Concentration-dependent Increase Research Articles

Eco-Friendly Mycogenic Synthesis of Iron Oxide Nanoparticles Using Volvariella volvacea and Unveiling its Potential as Antibiofilm and Anticancer Agents

Abstract This research explores the eco-friendly creation of functional, biocompatible nanomaterials through green chemistry, utilizing natural extracts over chemicals to produce metal and metal oxide nanoparticles. The study focuses on iron oxide nanoparticles synthesized with Volvariella volvacea (GIONP) and evaluates their physical, chemical, and biological traits, including their anticancer capabilities, against traditionally made IONPs (CIONP). GIONPs, confirmed by UV-visible spectroscopy and dynamic light scattering, showed enhanced stability and consistent size distribution. They also demonstrated smaller sizes via Fe-scanning electron microscopy analysis, and X-ray diffraction and Fourier transform infrared studies verified their crystalline structure and organic functional groups. Notably, GIONPs exhibited strong antioxidant properties, low toxicity to blood cells, promising for intravenous use, and greater antimicrobial and antibiofilm activities against various bacterial strains than CIONPs. The study revealed that both GIONPs and CIONPs exhibit a similar degree of toxicity towards MDA-MB 231 cancer cells. The internalization of GIONPs within these cells was verified through a Prussian blue assay and further supported by the concentration-dependent increase in intracellular iron levels post-treatment. These findings underscore the successful formulation of GIONPs that are not only biocompatible and eco-friendly but also capped with bioactive compounds, highlighting their promising applications in the field of biomedicine.

Antimicrobial Effects of Chitosan Extracted from Crayfish Shells in Cream Formulations

The objective of the present study was to investigate the antimicrobial properties of a chitosan-based cream. To achieve this, the antimicrobial effects a cream enriched with chitosan were compared with those of a control group. Chitosan, sourced from crayfish obtained frozen from Eğirdir Lake, Eğirdir, İsparta, served as the primary material. The study involved a comparison between control (F1) and treatment (F2) groups. While both cream formulations exhibited bacterial inhibition, only the F1 formulation demonstrated significant reduction in viable microorganisms for C. albicans. The cytotoxicity assessment revealed a concentration-dependent increase in cytotoxic effects of the samples. Notably, the F1 formulation exhibited higher toxicity on healthy cells compared to the F2 formulation. In conclusion, further investigation is necessary to understant the mechanisms underlying their cytotoxic effects and to optimize their formulations to enhance biocompatibility. Moreover, the chitosan-based cream developed in this study demonstrated notable antimicrobial efficacy against the tested bacteria.

Integrator complex subunit 6 promotes hepatocellular steatosis via β-catenin-PPARγ axis

Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, β-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r2 = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of β-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via β-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH.

Protective effects of Amauroderma rugosum on dextran sulfate sodium-induced ulcerative colitis through the regulation of macrophage polarization and suppression of oxidative stress

BackgroundAmauroderma rugosum (AR) is a medicinal mushroom commonly used to treat inflammation, gastric disorders, epilepsy, and cancers due to its remarkable anti-inflammatory and anti-oxidative properties. This study was designed to evaluate the pharmacological effects of AR and its underlying mechanism of action against ulcerative colitis (UC) in vitro and in vivo. MethodsA UC mouse model was established by administration of dextran sulfate sodium (DSS). AR extract was administered intragastrically to mice for 7 days. At the end of the experiment, histopathology, macrophage phenotype, oxidative stress, and inflammatory status were examined in vivo. Furthermore, RAW 264.7, THP-1, and Caco-2 cells were used to elucidate the mechanism of action of AR in vitro. ResultsAR extract (0.5–2 mg/mL) significantly suppressed lipopolysaccharide (LPS) and interferon-gamma (IFN-γ)-induced M1 macrophage (pro-inflammatory) polarization in both RAW 264.7 and THP-1 cells. LPS-induced pro-inflammatory mediators (nitric oxide, TNF-α, IL-1β, MCP-1, and IL-6) were reduced by AR extract in a concentration-dependent manner. Similarly, AR extract downregulated MAPK signaling activity in LPS-stimulated RAW 264.7 cells. AR extract elicited a concentration-dependent increase in the mRNA expression of M2 (anti-inflammatory) phenotype markers (CD206, Arg-1, Fizz-1, and Ym-1) in RAW 264.7 cells. Moreover, AR extract suppressed DSS-induced ROS generation and mitochondrial dysfunction in Caco-2 cells. The in vivo experiment revealed that AR extract (200 mg/kg) increased colon length compared to the DSS-treated group. In addition, disease activity index, spleen ratio, body weight, oxidative stress, and colonic inflammation were markedly improved by AR treatment in DSS-induced UC mice. Finally, AR suppressed M1 and promoted M2 macrophage polarization in UC mice. ConclusionThe AR extract protected against DSS-induced UC by regulating macrophage polarization and suppressing oxidative stress. These valuable findings suggest that adequate intake of AR can prevent and/or treat UC.

