Background: Non-small cell lung cancer (NSCLC) remains a major cause of cancer mortality. Isoginkgetin, a natural biflavonoid, has shown pharmacological potential, yet its antitumor mechanisms in NSCLC are not well defined. Purpose: This study investigated the antitumor activity of isoginkgetin in NSCLC and explored its molecular targets and underlying mechanisms. Study design: Cell-based assays and in vivo xenograft models combined with transcriptomic profiling, redox an-alyses, and in silico target identification/validation. Methods: Cell-based assays were performed to evaluate the effects of isoginkgetin on NSCLC cell growth, migration, apoptosis, and epithelial-mesenchymal transition (EMT). Transcriptome profiling and redox analyses were conducted to assess mechanistic pathways. Target identification was conducted through in silico screening, followed by drug-target binding validation and functional characterization, including further validation through Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) overexpression and silencing. The antitumor efficacy of isoginkgetin was further examined in NSCLC xenograft models, and the safety was assessed through acute toxicity experiments. Results: Isoginkgetin suppressed proliferation and migration, induced apoptosis, and blocked EMT in NSCLC cells. It disrupted redox homeostasis by enhancing oxidative stress, mediated by elevated reactive oxygen species (ROS) accumulation and activating endoplasmic reticulum (ER) stress and mitochondrial apoptosis. MTHFD2 was identified as a direct target of isoginkgetin, which binds to MTHFD2 and suppresses its functional role, ultimately leading to NADPH depletion and oxidative stress. Silencing MTHFD2 reproduced the effects of iso-ginkgetin, while overexpression of MTHFD2 partly attenuated these effects. In vivo, isoginkgetin markedly reduced tumor growth without systemic toxicity. Conclusion: Isoginkgetin exerts potent antitumor effects in NSCLC by targeting MTHFD2 and inducing redox imbalance, supporting its promise as a novel therapeutic candidate.

Asthma is a prevalent chronic airway disorder characterized by airway hyperresponsiveness (AHR), persistent airway inflammation, and airway remodeling. Emerging evidence implicates ubiquitination-a critical post-translational modification-in asthma pathogenesis. The study identifies ovarian tumor deubiquitinase 6A (OTUD6A), a deubiquitinase with established oncogenic roles, as a novel regulator of airway inflammation and remodeling. The study finds a significantly upregulation of OTUD6A in asthma patients and murine lungs, with predominant localization in airway epithelial cells. Genetic ablation of Otud6a prevents house dust mite (HDM)-induced AHR, airway inflammation, mucin hypersecretion in both chronic and acute asthma models, as well as airway remodeling in chronic asthma model. Mechanistically, multi-omics analysis identifies the secreted cytokine human (h)Resistin/mouse resistin-like molecule α (mRELMα) as a substrate of OTUD6A. OTUD6A deubiquitinates and stabilizes hResistin by specifically removing its K48-linked polyubiquitin chains at lysines K2 and K19 via the catalytic residue C152, thereby blocking its proteasomal degradation and promoting its secretion. The consequent accumulation of hResistin potentiates epithelial alarms production and facilitates epithelial-mesenchymal transition, driving airway inflammation and airway remodeling. Furthermore, adeno-associated virus 6-mediated OTUD6A silencing in murine lungs markedly ameliorates asthma phenotypes. These findings establish a pathogenic OTUD6A-hResistin/mRELMα axis and nominating OTUD6A as a promising therapeutic target for asthma intervention.

Carrier-free nanomedicines, with their high drug-loading capacity and low carrier-associated toxicity, offer a promising strategy for synergistic cancer therapy. Here, we developed a reactive oxygen species (ROS)-responsive, carrier-free nanoparticle (PRO/OCA NP) self-assembled from a resveratrol prodrug (PRO) and the immune adjuvant obeticholic acid (OCA). The oxalate ester linkage enabled selective cleavage in the ROS-enriched tumor microenvironment, ensuring precise co-release of Res and OCA. This dual delivery suppressed hepatocellular carcinoma (HCC) proliferation, induced apoptosis and cell cycle arrest, and inhibited PI3K/AKT/mTOR signaling. Meanwhile, PRO/OCA NPs trigger immunogenic cell death in tumor cells, activating NK and NKT cells and enhancing their cytotoxic functions, thereby amplifying the innate immune responses. In an orthotopic HCC mouse model, PRO/OCA markedly inhibited both primary and metastatic tumors while exhibiting favorable biocompatibility. Compared with monotherapy or simple drug combinations, this platform achieves a "1 + 1 > 2" chemo-immunotherapeutic synergy, offering a strategy with translational potential for comprehensive HCC treatment.

