Pharmaceutical Research, Journal Year: 2022, Volume and Issue: 39(8), P. 1881 - 1890
Published: June 8, 2022
Language: Английский
Cells, Journal Year: 2022, Volume and Issue: 11(4), P. 632 - 632
Published: Feb. 11, 2022
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It usually diagnosed in an advanced stage characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy relapse after treatment. There therefore vast need for understanding underlying mechanisms that contribute resistance developing therapeutic strategies would overcome this. The rapid proliferation tumor cells, combination with highly inflammatory microenvironment, causes chronic increase protein synthesis different hepatic cell populations. This leads intensified demand folding, which inevitably accumulation misfolded or unfolded proteins lumen endoplasmic reticulum (ER). process called ER stress triggers response (UPR) order restore or—in case severe prolonged stress—to induce death. Interestingly, three arms signaling pathways have been shown drive chemoresistance several tumors could form promising target. review provides overview how activation UPR contributes HCC.
Language: Английский
Citations
54
Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)
Published: March 15, 2024
Abstract The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous cations, influencing both metabolism drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics many drugs, making interactions with a key consideration novel development drug–drug interactions. Notably, metformin, frontline medication for type 2 diabetes, prominent substrate. Conversely, can be inhibited by agents such spironolactone, steroid analog inhibitor aldosterone receptor, necessitating deep understanding hOCT1–drug new pharmacological treatments. Despite extensive study, specifics transport inhibition mechanisms remain elusive at molecular level. Here, we present cryo-electron microscopy structures hOCT1-metformin complex three distinct conformational states — outward open, occluded, inward occluded well substrate-free partially fully open states. We spironolactone facing conformations. These provide atomic-level insights into dynamic metformin transfer process via mechanism which inhibits it. Additionally, identify ‘YER’ motif critical flexibility likely other SLC22 family transporters. Our findings significantly advance function offer foundational framework design targeting this transporter.
Language: Английский
Citations
15
Cell chemical biology, Journal Year: 2025, Volume and Issue: unknown
Published: March 1, 2025
Language: Английский
Citations
1
Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)
Published: Aug. 11, 2022
Glutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular retrieved by the glial transporter, Excitatory Amino Acid Transporter 2 (EAAT2), belonging to SLC1A family. However, some cancers, EAAT2 expression enhanced and resistance therapies metabolic disturbance. Despite its crucial roles, detailed structural information about has not been available. Here, we report cryo-EM structures of human substrate-free selective inhibitor WAY213613-bound states at 3.2 Å 2.8 Å, respectively. forms trimer, with each protomer consisting transport scaffold domains. Along glutamate-binding site, domain possesses cavity that could be disrupted during cycle. WAY213613 occupies both site interfere alternating access, where sensitivity defined inner environment cavity. We provide characterization molecular features inhibition mechanism may facilitate structure-based drug design for EAAT2.
Language: Английский
Citations
33
Biophysical Reviews, Journal Year: 2022, Volume and Issue: 14(1), P. 145 - 162
Published: Feb. 1, 2022
Abstract The proposition of a post-antimicrobial era is all the more realistic with continued rise antimicrobial resistance. development new antimicrobials failing to counter ever-increasing rates bacterial This necessitates novel and drug targets. cell membrane an essential highly conserved cellular component in bacteria acts as primary barrier for entry into cell. Although previously under-exploited target, attractive due its importance pathogen viability. Bacterial membranes are diverse assemblies macromolecules built around central lipid bilayer core. governs overall biophysical properties function membrane-embedded proteins. mini-review will outline mechanisms by which causes controls resistance, focus on alterations composition, chemical modification constituent lipids, efflux systems. Thorough insight interplay between membrane-active lipid-mediated resistance needed enable rational antimicrobials. In particular, union computational approaches experimental techniques innovative efficacious explored.
