DESIGN, SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF QUINAZOLINAMINE DERIVATIVES AS BCRP AND P-GP INHIBITORS WITH IMPROVED METABOLIC STABILITY

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on BCRP and P-gp was synthesized. The reversal study showed that when combined with the potent dual BCRP and P-gp inhibitors 7-8, 29-31, and 34, the IC50 value of mitoxantrone was decreased from 6.50 µM to the range of 0.24 - 0.35 µM for BCRP, and IC50 value of colchicine was decreased from 7.34 μM to the range of 0.12 - 0.29 µM for P-gp. Cyclopropyl quinazolinamine 29 (VKCY-1), which was a dual BCRP and P-gp inhibitor, and azide quinazolinamine 40 (VKCY-2), which was a BCRP inhibitor, were selected for mechanistic studies. The results revealed that target compound 29 (VKCY-1) changed the localization of BCRP in H460/MX20 cells and P-gp in KB-C2 cells rather than altering the expression level of BCRP or P-gp proteins, thus inhibiting the efflux of the anticancer drugs, which is different from the mechanisms of other reported ABC transporter inhibitors. Azide quinazolinamine 40 (VKCY-2), on the other hand, did not change the expression level or the localization of BCRP protein. In addition, compounds 29 (VKCY-1) and 40 (VKCY-2) significantly stimulated the ATP hydrolysis of BCRP transporter indicating that they can be competitive substrates of BCRP transporter, and thereby significantly increasing the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide quinazolinamine 40 (VKCY-2) with photoaffinity label can be a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. After activation by the UV light, azide quinazolinamine 40 (VKCY-2) showed greater inhibitory effect on BCRP. Overall, this study indicated that quinazolinamine analogues can significantly reverse both BCRP- and P-gp-mediated MDR by blocking the efflux of anticancer drugs. Target compounds have the potential to be useful as BCRP and P-gp modulators to overcome MDR. The target quinazolinamine derivatives 7-8, 29-32, and 34 exhibited potency similar to that of the known BCRP inhibitor, Ko143. In addition, the P-gp inhibitory activities of quinazolinamine derivatives 7-8, 29-31, and 34 were greater than that of verapamil. Notably, the selected dual BCRP and P-gp inhibitors 7-8, 29-31, 34, and 40 showed improved metabolic stability than the standard pharmacologic tool Ko143

Case Report: Morbihan disease treated with tofacitinib successfully

IntroductionTo date, there is no standard treatment for Morbihan disease. Several studies have reported that Morbihan disease responds well to systemic corticosteroids (prednisone and prednisolone), systemic antibiotics (tetracyclines), antihistamines (ketotifen) and surgical therapy (Lymphaticovenous anastomosis). To our knowledge, Tofacitinib, as a Janus-activated kinase (JAK) inhibitor, plays a vital role in the treatment of inflammatory and autoimmune disorders. Therefore, Tofacitinib may be a promising medical option for patients with Morbihan disease.Case PresentationThe first case involves a 43-year-old Chinese man who presented a 12-month history of progressive painless swelling of the left upper eyelid. According to the skin biopsy, perivascular dermal edema with dilatation of lymphatic vessels and telangiectasia was observed, accompanied by mixed lymphocyte infiltrate, including histiocytes, plasma cells, and a few eosinophils. The second case involves a Chinese female patient who presented a 2-year history of progressive left-sided facial edema, which was eventually diagnosed as Morbihan disease. The skin biopsy revealed lymphocyte infiltration in the superficial vessels of dermis and some accessories. Based on patients’ clinical presentation, skin biopsy results, and exclusion of differential diagnoses such as systemic lupus erythematosus (SLE), they were diagnosed with Morbihan disease. They were both treated with Tofacitinib (5mg, po twice daily).OutcomesPatient 1 underwent a trial of Tofacitinib at a dosage of 5 mg twice daily for one month, with notable improvement. His edema and erythema present on the left face were alleviated. Patient 1 reduced the dosage of Tofacitinib by half (5mg, once daily) and continued using it for 5 months. During the 6-month follow-up, the facial erythema in the patient subsided, and there was a noticeable improvement in the swelling of the left eyelid compared to before. Patient 2, her lesions gradually improved after one-week treatment. She received a one-month treatment of Tofacitinib, and during the subsequent six-month follow-up, there was no evidence of eruption recurrence.ConclusionWe present the first cases of two patients receiving short-term Tofacitinib as therapy for Morbihan disease and retrieving huge succession. Tofacitinib may be a promising oral alternative for patients with Morbihan disease. However, its safety and efficacy require further assessment through clinical trials

