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1.
Design of Antimicrobial Peptides: Progress Made with Human Cathelicidin LL-37.
Wang, G, Narayana, JL, Mishra, B, Zhang, Y, Wang, F, Wang, C, Zarena, D, Lushnikova, T, Wang, X
Advances in experimental medicine and biology. 2019;:215-240
Abstract
The incorporation of the innate immune system into humans is essential for survival and health due to the rapid replication of invading microbes and the delayed action of the adaptive immune system. Antimicrobial peptides are important components of human innate immunity. Over 100 such peptides have been identified in various human tissues. Human cathelicidin LL-37 is best studied, and there has been a growing interest in designing new peptides based on LL-37. This chapter describes the alternative processing of the human cathelicidin precursor, protease digestion, and lab cutting of LL-37. Both a synthetic peptide library and structure-based design are utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region. The minimal region of LL-37 can be function-dependent. We discuss the design and potential applications of LL-37 into antibacterial, antibiofilm, antiviral, antifungal, immune modulating, and anticancer peptides. LL-37 has been engineered into 17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. Both 17BIPHE2 and SAAP-148 can eliminate the ESKAPE pathogens and show topical in vivo antibiofilm efficacy. Also discussed are other application strategies, including peptide formulation, antimicrobial implants, and peptide-inducing factors such as vitamin D and sunlight. Finally, we summarize what we learned from peptide design based on human LL-37.
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Antimicrobial Tolerance and Metabolic Adaptations in Microbial Biofilms.
Crabbé, A, Jensen, PØ, Bjarnsholt, T, Coenye, T
Trends in microbiology. 2019;(10):850-863
Abstract
Active bacterial metabolism is a prerequisite for optimal activity of many classes of antibiotics. Hence, bacteria have developed strategies to reduce or modulate metabolic pathways to become tolerant. This review describes the tight relationship between metabolism and tolerance in bacterial biofilms, and how physicochemical properties of the microenvironment at the host-pathogen interface (such as oxygen and nutritional content) are key to this relationship. Understanding how metabolic adaptations lead to tolerance brings us to novel approaches to tackle antibiotic-tolerant biofilms. We describe the use of hyperbaric oxygen therapy, metabolism-stimulating metabolites, and alternative strategies to redirect bacterial metabolism towards an antibiotic-susceptible phenotype.
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3.
Omics of antimicrobials and antimicrobial resistance.
Chernov, VM, Chernova, OA, Mouzykantov, AA, Lopukhov, LL, Aminov, RI
Expert opinion on drug discovery. 2019;(5):455-468
Abstract
The development of new antimicrobials has become an urgent priority because of a global challenge emerging from the rise of antimicrobial resistant pathogens. Areas covered: In this review, the authors discuss the opportunities offered by modern omics approaches to address the challenge and the use of this approach in antimicrobial development. Specifically, the authors focus on the role of omics technologies and bioinformatics for the revelation of the effects of antimicrobials in a variety of microbial cellular processes, as well as the identification of potential cellular targets, the mechanisms of antimicrobial resistance, and the development of new antimicrobials. Expert opinion: Prevention of antimicrobial resistance does not only depend on rational drug design such as narrow-spectrum antimicrobials but on several factors. It is the opinion of the authors that the use of a multi-omics bioinformatics approach should become an integral part of antimicrobial drug discovery as well as in the prevention of antimicrobial resistance.
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The treatment of black stain associated with of iron metabolism disorders with lactoferrin: a litterature search and two case studies.
