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Morpholino-driven blockade of Dkk-1 in osteosarcoma inhibits bone damage and tumour expansion by multiple mechanisms.

BackgroundOsteosarcoma (OS) is the most common primary bone malignancy. Chemotherapy plays an essential role in OS treatment, potentially doubling 5-year event-free survival if tumour necrosis can be stimulated. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) enhances OS survival in part through upregulation of aldehyde-dehydrogenase-1A1 which neutralises reactive oxygen species originating from nutritional stress and chemotherapeutic challenge.MethodsA vivo morpholino (DkkMo) was employed to block the expression of Dkk-1 in OS cells. Cell mitosis, gene expression and bone destruction were meas

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… DkkMo also downregulated S1pr2, encoding sphingosine-1-phosphate-receptor-2, regulator of osteoblast chemotaxis and inverse marker of osteoblast differentiation [ 51 ]. … Meshcheryakova A Mechtcheriakova D Pietschmann P Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential Expert Opin Ther Targets 2017 21 725 37 28524744 10.1080/14728222.2017.1332180 PMC5470107 52. …

Extracellular Vesicles in Bone Metastasis: Key Players in the Tumor Microenvironment and Promising Therapeutic Targets.

Extracellular vesicles (EVs) are lipid membranous vesicles that are released from every type of cell. It has become clear that EVs are involved in a variety of biological phenomena, including cancer progression, and play critical roles in intracellular communication through the horizontal transfer of cellular cargoes such as proteins, DNA fragments, RNAs including mRNA and non-coding RNAs (microRNA, piRNA, and long non-coding RNA) and lipids. The most common cause of death associated with cancer is metastasis. Recent investigations have revealed that EVs are deeply associated with metastasis.

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… It is also known that osteoclasts can autonomously induce osteoblast differentiation and activation by secreting factors such as sphingosine-1-phosphate (S1P) [ 31 , 32 ]. S1P is a metabolic product of sphingolipids, a component of biological membranes, and promotes the migration of target cells. … Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast–osteoblast coupling EMBO J. 2006 25 5840 5851 10.1038/sj.emboj.7601430 17124500 PMC1698879 33. Takeshita S. Fumoto T. Matsuoka K. Park K.A. Aburatani H. Kato S. Ito M. Ikeda K. …

Bone Pain in Cancer Patients: Mechanisms and Current Treatment.

The skeletal system is the third most common site for cancer metastases, surpassed only by the lungs and liver. Many tumors, especially those of the breast, prostate, lungs, and kidneys, have a strong predilection to metastasize to bone, which causes pain, hypercalcemia, pathological skeletal fractures, compression of the spinal cord or other nervous structures, decreased mobility, and increased mortality. Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components. Its treatment should be

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… Following tumor implantation in mice, levels of ceramides decreased, with corresponding increases in sphingosine and sphingosine 1-phosphate (S1P), which is a potent inflammatory metabolite. S1P may play a role in neuropathic pain, as well. …

Высокоэффективная терапия для предотвращения образования лимфоидных органов менингеля после скрининга индекса CXCL13 при раннем множественном склерозе.

Посмертные исследования показали наличие подпийного воспаления с высшими лимфоидными органами (ТЛО) в менингах пациентов с прогрессивным множественным склерозом, играющих важную роль в патофизиологии болезни. Химокин (C-X-C-motif) лиганд 13 (CXCL13) вызывает образование этих лимфоидных органов, тем самым поощряя активность болезни. Заболеваемость при множественном склерозе сократилась благодаря воздействию изменяющейся терапии. Однако, несмотря на успехи в лечении болезней иммуномодуляционными агентами, у нас по-прежнему нет специальных лабораторных биомаркеров, которые могли бы указывать на с

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… In two EAE studies, siponimod, a modulator of the sphingosine-1-phosphate receptors 1,5 that induces lymphopenia and is known to cross the BBB, was able to reduce the formation of the TLO ( Brand et al., 2022 ; Gentile et al., 2016 ). …

Gaucher Disease Types I and III Responded Well to Substrate Reduction Therapy Using Eliglustat.

