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1.
Food Funct ; 15(10): 5466-5484, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38690672

ABSTRACT

Inflammatory bowel disease (IBD) is difficult to cure, and formulating a dietary plan is an effective means to prevent and treat this disease. Wheat peptide contains a variety of bioactive peptides with anti-inflammatory and antioxidant functions. The results of this study showed that preventive supplementation with wheat peptide (WP) can significantly alleviate the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. WP can increase body weight, alleviate colon shortening, and reduce disease activity index (DAI) scores. In addition, WP improved intestinal microbial disorders in mice with colitis. Based on LC-MS, a total of 313 peptides were identified in WP, 4 of which were predicted to be bioactive peptides. The regulatory effects of WP and four bioactive peptides on the Keap1-Nrf2 signaling pathway were verified in Caco-2 cells. In conclusion, this study demonstrated that WP alleviates DSS-induced colitis by helping maintain gut barrier integrity and targeting the Keap1-Nrf2 axis; these results provided a rationale for adding WP to dietary strategies to prevent IBD.


Subject(s)
Colitis , Dextran Sulfate , Kelch-Like ECH-Associated Protein 1 , Mice, Inbred C57BL , NF-E2-Related Factor 2 , Peptides , Signal Transduction , Triticum , Animals , NF-E2-Related Factor 2/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Mice , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Dextran Sulfate/adverse effects , Signal Transduction/drug effects , Humans , Triticum/chemistry , Caco-2 Cells , Peptides/pharmacology , Male , Disease Models, Animal , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects
2.
J Appl Oral Sci ; 32: e20230447, 2024.
Article in English | MEDLINE | ID: mdl-38695448

ABSTRACT

OBJECTIVE: To evaluate whether antimicrobial photodynamic therapy (aPDT) repairs bisphosphonate-related osteonecrosis of the jaw (BRONJ) modulated by the reduction of NF-kB protein in a murine model. METHODOLOGY: Male Wistar rats (N=30) were divided into the following groups (n=6/group): negative control (NC); experimental osteonecrosis (ONE); ONE + photosensitizer (PS); ONE + photobiomodulation (PBM); and ONE + aPDT. Over 8 weeks, ONE was induced by zoledronic acid 250 µg/kg injections, except in the NC group, which received sterile 0.9% saline, followed by extraction of the lower left first molar. Red light laser irradiation (wavelength ~660 nm, power 50 mW, energy of 2 J, energy dose of 66.67 J/cm2 for 40 s) was performed once a week for 4 weeks. Methylene blue 0.3% was used as PS. The animals were euthanized and examined macroscopically for the presence of exposed bone and epithelial repair and microscopically by histochemical (hematoxylin-eosin and Masson's trichrome staining) and immunohistochemical (anti-NF-kB) methods. Macroscopic and histomorphometric data were analyzed by one-way ANOVA and Tukey's post-test (p<0.05). RESULTS: Mucosal repair, viable osteocytes, and NF-kB immunostaining were observed in the NC, ONE+PS, ONE+PBM, and ONE+aPDT groups. The ONE group showed no mucosal repair, showing empty lacunae and multifocal immunostaining for NF-kB. The ONE+PBM and ONE+aPDT groups had greater deposition of extracellular matrix and less necrotic bone tissue (p<0.05). CONCLUSION: PBM and aPDT treatments for BRONJ were effective for bone and epithelial repair, in addition to reducing inflammation mediated by the decrease of NF-kB protein in the irradiated regions.


Subject(s)
Bisphosphonate-Associated Osteonecrosis of the Jaw , Disease Models, Animal , Immunohistochemistry , NF-kappa B , Photochemotherapy , Photosensitizing Agents , Rats, Wistar , Animals , Male , Photochemotherapy/methods , Bisphosphonate-Associated Osteonecrosis of the Jaw/pathology , NF-kappa B/analysis , Photosensitizing Agents/pharmacology , Time Factors , Reproducibility of Results , Zoledronic Acid/pharmacology , Treatment Outcome , Imidazoles/pharmacology , Diphosphonates/pharmacology , Low-Level Light Therapy/methods , Methylene Blue/pharmacology , Methylene Blue/therapeutic use , Analysis of Variance , Random Allocation , Bone Density Conservation Agents/pharmacology
3.
Arthritis Res Ther ; 26(1): 94, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702742

ABSTRACT

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-ß1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. METHODS: To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. RESULTS: On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. CONCLUSIONS: Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.


