Acta biochimica et biophysica Sinica最新文献

AXL, a member of the TAM (Tyro3, AXL, and Mertk) subfamily of RTKs, is abundantly expressed in lung tissue and has been implicated in viral infections and lung injury. PROS1, one of the ligands known to activate AXL, functions as an immunomodulator in many diseases. However, the role of PROS1/AXL signaling in influenza A virus (IAV) infection and infection-induced lung injury is largely unknown. In this study, we find that the exogenous administration of PROS1 mitigates lung injury and protects mice from lethal infection by IAVs through the activation of AXL. PROS1 induces the phosphorylation of AXL, which in turn recruits Gab1 and p85, a regulatory subunit of PI3K, to form a complex that activates Gab1 and its downstream PI3K/AKT/mTOR in alveolar macrophages. Gab1 knockdown in vivo, or LY294002 (a PI3K inhibitor), abolishes the PROS1/AXL-induced protective activity against lethal influenza infection in mice. We also show that PROS1/AXL signaling induces M2 polarization of alveolar macrophages through Gab1 activation both in vitro and in vivo. Gab1 knockdown inhibits M2 macrophage accumulation in IAV-infected lungs and attenuates the protective effect of PROS1. These results indicate that PROS1/AXL signaling can activate Gab1 in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype, thereby eliciting protective activity against lethal infection with IAVs. These data also highlight the PROS1/AXL signal as a novel therapeutic target for IAV infection.

Circadian disruptions appear at the presymptomatic stage of Alzheimer's disease (AD) and may exacerbate mental dysfunction in AD. The downregulation of brain and muscle ARNT-like protein 1 (BMAL1), a key clock element for the maintenance of circadian rhythms, has been linked to epigenetic mechanisms. Our previous study revealed that the mRNA level of DNA demethylase ten-eleven translocation ( Tet) 3 was reduced in the hippocampi of APPswe/PS1dE9 (APP/PS1) mice. However, the effects of TET3 on BMAL1 downregulation and circadian dysregulation in AD are still unclear. Our investigation first confirms that Tet3 mRNA and protein levels are decreased in both APP/PS1 mice and APPswe cells. In addition, decreased levels of 5hmC are observed in HT22 cells after TET3 knockdown, whereas TET3 overexpression reverses the reduction in 5hmC. Critically, we report that TET3 knockdown remethylates the Bmal1 promoter, thus downregulating BMAL1 expression in HT22 cells. In contrast, TET3 overexpression could upregulate BMAL1 by decreasing its methylation level. These results indicate that reduced TET3 is responsible for BMAL1 downregulation through decreased TET3 demethylation. Additionally, TET3 knockdown could lead to circadian disruption of BMAL1 in U2OS cells, whereas overexpression of TET3 alleviates the dysregulated biological rhythm in Aβ-treated U2OS cells. Our data suggest that TET3 plays a vital role in modulating the circadian rhythm at the epigenetic level through DNA demethylation.

Sepsis-associated acute liver injury (SALI) is a frequent and clinically severe complication of sepsis, in which inflammatory responses and oxidative stress are involved. Angelicin (ANG), one of the main active components in the traditional Chinese medicine Psoralea corylifolia Linn., has anti-inflammatory and antioxidant bioactivities. In this study, the protective effect of ANG on SALI and its specific mechanism are investigated by establishing a mouse model of caecal ligation and puncture (CLP)-induced SALI and an in vitro sepsis model in LPS-stimulated AML12 cells. These results show that ANG can alleviate liver injury and improve liver function in SALI mice. ANG decreases the mRNA expression levels of the pro-inflammatory factors Il-1β, Il-6, and Tnf-α and increases the mRNA expression level of the anti-inflammatory factor Il-10, which suggests its anti-inflammatory effects. The results of the biochemical kit assay and DHE staining show that ANG can decrease the levels of MDA and ROS and increase the level of GSH and the activities of CAT and SOD, which suggests that ANG has antioxidant effects. Mechanistically, ANG exerts anti-inflammatory effects by inhibiting the NF-κB and p38 MAPK pathways and exerting antioxidant effects by activating the Nrf2/Keap1 pathway. Additionally, cell transfection experiments indicate that activation of the Nrf2/Keap1 pathway by ANG may depend on the inhibition of the NF-κB pathway. In conclusion, ANG attenuates SALI by inhibiting the NF-κB and p38 MAPK pathways, thereby activating the Nrf2/Keap1 pathway and making it a promising therapeutic intervention for SALI.

