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Marine Drugs Dec 2015Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Current approved drugs may only ameliorate symptoms in a restricted number of patients and for a... (Review)
Review
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Current approved drugs may only ameliorate symptoms in a restricted number of patients and for a restricted period of time. Currently, there is a translational research challenge into identifying the new effective drugs and their respective new therapeutic targets in AD and other neurodegenerative disorders. In this review, selected examples of marine-derived compounds in neurodegeneration, specifically in AD field are reported. The emphasis has been done on compounds and their possible relevant biological activities. The proposed drug development paradigm and current hypotheses should be accurately investigated in the future of AD therapy directions although taking into account successful examples of such approach represented by Cytarabine, Trabectedin, Eribulin and Ziconotide. We review a complexity of the translational research for such a development of new therapies for AD. Bryostatin is a prominent candidate for the therapy of AD and other types of dementia in humans.
Topics: Alzheimer Disease; Aquatic Organisms; Bryostatins; Clinical Trials as Topic; Humans; Neuroprotective Agents; Seawater
PubMed: 26712769
DOI: 10.3390/md14010005 -
Cell Chemical Biology Apr 2021Neuroinflammation characterizes multiple neurologic diseases, including primary inflammatory conditions such as multiple sclerosis and classical neurodegenerative...
Neuroinflammation characterizes multiple neurologic diseases, including primary inflammatory conditions such as multiple sclerosis and classical neurodegenerative diseases. Aberrant activation of the innate immune system contributes to disease progression, but drugs modulating innate immunity, particularly within the central nervous system (CNS), are lacking. The CNS-penetrant natural product bryostatin-1 attenuates neuroinflammation by targeting innate myeloid cells. Supplies of natural bryostatin-1 are limited, but a recent scalable good manufacturing practice (GMP) synthesis has enabled access to it and its analogs (bryologs), the latter providing a path to more efficacious, better tolerated, and more accessible agents. Here, we show that multiple synthetically accessible bryologs replicate the anti-inflammatory effects of bryostatin-1 on innate immune cells in vitro, and a lead bryolog attenuates neuroinflammation in vivo, actions mechanistically dependent on protein kinase C (PKC) binding. Our findings identify bryologs as promising drug candidates for targeting innate immunity in neuroinflammation and create a platform for evaluation of synthetic PKC modulators in neuroinflammatory diseases.
Topics: Animals; Bryostatins; Drug Design; Female; Immunity, Innate; Inflammation; Mice; Mice, Inbred C57BL; Molecular Conformation; Pregnancy; Protein Kinase C-delta; Protein Kinase Inhibitors; Stereoisomerism
PubMed: 33472023
DOI: 10.1016/j.chembiol.2020.12.015 -
Marine Drugs May 2022Flexible marine natural products (MNPs), such as eribulin and bryostatin, play an important role in the development of modern marine drugs. However, due to the multiple... (Review)
Review
Flexible marine natural products (MNPs), such as eribulin and bryostatin, play an important role in the development of modern marine drugs. However, due to the multiple chiral centers and geometrical uncertainty of flexible systems, configuration determinations of flexible MNPs face great challenges, which, in turn, have led to obstacles in druggability research. To resolve this issue, the comprehensive use of multiple methods is necessary. Additionally, configuration assignment methods, such as X-ray single-crystal diffraction (crystalline derivatives, crystallization chaperones, and crystalline sponges), NMR-based methods (JBCA and Mosher's method), circular dichroism-based methods (ECCD and ICD), quantum computational chemistry-based methods (NMR calculations, ECD calculations, and VCD calculations), and chemical transformation-based methods should be summarized. This paper reviews the basic principles, characteristics, and applicability of the methods mentioned above as well as application examples to broaden the research and applications of these methods and to provide a reference for the configuration determinations of flexible MNPs.
Topics: Biological Products; Circular Dichroism; Crystallography, X-Ray; Magnetic Resonance Spectroscopy; Molecular Structure
PubMed: 35621984
DOI: 10.3390/md20050333 -
Scientific Reports Oct 2020Fragile X syndrome (FXS), an X-chromosome linked intellectual disability, is the leading monogenetic cause of autism spectrum disorder (ASD), a neurodevelopmental...
