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Objective: This study aimed to analyze the impact of HGF on cardiomyocyte injury, apoptosis, and inflammatory response induced by lipopolysaccharide (LPS)., Methods: Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify the levels of HGF, interleukin (IL)-6, IL-10, creatine phosphokinase-isoenzyme-MB (CK-MB), and cardiac troponin I (cTnI) in the samples. qPCR and Western blotting (WB) were employed to assess the mRNA and protein expressions of HGF, IL-10, IL-6, PI3K, AKT, p-PI3K, and p-AKT., Results: The outcomes of the in vivo experiment revealed that serum levels of IL-6, IL-10, HGF and SOFA scores in the SC group were elevated in contrast to the non-SC group. The correlation analysis indicated a substantial and positive association among serum HGF, IL-6, and IL-10 levels and SOFA scores. Relative to IL-6, IL-10 levels, and SOFA scores, serum HGF demonstrated the highest diagnostic value for SC. Following LPS administration to stimulate H9c2 cells across various periods (0, 12, 24, 48, and 72 h), the levels of myocardial injury markers (CK-MB and cTnI) in the cell supernatants, intracellular inflammatory factors (mRNA and protein levels of IL-10 and IL-6), apoptosis and ROS levels, exhibited a gradual increase followed by a subsequent decline. Following the overexpression of HGF, there was an increase in cell viability, and a decrease in apoptosis, inflammation, oxidative stress injuries, and the protein phosphorylation expressions of PI3K and AKT. After knockdown of HGF expression, the activity of LPS-induced H9c2 cells was further reduced, leading to increased cell injury, apoptosis, inflammation, oxidative stress,and the expression levels of PI3K and Akt protein phosphorylation were further elevated., Conclusion: HGF was associated with decreased LPS-induced H9c2 apoptosis and inflammation in H9c2 cells, alongside an improvement in cell viability, indicating potential cytoprotective effects. The mechanism underlying these impacts may be ascribed to the suppression of the PI3K/AKT signaling 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 Elsevier B.V. All rights reserved.)

There is an association between noise exposure and cognitive impairment, and noise may have a more severe impact on patients with Alzheimer's disease (AD) and mild cognitive impairment; however, the mechanisms need further investigation. This study used the classic AD animal model APP/PS1 mice to simulate the AD population, and C57BL/6J mice to simulate the normal population. We compared their cognitive abilities after noise exposure, analyzed changes in Cluster of Differentiation (CD) between the two types of mice using transcriptomics, identified the differential CD molecule: CD36 in APP/PS1 after noise exposure, and used its pharmacological inhibitor to intervene to explore the mechanism by which CD36 affects APP/PS1 cognitive abilities. Our study shows that noise exposure has a more severe impact on the cognitive abilities of APP/PS1 mice, and that the expression trends of differentiation cluster molecules differ significantly between C57BL/6J and APP/PS1 mice. Transcriptomic analysis showed that the expression of CD36 in the hippocampus of APP/PS1 mice increased by 2.45-fold after noise exposure (p < 0.001). Meanwhile, Western Blot results from the hippocampus and entorhinal cortex indicated that CD36 protein levels increased by approximately 1.5-fold (p < 0.001) and 1.3-fold (p < 0.05) respectively, after noise exposure in APP/PS1 mice. The changes in CD36 expression elevated oxidative stress levels in the hippocampus and entorhinal cortex, leading to a decrease in PI3K/AKT phosphorylation, which in turn increased M1-type microglia and A1-type astrocytes while reducing the numbers of M2-type microglia and A2-type astrocytes. This increased neuroinflammation in the hippocampus and entorhinal cortex, causing synaptic and neuronal damage in APP/PS1 mice, ultimately exacerbating cognitive impairment. These findings may provide new insights into the relationship between noise exposure and cognitive impairment, especially given the different expression trends of CD molecules in the two types of mice, which warrants further research., 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.)

Acetaminophen (APAP) overdose is still a leading cause of drug-induced liver injury (DILI), accompanied with severe inflammatory response. However, the therapy for APAP-induced DILI is rather limited. The combined application of natural products to treat DILI induced by APAP may be a new direction of the research. This study was conducted to evaluate the dual anti-inflammatory activity of curcumin (CUR) combined with berberine (BBR) against APAP-mediated DILI. Network pharmacology found that PI3K-Akt and PPAR signaling pathways were primarily involved in anti-DILI of the combination of CUR and BBR. APAP injection enhanced the levels of ALT, AST, IL-1β, IL-6, and TNF-α in mice, while such phenomenon was significantly reversed by the cotreatment of CUR and BBR, which was more effective than either single treatment. The increase of p-NF-κB and p-IKKα/β protein expression and the decrease of p-PI3K, p-AKT, and PPARγ protein expression in APAP-treated mice were markedly inhibited by the coadministration of CUR and BBR. Molecular docking further demonstrated that both CUR and BBR could stably bind to PI3K, AKT, and PPARγ protein. In conclusion, the combination of CUR and BBR more effectively protected liver from APAP-triggered DILI than individual treatment. The mechanism is to alleviate hepatic inflammation by inhibiting NF-κB activation, which is possibly mediated by PI3K/Akt and PPARγ signaling pathways., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a challenging condition to treat with myocardial fibrosis being a pivotal pathological component. Previous studies have suggested a role for inducible nitric oxide synthase (iNOS) in the progression of this condition, but the precise mechanisms remain unclear. This study aimed to investigate the role of iNOS in HFpEF-related myocardial fibrosis and identify potential therapeutic targets., Methods: A 'two-hit' mouse model of HFpEF was established, and echocardiography, histopathology and biochemical analyses were performed. In vitro experiments were conducted in mouse cardiac fibroblasts, with iNOS overexpression and application of iNOS or phosphatidylinositol 3 kinase (PI3K) inhibitors. The iNOS-S-nitrosylated phosphatase and TENsin homolog (SNO-PTEN)-phosphorylated-protein kinase B (p-AKT) pathway was investigated, along with the effects on fibrotic markers and cell proliferation and migration., Results: HFpEF mice exhibited significant cardiac dysfunction and fibrosis, with increased expression of iNOS, SNO-PTEN, and p-AKT, indicative of the activation of the iNOS-SNO-PTEN-p-AKT pathway. iNOS overexpression in mouse cardiac fibroblasts led to increased SNO-PTEN, decreased PTEN, activated phosphorylated PI3K (p-PI3K) and p-AKT, and enhanced cell proliferation and migration, as well as increased collagen I and III expression. The use of an iNOS inhibitor (L-NIL) or a PI3K inhibitor (LY294002) partially reversed these changes., Conclusion: Our findings suggest that the iNOS-SNO-PTEN-p-AKT pathway may play a crucial role in HFpEF-related myocardial fibrosis, with iNOS and PI3K inhibitors offering potential therapeutic benefits. These insights may pave the way for the development of effective drug therapies for HFpEF., 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. The authors report no conflicts of interest in this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In vitro studies have revealed that hepatitis B virus (HBV) infection upregulates interleukin-8 (IL-8), which enhances HBV replication. Clinically, elevated IL-8 levels in chronic HBV patients are associated with diminished therapeutic efficacy of interferon-α (IFN-α). Our study advances these findings by demonstrating that IL-8 promotes the expression of myxovirus resistance A (MxA) and protein kinase R (PKR) in HepG2 cells via the PI3K-AKT pathway. However, HBV-infected cells fail to exhibit IL-8-induced upregulation of MxA and PKR, likely due to HBV's upregulation of PP2A that inhibits the PI3K-AKT pathway. Notably, IL-8 targets the C/EBPα transcription factor, increasing HBV promoter activity and viral replication, which in turn partially suppresses the expression of MxA and PKR induced by IFN-α. Our findings uncover a mechanism by which HBV may evade immune responses, suggesting potential new strategies for immunotherapy against chronic HBV infection., 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.)

The biological role and precise molecular mechanisms of Notch receptor 3 (NOTCH3) in the malignant progression of bladder cancer (BLCA) remain unclear. In this study, we found that NOTCH3 was significantly upregulated and associated with poor prognosis in BLCA patients. Functional experiments demonstrated that NOTCH3 knockdown inhibited BLCA cell proliferation, migration, invasion and significantly suppressed tumor growth and metastasis in vivo as well. Mechanically, chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that NOTCH3 could promote the transcription of secreted phosphoprotein 1 (SPP1), a potential downstream target gene of NOTCH3, by binding to the CSL elements in the SPP1 promoter. Moreover, we also found that targeting NOTCH3 inhibited BLCA growth and metastasis by suppressing the SPP1-PI3K/AKT axis. Our study highlights the critical role of NOTCH3-SPP1-PI3K/AKT axis in the malignant progression of BLCA, suggesting that NOTCH3 may be a potential therapeutic target for BLCA., Competing Interests: Competing interests The authors declare no competing interests. Ethical Approval and Consent to Participate The study was carried out in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all subjects. This study was approved by Ethics Committee of Affiliated Hospital of Qingdao University., (© 2024. The Author(s).)