Self-Assembling Peptide-Based High-Relaxivity Targeted MRI Contrast Agents.

Concentration-dependent increases in relaxivity (r1) were found to be induced by self-assembly when Fmoc is adjacent to tryptophan in peptide-based MRI contrast agents featuring Gd-DOTA. A series of di- and tri-peptides were synthesized to test the effect of ionic strength, N-terminal substituent, peptide length, net charge, and relative location of Fmoc and tryptophan on r1 and critical aggregation concentration (CAC) at 1.0 Tesla. Compared to nominal r1 values of 3.5-7.4 mM-1s-1 per Gd(III), r1 values increased dramatically to 13.2-16.9 mM-1s-1 per Gd(III) upon self-assembly, with CACs between 0.22 and 2.59 mM when tested in H2O or PBS. When tested in fetal bovine serum (FBS), the compounds maintained high r1 values of 11.2-13.0 mM-1s-1, but had dramatically lower CAC values below 25 µM. These findings guided the synthesis of two targeted, high-relaxivity MRI contrast agents that contained PSMA-binding ligand, DCL. Their r1 values in H2O or PBS increased from 5.9-7.4 mM-1s-1 to 13.5-14.8 mM-1s-1 with CAC values of 1.65-2.70 mM. In FBS, their r1 values were found to be 11.2-11.9 mM-1s-1, with CAC values below 25 µM. By the conjugation of targeting agents in the last step of synthesis, a broadly applicable route to targeted, high-relaxivity MRI contrast agents is offered.

Chamber-specific contractile responses of atrial and ventricular hiPSC-cardiomyocytes to GPCR and ion channel targeting compounds: A microphysiological system for cardiac drug development

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) have found utility for conducting in vitro drug screening and disease modelling to gain crucial insights into pharmacology or disease phenotype. However, diseases such as atrial fibrillation, affecting >33 M people worldwide, demonstrate the need for cardiac subtype-specific cells. Here, we sought to investigate the base characteristics and pharmacological differences between commercially available chamber-specific atrial or ventricular hiPSC-CMs seeded onto ultra-thin, flexible PDMS membranes to simultaneously measure contractility in a 96 multi-well format. We investigated the effects of GPCR agonists (acetylcholine and carbachol), a Ca2+ channel agonist (S-Bay K8644), an HCN channel antagonist (ivabradine) and K+ channel antagonists (4-AP and vernakalant). We observed differential effects between atrial and ventricular hiPSC-CMs on contractile properties including beat rate, beat duration, contractile force and evidence of arrhythmias at a range of concentrations.As an excerpt of the compound analysis, S-Bay K8644 treatment showed an induced concentration-dependent transient increase in beat duration of atrial hiPSC-CMs, whereas ventricular cells showed a physiological increase in beat rate over time. Carbachol treatment produced marked effects on atrial cells, such as increased beat duration alongside a decrease in beat rate over time, but only minimal effects on ventricular cardiomyocytes. In the context of this chamber-specific pharmacology, we not only add to contractile characterization of hiPSC-CMs but propose a multi-well platform for medium-throughput early compound screening.Overall, these insights illustrate the key pharmacological differences between chamber-specific cardiomyocytes and their application on a multi-well contractility platform to gain insights for in vitro cardiac liability studies and disease modelling.

Fisetin induces G2/M phase arrest and caspase-mediated cleavage of p21Cip1 and p27Kip1 leading to apoptosis and tumor growth inhibition in HNSCC.

