Identifying potential relationships between air pollutants and neutrophil extracellular traps formation in metabolic dysfunction-associated fatty liver disease by integrating computational toxicology and multi-omics data.

SUMOylation plays critical roles in both initiation and development of atherosclerosis. SUMO-specific protease 3 (SENP3), a SUMO-specific protease that targets SUMO2/3 for deSUMOylation, is involved in vascular remodeling and the modulation of macrophage functions. Here, we probed for the role of SENP3 in macrophages in the development of atherosclerosis. Stable and unstable plaques were collected from patients with atherosclerosis. A macrophage-specific SENP3 knockout mouse (Senp3Mac-KO) was generated and performed for a murine atherosclerosis model. Transcriptional sequencing was performed to identify potential mechanisms. SENP3 expression in macrophages was increased in unstable plaques, compared to stable plaques. The mean fluorescence intensity of SENP3 in macrophages infiltrating carotid plaques was positively correlated with circulating pro-inflammatory cytokines, low density lipoprotein (LDL-C), and triglycerides in atherosclerosis patients. Senp3Mac-KO mice exhibited a markedly reduced atherosclerotic plaque area in the aorta, compared to wild-type mice. Knockdown of SENP3 in macrophages resulted in decreased secretion of pro-inflammatory cytokines, increased secretion of anti-inflammatory factors, and reduced foam cell formation. Transcriptional analysis identified significant enrichment in Toll-like receptor (TLR4) signaling pathway modulated by SENP3. Genetic deletion of either TLR4 (Tlr4-/-) or Sterol O-Acyltransferase 2 (SOAT2) (Soat2-/-) attenuated the exacerbation of atherosclerosis development induced by SENP3 overexpression. Furthermore, SENP3 regulated TLR4 and SOAT2 expression indirectly via the transcription factor MYC rather than through direct deSUMOylation of TLR4 or SOAT2 themselves. Downregulation of SENP3 in macrophages suppresses pro-inflammatory cytokine release by inhibiting TLR4 signaling and reduces foam cell formation by impeding SOAT2 expression, both mediated by the transcription factor MYC, thereby attenuating the development of atherosclerosis. Hence, SENP3 may represent a potential therapeutic target in atherosclerosis.

Ornithine (OR) is a key intermediate metabolite; however, its molecular role in obesity remains unclear. This study aimed to investigate the effects of OR and its rate-limiting enzyme, ornithine decarboxylase 1 (ODC1), on lipid metabolism using high-fat diet (HFD)-induced obese C57BL/6 mice and C3H10T1/2 cell models. The results showed that OR supplementation and ODC1 overexpression exerted similar effects, including significantly aggravated HFD-induced obesity, elevated serum polyamine levels, impaired glucose tolerance, reduced oxygen consumption, and hepatic steatosis. Transcriptomic analysis combined with protein validation indicated that ODC1-promoted lipid deposition is associated with suppression of the AMPK/ACC pathway. Invitro, ODC1 overexpression promoted adipocyte proliferation and differentiation, accompanied by elevated levels of polyamines, including putrescine, spermidine, and spermine. Increased polyamine turnover further induced polyamine catabolic enzymes spermidine/spermine N1-acetyltransferase 1 (SAT1) and polyamine oxidase (PAOX), resulting in increased reactive oxygen species (ROS) accumulation, lipid peroxidation, and mitochondrial dysfunction. These changes were associated with suppression of the AMPK/ACC pathway, resulting in increased intracellular triglyceride (TG) accumulation. Conversely, treatment with the ODC1 inhibitor DFMO or knockdown ODC1 markedly alleviated oxidative stress and lipid accumulation. Furthermore, OR supplementation failed to reverse oxidative stress and adipogenesis following ODC1 knockdown, indicating that its metabolic effects are largely dependent on ODC1 activity. Taken together, our findings reveal that ODC1-mediated polyamine synthesis links SAT1/PAOX-associated ROS production to AMPK/ACC and increased lipid accumulation, highlighting ODC1 as a potential therapeutic target for obesity and lipid metabolic disorders.

Piezo1: A potential therapeutic target for endothelial dysfunction-related diseases.

Knockdown of histone deacetylase 9 ameliorates immunoglobulin a nephropathy by modulating immune response.

Microglial efferocytosis dysfunction contributes to depression-like behaviors and cognitive impairment in aged mice following chronic sleep deprivation.

