Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus

The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains in hospital and community settings presents a great challenge to public health and illustrates the urgency of discovering new antibiotics. Marinopyrrole A is a member of a structurally novel class of compounds identified from a species of marine-derived streptomycetes with evidence of antistaphylococcal activity. We show that marinopyrrole A has potent concentration-dependent bactericidal activity against clinically relevant hospital- and community-acquired MRSA strains, a prolonged postantibiotic effect superior to that of the current first-line agents vancomycin and linezolid, and a favorable resistance profile. Marinopyrrole A showed limited toxicity to mammalian cell lines (at >20× MIC). However, its antibiotic activity against MRSA was effectively neutralized by 20% human serum. A variety of marinopyrrole analogs were isolated from culture or synthetically produced to try to overcome the inhibitory effect of serum. While many of these compounds retained potent bactericidal effect against MRSA, their activities were also inhibited by serum. Marinopyrrole A has significant affinity for plastic and may therefore have potential as a potent anti-MRSA agent in cutaneous, intracatheter, or antibiotic-lock applications.     

The identification and characterization of the marine natural product scytonemin as a novel antiproliferative pharmacophore

Marine natural products provide a rich source of chemical diversity that can be used to design and develop new, potentially useful therapeutic agents. We report here that scytonemin, a pigment isolated from cyanobacteria, is the first described small molecule inhibitor of human polo-like kinase, a serine/threonine kinase that plays an integral role in regulating the G(2)/M transition in the cell cycle. Scytonemin inhibited polo-like kinase 1 activity in a concentration-dependent manner with an IC(50) of 2 microM against the recombinant enzyme. Biochemical analysis showed that scytonemin reduced GST-polo-like kinase 1 activity in a time-independent fashion, suggesting reversibility, and with a mixed-competition mechanism with respect to ATP. Although scytonemin was less potent against protein kinase A and Tie2, a tyrosine kinase, it did inhibit other cell cycle-regulatory kinases like Myt1, checkpoint kinase 1, cyclin-dependent kinase 1/cyclin B, and protein kinase Cbeta2 with IC(50) values similar to that seen for polo-like kinase 1. Consistent with these effects, scytonemin effectively attenuated, without chemical toxicity, the growth factor- or mitogen-induced proliferation of three cell types commonly implicated in inflammatory hyperproliferation. Similarly, scytonemin (up to 10 microM) was not cytotoxic to nonproliferating endotoxin-stimulated human monocytes. In addition, Jurkat T cells treated with scytonemin were induced to undergo apoptosis in a non-cell cycle-dependent manner consistent with its activities on multiple kinases. Here we propose that scytonemin's dimeric structure, unique among natural products, may be a valuable template for the development of more potent and selective kinase inhibitors used for the treatment of hyperproliferative disorders.     

Synthetic glucocorticoid therapy--recent progress

Synthetic glucocorticoids are administered systematically in the treatment of a large number of nonendocrine and endocrine diseases. Efforts have been made to reduce the side effects and to increase the pharmacological effects of these glucocorticoids. To avoid complications compartmental administration(topical, inhaled, suppository, ophthalmic, intra-articular) and alternate-day administration of intermediate acting glucocorticoids are recommended. Careful monitoring of the patients under therapy and gradual reduction of glucocorticoids should be performed to avoid adrenal insufficiency or reactivation of the disease. The understanding of molecular mechanisms of glucocorticoid actions may lead to the development of novel glucocorticoids, which are more active in anti-inflammatory actions than endocrine and metabolic actions(adverse effects of glucocorticoids).     

Synthetic efforts on the road to marine natural products bearing 4-O-2,3,4,6-tetrasubstituted THPs: an update

