Cell Biochemistry and Function最新文献

Due to their stable nature and medical applicability properties, coumarin derivatives have fascinated medicinal chemists in the discovery of novel therapeutics. In this study, the cytotoxic/anticancer properties of some newly synthesized coumarin derivatives were aimed at designing, synthesizing, and examining cultured human neuroblastoma cells. Moreover, molecular docking studies were carried out to determine the potential mechanism. In addition, ADMET properties were evaluated to examine the drug-likeness of newly designed coumarin derivatives. To detect the cytotoxic action of compounds, 3-(4,5-dimethylthiazol-2-yl)-2,5 2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays were carried out. In addition, Hoechst 33258 staining was used to detect abnormal nuclear structures. In silico, the estimates for all compounds (3a-3c) used in the study revealed that they possessed desirable physicochemical properties for bioavailability. The results of our study showed that all tested compounds exhibited remarkable cytotoxic effects on human neuroblastoma cell lines (p < 0.05). Additionally, among the compounds tested, 3a and 3c showed selective effects on neuroblastoma cells effectively at all tested concentrations. However, it was found that the selective feature of 3b, unlike the others, was concentration-dependent. Our findings clearly showed that novel coumarin derivatives exerted potent and selective anticancer effects. Results of molecular docking studies were in parallel with in vitro studies. Unlike the majority of hybrid coumarin derivatives reported in anticancer research, the present study introduces minimalist, heteroatom-free coumarins bearing bulky aliphatic substituents. These compounds demonstrated selective cytotoxicity against SH-SY5Y neuroblastoma cells and a favorable multi-target binding profile, highlighting a distinct hydrophobic volume-based SAR. As a result, the obtained data exhibited that all used molecules may be good multitarget drug alternatives for the treatment of neuroblastoma.

FUN14 domain-containing 1 (FUNDC1), an outer mitochondrial membrane protein, has emerged as a critical regulator of mitochondrial quality control and cellular homeostasis. Initially identified as a mitophagy receptor, FUNDC1 orchestrates hypoxia-induced mitophagy through phosphorylation-dependent interactions with LC3. Recent studies reveal its multifaceted roles in mitochondrial dynamics (fission/fusion), mitochondria-associated endoplasmic reticulum membranes (MAMs), and metabolic regulation, mediated by posttranslational modifications (phosphorylation, ubiquitination, acetylation). FUNDC1 dysfunction is implicated in cardiovascular diseases, neurodegeneration, cancer, and dermatological pathologies. It modulates oxidative stress primarily through impaired clearance of ROS-generating mitochondria via disrupted mitophagy, while also influencing apoptosis, pyroptosis, and inflammation via crosstalk with Bcl-2 family proteins, MOMP, mPTP, and cGAS–STING pathways. This review synthesizes FUNDC1's molecular mechanisms, highlighting its dual role as a protector (clearing damaged mitochondria) and potentiator of injury (excessive mitophagy). We also discuss therapeutic targeting of FUNDC1-dependent pathways in mitochondrial disorders.

Age-related neuronal loss is a critical feature of neurodegenerative disorders, including Alzheimer's disease (AD), but its underlying molecular mechanisms, particularly those involving epigenetic regulation, remain incompletely understood. To analyze DNA methylation patterns in early-stage AD pathogenesis, we employed female presenilin-1/presenilin-2 double knockout (PSEN1/PSEN2 dKO, hereafter referred to as dKO) mice as a model system, This animal model have the age-dependent progressive neurodegenerative changes characteristic of neurodegenerative disorders. Using reduced representation bisulfite sequencing (RRBS), we comprehensively profiled hippocampal DNA methylation patterns in 9-month-old dKO mice compared with age-matched wild-type controls. Based on RRBS detection results, subsequent bioinformatics analysis through Bismark (v0.7.4) and DAVID v6.8 revealed 1216 differentially methylated sites across multiple chromosomes, corresponding to 796 genes. Through stringent filtering criteria, we identified 50 candidate genes exhibiting significant methylation changes in dKO hippocampal tissue as shown in hierarchical clustering. These genes were functionally enriched in DNA-dependent transcriptional regulation (p < 0.01) and protein binding activities (p < 0.05), with pathway analysis highlighting their involvement in ErbB signaling (FDR = 0.03), melanogenesis (FDR = 0.04), and oncogenic pathways (FDR = 0.05). Our study identifies significant hippocampal DNA methylation changes during the early stages of neurodegeneration in dKO mice. These epigenetic alterations highlight pathways potentially contributing to presenilin-dependent neuronal loss and suggests potential targets for modulating neurodegeneration linked to presenilin dysfunction.

