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Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.

The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic

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… Lee and colleagues [ 35 ] investigated the effect of an abnormal vascular endothelial growth factor (VEGF)/Sphingosine kinase (SphK) pathway and sphingosine levels on autophagy in human iPS-derived NPC1-deficient neurons. …

Molecular Approaches To Target GPCRs in Cancer Therapy

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… An antibody against S1P was developed at phase I, while a phase III trial is evaluating an inhibitor of sphingosine kinase (phenoxodiol) for various indications (including acute lymphoblastic leukemia, fallopian tube, ovarian and prostate cancers). … The desensitization based approach was instead applied to develop FTY720, a synthetic sphingosine analog that, like sphingosine, is phosphorylated by sphingosine kinase and binds to S1P receptors. …

Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects.

The prognosis of patients with systemic lupus erythematosus has greatly improved since treatment regimens combining corticosteroids and immunosuppressive medications have been widely adopted in therapeutic strategies given to these patients. Immune suppression is evidently efficient but also leads to higher susceptibility to infectious and malignant diseases. Toxic effects and sometimes unexpectedly dramatic complications of current therapies have been progressively reported. Identifying novel molecular targets therefore remains an important issue in the treatment of lupus. The aim of this rev

Polypharmacology: new drugs in 2023-2024.

Polypharmacology is an emerging approach to drug design and development that involves the use of multi-target-directed ligands (MTDLs), agents capable of interacting with multiple biological targets simultaneously. The effective treatment of chronic and multifactorial conditions, driven by the dysregulation of multiple interconnected pathways, such as cancer, autoimmune and metabolic disorders, cardiovascular and neurodegenerative diseases, is one of the most substantial challenges in contemporary pharmacology. 'Traditional' single-target-based treatment frequently shows limited effectiveness,

Воздействие фингозина-1-фосфатных модуляторов рецепторов на ремиелионацию при множественном склерозе: данные экспериментов in vitro, модели животных и исследования человека.

Сфингосин-1-фосфат (S1P) является классом терапевтических агентов, используемых для лечения множественного склероза (MS). В настоящее время Управление по контролю за продуктами питания и лекарствами/Европейское медицинское агентство (FDA/EMA) утвердило четыре модулятора S1P: финголимод, сипонимоз, понизимод и озанимод. Помимо их хорошо зарекомендовавших себя иммунодуляционных свойств, накапливаемые данные свидетельствуют о том, что эти молекулы оказывают прямое воздействие на клетки потомков олигодендроцитов (ОРК) и зрелые олигодендроциты, содействуя ремонту миелина с помощью различных механиз

Potential drug development and therapeutic approaches for clinical intervention in COVID-19.

While the vaccination is now available to many countries and will slowly dissipate to others, effective therapeutics for COVID-19 is still illusive. The SARS-CoV-2 pandemic has posed an unprecedented challenge to researchers, scientists, and clinicians and affected the wellbeing of millions of people worldwide. Since the beginning of the pandemic, a multitude of existing anti-viral, antibiotic, antimalarial, and anticancer drugs have been tested, and some have shown potency in the treatment and management of COVID-19, albeit others failed to leave any positive impact and a few also became cont

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… Opaganib Opaganib (ABC294640) ( Fig. 4 ) is a selective sphingosine kinase-2 (sk2) inhibitor [150] and is being investigated in clinical trials as anti-cancer drugs for advanced cholangiocarcinoma ( NCT03377179 ) and metastatic castration-resistant prostate cancer ( NCT04207255 ). …

Обнаружение сфингосин-1-Фосфатных модуляторов-рецепторов в качестве потенциальных CHI3L1 Inhibitors с помощью лигандского виртуального скрининга и моделирования молекулярной динамики.

Множественный склероз характеризуется воспалением центральной нервной системы, обезвоживанием и нейронным дегенерацией. Нынешние методы диагностики и прогнозирования не являются точными, что требует использования биомаркеров для индивидуализированных методов лечения. Читинас 3-подобный 1 (CHI3L1) стал потенциальным прогнозным маркером с повышенными уровнями, связанными с серьезностью заболеваний и риском рецидива. Несмотря на его терапевтический потенциал, было выявлено несколько ингибиторов CHI3L1. На основе виртуального скрининга на основе лиганда и моделирования молекулярной динамики разреш

Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer.

