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Fulltext Cardioprotective effects of arjunolic acid in LPS-stimulated H9C2 and C2C12 myotubes via the My88-dependent TLR4 signaling pathway

Hasan MM, Madhavan P, Ahmad Noruddin NA, Lau WK, Ahmed QU, Arya A, et al.

Pharm Biol, 2023 Dec;61(1):1135-1151.
PMID: 37497554 DOI: 10.1080/13880209.2023.2230251

CONTEXT: Arjunolic acid (AA) is a triterpenoid saponin found in Terminalia arjuna (Roxb.) Wight & Arn. (Combretaceae). It exerts cardiovascular protective effects as a phytomedicine. However, it is unclear how AA exerts the effects at the molecular level.
OBJECTIVE: This study investigates the cardioprotective effects of arjunolic acid (AA) via MyD88-dependant TLR4 downstream signaling marker expression.
MATERIALS AND METHODS: The MTT viability assay was used to assess the cytotoxicity of AA. LPS induced in vitro cardiovascular disease model was developed in H9C2 and C2C12 myotubes. The treatment groups were designed such as control (untreated), LPS control, positive control (LPS + pyrrolidine dithiocarbamate (PDTC)-25 µM), and treatment groups were co-treated with LPS and three concentrations of AA (50, 75, and 100 µM) for 24 h. The changes in the expression of TLR4 downstream signaling markers were evaluated through High Content Screening (HCS) and Western Blot (WB) analysis.
RESULTS: After 24 h of co-treatment, the expression of TLR4, MyD88, MAPK, JNK, and NF-κB markers were upregulated significantly (2-6 times) in the LPS-treated groups compared to the untreated control in both HCS and WB experiments. Evidently, the HCS analysis revealed that MyD88, NF-κB, p38, and JNK were significantly downregulated in the H9C2 myotube in the AA treated groups. In HCS, the expression of NF-κB was downregulated in C2C12. Additionally, TLR4 expression was downregulated in both H9C2 and C2C12 myotubes in the WB experiment.
DISCUSSION AND CONCLUSIONS: TLR4 marker expression in H9C2 and C2C12 myotubes was subsequently decreased by AA treatment, suggesting possible cardioprotective effects of AA.
Fulltext Phytochemical analysis, antioxidant, α-glucosidase inhibitory activity, and toxicity evaluation of Orthosiphon stamineus leaf extract

Ahda M, Jaswir I, Khatib A, Ahmed QU, Mahfudh N, Ardini YD, et al.

Sci Rep, 2023 Oct 09;13(1):17012.
PMID: 37813908 DOI: 10.1038/s41598-023-43251-2

Ocimum aristatum, commonly known as O. stamineus, has been widely studied for its potential as an herbal medicine candidate. This research aims to compare the efficacy of water and 100% ethanolic extracts of O. stamineus as α-glucosidase inhibitors and antioxidants, as well as toxicity against zebrafish embryos. Based on the study findings, water extract of O. stamineus leaves exhibited superior inhibition activity against α-glucosidase, ABTS, and DPPH, with IC50 values of approximately 43.623 ± 0.039 µg/mL, 27.556 ± 0.125 µg/mL, and 95.047 ± 1.587 µg/mL, respectively. The major active compounds identified in the extract include fatty acid groups and their derivates such as linoleic acid, α-eleostearic acid, stearic acid, oleanolic acid, and corchorifatty acid F. Phenolic groups such as caffeic acid, rosmarinic acid, 3,4-Dihydroxybenzaldehyde, norfenefrine, caftaric acid, and 2-hydroxyphenylalanine and flavonoids and their derivates including 5,7-Dihydroxychromone, 5,7-Dihydroxy-2,6-dimethyl-4H-chromen-4-one, eupatorin, and others were also identified in the extract. Carboxylic acid groups and triterpenoids such as azelaic acid and asiatic acid were also present. This study found that the water extract of O. stamineus is non-toxic to zebrafish embryos and does not affect the development of zebrafish larvae at concentrations lower than 500 µg/mL. These findings highlight the potential of the water extract of O. stamineus as a valuable herbal medicine candidate, particularly for its potent α-glucosidase inhibition and antioxidant properties, and affirm its safety in zebrafish embryos at tested concentrations.
Fulltext Ethanolic Extract of Polygonum minus Protects Differentiated Human Neuroblastoma Cells (SH-SY5Y) against H2O2-Induced Oxidative Stress

Sayuti NH, Zulkefli N, Tan JK, Saad N, Baharum SN, Hamezah HS, et al.