Cardiac hypertrophy is a major risk factor for cardiovascular disease worldwide, and Mediterranean diet has shown great benefits in reducing cardiovascular disease-related mortality and morbidity. Numerous studies have ascertained that the protective effect of olive oil on the heart is mainly attributed to its active component, oleuropein (OLE); however, the mechanism remains unknown. We hypothesised that OLE provides cardioprotective effects against cardiac hypertrophy through the alleviation of endoplasmic reticulum stress. In the present study, different dosage regimens (10, 30 and 60 mg/kg) of OLE were intragastrically administered to an isoproterenol (ISO) (7.5 mg/kg)-induced cardiac hypertrophy mouse model. OLE alleviates ISO-induced cardiac hypertrophy and apoptosis. In addition, the increased expression of endoplasmic reticulum (ER) stress-related genes, such as Glucose-Regulated Protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein homologous protein (CHOP), and protein kinase RNA-like ER kinase (PERK), was blunted by OLE, with reduced Sirtuin-1 (SIRT1) levels. Furthermore, after pretreatment with EX527 (a SIRT1 inhibitor), the anti-hypertrophic, anti-apoptosis and ER stress effects of OLE were diminished, implying a key role of SIRT1 in ER stress inhibition. Our study indicates that OLE ameliorates ISO-induced cardiac hypertrophy through SIRT1 activation via ER stress inhibition.

In the present study, the synthesis, characterization, and therapeutic effects in treating second-degree burn wounds of the green synthesis ZnO NPs using Ferulago angulata extract and its doping with magnesium were evaluated. The prepared materials were characterized using powder X-ray diffraction, field emission scanning electron microscopy, UV-Vis absorption spectra, and Fourier transform infrared spectroscopy. The antioxidant properties of materials were investigated by DPPH (2, 2-diphenyl-1-picrylhydrazyl) assay. The concentration of 500 µg/mL of Mg-doped ZnO NPs was associated with the highest level of DPPH radical reduction among the several substances (F. angulata extract, ZnO NPs, and Mg-doped ZnO NPs) (p < 0.05). The Pasteur Institute cell bank was employed to obtain the Huvec cell line for the cytotoxicity test. The viability of the cells decreased as compared to the control group (p < 0.05) after 24 h of exposure. The lowest viability rate was seen when these substances were added at 1000 µg/mL. The antibacterial and antifungal properties of nanoparticles and ointments prepared from these nanoparticles with different concentrations were investigated. Examining the antibacterial and antifungal effect of zinc oxide and Mg-doped ZnO nanoparticles showed that these compounds had antibacterial and antifungal effects on mesophilic aerobic bacteria, Escherichia coli, Pseudomonas aerogenosa, Staphylococcus aureus, Salmonella, Candida albicans, mold, and yeast. After 21 days of treatment with various ointments, the speed of wound closure and hair growth was observed in groups Mg-doped ZnO NPs (0.05% and 1%), Zn-NPs (0.05% and 1%), Adib Derm and Eucerin groups, respectively. The microscopic analysis of the wound site in the group treated with 0.1% of Mg-doped ZnO NPs showed that after 21 days, collagenization and epithelialization occurred. The epidermis and the stratum corneum were well-formed, and the formation of hair follicles increased in number. The presence of sebaceous glands around the hair follicles also indicated complete wound healing and improved skin.

Spinal muscular atrophy (SMA) is the most common genetic disease leading to infant mortality, primarily characterized by the deficiency of survival motor neuron (SMN) protein. The effects of SMA are not limited to the nervous system but also encompass multiple cell types. Fibroblasts have been extensively employed as primary disease model cells in SMA pathophysiological studies. Here, we present a comprehensive summary of the pivotal roles fibroblasts play in SMA research, focusing on how SMN deficiency modulates the response characteristics of fibroblasts. Our findings reveal distinct reactivity patterns in fibroblasts, which serve as representative Non-neuronal cells, compared to motor neurons in SMA. This review underscores the crucial roles of fibroblasts in elucidating mechanistic changes, advancing drug discovery, and identifying reliable biomarkers for SMA. These insights underscore the indispensable potential of fibroblasts in future SMA research endeavors.

The fate of mRNA in human cells is a critical aspect of gene regulation, encompassing both post-translation degradation and subcellular localization. This review explores the critical role of mRNA fate in human cells, focusing on post-translation degradation and subcellular localization. mRNA degradation, including mechanisms like nonsense-mediated decay, ensures the elimination of defective and unnecessary transcripts, thereby preventing harmful protein accumulation. Simultaneously, subcellular localization directs mRNA to specific organelles, such as the endoplasmic reticulum and mitochondria, facilitating localized protein synthesis essential for cellular function. We highlight the importance of these processes in maintaining cellular homeostasis, particularly in neurons and cancer cells, where dysregulation can lead to disease. By understanding these processes, new therapeutic strategies can be developed to target diseases associated with mRNA dysregulation.