The current pharmacological pretreatment and medical treatment of nerve agent poisoning is an insufficiently addressed medical task. The prophylactic efficacy of a novel compound acting dually as an acetylcholinesterase inhibitor and NMDA receptor antagonist (K1959) and the therapeutic efficacy of a novel NMDA receptor antagonist (K2060) were evaluated in the NMRI mice model of nerve agent poisoning by tabun, soman and sarin. Their added value to the standard antidotal treatment (a combination of oxime reactivator and atropine) was also analyzed. The novel dually acting prophylactic drug (K1959) did not bring any additional benefit compared to the commonly used pyridostigmine. By contrast, an increase in the therapeutic efficacy of classic antidotal treatment was observed when the novel NMDA receptor antagonist (K2060) was combined with commonly used antidotes (oxime reactivator in combination with atropine). This novel combination reduced the acute toxicity of tabun, soman, and sarin more than two-fold, four-fold, and five-fold, respectively. These results highlight the possibility of NMDA antagonists such as K2060 as a supportive drug for the classic therapy of organophosphorus poisoning.

Nonalcoholic Steatohepatitis (NASH) is a common liver disease with limited treatment options. Oxymatrine (OMT) has been reported to treat liver diseases effectively. This study aims to explore the mechanisms of OMT in NASH. Male Sprague-Dawley rats were fed a high-fat and high-sucrose diet and hepatocytes were stimulated with oleic acid (OA) to establish NASH models, then, NASH models were intervened with OMT. In vivo, liver injury and lipid accumulation extents were evaluated by serum and liver biochemical indexes, and histological analysis. In vitro, cell viability and lipid accumulation degrees were measured. Additionally, the relationships between perilipin 2 (Plin2) and liver X-activated receptor alpha (LXRα) as well as Plin2 and sterol regulatory element binding protein-1c (SREBP-1c), sirtuin 1 (Sirt1)/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway-, liver X-activated receptor (LXR)/Plin2/SREBP-1c pathway- and lipid synthesis-related proteins were detected both in vivo and in vitro. Finally, Sirt1 was knocked down in hepatocytes. OMT not only reduced serum alanine aminotransferase activity and triglyceride content, liver triglyceride and free fatty acid levels in NASH rats, but also improved hepatic injury and lipid accumulation. In vitro, OMT enhanced viability, and downregulated lipid accumulation in OA-induced hepatocytes. Both in vivo and in vitro results revealed Plin2 directly interacted with LXRα and SREBP-1c, and OMT activated Sirt1/AMPK pathway but inhibited the expressions of LXR/Plin2/SREBP-1c pathway and lipid synthesis (acetyl-CoA carboxylase, fatty acid synthase, stearoyl-Coenzyme A desaturase 1) related proteins in NASH models. Importantly, Sirt1 knockdown reversed the protective effects of OMT in OA-stimulated hepatocytes. OMT may reduce hepatic lipid synthesis in NASH by activating the Sirt1/AMPK pathway and inhibiting the LXR/Plin2/SREBP-1c pathway, suggesting that OMT may be a promising strategy for treating NASH.

This study involves the design, divergent synthesis, conformational and structural analysis, target prediction, and molecular docking simulations of novel nano N-thiazolylpyridylamines 2-7 and 10 as potential cyclin-dependent kinase 2 (CDK2) inhibitors. Using a divergent synthesis approach, the compounds were designed with structural variation and optimization in mind. The conformational and structural properties were explored through various spectroscopic techniques, confirming the structure, stability, and preferred conformations. Additionally, nanocrystalline characterization, including X-ray diffraction analysis, revealed the nanoscale structural features of the synthesized molecules. Most compounds exhibited a crystalline nature with crystallite sizes ranging from 10.75 to 57.77 nm, which is crucial for improving cellular uptake and anticancer efficacy. Biological testing was performed to evaluate the cytotoxicity of compounds 2-7 and 10 against cancer cell lines, including HepG2, MCF-7, and HCT-116. Compound 5 exhibited significant cytotoxicity with IC values of 10.9 ± 0.5 μM, 6.98 ± 0.3 μM, and 6.3 ± 0.2 μM against MCF-7, HePG2, and HCT116, respectively. Other compounds demonstrated varied activities, with compounds 4, 6, and 10 showing moderate activity against the MCF-7 cell line. Computational techniques suggested a strong probability of these compounds targeting CDK2, with molecular docking and dynamics used to predict their binding mechanisms. These findings suggest that N-thiazolylpyridylamines may serve as new anticancer agents for further lead optimization.

