Journal of Biochemical and Molecular Toxicology最新文献

Cardiovascular diseases are a threat to human health and are associated with increased mortality. Gallic acid (GA) (3,4,5-trihydroxybenzoic acid) is a naturally occurring polyphenolic compound with cardiovascular preventive properties. However, the precise mechanism underlying its cardioprotective effect is not fully understood. The Notch signaling system is essential in heart injury/repair mechanisms, and clarifying this mechanism in a Lipopolysaccharide (LPS) stimulated zebrafish embryo larvae (ZFEL) model for cardioprotective function. This study aimed to elucidate the cardioprotective activity of GA in LPS stimulated ZFEL via Notch signaling pathway. In this study, an in vivo cardiac injury model was developed in ZFEL using LPS induction. The GA cardioprotective property was investigated by LC_50, survival analysis, morphological assessment, heart rate assessment, cell death, and nitric oxide determination. Expression of Notch signaling and the cardiac biomarker protein were done by immunoblotting and in addition whole mount immunohistochemistry was performed for NICD, MMP 9, and MMP 13. GA protects LPS-induced ZFEL by increasing survival rates, normalizing morphological anomalies, restoring abnormal heart rate, preventing cell death, and inhibiting NO generation. It suppressed the Notch signaling pathway (Notch1, Delta1, Hey1, and Hes1) and cardiac biomarker proteins (MPO, MMP-9, MMP-13, and NO) in LPS-stimulated ZFEL, indicating cardioprotective property. Our findings showed that GA suppressed both molecular and cellular events during LPS-induced heart damage via the Notch signaling pathway.

Circular RNAs (circRNAs) are a class of non-coding RNAs characterized by their covalently closed loop structures, which confer remarkable stability. Recent studies have highlighted the role of exosomal circRNAs, which are encapsulated within extracellular vesicles known as exosomes, in intercellular communication and tumor progression. In colorectal cancer (CRC), exosomal circRNAs have been implicated in various oncogenic processes, including cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. These molecules exhibit dysregulated expression patterns in CRC tissues and bodily fluids, making them promising candidates for non-invasive biomarkers. Moreover, their functional roles in modulating signaling pathways and the tumor microenvironment suggest their potential therapeutic applications. This review summarizes our current understanding of exosomal circRNA biology, highlights their roles in the CRC development and progression, and discusses their clinical significance as diagnostic, prognostic and therapeutic tools.

Esculetin (ESC), a naturally occurring coumarin derivative identified in various medicinal plants, has garnered significant interest owing to its multifaceted pharmacological attributes. This narrative review synthesizes contemporary experimental data derived from in silico, in vitro, and in vivo investigations pertaining to ESC within cancer-associated frameworks and chemotherapy-induced organ toxicities. The extant literature indicates that ESC possesses antioxidant and anti-inflammatory properties and influences numerous signaling cascades pertinent to oxidative stress, inflammation, and oncogenic mechanisms. Within the scope of experimental investigations, ESC has been documented to amplify the anticancer efficacy of specific chemotherapeutic agents while concurrently mitigating chemotherapy-related toxicities in vital organs. The aforementioned protective effects are primarily ascribed to the preservation of redox equilibrium, attenuation of pro-inflammatory mediators, and the induction of cytoprotective pathways. Notwithstanding, clinical trials assessing ESC within these contexts are presently deficient, and discrepancies in experimental paradigms, dosing strategies, and bioavailability concerns related to formulation may impede direct translation to clinical practice. Collectively, this review elucidates ESC's structural and chemical attributes, principal pharmacological mechanisms, and its burgeoning preclinical significance in cancer models and the management of chemotherapy-induced toxicity. Subsequent research endeavors should emphasize the establishment of standardized experimental frameworks, pharmacokinetic validation, and clinical assessment to ascertain translational significance.

