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Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

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Neural Regeneration Research 2025年第8期20卷 2325-2336页

作者： Yafan Bai Hui Ma Yue Zhang Jinfeng Li Xiaojuan Hou Yixin Yang Guyan Wang Yunfeng Li department of Anesthesiology Beijing Tongren HospitalCapital Medical UniversityBeijingChina Beijing Institute of Basic Medical Sciences BeijingChina Hebei North University ZhangjiakouHebei ProvinceChina Beijing Institute of pharmacology and toxicology State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Key Laboratory of NeuropsychopharmacologyBeijingChina

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary *** this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain *** experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain ***,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 ***,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain ***,YL-0919 effectively combated oxidative stress both in vivo and in *** protective effects of YL-0919 were partially inhibited by *** results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist ***-0919 may have potential as a new treatment for traumatic brain injury.

关键词： antidepressant drug blood-brain barrier cognitive function hypidone hydrochloride(YL-0919) neurological function nuclear factor-erythroid 2 related factor 2 oxidative stress sigma-1 receptor superoxide dismutase traumatic brain injury

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Isolated Systolic Hypertension in Geriatrics

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International Journal of clinical Medicine 2025年第1期16卷 29-53页

作者： Soumya Erri Terry Oroszi department of pharmacology & toxicology Boonshoft School of Medicine WSU Fairborn OH USA

Hypertension, often called the “silent killer”, is a major risk factor for heart attacks and strokes in the elderly. Its effective management is crucial to prevent damage to the heart, brain, and kidneys. Isolated systolic hypertension (ISH) is particularly critical in the elderly population. Cardiovascular risk factors, including pulse pressure and wave velocity, are closely associated with systolic blood pressure and influenced by arterial stiffness and wave reflections. Managing ISH is complex due to the potential negative effects of certain medications and individual variability in treatment response. This paper will address these issues, evaluating antihypertensive drugs, combination therapy, personalized treatment plans, and updated guidelines for managing ISH.

关键词： Hypertension Geriatric or Elderly or Adults Types of Hypertension Tests First-Line Treatment Drugs Isolated Systolic Hypertension Other Diseases

The Inheritance, Pathophysiology, and Treatment for Polycystic Kidney Disease and Its Effects on the Heart—A Literature Review

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International Journal of clinical Medicine 2025年第1期16卷 95-111页

作者： Harika Paruchuri Kelley Williams Terry Oroszi department of pharmacology & toxicology Boonshoft School of Medicine WSU Fairborn OH USA

Polycystic kidney disease (PKD) is an autosomal dominant genetic disorder that causes the formation of multiple cysts in the kidneys, leading to kidney failure. PKD is a common condition affecting approximately 1 in 500 individuals worldwide. The most prevalent type of PKD is autosomal dominant PKD (ADPKD). ADPKD is caused by mutations in either the PKD1 or PKD2 genes, which encode for proteins involved in cell growth and differentiation. These mutations lead to the formation of fluid-filled cysts in the kidneys, which can eventually lead to kidney failure. In addition to affecting the kidneys, PKD can also cause cysts in other organs, such as the liver, pancreas, and spleen. PKD can also lead to various complications, including high blood pressure, heart valve abnormalities, and brain aneurysms. This review focuses on the inheritance, pathophysiology, and treatment of PKD, with a specific emphasis on its effects on the cardiovascular system. Currently, there is no cure for PKD. However, several treatments are available to manage the symptoms and complications of the disease. These treatments include medications to control blood pressure, pain relievers, antibiotics for infections, and dialysis or kidney transplantation for kidney failure. Tolvaptan is the only FDA-approved drug specifically for ADPKD and has been shown to slow disease progression. In addition to summarizing current treatment options, this review will discuss promising future treatments, such as gene therapy and stem cell therapy.