The chromodomain-containing NH2-terminus of Chromator interacts with histone H1 and is required for correct targeting to chromatin

The chromodomain protein, Chromator, can be divided into two main domains, a NH2-terminal domain (NTD) containing the chromodomain (ChD) and a COOH-terminal domain (CTD) containing a nuclear localization signal. During interphase Chromator is localized to chromosomes; however, during cell division Chromator redistributes to form a macro molecular spindle matrix complex together with other nuclear proteins that contribute to microtubule spindle dynamics and proper chromosome segregation during mitosis. It has previously been demonstrated that the CTD is sufficient for targeting Chromator to the spindle matrix. In this study, we show that the NTD domain of Chromator is required for proper localization to chromatin during interphase and that chromosome morphology defects observed in Chromator hypomorphic mutant backgrounds can be largely rescued by expression of this domain. Furthermore, we show that the ChD domain can interact with histone H1 and that this interaction is necessary for correct chromatin targeting. Nonetheless, that localization to chromatin still occurs in the absence of the ChD indicates that Chromator possesses a second mechanism for chromatin association and we provide evidence that this association is mediated by other sequences residing in the NTD. Taken together these findings suggest that Chromator\u27s chromatin functions are largely governed by the NH2-terminal domain whereas functions related to mitosis are mediated mainly by COOH-terminal sequences

Improved colonic inflammation by nervonic acid via inhibition of NF-κB signaling pathway of DSS-induced colitis mice

Background: Nervonic acid (C24:1Δ15, 24:1 ω-9, cis-tetracos-15-enoic acid; NA), a long-chain monounsaturated fatty acid, plays an essential role in prevention of metabolic diseases, and immune regulation, and has anti-inflammatory properties. As a chronic, immune-mediated inflammatory disease, ulcerative colitis (UC) can affect the large intestine. The influences of NA on UC are largely unknown. Purpose: The present study aimed to decipher the anti-UC effect of NA in the mouse colitis model. Specifically, we wanted to explore whether NA can regulate the levels of inflammatory factors in RAW264.7 cells and mouse colitis model. Methods: To address the above issues, the RAW264.7 cell inflammation model was established by lipopolysaccharide (LPS), then the inflammatory factors tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and Interleukin-10 (IL-10) were detected by Enzyme-linked immunosorbent assay (ELISA). The therapeutic effects of NA for UC were evaluated using C57BL/6 mice gavaged dextran sodium sulfate (DSS). Hematoxylin and eosin (H&E) staining, Myeloperoxidase (MPO) kit assay, ELISA, immunofluorescence assay, and LC-MS/MS were used to assess histological changes, MPO levels, inflammatory factors release, expression and distribution of intestinal tight junction (TJ) protein ZO-1, and metabolic pathways, respectively. The levels of proteins involved in the nuclear factor kappa-B (NF-κB) pathway in the UC were investigated by western blotting and RT-qPCR. Results: In vitro experiments verified that NA could reduce inflammatory response and inhibit the activation of key signal pathways associated with inflammation in LPS-induced RAW264.7 cells. Further, results from the mouse colitis model suggested that NA could restore intestinal barrier function and suppress NF-κB signal pathways to ameliorate DSS-induced colitis. In addition, untargeted metabolomics analysis of NA protection against UC found that NA protected mice from colitis by regulating citrate cycle, amino acid metabolism, pyrimidine and purine metabolism. Conclusion: These results suggested that NA could ameliorate the secretion of inflammatory factors, suppress the NF-κB signaling pathway, and protect the integrity of colon tissue, thereby having a novel role in prevention or treatment therapy for UC. This work for the first time indicated that NA might be a potential functional food ingredient for preventing and treating inflammatory bowel disease (IBD).National Key Research and Development, China | Ref. 2021YFE0109200Universidade de Vigo/CISUGThe Provincial Major Scientific and Technological Innovation Project of Shandong | Ref. 2022TZXD0029The Provincial Major Scientific and Technological Innovation Project of Shandong | Ref. 2022TZXD0032The Provincial Major Scientific and Technological Innovation Project of Shandong | Ref. 2021SFGC0904The Provincial Major Scientific and Technological Innovation Project of Shandong | Ref. 2021TZX D004The Natural Science Foundation of Shandong | Ref. ZR2020MH401The Natural Science Foundation of Shandong | Ref. ZR2021QH351National Wheat Industry Technology System of China | Ref. CARS-03–2

