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Non-nutritive artificial sweeteners as an emerging contaminant in environment: A global review and risks perspectives

Praveena SM, Cheema MS, Guo HR

Ecotoxicol Environ Saf, 2019 Apr 15;170:699-707.
PMID: 30580164 DOI: 10.1016/j.ecoenv.2018.12.048

Generally, non-nutritive artificial sweeteners are widely utilized as sugar substitute in various applications. With various applications, non-nutritive artificial sweeteners are now being recognized as emerging contaminants with high water persistence and are chemically stable in environment. Although non-nutritive artificial sweeteners were documented on their occurrence in environment, yet their potential impacts to environment and human health remain ambiguous. Therefore, this review was prepared to provide a more comprehensive insight of non-nutritive artificial sweeteners in environment matrixes by highlighting special concerns on human health and environmental risks. Precisely, this review monitors the exploration of non-nutritive artificial sweeteners occurrences as an emerging contaminants in environment worldwide and their associated risks to human as well as environment. At present, there are a total of 24 non-nutritive artificial sweeteners' studies with regards to their occurrence in the environment from 38 locations globally, spanning across Europe including United Kingdoms, Canada, United States and Asia. Overall, the quantitative findings suggested that the occurrence of non-nutritive artificial sweeteners is present in surface water, tap water, groundwater, seawater, lakes and atmosphere. Among these environmental matrixes, surface water was found as the most studied matrix involving non-nutritive artificial sweeteners. However, findings on non-nutritive artificial sweeteners impacts on human health and environment are limited to understanding its overall potential impacts and risks. Additionally, this review also serves as a framework for future monitoring plans and environmental legislative to better control these emerging contaminants in environment.
Fulltext Mainstreaming responsible conduct of research education in Malaysia

Chau DM, Chai LC, Cheema MS, Veerakumarasivam A

Forensic Sci Res, 2021;6(4):338-340.
PMID: 35111352 DOI: 10.1080/20961790.2021.1987619
Comparative ultrastructural hepatic alterations induced by free and liposome-encapsulated mefenamic acid

Jarrar QB, Hakim MN, Cheema MS, Zakaria ZA

Ultrastruct Pathol, 2017 8 23;41(5):335-345.
PMID: 28829237 DOI: 10.1080/01913123.2017.1349850

Mefenamic acid (MFA) is used as an anti-inflammatory, antinociceptive, and antipyretic agent for treatment of a wide range of pathological disorders. While the uncertainty of its safety and the poor oral bioavailability constitute the major limiting factors of its medical use, considerable efforts including liposomal encapsulation are needed to achieve maximum therapeutic advantages. The current work was conducted to investigate the ultrastructural alterations in the liver induced by free MFA and its liposomal preparation. Female Sprague-Dawley rats were treated with daily oral doses of either free MFA or MFA entrapped in Tween 80 inoculated liposomes at the concentration of 80 mg/kg for 28 days. Ultrathin sections were prepared from biopsies taken from the liver of each member of all animals under study and subjected to examination by transmission electron microscopy. The liver of rats that were exposed to liposomal MFA showed more ultrastructural alterations than the rats treated with the free drug. While both groups of rats demonstrated sinusoidal dilatation, Kupffer cell hyperplasia, mitochondrial damage, and nuclear alterations, rats treated with liposome-encapsulated MFA induced an increase in the multiple lysosomes formation, hepatocytic steatosis, and apoptotic activity than free MFA-treated rats. The ultrastructural findings of the present study indicate that the use of liposomal MFA induces more hepatic damage than the use of free MFA.
Heavy metal quantification of classroom dust in school environment and its impacts on children health from Rawang (Malaysia)

Tan SY, Praveena SM, Abidin EZ, Cheema MS

Environ Sci Pollut Res Int, 2018 Dec;25(34):34623-34635.
PMID: 30315534 DOI: 10.1007/s11356-018-3396-x

