Cell-free adipose tissue extracts as a novel treatment for rosacea by downregulating TRPV1.

Rosacea is a chronic inflammatory skin disease that typically affects the central facial area. Its main clinical symptoms include paroxysmal flushing, telangiectasia, and non-temporary erythema. Cell-free adipose tissue extracts (ATEs) are liquid components extracted from human adipose tissue that contain large amounts of growth factors. Despite the scar-reducing, anti-aging, and wound-healing effects of ATEs, the efficacy of ATEs in rosacea remains unknown. Therefore, the anti-rosacea effects of ATEs were investigated in human cathelicidin peptide (LL-37) induced rosacea mice and capsaicin (CAP)-stimulated HaCaT keratinocytes. In vitro, ATEs significantly reduced TRPV1 expression, intracellular calcium ions influx and the release of inflammatory factors (such as KLK5, IL-6, IL-8 and TNF-α) after intervening in CAP-stimulated cells. The in vivo results revealed that ATEs alleviated rosacea symptoms, such as erythema score, erythema area, transepidermal water loss, abnormal epidermal thickness, mast cell infiltration and telangiectasia upon downregulating TRPV1 and CD31 expression. Moreover, the up-regulated TRPV1 protein expression was also recovered by ATEs administration in vivo and in vitro. Meanwhile, ATEs demonstrated good biocompatibility. In summary, ATEs could be a potential therapeutic agent for rosacea by regulating inflammation and alleviating telangiectasia.

In vivo overexpression of the avian interleukin-17 in a necrotic enteritis disease model modulates the expression of antimicrobial peptides in the small intestine of broilers.

In humans and mice, the induction of interleukin (IL)-17 expression enhances epithelial barrier integrity through the secretion of antimicrobial peptides (AMP), thereby improving antibacterial defense. However, it is unclear whether IL-17 has similar antibacterial effects in chickens by modulating the expression of AMPs, such as avian beta-defensins (also known as gallinacins) and cathelicidins. This study evaluated the in vivo effects of inoculating 20-day-old broiler chickens with two doses of a plasmid encoding chicken IL-17 (pCDNA3.1/rchIL-17-V5-HIS TOPO plasmid [pCDNA3.1-IL-17]; 5 or 10 µg/bird). On day 23 of age, all broilers, except those in the negative control group, were orally challenged with a virulent Clostridium perfringens strain for three days. To investigate IL-17-mediated effects against C. perfringens infection, the expression of avian beta-defensin 1 (avBD1), avBD2, avBD4, avBD6, cathelicidins, and inducible nitric oxide synthase (iNOS) genes were quantified, and gross necrotic enteritis (NE) lesion scores were assessed in the small intestine. The results showed that broilers receiving the higher dose of pCDNA3.1-IL-17 (10 µg) had significantly lower NE lesion scores compared to those receiving the lower dose (5 µg), the vector control, and the positive control groups. Furthermore, the expression of all avian beta-defensins and cathelicidin genes was detectable across all groups, regardless of treatment and time points. IL-17 treatment led to significantly higher expression of avBD1, avBD2, avBD4, avBD6, cathelicidin, and iNOS in the duodenum, jejunum, and ileum compared to control chickens. In C. perfringens-infected chickens, the expression of avBD1, avBD2, avBD4, cathelicidin, and iNOS in the ileum was significantly higher than in control chickens. Pre-treatment with the higher dose of pCDNA3.1-IL-17 (10 µg) in infected chickens was associated with reduced NE lesion severity and increased expression of avBD1, avBD2, cathelicidin, and iNOS in the ileum, but not avBD4 and avBD6. These findings provide new insights into the potential effect of IL-17 and reduction in NE lesion severity by modulating AMP expression which may be involved in mediating protective immunity against intestinal infection with C. perfringens.

Exploring the neuroprotective potential of KC14 peptide from Cyprinus carpio against oxidative stress-induced neurodegeneration by regulating antioxidant mechanism.

