Natural Antagonist Research Articles

Can Agricultural Practices in Strawberry Fields Induce Plant-Nematode Interaction towards Meloidogyne-Suppressive Soils?

The importance of benign approaches to manage the root-knot nematodes (RKNs, Meloidogyne spp.) in strawberry farms has become more evident with increasing strawberry production and export in Egypt. Therefore, data accumulated on biosolarization and soil amendments to favor beneficial microorganisms and maximize their impact on RKN management are built on a robust historical research foundation and should be exploited. We examined RKN population levels/parameters in three strawberry export governorates, six farms per governorate, to characterize the exact production practices that are responsible for RKN-suppressive soils. All selected farms enjoyed soil biodisinfestation resulting from incorporating organic amendments followed by a plastic cover to suppress soil pathogens. Various safe and inexpensive agricultural practices in the El-Ismailia and El-Beheira governorates were compared to the toxic and expensive fumigants that could eliminate RKNs in the Al-Qalyubia governorate. Two farms at El-Ismailia were of special interest as they ultimately showed almost zero counts of RKNs. The two farms were characterized by incorporating cow manure [containing 0.65% total nitrogen, 21.2 carbon to nitrogen (C/N) ratio] and poultry manure (0.72% total nitrogen, 20.1 C/N ratio) followed by soil solarization via transparent, 80-µm thick plastic covers for 60–65 summer days as pre-strawberry cultivation practices, and similar covers were used after transplanting. Typically, the longer the pre-plant soil solarization period with thicker transparent plastic covers, the better it could suppress the RKN population densities in the tested farms. Their soils were characterized by relatively high pH and low electrical conductivity. The significant development in biocontrol genera/species abundance and frequency could explain the lower (p < 0.0001) RKN population levels inhabiting the farms of El-Ismailia than the El-Beheira governorate. These factors could provide the first approximation of key practices and factors that could collectively contribute to distinguishing and exploiting soil suppressiveness against RKNs. We discussed edaphic properties and production practices that could modulate populations of natural RKN antagonists for sustainable strawberry cultivation.

Algicidal activity of Morganella morganii against axenic and environmental strains of Microcystis aeruginosa: Compound combination effects

Cyanobacterial harmful algal blooms (cyanoHABs) are a global problem with serious consequences for public health and many sectors of the economy. The use of algicidal bacteria as natural antagonists to control bloom-forming cyanobacteria is a topic of growing interest. However, there are still unresolved questions that need to be addressed to better understand their mode of action and to implement effective mitigation strategies. In this study, thirteen bacterial strains isolated from both scums and concentrated bloom samples exhibited algicidal activity on three Microcystis aeruginosa strains with different characteristics: the axenic microcystin (MC)-producing strain M. aeruginosa PCC7820 (MaPCC7820), and two environmental (non-axenic) M. aeruginosa strains isolated from two different water bodies in Poland, one MC-producer (MaSU) and another non-MC-producer (MaPN). The bacterial strain SU7S0818 exerted the highest average algicidal effect on the three cyanobacterial strains. This strain was identified as Morganella morganii (99.51% similarity) by the 16S rRNA gene analyses; hence, this is the first study that demonstrates the algicidal properties of these ubiquitous bacteria. Microscopic cell counting and qPCR analyses showed that M. morganii SU7S0818 removed 91%, 96%, and 98.5% of MaPCC7820, MaSU and MaPN cells after 6 days of co-culture, respectively. Interestingly, the ultra-high-performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS) analyses showed that this bacterium was involved on the release of several substances with algicidal potential. It was remarkable how the profile of some compounds evolved over time, as in the case of cadaverine, tyramine, cyclo[Pro-Gly] and cyclo[Pro-Val]. These dynamic changes could be attributed to the action of M. morganii SU7S0818 and the presence of associated bacteria with environmental cyanobacterial strains. Therefore, this study sheds light on how algicidal bacteria may adapt their action on cyanobacterial cells by releasing a combination of compounds, which is a crucial insight to exploit them as effective biological tools in the control of cyanoHABs.

