isorhapontigenin and Disease-Models--Animal

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease that is the most common cause of dementia in the elderly. Aβ1‑42 is significantly associated with memory deficits and it can increase the level of acetylcholine, promote the activity of acetylcholinesterase (AChE), and cause cognitive dysfunction. Isorhapontigenin (ISO) is a stilbene derivative that has antioxidant, anti‑tumor, and anti‑inflammatory effects. However, it is still unclear whether ISO can affect β‑amyloid‑associated cognitive impairments. In this study, we found that ISO improved cognitive dysfunction induced by Aβ1‑42 in rats. It inhibited the Aβ‑induced activation of M1 microglia and reduced the release of inflammatory cytokines. It alleviated amyloid beta‑induced oxidative stress and led to an overall improvement in AD symptoms. Cellularly, we found that ISO alleviated Aβ‑induced inflammation and oxidative stress by activating the PI3K/AKT/GSK‑3β pathway and ultimately improved cognitive dysfunction in AD rats.

Topics: Acetylcholine; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Antioxidants; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Neurodegenerative Diseases; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Stilbenes

Isorhapontigenin (ISO) is one of the main bioactive components of Gnetum cleistostachyum and was shown to possess antioxidant and antitumor functions. Herein, we hope to examine the neuroprotection impacts of ISO in rats subjected to transient middle cerebral artery occlusion/reperfusion (MCAO/R, 2/24 h) injuries. ISO was injected intraperitoneally into the rats immediately after cerebral ischemia. After 24 h of the reperfusion, infarct volume, brain water contents, neurological deficit, and cerebral blood flow were assessed. Hippocampus histopathology change was detected by H&E and TUNEL staining. The expressions of cleaved caspase-3, Bax and Bcl-2, and phospho-Akt (p-Akt) were investigated by real-time RT-PCR or western blot analysis. We found that ISO significantly suppressed the infarct volumes, brain water contents, and neurological deficit, increased CBF, and relieved histopathologic change in a dose-dependent manner. Reduced malondialdehyde (MDA) and elevated activities of superoxide dismutase (SOD) and GSH and glutathione peroxidase (GSH-PX) were observed in ISO group. ISO remarkably decreased caspase-3 and Bax and increased levels of Bcl-2. Additionally, ISO upregulated p-Akt expression. Blocking of PI3K activities by wortmannin can abolish the ISO-caused decrease in infarct volumes and neurologic deficit scores and abrogate the promotion of p-Akt. The data indicated that ISO played neuroprotective impacts against focal I/R injuries, possibly related to the activating of PI3K/Akt signaling.

Topics: Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Disease Models, Animal; Hippocampus; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Stilbenes

Our recent studies found that isorhapontigenin (ISO) showed a significant inhibitory effect on human bladder cancer cell growth, accompanied with cell-cycle G0-G1 arrest as well as downregulation of Cyclin D1 expression at transcriptional level via inhibition of Sp1 transactivation in bladder cancer cells. In the current study, the potential ISO inhibition of bladder tumor formation has been explored in a xenograft nude mouse model, and the molecular mechanisms underlying ISO inhibition of Sp1 expression and anticancer activities have been elucidated both in vitro and in vivo. Moreover, the studies demonstrated that ISO treatment induced the expression of miR-137, which in turn suppressed Sp1 protein translation by directly targeting Sp1 mRNA 3'-untranslated region (UTR). Similar to ISO treatment, ectopic expression of miR-137 alone led to G0-G1 cell growth arrest and inhibition of anchorage-independent growth in human bladder cancer cells, which could be completely reversed by overexpression of GFP-Sp1. The inhibition of miR-137 expression attenuated ISO-induced inhibition of Sp1/Cyclin D1 expression, induction of G0-G1 cell growth arrest, and suppression of cell anchorage-independent growth. Taken together, our studies have demonstrated that miR-137 induction by ISO targets Sp1 mRNA 3'-UTR and inhibits Sp1 protein translation, which consequently results in reduction of Cyclin D1 expression, induction of G0-G1 growth arrest, and inhibition of anchorage-independent growth in vitro and in vivo. Our results have provided novel insights into understanding the anticancer activity of ISO in the therapy of human bladder cancer.