Molecular phylogeny and macroevolution of Chaitophorinae aphids (Insecta: Hemiptera: Aphididae)

Chaitophorinae is a predominantly Northern Hemisphere aphid subfamily characterized by numerous setae on the body. Two constituent tribes are associated with different host plants, with Chaitophorini feeding on deciduous trees and shrubs and Siphini colonizing grasses. Based on data from multiple genes (COI, COII, Cytb and EF-1α), geographical distribution and host association, this study investigated the phylogeny and macroevolution of Chaitophorinae using phylogenetic reconstruction, molecular dating, model-based ancestral area and character estimations and diversification rate calculation. Our results support the monophyly of Chaitophorinae and two tribes, indicate that Sipha and the two largest genera Chaitophorus and Periphyllus are not monophyletic, and suggest a need for a change in the taxonomic status of Lambersaphis, which was nested within Chaitophorus in the phylogenetic tree. We recovered an origin of Chaitophorinae on Acer plants from eastern Asia during the Late Cretaceous to early Palaeocene, followed by multiple dispersals into other areas that were responsible for its contemporary distribution. The origins of Siphini and Chaitophorus + Lambersaphis coincided with colonizations of novel host plants. An increase in diversification rate occurred within Chaitophorus in the Miocene and was associated with range expansion and switching onto new host plants, highlighting the roles of dispersal and host shift in aphid diversification

Genetic Variants in KIR/HLA-C Genes Are Associated With the Susceptibility to HCV Infection in a High-Risk Chinese Population

BackgroundKIR/HLA-C signaling pathway influences the innate immune response which is the first defense to hepatitis C virus (HCV) infection. The aim of this study was to determine the association between the genetic polymorphisms of KIR/HLA-C genes and the outcomes of HCV infection in a high-risk Chinese population.MethodsIn this case-control study, four single nucleotide polymorphisms (SNPs) of KIR/HLA-C genes (KIR2DS4/KIR2DS1/KIR2DL1 rs35440472, HLA-C rs2308557, HLA-C rs1130838, and HLA-C rs2524094) were genotyped by TaqMan assay among drug users and hemodialysis (HD) patients including 1,378 uninfected control cases, 307 subjects with spontaneous viral clearance, and 217 patients with persistent HCV infection. Bioinformatics analysis was used to functionally annotate the SNPs.ResultsAfter logistic regression analysis, the rs35440472-A and rs1130838-A alleles were found to be associated with a significantly elevated risk of HCV infection (OR = 1.562, 95% CI: 1.229–1.987, P < 0.001; OR = 2.134, 95% CI: 1.180–3.858, P = 0.012, respectively), which remained significant after Bonferroni correction (0.05/4). The combined effect of their risk alleles and risk genotypes (rs35440472-AA and rs1130838-AA) were linked to the increased risk of HCV infection in a locus-dosage manner (all Ptrend < 0.001). Based on the SNPinfo web server, rs35440472 was predicted to be a transcription factor binding site (TFBS) while rs1130838 was predicted to have a splicing (ESE or ESS) function.ConclusionKIR2DS4/KIR2DS1/KIR2DL1 rs35440472-A and HLA-C rs1130838-A variants are associated with increased susceptibility to HCV infection in a high-risk Chinese population