Molecules, 2023 Sep 20;28(18).
PMID: 37764502 DOI: 10.3390/molecules28186726

Neuronal models are an important tool in neuroscientific research. Hydrogen peroxide (H2O2), a major risk factor of neuronal oxidative stress, initiates a cascade of neuronal cell death. Polygonum minus Huds, known as 'kesum', is widely used in traditional medicine. P. minus has been reported to exhibit a few medicinal and pharmacological properties. The current study aimed to investigate the neuroprotective effects of P. minus ethanolic extract (PMEE) on H2O2-induced neurotoxicity in SH-SY5Y cells. LC-MS/MS revealed the presence of 28 metabolites in PMEE. Our study showed that the PMEE provided neuroprotection against H2O2-induced oxidative stress by activating the Nrf2/ARE, NF-κB/IκB and MAPK signaling pathways in PMEE pre-treated differentiated SH-SY5Y cells. Meanwhile, the acetylcholine (ACH) level was increased in the oxidative stress-induced treatment group after 4 h of exposure with H2O2. Molecular docking results with acetylcholinesterase (AChE) depicted that quercitrin showed the highest docking score at -9.5 kcal/mol followed by aloe-emodin, afzelin, and citreorosein at -9.4, -9.3 and -9.0 kcal/mol, respectively, compared to the other PMEE's identified compounds, which show lower docking scores. The results indicate that PMEE has neuroprotective effects on SH-SY5Y neuroblastoma cells in vitro. In conclusion, PMEE may aid in reducing oxidative stress as a preventative therapy for neurodegenerative diseases.
Fulltext Flavonoids as Potential Wound-Healing Molecules: Emphasis on Pathways Perspective

Zulkefli N, Che Zahari CNM, Sayuti NH, Kamarudin AA, Saad N, Hamezah HS, et al.

Int J Mol Sci, 2023 Feb 27;24(5).
PMID: 36902038 DOI: 10.3390/ijms24054607

Wounds are considered to be a serious problem that affects the healthcare sector in many countries, primarily due to diabetes and obesity. Wounds become worse because of unhealthy lifestyles and habits. Wound healing is a complicated physiological process that is essential for restoring the epithelial barrier after an injury. Numerous studies have reported that flavonoids possess wound-healing properties due to their well-acclaimed anti-inflammatory, angiogenesis, re-epithelialization, and antioxidant effects. They have been shown to be able to act on the wound-healing process via expression of biomarkers respective to the pathways that mainly include Wnt/β-catenin, Hippo, Transforming Growth Factor-beta (TGF-β), Hedgehog, c-Jun N-Terminal Kinase (JNK), NF-E2-related factor 2/antioxidant responsive element (Nrf2/ARE), Nuclear Factor Kappa B (NF-κB), MAPK/ERK, Ras/Raf/MEK/ERK, phosphatidylinositol 3-kinase (PI3K)/Akt, Nitric oxide (NO) pathways, etc. Hence, we have compiled existing evidence on the manipulation of flavonoids towards achieving skin wound healing, together with current limitations and future perspectives in support of these polyphenolic compounds as safe wound-healing agents, in this review.
Fulltext The role of lutein-rich purple sweet potato leaf extract on the amelioration of diabetic retinopathy in streptozotocin-induced Sprague-Dawley rats

Hisamuddin ASB, Naomi R, Manan KAB, Bahari H, Othman F, Embong H, et al.

Front Pharmacol, 2023;14:1175907.
PMID: 37274105 DOI: 10.3389/fphar.2023.1175907

The objective of this study is to access the effect of purple sweet potato leaf (PSPL) extract on diabetic retinopathy (DR) of streptozotocin (STZ)-induced male Sprague-Dawley (SD) rats. In this study, rats were injected intraperitoneally with a single dose of 60 mg/kg STZ, and diabetes was confirmed on day 7. Rats were further divided into a few groups, which were then orally administered with one of the following treatments: 25 mg/kg of gliclazide (D25G), 200 mg/kg of PSPL extract (DT 200), and 400 mg/kg of PSPL extract (DT 400). However, the normal control (NS) and control group for diabetic (DNS) were given normal saline (NS) for 12 weeks. The results show that the treated group demonstrated a reduction in serum oral glucose tolerance test (OGTT) levels of DT 200 and DT 400, and an increase in the serum and retinal insulin levels, and restored oxidative stress markers in serum and retina on week 12. The PSPL extract exhibited protective effects in maintaining the kidney, liver, retina, and pancreas architecture in 400 mg/kg compared to the 200 mg/kg treated group and D25G, thereby restoring fully transparent lenses in diabetes-induced rats. In conclusion, 400 mg/kg PSPL is the most effective dose for the amelioration of STZ-induced DR pathology in male SD rats.
Fulltext In Vitro, In Silico and Network Pharmacology Mechanistic Approach to Investigate the α-Glucosidase Inhibitors Identified by Q-ToF-LCMS from Phaleria macrocarpa Fruit Subcritical CO2 Extract

Mia MAR, Ahmed QU, Ferdosh S, Helaluddin ABM, Awal MS, Sarian MN, et al.

