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The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3266-3280页

作者： Wenfeng Li Shuming Chen Jing Lang Jing Luo Jiahui Chen Liping Zhang Zhijie Sun Deli Dong Department of pharmacology China Pharmaceutical UniversityNanjing 210009China

The drugs extending healthspan in clinic have always been *** is an FDA-approved clinical antiprotozoal *** is rapidly metabolized to tizoxanide after absorption in *** previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK,oral nitazoxanide protects against experimental hyperlipidemia,hepatic steatosis,and ***,we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 ***,both nitazoxanide and tizoxanide improve high glucose-induced shortening of *** *** has been a clinical drug with a good safety profile,we suggest that it is a novel anti-aging drug.

关键词： Nitazoxanide Tizoxanide C.elegans Healthspan Lifespan AMPK Akt Mitochondrial uncoupling

Modern View on Potentials of Forensic Pharmaceutical and Pharmacological Expertise

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Journal of Forensic Science and Medicine 2024年第1期10卷 62-67页

作者： Elena M.Vazhnichaya Nataliia M.Deviatkina Department of pharmacology Clinical Pharmacology and PharmacyPoltava State Medical UniversityPoltavaUkraine

The great number of drugs and their variety have increased the potential of therapy but increased the risks of crimes related to the production,sale,and use of *** prosecution of such crimes requires pharmaceutical or pharmacological *** development of forensic pharmacy and forensic pharmacology is relevant and needs consideration of their modern *** purpose of the work is to analyze literature data on the scientific basis of forensic pharmaceutical and pharmacological expertise and their modern *** texts of articles,book chapters,and websites were studied using keywords relevant to the purpose of the *** is shown,that modern forensic pharmaceutical expertise is a separate type of expertise that focuses on the study of drugs and documents that regulate the production,distribution,and quality of *** uses the latest analytical methods of pharmacy.A pharmacologist analyzes body fluids and tissues and interprets the resulting data to help courts and investigators assess the role of a drug in the person’s behavior,illness,injury,or *** range of issues included in the pharmacological examination is fully within the competence of the forensic medical examination,which can be appointed in civil cases or criminal proceedings connected with harm to health or *** pharmacology is not the same as forensic toxicology or pharmacovigilance and requires a separate approach based on purely pharmacological knowledge.

关键词： Drug expertise forensic pharmacology forensic pharmacy

Targeting KRAS in pancreatic cancer

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Oncology Research 2024年第5期32卷 799-805页

作者： SANDRA STICKLER BARBARA RATH GERHARD HAMILTON Institute of pharmacology Medical University of ViennaViennaA-1090Austria

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient *** Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for ***,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung *** G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of ***,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in *** other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives *** agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

关键词： Pancreatic cancer PDAC KRAS SOS1 PROTAC

CRABP1-mediated non-canonical retinoic acid signaling in motor neurons and neural stem cells

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Neural Regeneration Research 2024年第6期19卷 1169-1170页

作者： Li-Na Wei Department of pharmacology University of Minnesota Medical SchoolMinneapolisMNUSA

Retinoic acid(RA),the active metabolite of vitamin A(the retinoids),elicits a wide spectrum of biological activities critical to the development and health of most of the organ systems including the nervous systems(Corcoran et al.,2002).The effects of RA are mediated by two very distinct pathways;the first is manifested in the nucleus by binding to a large family of nuclear RA receptors(RARs)to regulate proper expression of RAtargeted genes.

关键词： canonical spectrum critical

Development of PROTACS degrading KRAS and SOS1

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Oncology Research 2024年第8期32卷 1257-1264页

作者： GERHARD HAMILTON MARIE-THERESE EGGERSTORFER SANDRA STICKLER Institute of pharmacology Medical University of ViennaVienna1090Austria

The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung ***,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of ***,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 *** approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of ***,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal *** of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not *** CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental *** to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin *** highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

关键词： Proteolysis-targeting chimeras(PROTACs) Kirsten rat sarcoma virus(KRAS) Son of sevenless 1(SOS1) Von Hippel-Lindau Cereblon

Implications of MMP-12 in the pathophysiology of ischaemic stroke

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Stroke & Vascular Neurology 2024年第2期9卷 97-107页

作者： Krishna Kumar Veeravalli Cancer Biology and pharmacology University of Illinois College of Medicine at PeoriaPeoriaIllinoisUSA

This article focuses on the emerging role of matrix metalloproteinase-12(MMP-12)in ischaemic stroke(IS).MMP-12 expression in the brain increases dramatically in animal models of IS,and its suppression reduces brain damage and promotes neurological,sensorimotor and cognitive functional ***,MMP-12 could represent a potential target for the management of *** article provides an overview of MMP-12 upregulation in the brain following IS,its deleterious role in the post-stroke pathogenesis(blood-brain barrier disruption,inflammation,apoptosis and demyelination),possible molecular interactions and mechanistic insights,its involvement in post-ischaemic functional deficits and recovery as well as the limitations,perspectives,challenges and future directions for further *** to testing any MMP-12-targeted therapy in patients with acute IS,additional research is needed to establish the effectiveness of MMP-12 suppression against IS in older animals and in animals with *** article also examines the clinical implications of suppressing MMP-12 alone or in combination with MMP-9 for extending the currently limited tissue plasminogen activator therapy time *** of MMP-12 is expected to have a profound influence on the therapeutic management of IS in the future.

