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2.
Harmful Algae ; 135: 102635, 2024 May.
Article in English | MEDLINE | ID: mdl-38830716

ABSTRACT

Ongoing research on cyanotoxins, driven by the socioeconomic impact of harmful algal blooms, emphasizes the critical necessity of elucidating the toxicological profiles of algal cell extracts and pure toxins. This study comprehensively compares Raphidiopsis raciborskii dissolved extract (RDE) and cylindrospermopsin (CYN) based on Daphnia magna assays. Both RDE and CYN target vital organs and disrupt reproduction, development, and digestion, thereby causing acute and chronic toxicity. Disturbances in locomotion, reduced behavioral activity, and weakened swimming capability in D. magna have also been reported for both RDE and CYN, indicating the insufficiency of conventional toxicity evaluation parameters for distinguishing between the toxic effects of algal extracts and pure cyanotoxins. Additionally, chemical profiling revealed the presence of highly active tryptophan-, humic acid-, and fulvic acid-like fluorescence compounds in the RDE, along with the active constituents of CYN, within a 15-day period, demonstrating the chemical complexity and dynamics of the RDE. Transcriptomics was used to further elucidate the distinct molecular mechanisms of RDE and CYN. They act diversely in terms of cytotoxicity, involving oxidative stress and response, protein content, and energy metabolism, and demonstrate distinct modes of action in neurofunctions. In essence, this study underscores the distinct toxicity mechanisms of RDE and CYN and emphasizes the necessity for context- and objective-specific toxicity assessments, advocating nuanced approaches to evaluate the ecological and health implications of cyanotoxins, thereby contributing to the precision of environmental risk assessments.


Subject(s)
Alkaloids , Bacterial Toxins , Cyanobacteria Toxins , Cyanobacteria , Daphnia , Animals , Bacterial Toxins/toxicity , Daphnia/drug effects , Alkaloids/toxicity , Cyanobacteria/chemistry , Uracil/analogs & derivatives , Uracil/toxicity , Cell Extracts/chemistry , Cell Extracts/pharmacology , Harmful Algal Bloom
3.
BMC Cancer ; 24(1): 674, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38825703

ABSTRACT

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bevacizumab , Colorectal Neoplasms , Drug Combinations , Pyrrolidines , Thymine , Trifluridine , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , Bevacizumab/therapeutic use , Bevacizumab/administration & dosage , Trifluridine/therapeutic use , Trifluridine/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Pyrrolidines/therapeutic use , Pyrrolidines/administration & dosage , Neoplasm Metastasis , Progression-Free Survival , Uracil/analogs & derivatives , Uracil/therapeutic use , Uracil/administration & dosage , Drug Resistance, Neoplasm
4.
Sci Rep ; 14(1): 12658, 2024 06 03.
Article in English | MEDLINE | ID: mdl-38830895

ABSTRACT

The combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We evaluated the efficacy and safety of this combination compared with those of FTD/TPI monotherapy in patients with AGC. We retrospectively reviewed data of patients with AGC who received FTD/TPI plus ramucirumab or FTD/TPI monotherapy as third- or later-line treatment. This study included 36 patients treated with FTD/TPI plus ramucirumab and 70 patients receiving FTD/TPI monotherapy. The objective response rate (ORR) and disease control rate (DCR) were 25.8% and 58.1%, respectively, in the FTD/TPI plus ramucirumab group and 5.0% and 38.3%, respectively, in the FTD/TPI group (ORR, P = 0.007; DCR, P = 0.081). The median progression-free survival (PFS) was significantly longer in the FTD/TPI plus ramucirumab group (median PFS, 2.9 vs. 1.8 months; hazard ratio [HR]: 0.52; P = 0.001). A numerical survival benefit was also observed (median overall survival, 7.9 months vs. 5.0 months; HR: 0.68, P = 0.089). In the multivariate analysis, PFS was significantly longer in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy group (HR: 0.61, P = 0.030). The incidence of febrile neutropenia was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI group (13.8% vs. 2.9%); however, no new safety signals were identified. Compared with FTD/TPI monotherapy, FTD/TPI plus ramucirumab offers clinical benefits with acceptable toxicity in heavily pretreated patients with AGC. Further investigation via randomized trials is warranted to confirm these findings.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Drug Combinations , Pyrrolidines , Ramucirumab , Stomach Neoplasms , Thymine , Trifluridine , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Stomach Neoplasms/mortality , Male , Female , Middle Aged , Aged , Trifluridine/therapeutic use , Trifluridine/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Pyrrolidines/therapeutic use , Pyrrolidines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Retrospective Studies , Adult , Aged, 80 and over , Treatment Outcome , Uracil/analogs & derivatives , Uracil/therapeutic use , Uracil/administration & dosage , Progression-Free Survival
5.
Proc Natl Acad Sci U S A ; 121(25): e2404457121, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38865275

