Accumulation of misfolded proteins in proteinaceous inclusions is a prominent pathological feature common to many age-related neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In cultured cells, when the production of misfolded proteins exceeds the capacity of the chaperone refolding system and the ubiquitin-proteasome degradation pathway, misfolded-proteins are actively transported to a cytoplasmic juxtanuclear structure called an aggresome. Aggresome formation is recognized as a cytoprotective response serving to a sequester potentially toxic misfolded proteins and facilitate their clearance by autophagy. Recent evidence indicates that aggresome formation is mediated by dynein/dynactin-mediated microtubule-based transport of misfolded proteins to the centrosome and involves several regulators, including histone deacetylase 6, E3 ubiquitin-protein ligase parkin, deubiquitinating enzyme ataxin-3, and ubiquilin-1. Characterization of the molecular mechanisms underlying aggresome formation and its regulation has begun to provide promising therapeutic targets that may be relevant to neurodegenerative diseases. In this review, we provide an overview of the molecular machinery controlling aggresome formation and discuss potential. useful compounds and intervention strategies for preventing or reducing the cytotoxicity of misfolded and aggregated proteins.
Background
Pharmacies are an important source of sterile syringes for people who inject drugs (PWID) in Tajikistan who are under high risk of HIV and hepatitis C virus. Accessibility of sterile syringes at pharmacies without prescription may depend on pharmacists’ attitudes towards PWID. This qualitative inquiry examines meanings and processes of stigmatization of PWID among pharmacists and pharmacy students in Tajikistan.
Methods
We conducted semi-structured interviews with 19 pharmacists and 9 students (N = 28) in the cities of Dushanbe and Kulob, Tajikistan. The interview topics included personal attitudes towards drug use and PWID, encounters with PWID, awareness and beliefs related to drug dependence and HIV, and attitudes and practices related to providing syringes to PWID. Interview transcripts were analysed using thematic analysis methods.
Results
The main themes included the significance of religion in defining attitudes towards drug use, labelling of PWID, negative stereotypes (PWID are prone to crime, violence, and irrational aggression; inflict harm to families and society; are able to control drug use), emotions triggered by PWID (fear, sympathy) and discrimination against PWID (rejection, isolation, ostracism, limiting resources to PWID). The religious ban on drug use and pharmacists’ moral and legal responsibility for the consequences of drug use were frequently mentioned as reasons for rejecting syringe sales. Still, many participants acknowledged the need for distributing syringes to PWID to prevent HIV.
Conclusions
Stigma against PWID in Tajikistan plays an important role in shaping pharmacists’ attitudes towards provision of services to this population. Local sociocultural context, in particular religious beliefs and social conservatism, may facilitate stigmatizing beliefs.
Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl) quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 μM, in agreement with its DNMT3A inhibitory potency.
XR5944, a deoxyribonucleic acid (DNA) bis-intercalator with potent anticancer activity, can bind the estrogen response element (ERE) sequence to inhibit estrogen receptor-α activities. This novel mechanism of action may be useful for overcoming drug resistance to currently available antiestrogen treatments, all of which target the hormone-receptor complex. Here we report the nuclear magnetic resonance solution structure of the 2:1 complex of XR5944 with the naturally occurring TFF1-ERE, which exhibits important and unexpected features. In both drug-DNA complexes, XR5944 binds strongly at one intercalation site but weakly at the second site. The sites of intercalation within a native promoter sequence appear to be context and sequence dependent. The binding of one drug molecule influences the binding site of the second. Our structures underscore the fact that the DNA binding of a bis-intercalator is directional and different from the simple addition of two single intercalation sites. Our study suggests that improved XR5944 bis-intercalators targeting ERE may be designed through optimization of aminoalkyl linker and intercalation moieties at the weak binding sites.
Antimicrobial resistance is a global issue that threatens the effective practice of modern medicine and global health. The emergence of multidrug-resistant (MDR) fungal strains of Candida auris and azole-resistant Aspergillus fumigatus were highlighted in the Centers for Disease Control and Prevention’s (CDC) 2019 report, Antibiotic Resistance Threats in the United States. Conventional antifungals used to treat fungal infections are no longer as effective, leading to increased mortality. Compounding this issue, there are very few new antifungals currently in development. Plants from traditional medicine represent one possible research path to addressing the issue of MDR fungal pathogens. In this commentary piece, we discuss how medical ethnobotany—the study of how people use plants in medicine—can be used as a guide to identify plant species for the discovery and development of novel antifungal therapies.
by
Craig Hansen;
Susan E. Andrade;
Heatjer Freiman;
Sascha Dublin;
Katie Haffenreffer;
William O. Cooper;
T. Craig Cheetham;
Sengwee Toh;
De-Kun Li;
Marsha A. Raebel;
Jennifer L. Kuntz;
Nancy Perrin;
A. Gabriela Rosales;
Shelley Carter;
Pamela A. Pawloski;
Elizabeth M. Maloney;
David J. Graham;
Leyla Sahin;
Pamela E. Scott;
John Yap;
Robert Davis
Background:
Sulfonamide antibacterials are widely used in pregnancy, but evidence about their safety is mixed. The objective of this study was to assess the association between first-trimester sulfonamide exposure and risk of specific congenital malformations.
Methods:
Mother-infant pairs were selected from a cohort of 1.2 million live-born deliveries (2001-2008) at 11 US health plans comprising the Medication Exposure in Pregnancy Risk Evaluation Program. Mothers with first-trimester trimethoprim-sulfonamide (TMP-SUL) exposures were randomly matched 1:1 to (i) a primary comparison group (mothers exposed to penicillins and/or cephalosporins) and (ii) a secondary comparison group (mothers with no dispensing of an antibacterial, antiprotozoal, or antimalarial medication during the same time period). The outcomes were cardiovascular abnormalities, cleft palate/lip, clubfoot, and urinary tract abnormalities.
