Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 3.457
Filter
1.
Int Immunopharmacol ; 136: 112383, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-38843642

ABSTRACT

The treatment of autoimmune and inflammatory diseases often requires targeting multiple pathogenic pathways. KYS202004A is a novel bispecific fusion protein designed to antagonize TNF-α and IL-17A, pivotal in the pathophysiology of autoimmune and inflammatory diseases. Our initial efforts focused on screening for optimal structure by analyzing expression levels, purity, and binding capabilities. The binding affinity of KYS202004A to TNF-α and IL-17A was evaluated using SPR. In vitro, we assessed the inhibitory capacity of KYS202004A on cytokine-induced CXCL1 expression in HT29 cells. In vivo, its efficacy was tested using a Collagen-Induced Arthritis (CIA) model in transgenic human-IL-17A mice and an imiquimod-induced psoriasis model in cynomolgus monkeys. KYS202004A demonstrated significant inhibition of IL-17A and TNF-α signaling pathways, outperforming the efficacy of monotherapeutic agents ixekizumab and etanercept in reducing CXCL1 expression in vitro and ameliorating disease markers in vivo. In the CIA model, KYS202004A significantly reduced clinical symptoms, joint destruction, and serum IL-6 concentrations. The psoriasis model revealed that KYS202004A, particularly at a 2  mg/kg dose, was as effective as the combination of ixekizumab and etanercept. This discovery represents a significant advancement in treating autoimmune and inflammatory diseases, offering a dual-targeted therapeutic approach with enhanced efficacy over current monotherapies.


Subject(s)
Arthritis, Experimental , Interleukin-17 , Macaca fascicularis , Psoriasis , Recombinant Fusion Proteins , Tumor Necrosis Factor-alpha , Animals , Interleukin-17/metabolism , Tumor Necrosis Factor-alpha/metabolism , Humans , Psoriasis/drug therapy , Psoriasis/immunology , Psoriasis/chemically induced , Recombinant Fusion Proteins/therapeutic use , Recombinant Fusion Proteins/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/immunology , Mice , Chemokine CXCL1/metabolism , Chemokine CXCL1/genetics , HT29 Cells , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Mice, Transgenic , Disease Models, Animal , Antibodies, Bispecific/therapeutic use , Antibodies, Bispecific/pharmacology , Male , Drug Evaluation, Preclinical , Imiquimod , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Mice, Inbred DBA
2.
Theranostics ; 14(8): 3339-3357, 2024.
Article in English | MEDLINE | ID: mdl-38855186

ABSTRACT

Rationale: Skin cells actively metabolize nutrients to ensure cell proliferation and differentiation. Psoriasis is an immune-disorder-related skin disease with hyperproliferation in epidermal keratinocytes and is increasingly recognized to be associated with metabolic disturbance. However, the metabolic adaptations and underlying mechanisms of epidermal hyperproliferation in psoriatic skin remain largely unknown. Here, we explored the role of metabolic competition in epidermal cell proliferation and differentiation in psoriatic skin. Methods: Bulk- and single-cell RNA-sequencing, spatial transcriptomics, and glucose uptake experiments were used to analyze the metabolic differences in epidermal cells in psoriasis. Functional validation in vivo and in vitro was done using imiquimod-like mouse models and inflammatory organoid models. Results: We observed the highly proliferative basal cells in psoriasis act as the winners of the metabolic competition to uptake glucose from suprabasal cells. Using single-cell metabolic analysis, we found that the "winner cells" promote OXPHOS pathway upregulation by COX7B and lead to increased ROS through glucose metabolism, thereby promoting the hyperproliferation of basal cells in psoriasis. Also, to prevent toxic damage from ROS, basal cells activate the glutathione metabolic pathway to increase their antioxidant capacity to assist in psoriasis progression. We further found that COX7B promotes psoriasis development by modulating the activity of the PPAR signaling pathway by bulk RNA-seq analysis. We also observed glucose starvation and high expression of SLC7A11 that causes suprabasal cell disulfide stress and affects the actin cytoskeleton, leading to immature differentiation of suprabasal cells in psoriatic skin. Conclusion: Our study demonstrates the essential role of cellular metabolic competition for skin tissue homeostasis.


Subject(s)
Cell Differentiation , Cell Proliferation , Glucose , Keratinocytes , Psoriasis , Psoriasis/metabolism , Psoriasis/pathology , Glucose/metabolism , Humans , Animals , Mice , Keratinocytes/metabolism , Disease Models, Animal , Single-Cell Analysis , Epidermal Cells/metabolism , Reactive Oxygen Species/metabolism , Energy Metabolism , Epidermis/metabolism , Epidermis/pathology , Imiquimod , Male
3.
J Exp Med ; 221(8)2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38861030

ABSTRACT

Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.