BACKGROUND: Oxidative stress, a condition characterized by excessive production of reactive oxygen species (ROS), can cause significant damage to cellular macromolecules, leading to neurodegeneration. This underscores the need for effective antioxidant therapies that can mitigate oxidative stress and its associated neurodegenerative effects. KC14 peptide derived from liver-expressed antimicrobial peptide-2 A (LEAP 2 A) from Cyprinus carpio L. has been identified as a potential therapeutic agent. This study focuses on the antioxidant and neuroprotective properties of the KC14 peptide is to evaluate its effectiveness against oxidative stress and neurodegeneration. METHODS: The antioxidant capabilities of KC14 were initially assessed through in silico docking studies, which predicted its potential to interact with oxidative stress-related targets. Subsequently, the peptide was tested at concentrations ranging from 5 to 45 µM in both in vitro and in vivo experiments. In vivo studies involved treating H2O2-induced zebrafish larvae with KC14 peptide to analyze its effects on oxidative stress and neuroprotection. RESULTS: KC14 peptide showed a protective effect against the developmental malformations caused by H2O2 stress, restored antioxidant enzyme activity, reduced neuronal damage, and lowered lipid peroxidation and nitric oxide levels in H2O2-induced larvae. It enhanced acetylcholinesterase activity and significantly reduced intracellular ROS levels (p < 0.05) dose-dependently. Gene expression studies showed up-regulation of antioxidant genes with KC14 treatment under H2O2 stress. CONCLUSIONS: This study highlights the potent antioxidant activity of KC14 and its ability to confer neuroprotection against oxidative stress can provide a novel therapeutic agent for combating neurodegenerative diseases induced by oxidative stress.

Effects of CRAMP on the gut-brain axis in experimental sepsis.

The collaboration between the microbiota, mucosa, and intestinal epithelium is crucial for defending against pathogens and external antigens. Dysbiosis disrupts this balance, allowing pathogens to thrive and potentially enter the bloodstream, triggering immune dysregulation and potentially leading to sepsis. Antimicrobial peptides like LL-37 and CRAMP are pivotal in innate immune defense. Their expression varies with infection severity, exhibiting a dual pro- and anti-inflammatory response. Understanding this dynamic is key to comprehending sepsis progression. In our study, we examined the inflammatory response in CRAMP knockout mice post-cecal ligation and puncture (CLP). We assessed its impact on brain tissue damage and the intestinal microbiota. Our findings revealed higher gene expression of S100A8 and S100A9 in the prefrontal cortex of wild-type mice versus CRAMP-knockout mice. This trend was consistent in the hippocampus and cerebellum, although protein concentrations remained constant. Notably, there was a notable increase in Escherichia coli, Lactobacillus spp., and Enterococcus faecalis populations in wild-type mice 24 h post-CLP compared to the CRAMP-deficient group. These results align with our previous data suggesting that the absence of CRAMP may confer protection in this sepsis model.

The potential role of heparin-binding protein in neonatal sepsis: research progress.

Neonatal sepsis is a major global health challenge, leading to significant morbidity and mortality in newborns. The search for precise biomarkers for its early prediction in clinical settings has been ongoing, with heparin-binding protein (HBP) emerging as a promising candidate. Originating from granules in neutrophils, HBP is released into the bloodstream in response to infection and plays a pivotal role in the body's inflammatory response. Its significance extends beyond its inflammatory origins; research indicates dynamic changes in HBP levels are strongly linked to reduce in-hospital mortality, offering a prognostic advantage over existing biomarkers. Furthermore, HBP has demonstrated considerable clinical utility in the early diagnosis and stratification of neonatal sepsis, suggesting its potential as a reliable blood marker for early prediction of the disease and its severity. Its application may extend to guiding the judicious use of antibiotics in treating newborns, addressing a critical aspect of neonatal care. Despite these encouraging results, the precise clinical utility of HBP for diagnosing and treating sepsis in neonates still demands further clarification through extensive research. This review delves into the current scientific understanding of HBP's contribution to diagnosing, prognosticating, and treating neonatal sepsis, while considering its future clinical applications.

Synergistic collaboration between AMPs and non-direct antimicrobial cationic peptides.

