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Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis:a narrative review

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Neural Regeneration Research 2024年第4期19卷 747-753页

作者： Peter H.King Department of Neurology and Center for Neurodegeneration and experimental therapeutics The University of Alabama at BirminghamBirminghamALUSA Birmingham Veterans Affairs Medical Center BirminghamALUSA

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary *** progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease *** on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom *** 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for *** Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the *** muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal *** accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real *** advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and *** technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of *** are two major goals of this *** first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activi

关键词： amyotrophic lateral sclerosis biomarkers clinicopathological correlation disease progression muscle biomarkers neurogenic atrophy neuromuscular junction non-coding RNAs presymptomatic stages skeletal muscle SOD1G93A mouse model

Mission of the National Cancer Center Hospital in Japan to promote clinical trials for precision medicine

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Cancer Biology & Medicine 2024年第1期21卷 1-3页

作者： Kazuaki Shimada Kenichi Nakamura Noboru Yamamoto Department of Hepatobiliary and Pancreatic Surgery National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce National Cancer Center HospitalTokyo 104-0045Japan Department of experimental therapeutics National Cancer Center HospitalTokyo 104-0045Japan

Precision medicine is a growing field *** its potential benefit to many patients,several major obstacles must be overcome before precision medicine can be more widely used in clinical *** main obstacles are associated... 详细信息

关键词： clinical Cancer overcome

Interaction between inflammatory bowel disease,physical activity,and myokines:Assessment of serum irisin levels

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World Journal of Gastroenterology 2024年第22期30卷 2923-2926页

作者： Marwan SM Al-Nimer Department of therapeutics and Clinical Pharmacology College of MedicineUniversity of DiyalaBaqubah 32001Iraq

Inflammatory bowel disease(IBD),including Crohn’s disease and ulcerative colitis,showed a wide spectrum of intestinal and extra-intestinal manifestations,which rendered the patients physically inactive and impaired their quality of *** has been found that physical activity is a non-pharmacological intervention that improves the quality of life for those *** is one member of the myokines secreted by muscle contraction during exercise and could be used as an antiinflammatory biomarker in assessing the physical activity of IBD *** addition,experimental studies showed that exogenous irisin significantly decreased the inflammatory markers and the histological changes of the intestinal mucosa observed in experimental ***,irisin produces changes in the diversity of the ***,endogenous or exogenous irisin,via its anti-inflammatory effects,will improve the health of IBD patients and will limit the barriers to physical activity in patients with IBD.

关键词： Irisin Inflammatory bowel disease Physical activity Myokines Prognostic marker

Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance

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Genes & Diseases 2024年第1期11卷 189-204页

作者： Ebrahim H.Maleki Ahmad Reza Bahrami Maryam M.Matin Department of Biology Faculty of ScienceFerdowsi University of Mashhad*** MashhadIran Jagiellonian Centre for experimental therapeutics(JCET) Jagiellonian University31-007 KrakowPoland Doctoral School of Exact and Natural Sciences Jagiellonian University30-348 KrakowPoland Industrial Biotechnology Research Group Institute of BiotechnologyFerdowsi University of Mashhad*** MashhadIran Novel Diagnostics and therapeutics Research Group Institute of BiotechnologyFerdowsi University of Mashhad***MashhadIran Stem Cell and Regenerative Medicine Research Group Iranian Academic Center for EducationCulture and Research(ACECR)Khorasan Razavi Branch917751376 MashhadIran

Intra-tumor heterogeneity is now arguably one of the most-studied topics in tumor biology,as it represents a major obstacle to effective cancer *** tumor cells are highly diverse at genetic,epigenetic,and phenotypic levels,intra-tumor heterogeneity can be assumed as an important contributing factor to the nullification of chemotherapeutic effects,and recurrence of the *** on the role of heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics and behavior during cancer progression and treatment;herein,we aim to establish a comprehensive definition for adaptation of neoplastic cells against *** discuss two parallel and yet distinct subpopulations of tumor cells that play pivotal roles in reducing the effects of chemotherapy:"resistant"and"tolerant"***,this review also highlights the impact of the quiescent phase of the cell cycle as a survival mechanism for cancer *** understanding the mechanisms under-lying the quiescence,it provides an insightful perspective on cancer stem cells(CsCs)and their dual and intertwined functions based on their cell cycle state in response to ***-over,CSCs,epithelial-mesenchymal transformed cells,circulating tumor cells(CTCs),and disseminated tumor cells(DTCs),which are mostly in a quiescent state of the cell cycle are proved to have multiple biological links and can be implicated in our viewpoint of cell cycle heterogeneity in ***,increasing our knowledge of cell cycle heterogeneity is a key to identifying new therapeutic solutions,and this emerging concept may provide us with new opportunities to prevent the dreadful cancer recurrence.

关键词： Cancer stem cells(CSCs) Carcinoma Cell cycle heterogeneity Quiescence Therapy resistance Therapy tolerance Tumor dormancy

Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomics

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Journal of Pharmaceutical Analysis 2024年第2期14卷 196-210页

作者： Mariola Olkowicz Khaled Ramadan Hernando Rosales-Solano Miao Yu Aizhou Wang Marcelo Cypel Janusz Pawliszyn Department of Chemistry University of WaterlooWaterlooONCanada Jagiellonian Centre for experimental therapeutics(JCET) Jagiellonian UniversityKrakowPoland Latner Thoracic Surgery Research Laboratories Toronto General Hospital Research InstituteUniversity Health NetworkTorontoONCanada The Jackson Laboratory JAX Genomic MedicineFarmingtonCTUSA Division of Thoracic Surgery Department of SurgeryUniversity Health NetworkUniversity of TorontoToronto Lung Transplant ProgramTorontoONCanada

Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.

