Abstract:
:It is currently thought that the dementia of Alzheimer's disease is due to the neurotoxicity of the deposits or aggregates of amyloid-β (Aβ) in the extracellular space of the cerebral cortex. This model has been widely criticized because there is a poor correlation between deposits and dementia. Others have questioned whether Aβ is truly neurotoxic. Yet, in spite of these concerns, the search for therapeutic agents has been based on the development of mouse models transfected with mutant genes associated in humans with early onset Alzheimer's disease. A major limitation of these models is that although they exhibit many of the pathological and clinical manifestation of the human disease, the bulk of individuals who develop the dementia of Alzheimer's disease have none of these mutant genes. Furthermore, nine clinical trials of drugs that were effective in transgenic mice failed to show any benefit in patients. Finally, a major unresolved issue with the Aβ model is that since Aβ is produced in everyone, why are deposits only seen in the elderly? This issue must be resolved if we are to understand the etiology of the disease and develop test systems for both diagnosis and drug discovery. Published studies from my laboratory demonstrate that in human cerebrospinal fluid immunoreactive Aβ is only present as a complex with two chaperones, ERp57 and calreticulin and is N-glycosylated. This complex formation is catalyzed by the posttranslational protein processing system of the endoplasmic reticulum (ER). Others have reported that in plaque Aβ is present only as the naked peptide. Together these results suggest that both plaque and dementia are secondary to an age related decline in the capacity of the ER to catalyze protein, posttranslational processing. Since the synaptic membrane proteins necessary for a functioning memory are also processed in the ER, these findings would suggest that the loss of cognition is due to a decline in the capacity of the neuron to produce and maintain functioning synapses. Work from my laboratory and from others further indicate that the components of the ER, posttranslational, protein processing pathway do dramatically decline with age. These data suggest that this decline may be found in all cells and could account not only for the dementia of Alzheimer's disease, but also for many of the other manifestations of the aging process. These observations also suggest that declining ER function has a role in two well-recognized phenomena associated with aging: a loss of mitochondrial function and a decrease in myelin. Finally, based on this paradigm I propose new cellular and animals models for high-throughput screening for drug discovery.
journal_name
Front Pharmacoljournal_title
Frontiers in pharmacologyauthors
Holtzman JLdoi
10.3389/fphar.2013.00059subject
Has Abstractpub_date
2013-05-13 00:00:00pages
59issn
1663-9812journal_volume
4pub_type
杂志文章abstract::Osteosarcoma (OS) is a malignant primary bone tumor with high metastatic rate. C-X-C motif chemokine ligand 6 (CXCL6) and its receptor C-X-C motif chemokine receptor 1/2 (CXCR1/2) have been found to participate in the process of carcinogenesis. In this study, we evaluated the role of CXCL6/CXCR1/2 axis in proliferatio...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00307
更新日期:2019-03-28 00:00:00
abstract::Abelmoschus manihot (L.) Medik. (Malvaceae) is a herb used in traditional Chinese medicine to treat some kidney diseases. To date, the detailed mechanisms by which A. manihot improves some kinds of renal disease are not fully understood. In this study, we established Adriamycin-induced NRK-52E cells, the normal rat ki...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00567
更新日期:2019-05-28 00:00:00
abstract::Ethanol-induced gastric mucosal injury is a common gastrointestinal disorder. Polysaccharides separated from herbs have been shown to be effective for ethanol-induced gastric mucosal injury, but whether the polysaccharides from Dendrobium officinale Kimura & Migo leaves (LDOP-1) protected mucosa from ethanol-induced i...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2020.526349
更新日期:2020-11-11 00:00:00
abstract::Rheumatoid arthritis (RA) is a chronic autoimmune disease that is primarily characterized by synovial inflammation. In this study, we found that a traditional Chinese decoction, Juanbi-Tang (JBT), JBT attenuated the symptoms of collagen-induced arthritis (CIA) mice and in tumor necrosis factor transgenic (TNF-Tg) mice...
journal_title:Frontiers in pharmacology
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doi:10.3389/fphar.2020.00045
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abstract::We report on a patient who developed acute liver failure while being treated with metamizole. After liver transplantation, the patient recovered rapidly. Liver biopsy showed massive necrosis and lobular infiltration of lymphocytes. A lymphocyte transformation test performed 20 months after transplantation was positive...
