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With increasing numbers of patients worldwide diagnosed with diabetes mellitus, renal disease, and iatrogenic immune deficiencies, an increased understanding of the role of electrolyte interactions in mitigating pathogen virulence is necessary. The levels of divalent cations affect host susceptibility and pathogen survival in persons with relative immune insufficiency. For instance, when host cellular levels of calcium are high compared to magnesium, this relationship contributes to insulin resistance and triples the risk of clinical tuberculosis. The movement of divalent cations within intracellular spaces contributes to the host defense, causing apoptosis or autophagy of the pathogen. The control of divalent cation flow is dependent in part upon the mammalian natural resistance-associated macrophage protein (NRAMP) in the host. Survival of pathogens such as M tuberculosis within the bronchoalveolar macrophage is also dependent upon NRAMP. Pathogens evolve mutations to control the movement of calcium through external and internal channels. The host NRAMP as a metal transporter competes for divalent cations with the pathogen NRAMP in M tuberculosis (whether in latent, dormant, or active phase). This review paper summarizes mechanisms of pathogen offense and patient defense using inflow and efflux through divalent cation channels under the influence of parathyroid hormone vitamin D and calcitonin. [ABSTRACT FROM AUTHOR]

The pigments responsible for eggshell color and patterning in birds are protoporphyrin IX (PP) and biliverdin (BV). Both are involved in the catalytic degradation of the hemo group. Bilirubin (BR), another pigment, is produced when BV is broken down. PP, BV, and BR are free radical scavengers. In this study, we theoretically investigated the antioxidant capacities of these three biological meaningful molecules using Density Functional Theory calculations. First, two antioxidant mechanisms were analyzed for PP, BV, and BR: electron transfer and Hydrogen Atom Transfer. Second, since PP and BV interact with the calcium carbonate matrix of the eggshell, we analyzed the interaction of these pigments with Ca2+ and investigated their chelate compounds. Third, we explored the pro-oxidant properties of PP and BV, which have been proposed for PP when photoactivated to the triplet state, but not for BV. Our results show that PP, BV, and BR are just as good antiradical as other important natural pigments (carotenoids). Neither the antiradical properties of PP and BV nor the UV-visible spectra change due to the presence of calcium, suggesting that the signaling function of these pigments is not affected by the link with Ca2+. Finally, we found that both PP and BV (alone and when linked to Ca2+) can transfer energy from its triplet state to molecular-oxygen-producing singlet oxygen, indicating their pro-oxidant capacity. This investigation answers important questions about the function of these pigments, which may help to understand their influence on the reproductive success of birds. [ABSTRACT FROM AUTHOR]

Human breast milk (HBM)-derived exosomes contain various biological and immunological components. However, comprehensive immune-related and antimicrobial factor analysis requires transcriptomic, proteomic, and multiple databases for functional analyses, and has yet to be conducted. Therefore, we isolated and confirmed HBM-derived exosomes by detecting specific markers and examining their morphology using western blot and transmission electron microscopy. Moreover, we implemented small RNA sequencing and liquid chromatography-mass spectrometry to investigate substances within the HBM-derived exosomes and their roles in combating pathogenic effects, identifying 208 miRNAs and 377 proteins associated with immunological pathways and diseases. Integrated omics analyses identified a connection between the exosomal substances and microbial infections. In addition, gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses demonstrated that HBM-derived exosomal miRNA and proteins influence immune-related functions and pathogenic infections. Finally, protein–protein interaction analysis identified three primary proteins (ICAM1, TLR2, and FN1) associated with microbial infections mediating pro-inflammation, controlling infection, and facilitating microbial elimination. Our findings determine that HBM-derived exosomes modulate the immune system and could offer therapeutic strategies for regulating pathogenic microbial infection. [ABSTRACT FROM AUTHOR]