Subject(s)
Antibodies, Monoclonal , Chemokine CX3CL1 , Disease Models, Animal , Graft vs Host Disease , Pulmonary Fibrosis , Scleroderma, Systemic , Skin , Animals , Graft vs Host Disease/drug therapy , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/pathology , Scleroderma, Systemic/immunology , Mice , Chemokine CX3CL1/metabolism , Chemokine CX3CL1/antagonists & inhibitors , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/prevention & control , Skin/pathology , Skin/drug effects , Skin/metabolism , Skin/immunology , Fibrosis , Female , Mice, Inbred C57BL , Humans , Lung/pathology , Lung/drug effects , Lung/metabolism , Lung/immunology
4.
Eur J Pharm Biopharm ; 199: 114309, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38704102

ABSTRACT

Oral colon targeted drug delivery system (OCTDDS) is desirable for the treatment of ulcerative colitis (UC). In this study, we designed a partially oxidized sodium alginate-chitosan crosslinked microsphere for UC treatment. Dissipative particle dynamics (DPD) was used to study the formation and enzyme response of gel beads from a molecular perspective. The formed gel beads have a narrow particle size distribution, a compact structure, low cytotoxicity and great colon targeting in vitro and in vivo. Animal experiments demonstrated that gel beads promoted colonic epithelial barrier integrity, decreased the level of pro-inflammatory factors, accelerated the recovery of intestinal microbial homeostasis in UC rats and restored the intestinal metabolic disorders. In conclusion, our gel bead is a promising approach for the treatment of UC and significant for the researches on the pathogenesis and treatment mechanism of UC.


Subject(s)
Alginates , Chitosan , Colitis, Ulcerative , Drug Delivery Systems , Gels , Microspheres , Saponins , Colitis, Ulcerative/drug therapy , Animals , Rats , Alginates/chemistry , Chitosan/chemistry , Drug Delivery Systems/methods , Male , Saponins/pharmacology , Saponins/administration & dosage , Saponins/chemistry , Particle Size , Humans , Colon/drug effects , Colon/metabolism , Colon/pathology , Rats, Sprague-Dawley , Polymers/chemistry , Disease Models, Animal , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Administration, Oral
5.
Toxicol Appl Pharmacol ; 486: 116952, 2024 May.
Article in English | MEDLINE | ID: mdl-38705399

ABSTRACT

The incidence of contrast-induced acute kidney injury (CI-AKI) has escalated to become the third most prevalent cause of hospital-acquired AKI, with a lack of efficacious interventions. Berberine (BBR) possesses diverse pharmacological effects and exhibits renoprotective properties; however, limited knowledge exists regarding its impact on CI-AKI. Therefore, our study aimed to investigate the protective effects and underlying mechanisms of BBR on CI-AKI in a mice model, focusing on the nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3) inflammasome and mitophagy. The CI-AKI mice model was established by administering NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg), indomethacin (10 mg/kg), and iohexol (11 g/kg) following water deprivation. A pretreatment of 100 mg/kg of BBR was orally administered to the mice for two weeks. Renal injury markers, damage-associated molecular patterns (DAMPs), renal histopathology, mitochondrial morphology, autophagosomes, and potential mechanisms were investigated. BBR effectively reduced levels of renal injury biomarkers such as serum cystatin C, urea nitrogen, and creatinine, downregulated the protein level of kidney injury molecule 1 (KIM1), and mitigated renal histomorphological damage. Moreover, BBR reduced DAMPs, including high mobility group box-1 (HMGB1), heat shock protein 70 (HSP70), and uric acid (UA). It also alleviated oxidative stress and inflammatory factors such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß). Furthermore, the activation of NLRP3 inflammasome was attenuated in the BBR pretreatment group, as evidenced by both mRNA and protein levels. Electron microscopy and western blotting examination revealed that BBR mitigated mitochondrial damage and enhanced mitophagy. Additionally, BBR increased the P-AMPK/AMPK ratio. These findings indicated that BBR exerted a protective effect against CI-AKI by suppressing NLRP3 inflammasome activation and modulating mitophagy, providing a potential therapeutic strategy for its prevention.