Non-direct antimicrobial cationic peptides (NDACPs) are components of the animal innate immune system. But their functions and association with antimicrobial peptides (AMPs) are incompletely understood. Here, we reveal a synergistic interaction between the AMP AW1 and the NDACP AW2, which are co-expressed in the frog Amolops wuyiensis. AW2 enhances the antibacterial activity of AW1 both in vitro and in vivo, while mitigating the development of bacterial resistance and eradicating biofilms. AW1 and AW2 synergistically damage bacterial membranes, facilitating cellular uptake and interaction of AW2 with the intracellular target bacterial genomic DNA. Simultaneously, they trigger the generation of ROS in bacteria, contributing to cell death upon reaching a threshold level. Moreover, we demonstrate that this synergistic antibacterial effect between AMPs and NDACPs is prevalent across diverse animal species. These findings unveil a robust and previously unknown correlation between AMPs and NDACPs as a widespread antibacterial immune defense strategy in animals.

Membrane Adsorption Enhances Translocation of Antimicrobial Peptide Buforin 2.

Despite ongoing research on antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), their precise translocation mechanism remains elusive. This includes Buforin 2 (BF2), a well-known AMP, for which spontaneous translocation across the membrane has been proposed but a high barrier has been calculated. Here, we used computer simulations to investigate the effect of a nonequilibrium situation where the peptides are adsorbed on one side of the lipid bilayer, mimicking experimental conditions. We demonstrated that the asymmetric membrane adsorption of BF2 enhances its translocation across the lipid bilayer by lowering the energy barrier by tens of kJ mol-1. We showed that asymmetric membrane adsorption also reduced the free energy barrier of lipid flip-flop but remained unlikely even at BF2 surface saturation. These results provide insight into the driving forces behind membrane translocation of cell-penetrating peptides in nonequilibrium conditions, mimicking experiments.

GHSR signalling in perinatal phases is involved in liver metabolism at puberty.

Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1-14]. For this, two experimental models were used: (i) LEAP2[1-14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1-14] or MK677. Perinatal GHSR modulation by LEAP2[1-14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood.

Antileishmanial Activity of Cathelicidin and its Modulation by Leishmania donovani in a cAMP Response Element Modulator-Dependent Manner in Infection.

Concerns regarding toxicity and resistance of current drugs in visceral leishmaniasis have been reported. Antimicrobial peptides are considered to be promising candidates and among them human cathelicidin hCAP18/LL-37 showed significant parasite killing on drug-sensitive and resistant Leishmania promastigotes, in addition to its apoptosis-inducing role. Administration of hCAP18/LL-37 to infected macrophages also decreased parasite survival and increased the host favorable cytokine interleukin 12. However, 1,25-dihydroxyvitamin D3 (vitamin D3)-induced endogenous hCAP18/LL-37 production was hampered in infected THP-1 cells. Infection also suppressed the vitamin D3 receptor (VDR), transcription factor of hCAP18/LL-37. cAMP response element modulator (CREM), the repressor of VDR, was induced in infection, resulting in suppression of both VDR and cathelicidin expression. PGE2/cAMP/PKA axis was found to regulate CREM induction during infection and silencing CREM in infected cells and BALB/c mice led to decreased parasite survival. This study documents the antileishmanial potential of cathelicidin and further identifies CREM as a repressor of cathelicidin in Leishmania infection.

Evaluation of Kynu, Defb2, Camp, and Penk Expression Levels as Psoriasis Marker in the Imiquimod-Induced Psoriasis Model.

