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5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorptioncaused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expressionof intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induceddiabetes mellitus. In summary, our findings indicate that diabetes mellitus affects the absorption and metabolism of tofacitinib,causing faster metabolism and decreased intestinal absorption in rats with streptozotocin-induced diabetes mellitus.Econazole, a potent broad-spectrum antifungal agent and a Ca2+ channel antagonist, induces cytotoxicity in leukemia cells andis used for the treatment of skin infections. However, little is known about its cytotoxic effects on solid tumor cells. Here, weinvestigated the molecular mechanism underlying econazole-induced toxicity in vitro and evaluated its regulatory effect on themetastasis of gastric cancer cells. Using the gastric cancer cell lines AGS and SNU1 expressing wild-type p53 we demonstratedthat econazole could significantly reduce cell viability and colony-forming (tumorigenesis) ability. Econazole induced G0/G1 phasearrest, promoted apoptosis, and effectively blocked proliferation- and survival-related signal transduction pathways in gastric cancercells. In addition, econazole inhibited the secretion of matrix metalloproteinase- 2 (MMP-2) and MMP-9, which degrade theextracellular matrix and basement membrane. Econazole also effectively inhibited the metastasis of gastric cancer cells, as confirmedfrom cell invasion and wound healing assays. The protein level of p53 was significantly elevated after econazole treatmentof AGS and SNU1 cells. However, apoptosis was blocked in econazole-treated cells exposed to a p53-specific small-interferingRNA (siRNA) to eliminate p53 expression. These results provide evidence that econazole could be repurposed to induce gastriccancer cell death and inhibit cancer invasion.Alzheimer's disease (AD) is associated with the accumulation and deposition of a beta-amyloid (Αβ) peptide in the brain, resulting in increased neuroinflammation and synaptic dysfunction. Intranasal delivery of targeted drugs to the brain represents a noninvasive pathway that bypasses the blood-brain barrier and minimizes systemic exposure. The aim of this study was to evaluate the therapeutic effect of intranasally delivered 9-cis retinoic acid (RA) on the neuropathology of an AD mouse model. Herein, we observed dramatically decreased Αβ deposition in the brains of amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice (APP/PS1) treated intranasally with 9-cis RA for 4 weeks compared to that in the brains of vehicle-treated mice. selleck inhibitor Importantly, intranasal delivery of 9-cis RA suppressed Αβ-associated astrocyte activation and neuroinflammation and ultimately restored synaptic deficits in APP/PS1 transgenic mice. These results support the critical roles of Αβ-associated neuroinflammation responses to synaptic deficits, particularly during the deposition of Αβ. Our findings provide strong evidence that intranasally delivered 9-cis RA attenuates neuronal dysfunction in an AD mouse model and is a promising therapeutic strategy for the prevention and treatment of AD.TET family members (TETs) encode proteins that represent crucial factors in the active DNA demethylation pathway. Evidence has proved that TET2 mutation is associated with leukemogenesis, drug response, and prognosis in acute myeloid leukemia (AML). However, few studies revealed the TETs expression and its clinical significance in AML. We conducted a detailed expression and prognosis analysis of TETs expression in human AML cell lines and patients by using public databases. We observed that TETs expression especially TET2 and TET3 was closely associated with AML among various human cancers. TET1 expression was significantly reduced in AML patients, whereas TET2 and TET3 expression was significantly increased. Kaplan-Meier analysis showed that only TET3 expression was associated with overall survival (OS) and disease-free survival (DFS) among both total AML as well as non-M3 AML, and was confirmed by another independent cohort. Moreover, Cox regression analysis revealed that TET3 expression may act as an independent prognostic factor for OS and DFS in total AML. Interestingly, patients that received hematopoietic stem cell transplantation (HSCT) did not show significantly longer OS and DFS than those who did not receive HSCT in TET3 high-expressed groups; whereas, in TET3 low-expressed groups, patients that accepted HSCT showed significantly longer OS and DFS than those who did not accept HSCT. By bioinformatics analysis, TET3 expression was found positively correlated with tumor suppressor gene including CDKN2B, ZIC2, miR-196a, and negatively correlated with oncogenes such as PAX2 and IL2RA. Our study demonstrated that TETs showed significant expression differences in AML, and TET3 expression acted as a potential prognostic biomarker in AML, which may guide treatment choice between chemotherapy and HSCT.Long noncoding RNAs (lncRNAs) play critical roles in tumour progression and metastasis. Emerging evidence indicates that the lncRNA X inactive-specific transcript (XIST) is dysregulated in several tumor types, including non-small cell lung cancer (NSCLC). However, in NSCLC and other cancers the oncogenic mechanism of XIST remains incompletely understood. Here, we confirmed that XIST is upregulated in human NSCLC specimens, and is especially overexpressed in tumors previously treated with cisplatin (cis-diamminedichloroplatinum(II); DDP). In vitro, XIST knockdown inhibited NSCLC cell growth and promoted DDP chemosensitivity by stimulating apoptosis and pyroptosis. Moreover, XIST's oncogenic effects and ability to promote DDP chemoresistance were largely related to its binding to the TGF-β effector SMAD2, which inhibited its translocation to the nucleus and prevented the transcription of p53 and NLRP3, crucial regulators of apoptosis and pyroptosis, respectively. Using DDP-resistant NSCLC cells, mouse xenograft studies verified the oncogenic function of XIST and its ability to inhibit programmed cell death, thereby mediating DDP chemoresistance.