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Haematologica Jun 2020The introduction of anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, or obinutuzumab improved the therapy of B-cell malignancies even though the precise... (Review)
Review
The introduction of anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, or obinutuzumab improved the therapy of B-cell malignancies even though the precise physiological role and regulation of CD20 remains unclear. Furthermore, CD20 expression is highly variable between different B-cell malignancies, patients with the same malignancy, and even between intraclonal subpopulations in an individual patient. Several epigenetic (EZH2, HDAC1/2, HDAC1/4, HDAC6, complex Sin3A-HDAC1) and transcription factors (USF, OCT1/2, PU.1, PiP, ELK1, ETS1, SP1, NFκB, FOXO1, CREM, SMAD2/3) regulating CD20 expression (encoded by ) have been characterized. CD20 is induced in the context of microenvironmental interactions by CXCR4/SDF1 (CXCL12) chemokine signaling and the molecular function of CD20 has been linked to the signaling propensity of B-cell receptor (BCR). CD20 has also been shown to interact with multiple other surface proteins on B cells (such as CD40, MHCII, CD53, CD81, CD82, and CBP). Current efforts to combine anti-CD20 monoclonal antibodies with BCR signaling inhibitors targeting BTK or PI3K (ibrutinib, acalabrutinib, idelalisib, duvelisib) or BH3-mimetics (venetoclax) lead to the necessity to better understand both the mechanisms of regulation and the biological functions of CD20. This is underscored by the observation that CD20 is decreased in response to the "BCR inhibitor" ibrutinib which largely prevents its successful combination with rituximab. Several small molecules (such as histone deacetylase inhibitors, DNA methyl-transferase inhibitors, aurora kinase A/B inhibitors, farnesyltransferase inhibitors, FOXO1 inhibitors, and bryostatin-1) are being tested to upregulate cell-surface CD20 levels and increase the efficacy of anti-CD20 monoclonal antibodies. Herein, we review the current understanding of CD20 function, and the mechanisms of its regulation in normal and malignant B cells, highlighting the therapeutic implications.
Topics: Antibodies, Monoclonal; Antigens, CD20; B-Lymphocytes; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pyrimidines; Rituximab
PubMed: 32482755
DOI: 10.3324/haematol.2019.243543 -
Frontiers in Pharmacology 2023The central nervous system (CNS) is the most complex system in human body, and there is often a lack of effective treatment strategies for the disorders related with... (Review)
Review
The central nervous system (CNS) is the most complex system in human body, and there is often a lack of effective treatment strategies for the disorders related with CNS. Natural compounds with multiple pharmacological activities may offer better options because they have broad cellular targets and potentially produce synergic and integrative effects. Bryostatin-1 is one of such promising compounds, a macrolide separated from marine invertebrates. Bryostatin-1 has been shown to produce various biological activities through binding with protein kinase C (PKC). In this review, we mainly summarize the pharmacological effects of bryostatin-1 in the treatment of multiple neurological diseases in preclinical studies and clinical trials. Bryostatin-1 is shown to have great therapeutic potential for Alzheimer's disease, multiple sclerosis, fragile X syndrome, stroke, traumatic brain injury, and depression. It exhibits significant rescuing effects on the deficits of spatial learning, cognitive function, memory and other neurological functions caused by diseases, producing good neuroprotective effects. The promising neuropharmacological activities of bryostatin-1 suggest that it is a potential candidate for the treatment of related neurological disorders although there are still some issues needed to be addressed before its application in clinic.
PubMed: 37351510
DOI: 10.3389/fphar.2023.1187411 -
Journal of Virology Feb 2022While combination antiretroviral therapy maintains undetectable viremia in people living with HIV (PLWH), a lifelong treatment is necessary to prevent viremic rebound...
While combination antiretroviral therapy maintains undetectable viremia in people living with HIV (PLWH), a lifelong treatment is necessary to prevent viremic rebound after therapy cessation. This rebound seemed mainly caused by long-lived HIV-1 latently infected cells reverting to a viral productive status. Reversing latency and elimination of these cells by the so-called shock-and-kill strategy is one of the main investigated leads to achieve an HIV-1 cure. Small molecules referred to as latency reversal agents (LRAs) proved to efficiently reactivate latent CD4 T cells. However, the LRA impact on infection or HIV-1 production in productively infected macrophages remains elusive. Nontoxic doses of bryostatin-1, JQ1, and romidepsin were investigated in human monocyte-derived macrophages (MDMs). Treatment with bryostatin-1 or romidepsin resulted in a downregulation of CD4 and CCR5 receptors, respectively, accompanied by a reduction of R5 tropic virus infection. HIV-1 replication was mainly regulated by receptor modulation for bryostatin-1, while romidepsin effects rely on upregulation of SAMHD1 activity. LRA stimulation of chronically infected cells did not enhance HIV-1 production or gene expression. Surprisingly, bryostatin-1 caused a major decrease in viral production. This effect was not viral strain specific but appears to occur only in myeloid cells. Bryostatin-1 treatment of infected MDMs led to decreased amounts of capsid and matrix mature proteins with little to no modulation of precursors. Our observations revealed that bryostatin-1-treated myeloid and CD4 T cells respond differently upon HIV-1 infection. Therefore, additional studies are warranted to more fully assess the efficiency of HIV-1 eradicating strategies. HIV-1 persists in a cellular latent form despite therapy that quickly propagates infection upon treatment interruption. Reversing latency would contribute to eradicate these cells, closing the gap to a cure. Macrophages are an acknowledged HIV-1 reservoir during therapy and are suspected to harbor latency establishment . However, the impact of latency reversal agents (LRAs) on HIV-1 infection and viral production in human macrophages is poorly known but nonetheless crucial to probe the safety of this strategy. In this study, we discovered encouraging antireplicative features of distinct LRAs in human macrophages. We also described a new viral production inhibition mechanism by protein kinase C agonists that is specific to myeloid cells. This study provides new insights into HIV-1 propagation restriction potentials by LRAs in human macrophages and underline the importance of assessing latency reversal strategy on all HIV-1-targeted cells.
