The cyclic five-membered disulfide 1,2-dithiolane, known for its moderate reactivity and ease of preparation, holds significant promise as a recognition unit in probe design and drug development. However, potential limitations in activation specificity-most notably the diminished selectivity toward thioredoxin reductase (TrxR) caused by nonspecific reactions with abundant low-molecular-weight (LMW) thiols such as glutathione (GSH)-raise concerns about its reliability in biological settings. Here we systematically evaluate the activation behavior of 1,2-dithiolane by synthesizing a panel of prodrugs and fluorescent probes incorporating either amine- or hydroxyl-linked cargoes. Our results reveal that TrxR-mediated selective activation of the 1,2-dithiolane unit is achievable when the cargo is incorporated within an amine-based framework. In contrast, hydroxyl-linked conjugates undergo rapid cleavage by physiological GSH levels, resulting in a pronounced loss of TrxR selectivity. Generally, the recognition site 1,2-dithiolane, the linker unit and the leaving group in a cargo coordinate to determine the selectivity activated by TrxR. Overall, this study resolves ambiguities in previous reports, reconciles conflicting observations, and provides new conceptual guidance for the use of the 1,2-dithiolane scaffold in the design of biofunctional molecules.

EZY-1, a bioactive compound derived from the edible seaweed Eucheuma, was identified as a potent and selective mechanistic target of rapamycin complex 2 (mTORC2) inhibitor. This agent showed significant anti-fibrotic efficacy in a bleomycin-induced pulmonary fibrosis model by targeting multiple pathological pathways. Treatment with EZY-1 significantly reduced extracellular matrix deposition, as confirmed by reduced collagen accumulation and suppressed expression of fibrosis-associated markers. EZY-1 attenuated cellular senescence by downregulating senescence indicators such as p53, p27, p21, p16, and the senescence-associated β-galactosidase (SA-β-gal) activity, decreasing the secretion of senescence-associated secretory phenotype factors. EZY-1 also restored G1/S phase cell cycle progression by upregulating cyclin-dependent kinase 4 (CDK4) and CDK2 levels. These molecular responses substantially suppress epithelial-mesenchymal transition and fibroblast activation. Mechanistic studies revealed that the anti-fibrotic effect of EZY-1 is primarily mediated through suppression of the mTORC2/PI3K/Akt signaling cascade, modulating the mTORC2 → Akt → p53/p21 → CDK4/2 axis. In vitro analyses confirmed these effects on mTORC2 inhibition. These findings propose EZY-1 as a promising therapeutic candidate for treating idiopathic pulmonary fibrosis via its multi-target role against core fibrotic mechanisms.

Nuclear factor erythroid 2 related factor 2 (Nrf2) is closely associated with neurodegenerative diseases, and the Nrf2-mediated activation of antioxidant response elements (AREs) brings about validated strategies for treating neurodegenerative diseases. Here, we discovered that troglitazone, a clinical medication for diabetes mellitus, could serve as a Nrf2 activator to rescue neuronal damages both in vitro and in vivo. The mechanism of troglitazone action involves binding with kelch-like ECH-associated protein 1 (Keap1) and the activation of Nrf2. This process leads to the migration of Nrf2 to the cell nucleus and transactivates the AREs. Troglitazone exhibits significant alleviation of oxidative stress in PC12 cells induced by hydrogen peroxide or 6-hydroxydopamine (6-OHDA). In vivo studies indicate that troglitazone could rescue the motor activity and neurodevelopmental deficiency in zebrafish induced by 6-OHDA. Additionally, mass spectrometry imaging demonstrates that troglitazone could cross the zebrafish blood-brain barrier, supporting the application of troglitazone in treating neurodegenerative diseases. Overall, this work reveals that the novel Nrf2 activator troglitazone has potential therapeutic value for neurodegeneration and provides a foundation for its repurposing.