关键词： Polycystic Kidney Disease Autosomal Dominant Autosomal Recessive End-Stage Renal Disease Epidemiology Pathophysiology Cardiovascular Diseases

Role of P-Gp in Treatment of Cancer

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Journal of Cancer Therapy 2025年第1期16卷 1-17页

作者： Venkata Sai Nithin Reddy Yendapalli Kelley Williams Terry Oroszi department of pharmacology & toxicology Boonshoft School of Medicine WSU Fairborn OH USA

P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) family of transporters, plays a crucial role in the development of multi-drug resistance (MDR) in cancer treatment. P-gp actively pumps chemotherapeutic drugs out of cancer cells, reducing their intracellular concentrations and thereby diminishing their efficacy. This review explores the mechanisms by which P-gp contributes to MDR, including intrinsic and acquired resistance. It also discusses various strategies to inhibit P-gp, such as blocking drug binding sites, interfering with ATP hydrolysis, and altering cell membrane integrity. The potential of fourth-generation P-gp inhibitors and other novel approaches to enhance the effectiveness of cancer therapies is also examined. Understanding and overcoming P-gp-mediated MDR is essential for improving therapeutic outcomes in cancer patients.

关键词： P-Glycoprotein (P-Gp) Multi-Drug Resistance (MDR) Cancer Treatment ABC Transporters Chemotherapy Resistance P-Gp Inhibitors Drug Efflux Mechanisms Fourth-Generation Inhibitors

A Comprehensive Review of Pediatric Hydrocephalus

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Open Journal of Pediatrics 2025年第1期15卷 21-37页

作者： Lakshmi C. Devarapalli Kelley J. Williams Terry L. Oroszi department of pharmacology & toxicology Boonshoft School of Medicine Wright State University Fairborn USA

Hydrocephalus is a medical condition caused by an abnormal cerebrospinal fluid (CSF) buildup in the brain’s ventricles. This excess fluid causes the ventricles to enlarge, increasing pressure within the brain. CSF typically flows through the ventricles and around the spinal column, bathing the brain. However, the increased pressure from excess CSF associated with hydrocephalus can damage brain tissue and lead to various problems with cognitive function. While it can occur at any age, hydrocephalus is the most common in infants and adults over 60. It has been a subject of fascination for physicians throughout history due to its striking presentation. Two main types of hydrocephalus exist: obstructive (noncommunicating) and communicating. A blockage in the CSF flow causes obstructive hydrocephalus, while communicating hydrocephalus occurs when the body’s ability to absorb CSF is impaired. The review delves into the intricacies of hydrocephalus, exploring its causes, symptoms, and pathophysiology. The latest research on the topic has been examined, including innovative treatment approaches and ongoing challenges in managing this complex condition.

关键词： Hydrocephalus CSF Ventricles Pathogenesis Pediatric

The Cause of Hirschsprung’s Disease in Bardet Biedl Syndrome in Children

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Surgical Science 2025年第1期16卷 15-25页

作者： Naga Venkata Chakra Satyanarayana Amarthi Terry Oroszi department of pharmacology and toxicology Boonshoft School of Medicine Wright State University Dayton Ohio USA

Hirschsprung’s disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the distal colon, leading to functional obstruction. Bardet-Biedl syndrome (BBS) is a rare ciliopathy associated with various clinical features, including HSCR. This review article aims to explore the underlying causes of HSCR in children with BBS, focusing on the genetic and developmental factors contributing to the pathogenesis of both conditions. We reviewed relevant literature, including peer-reviewed journal articles and case reports, to provide a comprehensive overview of the current understanding of the relationship between HSCR and BBS. Our findings highlight the complex interplay of genetic mutations, signaling pathways, and developmental processes involved in the pathogenesis of HSCR in BBS. Further research is needed to elucidate the precise mechanisms underlying this association and to develop targeted therapeutic strategies for children with HSCR and BBS.

