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Scientific Reports Jun 2022Although various body fluid biomarkers for amyotrophic lateral sclerosis (ALS) have been reported, no biomarkers specifically reflecting abnormalities in axonal...
Although various body fluid biomarkers for amyotrophic lateral sclerosis (ALS) have been reported, no biomarkers specifically reflecting abnormalities in axonal excitability indices have currently been established. Capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry were used to perform a comprehensive metabolome analysis of plasma from seven ALS patients and 20 controls, and correlation analysis with disease phenotypes was then performed in 22 other ALS patients. Additionally, electrophysiological studies of motor nerve axonal excitability were performed in all ALS patients. In the ALS and control groups, levels of various metabolites directly associated with skeletal muscle metabolism, such as those involved in fatty acid β-oxidation and the creatine pathway, were detected. Receiver operating characteristic curve analysis of the top four metabolites (ribose-5-phosphate, N6-acetyllysine, dyphylline, 3-methoxytyrosine) showed high diagnostic accuracy (area under the curve = 0.971) in the ALS group compared with the control group. Furthermore, hierarchical cluster analysis revealed that taurine levels were correlated with the strength-duration time constant, an axonal excitability indicator established to predict survival. No significant effects of diabetes mellitus and treatment (Riluzole and Edaravone) on this relationship were detected in the study. Therefore, plasma taurine is a potential novel axonal excitability-translatable biomarker for ALS.
Topics: Amyotrophic Lateral Sclerosis; Axons; Biomarkers; Humans; Motor Neurons; Taurine
PubMed: 35650294
DOI: 10.1038/s41598-022-13397-6 -
Biomedicines Jan 2022Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids...
Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids and long-acting β2-adrenoceptor agonists (LABAs). In addition, biological drugs provide another therapeutic option, especially for patients with severe asthma. However, these drugs were less effective in preventing severe asthma exacerbation, and other drug options are still limited. Herein, we extracted asthma-associated single nucleotide polymorphisms (SNPs) from the genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) catalog and prioritized candidate genes through five functional annotations. Genes enriched in more than two categories were defined as "biological asthma risk genes." Then, DrugBank was used to match target genes with FDA-approved medications and identify candidate drugs for asthma. We discovered 139 biological asthma risk genes and identified 64 drugs targeting 22 of these genes. Seven of them were approved for asthma, including reslizumab, mepolizumab, theophylline, dyphylline, aminophylline, oxtriphylline, and enprofylline. We also found 17 drugs with clinical or preclinical evidence in treating asthma. In addition, eleven of the 40 candidate drugs were further identified as promising asthma therapy. Noteworthy, is considered a target for asthma drug repurposing based on its high target scores. Through in silico drug repurposing approach, we identified sarilumab and satralizumab as the most promising drug for asthma treatment.
PubMed: 35052792
DOI: 10.3390/biomedicines10010113 -
BMC Pharmacology & Toxicology Nov 2017Zebrafish embryos are emerging as a model for pharmacological and toxicological studies. We used zebrafish embryos to study the general toxicity and cardiovascular...
BACKGROUND
Zebrafish embryos are emerging as a model for pharmacological and toxicological studies. We used zebrafish embryos to study the general toxicity and cardiovascular effects of eight methylxanthines: aminophylline, caffeine, diprophylline, doxofylline, etophylline, 3-isobutyl-1-methylxanthine (IBMX), pentoxifylline and theophylline.
METHODS
Microinjections of the eight methylxanthines were performed in 1-2 cell stage zebrafish embryos and the general toxicity and cardiovascular effects were analyzed at different time points. Embryotoxicity and teratogenicity were evaluated to understand the general toxicity of these compounds. Structural and functional alterations of the heart were evaluated to assess the cardiovascular effects.
RESULTS
Our results showed different activity patterns of the methylxanthines drugs. Caffeine, IBMX, pentoxifylline and theophylline were highly embryotoxic and teratogenic; aminophylline, doxofylline and etophylline were embryotoxic and teratogenic only at higher doses, and diprophylline showed a minimal (<10%) embryotoxicity and teratogenicity. Most of these drugs induced structural alteration of the heart in 20-40% of the injected embryos with the maximum dose. This structural alteration was fatal with the embryos ultimately dying within 120 hpf. All the drugs induced a transient increase in heart rate at 48 hpf which returned to baseline within 96 hpf. This functional effect of methylxanthines showed similarity to the studies done in humans and other vertebrates.
