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Aptamers and Antisense Oligonucleotides for Diagnosis and Treatment of Hematological Diseases.

Aptamers or chemical antibodies are single-stranded DNA or RNA oligonucleotides that bind proteins and small molecules with high affinity and specificity by recognizing tertiary or quaternary structures as antibodies. Aptamers can be easily produced in vitro through a process known as systemic evolution of ligands by exponential enrichment (SELEX) or a cell-based SELEX procedure. Aptamers and modified aptamers, such as slow, off-rate, modified aptamers (SOMAmers), can bind to target molecules with less polar and more hydrophobic interactions showing slower dissociation rates, higher stability,

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… In addition, BCR-ABL can also increase the expression of several pro-inflammatory cytokines and growth factors [ 67 ]. β-arrestins which are scaffolding proteins for regulation of signal transduction at G protein-coupled receptors are essential for the activation of the Hedgehog/Smoothened and Wingless … Targeted disruption of β-arrestin 2-mediated signaling pathways by aptamer chimeras leads to inhibition of leukemic cell growth PLoS ONE 2014 9 e93441 10.1371/journal.pone.0093441 24736311 PMC3988186 69. Hallek M. …

A Phase II Trial of Selinexor (KPT-330) for Metastatic Triple-Negative Breast Cancer.

Lessons learnedSingle-agent selinexor has limited activity in heavily pretreated patients with metastatic triple-negative breast cancer.Selinexor 60 mg by mouth twice weekly was generally well tolerated with a side-effect profile consistent with previous clinical trials.Future studies of selinexor in this population should focus on combination approaches and a biomarker-driven strategy to identify patients most likely to benefit.BackgroundThis phase II trial evaluated the safety, pharmacodynamics, and efficacy of selinexor (KPT-330), an oral selective inhibitor of nuclear export (SINE) in pati

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… A recent publication demonstrated the ability of selinexor to inhibit proliferative and migratory processes in TNBC cells by restoring arrestin‐related domain‐containing protein 3 [ 14 ]. …

Бенефициарное воздействие Омега-3 Жировых кислот на ожирение и связанные с ним метаболические и хронические воспаленные заболевания.

Известно, что омега-3 полинунасыщенные жирные кислоты (N-3 PUFA) помогают решить проблему воспаления посредством создания антивоспалительных эйкосаноидов и специализированных посредников по восстановлению, включая резолвинов, защитных сооружений и мареинов. Благодаря привязке к рецептору GPR120/FFAR4 они оказывают благоприятное воздействие в результате фосфолипидной реконструкции мембраны, повреждения воспалительных сигнальных молекул, последующего ингибирования NF-ИВ и воспаления активации, а также уменьшения окислительного стресса. Ожирение, хроническое воспалительное заболевание, которое пр

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… This leads to the recruitment of β-arrestin 2 to the plasma membrane. The GPR120/β-arrestin 2 complex is then internalized into the cytoplasmic compartment, where it binds to the TAK1-binding protein (TAB1) and blocks its association with TAK1. …

Chemokines in COPD: From Implication to Therapeutic Use.

: Chronic Obstructive Pulmonary Disease (COPD) represents the 3rd leading cause of death in the world. The underlying pathophysiological mechanisms have been the focus of extensive research in the past. The lung has a complex architecture, where structural cells interact continuously with immune cells that infiltrate into the pulmonary tissue. Both types of cells express chemokines and chemokine receptors, making them sensitive to modifications of concentration gradients. Cigarette smoke exposure and recurrent exacerbations, directly and indirectly, impact the expression of chemokines and chem

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… For example, monomeric and dimeric CXCL12 induce selective signal transduction pathways and differ in β-arrestin recruitment, and only the monomeric type promotes cell migration [ 30 , 43 ]. … Other molecules, called “biased antagonists”, selectively inhibit G protein signalization without preventing β-arrestins recruitment to the receptor. These biased antagonists could offer in the future a solution for patients developing tolerance. …

Chronic stress: a fourth etiology in tumorigenesis?

