UNASSIGNED: The objective of this investigation was to elucidate the key active compounds and molecular mechanisms underlying the therapeutic potential of airpotato yam rhizome (AYR) in colorectal cancer (CRC) treatment.
UNASSIGNED: By utilizing network pharmacology and molecular docking, key targets and signaling pathways of AYR against CRC were predicted and subsequently validated in cellular and mouse xenograft models.
UNASSIGNED: This study initially predicted that quercetin was the primary compound in AYR that might have potential efficacy against CRC and that EGFR and AKT1 could be the main targets of AYR, with the EGF/EGFR-induced PI3K/AKT signaling pathway potentially playing a crucial role in the anti-CRC effects of AYR. Molecular docking analysis further indicated a strong binding affinity between quercetin and EGFR, primarily through hydrogen bonds. Additionally, the AYR-derived drug-containing serum was found to inhibit the PI3K/AKT signaling pathway, as demonstrated by decreased levels of p-PI3K, p-AKT, and BCL2, which ultimately led to enhanced apoptosis of HCT116 and HT29 cells. The potential antitumor effects of AYR were investigated in nude mouse xenograft models of human HCT116 and HT29 cells, in which AYR was found to induce tumor cell apoptosis and inhibit tumor formation.
UNASSIGNED: AYR may promote CRC cell apoptosis by suppressing the PI3K/AKT signaling pathway, which provides a basis for further research on the safe and effective use of AYR for the treatment of CRC.

Acute myeloid leukemia (AML) is a kind of heterogeneous hematologic malignancy with high incidence, which is usually treated by intensive and maintenance treatment with large dose of conventional chemotherapy drugs. However, cell resistance is still an unsolved problem. The abnormal expression of miRNAs is closely related to the pathogenesis and progression of AML, and affects the drug resistance of cancer cells. miR-149-3p plays an important role in the resistance of cancer cells to cisplatin, and plays an excellent anti-tumor activity. By studying the function of miR-149-3p, it is expected to find new therapeutic methods to reverse chemotherapy resistance. In order to explore the mechanism of action of miR-149-3p on AML chemotherapeutic drug sensitivity, we explored the relationship between the Warburg effect and AML chemotherapeutic drug resistance. Based on AML cells, transfection of miR-149-3p inhibitor/NC and Warburg effect inhibitor (2DG) and PI3K/AKT pathway inhibitor (LY294002) were used to investigate the mechanism of IFN-γ regulating chemotherapy resistance of AML cells through Warburg effect. Down-regulation of miR-149-3p significantly inhibited drug sensitivity of AML cells. Down-regulation of miR-149-3p significantly promoted proliferation and invasion of AML cells while inhibiting apoptosis by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax. Down-regulation of miR-149-3p significantly promoted the expression of Warburg effect-related proteins hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and Glucose transporter 1 (GLUT1), glucose consumption, lactic acid, and intracellular ATP production. After inhibiting the Warburg effect with 2DG, the effect of miR-149-3p was inhibited, suggesting that upregulation of miR-149-3p reversed AML cell resistance by inhibiting the Warburg effect. In addition, miR-149-3p interacted with AKT1. Down-regulation of miR-149-3p increased the expression of inosine phosphate 3 kinase (PI3K), protein kinase B (AKT), and multi-drug resistance protein (MDR1). LY294002 inhibited the expression of these proteins, and down-regulation of miR-149-3p reversed the effect of LY294002 and improved the drug resistance of cells. Upregulation of miR-149-3p expression may potentially be a therapeutic target for AML resistance. It has been shown to inhibit PI3K/AKT pathway activation, thereby inhibiting the Warburg effect, and affecting cell proliferation, apoptosis, and drug resistance.