关键词： Pulmonary metastases Colorectal cancer Adjuvant chemotherapy In vivo lung chemo-perfusion Solid-phase microextraction(SPME)microprobes Spatial metabolomics

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

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Oncology Research 2024年第4期32卷 769-784页

作者： HUAN GAO JIE ZHANG TONY GKLEIJN ZHAOYONG WU BING LIU YUJIN MA BAOYUE DING DONGFENG YIN Jiaxing Key Laboratory for Photonanomedicine and experimental therapeutics Department of PharmaceuticsCollege of MedicineJiaxing UniversityJiaxing314001China Department of Pharmacy The General Hospital of Xinjiang Military RegionUrumqi830000China Department of Pathology and Medical Biology University Medical Center GroningenUniversity of GroningenGroningen9713 GZThe Netherlands Department of Pathology Laboratory of Experimental OncologyErasmus MCRotterdam3015 GDThe Netherlands Department of Pharmacy Jiaxing Maternal and Child Health Care HospitalAffiliated Hospital of Jiaxing UniversityJiaxing314001China Qinghai Enlu Biotechnology Co. Ltd.Haidong810700China

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and *** treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic *** improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone ***(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size *** in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX *** micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated *** binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis *** vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic *** conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

关键词： Pluronic micelles Targeted nanotherapeutics Nanoparticulate drug delivery system Breast cancer with bone metastasis Therapeutic efficacy

The NORE1A/RASSF5 Tumor Suppressor Forms a Complex with GSK-3β to Regulate β-Catenin

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Journal of Biosciences and Medicines 2024年第8期12卷 60-75页

作者： M. Lee Schmidt Howard Donninger Geoffrey J. Clark Department Pharmacology and Toxicology University of Louisville Louisville USA US Worldmeds LouisvilleUSA Department of Medicine University of Louisville Louisville USA experimental therapeutics Program James Graham Brown Cancer Center University of Louisville Louisville USA

NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin by binding and modulating the ubiquitin ligase substrate recognition factor β-TrCP. β-catenin is a major executor of the Wnt pathway. The ubiquitin SCF-β-TrCP ligase complex acts on a phospho-degron site in β-catenin that can be phosphorylated by GSK-3β. We now show that in addition to binding β-TrCP, NORE1A also promotes the phosphorylation of the β-catenin phospho-degron by complexing with the kinase GSK-3β. Indeed, NORE1A enhances the formation of a GSK-3β/β-TrCP complex. A structural mutant of NORE1A that retains β-TrCP binding but will no longer interact with GSK-3β inhibits the β-catenin degrading action of NORE1A. The GSK-3β interaction with NORE1A plays an important role in the biology of NORE1A as a GSK-3β inhibitor blocks NORE1A induced senescence. Thus, we identify a new role for the tumor suppressor NORE1A: The regulation of GSK-3β. GSK-3β has many other substrates including multiple transcription factors and co-activators such as p53 and the Hippo component TAZ. The work implies that NORE1A may be able to influence all of them via this new kinase scaffolding interaction.

关键词： RAS NORE1A RASSF5 GSK-3β Beta Catenin HIPPO

The interplay of drug therapeutics and immune responses to SARS-CoV-2

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Cellular & Molecular Immunology 2024年第2期21卷 197-200页

作者： Valeria Fumagalli Matteo Iannacone Division of Immunology Transplantationand Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilanItaly Vita-Salute San Raffaele University MilanItaly experimental Imaging Centre IRCCS San Raffaele Scientific InstituteMilanItaly

The SARS-CoV-2 pandemic has necessitated rapid therapeutic and preventative *** vaccines form the frontline of defense,antiviral treatments such as nirmatrelvir have emerged as vital adjunctive measures,particularly for those unable or unwilling to be *** review delves into the potential influence of nirmatrelvir on enduring *** parallel,the potential of drug repurposing is explored,with bisphosphonates being examined for their possible effects against COVID-19 due to their immunomodulatory *** importance of rigorous clinical trials and careful interpretation of preliminary data is emphasized.

关键词： SARS-CoV-2 Nirmatrelvir Bisphosphonates Adaptive immunity Drug repurposing

Utilizing zebrafish and okadaic acid to study Alzheimer's disease

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Neural Regeneration Research 2018年第9期13卷 1538-1541页

作者： Daniel Koehler Frederick E.Williams Department of Pharmacology and experimental therapeutics University of Toledo

Despite the many years of extensive research using rodent models to study Alzheimer＇s disease （AD）, no cure or disease halting drug exists. An increasing number of people are suffering from the disease and a therapeutic intervention is needed. Therefore, it is necessary to have complementary models to aid in the drug discovery. The zebrafish animal model is emerging as a valuable model for the investigation of AD and neurodegenerative drug discovery. The main genes involved in human AD have homologous counter- parts in zebrafish and have conserved function. The basic brain structure of the zebrafish is also conserved when compared to the mammalian brain. Recently an AD model was established by administering okadaic acid to zebrafish. It was used to test the efficacy of a novel drug, lanthionine ketimine-5-ethyl ester, and to elucidate its mechanism of action. This demonstrated the ability of the okadaic acid-induced AD zebrafish model to be implemented in the drug discovery process for therapeutics against AD.

关键词： Alzheimer's disease Zebrafish okadaic acid protein phosphatase 2A learning and memory lanthionine ketimine-5-ethyl ester