Leveraging disulfide (-S-S-) or diselenide (-Se-Se-) units as triggers in the design of small-molecule fluorescent probes for detecting intracellular reductive species has demonstrated high efficacy. However, selenenylsulfides, which exhibit reactivity between diselenides and disulfides, remain relatively unexplored. In this work, we compare the efficiency of -S-S-, seleno-sulfur (-Se-S-), and sulfur-selenium (-S-Se-) structural units in constructing thiol probes, disclose the scaffold of -Se-S- as a versatile recognition site for thiols, and successfully apply this unit to design a near-infrared (NIR) probe, ASC-SeS. The mechanism reveals that breaking the -Se-S- bond leads to a selenolate, which undergoes faster cyclization than the corresponding thiolate that is from the cleavage of the -S-S- or -S-Se- bond. Conjugation of this trigger unit with multiple NIR fluorophores validates the general applicability of linear selenenylsulfides in accelerating the response rate to thiols. By harnessing the superior thiol responsiveness of ASC-SeS, we employ this probe in live cells and in vivo, and elucidate a severe depletion of thiols in the drug-induced liver injury (DILI).

A fluorescence quenching mechanism using linear diselenides was proposed for the first time through a combination of intramolecular charge transfer (ICT) and Förster resonance energy transfer (FRET).

Acute pulmonary embolism (PE) remains a life-threatening condition. A critical therapeutic dilemma exists for a significant proportion of patients at high bleeding risk（approximately 30%-50%）. For these patients, anticoagulation is the mainstay, but the use of conventional agents (warfarin, DOACs, heparins) is severely limited by the risk of major bleeding, creating a substantial unmet medical need. Abelacimab addresses this unmet need through a novel mechanism: dual inhibition of factor XI (FXI) and activated FXI (FXIa). This paradigm shift uncouples potent antithrombotic efficacy from hemostasis, selectively suppressing contact pathway-driven thrombosis while preserving tissue factor-mediated hemostasis. We synthesize its unique mechanism of action, pharmacokinetic profile, and existing clinical evidence to evaluate its role in addressing this clinical gap. Abelacimab's mechanism selectively inhibits the contact activation pathway-crucially overactive in the RBC-rich thrombi characteristic of PE-while preserving tissue factor-mediated physiological hemostasis. Clinically, abelacimab demonstrated significantly lower rates of major bleeding or clinically relevant non-major bleeding compared to rivaroxaban in atrial fibrillation prophylaxis (AZALEA-TIMI 71 trial) and to enoxaparin in post-arthroplasty venous thromboembolism prevention (ANT-005 trial), establishing a favorable clinical safety profile. Its favorable pharmacokinetics (long half-life supporting monthly subcutaneous administration, with minimal renal/hepatic clearance) further simplify management and enhance its suitability for patients with PE. However, current evidence is extrapolated from AF/VTE prophylaxis studies, lacking direct human data for acute PE management. Urgent phase III trials (eg, PE-FOCUS) are therefore essential to validate efficacy and safety in acute PE, potentially redefining the anticoagulation paradigm.

Pyruvate kinase M2 (PKM2), a crucial enzyme in the glycolysis pathway, is commonly documented as being overexpressed in cancer cells. Inhibiting PKM2, a strategy to mitigate cancer cell-dependent glycolysis, has demonstrated efficacy in anticancer treatment. In this study, plumbagin, which was originally extracted from the plant Plumbago zeylanica L., was discovered as a novel PKM2 inhibitor and it could bind to PKM2 to inhibit the enzymatic activity. Treatment with plumbagin in HepG2 cells resulted in the decrease of PKM2 expression, which in turn reduced the protein kinase function. The mRNA levels of its downstream genes, such as LDHA and MYC, were suppressed. Additionally, plumbagin downregulated the expression of intracellular antioxidant proteins, which induced oxidative stress and mitochondrial damage, ultimately triggering apoptosis. Moreover, plumbagin also reduced the migration and proliferation of HepG2 cells. This study offered valuable insights into the molecular mechanism of plumbagin and advocated for the exploration of PKM2 inhibitors as viable possibilities for anticancer therapeutics.