Phytophages and mycobiots of white mistletoe

Aim. The aim of the study was to investigate the natural antagonists of white mistletoe (Viscum album L.), which may affect the number and speed of spread of this species. Methods. The plant material of V. album, collected in urban plantations of Kyiv, was used in the study. The research was conducted mainly in park zones and urban plantations of Podilskyi district. Samples of affected white mistletoe were collected by the route method during 2019-2021. Plant material was also inspected during the sanitary cutting of utilities. Results. Different species of vertebrates and invertebrates, fungi, lichens and bacteria that form close ecological links with V. album were analyzed. It has been established that several species of fungi can parasitize on V. album, showing a fairly high level of specialization. Hyperparasitic disease has also been reported. Conclusions. A list of species associated with white mistletoe was identified and the possibility of their use in the development of biological methods to control the semi-parasite was assessed.

Clonostachys spp., natural mosquito antagonists, and their prospects for biological control of Aedes aegypti.

Aedes aegypti (Linnaeus, 1762) is an important vector of arboviruses in the tropics and subtropics. New control strategies based on natural enemies such as entomopathogenic fungi are of utmost importance, and the present study reports the first isolation of Clonostachys spp. (Hypocreales: Bionectriaceae) from mosquitoes and their activity against A. aegypti. Entomopathogenic fungi were surveyed in central Brazil using A. aegypti larvae as sentinels and, also, a CDC light trap. Clonostachys eriocamporesii R.H. Perera & K.D. Hyde, 2020 (IP 440) and Clonostachys byssicola Schroers, 2001 (IP 461) were identified by sequence analysis of the nuclear ribosomal internal transcribed spacer gene, and tested against eggs, larvae, and adults. Both strains were highly active against A. aegypti third instar larvae, with mortalities ≥ 80% at 107 conidia/mL after 5days but distinctly less active against eggs and adults. This is the first report of both C. eriocamporesii and C. byssicola as naturally occurring pathogens affecting mosquitoes, and IP 440 appears to be a promising control agent against aquatic stages of A. aegypti.

Antifungal activity of lactic acid bacteria isolated from raw camel milk againts Alternaria alternata and identification of antifungal substance

The phytopathogenic filamentous fungi are responsible for the deterioration of various food products, such as fruits or vegetables, causing significant economic losses. They are also capable of producing several mycotoxins in infected plants and fruits.Lactic acid bacteria (LAB) are considered to be natural antagonists of these dangerous microorganisms. In the present study, 16 strains of LAB isolated from raw camel milk from various regions of Algeria, were the subject of phenotypic and genotypic identification, and they were tested for their antifungal activity. The well method was performed on five strains of lactic acid bacteria against four strains of the toxigenic and spoilage phytopathogenic fungus, Alternaria alternata, isolated from the stems, leaves, roots and fruits of tomatoes and carrots. A study of nature metabolites showed that these metabolites are stable at temperature, and keep the nature of the metabolites with the treatment with proteolytic enzymes such as Pepsin, Lysozyme and Trypsin, so their activity increases with increasing the pH of the culture medium. No loss of antifungal activity of the five selected strains was observed after treatment of the metabolites by heating at 4°C, 30°C, 45°C and 90°C. Internal transcribed spacer polymerase chain reaction (ITS-PCR) analysis and 16S rDNA sequencing were used to characterize and identify LAB isolates that showed varying levels of inhibition of fungal growth. Two strains of LAB, identified as Enterococcus lactis and E. faecium, had the strongest antifungal activity, suggesting potential application in food technology as bio-preservatives against phytopathogenic and food-altering fungi.

Vitamin D receptor and STAT6 interactome governs oesophageal epithelial barrier responses to IL-13 signalling

ObjectiveThe contribution of vitamin D (VD) deficiency to the pathogenesis of allergic diseases remains elusive. We aimed to define the impact of VD on oesophageal allergic inflammation.DesignWe assessed the genomic...

