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Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), a highly malignant tumour of the central nervous system, presents with a dire prognosis and low survival rates. The heterogeneous and recurrent nature of GBM renders current treatments relatively ineffective. In our study, we utilized an integrative systems biology approach to uncover the molecular mechanisms driving GBM progression and identify viable therapeutic drug targets for developing more effective GBM treatment strategies. Our integrative analysis revealed an elevated expression of CHST2 in GBM tumours, designating it as an unfavourable prognostic gene in GBM, as supported by data from two independent GBM cohorts. Further, we pinpointed WZ-4002 as a potential drug candidate to modulate CHST2 through computational drug repositioning. WZ-4002 directly targeted EGFR (ERBB1) and ERBB2, affecting their dimerization and influencing the activity of adjacent genes, including CHST2. We validated our findings by treating U-138 MG cells with WZ-4002, observing a decrease in CHST2 protein levels and a reduction in cell viability. In summary, our research suggests that the WZ-4002 drug candidate may effectively modulate CHST2 and adjacent genes, offering a promising avenue for developing efficient treatment strategies for GBM patients. [ABSTRACT FROM AUTHOR]

AbstractAcrylamide (ACR) can have adverse environmental effects because of its multiple applications. Relevant scientific literatures of the existence of ACR residues in foods following processing steps have raised concern in the biochemistry, chemistry and safety of this vinyl substance. The interest has focused on the hepatotoxicity of ACR in animals and humans and on the ACR content mitigation and its detoxification. Borax (BX), as a naturally occurring antioxidant featured boron compound, was selected in this investigation to assess its possible neuro-protective potential against ACR-induced neurotoxicity. Nrf2 axis signaling pathways and detoxification response to oxidative stress after exposure to ACR in brains of rainbow trout, and the effect of BX application on reducing ACR-induced neurotoxicity were investigated. Rainbow trout were acutely exposed to ACR (12.5 mg/L) alone or simultaneously treated with BX (0.75 mg/L) during 96h. The exposed fish were sampled at 48th and 96th and oxidative stress response endpoints, 8-OHdG, Nrf2, TNF-α, caspase-3, in addition to IL-6 activities and the levels of AChE and BDNF in brain tissues of rainbow trout (Oncorhynchus mykiss) were evaluated. Samples showed decreases in the levels of ACR-mediated biomarkers used to assess neural toxicity (SOD, CAT, GPx, AChE, BDNF, GSH), increased levels of MDA, MPO, DNA damage and apoptosis. ACR disrupted the Nrf2 pathway, and induced neurotoxicity. Inhibited activities’ expressions under simultaneous administration experiments, revealed the protective effects of BX against ACR-induced toxicity damage. The obtained data allow the outline of early multi-parameter signaling pathways in rainbow trout [ABSTRACT FROM AUTHOR]

Starting compound 1 was synthesized according to reference.1 Benzylidene thiazole pyrimidin-3(5H)-ones were synthesized reactions of 1 with bromoacetic acid and various aryl-aldehydes in the same vessel via one-step, unlike studies in the literature. Quantum chemical parameters and full geometry optimizations for all compounds were computed using DFT based on B3LYP. Cytotoxic action potential of synthesized compounds was evaluated using trypan blue dye exclusion and MTT assays in different cell lines including adenocarcinoma alveolar basal epithelial-like adherent A549 cells, the colon adenocarcinoma HT-29 cells, prostate adenocarcinoma DU-145 cells, and diploid ARPE-19 retinal pigment epithelial cells. Embryotoxicity and genotoxicity assessments were performed on pluripotent human embryonal carcinoma NT2 and human lymphocyte cells, respectively. Compound A1 exhibited good anticancer activity on A549 and DU-145 cell lines, and the compounds including A3, 4, 6, and 9 induced cytotoxicity on A549 cells. The compounds A1-10 also showed a good biosafety profile at relatively lower concentrations. [ABSTRACT FROM AUTHOR]

Nowadays, the unique features of nanoparticles (NPs) have encouraged new applications in different areas including biology, medicine, agriculture, and electronics. Their quick joining into daily life not only enhances the uses of NPs in a wide range of modern technologies but also their release into the aquatic environment causes inevitable environmental concerns. On the other hand boron exhibits key physiological effects on biological systems. This research was designed for evaluating the toxicity of magnetite nanoparticles (Fe3O4-MNPs) on aquatic organisms and obtaining data for the information gap in this area. In this study, Rainbow trout (Oncorhynchus mykiss) was considered as an aquatic indicator, and trials were designed as Ulexite (a boron mineral, UX) treatment against exposure to Fe3O4-MNPs. Synthesized and characterized Fe3O4-MNPs were exposed to rainbow trouts in wide spectrum concentrations (0.005–0.08 mL/L) to analyze its lethal dose (LC50) and cytoprotective properties by UX treatment were assessed against Fe3O4-MNPs applications for 96 h. For the initial toxicity analysis, hematological parameters (blood cell counts) were examined in experimental groups and micronucleus (MN) assay was performed to monitor nuclear abnormalities after exposure to NPs. Biochemical analyzes in both blood and liver samples were utilized to assess antioxidant/oxidative stress and inflammatory parameters. Also, 8-hydroxy-2'-deoxyguanosine (8-OHdG) assay was used to investigate oxidative DNA lesions and Caspase-3 analysis was performed on both blood and liver tissues to monitor apoptotic cell death occurrence. When antioxidant enzymes in blood and liver tissue were examined, time-dependent decreases in activity were determined in SOD, CAT, GPx, and GSH enzymes, while increased levels of MDA and MPO parameters were observed in respect to Fe3O4-MNPs exposure. It was found that TNF-α, Il-6 levels were enhanced against Fe3O4-MNPs treatment, but Nrf-2 levels were decreased at the 46th and 96th h. In the 96th application results, all parameters were statistically significant (p < 0.05) in blood and liver tissue, except for the IL-6 results. It was determined that the frequency of MN, the level of 8-OHdG and caspase-3 activity increased in respect to Fe3O4-MNPs exposure over time. Treatment with UX alleviated Fe3O4-MNPs-induced hematotoxic and hepatotoxic alterations as well as oxidative and genetic damages. Our findings offer strong evidence for the use of UX as promising, safe and natural protective agents against environmental toxicity of magnetite nanoparticles. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients. [ABSTRACT FROM AUTHOR]

