Asia Pacific Academy of Science Pte. Ltd.
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Warfarin Promotes Osteoclast Differentiation by Inhibiting the Expression of MGP through ERK Signaling
No full textBackground: Osteoporosis, an osteolytic disease, is characterized by excess osteoclast activity. Warfarin, a widely prescribed oral anticoagulant, has been linked to an increased risk of long-term osteoporosis and fractures. However, the precise role of warfarin plays in osteoclast function remains unclear. Objective: This work aims to assess the impact of warfarin on the Receptor Activator of Nuclear Factor-κ B Ligand (RANKL)-caused osteoclastogenesis, as well as the underlying mechanisms. Methods: We extracted the bone marrow-derived macrophages (BMMs) from C57BL/6 mice (aged 6 weeks, male). A Microplate reader (450 nm, Tecan, RNE-90002, Hong Kong, China) was applied to assess the absorbance. Before the experiment, we extracted several drops of BMMs in equal quantities after cell culture for control and warfarin. The effect of warfarin on RANKL-modulated osteoclast differentiation was assessed by Tartrate-resistant acid phosphatase (TRAP) staining and F-actin detection, which was verified by examining osteoclast-related gene level. We also examined the expression of matrix gla protein (MGP) via Quantitative Real-time PCR (qRT-PCR) and western blot. Osteoclastogenesis-associated signaling pathways were assessed by western blot. Results: Warfarin significantly inhibits the expression of MGP (p < 0.05). TRAP staining illustrated that the warfarin treatment group formed more TRAP-positive osteoclasts. Under a fluorescence microscope, the area of F-actin rings was significantly increased in the warfarin treatment group (p < 0.01). On the other hand, Warfarin up-regulated osteoclast-related gene levels, including Cathepsin K (CTSK), TRAP, Calcitonin receptor (CTR), Dendritic cell-specific transmembrane proteins (DC-STAMP), Guided growth factor (c-Fos). Warfarin up-regulates the expression of RANKL-induced osteoclast differentiation marker genes (p < 0.01 or p < 0.001) significantly. Studies on molecular mechanisms have confirmed that warfarin inhibits the matrix gla protein (MGP) level and activates RANKL-induced ERK (extracellular signal-regulated kinase) signaling. Conclusions: These findings suggest that warfarins promotion of osteoclast differentiation may be linked to the inhibition of MGP and activation of ERK signaling. Consequently, this sheds light on the causes of bone loss associated with warfarin treatment and could have significant implications for clinical practice
Astragaloside IV Ameliorates Diabetic Nephropathy by Regulating NFAT5/Notch/Snail Pathway
No full textBackground: Diabetic nephropathy (DN) is a common complication of diabetes with intricate mechanisms. Our objective was to investigate the potential improvement effects of astragaloside IV (ASV) in a DN cell model and its underlying molecular mechanisms. Methods: High glucose (HG) was employed to induce DN cell model in HK-2 cells, a human renal tubular epithelial cell line. In the initial in vitro experiment, aimed at assessing the impact of ASV on the DN cell model, HK-2 cells were subjected to ASV treatment following HG stimulation. The experimental groups were comprised of Control group, HG group, and HG + ASV treatment group. In the second in vitro experiment, five groups were studied, including Control group, HG group, HG + ASV treatment group, HG + ASV + pcDNA group, and HG + ASV + nuclear factor of activated T cells 5 (NFAT5) group, to elucidate the mechanisms underlying ASVs influence on DN progression. To evaluate the levels of NFAT5, reverse transcription-quantitative PCR (RT-qPCR) was employed. Cell proliferation and apoptosis were measured using flow cytometry, Cell Counting Kit-8 (CCK-8), and 5-Ethynyl-2-deoxyuridine (EdU) assays. Western blot analysis was performed to assess the expression of Collagen Type I (Col. I), α-Smooth Muscle Actin (α-SMA), Fibronectin (FN), Notch1, E-cadherin, Transforming Growth Factor-beta 1 (TGF-β1), NFAT5, Vimentin, Hes1, Jagged1, and Snail. Results: ASV treatment effectively alleviated HG-induced cell damage by enhancing the proliferative capacity, inhibiting cell apoptosis, and suppressing epithelial-mesenchymal transition (EMT) and fibrosis in HK-2 cells (p < 0.05 or p < 0.01). Following HG stimulation, NFAT5 level was increased, and the Notch/Snail pathway was activated (p < 0.01). These effects were significantly ameliorated by ASV treatment (p < 0.01). ASV also demonstrated a direct ability to reduce NFAT5 expression (p < 0.01). Moreover, the positive impact of ASV on cell proliferation and its inhibitory effects on cell apoptosis, EMT, and fibrosis were compromised by NFAT5 overexpression in HK-2 cells after HG stimulation (p < 0.01). Additionally, ASV treatment restrained HG-induced activation of the Notch/Snail pathway (p < 0.01), which was counteracted by NFAT5 overexpression (p < 0.01). Conclusion: ASV demonstrated the protective effects against cell damage induced by HG in HK-2 cells through downregulating NFAT5 and inactivating the Notch/Snail pathway
Contents and Diagnostic Value of β2-MG and UPQ in Patients with Renal Injury from Mercury Poisoning
No full textObjective: We aimed to explore the changes of β2-microglobulin (β2-MG) and urinary protein quantity (UPQ) in mercury poisoning-induced renal injury and their diagnostic significance. Methods: 25 inpatients with mercury poisoning admitted to our hospital from January 2019 to January 2022 were selected as the study group, and 25 healthy controls with no history of mercury exposure were enrolled as the control group. Urine β2-MG was detected by immunoturbidimetric method in midstream urine, UPQ was determined quantitatively by 24 h urine protein, and serum creatinine (Scr) and blood urea nitrogen (BUN) levels were detected by fasting venous blood in the morning. Then the receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of each index for renal injury caused by mercury poisoning. Results: The β2-MG and UPQ of the study group were (0.17 ± 0.12) mg/24 h and (0.14 ± 0.09) mg/24 h respectively, which were significantly higher than the average level of the control group (both p < 0.05). However, the mean levels of Scr and BUN in the study group were (63.64 ± 7.21) μmol/L and (5.08 ± 0.80) mmol/L, respectively, showing no statistical difference compared with the control group (both p > 0.05). The ROC results showed that the area under the curve (AUC) values of β2-MG and UPQ for the diagnosis of mercury poisoning-induced renal injury were 0.586 and 0.617, respectively, while the AUC value of the three combined diagnosis was 0.828, which was significantly higher than that of each parameter alone. Conclusions: Urine β2-MG and UPQ levels are significantly increased in patients with mercury poisoning. The efficacy of the combined three in diagnosing renal injury caused by mercury poisoning is encouraging, contributing immensely to the clinical diagnosis of renal injury caused by mercury poisoning
Adipose-Derived Stem Cells Transfected with GCP-2 Alleviate Pulmonary Arterial Hypertension in Rats by Modulating Apelin/APJ System and eNOS Signaling
No full textObjectives: Pulmonary arterial hypertension (PAH) is a disease characterized by the dysfunction of the lung endothelium and angiogenesis. In this study, we aimed to investigate the effects of granulocyte chemoattractant protein 2 (GCP-2) overexpression on adipose-derived stem cells (ADSCs) and the role of ADSCs overexpressing GCP-2 (ADSC-GCP-2) in PAH. Methods: ADSCs were obtained from the adipose tissues of rats and the expression of CD29 and CD45 surface antigens was detected by flow cytometry. The symptoms and tissue damage of PAH rats induced by monocrotaline were evaluated by observing the weight, heart rate, mean blood pressure (MBP) and hematoxylin-eosin (HE) staining. The mRNA and protein expression of genes were tested by Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. Transwell® and tube formation assays were adopted to measure cell migration and tube formation capacity. Finally, the levels of vascular