ABSTRACT

The fat mass and obesity-associated fatso (FTO) protein is a member of the Alkb family of dioxygenases and catalyzes oxidative demethylation of N6-methyladenosine (m6A), N1-methyladenosine (m1A), 3-methylthymine (m3T), and 3-methyluracil (m3U) in single-stranded nucleic acids. It is well established that the catalytic activity of FTO proceeds via two coupled reactions. The first reaction involves decarboxylation of alpha-ketoglutarate (αKG) and formation of an oxyferryl species. In the second reaction, the oxyferryl intermediate oxidizes the methylated nucleic acid to reestablish Fe(II) and the canonical base. However, it remains unclear how binding of the nucleic acid activates the αKG decarboxylation reaction and why FTO demethylates different methyl modifications at different rates. Here, we investigate the interaction of FTO with 5-mer DNA oligos incorporating the m6A, m1A, or m3T modifications using solution NMR, molecular dynamics (MD) simulations, and enzymatic assays. We show that binding of the nucleic acid to FTO activates a two-state conformational equilibrium in the αKG cosubstrate that modulates the O2 accessibility of the Fe(II) catalyst. Notably, the substrates that provide better stabilization to the αKG conformation in which Fe(II) is exposed to O2 are demethylated more efficiently by FTO. These results indicate that i) binding of the methylated nucleic acid is required to expose the catalytic metal to O2 and activate the αKG decarboxylation reaction, and ii) the measured turnover of the demethylation reaction (which is an ensemble average over the entire sample) depends on the ability of the methylated base to favor the Fe(II) state accessible to O2.


Subject(s)
Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Iron , Ketoglutaric Acids , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/chemistry , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics , Ketoglutaric Acids/metabolism , Ketoglutaric Acids/chemistry , Iron/metabolism , Iron/chemistry , Humans , Substrate Specificity , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/chemistry , Protein Conformation , Uracil/metabolism , Uracil/analogs & derivatives , Uracil/chemistry , Molecular Dynamics Simulation , Thymine/analogs & derivatives
6.
Nat Commun ; 15(1): 4885, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38849353

ABSTRACT

Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.


Subject(s)
Molecular Dynamics Simulation , Myocardial Contraction , Urea , Myocardial Contraction/drug effects , Crystallography, X-Ray , Humans , Urea/analogs & derivatives , Urea/pharmacology , Urea/chemistry , Cardiac Myosins/metabolism , Cardiac Myosins/chemistry , Cardiac Myosins/genetics , Ventricular Myosins/metabolism , Ventricular Myosins/chemistry , Ventricular Myosins/genetics , Animals , Benzylamines , Uracil/analogs & derivatives
7.
Cell ; 187(12): 2897-2897.e1, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38848671

ABSTRACT

Resmetirom is an oral selective THR-ß agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom restores mitochondrial and hepatic metabolic function; reduces atherogenic lipids; improves hepatic steatosis, inflammation, and fibrosis; and has no significant effect on THR-α. To view this Bench to Bedside, open or download the PDF.


Subject(s)
Liver Cirrhosis , Pyridazines , Uracil , Animals , Humans , Liver/metabolism , Liver/drug effects , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Mitochondria/metabolism , Mitochondria/drug effects , Pyridazines/therapeutic use , Uracil/analogs & derivatives
8.
Clin Adv Hematol Oncol ; 22 Suppl 4(5): 1-20, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38805297

ABSTRACT

The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Neoplasm Metastasis , Patient Selection , Phenylurea Compounds , Pyridines , Trifluridine , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pyridines/therapeutic use , Trifluridine/therapeutic use , Phenylurea Compounds/therapeutic use , Thymine/therapeutic use , Bevacizumab/therapeutic use , Pyrrolidines/therapeutic use , Drug Combinations , Uracil/analogs & derivatives , Uracil/therapeutic use
9.
Eur J Pharmacol ; 975: 176635, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38734296

