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Effects of novel diarylpentanoid analogues of curcumin on secretory phospholipase A2 , cyclooxygenases, lipo-oxygenase, and microsomal prostaglandin E synthase-1

Ahmad W, Kumolosasi E, Jantan I, Bukhari SN, Jasamai M

Chem Biol Drug Des, 2014 Jun;83(6):670-81.
PMID: 24406103 DOI: 10.1111/cbdd.12280

Arachidonic acid and its metabolites have generated a heightened interest due to their significant role in inflammation. Inhibiting the enzymes involved in arachidonic acid metabolism has been considered as the synergistic anti-inflammatory effect. A series of novel curcumin diarylpentanoid analogues were synthesized and evaluated for their inhibitory effects on activity of secretory phospholipase A2 , cyclooxygenases, soybean lipo-oxygenase as well as microsomal prostaglandin E synthase-1. Among the curcumin analogues, compounds 3, 6, 9, 12, and 17 exhibited strong inhibition of secretory phospholipase A2 activity, with IC50 values ranging from 5.89 to 11.02 μm. Seven curcumin analogues 1, 3, 6, 7, 9, 11, and 12 showed inhibition of cyclooxygenases-2 with IC50 values in the range of 46.11 to 94.86 μm, which were lower than that of curcumin. Compounds 3, 6, 7, 12, and 17 showed strong inhibition of lipo-oxygenase enzyme activity. Preliminary screening of diarylpentanoid curcumin analogues for microsomal prostaglandin E synthase-1 activity revealed that four diarylpentanoid curcumin analogues 5, 6, 7, and 13 demonstrated higher inhibition of microsomal prostaglandin E synthase-1 activity with IC50 ranging from 2.41 to 4.48 μm, which was less than that of curcumin. The present results suggest that some of these diarylpentanoid analogues were able to inhibit the activity of these enzymes. This raises the possibility that diarylpentanoid analogues of curcumin might serve as useful starting point for the design of improved anti-inflammatory agents.
Fulltext Platelet-activating factor (PAF) antagonistic activity of a new biflavonoid from Garcinia nervosa var. pubescens King

Jalil J, Jantan I, Ghani AA, Murad S

Molecules, 2012 Sep 10;17(9):10893-901.
PMID: 22964504 DOI: 10.3390/molecules170910893

The methanol extract of the leaves of Garcinia nervosa var. pubescens King, which showed strong inhibitory effects on platelet-activating factor (PAF) receptor binding, was subjected to bioassay-guided isolation to obtain a new biflavonoid, II-3,I-5, II-5,II-7,I-4',II-4'-hexahydroxy-(I-3,II-8)-flavonylflavanonol together with two known flavonoids, 6-methyl-4'-methoxyflavone and acacetin. The structures of the compounds were elucidated by spectroscopic methods. The compounds were evaluated for their ability to inhibit PAF receptor binding to rabbit platelets using ³H-PAF as a ligand. The biflavonoid and acacetin showed strong inhibition with IC₅₀ values of 28.0 and 20.4 µM, respectively. The results suggest that these compounds could be responsible for the strong PAF antagonistic activity of the plant.
Inhibitory effect of compounds from Goniothalamus tapis Miq. and Goniothalamus uvaroides King on platelet-activating factor receptor binding

Moharam BA, Jantan I, Jalil J, Ahmad F

Phytother Res, 2012 May;26(5):687-91.
PMID: 22002630 DOI: 10.1002/ptr.3620

Phytochemical investigation on the bark of Goniothalamus tapis Miq. and G. uvaroides King has resulted in the isolation of eight styryl-lactones, (-)-cryptomeridiol, liriodenine, 3-methyl-1H-benz[f]indole-4,9-dione, (-)-stigmasterol and dimethyl terephthalate. The structures of the compounds were elucidated by spectroscopic techniques. The compounds were evaluated for their effect on platelet-activating factor (PAF) receptor binding on rabbit platelets using (3) H-PAF as a ligand. Among the compounds tested, (-)-cryptomeridiol, (+)-goniothalamin and (+)-isoaltholactone exhibited a significant and concentration-dependent inhibitory effect on PAF receptor binding, with inhibitory concentration (IC)(50) values of 17.5, 19.7 and 46.5 µm, respectively. The inhibitory effects of the first two compounds were comparable to that obtained from the positive control, cedrol. The results indicated that these compounds were strong PAF receptor binding inhibitors.
Fulltext Antiplatelet aggregation and platelet activating factor (PAF) receptor antagonistic activities of the essential oils of five Goniothalamus species

