patients with resistant hypertension. Increased arterial stiffness has been associated with less favorable responses to pharmacologic BP lowering therapies. In this post-hoc analysis, we investigated the impact of arterial stiffness, assessed by the ambulatory arterial stiffness index (AASI), on the BP lowering effect of aprocitentan. Methods: The study included a 4-week double blind period (aprocitentan 12.5 mg, 25 mg, or placebo) and a 32-week single blind period (aprocitentan 25 mg). A total of 730 patients with resistant hypertension were randomized and 633 had available ambulatory BP monitoring (ABPM) results at baseline. The AASI was calculated from ABPM data as 1 minus the regression slope of diastolic on systolic BP. The patient population was dichotomized into two groups according to the baseline median AASI. Results: Patients with higher baseline AASI (≥0.54) tended to be older (63±11 versus 60±10) and to have a higher 24-hour ambulatory systolic BP (140±14 versus 135±14 mmHg) than patients with lower AASI (<0.54). These patients with higher baseline AASI were also more likely to have chronic kidney disease stage 3-4 corresponding to an estimated glomerular filtration rate in the 15 to 60 mL/min/1.73 m 2 range (27% versus 18%). The BP lowering effect of aprocitentan at Week 4 was similar for both the patients with stiffer vasculature who have a higher baseline AASI (≥0.54) and for those with a lower AASI (<0.54) (Table 1). No relevant change in AASI was reported with aprocitentan treatment at Week 4 (end of the double-blind period) or Week 36 (end of the single-blind period). Conclusion: Aprocitentan is an effective BP lowering therapy across the arterial stiffness continuum observed in patients with resistant hypertension. Longer observation times are needed to fully assess the impact of treatment on this structural and functional parameter.

Chronic Administration of Red Yeast Rice Mitigates Endothelial Dysfunction in Spontaneously Hypertensive Rats by Inhibiting Oxidative Stress and Endothelial Nitric Oxide Synthase Uncoupling.

Hypertension is associated with endothelial dysfunction. An imbalance in the production of Nitric Oxide (NO) and Reactive Oxygen Species (ROS), leading to impaired NO-cyclic Guanosine Monophosphate (cGMP) pathway, contributes to this disorder. Red Yeast Rice (RYR), produced from the fermentation of rice with Monascus purpureus, is a traditional functional food originating from China. Although recognized for its anti-dyslipidemia properties, there has been growing evidence regarding the anti-hypertensive effects of RYR. However, these studies only focused on its direct and short-term effects. This study aims to investigate the vasoprotective effects of chronic oral RYR administration using Spontaneously Hypertensive Rats (SHR). SHR were randomly divided into 3 groups: SHR - Control; SHR - RYR extract (100 mg/kg/day); SHR - lovastatin (10 mg/kg/day). Wistar-Kyoto Rats (WKY) were used as normotensive controls. All animals were treated for 12 weeks by oral gavage. Systolic Blood Pressure (SBP) was measured weekly (tail-cuff method). Vascular reactivity was determined using isolated rat aortic rings in an organ bath. Aortic ROS, NO, tetrahydrobiopterin (BH4), and cGMP levels were evaluated. Administration of RYR attenuated SBP elevation and enhanced endothelium-dependent vasodilation in aortic rings. In addition, RYR decreased ROS production and significantly improved the level of vascular NO, BH4, and cGMP. In an SHR model, treatment with RYR for 12 weeks exerts an SBP lowering effect that can be attributed to improved vascular function via reduction of oxidative stress, decreased endothelial NO Synthase (eNOS) uncoupling and enhanced NO-cGMP pathway.