Chronic psychosocial stress is increasingly recognized as a key risk factor for dry eye disease, potentially because of its disruption of the circadian transcriptome and lacrimal gland function, which impacts eye health. In this study, we test this hypothesis by using two mouse models (high platform and restraint experiments) of psychological stress and report that both models uniquely alter the circadian transcriptome and signaling pathways of the lacrimal gland. Psychosocial stress significantly affects the normal rhythmic oscillations of extraorbital lacrimal gland (ELG) immune cell trafficking, secretion response, and lipid deposition. Both models significantly reduce the volume of stimulated lacrimal secretions as well as the recruitment of immune cells to the lacrimal gland. Importantly, treatment with beta-adrenergic receptor blockers or glucocorticoid synthesis inhibitors significantly improves these secretory functions and histopathological changes. Collectively, these findings demonstrate the detrimental effects of chronic psychosocial stress on lacrimal gland circadian transcriptome homeostasis and suggest potential clinical applications for patients with both psychological stress and dry eye disease.

Bone remodeling represents a dynamic equilibrium orchestrated by mechanobiological and endocrine signals, with YAP/TAZ and ERα emerging as pivotal regulators of skeletal adaptation. YAP/TAZ functions as the central mechanotransduction hub of the Hippo pathway, converting biomechanical cues, including microenvironment matrix stiffness and shear stress, into osteogenic transcriptional programs. Concurrently, ERα integrates both mechanical stimuli and estradiol (E2) signaling to coordinate osteoblast-osteoclast coupling through the transcriptional regulation of RUNX2 activity and RANKL suppression. Although increasing evidence suggests that these two systems might engage in functional crosstalk, there is still no consensus on this issue. This review synthesizes the current understanding of YAP/TAZ-ERα interactions across three dimensions: (1) mechanohormonal integration in skeletal remodeling, (2) context-dependent reciprocity in breast carcinogenesis, and (3) tissue-specific regulatory paradigms in extra-skeletal systems. Key findings reveal that YAP/TAZ and ERα exhibit both synergistic cooperation (enhanced osteogenic differentiation via promoter co-occupancy) and pathway antagonism (competitive TEAD binding), with their interaction dynamics being critically shaped by the cellular microenvironmental context. Notably, mechanical potentiation of ERα transcriptional activity requires YAP/TAZ co-activation in bone mesenchymal stem cells, whereas estrogen signaling modulates YAP mechanosensitivity through cytoskeletal remodeling. These mechanistic insights indicate that the YAP/TAZ-ERα axis is a promising therapeutic target for osteoporotic bone loss, particularly in alveolar bone preservation. By bridging endocrine and mechanobiological perspectives, this work provides a conceptual framework for developing combinatorial therapies that simultaneously address hormonal imbalance and mechanical insufficiency in skeletal pathologies.