Gaucher disease (GD) causes the accumulation of glucocerebrosides in various organs, resulting in hepatosplenomegaly, anemia, decreased platelet counts, and bone disorders. Glucosylsphingosine accumulates in the brain and causes central nervous system (CNS) disorders. GD can be classified into types I (without CNS disorders), II, and III. Substrate reduction therapy (SRT) is an oral therapy that improves patients' quality of life; however, its effect on type III GD is unknown. We administered SRT to GD types I and III patients and found it effective. Malignancy is a late complication of GD, bu…

Новинка сывороточных биомаркеров с 7 кортикальными повреждениями Тесла МРТ, лептоминированием и глубоким объемом серого вещества в ранних множественных склерозах.

Повреждения серой материи, атрофии мозга и воспаления менингеев, гипотезы гипотезы имеют отношение к множественным склерозовым (MS) патогенезам, хотя их связь с иммунными изменениями в ранних склерозах не является достаточной. Цель этого исследования состоит в изучении корреляции между концентрацией 112 белков сыворотки и 7 показателями серьезности заболеваний у пациентов с ранним синдромом MS, определяемыми МРТ Тесла. В этот анализ были включены пациенты из СНГ или MS, имеющие МРТ мозга 7 Tesla и образцы крови в течение пяти лет с момента диагностирования MS (n = 57). Корреляционный анализ бы

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… nCDase is an enzyme that hydrolyzes ceramide into sphingosine 45 . … It is expressed ubiquitously, though at high rates in the intestine. nCDase knockout mice demonstrate defective IL-1B processing via the inflammasome/caspase-1 pathway, indicating macrophages use sphingosine to sense immune pathogens in the intestine 46 . …

Curcumol inhibits the malignant progression of prostate cancer and regulates the PDK1/AKT/mTOR pathway by targeting miR‑9.

Curcumol has been reported to exert anti‑tumor activity, but its intrinsic molecular mechanism in prostate cancer remains to be elucidated. The present study aimed to analyze the effect of curcumol on prostate cancer and identify its possible internal regulatory pathway using in vitro cell culture and in vivo tumor model experiments. The cytotoxicity of curcumol was detected using a Cell Counting Kit‑8 assay and it was found that curcumol had no obvious toxicity or side effects on RWPE‑1 cells. Wound healing, Transwell and flow cytometry assays demonstrated that curcumol could affect the activ

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… shown that miR-9 can promote the development of multiple myeloma by regulating the tripartite motif-containing protein 56/NF-κB pathway ( 25 ). miR-9 can promote cell migration and invasion of synovial osteosarcoma by directly targeting E-cadherin ( 26 ). miR-9 can induce angiogenesis by targeting sphingosine … Yao X, Xie L, Zeng Y. miR-9 promotes angiogenesis via targeting on sphingosine-1-phosphate receptor 1. Front Cell Dev Biol. 2020;8:755. doi: 10.3389/fcell.2020.00755. 28. …

Advances in the treatment of systemic lupus erythematosus: Biologicals, small-molecular agents, and cell-depleting therapies coming to the clinic.

Systemic lupus erythematosus (SLE; lupus) remains a particular challenge for the practicing clinician on account of its chronic undulating and unpredictable course, its diverse manifestations, and-until recently-limited treatment options all associated with considerable downsides. However, a major change in this situation is currently taking place. Over the past few years, several new biological therapeutics have been approved for the treatment of SLE (belimumab and anifrolumab) or specifically for its renal organ manifestation (obinutuzumab), along with one new small molecular treatment for t

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… Cenerimod is a small‐molecular antagonist of the sphingosine‐1‐phosphate receptor [ 74 ]. By blocking this receptor, lymphocyte efflux from lymph nodes and lymphocyte trafficking are reduced. … Abbreviations: APRIL, a proliferation‐inducing ligand; BAFF, B‐cell activating factor; BDCA, blood dendritic cell antigen; CD40L, CD40‐ligand; IFN, interferon; IL, interleukin; JAK, Janus kinase; LN, lupus nephritis; pDC, plasmacytoid dendritic cell; S1P1, sphingosine‐1‐phosphate; Tyk‐2, tyrosine kinase …

Cannabidiol-from Plant to Human Body: A Promising Bioactive Molecule with Multi-Target Effects in Cancer.