Metabolomics study of lipid lowering effect and lysophospholipids regulation by Alismatis rhizoma and processed forms in hyperlipidemia mice

Alismatis rhizoma (AR) is a traditional herb used for its lipid-regulating properties. Its processed forms, salt-processed AR (SAR) and bran-processed AR (BAR), are widely used. This study investigates the lipid-lowering effects of AR and its processed forms in hyperlipidemic mice, with a focus on lysophospholipid regulation. Three types of serum lysophospholipids were characterized using UHPLC-QTOF-MS/MS, and their metabolic changes were analyzed with multivariate statistical statistics. The results showed that AR effectively reduced total cholesterol (TC), while SAR and BAR excelled in lowering low-density lipoprotein-cholesterol (LDL-C). BAR demonstrated superior effects on the TC/high-density lipoprotein-cholesterol (HDL-C) ratio, atherogenic index (AI), and protecting kidney function, making it the most effective processed form. Additionally, a total of 216 lysophospholipids, including 153 lysophosphatidylcholines (Lyso-PCs), 49 lysophosphatidylethanolamines (Lyso-PEs), and 14 lysophosphatidylserines (Lyso-PSs), were identified in serum samples. Metabolomics analysis revealed 102 differential lysophospholipids associated with hyperlipidemia, among which 29, 21, and 22 were significantly (VIP > 1.0, P< 0.05) regulated by AR, SAR, and BAR, respectively. AR showed the most comprehensive regulation of lysophospholipids, increasing unsaturated Lyso-PCs and decreasing Lyso-PEs and Lyso-PSs, which might reduce inflammation and improve cardiovascular health. This study is the first to comprehensively compare the lipid-lowering effects of AR and its processed forms, highlighting their role in modulating lysophospholipid metabolism in hyperlipidemia.

Oxygen isotope fractionation during amorphous to crystalline calcium carbonate transformation at varying relative humidity and temperature

Crystalline calcium carbonate isotope compositions have been widely used to reconstruct past environments. However, if their isotopic compositions are modified because of crystallization from an amorphous precursor, their reliability as paleo-geochemical proxies can be compromised. This study explored the changes in the oxygen isotope compositions during the transformation of amorphous calcium carbonate (ACC) into crystalline carbonate under different conditions of relative humidity (RH of 33–95 %), temperature (T of 5 °C and 20 °C) and in the presence/absence of atmospheric CO2. The data showed that at low RH and T (e.g., RH ≤ 45 % and 5 °C) when a complete ACC-crystalline carbonate transformation did not take place then the original ACC δ18O values (δ18OCaCO3 = −15.9 ± 1.0 ‰, VPDB) were preserved throughout the experimental runtime (up to 144 days). In contrast, in fully crystallized CaCO3 (e.g., at RH ≥ 60 %) the δ18OCaCO3 values increased rapidly over the first few days, followed by a slower and gradual increase. By the end of the experiments (i.e., after 103–144 days) the crystalline δ18OCaCO3 values ranged from −10.4 ‰ to −8.1 ‰ in the presence of atmospheric CO2 and from −12.6 ‰ to −9.5 ‰ in the CO2-free experiments. These changes in oxygen isotope compositions of the CaCO3 reaction products (calcite and/or vaterite) were mainly driven by exchange with H2O from the hydrated ACC i.e. the synthesis fluid. In CO2-present experiments, oxygen isotope fractionation factors between the CaCO3 reaction products and the synthesis fluid (18αc–w) approached or exceeded oxygen isotope equilibrium values. This could be explained by a decrease in the initially high pH of the aqueous fluid released from ACC dissolution during CO2 hydration/hydroxylation, which would have increased the oxygen isotope exchange kinetics between H2O and dissolved inorganic carbon (DIC). In some experiments, the hydration/hydroxylation of 18O-enriched CO2, due to isotopic salt-effects, might have also resulted in 18O-enriched calcium carbonates and calculated fractionation factors that exceeded equilibrium values. In the CO2-free experiments, isotopic equilibrium between the crystalline phase and the synthesis fluid was not reached. This oxygen isotope disequilibrium suggests that without the pH lowering effect of the hydroxylation/hydration of CO2, the CO32− released during ACC/calcite dissolution-reprecipitation may have not isotopically equilibrated with the high pH synthesis fluid due to the long equilibration times required to reach isotope equilibrium at high pH values, leading to the self-buffering of δ18OCaCO3 values. The results suggest that the oxygen isotopic compositions of natural carbonates formed from ACC transformation in air and at low water/solid ratio (e.g., biominerals or carbonates formed in caves) are complex and cannot be used as simple proxies if the reaction kinetics (RH/CO2/T) and H2O sources are not known and quantified.

