PMID: 

Environ Toxicol. 2018 Dec ;33(12):1237-1244. Epub 2018 Sep 6. PMID: 30187994

Abstract Title: 

Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression.

Abstract: 

To improve the clinical outcome of tumor chemotherapy, more effective combination treatments against tumor metastasis and recurrence are required. Licochalcone A (LicA) is the root of Glycyrrhiza inflata and has been reported to possess anti-inflammatory, antimicrobial, and antitumor effects. Sorafenib (Sor), a multikinase inhibitor, is used to treat patients with solid tumors such as advanced hepatocellular carcinoma (HCC). However, the synergistic effects of LicA and Sor on the metastasis of human HCC cells have not been reported. We found that LicA and Sor did not have cytotoxic effects or arrest growth in human SK-Hep-1 and Huh-7 cells. In addition, treatment with LicA or Sor alone inhibited migration and invasion in human SK-Hep-1 and Huh-7 HCC cells. Furthermore, cotreatment with LicA and Sor synergistically inhibited the migration and invasion of HCC cells and significantly inhibited uPA protein expression. Notably, cotreatment of LicA and Sor synergistically and significantly downregulated MKK4-JNK expression. Through tail vein injection in nude mice, the aforementioned cotreatment synergistically suppressed SK-Hep-1 cell-mediated lung metastasis. These findings first revealed the synergistic effects of LicA and Sor cotreatment against human HCC cells, further suggesting that beneficial effects on tumor regression could be confirmed through prospective clinical trials.

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PMID: 

Mol Cell Neurosci. 2018 12 ;93:1-9. Epub 2018 Sep 22. PMID: 30253196

Abstract Title: 

Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function inβ-amyloid overexpressing mice.

Abstract: 

Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuatesβ-amyloid (Aβ)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Aβ-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Aβ accumulation. Seven month old 5xFAD female mice were treated with CAW (2 mg/mL) in their drinking water for two weeks prior to behavioral testing. Learning, memory and executive function were assessed using the object location memory task (OLM), conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) test. Mitochondrial function was profiled using the Seahorse XF platform in hippocampal mitochondria isolated from these animals and tissue was harvested for assessmentof mitochondrial, antioxidant and synaptic proteins. CAW improved performance in all behavioral tests in the 5xFAD but had no effect on WT animals. Hippocampal mitochondrial function was improved and hippocampal and cortical expression of mitochondrial genes was increased in CAW-treated 5xFAD mice.Gene expression of the transcription factor NRF2, as well as its antioxidant target enzymes, was also increased with CAW treatment in both WT and 5xFAD mice. CAW treatment also decreased Aβ-plaque burden in the hippocampus of treated 5xFAD mice but had no effect on plaques in the cortex. These data show that CAW can improve many facets of Aβ-related cognitive impairment in 5xFAD mice. Oral treatment with CAW also attenuates hippocampal mitochondrial dysfunction in these animals. Because mitochondrial dysfunction and oxidative stress accompany cognitive impairment in many pathological conditions beyond Alzheimer's disease, this suggests potentially broad therapeutic utility of CAW.

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PMID: 

Acta Pharmacol Sin. 2019 Nov 8. Epub 2019 Nov 8. PMID: 31705123

Abstract Title: 

Asiatic acid prevents renal fibrosis in UUO rats via promoting the production of 15d-PGJ2, an endogenous ligand of PPAR-γ.

Abstract: 

Renal fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Recently, asiatic acid (AA), a triterpenoid compound from Chinese medicine Centella asiatica, has been found to attenuate renal fibrosis. In the current study, we explored the mechanisms underlying antifibrotic effect of AA on UUO model. SD rats and ICR mice were subjected to unilateral ureteral occlusion (UUO) surgery. Prior the surgery, rats were administered AA (10 mg·kgper day, ig) for 7 days, whereas the mice received AA (15 mg·kgper day, ig) for 3 days. UUO group displayed significant degree of renal dysfunction, interstitial fibrosis, oxidative stress, and activation of the TGF-β/Smad and Wnt/β-catenin signaling pathway in the kidney, these pathological changes were greatly ameliorated by pretreatment with AA. In addition, we found that co-treatment with GW9662, a selective PPAR-γ antagonist (1 mg·kgper day, ip) for 7 days, abolished the protective effects of AA. We further revealed that AA pretreatment did not significantly change the expression levels of PPAR-γ in the kidney, but markedly increase the plasma levels of 15d-PGJ2, an endogenous ligand of PPAR-γ. In UUO mice, pretreatment with 15d-PGJ2 (24 μg·kgper day, ip, for 7 days) produced similar protective effect as AA. Moreover, AA pretreatment upregulated the expression levels of active, nuclear-localized SREBP-1 (nSREBP-1), whereas fatostatin, a specific inhibitor of SREBP-1, decreased the expression of nSREBP-1, as well as the level of 15d-PGJ2. These results provide new insight into the antifibrotic mechanism of AA and endogenous metabolites might become a new clue for investigation of drug mechanism.