Capsaicin, a polyphenol, is known to regulate energy expenditure and thermogenesis in adipocytes and muscles. However, its role in modulating uncoupling proteins (UCPs) and adenosine triphosphate (ATP)-dependent thermogenesis in muscles remains unclear. This study investigated the mechanisms underlying the role of capsaicin in modulating the UCP- and ATP-dependent thermogenesis in C2C12 myoblasts, as well as the gastrocnemius (GM) and soleus muscles (SM) of mice. We employed molecular dynamics (MD), quantitative real-time polymerase chain reactions (qRT-PCR), immunoblots, staining methods, and assay kits to investigate the role of capsaicin on thermogenesis and its modulatory roles on the transient receptor potential cation channel subfamily V member 1 (TRPV1) and α-/β-adrenergic receptors (ARs) using in vitro and in vivo models. Our findings demonstrate that capsaicin treatment in high-fat diet-induced obese mice reduces weight gain and elevates the expression of UCP- and ATP-dependent thermogenic effectors through ATP-consuming calcium and creatine futile cycles. In vitro and in vivo models capsaicin treatment elevated the expression of sarcoendoplasmic/endoplasmic reticulum calcium ATPases (SERCA-1 and -2), ryanodine receptors (RYR-1 and -2), uncoupling proteins (UCP-2 and -3), creatine kinase B (CKB), and creatine kinase mitochondrial 2 (CKMT2), through activation of TRPV1, α1-, β2-, and β3-AR as well as the suppressed expression of α2-AR. Furthermore, our results also indicate that capsaicin promotes myotube development and enhances lipid metabolism in C2C12 cells. We found that capsaicin increased intracellular Ca levels and the expression of the voltage-dependent anion channel (VDAC) and mitochondrial calcium uniporter (MCU), suggesting that elevated mitochondrial Ca levels boost the expression of oxidative phosphorylation protein complexes via the activation of the ATP-futile cycle. Mechanistic studies in C2C12 cells revealed that TRPV1 is likely dispensable for capsaicin-induced thermogenesis, and TRPV1 and α1-AR may synergistically induce thermogenesis. Collectively, our findings have uncovered a novel mechanism of UCP- and ATP-dependent thermogenesis and its associated pathways in both cellular and animal models which is crucial for designing therapeutic strategies to address obesity and associated metabolic diseases.

Microcystins (MCs) occur frequently during cyanobacterial blooms worldwide, representing a group of currently about 300 known MC congeners, which are structurally highly similar. Human exposure to MCs via contaminated water, food or dietary supplements can lead to severe intoxications with ensuing high morbidity and in some cases mortality. Currently, one MC congener (MC-LR) is almost exclusively considered for risk assessment (RA) by the WHO. Many MC congeners co-occur during bloom events, of which MC-LR is not the most toxic. Indeed, MC congeners differ dramatically in their inherent toxicity, consequently raising question about the reliability of the WHO RA and the derived guidance values. Molecular dynamics (MD) simulation can aid in understanding differences in toxicity, as experimental validation for all known MC congeners is not feasible. Therefore, we present MD simulations of a total of twelve MC congeners, of which eight MC congeners were simulated for the first time. We show that depending on their structure and toxicity class, MCs adapt to different backbone conformations. These backbone conformations are specific to certain MC congeners and can change or shift to other conformations upon binding to PPP1, affecting the stability of the binding. Analysis of the interactions with PPP1 demonstrated that there are frequently occurring patterns for individual MC congeners, and that published PPP interactions could be reproduced. In addition, common but also unique patterns were found for individual MC congeners, suggesting differences in binding behaviour. The MD simulations presented here therefore enhance our understanding of MC congener-specific differences and demonstrated that congener-specific investigations are prerequisite for allowing characterisation of yet untested or even unknown MC congeners, thereby allowing for a novel potential approach in support of an improved RA of microcystins in humans.

