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Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily initially identified without clearly defined endogenous high-affinity ligands. Nevertheless, increasing evidence demonstrates that they play essential roles in regulating metabolism, development, neural function, and tumorigenesis. Recent advances in structural biology, chemical biology, and systems biology have improved understanding of ligand recognition and regulatory mechanisms in these receptors. This review summarizes current progress in ONRs ligand research. ONRs are categorized according to their physiological roles in metabolic homeostasis, development and reproduction, and neuro-immune and cancer-related regulation, highlighting their involvement in diseases such as metabolic disorders, cancers, neurological diseases, and reproductive abnormalities. We discuss the structural basis of ligand recognition, focusing on conserved features of the ligand-binding domain (LBD) and structural variations, particularly in the α10 and AF-2 helices, that influence ligand accessibility and transcriptional regulation. Structural studies have revealed ligand-receptor complexes for representative ONRs, including ROR, HNF-4, REV-ERB, ERR, SF-1, and LRH-1, identifying ligand types such as lipids, heme, and phospholipids. In contrast, other receptors, including TR4, DAX-1, COUP-TFII, and Nur77, currently have only functional evidence supporting potential ligand interactions. Key strategies for ligand discovery include endogenous ligand co-purification, phenotype-based high-throughput screening, structural biology approaches, and structure-based virtual screening combined with molecular dynamics simulations. Major challenges include difficulties in endogenous ligand identification, context-dependent regulation, and limitations in achieving receptor subtype selectivity in drug development. Future progress will rely on integrating structural, biochemical, and multi-omics approaches to facilitate therapeutic targeting of ONRs.

Determining trace heavy metals (Cd, Pb, Hg, As) in food remains challenging due to complex matrix interferences from proteins, lipids, and coexisting ions. Metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) are promising sensing platforms owing to their high surface area and task-specific functionalization. Crucially, MOF-COF hybrids engineered via precise interfacial design exhibit enhanced conductivity, stability, and anti-interference capabilities, significantly improving robustness in food matrices. This review summarizes recent progress in utilizing functional MOFs, COFs, and their hybrids for food safety monitoring. It emphasizes synergistic structural design, sensing mechanisms, and matrix-resistant signal transduction. Furthermore, we discuss representative applications and portable point-of-care testing (POCT) devices. Finally, the review outlines current limitations and future directions to guide the practical deployment of robust MOF/COF sensors for accurate heavy metal detection in real food samples.

Extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles, are small particles surrounded by lipid bilayers that almost all cell types produce. They are essential for cell signaling because they transport bioactive molecules, including DNA, RNA, proteins, and lipids. The amount and make-up of EXOs are linked to several illnesses, including inflammatory diseases, cancer, metabolic diseases, and the one we're communicating about here, female infertility. Bacteria, fungi, viruses, and parasites are just a few of the organisms known to affect the reproductive system in both men and women. EVs are very important for reproductive health, and they can be a cause of infections that make women unable to have children. EVs play a significant role in cell communication and can influence both healthy and pathological processes in the female reproductive system. We looked into the use of EVs as an alternative way to treat vaginal infections (VIs), like bacterial vaginosis, viral vaginitis, and vaginal yeast infections, because traditional treatments for these diseases have some problems. In this study, we also examined the role of EVs in infertility associated with VI. Then, the pros and cons of this method for treating this sickness in the future are discussed.

