Comparison of Effects of Aminosalicylic Acid, Glucocorticoids and Immunosuppressive Agents On The Expression of Multidrug-Resistant Genes in Ucerative Colitis

Objective: To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressive agents on the expression levels of multidrug-resistant genes in ucerative colitis (UC) patients, aiming to provide theoretical and therapeutic basis for the diagnosis, treatment and prevention of UC.Methods: Fresh specimen of colon mucosal tissues pathological mucosal tissues under endoscopy or postoperative pathological biopsy tissues were collected from 148 UC patients and then prepared for subsequent experiment.Immunohistochemical staining was conducted to detect the distribution site and pattern of P-glycoprotein （P-gp）. The effects of ASA glucocorticoids and immunosupresive agents on P-gp were statistically compared.The expression levels of Multidrug resistance gene （MDR1）mRNA before and after corresponding treatment were quantitatively measured by using RT-PCR. In addition, the effects of three agents upon MDR1 mRNA were also comparatively analyzed.Results: Administration of 5-aminosalicylic acid (5-ASA) drugs were not correlated with the expression of multidrug resistance genes in UC, whereas delivery of glucocorticoids and immunosuppressant drugs was positively correlated with the expression profile. The expression levels of MDR1 gene and its product P-gp were significantly up-regulated in patients who were nonresponsive to glucocorticoids and immunosuppressant agents.Conclusions: Overall, the findings in the present study demonstrate that 5-ASA exerts no effect upon the expression levels of MDR1 and its product P-gp in patients diagnosed with UC. Nevertheless, administration of glucocorticoids and immunosuppressant drugs can up-regulate the expression levels of MDR1.

Emergence of the cfr gene in Vibrio diabolicus of seafood origin

The emergence and transmission of multidrug resistance gene cfr incur great public health concerns worldwide. Recently, Gram-negative pathogens were found to carry cfr by various mobile elements. Here, we investigated a cfr -positive Vibrio diabolicus by phenotyping and genomic analysis, and found cfr in a translocatable structure (IS 26 - hp - cfr -IS 26 ) among the MDR region in pNV27-cfr-208K, an emerging MDR plasmid in Vibrio species. This study highlights the necessity of surveillance of cfr in bacteria of diverse origins.

Novel genotyping assay for the nt230 (del4) ABCB1 gene mutation and its allele frequency in Border Collie dogs in Mexico

A 4-bp deletion in the ATP-binding cassette subfamily B member 1 ( ABCB1) gene, also referred to as the multidrug resistance gene ( MDR1), produces stop codons that cause premature termination of P-glycoprotein 1 (P-gp) synthesis. Dogs with the homozygous mutation do not express functional P-gp, which increases their sensitivity markedly to many common veterinary drugs. We detected the nt230 (del4) ABCB1 mutation in Border Collie dogs in western Mexico with a simple and affordable primer-introduced restriction analysis PCR (PIRA-PCR). PIRA-PCR clearly identified all genotypes in our sample of 104 dogs. Genotype frequencies were 0.952 (wild/wild), 0.029 (wild/mut) and 0.019 (mut/mut). Allele frequencies were 0.033 (mutant alleles) and 0.966 (wild-type alleles). In this small subset of the Mexican dog population, we found a higher prevalence of the nt230 (del4) MDR1/ABCB1 gene mutation than reported in other countries.

Molecular Characteristics of IS 1216 Carrying Multidrug Resistance Gene Cluster in Serotype III/Sequence Type 19 Group B Streptococcus

Most previously isolated group B streptococcus (GBS) strains express either the Srr1 or Srr2 glycoprotein, which plays an important role in bacterial colonization and invasion. These glycoproteins are potential protein vaccine candidates.

Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln−/− mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1−/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

First Sequencing of Caprine Mdr1 (Abcb1) mRNA Due to Suspected Neurological Adverse Drug Reaction in a Thuringian Goat Following Extra-Label Use of Doramectin

The multidrug resistance gene MDR1 encodes for an efflux transporter called P-glycoprotein (P-gp). In the canine Mdr1 gene, a nonsense mutation was identified in certain dog breeds causing increased drug sensitivity to various P-gp substrates such as antiparasitic macrocyclic lactones. Symptoms of neurologic toxicity include ataxia, depression, salivation, tremor, apparent blindness, and mydriasis. In the current report, a Thuringian goat developed similar neurological signs after treatment with doramectin, a compound from the macrocyclic lactone class. Therefore, Mdr1 might be defective in this individual goat. For diagnostic purposes, sequencing of the complete mRNA transcript coding for caprine Mdr1 was performed to investigate a potential missense mutation. The Mdr1 transcripts of two related goats without drug sensitivity were also sequenced to allow differential diagnosis and were compared to the suspected drug-sensitive goat. The only position where the Mdr1 sequence from the suspected drug-sensitive goat differed was in the 3′-untranslated region, being a heterozygous single nucleotide polymorphism c.3875C>A. It can be suspected that this variant affects the expression level, stability, or translation efficiency of the Mdr1 mRNA transcript and therefore might be associated with the suspected drug sensitivity. To clarify this, further studies are needed, particularly investigating the Mdr1 mRNA and protein expression levels from brain material of affected goats. In conclusion, Mdr1 variants may exist not only in dogs, but also in individual goats. The current report provides the first Mdr1 mRNA transcript sequence of a goat and therefore represents the basis for more detailed Mdr1 sequence and expression analyses.

