PMID: 

Cell Death Dis. 2019 04 5 ;10(4):313. Epub 2019 Apr 5. PMID: 30952839

Abstract Title: 

Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A.

Abstract: 

Licochalcone A (Lico A), isolated from Xinjiang licorice Glycyrrhiza inflate, has been shown to have antioxidative potential via the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, which is involved in the prevention of acetaminophen-induced hepatotoxicity. The purpose of the current study was to further explore the protective effect of Lico A against lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury (ALI) and its underlying molecular mechanisms. Our results found that treatment with Lico A significantly reduced in LPS/GalN-induced hepatotoxicity by lessening lethality, alleviating histopathological liver changes, decreasing the alanine transaminase, and aspartate aminotransferase levels, attenuating the secretion of inflammatory cytokines, and regulating oxidative markers. Furthermore, Lico A efficiently alleviated LPS-induced inflammatory response by inhibiting TLR4-MAPK and -NF-κB, as well as the Txnip-NLRP3 signaling pathway. Meanwhile, Lico A induced the activation of Nrf2 and QSTM1 (P62) signaling and promoted autophagy involved in AMP-activated protein kinase (AMPK)-the transcription factor EB (TFEB) signaling, which may contribute to its hepatoprotective activity. Additional mechanistic investigations to evaluate the dependence of the hepatoprotective role of Lico A on Nrf2 revealed that a lack of Nrf2 promoted Lico A-induced autophagy, which contributed to the hepatoprotective effect of Lico A in Nrf2mice. In addition, cotreatment with autophagy inhibitor (3-methyladenine, 3-MA) alleviated but did not abrogate the hepatoprotective effect of Lico A, which may be attributed to its ability to activate Nrf2. Our study firstly suggests that Lico A has protective potential against LPS/GalN-induced hepatotoxicity, which may be strongly associated with activation of Nrf2 and autophagy.

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PMID: 

Int J Mol Sci. 2019 Sep 26 ;20(19). Epub 2019 Sep 26. PMID: 31561416

Abstract Title: 

Ursolic Acid Suppresses Cholesterol Biosynthesis and Exerts Anti-Cancer Effects in Hepatocellular Carcinoma Cells.

Abstract: 

Abnormally upregulated cholesterol and lipid metabolism, observed commonly in multiple cancer types, contributes to cancer development and progression through the activation of oncogenic growth signaling pathways. Although accumulating evidence has shown the preventive and therapeutic benefits of cholesterol-lowering drugs for cancer management, the development of cholesterol-lowering drugs is needed for treatment of cancer as well as metabolism-related chronic diseases. Ursolic acid (UA), a natural pentacyclic terpenoid, suppresses cancer growth and metastasis, but the precise underlying molecular mechanism for its anti-cancer effects is poorly understood. Here, using sterol regulatory element (SRE)-luciferase assay-based screening on a library of 502 natural compounds, this study found that UA activates sterol regulatory element-binding protein 2 (SREBP2). The expression of cholesterol biosynthesis-related genes and enzymes increased in UA-treated hepatocellular carcinoma (HCC) cells. The UA increased cell cycle arrest and apoptotic death in HCC cells and reduced the activation of oncogenic growth signaling factors, all of which was significantly reversed by cholesterol supplementation. As cholesterol supplementation successfully reversed UA-induced attenuation of growth in HCC cells, it indicated that UA suppresses HCC cells growth through its cholesterol-lowering effect. Overall, these results suggested that UA is a promising cholesterol-lowering nutraceutical for the prevention and treatment of patients with HCC and cholesterol-related chronic diseases.

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PMID: 

Heliyon. 2019 Nov ;5(11):e02772. Epub 2019 Nov 14. PMID: 31844708

Abstract Title: 

Ethanolic extract. induces an apoptosis in human lung adenocarcinoma (A549) cells.