Chronic stress, driven by persistent psychological, environmental, or physiological factors, is a prolonged heightened state of stress response that disrupts homeostasis. When unmanaged, it will lead to sustained negative emotions such as depression, loneliness, anxiety, and emotional adversity. This persistent emotional distress not only exacerbates mental health disorders but also poses significant risks to physical health. Increasing evidence suggests a strong link between chronic stress, stress-related hormones, and the rising incidence of malignancies. As a result, chronic stress might be

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… It is reported that stress responses through β2-AR cause DNA damage via Gs-PKA, and arrestin beta 1 (ARRB1). Morevoer, chronic activation of the β2-AR by isoproterenol, adrenaline, or noradrenaline, whether in mice or cultured U2OS cells, resulted in reduced p53 levels and accumulated DNA damage. … Mechanistically, isoproterenol triggered murine double minute 2 (MDM2) activation through a beta-arrestin-dependent phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, leading to phosphorylation of MDM2 and subsequent p53 degradation [ 82 ], declaring the critical step of tumor initiation. …

Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer.

The G protein-coupled receptor Smoothened (Smo) is a central signal transducer of the Hedgehog (Hh) pathway which has been linked to diverse forms of tumours. Stimulated by advancements in structural and functional characterisation, the Smo receptor has been recognised as an important therapeutic target in Hh-driven cancers, and several Smo inhibitors have now been approved for cancer therapy. This receptor is also known to be an oncoprotein itself and its gain-of-function variants have been associated with skin, brain, and liver cancers. According to the COSMIC database, oncogenic mutations o

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… Alongside protein–protein interactions with G i , Smo has been found to oligomerise, interact with β-arrestin and recently with G 12 [ 50 , 51 , 52 ], but these aspects of Smo regulation are outside the scope of this review. 3.2.1. … Activity-Dependent Internalization of Smoothened Mediated by ß-Arrestin 2 and GRK2 Science 2004 306 2257 2260 10.1126/science.1104135 15618519 53. Marada S. Navarro G. Truong A. Stewart D.P. Arensdorf A.M. Nachtergaele S. Angelats E. Opferman J.T. Rohatgi R. McCormick P.J. …

Neurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer.

Research on the neurobiology of cancer, which lies at the border of neuroscience and oncology, has elucidated the mechanisms and pathways that enable the nervous system to modulate processes associated with cancer initiation and progression. This research has also shown that several drugs which modulate interactions between the nervous system and the tumor micro- and macroenvironments significantly reduced the progression of cancer in animal models. Encouraging results were also provided by prospective clinical trials investigating the effect of drugs that reduce adrenergic signaling on the co

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… A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1 Nature 2011 477 349 353 10.1038/nature10368 21857681 PMC3628753 16. Hara M.R. Sachs B.D. Caron M.G. Lefkowitz R.J. … Pharmacological blockade of a beta(2)AR-beta-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model Cell Cycle 2013 12 219 224 10.4161/cc.23368 23287463 PMC3575451 17. Sun F. Ding X.P. An S.M. Tang Y.B. Yang X.J. Teng L. Zhang C. Shen Y. Chen H.Z. Zhu L. …

Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning in a zebrafish model of neurofibromatosis.

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder caused by loss-of-function mutations in the gene neurofibromin 1 (NF1). NF1 encodes neurofibromin, a multifunctional tumor-suppressing protein that regulates Ras, cAMP and dopamine signaling. NF1 predisposes patients to a wide range of symptoms, including peripheral nerve tumors, brain tumors and cognitive dysfunction. Despite considerable work using animal models to investigate the role of neurofibromin in behavior, translating research into treatment for NF1-associated cognitive dysfunction has not yet been successful. Here, we provid

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… ACKR3 is an atypical chemokine receptor that can scavenge CXCL12 ligand or signal through recruitment of β-arrestin and kinase assembly ( Gritsina et al., 2023 ; Rajagopal et al., 2010 ; Ray et al., 2012 ). … Conversely, plerixafor treatment inhibits CXCR4 receptor signaling by blocking CXCL12 binding and stimulating β-arrestin recruitment which is predicted to decrease RAS and increase cAMP signaling. …

Ablation of retinal horizontal cells from adult mice leads to rod degeneration and remodeling in the outer retina.

In the brain, including the retina, interneurons show an enormous structural and functional diversity. Retinal horizontal cells represent a class of interneurons that form triad synapses with photoreceptors and ON bipolar cells. At this first retinal synapse, horizontal cells modulate signal transmission from photoreceptors to bipolar cells by feedback and feedforward inhibition. To test how the fully developed retina reacts to the specific loss of horizontal cells, these interneurons were specifically ablated from adult mice using the diphtheria toxin (DT)/DT-receptor system and the connexin5

New insights into the phenomenon of remissions and relapses in autoimmune diseases and the puzzle of benign autoantibodies in healthy individuals.

