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"Wo, Da"
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Lycium barbarum Glycopeptide Inhibits Colorectal Cancer Cell Proliferation via Activating p53/p21 Pathway and Inducing Cellular Senescence
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Its sustained proliferative signaling poses a major challenge for effective therapeutic intervention. Since CRC originates from aberrantly proliferating crypt cells, limiting proliferation or inducing senescence may offer a promising treatment approach. Lycium barbarum glycopeptide (LbGP), a traditional Chinese medicine component, is known for its immunomodulatory and other beneficial effects. This study aims to examine the anti-tumor effects of LbGP in CRC as well as its underlying mechanisms of action. We used CT26 CRC cells to investigate the effects of LbGP on tumor proliferation both in vitro and in an allograft mouse model. LbGP treatment significantly inhibited CT26 cell proliferation in vitro and suppressed tumor growth in CT26-implanted mice. Furthermore, LbGP treatment significantly upregulated p53/p21 levels both in vitro and in vivo, leading to CT26 cell cycle arrest in the S phase and the induction of tumor cell senescence. These findings demonstrate that LbGP effectively induces CRC cell cycle arrest and senescence via the p53/p21 pathway and may serve as a promising candidate for CRC adjuvant therapy.
Journal Article
FOXD2-AS1 is modulated by METTL3 with the assistance of YTHDF1 to affect proliferation and apoptosis in esophageal cancer
This study aims to investigate the regulatory mechanisms of METTL3, YTHDF1, and the long non-coding RNA FOXD2-AS1 in the proliferation and apoptosis of esophageal cancer, with the goal of providing a basis for molecular diagnosis and targeted therapies. Gene expression was evaluated using qRT-PCR (METTL3/14) and Western blot analysis. The Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and Transwell assay were employed to assess cell proliferation and apoptosis. The EpiQuik m6A RNA Methylation Quantification Kit was utilized to quantify total m6A levels. The interaction between YTHDF1, FOXD2-AS1, and METTL3 was confirmed using RNA Binding Protein Immunoprecipitation (RIP), Co-Immunoprecipitation (CO-IP), and RNA pull-down assays. Methylated RNA Immuno preci pitation (MeRIP) was employed to assess the m6A modification levels of FOXD2-AS1. Tissue samples from animal models were analyzed via Hematoxylin-eosin staining (HE) staining and immunohisto-chemistry to assess METTL3 expression.
The expression of
was up-regulated in esophageal cancer tissues and cells. Flow cytometry and CCK-8 detection showed that silencing
could inhibit the proliferation of esophageal cancer cells but accelerate their apoptosis. MeRIP-qPCR and Prediction of m6A-modified sites indicated that METTL3 regulated the m6A modification of FOXD2-AS1.
and
experiments showed that YTHDF1 binds to METTL3 and regulates the m6A modification of FOXD2-AS1 to affect esophageal cancer. Our results indicate that METTL3 regulates FOXD2-AS1 in an m6A-dependent manner through its interaction with YTHDF1, thereby influencing EC proliferation and apoptosis. This suggests a potential therapeutic target for the treatment of esophageal cancer.
Journal Article
Qishen Yiqi Dropping Pills Protect Against Myocardial Infarction in Mice via Activating SIRT3/FOXO3a Signaling Pathway
Background: Myocardial infarction (MI) is the leading cause of morbidity and mortality globally. A major pathological progression of MI is the excess generation of reactive oxygen species (ROS), which results in oxidative stress and damage to the ischemic heart. Because damage to the myocardium is irreversible, the development of new therapeutic agents that can decrease the degree of ischemic damage following MI is crucial. The traditional Chinese medicine formulation, Qishen Yiqi dropping pills (QSYQ), has been clinically used in the treatment of various cardiovascular diseases; however, the precise mechanisms underlying its therapeutic effects remain unelucidated. Methods: In this study, we established murine models of MI via coronary artery ligation to investigate the protective effects and mechanisms of QSYQ following MI. Results: The administration of QSYQ significantly improved cardiac function, reduced infarct size, and attenuated ventricular remodeling in mice that underwent MI. Moreover, MI-induced oxidative stress and downregulated levels of antioxidant enzymes were prevented in mice administered QSYQ via upregulating the SIRT3/FOXO3a signaling pathway. Importantly, pretreatment with a selective SIRT3 inhibitor 3-TYP abolished the cardioprotective effects of QSYQ. Conclusions: Our findings elucidate the role and mechanism of QSYQ in protecting against oxidative damage and restoring redox homeostasis following myocardial infarction. This study provides support for the therapeutic potential of QSYQ in the clinical treatment of myocardial ischemic diseases.