OBJECTIVE: Glioblastoma (GBM) is the most aggressive of intracranial gliomas. Despite the maximal treatment intervention, the median survival rate is still about 14-16 months. Nuclear receptor-binding protein 1 (NRBP1) has a potential growth-promoting role on biology function of cells. In this study, we investigated whether NRBP1 promotes GBM malignant phenotypes and the potential mechanisms.
METHODS: The correlation between NRBP1 and glioma grade, prognosis in TCGA/CGGA databases and our clinical data were analyzed. Next, we conducted knockout and overexpression of NRBP1 on GBM cells to verify that NRBP1 promoted cell proliferation, invasion, and migration in vitro and in vivo. Finally, we detected the impact of NRBP1 on PI3K/Akt signaling pathway and EMT.
RESULTS: There was a correlation between elevated NRBP1 expression and advanced stage glioma, as well as decreased overall and disease-free survival. The suppression of proliferation, invasion, and migration of tumor cells was observed upon NRBP1 knockout, and in vitro studies also demonstrated the induction of apoptotic cell death. Whereas, its overexpression is associated with high multiplication rate, migration, invasion, and apoptotic escape. GO enrichment and KEGG analysis revealed that NRBP1 regulated differentially expressed gene clusters are involved in PI3K/Akt signaling pathway, as well as EMT mediated by this pathway. Moreover, the effects of NRBP1 knockdown and overexpression on GBM were mitigated by MK-2206 and SC79, both of which respectively function as an inhibitor and an activator of the PI3K/Akt signaling pathway. Similarly, the suppression of NRBP1 led to a decrease in tumor growth, whereas its overexpression promoted tumor growth in a mouse model.
CONCLUSIONS: This study shows that NRBP1 promotes malignant phenotypes in GBM by activating PI3K/Akt pathway. Hence, it can function as both a predictive indicator and a new target for therapies in GBM treatment.

UNASSIGNED: Almonertinib is an important third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) exhibiting high selectivity to EGFR-sensitizing and T790M-resistant mutations. Almonertinib resistance is a major obstacle in clinical use. Baicalein possesses antitumor properties, but its mechanism of antitumor action against almonertinib-resistant non-small cell lung cancer (NSCLC) remains unelucidated.
UNASSIGNED: CCK-8 assay was used to examine the survival rate of H1975/AR and HCC827/AR cells following treatment for 24 h with different concentrations of baicalein, almonertinib or their combination. The changes in colony formation ability, apoptosis, and intracellular reactive oxygen species (ROS) levels of the treated cells were analyzed using colony formation assay and flow cytometry. Western blotting was performed to detect the changes in protein expressions in the cells. The effects of pre-treatment with NAC on proliferation, apoptosis, and PI3K/Akt signaling pathway were observed in baicalein- and/or almonertinib-treated cells. A nude mouse model bearing subcutaneous HCC827/AR cell xenograft were treated with baicalein (20 mg/kg) or almonertinib (15 mg/kg), and the tumor volume and body mass changes was measured.
UNASSIGNED: Both baicalein and almonertinib represses the viability of HCC827/AR and H1975/AR cells in a concentration-dependent manner. Compared with baicalein or almonertinib alone, the combined application of the two drugs dramatically attenuates cell proliferation; triggers apoptosis; causes cleavage of Caspase-3, PARP, and Caspase-9; downregulates the protein expressions of p-PI3K and p-Akt; and significantly inhibits tumor growth in nude mice. Furthermore, baicalein combined with almonertinib results in massive accumulation of reactive oxygen species (ROS) and preincubation with N-acetyl-L-cysteine (ROS remover) prevents proliferation as well as inhibits apoptosis induction, with partial recovery of the decline of p-PI3K and p-Akt.
UNASSIGNED: The combination of baicalein and almonertinib can improve the antitumor activity in almonertinib-resistant NSCLC through the ROS-mediated PI3K/Akt pathway.

BACKGROUND: While the annual incidence of diabetic kidney disease (DKD) has been soaring, the exact mechanisms underlying its onset and progression remain partially understood.
OBJECTIVE: The present study delved into the underlying mechanisms of Jisheng Shenqi Pill (JSP) in the treatment of DKD.
METHODS: The active constituents and prospective targets of JSP were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), while DKD-associated disease targets were obtained from the GeneCards database. Subsequently, Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the overlapping segment of drugs and disease targets. Meanwhile, a component-target-pathway network was constructed to identify pivotal components, targets, and pathways. Molecular docking and molecular dynamics simulation were also carried out to validate the binding efficacy of the pivotal components with the targets. Finally, animal experiments were conducted to corroborate the efficacy of the aforementioned targets and pathways.
RESULTS: According to bioinformatics analysis, the primary targets included JUN, TNF, and BAX, while the pivotal pathways involved were AGE/RAGE and PI3K/AKT signaling cascades. In vivo experiments demonstrated that JSP effectively mitigated renal impairment in DKD by reducing renal inflammation and apoptosis. This effect was presumably achieved by modulating the AGERAGE axis and the PI3K/AKT signaling pathway.
CONCLUSIONS: Our findings imply that JSP could ameliorate renal inflammation and apoptosis in DKD mice by modulating the AGE/RAGE axis and the PI3K/AKT signaling pathway. These findings provide valuable insights into traditional Chinese medicine-based treatments for DKD.

