Pemigatinib, a selective FGFR inhibitor overcomes ABCB1-mediated multidrug resistance in cancer cells.

P: -glycoprotein (P-gp/ABCB1) overexpression is one of the primary causes of multidrug resistance (MDR). Therefore, it is crucial to discover effective pharmaceuticals to combat multidrug resistance mediated by ABCB1. Pemigatinib is a selective the fibroblast growth factor receptor (FGFR) inhibitor that is used to treat a variety of solid tumors, Clinical Trials for Urothelial Carcinoma (NCT02872714) completed its research on Pemigatinib. This study aimed to determine whether Pemigatinib can reverse ABCB1-mediated multidrug resistance, as well as its mechanism of action. Pemigatinib substantially reversed ABCB1-mediated multidrug resistance, as determined by a CCK8 assay, and immunofluorescence experiments revealed that Pemigatinib had no effect on the intracellular localization of ABCB1. Pemigatinib was discovered to increase intracellular drug accumulation, thereby reversing multidrug resistance. In addition, Docking analysis revealed that Pemigatinib and ABCB1 have a high affinity for one another. This study concludes that Pemigatinib is capable of reversing the multidrug resistance mediated by ABCB1, offering ideas and references for the clinical application of Pemigatinib.

Astragulus embranaceus (Fisch.) Bge-Dioscorea opposita Thunb herb pair ameliorates sarcopenia in senile type 2 diabetes mellitus through Rab5a/mTOR-mediated mitochondrial dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Astragulus embranaceus (Fisch.) Bge (Huangqi) and Dioscorea opposita Thunb (Shanyao) are one of the most widely accepted herb pairs in traditional Chinese medicine prescriptions for treating sarcopenia. However, the mechanisms underlying the combination of these herbs for anti-sarcopenia treatment are not yet fully understood. AIM OF THE STUDY: To investigate the potential effect of the Astragulus embranaceus (Fisch.) Bge and Dioscorea opposita Thunb herb pair (Ast-Dio) on sarcopenia in mice that have been induced with senile type 2 diabetes mellitus, as well as to explore the underlying mechanisms related to the Rab5a/mTOR signaling pathway and mitochondrial quality control. MATERIALS AND METHODS: Network pharmacology was utilized to identify the main active ingredients of Ast-Dio and potential therapeutic targets for sarcopenia. Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to explore the underlying mechanisms of Ast-Dio in treating sarcopenia. The high-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry was developed to quantify the major constituents of Ast-Dio. Male C57/BL6 mice, aged 12 months, induced with type 2 diabetes mellitus via streptozotocin were divided into three groups for 8 weeks: the model group, Ast-Dio treatment group (7.8 g/kg), and metformin treatment group (100 mg/kg). Normal control groups included mice aged 3 and 12 months, respectively. The study monitored changes in fasting blood glucose levels, grip strength, and body weight during 8 weeks of intragastric administration. Liver and kidney function in mice was evaluated by measuring the levels of serum creatinine, alanine transaminase, and aspartate transaminase. Skeletal muscle mass condition was evaluated by muscle weight, and hematoxylin and eosin staining. Protein and mRNA expressions related to muscle atrophy, mitochondrial quality control, and the Rab5a/mTOR signaling pathway were detected using immunofluorescence staining, immunohistochemical staining, Western blotting, and quantitative real-time polymerase chain reaction. In addition, transmission electron microscopy was employed to investigate the condition of mitochondria in the groups. RESULTS: Through the prediction analysis of network pharmacology, we identified mTOR as one of the primary targets for Ast-Dio therapy of sarcopenia. Gene Ontology functional enrichment analysis revealed that mitochondrial control quality is crucial in the treatment of sarcopenia with Ast-Dio. Our findings showed that senile type 2 diabetes mellitus induced muscle mass loss and a reduction in grip strength, both of which were dramatically restored by Ast-Dio treatment. Notably, Ast-Dio increased Myogenin expression while decreasing Atrogin-1 and MuRF-1 expression. Additionally, Ast-Dio activated Rab5a/mTOR and its downstream effector AMPK. Moreover, Ast-Dio modulated mitochondrial quality control by decreasing Mitofusin-2 expression while increasing the expression of TFAM, PGC-1α, and MFF. CONCLUSIONS: Our results suggest that Ast-Dio treatment may alleviate sarcopenia in mice with senile type 2 diabetes mellitus through its effects on the Rab5a/mTOR pathway and mitochondrial quality control.