Subject(s)
Acute Kidney Injury , Berberine , Contrast Media , Disease Models, Animal , Inflammasomes , Mice, Inbred C57BL , Mitophagy , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Mitophagy/drug effects , Acute Kidney Injury/chemically induced , Acute Kidney Injury/pathology , Acute Kidney Injury/prevention & control , Acute Kidney Injury/metabolism , Acute Kidney Injury/drug therapy , Inflammasomes/metabolism , Inflammasomes/drug effects , Mice , Berberine/pharmacology , Male , Kidney/drug effects , Kidney/pathology , Kidney/metabolism
6.
Aging (Albany NY) ; 16(9): 7961-7978, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38709282

ABSTRACT

BACKGROUND: This study combined bioinformatics and experimental verification in a mouse model of intestinal ischemia-reperfusion injury (IRI) to explore the protection mechanism exerted by butyrate against IRI. METHODS: GeneCards, Bioinformatics Analysis Tool for Molecular Mechanisms of Traditional Chinese Medicine and GSE190581 were used to explore the relationship between butyrate and IRI and aging. Protein-protein interaction networks involving butyrate and IRI were constructed via the STRING database, with hub gene analysis performed through Cytoscape. Functional enrichment analysis was conducted on intersection genes. A mouse model of IRI was established, followed by direct arterial injection of butyrate. The experiment comprised five groups: normal, sham, model, vehicle, low-dose butyrate, and high-dose butyrate. Intestinal tissue observation was done via transmission electron microscopy (TEM), histological examination via hematoxylin and eosin (H&E) staining, tight junction proteins detection via immunohistochemistry, and Western blot analysis of hub genes. Drug-target interactions were evaluated through molecular docking. RESULTS: Butyrate protected against IRI by targeting 458 genes, including HMGB1 and TLR4. Toll-like receptor pathway was implicated. Butyrate improved intestinal IRI by reducing mucosal damage, increasing tight junction proteins, and lowering levels of HMGB1, TLR4, and MyD88. Molecular docking showed strong binding energies between butyrate and HMGB1 (-3.7 kcal/mol) and TLR4 (-3.8 kcal/mol). CONCLUSIONS: According to bioinformatics predictions, butyrate mitigates IRI via multiple-target and multiple-channel mechanisms. The extent of IRI can be reduced by butyrate through the inhibition of the HMGB1-TLR4-MyD88 signaling pathway, which is related to senescence.


Subject(s)
Butyrates , HMGB1 Protein , Myeloid Differentiation Factor 88 , Reperfusion Injury , Signal Transduction , Toll-Like Receptor 4 , Animals , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/genetics , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Myeloid Differentiation Factor 88/metabolism , Myeloid Differentiation Factor 88/genetics , HMGB1 Protein/metabolism , HMGB1 Protein/genetics , HMGB1 Protein/drug effects , Mice , Signal Transduction/drug effects , Butyrates/pharmacology , Male , Molecular Docking Simulation , Intestines/drug effects , Intestines/pathology , Disease Models, Animal , Mice, Inbred C57BL , Protein Interaction Maps
7.
Exp Anim ; 73(2): 233, 2024.
Article in English | MEDLINE | ID: mdl-38710612

ABSTRACT

Zhen Li, Mengfan He, Danqing Dai, Xiaofei Gao, Huazheng Liang and Lize Xiong Exp. Anim. 73(1), 109-123, 2024 https://doi.org/10.1538/expanim.23-0065 In the original publication of the article, the Funding section was incomplete. The correct Funding information is provided below: Funding This work was supported by a grant from the Shanghai Commission of Science and Technology (201409003500), Major Project of National Natural Science Foundation of China (No. 82293640, No. 82293643), Key Project of National Natural Science Foundation of China (No. 82130121), the second round of the three-year action plan for "strengthening and promoting Traditional Chinese Medicine" of Hongkou District (HKGYQYXM-2022-06), and Scientific and technological innovation 2030 - major project of Brain Science and Brain-Like Intelligence Technology (2021ZD0202804) to Dr. Lize Xiong, a grant from the National Natural Science Foundation of China (No.81974535) to Dr. Huazheng Liang, and the Talent Promotion Program of Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine (SY-XKZT-2019-3006) and the Discipline Promotion Program of Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine (SY-XKZT-2019-1012) to Dr. Zhen Li.


