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Ethnopharmacological Relevance: Dachaihu decoction (DCH) is a famous and ancient TCM formula, extensively utilized for over 1800 years in treating gastrointestinal and inflammatory conditions. Our previous study showed that DCH ameliorated intestinal damage and modulated the gut microflora in septic rats. However, the material basis for these effects and the underlying mechanism of action remains ill-defined. We aimed to explore the pharmaceutical ingredients of DCH and its mechanism in mitigating sepsis-induced intestinal epithelial barrier disruption (IEBD)., Materials and Methods: Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) was used to identify DCH composition. A septic rat model and Caco-2 cells were employed to investigate DCH's effects on IEBD. Transcriptomics and network pharmacology were used to predict potential mechanisms, which were further validated by molecular docking and dynamics simulations. The Modified Murine Sepsis Score (mMSS) and histological assessments were performed. Serum fluorescence intensity of FD4 and the expression of Occludin were evaluated to assess intestinal barrier integrity. And p-PI3K P85, PI3K P85, p-AKT, AKT, Bax and Bcl-2 were determined by Western blot. Cell viability was determined using CCK-8 assay, IL-6 and TNF-α by ELISA and quantitative Real-time PCR (RT-qPCR). The integrity and permeability of single layer of Caco-2 cells were assessed via transepithelial resistance (TEER), alkaline phosphatase (ALP) activity and FD4 permeability., Results: UHPLC-HRMS identified 180 compounds in DCH. DCH significantly reduced mMSS, improved pathological conditions in the ileum, decreased FD4 serum fluorescence, and enhanced Occludin expression. Transcriptomic and network pharmacology analyses identified the PI3K/AKT pathway as a critical mechanism of action. Molecular docking and dynamics simulations confirmed strong binding of DCH components to PIK3R1. DCH upregulated p-PI3K and p-AKT in ileum tissue of septic rats. DCH improved cell viability, decreased IL-6 and TNF-α, promoted cell survival and Occludin level, and upregulated p-PI3K and p-AKT in LPS-stimulated Caco-2 cells. DCH also maintained TEER, ALP activity and decreased FD4 permeability and these effects were reversed by PI3K inhibitor, LY294002. DCH also downregulated Bax expression and increased Bcl-2 levels in both septic rats and LPS-stimulated Caco-2 cells., Conclusion: DCH ameliorates sepsis-induced IEBD via PI3K/AKT pathway activation, offering a novel therapeutic perspective for sepsis-related intestinal dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The Yunpi-Xiefei-Huatan decoction (YXHD) is a traditional Chinese medicine that can improve asthma-related symptoms, including cough, phlegm in the throat, and shortness of breath. However, the YXHD mechanism on asthma has not yet been elucidated., Study Aim: The aim of this study is to investigate the effect of YXHD on airway inflammation, mucus hypersecretion, and autophagy modulation in asthma., Materials and Methods: The YXHD chemical constituents were observed and analyzed using high-performance liquid chromatography-mass spectrometry. Ovalbumin sensitization and stimulation were used to establish an asthma rat model. A total of 80 Sprague-Dawley (SD) rats were segmented into eight groups at random: a Normal (NC) group, a Model (Mod) group, a YXHD low-dose group (10 g/kg/d), a YXHD moderate-dose group (20 g/kg/d), a YXHD high-dose group (40 g/kg/d), a Rapamycin group (4 mg/kg/d), a 3-methyladenine (3-MA) group (15 mg/kg/d), and a Dexamethasone (DEX) group (0.5 mg/kg/d). Whole-body plethysmography (WBP) detection was used to evaluate airway hyperresponsiveness. An enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory factors in the peripheral blood. Inflammatory cells in the bronchoalveolar lavage fluid (BALF) were also counted. Pathological changes in the lung tissues were marked using hematoxylin and eosin (H&E) staining and periodic acid-Schiff (PAS) staining. The localization of MUC5AC and the co-localization of LC3B + MUC5AC were observed using immunofluorescence. The expressions of autophagy and the TGF-β3/Smad2/Smad3 pathway in the lung tissues were detected using a Western blot assay (WB) and qPCR, and the autophagosomes in the lung tissues were detected using a transmission electron microscope (TEM)., Results: Twenty signal peaks were identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. The TGF-β3/Smad2/Smad3 signal pathway activation was induced using ovalbumin (OVA) exposure in the rats. The upregulated expression of autophagy, enhanced MUC5AC fluorescence and LC3B fluorescence, and their co-localized expression in the airway epithelium indicated inflammatory cell infiltration and excessive mucus secretion in the lungs. This resulted in airway hyper-responsiveness. The YXHD inhibited the activation of the TGF-β3/Smad2/Smad3 signaling pathway, and autophagy expression reduced inflammatory factors, abnormal mucus secretion, and airway hyperresponsiveness., Conclusion: The YXHD improved lung function, relieved lung inflammation, and inhibited airway mucus secretions in asthmatic rat models. Its mechanism may have been related to the blockage of the TGF-β3/Smad2/Smad3 signaling pathway and autophagy downregulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

