Environmental Toxicology最新文献

The Himalayan plant Inula racemosa has medicinal properties and can be used to prevent or treat cancer. This is because it contains certain chemicals that are known to fight cancer cells with few or no side effects. I. racemosa has been used for this purpose for many years in traditional medicine and has shown promising results. The present study was crafted to explore the suppressive impacts on cellular proliferation of the root extract derived from I. racemosa via in vivo experimentation. I. racemosa (IR) root extract was tested at three different doses (100, 250, and 500 mg/Kg BW) for 18 weeks to assess its anti-neoplastic activity against mammary tumors in female rats. The assessment included various parameters such as hematological and biochemical indices, tumor parameters, oxidative stress analysis, gross and histopathological lesion determination, Masson's trichrome staining, immunohistochemical expression of Ki-67, MMP-9, and VEGF in mammary gland tissues, and molecular docking. The chemopreventive action of IR root extract was demonstrated by the inhibition of tumor parameters (tumor size and tumor volume), minimum changes in the liver (ALT, AST, and ALP) and kidney enzymes (BUN and creatinine), declined lipid peroxidation activity, decline gross, and histological changes in mammary gland tumors, reduced expression of KI-67, MMP-9, and VEGF and maximum binding affinity of isoalantolactone with VEGF through molecular docking. The study suggests that the active constituents (isoalantolactone and alantolactone) of I. racemosa roots have anti-neoplastic activity against mammary tumors, making them a valuable therapeutic regimen for the future.

Pentachlorophenol (PCP) was used widely as preservative and biocide and has been banned due to with various harmful effects, such as carcinogenicity and teratogenicity. However, the effects of PCP on colitis induced by dextrose sodium sulfate (DSS) remain largely unknown. Serum metabolomics and gut microbiota were investigated to elucidate the underlying mechanisms. Exposure to 20 μg/L PCP aggravated DSS-induced body weight loss, colon shortening, severe histological injuries, and upregulation of TNFα, iNOS, IL-1β, and IL-6. Serum metabolomics showed that both DSS and PCP could significantly disrupted tryptophan metabolism in normal mice. Interestingly, PCP exposure intensified the disturbance in purine metabolism but not tryptophan metabolism caused by DSS. Quantitative analysis of tryptophan and metabolites further confirmed that PCP exposure significantly increased the serum contents of serotonin, adenine, guanine, guanosine, inosine monophosphate (IMP), inosine, and hypoxanthine in DSS-treated mice. The overall gut microbial community was significantly modified by PCP and DSS treatment alone. Rikenellaceae_RC9_Gut_group, Colidextribacter, and Desulfovibrio were more abundant in colitis mice following PCP exposure. Further integrative analysis of differential bacteria and purine metabolites highlighted a significant correlation between Desulfovibrio and several purine metabolites, including guanine, guanosine, hypoxanthine, IMP, and inosine. Adenosine ribonucleotides de novo biosynthesis, inosine-5′-phosphate biosynthesis I, and urate biosynthesis/inosine 5′-phosphate degradation pathways were depleted in colitis mice upon PCP treatment. Taken together, PCP exposure delayed the recovery of colitis induced by DSS in association with altered gut microbiota and serum metabolites, which were enriched in tryptophan and purine metabolism.

Age-related macular degeneration (AMD), a leading cause of blindness, is characterized by mitochondrial dysfunction of retinal pigment epithelium (RPE) cells. EUK-134 is a mimetic of SOD2 and catalase, widely used for its antioxidant properties in models of light-induced damage or oxidative stress. However, its effects on the retina are not yet clear. Here, we investigated the capability of EUK-134 in averting AMD using sodium iodate (NaIO₃)-induced Balb/c mouse and ARPE-19 cells (adult RPE cell line). In vivo, EUK-134 effectively antagonized NaIO₃-induced retinal deformation and prevented outer and inner nuclear layer thinning. In addition, it was found that the EUK-134-treated group significantly down-regulated the expression of cleaved caspase-3 compared with the group treated with NaIO₃ alone. Our results found that EUK-134 notably improved cell viability by preventing mitochondrial ROS accumulation-induced membrane potential depolarization-mediated apoptosis in NaIO₃-inducted ARPE-19 cells. Furthermore, we found that EUK-134 could inhibit p-ERK, p-p38, p-JNK, p-p53, Bax, cleaved caspase-9, cleaved caspase-3, and cleaved PARP by increasing Bcl-2 protein expression. Additionally, we employed MAPK pathway inhibitors by SB203580 (a p38 inhibitor), U0126 (an ERK inhibitor), and SP600125 (a JNK inhibitor) to corroborate the aforementioned observation. The results support that EUK-134 may effectively prevent mitochondrial oxidative stress-mediated retinal apoptosis in NaIO₃-induced retinopathy.

Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Asiatic acid (AA) is a natural triterpene, which is recognized as effect of antioxidant and antitumor. Sorafenib (Sor), an orally target drug, has been applicate for the HCC therapy. However, the synergistic effect of AA and Sor on human HCC is still unclear. Here, we explore the effect of combined treatment with AA and Sor in the HCC cell line SK-HEP-1 and HepG2. Compared with treating alone, our results demonstrated that AA combined with Sor synergistically inhibited proliferative rates in MTT assay and colony formation assay. We also found that AA combined with Sor in HCC cells strongly caused cell cycle arrest in G0/G1 phase and affected the protein level of cyclin D1 and SKP2. Furthermore, combination treatment strongly enhanced ferroptosis through cellular accumulation of iron ions, lipid peroxidation, and ferroptosis-related proteins (GPX4 and FTH1) in HCC cells. In addition, the combined treatment resulted in higher phosphorylation of JNK1/2 in the promotion of ferroptosis than drug treatment alone. These results indicate that AA combined with Sor synergistically improved ferroptosis in HCC cells through the regulation of JNK1/2 signaling. Taken together, the combinatorial strategy may serve as the potential treatment in HCC.

Gossypol, a natural polyphenolic compound, possesses antivirus activity and induces cell death of different types of tumors. However, the efficacy of gossypol on lung carcinoma metastases and epithelial to mesenchymal transition remains unknown. The aim of the present work was to determine the cellular and molecular mechanism of the anti-cancer and anti-metastatic efficacies of gossypol on human lung carcinoma cells. Gossypol showed a marked suppression of the viability, motility, and invasion in H1299 and A549 cells. Zymography assay showed that gossypol was sufficient to suppress the activities of urokinase-type plasminogen activator and matrix metalloproteinase-2. Gossypol reversed TGF-β-induced epithelial to mesenchymal transition. Gossypol reduced vimentin, p-FAK, p-Src and p-paxillin. In vivo studies of gossypol were performed using subcutaneous inoculation and tail vein injection of A549 into immunodeficient BALB/c nude mice and severe combined immunodeficient mice.

Low expression of certain ribosomal proteins leads to the inactivation of p53, which is mediated mainly by RPL5 or RPL11 (ribosomal protein L11). It is also unknown what mechanisms drive aberrant ribosomal proteins expression in tumor. SRBD1 (S1 RNA-binding domain 1), as a highly conserved RNA-binding protein, is lowly expressed in glioma tissues and correlated with glioma prognosis. In this study, we observed that SRBD1 was closely related to p53 signaling. The upregulation of SRBD1 elevated p53 levels, thereby activating the p53 signaling pathway. As an RNA bind protein, SRBD1 could bind to the 5′-UTR of target genes and regulate RNA translation. We further conducted RNA immunoprecipitation using anti-SRDB1 antibody and noticed 29 hub RNA, including RPL11. RPL11 could inhibit MDM2-mediated p53 ubiquitination. SRBD1 upregulation promoted RPL11 binding to MDM2 via elevating RPL11 protein levels, which in turn activated the p53 signaling. Disrupting the p53 signaling blocked SRBD1-induced glioma suppression. In mouse xenograft model, SRBD1 ectopic expression was effective in reducing the total M2 tumor-associated macrophages (TAMs) density and suppressed glioma tumor growth. In summary, these data show that SRBD1 has a critical role in inhibition of glioma tumor growth and M2 macrophage polarization, and targeting RPL11-MDM2-p53 signaling may be an effective strategy to improve therapy and survival for glioma patients.