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Mechanism of Action of Hedyotis diffusa Extract in a Rat Model of Acute Lung Injury Based on Transcriptomic Analysis.

OBJECTIVE: This study established a rat model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) to evaluate pathological damage, c … Immunohistochemistry evaluated the expression of eight hub targets, including endothelin-1 (EDN1), sphingosine kinase 1 (SPHK1), intercellular adhesion molecule 1 (ICAM1), interleukin-17 (IL-17), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2), NF-κB p65 (encoded by RELA), WT1-associated protein (WTAP), and myeloperoxidase (MPO). UHPLC-Q-Orbitrap HRMS character …

FTY720 induces apoptosis of chronic myelogenous leukemia cells via dual activation of BIM and BID and overcomes various types of resistance to tyrosine kinase inhibitors.

PP2A activator FTY720 has been shown to possess the anti-leukemic activity for chronic myelogenous leukemia (CML), however, the cell killing mechanism underlying its anti-leukemic activity has remained to be verified. We investigated the precise mechanisms underlying the apoptosis induction by FTY720, especially focusing on the roles of BH3-only proteins, and the therapeutic potency of FTY720 for CML. Enforced expression of either BCL2 or the dominant-negative protein of FADD (FADD.DN) partly protected CML cells from apoptosis by FTY720, indicating the involvement of both cell extrinsic and in

Cyclic strain alters the expression and release of angiogenic factors by human tendon cells.

Angiogenesis is associated with the tissue changes underlying chronic overuse tendinopathy. We hypothesized that repetitive, cyclic loading of human tendon cells would lead to increased expression and activity of angiogenic factors. We subjected isolated human tendon cells to overuse tensile loading using an in vitro model (1 Hz, 10% equibiaxial strain). We found that mechanically stimulated human tendon cells released factors that promoted in vitro proliferation and tube formation by human umbilical vein endothelial cells (HUVEC). In response to cyclic strain, there was a transient increase i

Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation.

H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2

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… In turn, when sphingosine is phosphorylated by sphingosine kinases (SphK), S1P is produced, which has anti-apoptotic and proliferation-promoting effects [ 47 , 48 , 49 , 50 ]. … Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells Mol. Cancer Res. 2009 7 393 401 10.1158/1541-7786.MCR-08-0156 19240180 48. Greenspon J. Li R. Xiao L. Rao J.N. Marasa B.S. Strauch E.D. Wang J.-Y. Turner D.J. …

Спасение гиппокампальной синаптической пластичности и эффективности памяти Финголимода (FTY720) в модели APP/PS1 болезни Альцгеймера сопровождается коррекцией метаболизма финголипидов, полиаминов и фосфолипидного насыщенного состава.

Ранее, наши метаболомические, транскриптомные и геномные исследования характеризовали путь церамида/шфингомилена как терапевтическую цель в болезни Альцгеймера, и мы показали, что FTY720, фингозин-1-фосфахатный рецептор, утвержденный для лечения множественных склерозов, восстанавливает синаптическая пластичность и память в мышах APP/PS1. Для дальнейшего изучения того, как FTY720 спасает патологию, мы провели метаболический анализ мозга, плазмы и печени обученных APP/PS1 и диких мышей. APP/PS1 мыши продемонстрировали локальные нарушения мозга в полиаминах, фосфолипидах и сфинголипидах. Большинс

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… This reduction might be caused by the downregulation of sphingosine kinase (SphK) 1 and 2 30 , 33 , and the upregulation of sphingosine-1-phosphate lyase (S1PL) 32 , 33 . … Both the increase of sphingosine kinase activity and the decrease of sphingomyelinase activity are well-documented effects of FTY720 44 , 54 . …

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy.

Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxid

Repurposing anticancer drugs for the management of COVID-19.

Since its outbreak in the last December, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread worldwide at a pandemic proportion and thus is regarded as a global public health emergency. The existing therapeutic options for COVID-19 beyond the intensive supportive care are limited, with an undefined or modest efficacy reported so far. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options. With the emergence of COVID-19, drug repurposing has been la

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… Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells. PloS One. 2014;9(7) doi: 10.1371/journal.pone.0102314. 40. Dang W., Xu L., Ma B., et al. … Sphingosine kinase 2 in autoimmune/inflammatory disease and the development of sphingosine kinase 2 inhibitors. Trends Pharmacol Sci. 2017;38(7):581-591. doi: 10.1016/j.tips.2017.04.003. 144. Qian Z., Dominguez S.R., Holmes K.V. …

Перевозка и сдерживание движения sphingosine-1-phosphate Экспортеры SPNS2.