Metabolites, 2022 Dec 15;12(12).
PMID: 36557305 DOI: 10.3390/metabo12121267

The fruit of Phaleria macrocarpa have been traditionally used as an antidiabetic remedy in Malaysia and neighbouring countries. Despite its potential for diabetes treatment, no scientific study has ever been conducted to predict the inhibitor interaction of the protein α-glucosidase identified in an extract prepared with a non-conventional extraction technique. Hence, the major aim of this research was to evaluate the in vitro antioxidant, the α-glucosidase inhibitors, and the molecular dynamic simulations of the α-glucosidase inhibitors identified by Quadrupole Time-of-Flight Liquid Chromatography Mass Spectrometry (Q-ToF-LCMS) analysis. Initially, dry fruit were processed using non-conventional and conventional extraction methods to obtain subcritical carbon dioxide extracts (SCE-1 and SCE-2) and heating under reflux extract (HRE), respectively. Subsequently, all extracts were evaluated for their in vitro antioxidative and α-glucosidase inhibitory potentials. Subsequently, the most bioactive extract (SCE-2) was subjected to Q-ToF-LCMS analysis to confirm the presence of α-glucosidase inhibitors, which were then analysed through molecular dynamic simulations and network pharmacology approaches to confirm their possible mechanism of action. The highest inhibitory effects of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and α-glucosidase on SCE-2 was found as 75.36 ± 0.82% and 81.79 ± 0.82%, respectively, compared to the SCE-1 and HRE samples. The Q-ToF-LCMS analysis tentatively identified 14 potent α-glucosidase inhibitors. Finally, five identified compounds, viz., lupenone, swertianolin, m-coumaric acid, pantothenic acid, and 8-C-glucopyranosyleriodictylol displayed significant stability, compactness, stronger protein-ligand interaction up to 100 ns further confirming their potential as α-glucosidase inhibitors. Consequently, it was concluded that the SCE-2 possesses a strong α-glucosidase inhibitory effect due to the presence of these compounds. The findings of this study might prove useful to develop these compounds as alternative safe α-glucosidase inhibitors to manage diabetes more effectively.
Potential bioactive coating system for high-performance absorbable magnesium bone implants

Sarian MN, Iqbal N, Sotoudehbagha P, Razavi M, Ahmed QU, Sukotjo C, et al.

Bioact Mater, 2022 Jun;12:42-63.
PMID: 35087962 DOI: 10.1016/j.bioactmat.2021.10.034

Magnesium alloys are considered the most suitable absorbable metals for bone fracture fixation implants. The main challenge in absorbable magnesium alloys is their high corrosion/degradation rate that needs to be controlled. Various coatings have been applied to magnesium alloys to slow down their corrosion rates to match their corrosion rate to the regeneration rate of the bone fracture. In this review, a bioactive coating is proposed to slow down the corrosion rate of magnesium alloys and accelerate the bone fracture healing process. The main aim of the bioactive coatings is to enhance the direct attachment of living tissues and thereby facilitate osteoconduction. Hydroxyapatite, collagen type I, recombinant human bone morphogenetic proteins 2, simvastatin, zoledronate, and strontium are six bioactive agents that show high potential for developing a bioactive coating system for high-performance absorbable magnesium bone implants. In addition to coating, the substrate itself can be made bioactive by alloying magnesium with calcium, zinc, copper, and manganese that were found to promote bone regeneration.
Fulltext Preliminary Phytochemical Screening, In Vitro Antidiabetic, Antioxidant Activities, and Toxicity of Leaf Extracts of Psychotria malayana Jack

Nipun TS, Khatib A, Ahmed QU, Nasir MHM, Supandi F, Taher M, et al.

Plants (Basel), 2021 Dec 07;10(12).
PMID: 34961160 DOI: 10.3390/plants10122688

Psychotria malayana Jack belongs to the Rubiacea and is widespread in Southeast Asian countries. It is traditionally used to treat diabetes. Despite its potential medicinal use, scientific proof of this pharmacological action and the toxic effect of this plant are still lacking. Hence, this study aimed to investigate the in vitro antidiabetic and antioxidant activities, toxicity, and preliminary phytochemical screening of P. malayana leaf extracts by gas chromatography-mass spectrometry (GC-MS) after derivatization. The antidiabetic activities of different extracts of this plant were investigated through alpha-glucosidase inhibitory (AGI) and 2-NBDG glucose uptake using 3T3-L1 cell line assays, while the antioxidant activity was evaluated using DPPH and FRAP assays. Its toxicological effect was investigated using the zebrafish embryo/larvae (Danio rerio) model. The mortality, hatchability, tail-detachment, yolk size, eye size, beat per minute (BPM), and body length were taken into account to observe the teratogenicity in all zebrafish embryos exposed to methanol extract. The LC50 was determined using probit analysis. The methanol extract showed the AGI activity (IC50 = 2.71 ± 0.11 μg/mL), insulin-sensitizing activity (at a concentration of 5 µg/mL), and potent antioxidant activities (IC50 = 10.85 μg/mL and 72.53 mg AAE/g for DPPH and FRAP activity, respectively). Similarly, the water extract exhibited AGI activity (IC50 = 6.75 μg/mL), insulin-sensitizing activity at the concentration of 10 μg/mL, and antioxidant activities (IC50 = 27.12 and 33.71 μg/mL for DPPH and FRAP activity, respectively). The methanol and water extracts exhibited the LC50 value higher than their therapeutic concentration, i.e., 37.50 and 252.45 µg/mL, respectively. These results indicate that both water and methanol extracts are safe and potentially an antidiabetic agent, but the former is preferable since its therapeutic index (LC50/therapeutic concentration) is much higher than for methanol extracts. Analysis using GC-MS on derivatized methanol and water extracts of P. malayana leaves detected partial information on some constituents including palmitic acid, 1,3,5-benzenetriol, 1-monopalmitin, beta-tocopherol, 24-epicampesterol, alpha-tocopherol, and stigmast-5-ene, that could be a potential target to further investigate the antidiabetic properties of the plant. Nevertheless, isolation and identification of the bioactive compounds are required to confirm their antidiabetic activity and toxicity.
Fulltext Pseudocedrela kotschyi: a review of ethnomedicinal uses, pharmacology and phytochemistry

Alhassan AM, Ahmed QU, Malami I, Zakaria ZA

Pharm Biol, 2021 Dec;59(1):955-963.
PMID: 34283002 DOI: 10.1080/13880209.2021.1950776

CONTEXT: Pseudocedrela kotschyi (Schweinf) Harms (Meliaceae) is an important medicinal plant found in tropical and subtropical countries of Africa. Traditionally, P. kotschyi is used in the treatment of various diseases including diabetes, malaria, abdominal pain and diarrhoea.
OBJECTIVE: To provide an overview of traditional medicinal claims, pharmacological properties, and phytochemical principles of P. kotschyi as a basis for its clinical applications and further research and development of new drugs.
METHODS: Through interpreting already published scientific manuscripts retrieved from different scientific search engines, namely, Medline, PubMed, EMBASE, Science Direct and Google scholar databases, an up-to-date review on the medicinal potentials of P. kotschyi from inception until September, 2020 was compiled. 'Pseudocedrela kotschyi', 'traditional uses', 'pharmacological properties' and 'chemical constituents' were used as search words.
RESULTS: At present, more than 30 chemical constituents have been isolated and identified from the root and stem bark of P. kotschyi, among which limonoids and triterpenes are the main active constituents. Based on prior research, P. kotschyi has been reported to possess anti-inflammatory, analgesic, antipyretic, anthelminthic, antimalaria, anti-leishmaniasis, anti-trypanosomiasis, hepatoprotective, antioxidant, antidiabetic, antidiarrheal, antimicrobial, and anticancer effects.
CONCLUSIONS: P. kotschyi is reported to be effective in treating a variety of diseases. Current phytochemical and pharmacological studies mainly focus on antimalaria, anti-leishmaniasis, anti-trypanosomiasis and anticancer potential of the root and stem bark of P. kotschyi. Although experimental data support the beneficial medicinal properties of this plant, there is still a paucity of information on its toxicity profile. Nonetheless, this review provides the basis for future research work.
Fulltext Soft-Chewable Paracetamol Tablets by Melt Granulation Method: Formulation and Characterization

Sabere ASM, Suhaimi NANM, Ahmed QU, Mahat MM, Roslan NC, Azizi J

J Pharm Bioallied Sci, 2021 11 24;13(3):312-316.
PMID: 35017887 DOI: 10.4103/jpbs.JPBS_783_20