Abnormal lipid metabolism including synthesis, uptake, modification, degradation and transport has been considered a hallmark of malignant tumors and contributes to the supply of substances and energy for rapid cell growth. Meanwhile, abnormal lipid metabolism is also associated with lipid peroxidation, which plays an important role in a newly discovered type of regulated cell death termed ferroptosis. Long noncoding RNAs (lncRNAs) have been proven to be associated with the occurrence and progression of cancer. Growing evidence indicates that lncRNAs are key regulators of abnormal lipid metabo

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… Sphingosine kinases Sphingosine kinases (SphKs) are key regulatory enzymes that catalyze the formation of sphingosine-1-phosphate (S1P). SphK1 is a cytoplasmic protein. … kinases sphingosine-1-phosphate papillary thyroid carcinoma phospholipase D phosphatidylcholine phospholipase A2 DNA (Cytosin-5-)-methyltransferase 1 lipid hydrogen peroxide glutathione glutaminase2 nicotinamide adenine dinucleotide phosphate glutathione reductase oxidized glutathione Erythroid …

Recent advances in the management of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease presenting highly heterogeneous clinical manifestations and multi-systemic involvement. Patients are susceptible to relapse- and remission, thus making management challenging. Moreover, a considerable number of side effects may occur with conventional therapies; therefore, there is clearly a need for new therapeutic strategies. Since the pathogenesis of SLE is highly complex, it is far from being fully understood. However, greater understanding of the pathways and of the cellular and molecular mediators involved in SLE is being

Role of Stem Cells in the Ovarian Tissue Cryopreservation and Transplantation for Fertility Preservation.

Although the cancer survival rate has increased, cancer treatments, including chemotherapy and radiotherapy, can cause ovarian failure and infertility in women of reproductive age. Preserving fertility throughout cancer treatment is critical for maintaining quality of life. Fertility experts should propose individualized fertility preservation methods based on the patient's marital status, pubertal status, partner status, and the urgency of treatment. Widely practiced fertility preservation methods, including ovarian transposition and embryo and oocyte cryopreservation, are inappropriate for p

Keyword Index for Volume 106

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α2-3-sialylated Гликосфинголипиды при нейроинфламмации, иммунитете и запрограммированной смерти клеток: механистические доказательства и регулирование в зависимости от контекста: всеобъемлющий обзор.

α2-3-sialylated glycosphingolids (α2)3-GSLs) являются основными составляющими нейронных мембран и липидных плотов, где они формируют сепарацию рецепторов, комплекс сигналов и связь с клетками. Однако их биологическое воздействие варьируется в зависимости от молекулярного подтипа, типа клеток, стадии заболевания, концентрации и местной микроокружающей среды. В настоящем обзоре обобщены данные о перепончатых изменениях в α2-3-GSL профили и их связи с нейроинфламмацией, иммунной реакцией, протеостазом и запрограммированной клеточной смертностью через болезнь Паркинсона, болезнь Альцгеймера, болез

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… These lipids have also been linked to complement regulation, T-cell subset balance ( 23 , 26 ), and sphingomyelinase/sphingosine kinase 1 (SMase/SphK1)-related sphingolipid metabolism ( 107 , 108 , 110 ). …

Гипоксичная нейроинфламмация в патогенезе множественного склероза.

Множественный склероз (MS) — аутоиммунная болезнь, которая повреждает миелиновую оболочку вокруг аксонов центральной нервной системы, что приводит к неврологической дисфункции. Хотя первоначальное повреждение вызвано воспалением, гипоксия была зарегистрирована в нескольких районах мозга пациентов MS, однако значение этого для прогнозирования и лечения остается неясным. Нейроинфламмация может вызывать гипоксию, а гипоксия может вызывать и усугублять нейроинфламму, образуя порочный круг. Повреждения MS часто сопровождаются обезвоживанием, которое может восстановить неврологическую функцию. Однак

Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-sp

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… Ceramide is hydrolyzed by ceramidases to sphingosine that is phosphorylated by sphingosine kinases (SphK1 and 2) to produce sphingosine-1-phosphate (S1P; Spiegel and Milstien, 2011 ). … Neurol. 201 : 507 – 514 . 10.1016/j.expneurol.2006.05.007 16797537 PMC1805691 Snider A.J. , Orr Gandy K.A. , and Obeid L.M. 2010 Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation . …

Modulation of angiogenesis with siRNA inhibitors for novel therapeutics.