Subject(s)
Disease Models, Animal , Animals , Mice , Neurocognitive Disorders , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Male , Perioperative Period
8.
Front Immunol ; 15: 1370564, 2024.
Article in English | MEDLINE | ID: mdl-38711520

ABSTRACT

There are considerable avenues through which currently licensed influenza vaccines could be optimized. We tested influenza vaccination in a mouse model with two adjuvants: Sendai virus-derived defective interfering (SDI) RNA, a RIG-I agonist; and an amphiphilic imidazoquinoline (IMDQ-PEG-Chol), a TLR7/8 agonist. The negatively charged SDI RNA was formulated into lipid nanoparticles (LNPs) facilitating direct delivery of SDI RNA to the cytosol, where RIG-I sensing induces inflammatory and type I interferon responses. We previously tested SDI RNA and IMDQ-PEG-Chol as standalone and combination adjuvants for influenza and SARS-CoV-2 vaccines. Here, we tested two different ionizable lipids, K-Ac7-Dsa and S-Ac7-Dog, for LNP formulations. The LNPs were incorporated with SDI RNA to determine its potential as a combination adjuvant with IMDQ-PEG-Chol by evaluating the host immune response to vaccination and infection in immunized BALB/c mice. Adjuvanticity of IMDQ-PEG-Chol with and without empty or SDI-loaded LNPs was validated with quadrivalent inactivated influenza vaccine (QIV), showing robust induction of antibody titers and T-cell responses. Depending on the adjuvant combination and LNP formulation, humoral and cellular vaccine responses could be tailored towards type 1 or type 2 host responses with specific cytokine profiles that correlated with the protective responses to viral infection. The extent of protection conferred by different vaccine/LNP/adjuvant combinations was tested by challenging mice with a vaccine-matched strain of influenza A virus A/Singapore/gp1908/2015 IVR-180 (H1N1). Groups that received either LNP formulated with SDI or IMDQ-PEG-Chol, or both, showed very low levels of viral replication in their lungs at 5 days post-infection (DPI). These studies provide evidence that the combination of vaccines with LNPs and/or adjuvants promote antigen-specific cellular responses that can contribute to protection upon infection. Interestingly, we observed differences in humoral and cellular responses to vaccination between different groups receiving K-Ac7-Dsa or S-Ac7-Dog lipids in LNP formulations. The differences were also reflected in inflammatory responses in lungs of vaccinated animals to infection, depending on LNP formulations. Therefore, this study suggests that the composition of the LNPs, particularly the ionizable lipid, plays an important role in inducing inflammatory responses in vivo, which is important for vaccine safety and to prevent adverse effects upon viral exposure.


Subject(s)
Adjuvants, Immunologic , Influenza Vaccines , Liposomes , Mice, Inbred BALB C , Nanoparticles , Orthomyxoviridae Infections , Animals , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Mice , Adjuvants, Immunologic/administration & dosage , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/immunology , Female , Lipids , Vaccination/methods , Adjuvants, Vaccine , Antibodies, Viral/blood , Antibodies, Viral/immunology , Disease Models, Animal , Sendai virus/immunology , Influenza, Human/prevention & control , Influenza, Human/immunology
9.
Food Funct ; 15(10): 5579-5595, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38713055

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents via the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar-Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1-5 (DRD1-5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Dopamine , Memory, Short-Term , Rats, Inbred SHR , Rats, Inbred WKY , Theobromine , Animals , Male , Rats , Theobromine/pharmacology , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/metabolism , Memory, Short-Term/drug effects , Dopamine/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Plasma Membrane Transport Proteins/genetics , Frontal Lobe/metabolism , Frontal Lobe/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/drug effects , Tyrosine 3-Monooxygenase/metabolism , Tyrosine 3-Monooxygenase/genetics , Disease Models, Animal , Synaptosomal-Associated Protein 25/metabolism
10.
Aging (Albany NY) ; 16(9): 7946-7960, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38713160

