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New peperomin and polyketides from dichloromethane extract of Peperomia blanda Jack. (Kunth)

Al-Madhagi WM, Sharhan O, Jadan B, Hashim NM, Awadh N, Othman R

Trop Biomed, 2023 Dec 01;40(4):486-496.
PMID: 38308837 DOI: 10.47665/tb.40.4.015

Much of the new research and investigation in pharmacy sciences are concerned with developing therapeutic agents, and identifying and finding new drugs with their chemical structure to treat different human diseases such as infectious diseases from natural products. Therefore, the present findings relate to isolating five new compounds the dichloromethane extract of Peperomia blanda (Jacq.) Kunth grown on Socotra Island, Yemen. two new secolignans; which have been proposed as peperomin I & J. These compounds were isolated together with the other two polyketides presented as surinone D and dindygulerione F. The chemical structures were elucidated and confirmed with nuclear magnetic resonance (NMR) and liquid chromatography-mass spectroscopy (LCMS) analysis. These compounds were first isolated and reported from this plant. These new compounds' antimicrobial activity has been evaluated, and minimum inhibitory concentration has been recorded in the range of 125-250 µg/mL. The pharmacotherapeutic spectrum of compounds was predicated using PASS software which showed potential activity.
Fulltext The impact of a pressure ulcer prevention educational program based on the health belief model for persons with spinal cord injury

Hashim NM, Engkasan JP, Hasnan N

J Spinal Cord Med, 2022 Nov;45(6):898-906.
PMID: 33465010 DOI: 10.1080/10790268.2020.1860868

STUDY DESIGN: Pre- and post- trial.
OBJECTIVES: To determine the changes of health belief levels after a pressure ulcer (PrU) prevention educational program based on the Health Belief Model (HBM).
SETTING: Department of Rehabilitation Medicine, University Medical Centre, Malaysia.
METHODS: This study was conducted between May 2016 and May 2018. We created a multidisciplinary structured PrU prevention education program based on the HBM, consisting of didactic lectures, open discussions and a practical session. The content of the program was based on several PrU prevention guidelines. The education program focused on a group of 6-10 participants, and was conducted by a multidisciplinary team; i.e. doctor, physiotherapist, occupational therapist and a nurse. The skin care belief scales (SCBS) questionnaire was administered pre, post and 8-week post intervention, which measured the 9 domains of HBM. The data from the study was analyzed using repeated measures ANOVA to assess the effectiveness of the program.
RESULTS: Thirty spinal cord injured participants who fulfilled the inclusion and exclusion criteria completed this study. The results of the education program show statistically significant effects on Susceptibility; F (2,58) = 12.53, P < 0.05, Barriers to Skin Check Belief; F(2,58) = 5.74, P > 0.05, Benefits to Wheelchair Pressure Relief Belief; F(1.65,47.8) = 3.97, P < 0.05, Barriers to Turning and Positioning Belief; F(2,58) = 3.92, P
Incomplete paraplegia caused by extramedullary hematopoiesis in a patient with thalassemia intermedia

Hisamud-Din N, Mustafah NM, Fauzi AA, Hashim NM

Spinal Cord Ser Cases, 2017;3:17020.
PMID: 28503326 DOI: 10.1038/scsandc.2017.20

INTRODUCTION: Extramedullary hematopoiesis (EMH) is the production of blood cell precursors outside the bone marrow that occur in various hematological diseases. In patients with thalassemia intermedia, ineffective erythropoiesis drives compensatory EMH in the liver, pancreas, pleura, spleen, ribs and spine.
CASE PRESENTATION: We describe a patient with thalassemia intermedia who presented with acute neurological symptoms caused by paraspinal EMH, which responded well to combination therapy of steroid, hypertransfusion, laminectomy and excision of pseudotumor and hydroxyurea therapy to boost the formation of fetal haemoglobin.
DISCUSSION: Prompt recognition of EMH based on clinical presentation and typical radiological findings should be made. Early treatment is recommended to prevent irreversible damage to the spinal cord.
Fulltext Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Manganese (II) Complex against HCl/Ethanol-Induced Gastric Ulcerations in Rats

Ibrahim MY, Hashim NM, Dhiyaaldeen SM, Al-Obaidi MM, El-Ferjani RM, Adam H, et al.

