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Growth differentiation factor-15 serum concentrations reflect disease severity and anemia in patients with inflammatory bowel disease

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World Journal of Gastroenterology 2024年第13期30卷 1899-1910页

作者： Ante Tonkic Marko Kumric Ivna Akrapovic Olic Doris Rusic Piero Marin Zivkovic Daniela Supe Domic Zeljko Sundov Ivan Males Josko Bozic Biology of Neoplasms University of Split School of MedicineSplit 21000Croatia Department of Pathophysiology University of Split School of MedicineSplit 21000Croatia Department of Gastroenterology University Hospital of SplitSplit 21000Croatia Department of Pharmacy University of Split School of MedicineSplit 21000Croatia Department of Medical Laboratory Diagnostics University Hospital of SplitSplit 21000Croatia Department of Health Studies University of SplitSplit 21000Croatia Department of Internal medicine University of Split School of MedicineSplit 21000Croatia Department of Surgery University Hospital of SplitSplit 21000Croatia

BACKGROUND Population of patients with inflammatory bowel disease(IBD)is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity and mortality.Growth-differentiation factor-15(GDF-15)is often overexpressed under stress conditions,such as inflammation,malignancies,heart failure,myocardial ischemia,and many others.AIM To explore the association between GDF-15 and IBD as serum concentrations of GDF-15 were shown to be an independent predictor of poor outcomes in multiple diseases.An additional aim was to determine possible associations between GDF-15 and multiple clinical,anthropometric and laboratory parameters in patients with IBD.METHODS This cross-sectional study included 90 adult patients diagnosed with IBD,encompassing both Crohn’s disease(CD)and ulcerative colitis(UC),and 67 healthy age-and sex-matched controls.All patients underwent an extensive workup,including colonoscopy with subsequent histopathological analysis.Disease activity was assessed by two independent gastroenterology consultants specialized in IBD,employing well-established clinical and endoscopic scoring systems.GDF-15 serum concentrations were determined following an overnight fasting,using electrochemiluminescence immunoassay.RESULTS In patients with IBD,serum GDF-15 concentrations were significantly higher in comparison to the healthy controls[800(512-1154)pg/mL vs 412(407-424)pg/mL,P<0.001],whereas no difference in GDF-15 was found between patients with CD and UC[807(554-1451)pg/mL vs 790(509-956)pg/mL,P=0.324].Moreover,multiple linear regression analysis showed that GDF-15 levels predict CD and UC severity independent of age,sex,and C-reactive protein levels(P=0.016 and P=0.049,respectively).Finally,an association between GDF-15 and indices of anemia was established.Specifically,negative correlations were found between GDF-15 and serum iron levels(r=-0.248,P=0.021),as well as GDF-15 and hemoglobin(r=-0.351,P=0.021).Accordingly,in comparison to IBD patients with normal hemoglobin levels,GDF-15

关键词： Inflammatory bowel disease Crohn’s disease Ulcerative colitis Growth-differentiation factor-15 Anemia Extraintestinal manifestations

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Discontinuation of therapy in inflammatory bowel disease: Current views

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World Journal of Clinical Cases 2024年第10期12卷 1718-1727页

作者： Antonio Meštrović Marko Kumric Josko Bozic Department of Gastroenterology University Hospital of SplitSplit 21000Croatia Department of Pathophysiology University of Split School of MedicineSplit 21000Croatia

The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease(IBD).The therapeutic approach is still evolving in terms of the mechanism of action but also in terms of the possibility of maintaining remission.In patients with achieved long-term remission,the question of de-escalation or discontinuation of therapy arises,considering the possible side effects and economic burden of long-term therapy.For each of the drugs used in IBD(5-aminosalycaltes,immunomodulators,biological drugs,small molecules)there is a risk of relapse.Furthermore,studies show that more than 50%of patients who discontinue therapy will relapse.Based on the findings of large studies and meta-analysis,relapse of disease can be expected in about half of the patients after therapy withdrawal,in case of monotherapy with aminosalicylates,immunomodulators or biological therapy.However,longer relapse-free periods are recorded with withdrawal of medication in patients who had previously been on combination therapies immunomodulators and anti-tumor necrosis factor.It needs to be stressed that randomised clinical trials regarding withdrawal from medications are still lacking.Before making a decision on discontinuation of therapy,it is important to distinguish potential candidates and predictive factors for the possibility of disease relapse.Fecal calprotectin level has currently been identified as the strongest predictive factor for relapse.Several other predictive factors have also been identified,such as:High Crohn's disease activity index or Harvey Bradshaw index,younger age(40 years),smoking,young age of disease onset,steroid use 6-12 months before cessation.An important factor in the decision to withdraw medication is the success of re-treatment with the same or other drugs.The decision to discontinue therapy must be based on individual approach,taking into account the severi