The onset and relapse of autoimmune diseases (AIDs) are triggered by autoimmune attacks on target tissues. However, symptoms are unlikely to appear if damaged cells are rapidly replaced. Addressing the implications of this premise, the present work examines the balance between target tissue destruction and recovery rates as a key factor in the mechanisms of remissions and relapses in AIDs. The theory, supported by published clinical data, suggests that remissions are improbable in AIDs characterized by slow target tissue recovery. Conversely, a high recovery rate is a necessary (though not suf

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… S-Ag (β arrestin-1) belongs to the family of arrestins which play a role in regulating stem cell characteristics, including self-renewal, in non-malignant stem cells ( 118 ). …

Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function.

Estrogens exert their physiological and pathophysiological effects via cellular receptors, named ERα, ERβ, and G-protein coupled estrogen receptor (GPER). Estrogen-regulated physiology is tightly controlled by factors that regulate estrogen bioavailability and receptor sensitivity, while disruption of these control mechanisms can result in loss of reproductive function, cancer, cardiovascular and neurodegenerative disease, obesity, insulin resistance, endometriosis, and systemic lupus erythematosus. Restoration of estrogen physiology by modulating estrogen bioavailability or receptor activity

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… Oliceridine, a biased agonist for μ-opioid receptor was developed to favor Gαi-inhibition of adenylyl cyclase over Gβγ-dependent activation of β-arrestin ( 133 ) and has been evaluated in clinical trials for chronic pain. … Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther (2010) 335(3):572–9. 10.1124/jpet.110.173005 136. Nakai K, Hung MC, Yamaguchi H. …

RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges.

G protein-coupled receptors (GPCRs) are the major targets of existing drugs for a plethora of human diseases and dominate the pharmaceutical market. However, over 50% of the GPCRs remain undruggable. To pursue a breakthrough and overcome this situation, there is significant clinical research for developing RNA-based drugs specifically targeting GPCRs, but none has been approved so far. RNA therapeutics represent a unique and promising approach to selectively targeting previously undruggable targets, including undruggable GPCRs. However, the development of RNA therapeutics faces significant cha

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… When the receptor is activated, the transmembrane helices rearrangement enables binding of the C terminus of the G protein α subunit and stabilizes the activated GPCR. 21 , 22 The binding of ligands to the GPCR triggers the associated G proteins and/or β-arrestins to stimulate downstream signaling events … the FDA approved oliceridine (Olinvyk), a μ-OR-biased ligand, for restricted use to manage moderate to severe acute pain in adults. 38 Oliceridine acts as a "biased agonist" of the μ-OR and preferentially activates the G-protein-dependent pathway with minimal receptor phosphorylation to trigger the b-arrestin …

Invited Lectures : Overviews Purinergic signalling: past, present and future.

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The Role of the CCR5 Receptor in Neuropathic Pain Modulation: Current Insights and Therapeutic Implications.

Neuropathic pain, a chronic condition arising from injury or dysfunction of the somatosensory nervous system, is characterized by persistent hypersensitivity and spontaneous pain. The chemokine receptor CCR5 (C-C motif chemokine receptor 5) has recently been identified as a critical mediator in neuroinflammation and neuropathic pain signaling pathways. Expressed on immune cells and neurons, CCR5 regulates immune cell recruitment and activation, thereby contributing to neuronal sensitization and maintenance of pain states. This review examines the currently characterized molecular mechanisms th

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… Through this dual role, β-arrestins contribute both to signal desensitization (terminating G protein activation) and to the initiation of noncanonical signaling cascades, including those leading to ERK1/2 activation [ 77 ]. … Structural insight into the binding complex: β-arrestin/CCR5 complex. J. Biomol. Struct. Dyn. 2014;32:866–875. doi: 10.1080/07391102.2013.794373. 77. Petrovic I., Desai S., Isaikina P., Abiko L.A., Spang A., Grzesiek S. …

Current State of Human Gene Therapy: Approved Products and Vectors.

