TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells

Synlett

Glycans control various biological processes, depending on their structures. Particularly, core fucose, formed by α1,6-fucosyltransferase (FUT8), has a substantial influence on multiple biological processes. In this study, we investigated the development of FUT8 inhibitors with structural elements encompassing both the glycosyl donor (GDP-fucose) and acceptor (N-glycan) of FUT8. To efficiently optimize the structure of FUT8 inhibitors, we employed a strategy involving fragmentation of the target structure, followed by a structure optimization using a diversity-oriented synthesis approach. This study proposes an efficient strategy to accelerate the structural optimization of middle molecules.

Angewandte Chemie

Lipopolysaccharide (LPS), a cell surface component of Gram‐negative bacteria, activates innate immunity. Its active principle is the terminal glycolipid lipid A. Acetobacter pasteurianus is a Gram‐negative bacterium used in the fermentation of traditional Japanese black rice vinegar (kurozu). In this study, we focused on A. pasteurianus lipid A, which is a potential immunostimulatory component of kurozu. The active principle structure of A. pasteurianus lipid A has not yet been identified. Herein, we first systematically synthesized three types of A. pasteurianus lipid As containing a common and unique tetrasaccharide backbone. We developed an efficient method for constructing the 2‐trehalosamine skeleton utilizing borinic acid‐catalyzed glycosylation to afford 1,1’‐α,α‐glycoside in high yield and stereoselectivity. A common tetrasaccharide intermediate with an orthogonal protecting group pattern was constructed via …

Nature Communications

Periodontitis, which is induced by repeated bacterial invasion and the ensuing immune reactions that follow, is the leading cause of tooth loss. Periodontal tissue is comprised of four different components, each with potential role in pathogenesis, however, most studies on immune responses focus on gingival tissue. Here, we present a modified ligature-induced periodontitis model in male mice to analyze the pathogenesis, which captures the complexity of periodontal tissue. We find that the inflammatory response in the peri-root tissues and the expression of IL-6 and RANKL by Thy-1.2− fibroblasts/stromal cells are prominent throughout the bone destruction phase, and present already at an early stage. The initiation phase is characterized by high levels of ST2 (encoded by Il1rl1) expression in the peri-root tissue, suggesting that the IL-33/ST2 axis is involved in the pathogenesis. Both Il1rl1- and Il33-deficient mice …

International Journal of Molecular Sciences

Currently, targeted alpha therapy (TAT) is a new therapy involving the administration of a therapeutic drug that combines a substance of α-emitting nuclides that kill cancer cells and a drug that selectively accumulates in cancer cells. It is known to be effective against cancers that are difficult to treat with existing methods, such as cancer cells that are widely spread throughout the whole body, and there are high expectations for its early clinical implementation. The nuclides for TAT, including 149Tb, 211At, 212/213Bi, 212Pb (for 212Bi), 223Ra, 225Ac, 226/227Th, and 230U, are known. However, some nuclides encounter problems with labeling methods and lack sufficient preclinical and clinical data. We labeled the compounds targeting prostate specific membrane antigen (PSMA) with 211At and 225Ac. PSMA is a molecule that has attracted attention as a theranostic target for prostate cancer, and several targeted radioligands have already shown therapeutic effects in patients. The results showed that 211At, which has a much shorter half-life, is no less cytotoxic than 225Ac. In 211At labeling, our group has also developed an original method (Shirakami Reaction). We have succeeded in obtaining a highly purified labeled product in a short timeframe using this method.

Synlett

We established an innovative protective approach that disrupts intermolecular interactions to enhance substrate reactivity. Specifically, diacetylimide protection of acetamide prevents the formation of hydrogen bonds, while the incorporation of tert-butyl groups on the aromatic protecting group disrupts π-stacking interactions, both of which culminate in heightened reactivity in glycosylations. We explored the synergistic implementation of these protective measures and implemented applied them to the synthesis of 6-sulfo sialyl Lewis X.