ABSTRACT

BACKGROUND: Degeneration of the nigrostriatal dopaminergic pathway has been seen as a significant cause of movement disability in Parkinson's disease (PD) patients. However, the exact reason for these degenerative changes has remained obscure. In recent years, incretins have been neuroprotective in various pathologies. In the current study, we have investigated the neuroprotective potential of alogliptin (Alo), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, in a lipopolysaccharide (LPS) induced experimental model of PD. EXPERIMENTAL APPROACH: LPS (5µg/5 µl) was infused intranigrally to induce PD in experimental rats. Post-LPS infusion, these animals were treated with Alo for 21 days in three successive dosages of 10, 20, and 40 mg/kg/day/per oral. The study is well supported with the determinations of motor functions biochemical, neurochemical, and histological analysis. KEY RESULTS: Intranigral infusion of LPS in rats produced motor deficit. It was accompanied by oxidative stress, elevation in neuroinflammatory cytokines, altered neurochemistry, and degenerative changes in the striatal brain region. While Alo abrogated LPS-induced biochemical/neurochemical alterations, improved motor functions, and preserved neuronal morphology in LPS-infused rats. CONCLUSION: The observed neuroprotective potential of Alo may be due to its antioxidant and anti-inflammatory actions and its ability to modulate monoaminergic signals. Nonetheless, current findings suggest that improving the availability of incretins through DPP-IV inhibition is a promising strategy for treating Parkinson's disease.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Lipopolysaccharides , Neuroprotective Agents , Oxidative Stress , Piperidines , Uracil , Animals , Uracil/analogs & derivatives , Uracil/pharmacology , Uracil/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Male , Rats , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Oxidative Stress/drug effects , Rats, Wistar , Disease Models, Animal , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Cytokines/metabolism , Motor Activity/drug effects , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/pathology
10.
Arch Cardiovasc Dis ; 117(6-7): 427-432, 2024.
Article in English | MEDLINE | ID: mdl-38762345

ABSTRACT

BACKGROUND: The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a first-in-class treatment for symptomatic hypertrophic obstructive cardiomyopathy. AIMS: To assess the profile and burden of cardiac myosin inhibitor candidates in the hypertrophic cardiomyopathy prospective Register of hypertrophic cardiomyopathy (REMY) held by the French Society of Cardiology. METHODS: Data were collected at baseline and during follow-up from patients with hypertrophic cardiomyopathy enrolled in REMY by the three largest participating centres. RESULTS: Among 1059 adults with hypertrophic cardiomyopathy, 461 (43.5%) had obstruction; 325 (30.7%) of these were also symptomatic, forming the "cardiac myosin inhibitor candidates" group. Baseline features of this group were: age 58±15years; male sex (n=196; 60.3%); diagnosis-to-inclusion delay 5 (1-12)years; maximum wall thickness 20±6mm; left ventricular ejection fraction 69±6%; family history of hypertrophic cardiomyopathy or sudden cardiac death (n=133; 40.9%); presence of a pathogenic sarcomere gene mutation (n=101; 31.1%); beta-blocker or verapamil treatment (n=304; 93.8%), combined with disopyramide (n=28; 8.7%); and eligibility for septal reduction therapy (n=96; 29%). At the end of a median follow-up of 66 (34-106) months, 319 (98.2%) were treated for obstruction (n=43 [13.2%] received disopyramide), 46 (14.2%) underwent septal reduction therapy and the all-cause mortality rate was 1.9/100 person-years (95% confidence interval 1.4-2.6) (46 deaths). Moreover, 41 (8.9%) patients from the initial hypertrophic obstructive cardiomyopathy group became eligible for a cardiac myosin inhibitor. CONCLUSIONS: In this cohort of patients with hypertrophic cardiomyopathy selected from the REMY registry, one third were eligible for a cardiac myosin inhibitor.


