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Cell Metabolism Jan 2020Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial...
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
Topics: Adolescent; Animals; Anti-Bacterial Agents; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Cell Proliferation; Diamines; Dimerization; Duodenum; Feces; Female; Ferritins; Gastrointestinal Microbiome; Glyceraldehyde; Homeostasis; Humans; Iron; Lactobacillus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Organoids; Probiotics; Propane; Signal Transduction
PubMed: 31708445
DOI: 10.1016/j.cmet.2019.10.005 -
Clinical Cancer Research : An Official... Aug 2021Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated...
PURPOSE
Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.
PATIENTS AND METHODS
We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant (m) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.
RESULTS
Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.
CONCLUSIONS
Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m LGG.
Topics: Adolescent; Adult; Aged; Brain Neoplasms; Diamines; Disease Progression; Female; Glioma; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Pyridines; Young Adult
PubMed: 34078652
DOI: 10.1158/1078-0432.CCR-21-0611 -
The Lancet. Microbe Apr 2022Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for complex (MTBC). We aimed to generate a WHO...
BACKGROUND
Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for complex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.
METHODS
A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.
FINDINGS
15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.
INTERPRETATION
This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.
FUNDING
UNITAID, Wellcome, MRC, BMGF.
Topics: Antitubercular Agents; Drug Resistance; Ethambutol; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; World Health Organization
PubMed: 35373160
DOI: 10.1016/S2666-5247(21)00301-3 -
Journal of Extracellular Vesicles May 2022The ability to isolate extracellular vesicles (EVs) from blood is vital in the development of EVs as disease biomarkers. Both serum and plasma can be used, but few...
BACKGROUND
The ability to isolate extracellular vesicles (EVs) from blood is vital in the development of EVs as disease biomarkers. Both serum and plasma can be used, but few studies have compared these sources in terms of the type of EVs that are obtained. The aim of this study was to determine the presence of different subpopulations of EVs in plasma and serum.
METHOD
Blood was collected from healthy subjects, and plasma and serum were isolated in parallel. ACD or EDTA tubes were used for the collection of plasma, while serum was obtained in clot activator tubes. EVs were isolated utilising a combination of density cushion and SEC, a combination of density cushion and gradient or by a bead antibody capturing system (anti-CD63, anti-CD9 and anti-CD81 beads). The subpopulations of EVs were analysed by NTA, Western blot, SP-IRIS, conventional and nano flow cytometry, magnetic bead ELISA and mass spectrometry. Additionally, different isolation protocols for plasma were compared to determine the contribution of residual platelets in the analysis.
RESULTS
This study shows that a higher number of CD9 EVs were present in EDTA-plasma compared to ACD-plasma and to serum, and the presence of CD41a on these EVs suggests that they were released from platelets. Furthermore, only a very small number of EVs in blood were double-positive for CD63 and CD81. The CD63 EVs were enriched in serum, while CD81 vesicles were the rarest subpopulation in both plasma and serum. Additionally, EDTA-plasma contained more residual platelets than ACD-plasma and serum, and two centrifugation steps were crucial to reduce the number of platelets in plasma prior to EV isolation.
CONCLUSION
These results show that human blood contains multiple subpopulations of EVs that carry different tetraspanins. Blood sampling methods, including the use of anti-coagulants and choice of centrifugation protocols, can affect EV analyses and should always be reported in detail.
Topics: Blood Platelets; Edetic Acid; Extracellular Vesicles; Humans; Mass Spectrometry; Tetraspanins
PubMed: 35524458
DOI: 10.1002/jev2.12213 -
Autophagy Feb 2023Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore,...
Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population. Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in . Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.
Topics: Aged; Animals; Humans; Caenorhabditis elegans; Mitophagy; Diamines; Autophagy; Oxidative Stress
PubMed: 35579620
DOI: 10.1080/15548627.2022.2078069 -
Developmental Medicine and Child... Apr 2024Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The... (Review)
Review
Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.