Background: Oral drug delivery is the most preferred route for drug administration in the world, with tablets being one of the most common dosage forms. However, some people, particularly children and the elderly, have difficulty swallowing the tablets. Chewable tablets are the dosage form that can address the issue while also providing a valuable masking effect on drug taste, allowing patients to swallow the drugs more easily.
Materials and Methods: In this study, the chewable tablets were manufactured using the melt granulation method, which resulted in tablets with a chewy texture. The tablets contained paracetamol as well as Arabic gum, starch, agar, and mannitol.
Results: The drug release profiles for the fragmented form showed that 50% of the drug was released within 4 min and 100% was released within 30 min of the dissolution process. The intact form released nearly 90% of the drug within 2 h.
Conclusion: Formulation 2 was determined as the best formulation. This tablets' formulation had passed all characterization tests and displayed a moderate hardness and chewy texture.
In vivo anxiolytic and in vitro anti-inflammatory activities of water-soluble extract (WSE) of Nigella sativa (L.) seeds

Babar ZM, Jaswir I, Tareq AM, Ali Reza ASM, Azizi WM, Hafidz M, et al.

Nat Prod Res, 2021 Aug;35(16):2793-2798.
PMID: 31578877 DOI: 10.1080/14786419.2019.1667348

The WSE is a highly polar, gummy and mucilaginous bioactive content of the Nigella sativa (L.) seeds. This study reports the anxiolytic and anti-inflammatory effects of WSE investigated using Elevated Plus Maze (EPM) and Hole-Board Test (HBT) in adult mice and human RBCs haemolysis inhibition and protein denaturation respectively. The oral WSE treatment (100 & 200 mg/kg b.w/day) for 72 hours has exhibited slightly better anxiolytic effect (p
Fulltext An In Vitro Anticancer Activity Evaluation of Neolamarckia cadamba (Roxb.) Bosser Leaves' Extract and its Metabolite Profile

Razali S, Firus Khan AY, Khatib A, Ahmed QU, Abdul Wahab R, Zakaria ZA

Front Pharmacol, 2021;12:741683.
PMID: 34721030 DOI: 10.3389/fphar.2021.741683

The leaves of Neolamarckia cadamba (NC) (Roxb.) Bosser (family: Rubiaceae) are traditionally used to treat breast cancer in Malaysia; however, this traditional claim is yet to be scientifically verified. Hence, this study was aimed to evaluate the anticancer effect of NC leaves' ethanol extract against breast cancer cell line (MCF-7 cells) using an in vitro cell viability, cytotoxicity, and gene expression assays followed by the gas chromatography analysis to further confirm active principles. Results revealed 0.2 mg/ml as the half maximal inhibitory concentration (IC50) against MCF-7. The extract exerted anticancer effect against MCF-7 cells in a dose- and time-dependent manner. The cell cycle assay showed that the extract arrested MCF-7 cells in the G0/G1 phase, and apoptosis was observed after 72 h by the Annexin-V assay. The gene expression assay revealed that the cell cycle arrest was associated with the downregulation of CDK2 and subsequent upregulation of p21 and cyclin E. The extract induced apoptosis via the mediation of the mitochondrial cell death pathways. A chromatography analysis revealed the contribution of D-pinitol and myo-inositol as the two major bioactive compounds to the activity observed. Overall, the study demonstrated that NC leaves' ethanol extract exerts anticancer effect against MCF-7 human breast cancer cells through the induction of apoptosis and cell cycle arrest, thereby justifying its traditional use for the treatment of breast cancer in Malaysia.
Fulltext Characterization of α-Glucosidase Inhibitors from Psychotria malayana Jack Leaves Extract Using LC-MS-Based Multivariate Data Analysis and In-Silico Molecular Docking

Nipun TS, Khatib A, Ibrahim Z, Ahmed QU, Redzwan IE, Saiman MZ, et al.

Molecules, 2020 Dec 12;25(24).
PMID: 33322801 DOI: 10.3390/molecules25245885

Psychotria malayana Jack has traditionally been used to treat diabetes. Despite its potential, the scientific proof in relation to this plant is still lacking. Thus, the present study aimed to investigate the α-glucosidase inhibitors in P.malayana leaf extracts using a metabolomics approach and to elucidate the ligand-protein interactions through in silico techniques. The plant leaves were extracted with methanol and water at five various ratios (100, 75, 50, 25 and 0% v/v; water-methanol). Each extract was tested for α-glucosidase inhibition, followed by analysis using liquid chromatography tandem to mass spectrometry. The data were further subjected to multivariate data analysis by means of an orthogonal partial least square in order to correlate the chemical profile and the bioactivity. The loading plots revealed that the m/z signals correspond to the activity of α-glucosidase inhibitors, which led to the identification of three putative bioactive compounds, namely 5'-hydroxymethyl-1'-(1, 2, 3, 9-tetrahydro-pyrrolo (2, 1-b) quinazolin-1-yl)-heptan-1'-one (1), α-terpinyl-β-glucoside (2), and machaeridiol-A (3). Molecular docking of the identified inhibitors was performed using Auto Dock Vina software against the crystal structure of Saccharomyces cerevisiae isomaltase (Protein Data Bank code: 3A4A). Four hydrogen bonds were detected in the docked complex, involving several residues, namely ASP352, ARG213, ARG442, GLU277, GLN279, HIE280, and GLU411. Compound 1, 2, and 3 showed binding affinity values of -8.3, -7.6, and -10.0 kcal/mol, respectively, which indicate the good binding ability of the compounds towards the enzyme when compared to that of quercetin, a known α-glucosidase inhibitor. The three identified compounds that showed potential binding affinity towards the enzymatic protein in molecular docking interactions could be the bioactive compounds associated with the traditional use of this plant.
Fulltext Medicinal Potential of Isoflavonoids: Polyphenols That May Cure Diabetes