Background: Herbacetin, a flavonol abundant in traditional medicines, is documented as an anti-inflammatory agent. However, information regarding its attributes on lipopolysaccharide (LPS)-induced inflammatory immunopathies has not been delineated yet. The present study aimed to comprehend herbacetin effects on LPS-induced aspects of unwarranted, non-resolving inflammation, particularly via targeting the vicious circle of oxi-inflammatory stress, autophagy-apoptosis, macrophages polarization, impaired inflammasome activation, and inflammatory cascades., Methods and Results: In-vitro model of LPS-stimulated RAW 264.7 macrophage was recapitulated to investigate different inflammatory anomalies using enzyme-linked immunosorbent assay, qRT-PCR (Real-Time Quantitative Reverse Transcription PCR), immunoblotting. Concanavalin A challenged splenocytes and in silico studies were performed to measure Tregs population and binding affinity, respectively., Results: Herbacetin administration caused remarkable reduction in nitric oxide, reactive oxygen species, mitochondrial membrane potential hyperpolarization, tumor necrosis factor-α, interferon-γ, interleukin-6, inducible nitric oxide synthase and ratio of M1/M2 markers (inducible nitric oxide synthase/arginase-1/macrophage scavenger receptor-1/mannose receptor C type-1) in in vitro model of persistent inflammation. Suppression of interleukins-5,17 and matrix metalloproteinases-2,3,9,13 and proliferating cell nuclear antigen, signifies its anti-inflammatory attributes. Noticeable decline in monodansylcadaverine-Lysotracker staining, caspase-6, and enhanced p62, B-cell lymphoma-2 expression indicates apoptosis-autophagosome accumulation inhibition and lysosomal destabilization. These were accompanied by reduced NLRP3 activation, caspase-1, AIM-2 expression, and interleukin-1β release. Subsequently, up-regulated activation of TLR-4, NF-κB, PI3K, Akt, ERK1/2, and JNK was decisively thwarted by herbacetin. In silico investigation signified the interaction of herbacetin with these targets. Decreased cytokines and enhanced Tregs conferred its role in extenuating inflammation facilitated by T-cells depletion., Conclusion: Collectively, these findings comprehend attributes of herbacetin as an alternative therapeutic strategy in relieving LPS-associated chronic inflammatory disorders., Competing Interests: Declarations Research involving human participants and/or animals All animal experiment procedures were approved by Institutional Animal Ethics Committee (IAEC) of CSIR-IHBT Palampur with Approval no. IAEC/IHBT/P-5/April 2021. Informed consent All authors confirm their contribution to the manuscript. Human participants were not involved in the study; thus patient informed consent was not required. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Cancer progression is primarily driven by the uncontrolled activation of cellular signaling pathways, with the PI3K/Akt/mTOR (PAMT) pathway playing a central role. This pathway significantly contributes to the proliferation and survival of cancer cells, and its hyperactivity is a major challenge in managing several types of malignancies. This article delves into the promising potential of carotenoids, natural pigments found in abundance in fruits and vegetables, as a novel therapeutic strategy for cancer treatment. By specifically targeting and inhibiting the PAMT pathway, carotenoids may effectively disrupt the growth and survival of cancer cells. The article examines the complex mechanisms underlying these interactions and highlights the obstacles faced in cancer treatment. It proposes a compelling approach to developing therapies that leverage natural products to target this critical pathway, offering a fresh perspective on cancer treatment. Further research is essential to enhance the therapeutic efficacy of these compounds., Competing Interests: Declarations Conflict of interest The authors declare no competing interests. Ethical approval Not applicable. Consent to Participate Not applicable. Consent for Publication Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Angiogenesis following cerebral ischemia is crucial for restoring blood supply to the ischemic region. Extracellular vesicles (EVs) derived from endothelial progenitor cells (EPCs) offer potential therapeutic benefits in the treatment of cerebral ischemia. Houshiheisan (HSHS) has been shown to improve clinical outcomes in ischemic stroke patients, reduce cerebral ischemic damage in rats, and protect endothelial cells. However, the potential effects of HSHS-modified EPC-derived EVs (EVs HSHS ) for cerebral ischemia remain unexplored. This study investigated the impact of EVs HSHS on angiogenesis using rats with permanent middle cerebral artery occlusion (pMCAO) and brain microvascular endothelial cells (BMECs) subjected to oxygen-glucose deprivation (OGD). Results demonstrated that EVs HSHS promoted the proliferation, migration, and tube formation of BMECs in vitro. In vivo, high doses of EVs HSHS exhibited better performance than equivalent doses of unmodified EPC-derived EVs in reducing cerebral infarction volume, improving cortical blood perfusion, decreasing neurological deficit scores, and increasing cortical microvessel density at day 7 post-modeling. The pro-angiogenic effects of EVs HSHS following cerebral ischemia were associated with the regulation of miR-126 and the PIK3R2/PI3K/AKT pathway., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The SH2-containing inositol 5'-phosphatase SHIP2 plays a crucial role in negative regulation of the PI3K/AKT signaling pathway. Putative small molecule inhibitors of SHIP2, AS1949490 and K149 have been reported to elicit a range of beneficial effects in treating or preventing obesity as well as killing cancer cells. However, whether these effects are direct results of SHIP2 inhibition has not been carefully assessed, e.g., in the absence of expression of the protein. Here, we show that these inhibitors alter the PI3K/AKT signaling pathway irrespective of SHIP2 protein expression. Moreover, we found that AS1949490 and K149 alter cell growth in normal and cancer cells lacking both SHIP1 and SHIP2. Overall, our data provide evidence that the antiproliferative effects of AS1949490 and K149 cannot be attributed to SHIP1/2 inhibition., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Huperzine A (Hup A), an extract from Huperzia serrata, exerted its anti-inflammation and anti-oxidation effect to protect against neurodegenerative disorders and organ injury. Ferroptosis was indicated to involve in the development of acute lung injury (ALI) accompanying by lipid reactive oxygen species (ROS) overexpressed. However, there is little research focused on the protective effect of Hup A on ALI, and the underlying molecular mechanism remains elusive. This study aims to determine the therapeutic effect of Hup A on ALI in vivo and in vitro. Hup A attenuated lung injury and cellular damage in lipopolysaccharide-induced ALI (LPS-ALI) models, both in vivo and in vitro, accompanied by the upregulation of ferroptosis-associated proteins (SLC7A11 and GPX4). Furthermore, the pretreatment with Hup A decreased the abundance of inflammation factors (IL-6, TNF-α), MDA, lipid ROS, and Fe 2+ in the LPS-ALI model, while it also promoted the secretion of SOD and GSH to antagonize peroxidation. Mechanistically, RNA sequencing and network pharmacological analysis synergistically revealed the PI3K/Akt signaling pathway as a potential target of Hup A. In vitro experiments demonstrated that Hup A effectively activated GPX4 through the PI3K/Akt signaling pathway, which was subsequently reversed by LY294002, an inhibitor of the PI3K/Akt signaling pathway. Consequently, our results revealed that Hup A inhibited ferroptosis in LPS-ALI by activating the PI3K-Akt signaling pathway which indicated the potential therapeutical effect of Hup A and further emphasized the pivotal role of ferroptosis in ALI., 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: Laryngocarcinoma is a common malignancy in the upper respiratory tract. Enabled homolog (ENAH) is an actin-binding protein that is associated with the development of various cancers. However, its role and mechanism in laryngocarcinoma remain unknown., Methods: The ENAH level in laryngocarcinoma was examined in silico, in vitro and in vivo. The prognostic analysis of the ENAH level was assessed on laryngocarcinoma patients. Gain- and loss-of-function assays were conducted in AMC-HN-8 and TU686 cells. Sh-ENAH-containing AMC-HN-8 cells were implanted into naked mice. The role and mechanism of ENAH in laryngocarcinoma were investigated by CCK-8, transwell, immunofluorescence, dual luciferase, RT-qPCR, immunohistochemistry, and western blotting experiments., Results: The ENAH level was upregulated in laryngocarcinoma, which predicted a poor prognosis in laryngocarcinoma patients. Gain- and loss-of-function results showed that ENAH promoted proliferation, invasion and EMT of laryngocarcinoma cells. Moreover, ENAH was transcriptionally activated by YY1, and YY1/ENAH axis enhanced these malignant progresses of laryngocarcinoma cells. Besides, ENAH activated the PI3K/AKT pathway, and 740Y-P abolished the accelerative role of ENAH in proliferation, invasion and EMT of laryngocarcinoma cells. Furthermore, knockdown of ENAH reduced tumor size and weight, and the expression level of vimentin and PI3K/AKT pathway in tumor-bearing mice., Conclusion: ENAH transcriptionally activated by YY1 promotes cell growth, invasion and EMT of laryngocarcinoma through the activation of PI3K/AKT signaling., Competing Interests: Declaration of competing interest The authors allege no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC 50 value of 0.68 μM, outperforming the lead compound PAB (IC 50  = 5.44 μM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis., 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 Masson SAS. All rights reserved.)