As a fundamental component of antitumor therapy, chemotherapy-induced cardiotoxicity (CIC) has emerged as a leading cause of long-term mortality in patients with malignant tumors. Unfortunately, there are currently no effective therapeutic preventive or treatment strategies, and the underlying pathophysiological mechanisms of CIC remain inadequately understood. A growing number of studies have shown that different mechanisms of cell death, such as apoptosis, pyroptosis, and necroptosis, are essential for facilitating the cardiotoxic effects of chemotherapy. The PANoptosis mode represents a highly synchronized and dynamically balanced programmed cell death (PCD) process that integrates the principal molecular characteristics of necroptosis, apoptosis, and pyroptosis. Recent research has revealed a significant correlation between PANoptosis and the apoptosis of tumor cells. Chemotherapy drugs can activate PANoptosis, which is involved in the development of cardiovascular diseases. These findings suggest that PANoptosis marks the point where the effectiveness of chemotherapy against tumors overlaps with the onset and development of cardiovascular diseases. Furthermore, previous studies have demonstrated that CIC can simultaneously induce pyrodeath, apoptosis, and necrotic apoptosis. Therefore, PANoptosis may represent a potential mechanism and target for the prevention of CIC. This study explored the interactions among the three main mechanisms of PCD, pyroptosis, apoptosis, and necroptosis in CICs and analyzed the relevant literature on PANoptosis and CICs. The purpose of this work is to serve as a reference for future investigations on the role of PANoptosis in the development and mitigation of cardiotoxicity associated with chemotherapy.

Betel quid contains two major ingredients; Areca catechu and Piper betel, often consumed with slaked lime, tobacco, certain flavouring agents, colouring agents, herbs, and spices according to personal preferences. The areca nut alkaloids (arecoline, arecaidine, guvacine, and guvacoline), and tobacco alkaloids (nicotine, nornicotine) undergo nitrosation during chewing in the oral cavity with the presence of nitrite and thiocyanate and endogenously. Among the nitrosation products generated areca nut-derived nitrosamine (ADNA): 3-(methylnitrosamino) Propionitrile (MNPN) and the two tobacco-specific nitrosamines (TSNAs); N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) are considered Group 1 human carcinogens. The slaked lime increases pH, reactive oxygen species (ROS) generation, and inflammation further lead to oral potentially malignant disorders (OPMD). The juice swallowed results in carcinogenicity, mutagenicity, and toxicity in the gastrointestinal tract including hepatocytic carcinoma, stomach, and colon cancer. Areca nut pre-treatments (sun drying, roasting, boiling, and fermentation) increase the quid metabolism, and reduce the arecoline content and associated risks. We review biochemical carcinogenesis of betel quid ingredients and synergic adverse effects and possible mechanism of carcinogenesis of betel quid in the oral cavity and gastrointestinal tract to understand the implication of polyphenols and alkaloids of areca nut and betel quid on carcinogenic nitrosamine formation under oral, gastric, and intestinal conditions.

As a replacement of bisphenol A, bisphenol S (BPS) is commonly used in the wrappers and food containers of daily life. Epidemiological studies demonstrate a close link between BPS exposure and vascular diseases, where the biological activities of BPS remain scarcely known. Herein, the effects of BPS on endothelial function as well as the underlying mechanism were investigated in human umbilical vein endothelial cells (HUVECs) and mouse arteries. It was found that exposure of BPS dose-dependently induced endothelial dysfunction (i.e., decline of nitric oxide (NO) formation) in HUVECs, accompanied by the increase of reactive oxygen species (ROS) production and loss of mitochondria membrane potential. Mitochondria-specific antioxidant (Mito-Tempol) or superoxide scavenger (tiron) abolished the harmful effects of BPS, while superoxide dismutase (SOD)-specific siRNA exhibited negative influence, suggesting that mitochondrial ROS was responsible for BPS-induced endothelial dysfunction and SOD was a sensitive target of BPS. Consistently, plasma NO formation and endothelium-dependent vasodilation was significantly impaired in mice exposed to dietary BPS. In addition, the binding of bovine serum albumin (BSA, the most abundant protein in blood) to BPS considerably alleviated ROS formation and endothelial dysfunction in HUVECs. BPS primarily interacted with Sudlow site I of albumin to generate BSA-BPS complex through static mechanism, in which the hydrogen bonds and electrostatic forces played important roles. Altogether, dietary exposure to emerging BPS would disrupt vascular homeostasis via the induction of mitochondrial ROS formation and consequent endothelial dysfunction, highlighting the detoxification impact of albumin protein on the hazardous effects of environmental pollutants.