This study aimed to determine bioavailable heavy metal concentrations (As, Cd, Co, Cu, Cr, Ni, Pb, Zn) and their potential sources in classroom dust collected from children's hand palms in Rawang (Malaysia). This study also aimed to determine the association between bioavailable heavy metal concentration in classroom dust and children's respiratory symptoms. Health risk assessment (HRA) was applied to evaluate health risks (non-carcinogenic and carcinogenic) due to heavy metals in classroom dust. The mean of bioavailable heavy metal concentrations in classroom dust found on children's hand palms was shown in the following order: Zn (1.25E + 01 μg/g) > Cu (9.59E-01 μg/g) > Ni (5.34E-01 μg/g) > Cr (4.72E-02 μg/g) > Co (2.34E-02 μg/g) > As (1.77E-02 μg/g) > Cd (9.60E-03 μg/g) > Pb (5.00E-03 μg/g). Hierarchical cluster analysis has clustered 17 sampling locations into three clusters, whereby cluster 1 (S3, S4, S6, S15) located in residential areas and near to roads exposed to vehicle emissions, cluster 2 (S10, S12, S9, S7) located near Rawang town and cluster 3 (S13, S16, S1, S2, S8, S14, S11, S17, S5) located near industrial, residential and plantation areas. Emissions from vehicles, plantations and industrial activities were found as the main sources of heavy metals in classroom dust in Rawang. There is no association found between bioavailable heavy metal concentrations and respiratory symptoms, except for Cu (OR = 0.03). Health risks (non-carcinogenic and carcinogenic risks) indicated that there are no potential non-carcinogenic and carcinogenic risks of heavy metals in classroom dust toward children health.
Fulltext Antinociceptive activity of methanolic extract of Muntingia calabura leaves: further elucidation of the possible mechanisms

Zakaria ZA, Mohd Sani MH, Cheema MS, Kader AA, Kek TL, Salleh MZ

BMC Complement Altern Med, 2014;14:63.
PMID: 24555641 DOI: 10.1186/1472-6882-14-63

Muntingia calabura (Elaecoparceae) is a medicinal plant traditionally used, particularly, by the Peruvian people to alleviate headache and cold, pain associated with gastric ulcers or to reduce the prostate gland swelling. Following the recent establishment of antinociceptive activity of M. calabura leaf, the present study was performed to further elucidate on the possible mechanisms of antinociception involved.
Safety assessment of natural products in Malaysia: current practices, challenges, and new strategies

M Pauzi NA, Cheema MS, Ismail A, Ghazali AR, Abdullah R

Rev Environ Health, 2021 Sep 27.
PMID: 34582637 DOI: 10.1515/reveh-2021-0072

The belief that natural products are inherently safe is a primary reason for consumers to choose traditional medicines and herbal supplements for health maintenance and disease prevention. Unfortunately, some natural products on the market have been found to contain toxic compounds, such as heavy metals and microbes, as well as banned ingredients such as aristolochic acids. It shows that the existing regulatory system is inadequate and highlights the importance of thorough safety evaluations. In Malaysia, the National Pharmaceutical Regulatory Agency is responsible for the regulatory control of medicinal products and cosmetics, including natural products. For registration purpose, the safety of natural products is primarily determined through the review of documents, including monographs, research articles and scientific reports. One of the main factors hampering safety evaluations of natural products is the lack of toxicological data from animal studies. However, international regulatory agencies such as the European Food Safety Authority and the United States Food and Drug Administration are beginning to accept data obtained using alternative strategies such as non-animal predictive toxicological tools. Our paper discusses the use of state-of-the-art techniques, including chemometrics, in silico modelling and omics technologies and their applications to the safety assessments of natural products.
Fulltext The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation

Yap HM, Lee YZ, Harith HH, Tham CL, Cheema MS, Shaari K, et al.

Sci Rep, 2018 11 09;8(1):16640.
PMID: 30413753 DOI: 10.1038/s41598-018-34847-0

Increased airway smooth muscle (ASM) mass is a prominent hallmark of airway remodeling in asthma. Inhaled corticosteroids and long-acting beta2-agonists remain the mainstay of asthma therapy, however are not curative and ineffective in attenuating airway remodeling. The geranyl acetophenone 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), an in-house synthetic non-steroidal compound, attenuates airway hyperresponsiveness and remodeling in murine models of asthma. The effect of tHGA upon human ASM proliferation, migration and survival in response to growth factors was assessed and its molecular target was determined. Following serum starvation and induction with growth factors, proliferation and migration of human bronchial smooth muscle cells (hBSMCs) treated with tHGA were significantly inhibited without any significant effects upon cell survival. tHGA caused arrest of hBSMC proliferation at the G1 phase of the cell cycle with downregulation of cell cycle proteins, cyclin D1 and diminished degradation of cyclin-dependent kinase inhibitor (CKI), p27Kip1. The inhibitory effect of tHGA was demonstrated to be related to its direct inhibition of AKT phosphorylation, as well as inhibition of JNK and STAT3 signal transduction. Our findings highlight the anti-remodeling potential of this drug lead in chronic airway disease.
Renal ultrastructural alterations induced by various preparations of mefenamic acid