Background: Inhibiting PI3K/AKT pathway activation may hinder the occurrence and progression of cancer. The aim of this study was to evaluate the efficacy and safety of the PI3K/AKT inhibitors and determine the most appropriate inhibitor for different cancer types., Methods: Electronic databases up to June 2024 were used to examine the efficacy and safety of PI3K inhibitors (alpelisib, copanlisib, duvelisib, and idelalisib) and AKT inhibitors (capivasertib, ipatasertib and MK-2206) for the treatment of cancer. Data was assessed with a random-effect pairwise and network meta-analysis. Randomized controlled trials and retrospective studies were eligible if they compared PI3K or AKT inhibitors with non-PI3K/AKT controls with no restriction., Results: The results were based on 34 studies from 34 published articles and 6 online registration trials (6710 patients). According to pairwise meta-analysis, PI3K/AKT inhibitors showed to be highly effective, especially for treating mutant cancers, but had poor safety profiles. According to our network meta-analysis, PI3K/AKT inhibitors, especially the AKT inhibitor capivasertib, are effective for treating solid cancers such as breast cancer (BC). Moreover, PI3K inhibitors, especially idelalisib, were effective for treating hematologic cancers such as chronic lymphocytic leukemia (CLL)., Conclusions: The PI3K/AKT inhibitors are effective in patients with genetic mutations. For solid cancers such as BC, capivasertib was efficacy and safety. For hematological cancers represented by CLL, idelalisib was efficacy and safety. The above studies can be used when recommending appropriate targeted therapies for patients with different cancer types., Competing Interests: Declaration of competing interest The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Warburg effect occurs both in cancer cells and in inflammatory macrophages. The aim of our work was to demonstrate the role of PI3K-Akt-mTOR axis in the Warburg effect in HL-60 derived, rat peritoneal and human blood macrophages and to investigate the potential of selected inhibitors of this pathway to antagonize it. M1 polarization in HL-60-derived and human blood monocyte-derived macrophages was supported by the increased expression of NOS2 and inflammatory cytokines. All M1 polarized and inflammatory macrophages investigated expressed higher levels of HIF-1α and NOS2, which were reduced by selected kinase inhibitors, supporting the role of PI3K-Akt-mTOR axis. Using Seahorse XF plates, we found that in HL-60-derived and human blood-derived macrophages, glucose loading reduced oxygen consumption (OCR) and increased glycolysis (ECAR) in M1 polarization, which was antagonized by selected kinase inhibitors and by dichloroacetate. In rat peritoneal macrophages, the changes in oxidative and glycolytic metabolism were less marked and the NOS2 inhibitor decreased OCR and increased ECAR. Non-mitochondrial oxygen consumption and ROS production were likely due to NADPH oxidase, expressed in each macrophage type, independently of PI3K-Akt-mTOR axis. Our results suggest that inflammation changed the metabolism in each macrophage model, but a clear relationship between polarization and Warburg effect was confirmed only after glucose loading in HL-60 and human blood derived macrophages. The effect of kinase inhibitors on Warburg effect was variable in different cell types, whereas dichloroacetate caused a shift toward oxidative metabolism. Our findings suggest that these originally anti-cancer inhibitors may also be candidates for anti-inflammatory therapy., 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 B.V. All rights reserved.)

Uterine inflammation affects 8% of women in the United States and 32% in developing nations, often caused by uncontrolled inflammation and oxidative stress. This condition significantly impacts women's health, productivity, and quality of life, and increases the risk of related morbidities leading to higher healthcare costs. Research now focuses on natural antioxidants and anti-inflammatory, particularly berberine (BBR), an isoquinoline alkaloid known for its antioxidant, anti-inflammatory, and antiapoptotic activities. The present study sought to examine the potential therapeutic efficacy of BBR against uterine inflammation induced by the intrauterine infusion of an iodine (I 2 ) mixture in an experimental setting. Female Sprague Dawley rats (n = 6) were divided into five groups, control, sham, I 2 , I 2 and BBR 10 mg/kg, and I 2 and BBR 25 mg/kg-treated groups. Compared to I 2 infusion, BBR treatment effectively restored normal uterine histopathology and reduced inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor- kappa B (NF-κB), monocyte chemoattractant protein 1 (MCP1), and myeloperoxidase (MPO). It lowered oxidative markers like malondialdehyde (MDA), and increased antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). It balanced apoptotic genes by upregulating B-cell lymphoma 2 (Bcl-2) and downregulating Bcl-2-associated X protein (Bax). Furthermore, BBR reduced the expression of Toll-like receptor 2 (TLR-2), phosphorylated phosphatidylinositol 3‑kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) in the rats treated with intrauterine I 2 . Ultimately, the therapeutic benefits of BBR can be attributed, to some extent, to its antioxidant, anti-inflammatory, and antiapoptotic properties, in addition to its ability to modulate the TLR-2/p-PI3K/p-AKT axis., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Cerebral ischemia-reperfusion injury (CI/RI) is a leading cause of disability and mortality worldwide, with limited therapeutic options available. Erianin, a natural compound derived from traditional Chinese medicine, has been reported to possess anti-inflammatory and neuroprotective properties. This study aimed to investigate the therapeutic potential of Erianin in CI/RI and elucidate its underlying mechanisms. Network pharmacology analysis predicted that Erianin could target the PI3K/AKT pathway, which are closely associated with CI/RI. In vivo experiments using a rat model of CI/RI demonstrated that Erianin treatment significantly alleviated neurological deficits, reduced infarct volume, and attenuated neuronal damage. Mechanistically, Erianin inhibited microglial cell polarization towards the pro-inflammatory M1 phenotype, as evidenced by the modulation of specific markers. Furthermore, Erianin suppressed the expression of pro-inflammatory cytokines and mediators, such as TNF-α, IL-6, and COX-2, while enhancing the production of anti-inflammatory factors, including Arg1, CD206, IL-4 and IL-10. In vitro studies using oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated microglial cells corroborated the anti-inflammatory and anti-apoptotic effects of Erianin. Notably, Erianin inhibited the NF-κB signaling pathway by inhibiting p65 phosphorylation and preventing the nuclear translocation of the p65 subunit. Collectively, these findings suggest that Erianin represents a promising therapeutic candidate for CI/RI by targeting microglial cell polarization and inflammation., 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.)

The CRISPR-Cas system is a powerful gene editing technology, the clinical application of which is currently constrained due to safety concerns. A substantial body of safety research concerning Cas9 exists; however, scant attention has been directed toward investigating the safety profile of the emergent Cas13 system, which confers RNA editing capabilities. In particular, uncertainties persist regarding the potential cellular impacts of Cas13d in the absence of reliance on a cleavage effect. In this study, we conducted an initial exploration of the effects of Cas13d on HeLa cells. Total RNA and protein samples were extracted after transfection with a Cas13d-expressing plasmid construct, followed by transcriptomic and proteomic sequencing. Differential gene expression analysis identified 94 upregulated and 847 downregulated genes, while differential protein expression analysis identified 185 upregulated and 231 downregulated proteins. Subsequently, enrichment analysis was conducted on the transcriptome and proteome sequencing data, revealing that the PI3K-Akt signaling pathway is a common term. After intersecting the differentially expressed genes enriched in the PI3K-Akt signaling pathway with all the differentially expressed proteins, it was found that the expression of the related regulatory gene PFKFB4 was upregulated. Moreover, western blot analysis demonstrated that Cas13d can mediate PI3K-Akt signaling upregulation through overexpression of PFKFB4. CCK-8 assay, colony formation, and EdU experiments showed that Cas13d can promote cell proliferation. Our data demonstrate, for the first time, that Cas13d significantly impacts the transcriptomic and proteomic profiles, and proliferation phenotype, of HeLa cells, thus offering novel insights into safety considerations regarding gene editing systems., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Artemisia stechmanniana Besser, one of the most prevalent botanical medicines in Chinese, has been traditionally used for hepatitis treatment. However, the bioactive components and pharmacological mechanism on alcohol-induced liver injury remains unclear., Aim of the Study: To investigate the effect of A. stechmanniana on alcohol-induced liver damage, and further explore its mechanism., Materials and Methods: Phytochemical isolation and structural identification were used to determine the chemical constituents of A. stechmanniana. Then, the alcohol-induced liver damage animal and cell model were established to evaluate its hepato-protective potential. Network pharmacology, molecular docking and bioinformatics were integrated to explore the mechanism and then the prediction was further supported by experiments. Moreover, both compounds were subjected to ADMET prediction through relevant databases., Results: 28 compounds were isolated from the most bioactive fraction, ethyl acetate extract A. stechmanniana, in which five compounds (abietic acid, oplopanone, oplodiol, hydroxydavanone, linoleic acid) could attenuate mice livers damage caused by alcohol intragastration, reduce the degree of oxidative stress, and serum AST and ALT, respectively. Furthermore, abietic acid and hydroxydavanone exhibited best protective effect against alcohol-stimulated L-O2 cells injury among five bioactive compounds. Network pharmacology and bioinformatics analysis suggested that abietic acid and hydroxydavanone exhibiting drug likeliness characteristics, were the principal active compounds acting on liver injury treatment, primarily impacting to cell proliferation, oxidative stress and inflammation-related PI3K-AKT signaling pathways. Both of them displayed strong binding energies with five target proteins (HRAS, HSP90AA1, AKT1, CDK2, NF-κB p65) via molecular docking. Western blotting results further supported the predication with up-regulation of protein expressions of CDK2, and down-regulation of HRAS, HSP90AA1, AKT1, NF-κB p65 by abietic acid and hydroxydavanone., Conclusion: Alcohol-induced liver injury protection by A. stechmanniana was verified in vivo and in vitro expanded its traditional use, and its two major bioactive compounds, abietic acid and hydroxydavanone exerted hepatoprotective effect through the regulation of PI3K-AKT signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In our investigation, we investigated the role of macrophage migration inhibitory factor (MIF), a key cytokine, in chronic nonbacterial prostatitis (CNP), an underexplored pathology. Elevated MIF expression was observed in the serum of individuals with chronic prostatitis-like symptoms (CP-LS) as well as in serum and tissue samples from experimental autoimmune prostatitis (EAP) mouse model. Treatment with ISO-1, a specific MIF antagonist, effectively mitigated prostatic inflammation and macrophage infiltration, thereby emphasizing the critical role of MIF in orchestrating immune responses within the prostate microenvironment. Further analyses revealed that MIF stimulates the PI3K/AKT and NLRP3 inflammasome pathways, which are integral to inflammation and cellular immunity. Pharmacological inhibition of the PI3K/AKT pathway by LY294002 substantially reduced prostatic inflammation and macrophage infiltration, potentially by inhibiting NLRP3 inflammasome activation. These findings collectively suggest that MIF is a potential diagnostic marker for CNP and suggest that targeting MIF or its downstream signalling pathways, PI3K/AKT and NLRP3, might represent a novel therapeutic strategy for this condition., 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.)