Performance and mechanism of carbon sequestration of air-entraining wet shotcrete

CO2 curing concrete technology refers to the CO2 reacts with cement clinker minerals to obtain high-performance concrete and achieve the purpose of energy saving and emission reduction. The researches of air entrainment agent (AEA) focus on the development of new AEA and the study of concrete performance after adding some AEA. In the background of CO2 curing concrete technology, there are relatively few researches on the influence mechanism of different characteristics of bubbles introduced by different AEAs on carbon fixation performance of concrete. This paper demonstrates the characteristics of air bubbles introduced by SY-5 AEA (main component: triterpene saponin) and LAS AEA (main component: sodium dodecylbenzene sulfonate), compares the strength of concrete mixed with above two types of AEAs cured for 28 days and analyzed them by carbonization depth test, ultrasonic detection of fissure test, SEM, XRD and TG. Results show that different AEAs introduced different characteristics of air bubbles, which affected the internal pore characteristics of concrete, and then affected its mechanical properties and carbon sequestration properties. Compared with SY-5 AEA, LAS AEA had a slightly lower air-entraining effect. But the bubbles introduced were even and stable, the internal pores of the hardened concrete were uniform. Although the former had a high carbon sequestration, the latter had a higher intensity at 28 d, about 2.69 % higher. Under carbonization curing conditions, the improvement of concrete properties was more evident when appropriate AEAs were incorporated. The compressive strength and the splitting strength were increased by 5.57 % and 4.5 % respectively under the carbonization curing condition.

Nutritional Epigenomics: Bioactive Dietary Compounds in the Epigenetic Regulation of Osteoarthritis.

Nutritional epigenomics is exceptionally important because it describes the complex interactions among food compounds and epigenome modifications. Phytonutrients or bioactive compounds, which are secondary metabolites of plants, can protect against osteoarthritis by suppressing the expression of inflammatory and catabolic mediators, modulating epigenetic changes in DNA methylation, and the histone or chromatin remodelling of key inflammatory genes and noncoding RNAs. The combination of natural epigenetic modulators is crucial because of their additive and synergistic effects, safety and therapeutic efficacy, and lower adverse effects than conventional pharmacology in the treatment of osteoarthritis. In this review, we have summarized the chondroprotective properties of bioactive compounds used for the management, treatment, or prevention of osteoarthritis in both human and animal studies. However, further research is needed into bioactive compounds used as epigenetic modulators in osteoarthritis, in order to determine their potential value for future clinical applications in osteoarthritic patients as well as their relation with the genomic and nutritional environment, in order to personalize food and nutrition together with disease prevention.

The Abrasive Effect of Moon and Mars Regolith Simulants on Stainless Steel Rotating Shaft and Polytetrafluoroethylene Sealing Material Pairs.

For space missions to either the Moon or Mars, protecting mechanical moving parts from the abrasive effects of prevailing surface dust is crucial. This paper compares the abrasive effects of two lunar and two Martian simulant regoliths using special pin-on-disc tests on a stainless steel/polytetrafluoroethylene (PTFE) sealing material pair. Due to the regolith particles entering the contact zone, a three-body abrasion mechanism took place. We found that friction coefficients stabilised between 0.2 and 0.4 for all simulants. Wear curves, surface roughness measurements, and microscopic images all suggest a significantly lower abrasion effect of the Martian regoliths than that of the lunar ones. It applies not only to steel surfaces but also to the PTFE pins. The dominant abrasive micro-mechanism of the disc surface is micro-ploughing in the case of all tests, while the transformation of the counterface is mixed. The surface of pin material is plastically transformed through micro-ploughing, while the material is removed through micro-cutting due to the slide over hard soil particles.

Changes in chemical characteristics and toxicity of fluoxetine and humic acid during chlorination