Background: Psoriasis is a noncontagious auto-inflammatory chronic skin disease. So far, some of the inflammatory genes were upregulated in mouse model of psoriasis. This study examined changes in skin mRNA expression of L-kynureninase (Kynu), cathelicidin antimicrobial peptide (Camp), beta-defensin 2 (Defb2), and proenkephalin (Penk) in a mouse model of imiquimod-induced psoriasis. Materials and Methods: Tree groups of C57BL/6 female mice were allocated. The imiquimod (IMQ) cream was administered to the mice dorsal skin of the two groups to induce psoriatic inflammation. In the treatment group, IMQ was administered 10 min after hydrogel-containing M7 anti-IL-17A aptamer treatment. Vaseline (Vas) was administered to the negative control group. The psoriatic skin lesions were evaluated based on the psoriasis area severity index (PASI) score, histopathology, and mRNA expression levels of Kynu, Camp, Defb2, and Penk using real-time PCR. In order to assess the systemic response, the spleen and lymph node indexes were also evaluated. Results: The PASI and epidermal thickness scores were 6.01 and 1.96, respectively, in the IMQ group, and they significantly decreased after aptamer administration to 1.15 and 0.90, respectively (P < 0.05). Spleen and lymph node indexes showed an increase in the IMQ group, followed by a slight decrease after aptamer treatment (P > 0.05). Additionally, the mRNA expression levels of Kynu, Defb2, Camp, and Penk genes in the IMQ-treated region showed a significant 2.70, 4.56, 3.29, and 2.61-fold increase relative to the Vas mice, respectively (P < 0.05). The aptamer-treated region exhibited a significant decrease in these gene expression levels (P < 0.05). A positive correlation was found between Kynu, Penk, and Camp expression levels and erythema, as well as Camp expression with PASI, scaling, and thickness (P < 0.05). Conclusion: According to our results, it seems that Kynu, Camp, and Penk can be considered appropriate markers for the evaluation of psoriasis in IMQ-induced psoriasis. Also, the anti-IL-17 aptamer downregulated these important genes in this mouse model.

LncRNA NEAT1 targets miR-125/ADAM9 mediated NF-κB pathway in inflammatory response of rosacea.

OBJECTIVE: To investigate the role of NEAT1 targeted regulation of miR-125/ADAM9 mediated NF-κB pathway in inflammatory response in rosacea. METHOD: HaCaT cell rosacea phenotype was induced by LL37. The connection targeted by NEAT1 and miR-125a-5p was confirmed by Double-Luciferase report analysis. qPCR was employed to assess the levels of expression for NEAT1, miR-125a-5p, and ADAM9 genes. The levels of expression for ADAM9/TLR2/NF-κB P65 pathway proteins in each batch of cells were determined by Western blotting. The levels of expression for inflammatory factors, including TNF-α, IL-1ß, IL-6, and IL-18, were measured through ELISA experimentation. RESULTS: LL37 could successfully induce HaCaT cells to exhibit rosacea phenotype. The luciferase report experiment confirmed that NEAT1 could target and bind miR-125a-5p and inhibit its expression. ADAM9 exhibited increased expression in LL37-induced HaCaT cells, showing a positive association with NEAT1 expression and inverse relationship with miR-125a-5p activation. LL37 treatment promoted the expression of ADAM9/TLR2/NF-κB P65 pathway proteins. Silencing ADAM9 can inhibit the inflammatory signaling pathway and reduce the level of TNF-α, IL-1ß, IL-6, and IL-18 in HaCaT cells. CONCLUSION: NEAT1 can suppress the production of miR-125a-5p and activate the TLR2/NF-κB inflammatory pathway mediated by ADAM9, thereby promoting the inflammatory response in rosacea.

Lung antimicrobial proteins and peptides: from host defense to therapeutic strategies.

Representing severe morbidity and mortality globally, respiratory infections associated with chronic respiratory diseases, including complicated pneumonia, asthma, interstitial lung disease, and chronic obstructive pulmonary disease, are a major public health concern. Lung health and the prevention of pulmonary disease rely on the mechanisms of airway surface fluid secretion, mucociliary clearance, and adequate immune response to eradicate inhaled pathogens and particulate matter from the environment. The antimicrobial proteins and peptides contribute to maintaining an antimicrobial milieu in human lungs to eliminate pathogens and prevent them from causing pulmonary diseases. The predominant antimicrobial molecules of the lung environment include human α- and ß-defensins and cathelicidins, among numerous other host defense molecules with antimicrobial and antibiofilm activity such as PLUNC (palate, lung, and nasal epithelium clone) family proteins, elafin, collectins, lactoferrin, lysozymes, mucins, secretory leukocyte proteinase inhibitor, surfactant proteins SP-A and SP-D, and RNases. It has been demonstrated that changes in antimicrobial molecule expression levels are associated with regulating inflammation, potentiating exacerbations, pathological changes, and modifications in chronic lung disease severity. Antimicrobial molecules also display roles in both anticancer and tumorigenic effects. Lung antimicrobial proteins and peptides are promising alternative therapeutics for treating and preventing multidrug-resistant bacterial infections and anticancer therapies.

