Chrysin is a natural flavonoid currently under investigation due to its important biological anti-cancer properties. In most of the cancer cells tested, chrysin has shown to inhibit proliferation and induce apoptosis, and is more potent than other tested flavonoids in leukemia cells, where chrysin is likely to act via activation of caspases and inactivation of Akt signaling in the cells. Moreover, structure-activity relationships have revealed that the chemical structure of chrysin meets the key structural requirements of flavonoids for potent cytotoxicity in leukemia cells. It is possible that combination therapy or modified chrysin could be more potent than single-agent use or administration of unmodified chrysin. This study may help to develop ways of improving the effectiveness of chrysin in the treatment of leukemia and other human cancers in vitro.
This study aims to elucidate the effects of chrysin on human ER-negative breast cancer cell line, MDA-MB-231. The study demonstrated that treatment of MDA-MB-231 cells with 20 microM chysin for 48 h significantly inhibited the growth of MDA-MB-231 cells and induced cytoplasmic lipid accumulation in the cells, but that the observed of cell death was not caused by apoptosis. The expression of PPARalpha mRNA in chrysin-treated MDA-MB-231 cells was significantly increased, which was likely associated to the proliferation of the cells post chrysin treatment.
Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.
Diabetes cardiomyopathy is one of the key factors of mortality among diabetic patients around the globe. One of the prior contributors to the progression of diabetic cardiomyopathy is cardiac mitochondrial dysfunction. The cardiac mitochondrial dysfunction can induce oxidative stress in cardiomyocytes and was found to be the cause of majority of the heart morphological and dynamical changes in diabetic cardiomyopathy. To slow down the occurrence of diabetic cardiomyopathy, it is crucial to discover therapeutic agents that target mitochondrial-induced oxidative stress. Flavonoid is a plentiful phytochemical in plants that shows a wide range of biological actions against human diseases. Flavonoids have been extensively documented for their ability to protect the heart from diabetic cardiomyopathy. Flavonoids' ability to alleviate diabetic cardiomyopathy is primarily attributed to their antioxidant properties. In this review, we present the mechanisms involved in flavonoid therapies in ameliorating mitochondrial-induced oxidative stress in diabetic cardiomyopathy.
The effect of foliar application of salicylic acid (SA) at different concentrations (10-3 M and 10-5 M) was investigated on the production of secondary metabolites (flavonoids), chalcone synthase (CHS) activity, antioxidant activity and anticancer activity (against breast cancer cell lines MCF-7 and MDA-MB-231) in two varieties of Malaysian ginger, namely Halia Bentong and Halia Bara. The results of high performance liquid chromatography (HPLC) analysis showed that application of SA induced the synthesis of anthocyanin and fisetin in both varieties. Anthocyanin and fisetin were not detected in the control plants. Accordingly, the concentrations of some flavonoids (rutin and apigenin) decreased significantly in plants treated with different concentrations of SA. The present study showed that SA enhanced the chalcone synthase (CHS) enzyme activity (involving flavonoid synthesis) and recorded the highest activity value of 5.77 nkat /mg protein in Halia Bara with the 10-5 M SA treatment. As the SA concentration was decreased from 10-3 M to 10-5 M, the free radical scavenging power (FRAP) increased about 23% in Halia Bentong and 10.6% in Halia Bara. At a concentration of 350 μg mL-1, the DPPH antioxidant activity recorded the highest value of 58.30%-72.90% with the 10-5 M SA treatment followed by the 10-3 M SA (52.14%-63.66%) treatment. The lowest value was recorded in the untreated control plants (42.5%-46.7%). These results indicate that SA can act not only as an inducer but also as an inhibitor of secondary metabolites. Meanwhile, the highest anticancer activity against MCF-7 and MDA-MB-231 cell lines was observed for H. Bara extracts treated with 10-5 M SA with values of 61.53 and 59.88%, respectively. The results suggest that the high anticancer activity in these varieties may be related to the high concentration of potent anticancer components including fisetin and anthocyanin. The results thus indicate that the synthesis of flavonoids in ginger can be increased by foliar application of SA in a controlled environment and that the anticancer activity in young ginger extracts could be improved.
