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Cellular & Molecular Immunology 2023年第2期20卷 214-216页

作者： Ahmed Nadeem Sheikh F.Ahmad Department of pharmacology and toxicology College of PharmacyKing Saud UniversityRiyadhSaudi Arabia

In the current issue of this journal,Neumann et al.provide novel insights into the role of inositol-1,4,5-trisphosphate receptor subtype 3(IP3R3)in combined immunodeficiency[1].They show that subjects with heterozygous variants in IP3R3 have dysfunctional Ca2+mobilization from the endoplasmic reticulum and impaired proliferation of T and B cells.These observations demonstrate that adaptive immune cells such as T and B cells are prone to defects in IP3R3-Ca2+signaling.This highlights a new dimension to the function of IP3R3 in adaptive immune cells that was hitherto unknown.

关键词： impaired al. immune

Synthesis and evaluation of peptide-fentanyl analogue conjugates as dualμ/δ-opioid receptor agonists for the treatment of pain

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Chinese Chemical Letters 2022年第8期33卷 4107-4110页

作者： Jing Li Tao Zhang Jialin Sun Fengxia Ren Hongxin Jia Zixing Yu Jingchao Cheng Weiguo Shi State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China School of Chemical Engineering and Technology Tianjin UniversityTianjin 300350China

Novel peptide-fentanyl analogue conjugates were synthesized by the covalent coupling of carfentanyl derivatives to the C-terminus or N-terminus of the conformationally constrained dermorphin tetrapeptide BVD03 via a chemical linker.The carfentanyl-related analogues displayed distinct binding and functional activities atμ/δopioid receptors(MOR/DOR)and antinociceptive effects when conjugated to the peptide.The most potent compound,SW-LJ-11,displayed mixed MOR/DOR agonist properties in the low nanomolar range and significant analgesic efficacy in vivo in four classic mouse models of pain.Interestingly,SW-LJ-11 did not exhibit any physical dependence or respiratory depression,in contrast to an equipotent analgesic dose of morphine or BVD03,indicating that the use of opioid peptide-fentanyl analogue conjugates as dual MOR/DOR agonists may be a promising strategy for obtaining safer opioids.

关键词： Peptide-small molecule conjugates Dual MOR/DOR agonists Lead compound Analgesics Physical dependence

Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases

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Hepatobiliary & Pancreatic Diseases International 2023年第4期22卷 333-345页

作者： Karthik Shree Harini Devaraj Ezhilarasan Department of pharmacology Molecular Medicine and Toxicology LabSaveetha Dental CollegeSaveetha Institute of Medical and Technical Sciences(SIMATS)ChennaiTamil Nadu 600077India

Nonalcoholic fatty liver disease(NAFLD)is a global health concern associated with significant morbidity and mortality.NAFLD is a spectrum of diseases originating from simple steatosis,progressing through nonalcoholic steatohepatitis(NASH),fibrosis,and cirrhosis that may lead to hepatocellular carcinoma(HCC).The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflam-matory cytokines expression leading to inflammation,oxidative stress,and mitochondrial dysfunction de-noted as“two-hit hypothesis”,advancing with a“third hit”of insufficient hepatocyte proliferation,lead-ing to the increase in hepatic progenitor cells contributing to fibrosis and HCC.Wnt/β-catenin signaling is responsible for normal liver development,regeneration,hepatic metabolic zonation,ammonia and drug detoxification,hepatobiliary development,etc.,maintaining the overall liver homeostasis.The key regula-tors of canonical Wnt signaling such as LRP6,Wnt1,Wnt3a,β-catenin,GSK-3β,and APC are abnormally regulated in NAFLD.Many experimental studies have shown the aberrated Wnt/β-catenin signaling dur-ing the NAFLD progression and NASH to hepatic fibrosis and HCC.Therefore,in this review,we have em-phasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.

