Journal of Biochemical and Molecular Toxicology最新文献

This study focused on the role of the microRNA (miR)-373-3p/LATS2 axis in the prognosis and metastasis of thyroid cancer patients. miR-373-3p and LATS2 expression were assessed in thyroid cancer tissues and cells. The relationship between miR-373-3p and clinicopathological characteristics of patients with thyroid cancer and the impact of miR-373-3p and LATS2 expression levels on the survival and prognosis of thyroid cancer patients were analyzed. The targeting relationship between miR-373-3p and LATS2 was predicted and verified, and their impact on the malignant cell phenotype was assessed. Compared with adjacent normal tissues and normal human thyroid cells, miR-373-3p was highly expressed, while LATS2 was expressed at low levels in thyroid cancer tissues and cells (both p < 0.001). miR-373-3p expression was independent of age (p = 0.201) and gender (p = 0.516), and it was correlated with lymph node metastasis and TNM stage of thyroid cancer (both p < 0.001). Moreover, high miR-373-3p expression was associated with poor patient prognosis (p = 0.034). Interference with miR-373-3p or overexpression of LATS2 repressed KMH-2 cell malignant phenotypes (all p < 0.05). miR-373-3p targeted and suppressed LATS2 expression. Interference with miR-373-3p blocked its inhibition on LATS2, thereby repressing thyroid cancer progression and metastasis.

Gastric cancer (GC) represents a major global health concern, with over 1 million new cases diagnosed annually worldwide. Emerging studies have highlighted the significant correlation between long noncoding RNAs (lncRNAs) and the progression of GC. The objective of the current study is to investigate the roles and mechanism of lncRNA homeobox A10 antisense RNA (HOXA10-AS) in modulating malignant properties of GC cells. RT-qPCR was employed to detect HOXA10-AS expression in GC cells or human normal gastric epithelium cells. The cellular localization of HOXA10-AS and mRNA HOXA10 were detected using RNA fractionation assays. Colony forming assays and Transwell assays were performed to assess the proliferative, invasive, and migratory capabilities of GC cells. Western blot analysis was used to determine protein levels of epithelial mesenchymal transition (EMT) markers in GC cells. RNA immunoprecipitation, RNA pulldown assays and luciferase assays were conducted to explore gene interaction. As shown by experimental results, HOXA10-AS showed high expression in GC cells. The silencing of HOXA10-AS led to weakened proliferative, invasive, and migratory abilities of GC cells, as well as inhibition of the EMT process. Moreover, HOXA10-AS positively regulated HOXA10 expression by interacting with miR-29a/b/c-3p. Additionally, overexpression of HOXA10 counteracted the repressive impacts on malignant cellular process caused by the knockdown of HOXA10-AS. Furthermore, HOXA10-AS activated the p38 MAPK/STAT3 signaling pathway via upregulation of HOXA10. In conclusion, HOXA10-AS upregulates HOXA10 expression through interaction with miR-29a/b/c-3p. The resultant increase in HOXA10 expression activates the p38 MAPK/STAT3 signaling, thereby promoting GC cell growth, migration, invasion, and EMT process.

The present work explored the functions of circ_0070934 in regulating malignant phenotype of colorectal cancer (CRC) cells and its underlying mechanisms. Gene expression data set was acquired based on Gene Expression Omnibus (GEO) database for examining circ_0070934 levels within CRC cells and tissues through quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Kaplan–Meier curve and log-rank test were adopted for assessing CRC patient prognosis based on circ_0070934 level. Functional assays including Cell Counting Kit (CCK)-8, EdU incorporation, Transwell invasion, and scratch assays were conducted to determine CRC cell malignancy. Molecular interactions were predicted using circInteractome and StarBase databases, and validated through luciferase reporter assay. Circ_0070934 was upregulated within CRC cells and tissues, which was related to a dismal prognostic outcome in CRC patients. Knocking down circ_0070934 inhibited CRC cell proliferation, epithelial–mesenchymal transition (EMT), and migration. Further, we identified miR-203a-3p as a target miRNA of circ_0070934, and miR-203a-3p negatively regulated Homeobox A13 (HOXA13) expression. miR-203a-3p/HOXA13 axis mediates the function of circ_0070934 in modulating CRC cell malignancy. These data revealed that circ_0070934 was important for maintaining the malignant phenotype of CRC cells, and circ_0070934 knockdown undermined CRC cell malignancy. Targeting circ_0070934/miR-203a-3p/HOXA13 axis is the promising intervention approach for managing CRC.