Subject(s)
Cardiomyopathy, Hypertrophic , Cardiovascular Agents , Registries , Ventricular Function, Left , Humans , Male , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/mortality , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/diagnosis , Female , Middle Aged , France/epidemiology , Treatment Outcome , Aged , Time Factors , Ventricular Function, Left/drug effects , Cardiovascular Agents/therapeutic use , Cardiovascular Agents/adverse effects , Patient Selection , Prospective Studies , Cardiac Myosins/genetics , Benzylamines/therapeutic use , Adult , Risk Factors , Ventricular Outflow Obstruction/physiopathology , Ventricular Outflow Obstruction/drug therapy , Ventricular Outflow Obstruction/etiology , Uracil/analogs & derivatives
11.
Sci Rep ; 14(1): 11609, 2024 05 21.
Article in English | MEDLINE | ID: mdl-38773214

ABSTRACT

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis.


Subject(s)
Biomarkers, Tumor , Mouth Neoplasms , Pyrimidines , Uracil , Humans , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Uracil/metabolism , Biomarkers, Tumor/metabolism , Pyrimidines/metabolism , Female , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Male , Middle Aged , Tumor Microenvironment , Aged , Apyrase/metabolism
12.
Commun Biol ; 7(1): 529, 2024 May 04.
Article in English | MEDLINE | ID: mdl-38704509

ABSTRACT

Intra-organism biodiversity is thought to arise from epigenetic modification of constituent genes and post-translational modifications of translated proteins. Here, we show that post-transcriptional modifications, like RNA editing, may also contribute. RNA editing enzymes APOBEC3A and APOBEC3G catalyze the deamination of cytosine to uracil. RNAsee (RNA site editing evaluation) is a computational tool developed to predict the cytosines edited by these enzymes. We find that 4.5% of non-synonymous DNA single nucleotide polymorphisms that result in cytosine to uracil changes in RNA are probable sites for APOBEC3A/G RNA editing; the variant proteins created by such polymorphisms may also result from transient RNA editing. These polymorphisms are associated with over 20% of Medical Subject Headings across ten categories of disease, including nutritional and metabolic, neoplastic, cardiovascular, and nervous system diseases. Because RNA editing is transient and not organism-wide, future work is necessary to confirm the extent and effects of such editing in humans.


Subject(s)
APOBEC Deaminases , Cytidine Deaminase , RNA Editing , Humans , Cytidine Deaminase/metabolism , Cytidine Deaminase/genetics , Polymorphism, Single Nucleotide , Cytosine/metabolism , APOBEC-3G Deaminase/metabolism , APOBEC-3G Deaminase/genetics , Uracil/metabolism , Proteins/genetics , Proteins/metabolism , Cytosine Deaminase/genetics , Cytosine Deaminase/metabolism
13.
Chem Biol Interact ; 397: 111046, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38735451

ABSTRACT

Cylindrospermopsin, a potent hepatotoxin produced by harmful cyanobacterial blooms, poses environmental and human health concerns. We used a 3D human liver in vitro model based on spheroids of HepG2 cells, in combination with molecular and biochemical assays, automated imaging, targeted LC-MS-based proteomics, and lipidomics, to explore cylindrospermopsin effects on lipid metabolism and the processes implicated in hepatic steatosis. Cylindrospermopsin (1 µM, 48 h) did not significantly affect cell viability but partially reduced albumin secretion. However, it increased neutral lipid accumulation in HepG2 spheroids while decreasing phospholipid levels. Simultaneously, cylindrospermopsin upregulated genes for lipogenesis regulation (SREBF1) and triacylglycerol synthesis (DGAT1/2) and downregulated genes for fatty acid synthesis (ACLY, ACCA, FASN, SCD1). Fatty acid uptake, oxidation, and lipid efflux genes were not significantly affected. Targeted proteomics revealed increased levels of perilipin 2 (adipophilin), a major hepatocyte lipid droplet-associated protein. Lipid profiling quantified 246 lipid species in the spheroids, with 28 significantly enriched and 15 downregulated by cylindrospermopsin. Upregulated species included neutral lipids, sphingolipids (e.g., ceramides and dihexosylceramides), and some glycerophospholipids (phosphatidylethanolamines, phosphatidylserines), while phosphatidylcholines and phosphatidylinositols were mostly reduced. It suggests that cylindrospermopsin exposures might contribute to developing and progressing towards hepatic steatosis or metabolic dysfunction-associated steatotic liver disease (MASLD).