关键词： Steatosis Fatty liver Oxidative stress Chronic liver diseases Fibrosis Wnt/β-catenin

Circulating endothelial microvesicles and their carried miR-125a 5p:potential biomarkers for ischaemic stroke

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Stroke & Vascular Neurology 2023年第2期8卷 89-102页

作者： Xiaotang Ma Xiaorong Liao Jiehong Liu Yan Wang Xiang Wang Yanfang Chen Xiaojian Yin Qunwen Pan Department of Neurology Affiliated Hospital of Guangdong Medical UniversityZhanjiangChina pharmacology and toxicology Wright State University Boonshoft School of MedicineDaytonOhioUSA

Background Endothelial microvesicles(EMVs)are closely associated with the status of endothelial cells(ECs).Our earlier study has shown that EMVs could exert protective roles in ECs by transferring their carried miR-125a 5p.However,whether circulating EMVs and their carried miR-125a 5p can be used as biomarkers in ischaemic stroke(IS)are remain unknown.Methods We recruited 72 subjects with IS,60 subjects with high stroke risk and 56 age-matched controls.The circulating EMVs and their carried miR-125a 5p(EMV-miR 125a 5p)levels were detected.We used microRNA(miR)array to study expression changes of miRs in plasma EMVs samples of three IS patients and three matched healthy controls.Transient middle cerebral artery occlusion(tMCAO)was used to establish IS mouse model.Results EMVs level was obviously elevated in IS patients,with the highest level in acute stage,and was positively related to carotid plaque,carotid intima-media thickness(IMT),National Institutes of Health Stroke Scale(NIHSS),infarct volume.On the contrary,we observed that EMV-miR 125a 5p level was obviously reduced in IS,with the lowest level in acute stage,and was negatively correlated with carotid plaque,IMT,NIHSS scores,infarct volume.EMVs and EMV-miR 125a 5p levels were closely related with large artery atherosclerosis subgroup.Importantly,EMVs and EMV-miR 125a 5p levels could serve as independent risk factors,and receiver operating characteristic curve achieved an area under curve(AUC)of 0.720 and 0.832 for IS,respectively,and elevated to 0.881 after their combination.In IS mouse model,control EMVs or n-EMVs administration could decrease the infarct volume and neurological deficit score,while increase the cerebral blood flow of IS mice compared with vehicle group,while IS EMVs or oxygen and glucose deprivation(OGD)-EMVs administration aggravated the tMCAO induced ischaemic injury.In addition,we observed that OGD EMVmiR-125a 5p could partially ameliorate the OGD EMVs induced brain injury after IS.Conclusions These findings demonstrate that circulatin

关键词： miR elevated protective

COVID-19 and hepatic injury: cellular and molecular mechanisms in diverse liver cells

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World Journal of Gastroenterology 2023年第3期29卷 425-449页

作者： Fares E M Ali Mostafa K Abd El-Aziz Mahmoud M Ali Osama M Ghogar Adel G Bakr Department of pharmacology and toxicology Faculty of PharmacyAl-Azhar UniversityAssiut 71524Egypt Department of pharmacology Al-Azhar UniversityAssiut 71524Egypt Department of Biochemistry Faculty of Pharmacy Badr University in AssiutEgypt

The coronavirus disease 2019(COVID-19)represents a global health and economic challenge.Hepatic injuries have been approved to be associated with severe acute respiratory syndrome coronavirus(SARS-CoV-2)infection.The viral tropism pattern of SARS-CoV-2 can induce hepatic injuries either by itself or by worsening the conditions of patients with hepatic diseases.Besides,other factors have been reported to play a crucial role in the pathological forms of hepatic injuries induced by SARS-CoV-2,including cytokine storm,hypoxia,endothelial cells,and even some treatments for COVID-19.On the other hand,several groups of people could be at risk of hepatic COVID-19 complications,such as pregnant women and neonates.The present review outlines and discusses the interplay between SARS-CoV-2 infection and hepatic injury,hepatic illness comorbidity,and risk factors.Besides,it is focused on the vaccination process and the role of developed vac-cines in preventing hepatic injuries due to SARS-CoV-2 infection.