NLRP3 inflammasome activation is a pivotal area of research in innate immunity, yet the precise priming and activation signal remain unclear. In this study, we demonstrate that glycolysis inhibitor 2-Deoxy-D-glucose (2DG) triggers NLRP3-driven pyroptosis in human leukemia monocyte THP-1 cells by interfering glycosylation rather than glycolysis, which occurs independent of potassium efflux but requires the involvement of glycolysis rate-limiting enzyme PFKP. Using a CRISPR-Cas9 mediated large-scale screen, with 2DG as a new tool for probing NLRP3 activation, we identified that TLR2, rather than TLR4, initiates a rapid and robust priming signal for NLRP3 inflammasome activation. Importantly, both TLR2 and TLR4 depend entirely on MyD88, but not TRIF, for signal transduction. Furthermore, we discovered that TAK1, IKKβ and NEMO, but not IKKα, are essential for the priming signal. Additionally, we observed that deficiency in the linear ubiquitin assembly complex (LUBAC) subunits HOIP and HOIL-1, but not SHARPIN, is sufficient to inhibit 2DG-induced pyroptotic cell death. Collectively, our study reveals some common mechanism in the NLRP3 priming signals, as well as specific mechanisms upstream of NLRP3 triggered by 2DG, and underscores the potential of 2DG as a trigger to facilitate further detailed analysis of the underlying mechanisms of NLRP3 inflammasome activation. One Sentence Summary: Priming signal by IKKβ is essential for NLRP3 activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Repeated low-intensity noise exposure is prevalent in industrialized societies. It has long been considered risk-free until recent evidence suggests that the temporary threshold shift (TTS) induced by such exposure might be a high-risk factor for hearing loss. This study was conducted to further investigate the manner in which repeated low-intensity noise exposure contributed to hearing damage. Two-month-old C57BL/6 J mice were exposed to white noise at 96 dB SPL for 8 h per day over 7 days to induce TTS. Auditory brainstem response (ABR) was monitored to assess changes in hearing thresholds, tracking the effects of noise exposure until the mice reached 12 months of age. Our results indicated that noise-exposed mice exhibited accelerated age-related hearing loss spanning from high to low frequencies. Proteomics analysis revealed an upregulation in the receptor for the advanced glycation end-products (RAGE) signaling pathway, which was associated with an activated inflammatory response, vascular injury, and mitochondrial and synaptic dysfunction. Further analysis confirmed increased levels of inflammatory cytokines in the cochlear lymph fluid and significant macrophages infiltration in the cochlear lateral wall, accompanied by hyperpermeability of the blood-labyrinth barrier. Additionally, degenerated mitochondria in the outer hair cells and decreased synaptic ribbons in the inner hair cells were also observed. These pathological changes indicated that noise exposure damages the cochlear cellular components, increasing the cochlear susceptibility to age-related stress. Our findings suggest that TTS caused by repeated low-intensity noise exposure correlates with a severe sensorineural hearing loss during aging; targeting the RAGE signaling pathway may be a promising strategy to mitigate damage from low-intensity noise and slow down the progression of age-related hearing loss., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Citrus grandis fruit is a famous traditional Chinese medicine with various bioactivities, including cardioprotective effects. Polysaccharides are one of the key active ingredients responsible for its cardioprotective effects. This study aimed to investigate the structure and cardioprotective effect of a homogeneous polysaccharide from C. grandis fruit (CGP80-1) and explore its mechanism against myocardial ischemia-reperfusion (MI/R) injury. Structure analysis showed that CGP80-1 (11,917 Da) is an arabinan with compact coil chain conformation, containing →5)-α-L-Araf-(1→, →3,5)-α-L-Araf-(1→, and →2,3,5)-α-L-Araf-(1→ as the backbone, as well as →5)-α-L-Araf-(1→ and t-α-L-Araf as side-chains substituted at the C2 and C3 positions. Pharmacological experiments showed that pre-treatment with CGP80-1 could effectively alleviate MI/R injury by improving endogenous antioxidant enzymes and cardiac enzymes, reducing reactive oxygen species levels, and regulating apoptosis-related proteins such as caspase-3, Bax, and Bcl-2. The protective effects were correlated with the Nrf2/Keap1 and IRE1/GRP78 signaling pathways. Further analysis of structure-activity relationships revealed that the myocardial protection effects of CGP80-1 might be attributed to its appropriate molecular weight, high arabinose content, and unique compact coil chain conformation. Overall, our results provide insight into the chemical structure of CGP80-1 and its mechanism of action, suggesting that CGP80-1 could be a candidate drug for myocardial protection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Maternal vitamin D deficiency is associated with an increased risk of preeclampsia, a potentially life-threatening multi-system disorder specific to human pregnancy. Placental trophoblast dysfunction is a key factor in the development of preeclampsia, and the activation of NOD-like receptor protein 3 (NLRP3) inflammasome may play a crucial role in this process. Previous studies have suggested that vitamin D can exert beneficial effects by suppressing inflammasome activation, but the underlying mechanism has not been fully elucidated. This study aims to explore the protective effects of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] on the placenta and to investigate the mechanisms by which 1,25(OH) 2 D 3 attenuates NLRP3 inflammasome activation in a rat model of preeclampsia and hypoxia-cultured placental trophoblast cells., Results: Our findings demonstrated that supplementation of rats with 1,25(OH) 2 D 3 mitigated placental inflammation and prevented multi-organ dysfunction associated with preeclampsia. Treatment with 1,25(OH) 2 D 3 inhibited inflammasome-mediated inflammation in trophoblast cells via its receptor VDR by reducing the expression of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), decreasing IL-1β production, reducing mitochondrial reactive oxygen species generation, and enhancing the expression and enzymatic activity of Cu/Zn-superoxide dismutase (SOD). Mechanistically, 1,25(OH) 2 D 3 upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, subsequently suppressing NLRP3-mediated IL-1β overproduction in trophoblast cells., Conclusions: Our study indicates that 1,25(OH) 2 D 3 inhibits NLRP3-mediated inflammation in trophoblast cells during preeclampsia by stimulating the Nrf2 signaling pathway and inhibiting oxidative stress., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To investigate CHD1L's impacts and molecular processes in hypoxic cutaneous squamous cell carcinoma. Monoclonal proliferation assays and CCK-8 were used to detect the proliferation capacity of A431 cells and Colon16 cells; wound healing experiments and Transwell assays were used to examine the migration and invasion capacity of A431 cells and Colon16 cells; angiogenesis experiments were conducted to assess the influence of A431 cells on angiogenesis; a nude mouse tumor xenograft experiment and HE staining were utilized to evaluate the impact of CHD1L on the progression of cutaneous squamous cell carcinoma; western blot analysis was performed to detect the expression of p-PI3K, p-AKT, and PD-L1 in A431 cells, as well as CD9, TSG101, PD-L1 in exosomes, and CD206, Arginase-1, iNOS, IL-1β, p-AKT, p-mTOR, VEGF, COX-2, MMP2, MMP9, p-ERK1/2 in tumor-associated macrophages. Under hypoxic conditions, CHD1L promoted the proliferation, migration, invasion, and angiogenesis of cutaneous squamous cell carcinoma. Furthermore, CHD1L facilitated the progression of cutaneous squamous cell carcinoma. CHD1L also increased the relative protein expression of p-PI3K, p-AKT, and PD-L1 in A431 cells, as well as CD9, TSG101, PD-L1 in exosomes, CD206, Arginase-1, p-AKT, p-mTOR, VEGF, COX-2, MMP2, MMP9, and p-ERK1/2 in tumor-associated macrophages, while inhibiting the relative protein expression of iNOS and IL-1β. Under hypoxic conditions, CHD1L can promote the proliferation and migration of cutaneous squamous cell carcinoma., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: Animal experiments were performed according to the guidelines laid down by the Laboratory Animal Ethical and Welfare Committee of Affiliated Hospital of Hebei Engineering University (IACUC-Hebeu-2023-0019)., (© 2024. The Author(s).)

Background: Liver fibrosis is a sustained process of liver tissue damage and repair caused by various physiological and pathological factors, with the activation and proliferation of hepatic stellate cells being central. Therefore, understanding and clarifying the relevant mechanisms of hepatic stellate cell activation and death is of great clinical significance for the treatment of liver fibrosis diseases., Methods: In vivo, recombinant adeno-associated virus was used to infect the liver of experimental mice, overexpressing ASIC1a, and based on this, a liver fibrosis model treated with sorafenib was constructed. In vitro, using RNA plasmid technology to transfect HSC-T6 cells, ASIC1a was overexpressed or silenced in the cells, and on this basis, PDGF-BB and Sorafenib were used to stimulate HSC-T6 cells, causing activated HSC-T6 to undergo ferroptosis., Results: The ferroptosis inducers Sorafenib and erastin can induce ferroptosis in HSCs, effectively inhibiting or reversing the progression of liver fibrosis. We found that the expression level of ASIC1a was significantly reduced in the livers of mice with liver fibrosis treated with Sorafenib. After treatment with an adeno-associated virus overexpressing ASIC1a, the therapeutic effect of Sorafenib was inhibited, and the level of ferroptosis induced by Sorafenib was also inhibited. The induction of ferroptosis in hepatic stellate cells in vitro depends on the presence of ASIC1a. By further exploring the potential mechanism, we observed that the overexpression of ASIC1a can promote an increase in YAP nuclear translocation, thereby regulating the activity of Hippo/YAP pathway signaling. After treatment with Sorafenib, the influx of Ca 2+ significantly increased when ASIC1a was overexpressed, and BAPTA-AM intervention eliminated the intracellular Ca 2+ accumulation induced by ASIC1a overexpression., Conclusions: This indicated that the activation of YAP depends on the calcium ion influx induced by ASIC1a, which regulates ferroptosis in hepatic stellate cells by regulating the calcium ion-dependent Hippo/YAP pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Acute liver failure (ALF) is a fulminant clinical syndrome that usually leads to multiple organ failure and high mortality. Macrophages play a crucial role in the initiation, development, and recovery of ALF. Targeting macrophages through immunotherapy holds significant promise as a therapeutic strategy. These cells exhibit remarkable plasticity, enabling them to differentiate into various subtypes based on changes in their surrounding microenvironment. M1-type macrophages are associated with a pro-inflammatory phenotype and primarily rely predominantly on glycolysis. In contrast, M2-type macrophages, which are characterized by anti-inflammatory phenotype, predominantly obtain their energy from oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Shifting macrophage metabolism from glycolysis to OXPHOS inhibits M1 macrophage activation and promotes M2 macrophage activation, thereby exerting anti-inflammatory and reparative effects. This study elucidates the relationship between macrophage activation and glucose metabolism reprograming from an immunometabolism perspective. A comprehensive literature review revealed that several signaling pathways may regulate macrophage polarization through energy metabolism, including phosphatidyl-inositol 3-kinase/protein kinase B (PI3K/AKT), mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1 α (HIF-1 α ), nuclear factor- κ B (NF- κ B), and AMP-activated protein kinase (AMPK), which exhibit crosstalk with one another. Additionally, we systematically reviewed several traditional Chinese medicine (TCM) monomers that can modulate glucose metabolism reprograming and influence the polarization states of M1 and M2 macrophages. This review aimed to provide valuable insights that could contribute to the development of new therapies or drugs for ALF., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Junli Zhang et al.)