Allergic asthma stands as the predominant asthma phenotype propelled by aberrant type 2 immune response. Type-2 innate lymphoid cells (ILC2s) are significant for generating IL-5 and IL-13 cytokines, highlighting their vital role in triggering and escalating the progression of asthma. Myeloid differentiation primary response protein 88 (MyD88) controls innate and adaptive immune responses by orchestrating inflammatory signals. This work focused on investigating the influence of MyD88 in governing ILC2s-driven allergic airway disease alongside its underlying molecular mechanisms. We evaluated the effects of MyD88 in IL-33-induced or allergen-induced airway hyperreactivity (AHR) and airway inflammation. The role and mechanism of MyD88 in regulating ILC2s function were examined in vivo and in vitro by using transcriptome sequencing analysis, flow cytometry, clinical samples, ILC2-specific MyD88 knockout mice, and anti-Thy1.2 antibody against ILC2s in mice. The results showed heightened MyD88 expression in ILC2s sourced from allergic asthmatic patients and asthmatic mice. MyD88 knockout in ILC2s was able to mitigate IL-33-induced airway inflammation, while the MyD88 inhibitor LM8 proves efficacious in attenuating allergen-induced airway inflammation and AHR. After elimination of ILC2s via anti-Thy1.2 antibody, the pharmacological activity of LM8 diminished. Mechanistic studies revealed that MyD88 mediates the activation and proliferation of ILC2s through facilitation of P38-GATA3 complex formation. The research highlights MyD88 as a critical regulator of ILC2s activation, suggesting its potential utility as a therapeutic target for interventions in allergic asthma. The function of MyD88 in ILC2s promoting allergic airway inflammation and AHR through inducing ILC2s activation. MyD88 regulates ILC2s function through modulating the formation of the P38/GATA3 complex. Administration of MyD88 inhibitor LM8 effectively attenuates human ILC2s activation as well as IL-33 or Alt-induced airway inflammation.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and remains associated with high mortality despite advances in current therapies. Deoxypodophyllotoxin (DPT), a natural lignan derived from Anthriscus sylvestris, has been reported to exhibit antitumor activity in multiple cancer types; however, its molecular mechanism of action in LUAD has not been fully elucidated. In this study, we investigated the antitumor effects of DPT in LUAD and explored the involvement of Forkhead box O1 (FOXO1) signaling. Using LUAD cell lines and a xenograft mouse model, we found that DPT significantly inhibited cell proliferation and migration, induced apoptosis, and suppressed tumor growth in vivo. Mechanistic analyses revealed that FOXO1 was predominantly localized in the cytoplasm of LUAD cells under basal conditions. DPT treatment reduced FOXO1 phosphorylation and promoted its translocation into the nucleus, accompanied by enhanced FOXO1-associated antitumor effects. Functional experiments further supported a contributory role of FOXO1 in mediating the cellular response to DPT. Collectively, these findings demonstrate that DPT suppresses LUAD progression and identify FOXO1 as a mechanistically relevant downstream target of DPT. This study provides new insight into the molecular basis of DPT’s anticancer activity and highlights FOXO1 signaling as an important component of its antitumor mechanism in LUAD.