The coexistence of emerging pollutants and dissolved organic matter in wastewater complicates the transformation and generation of disinfection byproducts (DBPs) during chlorination treatment, which is essential for effective water quality evaluation and chlorination optimization. This study used fluoxetine (FLX) and humic acid (HA) as representative substances to analyze changes in their chemical characteristics and zebrafish embryonic developmental toxicity under different chlorination conditions. The analysis of the fluorescence characteristics and Fourier transform ion cyclotron resonance mass spectrometry indicated that chlorination treatment increased the aromatic compound content of the HA solution. FLX addition further increased the presence of aromatic ring structures and oxidized molecules, resulting in the formation of numerous Cl-DBPs with highly unsaturated and phenolic structures. Moreover, different responses in zebrafish embryo development and behavior were found with FLX, HA, and FLX + HA exposures. Cardiotoxicity was linked to changes in the concentration of cTn-I protein and expression of various genes. Prolonged chlorination conditions showed higher toxicities. Correlation analysis found a weak relation between chemical indicators and toxicity data, indicating that both analysis methods need to be considered when analyzing the impact of the chlorination. Further, a combination of chemical analyses and toxicity tests revealed that the FLX + HA solution with chlorination conditions of 3 mg/L for 30 min had lower chemical and toxic effects in this experiment. This study provides valuable scientific insights for the safe discharge of chlorinated water containing FLX and dissolved organic matter, as well as guidance for optimizing chlorination parameters in wastewater treatment.

Establishment of a Flow-Through System for the Macrophyte Growth Inhibition Test (OECD 239) Including Photosynthetic Activity Measurement to Determine Early Effects.

Maintaining constant exposure concentrations during ecotoxicological studies while testing rapidly degradable substances is a challenge. To achieve stable concentrations during exposure, flow-through systems are used. To assess the impact of substances on higher aquatic plants, the 14-day macrophyte water-sediment Myriophyllum spicatum growth inhibition test (Organisation for Economic Co-operation and Development [OECD, 2014a] test guideline 239) only includes a static or a semistatic test design. The main aim of our study was to investigate the applicability of a flow-through system for M. spicatum. The standard OECD test design was miniaturized, and a flow-through system with spill-over was developed to achieve stable exposure concentrations of a rapidly degrading substance. The main endpoints were total shoot length and fresh and dry weight. Photosynthetic activity was used as an endpoint for the identification of early effects using the noninvasive Image-Producing Pulse Amplitude Modulation (IMAGING-PAM) procedure. Atorvastatin (AV; fast degrading) and bentazone (BT; photosynthesis inhibitor) were used as model substances to observe differences of the effect concentration depending on the test design. At higher exposure levels of AV, stronger necrosis combined with lower effect concentrations was observed in the flow-through test compared with the semistatic test, indicating the applicability of the flow-through test for evaluating degradable substances. The test with BT demonstrated a concentration-dependent decrease in the photosynthetic yield (Y(II)) from day 3 onward even before macroscopically visible changes occurred. Our results show that the flow-through system in the macrophyte growth inhibition test (OECD test guideline 239; 2014a) is a suitable alternative when one is testing rapidly degradable substances such as AV. In addition, we showed that photosynthetic yield can serve as a supplementary endpoint, when one is testing substances with photosynthesis inhibition as a mode of action. Environ Toxicol Chem 2024;00:1-12. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Effect of Surfactants on Eliminating Stable Ultrafine Chalcopyrite Froth.

Chalcopyrite is a primary source of copper in nature. However, with the increasing need to process low-grade and complex chalcopyrite ores, overly stable froth is becoming more and more common and poses operational and safety challenges. No reliable strategy has been developed to address the issue. As a new initiative, this study investigated three different structured surfactants, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), and pentadecafluorooctanoic acid (PFOA), which vary in hydrophobic group, aiming to modify the surfaces of ultrafine chalcopyrite particles and adjust the interfacial tension at the gas-liquid interface to eliminate stable ultrafine chalcopyrite froth. The fundamental hypothesis was that an ideal surfactant structure could adjust the particle surface wettability and interfacial tension to eliminate overly stable froth. Based on contact angle measurements and interfacial tension measurements using a Theta Flow tensiometer by the pendant drop method and the sessile drop method, it was demonstrated that the contact angle played a dominant role in defoaming, while the reduction of gas-liquid interfacial tension had an adverse effect. Additionally, defoaming tests indicated that SDBS had lower defoaming effectiveness than SDS at low surfactant concentrations due to the steric hindrance in its structure, whereas the addition of SDBS could achieve a froth reduction efficiency as high as 93.75% at higher surfactant concentrations due to its stronger hydrophobicity and adsorption capacity to chalcopyrite particles, which could reduce the contact angle from 70 to 37.62°. However, PFOA exhibited lower defoaming effectiveness than both SDS and SDBS due to its lipophobic fluorocarbon tail of PFOA and weaker adsorption capacity to chalcopyrite particles, making it unsuitable for eliminating stable ultrafine chalcopyrite froth.