Sphingosine-1-phosphate (S1P) — сигнал лизолипида, имеющий решающее значение для развития сердца, иммунитета и слуха. Соответственно, мутации в переносчике S1P SPNS2 связаны с уменьшением числа белых клеток и нарушениями слуха. СПНС2 также экспортирует S1P-mimicking FTY720-P (Финголимод) и, таким образом, является центральным элементом фармакокинетики этого препарата при лечении множественного склероза. Здесь мы используем комбинацию крио-электронной микроскопии, иммунофлюоресценции, связывания in vitro и в vivo S1P-оценки экспорта, а также молекулярное моделирование динамики для исследования

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… Sphingosine-1-phosphate is generated from sphingosine in the cytoplasm by the sphingosine kinases 8 . The signaling lipid is subsequently exported to the extracellular space by several plasma membrane export proteins, including Spinster Homolog 2 (SPNS2), MFSD2B, ABCA1, ABCA7, ABCC1, and ABCG2 9 . … Media was collected from CHO cells overexpressing sphingosine kinase 1 (SphK1) and SPNS2, or its mutants, after incubation with 1 μM sphingosine. …

Dysregulation of sphingolipid metabolism in pain.

Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transducti

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… Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience 166, 132–144. 10.1016/j.neuroscience.2009.12.020 Ndengele M. M., Cuzzocrea S., Masini E., Vinci M. C., Esposito E., Muscoli C., et al. (2009). … Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J. Exp. Med. 201, 49–54. 10.1084/jem.20040559 Podbielska M., Ariga T., Pokryszko-Dragan A. (2022). …

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy.

Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) ne

Сверхклеточная везикла в качестве главных регуляторов иммунной модуляции в Мультимиломе.

Множественная миелома (ММ) — генетически и клинически разнородная плазменная порча клеток, характеризующаяся клональным расширением различных клеток В внутри костного мозга (БМ). Пациенты начинают с моноклональной гаммопатии неизвестного значения (MMUS) и переходят на промежуточную стадию под названием Smouldering multieloma (SMM), характеризующуюся несколькими генетическими изменениями, представляющими геномную основу злокачественного клона. Проходы на контрольно-пропускных пунктах иммунной системы играют ключевую роль в формировании иммуноподавляющей ниши BM, что способствует дисфункции Т-кл

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… For instance, Hagiwara et al. [ 119 ] identified sphingosine kinase 1 (SPHK1) as an EV-enriched factor implicated in immunosuppression. … Kinase 1 STAT3 Signal Transducer and Activator of Transcription 3 TCRs T-cell receptors TGF-β Tumour Growth Factor- beta TIGIT T-cell immunoreceptor with Ig and ITIM domains TIM-3 T-cell immunoglobulin and mucin domain-containing three TNF-α Tumour Necrosis Factor-α Tregs Regulatory T-cells ULBP1-6 …

Therapeutic potential of Fingolimod in triple negative breast cancer preclinical models.

Surgery followed by a chemotherapy agent is the first-line treatment for breast cancer patients. Nevertheless, new targets are required for women with triple-negative breast cancer (TNBC) in order to improve the treatment of this aggressive cancer subtype. Multiple pro-inflammatory molecules including lipid-based substances such as sphingosine-1-phosphate (S1P) promote cancer progression. In this preclinical study, we aim to investigate the efficacy of Fingolimod, an inhibitor of S1P / S1P receptors axis, already approved as an immunomodulator in multiple sclerosis. The impact of Fingolimod wa

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… Another component of the S1P signaling, Sphingosine Kinase 1, is also upregulated in breast cancer tissue samples [10] . These elements therefore suggest a potential prognosis and therapeutic value of the S1P pathway in breast cancer. … FTY720 (Fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1. Cancer Res. 2010;70:8651–8661. doi: 10.1158/0008-5472.CAN-10-1388. 18. Gstalder C., Ader I., Cuvillier O. …

Molecular interactions of miR-338 during tumor progression and metastasis.

BackgroundCancer, as one of the main causes of human deaths, is currently a significant global health challenge. Since the majority of cancer-related deaths are associated with late diagnosis, it is necessary to develop minimally invasive early detection markers to manage and reduce mortality rates. MicroRNAs (miRNAs), as highly conserved non-coding RNAs, target the specific mRNAs which are involved in regulation of various fundamental cellular processes such as cell proliferation, death, and signaling pathways. MiRNAs can also be regulated by long non-coding RNAs (lncRNAs) and circular RNAs (

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… Sphingosine kinase 2 (SphK2) is involved in formation of sphingosine-1-phosphate (SPP) as a lipid mediator in cellular functions. It also participates in transcriptional regulation by HDAC1 and HDAC2 suppression and histone acetylation [ 206 ]. … Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood. 2014;124(12):1915–1925. doi: 10.1182/blood-2014-03-559385. 206. Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, et al. …

Сравнительная эффективность и терпимость Sphingosine-1-Phosphate Рецептор-модуляторы в пациентах с множественным склерозом: сетевая мета-анализа случайных контролируемых испытаний.

