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1.
Int J Biol Sci ; 20(2): 606-620, 2024.
Article in English | MEDLINE | ID: mdl-38169654

ABSTRACT

Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor ß-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.


Subject(s)
Liver Diseases, Alcoholic , Nitric Oxide , Animals , Humans , Mice , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cytokines/metabolism , Endothelial Cells/metabolism , Inflammation/metabolism , Liver/metabolism , Liver Cirrhosis/metabolism , Liver Diseases, Alcoholic/genetics , Liver Diseases, Alcoholic/metabolism , Nitric Oxide/metabolism
2.
Gastric Cancer ; 26(1): 82-94, 2023 01.
Article in English | MEDLINE | ID: mdl-36125689

ABSTRACT

BACKGROUND: Gastric cancer (GC) is a common malignancy worldwide, with a major attribution to Helicobacter pylori. Interleukin (IL)-17A has been reported to be up-regulated in serum and tumor of GC patients, but the precise mechanisms underlying its involvement in gastric tumorigenesis are yet to be established. Here, we investigated the roles of IL-17A in the pathogenesis of H. pylori-induced GC. METHODS: GC was induced in IL-17A knockout (KO) and wild-type (WT) mice via N-methyl-N-nitrosourea (MNU) treatment and H. pylori infection. At 50 weeks after treatment, gastric tissues were examined by histopathology, immunohistochemistry, and immunoblot analyses. In vitro experiments on the human GC cell lines were additionally performed to elucidate the underlying mechanisms. RESULTS: Deletion of IL-17A suppressed MNU and H. pylori-induced gastric tumor development accompanied by a decrease in gastric epithelial cell growth, oxidative stress, and expression of gastric epithelial stem cells markers. In AGS cells, recombinant human IL-17A (rhIL-17A) inhibited apoptosis and G1/S phase transition arrest while promoting reactive oxygen species production, sphere formation ability of cancer stem cells (CSC), and expression of stemness-related genes. In addition, rhIL-17A induced expression of IL-17RC, leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels. Inhibition of NOX1 with GKT136901 attenuated rhIL-17A-mediated elevation of GC cell growth, ROS generation, and CSC stemness. Clinically, IL-17RC expressions were significantly upregulated in human GC compared with normal gastric tissues. CONCLUSION: Our results suggest that IL-17A promotes gastric carcinogenesis, in part, by regulating IL-17RC/NF-κB/NOX1 pathway, supporting its potential as a target in human GC therapy.


Subject(s)
Helicobacter Infections , Helicobacter pylori , Stomach Neoplasms , Animals , Humans , Mice , Carcinogenesis/metabolism , Epithelial Cells/metabolism , Gastric Mucosa/pathology , Helicobacter Infections/complications , Helicobacter Infections/pathology , Helicobacter pylori/genetics , Interleukin-17/metabolism , NF-kappa B/metabolism , Stomach Neoplasms/pathology , Receptors, Interleukin-17/metabolism
3.
Int Urol Nephrol ; 55(1): 17-28, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36107291

ABSTRACT

PURPOSE: Benign prostatic hyperplasia (BPH) is a urogenital disorder that affects approximately 85% of males who are over 50 years of age. Hydrocotyle ramiflora (HR), belonging to Apiaceae family, is used to treat urinary system diseases such as urine retention in traditional Chinese herbal medicine. In this study, we evaluated the effects of HR in the BPH animal model. METHODS: We induced BPH in rats via subcutaneous (sc) injections of testosterone propionate (TP, 3 mg/kg). Rats were also administered HR (150 mg/kg), finasteride (10 mg/kg), or vehicle via oral gavage. After induction, prostate glands were collected, weighed, and processed for further analysis, including histopathological examination and immunohistochemistry. In addition, the mRNA expression of inflammatory cytokines in prostatic tissues was determined by quantitative real-time PCR (qRT-PCR). The protein expression of pro-apoptotic markers was examined using western blotting. RESULTS: HR treatment significantly reduced the prostate weight, epithelial thickness, and proliferating cell nuclear antigen (PCNA) expression, with the levels of cleaved caspase-3 and Bcl-2-associated X (Bax) protein considerably increased compared to BPH group. HR also decreased inflammatory cell infiltration and pro-inflammatory cytokine levels compared with BPH group. Furthermore, the expression of phosphor-nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) were reduced by HR treatment. CONCLUSION: These results indicate that HR suppresses the development of BPH associated with anti-proliferative, pro-apoptotic, and anti-inflammatory effects, suggesting it is a potential alternative therapeutic agent for BPH.


