Targeting mTOR Kinase with Natural Compounds: Potent ATP-Competitive Inhibition Through Enhanced Binding Mechanisms DOI Creative Commons
Sulaiman K. Marafie, Eman Alshawaf, Fahd Al‐Mulla

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(12), P. 1677 - 1677

Published: Dec. 12, 2024

Background/Objectives: The mammalian target of the rapamycin (mTOR) signaling pathway is a central regulator cell growth, proliferation, metabolism, and survival. Dysregulation mTOR contributes to many human diseases, including cancer, diabetes, obesity. Therefore, inhibitors against mTOR’s catalytic kinase domain (KD) have been developed shown significant antitumor activities, making it promising therapeutic target. ATP–KD interaction particularly important for exert its cellular functions, such demonstrated efficient attenuation overall activity. Methods: In this study, we screened Traditional Chinese Medicine (TCM) database, which enlists natural products that capture relationships between drugs targets diseases. Our aim was identify potential ATP-competitive agonists mTOR-KD compete with ATP bind serving as potent inhibitors. Results: We identified two compounds interatomic interactions similar those ATP–mTOR. conformational stability dynamic features bound selected were tested by subjecting each complex 200 ns molecular (MD) simulations mechanics/generalized Born surface area (MM/GBSA) extract free binding energies. show effectiveness both in forming stable complexes mTOR-KD, more effective than mTOR-KD–ATP robust affinities. Conclusions: This study implies could serve mTOR, regulating function and, therefore, mitigating disease progression.

Language: Английский

Glycolipid Metabolic Disorders, Metainflammation, Oxidative Stress, and Cardiovascular Diseases: Unraveling Pathways DOI Creative Commons

Enzo Pereira de Lima,

Renato Cesar Moretti,

Karina Torres Pomini

et al.

Biology, Journal Year: 2024, Volume and Issue: 13(7), P. 519 - 519

Published: July 12, 2024

Glycolipid metabolic disorders (GLMDs) are various resulting from dysregulation in glycolipid levels, consequently leading to an increased risk of obesity, diabetes, liver dysfunction, neuromuscular complications, and cardiorenal vascular diseases (CRVDs). In patients with GLMDs, excess caloric intake a lack physical activity may contribute oxidative stress (OxS) systemic inflammation. This study aimed review the connection between GLMD, OxS, metainflammation, onset CRVD. GLMD is due causing dysfunction synthesis, breakdown, absorption glucose lipids body, excessive ectopic accumulation these molecules. mainly neuroendocrine dysregulation, insulin resistance, metainflammation. many inflammatory markers defense cells play vital role related tissues organs, such as blood vessels, pancreatic islets, liver, muscle, kidneys, adipocytes, promoting lesions that affect interconnected organs through their signaling pathways. Advanced glycation end products, ATP-binding cassette transporter 1, Glucagon-like peptide-1, Toll-like receptor-4, sphingosine-1-phosphate (S1P) crucial since they glucolipid metabolism. The consequences this system organ damage morbidity mortality.

Language: Английский

Citations

25
Mechanisms and early efficacy data of caloric restriction and caloric restriction mimetics in neurodegenerative disease DOI Creative Commons

Anchal Trisal,

Abhishek Kumar Singh

Neuroscience, Journal Year: 2025, Volume and Issue: 567, P. 235 - 248

Published: Jan. 5, 2025

Language: Английский

Citations

3
Strategic advancements in targeting the PI3K/AKT/mTOR pathway for Breast cancer therapy DOI Creative Commons
Pankaj Garg, Sravani Ramisetty, Meera G. Nair

et al.

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 116850 - 116850

Published: March 1, 2025

Breast cancer (BC) is a complex disease that affects millions of women worldwide. Its growing impact calls for advanced treatment strategies to improve patient outcomes. The PI3K/AKT/mTOR pathway key focus in BC therapy because it plays major role important processes like tumor growth, survival, and resistance treatment. Targeting this could lead better options present review explores how the becomes dysregulated BC, focusing on genetic changes PIK3CA mutations PTEN loss leads its aggravation. Current include use inhibitors targeting PI3K, AKT, mTOR with combination therapies showing promise overcoming drug improving effectiveness. Looking ahead, next-generation personalized plans guided by biomarker analysis may provide more accurate effective patients. Integrating these immunotherapy offers an exciting opportunity boost anti-tumor responses survival rates. This comprehensive summary current progress BC. It highlights future research directions therapeutic aimed at enhancing outcomes quality life.

Language: Английский

Citations

2
α-methyltryptophan-mediated protection against diabetic nephropathy in db/db mice as studied with a metabolomics approach DOI Creative Commons

Aimin Cai,

Dan Shen,

Qiushuang Xiong

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 20, 2025

Introduction Diabetic nephropathy (DN), a major complication of diabetes, presents with poor clinical outcomes and affects patients throughout their lifetime. α-Methyltryptophan (α-MT) is blocker the amino acid transporter. SLC6A14 also an inhibitor indoleamine 2,3-dioxygenase-1 (IDO1). Methods In this study, we employed nuclear magnetic resonance-based metabolomic approach to investigate therapeutic effects α-MT in db/db mouse model DN explore underlying molecular mechanisms. Results The results study demonstrated that significantly reduced urinary excretion albumin creatinine, improved kidney function, decreased renal fibrosis mice. Metabolomic analyses tissues urine samples indicated mice displayed increased activity enzyme IDO1, alongside pronounced metabolic disturbances. These disturbances are chiefly characterized by alterations metabolism, energy production pathways, membrane biochemical features, nicotinamide all which have been implicated mTOR signaling apoptotic pathways. Discussion Administration showed evidence IDO1 inhibition rectification dysfunctions concurrent suppression apoptosis. findings highlight potential as promising agent for diabetic nephropathy.