ABSTRACT

BACKGROUND: Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and emerging evidence indicates that trigeminal nerve electrical stimulation (TNS) is a promising therapeutic intervention for neurological impairment following TBI. However, the precise mechanisms underlying the neuroprotective effects of TNS in TBI are poorly understood. Thus, the objective of this study was to investigate the potential involvement of the orexin-A (OX-A)/orexin receptor 1 (OX1R) mediated TLR4/NF-κB/NLRP3 signaling pathway in the neuroprotective effects of TNS in rats with TBI. METHODS: Sprague-Dawley rats were randomly assigned to four groups: sham, TBI, TBI+TNS+SB334867, and TBI+TNS. TBI was induced using a modified Feeney's method, and subsequent behavioral assessments were conducted to evaluate neurological function. The trigeminal nerve trunk was isolated, and TNS was administered following the establishment of the TBI model. The levels of neuroinflammation, brain tissue damage, and proteins associated with the OX1R/TLR4/NF-κB/NLRP3 signaling pathway were assessed using hematoxylin-eosin staining, Nissl staining, western blot analysis, quantitative real-time polymerase chain reaction, and immunofluorescence techniques. RESULTS: The findings of our study indicate that TNS effectively mitigated tissue damage, reduced brain edema, and alleviated neurological deficits in rats with TBI. Furthermore, TNS demonstrated the ability to attenuate neuroinflammation levels and inhibit the expression of proteins associated with the TLR4/NF-κB/NLRP3 signaling pathway. However, it is important to note that the aforementioned effects of TNS were reversible upon intracerebroventricular injection of an OX1R antagonist. CONCLUSION: TNS may prevent brain damage and relieve neurological deficits after a TBI by inhibiting inflammation, possibly via the TLR4/NF-κB/NLRP3 signaling pathway mediated by OX-A/OX1R.


Subject(s)
Brain Injuries, Traumatic , NF-kappa B , NLR Family, Pyrin Domain-Containing 3 Protein , Orexin Receptors , Rats, Sprague-Dawley , Signal Transduction , Toll-Like Receptor 4 , Trigeminal Nerve , Animals , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/therapy , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/genetics , Orexin Receptors/metabolism , Orexin Receptors/genetics , Rats , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Male , Trigeminal Nerve/metabolism , Orexins/metabolism , Electric Stimulation Therapy/methods , Disease Models, Animal
11.
Neurosci Lett ; 832: 137806, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38714229

ABSTRACT

BACKGROUND: Trigeminal neuralgia (TN) is a common and difficult-to-treat neuropathic pain disorder in clinical practice. Previous studies have shown that Toll-like receptor 4 (TLR4) modulates the activation of the NF-κB pathway to affect neuropathic pain in rats. Voltage-gated sodium channels (VGSCs) are known to play an important role in neuropathic pain electrical activity. OBJECTIVE: To investigate whether TLR4 can regulate Nav1.3 through the TRAF6/NF-κB p65 pathway after infraorbital nerve chronic constriction injury (ION-CCI). STUDY DESIGN: ION-CCI modeling was performed on SD (Sprague Dawley) rats. To verify the success of the modeling, we need to detect the mechanical pain threshold and ATF3. Then, detecting the expression of TLR4, TRAF6, NF-κB p65, p-p65, and Nav1.3 in rat TG. Subsequently, investigate the role of TLR4/TRAF6/NF-κB pathway in ION-CCI model by intrathecal injections of LPS-rs (TLR4 antagonist), C25-140 (TRAF6 inhibitor), and PDTC (NF-κB p65 inhibitor). RESULTS: ION-CCI surgery decreased the mechanical pain threshold of rats and increased the expression of ATF3, TLR4, TRAF6, NF-κB p-p65 and Nav1.3, but there was no difference in NF-κB p65 expression. After inject antagonist or inhibitor of the TLR4/TRAF6/NF-κB pathway, the expression of Nav1.3 was decreased and mechanical pain threshold was increased. CONCLUSION: In the rat model of ION-CCI, TLR4 in the rat trigeminal ganglion regulates Nav1.3 through the TRAF6/NF-κB p65 pathway, and TLR4 antagonist alleviates neuropathic pain in ION-CCI rats.


Subject(s)
NAV1.3 Voltage-Gated Sodium Channel , Rats, Sprague-Dawley , Signal Transduction , TNF Receptor-Associated Factor 6 , Toll-Like Receptor 4 , Animals , Toll-Like Receptor 4/metabolism , TNF Receptor-Associated Factor 6/metabolism , Male , NAV1.3 Voltage-Gated Sodium Channel/metabolism , Signal Transduction/physiology , NF-kappa B/metabolism , Trigeminal Neuralgia/metabolism , Rats , Disease Models, Animal , Transcription Factor RelA/metabolism , Activating Transcription Factor 3/metabolism , Pain Threshold/physiology
12.
Sci Adv ; 10(19): eadh0798, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38718107

ABSTRACT

Mutations in the LMNA gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis underlying cardiac dysfunction remains elusive. Using a novel conditional deletion model capable of translatome profiling, we observed that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Before cardiac dysfunction, Lmna-deleted cardiomyocytes displayed nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation. Translatome profiling identified MED25 activation, a transcriptional cofactor that regulates Golgi stress. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the Golgi. Systemic administration of modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the LMNA cardiomyopathy development.