MDR1 Genotypes and Haplotypes Are Closely Associated with Postoperative Fentanyl Consumption in Patients Undergoing Radical Gastrectomy

Fentanyl is a powerful opioid analgesic, and its analgesic effect is greatly different among individuals. This study was aimed at exploring the effects of multidrug resistance gene-1 (MDR1) genetic variation on postoperative fentanyl consumption. A total of 135 patients, who planned to undergo radical gastrectomy with general anesthesia, were studied. The subjects received patient-controlled analgesia (PCA) by intravenous fentanyl within 48 hours after operation and maintained a numerical rating scale (NRS) score ≤ 3 . The consumption and side effects of fentanyl were recorded within 24 hours and 48 hours after the operation. Single nucleotide polymorphisms (SNPs) of all patients with MDR1 1236C>T, 2677G>T/A, and 3435C>T were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or DNA sequence analysis after PCR. There was no difference in postoperative fentanyl consumption among patients having 2677G>T/A and 3435C>T polymorphisms (all P > 0.05 ). MDR1 1236C>T polymorphisms and haplotypes combined by three SNPs, however, significantly affected postoperative fentanyl consumption (all P < 0.05 ). Moreover, 1236TT genotype carriers consumed more fentanyl during 24 hours ( P = 0.038 ) and 48 hours ( P = 0.003 ) postoperatively. The MDR1 TTT haplotype carriers needed more fentanyl compared with the CGC haplotype carriers during the first 48 hours after surgery ( P = 0.017 ). Nausea, vomiting, and dizziness were not found to have significant differences among the above three SNPs and their haplotypes ( P > 0.05 ). MDR1 1236C>T polymorphism and haplotypes were factors contributing to the individual variability in postoperative fentanyl consumption.

Prevalence of pfk13 and pfmdr1 polymorphisms in Bounkiling, Southern Senegal

Background Delayed Plasmodium falciparum parasite clearance has been associated with Single Nucleotide Polymorphisms (SNPs) in the kelch protein propeller domain (coded by pfk13 gene). SNPs in the Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) are associated with multi-drug resistance including the combination artemether-lumefantrine. To our knowledge, this is the first work providing information on the prevalence of k13-propeller and pfmdr1 mutations from Sédhiou, a region in the south of Senegal. Methods 147 dried blood spots on filter papers were collected from symptomatic patients attending a hospital located in Bounkiling City, Sédhiou Region, Southern Senegal. All samples were collected between 2015–2017 during the malaria transmission season. Specific regions of the gene pfk13 and pfmdr1 were analyzed using PCR amplification and Sanger sequencing. Results The majority of parasites (92.9%) harboured the pfk13 wild type sequence and 6 samples harboured synonymous changes. Regarding pfmdr1, wild-type alleles represented the majority except at codon 184. Overall, prevalence of 86Y was 11.9%, 184F was 56.3% and 1246Y was 1.5%. The mutant allele 184F decreased from 73.7% in 2015 to 40.7% in 2017. The prevalence of haplotype NFD decreased from 71.4% in 2015 to 20.8% in 2017. Conclusions This study provides the first description of pfk13 and pfmdr1 genes variations in Bounkiling, a city in the Sédhiou Region of Senegal, contributing to closing the gap of information on anti-malaria drug resistance molecular markers in southern Senegal.

Two functionally redundant FK506-binding proteins regulate multidrug resistance gene expression and govern azole antifungal resistance

Increasing resistance to antifungal therapy is an impediment to effective treatment of fungal infections. Candida glabrata is an opportunistic human fungal pathogen which is inherently less susceptible to cost-effective azole antifungals. Gain-of-function mutations in the Zn-finger pleiotropic drug resistance transcriptional activator-encoding gene, CgPDR1, are the most prevalent cause of azole resistance in clinical settings. CgPDR1 is also transcriptionally activated upon azole exposure, however, factors governing CgPDR1 gene expression are not yet fully understood. Here, we have uncovered a novel role for two FK506-binding proteins, CgFpr3 and CgFpr4, in regulation of the CgPDR1 regulon. We show that CgFpr3 and CgFpr4 possess peptidyl-prolyl isomerase domain, and act redundantly to control CgPDR1 expression, as Cgfpr3Δ4Δ mutant displayed elevated expression of CgPDR1 gene, along with overexpression of its target genes, CgCDR1, CgCDR2 and CgSNQ2, that code for ATP-binding cassette multidrug transporters. Further, CgFpr3 and CgFpr4 are required for maintenance of histone H3 and H4 protein levels, and fluconazole exposure leads to elevated H3 and H4 protein levels. Consistent with a role of histone proteins in azole resistance, disruption of genes coding for the histone demethylase CgRph1 and histone H3K36-specific methyltransferase CgSet2 leads to increased and decreased susceptibility to fluconazole, respectively, with Cgrph1Δ mutant displaying significantly lower basal expression of CgPDR1 and CgCDR1 genes. These data underscore a hitherto unknown role of histone methylation in modulating the most common azole antifungal resistance mechanism. Altogether, our findings establish a link between CgFpr-mediated histone homeostasis and CgPDR1 gene expression, and implicate CgFpr in virulence of C. glabrata.