Subject(s)
Centella , Prostatic Hyperplasia , Male , Humans , Rats , Animals , Prostatic Hyperplasia/chemically induced , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/metabolism , Testosterone/therapeutic use , Rats, Sprague-Dawley , Plant Extracts/adverse effects
4.
Pharm Biol ; 60(1): 2040-2048, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36267048

ABSTRACT

CONTEXT: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with respiratory symptoms and narrowing of airways. Gyeji-tang (GJT) is a traditional Asian medicine that has been used to relieve early-stage cold symptoms, headache, and chills. OBJECTIVE: We examined the effect and potential molecular action mechanism of GJT in a mouse model of COPD induced by cigarette smoke (CS) plus lipopolysaccharide (LPS). MATERIALS AND METHODS: COPD was induced in C57BL/6J mice via daily exposure to CS for 1 h for 8 weeks and intranasal administration of LPS on weeks 1, 3, 5, and 7. GJT (100 or 200 mg/kg) or roflumilast (5 mg/kg) was administrated daily for the final 4 weeks of COPD induction. RESULTS: Administration of GJT significantly suppressed the CS/LPS-induced increases in: the numbers of total cells and macrophages in bronchoalveolar lavage fluid; the expression levels of tumour necrosis factor-α, interleukin (IL)-6, IL-1ß, and IL-8; the activities (phosphorylation) of nuclear factor kappa B and signal transducer and activator of transcription 3; and the expression levels of the structural remodelling markers, transforming growth factor beta, matrix metallopeptidase (MMP)-7, and MMP-9. DISCUSSION AND CONCLUSIONS: These results demonstrate that GJT prevents the lung inflammation and airway remodelling induced by CS plus LPS exposure in mice, suggesting that GJT may have therapeutic potential for the treatment of COPD.


Subject(s)
Cigarette Smoking , Pulmonary Disease, Chronic Obstructive , Mice , Animals , Lipopolysaccharides/toxicity , Tumor Necrosis Factor-alpha/metabolism , STAT3 Transcription Factor/metabolism , NF-kappa B/metabolism , Matrix Metalloproteinase 9/metabolism , Interleukin-8/metabolism , Interleukin-8/pharmacology , Interleukin-8/therapeutic use , Mice, Inbred C57BL , Pulmonary Disease, Chronic Obstructive/chemically induced , Lung , Nicotiana , Disease Models, Animal , Anti-Inflammatory Agents/therapeutic use , Transforming Growth Factor beta/metabolism
5.
Res Rep Urol ; 14: 313-326, 2022.
Article in English | MEDLINE | ID: mdl-36187165

ABSTRACT

Introduction: Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease of the prostate. Eriochloa villosa (EV) reportedly possesses various pharmacological activities, including anti-lipase activity and modulation of various antioxidative enzymes. In this study, we investigate the therapeutic potential of EV against BPH in a testosterone-induced BPH rat model. Methods: Rats were subjected to a daily subcutaneous injection of testosterone (3 mg kg-1) for 4 weeks to induce BPH. Along with testosterone, rats in the treatment group were administered finasteride (10 mg kg-1) or EV (150 mg kg-1) via oral gavage. Prostatic cancer (LNCaP) cell line was used to examine the effect of EV. Results: Finasteride and EV significantly decrease the relative prostate weight, serum levels of dihydrotestosterone and testosterone, and prostate epithelial thickness. Testosterone injection induced prostatic hyperplasia and proliferating cell nuclear antigen expression; however, EV treatment significantly attenuated these effects. Moreover, finasteride- and EV-treated rats exhibit an increase in the number of TUNEL-positive cells and reduced Bcl-2 expression in the prostate tissues compared with the testosterone-treated animals. Furthermore, EV suppresses inflammatory cytokines, including interleukin (IL)-6 and IL-8, in the prostate tissues. Meanwhile, the expression of inflammatory mediator cyclooxygenase-2 is consistently upregulated in testosterone-treated rats, whereas EV treatment significantly reverses this effect. Notably, EV treatment suppresses malondialdehyde (MDA) levels and upregulates testosterone-induced catalase (CAT) expression. In addition, EV suppresses expression of androgen receptor (AR) and prostate-specific antigen (PSA) induced by testosterone in LNCaP cells. Conclusion: The present study results suggest that EV regulates prostatic proliferation, apoptosis, response to inflammation, and oxidative stress in the BPH rat model, and may, therefore, serve as a useful therapeutic agent for BPH.

6.
Article in English | MEDLINE | ID: mdl-35035511

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) refers to a lung disorder associated with symptoms of dyspnea, cough, and sputum production. Traditionally, Yijin-tang (YJT), a mixture of Pinellia ternate, Poria cocos, ginger, Chinese liquorice, and tangerine peel, has been prescribed for the treatment of respiratory system diseases caused by dampness phlegm. This experiment investigated the therapeutic effect of YJT in a mouse model of cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD. METHODS: COPD was induced by exposing mice to CS for 1 hour per day for 8 weeks, with intranasal delivery of LPS on weeks 1, 3, 5, and 7. YJT was administered at doses of 100 and 200 mg/kg 1 hour before CS exposure for the last 4 weeks. RESULTS: YJT significantly suppressed CS- and LPS-induced increases in inflammatory cell counts and reduced interleukin-1 beta (IL-1ß), IL-6, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) levels in bronchoalveolar lavage fluid (BALF) and lung tissue. In addition, YJT not only decreased airway wall thickness, average alveolar intercept, and lung fibrosis, but it also suppressed the expression of matrix metallopeptidase (MMP)-7, MMP-9, and transforming growth factor-B (TGF-ß) and collagen deposition. Moreover, YJT suppressed phosphorylation of nuclear factor-kappa B (NF-κB) as well as expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). CONCLUSION: Collectively, our findings show that YJT attenuates respiratory inflammation and airway remodeling caused by CS and LPS exposure; therefore, therapeutic applications in COPD can be considered.

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