Topics: 3' Untranslated Regions; Animals; Base Sequence; Binding Sites; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Ectopic Gene Expression; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Mice; MicroRNAs; Protein Biosynthesis; RNA Interference; RNA, Messenger; Sp1 Transcription Factor; Stilbenes; Tumor Burden; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Myocardial infarction (MI) is a common cause of mortality worldwide. Isorhapontigenin is a derivative of stilbene with chemical structure similar to resveratrol. The omega-3 fatty acids (FA) have beneficial effects on neurodegenerative, inflammatory, and cardiovascular diseases. The aim of this study was to investigate the effects of pretreatment with isorhapontigenin and omega-3 FA on rat model of isoproterenol-induced MI. Fifty-six rats were divided into seven groups: normal, normal + isorhapontigenin, normal + omega-3 FA, MI, MI + isorhapontigenin, MI + omega-3 FA, and MI + isorhapontigenin + omega-3 FA. Serum levels of cardiac marker enzymes [lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB)], cardiac troponin I (cTnI), inflammatory markers [tumor necrosis factor-alpha (TNF-α) and interleukin-6], and lipid profile [triglycerides, total cholesterol (T.Ch), high and low density lipoproteins (HDL, LDL), and phospholipids] as well as cardiac levels of malondialdehyde and anti-oxidants [reduced glutathione (GSH), superoxide dismutase (SOD), and catalase)] were measured in all rats. ECG and histopathological examination were performed. Isoproterenol caused a significant elevation of ST segment, decreased R wave amplitude, HDL, and anti-oxidants, and increased LDH, CK-MB, cTnI, TNF-α, interleukin-6, malondialdehyde, triglycerides, T.Ch, LDL, and phospholipids. Omega-3 FA or isorhapontigenin significantly decreased the ST segment elevation, LDH, CK-MB, cTnI, TNF-α, interleukin-6, malondialdehyde, and phospholipids and increased R wave amplitude and anti-oxidants. The effects of combined omega-3 FA and isorhapontigenin were more significant than either of them alone. Therefore, we conclude that omega-3 FA and isorhapontigenin have a cardioprotective effect on rats with isoproterenol-induced MI through their anti-oxidant and anti-inflammatory actions.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Cardiotonic Agents; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Heart; Inflammation Mediators; Isoproterenol; Lipid Peroxidation; Lipids; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Random Allocation; Rats, Sprague-Dawley; Stilbenes

Isorhapontigenin (ISO) is a new derivative of stilbene compound that was isolated from the Chinese herb Gnetum Cleistostachyum and has been used for treatment of bladder cancers for centuries. In our current studies, we have explored the potential inhibitory effect and molecular mechanisms underlying isorhapontigenin anticancer effects on anchorage-independent growth of human bladder cancer cell lines. We found that isorhapontigenin showed a significant inhibitory effect on human bladder cancer cell growth and was accompanied with related cell cycle G(0)-G(1) arrest as well as downregulation of cyclin D1 expression at the transcriptional level in UMUC3 and RT112 cells. Further studies identified that isorhapontigenin downregulated cyclin D1 gene transcription via inhibition of specific protein 1 (SP1) transactivation. Moreover, ectopic expression of GFP-cyclin D1 rendered UMUC3 cells resistant to induction of cell-cycle G(0)-G(1) arrest and inhibition of cancer cell anchorage-independent growth by isorhapontigenin treatment. Together, our studies show that isorhapontigenin is an active compound that mediates Gnetum Cleistostachyum's induction of cell-cycle G(0)-G(1) arrest and inhibition of cancer cell anchorage-independent growth through downregulating SP1/cyclin D1 axis in bladder cancer cells. Our studies provide a novel insight into understanding the anticancer activity of the Chinese herb Gnetum Cleistostachyum and its isolate isorhapontigenin.

Topics: Animals; Antineoplastic Agents, Phytogenic; Binding Sites; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Disease Models, Animal; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Promoter Regions, Genetic; Sp1 Transcription Factor; Stilbenes; Transcription, Genetic; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays