PMID: 

Int J Pharm. 2019 Nov 25 ;571:118751. Epub 2019 Oct 9. PMID: 31605722

Abstract Title: 

Doxorubicin combined with betulinic acid or lonidamine in RGD ligand-targeted pH-sensitive micellar system for ovarian cancer treatment.

Abstract: 

Synergistic combination therapy involving the integration of chemotherapeutics and chemosensitizers into micelles has demonstrated great potential for tumor-specific location release. Here, the natural product betulinic acid (BA) and chemical drug lonidamine (LN) were used as chemosensitizers in combination with doxorubicin (DOX) for ovarian cancer treatment. We designed pH-sensitive peptide derivatives and constructed an all-in-one multifunctional multidrug pH-sensitive targeting delivery system for the synergistic co-delivery of DOX and BA (or LN). The combination of DOX and BA was found to elicit better therapeutic effects and lower cardiotoxicity than the DOX and LN combination in Skvo3 cells. Further, loading DOX/BA into the present micellar systems enabled burst release at the tumor location, leading to enhanced anti-tumor effects and reduced off-target effects. More importantly, DOX/BA micelles elicited fewer adverse effects on cardiac function and leukocyte counts in Skvo3 subcutaneous xenograft models. These features suggest that the designed micelles represent a promising multifunctional strategy for the efficient treatment of ovarian cancer.

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PMID: 

Am J Transl Res. 2019 ;11(11):6952-6964. Epub 2019 Nov 15. PMID: 31814899

Abstract Title: 

Betulinic acid induces autophagy-mediated apoptosis through suppression of the PI3K/AKT/mTOR signaling pathway and inhibits hepatocellular carcinoma.

Abstract: 

Betulinic acid (BA) is a pentacyclic triterpenoid compound that widely exists in Chinese herbal medicine, and it has remarkable biological activity. However, the involved molecular targets and mechanisms of BA are still ambiguous. Here, we aim to validate the preventive effects and molecular mechanisms of BA against hepatocellular carcinoma via related experiments. We extracted the 2D and 3D structure of BA from the PubChem database. MTT assay and colony formation assay were used to determine the anti-proliferation and cytotoxicity of BA using in vitro cell models. Hoechst 33258 staining was used to investigate the extent of apoptosis after BA treatment. Western blot and immunofluorescence experiments were used to evaluate apoptosis-related and autophagy-related proteins and molecular mechanisms. We demonstrated that BA significantly inhibited cell proliferation in HepG2 and SMMC-7721 hepatocellular carcinoma cells, but with little cytotoxicity effects on l-02 normal liver cells. We further determined that the hepatocellular carcinoma prevention effects of BA were closely correlated with apoptosis and autophagy. Furthermore, our data indicated that BA-induced autophagy has a protective effect against cancer cell proliferation and promotes cell apoptosis. Additionally, apoptosis and autophagy were induced by BA through suppression of the PI3K/AKT/mTOR signaling pathway. Collectively, our study provides experimental evidence that BA inhibits cell proliferation and induces cell apoptosis and autophagy via suppressing the PI3K/AKT/mTOR pathway. Additionally, BA is a safe and effective herbal medicine compound that can be used for the prevention of hepatocellular carcinoma growth, and may be a potential therapeutic strategy against hepatocellular carcinoma.

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PMID: 

Artif Cells Nanomed Biotechnol. 2018 ;46(sup1):324-335. Epub 2018 Jan 9. PMID: 29316822

Abstract Title: 

Beneficial anti-inflammatory effect of paeonol self-microemulsion-loaded colon-specific capsules on experimental ulcerative colitis rats.

Abstract: 

Paeonol, as the main phenolic compound isolated from the Chinese herbs, has been confirmed to present anti-inflammatory effects on ulcerative colitis (UC) in our previous study. However, its poor solubility has hindered its development of being a favourable pharmaceutical product in treating colon diseases. In this study, we prepared the colon-specific delivery system (Pae-SME-CSC) with paeonol-loaded self-microemulsion (Pae-SMEDDS), and evaluated its in vitro and in vivo properties, especially the anti-inflammatory effects on UC rats. The anti-inflammatory effects were evaluated by the disease activity index, colon weight/length ratio, and macroscopic damage and microscopic damage scores. IL-17, IL-6, and TGF-β1 levels were also determined by enzyme-linked immunosorbent assay. The results showed that Pae-SME-CSC had good colon-targeting property in vivo and in vitro, with favourable stability. Efficacy evaluation showed that the dose of the paeonol group (100 mg/kg) exhibited no significant effect onUC (p > .05, compared with the model group), while the Pae-SME-CSC group (100 mg/kg) showed better anti-UC effects (p 

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PMID: 

Eur J Pharmacol. 2018 Sep 5 ;834:257-265. Epub 2018 Jul 25. PMID: 30053410

Abstract Title: 

Paeonol regulates hypoxia-induced proliferation of pulmonary artery smooth muscle cells via EKR 1/2 signalling.