ETHNOPHARMACOLOGICAL RELEVANCE:Linderalactone is a sesquiterpene lactone isolated from Linderae Radix, a traditional Chinese medicinal herb used for pain and inflammatory disorders. Given the roles of hypoxia-related signaling, oxidative stress, and iron-dependent lipid peroxidation in fibrotic lung remodeling, linderalactone was evaluated as a natural product-derived anti-fibrotic lead. AIM OF THE STUDY:To evaluate the anti-pulmonary fibrosis activity of linderalactone and determine whether modulation of HIF-1α-dependent ferroptotic stress contributes to its underlying mechanism. MATERIALS AND METHODS:BLM-induced pulmonary fibrosis mice and TGF-β1-stimulated lung fibroblasts were used. Histopathology, fibrosis markers, oxidative stress, ferroptotic stress-related markers, intracellular iron, and lipid peroxidation were assessed. HIF-1α was analyzed by immunostaining and manipulated by siRNA knockdown or DMOG-mediated stabilization. BODIPY-C11 and ferrostatin-1 were used to monitor lipid peroxidation and probe function. RESULTS:Linderalactone alleviated lung injury and collagen deposition and suppressed fibroblast-to-myofibroblast transition. HIF-1α, colocalized with α-SMA-positive myofibroblasts, was downregulated. Linderalactone reduced malondialdehyde, PTGS2, lipid peroxidation, and intracellular iron, and restored glutathione, SLC7A11/xCT, and GPX4. HIF-1α knockdown phenocopied, whereas DMOG weakened, its protective effects. Fer-1 partially suppressed fibroblast activation, supporting a functional role for ferroptotic stress. CONCLUSIONS:Linderalactone alleviates experimental pulmonary fibrosis by suppressing HIF-1α signaling and attenuating HIF-1α-associated oxidative stress and ferroptotic stress. These findings support the HIF-1α-ferroptotic stress axis as a plausible mechanism, provide proof-of-concept for linderalactone as a natural product-derived anti-fibrotic candidate, and warrant further pharmacokinetic and translational investigation.

Background Non-small-cell lung cancer (NSCLC) is one of the deadliest malignancies in the world. Signal transducer and activator of transcription 3 (STAT3) plays an important role in the progression of NSCLC. Bruceine D is a bioactive quassinoid compound extracted from Brucea javanica, a plant widely used in traditional Chinese medicine.Methods Tests of cell function were performed to observe the effects of bruceine D on human NSCLC cell lines (H460, PC-9, and SKMES-1). Levels of STAT3, phosphorylated STAT3, Survivin, and other apoptosis-related proteins were detected via Western blotting. The binding of bruceine D to STAT3 was examined using molecular dynamics simulations and surface plasmon resonance spectroscopy. The effect of bruceine D on STAT3 nuclear localization was examined by immunofluorescence. Furthermore, the glucose uptake, lactate production, and extracellular acidification rates of NSCLC cells were analyzed to confirm that bruceine D inhibited glycolysis in NSCLC. The efficacy of bruceine D in vivo was evaluated in a mouse xenotransplantation model.Results Bruceine D significantly reduced the viability of NSCLC cells, promoted apoptosis, and inhibited the growth of tumors in a mouse xenograft model. Bruceine D was found to bind directly to STAT3, inhibiting glycolysis in NSCLC cells. Western blotting results suggested that the antitumor effects of bruceine D might be mediated by the inhibition of the phosphorylation and nuclear translocation of STAT3.Conclusion Bruceine D exerts a strong inhibitory effect on NSCLC in vitro and in vivo. Bruceine D has potential application prospects in the field of anti-NSCLC therapy.

Curcumin, a polyphenol extracted from the plant turmeric rhizoma, is well known for its strong antioxidant capacity and beneficial effects on the treatment of obesity induced by a high-fat diet in mice. However, the exact mechanism of action by which it improves obesity remains elusive. The aim of this study was to investigate the effect of curcumin on the biological phenotype of HFD-induced obese mice, to determine the related metabolic pathways and to determine whether the intestinal flora is involved. C57BL/6 mice were fed HFD for 8 weeks and then gavaged with 200 mg/kg curcumin or the same volume of vehicle for 16 weeks. The body weight, blood glucose level, blood lipid level, insulin resistance and oxidative stress level of the mice were detected to determine the effect of the treatment on lipid metabolism. Liver transcriptome analysis combined with qPCR and cell experiments revealed that curcumin improves hepatic steatosis and insulin resistance in mice fed a high-fat diet by downregulating the JNK2/FOXO1/Bcl6 axis. Curcumin treatment can regulate the composition and structure of intestinal flora in high-fat diet-fed mice, and increase the relative abundance of beneficial bacteria such as Coriobacteriaceae, Mailhella, Faecalibaculum, Phocaeicola vulgatus, Parvibacter vulgatus, and Bacteroides intestinalis, which are associated with obesity and metabolic disorders, while reducing the relative abundance of harmful bacteria such as Alistipes, Oscillibacter, Lactobacillus johnsonii, and Acutalibacter muris. In conclusion, curcumin ameliorated hepatic steatosis and insulin resistance in HFD-fed mice by down-regulating hepatic JNK2/FOXO1/Bcl6 axis and altering the composition and structure of intestinal flora.