关键词： involvement alone directions

Kinetics of glyphosate and aminomethylphosphonic acid sorption onto montmorillonite clays in soil and their translocation to genetically modified corn

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Journal of Environmental Sciences 2024年第1期135卷 669-680页

作者： Meichen Wang Kelly J Rivenbark Timothy D Phillips Veterinary Physiology and pharmacology College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityTX 77845USA

The co-occurrence of glyphosate(GLP)and aminomethylphosphonic acid(AMPA)in contaminated water,soil,sediment and plants is a cause for concern due to potential threats to the ecosystem and human health.A major route of exposure is through contact with contaminated soil and consumption of crops containing GLP and AMPA ***,clay-based sorption strategies for mixtures of GLP and AMPA in soil,plants and garden produce have been very *** this study,in vitro soil and in vivo genetically modified corn models were used to establish the proof of concept that the inclusion of clay sorbents in contaminated soils will reduce the bioavailability of GLP and AMPA in soils and their adverse effects on plant *** of chemical concentration(1–10 mg/kg),sorbent dose(0.5%-3%in soil and 0.5%-1%in plants)and duration(up to 28 days)on sorption kinetics were *** time course results showed a continuous GLP degradation to *** inclusion of calcium montmorillonite(CM)and acid processed montmorillonite(APM)clays at all doses significantly and consistently reduced the bioavailability of both chemicals from soils to plant roots and leaves in a dose-and time-dependent manner without detectable *** treated with 0.5%and 1%APM inclusion showed the highest growth rate(p≤0.05)and lowest chemical bioavailability with up to 76%reduction in roots and57%reduction in *** indicated that montmorillonite clays could be added as soil supplements to reduce hazardous mixtures of GLP and AMPA in soils and plants.

关键词： Glyphosate AMPA Adsorption Soil remediation Plant Hydroponic system

CuInS_(2)quantum-dot-modified g-C_(3)N_(4)S-scheme heterojunction photocatalyst for hydrogen production and tetracycline degradation

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Journal of Materials Science & Technology 2024年第5期172卷 145-155页

作者： Jingjing Zhang Yue Zhao Kezhen Qi Shu-yuan Liu College of Pharmacy Dali UniversityDali 671000China Department of pharmacology Shenyang Medical CollegeShenyang 110034China

CuInS_(2)quantum-dot(CIS QD)-modified g-C_(3)N_(4)(CN)catalysts(CIS/CN)were prepared with the aid of an in-situ growth *** as-obtained photocatalysts were explored by measuring their crystallinity,surface morphology,binding energy and light absorption *** photocatalytic efficiency of the pho-tocatalysts was evaluated through photocatalytic water splitting for hydrogen production and tetracycline(TC)antibiotic degradation under the simulated solar light and visible light *** optimized sample(10CIS/CN)showed the best photocatalytic activity:producing 102.4μmol g^(-1)h^(-1)of hydrogen in 1 h,or degrading 52.16%of TC in 120 min,which were respectively 48 or 3.4 times higher than the photocatalytic activity of CN *** enhancement in the efficiency of the composite system was prin-cipally accredited to the enlargement of light absorption,the more effective in charge transfer and the dropping of the charge carrier pair recombination through a formed S-scheme heterojunctional *** work is an effort to adjust CN-based polysulfide QD for speedy *** enriched photo-catalytic activity grants a new sense for adjusting the optical properties of CN.

关键词： CuInS_(2)QDs g-C_(3)N_(4) Photocatalysis Hydrogen production S-scheme heterojunction

Colorectal cancer cell dormancy:An insight into pathways

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World Journal of Gastroenterology 2024年第33期30卷 3810-3817页

作者： Anil Kumar Lekha Saha Department of pharmacology Post Graduate Institute of Medical Education and ResearchChandigarh 160012India

Cancer cell dormancy(CCD)in colorectal cancer(CRC)poses a significant challenge to effective *** CRC,CCD contributes to tumour recurrence,drug resistance,and amplifying the disease's *** molecular mechanisms governing CCD and strategies for eliminating dormant cancer cells remain largely ***,understanding the molecular mechanisms governing dormancy is crucial for improving patient outcomes and developing targeted *** editorial highlights the complex interplay of signalling pathways and factors involved in colorectal CCD,emphasizing the roles of Hippo/YAP,pluripotent transcription factors such as NANOG,HIF-1αsignalling,and Notch signalling ***,ERK/p38α/β/MAPK pathways,AKT signalling pathway,and Extracellular Matrix Metalloproteinase Inducer,along with some potential less explored pathways such as STAT/p53 switch and canonical and non-canonical Wnt and SMAD signalling,are also involved in promoting colorectal *** their clinical significance,these findings may offer the potential for identifying key dormancy regulator pathways,improving treatment strategies,surmounting drug resistance,and advancing personalized medicine ***,insights into dormancy mechanisms could lead to the development of predictive biomarkers for identifying patients at risk of recurrence and the tailoring of targeted therapies based on individual dormancy *** is essential to conduct further research into these pathways and their modulation to fully comprehend CRC dormancy mechanisms and enhance patient outcomes.

关键词： Colorectal cancer Colorectal cancer cell dormancy Cancer cell dormancy Pathways in colorectal cancer dormancy