ИСТОРИЯ ВОПРОСА: Sphingosine-1-phosphate Рецепторные модуляторы (S1PRM) используются для лечения повторного множественных склерозов (MS). Каждый наркотик имеет разный S1PR-subtype избирательный подход. Они нацелены на G-протеиновые рецепторы, сцепленные с S1P, и оказывают значительное иммунодуляционное воздействие, например предотвращая появление новых CNS-повреждений и возобновление ранее существовавших повреждений. ЦЕЛЬ: Настоящее исследование направлено на изучение эффективности и безопасности S1PRM при обработке MS. МЕТОДЫ: В августе был проведен систематический поиск литературы в базах да

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… Sphingosine‐1‐phosphate (S1P) is a molecule derived from sphingosine through enzymes called sphingosine kinase 1 and 2 (Sk1, Sk2). It is a key cell‐signaling molecule, which plays a crucial role in the immune cell movement. …

Oxidized Lipids in Persistent Pain States.

Chemotherapy, nerve injuries, or diseases like multiple sclerosis can cause pathophysiological processes of persistent and neuropathic pain. Thereby, the activation threshold of ion channels is reduced in peripheral sensory neurons to normally noxious stimuli like heat, cold, acid, or mechanical due to sensitization processes. This leads to enhanced neuronal activity, which can result in mechanical allodynia, cold allodynia, thermal hyperalgesia, spontaneous pain, and may initiate persistent and neuropathic pain. The treatment options for persistent and neuropathic pain patients are limited; f

European experience of cladribine tablets in elderly patients with multiple sclerosis: Could it be the last treatment?

BACKGROUND: Recent studies support the need for early and intensive disease-modifying treatment (DMT) for patients with multiple sclerosis (PWMS). Abrupt DMT withdrawal may risk disease reactivation. Recent studies showed that MS disease activity was not rare after DMT withdrawal for PWMS aged >45/55 y. Immune reconstitution therapy (IRT) with cladribine tablets (CladT), may be an option for older PWMS who wish to stop DMT. OBJECTIVE: We retrospectively analysed PWMS aged >45 y who initiated CladT in 6 MS centers in Europe. RESULTS: One hundred and twenty nine PWMS (95 women/34 men, mean age

Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies.

Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, an

New Directions in the Study and Treatment of Metastatic Cancer.

Traditional cancer therapy has relied on a strictly cytotoxic approach that views non-metastatic and metastatic tumor cells as identical in terms of molecular biology and sensitivity to therapeutic intervention. Mounting evidence suggests that, in fact, non-metastatic and metastatic tumor cells differ in key characteristics that could explain the capacity of the metastatic cells to not only escape the primary organ but also to survive while in the circulation and to colonize a distant organ. Here, we lay out a framework for a new multi-pronged therapeutic approach. This approach involves modif

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… Sphingosine is released from ceramide through the actions of ceramidase and then is phosphorylated by sphingosine kinase to generate S1P. …

Adiponectin signalling in bone homeostasis, with age and in disease.

Adiponectin is the most abundant circulating adipokine and is primarily involved in glucose metabolism and insulin resistance. Within the bone, osteoblasts and osteoclasts express the adiponectin receptors, however, there are conflicting reports on the effects of adiponectin on bone formation and turnover. Many studies have shown a pro-osteogenic role for adiponectin in in vivo murine models and in vitro: with increased osteoblast differentiation and activity, alongside lower levels of osteoclastogenesis. However, human studies often demonstrate an inverse relationship between adiponectin conc

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… kinases 1 and 2, and then trafficked out of the cell via sphingosine transporters where it interacts with S1P receptors to mediate its effects. 47 Elevated levels of circulating S1P are observed in adiponectin-overexpressing transgenic mice. 17 However, very little is known about the possible consequence … Both osteoblast and osteoclast precursors express S1P receptors (S1PR1, S1PR2). 48 – 50 In addition, BMSC migrate towards S1P in vitro. 48 However, osteoclast precursors chemorepel from S1P, either through S1PR1/2 50 or S1PR2/3. 51 In addition, sphingosine kinase 1 activity was upregulated in osteoclasts …

Sphingolipid metabolism and hematologic disorders: current understanding and future directions.

Sphingolipids are not only key structural components of cell membranes but also serve as important signaling molecules, and their metabolic homeostasis is essential for the maintenance of cellular functions. In recent years, with the advancement of technologies such as metabolomics, studies have revealed that sphingolipid metabolic abnormalities are extensively involved in the occurrence and development of various hematological disorders, including immune thrombocytopenia, myeloproliferative neoplasms, graft-versus-host disease, hereditary hematological diseases, and hematologic malignancies.

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… Furthermore, resveratrol exerts antiproliferative and pro-apoptotic effects in FLT3-ITD-positive AML cells by downregulating the expression of sphingosine kinase-1 (SK-1) and glucosylceramide synthase (GCS) ( Ersöz and Adan, 2022 ). … In AML, studies have revealed that inhibiting sphingosine kinase induces the accumulation of ceramide platforms, which in turn activates the integrated stress response mediated by protein kinase R. …