Chemico-biological interactions最新文献

Neutrophils that are overactivated can cause inflammatory diseases. Neutrophils possess various surface receptors, including G-protein-coupled chemoattractant receptors, which assist in recognizing pathogen attacks and the inflammatory environment. Therefore, targeting G-protein-coupled chemoattractant receptors and their downstream molecules is important for preventing abnormal neutrophil activation. This study examines the effects and underlying mechanism of myriscagayanone C, a new compound obtained from the fruit of myristica cagayanensis, on neutrophil respiratory burst induced by fMLP. The immunoblotting assay was conducted to assess the mechanisms by which myriscagayanone C inhibits fMLP-induced respiratory burst by disrupting the translocation of Akt to the cellular membrane. Briefly, myriscagayanone C suppressed the production of superoxide anions induced by fMLP on human neutrophils in a concentration-dependent manner (IC₅₀: 4.73±0.68 μM). Myriscagayanone C blocked fMLP-induced Akt translocation to the cell membrane, inhibiting Akt^T308 and Akt^S473 phosphorylation by PDK1^Y373/376 and mTOR^S2481, respectively. Myriscagayanone C inhibited fMLP-induced p47^phox phosphorylation and translocation. Myriscagayanone C did not inhibit the activity of PI3K, the amount of phosphatidylinositol (3, 4, 5)-trisphosphate, or the translocation of phosphorylated-PDK1^Y373/376 and -mTOR^S2481 to the membrane. Myriscagayanone C did not inhibit fMLP-induced PKC, Src, ERK1/2, p38 phosphorylation, and intracellular calcium mobilization. Myriscagayanone C did not inhibit the chemotaxis and CD11b expression induced by fMLP. Myriscagayanone C did not inhibit PMA-induced superoxide anion production and neutrophil extracellular trap formation. According to this data, myriscagayanone C inhibits fMLP-induced neutrophil superoxide anion production by interrupting the translocation of Akt to the plasma membrane, which affects the NADPH oxidase activity by preventing p47^phox phosphorylation and translocation.

As the development of nanotechnology, the application of nanoproducts and the advancement of nanomedicine, the contact of nanoparticles (NPs) with human body is becoming increasingly prevalent. This escalation elevates the risk of NPs exposure for workers, consumers, researchers, and both aquatic and terrestrial organisms throughout the production, usage, and disposal stages. Consequently, evaluating nanotoxicity remains critically important, though standardized assessment criteria are still lacking. The diverse and complex properties of NPs further complicate the understanding of their toxicological mechanisms. Autophagy, a fundamental cellular process, exhibits dual functions-both pro-survival and pro-death. This review offers an updated perspective on the dual roles of autophagy in nanotoxicity and examines the factors influencing autophagic responses. However, no definitive framework exists for predicting NPs-induced autophagy. Beyond the conventional autophagy pathways, the review highlights specific transcription factors activated by NPs and explores metabolic reprogramming. Particular attention is given to NPs-induced selective autophagy, including mitophagy, ER-phagy, ferritinophagy, lysophagy, and lipophagy. Additionally, the review investigates autophagy's involvement in NPs-mediated biological processes such as ferroptosis, inflammation, macrophage polarization, epithelial-mesenchymal transition, tumor cell proliferation and drug resistance, as well as liver and kidney injury, neurotoxicity, and other diseases. In summary, this review presents a novel update on selective autophagy-mediated nanotoxicity and elucidates the broader interactions of autophagy in NPs-induced biological processes. Collectively, these insights offer valuable strategies for mitigating nanotoxicity through autophagy modulation and advancing the development of NPs in biomedical applications.