Neuropathic pain is a complex chronic condition resulting from injury to the nerve. Paclitaxel (PTX) is a commonly used chemotherapeutic drug, but it is usually associated with peripheral neuropathy. Costunolide (COS), a bioactive sesquiterpene lactone, exhibits potent neuroprotective, anti-inflammatory, antioxidant, and anti-apoptotic properties. The current study aimed to investigate the efficacy of COS in attenuating PTX-induced neuropathic pain using advanced spectroscopic, histological and biochemical analyses. Findings from the study revealed that administration with COS significantly improved the pain parameters, including mechanical allodynia, thermal hyperalgesia, and cold allodynia by increasing the pain thresholds. Muscle strength and motor coordination also improved significantly following administration of COS. Results from the Raman spectral analysis revealed distinct PTX-induced biochemical disruptions, especially in the lipids and proteins, which were subsequently normalized by COS. FTIR spectra demonstrated that COS mitigated PTX-induced damage to the myelin sheath, hence preserving the biochemical integrity. The tissue oxygenation (StO₂) profile was also improved. COS preserved neuronal architecture, reduced PTX-induced apoptosis, and maintained spinal cord and sciatic nerve structure. It also increased the level of antioxidants, that is, GSH, GST, and catalase, while reducing the level of oxidative stress markers (MPO, EPO, LPO, NO). Together, these findings establish COS as a promising candidate for the treatment of peripheral neuropathy. Its multimodal protective mechanisms-captured at both molecular and cellular levels- highlight its potential to counteract PTX-induced neurotoxicity.

Schiff bases, formed through the condensation of carbonyl compounds with primary amines, serve as valuable precursors for the development of anticancer nanomaterials. Their incorporation into metal-based nanoparticles, polymeric systems, and liposomal carriers has expanded the possibilities for targeted and effective cancer therapy. Current evidence indicates that Schiff base nanoparticles offer notable benefits over conventional therapies, particularly in improving drug efficacy and reducing systemic toxicity. This review outlines the synthesis of Schiff bases along with the methods used to develop their nanoparticles. The discussion also covers commonly used preparation methods, approaches for physicochemical characterization, and the major biological pathways through which these nanoparticles influence cancer cell survival. Despite the progress made, a number of issues still require attention, including the need for more precise nanoparticle designs, better understanding of long-term interactions in biological environments, and clearer links between laboratory findings and clinical translation. This review summarises the current progress and highlights the potential and the limitations of Schiff base functionalized nanoparticles as future anticancer agents.

Age-related macular degeneration (AMD), a primary cause of vision loss among older adults, is strongly associated with inflammatory processes. The current study aimed to elucidate the protective effects of irigenin, an isoflavonoid recognized for its anti-inflammatory, antioxidative, antiapoptotic, and anticancer activities, against blue light (BL)-induced damage in N-retinyl-N-retinylidene ethanolamine (A2E)-laden human adult retinal pigment epithelial (A2E-laden ARPE-19) cells. Pretreatment with irigenin markedly mitigated BL-induced cytotoxicity and preserved epithelial barrier function in a concentration-dependent manner. Moreover, irigenin significantly inhibited the expression of proinflammatory cytokines and activation of the nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, as evidenced by decreased expression of NLRP3, ASC, and both full-length and cleaved forms of gasdermin D (GSDMD), along with reduced caspase-1 activity. Further mechanistic analyses indicated that irigenin effectively suppressed the activation of the nuclear factor kappa B (NFκB) signaling pathway, as evidenced by phosphorylation of NFκB and inhibitor of NFκB (IκB)α, and both activation and translocation of NFκB, along with reduced phosphorylation of p38 mitogen-activated protein kinase (MAPK). These findings underscore the potential of irigenin to ameliorate BL-induced retinal pigment epithelial cell damage via modulation of inflammation and pyroptosis pathways, suggesting its therapeutic value for preventing AMD.