Modeling of adaptive counteraction of the induced biotic environment during the invasive process

Purpose is to develop a mathematical model for the analysis of a variant in the development of a population process with a non-trivially regulated confrontation between an invading species and a biotic environment. Relevance. The situation we are studying arises in invasive processes, but is a previously unexplored special variant of their development. The task of modeling is to describe the transition to a deep ν-shaped crisis after intensive growth. The model is based on examples of the adaptive dynamics of a bacterial colony and the suppression of mollusk populations, carriers of dangerous parasitic diseases, after targeted anti-epidemic introduction of their antagonists. Methods. In our work equations with a retarded argument in the range of parameter values that have a biological interpretation were studied. The model uses a logarithmic form of species regulation, taking into account the theoretically permissible capacity of the medium. In the equation we included the function of external influence with flexible threshold regulation relative to the current and previous population size. Results. It is shown that the proposed form of impact regulation leads to the formation of a stable adapted population after the crisis, which does not have a destructive impact on the habitat. With an increase in the reproductive potential of an invasive species, a deep crisis becomes critically dangerous. The form of the crisis passage depends on the reproductive potential, on the size of the initial group of individuals, and also on the time of activation of the adaptive counteraction from the environment. It is established that at a sufficient level of resistance, a non destructive equilibrium is established. Conclusion. The actual scenario of sudden depression of an actively spreading population with a large reproductive 𝑟-parameter, which is caused by the delayed activity of its natural antagonists, has been studied. The threshold form of biotic regulation is characteristic of insects, the abundance of which is regulated by competing species of parasitic hymenoptera. The variant of rapid phase change considered by us in the model is relevant as a description of one of the forms of developing the body’s immune response to the development of an acute infection with a significant delay. If the immune response is prematurely inhibited by the body itself, then the chronic focus of the disease persists. Examples of the dynamics of two real biological processes in experiments with biological suppression methods are given, which correspond to the invasion scenario obtained in the new model.

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases.

Natural soluble antagonist and decoy receptor on the surface of the cell membrane are evolving as crucial immune system regulators as these molecules are capable of recognizing, binding, and neutralizing (so-called inhibitors) their targeted ligands. Eventually, these soluble antagonists and decoy receptors terminate signaling by prohibiting ligands from connecting to their receptors on the surface of cell membrane. Interleukin-18 binding protein (IL-18BP) participates in regulating both Th1 and Th2 cytokines. IL-18BP is a soluble neutralizing protein belonging to the immunoglobulin (Ig) superfamily as it harbors a single Ig domain. The Ig domain is essential for its binding to the IL-18 ligand and holds partial homology to the IL-1 receptor 2 (IL-1R2) known as a decoy receptor of IL-1α and IL-1β. IL-18BP was defined as a unique soluble IL-18BP that is distinct from IL-18Rα and IL-18Rβ chain. IL-18BP is encoded by a separated gene, contains 8 exons, and is located at chr.11 q13.4 within the human genome. In this review, we address the difference in the biological activity of IL-18BP isoforms, in the immunity balancing Th1 and Th2 immune response, its critical role in autoimmune diseases, as well as current clinical trials of recombinant IL-18BP (rIL-18BP) or equivalent.

IL-36G promotes cancer-cell intrinsic hallmarks in human gastric cancer cells.

Interleukin-36 gamma (IL-36G) is a member of the IL-36 subfamily of cytokines and acts as a potent driver of inflammation. IL-36G has been extensively characterized in the pathogenesis of psoriasis and has been recently described to play roles in wound healing particularly in the gastrointestinal tract. However, the effects of IL-36G during cancer development including gastric cancer remain unexplored. Here, we show that IL-36G induced ERK1/2 activation in AGS, MKN1 and MKN45 human gastric cancer cell lines. Moreover, IL-36G induced colony formation, migration and invasion of these gastric cancer cell lines that was inhibited by the natural antagonist, IL-36 receptor antagonist (RA). Interrogation of TCGA stomach adenocarcinoma patient datasets revealed highly elevated IL-36G gene expression in human gastric cancer compared to normal tissue independent of tumor stage, and high IL-36G expression corresponded with poorer patient survival. Collectively, our results indicate for the first time that IL-36G supports a neoplastic phenotype in human gastric cancer cells.