In this paper, a simplified heat and mass transfer model for a pork burger cooked in an electric oven is presented. The aim was to relate model predictions to physicochemical and quality properties, providing a basis for optimizing electric oven cooking processes. The burgers were cooked for several times, and the numerical simulations showed good precision with experimental data, supporting the applicability of the proposed model. The heat transfer analysis identified three characteristic stages of temperature evolution at the burger center: initial slow heating, exponential increase, and a final constant temperature phase. For mass transfer, the drying curve confirmed that the process occurs exclusively in the falling rate period, with internal water diffusion being the predominant mechanism, suggesting that the meat protein-lipid emulsion may hinder moisture transport. The analysis of physicochemical and quality properties-including mass loss, pH, moisture, extractable lipids, surface color, and shear force-revealed complex interactions in the burger matrix. A positive and significant (P&#xa0;<&#xa0;0.05) Pearson's correlation was found between cooking time and pH decrease, higher lipid extractability, redness loss, and yellowness increase. However, tenderness did not show a correlation with the cooking process during the studied periods. Overall, the proposed approach highlights thermal control as a strategic tool for studying physicochemical changes during cooking. These results provide insights into process design and thermal treatments, which could also improve product quality and consumer acceptability, and also maximizing yield.

Understanding how complex organic contaminant mixtures change in composition, structure, and transformation behavior across wastewater treatment plants (WWTPs) is essential for improving pollutant control. However, stage-resolved knowledge of these processes remains limited. Here, we integrated non-targeted screening, paired mass distance (PMD) reactomics, CANOPUS-based structural annotation, and MS2Tox-based toxicity prediction to characterize compositional changes, dominant transformation behaviors, and toxicity implications throughout a full-scale anaerobic-anoxic-oxic (A/A/O) treatment and disinfection process through wastewater sampling in a WWTP. Across the treatments, chemical features progressively shifted toward lower molecular weight and higher hydrophilicity. Structural classification revealed the common pollutants (organic acids and derivatives, benzenoids, lipids and lipid-like molecules) and specific pollutants present in each unit. Reactomics revealed that methylation and dehydrogenation/oxidation were the most frequent transformation types, and each unit exhibited several distinct reaction types (e.g., stage-specific alkylation/dealkylation reactions during disinfection). Further correlating structure and reaction types reveal that pollutant transformations in wastewater are characterized by small mass shifts and generally retained the structural category of the reactant. Subsequently, toxicity prediction results suggested that most compounds exhibited no (65%) to low (31.6%) toxicity in WWTP. Biological treatment was associated with more predicted detoxification events, whereas chlorination disinfection showed more predicted toxicity-increase events that were frequently associated with alkylation-/methylation-related PMD signals. This study provides a stage-resolved interpretation of contaminant transformation across WWTP treatment units by linking feature attenuation, structural redistribution, PMD-derived reaction signatures, and MS2Tox-predicted toxicity shifts.

Tumor-associated macrophages (TAMs) are key regulators of the metastatic immune microenvironment, yet the specific TAM subsets that drive immune suppression and tumor progression in colorectal cancer liver metastasis (CRLM) remain poorly defined. Here, we integrated CyTOF, single-cell and spatial transcriptomics, bulk RNA sequencing, and lipidomics to identify a distinct population of lipid-laden, immunosuppressive TREM2+ TAMs enriched in CRLM. These cells exhibited high expression of lipid metabolism-related genes, including APOE, LIPA, and GPNMB, and accumulate abundant intracellular lipid droplets. Spatial analyses revealed their preferential localization at the invasive margins and within intratumoral colonic lumen-like structures-regions characterized by the buildup of APOE protein, mucinous material, and apoptotic tumor debris. Transcriptional analyses suggest these macrophages follow a Kupffer cell-related differentiation trajectory and acquire an immunoregulatory phenotype via uptake of tumor-derived lipids. Functionally, TREM2+ TAMs produced leukotrienes via the ALOX5/ALOX5AP pathway, which in turn sustained chronic inflammatory signaling. This inflammatory milieu potentiated neutrophil recruitment and fostered tumor cell stemness, thereby reinforcing an immunosuppressive metastatic niche and correlating with poor patient prognosis. In vivo murine depletion model and ex vivo organotypic tumor models confirmed that either selective ablation of TREM2+ TAMs or pharmacological inhibition of leukotriene synthesis alleviated immunosuppression and potentiate the efficacy of anti-PD-1 therapy. Our study defines a conserved lipid-associated TREM2+ TAM population as an essential contributor of immune evasion and microenvironment remodeling in liver metastasis, and suggest it as a potential therapeutic target in metastatic colorectal cancer.