Moharam BA, Jantan I, Ahmad Fb, Jalil J

Molecules, 2010 Aug;15(8):5124-38.
PMID: 20714290 DOI: 10.3390/molecules15085124

Nine essential oils, hydrodistilled from different parts of five Goniothalamus species (G. velutinus Airy-Shaw, G. woodii Merr., G. clemensii Ban, G. tapis Miq. and G. tapisoides Mat Salleh) were evaluated for their ability to inhibit platelet aggregation in human whole blood using an electrical impedance method and their inhibitory effects on platelet activating factor (PAF) receptor binding with rabbit platelets using 3H-PAF as a ligand. The chemical composition of the oils was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The bark oil of G. velutinus was the most effective sample as it inhibited both arachidonic acid (AA) and ADP-induced platelet aggregation with IC(50) values of 93.6 and 87.7 microg/mL, respectively. Among the studied oils, the bark oils of G. clemensii, G. woodii, G. velutinus and the root oil of G. tapis showed significant inhibitory effects on PAF receptor binding, with IC(50 )values ranging from 3.5 to 10.5 microg/mL. The strong PAF antagonistic activity of the active oils is related to their high contents of sesquiterpenes and sesquiterpenoids, and the individual components in the oils could possibly produce a synergistic effect in the overall antiplatelet activity of the oils.
Effect of prenylated flavonoids and chalcones isolated from Artocarpus species on platelet aggregation in human whole blood

Jantan I, Mohd Yasin YH, Jamil S, Sirat H, Basar N

J Nat Med, 2010 Jul;64(3):365-9.
PMID: 20349149 DOI: 10.1007/s11418-010-0410-0

Five prenylflavonoids and two prenylchalcones from Artocarpus lowii King, A. scortechinii King and A. teysmanii Miq., and acetylated derivatives of cycloheterophyllin and artonin E were investigated for their ability to inhibit arachidonic acid (AA), collagen and adenosine diphosphate (ADP)-induced platelet aggregation in human whole blood by using an electrical impedance method. Among the tested compounds, only cycloheterophyllin inhibited AA-induced platelet aggregation with an IC(50) value of 100.9 microM. It also showed strong inhibition against ADP-induced aggregation, with an IC(50) value of 57.1 microM. Isobavachalcone, 2',4'-dihydroxy-4-methoxy-3'-prenyldihydrochalcone, cycloartobiloxanthone, artonin E and artonin E triacetate showed selective inhibition against ADP-induced aggregation, with IC(50) values ranging from 55.3 to 192.0 microM, but did not show such effect against other inducers.
A new prenylated dihydrochalcone from the leaves of Artocarpus lowii

Jamil S, Sirat HM, Jantan I, Aimi N, Kitajima M

J Nat Med, 2008 Jul;62(3):321-4.
PMID: 18404311 DOI: 10.1007/s11418-008-0226-3

A new prenylated dihydrochalcone, 2',4'-dihydroxy-4-methoxy-3'-prenyldihydrochalcone (1), along with two known compounds, 2',4',4-trihydroxy-3'-prenylchalcone (2) and 2',4-dihydroxy-3',4'-(2,2-dimethylchromene)chalcone (3) were isolated from the leaves of Artocarpus lowii. The structures of 1-3 were elucidated by spectroscopic methods and by comparison with data reported in the literature. Compounds 1-3 showed strong free radical scavenging activity towards 2,2-diphenyl-1-picrylhydrazyl (DPPH) measured by electron spin resonance (ESR) spectrometry.
Antiplatelet activity of aporphine and phenanthrenoid alkaloids from Aromadendron elegans Blume