The cytotoxicity of four rhenium compounds: fac-[ReO₃(impy)CH₃] (1) (impy = 2-(1H-imidazol-2-yl)pyridine), fac-[Re(CO)₃(bzimpy)Cl] (2) (bzimpy = 2-(2-pyridyl)benzimidazole), fac-[Re(CO)₃(bibzimpy)Cl] (3) (bibzimpy = 2,6-bis(2-benzimidazolyl)pyridine) and fac-[Re(CO)₃(impy)Cl] (4) was assessed against cancer cell lines, namely, the cervical hormone-responsive HeLa and the triple-negative breast cancer (TNBC) HCC70 lines versus a non-tumorigenic control breast epithelial cell line, MCF12A. A rare facial trioxorhenium(VII) compound 1 was characterized via various physicochemical techniques. The rhenium compounds 1 - 4 were, in general, more cytotoxic to HeLa cells, compared to the TNBC HCC70 line, displaying half maximal inhibitory concentration (IC₅₀) values in the micromolar range, however, the compounds were not convincingly selective for cancer cells over non-cancerous cells. In particular, compound 4 was highly cytotoxic towards HCC70, HeLa, and MCF12A cells, displaying low micromolar toxicity with IC₅₀ values of 6.57 ± 1.11 μM, 8.88 ± 1.07 and 9.41 ± 1.04 μM in these three cell lines, respectively and was selected for further study as it displayed the greatest cytotoxicity against the highly treatment-resistant HCC70 TNBC cell line. Compound 4 was able to both bind to genomic DNA and act as an intercalator of CT-DNA, however, this did not lead to DNA damage as assessed by a comet assay. In addition, Compound 4 displayed a long-term dose-dependent effect on colony formation and long-term survival as a proxy of in vivo toxicity.

S-3'-hydroxy-7', 2', 4'-trimethoxyisoxane (ShtIX) is a novel isoflavane compound that exhibits significant anticancer activity against a variety of cancer cells. Our previous studies have confirmed that ShtIX induced ferroptosis by inhibiting Nr2/HO-1 pathway in non-small cell lung cancer (NSCLC) cells, both in vitro and vivo. Recent research has increasingly recognized ferroptosis as an autophagy-dependent form of cell death. However, it has not been previously explored whether ShtIX can activate autophagy during ferroptosis and its relationship with ferroptosis. In the present study, we discovered that ShtIX was able to trigger autophagy, and the activation of autophagy is essential for ShtIX-induced ferroptosis. These findings demonstrated that ShtIX induced an autophagy-dependent form of ferroptosis in NSCLC cells. Intriguingly, the autophagy triggered by ShtIX is independent of ferroptosis. Furthermore, our results indicated that ShtIX degraded ferritin through autophagy and promoted NCOA4-mediated ferritinophagy, which contributed significantly to ShtIX-induced ferroptosis in NSCLC cells. Additionally, the knockdown Nrf2 reinforced ShtIX-induced NCOA4-mediated ferritinophagy, while the inhibition of autophagy attenuated the suppressive effect of ShtIX on Nrf2 and HO-1. Taken together, our work uncovers a new mechanism by which ShtIX induced ferroptosis through inhibition the Nrf2 pathway and activation of NCOA4-mediated ferritinophagy in NSCLC cells. Targeting ferritinophagy to regulate ferroptosis offers a novel therapeutic strategy for the treatment of lung cancer with ShtIX.

Arsenic is a widespread environmental carcinogen, and its carcinogenic mechanism has been the focus of toxicology. N⁶-methyladenosine (m⁶A) binding protein YTH domain family protein 2 (YTHDF2) performs various biological functions by degrading m⁶A-modified mRNAs. However, the m⁶A-modified target mRNA of YTHDF2 in regulating arsenic carcinogenesis remains largely unknown. To explore the effect of YTHDF2 in regulating arsenic carcinogenicity, we exposed the human keratinocyte HaCaT cells to 1 μM sodium arsenite for 50 generations to create a cell model of arsenic carcinogenesis (HaCaT-T). Our results demonstrated that YTHDF2 protein levels were higher in HaCaT-T cells than HaCaT cells, and knockdown of YTHDF2 significantly inhibited arsenic-induced malignant phenotypes. In addition, m⁶A levels in HaCaT-T cells were remarkably elevated, accompanied by abnormal expression of m⁶A methyltransferases and m⁶A demethylases. Mechanistically, YTHDF2 bound to p53-induced death domain protein 1 (PIDD1) mRNA in an m⁶A-dependent manner, thereby promoting the degradation of PIDD1 mRNA. Moreover, the decay of PIDD1 mRNA inhibited the formation of PIDDosome complex that is essential for activating the apoptosis initiator caspase-2, leading to a decrease in caspase-2-dependent mitochondrial apoptosis and subsequently promoting the malignant phenotypes of HaCaT-T cells. Collectively, our study reveals the role of YTHDF2 in arsenic-induced malignant phenotypes of human keratinocytes through direct interaction with PIDD1 mRNA in an m⁶A-dependent manner, which provides new insight into the precise mechanism underlying arsenic-induced skin cancer.

