PMID: 

Chin J Integr Med. 2019 Sep ;25(9):691-695. Epub 2019 Oct 24. PMID: 31650487

Abstract Title: 

Phonopheresis Associated with Nanoparticle Gel from Phyllanthus amarus Relieves Pain by Reducing Oxidative Stress and Proinflammatory Markers in Adults with Knee Osteoarthritis.

Abstract: 

OBJECTIVE: To determine the changes in serum levels of inflammatory biomarkers and antioxidant levels among the knee osteoarthritis (OA) patients after treatment with Phyllanthus amarus (PP) by nanoparticle gel phonophoresis.METHODS: This study was a randomized, double-blind, placebo-control, parallel-group, clinical trial involving 30 subjects with mild-to-moderate degree of knee OA. The patients were allocated to two groups using a computer-generated random numbers, and received conventional ultrasound therapy (control group, 15 cases) and PP (treatment group, 15 cases) once daily for 10 sessions. The pain was evaluated by visual analogue scale (VAS). Serum levels of tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbnent assay (ELISA). Nitric oxide (NO) was determined by modified Griess reagent. The antioxidant effects, including superoxide dismutase (SOD) and total antioxidant capacity (TAC), were also measured by ELISA assay.RESULTS: The VAS score was significantly decreased in the treatment group compared with the control group after treatment (P

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PMID: 

Curr Pharm Des. 2019 ;25(35):3740-3750. PMID: 31692428

Abstract Title: 

New Applications of Oleanolic Acid and its Derivatives as Cardioprotective Agents: A Review of their Therapeutic Perspectives.

Abstract: 

Oleanolic acid is an analogue of pentacyclic triterpenoids. It has been used as a hepatic drug for over 20 years in China. Currently, there are only five approved drugs derived from pentacyclic triterpenoids, including oleanolic acid (liver diseases), asiaticoside (wound healing), glycyrrhizinate (liver diseases), isoglycyrrhizinate (liver disease) and sodium aescinate (hydrocephalus). To understand more about the bioactivity and functional mechanisms of oleanolic acid, it can be developed as a potent therapeutic agent, in particular, for the prevention and treatment of heart diseases that are the leading cause of death for people worldwide. The primary aim of this mini-review is to summarize the new applications of oleanolic acid and its derivatives as cardioprotective agents reported in recent years and to highlight their therapeutic perspectives in cardiovascular diseases.

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PMID: 

J Diabetes Res. 2019 ;2019:6753541. Epub 2019 Nov 19. PMID: 31828165

Abstract Title: 

The Haematological Effects of Oleanolic Acid in Streptozotocin-Induced Diabetic Rats: Effects on Selected Markers.

Abstract: 

Background: Sustained hyperglycaemia leads to the development of haematological alterations which, if left untreated, is associated with cardiovascular complications. Insulin is the mainstay drug in type 1 diabetes mellitus (T1D); however, the use of insulin is associated with haematological alterations that could further worsen cardiovascular complications. Therefore, the aim of the study was to investigate the haematological effects of oleanolic acid (OA) in streptozotocin- (STZ-) induced diabetic rats.Methods: The animals were separated into five groups; the nondiabetic group (ND), the diabetic control group (DC), and the treatment groups of insulin (170 g/kg, s.c), metformin (500 mg/kg, p.o), and OA (80 mg/kg, p.o). OA was administered orally twice a day. Thereafter, the animals were sacrificed, and blood and tissues were collected for haematological, hormonal, and oxidative status analysis.Results: Untreated diabetic rats exhibited hyperglycaemia, elevated glycated haemoglobin (HbA1c), oxidative stress, and a reduced erythropoietin (EPO) concentration when compared to ND rats. However, administration of OA attenuated hyperglycaemia, HbA1c, and EPO concentrations compared to DC rats. The reduction of blood glucose concentration, HbA1c, and improved EPO concentrations was further associated with a notable increase in red blood cell (RBC) count and other RBC indices. We also observed an increase in the antioxidant status of the RBCs with a concomitant decrease in oxidative stress.Conclusion: These findings suggest that OA improves diabetes-induced haematological changes caused by hyperglycaemia and attenuates the progression of cardiovascular complications in DM individuals.

