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Impact of Higenamine on the Hepatic Stellate Cells Activation Stimulated by TGF-β1 in Vitro
No full textObjective: The current research aimed to explore the impact of higenamine on the hepatic stellate cells (HCC) activation Stimulated by transforming growth factor-β (TGF-β1) in vitro. Methods: This is a prospective study, we investigated the impact of higenamine on the hepatic stellate cells (HSCs) activation stimulated by TGF-β1 in vitro and Liver fibrosis (LF) stimulated by tetrachloromethane (CCl4) in vivo. ‌Cell Counting Kit-8 (CCK-8) was adopted for detecting the proliferation of LX-2 cells, HSC stain. Reactive Oxygen Species (ROS) production was determined using fluoroprobe 2′,7′-dichlorodihydrofluorescein diacetate (H2DCF-DA). The expression levels of ROS-producing enzymes (NOX2 and NOX4), as well as Smad2, p-Smad3, p-Smad2, and Smad3 were quantified via western blot (WB). The mRNA/protein expression of extracellular matrix (ECM) proteins (collagen I (Col I) and α-smooth muscle actin (α-SMA)) was detected via Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) and WB. Haematoxylin and eosin (H&E) dyeing was conducted using liver tissues to examine histopathological damage and fibrosis. The serum levels of fibrosis biochemical markers including hyaluronic acid (HA), PC-III, as well as Col IV were tested by Enzyme-Linked Immunosorbent Assay (ELISA). Results: Higenamine suppressed the proliferation and ROS production in TGF-β1-intervened LX-2 cells. The increased levels of NOX2/NOX4 and NOX activity in TGF-β1-intervened LX-2 cells were reduced by higenamine. Higenamine inhibited the mRNA/protein expression of α-SMA and Col I in TGF-β1-intervened LX-2 cells. Furthermore, the TGF-β1-intevened phosphorylation of Smad3 and Smad2 was attenuated by higenamine. Conclusion: To sum up, these findings showed that higenamine prevented HSCs activation via the TGF-β1/Smad pathway. Higenamine also attenuated CCl4-caused hepatic damage and fibrosis in vivo. Thus, higenamine is one possible therapeutic agent for LF prevention
LncRNA SENCR Ameliorates Hypoxia-Induced Myocardial Infarction by Targeting the miR-206/SMAD4 Axis
No full textBackground: The long non-coding RNAs (lncRNAs) have been found crucial in the pathogenesis of cardiovascular diseases, including myocardial infarction (MI). Therefore, we aimed to investigate the role of lncRNA smooth muscle and endothelial cell-enriched migration/differentiation-associated lncRNA (SENCR) in MI. Methods: An in vitro model of MI was established by treating human cardiomyocytes (HCM) with hypoxia conditions. The quantitative real-time polymerase chain reaction (RT-qPCR) and western blot analysis were used to assess the expression of genes both at RNA and protein levels. However, Cell Counting Kit-8 (CCK-8) and flow cytometry analysis were employed for the assessment of HCM viability and apoptosis. Furthermore, RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and luciferase reporter assays were conducted to explore the regulatory relationship between SENCR and related molecules. Results: The expression levels of SENCR were found to be progressively reduced in HCM under hypoxia treatment (p < 0.01). Furthermore, overexpression of SENCR stimulated HCM viability and reduced apoptosis rate during hypoxia conditions (p < 0.01). Moreover, SENCR was found to function as a competing endogenous RNA (ceRNA) to sequester miR-206, consequently modulating SMAD family member 4 (SMAD4) expression (p < 0.01). Conclusions: LncRNA SENCR ameliorated hypoxia-induced MI by targeting the miR-206/SMAD4 axis. The findings of this research might offer novel insight for improving the treatment of MI
Construction of Novel GPC3 Antibodies in Diagnosis and Immunotherapy/Targeted Therapy of Hepatocellular Carcinoma: Results and Prospects Based on in Vitro and in Vivo Experiments
No full textBackground: Primary liver cancer (PLC) is the sixth most common malignant tumor in the world. Hepatocellular carcinoma is the most common form (85–90%) of PLC. We aimed to explore the construction of a new type of Glypican-3 (GPC3) antibody and determining its value in the diagnosis and immunotherapy/targeted therapy of hepatocellular carcinoma. Methods: Patients with or with hepatic benign tumors were recruited. Preoperative peripheral blood and postoperative paraffin samples of patients with HCC and peripheral blood samples of patients with benign liver tumors were collected. The expression of GPC3 protein was measured by immunohistochemical assay and enzyme-linked immunosorbent assay (ELISA). The Laser scanning confocal