Aerobic glycolysis is a metabolic reprogramming of tumor cells that is essential for sustaining their phenotype of fast multiplication by continuously supplying energy and mass. Pyruvate kinase M2 (PKM2) has a vital role in this process, which has given it high interest as a target for anticancer drug development. With potent toxicity to many types of cancer cells, polyphyllin II (PP2), a steroidal saponin isolated from the herbaceous plant Rhizoma paridis, brought to our attention that it might interfere with the PKM2 activity. In this study, we discovered that PP2 was a novel agonist of PKM2. PP2 activated recombinant PKM2 and changed the protein's oligomeric state to activate intracellular PKM2. At the same time, PP2 suppressed its protein kinase function by decreasing the content of nuclear PKM2. The mRNA levels of its downstream genes, such as Glut1, LDHA, and MYC, were inhibited. In addition, PP2 induced oxidative stress by downregulating the expression and activity of antioxidant proteins such as NQO1, TrxR, and Trx in HT-1080 cells, which in turn led to mitochondrial dysfunction and ultimately induced apoptosis. Moreover, PP2 reduced the proliferation and migration of HT-1080 cells. Thus, targeting the glycolysis pathway offers an unprecedented mode of action for comprehending PP2's pharmacological impacts and advances PP2's further development in fibrosarcoma therapy.

Abstract Background Sponge-associated microorganisms are promising resources for the production of bioactive compounds with cytotoxic potential. The main goal of our study is to isolate the fungal endophytes from the Red Sea sponge Hyrtios sp. followed by investigating their cytotoxicity against number of cell lines. Results The fungal strain UR3 was isolated from the Red Sea sponge using Sabouraud dextrose agar media. It was identified based on partial 18 S rRNA gene and ITS sequence analyses as Cladosporium sp. UR3. The in vitro cytotoxic potential of the ethyl acetate extract of the fungal isolate was evaluated using MTT assay against three cancer cell lines: CACO2, MCF7, and HEPG2. Metabolomics profiling of the obtained ethyl acetate extract using LC-HR-ESI-MS, along with molecular docking and pharmacological network studies for the dereplicated compounds were performed to explore its chemical profile and the possible cytotoxic mechanism of the sponge-associated fungi. Conclusion These results highlighted the role of sponge-associated fungi as a fruitful resource for the discovery of cytotoxic metabolites.

High levels of reactive oxygen species (ROS) have been associated with the progression of neurodegenerative diseases such as Alzheimer's disease. The activation of the NFE2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway may restore the neuron's redox balance and provide a therapeutic impact. Hydroxygenkwanin (HGK), a dominant flavone from Genkwa Flos, has received expanding attention due to its medicinal activities. Our investigation results demonstrated the ability of HGK to protect the PC12 cells from oxidative damage caused by an excessive hydrogen peroxide load. HGK also showed the ability to upregulate a panel of endogenous antioxidant proteins. Further investigations have demonstrated that the neuroprotection mechanism of HGK is dependent on the activation of the Nrf2/ARE signaling pathway. Activating the Nrf2/ARE pathway by HGK reveals a novel mechanism for understanding the pharmacological functions of HGK. These findings suggest that HGK could be considered for further development as an oxidative stress-related neurological pathologies potential therapeutic drug.

TP10, a classic cell-penetrating peptide, shows a high degree of similarity to AMPs in structure. Although TP10 has been widely used in drug delivery, the mechanism underlying its cytotoxicity is yet to be elucidated. Herein, we explored the cell-killing mechanism of TP10 against human leukemia Jurkat cells. TP10 induced necrosis in Jurkat cells via rapid disruption of cell membranes, particularly at high concentrations. Although mitochondria in Jurkat cells were damaged by TP10, mitochondria-mediated apoptosis did not occur, possibly due to intracellular ATP depletion. Necroptosis in TP10-treated Jurkat cells became an alternative route of apoptosis. Our results demonstrate that necrosis and necroptosis rather than apoptosis are involved in the cell-killing mechanism of TP10, which contributes to the understanding of its toxicity.