Jantan I, Raweh SM, Yasin YH, Murad S

Phytother Res, 2006 Jun;20(6):493-6.
PMID: 16619347

Six aporphine and one phenanthrenoid alkaloids isolated from Aromadendron elegans Blume were investigated for their ability to inhibit arachidonic acid (AA), collagen and ADP induced platelet aggregation in human whole blood. The antiplatelet activity of the compounds was measured in vitro by the Chrono Log whole blood aggregometer using an electrical impedance method. Of the compounds tested, (-)-N-acetylnornuciferine, (-)-N-acetylanonaine and 1-(N-acetyl-N-methylamino)ethyl-3,4,6-trimethoxy-7-hydroxyphenanthrene showed strong inhibition on platelet aggregation caused by all three inducers. (-)-N-acetylanonaine was the most effective antiplatelet compound as it inhibited both arachidonic acid, collagen and ADP-induced platelet aggregation with IC(50) values of 66.1, 95.1 and 80.6 microm, respectively.
Current prospects of synthetic curcumin analogs and chalcone derivatives against mycobacterium tuberculosis

Bukhari SN, Franzblau SG, Jantan I, Jasamai M

Med Chem, 2013 Nov;9(7):897-903.
PMID: 23305394

Tuberculosis, caused by Mycobacterium tuberculosis, is amongst the foremost infectious diseases. Treatment of tuberculosis is a complex process due to various factors including a patient's inability to persevere with a combined treatment regimen, the difficulty in eradicating the infection in immune-suppressed patients, and multidrug resistance (MDR). Extensive research circumscribing molecules to counteract this disease has led to the identification of many inhibitory small molecules. Among these are chalcone derivatives along with curcumin analogs. In this review article, we summarize the reported literature regarding anti tubercular activity of chalcone derivatives and synthetic curcumin analogs. Our goal is to provide an analysis of research to date in order to facilitate the synthesis of superior antitubercular chalcone derivatives and curcumin analogs.
Fulltext Immunosuppressive effects of the standardized extract of Phyllanthus amarus on cellular immune responses in Wistar-Kyoto rats

Ilangkovan M, Jantan I, Mesaik MA, Bukhari SN

Drug Des Devel Ther, 2015;9:4917-30.
PMID: 26347462 DOI: 10.2147/DDDT.S88189

Phyllanthus amarus (family: Euphorbiaceae) is of immense interest due to its wide spectrum of biological activities. In the present study, the standardized 80% ethanol extract of P. amarus was investigated for its modulatory activity on various cellular immune parameters, including chemotaxis of neutrophils, engulfment of Escherichia coli by neutrophils, and Mac-1 expression, in leukocytes isolated from treated/nontreated Wistar-Kyoto rats. The detailed cell-mediated activity of P. amarus was also investigated, including analysis of the effects on T- and B-cell proliferation and CD4(+) and CD8(+) T-cell subsets in splenic mononuclear cells, and estimation of serum cytokine production by activated T-cells. The main components of the extract, phyllanthin, hypophyllanthin, corilagin, geraniin, ellagic acid, and gallic acid were identified and quantitatively analyzed in the extracts, using validated reversed-phase high-performance liquid chromatography (HPLC) methods. N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophils isolated from rats administered with the extract of P. amarus, at doses ranging from 100 to 400 mg/kg for 14 days, revealed a significant dose-dependent reduction in neutrophil migration (P<0.05). Similar patterns of inhibition were also observed in phagocytic activity and in fMLP-induced changes in expression of β2 integrin polymorphonuclear neutrophils. The results in P. amarus-treated rats also demonstrated a dose-dependent inhibition of both lipopolysaccharide-stimulated B-cell proliferation and concanavalin A-stimulated T-cell proliferation as compared with sensitized control. At a dose of 400 mg/kg (P<0.01), there was a significant decrease in the (%) expression of CD4(+) and CD8(+) in splenocytes and in serum cytokines of T helper (Th1) (IL-2 and IFN-γ) and Th2 (IL-4). In conclusion, P. amarus showed effective immunosuppressive activities in cellular immune response, by various immune regulatory mechanisms, and may be useful for improvement of immune-related disorders.
Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

Ali-Seyed M, Jantan I, Vijayaraghavan K, Bukhari SN

Chem Biol Drug Des, 2016 Apr;87(4):517-36.
PMID: 26535952 DOI: 10.1111/cbdd.12682