Subject(s)
Gain of Function Mutation , Imiquimod , STAT3 Transcription Factor , Th17 Cells , Animals , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Th17 Cells/immunology , Mice , Humans , Imiquimod/pharmacology , Skin/pathology , Skin/metabolism , Skin/immunology , Interleukin-22 , Dermatitis/immunology , Dermatitis/genetics , Dermatitis/pathology , Dermatitis/metabolism , Mice, Inbred C57BL , Interleukins/genetics , Interleukins/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Inflammation/genetics , Inflammation/metabolism , Inflammation/immunology , Inflammation/pathology
4.
Int J Immunopathol Pharmacol ; 38: 3946320241260262, 2024.
Article in English | MEDLINE | ID: mdl-38876119

ABSTRACT

INTRODUCTION: TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin. METHODS: Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7th day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry. RESULTS: Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin. CONCLUSION: The combination of deucravacitinib and shikonin is a promising clinical application.


Subject(s)
Drug Therapy, Combination , Imiquimod , Naphthoquinones , Psoriasis , Skin , Animals , Psoriasis/drug therapy , Psoriasis/chemically induced , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Mice , Skin/drug effects , Skin/pathology , Skin/metabolism , Disease Models, Animal , Cytokines/metabolism , Mice, Inbred BALB C , Male , Female , Benzimidazoles , Quinolones
5.
Dev Comp Immunol ; 157: 105197, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38763479

ABSTRACT

Toll-like receptors (TLRs) are pivotal pattern recognition receptors (PRRs) and key mediators of innate immunity. Despite the significance of channel catfish (Ictalurus punctatus) in comparative immunology and aquaculture, its 20 TLR genes remain largely functionally uncharacterized. In this study, our aim was to determine the catfish TLR7 agonists, signaling potential, and cellular localization. Using a mammalian reporter system, we identified imiquimod and resiquimod, typical ssRNA analogs, as potent catfish TLR7 agonists. Notably, unlike grass carp TLR7, catfish TLR7 lacks the ability to respond to poly (I:C). Confocal microscopy revealed predominant catfish TLR7 expression in lysosomes, co-localizing with the endosomal chaperone protein, UNC93B1. Furthermore, imiquimod stimulation elicited robust IFNb transcription in peripheral blood leukocytes isolated from adult catfish. These findings underscore the conservation of TLR7 signaling in catfish, reminiscent of mammalian TLR7 responses. Our study sheds light on the functional aspects of catfish TLR7 and contributes to a better understanding of its role in immune defense mechanisms.


Subject(s)
Fish Proteins , Ictaluridae , Imidazoles , Imiquimod , Immunity, Innate , Lysosomes , Toll-Like Receptor 7 , Animals , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 7/agonists , Toll-Like Receptor 7/genetics , Imidazoles/pharmacology , Ictaluridae/immunology , Lysosomes/metabolism , Fish Proteins/genetics , Fish Proteins/metabolism , Signal Transduction , Humans , Aminoquinolines/pharmacology , Poly I-C/immunology
6.
Mol Pharm ; 21(6): 2813-2827, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38752564

ABSTRACT

Psoriasis, affecting 2-3% of the global population, is a chronic inflammatory skin condition without a definitive cure. Current treatments focus on managing symptoms. Recognizing the need for innovative drug delivery methods to enhance patient adherence, this study explores a new approach using calcipotriol monohydrate (CPM), a primary topical treatment for psoriasis. Despite its effectiveness, CPM's therapeutic potential is often limited by factors like the greasiness of topical applications, poor skin permeability, low skin retention, and lack of controlled delivery. To overcome these challenges, the study introduces CPM in the form of nanosuspensions (NSs), characterized by an average particle size of 211 ± 2 nm. These CPM NSs are then incorporated into a trilayer dissolving microneedle patch (MAP) made from poly(vinylpyrrolidone) and w poly(vinyl alcohol) as needle arrays and prefrom 3D printed polylactic acid backing layer. This MAP features rapidly dissolving tips and exhibits good mechanical properties and insertion capability with delivery efficiency compared to the conventional Daivonex ointment. The effectiveness of this novel MAP was tested on Sprague-Dawley rats with imiquimod-induced psoriasis, demonstrating efficacy comparable to the marketed ointment. This innovative trilayer dissolving MAP represents a promising new local delivery system for calcipotriol, potentially revolutionizing psoriasis treatment by enhancing drug delivery and patient compliance.