journal_title:Frontiers in pharmacology
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doi:10.3389/fphar.2019.00996
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abstract::Li-Ru-Kang (LRK), a formula of eight traditional Chinese medicines (TCM), has been used to treat hyperplasia of mammary gland (HMG) in TCM clinics. However, how LRK works in HMG patients is unclear. To explore the possible mechanisms of LRK against HMG, the network pharmacology was used to screen the potential targets...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2018.01318
更新日期:2018-11-20 00:00:00
abstract::SARS-CoV-2 is a positive sense RNA coronavirus that constitutes a new threat for the global community and economy. While vaccines against SARS-CoV-2 are being developed, the mechanisms through which this virus takes control of an infected cell to replicate remains poorly understood. Upon infection, viruses completely ...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,评审
doi:10.3389/fphar.2020.578599
更新日期:2020-08-28 00:00:00
abstract::[This corrects the article on p. 216 in vol. 5, PMID: 25295006.]. ...
journal_title:Frontiers in pharmacology
pub_type: 已发布勘误
doi:10.3389/fphar.2014.00250
更新日期:2014-11-19 00:00:00
abstract::Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term 'medical cannabis' refers to physician-recommended use o...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,评审
doi:10.3389/fphar.2018.01259
更新日期:2018-11-13 00:00:00
abstract::A detannified methanolic extract of Scrophularia lucida L. attenuated the formation of cancer cell-induced circular chemorepellent induced defects (CCIDs) in the lymph endothelial cell barrier, which resemble entry ports for the intravasating tumor into the vasculature as a prerequisite for lymph node metastasis. Ther...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2018.00304
更新日期:2018-04-03 00:00:00
abstract::Wenxin Keli (WXKL) is a widely used Chinese botanical drug for the treatment of arrhythmia, which is consisted of four herbs and amber. In the present study, we analyzed the chemical composition of WXKL using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) to tentatively identify 71 comp...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2018.01288
更新日期:2018-11-13 00:00:00
abstract::Nanomaterials with localized surface plasmon resonance (LSPR) have exquisite optical properties, which allow a wide range of applications. Non-stoichiometric copper sulfides with active LSPR have drawn great attention, because its LSPR peak falls in the NIR region that is suitable for deep bioimaging and photothermal ...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00141
更新日期:2019-02-26 00:00:00
abstract::Background and purpose: We have shown that in vitro treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism. The aim of the present study was to determine whether treatment with CBD in vivo would also...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2017.00248
更新日期:2017-05-18 00:00:00
abstract::Impaired homeostasis of the carboxylic acids oxalate and citrate, dramatically increases the risk for the formation of Ca2+-oxalate kidney stones, which is the most common form of kidney stones in humans. Renal homeostasis of oxalate and citrate is controlled by complex mechanisms including epithelial transport protei...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2020.00405
更新日期:2020-04-07 00:00:00
abstract::The cardiac action potential is critical to the production of a synchronized heartbeat. This electrical impulse is governed by the intricate activity of cardiac ion channels, among them the cardiac voltage-gated potassium (Kv) channels KCNQ1 and hERG as well as the voltage-gated sodium (Nav) channel encoded by SCN5A. ...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,评审
doi:10.3389/fphar.2020.00550
更新日期:2020-05-04 00:00:00
abstract::The development of compounds able to modify biological functions largely took advantage of parallel synthesis to generate a broad chemical variance of compounds to be tested for the desired effect(s). The budding yeast Saccharomyces cerevisiae is a model for pharmacological studies since a long time as it represents a...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2017.00170
更新日期:2017-03-30 00:00:00
abstract::Advances in molecular pathology have changed the landscape of oncology. The ability to interrogate tissue samples for oncogene amplification, driver mutations, and other molecular alterations provides clinicians with an enormous level of detail about their patient's cancer. In some cases, this information informs trea...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,评审
doi:10.3389/fphar.2016.00327
更新日期:2016-09-26 00:00:00
abstract::Novel therapeutic strategies for breast cancer are urgently needed due to the sustained development of drug resistance and tumor recurrence. Trivalent arsenic derivative (arsenite, AsIII) has been reported to induce cytotoxicity in breast cancer cells. We recently demonstrated that AsIII plus tetrandrine (Tetra), a Ch...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2020.01087
更新日期:2020-07-17 00:00:00
abstract::Studies on the abuse potential of modafinil, a psychostimulant-like drug used to treat narcolepsy, are still controversial. While some studies claim no potential for abuse, increasing evidence suggests that modafinil induces abuse-related effects, including rapid-onset behavioral sensitization (i.e., a type of sensiti...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00211
更新日期:2019-03-11 00:00:00
abstract::UV irradiation-induced oxidative stress and inflammation contribute to the development of skin diseases. Therefore, targeting oxidative stress and inflammation might contribute to reduce skin diseases. Resolvin D1 (RvD1) is a bioactive metabolite generated during inflammation to actively orchestrate the resolution of ...