Rapeseed oil is a nutritious vegetable oil, obtained from Brassica napus L. plants. To explore the changes of physicochemical properties and lipid content of rapeseed in the process of growth and post-harvest ripening (PHR), this study evaluated the impact of ripening (1-18d) and PHR (1-5d) on cold-pressed oil. Results demonstrated that optimal maturity (R6) produced the most favorable fatty acid profile, achieving 92.54% unsaturated fatty acids. Extending PHR to 5d significantly enhanced the retention of key bioactive compounds: tocopherols reached 385.47&#xa0;mg/kg, phytosterols accumulated to 1838.97&#xa0;mg/kg, and phenolic content peaked at 599.95&#xa0;mg/kg. Comprehensive lipidomics analysis revealed two processes during PHR: an initial hydrolysis phase marked by elevated free fatty acids and lysophospholipids, followed by a stabilization phase characterized by triacylglycerol re-synthesis and concomitant phospholipid degradation. These findings evidence that coordinated harvest timing and PHR duration improve the oxidative stability, functional composition, and nutritional quality of rapeseed oil.

Hypertension (HTN) increasingly originates in childhood and adolescence, with obesity and smoking as modifiable risk factors. However, longitudinal evidence on their independent and joint effects on HTN risk into early adulthood remains limited in non-Western populations. Using data from the Tehran Lipid and Glucose Study (TLGS), we followed 985 adolescents (mean age 15.01 years) for a median of 15.05 years. Adolescent overweight/obesity was defined using national BMI percentiles, and smoking status was self-reported. Incident adulthood HTN was defined as blood pressure&#x2009;&#x2265;&#x2009;140/90 mmHg or use of antihypertensive medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for potential confounders. Over follow-up, 95 participants developed HTN. In adjusted analyses, adolescent overweight/obesity was independently associated with higher adulthood HTN risk (HR: 1.73; 95% CI: 1.11-2.71). Adolescent smoking was not independently associated with adulthood HTN after adjustment (HR: 1.15; 95% CI: 0.63-2.09). In joint exposure analyses, overweight/obese non-smokers had a higher risk than normal-weight non-smokers (HR: 1.77; 95% CI: 1.10-2.84), whereas smokers did not show statistically significant excess risk regardless of weight status. The obesity-smoking interaction suggested a possible synergistic effect on HTN risk in adulthood. Adolescent overweight/obesity is an independent predictor of adulthood HTN. Although smoking was not independently associated after adjustment, the potential interaction between obesity and smoking merits further study. Prevention efforts should prioritize adolescent weight management to reduce long-term cardiovascular risk. Not applicable.

Difelikefalin acetate (DF) is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients undergoing hemodialysis. The marketed formulation is an injectable, while this study aims to develop an oral formulation to improve patient compliance. DF is designed to incorporated into lipid nanoparticles with 1,2-dipalmitoyl-rac-glycerol-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DSPG), and cholesterol (CHOL) (at a ratio of 8:2:6), which are mixed with 20% oleic acid, 20% medium-chain triglycerides (MCT), 24% PEG-40 hydrogenated castor oil (RH40), and 36% transcutol to prepare a self-microemulsifying concentrate. The concentrate can achieve self-emulsification in purified water, pH 1.2(HCl solution), pH 4.5(acetate buffer), and pH 6.8(phosphate buffer) media, with a droplet size of 53-59 nm, polydispersity index (PDI) of 0.09-0.27, zeta potential of -36.39 to -6.1 mV, and drug loading of 90.3%. In vitro release results showed that the DF solution was almost completely released at 8 h in pH 6.8 medium, while the DF self-microemulsion only achieved approximately 20% release at 24 h. Enzymatic degradation experiments demonstrated that trypsin, elastase, and &#x3b1;-chymotrypsin could not effectively degrade DF. The rat pharmacokinetic study showed that, relative to intravenous administration, the oral bioavailability of the DF solution was 0.656%, whereas that of DF self-microemulsifying drug delivery systems (SMEDDS) was 2.04%, representing a 3-fold increase. In the mouse pharmacodynamic test, the scratching episodes inhibition of orally administered DF SMEDDS at a dose of 5 mg/kg was comparable to that of DF injection at 0.3 mg/kg.

