- MeSH
- Anticoagulants administration & dosage adverse effects therapeutic use MeSH
- Administration, Oral MeSH
- Stroke epidemiology prevention & control MeSH
- Kidney Failure, Chronic epidemiology therapy MeSH
- Renal Dialysis adverse effects MeSH
- Atrial Fibrillation epidemiology drug therapy MeSH
- Risk Assessment MeSH
- Intracranial Hemorrhages chemically induced MeSH
- Practice Patterns, Physicians' MeSH
- Humans MeSH
- Risk Factors MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Abstracts MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Previous studies have demonstrated that central injection of L-carnosine (ß-alynyl-L-histidine), dipeptide synthesized in mammalian muscles, affects renal sympathetic nerve activity (RSNA) and blood pressure (BP) in anesthetized rats. In the present study, using urethane-anesthetized rats, we examined the dose-dependent effects of intravenous (IV) injection of various doses of anserine, dipeptide of similar structure to L-carnosine, on RSNA, BP and heart rate (HR). We found that injection of a low dose of anserine (1 µg) significantly suppressed RSNA, BP and HR. Conversely, a high dose (1000 µg) of anserine significantly elevated RSNA, BP and HR. Pretreatment with lateral cerebral ventricular (LCV) injection of thioperamide, a histaminergic H3-receptor antagonist, eliminated the effects of a low dose of anserine on RSNA, BP and HR. LCV injection of diphenhydramine, a histaminergic H1-receptor antagonist, abolished the effects of a high dose of anserine on RSNA, BP and HR. These findings suggest that anserine affects RSNA, BP and HR in a dose-dependent manner, and that the histaminergic nerve may be involved in the dose-different effects of anserine in rats.
- MeSH
- Anesthetics, Intravenous MeSH
- Anserine pharmacology MeSH
- Histamine H3 Antagonists pharmacology MeSH
- Histamine H1 Antagonists pharmacology MeSH
- Diphenhydramine pharmacology MeSH
- Dipeptides pharmacology MeSH
- Urethane MeSH
- Injections, Intravenous MeSH
- Blood Pressure physiology drug effects MeSH
- Rats MeSH
- Kidney physiology innervation blood supply MeSH
- Piperidines pharmacology MeSH
- Rats, Wistar MeSH
- Heart physiology drug effects MeSH
- Sympathetic Nervous System physiology drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- MeSH
- Bevacizumab MeSH
- Biomarkers MeSH
- Pharmacogenetics * methods MeSH
- Antibodies, Monoclonal, Humanized adverse effects therapeutic use MeSH
- Angiogenesis Inhibitors therapeutic use MeSH
- Protein Kinase Inhibitors therapeutic use MeSH
- Polymorphism, Single Nucleotide * MeSH
- Humans MeSH
- Neoplasms * drug therapy genetics blood supply MeSH
- Receptor Protein-Tyrosine Kinases * antagonists & inhibitors MeSH
- Vascular Endothelial Growth Factor A * genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- Publication type
- Meeting Abstract MeSH
The allelopathic potential of an artificially applied allelochemical, benzoic acid, on in vitro Fusarium oxysporum f.sp. niveum (a soil-borne pathogen causing watermelon wilt) was evaluated. Benzoic acid strongly inhibited its growth, sporulation and conidia germination, whereas it stimulated virulence factors of this pathogen. The biomass was reduced by 83-96 % and the conidia germinating rate and conidia production rate were decreased by 100 % at a concentration of >200 mg/L. However, phytopathogenic enzyme activities and mycotoxin production were stimulated with an increase of 10.2-1250 % for enzyme activities and 610-2630 % for mycotoxin yield.
Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
- MeSH
- Adult MeSH
- Risk Assessment MeSH
- Precision Medicine * MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local genetics pathology MeSH
- Survival Rate MeSH
- Mutation * MeSH
- Biomarkers, Tumor genetics MeSH
- Thyroid Neoplasms genetics pathology MeSH
- Follow-Up Studies MeSH
- Carcinoma, Papillary genetics pathology MeSH
- Prognosis MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.
- MeSH
- Acetylation MeSH
- Benzamides chemistry metabolism MeSH
- Charcot-Marie-Tooth Disease drug therapy metabolism pathology MeSH
- Quinolines chemistry metabolism therapeutic use MeSH
- Phenotype MeSH
- Histone Deacetylase 6 antagonists & inhibitors metabolism MeSH
- Histone Deacetylase Inhibitors chemistry metabolism therapeutic use MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Half-Life MeSH
- Protein Isoforms antagonists & inhibitors metabolism MeSH
- Molecular Docking Simulation MeSH
- Tubulin metabolism MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.
- MeSH
- Benzamides pharmacology MeSH
- Quinolines pharmacology MeSH
- Hippocampus drug effects metabolism MeSH
- Histone Deacetylase 6 antagonists & inhibitors MeSH
- Histone Deacetylase Inhibitors pharmacology MeSH
- Cognition drug effects MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Memory drug effects MeSH
- Protein Processing, Post-Translational drug effects MeSH
- Fragile X Syndrome enzymology physiopathology MeSH
- Learning drug effects MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- Antidepressive Agents pharmacology MeSH
- Anti-Anxiety Agents pharmacology MeSH
- Carthamus tinctorius * chemistry metabolism growth & development MeSH
- Chalcone analogs & derivatives MeSH
- Phytotherapy MeSH
- Humans MeSH
- Neuroprotective Agents pharmacology MeSH
- Nootropic Agents pharmacology MeSH
- Plant Extracts * pharmacology therapeutic use MeSH
- Salvia miltiorrhiza MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