Entomopathogenic fungi associated with Stomoxys calcitrans in Slovakia and efficacy of local fungal strains against the stable fly

The stable fly, Stomoxys calcitrans, is the most important ectoparasite of livestock throughout the world. Entomopathogenic fungi are natural antagonists of stable flies with the potential to be used as biocontrol agents in integrated management programmes of this pest. The prevalence and species diversity of entomopathogenic fungi in populations of the stable fly were documented on a dairy cattle farm in south-western Slovakia. The prevalence of fungal infection was low and the maximum percentage of infected flies reached 2.72% during the season. Three Beauveria species were identified from infected flies, B. bassiana, B. pseudobassiana and B. brongniartii. Beauveria pseudobassiana and B. brongniartii are reported from S. calcitrans for the first time. In laboratory tests, the pathogenicity of four entomopathogenic fungi B. bassiana, B. pseudobassiana, M. anisopliae and Isaria fumosorosea against adult stable flies was compared. The flies were susceptible to infection by the fungi and the most virulent isolate of B. bassiana (IKEP10) was selected for spore formulation testing and field trials. We tested three types of spore formulations and the aqueous spore suspension was more effective against stable flies than spores formulated in the powder or oil suspension. Repeated treatments of the interior of the stable with B. bassiana spores at fortnightly intervals during June–August resulted in a 10 times higher prevalence of fungal infection in the stable fly population compared with the untreated stable, but the treatments did not effectively reduce the fly population. The selected B. bassiana isolate may represent an interesting tool in the biocontrol of stable fly populations, but further experiments are needed to design an appropriate formulation and enhance its efficacy.

Mechanistic interrogation of mutation-independent disease modulators of RDEB identifies the small leucine-rich proteoglycan PRELP as a TGF-β antagonist and inhibitor of fibrosis

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic extracellular matrix disease caused by deficiency in type VII collagen (Col VII). The disease manifests with devastating mucocutaneous fragility leading to progressive fibrosis and metastatic squamous cell carcinomas. Although Col VII abundance is considered the main predictor of symptom course, previous studies have revealed the existence of mutation-independent mechanisms that control disease progression. Here, to investigate and validate new molecular modifiers of wound healing and fibrosis in a natural human setting, and toward development of disease-modulating treatment of RDEB, we performed gene expression profiling of primary fibroblast from RDEB siblings with marked phenotypic variations, despite having equal COL7A1 genotype. Gene enrichment analysis suggested that severe RDEB was associated with enhanced response to TGF-β stimulus, oxidoreductase activity, and cell contraction. Consistently, we found an increased response to TGF-β, higher levels of basal and induced reactive oxygen species (ROS), and greater contractile ability in collagen lattices in RDEB fibroblasts (RDEBFs) from donors with severe RDEB vs mild RDEB. Treatment with antioxidants allowed a reduction of the pro-fibrotic and contractile phenotype. Importantly, our analyses revealed higher expression and deposition in skin of the relatively uncharacterized small leucine-rich extracellular proteoglycan PRELP/prolargin associated with milder RDEB manifestations. Mechanistic investigations showed that PRELP effectively attenuated fibroblasts' response to TGF-β1 stimulus and cell contractile capacity. Moreover, PRELP overexpression in RDEBFs enhanced RDEB keratinocyte attachment to fibroblast-derived extracellular matrix in the absence of Col VII. Our results highlight the clinical relevance of pro-oxidant status and hyper-responsiveness to TGF-β in RDEB severity and progression. Of note, our study also reveals PRELP as a novel and natural TGF-β antagonist with a likely dermo-epidermal pro-adhesive capacity.

Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti–activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody–mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.

Fungal Communities of the Pine Wilt Disease Complex: Studying the Interaction of Ophiostomatales With Bursaphelenchus xylophilus.