Background: Ribosomal RNA processing 9 (RRP9) is a specific component of the U3 small nucleolar ribonucleoprotein (U3 snoRNP), which is involved in physiological processes and pathological disorders. The purpose of the current study was to investigate the biological roles of RRP9 in breast cancer (BC) progression., Methods: The expression levels of RRP9 in human BC were assessed by immunohistochemical (IHC) staining, qPCR assay and Western blot. Cells were transfected with shRNA plasmids to regulate RRP9 expression. The functional roles were explored by Celigo cell counting assay, colony formation assay, flow cytometry and Transwell assays, as well as construction of Xenograft tumor model. Furthermore, interaction between RRP9 and JUN was determined by Co-immunoprecipitation (Co-IP) assay, protein stability assay, and ubiquitination assay., Results: RRP9 expression was substantially upregulated in BC tissues and was positively associated with lymph node metastasis and poor prognosis. Functional experiments indicated that RRP9 depletion inhibited BC progression both in vitro and in vivo. Using a prime-view human gene expression array and IPA, JUN was identified as a potential downstream target of RRP9. Mechanistically, RRP9 interacted with the JUN protein, and RRP9 deletion decreased JUN protein stability by accelerating JUN ubiquitination and led to JUN degradation via MDM2. Moreover, the regulatory effects of RRP9 on BC cell phenotypes were attenuated by JUN knockdown or the AKT signalling pathway activator SC79., Conclusions: In conclusion, this study revealed the crucial role of RRP9 in BC progression and its probable novel mechanism, suggesting that RRP9 may be a promising candidate for the treatment of BC., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Shanghai Cancer Center (No. 050432-4-2108) and the Institutional Animal Care and Use Committee of Shanghai Cancer Center (No. FUSCC-IACUC-S2023-0419), Fudan University. Informed consent was obtained from each patient. Patient consent for publication: Not applicable. Disclosure of generative AI- and AI-assisted technology use in the writing process: This study, which was completed by these authors, was not written by generative AI or AI-assisted technologies; thus, it is entirely original. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Obstructive sleep apnea (OSA) is a common clinical condition linked to cognitive impairment, mainly characterized by chronic intermittent hypoxia (CIH). GLP-1 receptor agonist, known for promoting insulin secretion and reducing glucose levels, has demonstrated neuroprotective effects in various experimental models such as stroke, Alzheimer's disease, and Parkinson's disease. This study aims to investigate the potential role and mechanisms of the GLP-1 receptor agonist liraglutide in ameliorating OSA-induced cognitive deficits. CIH exposure, a well-established and mature OSA pathological model, was used both in vitro and in vivo. In vitro, CIH significantly activated oxidative stress, inflammation, and apoptosis in SH-SY5Y cells. Liraglutide enhanced the nuclear translocation of Nrf2, activating its downstream pathways, thereby mitigating CIH-induced injury in SH-SY5Y cells. Additionally, liraglutide modulated the MAPK/NF-κB signaling pathway, reducing the expression of inflammatory factors and proteins. In vivo, we subjected mice to an intermittent hypoxia incubator to mimic the pathogenesis of human OSA. The Morris water maze test revealed that CIH exposure substantially impaired spatial memory. Subsequent western blot analyses and histopathological examinations indicated that liraglutide could activate the Nrf2/HO-1 axis and inhibit the MAPK/NF-κB signaling pathway, thereby alleviating OSA-associated cognitive dysfunction in mice. These findings suggest that GLP-1 receptor agonists may offer a promising preventive strategy for OSA-associated cognitive impairment. By refining these findings, we provide new insights into GLP-1's protective mechanisms in combating cognitive deficits associated with CIH, underscoring its potential as a therapeutic agent for conditions linked to OSA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Pro-viral Insertion site for the Moloney Murine Leukemia virus 1 (PIM-1) is widely involved in various biological processes and diseases, which is based on its structure and functional sites. However, the relationship between active sites and function of PIM-1 kinase remains unclear due to the lack of effective study approaches in live cells. Herein, to visualize the effect of different active sites in PIM-1 protein on its function activity and relation with PI3K/Akt/mTOR pathway, three mutant probes of EPHY which was developed previously based on fluorescence resonance energy transfer (FRET) technology to detect PIM-1 kinase activity in living cells were further constructed and transfected into cells followed by treating with PIM-1 inhibitors, ATP and PI3K inhibitor, respectively. The results showed that Lys67 is related to substrate binding and catalytic activity of PIM-1 kinase, thereby directly regulating PI3K/Akt/mTOR signaling pathway. Pro81/Asn82 are primarily participated in PIM-1 binding to ATP, thus also involving in the modulation on PI3K/Akt/mTOR signaling pathway, but play less role in the interaction between PIM-1 protein and its substrate. Asp167 has few effects on both the catalytic function activity of PIM-1 and PI3K/AKT/mTOR pathway, even though the binding ability of PIM-1 protein to its substrate is dramatically inhibited by D167A mutation. Altogether, the mutant probes works well as visualization tools to unearth the function of active sites in PIM-1 kinase, not only facilitating the further clarification of molecular mechanism underlying PIM-1 related signaling pathways, but also shedding light on drug development and disease therapy targeting PIM-1 protein., (© 2024 Wiley‐VCH GmbH.)

Background: The progress of cardiac hypertrophy is modulated by JAK2/STAT3 signaling pathway. Cardiac glucose metabolism derangement exacerbates the progression of cardiac hypertrophy. Oxytocin (OT) has emerged as a significant hormone involved in cardiovascular homeostasis, especially in protecting against cardiac hypertrophy. The present study aims to explore whether the anti-hypertrophy effect of oxytocin is related to the JAK2/STAT3 signaling pathway and cardiac glucose metablism., Methods: Cardiac hypertrophy model was induced by angiotensin II (Ang II) in H9c2 cells and in mice with or without oxytocin treatment. Changes in cardiac histopathology were evaluated by hematoxylin and eosin (H&E), Masson staining, and wheat germ agglutinin (WGA) staining. The hypertrophy-related genes and JAK2/STAT3 pathway signaling molecules were analyzed by qRT-PCR and western blotting. The levels of glucose, pyruvic acid, lactic acid, and lactate dehydrogenase activity in H9c2 cells using the corresponding assay kits., Results: The results showed that OT inhibited hypertrophic and fibrotic changes. Furthermore, OT increased intracellular levels of glucose and pyruvic acid, and decreased lactate dehydrogenase activity and lactic acid levels. Mechanistically, Ang II decreased oxytocin receptors (OXTR) expression and facilitated JAK2 and STAT3 phosphorylation. OT treatment increased OXTR expression and blocked JAK2 and STAT3 phosphorylation The OXTR-specific siRNA-mediated depleted expression could abrogate OT-induced anti-hypertrophic effects in H9c2 cells following angiotensin II insult. However, the JAK2/STAT3 inhibitor AG490 rescued the protective effects of OT against cardiac hypertrophy under OXTR downregulation., Conclusion: OT exerts its protective effects against cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

SP0.1-1, derived from Sea buckthorn (Hippophae rhamnoides L.), has been discovered to exhibit unique antioxidant activity. In this study, we investigated the immunomodulatory activity and mechanisms of SP0.1-1 on macrophage RAW 264.7 cells in vitro and immunosuppressive mice induced by cyclophosphamide in vivo. The results indicated SP0.1-1 strengthened the immune functions via promoting the proliferation of RAW264.7 cells and phagocytic activity, along with stimulating the release of NO, ROS and cytokines including TNF-α, IL-6, IL-1β and IFN-γ. Western blot and molecular docking analysis demonstrated that SP0.1-1 attached to the prime receptors TLR2 and TLR4 in RAW264.7 cells, and triggered the activation of MyD88-mediated MAPK and NF-κB signaling pathways, thereby exerting the immune response in RAW264.7 cells. However, the intervention of specific inhibitors against TLR2, TLR4, JNK, ERK, p38 and NF-κB blocked the TLR-mediated MAPK and NF-κB signaling pathways and downregulated the levels of NO and the aforementioned cytokines, thus suppressing the activation of macrophages. Therefore, it can be speculated that SP0.1-1 activated the macrophages principally via the TLR2/4-MyD88-mediated MAPK and NF-κB signaling pathways. Additionally, SP0.1-1 could protect against the cyclophosphamide-induced immunosuppression in mice, manifested by the improvement of body weight, immune organ indices, phagocytic index, and the relievement of spleen damage, along with the enhancement of cytokines TNF-α, IL-6, IFN-γ and immunoglobulin IgG and IgM. These findings will shed light on the molecular mechanism of SP0.1-1 on the immunoregulatory effect, and lay the foundation for exploiting a potential immunostimulatory agent of SP0.1-1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Depression is a chronic and recurrent disorder with an unknown etiology. Efficacious antidepressant treatments with minimal side effects are urgently needed. Neuroinflammation may contribute to depression, as anti-inflammatory drugs have been shown to alleviate depressive symptoms in clinical practice. Rutin, a naturally occurring flavonoid derived from plants, is abundant in many antidepressant herbs, including Hemerocallis citrina Baroni. Historical Chinese medical texts, including the renowned Compendium of Materia Medica, document H. citrina Baroni as possessing antidepressant properties. Rutin, one of its primary active constituents, is recognized for its anti-inflammatory effects. Despite this, little is known about its specific target and mechanism., Methods: In the present study, molecular docking, and surface plasmon resonance imaging (SPRi) analysis were used to identify the special targets of rutin. Meanwhile, the potential antidepressant effects were evaluated in the chronic social defeat stress (CSDS) paradigm, an animal model of depression. Then, Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), Co-immunoprecipitation (Co-IP) as well as antagonists of PPAR-γ were utilized to investigate the mechanism underlying the antidepressant effect of rutin., Results: Both molecular docking and SPRi analysis showed high docking scores and interactions between rutin and PPAR-γ. In vivo, rutin promoted the nuclear translocation of PPAR-γ in the hippocampus of mice, inhibited NFκB-mediated inflammatory pathways, and subsequently reduced the expression of pro-inflammatory factors (e.g., iNOS, IL-6), aligning with an antidepressant effect. However, this therapeutic effect was attenuated by GW9662, a specific antagonist of PPAR-γ., Conclusion: As a result of activating PPAR-γ and inhibiting NFκB pathway activation, rutin reduces neuroinflammation and exhibits an antidepressant effect. These findings shed light on the antidepressant mechanism of rutin and could be valuable for the development of new antidepressants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

