Manganese (Mn) is an essential trace element involved in various physiological processes, but excessive exposure may lead to toxicity. The vascular endothelium, a monolayer of endothelial cells within blood vessels, is a primary target of Mn toxicity. This review provides a comprehensive overview of the impact of Mn on vascular endothelium, focusing on both peripheral and brain endothelial cells. In vitro studies have demonstrated that high concentrations of Mn can induce endothelial cell cytotoxicity, increase permeability, and disrupt cell-cell junctions through mechanisms involving oxidative stress, mitochondrial damage, and activation of signaling pathways, such as Smad2/3-Snail. Conversely, low concentrations of Mn may protect endothelial cells from the deleterious effects of high glucose and advanced glycation end-products. In the central nervous system, Mn can cross the blood-brain barrier (BBB) and accumulate in the brain parenchyma, leading to neurotoxicity. Several transport mechanisms, including ZIP8, ZIP14, and SPCA1, have been identified for Mn uptake by brain endothelial cells. Mn exposure can impair BBB integrity by disrupting tight junctions and increasing permeability. In vivo studies have corroborated these findings, highlighting the importance of endothelial barriers in mediating Mn toxicity in the brain and kidneys. Maintaining optimal Mn homeostasis is crucial for preserving endothelial function, and further research is needed to develop targeted therapeutic strategies to prevent or mitigate the adverse effects of Mn overexposure.

The number of available drugs for treating aquatic animals is insufficient, given the occurrence of a variety of parasites and difficulties in developing appropriate treatments, such as vaccines or immunostimulants. Consequently, repurposing livestock drugs for treating aquatic animals is a viable alternative. Several studies have demonstrated that albendazole (ABZ) is a good anthelmintic for humans and animals such as ruminants, poultry, and honeybees. Therefore, we investigated the toxicological studies, metabolic and residue depletion studies, and efficacy trials of ABZ in aquatic animals to identify its application potential as a drug for aquatic animals. ABZ was depleted within 24 h in the muscle tissues of hybrid striped bass, rainbow trout, and tilapia. In muscle tissue with adhering skin obtained from tilapia and largemouth bass, a significant quantity of the amino-sulfone metabolite of ABZ (ABZ-SO₂NH₂) was present, while no ABZ-SO₂NH₂ was detected in hybrid striped bass, channel catfish, and patinga. Fish exposed only to high doses of ABZ showed reduced red blood cell counts and hemoglobin levels and increased lymphocytes. Such signs of toxicity have also been observed in human patients and animal studies. At a dose of 100 mg/L, ABZ showed 100% efficacy in eels. In addition, albendazole sulfoxide (ABZSO) demonstrated efficacies of 96.1% and 100% in pirapatinga and ray-finned fish, respectively, at a dose 500 mg/L. ABZ was also highly effective in treating an intracellular parasite E. hepatopenaei in white shrimp. The application of ABZ in aquatic animals under the low-dose and short-term conditions is considered a reasonable solution to manage parasite infections. The types and residual periods of degradation products differed among fish species, suggesting dissimilar metabolic pathways. With a high demand for new alternative veterinary drugs in aquaculture by fish farmers, this review offers important evidence for considering the use of ABZ in Korean farmed fish, taking food safety issues into account.

Colorectal cancer (CRC) is one of the leading causes of death, accounting for more than half a million deaths annually. Even worse, an increasing number of cancer cases are diagnosed yearly, and two and a half million new cancer cases are estimated to be diagnosed in 2035. Some antipsychotic drugs, especially those targeting dopamine receptor (DR) D2, demonstrated anticancer activity. Studies have revealed the potential of DRD2 antagonists as anticancer therapeutics, whether alone or as an adjuvant, in treating breast cancer, lung cancer, and others. Emerging evidences indicate DRD2 is involved in the CRC biology, and the association between DRD2 and CRC could be utilized in treating CRC. This study selected DRD2 antagonists with anticancer activity to elucidate the possibility of DRD2 antagonists as new therapeutics for treating CRC.