Subject(s)
Administration, Cutaneous , Calcitriol , Drug Delivery Systems , Needles , Psoriasis , Rats, Sprague-Dawley , Psoriasis/drug therapy , Animals , Calcitriol/analogs & derivatives , Calcitriol/administration & dosage , Rats , Drug Delivery Systems/methods , Skin Absorption/drug effects , Skin/metabolism , Skin/drug effects , Skin/pathology , Particle Size , Male , Nanoparticles/chemistry , Imiquimod/administration & dosage , Suspensions , Dermatologic Agents/administration & dosage , Dermatologic Agents/pharmacokinetics , Transdermal Patch
7.
Int Immunopharmacol ; 134: 112183, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38705031

ABSTRACT

Psoriasis is a chronic inflammatory skin disease substantially affecting the quality of life, with no complete cure owing to its complex pathogenesis. Cornuside, a major bioactive compound present in Cornus officinalis Sieb. et Zucc., which is a well-known traditional Chinese medicine with a variety of biological and pharmacological activities, such as anti-apoptotic, antioxidant, and anti-inflammatory properties. However, its effects on psoriasis remain unclear. Our preliminary analysis of network pharmacology showed that cornuside may be involved in psoriasis by regulating the inflammatory response and IL-17 signaling pathway. Thus, we investigated the protective role and mechanism of cornuside in the pathogenesis of psoriasis in an imiquimod (IMQ)-induced psoriasis mouse model. In-vivo experiments demonstrated that cornuside-treated mice had reduced skin erythema, scales, thickness, and inflammatory infiltration. The Psoriasis Area Severity Index score was significantly lower than that of the IMQ group. Flow cytometry analysis indicated that cornuside effectively inhibited Th1- and Th17-cell infiltration and promoted aggregation of Th2 cells in skin tissues. Cornuside also inhibited the infiltration of macrophages to the skin. Furthermore, in-vitro experiments indicated that cornuside also decreased the polarization of M1 macrophages and reduced the levels of associated cytokines. Western blotting demonstrated that cornuside suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular receptor kinase (ERK) in bone marrow-derived macrophages. Our findings indicate that cornuside has a protective effect against IMQ-induced psoriasis by inhibiting M1 macrophage polarization through the ERK and JNK signaling pathways and modulating the infiltration of immune cells as well as the expression of inflammatory factors.


Subject(s)
Anti-Inflammatory Agents , Imiquimod , Mice, Inbred BALB C , Psoriasis , Skin , Th17 Cells , Animals , Psoriasis/drug therapy , Psoriasis/chemically induced , Psoriasis/immunology , Skin/drug effects , Skin/pathology , Skin/immunology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Mice , Th17 Cells/immunology , Th17 Cells/drug effects , Disease Models, Animal , Macrophages/drug effects , Macrophages/immunology , Cornus/chemistry , Humans , Interleukin-17/metabolism , Cytokines/metabolism , Female , Signal Transduction/drug effects , Th1 Cells/immunology , Th1 Cells/drug effects , Male
8.
Int Immunopharmacol ; 134: 112248, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38749332

ABSTRACT

Psoriasis, characterized by aberrant epidermal keratinocyte proliferation and differentiation, is a chronic inflammatory immune-related skin disease. Diosmetin (Dios), derived from citrus fruits, exhibits anti-inflammatory and anti-proliferative properties. In this study, IL-17A-induced HaCaT cell model and Imiquimod (IMQ)-induced mouse model were utilized to investigate the effects of Dios against psoriasis. The morphology and biomarkers of psoriasis were regarded as the preliminary evaluation including PASI score, skin thickness, H&E staining, EdU staining and inflammatory factors. Transcriptomics analysis revealed PGC-1α as a key target for Dios in ameliorating psoriasis. Specifically, Dios, through PGC-1α, suppressed YAP-mediated proliferation and inflammatory responses in psoriatic keratinocytes. In conclusion, Dios shows promise in psoriasis treatment and holds potential for development as targeted medications for application in psoriasis.


