Cell Biochemistry and Function最新文献

Cardiolipin (CL), an exclusive phospholipid, is predominantly found within the confines of the inner mitochondrial membrane, playing an indispensable role in the sustenance of mitochondrial operations and the regulation of cellular energy metabolism. The influence of CL on the pathways of cell death has garnered significant interest in recent scholarly discourse. This review delves into the multifaceted roles of CL across various modes of cell demise, encompassing apoptosis, autophagy, pyroptosis, ferroptosis, necrosis, and necroptosis. The discussion extends to the examination of CL's implications in a clinical context, particularly concerning cardiovascular maladies, neurological degeneration, and oncological conditions. Through an integrative analysis of contemporary research findings, the aim is to elucidate the intricate dynamics of CL's involvement in cell death phenomena. While acknowledging the inherent limitations and the hurdles faced by current research endeavors, the therapeutic potential of CL as a modulator of cell death pathways is nonetheless encouraging. Forthcoming investigations must surmount these obstacles, thereby uncovering the nuanced mechanisms and impacts of CL in the realm of cell death and associated pathologies, potentially paving the way for innovative clinical intervention strategies.

Our previous study reported that histone deacetylase 4 (HDAC4) expression is significantly downregulated in placental tissues of pre-eclampsia (PE) pregnancies. Cellular pyroptosis is a key event in the pathogenesis of PE that induces the release of factors into the maternal circulation. The aim of this study is to analyze the role and related molecular mechanisms of HDAC4 in PE trophoblast cell pyroptosis. Hypoxia and lipopolysaccharide (LPS)/ATP-treated immortalized human placental villous trophoblast cells HTR-8/SVneo were utilized to mimic the placental trophoblast cell state in PE. Both hypoxia and LPS/ATP treatments induced significant HTR-8/SVneo cell pyroptosis, whereas HDAC4 overexpression inhibited the induced cell pyroptosis. HDAC4 could bind to NLRP3 and GSDMD proteins, and lead to a decrease in acetylated NLRP3 and GSDMD proteins, thereby inhibiting cell pyroptosis. Hypoxia and LPS/ATP treatment significantly upregulated HDAC4-AS1 levels in HRT-8/SVneo cells. HDAC4-AS1 could bind to HDAC4 gene promoter sequences as well as CTCF protein. HDAC4-AS1 overexpression recruited the enrichment of CTCF on HDAC4 promoter sequences and further repressed HDAC4 transcription and expression. Targeting the transcriptional regulatory mechanism of HDAC4-AS1/HDAC4 may be able to ameliorate the clinical symptoms of PE maternal by inhibiting cellular pyroptosis in syncytiotrophoblast cells under stress.

In this study, the cytotoxic effects of pexidartinib (PLX), a tyrosine kinase inhibitor approved for tenosynovial giant cell tumor through inhibition of colony-stimulating factor 1 receptor (CSF1R), against A549 lung adenocarcinoma cells and Beas-2B healthy bronchial cells were investigated by in detailed in-vitro and in-silico studies. Through MTT assays, PLX demonstrated significant inhibition of A549 cell viability with IC₅₀ values of 2.15 and 1.3 µM at 24 and 48 h, respectively, while having minimal effects on Beas-2B cells, with IC₅₀ values of 36.2 and 9.3 µM. The high selectivity index indicates PLX's preferential action against cancerous cells. The mechanism of cell death induced by PLX was further explored using Annexin V/PI staining and flow cytometry, revealing that PLX primarily induces necrosis in A549 cells, with an increase in necrotic cell populations and reduced efficacy at higher concentrations. Western blot analysis showed an upregulation of necroptosis markers (RIP3 and pMLKL) in A549 cells, while apoptotic markers like Caspase-3 remained unchanged. In addition, wound healing assays demonstrated that PLX significantly inhibits A549 cell migration in a dose-dependent manner. Molecular docking studies identified key amino acids involved in PLX binding interactions with target proteins. RIPK1 showed the strongest binding affinity. MD simulations revealed that the PLX-VEGFR2 complex was the most stable. As conclusion, PLX, although approved for tenosynovial giant cell tumors, shows promising potential for lung adenocarcinoma treatment. It selectively inhibits cancer cell viability, induces necroptosis, and reduces cell migration. Its stronger binding to RIPK1 and VEGFR2 more than CSF1R.