Subject(s)
Cardiomyopathies , Lamin Type A , Myocytes, Cardiac , Nuclear Envelope , Animals , Lamin Type A/metabolism , Lamin Type A/genetics , Mice , Nuclear Envelope/metabolism , Cardiomyopathies/metabolism , Cardiomyopathies/etiology , Cardiomyopathies/pathology , Cardiomyopathies/genetics , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Autophagy , Stress, Physiological , Disease Models, Animal , Endoplasmic Reticulum Stress , Golgi Apparatus/metabolism , Mice, Knockout
13.
Thromb Res ; 238: 151-160, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38718473

ABSTRACT

It is crucial to develop a long-term therapy that targets hemophilia A and B, including inhibitor-positive patients. We have developed an Adeno-associated virus (AAV) based strategy to integrate the bypass coagulation factor, activated FVII (murine, mFVIIa) gene into the Rosa26 locus using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 mediated gene-editing. AAV vectors designed for expression of guide RNA (AAV8-gRNA), Cas9 (AAV2 neddylation mutant-Cas9), and mFVIIa (AAV8-mFVIIa) flanked by homology arms of the target locus were validated in vitro. Hemophilia B mice were administered with AAV carrying gRNA, Cas9 (1 × 1011 vgs/mouse), and mFVIIa with homology arms (2 × 1011 vgs/mouse) with appropriate controls. Functional rescue was documented with suitable coagulation assays at various time points. The data from the T7 endonuclease assay revealed a cleavage efficiency of 20-42 %. Further, DNA sequencing confirmed the targeted integration of mFVIIa into the safe-harbor Rosa26 locus. The prothrombin time (PT) assay revealed a significant reduction in PT in mice that received the gene-editing vectors (22 %), and a 13 % decline in mice that received only the AAV-FVIIa when compared to mock treated mice, 8 weeks after vector administration. Furthermore, FVIIa activity in mice that received triple gene-editing vectors was higher (122.5mIU/mL vs 28.8mIU/mL) than the mock group up to 15 weeks post vector administration. A hemostatic challenge by tail clip assay revealed that hemophilia B mice injected with only FVIIa or the gene-editing vectors had significant reduction in blood loss. In conclusion, AAV based gene-editing facilitates sustained expression of coagulation FVIIa and phenotypic rescue in hemophilia B mice.


Subject(s)
Dependovirus , Disease Models, Animal , Hemophilia B , Animals , Hemophilia B/therapy , Hemophilia B/genetics , Dependovirus/genetics , Mice , Phenotype , Gene Editing/methods , Hemorrhage/genetics , Hemorrhage/therapy , Factor VIIa , Humans , Genetic Therapy/methods , Mice, Inbred C57BL , Genetic Vectors , CRISPR-Cas Systems , Genetic Engineering/methods
14.
Biochem Biophys Res Commun ; 717: 150044, 2024 Jul 12.
Article in English | MEDLINE | ID: mdl-38718567

ABSTRACT

Pulpitis constitutes a significant challenge in clinical management due to its impact on peripheral nerve tissue and the persistence of chronic pain. Despite its clinical importance, the correlation between neuronal activity and the expression of voltage-gated sodium channel 1.7 (Nav1.7) in the trigeminal ganglion (TG) during pulpitis is less investigated. The aim of this study was to examine the relationship between experimentally induced pulpitis and Nav1.7 expression in the TG and to investigate the potential of selective Nav1.7 modulation to attenuate TG abnormal activity associated with pulpitis. Acute pulpitis was induced at the maxillary molar (M1) using allyl isothiocyanate (AITC). The mice were divided into three groups: control, pulpitis model, and pulpitis model treated with ProTx-II, a selective Nav1.7 channel inhibitor. After three days following the surgery, we conducted a recording and comparative analysis of the neural activity of the TG utilizing in vivo optical imaging. Then immunohistochemistry and Western blot were performed to assess changes in the expression levels of extracellular signal-regulated kinase (ERK), c-Fos, collapsin response mediator protein-2 (CRMP2), and Nav1.7 channels. The optical imaging result showed significant neurological excitation in pulpitis TGs. Nav1.7 expressions exhibited upregulation, accompanied by signaling molecular changes suggestive of inflammation and neuroplasticity. In addition, inhibition of Nav1.7 led to reduced neural activity and subsequent decreases in ERK, c-Fos, and CRMP2 levels. These findings suggest the potential for targeting overexpressed Nav1.7 channels to alleviate pain associated with pulpitis, providing practical pain management strategies.