Results:
We first identified 7615 infants in the TMP-SUL exposure group, of which 7595 (99%) were exposed to a combination of TMP-SUL and the remaining 1% to sulfonamides alone. After matching (1:1) to the comparator groups and only including those with complete data on covariates, there were 20064 (n=6688 per group) in the primary analyses. Overall, cardiovascular defects (1.52%) were the most common and cleft lip/palate (0.10%) the least common that were evaluated. Compared with penicillin/cephalosporin exposure, and no antibacterial exposure, TMP-SUL exposure was not associated with statistically significant elevated risks for cardiovascular, cleft lip/palate, clubfoot, or urinary system defects.
Conclusions:
First-trimester TMP-SUL exposure was not associated with a higher risk of the congenital anomalies studied, compared with exposure to penicillins and/or cephalosporins, or no exposure to antibacterials.
Glycoproteins in animal cells contain a variety of glycan structures that are added co- and/or posttranslationally to proteins. Of over 20 different types of sugar-amino acid linkages known, the two major types are N-glycans (Asn-linked) and O-glycans (Ser/Thr-linked). An abnormal mucin-type O-glycan whose expression is associated with cancer and several human disorders is the Tn antigen. It has a relatively simple structure composed of N-acetyl-D- galactosamine with a glycosidic αlinkage to serine/threonine residues in glycoproteins (GalNAcα1-O-Ser/Thr), and was one of the first glycoconjugates to be chemically synthesized. The Tn antigen is normally modified by a specific galactosyltransferase (T-synthase) in the Golgi apparatus of cells.
Expression of active T-synthase is uniquely dependent on the molecular chaperone Cosmc, which is encoded by a gene on the X chromosome. Expression of the Tn antigen can arise as a consequence of mutations in the genes for T-synthase or Cosmc, or genes affecting other steps of O-glycosylation pathways. Because of the association of the Tn antigen with disease, there is much interest in the development of Tn-based vaccines and other therapeutic approaches based on Tn expression. An abnormal sugar: The expression of the abnormal O-glycan called Tn antigen (see structure) in animal glycoproteins typically represents a disease condition. This Review discusses a broad range of chemical and biological studies on the Tn antigen that could lead to new diagnostics and therapeutics.
by
John J. Bowling;
Hari K. Pennaka;
Kelly Ivey;
Subagus Wahyuono;
Michelle Kelly;
Raymond F Schinazi;
Frederick A. Valeriote;
David E. Graves;
Mark T. Hamann
Aaptamine has potent cytotoxicity that may be explained by its ability to intercalate DNA. Aaptamine was evaluated for its ability to bind to DNA to validate DNA binding as the primary mechanism of cytotoxicity. Based on UV-vis absorbance titration data, the Kobs for aaptamine was 4.0 (±0.2) × 103 which was essentially equivalent to the known DNA intercalator N-[2-(diethylamino)ethyl]-9-aminoacridine-4-carboxamide. Semi-synthetic core modifications were performed to improve the general structural diversity of known aaptamine analogs and vary its absorption characteristics. Overall, 26 aaptamine derivatives were synthesized which consisted of a simple homologous range of mono and di-N-alkylations as well as some 9-O-sulfonylation and bis-O-isoaaptamine dimer products. Each product was evaluated for activity in a variety of whole cell and viral assays including a unique solid tumor disk diffusion assay. Details of aaptamine's DNA-binding activity and its derivatives' whole cell and viral assay results are discussed.
by
Huyen Thi Bui Dieu;
Xuan Nguyen Bai;
Cong Truong Dat;
Dan Wolf Meyrowitsch;
Jens Sondergaard;
Tine Gammeltoft;
Ib Christian Bygbjerg;
Jannie Nielsen
People with diabetes are at high risk of polypharmacy owing to complex treatment of diabetes and comorbidities. Polypharmacy is associated with increased risk of adverse reactions and decreased compliance. Therefore, the objectives of this study were to assess polypharmacy in people with type 2 diabetes (T2D) and associated diabetes-related factors in rural areas in Vietnam.
Objectives: Low back pain becomes a common orthopaedic disease today. It is mainly induced by the degeneration of the intervertebral disc. In this study, we tried to reveal the pathogenesis of the degeneration and the relative therapeutic strategy, which are still elusive. Materials and Methods: We collected 15 degenerative intervertebral tissues and five healthy donors. Nucleus pulposus and annulus fibrosus cells were subcultured. miR-640 expression was determined by qPCR. Computer analysis and luciferase reporter assay were used to confirm miR-640 target genes. Immunohistochemical and immunocytochemical staining was used to trace the proinflammatory cytokines and key transductor of signalling pathways. We also used β-galactosidase staining, flow cytometry, and cell viability assay to monitor the degenerative index. Results: miR-640 overexpressed in patients derived degenerative nucleus pulposus tissues and cells. The inflammatory environment promoted miR-640 expression via NF-κB signalling pathway. In addition, miR-640 targeted to LRP1 and enhances NF-κB signal activity, which built a positive feedback loop. miR-640 inhibited the expression of β-catenin and EP300, therefore, restrained WNT signal and induced the degeneration in nucleus pulposus cells. miR-640 inhibitor treatment exhibited the effects of anti-inflammation, reverse WNT signalling pathway exhaustion, and remission of degenerative characteristics in vitro. Conclusions: miR-640 plays an important role in the degeneration of intervertebral disc and the relative inflammatory microenvironment. It is a promising potential therapeutic target for the low back pain biotherapy.