Diabetes-induced endothelial dysfunction significantly contributes to cardiovascular complications, yet there is a limited availability of effective targeted therapies. This study assessed two novel imidazole derivatives, DMB-PTCI and ADBPI, through an integrated multiscale approach that includes quantum chemical analysis, in vivo validation, and computational modelling. Density functional theory revealed that DMB-PTCI exhibits a narrower HOMO-LUMO gap (2.96 vs. 3.91 eV), higher electrophilicity (1.88 vs. 1.25 eV), and greater softness (0.18 vs. 0.16 eV⁻¹) compared to ADBPI, indicating enhanced reactivity. In streptozotocin-induced diabetic rats, DMB-PTCI and ADBPI significantly reduced fasting blood glucose levels from 285.0 ± 15.5 mg/dL to 121.2 ± 6.7 mg/dL and 148.7 ± 6.5 mg/dL, respectively. Additionally, these treatments restored insulin levels from 3.9 ± 0.4 µIU/mL to 9.9 ± 0.4 µIU/mL and 9.2 ± 0.3 µIU/mL. Both compounds demonstrated improvements in lipid profiles, oxidative stress, inflammation, and endothelial biomarkers. Notably, DMB-PTCI exhibited stronger effects, as indicated by lower malondialdehyde levels (53.3 ± 1.9 nmol/g tissue) and higher nitric oxide levels (28.7 ± 0.7 nmol/g tissue). Molecular docking studies on human lysosomal acid-α-glucosidase revealed that DMB-PTCI binds more strongly (-8.455 kcal/mol) than ADBPI (-7.590 kcal/mol) and the reference ligand (-5.102 kcal/mol). This finding is further supported by MM-PBSA binding free energy calculations, which yielded a value of -11.60 ± 8.66 kcal/mol. Additionally, ADMET analysis indicated a prolonged half-life for DMB-PTCI (108.60 h), while ADBPI demonstrated higher oral bioavailability (0.97). Overall, DMB-PTCI consistently demonstrated superior performance across theoretical, experimental, and computational evaluations. This highlights its potential as a leading candidate for managing diabetes-associated endothelial dysfunction and suggests the need for further preclinical investigation.ADMET profiling revealed safety concerns, including the risk of hepatotoxicity and poor solubility associated with DMB-PTCI, indicating the need for further structural optimization and preclinical validation prior to clinical translation.

Radiation-induced skin injury (RISI) represents a significant clinical challenge in radiotherapy, owing to its high incidence and role in limiting therapeutic doses. Cellular senescence is a critical driver of RISI pathogenesis. Here, we identify LINP1 as a markedly upregulated lncRNA following ionizing radiation (IR), and functional assays indicates that LINP1 promotes cell survival and limites radiation-induced DNA damage accumulation. Mechanistically, LINP1 attenuates radiation-induced cellular senescence through modulation of the mTOR-p53 signaling axis. Specifically, LINP1 associates with the FAT domain of mTOR via a central nucleotide region termed the mTOR-binding domain (MBD) and attenuates the interaction between mTOR and p53, thereby reducing p53 Ser15 phosphorylation and downstream senescence-associated signaling. Validation in ex vivo human skin explants demonstrates that LINP1 depletion exacerbates radiation-induced tissue damage, persistent DNA damage accumulation, and senescence-associated phenotypes, supporting its physiological relevance in native human tissue. Collectively, our study not only identifies LINP1 as a key radioprotective lncRNA that regulates radiation-induced senescence through the mTOR-p53 axis, but also provides new mechanistic insights and a conceptual basis for future development of RNA-based radioprotective strategies.

Iron is indispensable for core physiological processes, and intracellular iron homeostasis is tightly governed by iron regulatory protein 1 (IRP1). Hydrogen sulfide (H2S), an endogenous gasotransmitter with well-established antioxidant and cytoprotective activities, remains poorly characterized for its regulatory roles in IRP1-dependent iron metabolism and fibroblast activation. Herein, we employed primary mouse embryonic fibroblasts (MEFs) to interrogate the functional crosstalk between NaHS (a H2S donor) and IRP1 governing iron balance and profibrotic responses. Our results reveal that IRP1 ablation or iron supplementation elevates the labile iron pool, triggers oxidative stress, and enhances cell adhesion, proliferation, and expression of profibrotic genes. Exogenous NaHS supplementation reduced labile iron accumulation and rescued iron-evoked cellular abnormalities, with this beneficial effect predominantly observed in wild-type MEFs. Mechanistically, NaHS upregulated IRP1 aconitase activity without altering the expression of transferrin receptor 1 or ferritin heavy chain. Although IRP1 deficiency and iron overload boosted endogenous H2S production, neither manipulation changed the protein abundance of three major H2S-synthesizing enzymes: cystathionine gamma-lyase (CSE), cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase. In vivo, intravenous iron administration elicited markedly greater cardiac profibrotic gene expression in CSE-knockout mice relative to wild-type littermates. Taken together, these data establish that H2S mitigates iron overload and subsequent fibrosis driven by IRP1 dysfunction, pointing toward promising therapeutic strategies for iron imbalance-associated fibrotic disorders.