The anticancer potential and associated mechanisms of flavonoid fisetin are yet to be fully investigated on human head and neck squamous cell carcinoma (HNSCC). In the present study, fisetin (25-75 µM for 24-48 h) dose-dependently inhibited growth and induced death in HNSCC Cal33 and UM-SCC-22B cells, without showing any death in normal cells. Fisetin (25-50 µM) induced G2/M phase arrest via decrease in Cdc25C, CDK1, cyclin B1 expression, and an increase in p53(S15). A concentration-dependent increase in fisetin-induced DNA damage and apoptosis in HNSCC cells was authenticated by comet assay, gamma-H2A.X(S139) phosphorylation, and marked cleavage of PARP protein. Interestingly, fisetin-induced cell death occurred independently of p53 and reactive oxygen species production. The activation of JNK and inhibition of PI3K/Akt, ERK1/2, EGFR, and STAT-3 signaling were identified. Further, fisetin-induced apoptosis was mediated, in part, via p21Cip1 and p27Kip1 cleavage by caspase, which was reversed by z-VAD-FMK, a pan-caspase inhibitor. Subsequently, fisetin was also found to induce autophagy; nevertheless, autophagy attenuation exaggerated apoptosis. Oral fisetin (50 mg/kg body weight) treatment to establish Cal33 xenograft in mice for 19 days showed 73% inhibition in tumor volume (p < 0.01) along with a decrease in Ki67-positive cells and an increase in cleaved caspase-3 level in tumors. Consistent with the effect of 50 µM fisetin in vitro, the protein levels of p21Cip1 and P27Kip1 were also decreased by fisetin in tumors. Together, these findings showed strong anticancer efficacy of fisetin against HNSCC with downregulation of EGFR-Akt/ERK1/2-STAT-3 pathway and activation of JNK/c-Jun, caspases and caspase-mediated cleavage of p21Cip1 and p27Kip1.

Cellular and Genomic Instability Induced by the Herbicide Glufosinate-Ammonium: An In Vitro and In Vivo Approach.

Glufosinate-ammonium (GLA), an organophosphate herbicide, is released at high concentrations in the environment, leading to concerns over its potential genotoxic effects. However, few articles are available in the literature reporting the possible cellular and nuclear effects of this compound. We assessed, by in vitro and in vivo micronucleus assays, the genotoxicity of GLA on cultured human lymphocytes and Lymnaea stagnalis hemocytes at six concentrations: 0.010 (the established acceptable daily intake value), 0.020, 0.050, 0.100, 0.200, and 0.500 µg/mL. In human lymphocytes, our results reveal a significant and concentration-dependent increase in micronuclei frequency at concentrations from 0.100 to 0.500 μg/mL, while in L. stagnalis hemocytes, significant differences were found at 0.200 and 0.500 μg/mL. A significant reduction in the proliferation index was observed at all tested concentrations, with the only exception of 0.010 μg/mL, indicating that the exposure to GLA could lead to increased cytotoxic effects. In L. stagnalis, a significant reduction in laid eggs and body growth was also observed at all concentrations. In conclusion, we provided evidence of the genomic and cellular damage induced by GLA on both cultured human lymphocytes and a model organism's hemocytes; in addition, we also demonstrated its effects on cell proliferation and reproductive health in L. stagnalis.

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

Effects of Amyloid Beta (Aβ) Oligomers on Blood-Brain Barrier Using a 3D Microfluidic Vasculature-on-a-Chip Model.

The disruption of the blood-brain barrier (BBB) in Alzheimer's Disease (AD) is largely influenced by amyloid beta (Aβ). In this study, we developed a high-throughput microfluidic BBB model devoid of a physical membrane, featuring endothelial cells interacting with an extracellular matrix (ECM). This paper focuses on the impact of varying concentrations of Aβ1-42 oligomers on BBB dysfunction by treating them in the luminal. Our findings reveal a pronounced accumulation of Aβ1-42 oligomers at the BBB, resulting in the disruption of tight junctions and subsequent leakage evidenced by a barrier integrity assay. Additionally, cytotoxicity assessments indicate a concentration-dependent increase in cell death in response to Aβ1-42 oligomers (LC50 ~ 1 μM). This study underscores the utility of our membrane-free vascular chip in elucidating the dysfunction induced by Aβ with respect to the BBB.

