scholarly journals Human Defensins: A Novel Approach in the Fight against Skin Colonizing Staphylococcus aureus

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 198 ◽  
Author(s):  
Olga Scudiero ◽  
Mariarita Brancaccio ◽  
Cristina Mennitti ◽  
Sonia Laneri ◽  
Barbara Lombardo ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Innate Immunity ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Interleukin 1 ◽  
Interleukin 17 ◽  
Skin Infections ◽  
Skin Disorders ◽  
Novel Approach ◽  
Pharmacological Potential

Staphylococcus aureus is a microorganism capable of causing numerous diseases of the human skin. The incidence of S. aureus skin infections reflects the conflict between the host skin′s immune defenses and the S. aureus’ virulence elements. Antimicrobial peptides (AMPs) are small protein molecules involved in numerous biological activities, playing a very important role in the innate immunity. They constitute the defense of the host′s skin, which prevents harmful microorganisms from entering the epithelial barrier, including S. aureus. However, S. aureus uses ambiguous mechanisms against host defenses by promoting colonization and skin infections. Our review aims to provide a reference collection on host-pathogen interactions in skin disorders, including S. aureus infections and its resistance to methicillin (MRSA). In addition to these, we discuss the involvement of defensins and other innate immunity mediators (i.e., toll receptors, interleukin-1, and interleukin-17), involved in the defense of the host against the skin disorders caused by S. aureus, and then focus on the evasion mechanisms developed by the pathogenic microorganism under analysis. This review provides the “state of the art” on molecular mechanisms underlying S. aureus skin infection and the pharmacological potential of AMPs as a new therapeutic strategy, in order to define alternative directions in the fight against cutaneous disease.

scholarly journals Abundant c-Fas–associated death domain–like interleukin-1–converting enzyme inhibitory protein expression determines resistance of T helper 17 cells to activation-induced cell death

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1026-1028 ◽  
Author(s):  
Yu Yu ◽  
Cristina Iclozan ◽  
Tomohide Yamazaki ◽  
Xuexian Yang ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Cell Death ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Interleukin 17 ◽  
Death Domain ◽  
Converting Enzyme ◽  
T Helper ◽  
Inhibitory Protein ◽  
Activation Induced Cell Death

Activation-induced cell death (AICD) plays an important role in peripheral T-cell tolerance. AICD in CD4 T helper (Th) cells, including Th1 and Th2 effectors, has been extensively studied. Recently, interleukin-17–producing CD4+ T cells (Th17 cells) have been identified as a unique Th subset, but their susceptibility to AICD and the underlying molecular mechanisms have not been defined. In this study, we found that Th17 cells were significantly less susceptible to AICD than Th1 cells, and Th17 cell resistance to AICD is due to the high levels of c-Fas–associated death domain–like interleukin-1–converting enzyme inhibitory protein preventing Fas-mediated apoptosis. The resistance of Th17 cells to AICD reveals a novel mechanism to explain the high pathogenicity of Th17 cells in autoimmune diseases, and may also provide a rationale to generate tumor-specific Th17 cells for adoptive immunotherapy.

scholarly journals Plant Derived Natural Products against Pseudomonas aeruginosa and Staphylococcus aureus: Antibiofilm Activity and Molecular Mechanisms

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5024
Author(s):  
Francesca Guzzo ◽  
Monica Scognamiglio ◽  
Antonio Fiorentino ◽  
Elisabetta Buommino ◽  
Brigida D’Abrosca
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Natural Products ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Antibiofilm Activity ◽  
Complex Structures ◽  
Skin Infections ◽  
Human Pathogens ◽  
And Staphylococcus Aureus