Fragile X syndrome (FXS), an X-chromosome linked intellectual disability, is the leading monogenetic cause of autism spectrum disorder (ASD), a neurodevelopmental condition that currently has no specific drug treatment. Building upon the demonstrated therapeutic effects on spatial memory of bryostatin-1, a relatively specific activator of protein kinase C (PKC)ε, (also of PKCα) on impaired synaptic plasticity/maturation and spatial learning and memory in FXS mice, we investigated whether bryostatin-1 might affect the autistic phenotypes and other behaviors, including open field activity, activities of daily living (nesting and marble burying), at the effective therapeutic dose for spatial memory deficits. Further evaluation included other non-spatial learning and memory tasks. Interestingly, a short period of treatment (5 weeks) only produced very limited or no therapeutic effects on the autistic and cognitive phenotypes in the Fmr1 KO2 mice, while a longer treatment (13 weeks) with the same dose of bryostatin-1 effectively rescued the autistic and non-spatial learning deficit cognitive phenotypes. It is possible that longer-term treatment would result in further improvement in these fragile X phenotypes. This effect is clearly different from other treatment strategies tested to date, in that the drug shows little acute effect, but strong long-term effects. It also shows no evidence of tolerance, which has been a problem with other drug classes (mGluR5 antagonists, GABA-A and -B agonists). The results strongly suggest that, at appropriate dosing and therapeutic period, chronic bryostatin-1 may have great therapeutic value for both ASD and FXS.
Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Bryostatins; Cognition Disorders; Fragile X Syndrome; Learning; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Protein Kinase C; Spatial Memory
PubMed: 33093534
DOI: 10.1038/s41598-020-74848-6 -
Journal of Alzheimer's Disease : JAD 2022In pre-clinical studies of Alzheimer's disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and...
BACKGROUND
In pre-clinical studies of Alzheimer's disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles.
OBJECTIVE
Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment.
METHODS
Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores. To mitigate confounding by a chance imbalance of 4.9 SIB baseline scores (Study #203), each patient was used as their own control with differences in 13-week SIB from baseline in single trial and pooled analyses to measure benefit at 13 weeks using general estimating equations (GEE) modeling.
RESULTS
Patients treated with bryostatin pre-specified at Mini-Mental State Examination scores 10-14, without memantine, showed baseline balance, complete safety, and SIB improvements at 13 weeks with multiple imputation analysis: Study #203 = 4.1 SIB points above baseline (p = 0.005), and Study #202 = 4.2 SIB points above baseline (p = 0.016). An increased power (N = 95) "pooled analysis" showed an increased SIB over time and a higher mean SIB at 13 weeks in the bryostatin treatment group (p < 0.001) but not significant (NS) for the placebo patients.
CONCLUSION
Pre-specified exploratory analyses for the individual trials and the pooled trials confirmed significant bryostatin-induced improvement over baseline (treatment p < 0.001, placebo NS).
Topics: Alzheimer Disease; Animals; Bryostatins; Clinical Trials, Phase II as Topic; Cognition; Controlled Clinical Trials as Topic; Double-Blind Method; Humans; Memantine; Mental Status and Dementia Tests; Mice; Treatment Outcome
PubMed: 35124654
DOI: 10.3233/JAD-215545 -
Journal of Virus Eradication Apr 2019Current antiretroviral therapy can suppress HIV replication, increase CD4 count and result in increased lifespan. However, it cannot eradicate the virus due to the...
OBJECTIVES
Current antiretroviral therapy can suppress HIV replication, increase CD4 count and result in increased lifespan. However, it cannot eradicate the virus due to the presence of latent provirus in cellular reservoirs, such as resting CD4+ T cells. Using combination latency-reversing agents to shock the virus out of latency for elimination through immune clearance or viral cytopathic effect is one of the most promising strategies for HIV eradication. Specifically, recent evidence shows that isoform-selective histone deacetylase inhibitors may be more effective than their non-selective counterparts. Therefore, identification and characterisation of new isoform-selective compounds are of prime importance. Here, we sought to determine the ability of two new isoform-targeted hydroxamic acid derivatives to reactivate HIV from latency.
METHODS
We used cell lines and infected primary resting CD4+ T cells. These were treated with these compounds with HIV reactivation measured using fluorescence-activated cell sorting, Western blots and luciferase luminescence. Isoform selectivity and acetylation of the HIV promoter were measured by Western blotting and chromatic immunoprecipitation.