An important method of drug discovery is examination of diverse life forms, including medicinal plants and natural products or bioactive compounds isolated from these sources. In cancer research, lead structures of compounds from natural sources can be used to design novel chemotherapies with enhanced biological properties. Betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid or BetA) is a naturally occurring pentacyclic triterpene with a wide variety of biological activities, including potent antitumor properties. Non-malignant cells and normal tissues are not affected by BetA. Because BetA exerts its effects directly on the mitochondrion and triggers death of cancerous cells, it is an important alternative when certain chemotherapy drugs fail. Mitochondrion-targeted agents such as BetA hold great promise to circumvent drug resistance in human cancers. BetA is being developed by a large network of clinical trial groups with the support of the U.S. National Cancer Institute. This article discusses recent advances in research into anticancer activity of BetA, relevant modes of delivery, and the agent's therapeutic efficacy, mechanism of action, and future perspective as a pipeline anticancer drug. BetA is a potentially important agent in cancer therapeutics.
Inhibitory Effects of the Standardized Extract of Phyllanthus amarus on Cellular and Humoral Immune Responses in Balb/C Mice

Ilangkovan M, Jantan I, Mesaik MA, Bukhari SN

Phytother Res, 2016 Aug;30(8):1330-8.
PMID: 27137750 DOI: 10.1002/ptr.5633

Phyllanthus amarus has been shown to have strong inhibitory effects on phagocytic activity of human neutrophils and on cellular immune responses in Wistar-Kyoto rats. In this study, we investigated the effects of daily treatment of standardized extract of P. amarus at 50, 100 and 200 mg/kg for 14 days in Balb/C mice by measuring the myeloperoxidase activity (MPO), nitric oxide (NO) release, macrophage phagocytosis, swelling of footpad in delayed type hypersensitivity (DTH), and serum immunoglobulins, ceruloplasmin and lysozyme levels. Qualitative and quantitative analyses of the extract using validated reversed-phase HPLC methods identified phyllanthin, hypophyllanthin, corilagin and geraniin as the biomarkers. Significant dose-dependent inhibitions of MPO activity and NO release were observed in treated mice. The extract also inhibited E. coli phagocytic capacity of peritoneal macrophages of treated mice and inhibited the sheep red blood cells (sRBC)-induced swelling rate of mice paw in the DTH. There was also a significant decrease in non-specific humoral immunity including ceruloplasmin and lysozyme levels in the extract-fed groups as well as the release of serum level immunoglobulins. The strong inhibitory effects of the extract on the cellular and humoral immune responses suggest the potential of the plant to be developed as an effective immunosuppressive agent. Copyright © 2016 John Wiley & Sons, Ltd.
Effects of Labisia pumila var alata extracts on the lipid profile, serum antioxidant status and abdominal aorta of high-cholesterol diet rats

Dianita R, Jantan I, Jalil J, Amran AZ

Phytomedicine, 2016 Jul 15;23(8):810-7.
PMID: 27288916 DOI: 10.1016/j.phymed.2016.04.004

BACKGROUND: Previous studies on Labisia pumila var. alata (LPva) have showed that it could inhibit low-density lipoprotein (LDL) oxidation and provide protection on myocardial infarction in rats.
HYPOTHESIS/PURPOSE: We hypothesized that LPva extracts can modulate the lipid profiles and serum antioxidant status of hypercholesterolemic rats. In the present study, we investigated the effects of aqueous and 80% ethanol extracts of LPva on atherogenic and serum antioxidant parameters as well as changes in abdominal aorta of high-cholesterol diet rats.
METHODS: The major components of the extracts, gallic acid, flavonoids and alkyl resorcinols were analyzed by using a validated reversed phase HPLC method. The rats were induced to hypercholesterolemic status with daily intake of 2% cholesterol for a duration of 8 weeks. Three different doses (100, 200 and 400mg/kg) of the extracts were administered daily on the 4th week onwards. The rats were then sacrificed and the blood was collected via abdominal aorta and serum was separated by centrifugation for biochemical analysis. Part of the aorta tissues were excised immediately for histopathological examination.
RESULTS: The serum of LPva treated rats showed significant reduction in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels and the abdominal aorta showed a significant decrease of atheroma lesions in treated rats. Serum lipid profiles of treated rats showed a decrease in total cholesterol, total triglycerides and low-density lipoprotein (LDL) levels as compared to control group. The atherogenic indices in treated rats were significantly improved along with an increasing level of serum high-density lipoprotein (HDL). The extracts also exhibited significant increase of antioxidant enzymes and decrease of MDA as a product of lipid peroxidation.
CONCLUSION: LPva extracts can reduce the risk of dyslipidemia by improving the serum lipid profiles and modulating serum antioxidants.
Standardized extract of Tinospora crispa stimulates innate and adaptive immune responses in Balb/c mice