Saikosaponin A and D attenuate skeletal muscle atrophy in chronic kidney disease by reducing oxidative stress through activation of PI3K/AKT/Nrf2 pathway.

BACKGROUND: Skeletal muscle atrophy in chronic kidney disease (CKD) leads to a decline in quality of life and increased risk of morbidity and mortality. We have obtained evidence that oxidative stress is essential in the progression of CKD-related muscle atrophy. Whether Saikosaponin A and D, two emerging antioxidants extracted from Bupleurum chinense DC, alleviate muscle atrophy remains to be further studied. The purpose of this study was to investigate the effects and mechanisms of these two components on CKD complicated with muscle atrophy. METHODS: In this research, muscle dystrophy model was established using 5/6 nephrectomized mice in vivo and in vitro with Dexamethasone (Dex)-managed C2C12 myotubes. RESULTS: The results of RNA-sequencing showed that exposure to Dex affected the antioxidant activity, catalytic activity and enzyme regulator activity of C2C12 cells. According to KEGG analysis, the largest numbers of differentially expressed genes detected were enriched in the PI3K/AKT pathway. In vivo, Saikosaponin A and D remain renal function, cross-section size, fiber-type composition and anti-inflammatory ability. These two components suppressed the expression of MuRF-1 and enhanced the expression of MyoD and Dystrophin. In addition, Saikosaponin A and D maintained redox balance by increasing the activities of antioxidant enzymes while inhibiting the excessive accumulation of reactive oxygen species. Furthermore, Saikosaponin A and D stimulated PI3K/AKT and its downstream Nrf2 pathway in CKD mice. The effects of Saikosaponin A and D on increasing the inner diameter of C2C12 myotube, reducing oxidative stress and enhancing expression of p-AKT, p-mTOR, p70S6K, Nrf2 and HO-1 proteins were observed in vitro. Importantly, we verified that these protective effects could be significantly reversed by inhibiting PI3K and knocking out Nrf2. CONCLUSIONS: In summary, Saikosaponin A and D improve CKD-induced muscle atrophy by reducing oxidative stress through the PI3K/AKT/Nrf2 pathway.

Overexpression of ABCB1 confers resistance to FLT3 inhibitor FN-1501 in cancer cells: in vitro and in vivo characterization.

FN-1501 is a potent FLT3 inhibitor with antitumor activity. A phase 1 trial of FN-1501 monotherapy in patients with advanced solid tumors and R/R AML is in progress. Since one of the primary causes of multidrug resistance (MDR) is the overexpression of ATP-binding cassette superfamily B member 1 (ABCB1), the objective of this study was to investigate the potential relationship between FN-1501 and the ABCB1 transporter. We found ABCB1 overexpressing-cancer cells conferred FN-1501 resistance, which could be reversed by an ABCB1 inhibitor. Molecular docking study revealed that FN-1501 docked the ligand binding site with an affinity score of -9.77 kcal/mol, denoting a strong interaction between FN-1501 and ABCB1. Additionally, the ABCB1 ATPase assay indicated that FN-1501 could significantly stimulate ABCB1 ATPase activity. Furthermore, we observed a similar trend of ABCB1-facilated FN-1501 resistance in tumor-bearing mice model. In sum, we demonstrate that FN-1501 is a substrate of ABCB1 transporter from both in vivo and in vitro studies. Therefore, our findings provide new insight on the mechanism of chemoresistance due to ABCB1 overexpression.

Methylation of the DKK3 promoter is associated with poor prognosis in patients with cervical adenocarcinoma.

OBJECTIVE: The aim of this study was to investigate the mRNA of DKK3 (Dickkopf-3) in cervical adenocarcinoma, and to explore correlations between methylation status of the DKK3 promoter and biological behaviors of cervical adenocarcinoma. METHODS: The mRNA expression level of DKK3 was detected by real-time quantitative reverse transcription PCR. Methylation-specific PCR (MSP) analysis was performed to detect the methylated degrees of the DNA of the DKK3 promoter. RESULTS: The mRNA expression levels of DKK3 in cervical adenocarcinoma tissues were lower than those in adjacent normal cervical tissues. MSP detection found DKK3 promoter methylation was 38% in cervical adenocarcinoma tissues, while no normal cervical tissues were found to be methylated.FIGO staging and pelvic lymph node metastasis were identified as relative factors of methylation status of the DKK3 promoter. Multivariate analysis demonstrated methylation status of the DKK3 promoter was an independent prognostic indicator of cervical adenocarcinoma. Patients with methylated DKK3 promoter exhibited significantly shorter OS than those with an unmethylated DKK3 promoter. CONCLUSIONS: The methylation status of the DKK3 promoter may indicate poor prognosis of patients with cervical adenocarcinoma.