Rheumatology

Objectives Platelets and low-density neutrophils (LDNs) are major players in the immunopathogenesis of SLE. Despite evidence showing the importance of platelet–neutrophil complexes (PNCs) in inflammation, little is known about the relationship between LDNs and platelets in SLE. We sought to characterize the role of LDNs and Toll-like receptor 7 (TLR7) in clinical disease. Methods Flow cytometry was used to immunophenotype LDNs from SLE patients and controls. The association of LDNs with organ damage was investigated in a cohort of 290 SLE patients. TLR7 mRNA expression was assessed in LDNs and high-density neutrophils (HDNs) using publicly available mRNA sequencing datasets and our own cohort using RT-PCR. The role of TLR7 in platelet binding was evaluated in platelet–HDN mixing studies using TLR7-deficient mice and Klinefelter syndrome …

Angewandte Chemie

Lipopolysaccharide (LPS), a cell surface component of Gram‐negative bacteria, activates innate immunity. Its active principle is the terminal glycolipid lipid A. Acetobacter pasteurianus is a Gram‐negative bacterium used in the fermentation of traditional Japanese black rice vinegar (kurozu). In this study, we focused on A. pasteurianus lipid A, which is a potential immunostimulatory component of kurozu. The active principle structure of A. pasteurianus lipid A has not yet been identified. Herein, we first systematically synthesized three types of A. pasteurianus lipid As containing a common and unique tetrasaccharide backbone. We developed an efficient method for constructing the 2‐trehalosamine skeleton utilizing borinic acid‐catalyzed glycosylation to afford 1,1’‐α,α‐glycoside in high yield and stereoselectivity. A common tetrasaccharide intermediate with an orthogonal protecting group pattern was constructed via …

Chemical Communications

We synthesized and evaluated Pam3CSK4-conjugated receptor binding domain (RBD)/deglycosylated RBD as potential anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidates. Our investigation revealed the critical importance of limiting the number of introduced Pam3CSK4 molecules to the RBD in order to preserve its antigenicity. We also confirmed the harmonious integration of the adjuvant-conjugation strategy with the glycan-shield removal strategy.

Phytochemistry

Seven previously undescribed preurianin-type limonoids, namely paraxylines A-G, and three known analogs were isolated from stem bark of Dysoxylum parasiticum. The structures, including absolute configurations, were established through spectroscopic analyses, quantum chemical calculations using the density functional theory method, as well as the DP4+ algorithm. Paraxylines A-G were identified as the first preurianin-type with full substitution at C, D-rings, leading to the highly oxygenated seco-limonoids skeleton. The secreted alkaline phosphate assay against an engineered human and murine TLR4 of HEK-Blue cells was performed to evaluate the immune regulating effects. Among them, paraxyline B was found to be a remarkable TLR4 agonist whereas two analogs (toonapubesins A and B) were found to antagonise lipopolysaccharide stimulation of the TLR4 pathway. Paraxylines A and C-E acted either …

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by inflammation in multiple organs. A few treatments for SLE currently exist, including antimalarials, glucocorticoids, immunosuppressants, and two recently approved antibody agents; however, an unmet medical need remains for SLE. In addition, developing new drugs targeting SLE is a challenge since no specific biomarkers exist for the prediction of disease progression or drug response. A new drug candidate, E6742, is a specific antagonist of the toll-like receptors 7/8. To address the challenges for drug development in SLE, the process of developing E6742 utilizes a unique system of the Japan Agency for Medical Research and Development (AMED), the Cyclic Innovation for Clinical Empowerment (CiCLE) program. In the CiCLE program, a Phase 1 study in healthy adults was completed (NCT04683185) and a Phase 1/2 study in …

Phytochemistry

Seven previously undescribed preurianin-type limonoids, namely paraxylines A-G, and three known analogs were isolated from stem bark of Dysoxylum parasiticum. The structures, including absolute configurations, were established through spectroscopic analyses, quantum chemical calculations using the density functional theory method, as well as the DP4+ algorithm. Paraxylines A-G were identified as the first preurianin-type with full substitution at C, D-rings, leading to the highly oxygenated seco-limonoids skeleton. The secreted alkaline phosphate assay against an engineered human and murine TLR4 of HEK-Blue cells was performed to evaluate the immune regulating effects. Among them, paraxyline B was found to be a remarkable TLR4 agonist whereas two analogs (toonapubesins A and B) were found to antagonise lipopolysaccharide stimulation of the TLR4 pathway. Paraxylines A and C-E acted either …