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PMID: 

Food Funct. 2020 Jan 29 ;11(1):1122-1132. PMID: 31825448

Abstract Title: 

Oleanolic acid enhances tight junctions and ameliorates inflammation in Salmonella typhimurium-induced diarrhea in mice via the TLR4/NF-κB and MAPK pathway.

Abstract: 

Salmonella typhimurium (S.T) is a common cause of acute, self-limiting food-borne diarrhea with severe intestinal inflammation and intestinal barrier damage. Oleanolic acid (OA), isolated from almost 2000 plant species, has been shown to have anti-inflammatory roles. The purpose of this study was to investigate the potential protective effects of OA on S.T-induced diarrhea and enteritis and to elucidate its anti-inflammatory mechanisms. A total of eighty BALB/c mice (4-week-old) were randomly divided into the control group (no S.T, no OA), the S.T group (S.T only), the S.T + OA group (S.T plus 100 mg kg-1 OA) and the OA group (100 mg kg-1 OA only). Compared with the S.T group, OA administration significantly reduced clinical symptoms and weight loss, and the severity of diarrhea and intestinal structural damage was significantly alleviated, which was confirmed by a decrease in the diarrhea index (DI) and jejunal histological damage. In addition, in the infected jejunum, OA maintained the expression and localization of occludin, claudin-1 and ZO-1 to protect the jejunal barrier, thereby maintaining the integrity of the gut barrier. Finally, OA treatment not only reduced the levels of COX-2 and iNOS but also inhibited the secretion of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Furthermore, western blotting results showed that OA treatment significantly inhibited IκB phosphorylation and degradation in intestinal tissues and the nuclear translocation of p65, and OA also decreased the level of TLR4 and the activation of the MAPK pathway. To summarise, OA can maintain the intestinal tight junction barrier and prevent diarrhea caused by S.T. as well as reduce intestinal inflammation through the NF-κB and MAPK signaling pathways.

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PMID: 

Drug Deliv. 2020 Dec ;27(1):191-199. PMID: 31924110

Abstract Title: 

Synergism of cisplatin-oleanolic acid co-loaded hybrid nanoparticles on gastric carcinoma cells for enhanced apoptosis and reversed multidrug resistance.

Abstract: 

Combined administration of different drugs is a widely acknowledged approach for effective cancer therapy. However, the limited targeting, as well as inferior drug loading capacities of current drug delivery systems (DDS), are still the bottleneck for better performance in cancer treatment. Herein, we successfully developed a cancer cell membrane (CM) decorated calcium carbonate (CC) hybrid nanoparticles (HN) for the co-delivery of cisplatin (CDDP) and oleanolic acid (OA). The physicochemical property of HN/CDDP/OA was evaluated, which revealed that the as-prepared DDS was core-shell structured and well-dispersed nanoparticles with size around 100 nm. The HN/CDDP/OA showed high stability and biocompatibility with pH-responsive drug release. Moreover, the CM modification in HN also demonstrated highly elevated tumor-homing nature than bare CC. Finally, the feasibility of HN/CDDP/OA in the treatment of gastric cancer (MGC-803 cell line) wasassessed. HN/CDDP/OA showed better performance than mono systems with enhanced apoptosis and capable of reversing multidrug resistance (MDR) of cancer cells.

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PMID: 

Biomed Pharmacother. 2020 Mar ;123:109752. Epub 2020 Jan 8. PMID: 31924596

Abstract Title: 

Oleanolic acid inhibits mouse spinal cord injury through suppressing inflammation and apoptosis via the blockage of p38 and JNK MAPKs.