Sangermano, R, Pernarella, S, Straker, M, Lepanto, MS, Rosa, L, Cutone, A, Valenti, P, Ottolenghi, L
La Clinica terapeutica. 2019;(5):e373-e381
Abstract
Among the various pathologies of the oral cavity, the formation of "unsightly black spots" on the surface of the tooth, universally known as Black Stain (BS) has recently been acquiring more interest. Usually BS is typically found in individuals in prepubertal age, even though it has been identified in adults associated with microbial exchange and / or with iron metabolism disorders. Microbial exchange concerns the possible exchange of bacteria between family members which can take place directly, through effusions, or indirectly, through brushes, cutlery or glasses. For this reason, it is recommended that toothbrushes of family members not be left damp and in contact with each other. The bathroom, being a warm-humid environment, is in fact an optimal habitat for microbial proliferation. Of specific importance in BS is the accumulation of iron in tissues and secretions which, together with chromogenic bacteria, are the primary cause of this pathology. In fact, among the metabolic products synthesized by bacteria in the oral cavity, hydrogen sulfide is of considerable interest, since upon reacting with iron available in saliva, in pathological conditions (iron metabolism disorders), it forms black precipitates consisting of ferric sulfide. These precipitates bind to the surface of the teeth, tending to form a stria that usually follows the contour of the gingiva, with an unsightly and variable chromatic intensity. In physiological situations, iron homeostasis is defined as the state of equilibrium between iron present in tissues and in secretions and that which is present in the circulation. Instead, in pathological conditions, defined as iron metabolism disorders, there is an accumulation of iron in tissues and secretions and a lack of it in the circulation. It is also important to remember that subjects affected by BS are more protected from carious processes than healthy subjects, probably due to a significant predominance of chromogenic bacteria compared to those responsible for caries. It should also be remembered that in young subjects BS tends to regress with pubertal development and the transition to adult life. In any case, using common professional hygiene procedures, it is possible to remove BS as well as plaque and tartar deposits. In particular, with ultrasonic scalers, polishing pastes and powders carried by air and water jets, the surfaces of the teeth can be restored to their natural healthy state. All the techniques for removing the precipitates, are not enough however, to fix and permanently eradicate their appearance, as these precipitates last only for short periods and recur very frequently. Due to the frequent recurrences, new oral microbiota control therapies are emerging; among these the use of lactoferrin (Lf) in the dental field and particularly in the treatment of BS appears to be very promising. Taken togheter, here the effect of Lf in subjects affected by BS has been investigated.
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5.
Therapeutic Opportunities for Hepcidin in Acute Care Medicine.
Chawla, LS, Beers-Mulroy, B, Tidmarsh, GF
Critical care clinics. 2019;(2):357-374
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Abstract
Iron homeostasis is often disrupted in acute disease with an increase in catalytic free iron leading to the formation of reactive oxygen species and subsequent tissue-specific oxidative damage. This article highlights the potential therapeutic benefit of exogenous hepcidin to prevent and treat iron-induced injury, specifically in the management of infection from enteric gram-negative bacilli or fungi, malaria, sepsis, acute kidney injury, trauma, transfusion, cardiopulmonary bypass surgery, and liver disease.
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An overview of electrospun membranes loaded with bioactive molecules for improving the wound healing process.
Miguel, SP, Sequeira, RS, Moreira, AF, Cabral, CSD, Mendonça, AG, Ferreira, P, Correia, IJ
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2019;:1-22
Abstract
Nowadays, despite the intensive research performed in the area of skin tissue engineering, the treatment of skin lesions remains a big challenge for healthcare professionals. In fact, none of the wound dressings currently used in the clinic is capable of re-establishing all the native features of skin. An ideal wound dressing must confer protection to the wound from external microorganisms, chemical, and physical aggressions, as well as promote the healing process by stimulating the cell adhesion, differentiation, and proliferation. In recent years different types of wound dressings (such as films, hydrocolloids, hydrogels, micro/nano fibers) have been developed. Among them, electrospun nanofibrous membranes due to their intrinsic properties like high surface area-to-volume ratio, porosity and structural similarity with the skin extracellular matrix have been regarded as highly promising for wound dressings applications. Additionally, the nanofibers available in these membranes can act as drug delivery systems, which prompted the incorporation of biomolecules within their structure to prevent skin infections as well as improve the healing process. In this review, examples of different bioactive molecules that have been loaded on polymeric nanofibers are presented, highlighting the antibacterial biomolecules (e.g. antibiotics, silver nanoparticles and natural extracts-derived products) and the molecules capable of enhancing the healing process (e.g. growth factors, vitamins, and anti-inflammatory molecules).
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Cepharanthine: An update of its mode of action, pharmacological properties and medical applications.
Bailly, C
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2019;:152956
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Abstract
BACKGROUND Cepharanthine (CEP) is a drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including treatment of leukopenia, snake bites, xerostomia and alopecia. It is the only approved drug for Human use in the large class of bisbenzylisoquinoline alkaloids. This natural product, mainly isolated from the plant Stephania cephalantha Hayata, exhibits multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic properties. PURPOSE The mechanism of action of CEP is multifactorial. The drug exerts membrane effects (modulation of efflux pumps, membrane rigidification) as well as different intracellular and nuclear effects. CEP interferes with several metabolic axes, primarily with the AMP-activated protein kinase (AMPK) and NFκB signaling pathways. In particular, the anti-inflammatory effects of CEP rely on AMPK activation and NFκB inhibition. CONCLUSION In this review, the historical discovery and development of CEP are retraced, and the key mediators involved in its mode of action are presented. The past, present, and future of CEP are recapitulated. This review also suggests new opportunities to extend the clinical applications of this well-tolerated old Japanese drug.