The pigments responsible for eggshell color and patterning in birds are protoporphyrin IX (PP) and biliverdin (BV). Both are involved in the catalytic degradation of the hemo group. Bilirubin (BR), another pigment, is produced when BV is broken down. PP, BV, and BR are free radical scavengers. In this study, we theoretically investigated the antioxidant capacities of these three biological meaningful molecules using Density Functional Theory calculations. First, two antioxidant mechanisms were analyzed for PP, BV, and BR: electron transfer and Hydrogen Atom Transfer. Second, since PP and BV interact with the calcium carbonate matrix of the eggshell, we analyzed the interaction of these pigments with Ca2+ and investigated their chelate compounds. Third, we explored the pro-oxidant properties of PP and BV, which have been proposed for PP when photoactivated to the triplet state, but not for BV. Our results show that PP, BV, and BR are just as good antiradical as other important natural pigments (carotenoids). Neither the antiradical properties of PP and BV nor the UV-visible spectra change due to the presence of calcium, suggesting that the signaling function of these pigments is not affected by the link with Ca2+. Finally, we found that both PP and BV (alone and when linked to Ca2+) can transfer energy from its triplet state to molecular-oxygen-producing singlet oxygen, indicating their pro-oxidant capacity. This investigation answers important questions about the function of these pigments, which may help to understand their influence on the reproductive success of birds.

Human breast milk (HBM)-derived exosomes contain various biological and immunological components. However, comprehensive immune-related and antimicrobial factor analysis requires transcriptomic, proteomic, and multiple databases for functional analyses, and has yet to be conducted. Therefore, we isolated and confirmed HBM-derived exosomes by detecting specific markers and examining their morphology using western blot and transmission electron microscopy. Moreover, we implemented small RNA sequencing and liquid chromatography-mass spectrometry to investigate substances within the HBM-derived exosomes and their roles in combating pathogenic effects, identifying 208 miRNAs and 377 proteins associated with immunological pathways and diseases. Integrated omics analyses identified a connection between the exosomal substances and microbial infections. In addition, gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses demonstrated that HBM-derived exosomal miRNA and proteins influence immune-related functions and pathogenic infections. Finally, protein–protein interaction analysis identified three primary proteins (ICAM1, TLR2, and FN1) associated with microbial infections mediating pro-inflammation, controlling infection, and facilitating microbial elimination. Our findings determine that HBM-derived exosomes modulate the immune system and could offer therapeutic strategies for regulating pathogenic microbial infection.

Mast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense. [ABSTRACT FROM AUTHOR]

Electronic cigarettes (ECs) have been growing rapidly in popularity among youth and adults in the United States over the last decade. This increasing prevalence is driven partially by the ability to customize devices, flavors, and nicotine content and the general notion that ECs are harmless, particularly in comparison with conventional cigarettes. In vitro and in vivo murine models have demonstrated a number of harmful biological effects of e-liquids and their aerosols. However, limited clinical data exist on whether these effects translate into detrimental long-term outcomes in human subjects. The short-term harmful respiratory effects of EC use demonstrated in nonsmokers argue against their use. However, slightly more favorable data exist for the respiratory benefits of substituting conventional cigarettes with ECs and the short-term efficacy of ECs as smoking cessation tools. Nonetheless, available research is severely limited in regard to long-term outcomes and by study designs fraught with bias, pointing to the need for additional research efforts with well-designed longitudinal studies to guide US Food and Drug Administration regulatory efforts. The hurdle presented by diverse device designs and e-liquid permutations, which contribute to the inconsistency of available data, also highlights the need for legislative standardization of ECs. [ABSTRACT FROM AUTHOR]

The Scavenger Receptor Cysteine-Rich (SRCR) proteins are an archaic group of proteins characterized by the presence of multiple SRCR domains. They are membrane-bound or secreted proteins, which are generally related to host defense systems in animals. Deleted in Malignant Brain Tumors 1 (DMBT1) is a SRCR protein which is secreted in mucosal fluids and involved in host defense by pathogen binding by its SRCR domains. Genetic polymorphism within DMBT1 leads to DMBT1-alleles giving rise to polypeptides with interindividually different numbers of SRCR domains, ranging from 8 SRCR domains (encoded by 6 kb DMBT1 variant) to 13 SRCR domains (encoded by the 8 kb DMBT1 variant). In the present study, we have investigated whether reduction from 13 to 8 amino-terminal SRCR domains leads to reduction of bacterial binding. The 6 kb variant bound ~20-45% less bacteria compared to the 8 kb variant. These results support the hypothesis that genetic variation in DMBT1 may influence microbial defense. [ABSTRACT FROM AUTHOR]