Abstract: 

Spinal cord injury (SCI) is reported as a devastating disease, leading to tissue loss and neurologic dysfunction. However, there is no effective therapeutic strategy for SCI treatment. Oleanolic acid (OA), as a triterpenoid, has anti-oxidant, anti-inflammatory, and anti-apoptotic activities. However, its regulatory effects on SCI have little to be elucidated, as well as the underlying molecular mechanisms. In this study, we attempted to explore the role of OA in SCI progression. Behavior tests suggested that OA treatments markedly alleviated motor function in SCI mice. Evans blue contents up-regulated in spinal cords of SCI mice were significantly reduced by OA in a dose-dependent manner, demonstrating the improved blood-spinal cord barrier. Moreover, we found that OA treatments significantly reduced the apoptotic cell death in spinal cord samples of SCI mice through decreasing the expression of cleaved Caspase-3. In addition, pro-inflammatory response in SCI mice was significantly attenuated by OA treatments. Furthermore, SCI mice exhibited higher activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways, but these effects were clearly blocked in SCI mice with OA treatments, as evidenced by the down-regulated phosphorylation of p38, c-Jun-NH 2 terminal kinase (JNK), IκB kinase α (IKKα), inhibitor of nuclear factor κB-α (IκBα) and NF-κB. The protective effectsof OA against SCI were confirmed in lipopolysaccharide (LPS)-stimulated mouse neurons mainly through the suppression of apoptosis and inflammatory response, which were tightly associated with the blockage of p38 and JNK activation. Together, our data demonstrated that OA treatments could dose-dependently ameliorate spinal cord damage through impeding p38- and JNK-regulated apoptosis and inflammation, and therefore OA might be served as an effective therapeutic agent for SCI treatment.

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PMID: 

Bioinformation. 2019 ;15(8):535-541. Epub 2019 Aug 31. PMID: 31719762

Abstract Title: 

Phyllanthus amarus protects against spatial memory impairment induced by lipopolysaccharide in mice.

Abstract: 

Phyllanthus amarus Schumach. and Thonn. is a wide spread medicinal herb with various traditional uses. It is well documented for its antioxidant, anti-inflammatory, and hepatoprotective activities. Therefore, it is of interest to evaluate the 80% ethanol extract of Phyllanthus amarus (PA) on spatial memory using the 8-radial arm maze (8-RAM) in mice after induction of neuro inflammation by lipopolysaccharide (LPS) in a 14- and 28-days treatment study. LC-MS/MS was performed to profile the chemical composition in PA extract. Mice were treated orally with 5% v/v tween 20, PA extract (100, 200 and 400 mg/kg), or ibuprofen (IBF 40 mg/kg) for 14 and 28 days. All groups were challenged with LPS (1 mg/kg) via intraperitoneal (i.p.) injection a day prior to the 8-RAM task except for the negative control group which received an i.p. injection of saline. Data obtained were analyzed with one-way ANOVA followed by post hoc Dunnett's test (comparison of all groups against vehicle control). Analysis of LC-MS/MS data revealed the presence of 16 compounds in the PA extract. Administration of PA extract at 200 and 400 mg/kg for 14 and 28 days significantly (*P

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PMID: 

J Cancer. 2019 ;10(23):5820-5831. Epub 2019 Oct 6. PMID: 31737119

Abstract Title: 

Polymeric micelles loading with ursolic acid enhancing anti-tumor effect on hepatocellular carcinoma.

Abstract: 

Ursolic acid (UA) is widely found in many dietary plants, which has been proved to be effective in cancer therapy. But unfortunately its hydrophobic property limits its clinical application. Polymer micelles (PMs) are constructed from amphiphilic block copolymers that tend to self-assemble and form the unique core-shell structure consisting of a hydrophilic corona outside and a hydrophobic inner core. PMs could entrap the hydrophobic substance into its hydrophobic inner core for solubilizing these poorly water-soluble drugs and it is widely applied as a novel nano-sized drug delivery system. This study aimed to develop the drug delivery system of UA-loaded polymer micelles (UA-PMs) to overcome the disadvantages of UA in clinical application thus enhancing antitumor effect on hepatocellular carcinoma. UA-PMs was prepared and characterized for the physicochemical properties. It was investigated the cell-growth inhibition effect of UA-PMs against the human hepatocellular carcinoma cell line HepG2 and human normal liver cell line L-02. UA-PMs was evaluated about thetoxicity and the antitumor activity. We took a diblock copolymer of methoxy poly (ethylene glycol)-poly(L-lactic acid) (mPEG-PLA) as carrier material to prepare UA-PMs by the thin-film dispersion method. MTT assay and wound-healing assay were investigated to assess the inhibition effect of UA-PMs against HepG2 cells on cell-growth and cell-migration. Further, we chose KM mice for the acute toxicity experiment and assessed the antitumor effect of UA-PMs on the H22 tumor xenograft. UA-PMs could markedly inhibit the proliferation and migration of HepG2 cells.study showed that UA-PMs could significantly inhibit the growth of H22 xenograft and prolong the survival time of tumor-bearing mice. It demonstrated that UA-PMs possess great potential in liver cancer therapy and may enlarge the application of UA in clinical therapy.