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Zinc finger protein transcription factors: Integrated line of action for plant antimicrobial activity.
Noman, A, Aqeel, M, Khalid, N, Islam, W, Sanaullah, T, Anwar, M, Khan, S, Ye, W, Lou, Y
Microbial pathogenesis. 2019;:141-149
Abstract
The plants resist/tolerate unfavorable conditions in their natural habitats by using different but aligned and integrated defense mechanisms. Such defense responses include not only morphological and physiological adaptations but also the genomic and transcriptomic reconfiguration. Microbial attack on plants activates multiple pro-survival pathways such as transcriptional reprogramming, hypersensitive response (HR), antioxidant defense system and metabolic remodeling. Up-regulation of these processes during biotic stress conditions directly relates with plant survival. Over the years, hundreds of plant transcription factors (TFs) belonging to diverse families have been identified. Zinc finger protein (ZFP) TFs have crucial role in phytohormone response, plant growth and development, stress tolerance, transcriptional regulation, RNA binding and protein-protein interactions. Recent research progress has revealed regulatory and biological functions of ZFPs in incrementing plant resistance to pathogens. Integration of transcriptional activity with metabolic modulations has miniaturized plant innate immunity. However, the precise roles of different zinc finger TFs in plant immunity to pathogens have not been thoroughly analyzed. This review consolidates the pivotal functioning of zinc finger TFs and proposes the integrative understanding as foundation for the plant growth and development including the stress responses.
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The Gut Microbiota in Causation, Detection, and Treatment of Cancer.
Murphy, CL, OʼToole, PW, Shanahan, F
The American journal of gastroenterology. 2019;(7):1036-1042
Abstract
The gut microbiota has emerged as an important consideration in clinical oncology. The role of the microbiome in cancer extends beyond causation and cancer risk. It is now known that the microbiome not only acts at a local epithelial level in the gut but also modifies immune responses within intestinal and extraintestinal tumors. Microbial signaling influences the clinical course of cancer including the efficacy, bioavailability, and toxicity of chemotherapeutic and immunotherapy agents. This has focused research on microbiota profiling in different cancer states with an aim of developing prognostic biomarkers of risk. The potential value of microbiome manipulation with live biotherapeutics or microbial transplantation has also become a realistic consideration. Maintenance of microbial diversity in patients with cancer is a variable challenge given the modifying influences of the tumor itself, chemotherapy, nutritional status, and sporadic antimicrobial therapy. Here, we address current evidence for the role of the microbiome in cancer therapy.
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10.
Vaginitis: Diagnosis and Treatment.
Paladine, HL, Desai, UA
American family physician. 2018;(5):321-329
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Abstract
Vaginitis is defined as any condition with symptoms of abnormal vaginal discharge, odor, irritation, itching, or burning. The most common causes of vaginitis are bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis. Bacterial vaginosis is implicated in 40% to 50% of cases when a cause is identified, with vulvovaginal candidiasis accounting for 20% to 25% and trichomoniasis for 15% to 20% of cases. Noninfectious causes, including atrophic, irritant, allergic, and inflammatory vaginitis, are less common and account for 5% to 10% of vaginitis cases. Diagnosis is made using a combination of symptoms, physical examination findings, and office-based or laboratory testing. Bacterial vaginosis is traditionally diagnosed with Amsel criteria, although Gram stain is the diagnostic standard. Newer laboratory tests that detect Gardnerella vaginalis DNA or vaginal fluid sialidase activity have similar sensitivity and specificity to Gram stain. Bacterial vaginosis is treated with oral metronidazole, intravaginal metronidazole, or intravaginal clindamycin. The diagnosis of vulvovaginal candidiasis is made using a combination of clinical signs and symptoms with potassium hydroxide microscopy; DNA probe testing is also available. Culture can be helpful for the diagnosis of complicated vulvovaginal candidiasis by identifying nonalbicans strains of Candida. Treatment of vulvovaginal candidiasis involves oral fluconazole or topical azoles, although only topical azoles are recommended during pregnancy. The Centers for Disease Control and Prevention recommends nucleic acid amplification testing for the diagnosis of trichomoniasis in symptomatic or high-risk women. Trichomoniasis is treated with oral metronidazole or tinidazole, and patients' sex partners should be treated as well. Treatment of noninfectious vaginitis should be directed at the underlying cause. Atrophic vaginitis is treated with hormonal and nonhormonal therapies. Inflammatory vaginitis may improve with topical clindamycin as well as steroid application.