Bacteria are social organisms able to build complex structures, such as biofilms, that are highly organized surface-associated communities of microorganisms, encased within a self- produced extracellular matrix. Biofilm is commonly associated with many health problems since its formation increases resistance to antibiotics and antimicrobial agents, as in the case of Pseudomonas aeruginosa and Staphylococcus aureus, two human pathogens causing major concern. P. aeruginosa is responsible for severe nosocomial infections, the most frequent of which is ventilator-associated pneumonia, while S. aureus causes several problems, like skin infections, septic arthritis, and endocarditis, to name just a few. Literature data suggest that natural products from plants, bacteria, fungi, and marine organisms have proven to be effective as anti-biofilm agents, inhibiting the formation of the polymer matrix, suppressing cell adhesion and attachment, and decreasing the virulence factors’ production, thereby blocking the quorum sensing network. Here, we focus on plant derived chemicals, and provide an updated literature review on the anti-biofilm properties of terpenes, flavonoids, alkaloids, and phenolic compounds. Moreover, whenever information is available, we also report the mechanisms of action.

scholarly journals Phosphocitrate Is Potentially a Disease-Modifying Drug for Noncrystal-Associated Osteoarthritis

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Yubo Sun ◽  
David R. Mauerhan ◽  
Atiya M. Franklin ◽  
James Norton ◽  
Edward N. Hanley ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Biological Activities ◽  
Interleukin 1 ◽  
Type I ◽  
Musculoskeletal Tissue ◽  
Prostaglandin Endoperoxide Synthase ◽  
Modifying Effect ◽  
Disease Modifying

Phosphocitrate (PC), a calcification inhibitor, inhibits the development of crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms underlying its disease-modifying effect remain elusive. This study sought to test the hypothesis that PC has calcium crystal-independent biological activities which are, at least in part, responsible for its disease-modifying activity. We found that PC inhibited the proliferation of OA fibroblast-like synoviocytes in the absence of calcium crystals. Consistent with its effect on cell proliferation, PC downregulated the expression of numerous genes classified in cell proliferation. PC also downregulated the expression of many genes classified in angiogenesis and inflammatory response including prostaglandin-endoperoxide synthase 2, interleukin-1 receptor, type I, and chemokine (C-C motif) ligand 2. In contrast, PC upregulated the expression of many genes classified in musculoskeletal tissue development, including aggrecan, type I collagen, and insulin-like growth factor binding protein 5. These findings suggest that PC is not only a promising disease-modifying drug for crystal-associated OA but also for noncrystal-associated OA.

Novel cross-talk within the IKK family controls innate immunity

2011 ◽  
Vol 434 (1) ◽  
pp. 93-104 ◽  
Author(s):  
Kristopher Clark ◽  
Mark Peggie ◽  
Lorna Plater ◽  
Ronald J. Sorcek ◽  
Erick R. R. Young ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Protein Kinases ◽  
Gene Transcription ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Tumour Necrosis Factor Receptor ◽  
Catalytic Subunits ◽  
Physiological Substrates

Members of the IKK {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase} family play a central role in innate immunity by inducing NF-κB- and IRF [IFN (interferon) regulatory factor]-dependent gene transcription programmes required for the production of pro-inflammatory cytokines and IFNs. However, the molecular mechanisms that activate these protein kinases and their complement of physiological substrates remain poorly defined. Using MRT67307, a novel inhibitor of IKKϵ/TBK1 (TANK {TRAF [TNF (tumour-necrosis-factor)-receptor-associated factor]-associated NF-κB activator}-binding kinase 1) and BI605906, a novel inhibitor of IKKβ, we demonstrate that two different signalling pathways participate in the activation of the IKK-related protein kinases by ligands that activate the IL-1 (interleukin-1), TLR (Toll-like receptor) 3 and TLR4 receptors. One signalling pathway is mediated by the canonical IKKs, which directly phosphorylate and activate IKKϵ and TBK1, whereas the second pathway appears to culminate in the autocatalytic activation of the IKK-related kinases. In contrast, the TNFα-induced activation of the IKK-related kinases is mediated solely by the canonical IKKs. In turn, the IKK-related kinases phosphorylate the catalytic subunits of the canonical IKKs and their regulatory subunit NEMO (NF-κB essential modulator), which is associated with reduced IKKα/β activity and NF-κB-dependent gene transcription. We also show that the canonical IKKs and the IKK-related kinases not only have unique physiological substrates, such as IκBα, p105, RelA (IKKα and IKKβ) and IRF3 (IKKϵ and TBK1), but also have several substrates in common, including the catalytic and regulatory (NEMO and TANK) subunits of the IKKs themselves. Taken together, our studies reveal that the canonical IKKs and the IKK-related kinases regulate each other by an intricate network involving phosphorylation of their catalytic and regulatory (NEMO and TANK) subunits to balance their activities during innate immunity.