Matrine inhibiting pancreatic cells epithelial-mesenchymal transition and invasion through ROS/NF-κB/MMPs pathway.

AIMS: Matrine has demonstrated an exclusive anti-tumor effect, including inhibiting cancer cells proliferation and inducing cancer cells apoptosis and autophagy. Whether it can inhibit cancer cells invasion is remain obscure. MAIN METHODS: The Panc-1 cells were cultured with matrine, NAC and methanol, wound healing assay and transwell invasion assay were applied to detect the migration and invasion ability. The expression of MMP-2 and MMP-9 were assessed, as well as the Epithelial-Mesenchymal Transition marker. Further detect the expression of pP65, total P65, pIκBα, total IκBα, MMP-2, MMP-9 and Panc-1 cells migration and invasion ability to detect whether NF-κB signaling pathway is involved. KEY FINDINGS: In matrine treated group, the expression of E-cadherin was up-regulated while N-cadherin, Vimentin was down-regulated. In addition, wound healing assay and transwell invasion assay showed that the cells treated with matrine expressed weaker migration and invasion ability, and MMP-2 and MMP-9 was down-regulated in matrine treated group. Further research reveals that the effect of Matrine could decreased the level of intracellular ROS. Furthermore, pP65, pIκBα level was down-regulated in the matrine and NAC group when compared to control group. The panc-1 cells showed less migration and invasion ability, as well as lower MMP-2 and MMP-9 expression in the group treated with NF-κBI along with H2O2 when compared with treated with H2O2 only. SIGNIFICANCE: Matrine inhibit pancreatic cancer cells migration and invasion through ROS/NF-κB/MMPs pathway, further validate the anticancer effect of matrine.

[The research progress about Wnt pathway of lung cancer stem cells].

Being the most critical signaling molecule in the Wnt pathway, the Wnt/ß-catenin signaling pathway plays an important role in the maintenance of the cell proliferation and clone formation of lung cancer stem cells. Since it is closely related to the WNT pathway, the proliferation of lung cancer stem cells can be restrained by blocking the WNT pathway or influencing its key protein. Such method provides a new method for the treatment of lung cancer. By summarizing the state of-the-art research of lung cancer stem cells and the Wnt pathway from 2005 to 2010, their relationship is investigated.

Bone disease in kidney transplant patients.

Chronic kidney disease and end-stage kidney disease are associated with significant disturbances in bone and mineral metabolism. With advances in the management of chronic kidney disease and improved outcomes of kidney transplantation, posttransplantation bone disease is a serious cause of morbidity in long-term survivors. The management of post-kidney transplantation bone disease is difficult because of its complex pathophysiology. Furthermore, studies of therapeutic options that may show improvement in bone mineral density have not necessarily been shown to decrease fracture risk. Evaluating and managing post-kidney transplantation bone disease remains an integral part of posttransplant medical care.

Sectoranopia: a stroke in the lateral geniculate nucleus or optic radiations?

BACKGROUND: The lateral geniculate nucleus (LGN) is the site at which ganglion cell axons of the optic tract synapse with neurons that form the optic radiations. Lesions of the perigeniculate visual pathway are characterized by distinct pupillary, visual field, and ophthalmoscopic findings. Such findings, combined with results from neuroimaging, enable one to precisely locate the area of the visual pathway that is involved. CASE REPORT: A patient who presented to our clinic with a complaint of narrowly missing several motor vehicle accidents recently was found to have a left horizontal sectoranopia on a screening visual field. Magnetic resonance imaging confirmed the presence of an old infarct involving the optic radiations. The patient's medical history was significant for high homocysteine levels that likely contributed to his having had several cerebral vascular accidents in the past, one of which affected the optic radiations. CONCLUSIONS: Damage to the LGN and optic radiations can produce sectoranopic visual field defects. Although it may not be possible to specify the exact location of a lesion, understanding the blood supply of the visual pathway and retinotopic organization of the LGN aids in the localization of infarcts that cause characteristic visual field defects.