Cannabis sativa L. is a plant long used for its textile fibers, seed oil, and oleoresin with medicinal and psychoactive properties. It is the main source of phytocannabinoids, with over 100 compounds detected so far. In recent years, a lot of attention has been given to the main phytochemicals present in Cannabis sativa L., namely, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Compared to THC, CBD has non-psychoactive effects, an advantage for clinical applications of anti-tumor benefits. The review is designed to provide an update regarding the multi-target effects of CBD in different

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… Sphingosine-1-phosphate (S1P) is an extracellular ligand for G protein-coupled receptor sphingosine-1-phosphate receptor 1 (S1PR1), and it can activate signal transducers and activators of transcription 3 (STAT-3), a pro-survival pathway implicated in the conversion of inflammation to oncogenesis. … The cellular, extracellular, and tissue concentrations of S1P are regulated by its irreversible degradation by sphingosine-1-phosphate lyase (SGPL1). This key enzyme appears to be an auspicious drug target for the design of immunosuppressants [ 134 ]. …

Endothelial activation and stress index is a reliable predictor for the prevalence and mortality outcomes of stroke.

The endothelial activation and stress index (EASIX) can predict endothelial intricacies as well as survival in distinct clinical circumstances. Accordingly, we hypothesize that EASIX may also serve as a predictor for stroke prevalence and mortality outcomes-all-cause mortality (ACM) and cardiovascular mortality (CVM) due to stroke. To validate our hypothesis, we deployed the National Health and Nutrition Examination Survey data. This cohort study employed 1999-2018 NHANES data. To evaluate EASIX effects on stroke risk, weighted logistic regression models were deployed. Meanwhile, we utilized t

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… Li YJ Shi SX Liu Q Shi FD Gonzales RJ Targeted role for sphingosine-1-phosphate receptor 1 in cerebrovascular integrity and inflammation during acute ischemic stroke Neurosci. Lett. 2020 735 135160 10.1016/j.neulet.2020.135160 32561451 Li, Y. J., Shi, S. X., Liu, Q., Shi, F. D. & Gonzales, R. J. … Targeted role for sphingosine-1-phosphate receptor 1 in cerebrovascular integrity and inflammation during acute ischemic stroke. Neurosci. Lett. 735 , 135160. 10.1016/j.neulet.2020.135160 (2020). 32561451 10.1016/j.neulet.2020.135160 9. …

From Development, Disease, and Decline: A Review of What Defines an Osteoclast Progenitor.

Our understanding of the different developmental origins of osteoclast progenitors and their respective roles during homeostatic bone remodeling at different skeletal sites as well as their roles within bone regeneration and degenerative conditions is evolving. In this narrative review article, we summarize what is known about the developmental origins, anatomical sources, and markers of osteoclast progenitors. We touch on how osteoclast progenitors vary during different disease contexts, including periodontitis, rheumatoid arthritis, and osteoarthritis. In addition, we also characterize osteo

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… Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A Blood 2011 117 5941 5952 10.1182/blood-2010-08-300772 21527515 PMC3112039 98. Thiyagarajan R. Zhang L. Glover O.D. Kwack K.H. Ahmed S. Murray E. …

Don't eat me/eat me signals as a novel strategy in cancer immunotherapy.