Increasing evidence suggests that tissue inhibitor of metalloproteinase 1 (TIMP1) played a pivotal role in immune regulation. Our study focused on examining the expression and function of TIMP1 in humans, particularly in its regulation of tumor-associated macrophages (TAMs) in papillary thyroid carcinoma (PTC). We observed an upregulation of TIMP1 in 16 different types of malignancies, including thyroid cancer. TIMP1 shaped the inflammatory TME in PTC. Inhibiting the expression of TIMP1 has been demonstrated to reduce the malignant biological traits of PTC cells. Furthermore, reducing TIMP1 expression impeded M2 macrophage polarization as well as facilitated M1 macrophage polarization in PTC. ELISA results demonstrated that downregulated TIMP1 expression correlated with decreased levels of IL10 and TGF-β in cell supernatants. Furthermore, the supernatant from polarized macrophages in the TIMP1-silenced group inhibited the motility of wild-type PTC cells. Therefore, TIMP1 may enhance the progression of PTC by stimulating the PI3K/AKT pathway via the secretion of IL10 and TGF-β, consequently influencing M2-type polarization in TAMs.

BACKGROUND: Mitochondrial dysfunction and metabolic reprogramming can lead to the development and progression of hepatocellular carcinoma (HCC). Ferredoxin 1 (FDX1) is a small mitochondrial protein and recent studies have shown that FDX1 plays an important role in tumor cuproptosis, but its role in HCC is still elusive. In this study, we aim to investigate the expression and novel functions of FDX1 in HCC.
METHODS: FDX1 expression was first analyzed in publicly available datasets and verified by immunohistochemistry, qRT-PCR and Western blot. In vitro and in vivo experiments were applied to explore the functions of FDX1. Non-targeted metabolomics and RNA-sequencing were used to determine molecular mechanism. mRFP-GFP-LC3 lentivirus transfection, Mito-Tracker Red and Lyso-Tracker Green staining, transmission electron microscopy, flow cytometry, JC-1 staining, etc. were used to analyze mitophagy or ROS levels. Hydrodynamic tail vein injection (HTVi) and patient-derived organoid (PDO) models were used to analyze effect of FDX1 overexpression.
RESULTS: FDX1 expression is significantly downregulated in HCC tissues. FDX1 downregulation promotes HCC cell proliferation, invasion in vitro and growth, metastasis in vivo. In addition, FDX1 affects metabolism of HCC cells and is associated with autophagy. We then confirmed that FDX1 deficiency increases ROS levels, activates mitophagy and the PI3K/AKT signaling pathway in HCC cells. Interestingly, scavenging ROS attenuates the tumor-promoting role and mitophagy of FDX1 downregulation. The results of HTVi and PDO models both find that FDX1 elevation significantly inhibits HCC progression. Moreover, low FDX1 expression is associated with shorter survival and is an independent risk factor for prognosis in HCC patients.
CONCLUSIONS: Our research had investigated novel functions of FDX1 in HCC. Downregulation of FDX1 contributes to metabolic reprogramming and leads to ROS-mediated activation of mitophagy and the PI3K/AKT signaling pathway. FDX1 is a potential prognostic biomarker and increasing FDX1 expression may be a potential therapeutic approach to inhibit HCC progression.

