scholarly journals Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Fumika Honda ◽  
Hiroto Tsuboi ◽  
Yuko Ono ◽  
Saori Abe ◽  
Hiroyuki Takahashi ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Therapeutic Target ◽  
Therapeutic Potential ◽  
Inflammatory Cells ◽  
Mouse Fibroblast ◽  
Therapeutic Effects ◽  
Fibrosis Score ◽  
Immunoglobulin G4 ◽  
Recombinant Mouse

Abstract Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggesting that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD, although whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analog of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice). Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3 T3) in vitro. Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3 T3. Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.

scholarly journals Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis

2021 ◽  
Author(s):  
Fumika Honda ◽  
Hiroto Tsuboi ◽  
Yuko Ono ◽  
Saori Abe ◽  
Hiroyuki Takahashi ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Therapeutic Target ◽  
Therapeutic Potential ◽  
Inflammatory Cells ◽  
Therapeutic Effects ◽  
Fibrosis Score ◽  
Immunoglobulin G4 ◽  
Recombinant Mouse ◽  
Nih 3T3

Abstract Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggest that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD. Although, whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analogue of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice).Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3T3) in vitro.Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells, and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3T3.Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.

scholarly journals Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiyuan Yan ◽  
Yingchi Zhang ◽  
Gaohong Sheng ◽  
Bowei Ni ◽  
Yifan Xiao ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Therapeutic Effects ◽  
Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

P13.08 Novel Thioridazine derivates: Antiproliferative and apoptosis-inducing activity on glioblastoma cells in vitro

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii34-ii34
Author(s):  
S G Schwab ◽  
K Sarnow ◽  
E Alme ◽  
R Goldbrunner ◽  
H Bjørsvik ◽  
...  
Keyword(s):  
Imaging System ◽  
Therapeutic Potential ◽  
Flow Cytometric Analysis ◽  
Annexin V ◽  
Therapeutic Effects ◽  
Cell Viability Assay ◽  
Selective Cytotoxicity ◽  
Viability Assay

Abstract BACKGROUND Although withdrawn from the market due to cardiotoxicity, we have shown that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of the presented project was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential. MATERIAL AND METHODS Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay as well as a real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment. RESULTS Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p<0,0001, U251 p<0,0001, LN18 p=0,0004) as well as on glioma stem cells (GSC) (P3 p<0,0001) compared to NHA and BOs respectively. Also, when BOs were confronted with GSC spheres in an invasion assay, a selective cytotoxicity was observed in the GSCs. Mechanistically, we show that both compounds induce apoptosis in the GBM cells. Moreover, intravenous delivery of increasing concentrations of EA01 and EA02 revealed no toxicity in animals at concentrations up to 21 mg/kg. CONCLUSION We have developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.

scholarly journals Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations

Pharmaceutics ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 424 ◽  
Author(s):  
Klaudia Siwowska ◽  
Patrycja Guzik ◽  
Katharina A. Domnanich ◽  
Josep M. Monné Rodríguez ◽  
Peter Bernhardt ◽  
...  
Keyword(s):  
Radionuclide Therapy ◽  
Therapeutic Potential ◽  
Folate Receptor ◽  
Tumor Growth Inhibition ◽  
Therapeutic Effects ◽  
Targeted Radionuclide Therapy ◽  
Decay Properties ◽  
Therapeutic Properties ◽  
Folate Conjugate

Targeted radionuclide therapy with 177Lu- and 90Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. 47Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β−-particles. In this study, 47Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of 177Lu-folate and 90Y-folate, respectively. In vitro, 47Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to 177Lu-folate, but 90Y-folate was more potent at equal activities due to the higher energy of emitted β−-particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with 47Sc-folate (12.5 MBq), 177Lu-folate (10 MBq), and 90Y-folate (5 MBq), respectively. The treatment resulted in increased median survival of 39, 43, and 41 days, respectively, as compared to 26 days in untreated controls. There were no statistically significant differences among the therapeutic effects observed in treated groups. Histological assessment revealed no severe side effects two weeks after application of the radiofolates, even at double the activity used for therapy. Based on the decay properties and our results, 47Sc is likely to be comparable to 177Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with 44Sc or 43Sc as a diagnostic match, enabling the realization of radiotheragnostics in future.