Topics: Anti-HIV Agents; Bryostatins; CD4 Antigens; CD4-Positive T-Lymphocytes; Depsipeptides; Diterpenes; HIV Core Protein p24; HIV-1; Humans; Macrophages; Receptors, CCR5; SAM Domain and HD Domain-Containing Protein 1; Virus Activation; Virus Latency; Virus Replication
PubMed: 34878918
DOI: 10.1128/JVI.01953-21 -
Cells Mar 2022Ischemia reperfusion injury (IRI) is a form of sterile inflammation whose severity determines short- and long-term graft fates in kidney transplantation. Neutrophils are...
Ischemia reperfusion injury (IRI) is a form of sterile inflammation whose severity determines short- and long-term graft fates in kidney transplantation. Neutrophils are now recognized as a key cell type mediating early graft injury, which activates further innate immune responses and intensifies acquired immunity and alloimmunity. Since the macrolide Bryostatin-1 has been shown to block neutrophil transmigration, we aimed to determine whether these findings could be translated to the field of kidney transplantation. To study the effects of Bryostatin-1 on ischemia-elicited neutrophil transmigration, an in vitro model of hypoxia and normoxia was equipped with human endothelial cells and neutrophils. To translate these findings, a porcine renal autotransplantation model with eight hours of reperfusion was used to study neutrophil infiltration in vivo. Graft-specific treatment using Bryostatin-1 (100 nM) was applied during static cold storage. Bryostatin-1 dose-dependently blocked neutrophil activation and transmigration over ischemically challenged endothelial cell monolayers. When applied to porcine renal autografts, Bryostatin-1 reduced neutrophil graft infiltration, attenuated histological and ultrastructural damage, and improved renal function. Our novel findings demonstrate that Bryostatin-1 is a promising pharmacological candidate for graft-specific treatment in kidney transplantation, as it provides protection by blocking neutrophil infiltration and attenuating functional graft injury.
Topics: Animals; Bryostatins; Endothelial Cells; Ischemia; Kidney Transplantation; Neutrophils; Reperfusion Injury; Swine
PubMed: 35326400
DOI: 10.3390/cells11060948 -
Marine Drugs Jan 2021Marine habitats offer a rich reservoir of new bioactive compounds with great pharmaceutical potential; the variety of these molecules is unique, and its production is... (Review)
Review
Marine habitats offer a rich reservoir of new bioactive compounds with great pharmaceutical potential; the variety of these molecules is unique, and its production is favored by the chemical and physical conditions of the sea. It is known that marine organisms can synthesize bioactive molecules to survive from atypical environmental conditions, such as oxidative stress, photodynamic damage, and extreme temperature. Recent evidence proposed a beneficial role of these compounds for human health. In particular, xanthines, bryostatin, and 11-dehydrosinulariolide displayed encouraging neuroprotective effects in neurodegenerative disorders. This review will focus on the most promising marine drugs' neuroprotective potential for neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. We will describe these marine compounds' potential as adjuvant therapies for neurodegenerative diseases, based on their antioxidant, anti-inflammatory, and anti-apoptotic properties.
Topics: Alzheimer Disease; Animals; Antioxidants; Aquatic Organisms; Humans; Marine Biology; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease
PubMed: 33430021
DOI: 10.3390/md19010024 -
Current Opinion in Infectious Diseases Feb 2014This review highlights recent studies undertaken to further advance the search for successful approaches to eradicate HIV infection. (Review)
Review
PURPOSE OF REVIEW
This review highlights recent studies undertaken to further advance the search for successful approaches to eradicate HIV infection.
RECENT FINDINGS
Small pharmacological compounds such as histone deacetylase inhibitors, inhibitors of bromodomain and extraterminal proteins such as JQ1, and protein kinase C activators such as bryostatin and prostratin are proposed as putative candidates for inducing the expression of latent HIV in a so-called 'shock and kill' or 'kick and kill' strategy for HIV eradication. However, in order to achieve viral clearance, it is thought likely these compounds will have to be administered in concert with strategies that augment clearance of virus-infected cells in patients that have long been aviremic on successful antiretroviral therapy (ART). Several candidate therapies for this purpose are at hand, such as therapeutic HIV vaccines - recently shown to promote robust cytotoxic T cell responses and blunt viral rebound after ART interruption in clinical studies. HIV-infected patients treated during early infection may be ideal candidates for early studies to test these strategies, as early ART has been shown to limit the establishment of an HIV reservoir.
