Toxicological Research最新文献

Sarcopenia is a disease characterized by decreased muscle fibers and mass. Although it mainly affects the older adults, it can also occur in various age groups as a secondary effect of medications used for treating certain diseases, such as cancer and diabetes. With population aging, sarcopenia has drawn significant attention owing to its increasing prevalence. However, its pathogenesis remains unclear, and no specific treatment is available. Natural products containing bioactive compounds have long been used as therapeutic agents and are crucial sources for drug development. However, the use of drugs derived from natural extracts is limited because of their ambiguous mechanisms of action and potential side effects. Therefore, a systematic analysis of the potential effects of using natural products is required. In this study, we investigated the effects of the antimalarial drug quinine on myogenic differentiation. Our findings revealed that quinine significantly inhibited the expression of marker genes and proteins associated with myogenic differentiation and markedly impaired muscle regeneration following injury. Furthermore, this reduction occurred when quinine selectively decreased the AKT signaling activity. Quinine reduced muscle protein and gene expression by modulating AKT signaling and inhibiting myogenic differentiation and muscle regeneration. Therefore, quinine may cause sarcopenia, and this risk should be considered when using quinine for treatment.

Plant homeodomain finger protein 20 (PHF20) plays a crucial role in various biological processes, but its involvement in renal fibrosis remains unclear. This study investigated the role of PHF20 in renal fibrosis using a unilateral ureteral obstruction (UUO) mouse model, a widely accepted model for chronic kidney disease. PHF20 transgenic (PHF20-TG) and wild-type (WT) mice were utilized to explore how PHF20 influences renal inflammation and fibrosis. After UUO surgery, serum analysis revealed elevated creatinine levels and increased inflammatory markers, indicating worsened renal function in PHF20-TG mice. Histological analyses, including H&E, PAS, and Sirius Red staining, confirmed significant tissue damage and fibrosis in the PHF20-TG group. Molecular investigations demonstrated enhanced activation of the TGF-β/SMAD2/3 and NF-κB signaling pathways, both of which are crucial in the progression of renal fibrosis. Our findings suggest that PHF20 overexpression accelerates early-stage renal fibrosis by amplifying inflammatory responses and promoting collagen deposition. This indicates that PHF20 expression could serve as an early marker for renal fibrosis progression.

Over the last decade, the functions of PHD finger protein 20 (PHF20) in several signaling processes have been studied, including those of protein kinase B (PKB)-mediated phosphorylation, p53 regulation, muscle differentiation, and histone modification including histone H3 lysine 4 (H3K4) methylation. One PHF20 human mutation lacks the first nonspecific lethal complex of the component that binds to H3K4me2 to facilitate cancer cell survival. In carcinoma cells, PHF20 expression is regulated by PKB; PHF20 becomes phosphorylated when DNA is damaged, thus inhibiting the p53 activity that maintains cancer cell survival. Given this regulatory effect, PHF20 is usually expressed not only in gliomas but also in breast cancers, colorectal cancers, and other diseases associated with skeletal muscle osteoblastosis and osteoporosis. Thus, PHF20 dysregulation and its downstream effects enhance the abnormalities associated with cancers or other diseases and encourage disease progression. Moreover, PHF20 serves as a nuclear factor kappa-light-chain enhancer of B cell activation, thus increasing pro-inflammatory cytokine production, associated with crosstalk involving the mouse double minute 2 homolog that in turn reduces the normal p53 levels not only in cancers but also in damaged or otherwise injured normal tissues. Despite the findings of various studies, the roles of PHF20 in terms of prognosis, diagnosis, and targeting of disease therapies remain unclear and should be further explored.

Imatinib mesylate is a targeted anti-cancer drug with skin pigmentation as a side effect. The action mechanism of imatinib mesylate on melanogenesis remains unclear. The purpose of this study was to elucidate the mechanism of imatinib mesylate on melanogenesis associated with the microphthalmia-associated transcription factor (MITF) signaling pathway in murine melanoma cells. This study revealed that imatinib mesylate increased tyrosinase activity but decreased hydrogen peroxide generation in B16F1 cells. Additionally, imatinib mesylate at 0.3-5 μM was nontoxic to the cells and promoted melanin production. Moreover, imatinib mesylate at 5 μM increased the expression levels of TRP-2 and p38 related to melanogenesis compared with the blank group in western blot and immunofluorescence staining analyses. The expression level of p-MITF in the nucleus was increased in the presence of imatinib mesylate compared with the blank group. These results suggest that imatinib mesylate could promote melanogenesis through the modulation of p38 and MITF.