Host-defence caerin 1.1 and 1.9 peptides suppress glioblastoma U87 and U118 cell proliferation through the modulation of mitochondrial respiration and induce the downregulation of CHI3L1.

Glioblastoma, the most aggressive form of brain cancer, poses a significant global health challenge with a considerable mortality rate. With the predicted increase in glioblastoma incidence, there is an urgent need for more effective treatment strategies. In this study, we explore the potential of caerin 1.1 and 1.9, host defence peptides derived from an Australian tree frog, in inhibiting glioblastoma U87 and U118 cell growth. Our findings demonstrate the inhibitory impact of caerin 1.1 and 1.9 on cell growth through CCK8 assays. Additionally, these peptides effectively curtail the migration of glioblastoma cells in a cell scratch assay, exhibiting varying inhibitory effects among different cell lines. Notably, the peptides hinder the G0/S phase replication in both U87 and U118 cells, pointing to their impact on the cell cycle. Furthermore, caerin 1.1 and 1.9 show the ability to enter the cytoplasm of glioblastoma cells, influencing the morphology of mitochondria. Proteomics experiments reveal intriguing insights, with a decrease in CHI3L1 expression and an increase in PZP and JUNB expression after peptide treatment. These proteins play roles in cell energy metabolism and inflammatory response, suggesting a multifaceted impact on glioblastoma cells. In conclusion, our study underscores the substantial anticancer potential of caerin 1.1 and 1.9 against glioblastoma cells. These findings propose the peptides as promising candidates for further exploration in the realm of glioblastoma management, offering new avenues for developing effective treatment strategies.

CRISPR/Cas9-induced LEAP2 and GHSR1a knockout mutant zebrafish displayed abnormal growth and impaired lipid metabolism.

Investigating the principles of fish fat deposition and conducting related research are current focal points in fish nutrition. This study explores the endocrine regulation of LEAP2 and GHSR1a in zebrafish by constructing mutantmodels andexamining the effects of the endocrine factors LEAP2 and its receptor GHSR1a on zebrafish growth, feeding, and liver fat deposition. Compared to the wild type (WT), the mutation of LEAP2 results in increased feeding and decreased swimming in zebrafish. The impact is more pronounced in adult female zebrafish, characterized by increased weight, length, width, and accumulation of lipid droplets in the liver.Incontrast, deficiency in GHSR1a significantly reduces the growth of male zebrafish and markedly decreases liver fat deposition.These research findings indicate the crucial roles of LEAP2 and GHSR1a in zebrafish feeding, growth, and intracellular fat metabolism. This study, for the first time, investigated the endocrine metabolic regulation functions of LEAP2 and GHSR1a in the model organism zebrafish, providing initial insights into their effects and potential mechanisms on zebrafish fat metabolism.

LL37/FPR2 regulates neutrophil mPTP promoting the development of neutrophil extracellular traps in diabetic retinopathy.