As immune cells, neutrophils serve as the first line of defense against infections; however, the mechanism by which neutrophils regulate lipid metabolism is unknown. The neutrophil depletion group was treated with 100 μg InVivoMAb anti-mouse Ly6G 6 times, whereas the control group mice were intraperitoneally injected with the same quantity of InVivoMAb rat IgG2a. Body fat content, triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) in the jejunum and ileum, as well as 9 long-chain fatty acids (LCFAs) in the intestinal contents were significantly decreased. Furthermore, genes involved in the absorption of lipids in each segment of the intestine also showed decreased expression. Neutrophil-depletion and control models were administered 25 μCi of ³H-cholesterol by gavage. The distribution of ³H cholesterol in the intestinal segment, heart, liver, serum, and feces was not altered by anti-Ly6G antibodies. Metagenomics was applied to investigate uncultured microorganisms in the intestinal contents to identify bacteria containing lipid metabolism genes. At the species level, 12 bacteria were involved in unsaturated LCFA synthesis, among which 2 increased and 10 decreased. The overall relative abundance of these bacteria decreased from 3.102% to 0.734%. Many genes involved in lipid metabolism were also reduced as a result, such as fatty acid synthase and peroxisome proliferator-activated receptor γ. In conclusion, neutrophil depletion does not affect intestinal lipid absorption in the diet but leads to a decrease in the overall relative abundance of gut bacteria involved in unsaturated LCFA synthesis. Consequently, intestinal lipid synthesis and absorption are reduced.

Aging is considered the contributory accumulation of abruptions occurring through cell signaling cascades, which ultimately cause changes in physical functions, cell fate, and damage across all organ systems. DNA damage response (DDR) also occurs through telomere shortening, tumor formation, mitochondrial dysfunction, and so forth. Cellular aging occurs through cell cycle arrest, which is the result of extended DDR cascade signaling networks via MDC1, 53BP1, H2AX, ATM, ARF, P53, P13-Akt, BRAF, Sirtuins, NAD + , and so forth. These persistent cell cycle arrests initiated by DDR and other associated stress-induced signals promote a permanent state of cell cycle arrest called senescence-associated secretory phenotype (SASP). However, cellular aging gets accelerated with faulty DNA repair systems, and the produced senescent cells further generate various promoting contributors to age-related dysfunctional diseases including SASP. Any changes to these factors contribute to age-related disease development. Therefore, this review explores anti-aging factors targeting DDR and SASP regulation and their detailed signaling networks. In addition, it allows researchers to identify anti-aging targets and anti-aging therapeutic strategies based on identified and nonidentified targets.

Microglia, as resident immune cells in the brain, adhere to the extracellular matrix and typically exhibit anti-inflammatory polarization under normal physiological conditions. Despite their pivotal roles, the regulatory effects of extracellular matrix properties on microglial function and the associated molecular mechanisms remain inadequately understood. Here, we elucidate how matrix stiffness modulates interleukin-10 (IL-10) secretion in human microglia (HMC3) via yes-associated protein (YAP)-mediated mechanotransduction. Using soft collagen Ⅰ-coated hydrogels, we observed a substantial reduction in IL-10 secretion, accompanied by a decrease in the expression and nuclear localization of YAP compared to cells adhered to glass substrates. With increasing hydrogel substrate stiffness, the expression and nuclear localization of YAP were enhanced, leading to an elevated secretion of IL-10. Subsequently, to further investigate the relationship between YAP and IL-10, we performed YAP depletion experiments, which revealed that nuclear exclusion of YAP suppressed IL-10 secretion. Interestingly, overexpression of YAP in microglia did not markedly affect IL-10 levels. We seeded YAP-knockdown microglia onto hydrogels of varying stiffness, and no significant differences were observed in IL-10 secretion. Our findings suggested that cytoskeletal polymerization was crucial for the regulation of IL-10 secretion mediated by YAP. Given the crucial role of IL-10 in the tumor microenvironment, we further found shYAP-microglia attenuated the pro-proliferative effect of microglia on gliomas. Besides, when YAP was silenced, actin of human microglia decreased, and their contractility was weakened. In summary, this study identifies YAP as a pivotal molecule in controlling cytokine secretion and sensing matrix stiffness in microglia. These insights offer potential therapeutic avenues for glioma treatment by targeting YAP-mediated pathways in microglial cells.