Chronic toxicity of sediment-bound triclosan on freshwater walking catfish Clarias magur: Organ level accumulation and selected enzyme biomarker responses

Triclosan (TCS) is a biocide widely used in personal care and medicinal products. TCS persists in sediments and has been detected worldwide, making sediments a vital route of TCS exposure to aquatic organisms. This experiment explored the bioaccumulation and toxicological effects of TCS-contaminated sediment. The study revealed that the half-life of TCS in the sediment-water system was 21.52 days. Exposure of Clarias magur juveniles to 0.4 and 0.8 mg kg−1 TCS-spiked sediment resulted in high Biota-Sediment Accumulation Factor (BSAF) with the highest bioaccumulation in the liver (29.62–73.61 mg kg−1), followed by gill (9.22–17.57 mg kg−1), kidney (5.04–9.76 mg kg−1), muscle (2.63–4.87 mg kg−1) and brain (1.53–3.20 mg kg−1). Furthermore, a concentration-dependent increase in oxidative stress biomarkers such as superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) was documented during 45 days of exposure in gill, liver, kidney, muscle, and brain tissues of exposed fish. A similar increasing trend was also recorded for liver transaminase enzymes such as glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) during the experimental period compared to control. Serum biochemical analysis revealed a significant time and concentration-dependent increase in serum glucose, serum GOT, and serum GPT, while serum total protein and albumin decreased significantly during exposure. These findings demonstrate high bioaccumulative and toxic nature of TCS in fish, promoting multiple physiological and biochemical dysfunctions through sediment exposure. The study underscores the urgent need for strengthened regulations and robust monitoring of triclosan across various environmental matrices, including sediment, to mitigate the detrimental impacts of TCS effectively.

Abstract PO5-12-08: QTc prolongation as Adverse Effect of CDK4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials

Abstract Introduction: CDK4/6 inhibitors (CDK4/6i), such as abemaciclib, ribociclib, and palbociclib, have significantly improved outcomes for patients with ER+/HER2− breast cancer. Nevertheless, they differ among each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. Ribociclib causes concentration-dependent increases in the QTc interval, particularly in combination with tamoxifen. However, the pathogenesis of ribociclib-induced QTc prolongation remains unclear. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. Methods: We performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to compare QTc prolongation in patients using CDK4/6i in combination with hormonal agents to patients that did not use CDK4/6i, including neoadjuvant, adjuvant, or metastatic scenarios in breast cancer. We searched Embase, PubMed and Cochrane Library databases from inception to June 2023. The outcomes evaluated were QTc prolongation of all grades. Statistical analysis was performed with R software version 2023.03.0+386. Results: We included 14 RCTs comprising 16,013 patients in the quantitative analysis, of whom 8,585 underwent therapy with CDK4/6i, and one more paper was included only in the qualitative analysis due to not reporting the exact number of events of QTc prolongation. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR 2.32; 95% CI 1.67–3.23; p=0.000001; I²=46%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a risk ratio of 3.07 (RR 3.07; 95% CI 2.17-4.36; p&amp;lt; 0.000001; I² = 21%) while the palbociclib subgroup had a risk ratio of 1.52 (RR 1.51; 95% CI 1.05-2.16; p=0.025, I²=0%). Conclusion: Our findings suggest that QTc prolongation may be a common adverse effect of CDK4/6i, with ribociclib carrying greater risk. These results are important for guiding clinical decision-making, and further investigation is warranted to better understand the mechanisms and clinical implications of CDK4/6 i-induced QTc prolongation. Citation Format: Bruno Carvalho, Pedro Cotta Abrahão Reis, Alice Marinho, Ana Carolina Comini, Debora Xavier, Beatriz Mella S. Pessoa, Felipe Batalini. QTc prolongation as Adverse Effect of CDK4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-12-08.

Ataxia Telengectesia Protein Influences Bleomycin-Induced DNA Damage in Human Fibroblast Cells.

Human cancer is caused mainly by exposure to genotoxic chemicals; therefore, cellular defence mechanisms against genotoxic stress are crucial. Genetic factors are essential to maintaining genome stability and play a vital role in overcoming this by repairing the genome damage caused by any agent in order to prevent chromosomal instability. To examine the influence of the genetic makeup in specific ataxia-telangiectasia (ATM), we have examined non-cancerous fibroblast cell lines (HLF, AG1522 and L6) and cells with ATM mutated deficiency (GM4405). Cell lines were exposed in vitro to bleomycin (0, 40 and 80 µg/mL). The induced DNA damages were measured using endpoints including the micronucleus assay (MN) to measure chromosome damage and gamma-H2AX (γ-H2AX) assay to measure DNA damage/repair foci formation. An increase in DNA damage were observed in bleomycin-treated cells compared to unexposed controls (p < 0.05). A concentration-dependent increase of MN and γ-H2AX foci was observed and the sensitivity differed among the cell lines as follows: GM4405 > HLF > AG1522 > L6 for MN frequency and HLF > AG1522 > GM4405 > L6 for γ-H2AX foci. These findings suggest that the genetic makeup of the cellular genome would play an essential role in repairing bleomycin-induced DNA damage. Signalling of DNA damage, and the genes responsible for the repair process, could contribute to the differential susceptibility of different tissues to carcinomas induced by environmental mutagens.