SUMMARY
HIV latency is multifactorial and thus the eradication of HIV infection may require multiple approaches. Translational efforts employing pharmacological methods to target HIV latency should evaluate in parallel the additional potential benefits of invigorating the immune response of HIV-infected individuals, and limiting the size of the reservoir via early ART.
Topics: Anti-HIV Agents; Disease Reservoirs; HIV Infections; Histone Deacetylase Inhibitors; Humans; Virus Latency
PubMed: 24296585
DOI: 10.1097/QCO.0000000000000026 -
BioRxiv : the Preprint Server For... Aug 2023In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and...
In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 prevented the activation of neurotoxic astrocytes while stimulating scavenger pathways, phagocytosis, and secretion of factors that promote oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and functionally related PKC modulators as myelin regenerative and neuroprotective agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.
PubMed: 37693473
DOI: 10.1101/2023.08.28.555084 -
Dose-response : a Publication of... 2019The role of viral infection in developing cancer was determined in the start of 20th century. Until now, 8 different virus-associated cancers have been discovered and... (Review)
Review
The role of viral infection in developing cancer was determined in the start of 20th century. Until now, 8 different virus-associated cancers have been discovered and most of them progressed in immunosuppressed individuals. The aim of the present study is to look into the benefits of natural products in treating virally infected cancers. The study focuses on bioactive compounds derived from natural sources. Numerous pharmaceutical agents have been identified from plants (vincristine, vinblastine, stilbenes, combretastatin, and silymarin), marine organisms (bryostatins, cephalostatin, ecteinascidins, didemnin, and dolastatin), insects (cantharidin, mastoparan, parectadial, and cecropins), and microorganisms (vancomycin, rhizoxin, ansamitocins, mitomycin, and rapamycin). Beside these, various compounds have been observed from fruits and vegetables which can be utilized in anticancer therapy. These include curcumin in turmeric, resveratrol in red grapes, S-allyl cysteine in allium, allicin in garlic, catechins in green tea, and β-carotene in carrots. The present study addresses various types of virally infected cancers, their mechanism of action, and the role of different cell surface molecules elicited during viral binding and entry into the target cell along with the anticancer drugs derived from natural products by targeting screening of bioactive compounds from natural sources.
PubMed: 30670935
DOI: 10.1177/1559325818813227 -
CNS Drug Reviews 2006Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been... (Review)
Review
Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been focused on its action in preventing tumor growth. Emerging evidence suggests, however, that bryostatin-1 exhibits additional important pharmacological activities. In preclinical studies bryostatin-1 has been shown at appropriate doses to have cognitive restorative and antidepressant effects. The underlying pharmacological mechanisms may involve an activation of PKC isozymes, induction of synthesis of proteins required for long-term memory, restoration of stress-evoked inhibition of PKC activity, and reduction of neurotoxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic potential of bryostatin-1 as a CNS drug should be further explored.
Topics: Alzheimer Disease; Animals; Antineoplastic Agents; Bryostatins; Central Nervous System; Depression; Enzyme Activation; Humans; Macrolides; Protein Kinase C
PubMed: 16834754
DOI: 10.1111/j.1527-3458.2006.00001.x -
Journal of Cellular Physiology Feb 2018Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen,...
Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub-nanomolar concentrations (0.03-0.3 nM), bryostatin-1 and its synthetic analog, picolog (0.1-10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation. Bryostatin-1 treatment stabilized human skin equivalents (HSEs), a bioengineered combination of primary human skin cells (keratinocytes and dermal fibroblasts) on an extracellular matrix composed of mainly collagen. Fibroblasts activated by bryostatin-1 protected the structural integrity of HSEs. Bryostatin-1 and picolog prolonged activation of Erk in fibroblasts to promote cell survival. Chronic stress promotes the progression of apoptosis. Dermal fibroblasts constitutively express all components of Fas associated apoptosis, including caspase-8, an initiator enzyme of apoptosis. Prolong bryostatin-1 treatment reduced apoptosis by decreasing caspase-8 and protected dermal fibroblasts. Our data suggest that bryostatin-1 and picolog could be useful in anti-aging skincare, and could have applications in tissue engineering and regenerative medicine.
Topics: Adult; Aged; Apoptosis; Apoptosis Regulatory Proteins; Bryostatins; Cell Line; Cell Survival; Coculture Techniques; Collagen; Culture Media, Serum-Free; Dermis; Dose-Response Relationship, Drug; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblasts; Humans; Keratinocytes; Male; Middle Aged; Rejuvenation; Signal Transduction; Stress, Physiological; Time Factors; Tissue Engineering
PubMed: 28590053
DOI: 10.1002/jcp.26043