Proteases from a variety of sources (viruses, bacteria, fungi, plants, and insects) have toxicity towards insects. Some of these insecticidal proteases evolved as venom components, herbivore resistance factors, or microbial pathogenicity factors, while other proteases play roles in insect development or digestion, but exert an insecticidal effect when over-expressed from genetically engineered plants or microbial pathogens. Many of these proteases are cysteine proteases, although insect-toxic metalloproteases and serine proteases have also been examined. The sites of protease toxic activity range from the insect midgut to the hemocoel (body cavity) to the cuticle. This review discusses these insecticidal proteases along with their evaluation and use as potential pesticides.

When western boxelder bugs, Boisea rubrolineata ( Barber) ( Hemiptera: Rhopalidae), form aggregations in warm sunlight, they release from their posterior dorsal abdominal gland an odorous blend of monoterpenes with heretofore unknown biological function. In laboratory analyses and experiments, we show that bugs in warm sunlight, but not in shade, exude and spread copious amounts of monoterpenes onto their cuticle. These monoterpenes do not serve as a pheromone, but rather as a means of sanitation. They inhibit germination of conidia of the fungal pathogen Beauveria bassiana ( Bals.- Criv.) Vuill. ( Hypocreales) as well as halt the growth of germinated spores. This prophylactic defense against pathogens appears adaptive for phytophagous insects, like B. rubrolineata, that are prone to infections by microbes thriving on leaf surfaces and in the insects' overwintering microhabitat. [ABSTRACT FROM AUTHOR]

The innate immune response system forms an important line of defense by deploying a limited number of receptors specific for conserved microbial components. This deployment generates a rapid inflammatory response, while activating the adaptive immune system. Improvements in our understanding of the innate immune system have allowed us to explore various therapeutic strategies via modulation of the immune response., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aryl hydrocarbon receptor (AHR) has been characterized as multifunctional sensor, integrator and ligand-activated transcription factor of the bHLH/PAS family. Regulation of inflammatory diseases and energy metabolism are among the putative functions of AHR. Challenges in AHR research include marked species differences, and cell, tissue and context dependence of AHR functions. The commentary is focused on AHR's role in the integration between energy expenditure and microbial and non-infectious inflammation, the latter exemplified by obesity-mediated nonalcoholic fatty liver disease. One of the mechanisms controlling energy-consuming inflammation is represented by a signalsome that is involved in retinoic acid-triggered neutrophil differentiation and regulation of the NADPH oxidase complex (NOX). Established signalsome components are AHR, CD38, multiple protein kinases and adaptors. To prevent chronic inflammatory diseases, the complex interplay between a range of inflammatory responses and energy expenditure must be precisely regulated. Surviving an infection requires both pathogen clearance and tissue protection from inflammatory damage. Defenses are energy-consuming anabolic programs. Therefore, anti-inflammatory, catabolic tolerance programs by metabolic reprogramming of macrophages have evolved. Therapeutic options of AHR agonists to reduce chronic inflammatory diseases are discussed. [ABSTRACT FROM AUTHOR]

The innate immune response system forms an important line of defense by deploying a limited number of receptors specific for conserved microbial components. This deployment generates a rapid inflammatory response, while activating the adaptive immune system. Improvements in our understanding of the innate immune system have allowed us to explore various therapeutic strategies via modulation of the immune response., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Proteases from a variety of sources (viruses, bacteria, fungi, plants, and insects) have toxicity towards insects. Some of these insecticidal proteases evolved as venom components, herbivore resistance factors, or microbial pathogenicity factors, while other proteases play roles in insect development or digestion, but exert an insecticidal effect when over-expressed from genetically engineered plants or microbial pathogens. Many of these proteases are cysteine proteases, although insect-toxic metalloproteases and serine proteases have also been examined. The sites of protease toxic activity range from the insect midgut to the hemocoel (body cavity) to the cuticle. This review discusses these insecticidal proteases along with their evaluation and use as potential pesticides.