Considered one of the most devastating plant–parasitic nematodes worldwide, Bursaphelenchus xylophilus (commonly known as pinewood nematode, PWN) is the causal agent of the pine wilt disease in the Eurasian coniferous forests. This migratory parasitic nematode is carried by an insect vector (Monochamus spp.) into the host tree (Pinus species), where it can feed on parenchymal cells and reproduce massively, resulting in the tree wilting. In declining trees, PWN populations are strongly dependent on fungal communities colonizing the host (predominantly ophiostomatoid fungi known to cause sapwood blue-staining, the blue-stain fungi), which not only influence their development and life cycle but also the number of individuals carried by the insect vector into a new host. Our main aim is to understand if PWN-associated mycobiota plays a key role in the development of PWD, in interaction with the PWN and the insect vector, and to what extent it can be targeted to disrupt the disease cycle. For this purpose, we characterized the fungal communities of Pinus pinaster trees infected and non-infected with PWN in three collection sites in Continental Portugal with different PWD temporal incidences. Our results showed that non-infected P. pinaster mycoflora is more diverse (in terms of abundance and fungal richness) than PWN-infected pine trees in the most recent PWD foci, as opposed to the fungal communities of long-term PWD history sites. Then, due to their ecological importance for PWN survival, representatives of the main ophiostomatoid fungi isolated (Ophiostoma, Leptographium, and Graphilbum) were characterized for their adaptative response to temperature, competition in-between taxa, and as food source for PWN. Under the conditions studied, Leptographium isolates showed promising results for PWN control. They could outcompete the other species, especially O. ips, and significantly reduce the development of PWN populations when compared to Botrytis cinerea (routinely used for PWN lab culturing), suggesting this to be a natural antagonist not only for the other blue-stain species but also for the PWN.

Soil-Borne Nematodes: Impact in Agriculture and Livestock and Sustainable Strategies of Prevention and Control with Special Reference to the Use of Nematode Natural Enemies.

Soil-borne parasitic nematodes cause severe deterioration in the health of crops and supply animals, leading to enormous economic losses in the agriculture and livestock industry worldwide. The traditional strategy to control these parasites has been based on chemically synthesised compounds with parasiticidal activity, e.g., pesticides and anthelmintic drugs, which have shown a negative impact on the environment. These compounds affect the soil’s beneficial microbiota and can also remain as toxic residues in agricultural crops, e.g., fruits and legumes, and in the case of animal products for human consumption, toxic residues can remain in milk, meat, and sub-products derived from the livestock industry. Other alternatives of control with much less negative environmental impact have been studied, and new strategies of control based on the use of natural nematode enemies have been proposed from a sustainable perspective. In this review, a general view of the problem caused by parasitic nematodes affecting the agriculture and livestock industry, traditional methods of control, and new strategies of control based on eco-friendly alternatives are briefly described, with a special focus on a group of natural nematode antagonists that have been recently explored with promising results against plagues of importance for agricultural and livestock production systems.

Influence of the micromycete Fusarium culmorum and its antagonists on the state of the antioxidant system of Melissa officinalis L.

In recent years, the popularity of herbal medicine has increased. Lemon balm (Melissa officinalis L.) is a perennial essential oil herb that has been used as a medicinal plant for more than 2 thousand years. It is known that the productivity of plants is directly related to their resistance to phytopathogens, in particular, micromycetes of the genus Fusarium. One of the main mechanisms of plant damage by phytopathogens is oxidative stress. Micromycetes of the genus Trichoderma and soil cyanobacteria (CB) occupy an important place among the natural antagonists of fungi of the genus Fusarium. The aim of the work was to study the state of the antioxidant system of Melissa officinalis L. plants when grown on substrates contaminated with the micromycete Fusarium culmorum and its antagonists – the cyanobacterium Fischerella muscicola and the micromycete Trichodеrma viride. It was found that the presence of the pathogenic micromycete F. culmorum in the soils for growing lemon balm for two months has a stressful effect on lemon balm plants: the intensity of lipid peroxidation, the content of phenolic compounds and the amount of antioxidants in the in plant leaves were significantly higher than in the control. At the same time, at elevated temperatures, the content of phenolic compounds increased, which may be due to increased metabolism and the level of oxidative stress. The introduction of microorganisms-antagonists F. muscicole and T. viride into the soil makes it possible to activate the work of the antioxidant system of plants and reduce the effects of oxidative stress almost to the level of control. The studied antagonists can be recommended as promising for the development of biological products on their basis in order to protect medicinal plants from fusarium diseases.