Language: Английский
Citations
30
Metabolites, Journal Year: 2024, Volume and Issue: 14(2), P. 80 - 80
Published: Jan. 23, 2024
Lipids are a crucial component of the human brain, serving important structural and functional roles. They involved in cell function, myelination neuronal projections, neurotransmission, neural plasticity, energy metabolism, neuroinflammation. Despite their significance, role lipids development mental disorders has not been well understood. This review focused on potential use as blood biomarkers for common illnesses, such major depressive disorder, anxiety disorders, bipolar schizophrenia. also discussed impact commonly used psychiatric medications, neuroleptics antidepressants, lipid metabolism. The obtained data suggested that could be useful diagnosing diseases, but further research is needed to better understand associations between identify specific biomarker combinations each disease.
Language: Английский
Citations
6
Membranes, Journal Year: 2023, Volume and Issue: 13(5), P. 462 - 462
Published: April 25, 2023
The major facilitator superfamily (MFS) of transporters consists three classes membrane transporters: symporters, uniporters, and antiporters. Despite such diverse functions, MFS are believed to undergo similar conformational changes within their distinct transport cycles, known as the rocker-switch mechanism. While similarities between noteworthy, differences also important since they could potentially explain functions antiporters superfamily. We reviewed a variety experimental computational structural data on select number antiporters, uniporters from family compare dynamics different transporters.
Language: Английский
Citations
12
Nano TransMed, Journal Year: 2023, Volume and Issue: 2(4), P. 100020 - 100020
Published: Dec. 1, 2023
The gastrointestinal system, often regarded as the 'second brain of humanity,' maintains a profound connection with cerebral realm. Unlocking intricate metabolic pathways gut microorganisms is paramount in treatment ailments. This review primarily focuses on biomimetic precision nanocarriers, harnessing metabolites derived from microbiota, to target disorders. Elaborating constituents, it illuminates unique interplay between originating microbiota and domain. Moreover, underscores symbiotic relationship nanocarriers fashioned microbiota-derived augmentation well-being. Offering comprehensive outlook, this sheds light recent applications, challenges, future prospects rooted across spectrum disease treatments. It presents an expansive perspective attributes engineered metabolites, facilitating deeper understanding nexus these
Language: Английский
Citations
12
Membranes, Journal Year: 2021, Volume and Issue: 11(12), P. 984 - 984
Published: Dec. 15, 2021
Heavy metal stress (HMS) is one of the most destructive abiotic stresses which seriously affects growth and development plants. Recent studies have shown significant progress in understanding molecular mechanisms underlying plant tolerance to HMS. In general, three core signals are involved plants’ responses HMS; these mitogen-activated protein kinase (MAPK), calcium, hormonal (abscisic acid) signals. addition signal components, other regulatory factors, such as microRNAs membrane proteins, also play an important role regulating HMS Membrane proteins interact with highly complex heterogeneous lipids cell environment. The function affected by interactions between lipid-membrane proteins. Our review findings indicate possibility protein-lipid-metal ion homeostasis cells. this review, we investigated specific substrate recognition homeostasis. possible interaction networks upstream downstream pathways developed. addition, ions, discussed provide new ideas for studying
Language: Английский
Citations
25
Cancers, Journal Year: 2021, Volume and Issue: 13(24), P. 6165 - 6165
Published: Dec. 7, 2021
Maintenance of the biophysical properties membranes is essential for cell survival upon external perturbations. However, links between a fluid membrane state and drug resistance cancer cells remain elusive. Here, we investigated role viscosity lipid composition in responses to oxaliplatin development chemoresistance. Plasma was monitored live colorectal tumor xenografts using two-photon excited fluorescence lifetime imaging microscopy (FLIM) fluorescent molecular rotor BODIPY 2. The profile analyzed time-of-flight secondary ion mass spectrometry (ToF-SIMS). It found that plasma increased treatment, both vitro vivo, this correlated with lower phosphatidylcholine higher cholesterol content. emergence accompanied by homeostatic adaptation lipidome, recovery viscosity. These results suggest maintaining constant via remodeling crucial cancer.
Language: Английский
Citations
24