Nutrients

The cellular and molecular mechanisms of atherosclerosis are still unclear. Type 2 innate lymphocytes (ILC2) exhibit anti-inflammatory properties and protect against atherosclerosis. This study aimed to elucidate the pathogenesis of atherosclerosis development using atherosclerosis model mice (ApoE KO mice) and mice deficient in IL-33 receptor ST2 (ApoEST2 DKO mice). Sixteen-week-old male ApoE KO and ApoEST2 DKO mice were subjected to an 8-week regimen of a high-fat, high-sucrose diet. Atherosclerotic foci were assessed histologically at the aortic valve ring. Chronic inflammation was assessed using flow cytometry and real-time polymerase chain reaction. In addition, saturated fatty acids (palmitic acid) and IL-33 were administered to human aortic endothelial cells (HAECs) to assess fatty acid metabolism. ApoEST2 DKO mice with attenuated ILC2 had significantly worse atherosclerosis than ApoE KO mice. The levels of saturated fatty acids, including palmitic acid, were significantly elevated in the arteries and serum of ApoEST2 DKO mice. Furthermore, on treating HAECs with saturated fatty acids with or without IL-33, the Oil Red O staining area significantly decreased in the IL-33-treated group compared to that in the non-treated group. IL-33 potentially prevented the accumulation of saturated fatty acids within atherosclerotic foci.

International Immunology

We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103− CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of …

ACS Central Science

Streptococcus gordonii is a Gram-positive bacterial species that typically colonizes the human oral cavity, but can also cause local or systemic diseases. Serine-rich repeat (SRR) glycoproteins exposed on the S. gordonii bacterial surface bind to sialylated glycans on human salivary, plasma, and platelet glycoproteins, which may contribute to oral colonization as well as endocardial infections. Despite a conserved overall domain organization of SRR adhesins, the Siglec-like binding regions (SLBRs) are highly variable, affecting the recognition of a wide range of sialoglycans. SLBR-N from the SRR glycoprotein of S. gordonii UB10712 possesses the remarkable ability to recognize complex core 2 O-glycans. We here employed a multidisciplinary approach, including flow cytometry, native mass spectrometry, isothermal titration calorimetry, NMR spectroscopy from both protein and ligand perspectives, and …

medRxiv

Objectives To evaluate the safety, tolerability, pharmacokinetics (PK), biomarker response, and efficacy of E6742 in a phase 1/2 study in patients with systemic lupus erythematosus (SLE). Methods Two sequential cohorts of SLE patients were enrolled and randomized to 12 weeks of twice-daily treatment with E6742 (100 or 200 mg; n = 8 or 9) or placebo (n = 9). Results The proportion of patients with any treatment-emergent adverse events (TEAEs) was 58.8% in the E6742 group (37.5% for 100 mg; 77.8% for 200 mg) and 66.7% in the placebo group. No Common Terminology Criteria for Adverse Events ≥ Grade 3 TEAEs occurred. PK parameter levels were similar between SLE patients and healthy adults in previous phase 1 studies. The interferon gene signature (IGS) and levels of proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α) after ex-vivo challenge with a Toll-like receptor 7/8 agonist were immediately decreased by E6742 treatment. Dose-dependent improvements in the British Isles Lupus Assessment Group-based Composite Lupus Assessment response were observed at Week 12 in the E6742 (37.5% for 100 mg; 57.1% for 200 mg) and placebo (33.3%) groups. E6742 also had therapeutic effects on other symptoms, including skin inflammation, arthritis, and levels of anti-double-stranded DNA antibodies and complements. Conclusions E6742 had a favorable safety profile and was well tolerated, with marked IGS responses and sufficient efficacy signals in patients with SLE. These results provide the first clinical evidence to support E6742 in the treatment of SLE, and support larger, longer-term clinical trials.

International Immunology

We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103− CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of …

International Immunology

Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including Toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to lysine 63-linked polyubiquitin chain through TAK1-binding proteins (TAB) 2 and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and …

Current Issues in Molecular Biology

Chisocheton plants from the family Meliaceae have traditionally been used to treat several diseases; however, scientific evidence is limited. The most abundant chemical constituents of this plant are the limonoids, which are known for their various biological activities, including anti-inflammatory effects. However, the anti-inflammatory effects and underlying mechanisms of action of the constituents of Chisocheton plants have not been fully explored. In this report, we evaluated the anti-inflammatory activity of 17 limonoid compounds from Chisocheton plant primarily by measuring their inhibitory effects on the production of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and MCP-1, in LPS-stimulated THP-1 cells using an ELISA assay. Compounds 3, 5, 9, and 14–17 exhibited significant activity in inhibiting the evaluated pro-inflammatory markers, with IC50 values less than 20 µM and a high selectivity index (SI) range. Compounds 3, 5, 9, and 15 significantly suppressed the expression of phosphorylated p38 MAPK in THP-1 cells stimulated with LPS. These findings support the use of limonoids from Chisocheton plants as promising candidates for anti-inflammatory therapy.