Subject(s)
NAV1.7 Voltage-Gated Sodium Channel , Pulpitis , Animals , NAV1.7 Voltage-Gated Sodium Channel/metabolism , NAV1.7 Voltage-Gated Sodium Channel/genetics , Mice , Male , Pulpitis/metabolism , Pulpitis/pathology , Trigeminal Ganglion/metabolism , Neurons/metabolism , Nerve Tissue Proteins/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Voltage-Gated Sodium Channel Blockers/pharmacology , Disease Models, Animal , Intercellular Signaling Peptides and Proteins
15.
Cell Death Dis ; 15(5): 324, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38724533

ABSTRACT

Severe aplastic anemia (SAA) is a rare, fatal disease characterized by severe cytopenias and loss of hematopoietic stem cells (HSCs). Immune-mediated destruction and inflammation are known drivers of SAA, however, the underlying mechanisms driving persistent inflammation are unknown. Current treatments for SAA rely on immunosuppressive therapies or HSC transplantation, however, these treatments are not always effective. Using an established mouse model of SAA, we observed a significant increase in apoptotic cells within the bone marrow (BM) and impaired efferocytosis in SAA mice, relative to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes and unique populations emerged during SAA characterized by increased inflammatory signatures and significantly increased expression of Sirpa and Cd47. CD47, a "don't eat me" signal, was increased on both live and apoptotic BM cells, concurrent with markedly increased expression of signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced accumulation of CD47-positive apoptotic cells. Lipidomic analysis revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA-induced mice relative to radiation controls. Treatment of SAA mice with Resolvin E1 (RvE1) improved efferocytic function, BM cellularity, platelet output, and survival. Our data suggest that impaired efferocytosis and inflammation resolution contributes to SAA progression and demonstrate that SPMs, such as RvE1, offer new and/or complementary treatments for SAA that do not rely on immune suppression.


Subject(s)
Anemia, Aplastic , CD47 Antigen , Eicosapentaenoic Acid , Animals , Anemia, Aplastic/pathology , Mice , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/pharmacology , CD47 Antigen/metabolism , CD47 Antigen/genetics , Apoptosis/drug effects , Phagocytosis/drug effects , Disease Models, Animal , Mice, Inbred C57BL , Receptors, Immunologic/metabolism , Receptors, Immunologic/genetics , Monocytes/metabolism , Monocytes/drug effects , Inflammation/pathology , Male , Efferocytosis
16.
Cells ; 13(9)2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38727292

ABSTRACT

Integrin α4ß7+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of α4ß7+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl4-induced liver fibrosis was associated with enrichment of intrahepatic α4ß7+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α4ß7 or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl4-treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α4ß7+ CD4 and CD8 T cells, suggesting that α4ß7/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α4ß7+ T cells promote hepatic fibrosis progression. Analysis of hepatic α4ß7+ and α4ß7- CD4 T cells revealed that α4ß7+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α4ß7+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α4ß7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.


Subject(s)
Cell Adhesion Molecules , Disease Progression , Integrins , Liver Cirrhosis , Liver , Mucoproteins , Animals , Liver Cirrhosis/pathology , Liver Cirrhosis/immunology , Liver Cirrhosis/metabolism , Cell Adhesion Molecules/metabolism , Mucoproteins/metabolism , Humans , Mice , Liver/pathology , Liver/metabolism , Integrins/metabolism , Male , Mice, Inbred C57BL , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Inflammation/pathology , CD8-Positive T-Lymphocytes/immunology , Immunoglobulins/metabolism , Disease Models, Animal , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Female , Antibodies, Monoclonal/pharmacology
17.
Food Funct ; 15(10): 5641-5654, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38726659