Hepatic steatosis is a notable feature of metabolic-associated fatty liver disease (MAFLD), which is associated with exosomal miR-122-5p. However, the mechanisms by which exosomal miR-122-5p is involved in the transport of free fatty acid (FFA) remain uncharacterized. The aim of the present study was to investigate the functional role of exosomal miR-122-5p derived from steatotic hepatocytes in hepatic CD36 translocation. Exosomes from PBS- or FFA-treated AML12 cells were extracted via ultracentrifugation (Ctrl-exo or steatotic hepatocyte-derived exosome (SH-exo)), and recipient AML12 cells were treated with them for 24h. Additionally, AML12 cells were transfected with miR-122-5p mimic or inhibitor for 24h. A dual-luciferase reporter assay was applied to identify miR-122-5p targeting 3' UTR of ATP6V1H mRNA. RT-qPCR and western blot assessed the expressions of miR-122-5p, CD36, and ATP6V1H in exosomes and recipient AML12 cells. The miR-122-5p down-regulates ATP6V1H expression by directly targeting the 3' UTR of ATP6V1H mRNA. SH-exo were absorbed by recipient AML12 cells and exhibited elevated levels of miR-122-5p. The SH-exo increased FFA uptake, promoted CD36 translocation, and disrupted v-ATPase assembly in recipient AML12 cells by down-regulating the ATP6V1H expression in an insulin-independent manner. MiR-122-5p mimic similarly increased FFA uptake and CD36 translocation by inhibiting ATP6V1H expression in AML12 cells. Furthermore, miR-122-5p inhibitor reduced the FFA content and increased ATP6V1H expression in SH-exo-treated AML12 cells. Our findings indicated that exosomal miR-122-5p, derived from steatotic hepatocytes, can increase FFA uptake and promote CD36 translocation in recipient hepatocytes by directly targeting ATP6V1H expression, suggesting that hepatic exosomal miR-122-5p may serve as a potential therapeutic target for MAFLD.

Sweroside ameliorates endothelial dysfunction via the KLF2-mediated repression of the FABP4/CCL20 signaling axis.

Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes the transfer of methyl groups to phosphatidylethanolamine to generate phosphatidylcholine (PC). PC produced de novo through this pathway is preferentially used for very-low-density lipoprotein assembly and is essential for its normal hepatic secretion as well as for bile acid detoxification. While human PEMT loss-of-function polymorphisms are linked to increased metabolic dysfunction-associated steatotic liver disease risk, the enzyme's role as a primary driver of progressive liver disease remains underexplored. We utilized PEMT knockout (PEMT KO) mice on a standard chow diet to model this deficiency. Histopathological analysis showed that while 2-month-old PEMT KO mice were protected, 6-month-old KOs of both sexes spontaneously developed extensive micro- and macrovesicular steatosis, parenchymal inflammation, and granulomatous inclusions. This severe, age-dependent pathology was confirmed by elevated hepatic triglyceride levels, bile acids, impaired methylation potential, and a cascade of secondary injuries, including increased oxidative stress, impaired proteasomal function, and the induction of cellular senescence markers. This bile acid toxicity and oxidative stress activated the central innate immune sensor, the NLRP3 inflammasome, driving pronounced macrophage infiltration and chronic inflammation. Picrosirius red staining and protein analysis confirmed the progression to severe pericellular fibrosis. Our study establishes that PEMT deficiency is sufficient to initiate and drive the complete progression from steatosis to advanced liver fibrosis, identifying PEMT as a critical metabolic checkpoint and a potent therapeutic target for mitigating progressive liver disease.

TCRVβ-targeting antibody-drug conjugates as a novel strategy to eliminate malignant T cells in T cell cancers.

Long non-coding RNA TTN-AS1 promotes acute liver injury in sepsis: A novel potential monitoring and therapeutic target.

Organoid-based modeling unveils Dnmt3a-driven epigenetic regulation of phenotypic plasticity in small cell lung cancer.

Connexin32 inhibits renal tubulointerstitial fibrosis in diabetic kidney disease by regulating NOX4/MRTF-A positive feedback loop.

SOX4 is a transcriptional activator for CTHRC1 in lung fibroblast activation.

Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.

14-3-3η protein ameliorates glomerular endothelial cell injury in lupus nephritis by regulating mTOR pathway-mediated autophagy.

Identification of key driver genes in idiopathic pulmonary arterial hypertension by single-cell RNA sequencing and experimental validation.

FFA4 inhibits bleomycin-induced pulmonary fibrosis in mice by suppressing IL-33.

Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.

MASH associated lipotoxicity perturbs the expression of hepatic vitamin D bioactivating gene CYP2R1 in humans and mice.