The invention provides a method for producing radiolabeled tyrosine derivatives with good purity and stability, by a safe method suitable for industrial production of pharmaceuticals. The invention relates to a method for producing Compound (5) and Radiolabeled Compound (6) as follows:

Nature

The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective 1, 2. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury 2, 3. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context 4, 5, 6, 7, 8, 9, 10, 11, 12. However, how neuro–immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the Na V 1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process …

International Immunopharmacology

Intervertebral disc degeneration (IVDD) stands as the primary cause of low back pain (LBP). A significant contributor to IVDD is nucleus pulposus cell (NPC) senescence. However, the precise mechanisms underlying NPC senescence remain unclear. Monoacylglycerol lipase (MAGL) serves as the primary enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), breaking down monoglycerides into glycerol and fatty acids. It plays a crucial role in various pathological processes, including pain, inflammation, and oxidative stress. In this study, we utilized a lipopolysaccharide (LPS)-induced NPC senescence model and a rat acupuncture-induced IVDD model to investigate the role of MAGL in IVDD both in vitro and in vivo. Initially, our results showed that MAGL expression was increased 2.41-fold and 1.52-fold within NP tissues from IVDD patients and rats induced with acupuncture, respectively. This …

International Immunopharmacology

PurposeMyocardial injury induced by sepsis can increase the patient’s mortality, which is an important complication of sepsis. Myocardial apoptosis plays a key role in septic myocardial injury. Here we explored the potential mechanism of astaxanthin (ATX) inhibiting myocardial apoptosis induced by lipopolysaccharide (LPS) in vitro.MethodsThe H9C2 cell experiment was conducted in three parts. In the first part, we set up three groups: control group, LPS group (10 µg/ml), a model of septic myocardial injury, and LPS + ATX (5, 10, 30 µM); In the second part, we set up four groups: control group, LPS group, LPS + PTP1B-IN-1, a protein tyrosine phosphatase 1B (PTP1B) inhibitor, and LPS + PTP1B-IN-1 + ATX; In the third part, we set up four groups: control group, LPS group, LPS + Anisomycin, a c-Jun N-terminal kinase (JNK) activator, and LPS + Anisomycin + ATX. We assessed H9C2 cell viability using the Cell …

International Immunopharmacology

Residing obligatorily as amastigotes within the mammalian macrophages, the parasite Leishmania donovani inflicts the potentially fatal, globally re-emerging disease visceral leishmaniasis (VL) by altering intracellular signaling through kinases and phosphatases. Because the phosphatases that modulate the VL outcome in humans remained unknown, we screened a human phosphatase siRNA-library for anti-leishmanial functions in THP-1, a human macrophage-like cell line. Of the 251 phosphatases, the screen identified the Ca++-activated K+-channel-associated phosphatase myotubularin-related protein-6 (MTMR6) as the only phosphatase whose silencing reduced parasite load and IL-10 production in human macrophages. Virulent, but not avirulent, L. donovani infection increased MTMR6 expression in macrophages. As virulent L. donovani parasites expressed higher lipophosphoglycan, a TLR2-ligand, we …

International Immunopharmacology

Growing evidence suggests that phosphoinositide 3-kinase (PI3K) and adenosine monophosphate-activated protein kinase (AMPK) signaling cascades are critical in ulcerative colitis (UC) pathophysiology by influencing gut mucosal inflammation. Recently, the coloprotective properties of dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged. Thus, this study assessed for the first time the potential mitigating impact of a DPP-IV inhibitor, vildagliptin (Vilda), on oxazolone (OXZ)-induced colitis in rats, targeting the role of PI3K/AKT/mTOR and AMPK/Nrf2 pathways. Thirty-two adult Albino rats were divided into four groups: control, Vilda (10 mg/kg/day orally), OXZ (300 µL of 5 % OXZ in 50 % aqueous ethanol solution introduced once into the colon via catheter), and Vilda+OXZ. Inflammatory cytokines (interleukin 13, tumor necrosis factor-α, interleukin 10), oxidative/endoplasmic reticulum stress markers …