Scientific literature is inundated with secondary metabolites from marine sources. In this ocean of natural products, the presence of recurring patterns has traditionally led scientists to unravel the biosynthetic mechanisms that naturally yield these products, as well as to imitate Nature to prepare them in the laboratory, especially when promising bioactivities and stimulating molecular architectures are involucrate. For instance, natural products containing multisubstituted oxygenated rings and macrocyclic lactones are recurrently selected as targets for developing total syntheses. Thus, in the last decades a noteworthy number of synthetic works regarding miyakolide, madeirolide A and representative compounds of polycavernosides, lasonolides and clavosolides have come to fruition. Up to now, these families of macrolides are the only marine natural products bearing a tetrasubstituted tetrahydropyran ring with carbon substituents at positions 2, 3 and 6, as well as an oxygen at position 4. Their splendid structures have received the attention of the synthetic community, up to the point of starring in dozens of articles, and even some reviews. This work covers all the synthetic studies towards miyakolide and madeirolide A, as well as the synthetic efforts performed after the previous specialised reviews about lasonolide A, polycavernoside A and clavosolides, published in 2006, 2007 and 2016, respectively. In total, this review summarises 22 articles in which these marine natural products with 4-O-2,3,4,6-tetrasubstituted tetrahydropyrans have the leading role.

A review covering the synthetic efforts directed to miyakolide, polycavernoside A, lasonolide A, clavosolide A and madeirolide A. They belong to the unique families of marine macrolides bearing 4-O-2,3,4,6 tetrasubstituted THPs.     

Fuscoside: an anti-inflammatory marine natural product which selectively inhibits 5-lipoxygenase. Part II: Biochemical studies in the human neutrophil.

Fuscoside (FSD) is a potent and long-lasting anti-inflammatory drug that selectively inhibits leukotriene production in murine models of inflammation. In the present study, the effects of FSD on the lipoxygenase pathways in human polymorphonuclear leukocytes are explored in order to better understand the mechanism of action of this novel drug. In adherent and suspended polymorphonuclear leukocytes, FSD irreversibly inhibits leukotriene B4 (LTB4) synthesis (IC50 = 10 microM) and the release of 14C-labeled LTB4 from neutrophils prelabeled with [14C]arachidonic acid. Unlike the reversible 5-lipoxygenase inhibitor L-651,896, FSD has no observable effect on LTB4 biosynthesis in whole blood, but does express activity as blood is successively diluted. In 10,000 x g supernatants of human platelets and polymorphonuclear leukocytes, FSD does not inhibit platelet 12-lipoxygenase, but is extremely effective in inhibiting the metabolism of arachidonic acid and 5-hydroperoxyeicosatetraenoic acid to LTB4 via neutrophil 5-lipoxygenase. FSD has no effect on the conversion of leukotriene A4 to LTB4 in this system. Interestingly, concurrent with FSD inhibition of leukotriene synthesis is a concentration-dependent increase in 5-hydroxyeicosatetraenoic acid, suggesting that FSD may selectively inhibit the leukotriene A4 synthase activity associated with human 5-lipoxygenase. FSD is therefore representative of a new class of nonantioxidant 5-lipoxygenase inhibitors that may be effective local therapeutic agents in the management of diseases such as psoriasis, arthritis and inflammatory bowel and lung diseases.     

A new integrated program for natural product development and the value of an ethnomedical approach

There is a need for less expensive alternative therapies, especially in the treatment of chronic illnesses. This presentation addresses the issues inherent in the use of natural products in a drug-discovery or development program and reviews a model program developed by the U.S. National Institutes of Health (NIH) and administered by the Fogarty International Center at the NIH. Eighty percent (80%) of the world's population relies on medicinal plants for their primary health care. The World Health Organization has been promoting traditional medicine as a source of less expensive, comprehensive medical care, especially in developing countries. Natural products have also been successful in drug development. Over 50% of the best-selling pharmaceuticals in use today are derived from natural products. In a natural-product drug development program, it is the diversity of the natural products that is especially interesting. Thanks to technologic advances, now is a good time to be looking for new drugs in the natural-product arena. But there are major hurdles to overcome in a natural-products development program, namely, time-to-lead, supply, and ownership. Time-to-lead is complex because most natural products are mixtures or crude extracts. It can be very difficult to isolate the active principles and elucidate their structures. The difficulty of obtaining sufficient supply is often given as a reason for not becoming involved in natural-product drug development or discovery. This presentation details some ways these seeming hurdles can be overcome. The concept of ownership has changed dramatically in recent years. Until recently, genetic resources were considered to belong to no one and to therefore be the heritage of everyone. The United Nations Convention on Biodiversity and the meetings in Rio de Janeiro in 1992, redefined biodiversity ownership. Genetic biodiversity has a potential value and belongs to the country of origin. The International Conservation of Biodiversity Groups (ICBGs) was founded in 1992 to address such issues. This presentation discusses the importance of integrating efforts in conservation, economic development, and drug development into one program. The presentation details a collaboration that includes an ICBG based at the Walter Reed Army Institute of Research and its four partner organizations and discusses the associated programs the collaboration has underway.     