In the realm of gene therapy, a pivotal moment arrived with Paul Berg's groundbreaking identification of the first recombinant DNA in 1972. This achievement set the stage for future breakthroughs. Conditions once considered undefeatable, like melanoma, pancreatic cancer, and a host of other ailments, are now being addressed at their root cause-the genetic level. Presently, the gene therapy landscape stands adorned with 22 approved in vivo and ex vivo products, including IMLYGIC, LUXTURNA, Zolgensma, Spinraza, Patisiran, and many more. In this comprehensive exploration, we delve into a rich ass

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… Arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs) | Non-viral | ARMMs, or arrestin domain-containing protein 1-mediated microvesicles, can transport various macromolecules, such as p53, RNAs, and CRISPR-Cas9/guide RNA, between cells. | The lipid bilayer membrane protects cargo … Arrestin Domain-Containing Protein 1 (ARRDC1)-Mediated Microvesicles (ARMMs) Arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs) are capable of delivering various macromolecules, including the tumor suppressor p53 protein, RNAs, and the genome-editing CRISPR-Cas9/guide RNA complex …

A comprehensive review on pain: Model, target, therapy, and prospect (Review).

Pain serves as both a protective physiological response essential for species survival and a global health issue affecting human well‑being and societal development. The present review systematically summarized and analyzed the research progresses on pain through a multidimensional analytical framework encompassing animal models, molecular targets, therapeutic approaches and future prospects. In animal modeling, neuropathic pain paradigms have evolved from traditional mechanical compression to composite models that combine dynamic displacement and chemical stimulation. Cancer‑induced pain mode

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… Molecularly, opioid receptors signal through inhibitory G protein and β-arrestin pathways. … Further optimization seeks enhanced G protein/β-arrestin signaling bias to maximize therapeutic indices. …

The role of LGR4 in bone metabolism and tumor bone metastasis.

The Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is a member of the G protein-coupled receptor family and plays an important role in bone metabolism and tumor bone metastasis. LGR4 affects bone metabolism by regulating the differentiation and activity of osteoblasts and osteoclasts, and is involved in the balance between bone resorption and bone formation. Deficiency of LGR4 leads to osteoporosis, whereas the up-regulation of LGR4 may help to alleviate the development of traumatic osteoarthritis. Furthermore, in breast cancer and multiple myeloma, LGR4 promotes tumor cell

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… Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics. Cell. (2022) 185:4560–4573.e19. doi: 10.1016/j.cell.2022.10.018 2. Luo CW, Hsueh AJ. Genomic analyses of the evolution of LGR genes. Chang Gung Med J. (2006) 29:2–8. 3. …

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma.

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm

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… This analysis also identified the significant induction of the tumor suppressor protein arrestin domain-containing 3 ( 25 ), induced by selinexor in triple-negative breast cancer cells to block tumor proliferation and migration ( 26 ). …

Not so Fast: Co-Requirements for Sonic Hedgehog Induced Brain Tumorigenesis.

The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a more nuanced role for Shh signaling. We postulate that Shh signaling does not work alone but requires co-activation of other signaling pathways for tumorigenesis and stem cell maintenance. This review will focus on the interplay between the Shh pathway and these pathways to promote tumor growth in brain tu

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… However, this pathway contains a built-in safety mechanism termed desensitization, whereby ligand binding also activates CXCR4 phosphorylation by G-protein coupled receptor kinases (GRKs), promoting its internalization via arrestin and clathrin recruitment and recycling via endosome. …

Exercise-mobilized donor lymphocyte infusions enhanced with cytokine stimulation for the prevention and treatment of leukemic relapse after allogeneic hematopoietic cell transplantation.

Donor lymphocyte infusions (DLI) are a standard therapy following allogeneic hematopoietic cell transplantation (alloHCT) for preventing and treating leukemic relapse in high-risk patients, particularly those with myeloid malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). However, the efficacy of DLI remains suboptimal and is accompanied by a significant risk of life-threatening graft-versus-host disease (GvHD), highlighting the urgent need for strategies that enhance graft-versus-leukemia (GvL) effects while mitigating GvHD.

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… There are two major downstream signaling pathways following β2-AR signaling; the canonical cAMP-PKA pathway, which, phosphorylates various downstream targets, including ion channels, enzymes, and transcription factors, leading to a wide range of cellular responses, and the β-arrestin pathway which initiates … The β1+β2-AR antagonist nadolol is known to inhibit downstream signaling via both pathways, whereas carvedilol (also a β1+β2-AR antagonist) inhibits cAMP-PKA but not β-arrestin signaling. …