Subject(s)
Cell Proliferation , Imiquimod , Keratinocytes , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Psoriasis , Signal Transduction , Psoriasis/drug therapy , Psoriasis/immunology , Animals , Keratinocytes/drug effects , Keratinocytes/metabolism , Humans , Signal Transduction/drug effects , Cell Proliferation/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Mice , Flavonoids/pharmacology , Flavonoids/therapeutic use , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , YAP-Signaling Proteins/metabolism , Disease Models, Animal , Transcription Factors/metabolism , Transcription Factors/genetics , HaCaT Cells , Cell Line , Mice, Inbred BALB C , Interleukin-17/metabolism , Male , Inflammation/drug therapy
9.
Int Immunopharmacol ; 134: 112261, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38761783

ABSTRACT

BACKGROUND: Psoriasis, a chronic inflammatory condition of the skin, is characterized by an atypical proliferation of epidermal keratinocytes and immune cell infiltration. Orientin is a flavonoid monomer with potent anti-inflammatory activities. However, the therapeutic effects of orientin on psoriasis and the underlying mechanisms have not been elucidated. OBJECTIVE: To investigate the therapeutic effect of orientin on psoriasis and the underlying mechanisms using network pharmacology and experimental studies. METHODS: A psoriasis-like mouse model was established using imiquimod (IMQ). Lipopolysaccharide (LPS) was used to stimulate the RAW264.7 and HaCaT cells in vitro. The therapeutic effects of orientin and the underlying mechanism were analyzed using histopathological, immunohistochemical, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, flow cytometry, and western blotting analyses. RESULTS: Orientin ameliorated skin lesions and suppressed keratinocyte proliferation and immune cell infiltration in the IMQ-induced psoriasis-like mouse model. Additionally, orientin inhibited the secretion of the pro-inflammatory factors interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, IL-8, IL-17, and IL-23 in the psoriasis-like mouse model and LPS-induced RAW264.7 and HaCaT cells. Furthermore, orientin mitigated the LPS-induced upregulation of reactive oxygen species and downregulation of IL-10 and glutathione levels. Orientin alleviated inflammation by downregulating the MAPK signaling pathway. CONCLUSION: Orientin alleviated psoriasis-like dermatitis by suppressing the MAPK signaling pathway, suggesting that orientin is a potential therapeutic for psoriasis.


Subject(s)
Anti-Inflammatory Agents , Cytokines , Disease Models, Animal , Flavonoids , Glucosides , HaCaT Cells , Imiquimod , Keratinocytes , Lipopolysaccharides , MAP Kinase Signaling System , Mice, Inbred BALB C , Psoriasis , Animals , Psoriasis/drug therapy , Psoriasis/immunology , Psoriasis/chemically induced , Psoriasis/pathology , Mice , Humans , RAW 264.7 Cells , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Flavonoids/pharmacology , Flavonoids/therapeutic use , Cytokines/metabolism , Keratinocytes/drug effects , Glucosides/therapeutic use , Glucosides/pharmacology , MAP Kinase Signaling System/drug effects , Skin/pathology , Skin/drug effects , Skin/immunology , Cell Proliferation/drug effects , Male , Reactive Oxygen Species/metabolism , Dermatitis/drug therapy , Dermatitis/pathology , Dermatitis/immunology , Cell Line
10.
Phytomedicine ; 130: 155544, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-38810554

ABSTRACT

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease that affects the quality of life and mental health of approximately 150 million people worldwide. Ze-Qi-Tang (ZQT) is a classic compound used in China for lung disease; however, its mechanism of action in psoriasis remains unclear. This study aimed to investigate the therapeutic effect of the ZQT formula on psoriasis and explore the underlying molecular mechanisms. METHODS: Peripheral blood samples were collected from patients with psoriasis and healthy individuals. Flow cytometry was used to detect changes in the proportions of myeloid-derived suppressor cells (MDSCs) and other immune cells. Psoriasis was induced in mice by the daily application of imiquimod. ZQT was administered separately or in combination with anti-Gr1 antibody to deplete MDSC. The glycolysis levels of the MDSCs were detected using a Seahorse analyzer. The p21/Hif1α/Glut1 pathway was identified and validated by mRNA sequence, RT-qPCR, WB, IF, and the application of p21 inhibitor UC2288. RESULTS: The number of MDSCs was significantly increased in patients with psoriasis, with the increased expression of p21, Hif1α, and Glut1 in MDSCs. ZQT significantly alleviated psoriasis-like skin lesions in mice. ZQT formula significantly reduced the number of MDSCs in psoriatic-like mice and enhanced their suppressive capacity for T cells. The efficacy of ZQT in alleviating psoriatic dermatitis is compromised by MDSC depletion. ZQT decreased the expressions of p21, Hif1α, and Glut1-induced glycolysis in MDSCs, thereby inhibiting Th17 cell differentiation. CONCLUSION: These suggest that ZQT alleviates IMQ-induced psoriatic dermatitis, by inhibiting p21/Hif1α/Glut1-induced glycolysis in MDSCs.


