Histones as Mediators of Host Defense, Inflammation and Thrombosis

Hoeksema, Marloes; Eijk, Martin van; Haagsman, Henk P.; Hartshorn, Kevan L.

doi:10.2217/fmb.15.151

Cited by 125 publications

(132 citation statements)

References 111 publications

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“…Taking into account the AMPs with different structures, we find histone‐like proteins (both histones and fragments of them), which, despite their main core and linker well‐known function, also possess demonstrated antimicrobial activity in vertebrates and so in teleost fish (Hoeksema et al . ; Valero et al . ).…”

Section: Antimicrobial Peptides Isolated From Fishmentioning

confidence: 94%

“…Taking into account the AMPs with different structures, we find histone-like proteins (both histones and fragments of them), which, despite their main core and linker wellknown function, also possess demonstrated antimicrobial activity in vertebrates and so in teleost fish (Hoeksema et al 2016;Valero et al 2013). High-density lipoproteins (HDL) are one of four major lipoprotein complexes that are divided according to their particle density (Kondo et al 2005;Dietrich et al 2014).…”

Section: Peptides With Other Structuresmentioning

confidence: 99%

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Antimicrobial peptides from fish: beyond the fight against pathogens

Valero

Saraiva‐Fraga

Costas

et al. 2018

Reviews in Aquaculture

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Fish antimicrobial peptides (AMPs) are small peptides whose actions have great implications in the innate immune response of teleost fish, being considered critical as the first line of defence against a wide spectrum of pathogens. Antibiotics have been widely used in aquaculture, resulting in bacterial resistance. The potential of AMPs as alternative to antibiotics makes them a very interesting tool as they represent lower‐risk peptides to develop resistances, or even in the fight against other pathogens such as viruses. Beyond their antimicrobial function, fish AMPs possess several relevant but little‐known characteristics and capabilities such as host‐defence peptides, antioxidants, active compounds of immunogenic drugs and as adjuvants. Moreover, their antitumour properties make them potential drugs to be used in oncological treatments in human subjects. Novel methodologies as clustered regularly interspaced short palindromic repeats associated proteins system (CRISPR‐Cas), or even their use as nutraceutics, seem to be promising instruments to enlarge the functions of fish AMPs. This review discusses these new methodologies, as well as the latest research on fish AMP functions, newly discovered properties of AMPs and their future applications in both the aquaculture industry and human health care.

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Section: Antimicrobial Peptides Isolated From Fishmentioning

confidence: 94%

Section: Peptides With Other Structuresmentioning

confidence: 99%

Antimicrobial peptides from fish: beyond the fight against pathogens

Valero

Saraiva‐Fraga

Costas

et al. 2018

Reviews in Aquaculture

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“…Furthermore, the inhibition of histones in these models resulted in improved survival. Though promising, the current treatments have unwanted cost, clinic feasibility, and toxicity (52)(53)(54). In this thesis (Chapter II), we will outline a cost-effective, non-toxic treatment for inhibiting histone-mediated toxicity.…”

Section: Role Of Histones In Sepsis/modsmentioning

confidence: 99%

“…Extracellular histone levels have been correlated with mortality for a multitude of diseases (48,49,(51)(52)(53). Histones normally reside in the nucleus of eukaryotic cells but are released during cellular injury, acting as damage-associated molecular patterns proteins (55,162).…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms by which histones mediated toxicity occurs can be separated into receptor-dependent and independent mechanisms. Receptor-dependent mechanisms primarily activate TLRs, which are present on many cell types, leading to sterile inflammation and platelet aggregation (52,53). Alternatively, the receptor-independent mechanism relies on interaction of the positively charged histones with the negatively charged cell membrane, resulting in the formation of micropores that cause a significant calcium influx followed by cell destruction.…”

Section: Introductionmentioning

confidence: 99%

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Detection and treatment of critical illnesses using oligonucleotides