Effect of bisphosphonates on selected markers of bone turnover in patients after total knee arthroplasty.

Osteoporosis is a problem for many patients after total knee arthroplasty (TKA). The aseptic loosening of the prosthesis is also a significant problem. Therefore, in these patients, bisphosphonates (BPs) are used that, by influencing the level of bone turnover markers, reduce the risk of osteoporotic fractures and aseptic revisions in TKA. The purpose of the study was to assess whether the Pamifos® present in bone cement has any effect on the level of selected bone turnover markers and cytokines in patients after total knee arthroplasty. The study group consisted of 30 women with degenerative changes of the knee joint, whose total knee prosthesis was stabilized with cement enriched with Pamifos®. The control group consisted of 30 women treated for degenerative changes of the knee joint without the use of bisphosphonate-enriched cement for prosthetic stabilization. In the study group, we found a decrease in tumour necrosis factor (TNF-α) levels 12weeks after surgery, whereas the control group experienced an almost twofold increase in TNF-α level. The concentration of OPG, a natural RANKL antagonist, was highest in patients of the study group sixweeks after surgery and was four times higher compared to the control group. Statistically significant differences were found in the RANKL level (P < 0.05). In the control group, there was a continuous increase in RANKL concentration from the first to the 12th week after surgery. The highest level of RANKL in patients of the study group was found sixweeks after the surgery, and 12weeks after knee arthroplasty, it was significantly lower. It was found that the concentration of osteocalcin (OC) in the study group was the lowest threeweeks after the surgery, then it increased and remained at a similar level after 12weeks. The concentrations of selected cytokines (IL-1β, IL-2, IL-6, IL-10, IL-17AF) also showed statistically significant differences. The BP-stimulated increase in the level of OPG and the decrease in the level of RANKL, as well as the impact on the level of the analyzed interleukins in the bone microenvironment, may be an important element of the mechanisms limiting bone resorption. Therefore, the use of BP-enriched cement implants appears to be justified.

Plant-associated microbiota as a source of antagonistic bacteria against the phytopathogen Erwinia amylovora.

Control of bacterial plant diseases is a major concern, as they affect economically important species and spread easily, such as the case of fire blight of rosaceous caused by Erwinia amylovora. In the search for alternatives to the use of agrochemicals and antibiotics, this work presents a screening of natural bacterial antagonists of this relevant and devastating phytopathogen. We recovered bacterial isolates from different plant tissues and geographical origins and then selected those with the strongest ability to reduce fire blight symptoms ex vivo and remarkable in vitro antagonistic activity against E. amylovora. None of them elicited a hypersensitivity reaction in tobacco leaves, most produced several hydrolytic enzymes and presented other biocontrol and/or plant growth-promoting activities, such as siderophore production and phosphate solubilization. These isolates, considered as biocontrol candidates, were identified by 16S rRNA sequencing as Pseudomonas rhizosphaerae, Curtobacterium flaccumfaciens, Enterobacter cancerogenus, Pseudomonas azotoformans, Rosenbergiella epipactidis and Serratia plymuthica. This is the first time that the last five bacterial species are reported to have biocontrol potential against E. amylovora.

A Novel Theanine Complex, Mg-L-Theanine Improves Sleep Quality via Regulating Brain Electrochemical Activity.