Purinergic ligand-gated ion channel 7 receptor (P2X7R) has essential functions in tumor proliferation, apoptosis, metastasis, and invasion, and the purpose of this study was to explore the effects of P2X7R on the biological behaviors of MCF-7 and MDA-MB-231 cells. A bioinformatics analysis of P2X7R expression in breast cancer was performed and its relationships with overall survival and immune cell infiltration were determined. P2X7R ion channel function was detected via a Fluo-4-AM assay. Proliferation, migration and invasion were investigated using CCK-8, scratch wound healing, and Transwell assays, respectively. The levels of P2X7R, JNK, p-JNK, Akt, p-Akt, E-cadherin, N-cadherin, vimentin and GAPDH were detected by western blotting. The role of P2X7R on the biological behaviors of MCF-7 cells was detected in vivo. Bioinformatics analysis revealed an obvious increase in the expression of P2X7R in breast cancer and differences were observed among the different subtypes. High expression of P2X7R was negatively correlated with overall survival and affected immune cell infiltration. The experimental results revealed that both types of cells express functional P2X7R. ATP and BzATP can promote proliferation, invasion, and metastasis after P2X7R activation; upregulate p-Akt, p-JNK, N-cadherin and vimentin; and downregulate E-cadherin compared with the control group, and the addition of the antagonist A438079 or oxATP or the knockdown of P2X7R could weaken these effects. The activation of P2X7R in breast cancer cells can promote their biological behaviors, indicating that P2X7R is a latent therapeutic target in breast cancer.

Substance P/high-affinity neurokinin-1 receptor (SP/NK1R) system plays a crucial role in the pathogenesis of dry eye disease (DED). NK1R antagonist can improve DED, but the mechanism of NK1R antagonist treating DED remains unclear. We examined the role of NK1R antagonist, CP-99,994 in DED model by possessing the phenol red cotton thread test, corneal fluorescein staining, and hematoxylin and eosin staining. Enzyme linked immunosorbent assay was performed to determine the concentration of inflammatory factors. Additionally, RNA sequencing, enrichment analysis and protein-protein interaction network were employed to identify the key targets. Real-time quantitative PCR and western blot analysis were utilized to determine the expression of hub genes. Plk1 inhibitor, GSK461364 was applied to explore the treatment mechanism of CP-99,994. The NK1R antagonist CP-99,994 alleviated dry eye symptoms and the concentrations of IL-6, IL-1β, and TNF-α were significantly decreased after CP-99,994 treatment. We obtained 68 differentially expressed genes after CP-99,994 treatment by RNA sequencing and pyroptosis-related genes (Plk1, Cdc25c, Cdk1) were identified from protein-protein interaction network as key targets of CP-99,994 treating DED. The expression levels of the Plk1, Cdc25c, and Cdk1 were significantly upregulated in the DED group, and CP-99,994 downregulated the expression of Plk1, Cdc25c, and Cdk1. Moreover, Plk1 inhibitor considerably promoted the therapeutic effect of CP-99,994 on DED model by reducing the release of IL-6, IL-1β, and TNF-α. The NK1R antagonist, CP-99,994 mitigated DED symptoms via inhibiting Plk1-Cdc25c-Cdk1 axis, which served as a novel therapeutic target for DED treatment.

Despite the worldwide surge in the prevalence of non-alcoholic fatty liver disease (NAFLD), however, no efficacious treatment has been clinically approved to date for combating this condition, necessitating elucidation of new therapeutic compounds. Our research presented evidence pertaining to the successful induction of NAFLD in C57BL/6 mice using a multiple liver insults paradigm. This was achieved by concurrently administering thioacetamide (100 mg/kg i.p.) along with high-fat and high-fructose diet (HFFrD) for 10 weeks. Following this, the beneficial effect of borneol, a bicyclic monoterpenoid, was observed in NAFLD mice in a dose-dependent manner. Borneol administration for 4 weeks led to significant improvement in morphometric, metabolic profiles, liver functions, and oxidative stress parameters. Accumulation of lipids in hepatic tissues, which is characteristic feature of NAFLD, was confirmed by H&E, as well as oil-red O staining was alleviated by borneol. Our investigation elucidated the pro-autophagic effect of borneol via AMPK activation, thereby leading to the downstream activation of autophagy effector proteins, that is, Beclin1, ATG5, ATG7, and LC3 I-II, which helps to diminish the hepatic lipid loads through augmentation of lipophagy. This study demonstrates that borneol combats NAFLD through augmentation of AMPK-mediated lipophagy offering a promising therapeutic strategy against NAFLD.