Preventive Effect of Astaxanthin on Diabetic Cataracts and Its Protective Effect on Lens Epithelial Cells

To better combat the development of diabetic cataracts (DC), we conducted a study on the use of astaxanthin (ATX) as an innovative antioxidant. Our research found that ATX exhibited good biocompatibility with lens epithelial cells (LECs) and increasing its concentration did not reduce cell activity. In the presence of high glucose, LECs experienced elevated oxidative stress levels, leading to a significant inhibition of their activity. However, the addition of ATX increased the antioxidant levels in LECs, resulting in a concentration-dependent increase in cell activity. Furthermore, when tested on diabetic rat models, higher concentrations of ATX application effectively prevented the development of DC and suppressed the level of oxidative stress in the lens. Our findings highlight the strong antioxidant effect of ATX, which can safeguard LEC activity in the presence of high glucose and inhibit the development of DC.

The Contribution of Na+ or Cl− to Central NaCl−induced Cardiovascular Responses in Rodents

A high salt diet elevates plasma and cerebrospinal fluid NaCl concentrations in salt-sensitive hypertensive humans and animals. Acute or chronic intracerebroventricular (ICV) infusion of hypertonic NaCl elevates sympathetic nerve activity and blood pressure. However, it is unclear which ion, Na+ or Cl−, contributes to this response. The purpose of the present study was to investigate the extent to which acute increases in cerebrospinal fluid Na+ and Cl− increase ABP and HR in rodents. Male Sprague Dawley rats (n=6; body weight: 270-350 g) were anesthetized with isoflurane (2-3% in 100% O2) and instrumented with a lateral ventricle cannula for ICV infusions. Additionally, arterial and venous catheters were implanted to record BP and administer drugs, respectively. At least 4 days after recovery, ABP and HR were measured in response to ICV infusion (10uL over 10 min) of the following solutions: artificial cerebrospinal fluid (aCSF); 0.3 M and 0.6 M NaCl; 0.15 M and 0.3 M Na2SO4, and 0.3 M and 0.6 M NH4Cl. Each animal received one ICV infusion of each solution every other day. Data are presented as mean ± SE. Baseline ABP and HR did not differ across each ICV infusion (ABP: from 98 ± 6 mmHg to 106 ± 6 mmHg; and HR: from 337 ± 17 bpm to 363 ± 12 bpm). As expected, ICV infusion of 0.3 M and 0.6 M NaCl produced concentration-dependent increases in ABP (Δpeak ABP 0.3 M NaCl: 17 ± 2 mmHg; 0.6 M NaCl: 26 ± 3 mmHg). While ICV infusions of Na2SO4 at both concentrations also increased ABP, the magnitudes were reduced compared to NaCl (Δpeak ABP 0.15 M Na2SO4: 11 ± 2 mmHg; 0.3 M Na2SO4: 17 ± 3 mmHg). On the other hand, infusion of NH4Cl produced a modest increase in ABP (Δpeak ABP 0.3 M NH4Cl: 8 ± 2 mmHg and 0.6 M NH4Cl: 9 ± 3 mmHg). However, it did not differ from aCSF (Δpeak ABP aCSF: 6 ± 2 mmHg). HR responses induced by NaCl varied greatly (Δpeak HR 0.3 M NaCl: 15 ± 22 bpm; 0.6 M NaCl: 19 ± 17 bpm). In contrast, both concentrations of Na2SO4 consistently increased HR (Δpeak HR 0.15 M Na2SO4: 64±10 bpm; 0.3 M Na2SO4: 60±10 bpm). Additionally, ICV infusions of NH4Cl also tended to enhance HR (Δpeak HR 0.3 M NH4Cl: 38 ± 13 bpm and 0.6 M NH4Cl: 41 ± 23 bpm). To end, ICV infusion of aCSF increased HR by 18 ± 3 bpm. These results suggest that the NaCl−induced pressor response is largely attributed to Na+. However, Na+ alone cannot fully account for the NaCl−induced pressor response. NIH R01 HL163906, HL152680, HL145875. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association between maternal heavy metal exposure and Kawasaki Disease, the Japan Environment and Children's Study (JECS).