To investigate the role of TopBP1-interacting checkpoint and replication regulator (TICRR) in the tumorigenesis and prognosis of lung adenocarcinoma (LUAD) patients. Wilcoxon signed-rank test and logistic regression were utilized to analyze the relationship between clinical characteristics and TICRR expression in LUAD from TCGA dataset. Kaplan–Meier plots and Cox regressions were used to assess the impact of TICRR impact on prognosis. ROC curves and nomograms were generated to further evaluate the relationship between TICRR expression and the risk of LUAD. Gene set enrichment analysis (GSEA) was conducted on TCGA dataset, and ssGSEA was employed to investigate the association between TICRR and immune infiltrates. The results showed that high TICRR expression was significantly associated with various clinical factors including gender, age, pathological stage, T stage, N stage, M stage, outcome of primary therapy and smoking status. ROC curves also demonstrated that TICRR was a promising biomarker for molecular pathology diagnosis in LUAD patients (AUC = 0.952). Further analysis using gene ontology (GO) term enrichment and GSEA revealed an abnormal correlation between TICRR expression and cell division. Interestingly, ssGSEA analysis showed that TICRR expression correlated with multiple immune cell types, such as Th2 cell, TFH cell, mast cell, iDC, eosinophils, and dendritic cell. Lastly, the KM-plotters indicated that LUAD patients with high TICRR expression obtained worse life expectancy (P < .001). TICRR has proven to be a valuable tool in predicting disease progression and prognosis in patients with LUAD, thereby establishing itself as a fitting biomarker for forecasting overall survival (OS) of LUAD patients.

BACKGROUND: Previous observational studies have linked serum albumin (ALB) to prognosis in patients with pulmonary embolism (PE). Nevertheless, the nature of the association between serum albumin and PE risk remains unclear, and the potential causality requires to be investigated. Our study aimed to integrate an observational study and a two-sample Mendelian randomization (MR) analysis to comprehensively assess the relationship between serum albumin and PE risk. METHODS: A total of 13,326 participants, consisting of 749 PE patients and 12,577 non-PE controls, were selected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database for an observational study. The effects of serum albumin on PE risk were assessed using propensity score matching (PSM) and restricted cubic spline (RCS) model analysis, adjusting for multiple covariates. Subsequently, a two-sample MR analysis was performed using summary statistics from genome-wide association studies (GWAS) to assess the causality between serum albumin and PE risk. Sensitivity analyses were carried out to confirm the robustness of MR results. RESULTS: The results of PSM indicated that the serum albumin levels were lower in PE patients (3.97 g/dL) than in non-PE controls (4.09 g/dL). The RCS model demonstrated a linear negative correlation between serum albumin and PE risk (P for nonlinear > 0.05). MR analysis confirmed a causality between serum albumin (OR = 0.744, 95% CI: 0.642~0.861, P < 0.001) and PE risk. CONCLUSION: Our study provided evidence that low serum albumin appeared to be associated with an increased risk of PE, and this association was possibly causal.

Macrophage differentiation is closely associated with idiopathic pulmonary fibrosis (IPF) initiation. Herein, we show that EZY-1, a novel peptide derived from Eucheuma, regulates macrophage differentiation to inhibit IPF. Macrophage differentiation was detected by analyzing the surface antigens of the macrophages using flow cytometry. The effect of EZY-1 on cell proliferation was assessed. Signaling molecules involved in macrophage differentiation and fibrosis were detected by Western blot and enzyme-linked immunosorbent assays. The results showed that EZY-1 suppressed BLM-induced pulmonary fibrosis, with a decrease in type M2 macrophages. Simultaneously, EZY-1 reduced the amount of TGF-β1 secreted by M2 macrophages. In addition, EZY-1 downregulated COL1A1, TGF-β, and p-Smad3 and upregulated p-β-catenin in fibroblasts induced by M2 macrophages. Our results confirmed that EZY-1 inhibits IPF by inhibiting type M2 macrophage differentiation, which may be associated with the expression of Rictor and SHP2. Thus, EZY-1 can potentially be used as a drug for treating IPF.