scholarly journals Vanillic Acid, a Bioactive Phenolic Compound, Counteracts LPS-Induced Neurotoxicity by Regulating c-Jun N-Terminal Kinase in Mouse Brain

2020 ◽  
Vol 22 (1) ◽  
pp. 361
Author(s):  
Rahat Ullah ◽  
Muhammad Ikram ◽  
Tae Ju Park ◽  
Riaz Ahmad ◽  
Kamran Saeed ◽  
...  
Keyword(s):  
Glial Cells ◽  
Vanillic Acid ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Interleukin 1 ◽  
Amyloid Β ◽  
Treated Group ◽  
Expression Level ◽  
Neuroprotective Effects ◽  
Necrosis Factor Alpha

The receptor for advanced glycation end products (RAGE), a pattern recognition receptor signaling event, has been associated with several human illnesses, including neurodegenerative diseases, particularly in Alzheimer’s disease (AD). Vanillic acid (V.A), a flavoring agent, is a benzoic acid derivative having a broad range of biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. However, the underlying molecular mechanisms of V.A in exerting neuroprotection are not well investigated. The present study aims to explore the neuroprotective effects of V.A against lipopolysaccharides (LPS)-induced neuroinflammation, amyloidogenesis, synaptic/memory dysfunction, and neurodegeneration in mice brain. Behavioral tests and biochemical and immunofluorescence assays were applied. Our results indicated increased expression of RAGE and its downstream phospho-c-Jun n-terminal kinase (p-JNK) in the LPS-alone treated group, which was significantly reduced in the V.A + LPS co-treated group. We also found that systemic administration of LPS-injection induced glial cells (microglia and astrocytes) activation and significantly increased expression level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) and secretion of proinflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1 β (IL1-β), and cyclooxygenase (COX-2). However, V.A + LPS co-treatment significantly inhibited the LPS-induced activation of glial cells and neuroinflammatory mediators. Moreover, we also noted that V.A treatment significantly attenuated LPS-induced increases in the expression of AD markers, such as β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) and amyloid-β (Aβ). Furthermore, V.A treatment significantly reversed LPS-induced synaptic loss via enhancing the expression level of pre- and post-synaptic markers (PSD-95 and SYP), and improved memory performance in LPS-alone treated group. Taken together; we suggest that neuroprotective effects of V.A against LPS-induced neurotoxicity might be via inhibition of LPS/RAGE mediated JNK signaling pathway; and encourage future studies that V.A would be a potential neuroprotective and neurotherapeutic candidate in various neurological disorders.

Targeting the Tumor Microenvironment by Intervention in Interleukin-1 Biology

2017 ◽  
Vol 23 (32) ◽  
pp. 4893-4905 ◽  
Author(s):  
Elena Voronov ◽  
Ron N. Apte
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Tumor Immunity ◽  
Biological Activities ◽  
Interleukin 1 ◽  
Tumor Development ◽  
Tumor Treatment ◽  
Tumor Invasiveness ◽  
First Line Therapy ◽  
Inflammatory Component