Ahmed QU, Ali AHM, Mukhtar S, Alsharif MA, Parveen H, Sabere ASM, et al.

Molecules, 2020 Nov 24;25(23).
PMID: 33255206 DOI: 10.3390/molecules25235491

In recent years, there is emerging evidence that isoflavonoids, either dietary or obtained from traditional medicinal plants, could play an important role as a supplementary drug in the management of type 2 diabetes mellitus (T2DM) due to their reported pronounced biological effects in relation to multiple metabolic factors associated with diabetes. Hence, in this regard, we have comprehensively reviewed the potential biological effects of isoflavonoids, particularly biochanin A, genistein, daidzein, glycitein, and formononetin on metabolic disorders and long-term complications induced by T2DM in order to understand whether they can be future candidates as a safe antidiabetic agent. Based on in-depth in vitro and in vivo studies evaluations, isoflavonoids have been found to activate gene expression through the stimulation of peroxisome proliferator-activated receptors (PPARs) (α, γ), modulate carbohydrate metabolism, regulate hyperglycemia, induce dyslipidemia, lessen insulin resistance, and modify adipocyte differentiation and tissue metabolism. Moreover, these natural compounds have also been found to attenuate oxidative stress through the oxidative signaling process and inflammatory mechanism. Hence, isoflavonoids have been envisioned to be able to prevent and slow down the progression of long-term diabetes complications including cardiovascular disease, nephropathy, neuropathy, and retinopathy. Further thoroughgoing investigations in human clinical studies are strongly recommended to obtain the optimum and specific dose and regimen required for supplementation with isoflavonoids and derivatives in diabetic patients.
Determination toxic effects of Hystrix Brachyura Bezoar extracts using cancer cell lines and embryo zebrafish (Danio rerio) models and identification of active principles through GC-MS analysis

Firus Khan AY, Ahmed QU, Nippun TS, Hilles A, Jalal TK, Teh LK, et al.

J Ethnopharmacol, 2020 Nov 15;262:113138.
PMID: 32726681 DOI: 10.1016/j.jep.2020.113138

ETHNOPHARMACOLOGICAL RELEVANCE: Porcupine bezoar (PB) is used as folk medicine for various medical conditions including cancer treatment in Malaysia. However, its toxicity profile has never been thoroughly ascertained to confirm its safe nature as an efficacious traditional medicine in the treatment of cancer as well as other ailments.
AIM OF THE STUDY: This study was aimed to reveal three different PBs' aqueous extracts(viz. PB-A, PB-B, PB-C) chemical constituent's profile using GC-MS analysis, anticancer property on A375, HeLa and MCF7 cancer cells, toxicity profile on zebrafish embryo morphology, EC50, LC50 and teratogenicity index.
MATERIALS AND METHODS: PBs' extracts characterization was performed through GC-MS analysis, in vitro anticancer effect was carried out on A375, HeLa and MCF7 cancer cell lines and finally and toxicity properties on three different PBs aqueous extracts (viz. PB-A, PB-B, PB-C) were determined using zebrafish embryo model.
RESULTS: The GC-MS analysis revealed 10 similar compounds in all PBs' extracts. Dilauryl thiodipropionate was found to be a major compound in all PBs' extracts followed by tetradecanoic acid. An in vitro anticancer study revealed PB extracts exerted median inhibition concentration (IC50) <50 μg/mL, on cancer cells viz. A375, HeLa and MCF7 with no significant toxicity on normal cells viz. NHDF cells. In vivo toxicity of PBs extracts found affecting tail detachment, hatching, craniofacial, brain morphology, soft tissues, edema, spinal, somites, notochord and cardiovascular system (brachycardia, disruption of blood circulation) deformities. The LC50 and EC50 demonstrated PB extracts effect as dose and time dependent with median concentration <150.0 μg/mL. Additionally, teratogenicity index (TI) viz. >1.0 revealed teratogenic property for PB extracts.
CONCLUSIONS: The findings revealed that all three PBs aqueous extracts possessed anticancer activity and exhibited significant toxicological effects on zebrafish embryos with high teratogenicity index. Hence, its use as an anticancer agent requires further investigation and medical attentions to determine its safe dose.
Fulltext Striatum Hyperactivity Triggers Relapse to Morphine and Methamphetamine (Polydrug) Dependence in Mice

Wasli NS, Ridzwan IE, Azzubaidi MS, Kasmuri AR, Ahmed QU, Ming LC, et al.