This study aimed to investigate the neuroprotective effects of cerebroprotein hydrolysate (CPH) against oxidative stress-induced HT22 cell death. Additionally, the effect of antioxidants such as quercetin (QC) and N-acetyl-L-cysteine (NAC) on the neuroprotective activity of CPH was evaluated. The mouse-derived hippocampal neuronal cell line HT22 was pretreated with CPH or a mixture of CPH and QC or NAC. HT22 cell death was induced by either 10 mM glutamate, 2.5 μM amyloid-β (Aβ)_25-35, and 300 μM cobalt chloride (CoCl₂). As results, CPH effectively alleviated HT22 cell death induced by glutamate, Aβ_25-35, and CoCl₂. In addition, CPH combination with QC augmented cell viability in both glutamate- and Aβ_25-35-stressed conditions but had no synergic effect on the CoCl₂-stressed condition. The synergic effect of CPH and NAC combination was observed under all cell death conditions. The neuroprotective actions of CPH and its combinations with QC or NAC against various oxidative stress-induced HT22 cell deaths were demonstrated, providing a promising strategy for developing CPH preparations for the prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease.

With the development of artificial intelligence (AI), technologies based on machines and deep learning are being used in many academic fields. In toxicopathology, research is actively underway to analyze whole slide image (WSI)-level images using AI deep-learning models. However, few studies have been conducted on models for diagnosing complex lesions comprising multiple lesions. Therefore, this study used deep learning segmentation models (YOLOv8, Mask R-CNN, and SOLOv2) to identify three representative lesions (tubular basophilia with atrophy, mononuclear cell infiltration, and hyaline casts) of chronic progressive nephropathy of the kidney, a complex lesion observed in a non-clinical test using rats and selected an initial model appropriate for diagnosing complex lesions by analyzing the characteristics of each algorithm. Approximately 2000 images containing three lesions were extracted using 33 WSI of rat kidneys with chronic progressive nephropathy. Among them, 1701 images were divided into first and second rounds of learning. The loss and mAP50 values were measured twice to confirm the performances of the three algorithms. Loss measurements were stopped at an appropriate epoch to prevent overfitting, and the loss value decreased in the second round based on the data learned in the first round. After measuring the accuracy twice, detection using Mask R-CNN showed the highest mAP50 in all lesions among the three models and was considered sufficient as an initial model for diagnosing complex lesions. By contrast, the YOLOv8 and SOLOv2 models showed low accuracy for all three lesions and had difficulty with segmentation tasks. Therefore, this paper proposes a Mask R-CNN as the initial model for segmenting complex lesions. Precise diagnosis is possible if the model can be trained by increasing the input data, thereby providing greater accuracy in diagnosing pathological images.

Breast cancer has the highest incidence of all cancer types in women. Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancer cases and is the most aggressive type, with a poor prognosis and limited treatment. Treatment failure in patients is largely due to resistance to chemotherapy. In this study, we aimed to identify the novel factors contributing to chemoresistance in TNBC using cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We found that transactivation of the heme-binding protein 2 (HEBP2) gene was common in surviving colonies of cells after exposure to two types of chemotherapeutic agents, namely cisplatin and BCNU, from genome-scale transcriptional activation library screening in the TNBC cell line MDA-MB-231. Analysis of a public database (Proteogenomic Landscape of Breast Cancer, CPTAC) indicated that HEBP2 mRNA expression was elevated in TNBC tissues compared to that in non-TNBC tissues. HEBP2 facilitates necrotic cell death under oxidative stress; however, it is not yet known whether HEBP2 affects cancer cell survival following chemotherapy. Therefore, we investigated the effects of HEBP2 expression on the sensitivity to cisplatin and BCNU in MDA-MB-231 cells. Overexpression of HEBP2 significantly enhanced the viability of MDA-MB-231 cells in response to cisplatin and BCNU, but not methyl methanesulfonate (MMS) and paclitaxel. In contrast, CRISPR/Cas9-mediated HEBP2-knockout greatly reduced cell viability in response to cisplatin and BCNU, but not to MMS and paclitaxel, in MDA-MB-231 cells. Moreover, the exogenous introduction of HEBP2 restored the resistance of HEBP2-deficient cells to cisplatin and BCNU to wild-type levels. These findings suggest that HEBP2 may play a significant role in resistance to cisplatin and BCNU, which induce intrastrand and interstrand DNA crosslinks, but not to monoalkylating or microtubule-stabilizing agents in TNBC cells. The possibility exists that HEBP2 serves as a biomarker for predicting response or a therapeutic target for overcoming resistance to platinum-based and alkylating anticancer agents in TNBC.

