Molecular & Cellular Toxicology最新文献

Background

Bone marrow mesenchymal stem cells (BMSCs) may be a promising target in the treatment of myocardial infarction (MI). However, the underlying molecular mechanisms of BMSC therapy remain unclear.

Objective

This study sought to evaluate the efficacy of direct intramyocardial transplantation of BMSCs in a mouse model of MI.

Methods

Mouse BMSCs were transfected with small interfering RNA or overexpression plasmid targeting TXNIP. The viability, proliferation, and apoptosis of BMSCs after hypoxia treatment were detected by MTT method, EdU analysis, and flow cytometry, respectively. A mouse model of MI was constructed, after which BSMCs were injected intramyocardially immediately. Cardiac ultrasound, HE staining, TUNEL staining and ELISA, IHC analysis, and Western blot were adopted to evaluate the effects of BSMC therapy on cardiac function, myocardial inflammation, and fibrosis in mice.

Results

In vitro experiments reported that ablating TXNIP increased viability and inhibited apoptosis of hypoxia-treated BMSCs while overexpressing TXNIP did the opposite. In vivo results stated that BSMCs improved cardiac function, myocardial inflammation, and fibrosis after MI, which was further improved by silencing TXNIP but reversed by overexpressing TXNIP. Meanwhile, in vivo cell tracking experiments showed that the retained BMSCs in the myocardium decreased after transplantation, and TXNIP depletion promoted the survival of BMSCs in MI mice, whereas TXNIP overexpression did the opposite.

Conclusion

In conclusion, BMSC transplantation improves cardiac function, myocardial inflammation, and fibrosis after MI by regulating the TXNIP/NLRP3 pathway.

Abstract

Background

The medicinal properties and benefits of collagen peptides (CPs) are widely recognized and utilized. However, the potential genotoxicity of CPs remains elusive.

Objective

The objective of this study was to assess the potential genotoxicity of CP derived from skate (Raja kenojei) skin (CPSS). To achieve this, we conducted a comprehensive study using three standard battery systems in accordance with the test guidelines provided by the Organisation for Economic Cooperation and Development and the Korean Ministry of Food and Drug Safety, as well as the principles of Good Laboratory Practice.

Results

We performed a bacterial reverse mutation (Ames) test using the pre-incubation method, with or without a metabolic activation system (S9 mixture). The Ames test, conducted on Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, as well as Escherichia coli strain WP2uvrA, demonstrated that CPSS did not cause gene mutations in any of the tested strains, regardless of the dose level. In addition, we performed an in vitro chromosome aberration test using cultured Chinese hamster lung fibroblast cells, with and without the S9 mixture, and an in vivo mouse bone marrow micronucleus test on specific pathogen-free male ICR mice. Both the in vitro chromosomal aberration test and the in vivo micronucleus test revealed no chromosomal aberrations resulting from CPSS treatment.

Conclusion

Our findings demonstrate that CPSS does not exhibit mutagenic or clastogenic activity in either in vitro or in vivo test systems, supporting its potential as a safe material for medical use.

Abstract

Background

Thyroid cancer is one of the most common malignant tumors of the endocrine system. Studies have demonstrated that maslinic acid (MA) has a wide range of antitumor activities via multiple cellular pathways. However, the role of MA in thyroid cancer remains poorly investigated.

Objective

To investigate the effects and underlying mechanisms of MA on thyroid cancer cells.

Results

MA inhibited cell viability and increased apoptosis in TPC1 and Cal62 cells. MA promoted apoptosis in TPC1 and Cal62 cells in a dose-dependent manner evidenced by flow cytometry and Western blotting. In addition, treatment with MA increased the expression of endoplasmic reticulum (ER) stress markers, such as Binding-immunoglobulin protein (BIP) and C/EBP homologous protein 10 (CHOP), in thyroid cancer cells. In cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, MA-induced apoptosis was partially reversed. Finally, treatment with MA inhibited thyroid cancer growth in a TPC1 cell xenograft model.