Subject(s)
Down-Regulation , Drugs, Chinese Herbal , Glucose Transporter Type 1 , Glycolysis , Hypoxia-Inducible Factor 1, alpha Subunit , Myeloid-Derived Suppressor Cells , Psoriasis , Animals , Psoriasis/drug therapy , Glucose Transporter Type 1/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Glycolysis/drug effects , Drugs, Chinese Herbal/pharmacology , Humans , Mice , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/metabolism , Male , Down-Regulation/drug effects , Female , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Disease Models, Animal , Adult , Signal Transduction/drug effects , Mice, Inbred BALB C , Imiquimod , Middle Aged
11.
Arch Dermatol Res ; 316(5): 176, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38758283

ABSTRACT

Psoriasis is a chronic immune mediated inflammatory skin disease with systemic manifestations. It has been reported that caloric restriction could improve severity of psoriasis patients. However, the mechanism of intermittent fasting effects on psoriasis has not been investigated. Caloric restriction is known to reduce the number of circulating inflammatory monocytes in a CCL2-dependent manner. However, it is still unknown whether caloric restriction can improve psoriasis by regulating monocytes through CCL2. In this study, we used imiquimod (IMQ)-induced psoriasis-like mouse model to explore the effects and the mechanisms of intermittent fasting on psoriasis-like dermatitis. We found that intermittent fasting could significantly improve IMQ-induced psoriasis-like dermatitis, and reduce the number of γδT17 cells and IL-17 production in draining lymph nodes and psoriatic lesion via inhibiting proliferation and increasing death of γδT17 cells. Furthermore, intermittent fasting could significantly decrease monocytes in blood, and this was associated with decreased monocytes, macrophages and DC in psoriasis-like skin inflammation. Reduced monocytes in circulation and increased monocytes in BM of fasting IMQ-induced psoriasis-like mice is through reducing the production of CCL2 from BM to inhibit monocyte egress to the periphery. Our above data shads light on the mechanisms of intermittent fasting on psoriasis.


Subject(s)
Chemokine CCL2 , Disease Models, Animal , Fasting , Imiquimod , Monocytes , Psoriasis , Animals , Psoriasis/immunology , Psoriasis/chemically induced , Psoriasis/pathology , Monocytes/immunology , Monocytes/metabolism , Mice , Fasting/blood , Chemokine CCL2/metabolism , Th17 Cells/immunology , Interleukin-17/metabolism , Skin/pathology , Skin/immunology , Humans , Mice, Inbred C57BL , Male , Cell Proliferation , Caloric Restriction , Intermittent Fasting
12.
Int J Biol Macromol ; 269(Pt 2): 132177, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38729484

ABSTRACT

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.


Subject(s)
Cancer Vaccines , Hyaluronic Acid , Hydrogels , Indoles , Nanoparticles , Polymers , Hyaluronic Acid/chemistry , Polymers/chemistry , Cancer Vaccines/chemistry , Cancer Vaccines/immunology , Indoles/chemistry , Indoles/pharmacology , Animals , Mice , Hydrogels/chemistry , Nanoparticles/chemistry , Humans , Imiquimod/chemistry , Imiquimod/pharmacology , Dendritic Cells/immunology , Vaccination , Cell Line, Tumor , Immunotherapy/methods , Cross-Linking Reagents/chemistry , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/drug effects
13.
Int J Nanomedicine ; 19: 4719-4733, 2024.
Article in English | MEDLINE | ID: mdl-38813391