Acetyl ferrocene (AFC) is being used commonly in several industrial applications and scientific diciplines. Hence, in this study we aimed to determine the LC50 value of AFC, and evaluate the toxicity potential by AFC exposure on rainbow trout (Oncorhynchus mykiss) for 96 h. We also focused to investigate whether UX conferred a protection against AFC-induced toxic insults in fish. For this purpose, some stress related endpoints were measured in blood and liver tissues in a multibiomarker approach. The exposure to AFC observed inhibition/induction of hematological parameters by AFC was slowed down after co-application with UX and AFC. However, UX was found to be ineffective for minimising AFC-induced micronucleus formation after 96 h. Moreover, it was determined that supplementation with UX exhibited activity in favour of antioxidants and inhibited MDA / MPO levels. Again, time-dependent inhibition of Nrf-2 levels, stimulation of IL-6 and TNF-α levels by AFC were ameliorated after co-application with UX. Ultimately, administration with UX suppressed the accumulation of 8-OHdG adducts and caspase-3 levels as compared to only AFC treatment. In a conclusion UX exerted significant protection potency against AFC-induced hematotoxic, oxidative, genotoxic and cytotoxic damages, hence could be a new source of natural protective agents in environment. [ABSTRACT FROM AUTHOR]

Background and Objectives: Favipiravir (FPV) is an antiviral medication and has an inhibitory effect on Cytochrome P450 (CYP2C8) protein, which is mainly involved in drug metabolism in the liver, and the expression of this gene is known to be enhanced in neuronal cells. The metabolization of Paclitaxel (PTX), a chemotherapeutic drug used in cancer patients, was analyzed for the first time in the human SH-SY5Y neuroblastoma cell line for monitoring possible synergistic effects when administered with FPV. Materials and Methods: Further, in vitro cytotoxic and genotoxic evaluations of FPV and PTX were also performed using wide concentration ranges in a human fibroblast cell culture (HDFa). Nuclear abnormalities were examined under a fluorescent microscope using the Hoechst 33258 fluorescent staining technique. In addition, the synergistic effects of these two drugs on cultured SH-SY5Y cells were determined by MTT cell viability assay. In addition, the death mechanisms that can occur in SHSY-5Y were revealed by using the flow cytometry technique. Results: Cell viability analyses on the HDFa healthy cell culture showed that both FPV and PTX have inhibitory effects at higher concentrations. On the other hand, there were no significant differences in nuclear abnormality numbers when both of the compounds were applied together. Cell viability analyses showed that FPV and PTX applications have higher cytotoxicity, which indicated synergistic toxicity against the SHSY-5Y cell line. Also, PTX exhibited higher anticancer properties against the neuroblastoma cell line when applied with FPV, as shown in both cytotoxicity and flow cytometry analyses. Conclusions: In light of our findings, the anticancer properties of PTX can be enhanced when the drug application is coupled with FPV exposure. Moreover, these results put forth that the anticancer drug dosage should be evaluated carefully in cancer patients who take COVID-19 treatment with FPV. [ABSTRACT FROM AUTHOR]

Micromeria fruticosa (L.) Druce subsp. serpyllifolia, which is widely used in folk medicine as a medicinal herbal tea, is grown in different areas of Turkey and the Mediterranean region. The present study was conducted to evaluate the aqueous extract of Micromeria fruticosa subsp. serpyllifolia for its antioxidant and antiproliferative activity on a human glioblastoma multiforme cell line (U-87 MG), which has not been reported before. Here, the extract was added to cultures at 8 different concentrations (0-200 μg/mL). Cell viability and cell membrane damage was determined using the MTT and LDH assays for 48 h, respectively. To examine the oxidative effects, total antioxidant capacity (TAC) and total oxidant status (TOS) levels were measured. The extract displayed considerable antiproliferative activities at the high concentrations of 175 and 200 μg/mL. Furthermore, the extract caused a significant increase in the release of the lactate dehydrogenase (LDH) enzyme in a concentration-dependent manner; 200 μg/mL of extract enhanced the release of LDH. Treatments with extract at higher doses increased TOS levels and decreased TAC levels in human U-87 MG cells. Our study suggests that the aqueous extract of Micromeria fruticosa ssp. serpyllifolia was capable of inducing growth inhibition of cancer cells. These results encourage further research to assess the value of the extract in modern phytotherapy.