The death rate due to liver cancer approaches 2 million annually, the majority is attributed to fibrosis. Currently, there is no efficient, safe, non-toxic, and anti-fibrotic drug available, suggesting room for better drug discovery. The current study aims to evaluate the anti-fibrotic role of reserpine, an alkaloid plant compound against CCl-induced liver fibrosis. In-silico docking analysis showed the interaction of reserpine with keap1 protein with the binding energy -9.0 kcal/mol. In-vitro, biochemical analysis, anti-oxidative indexes, and inflammatory cytokines analysis were performed in HepG2 cells. The non-toxic nature of the compound (<100 μg/ml) was evaluated through MTT assay in HepG2 and Vero cell lines. The antifibrotic potential of the reserpine compound (dose of 0.5 mg/kg) was assessed in CCl-administered C57BL/6J mice models. Hematoxylin & Eosin and Masson staining were performed to study the morphological changes of liver tissues. Immune histochemistry (IHC) analysis was performed to evaluate the effect of reserpine on the liver fibrosis marker. The biochemical assay indicated a significant decrease in ALT, AST, and MDA levels and increased catalase enzyme post-6-week reserpine treatment in mice models. Gene expression analysis revealed that the reserpine targets oxidative stress Keap1/Nrf2 pathway and down-regulated Keap1 expression by 5-fold and up-regulated Nrf2 and Nqo1 expression by 6 and 4.5-fold respectively showing its antioxidant response. It suppressed the expression of Cyp2e1 by 2.2-fold, illustrating the compound's ability to block lipid peroxidation. Histological and immunostaining exhibited improved hepatocyte morphology and reduced collagen deposition in liver tissues due to reserpine. Reserpine treatment lowered the fibrotic markers α-SMA and Col-1 by 1.3 and 1.5 folds respectively as compared to the control group and increased the expression of miR-200a and miR-29b by 15.5 and 8.2 folds (p < 0.05) while decreased miR-128-1-5p expression by 5-fold. A comprehensive In-silico, In-vitro, and In-vivo analysis revealed that reserpine has a strong anti-fibrotic effect against the CCl-induced liver fibrosis in C57BL/6J mice model by targeting the Keap1/Nrf2 pathway.

Copper, as a vital trace element and ubiquitous environmental pollutant, exhibits a positive correlation with the neurodegenerative diseases. Recent studies have highlighted ferroptosis's significance in heavy metal-induced neurodegenerative diseases, yet its role in copper-related neurotoxicity remains unclear. This study aimed to investigate the role of ferroptosis in copper-induced neurotoxicity. Previously, we established that copper induced motor behaviors inhibition and neuronal degeneration through oxidative stress in Caenorhabditis elegans (C. elegans). This study revealed that the behavior inhibition (head thrash, body bends, pumping frequency and defecation interval) and neuronal degeneration (GABAergic neurons and dopaminergic neurons) in copper-treated nematodes were reversed by the ferroptosis inhibitor Fer-1. Additionally, copper treatment increased the Fe level and MDA content, and decreased GSH content, suggesting copper activated the ferroptosis in C. elegans. Furthermore, studies found that copper exposure altered the expression of ferroptosis-related genes gpx-1, ftn-1, and acs-17 in C. elegans. The results showed RNAi of gpx-1 and RNAi of ftn-1 significantly promoted Cu-induced neurotoxicity, while the RNAi of acs-17 appeared to rescue the Cu-induced ferroptosis and neurotoxicity. In conclusion, Cu might induce behavior inhibition and neuronal degeneration through ferroptosis in C. elegans. The findings of this study provided new insights in the mechanisms underlying Cu-induced neurotoxicity.