ABSTRACT

Introduction: Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in nanotherapy, the limitations of single-treatment modalities and significant side effects persist. To tackle lung cancer effectively, we devised a temperature-sensitive hydrogel-based local injection system with near-infrared triggered drug release. Utilizing 2D MXene nanosheets as carriers loaded with R837 and cisplatin (DDP), encapsulated within a temperature-sensitive hydrogel-forming PEG-MXene@DDP@R837@SHDS (MDR@SHDS), we administered in situ injections of MDR@SHDS into tumor tissues combined with photothermal therapy (PTT). The immune adjuvant R837 enhances dendritic cell (DC) maturation and tumor cell phagocytosis, while PTT induces tumor cell apoptosis and necrosis by converting light energy into heat energy. Methods: Material characterization employed transmission electron microscopy, X-ray photoelectron spectroscopy, phase transition temperature, and near-infrared thermography. In vitro experiments assessed Lewis cell proliferation and apoptosis using CCK-8, Edu, and TUNEL assays. In vivo experiments on C57 mouse Lewis transplant tumors evaluated the photothermal effect via near-infrared thermography and assessed DC maturation and CD4+/CD8+ T cell ratios using flow cytometry. The in vivo anti-tumor efficacy of MDR@SHDS was confirmed by tumor growth curve recording and HE and TUNEL staining of tumor sections. Results: The hydrogel exhibited excellent temperature sensitivity, controlled release properties, and high biocompatibility. In vitro experiments revealed that MDR@SHDS combined with PTT had a greater inhibitory effect on tumor cell proliferation compared to MDR@SHD alone. Combining local immunotherapy, chemotherapy, and PTT yielded superior anti-tumor effects than individual treatments. Conclusion: MDR@SHDS, with its simplicity, biocompatibility, and enhanced anti-tumor effects in combination with PTT, presents a promising therapeutic approach for lung cancer treatment, offering potential clinical utility.


Subject(s)
Cisplatin , Imiquimod , Lung Neoplasms , Mice, Inbred C57BL , Animals , Cisplatin/pharmacology , Cisplatin/chemistry , Cisplatin/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice , Imiquimod/chemistry , Imiquimod/administration & dosage , Imiquimod/pharmacology , Hydrogels/chemistry , Apoptosis/drug effects , Nanostructures/chemistry , Photothermal Therapy/methods , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Drug Delivery Systems/methods , Humans , Temperature , Dendritic Cells/drug effects , Drug Carriers/chemistry , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/pathology
14.
ACS Appl Mater Interfaces ; 16(21): 27187-27201, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38747985

ABSTRACT

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.


Subject(s)
Glioma , Magnetic Resonance Imaging , Manganese Compounds , Theranostic Nanomedicine , Glioma/diagnostic imaging , Glioma/drug therapy , Glioma/therapy , Glioma/pathology , Animals , Mice , Humans , Manganese Compounds/chemistry , Manganese Compounds/pharmacology , Doxorubicin/chemistry , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Cancer Vaccines/chemistry , Immunotherapy , Oxides/chemistry , Oxides/pharmacology , Cell Line, Tumor , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/drug therapy , Brain Neoplasms/therapy , Brain Neoplasms/pathology , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Blood-Brain Barrier/metabolism , Nanogels/chemistry , Imiquimod/chemistry , Imiquimod/pharmacology , Nanovaccines
15.
Int J Biol Macromol ; 269(Pt 2): 132207, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38723823

ABSTRACT

To overcome the low efficacy of sonodynamic therapy (SDT) caused by hypoxia in the tumor microenvironment, we developed a multiple anti-tumor nanoplatform with synergistic SDT, photothermal therapy (PTT), and ferroptosis effects. PCN-224@FcCaO2/Mn/dihydroartemisinin/imiquimod/PDA (PFC) was prepared by modified with dihydroartemisinin (DHA), imiquimod (R837), CaO2, ferrocene (Fc) and Mn2+ on the PCN-224 (Cu) to achieve self-replenishment of H2O2/O2 and GSH consumption. FcCaO2 decomposed into H2O2 in the tumor microenvironment, triggering the Fenton effect to produce OH, and Cu2+ reduced the potential loss of OH by the depletion of GSH. Under ultrasonic (US) and laser irradiation, PFC exhibits exciting PTT and SDT effects from polydopamine (PDA) and PCN-224. Mn2+ not only promoted the reaction of H2O2 to produce O2 to effectively enhance SDT but also induced tumor cell apoptosis by Mn2+ combined with DHA. PFC induced ferroptosis via Fe interaction with DHA to produce ROS and reduce the expression of GPX4. The released R837 and tumor-associated antigens from SDT/PTT can produce damage associated molecular patterns (DAMPs), which can initiate adaptive immune responses to kill cancer cells, and released again to promote the tumor immune cycle. What's more, SDT/PTT and ferroptosis combined with aPD-L1 can effectively suppress both primary and distant tumor growth.


Subject(s)
Indoles , Metal-Organic Frameworks , Photothermal Therapy , Polymers , Indoles/chemistry , Indoles/pharmacology , Polymers/chemistry , Polymers/pharmacology , Humans , Animals , Mice , Photothermal Therapy/methods , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Cell Line, Tumor , Nanoparticles/chemistry , Apoptosis/drug effects , Ferroptosis/drug effects , Tumor Microenvironment/drug effects , Combined Modality Therapy , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/chemistry , Hydrogen Peroxide/pharmacology , Imiquimod/pharmacology , Metallocenes/chemistry , Metallocenes/pharmacology
16.
Clin Cancer Res ; 30(9): 1768-1777, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38592381

ABSTRACT

PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.