CD169+ macrophages are a newly defined macrophage subpopulation that can recognize and bind with other cells through related ligands, playing an essential role in antigen presentation and immune tolerance. However, its role in Allergic Rhinitis (AR) is still unclear. To investigate the characteristics of CD169+ macrophages in AR, this work first detects their expression patterns in the nasal mucosa of clinical patients. These results show a significant increase in CD169+ macrophages in the nasal mucosa of patients with AR. Subsequently, this work establishes an animal AR model using CD169 transgenic mice and compared the advantages of the two models. Moreover, this work also demonstrates the effects of CD169 knockout on eosinophils, Th cells, Treg cells, and the migration of dendritic cells (DCs). In addition, this metabolomic data shows that CD169+ macrophages can upregulate alanine production and increase reactive oxygen species (ROS) levels. This process may be mediated through the Keap1/Nrf2/HO-1 signaling pathway. In addition, this work also finds that SLC38A2 plays an essential role in the process of CD169+ macrophages promoting alanine uptake by DCs. This study confirms that CD169+ macrophages can upregulate their internal alanine production and increase ROS levels through the Keap1/Nrf2/HO-1 axis, playing an irreplaceable role in AR., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Digestive system cancers rank among the most prevalent malignant tumors, maintaining persistently high incidence and mortality rates. Notch signaling activity, often aberrant in esophageal, gastric, hepatic, pancreatic, and colorectal cancers, plays a pivotal role in the initiation, progression, and therapy resistance of these malignancies. As a highly conserved pathway, Notch signaling is integral to cell differentiation, survival, proliferation, stem cell renewal, development, and morphogenesis. Its dysregulation has been increasingly linked to various diseases, particularly digestive system cancers. In these malignancies, altered Notch signaling influences multiple biological processes, including cell proliferation, invasion, cell cycle progression, immune evasion, drug resistance, and stemness maintenance. Understanding the mechanisms of Notch signaling in digestive system cancers is essential for the development of novel targeted therapies. Numerous Notch pathway-targeting drugs are currently in preclinical studies, demonstrating promising efficacy both as monotherapies and in combination with conventional anti-cancer treatments. This review summarizes recent high-quality findings on the involvement of Notch signaling in digestive system cancers, focusing on the expression changes and pathological mechanisms of its dysregulated components. Special emphasis is placed on the potential of translating Notch-targeted approaches into therapeutic strategies, which hold promise for overcoming the limitations of existing treatments and improving the poor prognosis associated with these cancers., Competing Interests: Declaration of competing interest All authors declare no competing interests related to this review., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe -/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury., Competing Interests: Compliance with ethics guidelines. Conflicts of interest Yixiu Zhao, Zhiqi Wang, Jing Ren, Huan Chen, Jia Zhu, Yue Zhang, Jiangfei Zheng, Shifeng Cao, Yanxi Li, Xue Liu, Na An, Tao Ban, Baofeng Yang, and Yan Zhang declare that they have no conflict of interest. Baofeng Yang is a member of the Editorial Board of Frontiers of Medicine, who was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias. All institutional and national guidelines for the care and use of laboratory animals were followed., (© 2024. Higher Education Press.)

Aerobic glycolysis is involved in the pathogenesis of pulmonary hypertension (PH). The mechanisms by which glycolysis is increased and how it contributes to pulmonary vascular remodelling are not yet fully understood. In this study, we demonstrated that elevated lipocalin-2 (LCN2) in PH significantly enhances aerobic glycolysis in human pulmonary artery smooth muscle cells (PASMCs) by up-regulating LDHA expression. Knockout of Lcn2 or having heterozygous LDHA deficiency in mice significantly inhibits the progression of hypoxic PH. Our study reveals that LCN2 stimulates LDHA expression by activating Akt-HIF-1α signalling pathway. Inhibition of Akt or HIF-1α reduces LDHA expression and proliferation of PASMCs. Both Akt and HIF-1α play critical roles in the development of PH and are suppressed in the pulmonary vessels of hypoxic PH mice lacking LCN2. These findings shed light on the LCN2-Akt-HIF1α-LDHA axis in aerobic glycolysis in PH., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Our objective was to determine the role of acetyl-Hsp90 and its relationship with the NF-κB p65 signaling pathway in CVDs. We investigated the effect of acetyl-Hsp90 on cardiac inflammation and apoptosis after ischemia-reperfusion injury (I/RI). The results showed that the induction of acetyl-Hsp90 occurred in the heart during I/R and in primary cardiomyocytes during oxygen-glucose deprivation/reoxygenation (OGD/R). Moreover, the nonacetylated mutant of Hsp90 (Hsp90-K284R), through the regulation of ATPase activities within its N-terminal domain (NTD), indirectly or directly increases its interaction with NF-κB p65. This led to a reduction in the activation of the NF-κB p65 pathway, thereby attenuating inflammation, apoptosis, and fibrosis, ultimately leading to an improvement in cardiac function. Furthermore, we demonstrated that recombinant human interleukin-37 (rIL-37) exerts a similar cardioprotective effect by reducing acetylation at K284 of Hsp90 after inhibiting the expression of KAT2A., Competing Interests: Declarations. Conflict of Interest: The authors indicated no potential conflicts of interest., (© 2024. The Author(s).)