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PMID: 

Anticancer Agents Med Chem. 2019 Dec 10. Epub 2019 Dec 10. PMID: 31823705

Abstract Title: 

Anti-Cancer Effects of Asiatic Acid, A Triterpene From Centilla Asiatica L: A Literature Review.

Abstract: 

BACKGROUND: Centilla asiatica L is a medicinal herb that has been widely used in folk medicine to treat various diseases. Asiatic Acid (AA), a triterpene and a known component of this herb, has been shown to display important biological activities, including anti-inflammatory, antibacterial, antidiabetic and anti-hyperlipidemic, neuroprotective, anxiolytic and antidepressant, hepatoprotective, pancrease protective, and cardio-protective.OBJECTIVE: This review focuses on AA's anti-cancer effects on the basis of published literature found in a number of databases such as PubMed and Science. Emphasis has been given to the mechanisms of action of its anti-cancer effect.METHODS: A literature survey was conducted through May 2019 using known databases such as PubMed and Science Direct using the keyword 'Asiatic acid', pairing with 'cancer', 'tumor', 'anti-cancer effect', 'cytotoxic effect', 'anti-tumor activity', 'cell line', 'animal cancer', and 'human cancer'.RESULTS: Findings suggest that AA exerts anti-cancer effects in several test systems through various pathways, including oxidative/antioxidant, anti-inflammatory, cytotoxicity, apoptotic cell death, necrosis, anti-angiogenesis, inhibition of proliferation and cell migration, and chemoprevention.CONCLUSIONS: AA may be an effective plant-based cancer chemotherapeutic agent and a promising lead for the development of potent anticancer drugs.

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PMID: 

BMC Complement Altern Med. 2019 Aug 14 ;19(1):213. Epub 2019 Aug 14. PMID: 31412845

Abstract Title: 

Pharmacological properties of Centella asiatica hydrogel in accelerating wound healing in rabbits.

Abstract: 

BACKGROUND: Various extracts of Centella asiatica (Apiaceae) and its active constituent, asiaticoside, have been reported to possess wound healing property when assessed using various in vivo and in vitro models. In an attempt to develop a formulation with accelerated wound healing effect, the present study was performed to examine in vivo efficacy of asiaticoside-rich hydrogel formulation in rabbits.METHODS: Asiaticoside-rich fraction was prepared from C. asiatica aerial part and then incorporated into polyvinyl alcohol/polyethylene glycol (PVA/PEG) hydrogel. The hydrogel was subjected to wound healing investigation using the in vivo incision model.RESULTS: The results obtained demonstrated that: i) the hydrogel formulation did not cause any signs of irritation on the rabbits' skin and; ii) enhanced wound healing 15% faster than the commercial cream and > 40% faster than the untreated wounds. The skin healing process was seen in all wounds marked by formation of a thick epithelial layer, keratin, and moderate formation of granulation tissues, fibroblasts and collagen with no fibrinoid necrosis detected.CONCLUSION: The asiaticoside-rich hydrogel developed using the freeze-thaw method was effective in accelerating wound healing in rabbits.

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PMID: 

Drug Discov Ther. 2019 ;13(5):261-267. PMID: 31723097

Abstract Title: 

Centella asiatica (L.) extract attenuates inflammation and improve insulin sensitivity in a coculture of lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes and RAW 264.7 macrophages.

Abstract: 

Insulin resistance in obese condition is related to chronic low-grade inflammation which leads to insulin signaling impairment. Centella asiatica (L.) is an herb that exhibits anti-inflammatory and blood sugar-lowering activity (hypoglycemia). The study aims to investigate the molecular mechanism of C. asiatica extract in insulin sensitivity improvement in a coculture of lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes and RAW 264.7 macrophages. A coculture of 3T3-L1 adipocytes and RAW 264.7 macrophages were incubated with LPS to induce insulin resistance in the adipocytes. An extract of C. asiatica was added to coculture cells and after 24 hours, insulin sensitivity and inflammatory response were determined, including glucose consumption, glucose transporter-4 (GLUT-4), insulin receptor substrate-1 (IRS-1), and interleukin-6 (IL-6) mRNA expression. C. asiatica extract at a concentration of 500µg/mL increased glucose consumption and induced GLUT-4 and IRS-1 mRNA expression significantly in a coculture of LPS-induced 3T3-L1 adipocytes and RAW 264.7 macrophages. The pro-inflammatory cytokines IL-6 mRNA expression was decreased in the coculture cells after treatment with C. asiatica extractat a concentration of 500 µg/mL. This result indicates that C. asiatica has an effect to stimulate glucose consumption in the coculture cells that might be mediated via GLUT-4/IRS-1 pathway as a result of IL-6 inhibition. These findings suggest that the C. asiatica extract inhibits inflammation and improves insulin sensitivity in a coculture of LPS-induced 3T3-L1 adipocytes and RAW 264.7 macrophages.