Androgenetic alopecia (AGA) is a common form of hair loss due to genetic factors and is associated with alterations in the scalp microenvironment, which contribute to hair follicle miniaturization. In this study, we investigated the effects of tolerogenic dendritic cell (tolDC)-conditioned medium (CM) in a dihydrotestosterone (DHT)-treated mouse model. Administration of tolDC-CM promoted hair regrowth in the dorsal skin of mice and was associated with modulation of the follicular microenvironment. TolDC-CM treatment reduced pro-inflammatory cytokine expression and increased anti-inflammatory cytokine levels in the dorsal skin of mice. Histological analysis further demonstrated increased dermal thickness and hair follicle regeneration following tolDC-CM treatment. Furthermore, tolDC-CM treatment modulated the Wnt/β-catenin and MAPK/NF-κB signaling pathways. In addition, tolDC-CM with TGF-β neutralization suppressed hair regrowth in a DHT-treated mouse model, supporting the involvement of microenvironmental regulation. These results suggest that tolDC-CM may represent a potential approach for AGA, targeting the microenvironment to restore hair growth by modulating the follicular microenvironment.

This study focuses on the potential neuroprotective effects of gallic acid (GA) against docetaxel (DOC)-induced peripheral neuropathy, which arises particularly through oxidative stress and limits the clinical use of this effective anti-mitotic chemotherapy agent. Twenty-eight Wistar rats were randomly assigned to four groups (n = 7): Control (saline), Gallic acid (GA, 200 mg/kg/day, oral), Docetaxel (DOC, 30 mg/kg, single dose i.p.), and Docetaxel + Gallic acid (DOC + GA). Peripheral neuropathy due to DOC and the potential protective effects of GA were evaluated using behavioral tests, oxidative stress and antioxidant parameters, RT-PCR, histopathological and GFAP/BDNF immunohistochemical analyses. DOC administration significantly impaired motor functions. GA treatment administered concurrently with DOC significantly improved these behavioral impairments (p < 0.001). Additionally, DOC increased MDA levels and decreased antioxidant defenses (GSH, SOD, CAT, GPx), whereas GA reversed these changes. GA also significantly suppressed DOC-induced inflammation (NF-κB, TNF-α, nNOS; p < 0.001), apoptosis (caspase-3, Bax, Bcl-2; p < 0.001), autophagy (Beclin-1, LC3A; p < 0.001), and endoplasmic reticulum stress (PERK, ATF6; p < 0.001). Morphological and immunohistochemical analyses demonstrated that GA partially repaired DOC-induced sciatic nerve damage, characterized by decreased GFAP immunoreactivity and improved BDNF expression. This study provides a comprehensive evaluation of the multitarget effects of GA on oxidative stress-related and stress-associated molecular pathways in a DOC-induced peripheral neuropathy model, offering preliminary insight into its potential as a supportive therapeutic approach.

Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer. Heat shock protein family D member 1 (HSPD1 or HSP60), a multifunctional chaperone, has been implicated in promoting lung cancer progression by regulating tumor cell growth, cancer-associated fibroblast activation, and angiogenesis. Despite these roles, the molecular mechanisms underlying its oncogenic activity remain incompletely understood. In this study, we conducted a proteomic analysis and functional investigations on HSPD1-knockdown and control A549 cells. Knockdown of HSPD1 suppressed cell proliferation, disrupted cell-cycle progression, and had no significant effect on apoptosis. Additionally, HSPD1-knockdown cells exhibited reduced colony formation, wound closure, and invasion capabilities. Sequential Window Acquisition of All Theoretical fragment ions (SWATH)-targeted proteomics revealed 21 significantly altered proteins, primarily involved in ribosome-related functions and associated with overall survival in LUAD patients. Reduced levels of ribosomal proteins and translational capacity were further examined by Western blot and protein synthesis assays. A decrease in ribosome abundance was confirmed by immunofluorescence staining of ribosomal protein S3 (RPS3) and by direct visualization under transmission electron microscopy. Quantitative real-time PCR demonstrated downregulation of MTOR in HSPD1-knockdown cells. Moreover, HSPD1 knockdown sensitized cells to homoharringtonine, a chemotherapeutic drug targeting ribosomal activity. These effects on cell proliferation, ribosomal protein levels, and drug sensitivity were validated in an independent LUAD cell line, H1975. Collectively, these findings indicate that HSPD1 acts as an oncogenic driver in LUAD by modulating ribosome-related pathways and protein synthesis.