Subject(s)
Alkaloids , Bacterial Toxins , Cyanobacteria Toxins , Lipid Metabolism , Liver , Uracil , Humans , Alkaloids/pharmacology , Bacterial Toxins/metabolism , Uracil/analogs & derivatives , Uracil/metabolism , Lipid Metabolism/drug effects , Hep G2 Cells , Liver/metabolism , Liver/drug effects , Homeostasis/drug effects , Cell Survival/drug effects , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolism , Proteomics , Lipidomics , Lipogenesis/drug effects
14.
N Engl J Med ; 390(20): 1849-1861, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38739079

ABSTRACT

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).


Subject(s)
Cardiomyopathy, Hypertrophic , Cardiovascular Agents , Exercise Test , Aged , Female , Humans , Male , Middle Aged , Benzylamines , Cardiac Myosins/antagonists & inhibitors , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/physiopathology , Double-Blind Method , Exercise Tolerance/drug effects , Oxygen Consumption/drug effects , Uracil/analogs & derivatives , Valsalva Maneuver , Ventricular Outflow Obstruction/drug therapy , Ventricular Outflow Obstruction/physiopathology , Ventricular Outflow Obstruction/etiology , Cardiovascular Agents/pharmacology , Cardiovascular Agents/therapeutic use , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Administration, Oral
15.
J Chem Theory Comput ; 20(10): 4218-4228, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38720241

ABSTRACT

iso-Orotate decarboxylase (IDCase), which is involved in the thymidine salvage pathway, has attracted considerable interest owing to its chemical similarity to a hypothetical DNA decarboxylase in mammals. Although valuable insights into the active DNA demethylation of 5-methyl-cytosine can be obtained from the decarboxylation mechanism of 5-carboxyl-uracil (5caU) catalyzed by IDCase, this mechanism remains under debate. In this study, the catalytic mechanism of 5caU decarboxylation by IDCase was studied using hybrid quantum mechanics/molecular mechanics (QM/MM) methodologies and density functional theory (DFT) calculations with a truncated model. The calculations supported a mechanism involving three sequential stages: activation of the 5caU substrate via proton transfer from an arginine (R262') to the carboxyl group of 5caU, formation of a tetrahedral intermediate, and decarboxylation of the tetrahedral intermediate to generate uracil as the product. The reaction pathways and structures obtained using the QM/MM and DFT methods coincided with each other. These simulations provided detailed insights into the unique mechanism of IDCase, clarifying various unresolved issues, such as the critical role of R262'. In addition, aspartate D323 was found to act as a general base in the tetrahedral intermediate formation step and a general acid in the later C-C bond cleavage step.


Subject(s)
Density Functional Theory , Decarboxylation , Molecular Dynamics Simulation , Quantum Theory , Carboxy-Lyases/chemistry , Carboxy-Lyases/metabolism , Biocatalysis , Orotidine-5'-Phosphate Decarboxylase/chemistry , Orotidine-5'-Phosphate Decarboxylase/metabolism , Uracil/chemistry , Uracil/metabolism
16.
J Cardiovasc Med (Hagerstown) ; 25(7): 491-498, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38814051

ABSTRACT

AIMS: We aimed to comprehensively assess the safety and efficacy of mavacamten in hypertrophic cardiomyopathy (HCM) patients. METHODS: A systematic review and meta-analysis was conducted, and efficacy [changes in postexercise left ventricular outflow tract (LVOT) gradient, left ventricular ejection fraction (LVEF), peak oxygen consumption (pVO 2 ), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS), and the proportion of patients exhibiting an improvement of at least one New York Heart Association (NYHA) functional class from baseline)], safety (total count of treatment-emergent adverse events and SAEs, as well as the proportion of patients experiencing at least one adverse event or SAE), and cardiac biomarkers (NT-proBNP and cTnI) outcomes were evaluated. RESULTS: We incorporated data from four randomized controlled trials, namely EXPLORER-HCM, VALOR-HCM, MAVERICK-HCM, and EXPLORER-CN. Mavacamten demonstrated significant efficacy in reducing the postexercise LVOT gradient by 49.44 mmHg ( P  = 0.0001) and LVEF by 3.84 ( P  < 0.0001) and improving pVO 2 by 0.69 ml/kg/min ( P  = 0.4547), KCCQ CSS by 8.11 points ( P  < 0.0001), and patients with at least one NYHA functional class improvement from baseline by 2.20 times ( P  < 0.0001). Importantly, mavacamten increased 1.11-fold adverse events ( P  = 0.0184) 4.24-fold reduced LVEF to less than 50% ( P  = 0.0233) and 1.06-fold SAEs ( P  = 0.8631). Additionally, mavacamten decreased NT-proBNP by 528.62 ng/l ( P  < 0.0001) and cTnI by 8.28 ng/l ( P  < 0.0001). CONCLUSION: Mavacamten demonstrates both safety and efficacy in patients with HCM, suggesting its potential as a promising therapeutic strategy for this condition. Further research is warranted to confirm these results and explore its long-term effects.