technique was used to observe the phenomenon of endocytosis induced by antibodies and the localization of endocytosis bodies. The viral plasmid targeting GPC3 chimeric antigen receptor (CAR-GPC3) was constructed using BMK antibody and the gene sequences of # 5m and # 49m scFv. The antibody-radionuclide conjugate 131I-anti-GPC3 Conjugate (131I-aGPC3) was prepared by labeling # 49GPC3-mAb with 131I. A mouse model of subcutaneous xenograft tumor was established using 7721 cells without GPC3 and Hep3b cells with high expression of GPC3. The targeting effect of 131I-aGPC3 on tumors in mice was observed by single photon emission computed tomography (SPECT). Results: GPC3 protein was mainly expressed in the tumor cell membrane and cytoplasm. The antibody content in the peripheral blood of patients with positive expression of GPC3 protein was significantly higher than in patients with negative GPC3 protein and benign tumors (p < 0.01). The radiation signals were gradually enriched in the tissue of GPC3-positive tumors. 72 hours after injection, the background signal in vivo gradually disappeared, whereas the radiation signal in the tumor site concentrated significantly concentrated and could last longer. In addition, 131I-aGPC3 was gradually enriched in the tumor site of the Hep3b transplanted tumor model. The radiation signal was significantly enhanced, while in the 7721 transplanted tumors, the antibody was metabolically cleared, and there was no obvious radiation signal. Conclusion: CAR-GPC3-T, constructed with new antibody sequences of # 5GPC3-mAb and # 49GPC3-mAb, kills HCC tumor cells in vitro
The Emerging Trend of Phytochemicals and Nutraceuticals-Based Traditional Medicines and Their Role in Chronic Disease Management
No full textChronic diseases such as cancer, diabetes, heart disease, and obesity are increasingly prevalent and well-researched. The use of traditional medicinal plants may lead to the discovery of new and potent medicinal compounds (phytochemicals) for treating various ailments. Modern medicine currently uses over 7000 phytochemicals, many of which have been utilized for generations by traditional healers. Medicinal plant products have a global market value of over $100 billion annually. Phytochemicals are compounds that are derived from plants and are rich in nutrients. They are often used for medicinal purposes. They are mostly secondary metabolites that can provide nutritional elements and promote long-term health outcomes. Phytochemicals found in herbs, nuts, legumes, grains, fruits, and vegetables include alkaloids, glycosides, tannins, resins, phenolic compounds, terpenoids, pigments, and natural antioxidants that may play a role in managing chronic diseases. These nutritional phytochemicals are encapsulated in various dosage forms and are designated as nutraceuticals. Natural plant diets, nutraceuticals, and nutritional treatments have gained a lot of attention for their potential to improve health and combat ailments. Further research is required to determine the safety, efficacy, and toxicity of plant-derived phytochemicals and nutraceuticals used to treat chronic diseases and meet nutritional needs. This review presents valuable information on the use of phytochemicals and nutraceuticals for treating cancer, autoimmune inflammatory disorders, diabetes, cardiovascular and metabolic disorders, and obesity. It explains the potential ways in which these natural compounds can provide therapeutic benefits in managing chronic illnesses and provides data on their safety and toxicity
In Vitro and In Vivo Evaluation of a Novel Intracanal Medicament for Delayed Teeth Replantation
No full textBackground: In dental avulsion, delayed replantation usually has an uncertain prognosis. After tooth replantation, complex inflammatory responses promote a return to periodontal tissue homeostasis. Various types of cytokines are produced in the inflammatory microenvironment, and these cytokines determine the periodontal tissue response. This study aims to conduct in-depth research on developing a novel root canal medicament, which employed methylcellulose hydrogel as a carrier system and was loaded with clindamycin, acetazolamide and triamcinolone, to determine its triple action of antibacterial, anti-inflammatory and anti-resorptive capabilities in delaying tooth replantation and to preliminarily explore its potential mechanisms of action. Methods: The release concentration of the paste from human extracted root apices was determined using UV-spectrophotometry. The cytotoxicity of corresponding drug concentrations on HPDLFs (human periodontal ligament fibroblasts) was assessed