关键词： COVID-19 Hepatic injury Viral tropism COVID-19 comorbidity Vaccination

Improvements in SOD mimic AEOL-10150, a potent broad-spectrum antioxidant

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Military Medical Research 2019年第1期6卷 78-88页

作者： Xiao-rui Zhang Wen-xia Zhou Yong-xiang Zhang State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

AEOL-10150 is a broad-spectrum metalloporphyrin superoxidase dismutase(SOD) mimic specifically designed to neutralize reactive oxygen and nitrogen species. Research has shown that AEOL-10150 is a potent medical countermeasure against national security threats including sulfur mustard(SM), nerve agent exposure and radiation pneumonitis following a radiological/nuclear incident sufficient to cause acute radiation syndrome(ARS). AEOL-10150 performed well in animal safety studies, and two completed phase 1 safety studies in patients demonstrated that the drug was safe and well tolerated, indicating that AEOL-10150 has potential as a new catalytic antioxidant drug. In this article, we review improvements in AEOL-10150 in preclinical pharmacodynamic studies, especially regarding anti-SM,chlorine gas and radiation exposure studies.

关键词： Catalytic antioxidant Metalloporphyrins Chemical warfare agent Radiation damage Pharmacodynamics Pharmacokinetics

Therapeutic interventions target the NLRP3 inflammasome in ulcerative colitis:Comprehensive study

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World Journal of Gastroenterology 2023年第6期29卷 1026-1053页

作者： Fares E.M Ali Islam M.Ibrahim Osama M Ghogar Esraa K.Abd-alhameed Hanan S.Althagafy Emad H.M.Hassanein pharmacology and toxicology Faculty of PharmacyAl-Azhar UniversityAssiut BranchAssiut 71524Egypt Faculty of Pharmacy Al-Azhar UniversityAssiut BranchAssiut 71524Egypt pharmacology and toxicology Faculty of PharmacyBeni-Suef UniversityBeni-Suef 12345Egypt Department of Biochemistry Faculty of ScienceUniversity of JeddahJeddah 12345Saudi Arabia

One of the significant health issues in the world is the prevalence of ulcerative colitis(UC).UC is a chronic disorder that mainly affects the colon,beginning with the rectum,and can progress from asymptomatic mild inflammation to extensive inflammation of the entire colon.Understanding the underlying molecular mechanisms of UC pathogenesis emphasizes the need for innovative therapeutic approaches based on identifying molecular targets.Interestingly,in response to cellular injury,the NLR family pyrin domain containing 3(NLRP3)inflammasome is a crucial part of the inflammation and immunological reaction by promoting caspase-1 activation and the release of interleukin-1β.This review discusses the mechanisms of NLRP3 inflammasome activation by various signals and its regulation and impact on UC.

关键词： Ulcerative colitis NLR family pyrin domain containing 3 inflammasome Therapeutic strategies Phytochemicals Probiotics

Preparation of a porphyrin-polyoxometalate hybrid and its photocatalytic degradation performance for mustard gas simulant 2-chloroethyl ethyl sulfide

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Chinese Chemical Letters 2022年第5期33卷 2625-2629页

作者： Ying Yang Fangsheng Tao Lijuan Zhang Yunshan Zhou Yuxu Zhong Shubo Tian Yong’an Wang State Key Laboratory of Chemical Resource Engineering Institute of ChemistryBeijing University of Chemical TechnologyBeijing100029 China toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing100850China

By combining 5,10,15,20-tetra(4-chlorine)phenylporphyrin(TClPP)andα-Keggin polyoxometalate H_(5)PV_(2)Mo_(10)O_(40)(H 5 PVMo)via a simple ion-exchange method,an organic-inorganic hybrid material[C_(44)H_(28)N_(4)Cl_(4)]_(1.5)[H_(2)PMo_(10)V_(2)O_(40)]·2C_(2)H_(6)O(H_(2 )TClPP-H_(2) PVMo)was prepared and thoroughly characterized by a variety of techniques.The homogeneous photocatalytic degradation of 2-chloroethyl ethyl sulfide(CEES)(5μL)by H_(2) TClPP-H_(2) PVMo(1×10^(−6)mol/L)was studied in methanol and methanol-water mixed solvent(v/v=1:1),in which the degradation rate of CEES reached 99.52%and 99.14%,respectively.The reaction followed first-order reaction kinetics,and the half-life and kinetic constant in methanol and the mixed solvent were respectively 33.0min,−0.021 min−1 and 15.7min,−0.043 min−1.Mechanism analysis indicated that under visible light irradiation in the air,CEES was degraded via oxidation and alcoholysis/hydrolysis in methanol and the mixed solvent.O_(2)·−and ^(1)O_(2) generated by H_(2) TClPP-H_(2) PVMo selectively oxidized CEES into a nontoxic sulfoxide.Singlet oxygen capture experiments showed that H_(2) TClPP-H_(2) PVMo(φ=0.73)had a higher quantum yield of singlet oxygen than TClPP(φ=0.35)under an air atmosphere and visible light irradiation.

