Discovery of novel NLRP3 inhibitors based on machine learning and physical methods DOI Creative Commons
Tao Jiang, S. Qian, Jinhong Xu

и другие.

BMC Chemistry, Год журнала: 2024, Номер 18(1)

Опубликована: Окт. 28, 2024

The NLRP3 inflammasome plays a crucial role in inflammatory responses, particularly alcohol-related liver disease (ALD). Given that has emerged as potential therapeutic target for ALD, the development of effective inhibitors is great importance. In this study, we trained 11 regression models, and results showed LightGBM, Random Forest, XGBoost performed best, achieving R² values 0.774, 0.755, 0.719, respectively. Using machine learning models physical methods, screened more than 11.5 million compounds from Asinex, Princeton, UkrOrgSynthesis, Chemdiv, Chembridge, Alinda, Enamine, Lifechemicals, which led to identification 26 inhibitors. Furthermore, molecular dynamics simulations MMGBSA binding energy calculations confirmed stability interactions between three key molecules: 19,655,631 (source Chembridge), 38,214,692 Z1180203703 Enamine). Additionally, ADMET analysis revealed their favorable pharmacokinetic properties. This study provides insights candidate molecules discovering inhibitors, potentially applicable treating related diseases.

Язык: Английский

Acute anticonvulsant effects of dapsone on PTZ- and MES-induced seizures in mice: NLRP3 inflammasome inhibition and Nrf2/HO-1 pathway preservation DOI

Ali Lesani,

Fatemeh Mashaknejadian Behbahani,

Mohammad Amin Manavi

и другие.

Pharmacological Reports, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

Язык: Английский

Процитировано

2
Oridonin exerts anticonvulsant profile and neuroprotective activity in epileptic mice by inhibiting NLRP3-mediated pyroptosis DOI Creative Commons
Ting Zhao,

Xuefei Zhang,

Xiaoxiao Cui

и другие.

International Immunopharmacology, Год журнала: 2024, Номер 134, С. 112247 - 112247

Опубликована: Май 16, 2024

Epilepsy is a chronic disabling disease poorly controlled by available antiseizure medications. Oridonin, bioactive alkaloid with anti-inflammatory properties and neuroprotective effects, can inhibit the increased excitability of neurons caused glutamate accumulation at cellular level. However, whether oridonin affects neuronal it has antiepileptic potential not been reported in animal models or clinical studies. Pentylenetetrazol was injected into mice to create model epilepsy. Seizure severity assessed using Racine scale, duration latency seizures were observed. Abnormal discharge detected electroencephalography, calcium imaging. Damage hippocampal evaluated Hematoxylin-Eosin Nissl staining. The expression NOD-like receptor thermal protein domain associated 3 (NLRP3) inflammasome other pyroptosis-related proteins determined western blotting immunofluorescence. A pyroptosis established supernatant BV2 cells treated lipopolysaccharide adenosine triphosphate stimulate neurons. Oridonin (1 5 mg/kg) reduced damage, seizures, shortened fully kindled epilepsy mice. decreased abnormal during epileptic episodes suppressed excitability. In vitro experiments showed that alleviated HT22 exerts effects inhibiting through NLRP3/caspase-1 pathway It also reduces vitro, suggesting its as therapy for

Язык: Английский

Процитировано

6
Identification of novel NLRP3 inhibitors as therapeutic options for epilepsy by machine learning-based virtual screening, molecular docking and biomolecular simulation studies DOI Creative Commons

Maryam Zulfat,

Mohammed Ageeli Hakami, Ali Hazazi

и другие.