Esophageal cancer is an aggressive malignancy with a poor prognosis. NUC7738, a cordycepin derivative, has shown promise in overcoming the limited in vivo efficacy of its parent compound. This study compares the anticancer effects of NUC7738 and cordycepin in esophageal cancer and explores the molecular mechanisms of NUC7738 action. In vitro, NUC7738 and cordycepin were tested on normal (Het1A) and esophageal cancer cell lines (ECA109, KYSE510) using Cell Counting Kit-8 (CCK-8) and colony formation assays. Apoptosis was confirmed by inhibitors and flow cytometry. Western blot was performed to detect apoptosis-related protein. KEGG analysis identified potential downstream signaling pathways, while qPCR, western blot, and immunofluorescence staining were applied to assess p53 expression and stability. In vivo, ECA109 cells were xenografted into nude mice, and tumor tissues were analyzed for p53 expression using Immunohistochemical staining. Finally, CCK-8, colony formation, and subcutaneous tumor xenograft assays in nude mice were employed to assess the synergistic effects of NUC7738 and cisplatin. The results revealed that NUC7738, although less effective than cordycepin in vitro, demonstrated superior anticancer activity in vivo. NUC7738 induced apoptosis by stabilizing p53 via ubiquitination, inhibiting tumor growth. Additionally, NUC7738 combined with cisplatin showed enhanced anticancer effects both in vitro and in vivo. These findings highlight greater potential of NUC7738 for clinical application, particularly in improving p53 stability and augmenting chemotherapeutic efficacy.

Cyclophosphamide (CYC) is one of the most potent antineoplastic drugs; however, hepatonephrotoxicity, observed following its use, remains one of its most severe side effects. Previous studies have reported that syringaldehyde (SYA), a flavonoid compound, exhibits anti-inflammatory and antioxidant properties. However, it is unclear whether SYA has any effects on hepatonephrotoxicity caused by the side effects of antineoplastic drugs. In the present research, we thoroughly evaluated the effects of SYA on cyclophosphamide-induced hepatonephrotoxicity in a mouse model, focusing on Nrf2/HO-1 pathway activation. In the present study, SYA (25 and 50 mg/kg, p.o.) and CYC (30 mg/kg, i.p.) were delivered to male mice for 10 days to induce hepatonephrotoxicity. SYA treatment alleviated the elevated levels of AST, ALT, BUN, and creatinine caused by CYC. It further suppressed lipid peroxidation by lowering MDA levels and enhanced antioxidant defense by elevating GSH, SOD, and CAT levels. Additionally, SYA increased the mRNA expression levels of HO-1, Nrf2, and Bcl-2, which had been reduced due to oxidative stress, inflammatory, and apoptotic pathways, while suppressing the elevated gene expression levels of NFκB, TNF-α, Bax, and Cas-3. Furthermore, SYA regulated the altered protein expression levels of Nrf2, Cas-3, Bax, and Bcl-2 induced by CYC. Microscopically, SYA also mitigated liver and kidney tissue damage caused by CYC. In conclusion, SYA significantly reduced CYC-induced hepatonephrotoxicity by inhibiting inflammation, oxidative stress, and apoptosis by employing the Nrf2/NFκB/HO-1 pathway. These findings indicate that SYA has the possibility as a treatment option agent in the case of prevention of liver and kidney damage.

Highly active antiretroviral therapy (HAART), consisting of three or more antiretroviral drugs, is recommended for patients with HIV infection. HAART effectively reduces HIV RNA levels, lowers the risk of opportunistic infections, and improves immune function and survival rates. However, it is also associated with an increased risk of liver injury in HIV-infected individuals. This review aims to summarize the mechanisms underlying HAART-induced liver injury. A comprehensive search was conducted in PubMed and EMBASE using keywords such as “Antiretroviral/ARV drugs and drug-induced liver injury (DILI),” “HAART and DILI,” “Antiretroviral therapy and DILI,” and “HIV infection and DILI.” Relevant papers published before March 2024 were included. Experimental studies have demonstrated that zidovudine and efavirenz can cause structural alterations in mitochondria, impair the respiratory chain, generate free radicals, and deplete mitochondrial DNA, leading to oxidative and endoplasmic reticulum stress, as well as the accumulation of advanced glycation end products in liver tissue. Zidovudine disrupts lipid homeostasis by increasing fatty acid synthesis and reducing metabolism. Efavirenz and its metabolite, 8-hydroxyefavirenz, induce hepatocellular death and activate proapoptotic markers through c-Jun N-terminal kinase signaling. Additionally, lamivudine has been shown to induce liver injury and oxidative stress in rats. Clinically, approximately 50% of HIV patients on HAART regimens containing non-nucleoside reverse transcriptase inhibitors experience mild to moderate liver injury. HAART regimens that include efavirenz, lamivudine, and tenofovir impair glucose and lipid homeostasis in rats, highlighting the need for caution in HIV patients with fatty liver disease. Patients with viral hepatitis coinfection, those taking antitubercular drugs or cotrimoxazole, and those on nevirapine-containing regimens are at particularly high risk. Regular monitoring of liver function is essential to prevent liver damage associated with HAART in HIV-infected patients. While HAART significantly improves survival rates in HIV patients, it also poses a considerable risk of liver injury, necessitating careful monitoring and management.