During the birch pollen season an enhanced incidence of virus infections is noticed, raising the question whether pollen can affect anti-viral responses independent of allergic reactions. We previously showed that birch pollen-treatment of monocyte-derived dendritic cells (moDC) enhances human cytomegalovirus (HCMV) infection. Here we addressed how in moDC the relatively weak pollen response can affect the comparably strong response to HCMV. To this end, moDC were stimulated with aqueous birch pollen extract (APE), HCMV, and APE with HCMV, and transcriptomic signatures were determined after 6 and 24 h of incubation. Infection was monitored upon exposure of moDC to GFP expressing HCMV by flow cytometric analysis of GFP expressing cells. Principle component analysis of RNA sequencing data revealed close clustering of mock and APE treated moDC, whereas HCMV as well as APE with HCMV treated moDC clustered separately after 6 and 24 h of incubation, respectively. Communally induced genes were detected in APE, HCMV and APE with HCMV treated moDC. In APE with HCMV treated moDC, the comparably weak APE induced signatures were maintained after HCMV exposure. In particular, NF-κB/RELA and PI3K/AKT/MAPK signaling were altered upon APE with HCMV exposure. Earlier, we discovered that NF-κB inhibition alleviated APE induced enhancement of HCMV infection. Here we additionally found that impairment of PI3K signaling reduced HCMV infection in HCMV and APE with HCMV treated moDC. APE treated moDC that were exposed to HCMV show a unique host gene signature, which to a large extent is regulated by NF-κB activation and PI3K/AKT/MAPK signaling., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Hyssopus cuspidatus Boriss., a classic Uyghur medicine, is used to treat inflammatory lung diseases such as asthma. But the therapeutic effect and mechanism of the volatile oil of Hyssopus cuspidatus Boriss.(HVO) in asthma therapy remain unclear., Aim of the Study: We aim to characterize the constituents of HVO, investigate the therapeutic effect in OVA-induced allergic asthmatic mice and further explore the molecular mechanism., Materials and Methods: In this study, we applied two-dimensional gas chromatography quadrupole time-of-flight mass spectrometry (GC × GC-QTOF MS) to identify the ingredients of HVO. We established OVA-induced asthmatic model to investigate the therapeutic effect of HVO. To further explore the potential molecular pathways, we used network pharmacology approach to perform GO and KEGG pathways enrichment, and then built an ingredient-target-pathway network to identify key molecular pathways. Finally, LPS-induced RAW 264.7 macrophages and OVA-induced asthmatic model were used to validate the potential signaling pathways., Results: GC × GC-QTOF MS analysis revealed the presence of 123 compounds of HVO. The sesquiterpenes and monoterpenes are the main constituents. The in vivo study indicated that HVO suppressed OVA-induced eosinophilic infiltration in lung tissues, inhibited the elevation of IgE, IL-4, IL-5, and IL-13 levels, downregulated the expressions of phosphorylated PI3K, Akt, JNK and P38, and maintained epithelial barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin. The in vitro study also revealed an inhibition of NO release and downregulation of phosphorylated PI3K, Akt, JNK and P38 levels., Conclusion: HVO alleviates airway inflammation in OVA-induced asthmatic mice by inhibiting PI3K/Akt/JNK/P38 signaling pathway and maintaining airway barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin., 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: jinkui Shenqi Pill (JSP) is a classic traditional Chinese medicine used to treat "Kidney Yang Deficiency" disease. Previous studies indicate a protective effect of JSP on apoptosis in mouse neurons., Aim of the Study: This research, combining network pharmacology with in vivo experiments, explores the mechanism of JSP in preventing neural tube defects (NTDs) in mice., Materials and Methods: Network pharmacology analyzed JSP components and targets, identifying common genes with NTDs and exploring potential pathways. Molecular docking assessed interactions between key JSP components and pathway proteins. In an all-trans retinoic acid (atRA)-induced NTDs mouse model, histopathological changes were observed using HE staining, neuronal apoptosis was detected using TUNEL, and Western Blot assessed changes in the PI3K/AKT signaling pathway and apoptosis-related proteins., Results: Different concentrations of JSP led to varying degrees of reduction in the occurrence of neural tube defects in mouse embryos, with the highest dose showing the most significant decrease. Furthermore, it showed a better reduction in NTDs rates compared to folic acid (FA). Network pharmacology constructed a Drug-Active Ingredient-Gene Target network, suggesting key active ingredients such as Quercetin, Wogonin, Beta-Sitosterol, Kaempferol, and Stigmasterol, possibly acting on the PI3K/Akt signaling pathway. Molecular docking confirmed stable binding structures. Western Blot analysis demonstrated increased expression of p-PI3K, p-Akt, p-Akt1, p-Akt2, p-Akt3, downregulation of cleaved caspase-3 and Bax, and upregulation of Bcl-2, indicating prevention of NTDs through anti-apoptotic effects., Conclusion: We have identified an effective dosage of JSP for preventing NTDs, revealing its potential by activating the PI3K/Akt signaling pathway and inhibiting cell apoptosis in atRA-induced mouse embryonic NTDs., 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 Qinglongyi-Buguzhi herbal pair (QB) is one of commonly used herbal combinations for treating vitiligo in traditional Chinese medicine, consisting of the exocarp of the immature fruit of Juglans regia L. or Juglans mandshurica Maxim., and dried, mature fruit of Psoralea corylifolia L. However, the active components and potential mechanisms of QB in the treatment of vitiligo are still unclear., Aim of the Study: The purpose of this study is to clarify the effects and mechanisms of QB on vitiligo treatment through integration of network pharmacology and empirical examinations., Materials and Methods: The active components and targets of QB as well as the targets linked to vitiligo were obtained from network databases. Visualization networks were constructed with Cytoscape 3.9.1. GO and KEGG enrichment analysis were conducted to investigate the possible mechanism. Molecular docking was employed to evaluate the binding affinities between the primary active ingredients of QB and essential targets of the PI3K/Akt/Nrf2 pathway. In vivo and in vitro experiments were carried out to confirm the results of network pharmacology., Results: We evaluated 44 active compounds and 602 genes from QB, and 107 of these genes linked to vitiligo. GO analysis suggested QB might lessen vitiligo by regulating oxidative stress. KEGG pathway analysis indicated the PI3K/Akt pathway may be crucial for treating vitiligo. Molecular docking results demonstrated the key active ingredients of QB had good binding activity with the major targets in the PI3K/Akt/Nrf2 pathway. In vivo, QB significantly ameliorated vitiligo model mouse's skin pathologies by reducing ROS, elevating CAT and SOD levels. Western blot showed that QB increased the phosphorylation of PI3K and Akt and the expressions of Nrf2 and HO-1 in the skin. In vitro, QB reversed H 2 O 2 -induced oxidative injury of melanocytes, enhanced cell survival rate, reduced ROS level, upregulated SOD and CAT activities, and raised the content of melanin. Moreover, QB upregulated the expression levels of Akt, Nrf2, HO-1 mRNA, Akt phosphorylation, HO-1, and nuclear Nrf2 proteins, and also encouraged the nuclear translocation of Nrf2. However, LY294002 treatment significantly reversed the regulatory effect of QB on oxidative damage of melanocytes., Conclusions: This study revealed that the therapeutic effect of QB on vitiligo was achieved through multiple components, targets and pathways. Experimental investigation demonstrated that QB could improve vitiligo via reducing oxidative stress, which was probably accomplished by activating the PI3K/Akt/Nrf2 signaling pathway., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Periodontitis is a chronic inflammatory disease that affects about 45 %-50 % of adults worldwide, but the efficacy of current clinical therapies is unsatisfactory due to the complicated periodontal immune microenvironment. Thus, developing drugs that can regulate innate immune cells (e.g., macrophages) is a potent strategy to treat periodontitis. Here, we report that phloretin, a food plant-derived natural compound, is sufficient to alleviate periodontitis through immune regulation. In vivo, phloretin treatment could significantly reduce alveolar bone resorption and periodontal inflammation in mouse periodontitis models. In vitro, phloretin could suppress proinflammatory (M1-like) polarization and cytokine release in macrophages induced by LPS. Mechanistically, the immune regulatory role of phloretin in macrophages may be due to its metabolic regulation effect. Phloretin might restore the balance of M1/M2 macrophage transition in periodontitis by inhibiting HIF-1α-mediated glycolysis and PI3k/Akt pathways, thereby reducing the proinflammatory effect and immune disorder caused by over-activated M1 macrophages. Together, this study highlights that natural compound, such as phloretin, can restore periodontal immune homeostasis by metabolic regulation of macrophages, which may provide novel insight into the treatment of periodontitis., 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: Huangqin Tang (HQT), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of inflammatory bowel diseases. It has been reported that HQT exerts antitumor effects on colitis-associated colorectal cancer (CAC). However, the mechanism by which HQT interferes with the inflammation-to-cancer transformation remains unclear., Aims of the Study: The purpose of this study was to dynamically evaluate the efficacy of HQT in alleviating or delaying CAC and to reveal the underlying mechanism., Methods: We established a mouse model of CAC using azoxymethane combined with 1.5% dextran sodium sulphate. The efficacy of HQT was evaluated based on pathological sections and serum biochemical indices. Subsequently, amino acids (AAs) metabolism analyses were performed using ultra-performance liquid chromatography-tandem mass spectrometry, and the phosphatidylinositol 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway was detected by western blotting., Results: The data demonstrated that HQT could alleviate the development of CAC in the animal model. HQT effectively reduced the inflammatory response, particularly interleukin-6 (IL-6), in the inflammation induction stage, as well as in the stages of proliferation initiation and tumorigenesis. During the proliferation initiation and tumorigenesis stages, immunohistochemistry staining showed that the expression of the proliferation marker Ki67 was reduced, while apoptosis was increased in the HQT group. Accordingly, HQT substantially decreased the levels of specific AAs in the colon with CAC, including glutamic acid, glutamine, arginine, and isoleucine. Furthermore, HQT significantly inhibited the activated PI3K/AKT/mTOR pathway, which may contribute to suppression of cell proliferation and enhancement of apoptosis., Conclusion: HQT is effective in alleviating and delaying the colon "inflammation-to-cancer". The mechanism of action may involve HQT maintained AAs metabolism homeostasis and regulated PI3K/AKT/mTOR pathway, so as to maintain the balance between proliferation and apoptosis, and then interfere in the occurrence and development of CAC., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interests regarding the publication of this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Testicular germ cell tumor (TGCT) is a common malignant tumor in adolescents. Now, many long non-coding RNAs (LncRNAs) have been found to have an important function in TGCT. LINC00470 is specifically and highly expressed in TGCT, however, there is still no definite information concerning its role and underlying mechanism in TGCT. The purpose of this research was to look into the involvement of LINC00470 in TGCT and its intrinsic mechanism., Methods and Results: UCSC and GEPIA2 databases were used to analyze the expression of LINC00470, and the BEST website was used to perform GSEA enrichment analysis, immune infiltration analysis, and drug susceptibility analysis. SiRNA transfection was used to silence LINC00470 in TCAM-2 and NCCIT cells. Clone formation and Transwell assays were performed in TGCT cells to confirm the effects of LINC00470 on clone formation, migration, and invasion. Western Blot was performed to determine the expression of proteins related to the EMT and AKT signaling pathways. LINC00470 was specifically highly expressed in TGCT, and played a role in promoting tumor cell clone formation and cell metastasis by affecting the TGF-β and PI3K-AKT-mTOR signaling pathways to regulate the epithelial-mesenchymal transition (EMT) process; LINC00470 may also play a pro-tumor role by negatively regulating immune infiltration; in addition, the expression of LINC00470 was negatively correlated with the chemosensitivity of cisplatin in TGCT patients., Conclusions: LINC00470 may play a significant role in the etiology and metastasis of TGCT through EMT and AKT-mediated signaling pathways., Competing Interests: Declarations Conflict of interest The authors have no relevant financial or non-financial interests to disclose. Ethical approval This research does not involve human or animal subjects. Consent to participate Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Papillary thyroid cancer (PTC) is a malignant tumor that poses a serious threat to human health. LncRNA CASC9 serves as an oncogene in numerous tumors. The purpose of this study was to explore the mechanism of lncRNA CASC9 regulating doxorubicin (Dox) resistance in PTC., Methods: The expression of CASC9, miR-28-3p and BCL-2 in PTC tissues or dox-resistant cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot (WB). CCK-8, colony formation assay, flow cytometry and transwell assay were used to measure the semi-inhibitory concentration (IC50) of dox, cell proliferation, apoptosis and migration, respectively. Dual luciferase reporter gene assays were performed to verify the targeting relationship between miR-28-3p and CASC9 or BCL-2. Rescue experiments were applied to verify the mechanism of CASC9. Finally, the role of CASC9 was verified by xenograft modeling in vivo., Results: We discovered that CASC9 was enhanced in PTC tissues, cells and Dox-resistant cells (BCPAP/Dox and K1/Dox). Furthermore, CASC9 inhibition markedly restrained the proliferation, migration and facilitated apoptosis of Dox cells. In vivo experiments also showed that silencing of CASC9 inhibited tumor growth. Meanwhile, knockdown of CASC9 sensitized PTC cells to Dox. CASC9 enhanced tumor progression by activating the PI3K/AKT signaling pathway. Furthermore, bioinformatics analysis identified miR-28-3p as a downstream target of CASC9. MiR-28-3p inhibitor reversed the impact of CASC9 knockdown in BCPAP/Dox and K1/Dox. Further studies showed that CASC9 positively regulated BCL-2 expression through miR-28-3p. miR-28-3p weakened Dox resistance, proliferation, migration and accelerated apoptosis of PTC cells via BCL-2., Conclusion: CASC9, as an oncogenic lncRNA, has a promotional effect on Dox resistance and PTC progression via miR-28-3p/BCL-2 axis and PI3K/AKT signaling pathway., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Ganzhou People’s Hospital. All participants were provided with written informed consent at the time of recruitment, and all experiments involving human tissue specimens comply with the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Esophageal squamous carcinoma (ESCC) is the most prevalent pathological subtype of esophageal cancer (EC). It has the characteristics of significant local invasion, quick disease progression, high recurrence rates, and a dismal prognosis for survival. Phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K/AKT) is a signaling system whose aberrant activation regulates downstream factors, leading to the promotion of cancer development. This study looks at a protein called Glycerol-3-phosphate dehydrogenase 1-like (GPD1L), which strongly affects the development of several cancers. However, its association with ESCC development and its underlying mechanisms are not clear., Methods: In this paper, we analyzed six ESCC transcriptome data obtained from the GEO database. We utilized bioinformatics technology and immunohistochemistry to differentially analyze GPD1L levels of mRNA and protein expression in ESCC and normal adjacent tissues. Furthermore, we conducted survival, co-expression, enrichment, immune infiltration and drug sensitivity analysis. Moreover, we further investigated the role and mechanism of GPD1L by Western Blot (WB), Cell Counting Kit-8 (CCK8), wound healing assay, Transwell assay, and flow cytometry. Finally, the addition of IGF-1, the activator of PI3K/AKT, could rescue the inhibitory effect of GPD1L on ESCC., Results: The findings manifest that the expression of GPD1L was low in ESCC, and functional experiments showed that GPD1L promoted apoptosis in vitro while blocking cell migration, invasion, and proliferation. Based on mechanism research, GPD1L's impact on ESCC could be explained by its suppression of the PI3K/AKT signaling pathway's activation., Conclusion: To sum up, our findings imply that GPD1L may impede the initiation and advancement of ESCC via modulating the PI3K/AKT signaling pathway. GPD1L is considered to be a promising therapeutic target and biomarker to diagnose and treat ESCC., Competing Interests: Declarations Ethical approval This study was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Zhengzhou University (approval no.2023201). Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Although stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI., Methods: Cardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson's trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively., Results: NGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H 2 O 2 . Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro., Conclusions: NGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Animal Ethics Committee of Shanghai University of TCM (No. PZSHUTCM190628003, approved on June 30, 2019). The title of the approved project was ‘Mechanism of optimizing microenvironment in induced pluripotent stem cell transplantation for myocardial infarction by qi replenishing and blood activating traditional Chinese medicine’. Consent for publication Not applicable. Competing interests The authors declare that they have no conflicts of interest., (© 2024. The Author(s).)