Conclusion

Results indicated that MA promoted apoptosis in thyroid cancer cells via ER stress. These findings may provide new insights into novel therapeutic strategies for thyroid cancer.

Objective

Keloid is a kind of disfiguring pathological scarring specific to human skin. For various cutaneous and internal tumours, 5-aminolevulinic acid-photodynamic therapy (5-ALA-PDT) is a curative choice, and we explored its mechanism on keloid fibroblast (KFB) proliferation and invasion via regulating forkhead box protein O6 (FoxO6) antioxidant stress.

Methods

Human keloid fibroblasts (HKFs) were cultured in vitro, treated with 5-ALA-PDT and simultaneously transfected with overexpression plasmid (oe-FoxO6). HKF proliferation, invasion, apoptosis and cell cycle were assessed by CCK-8/Transwell/TUNEL/flow cytometry assays. The protein levels of Bax, Bcl-2, FoxO6, Cyclin D1, Cyclin A1 and Cyclin B1 were determined by Western blot. SOD and CAT activities, and MDA and ROS levels were examined using the kits.

Results

Pretreatment of 5-ALA-PDT prominently inhibited the proliferation of HKFs, up-regulated Bax level, down-regulated Bcl-2 level, promoted HKF apoptosis, and notably inhibited HKF invasion. 5-ALA-PDT treatment decreased the expression of FoxO6 protein, promoted oxidative stress in HKFs, up-regulated ROS and MDA levels in HKFs and reduced SOD and CAT antioxidant enzyme activities. In addition, 5-ALA-PDT pretreatment increased the level of cell cycle-associated protein Cyclin D1, decreased the levels of Cyclin A1 and Cyclin B1, and accelerated cell cycle arrest in the G₀/G₁ phase of HKFs. Overexpression of FoxO6 partially annulled the promoting effects of 5-ALA-PDT on G₀/G₁ phase cell cycle arrest and oxidative stress in HKFs and enhanced cell proliferation and invasion.

Conclusion

5-ALA-PDT limited HKF proliferation and invasion by down-regulating the expression of FoxO6.

Objective

Melanoma is a malignant skin cancer. This paper is dedicated to investigate the disease mechanism in regard to the axis of long noncoding RNA MAFG antisense 1 (MAFG-AS1)/microRNA (miR)-331-3p/KIT.

Methods

Levels of MAFG-AS1, miR-331-3p and KIT were analyzed in melanoma patients' cancer tissues and melanocytic nevi patients’ skin tissues. The correlation between prognosis of melanoma patients with MAFG-AS1 expression was observed. Loss- and gain-function tests were implemented to observe alternatives of cell biological activities.

Results

Melanoma patients’ cancer tissues expressed higher MAFG-AS1 and KIT and lower miR-331-3p. Patients with high MAFG-AS1 expression exhibited a poorer prognosis. After down-regulating MAFG-AS1 in A375 cells, cell proliferation, invasiveness, epithelial–mesenchymal transition (EMT) decreased, and apoptosis increased. Up-regulating MAFG-AS1 caused the opposite consequences. miR-331-3p inhibition or KIT overexpression eliminated the blockade of proliferation, invasion, and EMT caused by MAFG-AS1 silencing.

Conclusion

MAFG-AS1 competitively binds to miR-331-3p to elevate KIT expression, thereby enhancing the aggressiveness of melanoma cells.

Background

Diesel particulate matter (DPM) constitutes a significant air pollutant that adversely affects neurological health through the olfactory pathway. Although extensive human epidemiological and animal research exists, the specific mechanisms underlying DPM-induced olfactory dysfunction have not been definitively elucidated.

Objective

This study aimed to conduct a comprehensive analysis of the behavioral, histological, and molecular changes in the olfactory bulb (OB) of mice following intranasal exposure to 10 mg/kg DPM for a duration of four weeks.