J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S826-S830.
PMID: 33828384 DOI: 10.4103/jpbs.JPBS_379_19

Introduction: κ-opioid receptor (KOPr) system has been linked to relapse to many substances, especially opioids. Positive responses were recently reported in morphine and methamphetamine (polydrug)-dependent mice treated with buprenorphine and naltrexone, a functional κ antagonist.
Objectives: This study aimed to determine the specific brain region that is responsive to KOPr treatment following polydrug dependence.
Materials and Methods: The polydrug-dependent mice model was developed using conditioned place preference (CPP) method. Following successful withdrawal phase, the mice were treated with 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone. Four brain regions (hippocampus, prefrontal cortex, amygdala, and striatum) were investigated using immunohistochemistry technique. This is to quantify the changes in KOPr expression in each major brain region that was primarily involved in addiction neurocircuits of many substances. Unpaired Student's t test was used to analyze all results, where P < 0.05 is considered significant.
Results: The results showed that treatment with buprenorphine and naltrexone successfully attenuated relapse in 60% of mice (n = 14). A significant upregulation of KOPr was detected in striatum at the end of post-withdrawal phase (P < 0.01, n = 12). This treatment successfully suppressed KOPr in striatum (P < 0.001, n = 12), which supports the positive results seen in the CPP setting. No significant changes were observed in other brain regions studied.
Conclusion: The hyperactivity of striatum suggests that the affected brain region following KOPr antagonist treatment is the region that primarily controls the drug rewarding activity, in which nucleus accumbens is located. This indicates that manipulation of KOPr system is one of the potential targets to treat morphine- or methamphetamine-dependence problem.
Modulation of metabolic alterations of obese diabetic rats upon treatment with Salacca zalacca fruits extract using 1H NMR-based metabolomics

Saleh MSM, Siddiqui MJ, Mediani A, Ahmed QU, Mat So'ad SZ, Saidi-Besbes S, et al.

Food Res Int, 2020 11;137:109547.
PMID: 33233172 DOI: 10.1016/j.foodres.2020.109547

Fruit of salak (Salacca zalacca) is traditionally used and commercialized as an antidiabetic agent. However, the scientific evidence to prove this traditional use is lacking. This research was aimed to evaluate the metabolic changes of obese-diabetic (OBDC) rats treated with S. zalacca fruit extract using proton-nuclear magnetic resonance (1H NMR)-based metabolomics approach. This research presents the first report on the in vitro antidiabetic effect of S. zalacca fruits extract using this approach. The obtained results indicated that the administration of 400 mg/kg bw of 60% ethanolic S. zalacca extract for 6 weeks significantly decreased the blood glucose level and normalized the blood lipid profile of the OBDC rats. The potential biomarkers in urine were 2-oxoglutarate, alanine, leucine, succinate 3-hydroxybutyrate, taurine, betaine, allantoin, acetate, dimethylamine, creatine, creatinine, glucose, phenyl-acetylglycine, and hippurate. Based on the data obtained, the 60% ethanolic extract could not fully improved the metabolic complications of diabetic rats. The extract of S. zalacca fruit was able to decrease the ketones bodies as 3-hydroxybutyrate and acetoacetate. It also improved energy metabolism, involving glucose, acetate, lactate, 2-hydroxybutyrate, 2-oxoglutarate, citrate, and succinate. Moreover, it decreased metabolites from gut microflora, including choline. This extract had significant effect on amino acid metabolism, metabolites from gut microflora, bile acid metabolism and creatine. The result can further support the traditional claims of S. zalacca fruits in management of diabetes. This finding might be valuable in understanding the molecular mechanism and pharmacological properties of this medicinal plant for managing diabetes mellitus.
Fulltext Alpha-Glucosidase Inhibitory Effect of Psychotria malayana Jack Leaf: A Rapid Analysis Using Infrared Fingerprinting

Nipun TS, Khatib A, Ahmed QU, Redzwan IE, Ibrahim Z, Khan AYF, et al.