The PI3K/Akt pathway is overexpressed in nearly 50% of hepatocellular carcinomas and inhibits apoptosis by promoting the expression of antiapoptotic genes. Serine protease inhibitors have been shown to induce apoptosis in hepatoma cells by downregulating SPINK13 in the PI3K/Akt pathway. In this study, SPINK13 was expressed in lentiviral vectors. Changes in signaling pathway adapter proteins, apoptosis regulatory proteins, cell cycle regulatory proteins, and the biological behavior of hepatocellular carcinoma were observed in cell and nude mouse xenograft models. The underlying mechanism of endogenous SPINK13-induced apoptosis in hepatocellular carcinoma cells was explored via transcriptomics. As a result, endogenous SPINK13 might inhibit the activity of Furin protease, downregulate the Notch1/Hes1 pathway in a binding manner, activate the direct effector PTEN, inhibit Akt phosphorylation, inactivate the downstream PI3K/Akt pathway, and ultimately lead to mitochondrial apoptosis and cell cycle arrest in hepatoma cells. Therefore, the Notch1/Hes1/PTEN pathway may act upstream of SPINK13 to downregulate the PI3K/Akt signaling pathway. Our study helps elucidate the underlying mechanism of SPINK13 in anti-hepatocellular carcinoma and lays a theoretical foundation for the development of novel therapeutic serine protease inhibitors., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Renal fibrosis is a key process in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD), while the intricate mechanisms of renal fibrosis remain obscure. While the signal-transducing adaptor protein 2 (STAP2) was well-studied for its notable function in inflammation and immune-related disorders, its specific implication in renal fibrosis remains unclear. This study assessed the mechanism by which STAP2 could promote the progression of renal fibrosis., Methods: The expression level of STAP2 in fibrotic human samples, murine fibrosis models, and cellular fibrosis models was measured, respectively. Subsequently, immunoprecipitation (IP), mass spectrometry, and RNA sequencing (RNA-seq) were employed to identify HSP27 as an interacting protein and the PI3K-AKT signaling pathway. STAP2 was thereafter knocked down or overexpressed in both in vivo and in vitro models to assess the expression levels of pathway-related and fibrosis-related proteins. Finally, the important role of STAP2 in the fibrosis process in animal models induced by ischemia-reperfusion injury (IRI) and cisplatin was validated., Results: Functionally, in vivo assays demonstrated that the genetic knockout of STAP2 could remarkably mitigate epithelial-mesenchymal transition (EMT), diminish inflammatory cell infiltration, and reduce collagen deposition in mice with renal fibrosis. Conversely, in vitro assays employing STAP2-overexpressing cell models exacerbated the expression levels of fibrosis markers. The outcomes uncovered a potential mechanism by which STAP2 could modulate renal fibrosis through its impact on the expression level of phosphorylated HSP27, as well as modulating the PI3K/AKT signaling pathway., Conclusions: This comprehensive investigation delineated the noticeable function of STAP2 in the advancement of renal fibrosis, and the outcomes might contribute to the development of targeted therapies concentrated on STAP2 to mitigate renal fibrosis., Competing Interests: Declarations Ethical approval Animal experiments were approved by Experimental Animal Ethics Committee of Wuhan Third Hospital (WuSanYiShiLun SY2023-003). Collected clinical samples and conducted clinical research were approved by Ethics Committee of Wuhan Third Hospital (WuSanYiLun KY2023-057) and Ethics Committee of Huangshi Central Hospital (2024-17). Conflict of interest The authors confirmed the absence of conflict of interest., (© 2024. The Author(s).)