Familial hypercholesterolaemia (FH) is a common but underdiagnosed genetic condition that leads to high low-density lipoprotein cholesterol and premature cardiovascular disease. Cascade genetic testing remains underutilised as a screening approach. Implementation strategies can increase the diffusion of innovations such as genetic medicine into non-genetic specialty settings more rapidly through dissemination networks. This study aimed to evaluate the success of a multifaceted implementation strategy to increase cascade testing for relatives of a person diagnosed with FH using a primary-tertiary shared care model. A multisite effectiveness-implementation hybrid type III pre-post study was conducted between 2022 and 2024 to compare the implementation of a new shared care model for FH cascade testing in NSW, Australia. During the control period, cascade testing of relatives was offered to FH index cases by a genetic counsellor at the lipid clinic. In the implementation strategy period, FH index cases were offered a cascade testing expression of interest form to provide to their relatives. Relatives were contacted by a genetic counsellor and provided with a pre- and post-cascade testing package, which was also provided to their general practitioner. A total of n&#x2009;=&#x2009;25 index and n&#x2009;=&#x2009;6 cascade cases were included in the control period and n&#x2009;=&#x2009;81 index and n&#x2009;=&#x2009;56 cascade cases in the implementation period. The number of cascade genetic tests per index case increased significantly from 0.24 in the control period to 0.52 in the implementation strategy period (incident rate ratio&#x2009;=&#x2009;4.62; 95% CI: 0.39, 8.84; p&#x2009;=&#x2009;0.032). Among relatives tested, there was no difference in the proportion with a confirmed FH gene change per index case (IRR&#x2009;=&#x2009;2.15; 95% CI: 0.65, 7.01; p&#x2009;=&#x2009;0.207). There was no difference in the proportion of index cases with at least one cascade test (OR&#x2009;=&#x2009;1.49; 95% CI: 0.53, 4.19; p&#x2009;=&#x2009;0.442). Implementation of our model increased FH cascade testing compared to previous standard care. These findings suggest a greater role for cascade testing in primary care settings. This opens new opportunities for integrating genetic screening into routine general practice, particularly for autosomal dominant conditions such as FH.

The endoplasmic reticulum (ER) is a central hub coordinating protein homeostasis and lipid metabolism in eukaryotic cells. In microalgae, which inhabit highly fluctuating environments, ER stress is increasingly recognized as a driver of lipid remodeling rather than a secondary metabolic consequence. This review synthesizes recent advances in ER stress signaling in microalgae, focusing on Chlamydomonas reinhardtii, and places these findings in a comparative eukaryotic context. Microalgae retain a conserved, IRE1-centered unfolded protein response (UPR) while lacking auxiliary branches found in animals and land plants. Activation of ER stress induces extensive reprogramming of membrane lipid composition, fatty acid desaturation, sterol metabolism, and triacylglycerol (TAG) accumulation. Notably, the Chlamydomonas IRE1/bZIP1 pathway functions to restrain excessive TAG accumulation, thereby prioritizing membrane adaptation and ER homeostasis. The graded and dynamic nature of this response likely compensates for the simplified single-sensor architecture by enabling flexible modulation of downstream outputs depending on stress intensity and duration. Importantly, ER stress responses exhibit distinct modes depending on stress severity: moderate stress promotes adaptive membrane stabilization, whereas severe or prolonged stress redirects membrane-derived fatty acids into TAG for sequestration. This lipid-centered adaptation contrasts with land plants, which stabilize membrane composition without substantial TAG accumulation, and with yeast and animals, where membrane biogenesis and neutral lipid storage occur in parallel, with distinct regulatory features. By integrating insights across eukaryotes, this review highlights ER stress as a framework for understanding lipid remodeling in microalgae and discusses how UPR manipulation may enable rational engineering of lipid production platforms.