Hepatocyte phospholipase D1 ( PLD1) knockout alleviates metabolic dysfunction-associated steatotic liver disease (MASLD) in mice, but the underlying mechanism is largely unknown. In this study, the mice were divided into four groups: Con (wild-type mice with normal control diet), HFHC (wild-type mice with high-fat diet), Con_KO (hepatocyte PLD1-knockout mice with normal control diet), and HFHC_KO (hepatocyte PLD1-knockout mice with high-fat diet). Intestinal contents of mice are analyzed via metagenomics and metabolomics, and the liver bile acids are assessed by mass spectrometry imaging. The results show that at the phylum level the abundance of Bacillota in the intestines of MASLD model mice is significantly increased, whereas that of Bacteroidota significantly is decreased. However, after the deletion of hepatocyte PLD1, Pseudomonadota and Candidatus Bathyarchaeota are significantly decreased in the MASLD model mice. At the species level, compared with that in the Con group, the abundance of Faecalibaculum rodentium is significantly increased in the HFHC group, whereas hepatocyte PLD1 knockout causes the abundances of Desulfovibrionaceae bacterium LT0009 and Lachnospiraceae bacterium 10-1 to be significantly decreased. In terms of intestinal bile acids, the levels of two bile acids (hyodeoxycholic acid and glycolithocholic acid) differ between the HFHC_KO group and the HFHC group. Association analysis shows that Faecalibaculum co-occurs with DCA, βMCA, ΩMCA and αMCA, while probiotic Bacteroides uniformis is significantly correlated with UDCA, 12-KetoLCA, and 7-KetoLCA. Finally, mass spectrometry imaging reveals that the TCA and TDCA contents in the liver are significantly decreased after PLD1 knockout in hepatocytes. These findings demonstrate that hepatocyte PLD1 knockout alters the gut microbiota and bile acids profiles, suggesting that PLD1 deficiency may modulate MASLD progression by changing intestinal microbiota-bile acid homeostasis.

The tumor microenvironment (TME), which encompasses the extracellular matrix, cancer-associated fibroblasts, endothelial cells, pericytes, and immune cells, is intimately connected to tumor development and metastasis. TME is widely heterogeneous, and metabolic interactions among the different components contribute to reshaping TME. Lipid metabolism, referring to lipid uptake, synthesis, transport, and lipolysis, is essential for maintaining cellular homeostasis. The availability of nutrients in the TME constantly changes during tumor progression, and tumor cells must reprogram lipid metabolism to maintain their rapid proliferation, survival, invasion, and metastatic potential. The interactions of lipid metabolism among tumor cells and other cell subtypes reshape the microenvironment into a niche suitable for tumor development. In this review, we present the featured lipid metabolic interactions within the TME of different cancer types and discuss how targeting abnormal lipid metabolic pathways could be a promising strategy for cancer therapeutics.

Skeletal muscle-derived Musclin exerts multiple effects on the cardiovascular system. However, the role of Musclin in vascular intimal hyperplasia (IH) remains unclear. This study aims to investigate the role and underlying mechanism of Musclin in IH. We overexpress Musclin in skeletal muscle via adeno-associated virus serotype 6 (AAV6)-mediated gene transfer (AAV- Musclin) in an injury-induced mouse vascular IH model. Morphological analyses, including hematoxylin and eosin (H&E) staining and Ki-67 immunohistochemistry, are used to evaluate IH severity. Ki-67 immunofluorescence, transwell assay, wound healing assay, and analysis of vascular smooth muscle cell (VSMC) differentiation markers are conducted to assess VSMC phenotypic switching. The extracellular acidification rate (ECAR) assay is utilized to measure glycolysis in VSMCs. Following AAV- Musclin transfection, Musclin levels are increased in both skeletal muscle and peripheral blood. Muscle-specific Musclin overexpression ameliorates injury-induced vascular IH. In vitro, Musclin represses glycolysis, proliferation, and migration while increasing VSMC differentiation markers in PDGF-BB-stimulated VSMCs. Mechanistically, Musclin inhibits mammalian target of rapamycin complex 1 (mTORC1) activity and induces NPR3-raptor interaction. Restoring mTORC1 activity abolishes the inhibitory effects of Musclin on PDGF-BB-induced VSMC phenotypic switching and its protective role against injury-induced vascular IH. Additionally, NPR3 silencing abrogates Musclin-mediated suppression of mTORC1 activity, glycolysis, and phenotypic switching in PDGF-BB-treated VSMCs. Collectively, external Musclin supplementation may represent a promising therapeutic strategy for preventing vascular IH-related pathologies.