Research has consistently linked exposure to particulate matter (PM) with adverse health outcomes, including cardiovascular and pulmonary morbidity and mortality. Understanding the mechanisms by which PM leads to these effects on human health is crucial for developing effective mitigation strategies. One aspect of PM research that has gained increased attention in the past few years is the bioaccessibility of inhaled PM-bound pollutants that have potential to cause adverse health effects. To assess the bioaccessibility of PM-bound pollutants, such as polycyclic aromatic hydrocarbons, phthalate esters, organophosphorus flame retardants and metal(loid)s, simulated lung fluids (SLF) are used as a tool to mimic the conditions in the human respiratory system. In addition to different SLF, various extraction methodologies and experimental conditions (e.g., incubation period, solid to liquid ratio, and pH) have been employed to extract the bioaccessible part of these pollutants, though there is not yet a standardised procedure to do so. This review aims to critically evaluate existing inhalation bioaccessibility methodologies and explore their connection with PM characteristics. More research is needed, and a standardised procedure should be implemented to allow the comparation of data between studies. Better in vitro-in vivo relationships need to be established to enhance the feasibility of in vitro bioaccessibility assays as surrogates in human health exposure assessments. Long-term effects of bioaccessible pollutants and any potential synergetic effects between multiple contaminants should also be explored to assess health repercussions more thoroughly.

The rock oyster, Saccostrea cucullata, native to the Indo-Pacific region, is renowned for its nutritional and therapeutic benefits. A sulfated glycosaminoglycan (SCP-2) with β-(1→3)-GlcNSp and α-(1→4)-GlcAp as recurring units isolated from S. cucullata. SCP-2 exhibited substantial 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibition potential (IC 0.65 mg/mL) in comparison with atorvastatin (IC 0.72 mg/mL). An in vitro study of SCP-2 (0.1-160 μg/dL) revealed a 77-89% reduction in triglyceride levels in control Caco-2 cells after 4 days of incubation, similar to atorvastatin-treated cells (90%). The acute dyslipidemic efficacy of SCP-2 (at 90 mg/kg body weight) showed timely alleviation of triglyceride and cholesterol levels in tyloxapol-induced rats (∼43% and 81% inhibition at 5 h), which was analogous to the atorvastatin treatment group (∼66% and 71%). Furthermore, SCP-2 (at 90 mg/kg body weight) showed mitigation in triglyceride (> 50%) and cholesterol levels (> 25%) in high-fat high-cholesterol (HFHC) diet-induced rats, similar to the lovastatin treatment group (approximately 62% and 33% inhibition on the 45 day). Histopathological studies of SCP-2 also showed recovery in steatosis, inflammation, and ballooning degradation in liver tissues. Structure-activity relationship analysis suggested the sulfate groups in SCP-2 enhance its anti-dyslipidemic efficacy. The capability of SCP-2 to mitigate cholesterol, triglyceride, and HMGCR levels makes it a prospective functional food against dyslipidemia-related disorders.

Epithelial-mesenchymal transition (EMT) is implicated in the pathogenesis of silicosis. High mobility group box 1 (HMGB1) has been found to induce EMT in fibrotic diseases. Previous studies have revealed a critical role of HMGB1 in silicosis, whereas the detail mechanisms still obscure. Here, we observed that HMGB1 protein was increased in the serum of silicosis patients and in the lung tissues of silicotic mice. The levels of HMGB1, receptor for advanced glycation end products (RAGE) and β-catenin protein were increased in the alveolar EMT cell model established by the treatment of transforming growth factor β1 (TGF-β1) and conditioned mediums derived from silica-stimulated macrophages. The activation of HMGB1, RAGE, β-catenin, EMT process, as well as cell migration triggered by TGF-β1 in RLE-6TN cells could be enhanced by treatment with recombinant HMGB1 protein (rHMGB1) and decreased by HMGB1 chemical inhibitor glycyrrhizin or RAGE inhibitor FPS-ZM1. And RAGE suppression could alleviate HMGB1-mediated the aggravation of β-catenin signaling, cell migration and EMT process induced by TGF-β1. Furthermore, both HMGB1 inhibition and RAGE knockout effectively alleviated the lung function impairment, EMT process, pulmonary inflammation and fibrosis in silicotic mice. These findings suggested that HMGB1 might promote EMT through RAGE/β-catenin axis in silicosis. And HMGB1 might constitute a therapeutic target for ameliorating the fibrosis of silicosis.