Carboxylesterase 1 (CES1) is the most abundant hepatic hydrolase responsible for metabolizing many clinically important medications. Hepatic CES1 also plays a role in regulating lipid homeostasis. This study aimed to determine whether plasma CES1 protein levels reflect hepatic CES1 abundance and serve as a biomarker of the pharmacokinetics of CES1-substrate drugs and of metabolic dysfunction-associated steatotic liver disease (MASLD). We quantified CES1 protein levels in matched human livers and plasma from adults with biopsy-confirmed MASLD (n = 17), in normal liver tissues (n = 6), and in plasma from healthy volunteers enrolled in an enalapril pharmacokinetic study (n = 19). First, we found no correlation between hepatic and plasma CES1 levels in matched liver and plasma samples from patients with MASLD. Second, plasma CES1 correlated with enalaprilat exposure, although the correlation did not reach statistical significance. Third, plasma CES1 concentrations were approximately 8-fold higher in patients with MASLD than in healthy subjects (median 141.9 vs 16.2 ng/mL), whereas hepatic CES1 levels were comparable between MASLD and normal liver tissues. Moreover, plasma CES1 concentrations rose stepwise across histologic NAFLD activity score (NAS) strata (healthy < NAS 1-4 < NAS &#x2265; 5). Fourth, the machine learning model, Lasso logistic regression, showed that the CES1-informed classifier consistently outperformed those based on clinical features in differentiating MASLD patients from healthy subjects and across disease severity (NAS 1-4 vs NAS &#x2265; 5). Together, these data position plasma CES1 as a potential biomarker for diagnosing MASLD and staging the disease. SIGNIFICANCE STATEMENT: The findings of this study indicate that plasma carboxylesterase 1 may act as a substrate-dependent biomarker for the pharmacokinetics of drugs metabolized by the enzyme. Additionally, this study highlights plasma carboxylesterase 1 as a potential noninvasive biomarker of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis that can complement existing diagnostic tools and provide a more comprehensive assessment of disease progression.

Insect's body barriers rely on specialized extracellular matrices that protect against harmful environmental influences. The outer barrier is the cuticle, which is composed of chitin, cuticle proteins and lipids. The peritrophic matrix (PM) serves as an inner barrier lining the midgut epithelium. It is composed of chitin fibers that are organized by PM proteins. While cuticle and PM proteins have received considerable attention in the past, supramolecular organization and physicochemical properties of the chitin component - particularly of the PM - remain poorly understood. Here, we combine synchrotron-based X-ray diffraction data from the PMs of Manduca sexta and Zophobas morio with RNA interference (RNAi), mass spectrometric and histochemical analyses of the PM from Tribolium castaneum to determine chitin's allomorphic state and degree of acetylation. The chitin of the PM exhibits signatures characteristic of dihydrate &#x3b2;-chitin along the entire midgut. In contrast, the cuticle is made of tightly packed &#x3b1;-chitin nanofibrils. Mass spectrometry revealed that the PM's chitin is highly acetylated (>95%). RNAi silencing of gut-specific genes encoding chitin deacetylasesTcCDA6-9 further increases the degree of acetylation. Histochemical analyses staining chitin with different degrees of acetylation confirm the predominance of highly acetylated chitin in the PM. Notably, the larval cuticle has a layered organization with deacetylated chitin present in exo- and highly acetylated chitin in endocuticles. Depletion of both TcCDA1 or TcCDA2 impairs chitin deacetylation, which indicates that both proteins cooperate in their activity in the integument. These results establish fundamental principles of polysaccharide-based extracellular matrices, with broad implications for insect biology.