The precise mechanistic role of Interleukin-13 receptor alpha-2 (IL-13Rα2) in colorectal cancer (CRC) remains elusive, specifically regarding whether it functions as an active signaling receptor or a passive decoy. Its unique role in metastatic phenotypic plasticity remains poorly understood. We identified IL-13Rα2 as a powerful oncogenic signaling hub that significantly increases CRC cell proliferation, migration, and colony formation using shRNA knockdown and CRISPR activation to modify IL-13Rα2 across a range of CRC cell lines with different baseline characteristics. Most importantly, we found that its regulation of the epithelial-mesenchymal transition (EMT) is highly context-dependent. IL-13Rα2 controls the mesenchymal phenotype in highly plastic cells in a partial-EMT (p-EMT) stage (such as SW-480 and SW-620). Its removal completely reverses EMT and collapses core plasticity-driving nodes, such as AGR2 and p63. On the other hand, IL-13Rα2 precisely functions as a phenotypic amplifier limited by the cellular epigenetic landscape in strictly epithelial cells (such as HT-29), where it controls cellular survival but does not initiate EMT. The STAT6 signaling cascade is monopolized by IL-13Rα2. Targeted downregulation eliminates IL-13-induced STAT6 phosphorylation, which in turn causes severe cell cycle dysregulation marked by a delayed G1/S transition and intra-S phase arrest. In conclusion, our research demonstrates that IL-13Rα2 is a crucial, context-dependent signaling receptor that maintains the p-EMT state and malignant progression via the STAT6 axis, making it a precise therapeutic target for advanced, phenotypically plastic colorectal cancer.

Traumatic brain injury (TBI) remains a major cause of neurological morbidity worldwide, and mild TBI (mTBI) is frequently associated with emotional disturbances, including anxiety-like behavior. Although classical mechanisms of secondary injury have been extensively characterized, metabolic alterations, particularly those involving cerebral lipid homeostasis, remain incompletely defined. Given the structural and regulatory roles of lipids in the central nervous system, disruption of lipid metabolism may contribute to early post-traumatic dysfunction. We hypothesized that mTBI induces region-specific alterations in brain lipid metabolism and that these changes are associated with anxiety-like behavior during the acute post-injury phase. Adult male C57BL/6 mice were subjected to a weight-drop model of mTBI and evaluated 48-72 h post-injury using different behavioral paradigms. Lipid classes were quantified in the hippocampus, prefrontal cortex, and serum by thin-layer chromatography. mTBI induced anxiety-like behavior without locomotor impairment. Biochemical analyses revealed region-dependent lipid alteration predominantly in the ipsilateral hippocampus, characterized by reduced diacylglycerol and monoacylglycerol levels alongside increased total phospholipids and specific subclasses. Correlation analyses demonstrated significant associations between anxiety-related behavioral parameters and lipid classes across tissues. These findings indicate that mild TBI is accompanied by early, region-specific lipid alterations that are associated with behavioral changes during the acute post-injury period.

Pancreatic cancer (PC) is a malignant tumor that often presents no obvious symptoms in its early stages, leading to late diagnosis and poor prognosis. Therefore, developing molecular markers for PC is essential for improving early diagnosis, optimizing treatment strategies, and enhancing patient outcomes. In this study, PC tissue and matched adjacent non-cancerous tissue were collected from patients. For in vitro analysis, the PC cell lines BxPC-3 and SW1990 were used. M2 macrophages were induced in THP-1 cells. Gene expression at both mRNA and protein levels was measured using real-time quantitative PCR and Western blotting. Cell counting kit-8 assay was used to evaluate cell activity. Flow cytometry was used to assess the cell apoptosis rate and M2 macrophage biomarkers. Transwell and wound-healing assays were used to determine cell migration and invasiveness. Co-immunoprecipitation assay was used to evaluate the binding relationship between leucine-rich α-2 glycoprotein 1 (LRG1), chemokine receptor 1 (CCR1), and GALNT6. LRG1 expression was upregulated in PC tissues compared to that in normal tissues. Co-culture with M2 macrophages enhanced gemcitabine (GEM) resistance, cell migration, and PC cell invasion. LRG1 overexpression in PC cells enhanced the effect of M2 macrophage cells to exacerbate GEM resistance, cell migration, and invasion, while LRG1 knockdown exhibited an opposite effect. LRG1 interacted with CCR1 to enhance PI3K/AKT signaling, thereby affecting GEM resistance, migration, and PC cell invasion. Moreover, GALNT6 was confirmed as an upstream regulator of LRG1, which glycosylated LRG1 and increased its stability. Rescue experiments demonstrated that GALNT6 promoted GEM resistance, movement, and invasion abilities of PC cells by regulating LRG1. The role of LRG1 in the interaction between PC cells and M2 macrophages was also verified in the xenograft model. These findings demonstrate that GALNT6-glycosylated LRG1 mediates the interaction between M2 macrophages and PC cells by activating CCR1. This study may provide promising therapeutic targets for PC treatment.

Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10- 5 mol.L- 1) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.

N6-methyladenosine (m6A) methylation modification plays an essential role in cancer development. This study focused on the mechanism exploration of m6A methyltransferase 3 (METTL3) and its downstream target gene nuclear protein-1 (NUPR1) in hepatocellular carcinoma (HCC). Detection of mRNA and protein was completed using real-time quantitative polymerase chain reaction and Western blot. Cellular behaviors were evaluated by CCK-8, EdU, flow cytometry and transwell assay. Ferroptosis was analyzed via Fe2+ level and oxidative indicators. Methylated RNA immunoprecipitation (MeRIP) was performed for validating m6A modification. RIP and dual-luciferase reporter assay were used to confirm METTL3 and NUPR1 combination. Animal research was implemented for METTL3 and NUPR1 analysis in vivo. METTL3 was overexpressed in HCC. METTL3 silencing suppressed HCC cell proliferation and invasion, while enhancing apoptosis and partially inducing ferroptosis. METTL3 downregulation reduced NUPR1 level. METTL3 induced m6A modification of NUPR1 in an IGF2BP2-dependent manner. Tumor-inhibitory effects of METTL3 knockdown were counteracted by NUPR1 overexpression. METTL3 promoted HCC tumor growth and suppressed ferroptosis in vivo by regulating NUPR1. These findings suggested that METTL3 facilitated cell invasion and partially inhibited ferroptosis through catalyzing m6A methylation modification of NUPR1, validating the specific regulatory axis METTL3/NUPR1 in HCC progression.

Angiogenesis plays a significant role in the progression of idiopathic pulmonary fibrosis (IPF). The RNA-binding protein IGF2BP3 is associated with fibrosis and angiogenesis, but its role in IPF angiogenesis remain unclear. Additionally, Tianlongjie (TL) has been confirmed to inhibit IPF progression, but the role of IGF2BP3 in this process also needs to be elucidated. A bleomycin (BLM)-induced pulmonary fibrosis rat model was established via intratracheal instillation of BLM, and an angiogenesis cell model was constructed by treating HPMVECs with VEGF165. HE staining was used to detect lung tissue injury. Masson staining, HYP content measurement, Western blot, and Immunohistochemistry assessed to evaluate fibrosis and angiogenesis progression. EdU staining was employed to detect cell proliferation. RIP-qPCR and dual-luciferase reporter assays were performed to examine the interaction between IGF2BP3 and HIF-1α. IGF2BP3 was abnormally highly expressed in pulmonary fibrosis. IGF2BP3 knockdown reduced the expression of HYP, COL-I, COL-III, α-SMA, CD31, CD34, and VEGFA in pulmonary fibrosis rat lung tissues, increased E-cadherin expression, and inhibited pulmonary fibrosis progression and microvascular formation in rats. In vitro, IGF2BP3 knockdown suppressed cell proliferation, migration and vascular endothelial cell angiogenesis. Mechanistically, IGF2BP3 may promote HIF-1α stability through m6A modification, and HIF-1α overexpression attenuated the inhibitory effect of IGF2BP3 knockdown on angiogenesis. Furthermore, TL treatment was associated with reduced fibrosis and lower IGF2BP3/HIF-1α expression. In conclusion, IGF2BP3 can promote pulmonary fibrosis-related angiogenesis by stabilizing HIF-1α expression, and TL inhibits IGF2BP3 and HIF-1α expression, angiogenesis and fibrosis progression in pulmonary fibrosis rats.