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting young children, with an unclear etiology. We investigated the link between maternal heavy metal exposure and KD incidence in children using the Japan Environment and Children's Study, a large-scale nationwide prospective cohort with approximately 100,000 mother-child pairs. Maternal blood samples collected during the second/third trimester were analyzed for heavy metals [mercury (Hg), cadmium (Cd), lead (Pb), selenium (Se), manganese (Mn)], divided into four quartiles based on concentration levels. KD incidence within the first year of life was tracked via questionnaire. Among 85,378 mother-child pairs, 316 children (0.37%) under one year were diagnosed with KD. Compared with the lowest concentration group (Q1), the highest (Q4) showed odds ratios (95% confidence interval) for Hg, 1.29 (0.82-2.03); Cd, 0.99 (0.63-1.58); Pb, 0.84 (0.52-1.34); Se, 1.17 (0.70-1.94); Mn, 0.70 (0.44-1.11), indicating no concentration-dependent increase. Sensitivity analyses with logarithmic transformation and extended outcomes up to age 3 yielded similar results. No significant association was found between maternal heavy metal levels and KD incidence, suggesting that heavy metal exposure does not increase KD risk.

In-vitro comparative study of solvent effect on antioxidant properties of leaf extracts of Anthocleista djalonensis

This study demonstrated that the extraction solvents play an important role in the extraction of important bioactive compounds with antioxidant properties from the leaves of Anthocleista djalonensis. Anthocleista djalonensis, a plant native to tropical Africa, is believed to have antioxidant properties due to its bioactive composition. The powdered leaves were macerated using local gin, hot distilled water, and analytical ethanol to extract bioactive compounds. The in vitro antioxidant activity of these extracts was assessed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assays, nitric oxide scavenging assay, and hydrogen peroxide scavenging assay. Ascorbic acid was used as a reference. The DPPH and hydrogen peroxide scavenging tests showed concentration-dependent responses. Distilled water had the lowest IC50 value of 0.079 mg/ml and showed the most antioxidant potential in DPPH. Local gin demonstrated significant hydrogen peroxide scavenging ability with an IC50 value of 0.12 mg/ml, surpassing the standard drug. The nitric oxide scavenging assay showed a concentration-dependent increase in both ethanol and local gin extracts. Ethanol and local gin extracts showed maximum antioxidant activity, with ethanol extract showing 22.84% inhibition and local gin extract showing a higher activity of 46.29% inhibition. However, ascorbic acid showed the highest inhibition of nitric oxide production at 57.10%. The study highlights the importance of solvent selection in herbal preparation for optimal health benefits regarding antioxidant activity.

Antimicrobial Activity, Cytotoxicity, and Qualitative Phytochemistry of Leaf, stem bark, and root bark extracts from Prunus africana (Hook. F.) Kalkman

The rise of resistant strains poses a significant public health risk, particularly, in sub-Saharan Africa, where over 50% of global infectious disease-associated deaths occur, highlighting the urgent need for novel, safe, affordable, and accessible antimicrobials. Accordingly, we investigated the antimicrobial activity, cytotoxicity, and qualitative phytochemistry of the aqueous, hydroethanolic, and acetonic leaf, stem bark, and root bark extracts of Prunus africana (Hook. F.) Kalkman, based on its ethnomedicinal information. The results showed the aqueous root bark and aqueous/acetonic stem bark extracts demonstrated significant (p&lt;0.05) antimicrobial efficacy against S. aureus at 800 µg/ml, outperforming other extracts and the reference antibiotic. Growth inhibition zones for most extracts on S. aureus showed a concentration-dependent increase, though not significantly (p&gt;0.05) different. The acetonic root bark extract, particularly at 800 µg/ml, exhibited superior inhibitory effects against B. cereus compared to other extracts (p&lt;0.05), although the positive control antibiotic significantly (p&lt;0.05) outperformed all plant extracts. Notably, none of the studied extracts affected P. aeruginosa and E. coli, while varying effects were observed against C. albicans. Further we observed that the hydroethanolic and aqueous stem bark extracts' exceptionally low Minimum Inhibitory and Bactericidal Concentrations (MICs and MBCs) against S. aureus (3.125 µg/ml). Conversely, the acetonic leaf extract showed higher MIC and MBC values against S. aureus (100 µg/ml). Cytotoxicity assessments using brine shrimp nauplii revealed the percentage mortalities caused by Vincristine and aqueous root/stem bark extracts at 1000 µg/ml, were significantly (p&lt;0.05) higher than those caused by other extracts (Median lethal concentrations (LC50) of 513 µg/ml to 24327.82 µg/ml). Qualitative phytochemistry identified alkaloids in root bark and stem bark extracts, flavonoids, phenols, quinones, steroids, and terpenoids across all samples, with saponins in acetonic root bark and all three leaf extracts, and glycosides in acetonic stem bark, hydroethanolic root bark, and acetonic leaf extracts. These findings highlight the diverse antimicrobial and cytotoxic properties of P. africana extracts, suggesting potential therapeutic applications and emphasise the need for further exploration.