Subject(s)
Imiquimod , Papillomavirus Infections , Papillomavirus Vaccines , Uterine Cervical Dysplasia , Uterine Cervical Neoplasms , Humans , Imiquimod/administration & dosage , Female , Papillomavirus Vaccines/administration & dosage , Adult , Uterine Cervical Dysplasia/immunology , Uterine Cervical Dysplasia/drug therapy , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/virology , Papillomavirus Infections/immunology , Papillomavirus Infections/complications , Papillomavirus Infections/virology , Middle Aged , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Aminoquinolines/administration & dosage , Aminoquinolines/adverse effects , Aminoquinolines/therapeutic use , Treatment Outcome , CD8-Positive T-Lymphocytes/immunology , Precancerous Conditions/drug therapy , Precancerous Conditions/pathology , Precancerous Conditions/immunology , Neoplasm Grading , Young Adult
17.
Exp Mol Med ; 56(5): 1164-1177, 2024 May.
Article in English | MEDLINE | ID: mdl-38689088

ABSTRACT

Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.


Subject(s)
Cell Degranulation , Disease Models, Animal , Eosinophils , Imiquimod , Intestine, Small , Psoriasis , Toll-Like Receptor 7 , Animals , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 7/genetics , Psoriasis/pathology , Psoriasis/metabolism , Mice , Eosinophils/metabolism , Eosinophils/immunology , Humans , Intestine, Small/pathology , Intestine, Small/metabolism , Skin/pathology , Skin/metabolism , Inflammation/pathology , Inflammation/metabolism , Mice, Knockout , Caco-2 Cells , Membrane Glycoproteins
18.
J Interferon Cytokine Res ; 44(6): 260-270, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38563809

ABSTRACT

Psoriasis is a chronic, immune-mediated inflammatory skin disease characterized by epidermal thickening and inflammatory cell infiltration. Excessive proliferation of keratinocytes and resistance to apoptosis lead to thickening of the epidermis. Plasmacytoid dendritic cells are involved in the occurrence of psoriasis mainly by secreting interferon-alpha (IFN-α). IFN-α is a glycoprotein with antiviral, antitumor, and immunomodulatory effects, but its role in psoriasis remains unclear. In this investigation, a mild psoriatic phenotype was observed in mice upon topical application of IFN-α cream, and the inflammation was exacerbated when combined with imiquimod (IMQ). Immunohistochemical analyses demonstrated that IFN-α induces psoriatic inflammation in mice by stimulating phosphorylation of forkhead box O3, consistent with the involvement of this protein in cell proliferation, apoptosis, and inflammation. Our results suggested that topical IFN-α caused psoriatic inflammation and that the psoriatic inflammation was exacerbated by the combination of IFN-α and IMQ, possibly due to the dysfunction of forkhead box O3.


Subject(s)
Forkhead Box Protein O3 , Inflammation , Interferon-alpha , Psoriasis , Animals , Psoriasis/chemically induced , Psoriasis/drug therapy , Psoriasis/pathology , Psoriasis/metabolism , Psoriasis/immunology , Mice , Interferon-alpha/metabolism , Forkhead Box Protein O3/metabolism , Inflammation/chemically induced , Inflammation/pathology , Inflammation/metabolism , Phosphorylation/drug effects , Imiquimod , Disease Models, Animal , Female
19.
Int Immunopharmacol ; 133: 112033, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38608446

ABSTRACT

Psoriasis is an immuno-inflammatory disease characterized by excessive keratinocyte proliferation, requiring extensive lipids. 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) is an essential enzyme in the mevalonate pathway, involved in cholesterol synthesis and the inflammatory response. However, the role of HMGCS1 in psoriasis has remained elusive. This study aims to elucidate the mechanism by which HMGCS1 controls psoriasiform inflammation. We discovered an increased abundance of HMGCS1 in psoriatic lesions when analyzing two Gene Expression Omnibus (GEO) datasets and confirmed this in psoriatic animal models and psoriatic patients by immunohistochemistry. In a TNF-α stimulated psoriatic HaCaT cell line, HMGCS1 was found to be overexpressed. Knockdown of HMGCS1 using siRNA suppressed the migration and proliferation of HaCaT cells. Mechanistically, HMGCS1 downregulation also reduced the expression of IL-23 and the STAT3 phosphorylation level. In imiquimod-induced psoriatic mice, intradermal injection of HMGCS1 siRNA significantly decreased the expression of HMGCS1 in the epidermis, which in turn led to an improvement in the Psoriasis Area and Severity Index score, epidermal thickening, and pathological Baker score. Additionally, expression levels of inflammatory cytokines IL-23, IL1-ß, chemokine CXCL1, and innate immune mediator S100A7-9 were downregulated in the epidermis. In conclusion, HMGCS1 downregulation improved psoriasis in vitro and in vivo through the STAT3/IL-23 axis.


