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Fulltext Bioassay-Guided extraction of andrographis paniculata for intervention of in-vitro prostate cancer progression in metabolic syndrome environment

Idris MKH, Hasham R, Ismail HF

Daru, 2022 Dec;30(2):253-272.
PMID: 35922691 DOI: 10.1007/s40199-021-00414-8

BACKGROUND: Metabolic syndrome (MetS) is a risk factor for prostate cancer (PCa) progression. Thus, this life-threatening disease demands a proactive treatment strategy. Andrographis paniculata (AP) is a promising candidate with various medicinal properties. However, the bioactivity of AP is influenced by its processing conditions especially the extraction solvent.
OBJECTIVE: In the present study, bioassay-guided screening technique was employed to identify the best AP extract in the management of MetS, PCa, and MetS-PCa co-disease in vitro.
METHODS: Five AP extracts by different solvent systems; APE1 (aqueous), APE2 (absolute methanol), APE3 (absolute ethanol), APE4 (40% methanol), and APE5 (60% ethanol) were screened through their phytochemical profile, in-vitro anti-cancer, anti-obese, and anti-hyperglycemic properties. The best extract was further tested for its potential in MetS-induced PCa progression.
RESULTS: APE2 contained the highest andrographolide (1.34 ± 0.05 mg/mL) and total phenolic content (8.85 ± 0.63 GAE/gDW). However, APE3 has the highest flavonoid content (11.52 ± 0.80 RE/gDW). APE2 was also a good scavenger of DPPH radicals (EC50 = 397.0 µg/mL). In cell-based assays, among all extracts, APE2 exhibited the highest antiproliferative activity (IC50 = 57.5 ± 11.8 µg/mL) on DU145 cancer cell line as well as on its migration activity. In in-vitro anti-obese study, all extracts significantly reduced lipid formation in 3T3-L1 cells. The highest insulin-sensitizing and -mimicking actions were exerted by both APE2 and APE3. Taken together, APE2 showed collectively good activity in the inhibition of PCa progression and MetS manifestation in vitro, compared to other extracts. Therefore, APE2 was further investigated for its potential to intervene DU145 progression induced with leptin (10-100 ng/mL) and adipocyte conditioned media (CM) (10% v/v). Interestingly, APE2 significantly diminished the progression of the cancer cell that has been pre-treated with leptin and CM through cell cycle arrest at S phase and induction of cell death.
CONCLUSION: In conclusion, AP extracts rich with andrographolide has the potential to be used as an alternative to ameliorate PCa progression induced by factors highly expressed in MetS.
Fulltext Optimization of Ultrasound-Assisted Extraction Conditions Followed by Solid Phase Extraction Fractionation from Orthosiphon stamineus Benth (Lamiace) Leaves for Antiproliferative Effect on Prostate Cancer Cells

Suhaimi SH, Hasham R, Hafiz Idris MK, Ismail HF, Mohd Ariffin NH, Abdul Majid FA

Molecules, 2019 Nov 18;24(22).
PMID: 31752230 DOI: 10.3390/molecules24224183

Primarily, optimization of ultrasonic-assisted extraction (UAE) conditions of Orthospihon stamineus was evaluated and verified using a central composite design (CCD) based on three factors including extraction time (minutes), ultrasound amplitude (A), and solvent concentration (%). The response surface methodology (RSM) was performed to develop an extraction method with maximum yield and high rosmarinic acid content. The optimal UAE conditions were as follows: extraction time 21 min, ultrasound amplitudes 62 A, and solvent composition 70% ethanol in water. The crude extract was further fractionated using solid-phase extraction (SPE), where six sequential fractions that varied in polarity (0-100% Acetonitrile in water) were obtained. Next, the six fractions were evaluated for their antioxidant and anti-cancer properties. This study found that Fraction 2 (F2) contained the highest rosmarinic acid content and showed the strongest antioxidant activity. Additionally, F2 showed an anti-proliferative effect against prostate cancer (DU145) with no harmful effect on normal cells.
Fulltext Comparative study of herbal plants on the phenolic and flavonoid content, antioxidant activities and toxicity on cells and zebrafish embryo

Ismail HF, Hashim Z, Soon WT, Rahman NSA, Zainudin AN, Majid FAA

J Tradit Complement Med, 2017 Oct;7(4):452-465.
PMID: 29034193 DOI: 10.1016/j.jtcme.2016.12.006

Natural antioxidants derived from plants have shown a tremendous inhibitory effect on free radicals in actively metabolizing cells. Overproduction of free radicals increases the risk factor of chronic diseases associated with diabetes, cancer, arthritis and cardiovascular disease. Andrographis paniculata, Cinnamon zeylanicum, Curcuma xanthorrhiza, Eugenia polyantha and Orthosiphon stamineus are ethnomedicinal plants used in the Asian region to treat various illnesses from a common fever to metabolic disease. In this study, we have quantified the total phenolic (TPC) and flavonoid content (TFC) in these plants and its inhibitory effect on 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radicals as well as the cytotoxicity effect on cell lines proliferation and zebrafish embryogenesis. Results showed that Cinnamon zeylanicum and E. polyantha have the highest phenolic and flavonoid content. Furthermore, both herbs significantly inhibited the formation of DPPH and ABTS free radicals. Meanwhile, O. stamineus exhibited minimum cytotoxicity and embryotoxicity on tested models. Good correlation between IC50 of 3T3-L1 cells and LC50 embyrotoxicity was also found. This study revealed the potent activity of antioxidant against free radical and the toxicology levels of the tested herbal plants.
Fulltext Bioassay-Guided Different Extraction Techniques of Carica papaya (Linn.) Leaves on In Vitro Wound-Healing Activities