Ahmad W, Jantan I, Kumolosasi E, Bukhari SN

Food Funct, 2016 Mar 16;7(3):1380-9.
PMID: 26839149 DOI: 10.1039/c5fo01531f

Standardized extract of Tinospora crispa has been shown to exhibit immunostimulatory effects on innate immune responses in Wistar-Kyoto rats by enhancing neutrophil and T cell-mediated immunity. In this study the immunostimulatory effects of T. crispa were further investigated on the cellular immune response by determining its effect on nitric oxide (NO) production ability, peritoneal macrophage phagocytosis and delayed type hypersensitivity (DTH), whereas the humoral immune response was evaluated through the measurement of serum immunoglobulins (IgG and IgM) and serum lysozyme levels. Male Balb/c mice were immunized with 200 μL of 5 × 10(9) sheep red blood cells (sRBCs) per mL on day 0 and orally administered with 50, 100 and 200 mg per kg of ethanol extract of T. crispa for 14 days. Syringin and magnoflorine were qualitatively and quantitatively analyzed in the extract as chemical markers by using a validated reversed-phase high performance liquid chromatography method. T. crispa extract (TCE) considerably improved the peritoneal macrophages' ability to engulf FITC-labeled E. coli in a dose-dependent manner. TCE also dose-dependently promoted NO production in peritoneal macrophages activated by a lipopolysaccharide (LPS) and markedly potentiated the sRBS-induced swelling rate of the mice paw in DTH. The extract significantly enhanced the level of serum immunoglobulins, showing maximum activity at 100 mg kg(-1). Compared to the control groups, the serum lysozyme level and myeloperoxidase (MPO) activity were significantly higher in extract-treated groups. These findings suggest that T. crispa possesses strong immunostimulatory activities and might act as a natural immunomodulator as well as a potential nutraceutical for the modulation of the immune response.
A Comprehensive Review on the Chemotherapeutic Potential of Piceatannol for Cancer Treatment, with Mechanistic Insights

Seyed MA, Jantan I, Bukhari SN, Vijayaraghavan K

J Agric Food Chem, 2016 Feb 3;64(4):725-37.
PMID: 26758628 DOI: 10.1021/acs.jafc.5b05993

Cancer is a diverse class of diseases characterized by uncontrolled cell growth that constitutes the greatest cause of mortality and morbidity worldwide. Despite steady progress, the treatment modalities of cancer are still insufficient. Several new concepts have emerged for therapeutic intervention in malignant diseases with the goal of identifying specific targets and overcoming resistance against current cytotoxic therapies. Many studies have reported the remarkable and significant properties of dietary plant polyphenols such as curcumin, resveratrol, flavopiridol, indirubin, magnolol, piceatannol, parthenolide, epigallocatechin gallate, and cucurbitacin as anticancer agents known for their pleiotropic effects on cancer, immune cells, and inflammation. Piceatannol, an analogue and metabolite of resveratrol, is a natural stilbene commonly found in grape skins and wine. Compared to resveratrol, this molecule exhibits superior bioactivities as an inhibitor of COX-1/2 and the CSN-associated kinase. Piceatannol is thought to be a potent natural compound with many therapeutic effects, such as the prevention of hypercholesterolemia, arrhythmia, atherosclerosis, angiogenesis, and cardiovascular diseases. It also demonstrates vasorelaxation, antioxidant, and anticancer activities. This comprehensive review summarizes the current data regarding the mechanisms of action of piceatannol, its chemopreventive properties, and its possible therapeutic potential against various types of human cancer.
Fulltext Mosquitocidal and Oviposition Repellent Activities of the Extracts of Seaweed Bryopsis pennata on Aedes aegypti and Aedes albopictus