Heliyon, Год журнала: 2024, Номер 10(15), С. e34410 - e34410

Опубликована: Июль 10, 2024

The NOD-Like Receptor Protein-3 (NLRP3) inflammasome is a key therapeutic target for the treatment of epilepsy and has been reported to regulate inflammation in several neurological diseases. In this study, machine learning-based virtual screening strategy investigated candidate active compounds that inhibit NLRP3 inflammasome. As potential accurately predict protein-ligand binding reduce false positives outcomes compared traditional screening. Briefly, classification models were created using Support Vector Machine (SVM), Random Forest (RF), K-Nearest Neighbor (KNN) learning methods. To determine most crucial features molecule's activity, feature selection was carried out. By utilizing 10-fold cross-validation, analyzed. Among generated models, RF model obtained best results as others. Therefore, used tool against large chemical databases. Molecular operating environment (MOE) PyRx software's applied molecular docking. Also, Amber Tools program, dynamics (MD) simulation potent inhibitors showed KNN, SVM, accuracy 0.911 %, 0.906 0.946 respectively. Moreover, shown sensitivity 0.82 0.78 0.86 % specificity 0.95 0.96 0.98 applying ZINC South African databases, we identified 98 39 compounds, respectively, potentially possessing

Язык: Английский

Процитировано

5
The role of quercetin in NLRP3-associated inflammation DOI

Jiaqi Wu,

Tongtong Lv, Yü Liu

и другие.

Inflammopharmacology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 22, 2024

Язык: Английский

Процитировано

5
Luteolin ameliorates pentetrazole-induced seizures through the inhibition of the TLR4/NF-κB signaling pathway DOI
Yahong Cheng,

Yiyuan Zhang,

Puxin Huang

и другие.

Epilepsy Research, Год журнала: 2024, Номер 201, С. 107321 - 107321

Опубликована: Фев. 14, 2024

Язык: Английский

Процитировано

4
Neuroimmune response and oxidative stress in the prefrontal cortex mediate seizure susceptibility in experimental colitis in male mice DOI

Fahimeh Moradipoor,

Nahid Jivad, Samira Asgharzade

и другие.

Journal of Biochemical and Molecular Toxicology, Год журнала: 2024, Номер 38(7)

Опубликована: Июнь 26, 2024

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder. Oxidative stress and inflammatory responses have vital role in the pathophysiology of IBD as well seizure. associated with extraintestinal manifestations. This study aimed to explore relationship between colitis susceptibility seizures, focus on roles neuroinflammation oxidative acetic acid-induced mice. Forty male Naval Medical Research Institute mice were divided into four groups: control, colitis, pentylenetetrazole (PTZ), + PTZ. Colitis was induced by intrarectal administration acid, seizures intravenous injection PTZ 7 days postcolitis induction. Following measurement latency seizure, killed, their colons prefrontal cortex (PFC) dissected. Gene expression markers including interleukin-1β, tumor necrosis factor-alpha, NOD-like receptor protein 3, toll-like 4, total antioxidant capacity (TAC), malondialdehyde (MDA), nitrite levels measured colon PFC. Histopathological evaluations performed samples. Data analyzed t-test or one-way variance analysis. decreased increased gene markers, altered MDA, nitrite, TAC both Simultaneous induction seizure exacerbated neuroimmune response PFC colon. Results concluded that at least partially mediate comorbid decrease colitis.

Язык: Английский

Процитировано

4
Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health DOI Creative Commons
Eugenio Caradonna, Francesca Abate, Elisabetta Schiano

и другие.

Metabolites, Год журнала: 2025, Номер 15(4), С. 220 - 220

Опубликована: Март 24, 2025

The intestinal microbiota, hosting trillions of microorganisms that inhabit the gastrointestinal tract, functions as a symbiotic organism plays crucial role in regulating health by producing biologically active molecules can enter systemic circulation. Among them, trimethylamine-N-oxide (TMAO), an organic compound derived from dietary sources and microbial metabolism, has emerged critical biomarker linking diet, gut host metabolism to various pathological conditions. This comprehensive review highlights TMAO’s biosynthesis, physiological functions, clinical significance, focusing on its mechanistic contributions cardiovascular neurodegenerative diseases. Notably, TMAO-mediated pathways include endothelial dysfunction, inflammation via NLRP3 inflammasome activation, cholesterol disruption, which collectively accelerate atherosclerosis disease progression. Nonetheless, this work underscores innovative potential targeting TMAO through dietary, nutraceutical, microbiota-modulating strategies mitigate effects, marking transformative approach prevention management TMAO-related disorders.