Impacts of quantum confinement effect on threshold voltage and drain-induced barrier lowering effect of junctionless surrounding-gate nanosheet NMOSFET including source/drain depletion regions

In order to modeling of junctionless (JL) surrounding-gate (SG) nanosheet MOSFET more accurately, a new model for determining threshold voltage and drain-induced barrier lowering (DIBL) effect of JL SG nanosheet NMOSFET is proposed through deriving the Poisson's equation under rectangular coordinate system. The model captures quantum confinement effect and source/drain depletion regions, it is validated through the Sentaurus TCAD simulation results. Variations of source/drain depletion regions with the channel width, height, doping concentration, the gate bias, the drain bias and variations of threshold voltage, DIBL with the channel width, height, doping concentration considering and not considering quantum confinement effect are studied, respectively. The results show influences of quantum confinement effect on source/drain depletion regions, threshold voltage and DIBL. The developed model will offer quantum corrections in JL SG nanosheet NMOSFET.

Alignment of behaviour and tDCS stimulation site induces maximum response: evidence from online tDCS and ERP

tDCS modulates the activity of the neuronal networks to induce the desired behavioural changes. Two factors determine its effectiveness- (1) whether the network being stimulated is relevant to the task, and (2) if there is a scope for improvement in behavioral performance. To explore this, both dorsal (sub-lexical) and ventral (lexical) reading networks were stimulated (20 min, 2 mA) in 25 healthy young volunteers. Participants performed two reading tasks with different levels of lexical involvement: word fragment completion tasks (WCT) and word association tasks (WAT), while event-related potentials (ERPs) were recorded simultaneously. The study used a within-subject design over three sessions, comparing various electrode montages targeting the dorsal pathway's left inferior parietal lobule or the ventral reading pathway's left middle temporal lobule, as well as sham stimulation. The impact of tDCS sessions (dorsal, ventral, & sham) and task type (WCT & WAT) on priming effects (primed vs. unprimed) of behavioral performance (accuracy and reaction times), and ERP parameters (N400 amplitudes and latencies) were statistically analyzed.It was found that tDCS modulated the performance of WAT only (a task with a lower priming effect). The failure to modulate WCT (larger priming effect) indicated that tDCS was effective for conditions with room for improvement compared to a task where performance has reached the ceiling. Ventral stimulation enhanced accuracy in the WAT condition and shortened the N400 latency of the priming effect. In contrast, dorsal stimulation delayed the priming effect reaction time in the WAT condition and enhanced the N400 amplitude. To conclude, enhancement in performance due to tDCS occurs when the network (ventral) being stimulated aligns with the cognitive demands of the task and there is a scope for improvement.

Simulation of Novel Nano Low-Dimensional FETs at the Scaling Limit.

The scaling of bulk Si-based transistors has reached its limits, while novel architectures such as FinFETs and GAAFETs face challenges in sub-10 nm nodes due to complex fabrication processes and severe drain-induced barrier lowering (DIBL) effects. An effective strategy to avoid short-channel effects (SCEs) is the integration of low-dimensional materials into novel device architectures, leveraging the coupling between multiple gates to achieve efficient electrostatic control of the channel. We employed TCAD simulations to model multi-gate FETs based on various dimensional systems and comprehensively investigated electric fields, potentials, current densities, and electron densities within the devices. Through continuous parameter scaling and extracting the sub-threshold swing (SS) and DIBL from the electrical outputs, we offered optimal MoS2 layer numbers and single-walled carbon nanotube (SWCNT) diameters, as well as designed structures for multi-gate FETs based on monolayer MoS2, identifying dual-gate transistors as suitable for high-speed switching applications. Comparing the switching performance of two device types at the same node revealed CNT's advantages as a channel material in mitigating SCEs at sub-3 nm nodes. We validated the performance enhancement of 2D materials in the novel device architecture and reduced the complexity of the related experimental processes. Consequently, our research provides crucial insights for designing next-generation high-performance transistors based on low-dimensional materials at the scaling limit.