Cancer and many other serious diseases are characterized by the uncontrolled growth of new blood vessels. Recently, RNA interference (RNAi) has reinvigorated the therapeutic prospects for inhibiting gene expression and promises many advantages over binding inhibitors, including high specificity, which is essential for targeted therapeutics. This article describes the latest developments using small-interfering RNA (siRNA) inhibitors to downregulate various angiogenic and tumor-associated factors, both in cell-culture assays and in animal disease models. The majority of research efforts are cur

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… VEGF stimulation of sphingosine kinase (SPK) affects not only endothelial cell signaling but also tumor cells expressing VEGF receptors [42] . … Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol. Cell. Biol. 2002;22:7758–7768. doi: 10.1128/MCB.22.22.7758-7768.2002. 43. Baldanzi G. …

Role of autophagy in cholangiocarcinoma: Pathophysiology and implications for therapy.

Cholangiocarcinoma (CCA) is a malignant tumour of the biliary system that originates from the neoplastic transformation of cholangiocytes. CCA is characterized by late diagnosis and poor outcome, with surgery considered as the last option for management. Autophagy is a physiological lysosomal degradation process, essential for cellular homeostasis and ubiquitous in all eukaryotic cells. Several studies have reported a potential involvement of autophagy in cancer, but it remains unclear whether activation of this process represents a survival mechanism of cancer cells. In the present review, we

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… ABC294640 is a novel sphingosine kinase 2 (Sphk2) inhibitor, a lipid kinase with oncogenic role in cancer. Pharmacological inhibition of Sphk2 by ABC294640 inhibits CCA cell growth and induced caspase-dependent apoptosis. … kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells Oncotarget 2016 7 20080 20092 26956050 10.18632/oncotarget.7914 PMC4991440 33 Fan Z Yu H Cui N Kong X Liu X Chang Y Wu Y Sun L Wang G ABT737 enhances cholangiocarcinoma sensitivity …

The Complosome: An Emerging Intracellular Complement Network in Cancer Development and Therapy.

The complement system is traditionally recognized as a major effector of innate immunity, essential for pathogen clearance, inflammation and the maintenance of tissue homeostasis. In recent years, however, its role in cancer has been substantially redefined. Beyond its canonical extracellular activity, complement has emerged as a multifaceted regulator of tumor biology, acting not only within the tumor microenvironment but also intracellularly through the recently described intracellular complement system (complosome). While extracellular complement primarily shapes immune responses and the tu

Сфингосин 1-phosphate рецептор 1 Модераторы оказывают нейрозащитное воздействие на нарушения центральной нервной системы.

Фингозин 1-phosphate (S1P) Пути подачи сигналов имеют важные и разнообразные функции. Рецепторы S1P (S1PR) участвуют в регулировании торговли лимфоцитами, сердечно-церебральной функции, сосудистой проницаемости и бронхиолярного тона и были признаны в качестве терапевтических целей для различных заболеваний. Ряд лекарственных средств, связанных с траекторией подачи сигналов S1P, был утвержден для клинического использования при лечении множественных склерозов, и многие аналогичные препараты в настоящее время также проходят испытания в ходе клинических испытаний на различных этапах. Как представл

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… Fingolimod is a prodrug that requires phosphorylation by intracellular sphingosine kinases to gain affinity for S1PRs ( Brinkmann et al., 2002 ). …

Communication in the Cancer Microenvironment as a Target for Therapeutic Interventions.

The tumor microenvironment (TME) is a complex system composed of multiple cells, such as non-cancerous fibroblasts, adipocytes, immune and vascular cells, as well as signal molecules and mediators. Tumor cells recruit and reprogram other cells to produce factors that maintain tumor growth. Communication between cancerous and surrounding cells is a two-way process and engages a diverse range of mechanisms that, in consequence, can lead to rapid proliferation, metastasis, and drug resistance, or can serve as a tumors-suppressor, e.g., through tumor-immune cell interaction. Cross-talk within the

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… High levels of extracellular S1P induced by enhanced expression of a regulatory sphingosine kinase increase migration and efficiency of vessel formation upon combined cultivation of tumor cells and lymphatic endothelial cells [ 137 ]. 3. … Despite intensive research on sphingolipid-signaling, there are only a few inhibitors of the sphingosine kinase (SK). …

Effects of the polyunsaturated fatty acids, EPA and DHA, on hematological malignancies: a systematic review.

Omega-3 polyunsaturated fatty acids (PUFAs) have well established anti-cancer properties. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among this biologically active family of macromolecules for which various anti-cancer effects have been explained. These PUFAs have a high safety profile and can induce apoptosis and inhibit growth of cancer cells both in vitro and in vivo, following a partially selective manner. They also increase the efficacy of chemotherapeutic agents by increasing the sensitivity of different cell lines to specific anti-neoplastic drugs. Various mechanisms