Cancer stands as one of the prominent global causes of death, with its incidence burden continuously increasing, leading to a substantial rise in mortality rates. Cancer treatment has seen the development of various strategies, each carrying its drawbacks that can negatively impact the quality of life for cancer patients. The challenge remains significant within the medical field to establish a definitive cancer treatment that minimizes complications and limitations. In the forthcoming years, exploring new strategies to surmount the failures in cancer treatment appears to be an unavoidable pur

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… Receptor-Related Protein 1 Macrophage Antigen 1 Mononuclear Phagocytic System Non-Hodgkin's Lymphoma Natural Killer Cell Phosphatidylcholine Programmed Death 1 Programmed Cell Death Ligand 1 Phosphatidylethanolamine Positron Emission Tomography Phosphatidylinositides Phosphatidylserine Sphingosine … These signals encompass lipid lysophosphatidylcholine (LPC), sphingosine 1-phosphate (S1P), fractalkine CX3CL1, nucleotides ATP, and UTP. Although diverse, all these molecules are linked to the attraction of macrophages or monocytes toward apoptotic cells [ 20 ]. …

Manipulating Macrophage/Microglia Polarization to Treat Glioblastoma or Multiple Sclerosis.

Macrophages and microglia are implicated in several diseases with divergent roles in physiopathology. This discrepancy can be explained by their capacity to endorse different polarization states. Theoretical extremes of these states are called M1 and M2. M1 are pro-inflammatory, microbicidal, and cytotoxic whereas M2 are anti-inflammatory, immunoregulatory cells in favor of tumor progression. In pathological states, these polarizations are dysregulated, thus restoring phenotypes could be an interesting treatment approach against diseases. In this review, we will focus on compounds targeting ma

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… Fingolimod is a modulator of the sphingosine-1-phosphate receptors indicated in the second line for background treatment of very active forms of multiple sclerosis. … Another modulator of the sphingosine-1-phosphate receptors is the fingolimod-derived compound siponimod. Siponimod is selective for S1P1 and S1P5 receptors, and lowers the risk of adverse cardiac events mediated through the S1P3 receptor subtype [ 32 ]. …

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets.

Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 reflects the cell environment; each isoform directs proteins toward different, parallel branches of the quality control cascade. The sum of these branches creates a net shift toward either homeostasis or apoptosis. With an established role in ALP, Bag3 is necessary for cell survival in stress conditions including th

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… The compensatory response of ALP in the absence of the UPS has been circumvented with the knock-out of the Bag3 gene or the inhibition of the autophagy stimulator sphingosine kinase 2 [ 126 , 127 ], suggesting that repression of autophagy is ultimately necessary to ensure consistent cell death. 3.4. … Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition Neoplasia 2022 24 1 11 10.1016/j.neo.2021.11.009 34826777 PMC8626806 127. Fernández Á.F. Sebti S. Wei Y. Zou Z. Shi M. McMillan K.L. He C. Ting T. Liu Y. Chiang W.C. …

Идентификация схемы рецептов на кладрибин в MS: итальянское многоцентральное исследование.

Характеристика рецептов кладрипиновых таблеток в повседневной клинической практике имеет решающее значение для оптимизации лечения множественным склерозом (МС). ЦЕЛИ: Описание эффективности, характеристик безопасности и новых предписаний в отношении корректирующей болезни терапии (ДМТ) после лечения кладрибина. DESIGN: Независимое ретроспективное когортное исследование пациентов проводилось в шести итальянских центрах MS. МЕТОДЫ: Пациенты, у которых был диагностирован повторный синдром MS (RMS) в соответствии с критериями McDonald 2017 года, включавшие кладрипин в период с января 2019 года по

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… To further investigate the impact of previous DMT, we then stratified on type of DMT switching from (1) injectable DMTs (Interferons and Glatiramer acetate); (2) oral DMTs (Teriflunomide and Dimethyl fumarate); (3) monoclonal antibodies (Natalizumab); (4) sphingosine-1-phosphate receptor modulators ( …

Прогнозирующие факторы развития инвалидности в множестве склерозов в реальной жизни: определение FSEP-высокой категории (OFSEP-HD) во Франции.