regulatory and inflammatory factors were measured by ELISA (Enzyme-Linked Immunosorbent Assay). Results: The improvement of cell migration ability, angiogenesis ability (upregulated VEGF (Vascular Endothelial Growth Factor)-A, FGF2 and TGF-β1), tube formation ability and decreased proinflammatory factors levels (downregulated IL (Interleukin) and TNF (Tumor Necrosis Factor)-α) in MBP induced by monocrotaline was significantly downregulated in the rats with ADSC-GCP-2 treatment compared with ADSC-vector, accompanied by improvement in pulmonary artery thickening and vascular remodeling (downregulated VEGF, HGF and α-actin). Moreover, ADSC-GCP-2 could also significantly reduce tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17A, and IL-23 levels and increase IL-10 levels to alleviate inflammation in PAH rats (p < 0.01). In addition, ADSC-GCP-2 activated the apelin/APJ (Angiotensin Receptor-Like 1) and eNOS signaling pathways in PAH rats. Conclusions: ADSC-GCP-2 significantly alleviated PAH progression by regulating the apelin/APJ and eNOS signaling pathways. This study provides a potential therapeutic direction for treating PAH
Atractylenolide I Enhances Cisplatin Sensitivity in Renal Cell Carcinoma through Activation of FOXO1/ATG5 Pathway-Regulated Autophagy Hyperactivation
No full textBackground: A previous study found that Kidney and Spleen Supplement Formula could induce apoptosis in renal cell cancer cells by enhancing autophagy. Atractylenolide I (AT-I), as one of the main active ingredients of Kidney and Spleen Supplement Formula, is believed to have anticancer and chemotherapy-enhancing effects. We mainly focused on the role and mechanism of AT-I in cisplatin chemotherapy of renal cell carcinoma. Methods: Renal cell carcinoma cells were treated with different concentrations of AT-I or cisplatin, and the effects of cell viability and proliferation were determined using Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine (EdU) staining assays. Forkhead box-1 (FOXO1) mRNA levels were detected using quantitative real-time polymerase chain reaction, and autophagy-associated proteins were determined using Western bolt. Results: AT-I concentration-dependently decreased cell viability and proliferation and enhanced the inhibitory effect of cisplatin on cell growth in renal cell carcinoma cells (p < 0.05). AT-I upregulated light chain 3 (LC3) II/LC3 I, Beclin 1, FOXO1, and autophagy-related gene 5 (ATG5) expression and decreased P62 protein levels (p < 0.05). Overexpression of FOXO1 enhanced the inhibitory effect of cisplatin on cell viability and proliferation, while FOXO1 silencing reversed the chemosensitizing effect of AT-I (p < 0.05). Moreover, AT-I promotion of ATG5, Beclin 1, LC3 II/LC3 I, and attenuation of P62 were also partially subverted by FOXO1 silencing (p < 0.01). Conclusion: AT-I enhances cisplatin sensitivity in renal cell carcinoma cells through activation of FOXO1-ATG5 pathway-mediated excessive autophagy
The Action and Mechanism of Action of Ligustrazine Promotes on Myocardial Infarction; An Animal Study
No full textPurpose: This study investigated the action and mechanism of Ligustrazine (TMP) on myocardial infarction (MI). Methods: A MI model was established, using adult male Sprague-Dawley (SD) rats. Heart function indicators were measured, using echocardiography. Real-time reverse transcription polymerase chain reaction (qRT-PCR) assay was used, to measure the micro ribonucleic acid-181a-5p (miR-181a-5p) expression. The therapeutic effect of (miR-181a-5p) on MI mice was investigated, using western blot. Hematoxylin-eosin (HE) staining was used, to determine the cross-section area (CSA) of myocardial cells. The expression of inflammatory cytokines was determined, using ELISA (enzyme-linked immunosorbent assay) kits. Results: The left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) significantly declined while the left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) obviously increased 14 days after MI was established. TMP treatment significantly promoted cardiac function of MI rats. The CSA was