Molecules, 2020 Sep 11;25(18).
PMID: 32932994 DOI: 10.3390/molecules25184161

The plant Psychotria malayana Jack belongs to the Rubiaceae family and is known in Malaysia as "meroyan sakat/salung". A rapid analytical technique to facilitate the evaluation of the P. malayana leaves' quality has not been well-established yet. This work aimed therefore to develop a validated analytical technique in order to predict the alpha-glucosidase inhibitory action (AGI) of P. malayana leaves, applying a Fourier Transform Infrared Spectroscopy (FTIR) fingerprint and utilizing an orthogonal partial least square (OPLS). The dried leaf extracts were prepared by sonication of different ratios of methanol-water solvent (0, 25, 50, 75, and 100% v/v) prior to the assessment of alpha-glucosidase inhibition (AGI) and the following infrared spectroscopy. The correlation between the biological activity and the spectral data was evaluated using multivariate data analysis (MVDA). The 100% methanol extract possessed the highest inhibitory activity against the alpha-glucosidase (IC50 2.83 ± 0.32 μg/mL). Different bioactive functional groups, including hydroxyl (O-H), alkenyl (C=C), methylene (C-H), carbonyl (C=O), and secondary amine (N-H) groups, were detected by the multivariate analysis. These functional groups actively induced the alpha-glucosidase inhibition effect. This finding demonstrated the spectrum profile of the FTIR for the natural herb P. malayana Jack, further confirming its medicinal value. The developed validated model can be used to predict the AGI of P. malayana, which will be useful as a tool in the plant's quality control.
Isolation and characterization of novel antibacterial compound from an untapped plant, Stereospermum fimbriatum

Izyani Awang AF, Ahmed QU, Shah SAA, Jaffri JM, Ghafoor K, Uddin ABMH, et al.

Nat Prod Res, 2020 Mar;34(5):629-637.
PMID: 30470132 DOI: 10.1080/14786419.2018.1494170

Stereospermum fimbriatum or locally known as "Chicha" is traditionally used for itchy skin, earache, stomachache and postpartum treatments. This study was designed to evaluate the antimicrobial potential of S. fimbriatum's stem bark against 11 pathogens and isolate its bioactive compound. Successive soxhlet extraction was conducted using n-hexane, dichloromethane (DCM) and methanol. Disc diffusion, minimum inhibitory and bactericidal concentration (MIC & MBC) assays were done to examine the antimicrobial activity. Bioassay-guided isolation was conducted on S. fimbriatum's extract. The DCM extract of stem bark (DS) was the most potent extract followed by n-hexane extract of the stem bark (NS). A novel compound was isolated and coded as C1 which demonstrated potent antibacterial effects with the MIC values as low as 3.13 µg/mL to 6.25 µg/mL, against S. epidermidis, MRSA and S. aureus. Thus, S. fimbriatum could be a potential source of antimicrobial agents for the treatment of skin infections, specifically, MRSA.
Fulltext Investigation of α-Glucosidase Inhibitory Metabolites from Tetracera scandens Leaves by GC-MS Metabolite Profiling and Docking Studies

Nokhala A, Siddiqui MJ, Ahmed QU, Ahamad Bustamam MS, Zakaria AZA

Biomolecules, 2020 02 12;10(2).
PMID: 32059529 DOI: 10.3390/biom10020287

Stone leaf (Tetracera scandens) is a Southeast Asian medicinal plant that has been traditionally used for the management of diabetes mellitus. The underlying mechanisms of the antidiabetic activity have not been fully explored yet. Hence, this study aimed to evaluate the α-glucosidase inhibitory potential of the hydromethanolic extracts of T. scandens leaves and to characterize the metabolites responsible for such activity through gas chromatography-mass spectrometry (GC-MS) metabolomics. Crude hydromethanolic extracts of different strengths were prepared and in vitro assayed for α-glucosidase inhibition. GC-MS analysis was further carried out and the mass spectral data were correlated to the corresponding α-glucosidase inhibitory IC50 values via an orthogonal partial least squares (OPLS) model. The 100%, 80%, 60% and 40% methanol extracts displayed potent α-glucosidase inhibitory potentials. Moreover, the established model identified 16 metabolites to be responsible for the α-glucosidase inhibitory activity of T. scandens. The putative α-glucosidase inhibitory metabolites showed moderate to high affinities (binding energies of -5.9 to -9.8 kcal/mol) upon docking into the active site of Saccharomyces cerevisiae isomaltase. To sum up, an OPLS model was developed as a rapid method to characterize the α-glucosidase inhibitory metabolites existing in the hydromethanolic extracts of T. scandens leaves based on GC-MS metabolite profiling.

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