Alzheimer\'s disease (AD), a prevalent cognitive disorder among the elderly, is frequently linked to the abnormal accumulation of myloid-β (Aβ), which is mainly as a result of neuronal death and inflammation. Diosmin, a flavonoid, is considered a potential drug for the treatment of AD. Our study aimed to uncover the molecular mechanism of diosmin in AD therapy. Here, rats were randomly divided into three groups: control, Aβ25-35, and Aβ25-35 + diosmin groups. AD model rats were induced by Aβ25-35 intraventricular injection, meanwhile 50 mg/kg diosmin was orally administered for 6-week intervention. Morris water maze test assessed learning and memory abilities. Hippocampal neuronal damage was determined by HE, Nissl, and TUNEL staining. These assays indicate that diosmin improves cognitive dysfunction and reduces hippocampal neuronal loss and apoptosis. Western blot showed that diosmin reduced Bax (1.21 ± 0.12) and cleaved caspase-3 (1.27 ± 0.12) expression, and increased Bcl-2 (0.70 ± 0.06), p-PI3K (0.71 ± 0.08), and p-AKT (0.96 ± 0.10) in the hippocampus. ELISA indicated diosmin reduces IL-1β, IL-6, and TNF-α levels, suggesting anti-inflammation effect. These results suggest that diosmin inhibits neuronal apoptosis and neuroinflammatory responses to improve cognitive dysfunction in AD rats, possibly related to upregulation of the PI3K/AKT pathway, providing a scientific basis for its use in AD treatment.

Thyroid cancer, as one of the most common cancers in many countries, has attracted increasing attention, but its pathogenesis is still unclear. This research explored the effects of miR-144-3p and GABRB2 on thyroid cancer cells and the underlying mechanism. Gene expression data was obtained from the GEO database to analyze differential expression of mRNAs and miRNAs in patients with thyroid cancer. CCK-8, transwell, scratch, and flow cytometry assays were performed to detect cell proliferation, invasion, migration, and apoptosis, respectively. Dual-luciferase reporters were used to detect the binding of miR-144-3p to GABRB2. GABRB2 was highly expressed and miR-144-3p was underexpressed in thyroid cancer. In thyroid cancer cells, inhibiting GABRB2 or upregulating miR-144-3p reduced proliferation, invasion, and migration and increased apoptotic rates; GABRB2 overexpression or miR-144-3p inhibition brought about the opposite results. miR-144-3p targeted GABRB2 and negatively regulated its expression. PI3K/AKT activation was reduced in thyroid cancer cells overexpressing miR-144-3p. GABRB2 overexpression partially mitigated the tumor-suppressive effect of miR-144-3p overexpression. In conclusion, miR-144-3p targets GABRB2 to inhibit PI3K/AKT activation, thereby inhibiting the progression of thyroid cancer in vitro.

BACKGROUND: Nanoplastics (NPs) are emerging pollutants that pose risks to living organisms. Recent findings have unveiled the reproductive harm caused by polystyrene nanoparticles (PS-NPs) in female animals, yet the intricate mechanism remains incompletely understood. Under this research, we investigated whether sustained exposure to PS-NPs at certain concentrations in vivo can enter oocytes through the zona pellucida or through other routes that affect female reproduction.
RESULTS: We show that PS-NPs disrupted ovarian functions and decreased oocyte quality, which may be a contributing factor to lower female fertility in mice. RNA sequencing of mouse ovaries illustrated that the PI3K-AKT signaling pathway emerged as the predominant environmental information processing pathway responding to PS-NPs. Western blotting results of ovaries in vivo and cells in vitro showed that PS-NPs deactivated PI3K-AKT signaling pathway by down-regulating the expression of PI3K and reducing AKT phosphorylation at the protein level, PI3K-AKT signaling pathway which was accompanied by the activation of autophagy and apoptosis and the disruption of steroidogenesis in granulosa cells. Since PS-NPs penetrate granulosa cells but not oocytes, we examined whether PS-NPs indirectly affect oocyte quality through granulosa cells using a granulosa cell-oocyte coculture system. Preincubation of granulosa cells with PS-NPs causes granulosa cell dysfunction, resulting in a decrease in the quality of the cocultured oocytes that can be reversed by the addition of 17β-estradiol.
CONCLUSIONS: This study provides findings on how PS-NPs impact ovarian function and include transcriptome sequencing analysis of ovarian tissue. The study demonstrates that PS-NPs impair oocyte quality by altering the functioning of ovarian granulosa cells. Therefore, it is necessary to focus on the research on the effects of PS-NPs on female reproduction and the related methods that may mitigate their toxicity.