Language: Английский

Citations

1
PAMAM/miR-144 Nanocarrier System Inhibits the Migration of Gastric Cancer by Targeting mTOR Signal Transduction Pathway DOI
Yuanyuan Qian, Dongxu Zhu,

XU Qiong

et al.

Colloids and Surfaces B Biointerfaces, Journal Year: 2025, Volume and Issue: 249, P. 114492 - 114492

Published: Jan. 5, 2025

Language: Английский

Citations

0
Wz4003 Sensitizes Hepatocellular Carcinoma to Osi-027 by Inhibiting Ark5-Mediated Autophagy DOI
Wei Chen,

Jieni Xiong,

Xiao Zhi

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0
Gerobiotics: Exploring the Potential and Limitations of Repurposing Probiotics in Addressing Aging Hallmarks and Chronic Diseases DOI
A.G.M.Sofi Uddin Mahamud,

Ishtiak Ahammed Tanvir,

Md. Ehsanul Kabir

et al.

Probiotics and Antimicrobial Proteins, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

Citations

0
Targeting mTOR in myeloid cells prevents infection-associated inflammation DOI Creative Commons
Yohana Camila Antunes Frederico, Jazz Munitz, Geoffrey Prévot

et al.

iScience, Journal Year: 2025, Volume and Issue: unknown, P. 112163 - 112163

Published: March 1, 2025

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that mammalian target rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation COVID-19 patients. Previously, developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) efficiently targets cells their progenitors bone marrow. vitro, demonstrated mTORi-nanobiologics potently inhibit infection-associated inflammation human primary cells. Next, investigated vivo effect mouse models hyperinflammation acute respiratory distress syndrome. Using 18F-FDG uptake flow cytometry readouts, mTORi-nanobiologic therapy to reduce hematopoietic organ metabolic activity levels comparable those healthy control animals. Together, show regulating myelopoiesis with is compelling therapeutic strategy prevent deleterious infection-related complications.

Language: Английский

Citations

0
Rapamycin combined with osimertinib alleviated non-small cell lung cancer by regulating the PARP, Akt/mTOR, and MAPK/ERK signaling pathways DOI Creative Commons
Qingping Ma, Kai Chen,

Haiping Xiao

et al.

Frontiers in Molecular Biosciences, Journal Year: 2025, Volume and Issue: 12

Published: March 7, 2025

Backgrounds Non-small cell lung cancer (NSCLC), one kind of common malignant tumor, is accompanied by high morbidity and mortality. The effects related mechanisms rapamycin (Rapa) combined with osimertinib (Osi) in treating NSCLC are still unclear. Therefore, this study aims to investigate the Rapa Osi on NSCLC. Methods In A549 PC-9 cells, Cell Counting Kit-8 (CCK-8) assay was used select optimal administrative concentrations evaluate viability. Transwell flow cytometry were determine migration, cycle, apoptosis, level Reactive Oxygen Species (ROS), respectively. protein mRNA expression Matrix Metalloproteinase-9 (MMP9), Caspase-3, Microtubule-Associated Protein 1 Light Chain 3 II/I (LC3 II/I), beclin1, Sequestosome (p62), Poly (ADP-ribose) Polymerase (PARP), Mitogen-Activated Kinase (MAPK), Extracellular Signal-Regulated (ERK), B (Akt), Mammalian Target Rapamycin (mTOR) determined Western blot Quantitative Reverse Transcription Reaction (qRT-PCR). Results 0.5 μM μM, Osimertinib significantly decreased viability quantity migrated levels ROS, as well MMP9 p62, LC3 II/I, beclin1. combination two drugs markedly more effective than use alone. Conclusion conclusion, demonstrated that can inhibit regulate promote autophagy increase ROS PARP, MAPK/EKR, Akt/mTOR pathways providing a novel theoretical basis for their clinical treatment

Language: Английский

Citations

0
Exploring Potential Therapeutic Applications of Tazarotene: Gene Regulation Mechanisms and Effects on Melanoma Cell Growth DOI Creative Commons
Chun‐Hua Wang, Lu‐Kai Wang, Fu‐Ming Tsai

et al.

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(4), P. 237 - 237

Published: March 28, 2025

Tazarotene, a retinoid derivative, is widely used in treating skin conditions such as psoriasis and acne. Recent studies have demonstrated its potential promising therapeutic agent for melanoma situ. Its primary mechanism of action involves the selective activation retinoic acid receptors (RAR-β RAR-γ), which play important roles regulating cell growth, differentiation, apoptosis. By activating these receptors, tazarotene influences expression several downstream inducible genes, tazarotene-induced gene-1 (TIG1), TIG2, TIG3. These genes crucial proliferation, invasiveness, immune responses tumor microenvironment. This review aims to provide comprehensive overview current status derivatives—particularly tazarotene—in treatment latest research regarding their molecular mechanisms. We will explore how suppresses growth through gene regulation mechanisms discuss role within Additionally, we assess advantages challenges using topical future clinical applications. contribute wider understanding tazarotene’s antitumor mechanisms, providing solid theoretical foundation option

Language: Английский

Citations

0