L-Theanine is commonly used to improve sleep quality through inhibitory neurotransmitters. On the other hand, Mg2+, a natural NMDA antagonist and GABA agonist, has a critical role in sleep regulation. Using the caffeine-induced brain electrical activity model, here we investigated the potency of L-theanine and two novel Mg-L-theanine compounds with different magnesium concentrations on electrocorticography (ECoG) patterns, GABAergic and serotonergic receptor expressions, dopamine, serotonin, and melatonin levels. Furthermore, we evaluated the sleep latency and duration in the pentobarbital induced sleep model. We herein showed that L-theanine, particularly its various complexes with magnesium increases the expression of GABAergic, serotonergic, and glutamatergic receptors, which were associated with decreased ECoG frequency, increased amplitude, and enhanced delta wave powers. Besides increased dopamine, serotonin, and melatonin; decreased MDA and increased antioxidant enzyme levels were also observed particularly with Mg-complexes. Protein expression analyses also showed that Mg-L-theanine complexes decrease inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) levels significantly. In accordance with these results, Mg complexes improved the sleep latency and duration even after caffeine administration. As a result, our data indicate that Mg-L-theanine compounds potentiate the effect of L-theanine on sleep by boosting slow-brain waves, regulating brain electrical activity, and increasing neurotransmitter and GABA receptor levels.

TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability

Successful treatment of chronic inflammatory diseases integrates both the cessation of inflammation and the induction of adequate tissue repair processes. Strikingly, targeting a single proinflammatory cytokine, tumor necrosis factor (TNF), induces both processes in a relevant cohort of inflammatory bowel disease (IBD) patients. However, the molecular mechanisms underlying intestinal repair following TNF blockade during IBD remain elusive. Using a novel humanized model of experimental colitis, we demonstrate that TNF interfered with the tissue repair program via induction of a soluble natural antagonist of IL-22 (IL-22Ra2; IL-22BP) in the colon and abrogated IL-22/STAT3-mediated mucosal repair during colitis. Furthermore, membrane-bound TNF expressed by T cells perpetuated colonic inflammation, while soluble TNF produced by epithelial cells (IECs) induced IL-22BP expression in colonic dendritic cells (DCs) and dampened IL-22-driven restitution of colonic epithelial functions. Finally, TNF induced IL-22BP expression in human monocyte-derived DCs and levels of IL22-BP correlated with TNF in sera of IBD patients. Thus, our data can explain how anti-TNF therapy induces mucosal healing by increasing IL-22 availability and implicates new therapeutic opportunities for IBD.

A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer.

Simple SummaryThe Inhibitor of Apoptosis (IAP) family of proteins has emerged as a potential pharmacological target in cancer. Abnormal expression of IAPs can lead to dysregulated cell suicide, promoting the development of different pathologies. In several cancer types, members of this protein family are overexpressed while their natural antagonist (Smac) appears to be downregulated, contributing to the acquisition of resistance to traditional therapy. The development of compounds that mimic the action of Smac showed promise in the re-sensitization of the cell suicide defense mechanism in cancer cells, particularly in combination with other treatments. Interaction with other molecules, such as tumor necrosis factor-α, in the tumor microenvironment reveals a complex interplay between IAPs and cancer.The Inhibitor of Apoptosis (IAP) family possesses the ability to inhibit programmed cell death through different mechanisms; additionally, some of its members have emerged as important regulators of the immune response. Both direct and indirect activity on caspases or the modulation of survival pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), have been implicated in mediating its effects. As a result, abnormal expression of inhibitor apoptosis proteins (IAPs) can lead to dysregulated apoptosis promoting the development of different pathologies. In several cancer types IAPs are overexpressed, while their natural antagonist, the second mitochondrial-derived activator of caspases (Smac), appears to be downregulated, potentially contributing to the acquisition of resistance to traditional therapy. Recently developed Smac mimetics counteract IAP activity and show promise in the re-sensitization to apoptosis in cancer cells. Given the modest impact of Smac mimetics when used as a monotherapy, pairing of these compounds with other treatment modalities is increasingly being explored. Modulation of molecules such as tumor necrosis factor-α (TNF-α) present in the tumor microenvironment have been suggested to contribute to putative therapeutic efficacy of IAP inhibition, although published results do not show this consistently underlining the complex interaction between IAPs and cancer.