CONCLUSION
Our results indicate the potential toxicity and teratogenicity of different methylxanthines in the embryos during embryonic development, the most sensitive period of life. Although interspecies differences need to be considered before drawing any conclusion, our study elucidated that a single exposure of methylxanthines at therapeutic range could induce cardiac dysfunction besides causing embryotoxicity and teratogenicity. Of all the drugs, diprophylline appeared to be safer, with lower degree of embryotoxicity, teratogenicity and cardiac toxicity as compared to other methylxanthines.
Topics: Animals; Embryo, Nonmammalian; Heart; Heart Rate; Xanthines; Zebrafish
PubMed: 29141695
DOI: 10.1186/s40360-017-0179-9 -
Chemical & Pharmaceutical Bulletin 2020The high-order functions of molecular capture and chiral recognition of tea gallated catechins (-)-epigallocatechin-3-O-gallate (EGCg) in water were investigated. A... (Review)
Review
The high-order functions of molecular capture and chiral recognition of tea gallated catechins (-)-epigallocatechin-3-O-gallate (EGCg) in water were investigated. A solution of equimolar amounts of a variety of heterocyclic compounds and EGCg in water afforded adhesive precipitates containing the heterocyclic compounds and EGCg at a molar ratio of 1 : 1, based on the integrated value of NMR proton signals. The molecular capture abilities of a variety of heterocyclic compounds using EGCg from the aqueous solutions were evaluated with the ratios of the heterocyclic compounds included in the precipitates of EGCg complex to the total heterocyclic compounds used. In the H-NMR spectrum of a solution containing cyclo(L-Pro-Gly), cyclo(D-Pro-Gly), and EGCg in a DO solution, a difference in the chemical shift of the H-NMR signal for some protons of the Pro residue was observed. Judging from the crystal structures of the 2 : 2 EGCg complexes of cyclo(L-Pro-Gly), cyclo(D-Pro-Gly), the difference in the chemical shift derived mainly from a magnetic anisotropic shielding effect by the ring current from the B ring of EGCg.In the H-NMR spectrum of a solution containing the pharmaceuticals racemic (R,S)-propranolol, (R,S)-diprophylline, (R,S)-proxyphylline and EGCg in DO, splitting of the H-NMR signals of the pharmaceuticals was observed. It was suggested that the pharmaceuticals formed diastereomers of EGCg complexes, as a result chirality of the pharmaceuticals was recognized by EGCg in the DO solution.
Topics: Catechin; Deuterium Oxide; Drug Development; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Stereoisomerism
PubMed: 33268646
DOI: 10.1248/cpb.c20-00197 -
Biomolecules Dec 2023Gout is characterized by the formation of monosodium urate crystals in peripheral joints. We carried out laboratory studies to investigate the effect of adding nine...
Gout is characterized by the formation of monosodium urate crystals in peripheral joints. We carried out laboratory studies to investigate the effect of adding nine different methylxanthines and two different methylated uric acid derivatives on the development of these crystals over the course of 96 h in a medium whose composition was similar to that of synovial fluid. Our results showed that 7-methylxanthine reduced or totally prevented crystal formation; 1-methylxanthine, 3-methylxanthine, 7-methyluric acid, and 1,3-dimethyluric acid had weaker effects, and the other molecules had no apparent effect. The presented results indicate that a 7-methylxanthine concentration of about 6 × 10 M (10 mg/L) prevented the formation of crystals for an initial urate concentration of 1.78 × 10 M (300 mg/L) in the presence of 0.4 M of Na for 96 h at 25 °C and a pH of 7.4. We attribute these results to alterations in thermodynamics, not kinetics. Our results suggest that prevention of crystallization in vivo could be achieved by direct oral administration of 7-methylxanthine or other methylxanthines that are metabolized to 7-methylxanthine. For example, the hepatic metabolism of theobromine leads to significant plasma levels of 7-methylxanthine (14% of the initial theobromine concentration) and 3-methylxanthine (6% of the initial theobromine concentration); however, 7-methyluric acid is present at very low concentrations in the plasma. It is important to consider that several of the specific molecules we examined (theobromine, caffeine, theophylline, dyphylline, etophylline, and pentoxifylline) did not directly affect crystallization.
Topics: Uric Acid; Theobromine; Solubility; Caffeine
PubMed: 38136640
DOI: 10.3390/biom13121769 -
Bioorganic Chemistry Oct 2022Alcohol dehydrogenases (ADHs; EC 1.1.1.1) have been widely used for the reversible redox reactions of carbonyl compounds (i.e., aldehydes and ketones) and primary or...