Excessive Ca²⁺ influx leads to mitochondrial oxidative injury and cell death, contributing to the development of age-related macular degeneration (AMD). The protective role of selenium nanoparticle (SeNPs), through inhibition of ADP-ribose- and hydrogen peroxide (H₂O₂)-induced TRPM2 cation channel stimulation, was recently reported in human retinal pigment epithelial 19 (ARPE-19) cells for hypoxia-induced oxidative cytotoxicity and cell death, but not for AMD. We aimed to investigate the protective effects of SeNPs through inhibition of TRPM2 on AMD (sodium iodate [NaI])-induced oxidative injury, cell death, and apoptosis in ARPE-19 cells. The ARPE-19 cells were divided into four main groups: control (CNT), SeNPs (2.5 μg/mL for 24 h), AMD (10 mM NaI for 24 h) and AMD + SeNPs. The AMD treatment increased TRPM2 current density and cytosolic Ca²⁺ and Zn²⁺ fluorescence intensities, as well as the percentage of cell death. It also elevated apoptotic markers (caspases 3, 8, and 9) and oxidative stress markers (mitochondrial membrane dysfunction, oxygen free radicals, and lipid peroxidation), while decreasing antioxidants (glutathione and glutathione peroxidase), cell viability and the number of live cells. TRPM2 stimulation further increased these markers. When SeNPs and TRPM2 antagonists were used to treat the AMD-induced increase in TRPM2 activation, they increased antioxidants and cell viability while decreasing oxidative stress and cell death markers. In conclusion, SeNP treatment reduced AMD-induced mitochondrial oxidative cytotoxicity and cell death by inhibiting TRPM2-mediated Ca²⁺ signaling. SeNP represents a potential therapeutic option for AMD-induced retinal disorders linked to abnormal oxygen free radical production and Ca²⁺ influx.

Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype constituting approximately 80% of all esophageal malignancies worldwide, represents a significant global disease burden with distinct geographical predilection. Fraxinellone (FRA) was reported to function as a tumor suppressor in several tumors, while the role of FRA in ESCC remains unclear. In the present study, we found that FRA treatment significantly inhibited cell proliferation and colony formation of ESCC cells. On the contrary, FRA treatment promoted cell apoptosis of ESCC cells by downregulating Bcl-2 protein and upregulating Bax and C-caspase3 proteins. Besides, FRA pretreatment suppressed proliferation and viability of CD8⁺ T cells but facilitated cell apoptosis in co-culturing system. Moreover, FRA pretreatment restrained immune evasion by attenuating CD8⁺ T cell activation. Mechanistically, FRA effectively inactivated HIF-1α/STAT3/PD-L1 signaling in ESCC cells and xenograft tumors. Ultimately, FRA treatment inhibited tumor growth in vivo. In conclusions, FRA inhibited ESCC cell growth and immune evasion by inactivating HIF-1α/STAT3/PD-L1 signaling in vitro and vivo. This study suggested that FRA may serve as a potential therapeutic agent for ESCC treatment.

α-amanitin (α-AMA), the primary lethal toxin of amanita, primarily targets the liver with a high toxicity and a low lethal dose. As the precise mechanism of intoxication is unclear, and specific antidotes are lacking, α-AMA-induced liver injury has a high mortality rate. As a selective PPAR-γ agonist, Rosiglitazone (RSG) alleviates liver injury by upregulating the PPAR-γ/Nrf2 signaling pathway, thereby enhancing antioxidant effects, mitigating inflammation, and reducing apoptosis. This study investigated the protective role and mechanism of action of RSG in α-AMA-induced acute liver injury in ICR mice. We established an experimental model and examined hepatic injury markers, focusing on PPAR-γ/Nrf2 pathway activation. Overall, α-AMA intoxication led to dose-dependent increases in serum ALT/AST levels, accompanied by hepatocellular necrosis. This was associated with the onset of oxidative stress, characterized by the accumulation of malondialdehyde (MDA), excessive ROS production, and reduced activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Furthermore, we observed the upregulation of pro-inflammatory mediators (TNF-α, IL-6, and IL-8), suppression of the PPAR-γ/Nrf2 cytoprotective axis, and hepatocyte apoptosis induced via activation of the P53/caspase-3 pathway, ultimately resulting in murine mortality. RSG treatment alleviated oxidative stress and the inflammatory response, reduced hepatocellular necrosis and apoptosis, and improved survival rates in α-AMA-intoxicated mice by upregulating the PPAR-γ/Nrf2 signaling pathway in hepatocytes. Early RSG intervention can thereby effectively mitigate α-AMA-induced acute liver injury by upregulating the PPAR-γ/Nrf2 signaling pathway. Future studies should focus on exploring the clinical potential of RSG as a therapeutic agent for amanita mushroom poisoning.