International Immunopharmacology

Dendritic cells (DCs) are specialized antigen-presenting cells that play an important role in inducing and maintaining immune tolerance. The altered distribution and/or function of DCs contributes to defective tolerance in autoimmune diseases such as type 1 diabetes (T1D). In human T1D and in NOD mouse models, DCs share some defects and are often described as less tolerogenic and excessively immunogenic. In the NOD mouse model, the autoimmune response is associated with a defect in the Stat5b signaling pathway. We have reported that expressing a constitutively active form of Stat5b in DCs of transgenic NOD mice (NOD.Stat5b-CA), re-established their tolerogenic function, restored autoimmune tolerance and conferred protection from diabetes. However, the role and molecular mechanisms of Stat5b signaling in regulating splenic conventional DCs tolerogenic signature remained unclear. In this study …

International Immunopharmacology

The anti-inflammatory and immunosuppressive drugs which are used in the treatment of Graft-versus-Host Disease (GVHD) have limited effects in controlling the severity of the disease. In this study, we aimed to investigate the prophylactic effect of Alantolactone (ALT) in a murine model of experimental GVHD.The study included 4 BALB/c groups as hosts: Naïve (n = 7), Control GVHD (n = 16), ALT-GVHD (n = 16), and Syngeneic transplantation (n = 10). Busulfan (20 mg/kg/day) for 4 days followed by cyclophosphamide (100 mg/kg/day) were administered for conditioning. Allogeneic transplantation was performed with cells collected from mismatched female C57BL/6, and GVHD development was monitored by histological and flow cytometric assays. Additionally, liver biopsies were taken from GVHD patient volunteers between ages 2–18 (n = 4) and non-GVHD patients between ages 2–50 (n = 5) and cultured ex …

International Immunopharmacology

Severe soft tissue infections caused by Aeromonas dhakensis, such as necrotizing fasciitis or cellulitis, are prevalent in southern Taiwan and around the world. However, the mechanism by which A. dhakensis causes tissue damage remains unclear. Here, we found that the haemolysin Ahh1, which is the major virulence factor of A. dhakensis, causes cellular damage and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathway. Deletion of ahh1 significantly downregulated caspase-1, the proinflammatory cytokine interleukin 1β (IL-1β) and gasdermin D (GSDMD) and further decreased the damage caused by A. dhakensis in THP-1 cells. In addition, we found that knockdown of the NLRP3 inflammasome confers resistance to A. dhakensis infection in both THP-1 NLRP3-/- cells and C57BL/6 NLRP3-/- mice. In addition, we demonstrated that severe soft-tissue infections treated …

International Immunopharmacology

Psoriasis is a devastating autoimmune illness resulting from excessive keratinocyte growth and leukocyte infiltration into the dermis/epidermis. In the pathogenesis of psoriasis, different immune cells such as myeloid cells and CD4 + T cells play a key role. Th17/Th1 immune responses and oxidant-antioxidant responses are critical in regulation of psoriatic inflammation. Di-2-ethylhexyl phthalate (DEHP) is one of the well-known plasticizers and has widespread use worldwide. DEHP exposure through ingestion may produce harmful effects on the skin through systemic inflammation and oxidative stress, which may modify psoriatic inflammation. However, the effect of oral DEHP exposure on inflammatory cytokines and Nrf2/iNOS signaling in myeloid cells and CD4 + T cells in the context of psoriatic inflammation has not been investigated earlier. Therefore, this study explored the effect of DEHP on systemic …

International Immunopharmacology

L-arginine, as an essential substance of the immune system, plays a vital role in innate immunity. MiR155, a multi-functional microRNA, has gained importance as a regulator of homeostasis in immune cells. However, the immunoregulatory mechanism between L-arginine and miR155 in bacterial infections is unknown. Here, we investigated the potential role of miR155 in inflammation and the molecular regulatory mechanisms of L-arginine in Streptococcus uberis (S. uberis) infections. And we observed that miR155 was up-regulated after infection, accompanying the depletion of L-arginine, leading to metabolic disorders of amino acids and severe tissue damage. Mechanically, the upregulated miR155 mediated by the p65 protein played a pro-inflammatory role by suppressing the suppressor of cytokine signaling 6 (SOCS6)-mediated p65 ubiquitination and degradation. This culminated in a violently inflammatory …