The kidneys have vital functions in the body, including maintaining homeostasis and blood pressure, controlling water-electrolyte balance, and eliminating metabolic wastes. Early identification of renal dysfunction disease and selection of effective treatment methods reduce mortality in patients. Nowadays, Common indicators of kidney function lack the necessary specificity and sensitivity, but recent studies have reported that cystatin C (CysC) may be an ideal marker for glomerular filtration. CysC, known as a cysteine protease inhibitor, is synthesized by nucleated cells and is easily filtered due to its positive charge and low molecular weight. Also, the synthesis and secretion of CysC is a stable process that is not affected by dietary factors, enhanced protein catabolism, and renal conditions. Various studies have reported that measuring the level of CysC in the body's biological fluids is necessary for the treatment and diagnosis of a wide range of diseases, especially chronic kidney disease (CKD).Despite evidence that positive correlation between the high risk and/or progression of CKD and CysC, it's applied in clinical practice is still rare. Biosensors have been widely developed and researched as an effective method for the pharmaceutical, environmental, and medical fields. Biosensors are designed to create an effective electronic signal commensurate with the concentration of a particular biochemical.Recently, many studies have used biosensor techniques to detect CysC in kidneys and other diseases. In this study, we attempt to examine studies that have used different biosensor techniques for the detect CysC.

Aflatoxin B1 (AFB1), a known human carcinogen, represents the most toxic aflatoxin metabolite. Exposure to AFB1 causes increased oxidative stress and immunotoxicity, which are important factors contributing to aging. However, the role of AFB1-induced toxicity in altered innate immunity and aging remains largely unclear. The nematode Caenorhabditis elegans is a suitable model organism for studying aging and toxicology due to its well-studied molecular mechanisms and short life cycle. Effects of AFB1 at 1, 2.5, and 5 μM (312, 781, and 1561 μg/L) on growth, reproduction, and lifespan were examined. The Pseudomonas aeruginosa PA14 slow-killing assay was performed to investigate innate immunity, followed by studying the possible mechanisms using transgenic strains and qPCR analysis. The results showed that early life long-term AFB1 exposure (2.5 and 5 μM) delayed development, reduced reproduction, and shortened lifespan in C. elegans. Furthermore, in aged worms, AFB1 exposure caused a dose-dependent decrease in survival of C. elegans against P. aeruginosa PA14 infection. At adulthood day 4 in the presence of live Escherichia coli OP50, AFB1 (2.5 μM) significantly increased lipofuscin levels (a hallmark of aging) compared to adult day 0, whereas no increase in lipofuscin was observed in nematodes (adulthood day 4) fed with dead E. coli OP50. Additionally, the increased lipofuscin was abolished in the skn-1 mutant with either live or dead E. coli OP50. Furthermore, AFB1 suppressed intestinal SKN-1::GFP translocation. Two-way ANOVA analysis revealed that the activity of E. coli OP50 and AFB1 interactively affected the expression of genes: skn-1, gst-4, hsp-16.1, hsp-16.49, and hsp-70. Our findings highlight the role of AFB1-induced toxicity in altered innate immunity and aging through the involvement of the transcription factor SKN-1/Nrf2.