Prostate cancer, the second leading cause of cancer-related mortality in men, exhibits distinct metabolic reprogramming involving zinc and citrate metabolism. This study investigated whether targeting this unique metabolic profile could offer an effective therapeutic approach. A series of novel oxindole derivatives were synthesized and evaluated for their inhibitory effects on transcription factors (TFs) and antiproliferative activity across various cancer cell lines. Among these, compound 3D showed the strongest inhibition of master TFs (HIF-1α, c-Myc, and SP-1) and demonstrated selective antiproliferative activity in prostate cancer cells. In PC-3 and LNCaP cells, compound 3D suppressed aerobic glycolysis by downregulating lactate-modulating genes (LDHA, MCT1/4, and CAIX) and the zinc influx transporter (ZIP1), without affecting the zinc efflux transporter (ZnT4). Notably, 3D selectively increased heme oxygenase-1 (HO-1) levels in prostate cancer cells, as shown by the proteome profiler oncogene array assay and confirmed by Western blotting. This response was reversed by ZnCl treatment. The decreases in LDHA, mitochondrial mass (measured by FACS), and cell proliferation induced by compound 3D were blocked by HO-1-IN-1, an HO-1 inhibitor, and ZnCl. Furthermore, 3D induced a more pronounced reduction in the oxygen consumption rate (OCR) than in the extracellular acidification rate (EACR), indicating a strong effect on oxidative metabolism. 3D exhibited dose-dependent antitumour efficacy in vivo comparable to that of docetaxel. These findings reveal that the oxindole derivative 3D substantially lowers intracellular zinc levels, yielding potent antitumour effects in prostate cancer through HO-1 upregulation, which impairs mitochondrial function more significantly than aerobic glycolysis.

Hyperhomocysteinemia (HHcy) is associated with the development and progression of chronic cardiovascular diseases through the deleterious effects of high levels of homocysteine (Hcy) on the cardiovascular system. However, the exact mechanism of action of Hcy on the acute injury of the cardiovascular system following ischemia/reperfusion (I/R) remains unclear. The present study demonstrated that copper mobilization occurs during cardiac I/R, and the interactive toxic effect of Hcy and mobile Cu during cardiac I/R induces necroptosis of cardiac microvascular endothelial cells (CMECs) and thus enhances cardiac dysfunction. In the present study, we utilized three cardiac I/R model: isolated rat heart, in vivo model as well as cell culture, and demonstrated that copper mobilization occurs during cardiac I/R, and the interactive toxic effect of Hcy and mobile Cu during cardiac I/R induces necroptosis of cardiac microvascular endothelial cells (CMECs) and thus enhances cardiac dysfunction. Furthermore, we proved that the Cu chelator TTM significantly mitigated the deleterious effects of Hcy and Cu on CMECs and cardiac function both in vitro and in vivo. Mechanismly, the combinative effect of Hcy and Cu are associated with the production of reactive oxygen species (ROS) and nitric oxide (NO) by NADPH oxidase (NOX) and endothelial nitric oxide synthase (eNOS), respectively. Subsequently, the overproduction of toxic peroxynitrite (ONOO) induces CMECs necroptosis. The application of ROS scavengers in CMECs resulted in a notable reduction in necroptosis mediated by Hcy and Cu under hypoxia/reperfusion (H/R) condition. These findings indicate that the mechanism by which Hcy and Cu enhances cardiac dysfunction under I/R condition may be attributed to the stimulation of both NOX and eNOS activity, resulting in the generation of excessive ONOO and subsequent necroptosis of CMECs.