on days 1, 3, 5, and 7 using the CCK-8 (cell counting kit-8) assay. The antibacterial activity against Fusobacterium nucleatum (F. nucleatum) was measured using the agar diffusion method. The gene and protein expression of inflammatory factors (IL-1β (interleukin-1β), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α) and bone metabolism molecules (RANK (Receptor Activator of Nuclear Factor-κB), RANKL (Receptor Activator of Nuclear Factor-κB Ligand), OPG (Osteoprotegerin)) in HPDLFs stimulated with Escherichia coli (E. coli) lipopolysaccharide were determined by ELISA (enzyme-linked immunosorbent assay) and RT-qPCR (real-time quantitative polymerase chain reaction), respectively. Furthermore, the rat delayed replantation tooth models were established and the resorption of incisors was analyzed by micro-CT (micro-computed tomography) after 60 days. The degree of root inflammation and resorption was evaluated by hematoxylin-eosin (HE) staining, and the expression of RANKL/OPG was assessed by immunohistochemical staining. Results: The novel paste showed sustained slow release in root canals for 60 days. In vitro, the experiments demonstrated good cell compatibility and antibacterial activity (p < 0.01). The paste suppressed the expression of IL-1β, IL-6 and TNF-α, and down-regulated the RNA and protein levels of RANKL and OPG in HPDLFs stimulated by E. coli (p < 0.05). In vivo experiments revealed that the novel paste down-regulated the expression of RANKL and OPG, effectively preventing inflammatory root resorption in rat delayed replantation teeth (p < 0.05). Conclusion: The novel paste can inhibit inflammatory root resorption by modulating the RANKL/RANK/OPG signaling pathway and has the potential to be used as an intracanal medicament for root canal treatment in delayed replantation teeth
Epigambogic Acid A from Gamboge Stalk Suppresses Non-Small Cell Lung Cancer Progression by Attenuating DIRC1 Expression
No full textBackground: Gamboge, a desiccating resin secreted by the gamboge tree, has shown potential anti-tumor effects. However, its impact and the underlying mechanisms against lung cancer are not well understood. This study explores the molecular mechanisms through which epigambogic acid A, a principal component of gamboge, inhibits the proliferation of non-small cell lung cancer (NSCLC) cells. Methods: Normal lung epithelial cells BEAS-2B and human NSCLC cells were exposed to various concentrations of epigambogic acid A for 48 and 72 hours (h). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) assay, while colony formation ability was determined through a colony formation assay. Transwell invasion and migration assays were used to evaluate the cells migratory and invasive capacities. Apoptotic processes were analyzed through flow cytometry, and expressions of associated biomarkers were investigated using Western blot. The Illumina HiSeq XTEN platform facilitated sequencing, while quantitative Real-time Polymerase chain reaction (qRT-PCR) quantified the expression of collagen type III alpha 1 chain (COL3A1) and disrupted in renal cancer 1 (DIRC1). Results: Epigambogic acid A significantly inhibited NSCLC cell growth, with a 99.94% inhibition rate. It also reduced cell colony formation and suppressed the migratory and invasive abilities of NSCLC cells, and promoted apoptosis (p < 0.05). Transcriptome sequencing and analysis revealed that epigambogic acid A significantly decreased oncogene levels, including DIRC1 and COL3A1. Furthermore, DIRC1 was found to enhance colony formation and proliferation of NSCLC cells (p < 0.05). Conclusions: This study demonstrates that epigambogic acid A effectively suppresses tumor growth in NSCLC by downregulating DIRC1 expression. These findings suggest that epigambogic acid A is a potential therapeutic target for NSCLC treatment
GATA6 Reduces Pancreatic Cancer Cell Stemness by Modulating Wnt/β-Catenin Signaling
No full textBackground: The stemness capacity of cancer cells has an important role in the initiation and development of pancreatic ductal adenocarcinoma (PDAC). An important regulator of cancer cell stemness is the Wnt/β-catenin signaling pathway. To further deepen the understanding of the pathogenesis of PDAC, the aim of this study was to investigate the regulatory mechanisms of cancer cell stemness. Methods: Genetic screening was performed to identify candidate proteins that might regulate cell stemness in PDAC. Subsequently, Western blot analysis and quantitative polymerase chain reaction (qPCR) assays were used to evaluate the expression of GATA Binding Protein 6 (GATA6) in PDAC cell lines. Stable cell lines