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PMID: 

Antioxidants (Basel). 2019 Dec 8 ;8(12). Epub 2019 Dec 8. PMID: 31817977

Abstract Title: 

Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice.

Abstract: 

(CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer's disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ – 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW's impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increasedin hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

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PMID: 

Biomolecules. 2020 Jan 25 ;10(2). Epub 2020 Jan 25. PMID: 31991751

Abstract Title: 

Asiatic Acid, Extracted fromand Induces Apoptosis Pathway through the Phosphorylation p38 Mitogen-Activated Protein Kinase in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells.

Abstract: 

Nasopharyngeal carcinoma (NPC) is an important issue in Asia because of its unique geographical and ethnic distribution. Cisplatin-based regimens are commonly the first-line used chemotherapy, but resistance and toxicities remain a problem. Therefore, the use of anticancer agents derived from natural products may be a solution. Asiatic acid (AA), extracted from, was found to have anticancer activity in various cancers. The aim of this study is to examine the cytotoxic effect and mediated mechanism of AA in cisplatin-resistant NPC cells. The results shows that AA significantly reduce the cell viability of cisplatin-resistant NPC cell lines (cis NPC-039 and cis NPC-BM) in dose and time dependent manners caused by apoptosis through the both intrinsic and extrinsic apoptotic pathways, including altered mitochondrial membrane potential, activated death receptors, increased Bax expression, and upregulated caspase 3, 8, and 9. The Western blot analysis of AA-treated cell lines reveals that the phosphorylation of MAPK pathway proteins is involved. Further, the results of adding inhibitors of these proteins indicates that the phosphorylation of p38 are the key mediators in AA-induced apoptosis in cisplatin-resistant human NPC cells. This is the first study to demonstrate the AA-induced apoptotic pathway through the phosphorylation p38 in human cisplatin-resistant nasopharyngeal carcinoma. AA is expected to be another therapeutic option for cisplatin-resistant NPC because of the promising anti-cancer effect and fewer toxic properties.

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PMID: 

Iran J Basic Med Sci. 2019 Oct ;22(10):1218-1224. PMID: 31998466

Abstract Title: 

(Gotu kola) ethanol extract up-regulates hippocampal brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling in chronic electrical stress model in rats.

Abstract: 

Objectives: Impairment of hippocampus function as a center for memory processing occurs due to stress.L. (Gotu kola) is known to improve memory, intelligence, and neural protection although the precise mechanism is not well understood. This study aimed to investigate the effects of ethanol extracts oftoward MAPK expression as down-stream signaling of brain-derived neurotrophic factor (BDNF).Materials and Methods: We performed a chronic electrical stress model on 20 male Sprague Dawley rats (2 months-old, 180-200 g). Rats were divided into four groups: normal control group (Control) which received distilled water, and three treatment groups receiving oral Gotu kola ethanol extracts in oral doses of 150 mg/kg BW (CeA150), 300 mg/kg BW (CeA300), and 600 mg/kg BW (CeA600) over four weeks. Memory acquisition was assessed with Morris water maze. Hippocampus was harvested, then extracted for protein and RNA analysis. MAPK proteins (p38, ERK1/2, JNK) were measured using Western blot, meanwhile, BDNF and TrkB receptor were analyzed with real-time PCR (RT-PCR).Results: CeA600 group revealed improvement of memory performance as shown by reduction in time and distance parameters compared to control during escape latency test. This finding associated with significant elevation of hippocampal BDNF protein and mRNA level with up-regulation of TrkB mRNA expression in CeA600 group compared to control. Western-blot analysis showed significant up-regulation of ERK1/2 protein level in CeA600 group (

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PMID: 

Nutrients. 2020 Jan 29 ;12(2). Epub 2020 Jan 29. PMID: 32013132

Abstract Title: 

L. Phytosome Improves Cognitive Performance by Promoting Bdnf Expression in Rat Prefrontal Cortex.

Abstract: 

A wide range of people in the world use natural remedies as primary approaches against illnesses. Accordingly, understanding the mechanisms of action of phytochemicals has become of great interest. In this context,L. is extensively used, not only as anti-inflammatory or antioxidant agent but also as brain tonic. On this basis, the purpose of this study was to evaluate whether the chronic administration ofL. to adult male rats was able to improve the expression of, one of the main mediators of brain plasticity. Moreover, we assessed whether the treatment could affect the cognitive performance in the novel object recognition (NOR) test. We confirmed the presence of the main compounds in the plasma. Furthermore,L. administration induced an increase ofin the prefrontal cortex, and the administration of the higher dose of the extract was able to improve cognitive performance. Finally, the increase in the preference index in the NOR test was paralleled by a further increase inexpression. Overall, we highlight the ability ofL. to affect brain functions by increasingexpression and by enhancing the cognitive performance.

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