To investigate the effect of miR-3571 on traumatic brain injury (TBI) via the regulation of neuronal apoptosis through F-box-only protein 31/phosphoinositide 3-kinase/protein kinase B (Fbxo31/PI3K/AKT). We established TBI rat and cell models. Hematoxylin‒eosin (HE) and Nissl staining were used to observe brain injury and the number of Nissl bodies, respectively. Cell proliferation and apoptosis were assessed by 5-ethynyl-2'-deoxyuridine (EdU), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and flow cytometry. Gene and protein expression was measured via reverse transcription quantitative polymerase chain reaction (RT‒qPCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). In this study, miR-3571 was highly expressed in TBI models. Inhibition of miR-3571 expression can suppress autophagy, reduce the expression of proinflammatory cytokines, and reduce neuronal apoptosis, thus alleviating the pathological conditions of tissue congestion, edema and structural damage after TBI. These experiments demonstrated that miR-3571 could target and regulate the level of Fbxo31. Knockdown of Fbxo31 weakened the remission effect of the miR-3571 inhibitor on TBI and promoted neurological damage; moreover, overexpression of Fbxo31 enhanced the protective effect on neural function, whereas the PI3K/AKT pathway inhibitor LY294002 increased the damage caused by miR-3571 on neural function and weakened the protective effect of Fbxo31. In conclusion, miR-3571 regulates the PI3K/AKT signaling pathway by reducing Fbxo31 expression, promotes neuronal apoptosis and exacerbates TBI., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests. Consent for publication All the authors agreed on the publication of this manuscript. Ethics approval and consent to participate All animal procedures were approved by the Animal Ethics Committee of People’s Hospital of Hunan Province., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatic fibrosis is a common disease with high morbidity and mortality rates. The complex and poorly understood mechanisms underlying hepatic fibrosis represent a significant challenge for the development of more effective therapeutic strategies. MKP5 is a potential regulator of multiple fibrotic diseases. However, its precise role and mechanism of action in hepatic fibrosis remains unclear. This study identified a reduction in MKP5 expression in fibrotic liver tissues of mice treated with CCl 4 and observed that MKP5 knockout mice exhibited a more pronounced development of hepatic fibrosis. In addition, RNA-seq data indicated activation of protein processing in the endoplasmic reticulum signalling pathway in fibrotic liver tissues of mice lacking MKP5. Mechanistically, MKP5 inhibits the activation of hepatic stellate cells (HSCs) and hepatocyte apoptosis through the regulation of the IRE/XBP1 pathway. Based on these findings, we developed PLGA-MKP5 nanoparticles coated with a mesenchymal stem cell membrane (MSCM). Our results demonstrated that MSCM-PLGA-MKP5 was most effective in attenuating hepatic inflammation and fibrosis in murine models by modulating the IRE/XBP1 axis. This study contributes to the current understanding of the pathogenesis of hepatic fibrosis, suggesting that the targeted delivery of MKP5 via a nano-delivery system may represent a promising therapeutic approach to treat hepatic fibrosis., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were conducted in accordance with the Guidelines for Experimental Animals of Jilin University and approved by the Animal Experiment Ethics Committee of Jilin University (approval number: 20240038). Consent for publication: All authors have reviewed and agreed to the published version of the manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S-palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Optimal stomatal regulation is important for plant adaptation to changing environmental conditions and for maintaining crop yield. The guard cell signal γ-aminobutyric acid (GABA) is produced from glutamate by glutamate decarboxylase (GAD) during a reaction that generates CO2 as a by-product. Here, we investigated a putative connection between GABA signalling and the more clearly defined CO2 signalling pathway in guard cells. The GABA-deficient mutant Arabidopsis lines gad2-1, gad2-2, and gad1/2/4/5 were examined for stomatal sensitivity to various CO2 concentrations. Our findings show a phenotypical discrepancy between the allelic mutant lines gad2-1 and gad2-2-a weakened CO2 response in gad2-1 (GABI_474_E05) in contrast to a wild-type response in gad2-2 (SALK_028819) and gad1/2/4/5. Through transcriptomic and genomic investigation, we traced the response of gad2-1 to a deletion of full-length Mitogen-activated protein kinase 12 (MPK12) in the GABI-KAT line, thereafter renamed as gad2-1*. Guard cell-specific complementation of MPK12 in gad2-1* restored the wild-type CO2 phenotype, which confirms the proposed importance of MPK12 in CO2 sensitivity. Additionally, we found that stomatal opening under low atmospheric CO2 occurs independently of the GABA-modulated opening channel ALUMINIUM-ACTIVATED MALATE TRANSPORTER 9 (ALMT9). Our results demonstrate that GABA has a role in modulating the rate of stomatal opening and closing, but not in response to CO2per se., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Cadmium (Cd) is an environmental pollutant that can cause neurodegenerative disorders. Luteolin (Lut) is a natural flavonoid compound. However, whether Lut protects against Cd-induced nerve cell death remains unclear. In the present study, PC12 cells were used to investigate the neuroprotective effect of Lut against Cd poisoning. Changes in cell viability, apoptosis, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein expression, and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway activity were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Hoechst 33258 staining, flow cytometry, and western blotting. Lut markedly attenuated the Cd-induced reduction in cell viability, nuclear fragmentation, condensation, and the decrease in the Bcl-2/Bcl-2-associated X protein ratio in PC12 cells. Furthermore, Lut blocked the Cd-mediated activation of the Akt/mTOR signaling pathway. Moreover, inhibition of the Akt/mTOR signaling pathway with LY294002 (a PI3K inhibitor) enhanced the protective effect of Lut against Cd-induced cell death by suppressing Cd-induced activation of Akt, mTOR, and eukaryotic initiation factor 4E binding protein 1. The results showed that Lut prevented Cd-induced cell death partly by blocking the Akt/mTOR signaling pathway. Lut may be a potential agent for preventing Cd-induced nerve cell damage and neurodegenerative diseases., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Accumulation studies confirmed that oxidative stress caused by ischemia after myocardial infarction (MI) is an important cause of ventricular remodeling. Exosome secretion through hypoxic pretreatment adipose-derived mesenchymal stem cells (ADSCs) ameliorates myocardial damaging post-MI. However, if ADSCs exosome can improve the microenvironment and ameliorate cardiac damage post-MI still unknown. Next-generation sequencing (NGS) was used to study abnormally expressed circRNAs in hypoxic pretreatment ADSC exosomes (HExos) and untreated ADSC exosomes (Exos). Bioinformatics and luciferase reporting were used to elucidate interaction correlation related to circRNA, mRNA, and miRNA. HL-1 cells were used to analyze the reactive oxygen species (ROS) and apoptosis under hypoxic conditions using immunofluorescence and flow cytometry. An MI mouse model was constructed and the therapeutic effect of Exos was determined using immunohistochemistry, immunofluorescence, and ELISA. The results showed that HExos had a more pronounced treatment effect than ADSC Exos on cardiac damage amelioration after MI. NGS showed that circ-Stt3b plays a role in HExo-mediated cardiac damage repair after MI. Overexpression of circ-Stt3b decreased apoptosis, ROS level, and inflammatory factor expression in HL-1 cells under hypoxic conditions. Bioinformatics and luciferase reporting data validated miR-15a-5p and GPX4 as downstream circ-Stt3b targets. GPX4 downregulation or miR-15a-5p overexpression reversed protective effect regarding circ-Stt3b upon HL-1 cells after exposure to a hypoxic microenvironment. Overexpression of circ-Stt3b increased the treatment effect of ASDSC Exos on cardiac damage amelioration after MI. Taken together, the study results demonstrated that Exos from hypoxic pretreatment ADSCs ameliorate cardiac damage post-MI through circ-Stt3b/miR-15a-5p/GPX4 signaling activation and decreased ferroptosis., (© 2024. The Author(s).)

IL-6 signaling plays a crucial role in the survival and metastasis of skin cancer. NEDD4L acts as a suppressor of IL-6 signaling by targeting GP130 degradation. However, the effects of the NEDD4L-regulated IL-6/GP130 signaling pathway on skin cancer remain unclear. In this study, protein expression levels of NEDD4L and GP130 were measured in tumor tissues from patients with cutaneous squamous cell carcinoma. Skin tumors were induced in wild-type and Nedd4l-knockout mice, and activation of the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway was detected. The results indicated a negative correlation between the protein expression levels of NEDD4L and GP130 in cutaneous squamous cell carcinoma tissues from patients. Nedd4l deficiency significantly promoted 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin tumorigenesis and benign-to-malignant conversion by activating the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway, which was abrogated by supplementation with the GP130 inhibitor SC144. Furthermore, our findings suggested that NEDD4L can interact with GP130 and promote its ubiquitination in skin tumors. In conclusion, our results indicate that NEDD4L could act as a tumor suppressor in skin cancer, and inhibition of GP130 could be a potential therapeutic method for treating this disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Beta1-adrenergic receptor autoantibodies (β1-AAbs) promote atrial remodelling and ultimately lead to the development of atrial fibrillation (AF). Oroxin B is a natural flavonoid glycoside with a variety of biological activities, including anti-inflammatory and autophagy-promoting effects, and has therapeutic benefits for a variety of diseases. The aim of this study was to investigate the potential therapeutic role of Oroxin B in the development of β1-AAb-induced atrial fibrillation and to elucidate the underlying mechanisms involved. We established a rat model of β1-AAb-induced atrial fibrillation via active immunisation. The first stage was divided into three groups: the control group, the β1-AAb group and the β1-AAb + bisoprolol group. The second stage was divided into three groups: the control group, the β1-AAb group and the β1-AAb + Oroxin B group. Serum levels of β1-AAbs, atrial tissue levels of cyclic monophosphate (cAMP), atrial electrophysiological parameters, cardiac structure and function, mitochondrial structure, autophagy levels, cardiomyocyte apoptosis and myocardial fibrosis were examined. The results showed that bisoprolol, a β1-blocker, improved β1-AAb-induced atrial electrical remodelling, reduced atrial collagen deposition, ameliorated the increase in LAD and regulated the balance of autophagy and apoptosis in atrial myocytes through the PTEN/AKT/mTOR signalling pathway. Oroxin B, a PTEN agonist, can improve the impairment of autophagy homeostasis and apoptosis in atrial tissue by activating the PTEN/AKT/mTOR signalling pathway, thereby improving atrial structure and electrical remodelling. Moreover, Oroxin B may play a therapeutic role in β1AAb-induced atrial fibrillation. In conclusion, our results demonstrate the potential therapeutic role of Oroxin B in β1AAb-induced atrial fibrillation and the underlying mechanisms, suggesting that Oroxin B may be an effective antiarrhythmic medication., (© 2024 John Wiley & Sons Australia, Ltd.)