Correlation between the levels of CD133 (PROM1) mRNA with that of ALDH1A3 mRNA in lung adenocarcinoma tissues from TCGA portal

EZY-1 is an antifibrosis peptide purified from Eucheuma. In this study, we explored the acute toxicology of EZY-1 and the signaling pathways involved in its antifibrotic role. The mouse model of pulmonary fibrosis was induced by bleomycin. Pathological changes in lung tissue could be effectively inhibited by EZY-1. Acute toxicity and cell proliferation tests indicated that EZY-1 had no apparent toxicity to mice and cells. We identified proteins that could bind directly to EZY-1 in vitro on the basis of liquid chromatography-tandem mass spectrometry and bioinformatics analysis. EZY-1 inhibited pulmonary fibrosis via Wnt/β-catenin, transforming growth factor (TGF)-β/Smad, phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin, and activator of transcription 3 and Janus kinase 2/signal transducer pathways. A transwell micropore experiment showed that EZY-1 could inhibit cell migration and invasion. Western blotting analysis on transforming growth factor-β1 (TGF-β1)-induced A549 pulmonary fibrosis cell model suggested that EZY-1 could downregulate p-Smad3 (Ser423/Ser425), Smad4, β-catenin, vimentin, and N-cadherin expression. ELISA showed that EZY-1 could inhibit collagen-I secretion. EZY-1 alleviated idiopathic pulmonary fibrosis (IPF) through regulating TGF-β/Smad pathways, epithelial-mesenchymal transition processes, and collagen secretion, which provides a potential foundation for theoretical development of EZY-1 as a potential drug against IPF. PRACTICAL APPLICATIONS: We isolated a new 16-amino-acid peptide derived from the polypeptide extract of Eucheuma, named EZY-1. In vitro and in vivo assays show peptide EZY-1 is safe. The EZY-1 peptide alleviates IPF at lower doses than pirfenidone. EZY-1 alleviated idiopathic pulmonary fibrosis (IPF) through regulating TGF-β/Smad pathways, epithelial-mesenchymal transition (EMT) processes, and collagen secretion, which provides a theoretical basis for the development of EZY-1 as a potential drug against IPF.

Noninvasive and simple indicators for diagnosing latent tuberculosis (TB) infection (LTBI) and tracking progression from latent infection to active TB infection are still desperately needed. The aim of this study was to screen and identify possible biomarkers for diagnosing LTBI and monitoring the progression from latent infection to active TB infection, as well as to investigate the underlying processes and functions. To assess changes in metabolite composition associated with active tuberculosis infection in humans, whole blood supernatants were collected from patients with LTBI, drug-susceptible TB patients, drug-resistant TB patients, and healthy controls. The metabolites in all serum samples were extracted by oscillatory, deproteinization, and then detected by liquid chromatography-tandem mass spectrometry/MS analysis. Normalization by Pareto-scaling method, the difference analysis was carried out by Metaboanalyst 4.0 software, and 1-way analysis of variance analysis among groups showed that P -value < 0.05 was regarded as a different metabolite. To clarify the dynamic changes and functions of differential metabolites with disease progression, and explore its significance and mechanism as a marker by further cluster analysis, functional enrichment analysis, and relative content change analysis of differential metabolites. 65 metabolites were substantially different in four groups. Differential metabolites such as Inosine and Prostaglandin E1 may be important blood indicators for diagnosing mycobacterium tuberculosis latent infection, which were all tightly connected to amino acid metabolism, Biosynthesis of various secondary metabolites, Nucleotide metabolism, Endocrine system, Immune system, Lipid metabolism, and Nervous system. This study screened and identified Inosine, 16, 16-dimethyl-6-keto Prostaglandin E1, Theophylline, and Cotinine as potential serum biomarkers for diagnosing latent TB infection, and Cotinine as potential biomarkers for monitoring disease progression from healthy population to LTBI and then to active TB including drug-resistant TB infection and sensitive TB infection. Furthermore, this research provides a preliminary experimental basis to further investigate the development of metabolomics-based diagnosis of LTBI and monitoring the progress from latent infection to active TB infection.