ABSTRACT

Exposure to food allergens elicits fast changes in the intestinal microenvironment, which guides the development of allergic reactions. Investigating the key information about these changes may help in better understanding food allergies. In this research, we explored the relationship between a food allergy and extracellular adenosine triphosphate (ATP), a danger molecule that has been proved to regulate the onset of allergic asthma and dermatitis but has not been studied in food allergies, by developing a unique animal model through allergen-containing diet feeding. After consuming an allergen-containing diet for 7 days, the allergic mice exhibited severe enteritis with elevated luminal ATP levels. The dysregulated luminal ATP worsened food-induced enteritis by enhancing Th17 cell responses and increasing mucosal neutrophil accumulation. In vitro experiments demonstrated that ATP intervention facilitated Th17 cell differentiation and neutrophil activation. In addition, the diet-induced allergy showed noticeable gut dysbiosis, characterized by decreased microbial diversity and increased diet-specific microbiota signatures. As the first, we show that food-induced enteritis is associated with an elevated concentration of luminal ATP. The dysregulated extracellular ATP exacerbated the enteritis of mice to a food challenge by manipulating intestinal Th17 cells and neutrophils.


Subject(s)
Adenosine Triphosphate , Food Hypersensitivity , Neutrophil Activation , Neutrophils , Th17 Cells , Animals , Adenosine Triphosphate/metabolism , Mice , Food Hypersensitivity/immunology , Th17 Cells/immunology , Neutrophils/immunology , Neutrophils/metabolism , Disease Models, Animal , Female , Gastrointestinal Microbiome , Mice, Inbred C57BL , Allergens/immunology , Enteritis/immunology , Mice, Inbred BALB C , Humans
18.
Sci Adv ; 10(19): eadk9137, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38728395

ABSTRACT

Obesity, and the associated metabolic syndrome, is a risk factor for increased disease severity with a variety of infectious agents, including influenza virus. Yet, the mechanisms are only partially understood. As the number of people, particularly children, living with obesity continues to rise, it is critical to understand the role of host status on disease pathogenesis. In these studies, we use a diet-induced obese ferret model and tools to demonstrate that, like humans, obesity resulted in notable changes to the lung microenvironment, leading to increased clinical disease and viral spread to the lower respiratory tract. The decreased antiviral responses also resulted in obese animals shedding higher infectious virus for a longer period, making them more likely to transmit to contacts. These data suggest that the obese ferret model may be crucial to understanding obesity's impact on influenza disease severity and community transmission and a key tool for therapeutic and intervention development for this high-risk population.


Subject(s)
Disease Models, Animal , Ferrets , Obesity , Orthomyxoviridae Infections , Animals , Obesity/virology , Orthomyxoviridae Infections/transmission , Orthomyxoviridae Infections/virology , Lung/virology , Lung/pathology , Severity of Illness Index , Diet , Humans , Virus Shedding , Influenza, Human/transmission , Influenza, Human/virology
19.
Pathog Dis ; 822024 Feb 07.
Article in English | MEDLINE | ID: mdl-38730561

ABSTRACT

Antibiotic resistance (ATBR) is increasing every year as the overuse of antibiotics (ATBs) and the lack of newly emerging antimicrobial agents lead to an efficient pathogen escape from ATBs action. This trend is alarming and the World Health Organization warned in 2021 that ATBR could become the leading cause of death worldwide by 2050. The development of novel ATBs is not fast enough considering the situation, and alternative strategies are therefore urgently required. One such alternative may be the use of non-thermal plasma (NTP), a well-established antimicrobial agent actively used in a growing number of medical fields. Despite its efficiency, NTP alone is not always sufficient to completely eliminate pathogens. However, NTP combined with ATBs is more potent and evidence has been emerging over the last few years proving this is a robust and highly effective strategy to fight resistant pathogens. This minireview summarizes experimental research addressing the potential of the NTP-ATBs combination, particularly for inhibiting planktonic and biofilm growth and treating infections in mouse models caused by methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa. The published studies highlight this combination as a promising solution to emerging ATBR, and further research is therefore highly desirable.


Subject(s)
Anti-Bacterial Agents , Biofilms , Plasma Gases , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Plasma Gases/pharmacology , Animals , Humans , Biofilms/drug effects , Pseudomonas aeruginosa/drug effects , Mice , Methicillin-Resistant Staphylococcus aureus/drug effects , Drug Resistance, Bacterial , Drug Resistance, Microbial , Pseudomonas Infections/microbiology , Pseudomonas Infections/drug therapy , Disease Models, Animal , Staphylococcal Infections/microbiology , Staphylococcal Infections/drug therapy
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