Background: PCOS is the most prevalent endocrine and metabolic problem in women of reproductive age. This current study was formulated to thoroughly expound the ovary-protecting effects of NOX4 deficiency in PCOS and probe into the intrinsic mechanisms underlying the protective effects of NOX4 deficiency against DHEA injury in ovarian GCs., Methods: KGN cells were subjected to 20 nM DHEA for 48 h to establish PCOS cellular model. For loss-of-function experiments, KGN cells were transfected with si-NOX4. In addition, to investigate the biological roles of ERS and PERK/ATF4 pathway in the ovary-protecting effects of NOX4 deficiency in DHEA-treated ovarian GCs, KGN cells were pretreated with ERS agonist TM or PERK agonist CCT020312., Results: NOX4 was highly expressed in DHEA-treated ovarian GCs. NOX4 deficiency improved the impaired viability, inhibited the apoptosis and suppressed autophagy of DHEA-treated ovarian GCs. Besides, NOX4 deficiency inactivated PERK/ATF4 pathway in DHEA-treated ovarian GCs. NOX4 deficiency repressed DHEA-induced ERS of ovarian GCs through inactivating PERK/ATF4 pathway. Pretreatment with ERS agonist TM or pretreatment with PERK agonist CCT020312 can both reduced the viability, promoted the apoptosis and strengthened autophagy of ovarian GCs, partially abolishing the ovary-protecting effects of NOX4 deficiency in DHEA-treated ovarian GCs. In general, NOX4 deficiency could improve the impaired viability, inhibited the apoptosis and suppressed autophagy of DHEA-treated ovarian GCs through repressing ERS depending on inactivation of PERK/ATF4 pathway., Conclusion: To conclude, downregulation of NOX4 could exert ovary-protecting effects in DHEA-induced PCOS cellular model through repressing ERS via inactivating PERK/ATF4 pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no any potential conflicts of interest that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fatty liver disease (FLD), a chronic liver disease characterized by excessive lipid deposition, is affecting more and more people worldwide owing to the increasing global incidence of obesity and heavy alcohol consumption. However, there is still no effective strategy for prevention or treatment of alcohol and high-fat diet (HFD)-induced FLD. The purpose of this study was to investigate the effect of curcumol on alcohol and HFD-induced FLD and the underlying molecular mechanisms. The results showed that curcumol ameliorated alcohol and HFD-induced hepatocyte injury in vivo and in vitro, and the mechanism might be related to its up-regulation of ceruloplasmin and subsequent alleviation of iron overload. Moreover, curcumol inhibited alcohol and HFD-induced mitochondrial damage and mtDNA release in hepatocytes by modulating iron overload. Furthermore, curcumol's inhibition of mtDNA release could suppress the activation of cGAS-STING and subsequent inflammation, and this phenomenon could be reversed by cGAS overexpression. Notably, alcohol and HFD-induced mtDNA release from hepatocytes contributed to HSC activation and this effect could be weakened by curcumol. In conclusion, these findings elucidated that curcumol ameliorated alcohol and HFD-induced FLD via modulating ceruloplasmin/iron overload/mtDNA signaling pathway, which lead to the inhibition of inflammation and HSCs activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Asthma is a complex chronic respiratory inflammatory disease affected by both genetic and environmental factors. Therefore, our study explored the influence of TRIM11 on asthma and its underlying mechanisms. Our research involved patients diagnosed with asthma and healthy volunteers recruited from our hospital. We observed a reduction in serum TRIM11 expression in asthma patients, which positively correlated with the levels of anti-IgE or IgE. Additionally, both TRIM11 mRNA and protein expression in lung tissue were diminished. The introduction of the TRIM11 gene resulted in a reduction in inflammation in an in vitro asthma model and prevented the development of asthma in a mouse model. Moreover, the TRIM11 gene exhibited a suppressive effect on Ferroptosis and mitigated ROS-induced mitochondrial damage in the asthma model. TRIM11 was found to stimulate UBE2N-TAX1BP1 signaling in the asthma model, with UBE2N being identified as the specific target for TRIM11's effects on Ferroptosis. Furthermore, TRIM11 protein interacted with UBE2N protein and facilitated the dissociation of UBE2N-UBE2N in the asthma model. In conclusion, TRIM11 plays a vital role in preventing Ferroptosis in the asthma model through UBE2N-TAX1BP1 signaling. This indicates that targeting the TRIM11 mechanism could serve as a promising strategy for anti-Ferroptosis immunotherapy in asthma treatment., (© 2024. The Author(s).)

Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. CD4 + T cell reduction is crucial to sepsis-induced immunosuppression. Pyroptosis, a programmed necrosis, is concerned with lymphocytopenia. Peroxisome proliferator-activated receptor gamma (PPARγ) regulated by upstream mTOR, exerts anti-pyroptosis effects. To investigate the potential effects of mTOR-PPARγ on sepsis-induced CD4 + T cell depletion and the underlying mechanisms, we observed mTOR activation and pyroptosis with PPARγ-Nrf suppression through cecal ligation and puncture (CLP) sepsis mouse model. Further mechanism research used genetically modified mice with T cell-specific knockout mTOR or Tuberous Sclerosis Complex1 (TSC1). It revealed that mTOR mediated CD4 + T cell pyroptosis in septic mice by negatively regulating the PPARγ-Nrf2 signaling pathway. Taken together, mTOR-PPARγ-Nrf2 signaling mediated the CD4 + T cell pyroptosis in sepsis, contributing to CD4 + T cell depletion and immunosuppression., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and capecitabine (CAP). TYMS was identified to form a complex with Polo-like Kinase 1 (PLK1) and activate the PLK1 signaling pathway. Furthermore, we revealed that the combination of the PLK1 inhibitor volasertib (BI6727) with 5-FU or CAP had a synergistic effect repressing the proliferation, migration, and autophagy of melanoma cells. Overall, our research highlights the protective role of NOD2 in melanoma and suggests that targeting NOD2 and the TYMS/PLK1 signaling axis is a high-profile therapy that could be a prospect for melanoma treatment., (© 2024. The Author(s).)

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Na Li, Mei Han, Ning Zhou, Yong Tang, Xu-Shan Tang. MicroRNA-495 Confers Increased Sensitivity to Chemotherapeutic Agents in Gastric Cancer via the Mammalian Target of Rapamycin (mTOR) Signaling Pathway by Interacting with Human Epidermal Growth Factor Receptor 2 (ERBB2). Med Sci Monit, 2018; 24: CLR5990-5972. DOI: 10.12659/MSM.909458.

Acetaminophen (APAP) overdose is a prevalent cause of clinical pharmacological liver injury worldwide. Artemether (ART), a first-line antimalarial drug, has demonstrated hepatoprotective activity. However, its effect on APAP-induced acute liver injury (AILI) remains unclear. In this study, we investigated whether ART can protect against AILI and examined its underlying mechanisms. In vivo, ART mitigated APAP-induced liver histological changes, including mitochondrial damage, hepatocyte necrosis, hepatocyte apoptosis, and inflammatory infiltration. Additionally, ART reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in APAP-induced mice. ART also activated the Nrf2-HO-1/GPX4 signaling pathway, exerting antioxidant effects in both in vitro and in vivo models of AILI. To confirm Nrf2 as a target of ART in vivo, we pretreated C57BL/6 mice with the Nrf2 inhibitor, ML385. The results indicated that inhibiting Nrf2 diminishes the protective effect of ART against AILI. Overall, our findings suggest that ART's protective effect against AILI is mediated through the Nrf2-related antioxidant pathway., Competing Interests: Declaration of Competing Interest All authors disclosed no relevant relationships, (Copyright © 2024. Published by Elsevier Masson SAS.)