significantly elevated in MI rats and TMP treatment significantly abated CSA expression. TMP treatment significantly inhibited the inflammatory cytokines and significantly up-regulated apoptosis-related protein of cardiac tissues in MI rats. In addition, miR-181a-5p significantly increased in MI rats, significantly reversing the therapeutic effect of TMP on MI rats. Signal transducer and activator of transcription 3 (STAT3) was predicted to combine with miR-181a-5p. Conclusions: TMP treatment significantly promoted cardiac function and inhibited the levels of inflammatory cytokines to alleviate MI, by regulating the miR-181a-5p/STAT3 axis
Plasminogen Activator Inhibitor-1 as a Predictive Marker of Severity and Mortality in Sepsis: A Systematic Review and Meta-Analysis
No full textBackground: Sepsis is an abnormal immune response to infection with unknown pathogenesis, seeing unacceptably mortality. Identifying biomarkers could help to diagnose sepsis and monitor its progress. Objective: We aimed to assess the correlation between plasminogen activator inhibitor-1 (PAI-1) levels, and the severity of sepsis and mortality. Methods: PubMed, Cochrane Library, and Excerpta Medica dataBASE (EMBASE) databases were searched based on “plasminogen activator inhibitor-1/PAI-1” and “sepsis”. Weighted mean difference (WMD) with its 95% confidence intervals (CIs) were computed on the eligible trials. Results: 11 trials encompassing 1606 sepsis patients were included. The PAI-1 levels were significantly higher in patients with sepsis-related death than in survivors (p < 0.001) and significantly higher in severe sepsis patients than in nonsevere patients (p = 0.001). Conclusions: PAI-1 could be considered a pivotal biomarker for the severity of sepsis and mortality
The Immunologic Impact of Hashimotos Thyroiditis on Papillary Thyroid Carcinoma: A Systematic Research
No full textBackground: The immunological relationship and the molecular mechanisms underlying the co-occurrence of papillary thyroid carcinoma (PTC) and Hashimotos thyroiditis (HT) are yet to be known. This study aimed to explore the immunological and clinical association between papillary thyroid carcinoma (PTC) and Hashimotos thyroiditis (HT). Method: 680 PTC patients were evaluated for clinicopathological factors and serum thyroid-function level. Among 680 PTC patients, 129 PTC patients with or without HT were investigated the immune-related cytokine levels such as Interleukin, tumor necrosis factor and immune cell percentages (cluster of differentiation (CD)4, CD8, CD3) in the serum using the immunofluorescence-flow cytometry technique. We explored the characteristics of tumor immune microenvironment and the levels of immune cell infiltration of CD4, CD8, CD3, CD20 in tissues using Immunohistochemistry. Results: It was found that the patients with co-existing PTC and HT (PTC+HT) had lower levels of Interleukin-2 (IL-2) (p = 0.023) and Interferon-γ (IFN-γ) (p = 0.003) than those with PTC alone. There was no significant difference in the proportions of CD4, CD8, and CD3 cells in the two groups (p > 0.05). Additionally, the proportions of CD4 and CD3 cells were significantly lower in the PTC+HT group than those with HT alone (p < 0.05). Furthermore, the PTC+HT group had lower lymph node metastasis rates (p = 0.001) and showed no significant difference in the stratification of postoperative recurrence risk (p < 0.05) than those with PTC alone. Moreover, it was observed that the patients with HT had higher levels of CD4+ and CD3+ cell infiltration in their intact thyroid tissues than those with PTC+HT. The level of CD8+ cells was significantly higher in the PTC+HT group of patients than those with PTC alone. However, the level of CD4+ cells was found to be lower in the PTC+HT group of patients. The PTC+HT group of patients with negative lymph node status had more prominent CD4+ T cells intratumoral infiltration than those with positive lymph node metastasis (LNM) (p < 0.05). Moreover, PTC+HT and PTC patients with LNM+ status had lower CD8+ T cell infiltration levels than those with LNM-status (p < 0.05). Conclusion: HT does not attenuate the aggressive factor of lymph node metastasis in PTC patients. Patients with PTC+HT may have different anti-tumor immune mechanisms impacting lymph node metastasis and lower levels of CD4+Th1 cellular immunity than patients with PTC
