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The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases

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Neural Regeneration Research 2024年第6期19卷 1206-1211页

作者： Matihias T.Wyss Christine Heuer Marina Herwerth Institute of pharmacology and toxicology University of Zurich Neuroscience Center Zurich (ZNZ) University of Zurich and ETH Zurich 3. Neurology Department University Hospital of Zurich

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis. This is also reflected by the widespread expression of two families of purinergic receptors(P1 and P2) with numerous subtypes. In the last few decades, there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions. Mainly, signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies. Thus, interference with P2 receptors may be a promising strategy for the modulation of immune responses. Although only a few clinical studies have been conducted in isolated entities with limited success, preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune diseases. Despite the association of P2 receptors with several disorders from this field, the use of P2 receptor antagonists in clinical therapy is still very scarce. In this narrative review, we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune processes. We then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune events. Using suramin, a non-specific purinergic inhibitor, as an example, we further show that off-target effects could be responsible for observed effects in immunological settings, which may have interesting implications. Overall, we believe that it is worthwhile to further investigate this hitherto underexplored area.

关键词： autoimmune diseases neurological disorders purinergic system P2 receptor inhibitors suramin

Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury

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Neural Regeneration Research 2024年第3期19卷 629-635页

作者： Jingzhou Liu Xin Xin Jiejie Sun Yueyue Fan Xun Zhou Wei Gong Meiyan Yang Zhiping Li Yuli Wang Yang Yang Chunsheng Gao State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijingChina Academy of Medical Engineering and Translational Medicine Medical CollegeTianjin UniversityTianjinChina

Traumatic brain injury results in neuronal loss and glial scar *** neurons and eliminating the consequences of glial scar formation are essential for treating traumatic brain *** reprogramming is a promising strategy to convert glial scars to neural ***,previous studies have reported inconsistent *** this study,an AAV9P1 vector incorporating an astrocyte-targeting P1 peptide and glial fibrillary acidic protein promoter was used to achieve dual-targeting of astrocytes and the glial scar while minimizing off-target *** results demonstrate that AAV9P1 provides high selectivity of astrocytes and reactive ***,neuronal reprogramming was induced by downregulating the polypyrimidine tract-binding protein 1 gene via systemic administration of AAV9P1 in a mouse model of traumatic brain *** summary,this approach provides an improved gene delivery vehicle to study neuronal programming and evidence of its applications for traumatic brain injury.

关键词： AAV9P1 astrocytes astrocyte-to-neuron conversion GFAP promoter glial scar induced neurons neuronal reprogramming P1 peptide PTBP1 traumatic brain injury

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A mix & act liposomes of phospholipase A2-phosphatidylserine for acute brain detoxification by blood‒brain barrier selective-opening

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1827-1844页

作者： Zinan Zhang Wenbin Cao Huanchun Xing Shuai Guo Lijuan Huang Lin Wang Xin Sui Kui Lu Yuan Luo Yongan Wang Jun Yang State Key Laboratory of toxicology and Medical Countermeasures Beijing Institutes of Pharmacology and ToxicologyBeijing 100850China Tianjin University of Science and Technology Tianjin 300222China Hebei University of Science and Technology Shijiazhuang 050018China

In the treatment of central nervous system disease,the blood-brain barrier(BBB)is a major obstruction to drug delivery that must be *** this study,we propose a brain-targeted delivery strat-egy based on selective opening of the *** strategy allows some simple bare nanoparticles to enter the brain when mixed with special opening material;however,the BBB still maintains the ability to completely block molecules from passing *** on the screening of BBB opening and matrix delivery mate-rials,we determined that phospholipase A2-catalyzed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine li-posomes can efficiently carry drugs into the brain *** an effective dose,this delivery system is safe,especially with its effect on the BBB being *** mix&act delivery system has a simple structure and rapid preparation,making it a strong potential candidate for drug delivery across the BBB.

关键词： Liposomes Phospholipase A2 Phosphoserine Blood-brainbarrier Selectively open Mix&act

Targeting NRP1 axis as a strategy for treating energy metabolism impairment induced by SARS-CoV-2 spike

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Science China Life Sciences 2024年

作者： Lihui Zhang Wanting Hu Jingxuan Li Yuehan Li Feng Liu Wenyi Xiao Ning Jiang Zhiyong Xiao Lu Han Wenxia Zhou Beijing Institute of pharmacology & toxicology State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology & Toxicology School of Chinese Materia Medica Tianjin University of Traditional Chinese Medicine

Dear Editor,Free spike protein of SARS-CoV-2 alone can cause abnormal energy metabolism(Table S1 in Supporting Information), and limited research suggested a potential correlation between spike-induced mitochondrial damage and the ACE2 receptor(Lei et al., 2021; Yang et al., 2023). In order to further explore the mechanisms involved, we observed that the wild-type S1 protein of SARS-CoV-2 exerts a more potent inhibitory effect on host cell ATP compared to the wild-type S protein, S2protein, the Omicron variant S1 protein and HCoV-NL63 S1protein in HLMVEC and 293T cell lines(Figure 1A and B),indicating the importance of exploring the mechanism by which the S1 protein causes ATP decrease. Meanwhile, the S1protein did not lead to significant changes in cellular lactate levels, indicating that its primary mechanism involves impairing oxidative phosphorylation and mitochondrial damage(Figure 1C and D).