Journal Article
Resveratrol Prevents Breast Cancer Metastasis by Inhibiting Wnt/β-Catenin Pathway-Mediated Epithelial–Mesenchymal Transition
Background: Breast cancer is the most prevalent cancer in women, and metastatic breast cancer remains a major cause of cancer-related deaths. Resveratrol (RSV) is a natural compound found in various plants and is known to exhibit various anti-cancer effects. The present study aims to investigate the therapeutic effects and mechanisms of RSV in inhibiting breast cancer metastasis in a murine model of 4T1 breast tumor that shares close molecular features with human triple negative breast cancer. Methods: Murine breast cancer 4T1 cells were used to examine the effects of RSV on breast cancer metastasis and epithelial–mesenchymal transition (EMT). In vitro cell proliferation and Transwell migration assays and in vivo 4T1 tumor transplantation models were established in female Balb/c mice to determine the anti-metastatic effects of RSV and its mechanism of action. Results: RSV significantly inhibited 4T1 tumor cell migration and significantly decreased expression levels of EMT markers Snail and Vimentin, as well as the nuclear translocation of β-catenin both in vitro and in vivo. Knockdown of β-catenin similarly reduced the expression levels of EMT markers. RSV significantly decreased the number of lung metastases in 4T1-implanted mice by inhibiting Wnt/β-catenin signaling pathway activation. RSV (150 mg/kg/day) reduced the number of visible tumor metastatic nodules and the histological count of metastatic lung carcinomas by 51.82% and 62.58%, respectively, compared to vehicle administration. Conclusions: Our study provides important new mechanistic insight into the strong anti-cancer effects of RSV in inhibiting 4T1 breast cancer metastasis by preventing Wnt/β-catenin signaling pathway-mediated epithelial–mesenchymal transition. These findings suggest the therapeutic potential of RSV as a promising drug in the treatment of metastatic breast cancer.
Journal Article
Liensinine Prevents Acute Myocardial Ischemic Injury via Inhibiting the Inflammation Response Mediated by the Wnt/β-Catenin Signaling Pathway
Myocardial infarction (MI) is characterized by the sudden reduction in myocardial blood flow and remains the leading cause of death worldwide. Because MI causes irreversible damage to the heart, discovering drugs that can limit the extent of ischemic damage is crucial. Liensinine (LSN) is a natural alkaloid that has exhibited beneficial effects in various cardiovascular diseases, including MI; however, its molecular mechanisms of action remain largely unelucidated. In this study, we constructed murine models of MI to examine the potential beneficial effects and mechanisms of LSN in myocardial ischemic injury. Murine models of MI in wild-type and cardiomyocyte-specific β-catenin knockout mice were used to explore the role of LSN and Wnt/β-catenin signaling in MI-induced cardiac injuries and inflammatory responses. The administration of LSN markedly improved cardiac function and decreased the extent of ischemic damage and infarct size following MI. LSN not only prevented excessive inflammatory responses but also inhibited the aberrant activation of Wnt/β-catenin signaling, two factors that are critically involved in the exacerbation of MI-induced injury. Our findings provide important new mechanistic insight into the beneficial effect of LSN in MI-induced cardiac injury and suggest the therapeutic potential of LSN as a novel drug in the treatment of MI.
Journal Article
Paclitaxel alleviates spinal cord injury via activation of the Wnt/β-catenin signaling pathway
Background
Spinal cord injury (SCI) is a disability that causes severe traumatic damage to the central nervous system, with increasing prevalence worldwide. Paclitaxel (PTX) is a naturally occurring plant metabolite that has been shown to exhibit various neuroprotective effects in the central nervous system, however, the specific mechanisms underlying its protective effects in SCI remain unclear. In this study, we aimed to explore the therapeutic effects of PTX in SCI, as well as elucidate the underlying molecular mechanisms associated with its neuroprotective potential.
Methods
Murine models of spinal cord compression were performed followed by intrathecal administration of corresponding agents for 21 days. Mice were randomly divided into the following four groups: Sham, SCI + Saline, SCI + PTX, and SCI + PTX + XAV939. Recovery of lower limb function and strength, as well as muscular atrophy were examined via multiple scored tests. Degree of neuronal and axonal damage, as well as fibrosis were examined via immunohistochemical staining.
Results
PTX administration significantly improved the recovery of lower limb function and strength, prevented muscular atrophy, as well as decreased the extent of neuronal and axonal death following SCI surgery. PTX also robustly activated the Wnt/β-catenin protein signaling pathway that played a key role in its therapeutic effects. Co-administration with a Wnt/β-catenin pathway inhibitor - XAV939, significantly abolished the beneficial effects of PTX after SCI.
Conclusion
This study provides important new mechanistic insight on the beneficial effects of PTX in protecting against spinal cord injury, as well as the experimental basis for its potential therapeutic use.
Journal Article
Babao Dan Alleviates Cancer Cachexia in Mice Via Inhibiting IL-6/STAT3 Signaling Pathway
Background:
Cancer cachexia is a common but severe condition that causes muscle wasting, body weight loss, and progressive functional impairment, affecting over 50% of cancer patients. Currently, there are no effective treatments that can alleviate cachexia, and hence the discovery of new therapeutics that can effectively prevent or even reverse cancer cachexia is crucial. Babao Dan (BBD) is a Traditional Chinese Medicine (TCM) formula that has been used clinically in combating various cancers, however, its therapeutic potential in alleviating cancer cachexia remains unexplored. Our current study aims to determine the anti-cachectic effects of BBD treatment in alleviating cancer cachexia, as well as determining the underlying mechanisms involved.