Soib HH, Ismail HF, Husin F, Abu Bakar MH, Yaakob H, Sarmidi MR

Molecules, 2020 Jan 24;25(3).
PMID: 31991676 DOI: 10.3390/molecules25030517

Herbal plants are traditionally utilized to treat various illnesses. They contain phytochemicals that can be extracted using conventional methods such as maceration, soxhlet, and boiling, as well as non-conventional methods including ultrasonic, microwave, and others. Carica papaya leaves have been used for the treatment of dengue, fungal, and bacterial infections as well as an ingredient in anti-aging products. Phytochemicals analysis detected the presence of kaempferol, myricetin, carpaine, pseudocarpaine, dehydrocarpaine I and II, ferulic acid, caffeic acid, chlorogenic acid, β-carotene, lycopene, and anthraquinones glycoside. Conventional preparation by boiling and simple maceration is practical, simple, and safe; however, only polar phytochemicals are extracted. The present study aims to investigate the effects of three different non-conventional extraction techniques (ultrasonic-assisted extraction, reflux, and agitation) on C. papaya phytochemical constituents, the antioxidant capacity, and wound-healing activities. Among the three techniques, the reflux technique produced the highest extraction yield (17.86%) with the presence of saponins, flavonoids, coumarins, alkaloids, and phenolic metabolites. The reflux technique also produced the highest 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging with an IC50 value of 0.236 mg/mL followed by ultrasonic-assisted extraction (UAE) (IC50: 0.377 mg/mL) and agitation (IC50: 0.404 mg/mL). At tested concentrations (3.125 µg/mL to 500 µg/mL), all extracts do not exhibit a cytotoxicity effect on the human skin fibroblast, HSF1184. Interestingly, reflux and UAE were active fibroblast proliferators that support 85% (12.5 µg/mL) and 41% (6.25 µg/mL) better cell growth, respectively. Additionally, during the early 24 h of the scratch assay, the migration rate at 12.5 µg/mL was faster for all extracts with 51.8% (reflux), 49.3% (agitation), and 42.5% (UAE) as compared to control (21.87%). At 48 h, proliferated cells covered 78.7% of the scratch area for reflux extract, 63.1% for UAE, 61% for agitation, and 42.6% for control. Additionally, the collagen synthesis was enhanced for 31.6% and 65% after 24 and 48 h of treatment for reflux. An HPLC-MS/MS-QTOF (quadruple time-of-flight) analysis of reflux identified nine phytochemicals, including carpaine, kaempferol 3-(2G-glucosylrutinoside), kaempferol 3-(2″-rhamnosylgalactoside), 7-rhamnoside, kaempferol 3-rhamnosyl-(1->2)-galactoside-7-rhamnoside, luteolin 7-galactosyl-(1->6)-galactoside, orientin 7-O-rhamnoside, 11-hydroperoxy-12,13-epoxy-9-octadecenoic acid, palmitic amide, and 2-hexaprenyl-6-methoxyphenol. The results suggested that reflux was the best technique as compared to ultrasonic and agitation.
Fulltext In Silico and In Vitro Study of the Bromelain-Phytochemical Complex Inhibition of Phospholipase A2 (Pla2)

Mohamed Tap F, Abd Majid FA, Ismail HF, Wong TS, Shameli K, Miyake M, et al.

Molecules, 2018 Jan 19;23(1).
PMID: 29351216 DOI: 10.3390/molecules23010073

Phospholipase A2 (Pla2) is an enzyme that induces inflammation, making Pla2 activity an effective approach to reduce inflammation. Therefore, investigating natural compounds for this Pla2 inhibitory activity has important therapeutic potential. The objective of this study was to investigate the potential in bromelain-phytochemical complex inhibitors via a combination of in silico and in vitro methods. Bromelain-amenthoflavone displays antagonistic effects on Pla2. Bromelian-asiaticoside and bromelain-diosgenin displayed synergistic effects at high concentrations of the combined compounds, with inhibition percentages of more than 70% and 90%, respectively, and antagonistic effects at low concentrations. The synergistic effect of the bromelain-asiaticoside and bromelain-diosgenin combinations represents a new application in treating inflammation. These findings not only provide significant quantitative data, but also provide an insight on valuable implications for the combined use of bromelain with asiaticoside and diosgenin in treating inflammation, and may help researchers develop more natural bioactive compounds in daily foods as anti-inflammatory agent.
Fulltext Synacinn™: Bacterial reverse mutation test data in five histidine-requiring strains of Salmonella Typhimurium

Zainol SN, Fadhlina A, Rentala SV, Yalaka M, Vatsavai LK, Pillai R, et al.