Subject(s)
Cardiomyopathy, Hypertrophic , Randomized Controlled Trials as Topic , Ventricular Function, Left , Humans , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/physiopathology , Treatment Outcome , Ventricular Function, Left/drug effects , Stroke Volume/drug effects , Middle Aged , Male , Female , Natriuretic Peptide, Brain/blood , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Exercise Tolerance/drug effects , Biomarkers/blood , Adult , Recovery of Function , Oxygen Consumption/drug effects , Aged , Benzylamines , Uracil/analogs & derivatives
18.
J Clin Invest ; 134(9)2024 May 01.
Article in English | MEDLINE | ID: mdl-38690729

ABSTRACT

The myosin inhibitor mavacamten has transformed the management of obstructive hypertrophic cardiomyopathy (HCM) by targeting myosin ATPase activity to mitigate cardiac hypercontractility. This therapeutic mechanism has proven effective for patients with HCM independent of having a primary gene mutation in myosin. In this issue of the JCI, Buvoli et al. report that muscle hypercontractility is a mechanism of pathogenesis underlying muscle dysfunction in Laing distal myopathy, a disorder characterized by mutations altering the rod domain of ß myosin heavy chain. The authors performed detailed physiological, molecular, and biomechanical analyses and demonstrated that myosin ATPase inhibition can correct a large extent of muscle abnormalities. The findings offer a therapeutic avenue for Laing distal myopathy and potentially other myopathies. This Commentary underscores the importance of reevaluating myosin activity's role across myopathies in general for the potential development of targeted myosin inhibitors to treat skeletal muscle disorders.


Subject(s)
Benzylamines , Muscle, Skeletal , Uracil/analogs & derivatives , Humans , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/metabolism , Cardiomyopathy, Hypertrophic/genetics , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , Distal Myopathies/genetics , Distal Myopathies/drug therapy , Distal Myopathies/metabolism , Distal Myopathies/pathology , Animals , Mutation , Myosins/metabolism , Myosins/genetics
20.
J Phys Chem B ; 128(19): 4716-4727, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38708944

ABSTRACT

Hypertrophic cardiomyopathy is one of the most common forms of genetic cardiomyopathy. Mavacamten is a first-in-class myosin modulator that was identified via activity screening on the wild type, and it is FDA-approved for the treatment of obstructive hypertrophic cardiomyopathy (HCM). The drug selectively binds to the cardiac ß-myosin, inhibiting myosin function to decrease cardiac contractility. Though the drug is thought to affect multiple steps of the myosin cross-bridge cycle, its detailed mechanism of action is still under investigation. Individual steps in the overall cross-bridge cycle must be queried to elucidate the full mechanism of action. In this study, we utilize the rare-event method of transition path sampling to generate reactive trajectories to gain insights into the action of the drug on the dynamics and rate of the ATP hydrolysis step for human cardiac ß-myosin. We study three known HCM causative myosin mutations: R453C, P710R, and R712L to observe the effect of the drug on the alterations caused by these mutations in the chemical step. Since the crystal structure of the drug-bound myosin was not available at the time of this work, we created a model of the drug-bound system utilizing a molecular docking approach. We find a significant effect of the drug in one case, where the actual mechanism of the reaction is altered from the wild type by mutation. The drug restores both the rate of hydrolysis to the wildtype level and the mechanism of the reaction. This is a way to check the effect of the drug on untested mutations.


Subject(s)
Adenosine Triphosphate , Cardiomyopathy, Hypertrophic , Mutation , Humans , Hydrolysis , Adenosine Triphosphate/metabolism , Adenosine Triphosphate/chemistry , Cardiomyopathy, Hypertrophic/metabolism , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/drug therapy , Biocatalysis , Molecular Dynamics Simulation , Myosins/chemistry , Myosins/metabolism , Myosins/genetics , Benzylamines , Uracil/analogs & derivatives
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