BACKGROUND:Triple-negative breast cancer (TNBC) is characterized by its rapid progression and aggressive nature, with limited effective therapeutic interventions currently available. Cyclovirobuxine D (CVB-D), a natural alkaloid extracted from the traditional Chinese herb Buxus sinica, is renowned for its cardioprotective and anti-ischemic effects, demonstrating notable anti-cancer properties. Nevertheless, the anti-tumor effects of CVB-D on TNBC remain unverified. PURPOSE:This study seeks to investigate the effects of CVB-D on TNBC and to uncover the underlying mechanisms. STUDY DESIGN:Network pharmacology, SPR, DSF, and cell-based functional assays were conducted on TNBC cells to assess the impact of CVB-D. Findings were further corroborated using xenograft mouse models. METHODS:Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, transwell assays, flow cytometry, wound healing assays, immunofluorescence, and immunoblotting were employed to evaluate CVB-D's influence on TNBC cell lines. SPR, DSF and molecular docking techniques were utilized to assess the binding affinity of CVB-D to Yes-associated protein (YAP). The interaction between CVB-D and autophagy/mitophagy was further analyzed through plasmid transient transfection, JC-1 assay, TUNEL assay, and the use of autophagy inhibitors. The anti-TNBC mechanism of CVB-D was elucidated by overexpressing YAP in MDA-MB-231 cells. Additionally, the in vivo efficacy and safety of CVB-D were assessed in a xenograft mouse model. RESULTS:In vitro analyses revealed that CVB-D effectively suppressed G1 phase arrest and inhibited TNBC cell proliferation. Moreover, CVB-D induced mitochondrial-dependent apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, CVB-D exerted its anti-cancer effects by directly binding to YAP, thereby inhibiting the nuclear translocation of YAP/TAZ and suppressing the transcription of downstream oncogenic target genes. Furthermore, CVB-D triggered excessive mitophagy by activating the FOXO3a/PINK1-Parkin axis, promoting apoptosis and leading to mitochondrial dysfunction in TNBC cells. Elevated YAP expression counteracted the effects of CVB-D on TNBC, including the suppression of mitophagy-related protein expression induced by CVB-D, suggesting that YAP modulates mitophagy through the FOXO3a/PINK1-Parkin axis. The anti-tumor efficacy of CVB-D and its underlying mechanisms were further substantiated using a subcutaneous xenograft model. CONCLUSIONS:This study is the first to demonstrate that CVB-D can directly bind to the YAP target, proposing a novel therapeutic strategy for TNBC. CVB-D may serve both as a YAP/TAZ inhibitor and as an activator of the FOXO3a/PINK1-Parkin axis, leading to excessive mitophagy.

Pulmonary fibrosis (PF) is a refractory lung disease characterized by excessive extracellular matrix (ECM) deposition accompanied by inflammatory injury. Acetylshikonin (ASH), a naphthoquinone derivative primarily sourced from the root of Lithospermum erythrorhizon, possesses a diverse array of biological properties, including antitumor and anti-inflammatory activities, yet its potential in mitigating PF remains unexplored. We found that ASH ameliorated bleomycin-induced lung dysfunction and reduced lung inflammation levels, collagen deposition and Epithelial-mesenchymal transition (EMT) in mice. ASH also inhibited the TGF-β1-induced increase in ECM deposition and EMT and inhibited the migration of cultured cells. Notably, ASH inhibited STAT3 phosphorylation and nuclear translocation, and overexpression of STAT3 in MLE-12 cells reversed the effects of ASH on ECM deposition and cell migration. Collectively, our studies demonstrate that ASH alleviates PF through inhibition of the STAT3 signaling pathway and provide compelling evidence that ASH is a promising candidate drug for the treatment of PF.