Rapid eye movement sleep deprivation (REM-SD) is associated with increased oxidative stress, characterized by disruption of the oxidant-antioxidant balance and accumulation of reactive oxygen species (ROS). Melatonin may act as a potential modulator of REM-SD-associated oxidative alterations through its circadian regulatory effects, direct ROS scavenging activity, and support of endogenous antioxidant defense mechanisms. This study aimed to evaluate the effects of melatonin treatment administered during the six-day REM-SD period or during the recovery period following REM-SD on oxidative stress-related parameters in 8-12-week-old male Sprague-Dawley rats (n = 84). REM-SD was induced using the modified multiple platform method (MMPM). Biochemical markers reflecting oxidative balance, including total antioxidant status (TAS), total oxidant status (TOS), the lipid peroxidation product malondialdehyde (MDA), non-enzymatic antioxidant glutathione (GSH), and enzymatic antioxidants, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels, were assessed using the enzyme-linked immunosorbent assay (ELISA). The findings demonstrated that REM-SD predominantly affected enzymatic antioxidant defense-related parameters. Melatonin modulated these responses, mainly by increasing enzymatic antioxidant levels and reducing lipid peroxidation. However, no significant change was observed in TOS, whereas the effect on TAS was limited and time-dependent. During the recovery period, several oxidative stress markers partially normalized, indicating a possible reactivation of endogenous antioxidant defenses. In conclusion, six-day MMPM-induced REM-SD appears to alter oxidative stress-related parameters, while melatonin may help attenuate some of these alterations by modulating antioxidant defense mechanisms. These effects varied according to the timing of administration and the specific parameter examined.

The regulatory mechanism of the long noncoding RNA SNHG6 in acute pulmonary embolism (APE) remains unclear. This study aimed to investigate the potential molecular mechanisms of SNHG6 in APE. This study established a clinical cohort comprising 120 APE patients and 120 healthy controls. It combined in vitro experiments using human pulmonary arterial smooth muscle cells (PASMCs) with in vivo experiments employing an autologous blood clot model of APE in Sprague-Dawley (SD) rats, measuring mean pulmonary artery pressure (mPAP). RT-qPCR was used to detect target gene expression. The CCK-8 assay evaluated cell proliferation, while the ELISA and western blot assays measured the relevant protein levels. The RIP assay and dual luciferase assay validated the target binding relationship. SNHG6 was significantly overexpressed in both serum samples from APE patients and lung tissues from model rats. In this exploratory case-control cohort, serum SNHG6 exhibited significant discriminatory capacity between APE patients and healthy controls (AUC = 0.9145) and showed an independent cross‑sectional association with APE status in multivariate analysis within this selected cohort. However, because serum SNHG6 was measured after diagnosis, this association should be interpreted strictly as a correlative finding rather than as evidence of prospective predictive or etiologic value. These findings require validation in clinically relevant populations with differential diagnoses. Mechanistic studies revealed that SNHG6 targeted and regulated miR-429, which in turn targeted DUSP1. In cultured PASMCs, SNHG6 acted as a competitive endogenous RNA to sequester miR-429, thereby releasing its suppression on the downstream target gene DUSP1. This upregulated the expression of proliferation-related molecules such as NOR-1 and PCNA, positively regulating PDGF-BB-induced PASMC cell proliferation. Animal experiments performed at a 7‑day subacute endpoint demonstrated that SNHG6 perturbation was associated with altered mean pulmonary artery pressure and early proliferative molecular markers during the early phase following embolic challenge. In cultured PASMCs, specific sponging of miR-429 by SNHG6 may attenuate the inhibitory effect of miR-429 on DUSP1, potentially contributing to exacerbated APE pathological manifestations.

Epidemiological studies indicate that modern lifestyle choices are closely linked to the global rise in chronic inflammatory diseases. While considerable research has explored the role of the microbiome in inflammation, a definitive causal relationship has yet to be established. Intestinal epithelial cells (IECs) play a critical role in maintaining a protective barrier that prevents the translocation of harmful molecules and pathogens. Any disruption or compromise to the integrity of these cells can impair this barrier function, facilitating the entry of potentially harmful substances and microorganisms, which subsequently triggers acute inflammatory responses. Microbial dysbiosis is one of the most prominent outcomes of inflammation in the gut, and various therapeutic strategies are currently under investigation to address this imbalance. Among these, probiotics have demonstrated potential in modulating immune and inflammatory responses by altering the composition of the gut microbiota. However, findings from preclinical and clinical studies suggest that probiotics may interfere with the re-establishment of native microbial communities and, in some vulnerable individuals, may even aggravate inflammation. In contrast, postbiotics bioactive compounds produced during the fermentation process by probiotics are emerging as a promising and safer alternative. Increasing scientific evidence supports their beneficial biological effects. In this review, we aim to discuss the most recent findings regarding the anti-inflammatory and immunomodulatory properties of postbiotics, with particular emphasis on key parental probiotic strains.