ЦЕЛЬ: Определение прогнозируемых факторов инвалидности при множественном склерозе (МС), т.е.1) выявлять факторы, определяющие динамику развития инвалидности;2) изучение эффективности методов лечения с целью видоизменения заболеваний (ДМТ);3) объединить детерминанты и ДРТ для создания ориентированных на пациента средств прогнозирования и ()4) проводить экономический анализ. УЧАСТНИКИ: Лица, зарегистрированные во Французской базе данных Французской обсерватории по склерозам в плаке (OFSEP), были включены в эту группу лиц с высоким определением FOSEP, если они имели диагноз MS, ≥15 :: возраст и у

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… These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine and five types of monoclonal antibodies. 8 49 Findings to date A cohort of 2842 individuals has been recruited from July 2018 to September 2020. …

Наркотики и вакцины: систематический обзор литературы.

Калановые лимфомы Т-клеток (КХЛ) представляют собой тип неходгкинской лимфомы, которая обычно связана с кожей. Она имеет различные подтипы, включая микоз-фангоиды (MF), синдром Сезари (SS), первичную анапластическую большую лимфому (PC-ALCL), лимфоматоидный папулос (LyP) и подкожную панникулитную лимфому, аналогичную Т-клеток (SPTCL). Имеется несколько сообщений о случаях, рецидивах или прогрессе в работе ЦТИКС путем использования конкретных лекарственных средств. Мы стремимся определить характерные особенности ТХМЛ, связанные с наркотиками и вакцинами. Систематический поиск проводился с испол

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… Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator, sequesters lymphocytes in lymph nodes and reduces their circulation in the bloodstream [ 86 ]. …

Sexual dimorphism in cancer: molecular mechanisms and precision oncology perspectives.

Sex differences play a crucial role in determining tumor incidence, treatment sensitivity, and prognosis among men and women. However, current clinical cancer treatment strategies fail to account for these differences. Furthermore, the underlying mechanisms of tumor disparities between sexes remain elusive. Sex differences in sex chromosomes, hormone levels, metabolism, and immunity synergistically contribute to tumor-related disparities. As the demand for precision medicine escalates, there is an urgent need to conduct further exploration and research to address the tumor differences between

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… It also promotes drug resistance, particularly through enhanced sphingosine-1-phosphate (S1P) export. Inhibiting tumor development Sex hormones can inhibit tumor initiation and progression, exerting anti-tumor effects. … After stimulating ERα, E2 enhances the export of sphingosine 1-phosphate (S1P) in MCF-7 cells through ABCC1 and ABCG1 and promotes the progression and drug resistance of breast cancer [ 108 ]. …

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Unders

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… Sphingolipid Metabolism Sphingolipids, such as ceramides, sphingosine, dihydroceramide and sphingosine 1 phosphate (SP1), regulate different aspects of cellular homeostasis, such as signalling and signal transduction, cell growth, differentiation and death [ 111 ]. … AC cleaves ceramides and allows for an increment in SP1 levels, which is also supported by an increment in SP1 biosynthesis by the sphingosine kinase enzyme, which is constitutively overexpressed in AML [ 156 , 157 ]. …

Progressive multiple sclerosis: Evaluating current therapies and exploring future treatment strategies.

Progressive forms of multiple sclerosis (MS) include primary progressive MS (PPMS) and secondary progressive MS (SPMS). Unlike relapsing-remitting MS (RRMS), progressive MS is recognized by relentless progression with accumulating disability, rare to no relapses nor new activity on MRIs. Clinically, neurologic worsening in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, a progressive disease course is the dominant factor related to accumulating disability. There is persistent central nervous system (CNS) compa

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… Similarly, in the EXPAND trial [ 21 ], Siponimod demonstrated benefits in reducing progression in SPMS by modulating sphingosine-1-phosphate receptors, reducing neuroinflammation and preserving neurons. … Secondary progressive MS Siponimod, a selective sphingosine-1-phosphate (S1P) receptor modulator, was studied in the EXPAND trial [ 21 ], which included patients with active SPMS. The trial demonstrated a 21 ​% reduction in disability progression compared to placebo. …