Dietary curcumin supplementation has been shown to improve growth, antioxidative and anti-inflammatory status in different fish species. Yet, studies focusing on its effect during the early developmental stages of fish remains limited. The recent study aimed at assessing the effect of dietary curcumin supplementation at different levels on the growth performance, antioxidant enzymes and immune response of seabass larvae (Dicentrarchus labrax). To this end, seabass larvae were reared from 21 to 60&#xa0;days after hatching, feeding on a standard feeding regime (CONTROL) and diets where LOW, medium (MED) and HIGH curcumin levels were supplemented. Fish were analyzed at the end of the experimental period for biometrical parameters, immune-related genes and activity of antioxidant-related parameters. At the end of the trial, fish from the HIGH treatment had a significantly higher dry weight than fish from the CONTROL, although no significant differences were observed for fish survival. Curcumin supplementation did not affect isolated antioxidant parameters, such as catalase activity, superoxide dismutase, and lipid peroxidation, glutathione peroxidase, but a multivariate analysis where these parameters were included unraveled a significant difference between treatments CONTROL and HIGH in the overall growth, antioxidant and immune response. Furthermore, a significant reduction of Immunoglobulin M (IgM) was found in treatments MED and HIGH in comparison to CONTROL, indicating the modulation of this parameter in seabass larvae may be dosage dependent. In conclusion, dietary curcumin supplementation at HIGH level was able to improve seabass weight and increase its overall health status during the early developmental stages.

Endothelial dysfunction (ED) represents an early key event in atherogenesis. Our aim was to evaluate the efficacy of six months add-on PCSK9 monoclonal antibodies (mAbs) on endothelial function assessed by endocan plasma levels and PWV in a cohort of HeFH subjects; furthermore, we investigated the association of endocan lowering and PWV variation. In this prospective observational study, we evaluated 30 FH subjects on high-intensity statins plus ezetimibe and with an off-target LDL-C. All patients received PCSK9 mAbs therapy and obtained biochemical analysis as well as endocan measurement and PWV evaluation at baseline and after six months of PCSK9 mAbs. After six months of add-on PCSK9 mAbs therapy, a significant reduction of TC, LDL-C, Non-HDL-C, TG, Lp(a) and ApoB was observed; moreover, both PWV and endocan significantly improved after six months of treatment. Finally, univariate linear regression analysis showed that &#x394;PWV was significantly associated with &#x394;Endocan (p value&#x202f;<&#x202f;0.001). PCSK9 inhibition was associated with significant improved endocan levels and PWV in a cohort of HeFH subjects. &#x394;Endocan was significantly associated with &#x394;PWV. Our exploratory findings demonstrate endothelial benefits of PCSK9 mAbs in addition to LDL-C lowering and support endocan and PWV as complementary markers of vascular response in FH.

Compost tea is a widely used organic fertilizer for enhancing tomato quality, yet its underlying mechanisms remain unclear. This study cultivated four compost tea-treated tomato groups (T1-Fr, T2-Fr, T3-Fr, T4-Fr) with distinct compost teas (T1-NS, T2-NS, T3-NS, T4-NS). In compost tea-treated tomatoes, we observed elevated levels of reducing sugars, ascorbic acid, and lycopene, alongside coordinated down-regulation of five alkaloids and four terpenoids and up-regulation of five flavonoids. Integrated metabolomics demonstrated that compost tea reshapes the fruit metabolic profile through both direct uptake of metabolites and systemic regulation of metabolic pathways. KEGG and WGCNA analyses revealed that lipid metabolites in compost tea potentially contribute to modulating lipid metabolism and enhancing the accumulation of glucose, fructose, and ascorbic acid in tomato fruits. Exogenous application of myristic acid, oleic acid, and arachidonic acid enhanced the accumulation of reducing sugars and ascorbic acid. Our study provides a scientific basis for the targeted optimization of compost tea formulations.