Data Brief, 2021 Jun;36:107075.
PMID: 34041312 DOI: 10.1016/j.dib.2021.107075

The present data described the analysis of mutagenicity in SynacinnTM by assessing the point mutations occurring due to Synacinn™ exposure to five tester strains of Salmonella typhimurium (TA1537, TA1535, TA98, TA100 and TA102), in the presence or absence of an exogenous mammalian metabolic activation system (S9). It was conducted in two Phases - Phase I (Dose Range Finding experiment-DRF) and Phase II (Mutagenicity Assay 1 and 2). DRF and Mutagenicity Assay 1 was conducted employing plate incorporation method, while Mutagenicity Assay 2 was performed using pre-incubation method. Formulation analysis pertaining to SynacinnTM was performed for both Mutagenicity Assay 1 and 2. Dose formulations were prepared fresh on each day of the experiment. Adventol 50% v/v in purified water was selected as a suitable vehicle based on the preliminary solubility test. Based on the Phase I analysis, 5 mg/plate was selected as the highest concentration of SynacinnTM followed by lower concentrations of 2.5, 1.25, 0.625 and 0.313 mg/plate for the Mutagenicity Assays. Genetic integrity of all the tester strains used was confirmed by performing genotyping before their use. All the data acceptability criteria were fulfilled confirming the validity of the test.
Evaluation of Herb-Drug Interaction of Synacinn™ and Individual Biomarker through Cytochrome 450 Inhibition Assay

Ab Rahman NS, Abd Majid FA, Abd Wahid ME, Zainudin AN, Zainol SN, Ismail HF, et al.

Drug Metab Lett, 2018;12(1):62-67.
PMID: 29542427 DOI: 10.2174/1872312812666180314112457

BACKGROUND: SynacinnTM contains five standardized herbal extracts of Orthosiphon Stamineus (OS), Syzygium polyanthum (SZ), Curcuma xantorrizza (CX), Cinnamomum zeylanicum (CZ) and Andrographis paniculata (AP) and is standardized against phytochemical markers of rosmarinic acid, gallic acid, curcumin, catechin and andrographolide respectively. This herbal medicine has been used as health supplement for diabetes. SynacinnTM is recommended to be consumed as supplement to the diabetic drugs. However, herb-drug interaction of SynacinnTM polyherbal with present drugs is unknown.
METHODS: This study was designed to investigate the effect of SynacinnTM and its individual biomarkers on drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam), CYP3A4 (Testosteron)), to assess its herb-drug interaction potential through cytochrome P450 inhibition assay. This study was conducted using liquid chromatography- tandem mass spectroscopy (LC-MS/MS) using probe substrates using human liver microsomes against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron).
RESULTS: Result showed that SynacinnTM at maximum concentration (5000 µg/ml) 100% inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron). IC50 values determined were 0.23, 0.60, 0.47, 0.78, 1.23, 0.99, 1.01, and 0.91 mg/ml for CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 (midazolam) and 3A4 (testosterone), respectively. Meanwhile, all individual biomarkers showed no, less or moderate inhibitory effect towards all the tested CYP450 except for curcumin that showed inhibition of CYP2C8 (91%), CYP2C9 (81%) and CYP2C19 (72%) at 10µM.
CONCLUSION: Curcumin was found to be an active constituent that might contribute to the inhibition of SynacinnTM against CYP2C8, CYP2C9 and CYP2C19. It can be suggested that SynacinnTM can be consumed separately from a drug known to be metabolized by all tested CYP450 enzymes.
Fulltext Analytical method cross validation by HPLC for identification of five markers and quantification of one marker in SynacinnTM formulations and its in vivo bone marrow micronucleus test data

Zainol SN, Fadhlina A, Rentala SV, Pillai R, Yalaka M, Bansal I, et al.

Data Brief, 2021 Jun;36:107001.
PMID: 33997190 DOI: 10.1016/j.dib.2021.107001

A HPLC method has been validated for identifying five markers (gallic acid, rosmarinic acid, catechin, andrographolide and curcumin) and quantifying curcumin in SynacinnTM formulation. The validation (bracketed strengths of 10 mg/mL and 100 mg/mL) involved assessment of selectivity, precision, Limit of Detection (LOD), Limit of Quantification (LOQ), linearity, accuracy, stability in diluent and formulation stability. Meanwhile, in vivo bone marrow micronucleus test data was presented to evaluate the toxicity potential of Synacinn™ to cause clastogenicity and/or disruption of the mitotic apparatus, as measured by its ability to induce micronucleated polychromatic erythrocytes (MN PCE) in Sprague Dawley rat bone marrow. The test was conducted in two phases viz., Phase I (Dose Range Finding experiment) and Phase II (Definitive experiment). Phase I was conducted to assess general toxicity and bone marrow cytotoxicity of Synacinn™, and to select the doses for the definitive experiment. In-life observations included mortality, clinical signs of toxicity and body weight. Bone marrow samples were collected and extracted from the femur bone using fetal bovine serum. The pellet obtained after the centrifugation was used for preparing bone marrow smears to evaluate the number of immature and mature erythrocytes.