Abstract: 

(OS) is tropical herbal plant which is easy to find and widely used as a vegetable food in Indonesia. In last decade, lung adenocarcinoma was in top position as male cancer disease in Indonesia. Recently, emerging data showing the extracts of different species ofexhibiting the anti-tumor properties. Further studies on lung lewis carcinoma demonstrated pro-apoptosis effects after the treatment withextracts. However, the effect of OS of Indonesian origin in human alveolar pulmonary adenocarcinoma A549 cells remain unclear. Therefore, we aimed to investigate effects of ethanolic extract OS (EEOS) in A549 cell culture systems. Cell adhesion and viability assays revealed that EEOS significantly decreased the attachment into extracellular matrix of A549 cells. Morphological examination AO/EB and DAPI staining indicated that EEOS induced the cells shrinkage, DNA fragmentation and condensation of A549 cells. Further, EEOS treatment induced the apoptosis rate followed by up-regulation of reactive oxygen species (ROS), caspase-3 expression and decreased anti-apoptotic protein Bcl-2. This condition also suppressed the expression of SOD2 as well as the GPx. In conclusion, our findings indicate that EEOS suppressed the viability of A549 cells, which may result from the activation of ROS promoting the apoptosis signaling via mitochondrial intrinsic pathway. Taken together, EEOS might be a good therapeutic potential to further understand its properties in the treatment of lung carcinoma.

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PMID: 

J Food Biochem. 2020 Feb 3:e13160. Epub 2020 Feb 3. PMID: 32010989

Abstract Title: 

The protective effects of Salvia officinalis essential oil compared to simvastatin against hyperlipidemia, liver, and kidney injuries in mice submitted to a high-fat diet.

Abstract: 

The present study was undertaken to evaluate the effects of Salvia officinalis essential oil (SEO) and simvastatin in hyperlipidemic mice. Animals were randomly divided into four groups. The control group received a standard diet. The high-fat diet (HFD) group received HFD. The third and fourth groups received HFD associated either with simvastatin (2.5 mg/kg bw) or with SEO (4 mg/kg bw). All animals were sacrificed after 8 weeks of treatment. SEO and simvastatin reduced in HFD mice body weight gain, hyperlipidemia, disruption of liver and renal functions and reactive oxygen species production. In fact, total cholesterol, triglycerides, totallipids, and low-density lipoprotein cholesterol levels, as well as aspartate transaminase, alanine transaminase, gamma-glutamyltranspeptidase and lactate dehydrogenase activities were reduced, while fecal lipids increased compared to those of HFD mice. The lipid-lowering effect of SEO was more effective than that of simvastatin. PRACTICAL APPLICATIONS: High-fat diet provokes hyperlipidemia, atherosclerosis, and abnormal lipid metabolism leading to the development of hepatic and renal dysfunctions as well as perturbations of the antioxidant status in liver and kidney. The results of this research highlight the beneficial effects of SEO in the management of these disorders without inducing side effects; in fact, the plant essential oil decreased lipids and improved the antioxidant status more than did a synthetic drug.

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PMID: 

Curr Pharm Biotechnol. 2018 ;19(14):1156-1169. PMID: 30539691

Abstract Title: 

Suppressive Effects of the Standardized Extract of Phyllanthus amarus on Type II Collagen-induced Rheumatoid Arthritis in Sprague Dawley Rats.

Abstract: 

BACKGROUND: Standardized extract of Phyllanthus amarus has been shown to possess inhibitory effects on cellular and humoral immune responses in Wistar-Kyoto rats and Balb/c mice.OBJECTIVE: In the present study, the standardized extract of P. amarus was investigated for its suppressive effects on type II collagen-induced rheumatoid arthritis (TCIA) in Sprague Dawley rats.METHOD: The major components of the extracts, lignans and phenolic compounds were analysed by using a validated reversed phase HPLC and LC-MS/MS. A rheumatoid arthritis rat model was induced by administering a bovine type II collagen emulsion subcutaneously at the base of tail, on day 0 and 7 of the experiment. Effects of the extract on severity assessment, changes in the hind paw volume, bone mineral density, body weight and body temperature were measured. Concentrations of cytokines (TNF-α, IL-1β, IL-1α, IL-6) released, matrix metalloproteinases (MMP-1, MMP-3 MMP-9) and their inhibitor (TIMP-1), haematological and biochemical changes were also measured. ELISA was used to measure the cytokines and proteinases in the rat serum and synovial fluid according to manufacturer's instructions.RESULTS: The extract dose-dependently modulated the progression in physical parameters (i.e. decrease in body weight, increase in body temperature, reduced hind paw volume, reduced the severity of arthritis), bone mineral density, haematological and biochemical perturbations, serum cytokines production and levels of matrix metalloproteinases and their inhibitor in the synovial fluid. Histopathological examination of the knee joint also revealed that the extract effectively reduced synovitis, pannus formation, bone resorption and cartilage destruction.CONCLUSION: The results suggest that the oral administration of a standardized extract of P. amarus was able to suppress the humoral and cellular immune responses to type II collagen, resulting in the reduction of the development of TCIA in the rats.