Alcohol dehydrogenases (ADHs; EC 1.1.1.1) have been widely used for the reversible redox reactions of carbonyl compounds (i.e., aldehydes and ketones) and primary or secondary alcohols, often resulting in optically pure hydroxyl products with high added value. In this work, we report a concise chemoenzymatic route toward xanthine-based enantiomerically pure active pharmaceutical ingredients (API) - proxyphylline, xanthinol, and diprophylline employing various recombinant short-chain ADHs with (R)- or (S)-selectivity as key biocatalysts. By choosing the appropriate ADH, the (R)- as well as the (S)-enantiomer of proxyphylline was prepared in excellent enantiomeric excess (99-99.9% ee), >99% conversion, and the isolated yield ranging from 65% to 74%, depending on the used biocatalyst (ADH-A from Rhodococcus ruber or a variant derived from Lactobacillus kefir, Lk-ADH-Lica). In turn, E. coli/ADH-catalyzed bioreduction of the carbonylic precursor of xanthinol and diprophylline furnished the corresponding (S)-chlorohydrin in >99% ee, >99% conversion, and 80% yield (in the case of Lk-ADH-Lica); while the (R)-counterpart was afforded in 94% ee, 64% conversion, and 41% yield (in the case of SyADH from Sphingobium yanoikuyae). After further chemical functionalization of the key (S)-chlorohydrin intermediate, the desired homochiral (R)-xanthinol (>99% ee) was obtained in 97% yield and (S)-diprophylline (>99% ee) in 90% yield. The devised biocatalytic method is straightforward and thus might be considered practical in the manufacturing of title pharmaceuticals.
Topics: Biocatalysis; Chlorohydrins; Dyphylline; Escherichia coli; Hydrogen; Stereoisomerism; Theophylline
PubMed: 35777234
DOI: 10.1016/j.bioorg.2022.105967 -
Bioscience Reports Jun 2020Serous ovarian cancer is one of the most fatal gynecological tumors with an extremely low 5-year survival rate. Most patients are diagnosed at an advanced stage with...
Serous ovarian cancer is one of the most fatal gynecological tumors with an extremely low 5-year survival rate. Most patients are diagnosed at an advanced stage with wide metastasis. The dysregulation of genes serves an important role in the metastasis progression of ovarian cancer. Differentially expressed genes (DEGs) between primary tumors and metastases of serous ovarian cancer were screened out in the gene expression profile of GSE73168 from Gene Expression Omnibus (GEO). Cytoscape plugin cytoHubba and weighted gene co-expression network analysis (WGCNA) were utilized to select hub genes. Univariate and multivariate Cox regression analyses were used to screen out prognosis-associated genes. Furthermore, the Oncomine validation, prognostic analysis, methylation mechanism, gene set enrichment analysis (GSEA), TIMER database analysis and administration of candidate molecular drugs were conducted for hub genes. Nine hundred and fifty-seven DEGs were identified in the gene expression profile of GSE73168. After using Cytoscape plugin cytoHubba, 83 genes were verified. In co-expression network, the blue module was most closely related to tumor metastasis. Furthermore, the genes in Cytoscape were analyzed, showing that the blue module and screened 17 genes were closely associated with tumor metastasis. Univariate and multivariate Cox regression revealed that the age, stage and STMN2 were independent prognostic factors. The Cancer Genome Atlas (TCGA) suggested that the up-regulated expression of STMN2 was related to poor prognosis of ovarian cancer. Thus, STMN2 was considered as a new key gene after expression validation, survival analysis and TIMER database validation. GSEA confirmed that STMN2 was probably involved in ECM receptor interaction, focal adhesion, TGF beta signaling pathway and MAPK signaling pathway. Furthermore, three candidate small molecule drugs for tumor metastasis (diprophylline, valinomycin and anisomycin) were screened out. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot showed that STMN2 was highly expressed in ovarian cancer tissue and ovarian cancer cell lines. Further studies are needed to investigate these prognosis-associated genes for new therapy target.
Topics: Age Factors; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Databases, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Protein Interaction Maps; Signal Transduction; Stathmin
PubMed: 32510146
DOI: 10.1042/BSR20194324 -
Journal of Hepatology Apr 2022Antiepileptic drugs (AEDs) are a common cause of drug-induced liver injury (DILI). Over the last few decades, several newer AEDs were approved for marketing in the...
BACKGROUND & AIMS
Antiepileptic drugs (AEDs) are a common cause of drug-induced liver injury (DILI). Over the last few decades, several newer AEDs were approved for marketing in the United States, and they are increasingly prescribed for indications other than seizures. Contemporaneous data related to trends and characteristics of AED-related liver injury are sparse.