Regeneration of the sciatic nerve is a sophisticated process that involves the interplay of several signaling pathways that orchestrate the cellular responses critical to regeneration. Among the key pathways are the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT, cyclic adenosine monophosphate (cAMP), and Janus kinase/signal transducers and transcription activators (JAK/STAT) pathways. In particular, the cAMP pathway modulates neuronal survival and axonal regrowth. It influences various cellular behaviors and gene expression that are essential for nerve regeneration. MAPK is indispensable for Schwann cell differentiation and myelination, whereas PI3K/AKT is integral to the transcription, translation, and cell survival processes that are vital for nerve regeneration. Furthermore, GTP-binding proteins, including those of the Ras homolog gene family (Rho), regulate neural cell adhesion, migration, and survival. Notch signaling also appears to be effective in the early stages of nerve regeneration and in preventing skeletal muscle fibrosis after injury. Understanding the intricate mechanisms and interactions of these pathways is vital for the development of effective therapeutic strategies for sciatic nerve injuries. This review underscores the need for further research to fill existing knowledge gaps and improve therapeutic outcomes., Competing Interests: Declarations Ethics Approval We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Conflict of Interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: KRAS G12C and KRAS G12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms., Methods: We contrasted tumor development between Kras G12C and Kras G12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of Kras G12C and Kras G12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRAS G12C or KRAS G12D -mutant NSCLC., Results: KRAS G12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRAS G12D GEMMs compared to KRAS G12C . This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRAS G12C oncogenicity and downstream pathway activation were comparable with KRAS G12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRAS G12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRAS G12C models on the MAPK pathway. Specifically, KRAS G12D inhibition was enhanced by AKT inhibition in vitro and in vivo., Conclusions: Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling., Competing Interests: Declarations Ethics approval and consent to participate For in vivo work in mice, studies were carried out in compliance with UK Home Office regulations with protocols approved by the Cancer Research UK Manchester Institute Animal Welfare and Ethical Review Advisory Body. Chicken egg experiments did not require ethical approval before as they were carried out before day 14 of develop. For patient studies, data collection protocols were approved by local governance committee. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

This current study seeks to examine the pre-protective function of Quercetin in Cadmium (Cd)-induced liver damage, along with its modulation of the PI3K/Akt/NF-kappaB signaling pathway. A total of 60 male C57BL/6J mice were randomly assigned to four groups: control (C), quercetin (Q, 100 mg/kg/day), Cd (Cd, 2.5 mg/kg/day), and quercetin and Cd (Q+Cd). Before receiving Cd treatment, quercetin was administered intragastrically for 4 weeks. In the present study, liver markers, oxidative stress parameters, pro-inflammatory cytokines, liver histopathology, apoptotic markers and PI3K/Akt/NF-kappaB signaling molecules were examined. We observed that the body weight of the Cd-treated mice dramatically rise after 4 weeks of quercetin pre-administration, and the Cd concentration was significantly decreased. Liver function markers like alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were significantly reduced in quercetin treatment in Cd-induced mice. Additionally, we observed that quercetin reduced Cd-mediated liver injury in mice by assessing the level of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) concentrations and the histological alterations. By monitoring tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), quercetin successfully reduced the inflammatory cytokines that the Cd metal caused in the liver. Additionally, in the liver tissues of Cd-mediated, quercetin could enhance the expression of Bcl-2 and decrease the expression of p-Akt, p-PI3K, Bax, Caspase-9, Caspase-3, NF-kappaB. In conclusion, quercetin protects against Cd induced liver injury via several pathways, including oxidative stress, inflammation and apoptosis, and its protective effect correlates with antioxidant activity.

Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life., Competing Interests: Declaration of competing interest The authors report no conflict of interest concerning the material or methods used in this study or the findings specified in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chemotherapy detrimentally impacts fertility via depletion of follicular reserves in the ovaries leading to ovarian failure (OF) and development of estrogen deficiency-related complications. The currently proposed options to preserve fertility such as Oocyte or ovarian cortex cryopreservation are faced with many technical obstacles that limit their effective implementation. Therefore, developing new modalities to protect ovarian function remains a pending target. Exosomes are nano-sized cell-derived extracellular vesicles (EVs) with documented efficacy in the field of regenerative medicine. The current study sought to determine the potential beneficial effects of mesenchymal stem cells (MSCs)-derived EVs in experimentally induced OF. Female albino rats were randomly allocated to four groups: control, OF group, OF + MSCs-EVs group, OF + Rapamycin (mTOR inhibitor) group, and OF + Quercetin (PI3K/AKT inhibitor) group. Follicular development was assessed via histopathological and immunohistochemical examination, and ovarian function was evaluated by hormonal assay. PI3K/Akt/mTOR signaling pathway as a key modulator of ovarian follicular activation was also assessed. MSCs-EVs administration to OF rats resulted in restored serum hormonal levels, preserved primordial follicles and oocytes, suppressed ovarian PI3K/AKT axis and downstream effectors (mTOR and FOXO3), modulated miRNA that target this axis, decreased expression of ovarian apoptotic markers (BAX, BCl2) and increased expression of proliferation marker Ki67. The present study validated the effectiveness of MSCs-EVs therapy in preventing ovarian insufficiency induced by chemotherapy. Concomitant MSCs-EVs treatment during chemotherapy could significantly preserve ovarian function and fertility by suppressing the PI3K/Akt axis, preventing follicular overactivation, maintaining normal ovarian cellular proliferation, and inhibiting granulosa cell apoptosis., Competing Interests: Declarations Institutional review board statement The experimental procedure was conducted in compliance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals (NIH publication No. 85–23, revised 2011) and carried out following the institutional review board for animal experiments of the Faculty of Medicine, Benha University, Egypt (BUFVTM 07-07-22). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Fibroblast activation plays an important role in the occurrence and development of idiopathic pulmonary fibrosis (IPF), which is a progressive, incurable, and fibrotic lung disease. However, the underlying mechanism of fibroblast activation in IPF remains elusive. Here, we showed that the expression levels of STX11 and SNAP25 were downregulated in the lung tissues from patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis as well as in the activated fibroblasts. Upregulation of STX11 or SNAP25 suppressed TGF-β1-induced activation of human lung fibroblasts (HLFs) via promoting autophagy. However, they failed to suppress fibroblast actviation when autophagy was blocked with the use of chloroquine (CQ). In addition, STX11 or SNAP25 could inhibit TGF-β1-induced fibroblast proliferation and migration. In vivo, overexpression of STX11 exerted its protective role in the mice with BLM-induced lung fibrosis. STX11 and SNAP25 mutually promoted expression of each other. Co-IP assay indicated that STX11 has an interaction with SNAP25. Mechanistically, STX11-SNAP25 interaction activated fibroblast autophagy and further inhibited fibroblast activation via blocking the PI3K/AKT/mTOR pathway. Overall, the results suggested that STX11-SNAP25 interaction significantly inhibited lung fibrosis by promoting fibroblast autophagy and suppressing fibroblast activation via blocking the PI3K/ATK/mTOR signaling pathway. Therefore, STX11 serves as a promising therapeutic target in IPF., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Cysteine-aspartic proteases (caspases) are critical drivers of apoptosis, exhibiting expansion and domain shuffling in mollusks. However, the functions and regulatory mechanisms of these caspases remain unclear. In this study, we identified a group of Caspase-3/6/7 in Bivalvia and Gastropoda with a long inter-subunit linker (IL) that inhibits cleavage activation. Within this region, we found that conserved phosphorylation at Thr260 in oysters, mediated by the PI3K-AKT pathway, suppresses heat-induced activation. This mechanism is involved in divergent temperature adaptation between two allopatric congeneric oyster species, the relatively cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata. Our study elucidates the role of these effector caspase members and their long IL in bivalves, revealing that the PI3K-AKT pathway phosphorylates Thr260 on CgCASP3/6/7's linker to inhibit heat-induced activation. These findings provide insights into the evolution and function of apoptotic regulatory mechanisms in bivalves., (© 2024. The Author(s).)

Background: Solute carrier family 38 member 5 (SLC38A5) is an amino acid transporter that plays a significant role in various cellular biological processes and may be involved in regulating the progression of tumors However, its function and underlying mechanism in osteosarcoma remain unexplored., Methods: Utilizing various database analyses and experiments, we have explored the dysregulation of SLC38A5 in osteosarcoma and its prognostic value. A series of in vitro functional experiments, including CCK-8, colony formation, wound healing, and transwell invasion assays, were conducted to evaluate the effects of SLC38A5 on the proliferation, migration, and invasion of osteosarcoma cells. Downstream pathways of SLC38A5 were explored through methods such as western blot and metabolic assays, followed by a series of validations. Finally, we constructed a subcutaneous xenograft tumor model in nude mice to explore SLC38A5 function in vivo., Results: SLC38A5 is upregulated in osteosarcoma and is associated with poor prognosis in patients. Upregulation of SLC38A5 promotes proliferation, migration, and invasion of osteosarcoma cells, while the PI3K inhibitor BKM120 can counteract these effects. Additionally, silencing of SLC38A5 inhibits tumor growth in vivo. Mechanistically, SLC38A5 mediates the activation of the PI3K/AKT/mTOR signaling pathway by transporting glutamine, which subsequently enhances the SREBP1/SCD-1 signaling pathway, thereby suppressing ferroptosis in osteosarcoma cells., Conclusion: SLC38A5 promotes osteosarcoma cell proliferation, migration, and invasion via the glutamine-mediated PI3K/AKT/mTOR signaling pathway and inhibits ferroptosis. Targeting SLC38A5 and the PI3K/AKT signaling axis may provide a meaningful therapeutic strategy for the future treatment of osteosarcoma., (© 2024. The Author(s).)

Background: Lung adenocarcinoma (LUAD) is the most common lung cancer subtype, and the prognosis of affected patients is generally poor. The traditional Chinese medicine Uncaria rhychophaylla has been reported to exhibit anti-lung cancer properties. Accordingly, the main bioactive ingredient in Uncaria rhychophaylla, Corynoxine, may hold great value as a treatment for lung cancer., Methods: The impact of Corynoxine on the viability of LUAD cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in A549 cells was evaluated via flow cytometry. Migration and invasion capabilities were determined through wound healing and Transwell assays, respectively. The key pathways targeted by Corynoxine in LUAD were identified using a network pharmacology approach. Additionally, Western immunoblotting, quantitative real-time PCR (qRT-PCR), and ELISA assays were conducted to validate the underlying mechanisms. The in vivo anti-tumor efficacy of Corynoxine was assessed in xenograft nude mice., Results: In this study, Corynoxine treatment was found to markedly suppress in vitro LUAD cell proliferative, migratory, and invasive activity. It additionally downregulated Vimentin and promoted E-cadherin upregulation consistent with the disruption of epithelial-mesenchymal transition (EMT) induction while also accelerating apoptotic death. Furthermore, network pharmacology analysis revealed that the PI3K/AKT pathway is a potential target of Corynoxine in LUAD. In vitro assays demonstrated that treatment with Corynoxine resulted in the suppression of PI3K/AKT signaling and a consequent drop in cyclooxygenase-2 (COX-2) expression. These findings were further confirmed in vivo in mice harboring A549 tumor xenografts in which Corynoxine was able to interfere with the PI3K/AKT/COX-2 signaling axis., Conclusion: This study elucidated the potential effects of Corynoxine in suppressing proliferation and metastasis in LUAD, along with investigating the underlying mechanisms. These data highlight the promise of Corynoxine as a novel therapeutic tool for the treatment of individuals diagnosed with LUAD., (© 2024. The Author(s).)

Background: Oral cancer accounts for 2% of cancer-related deaths globally, with over 90% of cases being oral cavity squamous cell carcinomas (OSCCs). Approximately 50% of patients with OSCC succumb to the disease within 5 years, primarily due to the advanced stage at which it is typically diagnosed. This underscores an urgent need to identify proteins related to OSCC progression to develop effective diagnostic and therapeutic strategies., Methods: To identify OSCC progression-related proteins, we conducted integrated proteome and transcriptome analyses on cancer tissues from patients and patient-derived xenograft (PDX) model mice. We investigated the role of protein-enabled homolog (ENAH), identified as an OSCC progression-associated protein, through proliferation, transwell migration, and invasion assays in OSCC cells. The mechanisms underlying ENAH-mediated functions were elucidated using gene knockdown and ectopic expression techniques in OSCC cells., Results: ENAH was identified as a candidate associated with OSCC progression based on integrated analyses, which showed increased ENAH levels in primary OSCC tissues compared with adjacent noncancerous counterparts, and sustained overexpression in the cancer tissues of PDX models. We confirmed that level of ENAH is increased in OSCC tissues and that its elevated expression correlates with poorer survival rates in patients with OSCC. Furthermore, the upregulation of ENAH in OSCC cells results from the activation of the GSK3β/β-catenin axis by the EGFR/PI3K/AKT cascade. ENAH expression enhances cell proliferation and mobility by upregulating integrin β5 in oral cancer cells., Conclusions: The upregulation of ENAH through a PI3K/AKT/β-catenin signaling cascade enhances oral cancer cell migration and growth via the ITGB5/Src axis. These findings offer a new interpretation of the ENAH function in the OSCC progression and provide crucial information for developing new OSCC treatment strategies., (© 2024. The Author(s).)

Patients with advanced and recurrent cervical cancer often lack satisfactory treatment outcomes. Thus, it is necessary to seek reliable biomarkers that provide the ability to identify the disease at an early stage and predict the patient prognosis, providing new strategies for the treatment of cervical cancer. The sequencing data of ITGA3 were retrieved from public datasets. Immune infiltration and sensitivity of potential immunotherapy and chemotherapy have been analyzed between two subgroups. Functional analysis was applied to excavate the related pathways of ITGA3 in cervical cancer. Furthermore, the impact of ITGA3 in tumor progression has been verified in vitro. The results revealed that the level of ITGA3 was upregulated in cervical cancer, and was positively correlated with worse prognosis. The tumor microenvironment of patients in the high-risk group was immunosuppressed. Patients in high-risk group may not benefit from immunotherapy, but be may be sensitive to several chemotherapy drugs. Notably, the angiogenesis, epithelial mesenchymal transition, and PI3K pathway were increased in high-risk group. Collectively, ITGA3 is a marker of poor prognosis and promotes tumor progression by regulating PI3K/AKT pathway in cervical cancer. Our results provide new insights for potential molecular targeted therapy and prognostic prediction of cervical cancer., (© 2024. The Author(s).)