Results

Exposure to DPM led to notable olfactory impairment in the mice, characterized by an elevation in Iba-1-positive microglia, though without inducing neuronal cell death. Transcriptomic evaluation revealed 84 differentially expressed genes (DEGs) in the OB that met the criteria of fold change greater than 1.5 and a p value less than 0.05. Within this set, 55 genes were upregulated and 29 were downregulated. Gene ontology-based functional analysis revealed that these DEGs were primarily related to sensory organ morphogenesis, energy homeostasis, and the regulation of monocyte aggregation. Subsequent investigation using the Kyoto Encyclopedia of Genes and Genomes database identified enriched pathways connected to neuroactive ligand-receptor interactions and calcium signaling.

Conclusion

Our findings suggest a plausible association between DPM-induced olfactory dysfunction and disruptions in a range of molecular pathways. This hypothesis is supported by observed alterations in gene expression and the presence of mild neuroinflammation, primarily driven by microglial activation.

Background

Silibinin, a flavonolignan, is known to have a variety of pharmacological activities, including antioxidant activity, but its antioxidant mechanism in the eye is unclear.

Objective

This study aimed to evaluate whether silibinin could protect human retinal pigment epithelial ARPE-19 cells from oxidative injury.

Results

Silibinin attenuated cell viability reduction and DNA damage in ARPE-19 cells treated with hydrogen peroxide (H₂O₂), while inhibiting intracellular reactive oxygen species (ROS) production and preserving diminished glutathione (GSH). Silibinin also antagonized H₂O₂-induced inhibition of the expression and activity of antioxidant enzymes, such as GSH peroxidase and manganese superoxide dismutase, which was associated with inhibition of mitochondrial ROS production. Moreover, silibinin rescued ARPE-19 cells from H₂O₂-induced apoptosis by restoring the reduced Bcl-2/Bax ratio and reducing caspase-3 activation. In addition, silibinin suppressed the release of mitochondrial cytochrome c into the cytoplasm, which was achieved by interfering with mitochondrial membrane disruption.

Conclusion

These findings imply that silibinin has potent ROS scavenging activity with the potential to protect against oxidative stress-mediated ocular diseases.

Background

Colorectal cancer (CRC) is one of the most common malignancies worldwide and a major threat to human life and health. Circular RNA (circRNA)-microRNA (miRNA)-mRNA mechanism is considered to occur in various cancers. However, the mechanism of circ_101692 in CRC is still unclear.

Methods

Quantitative real-time PCR was used to detect the expression of circ_101692, miR-449b-5p and Golgi phosphoprotein 3 (GOLPH3) in CRC tissues and cell lines. Cell proliferation was determined using cell counting kit-8 (CCK8), colony formation assay and 5-ethynyl-2′-deoxyuridine (EdU). Flow cytometry and transwell were performed to measure apoptosis and cell invasion, respectively. Besides, glucose uptake and lactate production were tested using commercial kits to determine the glycolytic of CRC. Furthermore, dual-luciferase reporter assay and RNA immunoprecipitation assay were employed to verify the relationship between miR-449b-5p and circ_101692 or GOLPH3. And the protein levels were monitored using western blot assay. The xenotransplantation model was established to study the role of circ_101692 in vivo.

Results

Circ_101692 and GOLPH3 were highly expressed, while miR-449b-5p expression was down-regulated in CRC tissues and cell lines compared to normal tissues and cell lines. Circ_101692 negatively targeted miR-449b-5p, and GOLPH3 was the downstream gene of miR-449b-5p. Silencing circ_101692 suppressed CRC cell proliferation, invasion and glycolysis, as well as promoted apoptosis, while these influences could be reverted by miR-449b-5p inhibitor. Similarly, overexpression of GOLPH3 abolished the influence of miR-449b-5p mimic on CRC cell behavior. In addition, silencing of circ_101692 restricted CRC tumor growth in vivo.

Conclusion

Our results showed that circ_101692 promoted CRC progression by modulating the miR-449b-5p/GOLPH3 axis, implying that circ_101692 might be a possible target for CRC treatment.

Graphical abstract