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Severe aconite poisoning successfully treated with veno-arterial extracorporeal membrane oxygenation:A case report

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World Journal of Clinical Cases 2024年第2期12卷 399-404页

作者： Saeko Kohara Yoshito Kamijo Ryoko Kyan Ichiro Okada Eiju Hasegawa Soichiro Yamada Koichi Imai Asuka Kaizaki-Mitsumoto Satoshi Numazawa department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical CenterTokyo 1900014Japan department of Clinical toxicology Saitama Medical UniversitySaitama 3500495Japan Saitama Prefectural Institute of Public Health Saitama Prefectural Institute of Public HealthSaitama 3550133Japan Division of toxicology Department of PharmacologyToxicology and TherapeuticsShowa University School of PharmacyTokyo 1428555Japan

BACKGROUND Most species of aconite contain highly toxic aconitines,the oral ingestion of which can be fatal,primarily because they cause ventricular *** describe a case of severe aconite poisoning that was successfully treated through venoarterial extracorporeal membrane oxygenation(VA-ECMO)and in which detailed toxicological analyses of the aconite roots and biological samples were performed using liquid chromatography-tandem mass spectrometry(LC-MS/MS).CASE SUMMARY A 23-year-old male presented to the emergency room with circulatory collapse and ventricular arrhythmia after ingesting approximately half of a root labeled,“Aconitum japonicum Thunb”.Two hours after arrival,VA-ECMO was initiated as circulatory collapse became refractory to antiarrhythmics and *** hours after arrival,an electrocardiogram revealed a return to sinus *** patient was weaned off VA-ECMO and the ventilator on hospital days 3 and 5,*** hospital day 15,he was transferred to a psychiatric *** other half of the root and his biological samples were toxicologically analyzed using LC-MS/MS,revealing 244.3 mg/kg of aconitine and 24.7 mg/kg of mesaconitine in the *** on admission contained 1.50 ng/mL of *** hospital day 2,neither were *** on admission showed 149.09 ng/mL of aconitine and 3.59 ng/mL of mesaconitine,but these rapidly decreased after hospital day *** The key to saving the life of a patient with severe aconite poisoning is to introduce VA-ECMO as soon as possible.

关键词： Aconite poisoning Fatal arrhythmia Veno-arterial extracorporeal membrane oxygenation Aconitine Mesaconitine Case report

Investigating epithelial-neuronal signaling contribution in visceral pain through colon organoid-dorsal root ganglion neuron co-cultures

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Neural Regeneration Research 2024年第6期19卷 1199-1200页

作者： Francesco Margiotia Lorenzo Di Cesare Mannelli Antonino Morabito Carla Ghelardini Elena Lucarini department of Neuroscience Psychology Drug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology Section University of Florence department of Neuroscience Psychology Drug Research and Child Health-NEUROFARBA University of Florence 3. Meyer Children's Hospital IRCCS

Abdominal pain is a common symptom associated with irritable bowel syndrome and inflammatory bowel diseases(IBDs), affecting about 20% of the global population(Grundy et al., 2019). Current pain therapies are poorly effective on visceral pain of intestinal origin and present several side effects, hence the need to identify novel molecular and cellular targets for drug development. The pathophysiology of visceral-abdominal pain,

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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 School

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,

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Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring

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Journal of Pharmaceutical Analysis 2024年第4期14卷 439-459页

作者： Lan Chen Yuan Zhang Yi-Xin Zhang Wei-Lai Wang De-Mei Sun Peng-Yun Li Xue-Song Feng Yue Tan School of Pharmacy China Medical UniversityShenyang110122China Institute of pharmacology and toxicology Institution National Engineering Research Center for Strategic DrugsBeijing100850China department of Gastroenterology Shengjing Hospital of China Medical UniversityShenyang110022China

Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling ***,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse ***,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different *** paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since *** also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing *** addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.

关键词： TKIs Microextraction technique HRMS methods Pharmacokinetic studies Therapeutic drug monitoring

Phomaketals A and B,pentacyclic meroterpenoids from a eupC overexpressed mutant strain of Phoma sp.

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Chinese Chemical Letters 2024年第7期35卷 350-354页

作者： Chuan Li Yangyang Han Yanan Zhai Ke Li Xingzhong Liu Zhuan Zhang Cai Jia Yongsheng Che NHC Key Laboratory of Biotechnology of Antibiotics Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China State Key Laboratory of toxicology&Medical Countermeasures Beijing Institute of Pharmacology&ToxicologyBeijing 100850China department of Microbiology College of Life SciencesNankai UniversityTianjin 300071China

Phomaketals A(1)and B(2),two tropolonic meroterpenoids with the unprecedented pentacyclic skeletons,were isolated from the solid-substrate fermentation cultures of a eupC overexpressed mutant strain of the fungus Phoma sp.,together with a biogenetically related secondary metabolite pughiinin B(3),and the known one noreupenifeldin B(4).The structures of 1–3 were elucidated primarily by nuclear magnetic resonance(NMR)*** absolute configurations of 1 and 2 were assigned by electronic circular dichroism calculations and the calculated NMR with DP4+analysis,while that of 3 was established by single-crystal X-ray diffraction analysis using Cu Kα***,phomaketals A(1)and B(2)could be derived from the hypothetical tropolonic sesquiterpene intermediates neosetophomone B(6)and 9-R-neosetophomone B(6),respectively,via different reactions *** 1 showed antiproliferative effect only against the SUPB15 cells,with an 50%inhibitory concentration(IC50)value of 4.85μmol/L,while the co-isolated known meroterpenoid 4 displayed potent effects against three tumor cell lines,SUPB15,EL4,and H9,showing IC50values of 0.36–27.08μmol/L.

关键词： Phoma sp. Tropolonic sesquiterpenes Biosynthetic pathways Hetero-Diels–Alder Cytotoxicity

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