Platycodin D Ameliorates Type 2 Diabetes-Induced Myocardial Injury by Activating the AMPK Signaling Pathway.

The current study aimed to assess the effectiveness of pharmacological intervention with Platycodin D (PD), a critically active compound isolated from the roots of Platycodon grandiflorum, in mitigating cardiotoxicity in a murine model of type 2 diabetes-induced cardiac injury and in H9c2 cells in vitro. Following oral administration for 4 weeks, PD (2.5 mg/kg) significantly suppressed the elevation of fasting blood glucose (FBG) levels, improved dyslipidemia, and effectively inhibited the rise of the cardiac injury markers creatine kinase isoenzyme MB (CK-MB) and cardiac troponin T (cTnT). PD treatment could ameliorate energy metabolism disorders induced by impaired glucose uptake by activating AMPK protein expression in the DCM mouse model, thereby promoting the GLUT4 transporter and further activating autophagy-related proteins. Furthermore, in vitro experiments demonstrated that PD exerted a concentration-dependent increase in cell viability while also inhibiting palmitic acid and glucose (HG-PA)-stimulated H9c2 cytotoxicity and activating AMPK protein expression. Notably, the AMPK activator AICAR (1 mM) was observed to upregulate the expression of AMPK in H9c2 cells after high-glucose and -fat exposure. Meanwhile, we used AMPK inhibitor Compound C (20 μM) to investigate the effect of PD activation of AMPK on cells. In addition, the molecular docking approach was employed to dock PD with AMPK, revealing a binding energy of -8.2 kcal/mol and indicating a tight interaction between the components and the target. PD could reduce the expression of autophagy-related protein p62, reduce the accumulation of autophagy products, promote the flow of autophagy, and improve myocardial cell injury. In conclusion, it has been demonstrated that PD effectively inhibits cardiac injury-induced type 2 diabetes in mice and enhances energy metabolism in HG-PA-stimulated H9c2 cells by activating the AMPK signaling pathway. These findings collectively unveil the potential cardioprotective effects of PD via modulation of the AMPK signaling pathway.

Vital role of oxidative stress in tadpole liver damage caused by polystyrene nanoparticles

Polystyrene nanoparticles are emerging as contaminants in freshwater environments, posing potential risks to amphibians exposed to extended periods of water contamination. Using tadpoles as a model, this study aimed to evaluate the toxicity of PS NPs. Pyrolysis-gas chromatography-tandem mass spectrometry (Py-GCMS) analysis revealed a concentration-dependent increase in polystyrene nanoparticles (PS NPs) levels in tadpoles with escalating exposure concentrations. Following exposure to 100 nm fluorescent microspheres, fluorescence was observed in the intestines and gills, peaking at 48 hours. Histopathological analysis identified degenerative necrosis and inflammation in the liver, along with atrophic necrosis of glomeruli and tubules in the kidneys. These results indicate a discernible impact of PS NPs on antioxidant levels, including reduced superoxide dismutase and catalase activities, elevated glutathione content, and increased malondialdehyde levels. Electron microscopy observations revealed the infiltration of PS NPs into Kupffer's cells and hepatocytes, leading to visible lesions such as nuclear condensation and mitochondrial disruption. The primary objective of this research was to elucidate the adverse effects of prolonged PS NPs exposure on amphibians.