关键词： Hirschsprung’s Disease Bardet-Biedl Syndrome Ciliopathy Genetics Developmental Disorder

Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

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Neural Regeneration Research 2025年第3期20卷 873-886页

作者： Ying Wang Xiang Zhang Henrik Biverstål Nicolas GBazan Shuai Tan Nailin Li Makiko Ohshima Marianne Schultzberg Xiaofei Li department of Neurobiology Care Sciences&SocietyDivision of NeurogeriatricsKarolinska InstitutetStockholmSweden department of Neurology Neuroscience CenterThe First Hospital of Jilin UniversityChangchunJilin ProvinceChina department of Physiology and pharmacology Karolinska InstitutetStockholmSweden department of Biosciences and Nutrition Karolinska InstitutetHuddingeSweden Neuroscience Center of Excellence Louisiana State UniversityNew OrleansLAUSA department of Medicine SolnaClinical Pharmacology GroupKarolinska University HospitalStockholmSweden

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

关键词： Alzheimer's disease amyloid-β maresin microglia monocyte neuroinflammation resolution RNA-sequencing specialized pro-resolving lipid mediator

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Emerging role of A-kinase anchoring protein 5 signaling in reward circuit function

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Neural Regeneration Research 2025年第10期20卷 2913-2914页

作者： William J.Flerlage Mark L.Dell’Acqua Brian M.Cox Fereshteh S.Nugent Uniformed Services University of the Health Sciences Department of Pharmacology and Molecular TherapeuticsBethesdaMDUSA department of pharmacology University of Colorado School of MedicineAnschutz Medical CampusAuroraCOUSA

There is a strong evidence supporting the hypothesis of synaptic dysfunction as a major contributor to neural circuit and network disruption underlying emotional and mood dysregulation in psychiatric disorders(Simmons et al.,2024).Diverse sets of distinct molecular signaling pathways converge on the synapse to regulate synaptogenesis,synaptic function,and synaptic plasticity in brain regions and circuits through complex interactions organized by numerous multivalent protein scaffolds,including the family of proteins known as A-kinase anchoring proteins(AKAPs).

关键词： function supporting

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Screening optimal target populations with symptomatic bradyarrhythmia for pharmacotherapy:a discriminant analysis pilot study

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Journal of Traditional Chinese Medicine 2025年第1期45卷 160-166页

作者： ZHANG Wantong YI Danhui LU Fang YANG Qiaoning SHI Shuai LI Qiuyan WENG Weiliang WANG Xujie ZHU Baochen Institute of clinical pharmacology Xiyuan HospitalChina Academy of Chinese Medical Sciences NMPA Key Laboratory for clinical Research and Evaluation of Traditional Chinese Medicine National clinical Research Center for Chinese Medicine Cardiology Xiyuan HospitalChina Academy of Chinese Medical Sciences School of Statistics Renmin University of China department of General Medicine Guanganmen HospitalChina Academy of Chinese Medical Sciences department of Pharmacy Dongzhimen HospitalBeijing University of Chinese Medicine

OBJECTIVE: To screen the target population with symptomatic bradyarrhythmia for pharmacotherapy. METHODS: This study use database from clinical trial that use Yuanjiang decoction(元姜方), a traditional Chinese medicinal prescription. Eligible participants were recruited and treated with Yuanjiang decoction(composed of 6 Chinese herbal medicines), 200 m L twice daily. Cross-contingency analysis, logistic regression analysis, interaction analysis, discriminant analysis and 10-fold cross validation methods were used to establish discriminant model. RESULTS: This study concluded that the clinical treatment of bradyarrhythmia has a clear effect. Low minimum heart rate, high maximum heart rate are risk factors that affect the efficacy. Patients with only one comorbid disease did not significantly affect the efficacy, but patient with two or more diseases of coronary heart disease, hypertension, paroxysmal atrial fibrillation, premature ventricular contraction and premature atrial contraction at the same time did not have a good effect. Using the discriminant analysis method to establish a efficacy prediction model, y = 0.07X1 + 0.16X2-0.65X3-1.12X4-0.71X5-0.75X6-0.91X7(X1 = 24 h mean heart rate, X2 = minimum heart rate, X3 = coronary heart disease, X4 = paroxysmal atrial fibrillation, X5 = premature ventricular contraction, X6= sinus block, X7 = atrioventricular block). CONCLUSION: Our model based on the clinical features of patients with bradyarrhythmia. Should be useful aid for predicting pharmacotherapy response and could screen the optimal pharmacotherapy target.

关键词： bradycardia discriminant analysis drug therapy health services needs and demand medicine, Chinese traditional