Mesenchymal stem cells (MSCs) are emerging as promising therapeutic agents due to their immunomodulatory effects, primarily mediated via paracrine signaling. Similarly, anthocyanins, such as cyanidin-3-glucoside (C3G), have demonstrated significant anti-inflammatory properties. In this context, this study investigated the immunomodulatory potential of C3G on MSCs, and subsequent effects on macrophage and lymphocyte responses. Cytotoxicity assays identified 50 µM as the highest nontoxic C3G concentration for MSCs. Flow cytometry confirmed that C3G treatment did not affect MSC viability or cell cycle distribution, even under LPS stimulation. Cytokine production by MSCs was evaluated after treatment with C3G and LPS. While no significant changes were observed in IL-6, IL-10, TGF-β, or PGE₂ levels, IL-1β production was significantly reduced in LPS-stimulated MSCs treated with C3G. Protein expression analysis revealed decreased NFκB phosphorylation in LPS-stimulated MSCs treated with C3G, with no changes detected in STAT-3 or PCNA expression. The immunomodulatory effects of MSC-derived conditioned media on macrophages and lymphocytes were also assessed. In LPS-stimulated macrophages, conditioned media from MSCs reduced the production of IL-1β, IL-6, and IL-12. Interestingly, conditioned media from C3G-treated MSCs specifically decreased TNF-α levels, enhanced IL-10 secretion, and further inhibited NFκB phosphorylation. In LPS-stimulated lymphocytes, conditioned media from C3G-treated MSCs suppressed IL-2 production while increasing IL-10 levels. In summary, these findings demonstrate that conditioned media from C3G-treated MSCs modulates immune cell responses more effectively than C3G alone. C3G influences the paracrine activity of MSCs, resulting in a shift in the secretory profile and subsequent effects on immune cell behavior.

Sepsis, defined as a systemic inflammatory response, is one of the conditions with the highest mortality rates. Crosin (CRO) is one of the active ingredients in saffron and known for its various pharmacological effects. It has been reported to have protective and healing effects on liver tissue. In this study, we aimed to investigate the protective role of CRO in lipopolysaccharide (LPS)-induced acute liver injury. 40 male Wistar Albino rats aged 8–12 weeks were randomly divided into 4 groups: Control, CRO (50 mg/kg, intraperitoneal administration for 9 days), LPS (30 mg/kg, single dose), and LPS + CRO (50 mg/kg CRO for 9 days along with a single dose of 30 mg/kg LPS). Following the experimental procedure, liver and blood samples were collected for further analyses. Histopathological analysis revealed a marked increase in liver damage in the LPS group, as evidenced by significant histopathological changes. In contrast, the liver histology in the LPS + CRO group closely resembled that of the Control and CRO groups, exhibiting substantially less damage compared to the LPS group. Immunohistochemical examinations showed a significant increase in the expressions of TLR4, HMGB1, NF-κB, TNF- α, HSP70, and HSP90 in the LPS group. However, in the LPS + CRO group, the levels of these markers were significantly lower compared to the LPS group. ELISA analyses showed a significant increase in MDA, IL-6, and TGF-β and a decrease in SOD, CAT, GSH levels in the LPS group. Conversely, in the LPS + CRO group, CRO applications exhibited a significant protective effect on these alterations. Additionally, AST, ALT, and LDH levels were significantly elevated in the LPS group, while albumin levels were lower in the LPS group. CRO applications in the LPS + CRO group were observed to have a protective effect on these parameters. We believe that CRO holds significant potential in the treatment of acute inflammatory diseases such as septic acute liver injury and should not be overlooked.

High rate of relapse, following chemotherapy, in acute myeloid leukemia (AML) is a major concern. The chemoprotection conferred by the bone marrow microenvironment has lately been recognized, in addition to autophagy-mediated chemoresistance. Thus, the present study explored the effect of osteoblast on autophagy in AML and its impact on sensitivity to cytarabine (Ara-C) in the context of endosteal niche. Co-culture of KG1-a, HL60, or THP-1 AML cells with osteoblastic Saos-2 cell line induced autophagy in AML cell lines under direct contact. HL60 cells when co-culture with Saos-2 demonstrated more resistance to Ara-C induced apoptosis, which was reversed upon chloroquine treatment. Similarly, inhibition of autophagy in AML cell by knocking down Beclin-1 enhanced HL60 sensitivity to Ara-C. An interesting observation was upregulation of autophagy even in Saos-2 cells upon co-culture with AML cell, and increase in HL60 apoptosis in response to Ara-C on Beclin-1 knockdown in osteoblast cell. This highlights that autophagy plays a chemoprotective role in the endosteal niche in AML against Ara-C.