Background and Objective Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia of unknown etiology. An increasing number of studies have reported that the incidence of IPF increases with age. Simultaneously, the number of senescent cells increased in IPF. Epithelial cell senescence, an important component of epithelial cell dysfunction, plays a key role in IPF pathogenesis. This article summarizes the molecular mechanisms associated with alveolar epithelial cell senescence and recent advances in the applications of drugs targeting pulmonary epithelial cell senescence to explore novel therapeutic approaches for the treatment of pulmonary fibrosis. Methods All literature published in English on PubMed, Web of Science, and Google Scholar were electronically searched online using the following keyword combinations: aging, alveolar epithelial cell, cell senescence, idiopathic pulmonary fibrosis, WNT/β-catenin, phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB). Key Content and Findings We focused on signaling pathways associated with alveolar epithelial cell senescence in IPF, including WNT/β-catenin, PI3K/Akt, NF-κB, and mTOR signaling pathways. Some of these signaling pathways are involved in alveolar epithelial cell senescence by affecting cell cycle arrest and secretion of senescence-associated secretory phenotype-associated markers. We also found that changes in lipid metabolism in alveolar epithelial cells can be induced by mitochondrial dysfunction, both of which contribute to cellular senescence and development of IPF. Conclusions Decreasing senescent alveolar epithelial cells may be a promising strategy for the treatment of IPF. Therefore, further investigations into new treatments of IPF by applying inhibitors of relevant signaling pathways, as well as senolytic drugs, are warranted.

Background:Epidemiological surveys in recent years have shown that the incidence of female lung adenocarcinomas has multiplied in both smoking and non-smoking populations. The cause of lung adenocarcinomas is still not clear. Protein post-translational modification is one of the causes of the development of cancer cells.Methods:Lung adenocarcinoma and paracancerous tissue samples were collected from female patients with no history of smoking. The differences in protein acetylation and succinylation of cancerous tissues and paracancerous tissues were analysed by LC-MS/MS with a TMT labelling method. We distinguished the differentially modified proteins and annotated these proteins in terms of Go annotation, protein domains, protein complex analysis and KEGG pathway analysis.Results:972 acetylation sites on 556 proteins were identified, among which 875 Kac sites on 507 proteins were quantified, 2373 succinylation sites on 1205 proteins were identified, and 2205 Ksu sites on 1131 proteins were quantified. The acetylation levels of proteins, which contribute to DNA binding and gene expression regulation, were up-regulated. The proteins for which the succinylation levels were up-regulated were mainly involved in mitochondria carboxylic acid metabolism. We also identified simultaneously up-regulated or down-regulated acetylated and succinylated proteins and depicted their interaction network.Conclusion:This study provides insight into lung adenocarcinomas acetylation and succinylation profile alterations in carcinoma pathogenesis and provides a potential therapeutic target for lung adenocarcinomas.

Cisplatin has strong broad‐spectrum anticancer activity and is one of the most effective anticancer drugs currently used. The clinical application of cisplatin has led to the resistance of cancer cells to cisplatin. Tachyplesin is an active, natural marine peptide with antitumour activity. In the present study, we investigated whether tachyplesin can be used in non‐small cell lung cancer (NSCLC) A549 and H460 cells as well as the cisplatin‐resistant human A549/DDP NSCLC cell line. The results revealed that tachyplesin treatment significantly inhibited proliferation and induced apoptosis in A549 and H460 cells and the combination of tachyplesin and cisplatin significantly suppressed migration and improved sensitivity to cisplatin in A549/DDP cells. Further mechanistic examination revealed that tachyplesin induced apoptosis in A549/DDP cells by increasing Fas, FasL and p‐RIPK1 levels. These results indicated that tachyplesin induces lung cancer death by activating the Fas, mitochondrial and necroptosis pathways. Tachyplesin could be developed as a candidate drug for cisplatin‐resistant NSCLC.