Jarrar QB, Hakim MN, Zakaria ZA, Cheema MS, Moshawih S

Ultrastruct Pathol, 2020 Jan 02;44(1):130-140.
PMID: 31967489 DOI: 10.1080/01913123.2020.1717705

Mefenamic acid (MFA) treatment is associated with a number of cellular effects that potentiate the incidence of renal toxicity. The aim of this study is to investigate the potential ultrastructural alterations induced by various preparations of MFA (free MFA, MFA-Tween 80 liposomes, and MFA-DDC liposomes) on the renal tissues. Sprague-Dawley rats were subjected to a daily dose of MFA preparations for 28 days. Renal biopsies from all groups of rats under study were processed for transmission electron microscopic examination. The findings revealed that MFA preparations induced various ultrastructural alterations including mitochondrial injury, nuclear and lysosomal alterations, tubular cells steatosis, apoptotic activity, autophagy, and nucleophagy. These alterations were more clear in rats received free MFA, and MFA-Tween 80 liposomes than those received MFA-DDC liposomes. It is concluded that MFA-DDC liposomes are less potential to induce renal damage than free MFA and MFA-Tween 80 liposomes. Thus, MFA-DDC liposomes may offer an advantage of safe drug delivery.
An orally active geranyl acetophenone attenuates airway remodeling in a murine model of chronic asthma

Lee YZ, Shaari K, Cheema MS, Tham CL, Sulaiman MR, Israf DA

Eur J Pharmacol, 2017 Feb 15;797:53-64.
PMID: 28089919 DOI: 10.1016/j.ejphar.2017.01.011

2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a synthetic compound that is naturally found in Melicope ptelefolia. We had previously demonstrated that parenteral administration of tHGA reduces pulmonary inflammation in OVA-sensitized mice. In this study, we evaluated the effect of orally administered tHGA upon airway remodeling in a murine model of chronic asthma. Female BALB/C mice were sensitized intraperitoneally with ovalbumin (OVA) on day 0, 7 and 14, followed by aerosolized 1% OVA 3 times per week for 6 weeks. Control groups were sensitized with saline. OVA sensitized animals were either treated orally with vehicle (saline with 1% DMSO and Tween 80), tHGA (80, 40, 20mg/kg) or zileuton (30mg/kg) 1h prior to each aerosolized OVA sensitization. On day 61, mice underwent methacholine challenge to determine airway hyperresponsiveness prior to collection of bronchoalveolar lavage (BAL) fluid and lung samples. BAL fluid inflammatory cell counts and cytokine concentrations were evaluated while histological analysis and extracellular matrix protein concentrations were determined on collected lung samples. Oral tHGA treatment attenuated airway hyperresponsiveness and inhibited airway remodeling in a dose-dependent fashion. tHGA's effect on airway remodeling could be attributed to the reduction of inflammatory cell infiltration and decreased expression of cytokines associated with airway remodeling. Oral administration of tHGA attenuates airway hyperresponsiveness and remodeling in OVA-induced BALB/c mice. tHGA is an interesting compound that should be evaluated further for its possible role as an alternative non-steroidal pharmacological approach in the management of asthma.
Fulltext The Molecular Targets and Anti-Invasive Effects of 2,6-bis-(4-hydroxyl-3methoxybenzylidine) cyclohexanone or BHMC in MDA-MB-231 Human Breast Cancer Cells