This study first investigated how FNDC5 affected the development of oral cancer and revealed the role of FNDC5 in the migration and invasion of oral cancer. The present work evaluated differential FNDC5 expression within oral cancer samples versus matched non-carcinoma samples based on GEO database analysis and immunohistochemistry. We then generated oral cancer cell lines with FNDC5 overexpression and knockdown to determine the role of altered FNDC5 expression in the migration and invasion of oral cancer. PI3K inhibitor was used for investigating the possible mechanism underlying FNDC5 during EMT of oral cancer. Finally, these in-vitro results were validated using the lung metastatic nude mouse model. According to our results, FNDC5 level markedly decreased within oral cancer compared with adjacent samples and FNDC5 overexpression inhibited migration, invasion as well as EMT of oral cancer, while FNDC5 knockdown promoted oral cancer cell EMT. In addition, PI3K inhibitors blocked the induction of oral cancer cells EMT by FNDC5 knockdown. In vivo experiments further demonstrated the above results. This work is the first to illustrate the impact of FNDC5 on inhibiting migration and invasion of oral cancer, and our results suggest that FNDC5 affects EMT of oral cancer via the inhibition of PI3K/Akt/Snail pathway., (© 2024. The Author(s).)

To explore diagnostic and prognostic biomarkers in the progression of oral squamous cell carcinoma (OSCC) and to reveal their regulatory mechanisms in key pathways. A RayBiotech protein chip was used to screen differentially expressed serum proteins in OSCC, oral leukoplakia (OLK), and healthy participants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to determine the pathways enriched by characteristic differential proteins. Immunohistochemical analysis and western blotting were used to verify the expression of characteristic differential proteins and key regulatory factors in human tissues and in a nude mouse model. Fibroblast growth factor 6 (FGF6) was identified as a key differential protein and was weakly expressed in OSCC tissues. The mitogen-activated protein kinases (MAPK) and PI3K-AKT pathways were identified as key signaling pathways. The results showed that pERK, Cyclin D1, pAKT, and BCL2 were highly expressed in OSCC, Caspase9 was lowly expressed in OSCC. With an increase in FGF6 expression in nude mice, the expression of FGFR4, pERK, Cyclin D1, pAKT, BCL2, GPX4, and ACSL4 increased, and the expression of Caspase9 decreased. FGF6 may change the expression of apoptosis-related proteins and proliferation factors by binding to FGFR4 in the PI3K-AKT/MAPK pathway and may inhibit the ferroptosis of OSCC, thereby possibly participating in the process of inhibiting OSCC., (© 2024. The Author(s).)

Tubulin associated unit has been extensively studied in neurodegenerative diseases including Alzheimer's disease (AD), whereby its hyperphosphorylation and accumulation contributes to disease pathogenesis. Tau is abundantly expressed in the central nervous system but is also present in non-neuronal tissues and in tumours including sex hormone responsive cancers such as breast and prostate. Curiously, hormonal effects on tau also exist in an AD context from numerous studies on menopause, hormone replacement therapy, and androgen deprivation therapy. Despite sharing some risk factors, most importantly advancing age, there are numerous reports from population studies of, currently poorly explained inverse associations between cancer and Alzheimer's disease. We previously reviewed important components of the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signalling pathway and their differential modulation in relation to the two diseases. Similarly, receptor tyrosine kinases, estrogen receptor and androgen receptor have all been implicated in the pathogenesis of both cancer and AD. In this review, we focus on tau and its effects in hormone responsive cancer in terms of development, progression, and treatment and in relation to sex hormones and PI3K/Akt signalling molecules including IRS-1, PTEN, Pin1, and p53., (© 2024 The Author(s).)

Intramuscular fat (IMF) content is an economic trait in beef cattle that improves the meat quality. Studies have highlighted the correlation between long noncoding RNAs (lncRNAs) and IMF development. In this study, lncBNIP3 knockdown promoted bovine intramuscular preadipocyte differentiation. RNA-seq analysis of intramuscular preadipocytes with lncBNIP3 knockdown identified 230 differentially expressed genes. The PI3K-Akt and PPAR signaling pathways were enriched. lncBNIP3 interference promoted mRNA and protein expression of key genes in PI3K-Akt signaling pathway. LncBNIP3 interference reversed the effects of an AKT-inhibitor MK-2206 on Akt protein expression and lipid droplet accumulation, promoted mRNA and protein expression of essential genes in the PPAR signaling pathway, and ameliorated the inhibitory effects of a PPARg antagonist GW9662 on lipid accumulation. Therefore, lncBNIP3 inhibition of bovine intramuscular preadipocyte differentiation is likely mediated via the PI3K-Akt and PPAR signaling pathways. This study identified a valuable lncRNA with functional roles in IMF accumulation and revealed new strategies to improve beef quality.

Preeclampsia (PE) is a severe pregnancy complication linked to maternal and fetal health, yet its underlying causes and pathogenesis remain elusive. Circular RNA (circRNA), a form of non-coding RNA, is implicated in the progression of PE; nevertheless, the specific mechanism is not fully elucidated. This study aimed to identify and validate circRNAs that are pivotal in the pathophysiology of PE. Firstly, we constructed a ceRNA network using datasets from the GEO database and identified circ&#95;0022707 as our study target. Then, using qRT-PCR analysis, we validated that circ&#95;0022707 was downregulated in preeclamptic placentas compared to those of normal pregnant women. In situ hybridization assays revealed that circ&#95;0022707 existed in placental villous trophoblast cells. Additionally, Pearson correlation analysis revealed a negative relationship between the expression of circ&#95;0022707 and PE-related indicators (systolic and diastolic blood pressure, along with 24-h proteinuria levels). Furthermore, gain-of-function experiments confirmed that circ&#95;0022707 could promote trophoblast cell proliferation and cell cycle progression while suppressing apoptosis. In vivo experiments using a preeclampsia-like mouse model also demonstrated that circ&#95;0022707 administration could mitigate preeclampsia-like symptoms. Mechanistically, we confirmed that circ&#95;0022707 functions through the miR-3135b/GHR/PI3K/Akt pathway in trophoblast cells. Overall, our study has provided insight into the important function of circ&#95;002707 in the development of PE, enhancing our understanding of the disease's mechanism and proposing a viable therapeutic strategy for PE., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Eupatilin, a flavone isolated from Artemisia species, exerts anti-inflammatory, anti-oxidative, and anti-neoplastic activities. However, the effects of eupatilin on H. pylori-associated gastritis remain unclear. Thus, this study aimed to investigate the anti-inflammatory effects of eupatilin on gastric epithelial cells infected with cytotoxin-associated gene A (CagA)-positive Helicobacter pylori., Materials and Methods: AGS human gastric carcinoma cells were infected with a CagA-positive H. pylori strain and then treated with 10, 50, or 100 ng of eupatilin. After 24 h, the expression levels of CagA, phosphoinositide 3-kinase 1 (PI3K), nuclear factor (NF)-κB, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α in the cell lysates were measured using western blotting, and the mRNA levels of IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 were measured using real-time polymerase chain reaction., Results: CagA translocation into AGS cells resulted in an elongated cell morphology, which was significantly suppressed by eupatilin treatment in a dose-dependent manner. Immunofluorescence staining for anti-CagA showed that eupatilin treatment dose-dependently inhibited CagA expression in the H. pylori-infected AGS cells. H. pylori infection increased the levels of pro-inflammatory cytokines including IL-1β, TNF-α, IL-6, IL-8, and MCP-1, and eupatilin treatment significantly reduced the levels of these cytokines in a dose-dependent manner. Additionally, eupatilin treatment dose-dependently suppressed the expression of PI3K and NF-κB., Conclusions: Eupatilin treatment demonstrated anti-inflammatory effects on CagA-positive H. pylori-infected gastric epithelial cells by inhibiting CagA translocation, thereby suppressing the NF-κB signaling pathway. These results suggest that eupatilin plays a protective role against CagA-positive H. pylori-induced gastritis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

PI3K inhibitors have emerged as promising therapeutic agents due to their critical role in various cellular processes, particularly in cancer, where the PI3K pathway is frequently dysregulated. This review explores the evolutionary path of PI3K inhibitors from laboratory discovery to clinical application. The journey begins with early laboratory investigations into PI3K signaling and inhibitor development, highlighting fundamental discoveries that laid the foundation for subsequent advancements. Optimization strategies, including medicinal chemistry approaches and structural modifications, are scrutinized for their contributions to enhancing inhibitor potency, selectivity, and pharmacokinetic properties. The translation from preclinical studies to clinical trials is examined, emphasizing pivotal trials that evaluated efficacy and safety profiles. Challenges encountered during clinical development are critically assessed. Finally, the review discusses ongoing research directions and prospects for PI3K inhibitors, underscoring these agents' continuous evolution and therapeutic potential., 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 Masson SAS. All rights reserved.)