Sci Rep, 2016 05 27;6:26819.
PMID: 27229938 DOI: 10.1038/srep26819

Manganese is a crucial element for health. In this study, the gastroprotective efficacy of Mn (II) complex (MDLA) against acidified ethanol (HCl/Ethanol)-induced gastric ulceration in rats was evaluated. The animals were distributed into 5 groups. Groups 1 and 2 received carboxymethylcellulose (CMC), group 3 was pretreated with omeprazole, and groups 4 and 5 were given 10 and 20 mg/kg of MDLA, respectively. After one hour, CMC and HCl/Ethanol were given to groups 2-5 whilst the animals in group 1 were ingested with CMC. After sacrifice, gastric lesions were evaluated by wall mucus, gross appearance, histology, antioxidant enzymes and immunohistochemistry. Group 2 displayed severe gastric damage with a significant reduction in wall mucus. Conversely, gastric lesions were reduced in groups 3-5 by 85.72%, 56.51% and 65.93%, respectively. The rats in groups 3-5 showed up-regulation of heat shock protein 70 (Hsp70) with down-regulation of Bcl-2-associated protein x (Bax). Pretreatment with omeprazole or MDLA led to an increase in the uptake of Periodic Acid Schiff (PAS) stain in the glandular part of the gastric tissue, raised levels of prostaglandin E2 (PGE2) and superoxide dismutase (SOD), and a reduction in malondialdehyde (MDA) concentrations. These results suggested the gastroprotective action of Mn (II) complex.
Fulltext Retraction Note: Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Manganese (II) Complex against HCl/Ethanol-Induced Gastric Ulcerations in Rats

Ibrahim MY, Hashim NM, Dhiyaaldeen SM, Al-Obaidi MMJ, El-Ferjani RM, Adam H, et al.

Sci Rep, 2020 04 17;10(1):6792.
PMID: 32303687 DOI: 10.1038/s41598-020-63217-y

This paper has been retracted.
Fulltext Comparison of apoptotic responses in Blastocystis sp. upon treatment with Tongkat Ali and Metronidazole

Girish S, Kumar S, Aminudin N, Hashim NM

Sci Rep, 2021 04 09;11(1):7833.
PMID: 33837230 DOI: 10.1038/s41598-021-81418-x

Blastocystis sp. infection, although many remain asymptomatic, there is growing data in recent studies that suggests it is a frequent cause of gastrointestinal symptoms in children and adults. This proposes that treatment against this infection is necessary however metronidazole (MTZ), which is the current choice of treatment, has expressed non-uniformity in its efficacy in combating this infection which has led to the study of alternative treatment. In our previous study, it was established that Tongkat Ali fractions exhibited promising anti-protozoal properties which leads to the current aim of the study, to further narrow down the purification process in order to identify the specific active compound promoting the anti-protozoal effect through HPLC analysis. Based on the data analysis and in-vitro susceptibility assay, the collected Tongkat Ali fraction that demonstrated anti-blastocystis property was shown to contain eurycomanone. Previous studies have suggested that there is a mechanism in Blastocystis sp. that regulates the apoptotic process to produce higher number of viable cells when treated. In reference to this, our current study also aims to investigate the apoptotic response of Tongkat Ali extract and eurycomanone across different subtype groups with comparison to MTZ. Based on our investigation, both Tongkat Ali extract and eurycomanone induced the high apoptotic rate however exhibited a reduction in viable cell count (p
Fulltext Anticancer activity of a monobenzyltin complex C1 against MDA-MB-231 cells through induction of Apoptosis and inhibition of breast cancer stem cells

Fani S, Kamalidehghan B, Lo KM, Nigjeh SE, Keong YS, Dehghan F, et al.

Sci Rep, 2016 Dec 15;6:38992.
PMID: 27976692 DOI: 10.1038/srep38992

In the present study, we examined the cytotoxic effects of Schiff base complex, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, and C1 on MDA-MB-231 cells and derived breast cancer stem cells from MDA-MB-231 cells. The acute toxicity experiment with compound C1 revealed no cytotoxic effects on rats. Fluorescent microscopic studies using Acridine Orange/Propidium Iodide (AO/PI) staining and flow cytometric analysis using an Annexin V probe confirmed the occurrence of apoptosis in C1-treated MDA-MB-231 cells. Compound C1 triggered intracellular reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) releases in treated MDA-MB-231 cells. The Cellomics High Content Screening (HCS) analysis showed the induction of intrinsic pathways in treated MDA-MB-231 cells, and a luminescence assay revealed significant increases in caspase 9 and 3/7 activity. Furthermore, flow cytometric analysis showed that compound C1 induced G0/G1 arrest in treated MDA-MB-231 cells. Real time PCR and western blot analysis revealed the upregulation of the Bax protein and the downregulation of the Bcl-2 and HSP70 proteins. Additionally, this study revealed the suppressive effect of compound C1 against breast CSCs and its ability to inhibit the Wnt/β-catenin signaling pathways. Our results demonstrate the chemotherapeutic properties of compound C1 against breast cancer cells and derived breast cancer stem cells, suggesting that the anticancer capabilities of this compound should be clinically assessed.
Occupational hazard in Malaysian traffic police: special focus on air pollutants

Mohamad Jamil PAS, Karuppiah K, Rasdi I, How V, Mohd Tamrin SB, Mani KKC, et al.

