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Background Aging is associated with fat atrophy and fibrosis with loss of adipocyte differentiation from preadipocytes. New approaches to this loss involve agents that can renew the proliferative and differentiative capacities of preadipocytes with the aim of creating new healthy adipose tissue that secrete adipokines that positively impact on skin health. Material & Methods We investigated the effect of Magnolol (ML), a naturally derived compound, on human primary pre‐adipocyte viability and proliferation as well as adipogenic gene expression and increase in lipid production. Cell proliferation was assessed using fluorescent signaling, and adipocyte differentiation was monitored by following morphological and microscopic changes. RNA purification and real‐time PCR were undertaken to examine gene expression changes, and Oil red O staining was used to confirm adipose cell transformation. Adipokine expression, in particular adiponectin quantification, was also undertaken. Results Magnolol, at a relatively low concentration, demonstrated clear adipogenic activity: with a significant increase in preadipocyte proliferation after 48 h and a significant accumulation of adipocytes as demonstrated by oil red staining. Increased gene expression of PLN1 and FABP4 and a significant increase in adiponectin protein expression was demonstrated. Conclusion Magnolol stimulates preadipocyte proliferation and conversion to adipokine‐producing adipocytes. This has the potential for a positive skin health and volumizing effect if used in a topical formulation.

Saussurea costus is a plant traditionally used for the treatment of several ailments. Our study accomplished the UPLC/T-TOF–MS/MS analysis of a methanol extract of Saussurea costus roots (MESC), in addition to lipoidal matter determination and assessment of its in vivo hepatoprotective activity. In this study, we were able to identify the major metabolites in MESC rather than the previously known isolated compounds, improving our knowledge of its chemical constituents. The flavones apigenin, acacetin, baicalein, luteolin, and diosmetin, and the flavonol aglycones quercetin, kaempferol, isorhamnetin, gossypetin, and myricetin and/or their glycosides and glucuronic derivatives were the major identified compounds. The hepatoprotective activity of MESC was evaluated by measuring catalase activity using UV spectrophotometry, inflammatory cytokines and apoptotic markers using ELISA techniques, and genetic markers using PCR. Paracetamol toxicity caused a significant increase in plasma caspase 2, cytokeratin 18 (CK18), liver tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), miRNA-34a, and miRNA-223, as well as a significant decrease in liver catalase (CAT) activity and in the levels of liver nuclear factor 1α (HNF-1α), sirtuin-1, and C/ebpα. Oral pretreatment with MESC (200 mg/kg) showed a significant decrease in caspase 2, CK18, TNF-α, IL-6 and a significant increase in liver CAT activity. MESC decreased the levels of liver miRNA-34a and miRNA-223 and induced HNF-1α, sirtuin-1, and C/ebpα gene expression. The histological examination showed a significant normalization in rats pretreated with MESC. Our findings showed that Saussurea costus may exert a potent hepatoprotective activity through the modulation of the expression of cellular cytokines, miRNA-34a, and miRNA-223.

Introduction and Aims Alzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid‐beta (Aβ) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and modulation of these miRNAs can influence the development of tau and Aβ pathology. The brain‐specific miRNA miR‐128, encoded by MIR128‐1 and MIR128‐2, is important for brain development and dysregulated in AD. In this study, the role of miR‐128 in tau and Aβ pathology as well as the regulatory mechanism underlying its dysregulation were investigated. Methods The effect of miR‐128 on tau phosphorylation and Aβ accumulation was examined in AD cellular models through miR‐128 overexpression and inhibition. The therapeutic potential of miR‐128 in AD mouse model was assessed by comparing phenotypes of 5XFAD mice administered with miR‐128‐expressing AAVs with 5XFAD mice administered with control AAVs. Phenotypes examined included behavior, plaque load, and protein expression. The regulatory factor of miR‐128 transcription was identified through luciferase reporter assay and validated by siRNA knockdown and ChIP analysis. Results Both gain‐of‐function and loss‐of‐function studies in AD cellular models reveal that miR‐128 represses tau phosphorylation and Aβ secretion. Subsequent investigations show that miR‐128 directly inhibits the expression of tau phosphorylation kinase GSK3β and Aβ modulators APPBP2 and mTOR. Upregulation of miR‐128 in the hippocampus of 5XFAD mice ameliorates learning and memory impairments, decreases plaque deposition, and enhances autophagic flux. We further demonstrated that C/EBPα transactivates MIR128‐1 transcription, while both C/EBPα and miR‐128 expression are inhibited by Aβ. Conclusion Our findings suggest that miR‐128 suppresses AD pathogenesis, and could be a promising therapeutic target for AD. We also find a possible mechanism underlying the dysregulation of miR‐128 in AD, in which Aβ reduces miR‐128 expression by inhibiting C/EBPα. MiR‐128 can suppress tau phosphorylation by directly targeting GSK3β, and reduce Aβ levels by repressing Aβ generation and enhancing Aβ clearance through targeting APPBP2 and mTOR, respectively. In turn, Aβ can reduce miR‐128 expression by decreasing C/EBPα.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by an abnormal epithelial‒mesenchymal transition (EMT) and fibroblast activation, although the molecular mechanisms driving these processes remain unclear. Here, we report that the expression of CCAAT enhancer binding protein γ (C/EBPγ), a transcription factor, is significantly upregulated in lung tissues from patients with IPF and the lungs of mice with bleomycin-induced fibrosis. In A549 epithelial cells, C/EBPγ overexpression promoted the EMT, as indicated by decreased E-cadherin expression and increased N-cadherin and vimentin expression. In MRC-5 fibroblasts, C/EBPγ overexpression increased cell migration and upregulated the expression of fibrotic markers, including collagen I, fibronectin, and α-SMA. Mechanistically, C/EBPγ activated the β-catenin pathway by stabilizing β-catenin through the transcriptional repression of AXIN1, a key component of the degradation complex. This repression occurred via an interaction with C/EBPα, antagonizing its promotion of AXIN1 expression, as confirmed by ChIP‒qPCR, luciferase assays, coimmunoprecipitation, immunofluorescence staining, and rescue experiments. In vivo, adeno-associated virus-mediated C/EBPγ overexpression aggravated bleomycin-induced pulmonary fibrosis in mice, increasing collagen deposition, inflammation, and β-catenin expression, whereas C/EBPγ knockdown alleviated these changes. Collectively, these findings suggest that the downregulation of C/EBPγ expression attenuates fibrosis progression through the C/EBPα–AXIN1–β-catenin axis, underscoring its involvement in β-catenin pathway regulation and advancing the understanding of IPF pathogenesis.

Mast cells have been implicated in allergic diseases such as asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria, and anaphylaxis. However, it is now well established that they also fulfill critical roles in tissue homeostasis, repair, and defense. Despite considerable progress, their ontogeny, proliferation, and differentiation remain subjects of debate, as does their involvement in a wide spectrum of diseases, including cancer and cardiovascular disorders. What remains indisputable is their essential contribution to both innate and adaptive immune responses. Importantly, the activity of their effector molecules can elicit either protective or deleterious outcomes. A complete absence of mast cells (MCs) in humans would undoubtedly provide valuable insight into their fundamental role in immunity, much as neutropenia and agranulocytosis have historically clarified the functions of neutrophils. In this review, we provide a comprehensive overview of mast cell (MC) biology, emphasizing their functional diversity and pathogenic potential. Furthermore, we highlight emerging therapeutic strategies, particularly the use of inhibitors and monoclonal antibodies, which are reshaping current approaches to conditions such as allergy, mastocytosis, and related disorders.

Background Stroke is a major cause of disability and mortality worldwide, with ischemic stroke (IS) being the most common form. The blood-brain barrier (BBB) plays a critical role in protecting the brain, and its dysfunction after stroke exacerbates neuronal damage. Therefore, restoring BBB integrity is a promising therapeutic strategy. Tirzepatide (TZP), a dual GLP-1 and GIP receptor agonist, has demonstrated neuroprotective effects, but its role in BBB restoration post-stroke remains unclear. Objective This study aims to evaluate the potential of TZP in preventing BBB dysfunction and restoring its integrity in ischemic stroke models. Methods Using a middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke, we assessed the effects of TZP on neurological deficits, BBB permeability, and the expression of tight junction (TJ) proteins, particularly Claudin-1. In vitro, human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate ischemic conditions. The involvement of C/EBP-α, a key transcription factor regulating TJ proteins, was also investigated. Results TZP treatment significantly improved neurological scores and reduced BBB permeability in MCAO mice. It also restored Claudin-1 expression, which was downregulated in stroke conditions. In vitro, TZP reduced endothelial permeability and enhanced Claudin-1 expression in OGD/R-treated HBMVECs. Silencing C/EBP-α abolished the protective effects of TZP on both BBB integrity and Claudin-1 expression, indicating that C/EBP-α signaling is crucial for TZP’s action. Conclusion TZP ameliorates BBB dysfunction and protects against ischemic stroke by activating C/EBP-α signaling and restoring Claudin-1-mediated tight junction integrity. These findings suggest that TZP holds promise as a therapeutic agent for stroke, offering a novel strategy for maintaining BBB function and reducing neuronal damage. Further studies are needed to explore the detailed mechanisms underlying TZP’s neuroprotective effects and its clinical potential in stroke therapy.

Liver fibrosis is a reversible phase of arsenic-induced chronic liver injury, with bile acid metabolic alterations closely associated with this pathological process. SIRT1 is a key metabolic regulator and promising therapeutic candidate, while its role in bile acid metabolism during arsenic-induced liver fibrosis remains poorly defined. This study established time-dependent rat models of arsenic-induced liver fibrosis with resveratrol intervention to investigate the potential association between SIRT1, bile acid metabolic disturbance, and liver fibrosis, as well as resveratrol's hepatoprotective effects. Arsenic exposure induces progressive accumulation of hydrophobic bile acids in the liver, inflammation, hepatic stellate cell activation, and fibrosis, accompanied by suppressed expression of bile acid phase II detoxification genes ( , , ) and the bile acid efflux transporter gene (BSEP). Arsenic exposure reduces SIRT1 expression and increases C/EBPα acetylation, which may relate to impaired transcription of the aforementioned bile acid metabolic genes. Resveratrol may restore SIRT1 expression, normalize C/EBPα acetylation and bile acid homeostasis, and reduce hepatic arsenic accumulation, thereby alleviating liver fibrosis. Collectively, the SIRT1/C/EBPα axis and bile acid metabolism may be linked to the progression of arsenic-induced liver fibrosis. Resveratrol may exert protective effects via multiple mechanisms, including regulating these molecular targets and reducing hepatic arsenic accumulation.