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PMID: 

Front Pharmacol. 2019 ;10:1321. Epub 2019 Nov 1. PMID: 31736766

Abstract Title: 

Ursolic Acid Improves Intestinal Damage and Bacterial Dysbiosis in Liver Fibrosis Mice.

Abstract: 

Liver fibrosis is a reversible process of extracellular matrix deposition or scar formation after liver injury. Intestinal damage and bacterial dysbiosis are important concomitant intestinal changes in liver fibrosis and may in turn accelerate the progression of liver fibrosis through the gut-liver axis. RhoA, an important factor in the regulation of the cytoskeleton, plays an important role in intestinal damage. We investigated the effects of ursolic acid (UA), a traditional Chinese medicine with anti-fibrotic effects, on intestinal damage and bacterial disorder through the RhoA pathway. UA treatment reduced intestinal damage by inhibiting the inflammatory factor TNF-α and increasing the expression of tight junction proteins and antibacterial peptides to protect the intestinal barrier. Moreover, the corrective effect of UA on bacterial dysbiosis was also confirmed by sequencing of the 16S rRNA gene. Potential beneficial bacteria, such as the phylum Firmicutes and the generaand, were increased in the UA group compared to the CClgroup. In liver fibrosis mice with RhoA inhibitioninjection of adeno-associated virus, the liver fibrosis, intestinal damage, and flora disturbances were improved. Moreover, UA inhibited the expression of RhoA pathway components. In conclusion, UA improves intestinal damage and bacterial dysbiosis partlythe RhoA pathway. This may be a potential mechanism by which UA exerts its anti-fibrotic effects and provides effective theoretical support for the future use of UA in clinical practice.

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PMID: 

J Biosci Bioeng. 2019 Dec 5. Epub 2019 Dec 5. PMID: 31813671

Abstract Title: 

Antibacterial and antibiofilm activity of ursolic acid against carbapenem-resistant Enterobacter cloacae.

Abstract: 

Recent studies demonstrate that ursolic acid (UA) presents potent antimicrobial activity against a few microorganisms, however, the underlying mechanisms remain elusive. Moreover, little is known about the effect of UA on carbapenem-resistant Enterobacter cloacae (CREC). In this study, we aimed to investigate the mechanisms underlying-antimicrobial activity of UA and its mode of action against CREC. Minimum inhibitory concentrations (MIC) of UA against CREC were determined by the agar dilution method. The antibacterial effect of UA against CREC was elucidated by evaluating changes in intracellular ATP concentration, intracellular pH, membrane potential, membrane integrity, and cell morphology. A crystal violet assay, field emission scanning electron microscopy (FESEM), and confocal laser scanning microscopy (CLSM) were applied to examine the effect of UA on biofilm formation. Furthermore, the inactivation of CREC cells in biofilms was explored by CLSM. Our results showed that UA has a MIC of 0.1 mg/mL against CREC. UA treatment inhibited CREC growth and impaired membrane integrity of CREC cells, as measured by the decrease in intracellular ATP level, pH, and membrane potential, as well as distinctive deformation in cellular morphology. Moreover, UA exerted a significant inhibitory effecton biofilm formation of CREC and inactivated CREC cells within biofilms. These findings reveal that UA has potent antibacterial and antibiofilm activity against CREC and, thus, can be used as a natural food preservative to reduce CREC-related infections.

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