关键词： Inflammatory bowel disease Therapy discontinuation Therapy de-escalation Ulcerative colitis Crohn’s disease

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Cardiovascular mechanisms of thyroid hormones and heart failure:Current knowledge and perspectives

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World Journal of Cardiology 2024年第5期16卷 226-230页

作者： Viktor Culic Department of Cardiology and Angiology University Hospital Centre SplitUniversity of Split School of MedicineSplit 21000Croatia

A multiple hormonal imbalance that accompanies heart failure(HF)may have a significant impact on the clinical course in such patients.The non-thyroidal illness syndrome(NTIS),also referred to as euthyroid sick syndrome or low triiodothyronine syndrome,can be found in about 30%of patients with HF.NTIS represents a systemic adaptation to chronic illness that is associated with increased cardiac and overall mortality in patients with HF.While conclusions on thyroid-stimulating hormone,free triiodothyronine,total and free thyroxine are currently unresolved,serum total triiodothyronine levels and the ratio of free triiodothyronine to free thyroxine seem to provide the best correlates to the echocardiographic,laboratory and clinical parameters of disease severity.HF patients with either hyper-or hypothyroidism should be treated according to the appropriate guidelines,but the therapeutic approach to NTIS,with or without HF,is still a matter of debate.Possible treatment options include better individual titration of levothyroxine therapy,combined triiodothyronine plus thyroxine therapy and natural measures to increase triiodothyronine.Future research should further examine the cellular and tissue mechanisms of NTIS as well as new therapeutic avenues in patients with HF.

关键词： Heart failure Non-thyroidal illness syndrome Low triiodothyronine syndrome Therapy Thyroxine Triiodothyronine

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Regenerative medicine strategies for chronic complete spinal cord injury

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Neural Regeneration Research 2024年第4期19卷 818-824页

作者： Shogo Hashimoto Narihito Nagoshi Masaya Nakamura Hideyuki Okano Department of Orthopedic Surgery Keio University School of Medicine Department of Physiology Keio University School of Medicine

Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases.While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable,most research in this field has focused on the early phase of incomplete injury.However,the majority of patients have chronic severe injuries;therefore,treatments for these situations are of fundamental importance.The reason why the treatment of complete spinal cord injury has not been studied is that,unlike in the early stage of incomplete spinal cord injury,there are various inhibitors of neural regeneration.Thus,we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies.First,we established a combination therapy of cell transplantation and drug-releasing scaffolds,which contributes to functional recovery after chronic complete transection spinal cord injury,but we found that functional recovery was limited and still needs further investigation.Here,for the further development of the treatment of chronic complete spinal cord injury,we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss,with reference to the literature,which combination of treatments is most effective in achieving functional recovery.

关键词： cell transplantation chronic phase complete transection regenerative medicine spinal cord injury

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Cannabinoids and endocannabinoids as therapeutics for nervous system disorders:preclinical models and clinical studies

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Neural Regeneration Research 2024年第4期19卷 788-799页

作者： R.Scott Duncan Sean M.Riordan Matthew C.Gernon Peter Koulen Department of Ophthalmology School of MedicineUniversity of Missouri Department of Biomedical Sciences School of MedicineUniversity of Missouri

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body.They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.Some of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric disorders.In addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS diseases.This review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies.In addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

关键词： anandamide cannabidiol cannabinoid endocannabinoid epilepsy multiple sclerosis neurodegeneration neuroprotection tetrahydrocannabinol

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Research on Hepatocyte Regulation of PCSK9-LDLR and Its Related Drug Targets

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Chinese Journal of Integrative medicine 2024年第7期30卷 664-672页

作者： LIU Su-su YU Tong QIAO Yan-fang GU Shu-xiao CHAI Xin-lou school of Traditional Chinese medicine Beijing University of Chinese Medicine

The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol(LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor(LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9(PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs.

关键词： hyperlipidemia proprotein convertase subtilisin/kexin type 9 low-density lipoprotein receptor intracellular pathway extracellular pathway

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Pathophysiological changes of muscle after ischemic stroke:a secondary consequence of stroke injury

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Neural Regeneration Research 2024年第4期19卷 737-746页

作者： Hu Qi Dan Tian Fei Luan Ruocong Yang Nan Zeng State Key Laboratory of Southwestern Chinese medicine Resources Chengdu University of Traditional Chinese Medicine school of Pharmacy Chengdu University of Traditional Chinese Medicine Acupuncture and Tuina school Chengdu University of Traditional Chinese Medicine