Background:Psoriasis, an immune-mediated chronic inflammatory skin disease, is characterized by keratinocyte proliferation and inflammatory cell infiltration. T ripterygium wilfordii is a potential treatment option for psoriasis, and triptolide (TP) is one of its active components. TP may possess the potential to treat psoriasis; however, its mechanism of action remains unknown. Objective:The research aims to explore the therapeutic effect of TP on psoriasis and elucidate its potential targets. Methods:The imiquimod-induced psoriasis-like lesion mouse model was used to identify the mechanism underlying the therapeutic effect of TP.RNA-seq strategy was utilized to forecast the targets and mechanisms of TP in the context of psoriasis.Finally, we verify the effect of TP in the IL-17A-induced keratinocyte hyperproliferation and inflammation model. Results:TP reduced epidermal hyperplasia as well as psoriasis area and severity index scoring. Moreover, treatment with TP inhibited IMQ-induced splenomegaly and T-helper 17 cell differentiation in the psoriatic mice. Additionally, the treatment reduced the serum levels of pro-inflammatory cytokines such as interleukin (IL)-17A, IL-22, IL-23, IL-6, and tumor necrosis factor-α in the mice. The sequencing of RNA obtained from skin lesions of the psoriatic mice indicated that treatment with TP significantly downregulated Wnt5a RNA levels. Moreover, the Wnt5a/β-catenin pathway upregulated by IMQ was downregulated by treatment with TP. Additionally, IL-17A induced and upregulated Wnt5A and β-catenin mRNA expression, and TP inhibited this upregulated expression in HaCaT cells. Furthermore, TP inhibited proliferation, promoted apoptosis, and arrested the cell cycle in the IL-17A-induced keratinocyte hyperproliferation and inflammation model, thereby exhibiting its anti-inflammatory properties. Conclusion:TP alleviated psoriasis in mice by exerting anti-inflammatory effects and inhibited keratinocyte proliferation, which was partly achieved by regulating the Wnt5a/β-catenin signaling pathway.

BACKGROUND:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with limited effective therapies and poor prognosis. Although sorafenib and lenvatinib are approved for advanced HCC, their clinical efficacy is often compromised by drug resistance and adverse effects. Bruceine D (BD) has shown antitumor potential in several cancers, but its mechanisms in HCC remain poorly defined. METHODS:The effects of BD on HCC cell proliferation, apoptosis, and migration were assessed by MTT, colony formation, EdU incorporation, flow cytometry, wound healing, and transwell assays. Differentially expressed genes were identified by RNA sequencing and validated by RT-qPCR, with particular focus on Hsp70 family members. Protein expression and interactions were analyzed using Western blotting, co-immunoprecipitation (Co-IP), and Cellular Thermal Shift Assay (CETSA). Molecular docking was performed to predict BD binding sites on Hsp70. The antitumor efficacy and safety of BD were further evaluated in BALB/c nude mouse xenograft models. RESULTS:BD significantly inhibited HCC cell growth, induced apoptosis, and suppressed migration in a dose-dependent manner in vitro study. Transcriptomic profiling revealed downregulation of Hsp70 family members (HspA1A, HspA1B, HspA8), confirmed by RT-qPCR and Western blotting. Molecular docking suggested hydrogen bond interactions of BD with multiple residues in the Hsp70 domain. Co-IP assays demonstrated that Hsp70 binds STAT3, and BD disrupted this interaction, resulting in reduced STAT3 phosphorylation and suppression of downstream effectors (MCL-1, survivin). CETSA proved BD protected HSP70 at various temperature gradients in HCC cells. In vivo, BD markedly reduced tumor volume without affecting body weight or causing histopathological abnormalities in major organs. CONCLUSIONS:This study demonstrates that BD exerts potent antitumor effects against HCC by inhibiting proliferation, inducing apoptosis, and suppressing migration, primarily through disruption of the Hsp70/STAT3 signaling axis. With its favorable safety profile, BD represents a promising candidate for further development as a therapeutic agent in HCC.