journal_title:Frontiers in pharmacology
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doi:10.3389/fphar.2018.01242
更新日期:2018-10-31 00:00:00
abstract::Photodamages caused by UVA radiation induced oxidative injuries are closely related to photoaging and skin cancer. Paeoniflorin (PF), extracted from the root of Paeonia lactiflora, has been reported to be an effective antioxidant. PLIN2, known as adipose differentiation-related protein, has been previously involved in...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2020.00736
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abstract::Objectives: Indigenous Latin American populations have used extracts from Calophyllum brasiliense, a native hardwood, to treat gastrointestinal symptoms for generations. The hexane extract of Calophyllum brasiliense stem bark (HECb) protects against ethanol-mediated gastric ulceration in Swiss-Webster mice. We investi...
journal_title:Frontiers in pharmacology
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doi:10.3389/fphar.2017.00092
更新日期:2017-02-27 00:00:00
abstract::Oxidative insult, inflammation, apoptosis and autophagy play a pivotal role in the etiology of diabetic nephropathy, a global health concern. Ferulic acid, a phytochemical, is reported to protect against varied diseased conditions. However, the ameliorative role and mechanisms of ferulic acid in averting STZ-mediated ...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00027
更新日期:2019-02-05 00:00:00
abstract::Postoperative ileus (POI) and postoperative gastrointestinal tract dysfunction (POGD) are well-known complications affecting patients undergoing intestinal surgery. GI symptoms include nausea, vomiting, pain, abdominal distention, bloating, and constipation. These iatrogenic disorders are associated with extended hosp...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,评审
doi:10.3389/fphar.2020.583422
更新日期:2020-11-24 00:00:00
abstract::Prostate cancer (PCa) is one of the most prevalent male cancers in western world. Radiation therapy (RT) is commonly used to treat PCa patients. However, a certain proportion of patients develop radioresistant PCa cells, which results in metastatic disease. Statins, which inhibit 3-hydroxy-3-methyl glutaryl coenzyme A...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2018.00600
更新日期:2018-06-13 00:00:00
abstract::Purpose: Gender differences exist in the prevalence of asthma and allergic diseases, partially due to the effects of sex hormones on the development of allergic manifestations. Women, compared with men, are more prone to suffer allergic asthma, experience difficulties in controlling asthma symptoms, and show adverse r...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.01094
更新日期:2019-09-24 00:00:00
abstract:Background:5α-reductase type 2 deficiency (5αRD) is an autosomal recessive hereditary disease of the group of 46, XY disorders of sex development (DSD). Objective:To study the growth pattern in Chinese pediatric patients with 5αRD. Subjects:Data were obtained from 141 patients with 5αRD (age: 0-16 years old) who visi...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00173
更新日期:2019-03-15 00:00:00
abstract::Background and Purpose:Drynaria fortunei J. Sm (D. fortunei), known as Gu-Sui-Bu, is used in traditional Chinese medicine to treat common injuries, including bone fractures and bruising. The specific functional mechanisms of the angiogenic and endothelial cell migration properties of D. fortunei are currently unclear....
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2018.00979
更新日期:2018-09-21 00:00:00
abstract::As an oxidative stress sensor, transient receptor potential melastatin 2 (TRPM2) channel is involved in many physiological and pathological processes including warmth sensing, ischemia injury, inflammatory diseases and diabetes. Intracellular calcium is critical for TRPM2 channel activation and the IQ-like motif in th...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2018.00581
更新日期:2018-06-04 00:00:00
abstract::Scoring functions play an important role in structure-based virtual screening. It has been widely accepted that target-specific scoring functions (TSSFs) may achieve better performance compared with universal scoring functions in actual drug research and development processes. A method that can effectively construct T...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2019.00924
更新日期:2019-08-22 00:00:00