Sufficient clinical evidence suggests that the damage caused by ischemic stroke to the body occurs not only in the acute phase but also during the recovery period,and that the latter has a greater impact on the long-term prognosis of the patient.However,current stroke studies have typically focused only on lesions in the central nervous system,ignoring secondary damage caused by this disease.Such a phenomenon arises from the slow progress of pathophysiological studies examining the central nervous system.Further,the appropriate therapeutic time window and benefits of thrombolytic therapy are still controversial,leading scholars to explore more pragmatic intervention strategies.As treatment measures targeting limb symptoms can greatly improve a patient’s quality of life,they have become a critical intervention strategy.As the most vital component of the limbs,skeletal muscles have become potential points of concern.Despite this,to the best of our knowledge,there are no comprehensive reviews of pathophysiological changes and potential treatments for post-stroke skeletal muscle.The current review seeks to fill a gap in the current understanding of the pathological processes and mechanisms of muscle wasting atrophy,inflammation,neuroregeneration,mitochondrial changes,and nutritional dysregulation in stroke survivors.In addition,the challenges,as well as the optional solutions for individualized rehabilitation programs for stroke patients based on motor function are discussed.

关键词： inflammation ischemic stroke mitochondria muscle atrophy muscle fiber muscle nutrition quality of life rehabilitation ubiquitin

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Intranasal administration of stem cell-derived exosomes for central nervous system diseases

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Neural Regeneration Research 2024年第6期19卷 1249-1255页

作者： Shuho Gotoh Masahito Kawabori Miki Fujimura Department of Neurosurgery Hokkaido University Graduate School of Medicine

Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including antiapoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

关键词： central nervous system disease exosome extracellular vesicle intranasal administration stem cell

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Anti-N-methyl-D-aspartate receptor type autoimmune encephalitis with severe pneumonia:a case report

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World Journal of Emergency medicine 2024年第2期15卷 142-146页

作者： Yi Gu Xiandong Liu Tiancao Dong Qian Yang Xiaowei Bao Dongyang Zhao Lunxian Tang Department of Internal Emergency medicine Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200120China school of medicine Tongji UniversityShanghai 200120China

Autoimmune encephalitis(AE)is a type of encephalitis caused by autoimmune disease.AE was included on a list of the first batch of 121 rare diseases published by the Chinese National Health Commission on 11^(th)May 2018.Currently,patients with AE account for 10%-20% of encephalitis cases,with 54%-80% of those cases classified as the anti-N-methyl-D-aspartate receptor(NMDAR)type,which is the most common type.[1]In 2010,China reported the first case of a patient withanti-NMDARtype AE.

关键词： encephalitis autoimmune aspartate

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Prediction of cell-cell communication patierns of dorsal root ganglion cells: single-cell RNA sequencing data analysis

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Neural Regeneration Research 2024年第6期19卷 1367-1374页

作者： Yanna Lian Cheng Wu Li Liu Xiangyao Li National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration School of Brain Science and Brain Medicine Zhejiang University International Institutes of medicine the Fourth Affiliated Hospital of Zhejiang University School of Medicine Zhejiang university-university of Edinburgh Institute Zhejiang University School of Medicine Zhejiang University 4. Biomedical Sciences College of Medicine and Veterinary Medicine The University of Edinburgh Core Facilities of the school of medicine Zhejiang University

Dorsal root ganglion neurons transmit peripheral somatic information to the central nervous system, and dorsal root ganglion neuron excitability affects pain perception. Dorsal root ganglion stimulation is a new approach for managing pain sensation. Knowledge of the cell-cell communication among dorsal root ganglion cells may help in the development of new pain and itch management strategies. Here, we used the single-cell RNA-sequencing(scRNA-seq) database to investigate intercellular communication networks among dorsal root ganglion cells. We collected scRNA-seq data from six samples from three studies, yielding data on a total of 17,766 cells. Based on genetic profiles, we identified satellite glial cells, Schwann cells, neurons, vascular endothelial cells, immune cells, fibroblasts, and vascular smooth muscle cells. Further analysis revealed that eight types of dorsal root ganglion neurons mediated proprioceptive, itch, touch, mechanical, heat, and cold sensations. Moreover, we predicted several distinct forms of intercellular communication among dorsal root ganglion cells, including cell-cell contact, secreted signals, extracellular matrix, and neurotransmitter-mediated signals. The data mining predicted that Mrgpra3-positive neurons robustly express the genes encoding the adenosine Adora2b(A2B) receptor and glial cell line-derived neurotrophic factor family receptor alpha 1(GFRα-1). Our immunohistochemistry results confirmed the coexpression of the A2B receptor and GFRα-1. Intrathecal injection of the A2B receptor antagonist PSB-603 effectively prevented histamine-induced scratching behaviour in a dose-dependent manner. Our results demonstrate the involvement of the A2B receptor in the modulation of itch sensation. Furthermore, our findings provide insight into dorsal root ganglion cell-cell communication patterns and mechanisms. Our results should contribute to the development of new strategies for the regulation of dorsal root ganglion excitability.

关键词： cell-cell communications CellChat dorsal root ganglion scRNA-Seq database

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