International Immunopharmacology

BackgroundAcute lung injury (ALI) has garnered significant attention in the field of respiratory and critical care due to its high mortality and morbidity, and limited treatment options. The role of the endothelial barrier in the development of ALI is crucial. Several bacterial pathogenic factors, including the bacteria-derived formyl peptide (fMLP), have been implicated in damaging the endothelial barrier and initiating ALI. However, the mechanism by which fMLP causes ALI remains unclear. In this study, we aim to explore the mechanisms of ALI caused by fMLP and evaluate the protective effects of MOTS-c, a mitochondrial-derived peptide.MethodsWe established a rat model of ALI and a human pulmonary microvascular endothelial cell (HPMVEC) model of ALI by treatment with fMLP. In vivo experiments involved lung histopathology assays, assessments of inflammatory and oxidative stress factors, and measurements of …

International Immunopharmacology

BackgroundFibroblasts are necessary to the progression of cancer. However, the role of fibroblasts in peritoneal metastasis (PM) of gastric cancer (GC) remains elusive. In this study, we would explore the role of fibroblasts mediated cell interaction in PM of GC.MethodsSingle-cell sequencing data from public database GSE183904 was used to explore the specific fibroblast cluster. Fibroblasts were extracted from PM and GC tissues. The expression level of CXCR7 was verified by western blot, immunohistochemistry. The role of CLDN11 was investigate through in vitro and in vivo study. Multiple immunohistochemistry was used to characterize the tumor microenvironment.ResultsCXCR7-positive fibroblasts were significantly enriched in PM of GC. CXCR7 could promote the expression of CLDN11 through activation of the AKT pathway in fibroblasts. Fibroblasts promote the GC proliferation and peritoneal metastasis …

International Immunopharmacology

BackgroundSystemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear genes, deposition of immune complexes, and autoimmune T cells, through which, tissue damage would ultimately occur. Furthermore, loss of immune tolerance and imbalance of Th1/Th2 cells in addition to Th17/Treg are contributed to the pathogenesis of SLE. Mesenchymal stromal cells (MSCs) infusion is a potential therapy for SLE disease. Despite a majority of SLE patients achieving clinical remission after allogeneic MSC infusion from healthy individuals, SLE patients have less benefited from autologous MSC infusion, justifying the probable compromised function of SLE patients-derived MSCs. In this study, we aim to further investigate the potential immunoregulatory mechanisms in which mesenchymal stromal cells derived from pristane-induced lupus mice …

International Immunopharmacology

Influenza virus is a kind of virus that poses several hazards of animal and human health. Therefore, it is important to develop an effective vaccine to prevent influenza. To this end we successfully packaged recombinant adenovirus rAd-NP-M2e-GFP expressing multiple copies of influenza virus conserved antigens NP and M2e and packaged empty vector adenovirus rAd-GFP. The effect of rAd-NP-M2e-GFP on the activation of dendritic cell (DC) in vitro and in vivo was detected by intranasal immunization. The results showed that rAd-NP-M2e-GFP promoted the activation of DC in vitro and in vivo. After the primary immunization and booster immunization of mice through the nasal immune way, the results showed that rAd-NP-M2e-GFP induced enhanced local mucosal-specific T cell responses, increased the content of SIgA in broncho alveolar lavage fluids (BALF) and triggered the differentiation of B cells in the …

International Immunopharmacology

BackgroundAnkylosing spondylitis (AS) is a chronic autoimmune arthritis that mainly affects spine joints. To date, the pathogenesis of AS remains unclear, although immune cells and innate immune response cytokines have been suggested to be crucial players. Methods: By adopting a single-cell RNA sequencing approach in the AS cynomolgus model, we profiled and characterized PBMC proportions along disease progression. Results: Here, our primary focus was on the activation of an immune cascade-initiating lymphocyte subtype known as CD4+CXCR5+ T follicular helper (Tfh) cells. These Tfhs demonstrated a localized residence in AS bone lesion as an ectopic lymphoid structure. Moreover, Tfhs would serve as an upstream initiator for a pro-angiogenic cascade. Then, an expansion in CD14+ monocytes and DC cells subsets resulted in enhanced expression of angiogenesis genes in these AS cynomolgus …