Harun SNA, Israf DA, Tham CL, Lam KW, Cheema MS, Md Hashim NF

Molecules, 2018 Apr 10;23(4).
PMID: 29642589 DOI: 10.3390/molecules23040865

In order to metastasize, tumor cells need to migrate and invade the surrounding tissues. It is important to identify compound(s) capable of disrupting the metastasis of invasive cancer cells, especially for hindering invadopodia formation, so as to provide anti-metastasis targeted therapy. Invadopodia are thought to be specialized actin-rich protrusions formed by highly invasive cancer cells to degrade the extracellular matrix (ECM). A curcuminoid analogue known as 2,6-bis-(4-hydroxy-3-methoxybenzylidine)cyclohexanone or BHMC has shown good potential in inhibiting inflammation and hyperalgesia. It also possesses an anti-tumor effects on 4T1 murine breast cancer cells in vivo. However, there is still a lack of empirical evidence on how BHMC works in preventing human breast cancer invasion. In this study, we investigated the effect of BHMC on MDA-MB-231 breast cancer cells and its underlying mechanism of action to prevent breast cancer invasion, especially during the formation of invadopodia. All MDA-MB-231 cells, which were exposed to the non-cytotoxic concentrations of BHMC, expressed the proliferating cell nuclear antigen (PCNA), which indicate that the anti-proliferative effects of BHMC did not interfere in the subsequent experiments. By using a scratch migration assay, transwell migration and invasion assays, we determined that BHMC reduces the percentage of migration and invasion of MDA-MB-231 cells. The gelatin degradation assay showed that BHMC reduced the number of cells with invadopodia. Analysis of the proteins involved in the invasion showed that there is a significant reduction in the expressions of Rho guanine nucleotide exchange factor 7 (β-PIX), matrix metalloproteinase-9 (MMP-9), and membrane type 1 matrix metalloproteinase (MT1-MMP) in the presence of BHMC treatment at 12.5 µM. Therefore, it can be postulated that BHMC at 12.5 µM is the optimal concentration for preventing breast cancer invasion.
Fulltext Exploring the effectiveness of technology-based learning on the educational outcomes of undergraduate healthcare students: an overview of systematic reviews protocol

Romli MH, Cheema MS, Mehat MZ, Md Hashim NF, Abdul Hamid H

BMJ Open, 2020 Nov 23;10(11):e041153.
PMID: 33234650 DOI: 10.1136/bmjopen-2020-041153

INTRODUCTION: Rapid technology development due to the introduction of Industrial Revolution 4.0 and Internet of Things has created a demand and gradual transition from traditional teaching and learning to technology-based learning in higher education, including healthcare education. The COVID-19 pandemic has accelerated this process, with educators now required to quickly adapt to and adopt such changes. The abundance of available systematic reviews has made the effectiveness of such approaches ambiguous especially in healthcare education. Therefore, a protocol of the overview of systematic reviews (OoSR) is planned to extrapolate the effectiveness of technology-based learning in undergraduate healthcare education.
METHODS AND ANALYSIS: Scopus, CINAHL, Academic Search Complete, Cochrane Library, MEDLINE and Psychology and Behavioral Sciences Collection databases were selected. Screening was conducted independently by at least two authors and the decision for inclusion was done through discussion or involvement of an arbiter against a predetermined criteria. Included articles will be evaluated for quality using A MeaSurement Tool to Assess systematic Reviews and Risk of Bias in Systematic Review tools, while primary systematic review articles will be cross-checked and reported for any overlapping using the 'corrected covered area' method. Only narrative synthesis will be employed according to the predefined themes into two major dimensions-theory and knowledge generation (focusing on cognitive taxonomy due to its ability to be generalised across disciplines), and clinical-based competence (focusing on psychomotor and affective taxonomies due to discipline-specific influence). The type of technology used will be identified and extracted.
ETHICS AND DISSEMINATION: The OoSR involves analysis of secondary data from published literature, thus ethical approval is not required. The findings will provide a valuable insight for policymakers, stakeholders, and researchers in terms of technology-based learning implementation and gaps identification. The findings will be published in several reports due to the extensiveness of the topic and will be disseminated through peer-reviewed publications and conferences.
PROSPERO REGISTRATION NUMBER: CRD4202017974.
Fulltext Cosmos caudatus extract/fractions reduce smooth muscle cells migration and invasion in vitro : A potential benefit of suppressing atherosclerosis