Acovenosigenin A β-glucoside (AAG) is a cardiac glycoside derived from Streptocaulon juventas (Lour.) Merr, which exhibited the potential in treating lung cancer in our previous research. However, the action mechanism remains unclear. In this research, JAK2-STAT3 signaling pathway was predicted to be the critical regulation pathway based on the integrative analysis of transcriptome and proteome. Western blotting and qPCR assays were performed to identify that AAG can regulate JAK2-STAT3 signaling pathway and its downstream genes, such as c-Myc, Survivin, Cyclin B1, CDK1, Bcl-2. And this action of AAG depended on the suppression of STAT3 phosphorylation and its nuclear translocation through the experiments of Immunofluorescence, transient transfection and cryptotanshinone treatment. Additionally, AAG was discovered to mediate the JAK2-STAT3 pathway in IL-6-driven A549 and H460 cells, which in turn inhibited cell proliferation, promoted mitochondria-related apoptosis, and arrested the cell cycle progression. By molecular docking analysis, CETSA and SIP experiments, the protein of GP130 was identified as the specific target of AAG in A549 and H460 cells. Further studies suggested that AAG inhibited JAK2-STAT3 pathway and its downstream genes by targeting GP130 in nude mice xenograft model in vivo. This research presented that AAG exhibits the promising potential in the treatment of NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Twelve polyphenol derivatives were obtained in a protective activity-guided isolation from the Portulaca oleracea L. extract on a cell model of human umbilical vein endothelial cells (HUVECs) under diethylhexyl phthalate (DEHP) exposure. Among them, methyl (3,4,5-trimethoxybenzoyl) valylprolinate (PP-10) performed the most protective activity and inhibited DEHP exposure-induced HUVECs' apoptosis. PP-10 also inhibited the DEHP-induced inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-8) and adhesion molecule (ICAM-1 andVCAM-1) overexpression. Furthermore, DEHP-induced NLRP3 inflammasomes' and NF-κB signaling pathway activation was significantly inhibited after the PP-10 treatments. Of note, the current results suggest the potential application of Portulaca oleracea L. and PP-10 in the prevention of DEHP-induced inflammatory damages in HUVECs.

T-2 toxin is one of the mycotoxins widely distributed in human food and animal feed. Our recent work has shown that microglial activation may contribute to T-2 toxin-induced neurotoxicity. However, the molecular mechanisms involved need to be further clarified. To address this, we employed high-throughput transcriptome sequencing and found altered B cell translocation gene 2 (BTG2) expression levels in microglia following T-2 toxin treatment. It has been shown that altered BTG2 expression is involved in a range of neurological pathologies, but whether it's involved in the regulation of microglial activation is unclear. The aim of this study was to investigate the role of BTG2 in T-2 toxin-induced microglial activation. The results of animal experiments showed that T-2 toxin caused neurobehavioral disorders and promoted the expression of microglial BTG2 and pro-inflammatory activation of microglia in hippocampus and cortical, while microglial inhibitor minocycline inhibited these changes. The results of in vitro experiments showed that T-2 toxin enhanced BTG2 expression and pro-inflammatory microglial activation, and inhibited BTG2 expression weakened T-2 toxin-induced microglial activation. Moreover, T-2 toxin activated PI3K/AKT and its downstream NF-κB signaling pathway, which could be reversed after knock-down of BTG2 expression. Meanwhile, the PI3K inhibitor LY294002 also blocked this process. Therefore, BTG2 may be involved in T-2 toxin's ability to cause microglial activation through PI3K/AKT/NF-κB pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe 2+ , and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe 2+ content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice., (© 2024 The Author(s). Molecular Carcinogenesis published by Wiley Periodicals LLC.)

As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD + and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD + /AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD + and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD + /AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.

Feline infectious peritonitis (FIP), a serious infectious disease in cats, has become a challenging problem for pet owners and the industry due to the lack of effective vaccinations and medications for prevention and treatment. Currently, most natural compounds have been proven to have good antiviral activity. Hence, it is essential to develop efficacious novel natural compounds that inhibit FIPV infection. Our study aimed to screen compounds with in vitro anti-FIPV effects from nine natural compounds that have been proven to have antiviral activity and preliminarily investigate their mechanisms of action. In this study, the CCK-8 method was used to determine the maximum noncytotoxic concentration (MNTC), 50% cytotoxic concentration (CC 50 ), and 50% effective concentration (EC 50 ) of natural compounds on CRFK cells and the maximum inhibition ratio (MIR) of the compounds inhibit FIPV. The effect of natural compounds on FIPV-induced apoptosis was detected via Annexin V-FITC/PI assay. Network pharmacology (NP), molecular docking (MD), and 4D label-free quantitative (4D-LFQ) proteomic techniques were used in the joint analysis the mechanism of action of the screened natural compounds against FIPV infection. Finally, Western blotting was used to validate the analysis results. Among the nine natural compounds, baicalin had good antiviral effects, with an MIR > 50% and an SI > 3. Baicalin inhibited FIPV-induced apoptosis. NP and MD analyses showed that AKT1 was the best target of baicalin for inhibiting FIPV infection. 4D-LFQ proteomics analysis showed that baicalin might inhibit FIPV infection by modulating the PI3K-AKT pathway and the apoptosis pathway. The WB results showed that baicalin promoted the expression of EGFR, PI3K, and Bcl-2 and inhibited the expression of cleaved caspase 9 and Bax. This study found that baicalin regulated the PI3K-AKT pathway and the apoptosis pathway in vitro and inhibited FIPV-induced apoptosis, thus exerting anti-FIPV effects.

Cisplatin (CDDP) is extensively utilized in the management of diverse types of cancers, but its ototoxicity cannot be ignored, and clinical interventions are not ideal. Histidine decarboxylase (HDC) is the exclusive enzyme for histamine synthesis. Anti-histamine receptor drugs are ubiquitously employed in the therapeutics of allergies and gastrointestinal diseases. Yet, the specific role of histamine and its signaling in the inner ear is not fully understood. This study utilized cisplatin treated mice and HEI-OC1 auditory hair cell line to establish a cisplatin-induced ototoxicity (CIO) model. Histidine decarboxylase knockout (HDC -/- ) mice and histamine receptor 1 (H 1 R) antagonist were utilized to investigate the influence of HDC/histamine/H 1 R signaling on ototoxicity. The results identified HDC and H 1 R expression in mouse hair cells. Transcriptomics indicated that the expression levels of oxidative stress-related genes in the cochlea of HDC -/- mice increased. Furthermore, histamine deficiency or suppression of H 1 R signaling accelerated HC ferroptosis, a pivotal factor underlying the aggravation of CIO in vivo and in vitro, conversely, the supplementation of exogenous histamine reversed these deleterious effects. Mechanistically, this study revealed that the malfunction of HDC/histamine/H 1 R signaling induced upregulation of NRF2 expression, accompanied by the upregulation of ACSL4 and downregulation of GPX4 expression, which are major regulatory factors of ferroptosis. In summary, histamine deficiency may induce hair cell death by regulating the H 1 R pathway and exacerbate CIO. Our findings have indicated a potential therapeutic target for CIO., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus, and Prolyl 4-Hydroxylase Subunit Beta (P4HB) expression is increased in high glucose (HG)-induced renal tubular epithelial cells (TECs). But it's role in HG-induced TECs remains to be elucidated., Methods: The HK-2 cells were induced using HG and transfected with SiRNA-P4HB. DCFH-DA staining was utilized for the detection of cellular levels of ROS. WB and immunofluorescence were utilized to detect the expression of P4HB, epithelial-mesenchymal transition (EMT), fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells. Online databases were utilized for predicting the interaction target of P4HB, and immunoprecipitation (IP) experiments were employed to validate the binding of P4HB with the target. SiRNA and overexpression vectors of target gene were used to verify the mechanism of action of P4HB., Results: HG induced an increase in the expression of P4HB and TGFβ, p-SMAD3, and ROS in HK-2 cells. Furthermore, HG downregulated the expression of E-cadherin and upregulated the expression of N-cadherin, Vimentin, α-SMA, Fibronectin, Collagen IV, SNAIL, and SLUG in HK-2 cells. Interfering with P4HB significantly reversed the expression of these proteins. Database predictions and IP experiments showed that P4HB interacts with PRMT1, and the expression of PRMT1 was increased in HG-induced HK-2 cells. Interfering with PRMT1 inhibited the changes in expression of EMT and fibrosis related proteins induced by HG. However, overexpression of PRMT1 weakened the regulatory effect of P4HB interference on the EMT, fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells., Conclusion: P4HB regulated the TGFβ/SMAD3 signaling pathway through PRMT1 and thus participates in HG-induced EMT and fibrosis in HK-2 cells., (© 2024. The Author(s).)