The importance of anti-tumor immunity in the outcome of cancer is now unequivocally established and recent achivements in the field have stimulated the development of new immunotherapeutical approaches. In invasive tumors, widespread inflammation promotes invasiveness and concomitantly also inhibits anti-tumor immune responses. We suggest that efficient tumor treatment should target both the malignant cells and the tumor microenvironment. Interleukin-1 (IL-1) is a pro-inflammatory as well as an immunostimulatory cytokine that is abundant in the tumor microenvironment. Manipulation of IL-1 can thus serve as an immunotherapeutical approach to reduce inflammation/immunosuppression and thus enhance anti-tumor immunity. The two major IL-1 agonistic molecules are IL-1α and IL-1β, which bind to the same IL-1 signaling receptor and induce the same array of biological activities. The IL-1 receptor antagonist (IL-Ra) is a physiological inhibitor of IL-1 that binds to its receptor without transmition of activation signals and thus serves as a decoy target. We have demonstrated that IL-1α and IL-1β are different in terms of the producing cells and their compartmentalization and the amount. IL-1α is mainly expressed intracellularly, in the cytosol, in the nucleus or exposed on the cell membrane, however, it is rarely secreted. IL-1β is active only as a secreted molecule that is mainly produced by activated myeloid cells. We have shown different functions of IL-1α and IL-1β in the malignant process. Thus, in its membrane- associated form, IL-1α is mainly immunostimulatory, while IL-1β that is secreted into the tumor microenvironment is mainly pro-inflammatory and promotes tumorigenesis, tumor invasiveness and immunosuppression. These distinct functions of the IL-1 agonistic molecules are mainly manifested in early stages of tumor development and the patterns of their expression dictate the direction of the malignant process. Here, we suggest that IL-1 modulation can serve as an effective mean to tilt the balance between inflammation and immunity in tumor sites, towards the latter. Different agents that neutralize IL-1, mainly the IL-Ra and specific antibodies, exist. They are safe and FDA-approved. The IL-1Ra has been widely and successfully used in patients with Rheumatoid arthritis, autoinflammatory diseases and various other diseases that have an inflammatory component. Here, we provide the rationale and experimental evidence for the use of anti-IL-1 agents in cancer patients, following first line therapy to debulk the major tumor's mass. The considerations and constraints of using anti-IL-1 treatments in cancer are also discussed. We hope that this review will stimulate studies that will fasten the application of IL-1 neutralization at the bedside of cancer patients.

Ginger and Heart Health: From Mechanisms to Therapeutics

2020 ◽  
Vol 13 ◽  
Author(s):  
Sajad Fakhri ◽  
Jayanta Kumar Patra ◽  
Swagat Kumar Das ◽  
Gitishree Das ◽  
Mohammad Bagher Majnooni ◽  
...  
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Health Benefits ◽  
Herbal Medicines ◽  
Cardiovascular Complications ◽  
National Database ◽  
Heart Health ◽  
Natural Entities ◽  
Cardioprotective Effects

Background: As a major cause of morbidity and mortality, cardiovascular diseases (CVDs) are globally increasing. In spite of recent development in the management of cardiovascular complications, CVDs have remained a medical challenge. Numerous conventional drugs are used to play cardioprotective roles; however, they are associated with several side effects. Considering the rich phytochemistry and fewer side effects of herbal medicines, they have gained particular attention to develop novel herbal drugs with cardioprotective potentials. Amongst natural entities, ginger is an extensively used and well-known functional food and condiment, possessing plentiful bioactivities, like antiinflammatory, antioxidant, and antimicrobial properties in several disorders management. Objective: The current review deliberated phytochemical properties as well as the ginger/ginger constituents' biological activities and health benefits in several diseases, with particular attention to cardiovascular complications. Methods: A comprehensive research was conducted using multiple databases, including Scopus, PubMed, Medline, Web of Science, national database (Irandoc and SID), and related articles in terms of the health benefits and cardioprotective effects of ginger/ginger constituents. These data were collected from inception until August 2019. Results: In recent years, several herbal medicines were used to develop new drugs with more potency and also minor side effects. Amongst natural entities, ginger is an extensively used traditional medicine in several diseases. The crude extract, along with related pungent active constituents, is mostly attributed to heart health. The cardioprotective effects of ginger are contributed to its cardiotonic, antihypertensive, anti-hyperlipidemia, and anti-platelet effects. The signaling pathways and molecular mechanisms of ginger regarding its cardioprotective effects are also clarified. Conclusion: This study revealed the biological activities, health benefits, and cardioprotective properties of ginger/ginger constituents along with related mechanisms of action, which gave new insights to show new avenue in the treatment of CVDs.

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