This study involves adaptation of bulk or sequential technique to load multiple flavonoids in a single phytosome, which can be termed as "flavonosome". Three widely established and therapeutically valuable flavonoids, such as quercetin (Q), kaempferol (K), and apigenin (A), were quantified in the ethyl acetate fraction of Moringa oleifera leaves extract and were commercially obtained and incorporated in a single flavonosome (QKA-phosphatidylcholine) through four different methods of synthesis - bulk (M1) and serialized (M2) co-sonication and bulk (M3) and sequential (M4) co-loading. The study also established an optimal formulation method based on screening the synthesized flavonosomes with respect to their size, charge, polydispersity index, morphology, drug-carrier interaction, antioxidant potential through in vitro 1,1-diphenyl-2-picrylhydrazyl kinetics, and cytotoxicity evaluation against human hepatoma cell line (HepaRG). Furthermore, entrapment and loading efficiency of flavonoids in the optimal flavonosome have been identified. Among the four synthesis methods, sequential loading technique has been optimized as the best method for the synthesis of QKA-phosphatidylcholine flavonosome, which revealed an average diameter of 375.93±33.61 nm, with a zeta potential of -39.07±3.55 mV, and the entrapment efficiency was >98% for all the flavonoids, whereas the drug-loading capacity of Q, K, and A was 31.63%±0.17%, 34.51%±2.07%, and 31.79%±0.01%, respectively. The in vitro 1,1-diphenyl-2-picrylhydrazyl kinetics of the flavonoids indirectly depicts the release kinetic behavior of the flavonoids from the carrier. The QKA-loaded flavonosome had no indication of toxicity toward human hepatoma cell line as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide result, wherein even at the higher concentration of 200 µg/mL, the flavonosomes exert >85% of cell viability. These results suggest that sequential loading technique may be a promising nanodrug delivery system for loading multiflavonoids in a single entity with sustained activity as an antioxidant, hepatoprotective, and hepatosupplement candidate.
Interaction of flavokawain B (FB), a multitherapeutic flavonoid from Alpinia mutica with the major transport protein, human serum albumin (HSA), was investigated using different spectroscopic probes, i.e., intrinsic, synchronous, and three-dimensional (3-D) fluorescence, circular dichroism (CD), and molecular modeling studies. Values of binding parameters for FB-HSA interaction in terms of binding constant and stoichiometry of binding were determined from the fluorescence quench titration and were found to be 6.88 × 10(4) M(-1) and 1.0 mol of FB bound per mole of protein, respectively, at 25 °C. Thermodynamic analysis of the binding data obtained at different temperatures showed that the binding process was primarily mediated by hydrophobic interactions and hydrogen bonding, as the values of the enthalpy change (ΔH) and the entropy change (ΔS) were found to be -6.87 kJ mol(-1) and 69.50 J mol(-1) K(-1), respectively. FB binding to HSA led to both secondary and tertiary structural alterations in the protein as revealed by intrinsic, synchronous, and 3-D fluorescence results. Increased thermal stability of HSA in the presence of FB was also evident from the far-UV CD spectral results. The distance between the bound ligand and Trp-214 of HSA was determined as 3.03 nm based on the Förster resonance energy transfer mechanism. Displacement experiments using bilirubin and warfarin coupled with molecular modeling studies assigned the binding site of FB on HSA at domain IIA, i.e., Sudlow's site I.
Phytochemical and bioactivity studies of the leaves and stem barks of Tibouchina semidecandra L. have been carried out. The ethyl acetate extract of the leaves yielded four flavonoid compounds, identified as quercetin, quercetin 3-O-α-l-(2''-O-acetyl) arabinofuranoside, avicularin, and quercitrin, while the stem barks gave one ellagitannin, identified as 3,3'-O-dimethyl ellagic acid 4-O-α-l-rhamnopyranoside. Evaluation of the antioxidative activity on the crude extracts and pure compounds by electron spin resonance (ESR) and ultraviolet-visible (UV-vis) spectrophotometric assays showed that the pure isolated polyphenols and the EtOAc extract possessed strong antioxidative capabilities. Quercetin was found to be the most active radical scavenger in DPPH-UV and ESR methods with SC(50) values of 0.7 μM ± 1.4 and 0.7 μM ± 0.6 μM, respectively, in the antioxidant assay. A combination of quercetin and quercitrin was tested for synergistic antioxidative capacity;, however, there was no significant improvement observed. Quercetin also exhibited strong antityrosinase activity with a percent inhibition of 95.0% equivalent to the positive control, kojic acid, in the tyrosinase inhibition assay.
Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in breast cancer. The major snag faced by the human population is the development of chemoresistance to HER2 inhibitors by advanced stage breast cancer cells. Moreover, recent researchers focussed on fisetin as an antiproliferative and chemotherapeutic agent. Therefore, this study was intended to analyze the effects of fisetin on HER2/neu-overexpressing breast cancer cell lines. Our results depicted that fisetin induced apoptosis of these cells by various mechanisms, such as inactivation of the receptor, induction of proteasomal degradation, decreasing its half-life, decreasing enolase phosphorylation, and alteration of phosphatidylinositol 3-kinase/Akt signaling.
Chondrosenescence (chondrocyte senescence) and subchondral bone deterioration in osteoarthritic rats were analyzed after treatment with the estrogenic herb Labisia pumila (LP) or diclofenac. Osteoarthritis (OA) was induced in bilaterally ovariectomized (OVX) rats by injecting mono-iodoacetate into the right knee joints. Rats were grouped (n = 8) into nontreated OVX+OA control, OVX+OA + diclofenac (5 mg/kg) (positive control), OVX+OA + LP leaf extract (150 and 300 mg/kg) and healthy sham control. After 8 weeks' treatment, their conditions were evaluated via serum biomarkers, knee joint histology, bone histomorphometry, protein and mRNA expressions. The LP significantly reduced cartilage erosion, femur bone surface alteration, bone loss and porosity and increased trabecular bone thickness better than diclofenac and the non-treated OA. The cartilage catabolic markers' (matrix metalloproteinase (MMP)-13, RUNX2, COL10a, ERa, CASP3 and HIF-2 alpha) mRNA expressions were down-regulated and serum bone formation marker, PINP, was increased by LP in a dose-dependent manner. The LP (containing myricetin and gallic acid) showed protection against chondrosenescence, chondrocyte death, hypoxia-induced cartilage catabolism and subchondral bone deterioration. The bone and cartilage protective effects were by suppressing proteases (collagen break-down), bone resorption and upregulating subchondral bone restoration. The cartilage ER alpha over-expression showed a strong positive correlation with MMP-13, COL10 alpha1, histological, micro-computed tomography evidence for cartilage degradation and chondrosenescence.
Flavonoids are known to possess cardioprotective properties. Vascular endothelial function is a surrogate marker for cardiovascular diseases, including hypertension. We have studied the effects of chronic flavonoid treatment on vascular endothelial functions in spontaneously hypertensive rats (SHR). Starting from 6-7 weeks old, SHR were given flavonoids (baicalein, flavone, or quercetin) orally (10 mg/kg, once daily) to the SHRs for 4 weeks. Aortas from all the flavonoid-treated animals showed remarkably higher endothelium-dependent relaxations to acetylcholine, to a similar extent as those pretreated with the angiotensin-converting enzyme inhibitor, captopril. However, in contrast to other experimental groups, flavone pretreatment also enhanced the endothelium-independent relaxations to sodium nitroprusside. In addition, treatment with either flavone or quercetin induced a significant attenuation in systolic blood pressure of the hypertensive animals. The present results suggest that chronic treatment with the flavonoids (baicalein, flavone, and quercetin) preserves vascular endothelial functions in hypertensive animals through several possible actions, including increasing endothelial nitric oxide production and bioavailability and reduction in blood pressure.