Abstract: 

Pulmonary hypertension (PH) is a disease with a developmental origin characterized by obstructive vascular remodelling that is partially due to excessive pulmonary arterial smooth muscle cells (PASMCs) proliferation. Paeonol has important effects on vascular cell proliferation, migration, and inflammation, but researchers have not determined whether paeonol participates in the development and progression of pulmonary vascular remodelling. We explored the remarkable anti-proliferative effects of paeonol on hypoxic PASMCs, which are postulated to be mediated by the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signalling pathway. In this study, hypoxic rodent PH models, Western blotting, flow cytometry, immunochemistry, and morphometric analyses of the lung vasculature and right ventricle (RV) vessels were performed. Paeonol reversed hypoxia-induced increases in right ventricular function, right ventricular systolic pressure and thickening of medial walls. Meanwhile, paeonol ameliorated the hypoxia-induced PASMCs proliferation. Furthermore, paeonol modulated cell proliferation and cell cycle transitions from G/Gphase to S phase and G/M phase in an ERK1/2-dependent manner. Our findings emphasize the central function of paeonol in regulating PASMCs proliferation in subjects with PH. Therefore, paeonol represents a potential novel therapeutic approach for the treatment of PH.

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PMID: 

J Cell Physiol. 2019 Aug ;234(8):14351-14363. Epub 2019 Feb 4. PMID: 30714138

Abstract Title: 

Paeonol reverses promoting effect of the HOTAIR/miR-124/Notch1 axis on renal interstitial fibrosis in a rat model.

Abstract: 

Renal interstitial fibrosis (RIF) is a common manifestation of inflammatory and noninflammatory renal diseases, which correlates to renal excretory dysfunction. Recently, the long noncoding RNAs (lncRNAs) have been demonstrated to be involved in the development of various renal diseases. Here, we aim to determine whether paeonol (PAE) affects RIF with involvement of the lncRNA HOX transcript antisense intergenic RNA (HOTAIR)/microRNA-124 (miR-124)/Notch1 axis. RIF rat models were established by performing unilateral ureteral occlusion (UUO), in which interactions between HOTAIR, Notch1, and miR-124 were determined. To identify the roles of PAE and HOTAIR in RIF, rats were injected with HOTAIR or PAE. Subsequently, to further investigate the underlying mechanism of PAE in RIF, epithelial to mesenchymal transition (EMT)- and migration-related genes in NRK-49F cells were measured. Next, rats were further treated with IMR-1 (inhibitor of the Notch1/Jagged1 signaling pathway) to determine how PAE influences the Notch1/Jagged1 signaling pathway. HOTAIR interacted with miR-124, and miR-124 directly targeted Notch1, and HOTAIR was observed to be upregulated in RIF rats. PAE was found to decrease HOTAIR and Notch1 expression but to increase the miR-124 expression in RIF rats. PAE inhibited EMT and migration of NRK-49F cells facilitated by HOTAIR. HOTAIR activated the Notch1/Jagged1 signaling pathway by downregulating miR-124, while PAE reversed these effects of HOTAIR on the Notch1/Jagged1 signaling pathway. Overall, our study demonstrates the contributory effect of lncRNA HOTAIR on RIF by activating the Notch1/Jagged1 signaling pathway via inhibition of miR-124, whereas administration of PAE can alleviate the effects of HOTAIR on RIF.

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PMID: 

Psychol Rep. 2002 Apr ;90(2):639-53. PMID: 12061608

Abstract Title: 

Self-reported changes in subjective health and anthrax vaccination as reported by over 900 Persian Gulf War era veterans.

Abstract: 

A 1999 study of United Kingdom servicemembers by Unwin, et al. recently found significant relationships between anthrax and other vaccinations, reactions to those vaccines, and later health problems for male current or former active military Gulf War veterans. Likewise, in 2000 Steele and in 1998 Gilroy found possible adverse effects of vaccinations on Gulf War veterans. However, the role of such vaccinations remains controversial; more recent government reports continue to dispute the existence of any data that might reflect adversely on the role of vaccinations on the health of Gulf War veterans. To address this controversy, the current study assessed similar relationships for over 900 Reserve Component Gulf War Era veterans from Ohio and nearby states. Gulf War veterans were more likely to report poorer health than non-Gulf veterans. Female veterans were more likely to report mild or severe reactions to vaccines than male veterans. Those veterans who received anthrax vaccine reported more reactions to vaccines than those who did not receive anthrax vaccine. Declines in long-term subjective health were associated with receipt of anthrax vaccine by Gulf War veterans but not for those who did not deploy to the Gulf, although few of the latter received anthrax vaccine. Regardless of deployment status, veterans who reported more severe reactions to vaccines were more likely to report declines in subjective health. Female veterans reported poorer health during the Gulf War than did male veterans, but sex was not related to veterans' reports of subjective health at subsequent times. It is recommended that servicemembers who experience severe reactions to anthrax vaccine be medically reevaluated before receiving further anthrax vaccine and that careful follow-ups be conducted of those receiving the vaccine currently, in accordance with Nass's 1999 recommendations. We also recommend that safer alternatives to thimerosal (a mercury sodium salt, 50% mercury) be used to preserve all vaccines.