Macrophage polarization is involved in the pathogenesis of acute respiratory distress syndrome (ARDS). However, the upstream regulators that shape macrophage inflammatory phenotypes under pathological conditions remain poorly understood. Pro-brain-derived neurotrophic factor (proBDNF) has recently been implicated in immune regulation, but its role in macrophage polarization and the underlying mechanisms are still unclear. Lipopolysaccharide (LPS) stimulation of NR8383 alveolar macrophages was used to model inflammation in vitro. ProBDNF expression was manipulated via adenoviral overexpression or knockdown. Polarization-related gene expression was measured by RT-qPCR, cytokine secretion was assessed by ELISA, and protein levels were examined by Western blotting and immunofluorescence. Neurotrophin receptor expression, including Ngfr/p75NTR and Ntrk2/TrkB, was also evaluated by RT-qPCR. Notch1 pathway activation was assessed by examining NICD levels and the expression of its downstream targets, Hes1 and Hes5. To further assess pathway involvement, NICD knockdown experiments were performed. LPS stimulation significantly increased proBDNF expression in NR8383 cells. Overexpression of proBDNF promoted a shift toward a pro-inflammatory (M1) phenotype, as indicated by increased expression of Cxcl9 and Nos2 and reduced expression of M2 markers (Arg1 and Mrc1). In contrast, proBDNF knockdown produced the opposite effect. Consistently, proBDNF overexpression increased TNF-&#x3b1; secretion and reduced IL-10 production, whereas proBDNF knockdown produced the opposite trend. NR8383 cells expressed Ngfr/p75NTR and Ntrk2/TrkB, with Ngfr showing a more inflammation-responsive pattern. These changes were accompanied by corresponding alterations in Notch1 signaling activity, reflected by changes in NICD, Hes1, and Hes5 expression. Importantly, silencing NICD markedly attenuated the pro-inflammatory polarization induced by proBDNF overexpression. In contrast, inhibition of Notch1 signaling did not affect proBDNF expression, supporting the interpretation that Notch1 functions downstream of proBDNF in this model. ProBDNF promotes macrophage polarization toward pro-inflammatory phenotypes under LPS stimulation, at least in part via Notch1 pathway activation. These findings identify a proBDNF-Notch1 regulatory axis in macrophage-driven inflammation and offer new insight into neuroimmune mechanisms underlying inflammatory lung injury.

MicroRNAs (miRNAs) and the NAD+-dependent deacetylase SIRT1 are critical regulators of hepatic metabolism, inflammation, and stress responses. Growing evidence suggests that miRNA-SIRT1 interactions are frequently disrupted during the pathogenesis of liver diseases, including Metabolism-Associated Steatotic Liver Disease (MASLD), Alcohol-Associated Liver Disease, Drug-Induced Liver Injury (DILI), fibrosis, and hepatocellular carcinoma (HCC).In the context of metabolic liver diseases, specific miRNAs, such as miR-122, miR-93, miR-132, miR-34a, and miR-141, regulate lipid and energy metabolism by modulating SIRT1 and its downstream targets, notably AMPK and PGC-1&#x3b1;. Furthermore, miRNAs can suppress SIRT1 activity during liver injury, exacerbating oxidative stress, mitochondrial dysfunction, and inflammation. In HCC, the role of SIRT1 is context-dependent; influenced by the stage of differentiation and genetic factors such as p53, SIRT1 may exert either tumor-suppressive or tumor-promoting effects. While preclinical studies demonstrate the therapeutic potential of targeting the miRNA-SIRT1 pathway, current evidence remains largely experimental. Pharmacological modulation, via SIRT1 activators, small-molecule compounds, or RNA-based therapeutics, has shown promise in experimental models. However, significant hurdles impede clinical translation, including poor bioavailability, off-target effects, and, most critically, the complex, context-specific biological role of SIRT1 within the liver. Ultimately, while the miRNA-SIRT1 axis appears to be a central regulatory pathway in liver disease, its translational potential and safety in humans require further mechanistic and clinical investigation.