Yu KX, Wong CL, Ahmad R, Jantan I

Molecules, 2015;20(8):14082-102.
PMID: 26247928 DOI: 10.3390/molecules200814082

The ever-increasing threat from infectious diseases and the development of insecticide resistance in mosquito populations drive the global search for new natural insecticides. The aims of this study were to evaluate the mosquitocidal activity of the extracts of seaweed Bryopsis pennata against dengue vectors Aedes aegypti and Aedes albopictus, and determine the seaweed's toxic effect on brine shrimp nauplii (as a non-target organism). In addition, the chemical compositions of the active larvicidal extract and fraction were analyzed by using liquid chromatography-mass spectrometry (LC-MS). Chloroform extract exhibited strong ovicidal activity (with LC50 values of 229.3 and 250.5 µg/mL) and larvicidal activity against Ae. aegypti and Ae. albopictus. The larvicidal potential of chloroform extract was further ascertained when its A7 fraction exhibited strong toxic effect against Ae. aegypti (LC50 = 4.7 µg/mL) and Ae. albopictus (LC50 = 5.3 µg/mL). LC-MS analysis of the chloroform extract gave a tentative identification of 13 compounds; Bis-(3-oxoundecyl) tetrasulfide was identified as the major compound in A7 fraction. Methanol extract showed strong repellent effect against female oviposition, along with weak adulticidal activity against mosquito and weak toxicity against brine shrimp nauplii. The mosquitocidal results of B. pennata suggest further investigation for the development of effective insecticide.
Fulltext Immunostimulatory effects of the standardized extract of Tinospora crispa on innate immune responses in Wistar Kyoto rats

Ahmad W, Jantan I, Kumolosasi E, Bukhari SN

Drug Des Devel Ther, 2015;9:2961-73.
PMID: 26089645 DOI: 10.2147/DDDT.S85405

Tinospora crispa (TC) has been used in folkloric medicine for the treatment of various diseases and has been reported for several pharmacological activities. However, the effects of TC extract on the immune system are largely unknown. Therefore, the present study was aimed to investigate the immunomodulatory effects of a standardized 80% ethanol extract of the stem of TC on innate immune responses. Male Wistar Kyoto rats were treated daily at 100 mg/kg, 200 mg/kg, and 400 mg/kg doses of the extract for 21 days by oral gavage. The immunomodulatory potential of TC was evaluated by determining its effect on chemotaxis and phagocytic activity of neutrophils isolated from the blood of rats. To further elucidate the mechanism of action, its effects on the proliferation of T- and B-lymphocytes and T-lymphocytes subsets (CD4+ and CD8+) and on the secretion of Th1 and Th2 cytokines were also monitored. The main components of the extracts, syringin and magnoflorine, were identified and quantitatively analyzed in the extracts by using a validated reversed-phase high-performance liquid chromatography method. It was observed that the chemotactic activity of neutrophils obtained from extract-treated rats increased as compared to controls. A dose-dependent increase in the number of migrated cells and phagocytosis activity of neutrophils was observed. Dose-dependent increase was also observed in the T- and B-lymphocytes proliferation stimulated with concanavalin A (5 μg/mL) and lipopolysaccharide (10 μg/mL), and was statistically significant at 400 mg/kg (P>0.01). Apart from cell-mediated immune response, the concentrations of Th1 (TNF-α, IL-2, and IFN-γ) and Th2 (IL-4) cytokines were significantly increased in sera of rats treated with different doses as compared with the control group. From these findings, it can be concluded that TC possesses immunostimulatory activity and has therapeutic potential for the prevention of immune diseases.
Fulltext Protective effects of Labisia pumila var. alata on biochemical and histopathological alterations of cardiac muscle cells in isoproterenol-induced myocardial infarction rats

Dianita R, Jantan I, Amran AZ, Jalil J

Molecules, 2015 Mar 16;20(3):4746-63.
PMID: 25786162 DOI: 10.3390/molecules20034746