A series of eight gold(I) N-heterocyclic carbene (NHC) complexes [Au(IMes)(Ln)] based on 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene (IMes) and 7-azaindole derivatives (HLn), where n = 1-8 for HL1 = 5-fluoro-7-azaindole, HL2 = 5-bromo-7-azaindole, HL3 = 3-chloro-7-azaindole, HL4 = 3-iodo-7-azaindole, HL5 = 5-bromo-3-chloro-7-azaindole, HL6 = 5-bromo-3-iodo-7-azaindole, HL7 = 4-chloro-2-methyl-7-azaindole and HL8 = 7-azaindole, was prepared, characterised and studied for their in vitro anti-cancer and anti-inflammatory effects. The complexes showed significant cytotoxicity on human ovarian cancer cell lines (A2780, IC ≈ 8-19 μM and A2780R, IC ≈ 8-19 μM) and lowered toxicity in normal HaCat and MRC-5 cells. Cellular effects of the selected complexes 1 and 7 were evaluated in A2780 cells using flow cytometry. Moreover, the time-dependent cellular uptake in A2780 cells, a shotgun proteomic analysis, an ESI-MS study of hydrolysis and interactions with l-cysteine and reduced glutathione (GSH) were performed. Complexes 1 and 7 revealed remarkable anti-inflammatory effects via inhibition of NF-κB activity in human endothelial cells.

Glioblastoma is the most aggressive brain cancer in humans with very poor prognosis and high mortality rate. Despite advances in treatment, glioblastoma almost always recurs and new therapeutic methods are urgently needed. This study aimed at assessing the cytotoxic and antiproliferative effects of AM 1172 and cannabidiol (two cannabinoid receptor ligands) in vitro, when used alone and in combination with cisplatin (a standard cytotoxic drug), in various human neuroblastoma (CHP-134, KELLY), human glioblastoma (U-87MG and T98G) and rat glioblastoma (C6) cell lines. Our experiments showed that AM 1172 and cannabidiol inhibited cell proliferation with IC values in the range of 2.29-17.21 μM (for AM 1172) and 11.61-20.35 μM (for cannabidiol), respectively. The selectivity index for AM 1172 ranged from 0.61 to 4.60 and that for cannabidiol ranged from 1.45 to 2.55 in the studied glioblastoma and neuroblastoma cell lines. With isobolographic analysis, it was found that AM 1172 combined with cisplatin exerted a synergistic interaction in the CHP-134 cell line (p < 0.01). In contrast, AM 1172 when combined with cisplatin produced an antagonistic interaction in the C6 cell line (p < 0.01). The remaining combinations of AM 1172 with cisplatin in the U-87MG, KELLY and T98G cell lines were additive. In case of cannabidiol, its combination with cisplatin produced an antagonistic interaction in the T98G cell line (p < 0.0001), whereas the combinations of cannabidiol with cisplatin in the CHP-134, U-87MG, KELLY, and C6 cell lines were additive in nature. The synergistic and additive interactions for the combination of AM 1172 and cannabidiol with cisplatin seem to be a promising direction in glioblastoma therapy. Unfortunately, the combinations producing antagonistic interactions (AM 1172+cisplatin in C6, and cannabidiol + cisplatin in T98G cell lines) should be avoided due to the antagonistic antiproliferative effect of two-drug mixtures.

This study systematically evaluated the toxic effects of fluconazole on the cardiovascular development of zebrafish. Zebrafish embryos were treated with different concentrations of fluconazole (200, 400, and 800 μg/ml) to observe its impact on heart development, reactive oxygen species (ROS) generation, apoptosis, and hemoglobin production. The results showed that as the concentration of fluconazole increased, significant changes in zebrafish heart structure were observed, along with a notable reduction in heart rate. Pericardial edema and cardiac morphological abnormalities were particularly prominent in the high-dose group. In addition, fluconazole treatment significantly increased ROS levels and induced apoptosis in cardiac cells. Enzyme-linked immunosorbent assay (ELISA) results showed that fluconazole treatment significantly increased the malondialdehyde (MDA) content and reduced superoxide dismutase (SOD) and catalase (CAT) activity, suggesting that oxidative stress and cell death may play a key role in its cardiotoxicity. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that fluconazole treatment significantly affected the expression of several key genes related to heart development and function, particularly cardiac myosin light chain 2 (cmlc2), ventricular myosin heavy chain (vmhc), and myosin heavy chain 6 (myh6), whose expression changes were closely associated with alterations in heart morphology and function. Transcriptomic analysis showed that several signaling pathways related to cardiac development, apoptosis, and metabolism were affected. In summary, this study reveals the multifaceted cardiotoxic mechanisms of fluconazole in zebrafish and provides new insights into drug safety assessment.