Comparison of the therapeutic potential of adult and embryonic neural precursor cells in a rat model of Parkinson disease

2008 ◽  
Vol 108 (1) ◽  
pp. 149-159 ◽  
Author(s):  
Kenichiro Muraoka ◽  
Tetsuro Shingo ◽  
Takao Yasuhara ◽  
Masahiro Kameda ◽  
Wen Ji Yuen ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Rat Model ◽  
Fluorescent Protein ◽  
Therapeutic Potential ◽  
Precursor Cells ◽  
Neural Precursor Cells ◽  
Neural Precursor ◽  
Therapeutic Effects ◽  
Adenoviral Infection

Object The therapeutic effects of adult and embryonic neural precursor cells (NPCs) were evaluated and their therapeutic potential compared in a rat model of Parkinson disease. Methods Adult NPCs were obtained from the subventricular zone and embryonic NPCs were taken from the ganglionic eminence of 14-day-old embryos. Each NPC type was cultured with epidermal growth factor. The in vitro neuronal differentiation rate of adult NPCs was approximately equivalent to that of embryonic NPCs after two passages. Next, the NPCs were transfected with either green fluorescent protein or glial cell line–derived neurotrophic factor (GDNF) by adenoviral infection and transplanted into the striata in a rat model of Parkinson disease (PD) induced by unilateral intrastriatal injection of 6-hydroxydopamine. An amphetamine-induced rotation test was used to evaluate rat behavioral improvement, and immunohistochemical analysis was performed to compare grafted cell survival, differentiation, and host tissue changes. Results The rats with GDNF-transfected NPCs had significantly fewer amphetamine-induced rotations and less histological damage. Except for the proportion of surviving grafted cells, there were no significant differences between adult and embryonic NPCs. Conclusions Adult and embryonic NPCs have a comparable therapeutic potential in a rat model of PD.

scholarly journals Pharmacological effects of saffron and its constituents in ocular disorders from in vitro studies to clinical trials; a systematic review

2020 ◽  
Vol 18 ◽  
Author(s):  
Samaneh Sepahi ◽  
Adel Ghorani-Azam ◽  
Seyedeh Maryam Hossieni ◽  
Seyed Ahmad Mohajeri ◽  
Elham Khodavrdi
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Therapeutic Potential ◽  
In Vitro Studies ◽  
Therapeutic Effects ◽  
Potential Candidate ◽  
Retinal Cells ◽  
Age Related ◽  
Eye Disorders

Introduction: Some medicinal plants have shown promising therapeutic potential for management of the diseases. We aimed to systematically review the literature wherein the therapeutic effects of saffron have been studied on eye disorders. Methods: A systematic literature search was performed in PubMed, Scopus, Web of Science, Google scholar and other databases using eye disorders, and saffron as key terms. No strict inclusion criteria were defined, and almost all clinical studies, as well as in vivo and in vitro studies were included. The reported data in each study were extracted and then qualitatively described. Results: Finally, 78 articles were found but only 29 relevant articles were included. Nine articles are clinical trials and 20 articles were done on cellular and molecular aspects of saffron on eye disorders. According to the included studies, crocin prevented the pro-inflammatory response in retinal cells and decreased glucose level in diabetic mice. Also, crocetin prevented retinal degeneration and saffron protected photoreceptors from light-induced damage in retinal cells. Saffron also improved visual function in age-related macular edema and decreased intraocular pressure in patients with glaucoma. In addition, it was shown that crocin can improve best corrected visual acuity and decreased central macular thickness in patients with diabetic maculopathy. Conclusion: The results of this review indicated that saffron and its main ingredients such as crocin could be a potential candidate for the treatment of ocular disease especially eye inflammation; however, further clinical studies are needed to confirm such efficiency.

scholarly journals Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis

2021 ◽  
Vol 23 (1) ◽  
pp. 126
Author(s):  
Alasdair G. Kay ◽  
Kane Treadwell ◽  
Paul Roach ◽  
Rebecca Morgan ◽  
Rhys Lodge ◽  
...  
Keyword(s):  
T Cell ◽  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Histopathological Analysis ◽  
Therapeutic Effects ◽  
Synovial Joint ◽  
Paracrine Signalling

Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA. All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation.

scholarly journals Cytotoxic lanthanum oxide nanoparticles sensitize glioblastoma cells to radiation therapy and temozolomide: an in vitro rationale for translational studies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Victor M. Lu ◽  
Toni Rose Jue ◽  
Kerrie L. McDonald
Keyword(s):  
Radiation Therapy ◽  
Lanthanum Oxide ◽  
Therapeutic Potential ◽  
Chemical Properties ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Radical Oxygen Species ◽  
Apoptosis Pathway ◽  
Dismal Prognosis