The expanding applications of graphene oxide (GO) nanomaterials have attracted interest in understanding their potential adverse effects on embryonic and fetal development. Numerous studies have revealed the importance of the maternal gut microbiota in pregnancy. In this study, we established a mouse GO exposure model to evaluate embryo toxicity induced by intravenous administration of GO during pregnancy. We also explored the roles of gut microbiota and fecal metabolites using a fecal microbiota transplantation (FMT) intervention model. We found that administration of GO at doses up to 1.25 mg/kg caused embryo toxicity, characterized by significantly increased incidences of fetal resorption, stillbirths, and decreased birth weight. In pregnant mice with embryo toxicity, the richness of the maternal gut microbiota was dramatically decreased, and components of the microbial community were disturbed. FMT alleviated the decrease in birth weight by remodeling the gut microbiota, especially via upregulation of the Firmicutes/Bacteroidetes ratio. We subsequently used untargeted metabolomics to identify characteristic fecal metabolites associated with GO exposure. These metabolites were closely correlated with the phyla Actinobacteria, Proteobacteria, and Cyanobacteria. Our findings offer new insights into the embryo toxic effects of GO exposure during pregnancy; they emphasize the roles of gut microbiota-metabolite interactions in adverse pregnancy outcomes induced by GO or other external exposures, as demonstrated through FMT intervention.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), resulting in poor clinical outcomes and high mortality. The present study was aimed to evaluate the efficacy of Punicalagin (PCG), a polyphenol obtained from the Punica granatum, against TNBC. We evaluated the therapeutic potential of PCG in TNBC (MDA-MB-231, BT-20) and ER+(MCF-7) breast cancer cells. A dose-dependent inhibition of MDA-MB-231 cell proliferation was observed with PCG (12.5-100 µM). However, only 50 and 100 µM doses of PCG inhibited the growth of BT-20 and MCF-7 cells. PCG significantly increased mitochondrial ROS in TNBC cells and induced autophagy across all cell lines, as evidenced by an increase in autophagic vacuoles and a decrease in the ratio of LC3-II/LC3-I. PCG suppressed PI3K/Akt and activated phosphorylated c-Jun N-terminal kinase (p-JNK) signaling. Based on these findings, it can be concluded that PCG is capable of significantly inhibiting the proliferation of TNBC cells through the suppression of the PI3K/Akt pathway as well as the initiation of the JNK pathway. PCG could thus be potentially useful as a therapeutic agent for the treatment of TNBC.

MicroRNAs (miRNAs), molecules comprising 18-22 nucleotides, regulate expression of genes post-transcriptionally at the 3' untranslated region of target mRNAs. However, the biological roles and mechanisms of action of miRNAs in breast cancer remain unelucidated. Thus, in this study, we aimed to investigate the functions and possible mechanisms of action of miRNAs in breast cancer to suppress carcinogenesis. Using miRNA databases, we selected miR-34a and miR-605-5p to downregulate MDM4 and MDM2, respectively, because these ubiquitin E3 ligases degrade p53 and promote carcinogenesis. Results showed that miR-34a and miR-605-5p suppressed MDM4 and MDM2 expression, respectively. Moreover, they reduced the expression of yes-associated protein 1 (YAP1), a well-known oncogene involved in Hippo signaling, but upregulated the mRNA and protein expression of yippee-like 3 (YPEL3). To elucidate whether these miRNAs promote cellular senescence and death through YPEL3 upregulation, we examined their effects on cellular proliferation, SA-β-gal activity, and mitochondrial activity in human breast cancer MCF-7 cells. Given their upregulating effect on YPEL3 expression, miR-34a and miR-605-5p increased the number of β-galactosidase-positive cells and depolarized live cells (by 10%-12%). These data suggest that miR-34a and miR-605-5p promote cellular senescence and cell death. Thus, they may act as tumor suppressors by inducing Hippo signaling and may serve as novel therapeutic agents in breast cancer treatment.