关键词： Chemical warfare agent Mustard gas simulant Porphyrin Polyoxometalate Photooxidation

Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in nonalcoholic steatohepatitis patients

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Acta Pharmaceutica Sinica B 2023年第1期13卷 1-28页

作者： Solène Marie Kayla L.Frost Raymond K.Hau Lucy Martinez-Guerrero Jailyn M.Izu Cassandra M.Myers Stephen H.Wright Nathan J.Cherrington College of Pharmacy Department of Pharmacology&ToxicologyUniversity of ArizonaTucsonAZ 85721USA College of Medicine Department of PhysiologyUniversity of ArizonaTucsonAZ 85724USA

The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters.Non-alcoholic steatohepatitis(NASH)causes disease-specific alterations to the absorption,distribution,metabolism,and excretion(ADME)processes,including a decrease in protein expression of basolateral uptake transporters,an increase in efflux transporters,and modifications to enzyme activity.This can result in increased drug exposure and adverse drug reactions(ADRs).Our goal was to predict drugs that pose increased risks for ADRs in NASH patients.Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease,mainly non-alcoholic fatty liver disease(NAFLD),54 of which are known substrates of transporters and/or metabolizing enzymes.Since NASH is the progressive form of NAFLD but is most frequently undiagnosed,we identified other drugs at risk based on NASH-specific alterations to ADME processes.Here,we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH,based on their transport and/or metabolism processes.It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients,especially when eliminated through multiple pathways altered by the disease.Therefore,these results may inform clinicians regarding the selection of drugs for use in NASH patients.

关键词： Non-alcoholic steatohepatitis Hepatic elimination Transporter Enzyme Pharmacokinetics Drug-drug interaction Liver Adverse drug reaction

Decision-Making and Management of Self-Care in Persons with Traumatic Spinal Cord Injuries: A Preliminary Study

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Journal of Behavioral and Brain Science 2024年第2期14卷 47-63页

作者： Paul E. Plonski Jasmin Vassileva Ryan Shahidi Paul B. Perrin William Carter Lance L. Goetz Amber Brochetti James M. Bjork Institute for Drug and Alcohol Studies Virginia Commonwealth University Richmond VA USA Richmond Veterans Affairs Medical Center Richmond VA USA Department of Psychiatry Virginia Commonwealth University Richmond VA USA Department of Psychology Virginia Commonwealth University Richmond VA USA Department of Physical Medicine and Rehabilitation Virginia Commonwealth University Richmond VA USA Department of Spinal Cord Injury Cleveland Veterans Affairs Medical Center Cleveland OH USA Department of pharmacology and toxicology Virginia Commonwealth University Richmond VA USA

Patients and physicians understand the importance of self-care following spinal cord injury (SCI), yet many individuals with SCI do not adhere to recommended self-care activities despite logistical supports. Neurobehavioral determinants of SCI self-care behavior, such as impulsivity, are not widely studied, yet understanding them could inform efforts to improve SCI self-care. We explored associations between impulsivity and self-care in an observational study of 35 US adults age 18 - 50 who had traumatic SCI with paraplegia at least six months before assessment. The primary outcome measure was self-reported self-care. In LASSO regression models that included all neurobehavioral measures and demographics as predictors of self-care, dispositional measures of greater impulsivity (negative urgency, lack of premeditation, lack of perseverance), and reduced mindfulness were associated with reduced self-care. Outcome (magnitude) sensitivity, a latent decision-making parameter derived from computationally modeling successive choices in a gambling task, was also associated with self-care behavior. These results are preliminary;more research is needed to demonstrate the utility of these findings in clinical settings. Information about associations between impulsivity and poor self-care in people with SCI could guide the development of interventions to improve SCI self-care and help patients with elevated risks related to self-care and secondary health conditions.

关键词： Spinal Cord Injury Self-Care Decision-Making Paraplegia Impulsive Behavior Health Care