3-Nitropropionic acid (3-NP) is a naturally occurring mycotoxin produced by various species of fungi and plants. However, the potential impact of 3-NP exposure on reproductive health remains unclear. To address this gap, we conducted an in vitro study to investigate the toxic effects of 3-NP on the developmental processes of mouse embryos. The results showed that embryos exposed to 50 μM 3-NP exhibited significant pre-implantation developmental arrest. Notably, most embryos were stalled at the 2-cell stage, indicating disruption of the normal developmental processes. Further analysis showed exposure to 3-NP altered embryonic gene expression, disrupted zygotic genome activation (ZGA) and maternal gene degradation (MGD), and therefore inhibited maternal-zygote transition (MZT). Moreover, 3-NP exposure led to mitochondrial dysfunction, which not only impaired cellular energy metabolism but also induced substantial intracellular oxidative stress, resulting in increased DNA damage. Additionally, we observed that 3-NP exposure caused alterations in embryonic epigenetic modifications, particularly the aberrant upregulation of histone methylation levels, including elevated H3K27me3 and H3K9me3, which are closely linked to gene expression silencing. In summary, the present study reveals the in vitro toxic effects of 3-NP on the developmental function of mouse embryos, suggesting potential adverse effects of 3-NP exposure on female reproductive health.

Oxidative stress induced by excess ethanol is an important factor in the progression of alcoholic liver disease (ALD). In recent years, inhibiting Kelch-like ECH-associated protein 1 (KEAP1) to activate the antioxidant regulator Nuclear factor erythroid 2-related factor 2 (NRF2) has been considered an effective strategy for treating oxidative stress-related diseases, but its application in ALD remains insufficiently explored. This study aims to discover high-affinity inhibitors targeting the KEAP1 receptor. We conducted virtual screening of a compound library based on a structure-based pharmacophore model, ultimately identifying the candidate compound Timosaponin B II (TBII). Subsequently, we established ALD models in AML-12 cells and C57BL/6 mice, and evaluated the therapeutic effects and mechanisms of TBII on ALD using methods including Immunofluorescence, Western blotting, RT-qPCR, Biochemical assays, and histological staining. Results indicate that TBII significantly improved ethanol-induced liver injury, inhibited the elevation of serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Total Cholesterol (T-CHO), and Triglycerides (TG) levels, and reduced lipid droplet accumulation in liver tissues. Furthermore, TBII treatment enhanced the antioxidant capacity of AML-12 cells and mouse liver, increasing Glutathione (GSH) and Superoxide Dismutase (SOD) levels while reducing Malondialdehyde (MDA) and Reactive Oxygen Species (ROS) levels. Mechanistic studies indicated that TBII inhibited the ethanol-induced increase in KEAP1 and reversed the ethanol-induced changes in NRF2 and its downstream targets. In conclusion, this study suggests that TBII may become a potential therapeutic agent for ALD by modulating the KEAP1-NRF2 pathway to alleviate oxidative stress and lipid metabolism abnormalities.

Gliomas constitute the most prevalent primary central nervous system tumors, often characterized by complex metabolic profile, genomic instability, and aggressiveness, leading to frequent relapse and high mortality rates. Traditional treatments are commonly ineffective because of gliomas increased heterogeneity, invasive characteristics and resistance to chemotherapy. Among several pathways affecting cellular homeostasis, cuproptosis has recently emerged as a novel type of programmed cell death, triggered by accumulation of copper ions. Although the precise molecular mechanisms of cuproptosis are not fully elucidated, there is evidence that copper ions can target mitochondrial lipoylated proteins, disrupting the tricarboxylic acid cycle and electron transport chain, thus leading to deregulated mitochondrial metabolism, protein aggregation and cell death. Of importance, altered expression of copper transporters and abnormally high intracellular copper levels have been observed in several cancer types, including gliomas, contributing to tumor growth and metastasis. Furthermore, a range of prognostic models incorporating cuproptosis-related genes and lncRNAs have been proposed and are currently under clinical validation. Drugs modulating cuproptosis or interfering with copper-binding proteins are under development, causing metabolic failure and cell death, thus offering potential new avenues for glioma diagnosis and therapy. In this article, we explore the role of copper metabolism in gliomas and the potential synergistic effects of cuproptosis-based treatments with current therapies, in effective targeting of tumor progression and chemoresistance.