expressing GATA6 were also established. Cell counting kit-8 (CCK8) assay, colony formation assay, and gemcitabine resistance assay were used to investigate the effect of GATA6 on the malignant behavior of PDAC cells. Experimental knockdown and overexpression groups were also studied. Western blot and qPCR assays were used to detect alterations in cancer stem cell characteristics after changing the GATA6 protein expression level in PDAC cells. Changes in the knockdown and overexpression groups were compared with controls. Dual-luciferase reporter assays and chromatin immunoprecipitation assays were also used to investigate the molecular mechanisms in this biological model. Results: Using a small range for overexpression screening, GATA6 overexpression was found to significantly reduce the stemness of PDAC cells. Furthermore, stably expressing cell lines were used to show that the malignant biological behavior of PDAC cells was significantly reduced following the overexpression of GATA6, and vice versa for the knockdown of GATA6 (p < 0.05). Western blot and qPCR assays showed that elevated GATA6 protein expression inhibited the stemness of PDAC cells through the Wnt/β-catenin signaling pathway (p < 0.01). Further experiments showed that GATA6 exerts its biological effects by binding to the β-catenin promoter region to inhibit its transcription. Conclusion: GATA6 can inhibit the stemness properties of PDAC cells via the Wnt/β-catenin signaling pathway
Impacts of Cerebral Oxygen Metabolism on Postoperative Nausea and Vomiting in Patients following Thyroid Surgery
Get PDFBackground: Postoperative nausea and vomiting (PONV) is a common side effect after thyroidectomy, which can affect the recovery of patients who underwent thyroid surgery. It has been reported that cerebral oxygen metabolism may affect the occurrence of postoperative adverse reactions. Therefore, this study aimed to investigate the relationship between cerebral oxygen metabolism and PONV incidence in patients after thyroidectomy. Methods: This study retrospectively analyzed the clinical data of 100 female patients who underwent thyroid surgery in a tertiary hospital between May 2022 and September 2023. The study participants were categorized into two groups: the Mannitol group (n = 50), patients who received an intravenous infusion of 0.5 g/kg mannitol at a rate of 150 drops/minute before the operation, and the Control group (n = 50), patients who intravenously received the equivalent volume of normal saline. All participants received the same anesthesia induction and maintenance treatment. During the surgery, we recorded their heart rate (HR), mean arterial pressure (MAP), urine volume, cerebral oxygen metabolism index (cerebral oxygen extraction ratio (CERO2) and difference in arteriovenous oxygen (Da-jvO2)) at each time point, including T0, 5 minutes after entering into the operating room; T1, 5 minutes after tracheal intubation; T2, immediately after cervical hyperextension; T3, immediately after the operation; T4, 50 minutes after the operation; T5, immediately at the operation stopped. Moreover, the incidence of PONV was assessed within 48 hours post-surgery. Results: There were no statistical differences in HR and MAP between the two groups at each time point (p > 0.05). Compared to the Control group, urine output in the Mannitol group showed no significant changes at T0, T1, T2, and T3 (p > 0.05) but significantly increased at T4 and T5 time points (p < 0.05). Da-jvO2 and CERO2 in T1, T2, T3, T4 and T5 time points were significantly reduced compared to T0 (p < 0.05). Compared to T2 and T3, Da-jvO2 and CERO2 at T4 and T5 were significantly reduced in the Mannitol group (p < 0.05), but they showed no substantial changes in the Control group (p > 0.05). Furthermore, Da-jvO2 and CERO2 were significantly decreased at T4 and T5 time points in the Mannitol group compared to the Control group (p < 0.05). Additionally, PONV incidence was significantly lower (26.0%) in the Mannitol group compared to the Control group (50.0%) within 48 hours post-surgery (p < 0.05). The severity of PONV in the Control group was substantially higher than in the Mannitol group. Conclusion: The preoperative intravenous infusion of mannitol can affect cerebral oxygen metabolism, thereby reducing the incidence and severity of PONV in patients who underwent thyroid surgery
SRC-3 Promotes Osteogenic Differentiation by Regulating the Wnt/β-catenin Pathway to Alleviate Osteoporosis