The relationship between arsenic exposure and the development of diabetes mellitus has garnered significant interest in recent years. However, current experimental studies have not definitively established the role of arsenic in the onset of diabetes mellitus. To investigate this relationship specifically concerning type 1 diabetes mellitus, Streptozocin (STZ) was utilized as an inducer to initiate the fundamental pathological changes associated with the disease. A high dose of STZ (50 mg/kg) served as the positive control, while a low dose of STZ (20 mg/kg) was administered in combination with arsenic at varying doses. The objective was to determine whether arsenic enhances the effects of STZ, thereby leading to an expedited onset and progression of type 1 diabetes mellitus. The preliminary investigation into the impact of arsenic exposure on experimental type 1 diabetic mice focused on the NLRP3/Caspase-1/GSDMD mediated pyroptosis pathway. The results showed that fasting blood glucose (FBG) was increased, glucose tolerance was impaired, insulin sensitivity was decreased, fasting serum insulin and the homeostatic model assessment-β (HOMA-β) were significantly reduced, hair arsenic content was increased, reactive oxygen species(ROS), interleukin (IL)-1β and IL-18 contents were increased, and the pathological morphology of pancreas was more serious in the combined group. Moreover, the expression levels of proteins associated with the NLRP3/Caspase-1/GSDMD-mediated pyroptosis pathway were elevated in the combined group. This study illustrates that exposure to arsenic, along with low-dose STZ, not only leads to pancreatic injury in mice, impacting insulin secretion and causing elevated blood glucose levels, thereby hastening the progression of type 1 diabetes, but also induces pyroptosis in pancreatic tissues by influencing the NLRP3/Caspase-1/GSDMD signaling pathway, further facilitating the development of type 1 diabetes.

Arsenic (As), a naturally occurring element with unique properties, has been recognized as the largest mass poisoning in the world by the World Health Organization (WHO). Approximately 200 million people worldwide are exposed to toxic levels of arsenic due to natural and anthropogenic activities. This widespread exposure necessitates a deeper understanding of microbe-arsenic interactions and their potential influence on host exposure and health risks. It is a major causative factor for metabolic diseases, including diabetes. Arsenic exposure has been linked to dysfunction in various cell types and tissues, notably affecting pancreatic islet cells. Numerous mechanisms have been identified to be responsible for arsenic exposure under both in vitro and in vivo conditions. These mechanisms contribute to the regulation of processes underlying diabetes etiology, such as glucose-stimulated insulin secretion from pancreatic beta cells. Unlike other toxic elements, arsenic undergoes metabolism by living organisms, including microbes, plants, and animals. Other toxic elements like Lead (Pb) and mercury (Hg) are generally not metabolized in the same way as Arsenic in microbes, plants and animals. In this review, we strive to initiate a dialogue by reviewing known aspects of microbe-arsenic interactions and placing it in the context of the potential for influencing host exposure and health risks. This review provides an up-to-date insight into arsenic metabolism by the human body and its associated microbiota, as well as the deciphered molecular pathways linking the different species of arsenic in the etiology of diabetes. Additionally, the future perspectives of mitigation and detoxification of arsenic in translational medicine and limitations in current scenarios are discussed. The comprehensive review presented here underscores the importance of exploring the complex interplay between arsenic metabolism, host-microbiota interactions, and their implications on glucose homeostasis and metabolic diseases. It emphasizes the need for continued research to develop effective strategies for mitigating arsenic-related health risks and fostering better translational medicine approaches.

Glioblastoma is the most common adult malignant brain tumor. This tumor is aggressive and the most lethal. Trials to improve the outcome of patients with this tumor remain critical. There are no effective therapies for malignant glioma. Glioblastoma is characterized by ligand-independent overexpression of epidermal growth factor (EGF) receptors. EGF receptor signaling can promote tumorigenesis by increasing cell proliferation and tissue invasion and by inhibiting apoptosis of cancer cells. The marine factor 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) has been shown to block oxidative stress by scavenging free radicals in various cell types. This study investigates the effects of DHMBA on human glioblastoma cells in vitro. Glioblastoma cells were cultured in DMEM-low glucose containing 10% fetal bovine serum (FBS) in the presence of DHMBA (0.1-250 μM). Culturing with DHMBA significantly suppressed cell proliferation in the presence of FBS or EGF. Mechanistically, DHMBA treatment significantly decreased the levels of PI3-kinase 100α, Akt, MAPK, phosphor-MAPK, and mTOR, which are promoters of cell growth, and increased the levels of tumor suppressors p53, p21, and Rb, leading to the reduction of cancer cell growth. DHMBA treatment significantly stimulated the death of glioblastoma cells by increasing the levels of caspase-3 and cleaved caspase-3. In addition, culture with DHMBA significantly inhibited metastatic activity, including adhesion and migration of cancer cells. Thus, DHMBA may have inhibitory effects on the activity of human glioblastoma cells in vitro. This study may provide a new strategy for the treatment of glioblastoma tumors.