CYP3A4 and GCK genetic polymorphisms are the risk factorsof tacrolimus-induced new-onset diabetes after transplantation in renaltransplant recipients

AbstractPurpose We intend to investigate the association between tacrolimus-induced new-onset diabetes after transplantation (NODAT)and polymorphisms of CYP3A4,CYP3A5,ATP-binding cassette transporter sub-family C member 8 (ABCC8), and glucokinase(GCK) in renal transplant recipients.Methods Polymorphisms of CYP3A4 *18B, CYP3A5 *3, ABCC8 T-3C, and GCK G-30A were genotyped in 169 renaltransplant recipients. Trough concentrations of tacrolimus were detected by an ELISA kit. The relative materials were collectedin all patients and volunteers. The association of NODAT and polymorphisms was analyzed.Results CYP3A4 *18B and GCK G-30A were related to NODAT (p < 0.05). The lower concentration/dose or fasting serumglucose was in CYP3A4 *1/*1 carriers than that in *18B/*18B carriers in all the renal transplant recipients (p < 0.05), respectively.Genotype of ABCC8 T-3C was associated with fasting serum glucose in both NODATand non-NODAT patients (p < 0.05).Furthermore, family history of DM (OR = 3.734, p = 0.002), concentration/dose above 70 ([ng/mL]/[mg/kg]) (OR = 2.154, p =0.034) and GCKG-30A(OR = 2.272, p = 0.026) were independently correlated with the incidence ofNODATin logistic regression.Conclusions The polymorphisms of CYP3A4 *18B and GCK G-30A were related to NODAT induced by tacrolimus.Keywords Tacrolimus . New-onset diabetes after transplantation . Single nucleotide polymorphisms . Cytochrome P450 .Glucokinase . Renal transplantatio

Research on power system fault prediction based on GA-CNN-BiGRU

Introduction: This paper proposes a power system fault prediction method that utilizes a GA-CNN-BiGRU model. The model combines a genetic algorithm (GA), a convolutional neural network (CNN), and a bi-directional gated recurrent unit network Bidirectional Gated Recurrent Unit to accurately predict and analyze power system faults.Methods: The proposed model employs a genetic algorithm for structural search and parameter tuning, optimizing the model structure. The CNN is used for feature extraction, while the bi-directional gated recurrent unit network is used for sequence modeling. This approach captures the correlations and dependencies in time series data and effectively improves the prediction accuracy and generalization ability of the model.Results and Discussion: Experimental validation shows that the proposed method outperforms traditional and other deep learning-based methods on multiple data sets in terms of prediction accuracy and generalization ability. The method can effectively predict and analyze power system faults, providing crucial support and aid for the operation and management of power systems

Glycolysis inhibition via mTOR suppression is a key step in cardamonin-induced autophagy in SKOV3 cells

Abstract Background Autophagy occurs in cells that undergoing nutrient deprivation. Glycolysis rapidly supplies energy for the proliferation of cancer cells. Cardamonin inhibits proliferation and enhances autophagy by mTORC1 suppression in ovarian cancer cells. Here, we investigate the relationship between cardamonin-triggered autophagy and glycolysis inhibition via mTORC1 suppression. Methods Treated with indicated compounds, ATP content and the activity of hexokinase (HK) and lactate dehydrogenase (LDH) were analyzed by the assay kits. Autophagy was detected by monodansylcadaverin (MDC) staining. The relationship between cardamonin-triggered autophagy and glycolysis inhibition via mTORC1 suppression was analyzed by Western blot. Results We found that cardamonin inhibited the lactate secretion, ATP production, and the activity of HK and LDH. The results demonstrated that cardamonin enhanced autophagy in SKOV3 cells, as indicated by acidic compartments accumulation, microtubule-associated protein 1 Light Chain 3-II (LC3-II) and lysosome associated membrane protein 1 up-regulation. Our results showed that the activation of mTORC1 signaling and the expression HK2 were reduced by cardamonin; whereas the phosphorylation of AMPK (AMP-activated protein kinase) was increased. We also confirmed that the AMPK inhibitor, Compound C, reversed cardamonin-induced upregulation of LC3-II. Conclusion These results suggest that cardamonin-induced autophagy is associated with inhibition on glycolysis by down-regulating the activity of mTORC1 in ovarian cancer cells

Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma

Abstract Background mTORC1 (mechanistic target of rapamycin complex 1) is associated with lymphoma progression. Oncogenic RRAGC (Rag guanosine triphosphatase C) mutations identified in patients with follicular lymphoma facilitate the interaction between Raptor (regulatory protein associated with mTOR) and Rag GTPase. It promotes the activation of mTORC1 and accelerates lymphomagenesis. Cardamonin inhibits mTORC1 by decreasing the protein level of Raptor. In the present study, we investigated the inhibitory effect and possible mechanism of action of cardamonin in RRAGC-mutant lymphoma. This could provide a precise targeted therapy for lymphoma with RRAGC mutations. Methods Cell viability was measured using a cell counting kit-8 (CCK-8) assay. Protein expression and phosphorylation levels were determined using western blotting. The interactions of mTOR and Raptor with RagC were determined by co-immunoprecipitation. Cells overexpressing RagC wild-type (RagCWT) and RagC Thr90Asn (RagCT90N) were generated by lentiviral infection. Raptor knockdown was performed by lentivirus-mediated shRNA transduction. The in vivo anti-tumour effect of cardamonin was assessed in a xenograft model. Results Cardamonin disrupted mTOR complex interactions by decreasing Raptor protein levels. RagCT90N overexpression via lentiviral infection increased cell proliferation and mTORC1 activation. The viability and tumour growth rate of RagCT90N-mutant cells were more sensitive to cardamonin treatment than those of normal and RagCWT cells. Cardamonin also exhibited a stronger inhibitory effect on the phosphorylation of mTOR and p70 S6 kinase 1 in RagCT90N-mutant cells. Raptor knockdown abolishes the inhibitory effects of cardamonin on mTOR. An in vivo xenograft model demonstrated that the RagCT90N-mutant showed significantly higher sensitivity to cardamonin treatment. Conclusions Cardamonin exerts selective therapeutic effects on RagCT90N-mutant cells. Cardamonin can serve as a drug for individualised therapy for follicular lymphoma with RRAGC mutations

Convolutional Neural Network Defect Detection Algorithm for Wire Bonding X-ray Images

To address the challenges of complex backgrounds, small defect sizes, and diverse defect types in defect detection of wire bonding X-ray images, this paper proposes a convolutional-neural-network-based defect detection method called YOLO-CSS. This method designs a novel feature extraction network that effectively captures semantic features from different gradient information. It utilizes a self-adaptive weighted multi-scale feature fusion module called SMA which adaptively weights the contribution of detection results based on different scales of feature maps. Simultaneously, skip connections are employed at the bottleneck of the network to ensure the integrity of feature information. Experimental results demonstrate that on the wire bonding X-ray defect image dataset, the proposed algorithm achieves mAP 0.5 and mAP 0.5–0.95 values of 97.3% and 72.1%, respectively, surpassing the YOLO series algorithms. It also exhibits certain advantages in terms of model size and detection speed, effectively balancing detection accuracy and speed

Additional file 2 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma

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Insights into the Action Mechanisms of Traditional Chinese Medicine in Osteoarthritis

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by articular cartilage destruction, synovial inflammation, and osteophyte formation. No effective treatments are available. The current pharmacological medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics, accompanied by possible adverse effects, might ameliorate OA symptoms. But they do not arrest the progression of OA. Traditional Chinese medicine (TCM) provides medical value by modification of disease and symptoms in OA. Valuable work on exploring TCM merits for OA patients has been investigated using modern technologies, although the complicated interacting network among the numerous components indicates the uncertainty of target specification. This review will provide an overview of the action mechanism of TCM in the last 5 years, discussing the TCM activities of anti-inflammation, antiapoptosis, antioxidation, anticatabolism, and proliferation in OA. TCM is a proposed medical option for OA treatment

Raptor couples mTORC1 and ERK1/2 inhibition by cardamonin with oxidative stress induction in ovarian cancer cells

Background A balance on nutrient supply and redox homeostasis is required for cell survival, and increased antioxidant capacity of cancer cells may lead to chemotherapy failure. Objective To investigate the mechanism of anti-proliferation of cardamonin by inducing oxidative stress in ovarian cancer cells. Methods After 24 h of drug treatment, CCK8 kit and wound healing test were used to detect cell viability and migration ability, respectively, and the ROS levels were detected by flow cytometry. The differential protein expression after cardamonin administration was analyzed by proteomics, and the protein level was detected by Western blotting. Results Cardamonin inhibited the cell growth, which was related to ROS accumulation. Proteomic analysis suggested that MAPK pathway might be involved in cardamonin-induced oxidative stress. Western blotting showed that cardamonin decreased Raptor expression and the activity of mTORC1 and ERK1/2. Same results were observed in Raptor KO cells. Notably, in Raptor KO cells, the effect of cardamonin was weakened. Conclusion Raptor mediated the function of cardamonin on cellular redox homeostasis and cell proliferation through mTORC1 and ERK1/2 pathways

Additional file 4 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma

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Additional file 5 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma

Supplementary Material