Lipopolysaccharide (LPS), a gut-derived endotoxin, is a recognized risk factor for both Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Rocaglamide-A (Roc-A), a natural compound derived from the genus Aglaia, is known for its pharmacological and immunosuppressive effects on various cell types. Although our recent investigations have unveiled Roc-A's anti-adipogenic role in adipocytes, its mechanism in hepatic inflammation remains elusive. This study delves into Roc-A's protective effects on LPS-induced hepatic inflammation. Our results demonstrated that Roc-A treatment significantly reduced the LPS-induced production of inflammatory cytokines in hepatocytes. Intriguingly, Roc-A decreased LPS-induced production of reactive oxygen species (ROS), upregulated antioxidant gene expression, and downregulated endoplasmic reticulum (ER) stress-related gene expression. Mechanistically, Roc-A significantly attenuated LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1). Notably, this effect was abolished by the JNK activator Anisomycin, while the JNK inhibitor SP600125 enhanced it. Furthermore, Roc-A suppressed the expression of NF-κB target genes, including inducible nitric oxide synthase (iNOS), thereby alleviating iNOS-derived nitric oxide (NO) production. These findings collectively indicate that Roc-A has the potential to alleviate LPS-induced nitrosative/oxidative stress and hepatic inflammation by inhibiting JNK phosphorylation. Thus, Roc-A emerges as a promising anti-inflammatory intervention for LPS-induced hepatic inflammation.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-024-00263-y.

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^∆hep) 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^∆hep 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.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-024-00264-x.

[This corrects the article DOI: 10.1007/s43188-024-00251-2.].

The aim of this study was to investigate genotoxicity of fucoidan-rich Undaria pinnatifida sporophyll (FUPS) using a three-component test battery. Our sulfate analysis method showed that FUPS extract contained 14% fucoidan sulfate. The reverse mutation assay showed that the FUPS extract did not increase the number of revertant colonies in any of the five bacterial strains tested, regardless of metabolic activation by S9 mix. Furthermore, FUPS did not induce chromosomal aberrations in the 6-h short-term test with or without S9, as well as in the 24-h continuous test without S9. Finally, bone marrow micronucleus examination of ICR mice at oral doses up to 5000 mg/kg/day did not show a significantly dose-dependent increase in the frequency of micronucleated polychromatic erythrocytes (MNPCEs) or the ratio of polychromatic erythrocytes (PCEs) to total erythrocytes. In conclusion, it was determined that the FUPS extract does not have a significant genotoxic potential under the expected conditions of use.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-024-00258-9.

Bacterial vaginosis (BV) is a microbial dysbiosis that shifts the paradigms of vaginal flora from lactobacilli to opportunistic pathogens. Globally, BV is treated with antibiotic therapy and recurrence rates are > 70% occurring within 6 months due to antibiotic resistance against pathogenic bacteria. An incorporation of lactobacilli orally or intravaginally for the recolonization of healthy microbes in vagina is the suggested course of treatment. Although Lactobacilli are suggested as a novel therapeutic for women's BV, evaluation of safety and toxicity have not been well understood previously. Therefore, in this study, we aimed to evaluate the safety profile of Lactobacillus plantarum ATG-K2 in subacute intravaginal animal toxicity in Sprague-Dawley rats under OECD guidelines and GLP regulations. Toxicological assessments were performed in a single-dose toxicity study by intravaginal administration with local tolerance study, 1-week repeated-dose intravaginal toxicity dose range finding (DRF) study, and a 2-week repeated-dose intravaginal toxicity study with a 2-week recovery period. Studies were performed at dose 3-18 × 10⁹ CFU/head/day. No toxicological changes in clinical signs, body weight, water and food consumption, urinalysis, hematology, clinical biochemistry, gross findings, or histopathological examination were observed in intravaginal repeated-dose toxicity. And Lactobacillus plantarum ATG-K2 did not show any local tolerance at the same doses as the intravaginal repeated-dose toxicity study. In conclusion, the no-observed-adverse-effect level (NOAEL) of Lactobacillus plantarum ATG-K2 was 12 × 10⁹ CFU/head/day and no target organ was identified in female rats. Our findings are the first to suggest that Lactobacillus plantarum is safe for use as an intravaginal treatment with no adverse effects observed in toxicological testing and has potential for application as a therapeutic agent or for other biological uses.

HemoHIM is a functional food ingredient comprising a triple herbal combination of extracts from Angelica gigas Nakai, Cnidium officinale Makino, and Paeonia lactiflora Pallas. It was developed to aid the recovery of impaired immune function. Although it is widely used to treat various immune disorders in Korea, its potential toxicity has not been extensively investigated. Therefore, a comprehensive study was conducted to assess the safety of HemoHIM, including acute oral dose toxicity, 28-day and 13-week repeated-dose toxicity, and genotoxicity. To evaluate its safety profile, the dose was increased to 2,000 mg/kg/day, which corresponds to the dose limit for acute toxicity as per the Organization for Economic Cooperation and Development Test Guideline 423. No abnormal findings were observed at the higher doses. For the 28-day and 13-week repeated-dose toxicity studies, HemoHIM was administered at doses of 500, 1,000, and 2,000 mg/kg/day to examine subchronic toxicity in male and female rats. No test item-related clinical signs or mortality was observed at any of the tested doses. Gross pathology, hematology, blood chemistry, and histopathology evaluations further supported the safety of HemoHIM. Therefore, the NOAEL of HemoHIM was considered to be at 2,000 mg/kg/day for both sexes of rats. Bacterial reverse mutation tests, a chromosome aberration test in human peripheral blood lymphocytes, and a mouse micronucleus test were conducted to determine the genotoxicity of HemoHIM, which revealed that HemoHIM was non-mutagenic and non-clastogenic. Collectively, these findings provide valuable evidence to support the safe use of HemoHIM as a functional food ingredient.