Triple-negative breast cancer (TNBC), is a highly aggressive tumor. Formosanin C (FC) is a diosgenin with immunomodulatory and antitumor properties, the precise mechanism through which it is against TNBC remains uncertain. Clarifying the mechanism of FC against TNBC. The impact of FC on two TNBC cell lines for 24 h was investigated through various techniques including the CCK8 assay, flow cytometry, transwell assay, scratch tests, immunoblot assay, and immunofluorescence. To elucidate the mechanism behind the anti-TNBC effect of FC, MDA-MB-231 cells were subjected to STAT3 overexpression. Moreover, the in vivo efficacy of FC was examined using a xenograft nude mice (BALB/C). Mice were divided into the control group (equal amount of PBS), the napabucasin group (5 mg/kg) and the FC groups (1 mg/kg, 2 mg/kg). The study duration was 30 days. FC exhibited inhibitory effects against MDA-MB-231 and Hs578T cells. FC can decrease the migratory capacity of TNBC cells by inhibiting epithelial–mesenchymal transition (EMT). Meanwhile, we demonstrated that the inhibition of phosphorylation of STAT3 (Y705) is the crucial mechanism of FC against TNBC. Moreover, FC also hindered the polarization of macrophage M2. This study is the first to show that FC restrains the EMT of TNBC cells by obstructing the STAT3 pathway and hinders the M2 polarization of macrophages and immune evasion. Therefore, FC holds the possibility of being utilized as a therapeutic remedy for TNBC.

Puerarin (PU) helps slow down and control the harmful progression of atherosclerosis (AS) by reducing inflammation, inhibiting foam cell formation, and exhibiting anticoagulant effects. However, its clinical application is limited due to its low bioavailability and other drawbacks. In recent years, nanoparticle-based therapeutic strategies targeting reactive oxygen species (ROS) at AS pathological sites and enhancing drug bioavailability and biocompatibility have shown great potential for AS treatment. In this study, we developed ROS-responsive cinnamaldehyde polymer nanoparticles loaded with PU (RGCP@PU NPs) for the treatment of AS. These nanoparticles demonstrate good stability and biocompatibility in physiological environments and can respond to ROS in the AS pathological environment, thereby releasing the encapsulated PU. In vitro experiments showed that these nanoparticles effectively inhibited oxidative stress and inflammation levels. In in vivo studies, RGCP@PU NPs were able to stabilize atherosclerotic plaques, prevent their further deterioration, and delay the progression of AS. Moreover, compared to free PU, these nanoparticles exhibited superior therapeutic effects in inhibiting AS progression. Therefore, RGCP@PU NPs represent a promising nanocarrier that not only effectively suppresses AS progression but also provides a new approach for the design of responsive drug delivery systems for AS treatment.

Colorectal cancer is the fourth most common malignant cancer worldwide, with limited treatment options for advanced cases. The natural compound hypocrellin B has been shown to inhibit tumor growth, but its effects and specific mechanisms of action in colorectal cancer remain unclear. Here, we explore the anti-tumor effect of hypocrellin B on human colorectal cancer cells and identify molecular targets. We found that hypocrellin B significantly inhibits proliferation and migration and promotes apoptosis of colorectal cancer cells in vitro by targeting the AKT/STING signaling pathway. Hypocrellin B also inhibited tumor growth in vivo in a mouse xenograft model. In summary, hypocrellin B exerts an anticolorectal cancer effect by inhibiting the phosphorylation of AKT, thus blocking a key pathway of tumor growth and survival. These results indicate that hypocrellin B is a promising candidate for the treatment of colorectal cancer, warranting further investigation.

PURPOSE:The aim of this study was to investigate the anti-tumor effects and mechanisms of Raddeanin A in NSCLC in vitro and in vivo. METHODS:The effects of Raddeanin A on cell cycle progression, proliferation, migration and invasion of NSCLC were assessed by flow cytometry and cell biological assays in multiple NSCLC cell lines. To identify possible targets of Raddeanin A in NSCLC, we employed a multifaceted approach incorporating network pharmacology, molecular docking, and molecular dynamics simulation, along with additional techniques such as SPR (Surface Plasmon Resonance), Co-IP (Co-Immunoprecipitation), and immunofluorescence. In vivo effects were investigated using a nude mouse xenograft tumor model. RESULTS:Raddeanin A inhibits NSCLC cell survival, inhibits invasion and migration and causes cell cycle arrest in G1 phase. Raddeanin A impacts NSCLC cellular activity by inhibiting CDK6, leading to anti-tumor effects. Molecular analysis confirms that the tight binding between Raddeanin A and CDK6, facilitated by specific hydrogen bonds at binding sites including VAL-101, HIS-100, GLN-149, LYS-147, THR-182, VAL-180, and ALA-23, stabilizes within the 40-100 ns interval. In a nude mouse xenograft tumor model, Raddeanin A also demonstrated an inhibitory effect on NSCLC tumor growth. CONCLUSIONS:Raddeanin A blocks the cell cycle in G1 phase by inhibiting CDK6. Raddeanin A is expected to be a novel antitumor agent against NSCLC.