Subject(s)
Hydroxymethylglutaryl-CoA Synthase , Interleukin-23 , Keratinocytes , Psoriasis , STAT3 Transcription Factor , Animals , Female , Humans , Male , Mice , Cell Line , Cell Proliferation/drug effects , Disease Models, Animal , HaCaT Cells , Hydroxymethylglutaryl-CoA Synthase/metabolism , Hydroxymethylglutaryl-CoA Synthase/genetics , Imiquimod , Interleukin-23/metabolism , Keratinocytes/drug effects , Keratinocytes/metabolism , Mice, Inbred BALB C , Psoriasis/chemically induced , Psoriasis/drug therapy , Psoriasis/immunology , Signal Transduction/drug effects , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics
20.
Cell Signal ; 119: 111171, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38604345

ABSTRACT

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease. MicroRNAs (miRNAs) are an abundant class of non-coding RNA molecules. Recent studies have shown that multiple miRNAs are abnormally expressed in patients with psoriasis. The upregulation of miR-374a-5p has been associated with psoriasis severity. However, the specific role of miR-374a-5p in the pathogenesis of psoriasis remain unclear. METHODS: qRT-PCR was employed to validate the expression of miR-374a-5p in psoriatic lesions and in a psoriasis-like cell model constructed using a mixture of M5 (IL-17A, IL-22, OSM, IL-1α, and TNF-α). HaCaT cells were transfected with miR-374a-5p mimic/inhibitor, and assays including EdU, CCK-8, and flow cytometry were conducted to evaluate the effect of miR-374a-5p on cell proliferation. The expression of inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α was verified by qRT-PCR. Bioinformatics analysis and dual-luciferase reporter gene assay were performed to detect the downstream target genes and upstream transcription factors of miR-374a-5p, followed by validation of their expression through qRT-PCR and Western blotting. A psoriasis-like mouse model was established using imiquimod cream topical application. The psoriasis area and severity index scoring, hematoxylin-eosin histology staining, and Ki67 immunohistochemistry were employed to validate the effect of miR-374a-5p on the psoriatic inflammation phenotype after intradermal injection of miR-374a-5p agomir/NC. Additionally, the expression of pathway-related molecules and inflammatory factors such as IL-1ß, IL-17a, and TNF-α was verified by immunohistochemistry. RESULTS: Upregulation of miR-374a-5p was observed in psoriatic lesions and the psoriasis-like cell model. In vitro experiments demonstrated that miR-374a-5p not only promoted the proliferation of HaCaT cells but also upregulated the expression of inflammatory cytokines, including IL-1ß, IL-6, IL-8, and TNF-α. Furthermore, miR-374a-5p promoted skin inflammation and epidermal thickening in the Imiquimod-induced psoriasis-like mouse model. Mechanistic studies revealed that miR-374a-5p led to downregulation of WIF1, thereby activating the Wnt5a/NF-κB signaling pathway. The transcription factor p65 encoded by RELA, as a subunit of NF-κB, further upregulated the expression of miR-374a-5p upon activation. This positive feedback loop promoted keratinocyte proliferation and abnormal inflammation, thereby facilitating the development of psoriasis. CONCLUSION: Our findings elucidate the role of miR-374a-5p upregulation in the pathogenesis of psoriasis through inhibition of WIF1 and activation of the Wnt5a/NF-κB pathway, providing new potential therapeutic targets for psoriasis.


Subject(s)
Adaptor Proteins, Signal Transducing , MicroRNAs , NF-kappa B , Psoriasis , Wnt-5a Protein , Animals , Humans , Mice , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cell Proliferation , Down-Regulation , HaCaT Cells , Imiquimod , MicroRNAs/metabolism , MicroRNAs/genetics , NF-kappa B/metabolism , Psoriasis/genetics , Psoriasis/pathology , Psoriasis/metabolism , Repressor Proteins/metabolism , Repressor Proteins/genetics , Up-Regulation , Wnt-5a Protein/metabolism , Wnt-5a Protein/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...