Methods:
Mouse models of cancer cachexia were induced via implantation of CT26 colon adenocarcinoma cells, and the anti-cachectic effects and mechanisms of BBD were determined via examinations of body weight and muscle mass, as well as serum and muscle markers of cachexia and muscle atrophy.
Results:
CT26 tumor implantation reduced in the rapid occurrence of cancer cachexia characterized by marked reductions in body weight and muscle mass, functional decrease in muscle function and accelerated deaths. BBD administration not only demonstrated robust anti-cachectic ability via preventing decreases in body weight, muscle mass, and muscle atrophy, but also markedly prolonged survival. The effects of BBD in alleviating cancer cachexia and its associated adverse effects were due to its ability in preventing the activation of IL-6/STAT3 signaling post-CT26 tumor implantation.
Conclusion:
Our findings demonstrated the robust ability of BBD in preventing cancer cachexia and alleviating the main cachexia-induced symptoms as well as prolonging survival via inhibiting activation of IL-6/STAT3 signaling pathway. Therefore, our study demonstrating the strong anti-cachectic effects of BBD in mice may provide a theoretical basis for the use of BBD as a safe and effective drug in the treatment of cancer cachexia.
Journal Article
Qingda granule prevents Ang II-induced cardiac hypertrophy via inhibiting NF-κB signaling pathway
Angiotensin II (Ang II) type 1 receptor (AT1R) signaling pathway is a key component of the renin-angiotensin-aldosterone system (RAAS) that is involved in the development of hypertension. Chronic Ang II overactivation results in pathological cardiac hypertrophy that progresses into decompensated cardiac dysfunction and impairment. Qingda granule (QDG) is a Traditional Chinese formula that has been used clinically in treating hypertension and its complications.
This study aimed to elucidate the role and underlying mechanisms of QDG in preventing Ang II-induced cardiac hypertrophy.
We used chronic Ang II infusion via minipumps in mice and administered QDG daily to examine the effects of QDG on preventing hypertension and various parameters of cardiac impairment.
QDG treatment significantly reduced Ang II-induced elevation in blood pressure. Furthermore, QDG exerted a robust cardioprotective effect on chronic Ang II-induced cardiac hypertrophy and decompensated cardiac dysfunction. QDG also inhibited Ang II-induced adverse NF-κB signaling activation and downstream pro-inflammatory targets, which were prevented via administration with SC75741, a specific NF-κB inhibitor.
Our findings provide further insight into the robust ability of QDG in preventing Ang II-induced cardiac hypertrophy via preventing NF-κB signaling activation and implicate its use in the clinical treatment of hypertension and cardiac hypertrophy.
Journal Article
Deletion of low-density lipoprotein-related receptor 5 inhibits liver Cancer cell proliferation via destabilizing Nucleoporin 37
Background
LRP5/6 are co-receptors in Wnt/β-catenin pathway. Recently, we discovered multiple β-catenin independent functions of LRP5/6 in tumor cells and in the diseased heart. Nucleoporin 37 (NUP37) is an important component of the nuclear pore complex (NPC), whose elevated expression is associated with worsened prognosis in liver cancer. Previous studies have shown that NUP37 interacted with YAP and activated YAP/TEAD signaling in liver cancer. Our preliminary findings showed a nuclear location of LRP5. We thus tested the hypothesis that LRP5 may act as a genuine regulator of YAP/TEAD signaling via modulating NUP37 in a β-catenin-independent way.
Methods
We performed siRNA knockdown of LRP5, LRP6, or β-catenin in liver cancer HepG2 cells to determine the effect on tumor cell proliferation. Protein expressions and interaction between LRP5 and NUP37 were determined using immunoprecipitation and western blot analyses.
Results
HepG2 cell proliferation was markedly inhibited by knockdown of LRP5 but not LRP6 or β-catenin, suggesting that LRP5 has a specific, β-catenin-independent role in inhibiting HepG2 cell proliferation. Knockdown of NUP37 by siRNA inhibited the proliferation of HepG2 cells, whereas overexpression of NUP37 reversed the decrease in cell proliferation induced by LRP5 knockdown. Immunoprecipitation assays confirmed that LRP5 bound to NUP37. Furthermore, LRP5 overexpression restored NUP37 knockdown-induced downregulation of YAP/TEAD pathway.
Conclusions
LRP5 deletion attenuates cell proliferation via destabilization of NUP37, in a β-catenin-independent manner. LRP5 therefore acts as a genuine regulator of YAP/TEAD signaling via maintaining the integrity of the NPC, and implicates a therapeutic strategy in targeting LRP5 for inhibiting liver cancer cell proliferation.
Journal Article