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PMID: 

Pharm Biol. 2019 Dec ;57(1):145-153. PMID: 30922154

Abstract Title: 

Effects of Phyllanthus amarus PHYLLPROleaves on hangover symptoms: a randomized, double-blind, placebo-controlled crossover study.

Abstract: 

CONTEXT: Phyllanthus amarus Schumach. and Thonn. (Euphorbiaceae) is traditionally known to improve general liver health. However, its effect on hangover is unknown.OBJECTIVE: This study evaluated PHYLLPRO™, a standardized ethanol extract of P. amarus leaves for protection against oxidative stress and recovery from hangover symptoms.MATERIAL AND METHODS: Ten days daily oral supplementation of 750 mg/day followed by intoxication was evaluated in a randomized placebo-controlled (containing only excipient), crossover study in 15 subjects (21-50 years old), for oxidative stress, liver damage, alleviating hangover symptoms (Hangover Severity Score: HSS) and mood improvement (Profile-of-Mood-Scores: POMS).RESULTS: PHYLLPRO™ was able to remove blood alcohol in the active group while the placebo group still had 0.05% at 12 h post-intoxication (p 

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PMID: 

Immunopharmacol Immunotoxicol. 2019 Feb ;41(1):55-67. Epub 2018 Dec 12. PMID: 30541359

Abstract Title: 

Phyllanthin and hypophyllanthin fromameliorates immune-inflammatory response in ovalbumin-induced asthma: role of IgE, Nrf2, iNOs, TNF-α, and IL's.

Abstract: 

Asthma is a chronic airway immunoinflammatory disorder characterized by airway remodeling.has been reported to possess antioxidant and anti-inflammatory potential.To evaluate the possible mechanism of action of isolated phytoconstituents from(PA) against ovalbumin (OVA)-induced experimental airway hyperresponsiveness (AHR).Phyllanthin and hypophyllanthin were isolated and characterized (HPLC) from the methanolic extract of PA. AHR was induced in Sprague-Dawley rats by OVA-challenged, and animals were treated with PA (50, 100, and 200 mg/kg, p.o.) for 28 days.The HPLC analysis showed the presence of phyllanthin and hypophyllanthin in methanolic extract of PA at RT of 25.243 and 26.832 min, respectively. OVA-induced alterations in hemodynamic parameters, lung functions test, peripheral blood oxygen level, total, and differential cell count in Bronchoalveolar Lavage Fluid was significantly attenuated ( 

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PMID: 

Microb Pathog. 2019 May ;130:242-246. Epub 2019 Mar 12. PMID: 30876871

Abstract Title: 

Antimicrobial activity of Phyllanthus amarus Schumach.&Thonn and inhibition of the NorA efflux pump of Staphylococcus aureus by Phyllanthin.

Abstract: 