Micro- and nano-plastics (MNPs) are ubiquitously distributed in the environment, infiltrate organisms through multiple pathways, and accumulate, thus posing potential threats to human health. MNP exposure elicits changes in microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), thereby precipitating immune, neurological, and other toxic effects. The investigation of MNP exposure and its effect on miRNA expression has garnered increasing attention. Following MNP exposure, circRNAs serve as miRNA sponges by modulating gene expression, while lncRNAs function as competing endogenous RNAs (ceRNAs) by fine-tuning target gene expression and consequently impacting protein translation and physiological processes in cells. Dysregulated miRNA expression mediates mitochondrial dysfunction, inflammation, and oxidative stress, thereby increasing the risk of neurodegenerative diseases, cardiovascular diseases, and cancer. This tract, blood, urine, feces, placenta, and review delves into the biotoxicity arising from dysregulated miRNA expression due to MNP exposure and addresses the challenges encountered in this field. This study provides novel insights into the connections between MNPs and disease risk.

Due to their robust migration capabilities, slow degradation, and propensity for adsorbing environmental pollutants, micro(nano)plastics (MNPs) are pervasive across diverse ecosystems. They infiltrate various organisms within different food chains through multiple pathways including inhalation and dermal contact, and pose a significant environmental challenge in the 21st century. Research indicates that MNPs pose health threats to a broad range of organisms, including humans. Currently, extensive detection data and studies using experimental animals and in vitro cell culture indicate that MNPs can trigger various forms of programmed cell death (PCD) and can induce various diseases. This review provides a comprehensive and systematic analysis of different MNP-induced PCD processes, including pyroptosis, ferroptosis, autophagy, necroptosis, and apoptosis, based on recent research findings and focuses on elucidating the links between PCD and diseases. Additionally, targeted therapeutic interventions for these diseases are described. This review provides original insights into the opportunities and challenges posed by current research findings. This review evaluates ways to mitigate various diseases resulting from cell death patterns. Moreover, this paper enhances the understanding of the biohazards associated with MNPs by providing a systematic reference for subsequent toxicological research and health risk mitigation efforts.

Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.

As the primary component of anti-tumor immunity, T cells are prone to exhaustion and dysfunction in the tumor microenvironment (TME). A thorough understanding of T cell exhaustion (TEX) in the TME is crucial for effectively addressing TEX in clinical settings and promoting the efficacy of immune checkpoint blockade therapies. In eukaryotes, numerous cell surface proteins are tethered to the plasma membrane via Glycosylphosphatidylinositol (GPI) anchors, which play a crucial role in facilitating the proper translocation of membrane proteins. However, the available evidence is insufficient to support any additional functional involvement of GPI anchors. Here, we investigate the signature of GPI-anchor biosynthesis in the TME of breast cancer (BC)patients, particularly its correlation with TEX. GPI-anchor biosynthesis should be considered as a prognostic risk factor for BC. Patients with high GPI-anchor biosynthesis showed more severe TEX. And the levels of GPI-anchor biosynthesis in exhausted CD8 T cells was higher than normal CD8 T cells, which was not observed between malignant epithelial cells and normal mammary epithelial cells. In addition, we also found that GPI -anchor biosynthesis related genes can be used to diagnose TEX status and predict prognosis in BC patients, both the TEX diagnostic model and the prognostic model showed good AUC values. Finally, we confirmed our findings in cells and clinical samples. Knockdown of PIGU gene expression significantly reduced the proliferation rate of MDA-MB-231 and MCF-7 cell lines. Immunofluorescence results from clinical samples showed reduced aggregation of CD8 T cells in tissues with high expression of GPAA1 and PIGU.