Topics: Humans; Child; Putrescine; Spermidine; Polyamines; Spermine; Eflornithine
PubMed: 37469105
DOI: 10.1111/dmcn.15687 -
Singapore Medical Journal Jan 2023With the increasing availability of genetic tests, more doctors are offering and ordering such tests for their patients. Ordering a genetic test appears to be a simple... (Review)
Review
With the increasing availability of genetic tests, more doctors are offering and ordering such tests for their patients. Ordering a genetic test appears to be a simple process of filling in paperwork, drawing 3 mL of blood in an ethylenediaminetetraacetic acid tube and receiving a test report. This is identical to sending off a full blood count. However, it is far more complex than that. There are many potential pitfalls, as shown by the increasing number of complaints and lawsuits filed against doctors and allied health staff. Furthermore, clinical genetics involves more than just ordering tests; in fact, focusing on genetic tests alone is a potential pitfall. In this review, we discuss the common pitfalls in clinical genetics and how doctors can avoid these pitfalls to ensure patient safety and to safeguard their practice.
Topics: Humans; Edetic Acid; Fenbendazole; Patient Safety; Physicians
PubMed: 36722517
DOI: 10.4103/singaporemedj.SMJ-2021-329 -
The Journal of Biological Chemistry Oct 2021
Review
Topics: Aniline Compounds; Animals; Calcium; Egtazic Acid; Fluorescent Dyes; Humans; Optical Imaging; Xanthenes
PubMed: 34508781
DOI: 10.1016/j.jbc.2021.101181 -
Applied and Environmental Microbiology Nov 2020Diamines are important monomers for polyamide plastics; they include 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane, among others. With... (Review)
Review
Diamines are important monomers for polyamide plastics; they include 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane, among others. With increasing attention on environmental problems and green sustainable development, utilizing renewable raw materials for the synthesis of diamines is crucial for the establishment of a sustainable plastics industry. Recently, high-performance microbial factories, such as and , have been widely used in the production of diamines. In particular, several synthetic pathways of 1,6-diaminohexane have been proposed based on glutamate or adipic acid. Here, we reviewed approaches for the biosynthesis of diamines, including metabolic engineering and biocatalysis, and the application of bio-based diamines in nylon materials. The related challenges and opportunities in the development of renewable bio-based diamines and nylon materials are also discussed.
Topics: Bacteria; Biocatalysis; Biosynthetic Pathways; Diamines; Metabolic Engineering; Nylons
PubMed: 32978133
DOI: 10.1128/AEM.01972-20 -
Renal Failure Dec 2023To investigate the effects of low-dose furosemide and aminophylline on the renal function in patients with septic shock. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To investigate the effects of low-dose furosemide and aminophylline on the renal function in patients with septic shock.
METHODS AND RESULTS
A total of 109 eligible septic shock patients in the intensive care unit were randomly divided into a control group ( = 55) and an intervention group ( = 54). The control group received normal saline, and the intervention group received low-dose furosemide (0.048 mg/kg.h) with aminophylline (0.3 mg/kg.h). The primary outcomes included the levels of serum creatinine (Scr), creatinine clearance rate (Ccr), blood urea nitrogen (BUN), glomerular filtration rate (GFR), and urine output on admission and on days 3, 7 and 14. The secondary outcomes were the sequential organ failure assessment (SOFA) scores, continuous renal replacement therapy (CRRT) time and intensive care unit (ICU) mortality, hospital mortality and 28-day mortality. There were no significant differences in the levels of Scr, Ccr, BUN, or GFR between the two groups, while the urine output was higher in the intervention group on days 3, 7, and 14. Compared with the control group, the SOFA scores, ICU mortality, hospital mortality and 28-day mortality were significantly lower in the intervention group on days 3, 7, and 14, the CRRT time was shorter, and the cumulative fluid balance was lower on days 3 and 7 in the intervention group.
CONCLUSIONS
Although low-dose furosemide and aminophylline have fewer protective effects on the renal function in septic shock patients, they could reduce the CRRT time and improve the prognosis.
Topics: Humans; Aminophylline; Furosemide; Shock, Septic; Glomerular Filtration Rate; Kidney
PubMed: 36856313
DOI: 10.1080/0886022X.2023.2185084