The steady increase of diabetes is becoming a major burden on health care systems. As diabetic complications arise from oxidative stress, an antioxidant therapy along with anti-diabetic drugs is recommended. Myrmecodia or ant plant is highly valued as a traditional medicine in West Papua. It is used as an alternative treatment for diabetes, as the substances produced by ants can reduce blood sugar levels. The aim of this study was to develop and establish high-performance thin-layer chromatographic (HPTLC)-bioautographic methods to measure the antioxidant and hypoglycemic effects in different extracts from Myrmecodia platytyrea and to compare them with sterol content. Antioxidant activity in methanol, ethanol, dichloromethane (DCM) and ethyl acetate (EA) extracts were measured with a direct HPTLC-2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) assay, while hypoglycemic effects were assessed using a newly developed α-amylase inhibitory activity assay. Stigmasterol is observed, after derivatization with anisaldehyde, as purple colored zones under visible light at hRF values of 0.66. The highest antioxidant activity was observed in the ethanol extract which is rich in polyphenols and flavonoids, while the DCM extract did not show antioxidant activity, but had significant α-amylase inhibitory activity. The highest α-amylase inhibitory activity was observed in the EA and DCM extracts and was related to their stigmasterol content.
ETHNOPHARMACOLOGICAL RELEVANCE: Lippia nodiflora has been traditionally used in the Ayurvedic, Unani, and Sidha systems, as well as Traditional Chinese Medicine (TCM) for the treatment of knee joint pain, lithiasis, diuresis, urinary disorder and swelling.
AIM OF THE STUDY: The present study aims to investigate the antihyperuricemic effect of the L. nodiflora methanol extract, fractions, and chemical constituents and their mechanism of action in the rat model.
MATERIALS AND METHODS: The mechanisms were investigated by performing xanthine oxidase inhibitory, uricosuric, and liver xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitory studies in potassium oxonate- and hypoxanthine-induced hyperuricemic rats. The plant safety profile was determined using acute toxicity study. The molecular docking of the active compound to the xanthine oxidase was simulated using computer aided molecular modeling analysis.
RESULTS: Oral administration of methanol extract showed a dose-dependent reduction effect on the serum uric acid level of hyperuricemic rats. F3 was the most potent fraction in lowering the serum uric acid level of hyperuricemic rats. Bioactivity-guided purification of F3 afforded two phenylethanoid glycosides, arenarioside (1) and verbascoside (2) and three flavonoids, 6-hydroxyluteolin (3), 6-hydroxyluteolin-7-O-glycoside (4), and nodifloretin (5). The highest serum uric acid reduction effect was exhibited by 3 (66.94%) in hyperuricemic rats, followed by 5 (55.97%), 4 (49.16%), 2 (29.03%), and 1 (22.08%) at 0.2 mmol/kg. Dose-response investigation on 3 at doses of 0.05, 0.1, and 0.3 mmol/kg produced a significant dose-dependent reduction on the serum uric acid level of hyperuricemic rats. Repeated administration of F3 or 3 to the hyperuricemic rats for 10 continuous days resulted in a significant and progressive serum uric acid lowering effect in hyperuricemic rats. In contrast, methanol extract and F3 did not reduce serum uric acid level of normoruricemic rats. In addition, F4 significantly increased the uric acid excretion of hyperuricemic rats at 200mg/kg. No toxic effect was observed in rats administered with 5000 mg/kg of methanol extract or F3.
CONCLUSION: The potential application of L. nodiflora against hyperuricemia in the animal in accordance with its traditional uses has been demonstrated in the present study for the first time. The antihyperuricemic effect possessed by L. nodiflora was contributed mainly by liver XOD/XDH inhibitory activities and partially by uricosuric effect. Flavonoids mainly accountable for the uric acid lowering effect of L. nodiflora through the inhibition of XOD/XDH activities.
KEYWORDS: Antihyperuricemic; Hypoxanthine-induced hyperuricemic rat; Lippia nodiflora; Liver xanthine oxidase and xanthine dehydrogenase; Serum uric acid; Uric acid excretion
Adipocytes are major tissues involved in glucose uptake second to skeletal muscle and act as the main adipocytokines mediator that regulates glucose uptake mechanism and cellular differentiation. The objective of this study were to examine the effect of the SDF7, which is a fraction consists of four flavonoid compounds (quercetin: p-coumaric acid: luteolin: apigenin=8: 26: 1: 3) from Scoparia dulcis Linn., on stimulating the downstream components of insulin signalling and the adipocytokines expression on different cellular fractions of 3T3-F442a adipocytes.