The study was designed to evaluate the cardioprotective effects of the standardized aqueous and 80% ethanol extracts of Labisia pumila var. alata (LPva) in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. The extracts were administered to Wistar rats orally for 28 days with three doses (100, 200 and 400 mg/kg of body weight) prior to ISO (85 mg/kg)-induced MI in two doses on day 29 and 30. The sera and hearts were collected for biochemical and histopathological analysis after the rats were sacrificed 48 h after the first induction. The main components of the extracts, gallic acid, alkylresorcinols and flavonoids were identified and quantitatively analyzed in the extracts by using a validated reversed phase HPLC method. The extracts showed significant protective effects as pretreated rats showed a significant dose-dependent decrease (p < 0.05) in cardiac enzyme activities, i.e., cardiac troponin I (cTnI), creatine kinase MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), alanine transaminase (ALT) and aspartate transaminase (AST), when compared with ISO-control rats. There were significant rises (p < 0.05) in the activity of oxidase enzymes, i.e., glutathione peroxide (GPx), catalase (CAT) and superoxide dismutase (SOD) of the pretreated rats, when compared with ISO-control group. Histopathological examination showed an improvement in membrane cell integrity in pre-treated rats compared to untreated rats. The major components of LPva extracts can be used as their biomarkers and contributed to the cardioprotective effects against ISO-induced MI rats.
Two new methyl chanofruticosinates from Kopsia flavida blume

Husain K, Jantan I, Said IM, Aimi N, Takayama H

J Asian Nat Prod Res, 2003 Mar;5(1):63-7.
PMID: 12608641

Two new indole alkaloids with the methyl chanofruticosinate skeletal system viz., methyl 3-oxo-12-methoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate (1) and methyl 3-oxo-11,12-methylenedioxy-N-decarbomethoxy-14,15-didehydrochanofruticosinate (2), together with four known compounds, methyl 12-methoxy-N1-decarbomethoxychanofruticosinate, methyl 12-methoxychanofruticosinate, methyl 11,12-dimethoxychanofruticosinate and methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate, were isolated in continuing studies on the leaves of Kopsia flavida Blume. The structures of the new indole alkaloids were assigned by NMR spectral data using various 2D-techniques.
Immunosuppressive effects of the standardized extract of Zingiber zerumbet on innate immune responses in Wistar rats

Ghazalee NS, Jantan I, Arshad L, Haque MA

Phytother Res, 2019 Apr;33(4):929-938.
PMID: 30618097 DOI: 10.1002/ptr.6285

Zingiber zerumbet rhizome has been used in traditional medicine mainly for the treatment of various immune-inflammatory related ailments and has been shown to exhibit a wide spectrum of biological effects especially antioxidant and anti-inflammatory activities. The present study was aimed to investigate the immunosuppressive effects of the standardized 80% ethanol extract of Z. zerumbet at 100, 200, and 400 mg/kg on the innate immune responses in male Wistar rats. The immune parameters determined were chemotaxis of neutrophils, Mac-1 expression, engulfment of Escherichia coli by neutrophils, reactive oxygen species production, and plasma lysozyme and ceruloplasmin levels. Zerumbone was qualitatively and quantitatively determined in the extract by using a validated reversed-phase HPLC, whereas liquid chromatography tandem-mass spectrometry (LC -MS/MS) was used to profile the secondary metabolites. Z. zerumbet significantly inhibited the migration of neutrophils, expressions of CD11b/CD18 integrin, phagocytic activity, and production of reactive oxygen species in a dose-dependent manner. The extract also dose-dependently inhibited the expressions of lysozyme and ceruloplasmin in the rat plasma. Z. zerumbet extract possessed strong inhibitory effects on the innate immune responses and has potential to be developed into an effective immunosuppressive agent.
Suppressive Effects of the Standardized Extract of Phyllanthus amarus on Type II Collagen-induced Rheumatoid Arthritis in Sprague Dawley Rats

Alam J, Jantan I, Kumolosasi E, Nafiah MA, Mesaik MA

Curr Pharm Biotechnol, 2018;19(14):1156-1169.
PMID: 30539691 DOI: 10.2174/1389201020666181211124954

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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