Язык: Английский

Процитировано

0
Neuroprotective potential of hispidulin and diosmin: a review of molecular mechanisms DOI

Anish Singh,

Lovedeep Singh,

D. C. Dalal

и другие.

Metabolic Brain Disease, Год журнала: 2025, Номер 40(5)

Опубликована: Апрель 21, 2025

Язык: Английский

Процитировано

0
Selective modulation of epileptic tissue by an adenosine A3 receptor‐activating drug DOI Creative Commons
Anwesha Ghosh, Leonor Ribeiro‐Rodrigues, Gabriele Ruffolo

и другие.

British Journal of Pharmacology, Год журнала: 2024, Номер 181(24), С. 5041 - 5061

Опубликована: Сен. 19, 2024

Abstract Background and Purpose Adenosine, through the A 1 receptor (A R), is an endogenous anticonvulsant. The development of adenosine agonists as antiseizure medications has been hampered by their cardiac side effects. moderately R‐selective agonist, MRS5474, reported to suppress seizures without considerable action. Hypothesizing that this drug could act other than R and/or a disease‐specific mechanism, we assessed effect MRS5474 on hippocampus. Experimental Approach Excitatory synaptic currents, field potentials, spontaneous activity, [ 3 H]GABA uptake GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in R) density tissue Western blot. Key Results (50–500 nM) was devoid upon excitatory signals slices, except when hyperexcitability previously induced vivo ex vivo. inhibited GABA transporter type (GAT‐1)‐mediated γ‐aminobutyric acid (GABA) uptake, action not blocked antagonist but mimicked agonist. overexpressed samples patients with epilepsy had focal resection surgery. concentration‐dependent potentiation GABA‐evoked oocytes micro‐transplanted membranes prepared epileptic non‐epileptic tissue, antagonist. Conclusion Implications We identified activates selective actions This underscores promising target for medications.

Язык: Английский

Процитировано

2
Metabolomic Profiling and In Vivo Antiepileptic Effect of Zygophyllum album Aerial Parts and Roots Crude Extracts against Pentylenetetrazole-Induced Kindling in Mice DOI Creative Commons
Asmaa R. Abdel-Hamed, Alaa S. Wahba, Dina M. Khodeer

и другие.

Metabolites, Год журнала: 2024, Номер 14(6), С. 316 - 316

Опубликована: Май 30, 2024

The chemical profiles of both Zygophyllum album (Z. album) aerial parts and roots extracts were evaluated with LC-ESI-TOF-MS/MS analysis. Twenty-four compounds detected. Among them, some are detected in the extracts, others only. mainly flavonoids, phenolic compounds, triterpenes other miscellaneous compounds. Such contribute to diverse pharmacological activities elicited by Z. species. This study aimed elucidate antiepileptic effect crude against pentylenetetrazole (PTZ)-induced kindling mice. Male albino mice divided into four groups, eight animals each. All except control group, kindled PTZ (35 mg/kg i.p.), once every alternate day for a total 15 injections. One group was left untreated (PTZ group). remaining two groups treated prior injection either or extract (400 mg/kg, orally). Pretreatment significantly reduced seizure scores, partially reversed histological changes cerebral cortex exerted antioxidant/anti-inflammatory efficacy evinced elevated hippocampal antioxidant capacity SOD catalase activities, parallel decrement MDA content, iNOS activity TXNIB/NLRP3 axis subsequent decrease caspase 1 activation release IL-1β IL-18. Moreover, suppressed neuronal apoptosis via upregulating Bcl-2 expression downregulating that Bax, indicating their neuroprotective potential. Importantly, much more potential than did.

Язык: Английский

Процитировано

0