METHODS
We report the trends, characteristics, and outcomes of patients with AED-related DILI enrolled into the DILIN Prospective Study between 2004 and 2020.
RESULTS
Among 1,711 participants with definite, highly likely, or probable DILI, 66 (3.9%) had AED-related DILI (lamotrigine [n = 18], phenytoin [n = 16], carbamazepine [n = 11], valproate [n = 10], gabapentin [n = 4], and others [n = 7]). The frequency of AED-related liver injury significantly decreased during the study period (from 8.5% of cases during 2004-2007 to 2.6% during 2015-2020, p = 0.01). AEDs other than phenytoin were commonly prescribed for non-seizure indications. Compared to non-AEDs, patients with AED-related liver injury were younger (mean age 38.5 vs. 50.1 years-old, p <0.001) and more likely African American (27% vs. 12%, p = 0.008). DRESS was common with liver injury caused by lamotrigine, phenytoin, and carbamazepine, but not valproate or gabapentin. Liver injury severity was moderate to severe in the majority: 5 died, and 3 underwent orthotopic liver transplantation (OLT). No patient with lamotrigine-related DILI, including 13 with hepatocellular jaundice, died or needed OLT, while 3 out of 16 patients (19%) with phenytoin-related DILI either died or required OLT.
CONCLUSION
The frequency of AED-related liver injury significantly decreased over the last 2 decades in our experience. AED-related liver injury has several distinctive features, including a preponderance in African American patients and those with immunoallergic skin reactions, with outcomes depending on the type of AED involved.
LAY SUMMARY
Medications used to treat epilepsy may sometimes cause severe liver injury. However, several new medications have been approved over the last 2 decades and they may not be as toxic to the liver as older antiepileptic medications (AEDs). This study shows that overall liver injury due to AEDs is decreasing, likely due to decreasing use of older AEDs. Liver injury due to AEDs appears to be more common in African Americans and is commonly associated with allergic skin reactions.
Topics: Adult; Anticonvulsants; Carbamazepine; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Dyphylline; Gabapentin; Humans; Lamotrigine; Middle Aged; Phenytoin; Prospective Studies; Seizures; United States
PubMed: 34953957
DOI: 10.1016/j.jhep.2021.12.013 -
Liver International : Official Journal... Jun 2022Leflunomide, a disease-modifying anti-rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory...
BACKGROUND
Leflunomide, a disease-modifying anti-rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory features and outcomes of 17 patients with leflunomide/teriflunomide hepatotoxicity from two large drug-induced liver injury (DILI) registries.
METHODS
Consecutive, adjudicated cases of leflunomide (n = 16)-or teriflunomide (n = 1)-related DILI from a single centre in Bangalore, India and the multicentre US Drug-Induced Liver Injury Network (DILIN) were reviewed.
RESULTS
Nine (0.8%) of the 1070 Indian patients and 8 (0.5%) of the 1400 DILIN patients fulfilled the criteria for DILI because of leflunomide- or teriflunomide. 89% of the Indian cases were women and all were associated with severe cutaneous adverse reaction (SCAR) and a median drug latency of 49 days, whereas 37.5% of the DILIN cases were female, none exhibited SCAR and the median drug latency was 166 days. Hepatocellular injury (70%) was more common in women than men (92% vs. 20%) and was associated with younger mean age (41 vs. 59 years), higher peak INR (2.3 vs. 1.2) and higher mortality (58% vs. 0%). Mortality was observed in six patients from India (2 of the three with myocarditis) and one received liver transplantation from the USA.
CONCLUSION
Leflunomide-induced liver injury is predominantly hepatocellular. Leflunomide hepatotoxicity is more likely accompanied by SCAR, a short latency and a higher mortality in the Indian cohort, with a predominance of females, compared to US DILIN patients. The differences in skin involvement, immunoallergic features and outcomes among subjects from India vs. the USA suggest that genetic or environmental factors are important in the pathogenesis of liver injury.
Topics: Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Drug-Related Side Effects and Adverse Reactions; Dyphylline; Female; Humans; India; Leflunomide; Male; Registries
PubMed: 35129282
DOI: 10.1111/liv.15189 -
Journal of Hepatology May 2022The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver...
BACKGROUND & AIMS
The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model.
METHODS
Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case.
RESULTS
Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients.
CONCLUSIONS
Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis.
LAY SUMMARY
The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.
Topics: Biopsy; Chemical and Drug Induced Liver Injury; Dyphylline; Humans; Risk Factors
PubMed: 35074471
DOI: 10.1016/j.jhep.2021.12.043