Urak¹

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Sepsis is among the most prevalent diagnosed critical illnesses in the United States today. Although advances have reduced the overall morbidity and mortality associated with this illness, the enormous number of deaths associated with it shows a need for improved diagnostic and therapeutic options. Our laboratory has utilized RNA based technologies to aid in the treatment of histone induced multiple organ dysfunction syndrome seen in sepsis.Histones are proteins found in the nucleus of every cell in our body and have been shown to be released during sepsis. Such release induces damage to other cells, causing a feed forward cycle that results in organ failure and death. Several therapeutics have been utilized to neutralize histones but have shown considerable toxicity. This thesis describes the generation of single stranded RNA aptamers to bind and neutralize histone mediate damage without unwanted toxicity. We demonstrate that our aptamers selectively bind to histones but not serum proteins. In addition, we establish that our aptamers can neutralize all histone mediated cellular response in vitro and in vivo. Finally, we determined that our aptamers are able inhibit the histone feed forward cycle in a temporal fashion in our murine model of multiple organ dysfunction. This novel therapeutic demonstrates the selectivity and effectiveness needed to inhibit histones in several critical illnesses. iv PUBLIC ABSTRACTThe most prevalent diagnosed critical illness in the western hemisphere is sepsis.Despite recent advances in treatments, the number of deaths associated with sepsis continues to grow, resulting in the need for improved diagnostic and therapeutic options.Our laboratory has utilized RNA based technologies to aid in the treatment and detection of the critical illness stated above.During a critical illness such as sepsis, cells are damaged causing the release of proteins from the nucleus (i.e. histones) resulting in further cellular damage that leads to organ failure and death. To date, one FDA approved therapeutic has been utilized to neutralize histones but resulted in considerable toxicity in the patients. In this thesis we describe a novel therapeutic (single-stranded RNA aptamers) to bind and neutralize histone mediated damage without the toxic side-effects. This novel therapeutic demonstrates the selectivity and efficacy needed to inhibit histones in several critical illnesses.

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Proteomic profiling of sporadic late‐onset nemaline myopathy

Naddaf

Dasari

Selcen

et al. 2022

Ann Clin Transl Neurol

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Objective To define the proteomic profile of sporadic late‐onset nemaline myopathy (SLONM) and explore its pathogenesis. Methods We performed mass spectrometry on laser‐dissected frozen muscle samples from five patients with SLONM, three of whom with an associated monoclonal protein (MP), and four controls, to determine the proteomic profile of SLONM. Furthermore, we assessed the role of the MP by evaluating the expression of the immunoglobulin light chain variable regions (IGVL). Results There were 294 differentially expressed proteins: 272 upregulated and 22 downregulated. Among the top 100 upregulated proteins, the most common categories were: nuclear or nucleic acid metabolism (24%), extracellular matrix and basal lamina (17%), immune response (13%), and actin dynamics (8%). Downregulated proteins consisted mostly of contractile proteins. Among upregulated proteins, there were 65 with a role related to the immune system, including eight proteins involved in major histocompatibility complex 1 (MHC1) and antigen processing, 15 in MHCII complex and phagocytosis, and 23 in B and/or T‐cell function. Among nine upregulated immunoglobulin proteins, there were two IGVL genes. However, these were also detected in SLONM cases without an MP, with no evidence of clonally dominant immunoglobulin deposition. In muscle sections from SLONM patients, nemaline rods tended to accumulate in atrophic fibers with marked rarefaction of the myofibrils. Increased MHC1 reactivity was present in fibers containing nemaline rods as well as adjacent nonatrophic fibers. Conclusion Our findings suggest that aberrant immune activation is present in SLONM, but do not support a direct causal relationship between the MP and SLONM.

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Histones as Mediators of Host Defense, Inflammation and Thrombosis

Cited by 125 publications

References 111 publications

Antimicrobial peptides from fish: beyond the fight against pathogens

Antimicrobial peptides from fish: beyond the fight against pathogens

Detection and treatment of critical illnesses using oligonucleotides

Proteomic profiling of sporadic late‐onset nemaline myopathy

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