International Immunopharmacology

IntroductionPhospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a common cause of nephrotic syndrome in nondiabetic adults who are also within the common age group for malignancy. How to treat patients with PLA2R-associated MN and malignancy effectively and safely still requires careful consideration. The aim of our study was to examine the outcomes and safety of rituximab (RTX) in these patients.MethodsRetrospective analysis of clinical data was performed on 15 patients with PLA2R-associated MN and malignancy. Patients were followed every 1–3 months for a minimum of 24 months. Clinical data were collected, including CD19+ B cells, anti-PLA2R antibodies, 24-hour urinary protein, serum albumin, and serum creatinine. The percentage of patients who achieved clinical remission and immunological remission was also measured.ResultsAmong these 15 patients, 14 …

International Immunopharmacology

BackgroundSynovial hypoxia, a critical pathological characteristic of rheumatoid arthritis (RA), significantly contributes to synovitis and synovial hyperplasia. In response to hypoxic conditions, fibroblast-like synoviocytes (FLS) undergo adaptive changes involving gene expression modulation, with hypoxia-inducible factors (HIF) playing a pivotal role. The regulation of BCL2/adenovirus e1B 19 kDa protein interacting protein 3 (BNIP3) and nucleotide-binding oligomerization segment-like receptor family 3 (NLRP3) expression has been demonstrated to be regulated by HIF-1. The objective of this study was to examine the molecular mechanism that contributes to the aberrant activation of FLS in response to hypoxia. Specifically, the interaction between BNIP3-mediated mitophagy and NLRP3-mediated pyroptosis was conjointly highlighted.MethodsThe research methodology employed Western blot and …

International Immunopharmacology

This study investigated the antioxidant, anticancer, antibacterial properties of Dioon rzedowskii extract, which had not been previously explored. We aimed to determine the extract's effect on liver and breast cancer cell lines and on solid Ehrlich carcinoma (SEC) mouse model to investigate the underlying molecular mechanisms. Three female albino mice groups were established: a tumor control group, a group treated with 100 mg/kg of the extract (D100), and a group treated with 200 mg/kg of the extract (D200) for 16 days after tumor development. Results showed that the D. rzedowskii extract inhibited cell growth in both MCF-7 and HepG2 cells in a concentration-dependent manner. This was achieved by suppressing the cell proliferation and inducing apoptosis. The extract also improved liver, heart, and kidney functions compared to the tumor control. Furthermore, oral administration of the extract reduced tumor …

International Immunopharmacology

ObjectivesInterstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls.MethodsPeripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression.ResultsThere was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical …

International Immunopharmacology

The anti-inflammatory and immunosuppressive drugs which are used in the treatment of Graft-versus-Host Disease (GVHD) have limited effects in controlling the severity of the disease. In this study, we aimed to investigate the prophylactic effect of Alantolactone (ALT) in a murine model of experimental GVHD.The study included 4 BALB/c groups as hosts: Naïve (n = 7), Control GVHD (n = 16), ALT-GVHD (n = 16), and Syngeneic transplantation (n = 10). Busulfan (20 mg/kg/day) for 4 days followed by cyclophosphamide (100 mg/kg/day) were administered for conditioning. Allogeneic transplantation was performed with cells collected from mismatched female C57BL/6, and GVHD development was monitored by histological and flow cytometric assays. Additionally, liver biopsies were taken from GVHD patient volunteers between ages 2–18 (n = 4) and non-GVHD patients between ages 2–50 (n = 5) and cultured ex …

International Immunopharmacology

BackgroundFibrin(ogen) deposition in the central nervous system (CNS) contributes to neuropathological injury; however, its role in ischemic stroke is unknown. In this study, we identified fibrinogen as a novel proinflammatory regulator of post-stroke neuroinflammation and revealed the neuro-protection effect of fibrin-derived γ377-395 peptide in stroke.MethodsFibrinogen depletion and fibrinogen-derived γ377-395 peptide treatment were performed 2 h after establishing a permanent middle cerebral artery occlusion (pMCAO) model. The infarction volume, neurological score, fibrin(ogen) deposition, and inflammatory response were evaluated 24 h after occlusion. Both in vivo and in vitro studies were conducted to assess the therapeutic potential of the γ377-395 peptide in blocking the interactions between fibrin(ogen) and neutrophils.ResultsFibrin(ogen) deposited in the infarct core promoted post-stroke …