Diabetic retinopathy (DR) is characterized by chronic, low-grade inflammation. This state may be related to the heightened production of neutrophil extracellular traps (NETs) induced by high glucose (HG). Human cathelicidin antimicrobial peptide (LL37) is an endogenous ligand of G protein-coupled chemoattractant receptor formyl peptide receptor 2 (FPR2), expressed on neutrophils and facilitating the formation and stabilization of the structure of NETs. In this study, we detected neutrophils cultured under different conditions, the retinal tissue of diabetic mice, and fibrovascular epiretinal membranes (FVM) samples of patients with proliferative diabetic retinopathy (PDR) to explore the regulating effect of LL37/FPR2 on neutrophil in the development of NETs during the process of DR. Specifically, HG or NG with LL37 upregulates the expression of FPR2 in neutrophils, induces the opening of mitochondrial permeability transition pore (mPTP), promotes the increase of reactive oxygen species and mitochondrial ROS, and then leads to the rise of NET production, which is mainly manifested by the release of DNA reticular structure and the increased expression of NETs-related markers. The PI3K/AKT signaling pathway was activated in neutrophils, and the phosphorylation level was enhanced by FPR2 agonists in vitro. In vivo, increased expression of NETs markers was detected in the retina of diabetic mice and in FVM, vitreous fluid, and serum of PDR patients. Transgenic FPR2 deletion led to decreased NETs in the retina of diabetic mice. Furthermore, in vitro, inhibition of the LL37/FPR2/mPTP axis and PI3K/AKT signaling pathway decreased NET production induced by high glucose. These results suggested that FPR2 plays an essential role in regulating the production of NETs induced by HG, thus may be considered as one of the potential therapeutic targets.

Molecular Dynamics Simulations Help Determine the Molecular Mechanisms of Lasioglossin-III and Its Variant Peptides' Membrane Interfacial Interactions.

Lasioglossin-III (LL-III) is a potent broad-spectrum antimicrobial peptide used in diverse antimicrobial applications. In this work, coarse-grained and all-atom molecular dynamics simulation strategies were used in tandem to interpret the molecular mechanisms involved in the interfacial dynamics of LL-III and its recombinant variants during interactions with diverse cell membrane systems. Our results indicate that the membrane charges act as the driving force for initiating the membrane-peptide interactions, while the hydrophobic or van der Waals forces help to reinforce the membrane-peptide bindings. The optimized charge-hydrophobicity ratio of the LL-III peptides helps ensure their high specificity toward bacterial membranes compared to mammalian membrane systems, which also helps explain our experimental observations. Overall, we hope that our work gives new insight into the antimicrobial action of LL-III peptides and that the adopted simulation strategy will help other scientists and engineers extract maximal information from complex molecular simulations using minimal computational power.

Zika virus infection suppresses CYP24A1 and CAMP expression in human monocytes.

Monocytes are the primary targets of Zika virus (ZIKV) and are associated with ZIKV pathogenesis. Currently, there is no effective treatment for ZIKV infection. It is known that 1,25-dihydroxy vitamin D3 (VitD3) has strong antiviral activity in dengue virus-infected macrophages, but it is unknown whether VitD3 inhibits ZIKV infection in monocytes. We investigated the relationship between ZIKV infection and the expression of genes of the VitD3 pathway, as well as the inflammatory response of infected monocytes in vitro. ZIKV replication was evaluated using a plaque assay, and VitD3 pathway gene expression was analyzed by RT-qPCR. Pro-inflammatory cytokines/chemokines were quantified using ELISA. We found that VitD3 did not suppress ZIKV replication. The results showed a significant decrease in the expression of vitamin D3 receptor (VDR), cytochrome P450 family 24 subfamily A member 1 (CYP24A1), and cathelicidin antimicrobial peptide (CAMP) genes upon ZIKV infection. Treatment with VitD3 was unable to down-modulate production of pro-inflammatory cytokines, except TNF-α, and chemokines. This suggests that ZIKV infection inhibits the expression of VitD3 pathway genes, thereby preventing VitD3-dependent inhibition of viral replication and the inflammatory response. This is the first study to examine the effects of VitD3 in the context of ZIKV infection, and it has important implications for the role of VitD3 in the control of viral replication and inflammatory responses during monocyte infection.

LL37/self-DNA complexes mediate monocyte reprogramming.