Impact of ABCA1 Gene Polymorphisms on the Risk of Coronary Artery Disease in Uyghur Population of Xinjiang, China
No full textBackground: ABCA1 (ATP-binding cassette transporter A1 gene) is a principal gene involved in the reverse cholesterol transport and HDL-C (high-density lipoprotein-cholesterol) formation, and ABCA1 polymorphism is related to the development of coronary artery disease (CAD). The objective of this study was to investigate genetic polymorphisms of the ABCA1 gene among Uyghur CAD patients in Xinjiang, China. Methods: The case-control study included 381 Uyghurs with CAD (258 males and 123 females) and 394 healthy Uyghurs (265 males and 129 females). The ABCA1 gene contains two single nucleotide polymorphisms (SNP) (rs2230806 and rs2230808) that were genotyped using SNP scan TM high-throughput genotyping technology. Results: Cases and controls were significantly different in rs2230806 allele distributions in the dominant model (GG vs. GA+AA) and additive model (AA+GG vs. GA) in Uyghur male subjects (p = 0.001 and p = 0.024, respectively). According to a univariate analysis, the GA genotype was correlated with a lessen risk of CAD (OR (odds ratio) = 0.543, 95% CI (confidence interval): 0.369–0.798;p = 0.002), as well as the AA genotype (OR = 0.536, 95% CI: 0.320–0.897;p = 0.018). After adjusting compounding factors such as TG (triglyceride), TC (total cholesterol), LP(a) (lipoprotein a), HDL-C, LDL-C (low-density lipoprotein cholesterol), diabetes, smoking, and hypertension, logistic regression analysis revealed that the AA genotype (OR = 0.570, 95% CI =0.328–0.991, p = 0.046) and GA genotype (OR = 0.484, 95% CI = 0.321–0.723, p = 0.001) of rs2230806 were still correlated with a reduced risk of CAD in Uyghur male subjects. Conclusions: A polymorphism in ABCA1 rs2230806 associated with the A allele in Uyghur men in Xinjiang, China, protects against the risk of CAD
AKT Inhibitor MK-2206 Attenuates Sepsis Acute Lung Injury (SALI) by Regulating Macrophage Polarization and Apoptosis
No full textBackground: Alveolar macrophages accumulation is the leading cause of sepsis acute lung injury (SALI). AKT (protein kinase B, PKB) signaling pathway is closely related to macrophages apoptosis and polarization. This study aimed to assess AKT inhibitor MK-2206 effect on lipopolysaccharide (LPS)-induced macrophages and on acute lung injury in a septic mice model. Methods: Cell Counting Kit-8 (CCK-8) was used to evaluate the impact of MK-2206 on macrophages proliferation in vitro. AKT-mTOR (mammalian target of rapamycin) pathway proteins expression level and apoptosis-related proteins were measured by western blot (WB). Macrophages phenotypic modulation and cell apoptosis level were assessed by flow cytometry. In vivo, survival rate and lung tissue wet: Dry weight ratio were evaluated to assess MK-2206 influence on SALI in septic mice. Immunohistochemistry (IHC) was used to assess alveolar macrophages infiltration. The level of inflammation-related factors were determined by ELISA in vivo and ex vivo. Results: Ex vivo, MK-2206 critically restrained Raw264.7 cell proliferation in a dose-dependent way. MK-2206 at 100 ng/mL could up-regulate macrophages apoptosis and skew macrophages from M1 towards M2, followed by an increased in IL (interleukin)-10 level and decreased TNF-α (tumor necrosis factor-α) level. In vivo, MK-2206 could significantly mitigate alveolar macrophages aggregation, reduce lung tissue edema, down-regulate IL-6 and TNF-α levels in peripheral blood, and improve survival in sepsis mice. Conclusions: This research revealed that MK-2206 may serve as a promising drug in SALI by regulating macrophage apoptosis and macrophage polarization, which consequently inhibits macrophage pro-inflammatory response by down-regulating AKT signaling pathway