Moshawih S, Cheema MS, Ibraheem ZO, Tailan ND, Hakim MN

Porto Biomed J, 2017;2(6):293-300.
PMID: 32258785 DOI: 10.1016/j.pbj.2017.03.008

HIGHLIGHTS: Cosmos caudatus Ethanolic extract fractionation by n-butanol produced a phenolics-saponin rich fraction.Cosmos caudatus butanol fraction was the most potent in all antioxidant and MTT assays.High concentrations of all fractions increased cells migration and invasion in vitro.Butanol fraction intermediate concentration maximally inhibited VSMC migration and invasion.Mild concentrations of crude and butanol fractions showed the best invasion inhibition index.
BACKGROUND: Cosmos caudatus Kunth is a medicinal herb used traditionally in Latin America and South East Asia to retard aging, rigidify bones and for several cardiovascular uses.
OBJECTIVE: Is to assess C. caudatus extract/fractions' antioxidant and vascular smooth muscle cells (VSMC) migration and invasion inhibition capacity in vitro.
METHODS: Cosmos caudatus shoots were extracted by cold maceration in 50% ethanol to produce crude (CEE), and then the extract was fractionated to butanol (Bu.F), and aqueous fractions (Aq.f). Phenolics and saponins were quantified in extract and fractions by colorimetric methods and their antioxidant capacity was assayed in four different tests. Cytotoxic effect and safety level concentrations were determined for the fractions by using MTT assay. Migration and invasion inhibitory potential were measured in vitro at three different concentrations equivalent to (IC10, IC25, and IC50). Finally, invasion inhibitory index was calculated to obtain the best fraction(s) that show(s) the highest ratio of cell invasion inhibition to the total cell migration inhibition.
RESULTS: Butanol fraction yield was the lowest; nevertheless, its phytochemical contents, antioxidant activities as well as its potency were the highest. Unlike other fractions, Bu.F was strongly correlated with all antioxidant assays experimented. In addition, it has the highest inhibitory effect at IC25 against VSMCs migration and invasion that accounts for 53.93% and 59.94% respectively. Unexpectedly, Bu.F and CEE at IC10 displayed the highest invasion inhibitory index (approx. 68%).
CONCLUSION: Butanol fraction of C. caudatus offers a potentiality for the discovery of new leads for preventing atherosclerosis.
Fulltext Hypoxia-Induced Neuroinflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Centella asiatica

Hambali A, Kumar J, Hashim NFM, Maniam S, Mehat MZ, Cheema MS, et al.

Front Physiol, 2021;12:712317.
PMID: 34721056 DOI: 10.3389/fphys.2021.712317

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.
Fulltext Knowledge, attitudes, and practices regarding Crimean-Congo hemorrhagic fever among general people: A cross-sectional study in Pakistan

Jamil H, Din MFU, Tahir MJ, Saqlain M, Hassan Z, Khan MA, et al.

PLoS Negl Trop Dis, 2022 Dec;16(12):e0010988.
PMID: 36480553 DOI: 10.1371/journal.pntd.0010988

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) continues to pose a serious threat to the fragile healthcare system of Pakistan with a continuous increase of morbidity and mortality. The present study aimed to assess the knowledge, attitudes, and practices regarding CCHF among general people who resided in Pakistan.
METHODS: An online cross-sectional survey design was applied, and a convenience sampling technique was used to recruit 1039 adult people from Pakistan. Data were collected from September 08 to October 12, 2021. The questionnaire consisted of a total of 32 questions in four parts assessing socio-demographics, as well as knowledge, attitudes, and practices regarding CCHF. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS), and logistic regression analyses were performed to determine the factors associated with good knowledge, positive attitudes, and good practices.
RESULTS: Alarmingly, 51.5% of participants heard about CCHF infection before administering the survey. Among these, 20.2%, 33.3%, and 48.2% of the study participants had demonstrated good knowledge, positive attitudes, and good practices, respectively. Binary logistic regression analysis revealed that education and income status had a significant impact on knowledge and attitudes (p<0.05). Similarly, the mean attitude scores differed significantly by age, education, and income status (p<0.05).
CONCLUSIONS: The findings reflected inadequate levels of knowledge, attitudes, and practices regarding CCHF among general people in Pakistan which may regard as lower than expected. As CCHF is a highly contagious disease, it's urgent to initiate a comprehensive approach to handle the situation before it spreads further in Pakistan.
Fulltext Methanolic Extract of Clinacanthus nutans Exerts Antinociceptive Activity via the Opioid/Nitric Oxide-Mediated, but cGMP-Independent, Pathways

Abdul Rahim MH, Zakaria ZA, Mohd Sani MH, Omar MH, Yakob Y, Cheema MS, et al.

Evid Based Complement Alternat Med, 2016;2016:1494981.
PMID: 27190528 DOI: 10.1155/2016/1494981