自然疗养因子的作用机制研究进展

自然疗养因子所涵盖的内容丰富,其生物学效应及形成复杂。现代疗养学在形成过程中相继提出自然疗养因子对机体作用的理论或假说。随着医学模式的转变和现代医学的发展,自然疗养因子作用机制研究从分子、细胞到组织器官,涉及机体物质代谢、神经系统、内分泌和免疫等功能的相互作用,形成整体的各个水平产生适应的作用机制;研究证实自然疗养因子的作用最根本的表现为改善机体内环境稳态和机体与外环境间的平衡,是靠机体的适应性反应机制实现的;其次与祖国医学“天人合一”整体观一脉相承。近年来,研究证实环境因素通过基因的重返表达对表观遗传产生影响,同时疗养因子参与机体的生物节律调控不断深入,机体对自然疗养因子的应答反应是受到多种因素的影响,包括机体状态、疗养因子的种类、性质、作用剂量、应用时间、季节及个体差异等。本文主要对自然疗养因子的作用机制及对机体的作用等方面进行总结。     

Mechanism of HIV antiretroviral drugs progress toward drug resistance

The rapid replication rate of HIV-1 RNA and its inherent genetic variation have led to the production of many HIV-1 variants with decreased drug susceptibility. The capacity of HIV to develop drug resistance mutations is a major obstacle to long-term effective anti-HIV therapy. Incomplete suppression of viral replication with an initial drug regimen diminishes the clinical benefit to the patient and may promote the development of broader drug resistance that may cause subsequent treatment regimens to be ineffective. The increased clinical use of combination antiretroviral treatment for HIV-1 infection has led to the selection of viral strains resistant to multiple drugs, including strains resistant to all licensed nucleoside analog RT inhibitors and protease inhibitors. Therefore, it is important to understand the influence of such mutations on viral properties such as replicative fitness, fidelity, and mutation rates. Although research continues to improve our understanding of resistance, leading to refined treatment strategies and, in some cases, improved outcome, resistance to antiretroviral therapy remains a major cause of treatment failure among patients living with HIV-1.     

Developing natural marine products for treating liver diseases

In recent years, marine-derived bioactive compounds have gained increasing attention because of their higher biodiversity vs land-derived compounds. A number of marine-derived compounds are proven to improve lipid metabolism, modulate the gut microbiota, and possess anti-inflammatory, antioxidant, antibacterial, antiviral, and antitumor activities. With the increasing understanding of the molecular landscape underlying the pathogenesis of chronic liver diseases, interest has spiked in developing new therapeutic drugs and medicine food homology from marine sources for the prevention and treatment of liver diseases.     

Report on the Fourth International Granulocyte Immunology Workshop: progress toward quality assessment

BACKGROUND: A formal quality assurance (QA) scheme has been established to facilitate proficiency testing for granulocyte antibodies and antigens. STUDY DESIGN AND METHODS: Fifteen laboratories participated in the Fourth International Granulocyte Immunology Workshop. The main objective of the workshop was to establish a formal QA scheme for granulocyte serology and molecular typing methods. A secondary objective was to determine the relative sensitivities of the granulocyte immunofluorescence test, granulocyte agglutination test, and MoAb immobilization assays using defined antisera and protocols. RESULTS: Laboratories scored between 16.7 and 100 percent (mean, 57.5%) of the maximum available in the serologic part of this QA exercise. There were particular problems in detecting granulocyte-specific human neutrophil antigen-1 (HNA-1a) IgM antibodies and HNA-2a antibodies in the presence of HNA-1b antibodies. The granulocyte immunofluorescence test was more sensitive than the granulocyte agglutination test in titration studies, but the latter method more readily identified the presence of HNA-3a antibodies. HNA genotyping was generally well performed, with nine laboratories obtaining 100-percent correct results for HNA-1a, HNA-1b, and HNA-1c. CONCLUSIONS: There is a need to standardize the detection of granulocyte-specific antibodies. Laboratories with good performance tended to use two methods for detecting granulocyte-specific antibodies and an HNA-typed panel of granulocytes. The use of a method for elucidating mixtures of granulocyte- and lymphocyte-reactive antibodies (e.g., MoAb immobilization assay) and the use of methods for detecting both cytotoxic and noncytotoxic HLA class I antibodies were also associated with a higher than average performance.     