Lead exposure has been implicated in the aetiopathogenesis of male infertility via an oxidative stress-sensitive pathway. Conversely, acetate has been shown to confer cellular protection by improving the antioxidant defense mechanism. Yet, the effect of acetate on lead-induced testicular toxicity, viz., dysregulation of testicular steroidogenesis and spermatogenesis, has not been reported. The present study probed the influence of acetate on lead-induced dysregulation of testicular steroidogenesis and spermatogenesis. In our study, a reduction in body weight gain and testicular weight was identified in lead-exposed rats. While histopathological results established distortion of testicular histoarchitecture, reduced germ cell count, and suppressed spermatogenesis, biochemical studies confirmed that lead-deregulated testicular steroidogenesis was associated with reduced circulating gonadotropin-releasing hormone and gonadotropins, as well as down-regulated testicular 3β-HSD and 17β-HSD activities. These findings were accompanied by increased testicular malondialdehyde, TNF-α, IL-1β, and IL-6, and reduced glutathione, thiol and non-thiol protein levels, total antioxidant capacity, superoxide dismutase, and catalase activities. In addition, lead exposure increased NFkB and Bax levels, as well as caspase 3 activity, but reduced Bcl-2 levels. However, co-administration of acetate ameliorated lead-induced alterations. Collectively, acetate attenuated lead-induced dysregulation of testicular steroidogenesis and spermatogenesis by targeting oxidative stress, NFkB-mediated inflammation, and caspase 3-driven apoptosis.

Pesticides are commonly employed to enhance agricultural productivity to meet the demands of the expanding global populace. Their harmful impact on non-target organisms is a severe cause of concern, and hence, new, presumably safer variants are developed. Flubendiamide is one such insecticide that targets caterpillars of insect pests. To evaluate its safety, we exposed early chicken embryos to technical-grade flubendiamide. Based on a dose range analysis, a lowest observed effect concentration (LOEC) of 25 ㎍/50µL (500 ppm) was selected for further experiments. LC-MS/MS analysis confirmed the presence of flubendiamide in the treated embryos. Gross morphology of embryos on days 2, 3 and 4 revealed reduced vascular area in the chorioallantoic membrane (CAM). The CAM vessel analysis showed reduced vascular networks in treated group. Hence, we hypothesized that flubendiamide, at LOEC, alters the expression patterns of the essential signaling molecules involved in angiogenesis, leading to compromised blood vessel development in CAM. An initial in silico study of flubendiamide was conducted with proteins involved in the CAM angiogenesis pathway. The docking scores revealed fubendiamide's direct influence on the functionality of angiogenic proteins. Hence, the expression patterns of key regulators of angiogenesis were studied on days 2, 3 and 4 at the transcript and protein levels. The results revealed a significant reduction in VEGFα, AKT, KDR, PCNA, PI3K, BMP2, BMP6, SHH and WNT7A expression in treated embryos, while expression of CASPASE-3 and RHOB were upregulated. Immunolocalization of Cl. Caspase-3 reaffirmed heightened apoptosis in the CAM of day 2 embryos. The study thus confirms that flubendiamide at a sublethal dose can hamper CAM angiogenesis and reduce the vascular networks in developing chick embryos by targeting the VEGF signaling cascade. This finding points to the teratogenic potential of flubendiamide and prompts throughput screening for safety.

Body odor is considered a diagnostic indicator of various infectious and chronic diseases. But, few studies have examined the odor markers for various toxic effects in the mammalian system. This study attempted to identify the novel diagnostic odor biomarkers for chemical-induced hepatotoxicity in animals. The changes in the concentration of odors were analyzed in the urine of Sprague Dawley (SD) rats treated with two dosages (100 or 200 mg/kg) of 1,2,3-trichloropropane (TCP) using gas chromatography-mass spectrometry (GC-MS). The TCP treatment induced significant toxicity, including a decrease in body weight, an increase in serum biochemical factors, and histopathological changes in the liver of SD rats. During this hepatotoxicity, the concentrations of six odors (ethyl alcohol, acrolein (2-propenal), methanesulfonyl chloride, methyl ethyl ketone, cyclotrisiloxane, and 2-heptanone) in urine changed significantly after the TCP treatment. Among them, acrolein, an acrid and pungent compound, showed the highest rate of increase in the TCP-treated group compared to the Vehicle-treated group. In addition, this increase in acrolein was accompanied by enhanced spermine oxidase (SMOX) expression, an acrolein metabolic enzyme, and the increased level of IL-6 transcription as a regulator factor that induces SMOX production. The correlation between acrolein and other parameters was conformed using correlagram analyses. These results provide scientific evidence that acrolein have potential as a novel diagnostic odor biomarker for TCP-induced hepatotoxicity.