Background Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive liver fat deposition, and progresses to liver cirrhosis, and even hepatocellular carcinoma. However, the invasive diagnosis of NAFLD with histopathological evaluation remains risky. This study investigated potential genes correlated with NAFLD, which may serve as diagnostic biomarkers and even potential treatment targets. Methods The weighted gene co-expression network analysis (WGCNA) was constructed based on dataset E-MEXP-3291. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to evaluate the function of genes. Results Blue module was positively correlated, and turquoise module negatively correlated with the severity of NAFLD. Furthermore, 8 driving genes (ANXA9, FBXO2, ORAI3, NAGS, C/EBPα, CRYAA, GOLM1, TRIM14) were identified from the overlap of genes in blue module and GSE89632. And another 8 driving genes were identified from the overlap of turquoise module and GSE89632. Among these driving genes, C/EBPα (CCAAT/enhancer binding protein α) was the most notable. By validating the expression of C/EBPα in the liver of NAFLD mice using immunohistochemistry, we discovered a significant upregulation of C/EBPα protein in NAFLD. Conclusion we identified two modules and 16 driving genes associated with the progression of NAFLD, and confirmed the protein expression of C/EBPα, which had been paid little attention to in the context of NAFLD, in the present study. Our study will advance the understanding of NAFLD. Moreover, these driving genes may serve as biomarkers and therapeutic targets of NAFLD.

Macrophages can acquire a variety of polarization status and functions: classically activated macrophages (M1 macrophages); alternatively activated macrophages (M2 macrophages). However, the molecular basis of the process is still unclear. Here, this study addresses that microRNA-181a (miR-181a) is a key molecule controlling macrophage polarization. We found that miR-181a is overexpressed in M2 macrophages than in M1 macrophages. miR-181a expression was decreased when M2 phenotype converted to M1, whereas it increased when M1 phenotype converted to M2. Overexpression of miR-181a in M1 macrophages diminished M1 phenotype expression while promoting polarization to the M2 phenotype. In contrast, knockdown of miR-181a in M2 macrophages promoted M1 polarization and diminished M2 phenotype expression. Mechanistically, Bioinformatic analysis revealed that Kruppel-like factor 6 (KLF6) and CCAAT/enhancer binding protein-α (C/EBPα) is a potential target of miR-181a and luciferase assay confirmed that KLF6 and C/EBPα translation is suppressed by miR-181a through interaction with the 3'UTR of KLF6 and C/EBPα mRNA. Further analysis showed that induction of miR-181a suppressed KLF6 and C/EBPα protein expression. Importantly, miR-181a also diminishes M2 macrophages-mediated migration and invasion capacity of tumor cells. Collectively, our results suggest that miR-181a plays a significant role in regulating macrophage polarization through directly target KLF6 and C/EBPα.

Long-term memory formation requires de novo RNA and protein synthesis. Using differential display PCR, we found that the NCoR1 cDNA fragment is differentially expressed between fast learners and slow learners, with fast learners showing a lower expression level than slow learners in the water maze learning task. Fast learners also show lower NCoR1 mRNA and protein expression levels. In addition, spatial training decreases both NCoR1 mRNA and protein expression, whereas NCoR1 conditional knockout (cKO) mice show enhanced spatial memory. In studying the molecular mechanism, we found that spatial training decreases the association between NCoR1 and DEC2. Both NCoR1 and DEC2 suppress the expression of BDNF, integrin α3 and SGK1 through C/EBPα binding to their DNA promoters, but overexpression of DEC2 in NCoR1 cKO mice rescues the decreased expression of these proteins compared with NCoR1 loxP mice overexpressing DEC2. Further, spatial training decreases DEC2 expression. Spatial training also enhances C/EBPα binding to Bdnf , Itga3 and Sgk1 promoters, an effect also observed in fast learners, and both NCoR1 and DEC2 control C/EBPα activity. Whereas knockdown of BDNF, integrin α3 or SGK1 expression impairs spatial learning and memory, it does not affect Y-maze performance, suggesting that BDNF, integrin α3 and SGK1 are involved in long-term memory formation, but not short-term memory formation. Moreover, NCoR1 expression is regulated by the JNK/c-Jun signaling pathway. Collectively, our findings identify DEC2 as a novel interacting protein of NCoR1 and elucidate the novel roles and mechanisms of NCoR1 and DEC2 in negative regulation of spatial memory formation.