Andrographis paniculata (AP), Centella asiatica (CA) and Orthosiphon stamineus (OS) are three popular herbs traditionally used worldwide. AP is known for the treatment of infections and diabetes and CA is good for wound healing and healthy skin while OS is usually consumed as tea to treat kidney and urinary disorders. Interaction of these herbs with human cytochrome P450 2C19 (CYP2C19), a major hepatic CYP isoform involved in metabolism of many clinical drugs has not been investigated to date.
Muntingia calabura (Elaeocarpaceae) is one of the most common roadside trees in Malaysia. Its leaves, barks, flowers and roots have been used as a folk remedy for the treatment of fever, incipient cold, liver disease, as well as an antiseptic agent in Southeast Asia. The aim of this study is to isolate and identify the antibacterial and cytotoxic compounds from the leaves of Muntingia calabura L.
Melicope lunu-ankenda leaves are used to treat diabetes in folklore medicinal practices in India and Malaysia. Here we report the isolation of an O-prenylated flavonoid (3,5,4'-trihydroxy-8,3'-dimethoxy-7-(3-methylbut-2-enoxy)flavone; OPF) from the leaves of M. lunu-ankenda and its antidiabetes activity against type-2 diabetes mellitus (T2DM).
A large phytochemical survey of the flora of the Malaysian Peninsula and Sabah is described, covering the systematic search for alkaloids, and partly, for saponins and flavonoids. Details of some chemical studies are reported. This emphasizes the great interest of such a study.
The electrically stimulated guinea-pig ileum and spontaneously contracting guinea-pig ileum preparations were employed in studies on the effects of an alcoholic extract and two flavonoid compounds, quercetin and quercetin-3-arabinoside, extracted from the leaves of Psidium guajava. The extract showed a morphine-like inhibition of acetylcholine release in the coaxially stimulated ileum, together with an initial increase in muscular tone, followed by a gradual decrease. The morphine-like inhibition was found to be due to quercetin, starting at concentrations of 1.6 micrograms/ml. The glycoside did not show any such action at concentrations of up to 1.28 mg/ml. The extract inhibited spontaneous contractions in the unstimulated ileum with a concentration-response relationship.
Preliminary phytochemical and flavonoid compounds of aqueous and ethanolic extracts of 6 aromatic Malaysian herbs were screened and quantified using Reverse-Phase High Performance Liquid Chromatography (RP-HPLC). The herbal extracts were tested for their antimicrobial activity against 10 food-borne pathogenic and food spoilage microorganisms using disk diffusion assay. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)/minimum fungicidal concentration (MFC) of herbal extracts were determined. In the phytochemical screening process, both aqueous and ethanolic extracts of P. hydropiper exhibited presence of all 7 tested phytochemical compounds. Among all herbal extracts, the aqueous P. hydropiper and E. elatior extracts demonstrated the highest antibacterial activity against 7 tested Gram-positive and Gram-negative bacteria with diameter ranging from 7.0 to 18.5 mm and 6.5 to 19 mm, respectively. The MIC values for aqueous and ethanolic extracts ranged from 18.75 to 175 mg/mL and 0.391 to 200 mg/mL, respectively while the MBC/MFC values for aqueous and ethanolic extracts ranged from 25 to 200 mg/mL and 3.125 to 50 mg/mL, respectively. Major types of bioactive compounds in aqueous P. hydropiper and E. elatior extracts were identified using RP-HPLC instrument. Flavonoids found in these plants were epi-catechin, quercetin, and kaempferol. The ability of aqueous Persicaria hydropiper (L.) H. Gross and Etlingera elatior (Jack) R.M. Sm. extracts to inhibit the growth of bacteria is an indication of its broad spectrum antimicrobial potential. Hence these herbal extracts may be used as natural preservative to improve the safety and shelf-life of food and pharmaceutical products.