Dynamic covalent hydrogel of natural product baicalin with antibacterial activities

Baicalin has been demonstrated to have multiple pharmacological activities but low solubility. Various baicalin hydrogels have been used to improve its solubility and break its limitation in clinical applications. However, traditional baicalin hydrogels contain numerous ingredients and usually show low baicalin loading capacity. Herein, we discovered a dynamic covalent hydrogel only consisting of baicalin and inorganic borate, in which baicalin is considered as the carrier and drug without other ingredients. The dynamic boronate bonds endow the hydrogel with excellent degradability and multi-stimuli-responsiveness. Moreover, the hydrogel displayed remarkable thixotropy, moldability, and self-healing properties. And the biocompatible baicalin hydrogel exhibited significant antibacterial activities, and can be considered as a potential drug delivery system for biomedical applications.

We discovered a dynamic covalent hydrogel with 3D pore structure, in which baicalin were linked by boronate esters. The baicalin hydrogel displayed remarkable thixotropy, moldability, self-healing, and multi-stimuli-responsive properties.     

Fuscoside: an anti-inflammatory marine natural product which selectively inhibits 5-lipoxygenase. Part I: Physiological and biochemical studies in murine inflammatory models.

The biological and biochemical pharmacology of fuscoside, a novel anti-inflammatory marine natural product isolated from the Caribbean gorgonian Eunicea fusca, has recently been characterized using murine (part I) and human (part II) models of inflammation. Topically applied fuscoside (FSD) effectively inhibits phorbol myristate acetate (PMA)-induced edema in mouse ears at levels comparable with indomethacin over a 3.3-hr exposure period, and is significantly more efficacious than indomethacin over 24 hr in the PMA model. Histological preparations and quantification of the neutrophil-specific marker, myeloperoxidase, demonstrate that FSD inhibits neutrophil infiltration into PMA-induced regions of edema and inflammation. In systemic studies, where FSD is injected i.p. before the topical application of PMA, negligible effects on ear inflammation are observed. FSD does not inhibit bee venom or human synovial fluid phospholipase A2 up to concentrations of 500 microM. In calcium ionophore-activated cultures of mouse peritoneal macrophages, FSD selectively and irreversibly inhibits leukotriene C4 biosynthesis (IC50 = 8 microM), yet has negligible effects on prostaglandin E2 production. FSD is also without effect on the conversion of arachidonic acid to prostaglandin E2 by ram seminal vesicle cyclooxygenase. Chromatographic and spectroscopic studies suggest that FSD is not metabolized, and that drug uptake/binding by macrophages is time dependent, saturable and independent of active transport mechanisms. These studies represent the first report of an anti-inflammatory marine natural product that selectively inhibits leukotriene biosynthesis.     

Bioactive natural products from marine sponges belonging to family Hymedesmiidae

Natural products of marine origin exhibit extensive biological activities, and display a vital role in the exploration of new compounds for drug development. Marine sponges have been reported at the top with respect to the discovery of biologically active metabolites that have potential pharmaceutical applications. The family Hymedesmiidae belonging to the Demospongiae class includes ten accepted genera, of which four genera were explored for their bioactive metabolites, namely Phorbas, Hamigera, Hemimycale, and Kirkpatrickia. Genus Phorbas has received more attention due to the isolation of various classes of compounds with unique structures mainly diterpenes, alkaloids, sesterterpenes, and steroids that exhibited diverse biological activities including: antiviral, antimicrobial, and anti-inflammatory, whereas anticancer compounds predominated. This review focuses on the isolated secondary metabolites from family Hymedesmiidae with their biological potential and covers the literature from 1989 to 2020.

Natural products of marine origin exhibit extensive biological activities, and display a vital role in the exploration of new compounds for drug development.