The aim of this study was to evaluate the antimicrobial activity of ethanoic extract of P. amarus (PAEE) and its compound Phyllanthin, as well as, investigate if these natural products could modulate the fluoroquinolone-resistance in S. aureus SA1199-B by way of overexpression of the NorA efflux pump. Microdilution tests were carried out to determine the minimal inhibitory concentration (MIC) of the PAEE or Phyllanthin against several bacterial and yeast strains. To evaluate if PAEE or Phyllanthin were able to act as modulators of the fluoroquinolone-resistance, MICs for Norfloxacin and ethidium bromide were determined in the presence or absence of PAEE or Phyllanthin against S. aureus SA1199-B. PAEE showed antimicrobial activity against Gram-negative strains, meanwhile Phyllanthin was inactive against all strains tested. Addition of PAEE or Phyllanthin, to the growth media at sub-inhibitory concentrations enhanced the activity of the Norfloxacin as well as, Ethidium Bromide, against S. aureus SA1199-B. These results indicate that Phyllanthin is able to modulate the fluoroquinolone-resistance possibly by inhibition of NorA. This hypothesis was supported by in silico docking analysis which confirmed that Phyllantin is a NorA ligand. Thus, this compound could be used as a potentiating agent of the Norfloxacin activity in the treatment of infections caused by fluoroquinolone-resistant S. aureus.

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PMID: 

Front Pharmacol. 2019 ;10:632. Epub 2019 Jun 4. PMID: 31231221

Abstract Title: 

Protective Effects ofAgainst Lipopolysaccharide-Induced Neuroinflammation and Cognitive Impairment in Rats.

Abstract: 

(PA) is widely studied for its hepatoprotective properties but has recently received increasing attention due to its diverse anti-inflammatory effects. However, the effects of PA in modulating immune responses in the central nervous system leading to protection against functional changes remain unexplored. Therefore, we sought to examine the protective effects of 80% v/v ethanol extract of PA on lipopolysaccharide (LPS)-induced non-spatial memory impairment and neuroinflammation.Selected major phytoconstituents of PA extract were identified and quantified using high-performance liquid chromatography. Subchronic neurotoxicity was performed in male Wistar rats given daily oral administration of 100, 200, and 400 mg/kg of the PA extract. Their neurobehavioral activities (functional observation battery and locomotor activity) were scored, and the extracted brains were examined for neuropathological changes. Rats were treated orally with vehicle (5% Tween 20), PA extract (100, 200, and 400 mg/kg), or ibuprofen (IBF; 40 mg/kg) for 14 and 28 days before being subjected to novel object discrimination test. All groups were challenged with LPS (1 mg/kg) given intraperitoneally a day prior to the behavioral tests except for the negative control group. At the end of the behavioral tests, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, nitric oxide (NO), inducible nitric oxide synthase (iNOS), CD11b/c integrin expression, and synaptophysin immunoreactivity were determined in the brain tissues.Gallic acid, ellagic acid, corilagin, geraniin, niranthin, phyllanthin, hypophyllanthin, phyltetralin, and isonirtetralin were identified in the PA extract. Subchronic administration of PA extract (100, 200, and 400 mg/kg) showed no abnormalities in neurobehavior and brain histology. PA extract administered at 200 and 400 mg/kg for 14 and 28 days effectively protected the rodents from LPS-induced memory impairment. Similar doses significantly (

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PMID: 

Sci Rep. 2019 Oct 18 ;9(1):14950. Epub 2019 Oct 18. PMID: 31628385

Abstract Title: 

Lignan enriched fraction (LRF) of Phyllanthus amarus promotes apoptotic cell death in human cervical cancer cells in vitro.

Abstract: 

Phyllanthus amarus is widely grown in this sub-continent and used traditionally to treat many common ailments. In the present study, lignan rich fraction of P. amarus extract was used on cervical cancer cell lines (HeLa, SiHa and C33A) to study it's mechanism of cell death induction. As the cells were treated with IC50 doses of LRF, characteristic apoptotic features were observed. Increased sub G0 population were observed both in Hela and C33 cells, while G1/S arrest was observed in SiHa cells than their untreated counterparts. Increased production of ROS and change in MMP were also detected in the treated cells. Presence of γH2AX, was observed by immunofluorescence. Reduced expression of HPV (16/18) as well as ET-1, an autocrine growth substance, were observed in the treated cells. Immunoblotting as well as ICFC studies showed enhanced expressions of BAX, Caspase 3 and PARP (cleaved) in the treated cells. A major lignan, phyllanthin was isolated from the chloroform fraction and showed strong irreversible affinities for viral E6 and MDM2 in in silico analysis. The study conclusively indicates that LRF has the potential to induce apoptotic cell death in cervical cancer cells by activation of p53 and p21 against DNA damage.

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