Objective: Esophageal squamous cell carcinoma (ESCC) is commonly diagnosed with high mortality worldwide. Cell proliferation and cell apoptosis are essential biological processes for the development of cancers. MiR-16-5p, a critical member of miRNAs family, is involved in cell apoptosis and tumor progression. However, the role of miR-16-5p in regulating esophageal squamous cell carcinoma and the underlying mechanism remain unclear., Methods: In this study, we used human ESCC tissue samples and human esophageal cells to determine the expression level of miR-16-5p in ESCC tissues and cells. Cell Counting Kit-8 assay and flow cytometry were used to test cell proliferation and apoptosis. Western blotting was used to detect protein expression levels. The scratch assay was used to analyze the level of cell migration, and the transwell assay was used to analyze the invasive ability of tumor cells., Results: The expression of miR-16-5p was up-regulated in ESCC tissues and cells. Knockdown of miR-16-5p significantly inhibited cell proliferation and promoted cell apoptosis. The knockdown of miR-16-5p also restrained cell migration and invasion. We revealed that AMPK/mTOR signaling pathway participated in the regulation of ESCC progression., Conclusion: miR-16-5p may promote the proliferation, migration, and invasion of ESCC through modulating AMPK/mTOR signaling pathway., (© 2024 by the Association of Clinical Scientists, Inc.)

The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yes‑associated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1‑targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.

Drug resistance is a key factor underlying the failure of tumor chemotherapy. It enhances the stem‑like cell properties of cancer cells, tumor metastasis and relapse. Luteolin is a natural flavonoid with strong anti‑tumor effects. However, the mechanism(s) by which luteolin protects against paclitaxel (PTX)‑resistant cancer cell remains to be elucidated. The inhibitory effect of luteolin on the proliferation of EC1/PTX and EC1 cells was detected by cell counting kit‑8 assay. Colony formation and flow cytometry assays were used to assess clonogenic capacity, cell cycle and apoptosis. Wound healing and Transwell invasion tests were used to investigate the effects of luteolin on the migration and invasion of EC1/PTX cells. Western blotting was used to detect the protein levels of EMT‑related proteins and stem cell markers after sphere formation. Parental cells and drug‑resistant cells were screened by high‑throughput sequencing to detect the differential expression of RNA and differential genes. ELISA and western blotting were used to verify the screened PI3K/Akt signaling pathway, key proteins of which were explored by molecular docking. Hematoxylin and eosin staining and TUNEL staining were used to observe tumor xenografts on morphology and apoptosis in nude mice. The present study found that luteolin inhibited tumor resistance (inhibited proliferation, induced cell cycle arrest and apoptosis and hindered migration invasion, EMT and stem cell spherification) in vitro in PTX‑resistant esophageal squamous cell carcinoma (ESCC) cells. In addition, luteolin enhanced drug sensitivity and promoted the apoptosis of drug‑resistant ESCC cells in combination with PTX. Mechanistically, luteolin may inhibit the PI3K/AKT signaling pathway by binding to the active sites of focal adhesion kinase (FAK), Src and AKT. Notably, luteolin lowered the tumorigenic potential of PTX‑resistant ESCC cells but did not show significant toxicity in vivo . Luteolin enhanced drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in PTX‑resistant ESCC and could be a promising agent for the treatment of PTX‑resistant ESCC cancers.

Retinopathy of prematurity (ROP) is a retinal disease-causing retinal neovascularization that can lead to blindness. Oxygen-induced retinopathy (OIR) is a widely used ROP animal model. Icariin (ICA) has anti-oxidative and anti-inflammation properties; however, whether ICA has a regulatory effect on OIR remains unclear. In this study, ICA alleviated pathological neovascularization, microglial activation and blood-retina barrier (BRB) damage in vivo. Further results indicated that endothelial cell tube formation, migration and proliferation were restored by ICA treatment in vitro. Proteomic microarrays and molecular mimicry revealed that ICA can directly bind to hexokinase 2 (HK2) and decrease HK2 protein expression in vivo and in vitro. In addition, ICA inhibited the AKT/mTOR/HIF1α pathway activation. The effects of ICA on pathological neovascularization, microglial activation and BRB damage disappeared after HK2 overexpression in vivo. Similarly, the endothelial cell function was revised after HK2 overexpression. HK2 overexpression reversed ICA-induced AKT/mTOR/HIF1α pathway inhibition in vivo and in vitro. Therefore, ICA prevented pathological angiogenesis in OIR in an HK2-dependent manner, implicating ICA as a potential therapeutic agent for ROP., (© 2024 John Wiley & Sons Ltd.)

Objective: The objective of this study was to examine the potential of USP7 as a target for senolytic therapy and to investigate the molecular mechanism by which its inhibitor selectively induced apoptosis in senescent HDF and enhanced DFU wound healing., Methods: Clinical samples of DFU were collected to detect the expression of USP7 and aging-related proteins using immunohistochemistry and Western blot. In addition, β-galactosidase staining, qPCR, flow cytometry, ROS and MMP kits, and Western blot were used to analyze the biological functions of P5091 on senescence, cycle, and apoptosis. RNAseq was employed to further analyze the molecular mechanism of P5091. Finally, the DFU rat model was established to evaluate the effect of P5091 on wound healing., Results: The expression of USP7 and p21 were increased in DFU clinical samples. After treatment with d-glucose (30 mM, 7 days), β-galactosidase staining was deepened, proliferation rate decreased. USP7 inhibitors (P5091) could reduce the release of SASP factors, activate the production of ROS, and reduce MMP. In addition, it induced apoptosis and selectively clears senescent cells through the p53 signaling pathway. Finally, P5091 can improve diabetic wound healing in rats., Conclusion: This study clarified the molecular mechanism of USP7 inhibitor (P5091) selectively inducing apoptosis of high glucose senescent HDF cells. This provides a new senolytics target and experimental basis for promoting DFU wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), which accounts for approximately one-fifth of all BCs, are highly invasive with a high rate of recurrence and a poor prognosis. Several studies have shown that growth factor receptor-bound protein 7 (GRB7) might be a potential therapeutic target for tumor diagnosis and prognosis. Nevertheless, the role of GRB7 in HER2+ BC and its underlying mechanisms have not been fully elucidated. The aim of this study was to investigate the biological function and regulatory mechanism of GRB7 in HER2+ BC., Methods: Bioinformatics analysis was performed using the TCGA, GEO and CancerSEA databases to evaluate the clinical significance of GRB7. RT quantitative PCR, western blot and immunofluorescence were conducted to assess the expression of GRB7 in BC cell lines and tissues. MTT, EdU, colony formation, wound healing, transwell, and xenograft assays were adopted to explore the biological function of GRB7 in HER2+ BC. RNA sequencing was performed to analyze the signaling pathways associated with GRB7 in SK-BR-3 cells after the cells were transfected with GRB7 siRNA. Chromatin immunoprecipitation analysis (ChIP) and luciferase reporter assay were employed to elucidate the potential molecular regulatory mechanisms of GRB7 in HER2+ BC., Results: GRB7 was markedly upregulated and associated with poor prognosis in BC, especially in HER2+ BC. Overexpression of GRB7 increased the proliferation, migration, invasion, and colony formation of HER2+ BC cells, while depletion of GRB7 had the opposite effects in HER2+ BC cells and inhibited xenograft growth. ChIP-PCR and luciferase reporter assay revealed that TCF12 directly bound to the promoter of the GRB7 gene to promote its transcription. GRB7 facilitated HER2+ BC epithelial-mesenchymal transition (EMT) progression by interacting with Notch1 to activate Wnt/β-catenin pathways and other signaling (i.e., AKT, ERK). Moreover, forced GRB7 overexpression activated Wnt/β-catenin to promote EMT progression, and partially rescued the inhibition of HER2+ BC proliferation, migration and invasion induced by TCF12 silencing., Conclusions: Our work elucidates the oncogenic role of GRB7 in HER2+ BC, which could serve as a prognostic indicator and promising therapeutic target., (© 2024. The Author(s).)