The objectives of the present study were to determine the mechanisms of antinociceptive effect of methanol extract of Clinacanthus nutans (Acanthaceae) leaves (MECN) using various animal nociceptive models. The antinociceptive activity of orally administered 10% DMSO, 100 mg/kg acetylsalicylic acid (ASA), 5 mg/kg morphine, or MECN (100, 250, and 500 mg/kg) was determined using the acetic acid-induced abdominal constriction (ACT), formalin-induced paw licking (FT), and hot plate tests (HPT). The role of opioid and nitric oxide/cyclic guanosine monophosphate (NO/cGMP) systems was also investigated. The results showed that MECN produced a significant (p < 0.05) antinociceptive response in all nociceptive models with the recorded ED50 value of 279.3 mg/kg for the ACT, while, for the early and late phases of the FT, the value was >500 mg/kg or 227.7 mg/kg, respectively. This antinociceptive activity was fully antagonized by naloxone (a nonselective opioid antagonist) but was partially reversed by l-arginine (l-arg; a nitric oxide [NO] precursor), Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; an NO synthase inhibitor), or their combinations thereof. In contrast, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ; a soluble guanylyl cyclase inhibitor) enhanced the extract's antinociception. UHPLC analysis revealed the presence of several flavonoid-based compounds with antinociceptive action. In conclusion, MECN exerted the peripherally and centrally mediated antinociceptive activity via the modulation of the opioid/NO-mediated, but cGMP-independent, systems.
Could protein phosphatase 2A and glycogen synthase kinase-3 beta be targeted by natural compounds to ameliorate Alzheimer's pathologies?

Manoharan SD, Abdul Hamid H, Md Hashim NF, Cheema MS, Chiroma SM, Mustapha M, et al.

Brain Res, 2024 Apr 15;1829:148793.
PMID: 38309553 DOI: 10.1016/j.brainres.2024.148793

Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and cognitive abilities, primarily in the elderly. The burden of AD extends beyond patients, impacting families and caregivers due to the patients' reliance on assistance for daily tasks. The main features of the pathogenesis of AD are beta-amyloid plaques and neurofibrillary tangles (NFTs), that strongly correlate with oxidative stress and inflammation. NFTs result from misfolded and hyperphosphorylated tau proteins. Various studies have focused on tau phosphorylation, indicating protein phosphatase 2A (PP2A) as the primary tau phosphatase and glycogen synthase kinase-3 beta (GSK-3β) as the leading tau kinase. Experimental evidence suggests that inhibition of PP2A and increased GSK-3β activity contribute to neuroinflammation, oxidative stress, and cognitive impairment. Hence, targeting PP2A and GSK-3β with pharmacological approaches shows promise in treating AD. The use of natural compounds in the drug development for AD have been extensively studied for their antioxidant, anti-inflammatory, anti-cholinesterase, and neuroprotective properties, demonstrating therapeutic advantages in neurological diseases. Alongside the development of PP2A activator and GSK-3β inhibitor drugs, natural compounds are likely to have neuroprotective effects by increasing PP2A activity and decreasing GSK-3β levels. Therefore, based on the preclinical and clinical studies, the potential of PP2A and GSK-3β as therapeutic targets of natural compounds are highlighted in this review.
Fulltext Semipurified Ethyl Acetate Partition of Methanolic Extract of Melastoma malabathricum Leaves Exerts Gastroprotective Activity Partly via Its Antioxidant-Antisecretory-Anti-Inflammatory Action and Synergistic Action of Several Flavonoid-Based Compounds

Ismail Suhaimy NW, Noor Azmi AK, Mohtarrudin N, Omar MH, Tohid SF, Cheema MS, et al.

Oxid Med Cell Longev, 2017;2017:6542631.
PMID: 28168011 DOI: 10.1155/2017/6542631

Recent study has demonstrated the gastroprotective activity of crude methanolic extract of M. malabathricum leaves. The present study evaluated the gastroprotective potential of semipurified extracts (partitions): petroleum ether, ethyl acetate (EAMM), and aqueous obtained from the methanolic extract followed by the elucidation of the gastroprotective mechanisms of the most effective partition. Using the ethanol-induced gastric ulcer assay, all partitions exerted significant gastroprotection, with EAMM being the most effective partition. EAMM significantly (i) reduced the volume and acidity (free and total) while increasing the pH of gastric juice and enhanced the gastric wall mucus secretion when assessed using the pylorus ligation assay, (ii) increased the enzymatic and nonenzymatic antioxidant activity of the stomach tissue, (iii) lost its gastroprotective activity following pretreatment with N-omega-nitro-L-arginine methyl ester (L-NAME; NO blocker) or carbenoxolone (CBXN; NP-SH blocker), (iv) exerted antioxidant activity against various in vitro oxidation assays, and (v) showed moderate in vitro anti-inflammatory activity via the LOX-modulated pathway. In conclusion, EAMM exerts a remarkable NO/NP-SH-dependent gastroprotective effect that is attributed to its antisecretory and antioxidant activities, ability to stimulate the gastric mucus production and endogenous antioxidant system, and synergistic action of several gastroprotective-induced flavonoids.

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