No full textBackground: The disorders of bone resorption and bone formation processes may contribute to the progression of osteoporosis (OP). Moreover, the human bone marrow mesenchymal stem cells (hBM-MSCs) are precursor cells of osteoblasts. Exploring the differentiation mechanism of hBM-MSCs holds immense significance for the prevention and treatment of OP. Furthermore, the steroid receptor coactivator-3 (SRC-3), an important co-activator of estrogen receptor and estrogen-related receptor α, may serve as an important regulator of bone metabolism. However, there are limited studies available on the role as well as the molecular mechanism of SRC-3 in postmenopausal OP (PMOP). Therefore, this study investigated the role of SRC-3 in hBM-MSCs osteogenic differentiation (OD) and delved into its underlying regulatory mechanism. Methods: A total of 60 study subjects, including 30 PMOP patients (OP group) and 30 healthy menopausal women (non-OP (NOP) group) were recruited in this study. Serum SRC-3 levels were assessed using enzyme-linked immunosorbent assay (ELISA). Furthermore, 10 nmol/L of dexamethasone, 10 mmol/L of β-glycerolphosphate, and 50 μg/mL of ascorbic acid were added to the culture medium to induce OD in hBM-MSCs. The expression level of SRC-3 was evaluated employing real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis following OD induction. The impact of SRC-3 on the OD and mineralization of hBM-MSCs was assessed by analyzing alkaline phosphatase (ALP) activity and alizarin red staining (ARS) procedure. Furthermore, changes in the expression levels of OD indicators and Wnt3a/β-catenin were determined by RT-qPCR and Western blot analysis. Results: The expression level of SRC-3 was significantly reduced in the serum of PMOP patients (p < 0.0001). However, OD was successfully induced (p < 0.01, p < 0.001, p < 0.0001) and the expression of SRC-3 was upregulated by SRC-3 overexpression vector (p < 0.01, p < 0.001). Furthermore, SRC-3 overexpression promoted OD of hBM-MSCs (p < 0.01, p < 0.001, p < 0.0001) as well as up-regulated the expression of Wnt3a and β-catenin (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, the inhibition of Wnt3a or β-catenin was found to reverse the promotion of SRC-3 on OD of hBM-MSCs (p < 0.05, p < 0.001, p < 0.0001). Conclusion: In summary, we observed significantly reduced serum SRC-3 level in PMOP patients. Furthermore, SRC-3 overexpression promoted OD and mineralization of hBM-MSCs through the activation of the Wnt/β-catenin signaling pathway, thereby ameliorating OP
Novel N6-Methyladenosine-Associated lncRNA Model for Predicting Biochemical Recurrence in Patients with Prostate Cancer
Get PDFBackground: Prostate cancer (PC) is a solid tumour that is highly prevalent worldwide, ranking as the second most common tumour in humans. The N6-methyladenosine modification of ribonucleic acid (RNA) (m6A) is the most prevalent epigenetic internal modification of both non-coding RNAs (ncRNAs) and messenger RNAs (mRNAs). This study aimed to investigate the link between m6A-related long non-coding RNAs (lncRNAs) and PC to provide a new solution for treating this disease. Methods: This study used a Pearsons correlation analysis to identify m6A-related lncRNAs. The expression and function of AC020907.4, one of the four selected m6A-related lncRNAs, were verified through experimental validation in PC tissue samples and cell lines. In addition, univariate Cox regression was employed to screen these m6A-related lncRNAs for PC. In the validation and entire groups, a least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to establish and validate the prognostic model for biochemical recurrence (BCR), and small interfering RNA (siRNA) was used to knockdown AC020907.4. Real-time quantitative polymerase chain reaction assay was used to detect the mRNA expression level. A cell counting kit-8 assay was used to detected cell viability. Results: In total, this study identified 204 m6A-related lncRNAs and found that 64 of the 204 were linked with BCR in patients diagnosed with PC. The LASSO Cox regression was employed to establish a BCR model containing four lncRNAs (AC020907.4, AC022364.1, AC099850.3 and AP001505.1). Kaplan–Meier curves confirmed the different outcomes in the low-risk and high-risk groups. The effectiveness of the model was evaluated using receiver operating characteristic and concordance index curves. The independence of the model for the prognosis prediction was analysed using univariate and multivariate Cox regression analyses. The knockdown of AC020907.4 reduced the cell viability of PC cells. Conclusions: This study constructed and validated an m6A-related lncRNA model for BCR prediction in patients with PC, providing new insights for research related to m6A and the clinical treatment of PC