Arsenic-induced diabetes, despite being a relatively newer finding, is now a growing area of interest, owing to its multifaceted nature of development and the diversity of metabolic conditions that result from it, on top of the already complicated manifestation of arsenic toxicity. Identification and characterization of the common and differentially affected cellular metabolic pathways and their regulatory components among various arsenic and diabetes-associated complications may aid in understanding the core molecular mechanism of arsenic-induced diabetes. This study, therefore, explores the effects of arsenic on human cell lines through 14 transcriptomic datasets containing 160 individual samples using in silico tools to take a systematic, deeper look into the pathways and genes that are being altered. Among these, we especially focused on the role of transcription factors due to their diverse and multifaceted roles in biological processes, aiming to comprehensively investigate the underlying mechanism of arsenic-induced diabetes as well as associated health risks. We present a potential mechanism heavily implying the involvement of the TGF-β/SMAD3 signaling pathway leading to cell cycle alterations and the NF-κB/TNF-α, MAPK, and Ca²⁺ signaling pathways underlying the pathogenesis of arsenic-induced diabetes. This study also presents novel findings by suggesting potential associations of four transcription factors (NCOA3, PHF20, TFDP1, and TFDP2) with both arsenic toxicity and diabetes; five transcription factors (E2F5, ETS2, EGR1, JDP2, and TFE3) with arsenic toxicity; and one transcription factor (GATA2) with diabetes. The novel association of the transcription factors and proposed mechanism in this study may serve as a take-of point for more experimental evidence needed to understand the in vivo cellular-level diabetogenic effects of arsenic.

The purpose of this study was to analyze the important medical events (IMEs) of anti-severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) monoclonal antibodies using the reports from the United States Food and Drug Administration (US FDA) adverse event reporting system (FAERS) and to detect safety signals. In this study, data from the FAERS from January 2020 to December 2022 were used to investigate signals associated with fve monoclonal antibody products (bamlanivimab, bamlanivimab/etesevimab, bebtelovimab, casirivimab/imdevimab, sotrovimab) in coronavirus disease 2019 (COVID-19) patients and one monoclonal antibody product (tixagevimab/cilgavimab) in patients wherein COVID-19 vaccination was not recommended. Disproportionality analyses were conducted using the reporting odds ratio, and an information component to identify safety signals. There were 17,937,860 drug AE reports associated with all drugs in the FAERS documented during research period. Among them, 42,642 were AE reports associated with anti-SARS-CoV-2 monoclonal antibodies. The SOCs including respiratory, thoracic and mediastinal, and vascular disorders were frequently reported for all the six products. The three most commonly detected IMEs were hypoxia, COVID-19 pneumonia, and anaphylactic reaction due to SARS-CoV-2 neutralizing antibodies. Even though the purposes of use were different, the types of signals between drugs were similar. Careful monitoring of these AEs should be considered for certain COVID-19 patients, at risk, when they are treated with monoclonal antibody products.

Pattern recognition receptor (PRR)-mediated inflammation is an important determinant of the initiation and progression of metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we investigated whether RIG-I is involved in hepatic metabolic reprogramming in a high-fat diet (HFD)-induced MASLD model in hepatocyte-specific RIG-I-KO (RIG-I^Δhep) mice. Our study revealed that hepatic deficiency of RIG-I improved HFD-induced metabolic imbalances, including glucose impairment and insulin resistance. Hepatic steatosis and liver triglyceride levels were reduced in RIG-I-deficient hepatocytes in HFD-induced MASLD mice, and this was accompanied by the reduced expression of lipogenesis genes, such as PPARγ, Dga2, and Pck1. Hepatic RIG-I deficiency alters whole-body metabolic rates in the HFD-induced MASLD model; there is higher energy consumption in RIG-I^Δhep mice. Deletion of RIG-I activated glycolysis and tricarboxylic acid (TCA) cycle-related metabolites in hepatocytes from both HFD-induced MASLD mice and methionine-choline-deficient diet (MCD)-fed mice. RIG-I deficiency enhanced AMPK activation and mitochondrial function in hepatocytes from HFD-induced MASLD mice. These findings indicate that deletion of RIG-I can activate cellular metabolism in hepatocytes by switching on both glycolysis and mitochondrial respiration, resulting in metabolic changes induced by a HFD and stimulation of mitochondrial activity. In summary, RIG-I may be a key regulator of cellular metabolism that influences the development of metabolic diseases such as MASLD.