Abstract Glioblastoma (GBM) is a malignant brain tumour with a dismal prognosis, despite best treatment by surgical resection, radiation therapy (RT) and chemotherapy with temozolomide (TMZ). Nanoparticle (NP) therapy is an emerging consideration due to the ability of NPs to be formulated and cross the blood brain barrier. Lanthanum oxide (La2O3) NPs are therapeutically advantageous due to the unique chemical properties of lanthanum making it cytotoxic to cancers, and able to enhance existing anti-cancer treatments. However, La2O3 NPs have yet to be thoroughly investigated in brain tumors. We show that these NPs can reach the brain after venous injection, penetrate into GBM cells via endocytosis, dissociate to be cytotoxic, and enhance the therapeutic effects of RT and TMZ. The mechanisms of cell death by La2O3 NPs were found to be multifaceted. Increasing NP concentration was correlated to increased intrinsic and extrinsic apoptosis pathway markers in a radical oxygen species (ROS)-dependent manner, as well as involving direct DNA damage and autophagic pathways within GBM patient-derived cell lines. NP interactions to sensitize GBM to RT and TMZ were shown to involve these pathways by enhancing ROS and apoptotic mechanisms. We therefore demonstrate the therapeutic potential of La2O3 NPs to treat GBM cells in vitro, and encourage translational exploration in the future.

Cordycepin in Anticancer Research: Molecular Mechanism of Therapeutic Effects

2020 ◽  
Vol 27 (6) ◽  
pp. 983-996 ◽  
Author(s):  
Md. Asaduzzaman Khan ◽  
Mousumi Tania
Keyword(s):  
Anticancer Activity ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cancer Drug ◽  
Therapeutic Effects ◽  
Anticancer Activities ◽  
Cancer Cell Growth ◽  
Ongoing Research

Background: Cordycepin is a nucleotide analogue from Cordyceps mushrooms, which occupies a notable place in traditional medicine. Objective: In this review article, we have discussed the recent findings on the molecular aspects of cordycepin interactions with its recognized cellular targets, and possible mechanisms of its anticancer activity. Methods: We have explored databases like pubmed, google scholar, scopus and web of science for the update information on cordycepin and mechanisms of its anticancer activity, and reviewed in this study. Results: Cordycepin has been widely recognized for its therapeutic potential against many types of cancers by various mechanisms. More specifically, cordycepin can induce apoptosis, resist cell cycle and cause DNA damage in cancer cells, and thus kill or control cancer cell growth. Also cordycepin can induce autophagy and modulate immune system. Furthermore, cordycepin also inhibits tumor metastasis. Although many success stories of cordycepin in anticancer research in vitro and in animal model, and there is no successful clinical trial yet. Conclusion: Ongoing research studies have reported highly potential anticancer activities of cordycepin with numerous molecular mechanisms. The in vitro and in vivo success of cordycepin in anticancer research might influence the clinical trials of cordycepin, and this molecule might be used for development of future cancer drug.

scholarly journals Anti-Proliferative Effects of Standardized Cornus officinalis on Benign Prostatic Epithelial Cells via the PCNA/E2F1-Dependent Cell Cycle Pathway

2020 ◽  
Vol 21 (24) ◽  
pp. 9567
Author(s):  
Bo-Ram Jin ◽  
Se-Yun Cheon ◽  
Hyo-Jung Kim ◽  
Myoung-Seok Kim ◽  
Kwang-Ho Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Therapeutic Potential ◽  
Ethanol Extract ◽  
Therapeutic Effects ◽  
Proliferative Effect ◽  
Cornus Officinalis ◽  
Dependent Cell

Cornus officinalis, widely used in traditional Chinese medicine, exhibits pharmacological effects against erectile dysfunction and pollakisuria, which are pathological symptoms of benign prostatic hyperplasia (BPH). Although traditional usage and a study on BPH have been reported, to our knowledge, no study has investigated the exact molecular mechanism(s) underlying the anti-proliferative effects of standardized C. officinalis on prostatic cells. We standardized C. officinalis 30% ethanol extract (COFE) and demonstrated the therapeutic effects of COFE on human BPH epithelial cells and testosterone-induced BPH in rats. In vitro studies using BPH-1 cells demonstrated an upregulation of BPH-related and E2F Transcription Factor 1(E2F1)-dependent cell cycle markers, whereas treatment with COFE clearly inhibited the proliferation of BPH epithelial cells and reduced the overexpression of G1 and S checkpoint genes. Additionally, COFE administration alleviated the androgen-dependent prostatic enlargement in a testosterone-induced BPH animal model. COFE exerted these anti-BPH effects by the inhibition of anti-apoptotic markers, suppression of PCNA expression, and regulation of E2F1/pRB-dependent cell cycle markers in rats with BPH. These results suggest that COFE exerts anti-proliferative effect by regulating PCNA/E2F1-dependent cell cycle signaling pathway both in vivo and in vitro. These findings reveal the therapeutic potential of COFE, which could be used as a substitute for BPH treatment.

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