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PMID: 

Int Immunopharmacol. 2019 Jul ;72:413-421. Epub 2019 Apr 25. PMID: 31030097

Abstract Title: 

Paeonol: pharmacological effects and mechanisms of action.

Abstract: 

Paeonia suffruticosa possesses various medicinal benefits and has been used extensively in traditional oriental medicine for thousands of years. Paeonol is the main component isolated from the root bark of Paeonia suffruticosa. The pharmacological effects of Paeonia suffruticosa are mostly attributed to paeonol. Paeonol injection has been successfully applied in China for nearly 50 years for inflammation/pain-related indications. Currently, the dosage forms of paeonol approved by China Food and Drug Administration include tablet, injection, and external preparations such as ointment and adhesive plaster. So far, the clinical applications of paeonol are mainly focusing on the anti-inflammatory activity. Studies of other pharmacological activities of paeonol are developing rapidly, and which may play an important role in the future. Besides, substantial mechanisms of pharmacological action of paeonol have been clarified in recent years. In this review, we summarize thepharmacological effects anti-inflammatory, neuroprotective, anti-tumor, anti-cardiovascular diseases and associated mechanisms of action of paeonol up to date.

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PMID: 

Vaccine. 2009 Jul 9 ;27(32):4278-83. Epub 2009 May 28. PMID: 19450636

Abstract Title: 

Serious adverse events rarely reported after trivalent inactivated influenza vaccine (TIV) in children 6-23 months of age.

Abstract: 

In October 2003 the Advisory Committee on Immunization Practices (ACIP) recommended influenza vaccination for all children ages 6-23 months. We evaluated the safety of this recommendation by querying the Vaccine Adverse Events Reporting System (VAERS) for serious adverse events (SAE) reported between July 1, 2003 and June 30, 2006 in 6-23 month old infants after trivalent inactivated influenza vaccine (TIV). Cases were reviewed and the causal relationship with vaccine assessed. One hundred and four SAE were reported; median time from vaccination to SAE onset was one day. The two most commonly reported SAE disease categories were fever (N=52) and seizure (N=35). Causality assessment revealed that none of the SAE was definitely related to TIV. Although the number of SAE increased over time, the most common types of events remained unchanged with no new or unexpected safety concerns identified with expanded TIV use.

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Cinnamon’s anticancer effects are well examined, but recent research suggests that the active ingredients in cinnamon have additional apoptotic effects on cancerous cells

PMID: 

Biosci Trends. 2019 Jul 22 ;13(3):253-260. Epub 2019 Jun 23. PMID: 31231109

Abstract Title: 

Protection of paeonol against epirubicin-induced hepatotoxicity: A metabolomic study.

Abstract: 

Paeonol extracted from the Moutan Cortex, possesses hepatoprotective activity against epirubicin (EPI)-induced liver damage. This study evaluated the protective effect of paeonol on EPI-induced hepatotoxicity and explored the underlying metabolomic mechanism. Breast tumor-bearing mice were randomly divided into three groups: control, EPI, and EPI + paeonol treatment. Mice received a tail i.v. injection of EPI every other day for 3 cycles or/and intragastrically (i.g.) administered paeonol daily for 6 days. Hematoxylin-eosin (HE) staining and biochemical detection were used to determine the degree of damage. A gas chromatography-mass spectrometry (GC-MS) technique was established to determine the metabolites. PLS-DA and PCA were used to investigate metabolic changes. HE staining and biochemical detection results showed that EPI caused serious liver damage while paeonol ameliorated it. The results of mass spectrogram, partial least squares-discriminate analysis (PLS-DA), and principal component analysis (PCA) demonstrated that lipid, amino acid, and energy metabolism involving seven metabolites were obviously changed by EPI and reversed by paeonol. Additionally, paeonol inhibited EPI-induced activation of adenosine monophosphate activated protein kinase/mammalian target of Rapamycin (AMPK/mTOR) signalling pathway. Our results demonstrated the hepatoprotective effect of paeonol on EPI-induced hepatotoxicity in mice, provided potential biomarkers for early assessment of EPI-induced liver injury and illuminated the metabolic mechanism underlying paeonol-related hepatic protection.

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