LL37 alone and in complex with self-DNA triggers inflammatory responses in myeloid cells and plays a crucial role in the development of systemic autoimmune diseases, like psoriasis and systemic lupus erythematosus. We demonstrated that LL37/self-DNA complexes induce long-term metabolic and epigenetic changes in monocytes, enhancing their responsiveness to subsequent stimuli. Monocytes trained with LL37/self-DNA complexes and those derived from psoriatic patients exhibited heightened glycolytic and oxidative phosphorylation rates, elevated release of proinflammatory cytokines, and affected naïve CD4+ T cells. Additionally, KDM6A/B, a demethylase of lysine 27 on histone 3, was upregulated in psoriatic monocytes and monocytes treated with LL37/self-DNA complexes. Inhibition of KDM6A/B reversed the trained immune phenotype by reducing proinflammatory cytokine production, metabolic activity, and the induction of IL-17-producing T cells by LL37/self-DNA-treated monocytes. Our findings highlight the role of LL37/self-DNA-induced innate immune memory in psoriasis pathogenesis, uncovering its impact on monocyte and T cell dynamics.

Reduced expression of central innate defense molecules in pancreatic biopsies from subjects with Type 1 diabetes.

AIMS/HYPOTHESIS: Defensins play a crucial role in the innate immune system's first defense against microbial threats. However, little is known about the defensin system in the pancreas, especially in relation to Type 1 diabetes. We explore the expression of defensins in different disease stages of Type 1 diabetes and correlated obtained findings to the degree of inflammation, providing new insights into the disease and the innate immune system. MATERIAL AND METHODS: Pancreases from non-diabetic human organ donors of different age groups and donors with Type 1 diabetes with different disease duration were examined. Sections from head, body and tail of the pancreas were stained for eight different defensins and for immune cells; CD3+, CD45+, CD68+ and NES+ (granulocytes). RESULTS: In non-diabetic adult controls the level of expression for defensins Beta-1,Alpha-1, Cathelicidin and REG3A correlated with the level of inflammation. In contrast, individuals with Type  1 diabetes exhibit a reduction or absence of several central defensins regardless of the level of inflammation in their pancreas. The expression of Cathelicidin is present in neutrophils and macrophages but not in T-cells in subjects with Type 1 diabetes. CONCLUSIONS: Obtained findings suggest a pancreatic dysfunction in the innate immune system and the bridging to the adaptive system in Type 1 diabetes. Further studies on the role of the local innate immune system in Type 1 diabetes is needed.

CXCR2, as a key regulatory gene of HDP-PG-1, maintains intestinal mucosal homeostasis.

The intestine defends against pathogenic microbial invasion via the secretion of host defense peptides (HDPs). Nutritional immunomodulation can stimulate the expression of endogenous HDPs and enhance the body's immune defense, representing a novel non-antibiotic strategy for disease prevention. The project aims to explore the regulatory mechanism of protegrin-1 (PG-1) expression using sodium phenylbutyrate (PBA) by omics sequencing technology and further investigate the role of key regulatory genes on intestinal health. The results showed that PBA promoted PG-1 expression in intestinal epithelial cells based on cell density through epidermal growth factor receptor (EGFR) and G protein-coupled receptor (GPR43). Transcriptome sequencing and microRNA sequencing revealed that C-X-C motif chemokine receptor 2 (CXCR2) exhibited interactions with PG-1. Pre-treatment cells with a CXCR2 inhibitor (SB225002) effectively suppressed the induction of PG-1 by PBA. Furthermore, SB225002 significantly suppressed the gene expression of HDPs in the jejunum of mice without influencing on the morphology, number of goblet cells, and proliferation of the intestine. CXCR2 inhibition significantly reduced the expression of HDPs during E. coli infection, and resulted in the edema of jejunal epithelial cells. The 16S rDNA analysis of cecal contents showed that the E. coli and SB225002 treatments changed gut microbiota diversity and composition at different taxonomic levels. Correlation analysis suggested a potential regulatory relationship between gut microbiota and HDPs. To that end, a gene involved in the HDP expression, CXCR2, has been identified in the study, which contributes to improving intestinal immune function. PBA may be used as a functional additive to regulate intestinal mucosal function, thereby enhancing the health of the intestinal and host.