RESULTS AND CONCLUSIONS
The two new hydroxamic acid derivatives, MC2625 and MC1742, potently reactivate HIV from latency. These compounds are isoform-selective histone deacetylate inhibitors that increase the levels of histone acetylation at the HIV promoter. In addition, they synergise effectively with the protein kinase C modulators bryostatin-1 and INDY, an inhibitor of the dual-specificity tyrosine phosphorylation regulated kinase 1A. We conclude that the combinations of new hydroxamic acid derivatives and bryostatin-1 or INDY could be a new tool for HIV reactivation in the cure efforts.
PubMed: 31191911
DOI: No ID Found -
Journal of Alzheimer's Disease : JAD 2017Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of... (Randomized Controlled Trial)
Randomized Controlled Trial
Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus -1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.
Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Animals; Antipsychotic Agents; Brain; Brain-Derived Neurotrophic Factor; Bryostatins; Cognition Disorders; Disks Large Homolog 4 Protein; Double-Blind Method; Female; Humans; Male; Mental Status Schedule; Mice; Mice, Inbred C57BL; Middle Aged; Neuropsychological Tests; Phosphopyruvate Hydratase; Protein Kinase C-epsilon; Psychometrics; Synaptophysin; Time Factors
PubMed: 28482641
DOI: 10.3233/JAD-170161 -
Daru : Journal of Faculty of Pharmacy,... Dec 2021Protein kinase C (PKC) is a promising drug target for various therapeutic areas. Natural products derived from plants, animals, microorganisms, and marine organisms have... (Review)
Review
INTRODUCTION
Protein kinase C (PKC) is a promising drug target for various therapeutic areas. Natural products derived from plants, animals, microorganisms, and marine organisms have been used by humans as medicine from prehistoric times. Recently, several compounds derived from plants have been found to modulate PKC activities through competitive binding with ATP binding site, and other allosteric regions of PKC. As a result fresh race has been started in academia and pharmaceutical companies to develop an effective naturally derived small-molecule inhibitor to target PKC activities. Herein, in this review, we have discussed several natural products and their derivatives, which are reported to have an impact on PKC signaling cascade.
METHODS
All information presented in this review article regarding the regulation of PKC by natural products has been acquired by a systematic search of various electronic databases, including ScienceDirect, Scopus, Google Scholar, Web of science, ResearchGate, and PubMed. The keywords PKC, natural products, curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, protocatechuic acid, tannic acid, PKC modulators from marine organism, bryostatin, staurosporine, midostaurin, sangivamycin, and other relevant key words were explored.
RESULTS
The natural products and their derivatives including curcumin, rottlerin, quercetin, ellagic acid, epigallocatechin-3 gallate, ingenol 3 angelate, resveratrol, bryostatin, staurosporine, and midostaurin play a major role in the management of PKC activity during various disease progression.
CONCLUSION
Based on the comprehensive literature survey, it could be concluded that various natural products can regulate PKC activity during disease progression. However, extensive research is needed to circumvent the challenge of isoform specific regulation of PKC by natural products.
Topics: Allosteric Regulation; Animals; Aquatic Organisms; Biological Products; Disease Progression; Gene Expression Regulation, Enzymologic; Humans; Phytochemicals; Protein Kinase C; Signal Transduction; Small Molecule Libraries
PubMed: 34216003
DOI: 10.1007/s40199-021-00401-z -
Journal of Pharmacy & Bioallied Sciences 2016Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the... (Review)
Review
Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses.
PubMed: 27134458
DOI: 10.4103/0975-7406.171700 -
Current Opinion in Biotechnology Dec 2010Bryostatins are a family of protein kinase C modulators that have potential applications in biomedicine. Found in miniscule quantities in a small marine invertebrate,... (Review)
Review
Bryostatins are a family of protein kinase C modulators that have potential applications in biomedicine. Found in miniscule quantities in a small marine invertebrate, lack of supply has hampered their development. In recent years, bryostatins have been shown to have potent bioactivity in the central nervous system, an uncultivated marine bacterial symbiont has been shown to be the likely natural source of the bryostatins, the bryostatin biosynthetic genes have been identified and characterized, and bryostatin analogues with promising biological activity have been developed and tested. Challenges in the development of bryostatins for biomedical and biotechnological application include the cultivation of the bacterial symbiont and heterologous expression of bryostatin biosynthesis genes. Continued exploration of the biology as well as the symbiotic origin of the bryostatins presents promising opportunities for discovery of additional bryostatins, and new functions for bryostatins.
Topics: Animals; Bacteria; Bryostatins; Invertebrates; Symbiosis
PubMed: 20971628
DOI: 10.1016/j.copbio.2010.09.018