Rev Environ Health, 2021 Jun 25;36(2):167-176.
PMID: 33594842 DOI: 10.1515/reveh-2020-0107

This paper provides a specific deliberation on occupational hazards confronted daily by Malaysian Traffic Police. Traffic police is a high-risk occupation that involves a wide range of tasks and, indirectly, faced with an equally wide variety of hazards at work namely, physical, biological, psychosocial, chemical, and ergonomic hazards. Thereupon, occupational injuries, diseases, and even death are common in the field. The objective of this paper is to collate and explain the major hazards of working as Malaysian traffic police especially in Point Duty Unit, their health effects, and control measures. There are many ways in which these hazards can be minimised by ensuring that sufficient safety measures are taken such as a wireless outdoor individual exposure indicator system for the traffic police. By having this system, air monitoring among traffic police may potentially be easier and accurate. Other methods of mitigating these unfortunate events are incorporated and addressed in this paper according to the duty and needs of traffic police.
Translation and validation of the Malay version of modified orthotics and prosthetics users' survey

Hashim NM, Che Daud AZ, Ibrahim AH, Ab Majid MH, Mohd Ghazali MN, Abdul Razak MM, et al.

Prosthet Orthot Int, 2024 Jan 01;48(1):89-99.
PMID: 37639558 DOI: 10.1097/PXR.0000000000000270

BACKGROUND: An excellent validated and reliable instrument is paramount in holistically evaluating the prosthetic and orthotic (P&O) service, encompassing functional outcomes, health-related quality of life (HRQoL), and patient satisfaction with devices and service.
OBJECTIVE: To perform a translation and cross-cultural adaptation of 3 modules of the Orthotics and Prosthetics Users' Survey (OPUS): (1) lower-extremity functional status (LEFS), (2) client satisfaction with device and services (CSDS), and (3) HRQoL in Malay language, and analyze its psychometric properties.
STUDY DESIGN: Translation and validation study.
METHODS: This translation process consisted of 4 phases: (1) a forward-backward translation, (2) content and face validity by utilizing content and face validity indices, (3) pilot testing and psychometric analysis using exploratory factor analysis, and (4) test-retest reliability.
RESULTS: One item from OPUS Health Quality of Life Index-Malay pilot version, 5 items from OPUS LEFS-Malay pilot version, and 4 items of OPUS Satisfaction with Device and Services-Malay pilot version were deleted because of poor factor loading of <0.6. The final version of Modified OPUS HRQoL-M, Modified OPUS LEFS-M, and Modified OPUS CSDS-M consisted of 22 items, 15 items, and 17 items, respectively. The final versions of all 3 Modified OPUS Malay version possess good internal consistency of 0.854, 0.927, and 0.98, and intraclass correlation of 0.773, 0.871, and 0.821, respectively .
CONCLUSION: Modified OPUS HRQoL-M, Modified OPUS LEFS-M, and Modified OPUS CSDS-M are valid and reliable instruments to be adopted into the local Malaysia population.
Fulltext Hybrid nanocomposite curcumin-capped gold nanoparticle-reduced graphene oxide: Anti-oxidant potency and selective cancer cytotoxicity

Al-Ani LA, Yehye WA, Kadir FA, Hashim NM, AlSaadi MA, Julkapli NM, et al.

PLoS One, 2019;14(5):e0216725.
PMID: 31086406 DOI: 10.1371/journal.pone.0216725

Nanotechnology-based antioxidants and therapeutic agents are believed to be the next generation tools to face the ever-increasing cancer mortality rates. Graphene stands as a preferred nano-therapeutic template, due to the advanced properties and cellular interaction mechanisms. Nevertheless, majority of graphene-based composites suffer from hindered development as efficient cancer therapeutics. Recent nano-toxicology reviews and recommendations emphasize on the preliminary synthetic stages as a crucial element in driving successful applications results. In this study, we present an integrated, green, one-pot hybridization of target-suited raw materials into curcumin-capped gold nanoparticle-conjugated reduced graphene oxide (CAG) nanocomposite, as a prominent anti-oxidant and anti-cancer agent. Distinct from previous studies, the beneficial attributes of curcumin are employed to their fullest extent, such that they perform dual roles of being a natural reducing agent and possessing antioxidant anti-cancer functional moiety. The proposed novel green synthesis approach secured an enhanced structure with dispersed homogenous AuNPs (15.62 ± 4.04 nm) anchored on reduced graphene oxide (rGO) sheets, as evidenced by transmission electron microscopy, surpassing other traditional chemical reductants. On the other hand, safe, non-toxic CAG elevates biological activity and supports biocompatibility. Free radical DPPH inhibition assay revealed CAG antioxidant potential with IC50 (324.1 ± 1.8%) value reduced by half compared to that of traditional citrate-rGO-AuNP nanocomposite (612.1 ± 10.1%), which confirms the amplified multi-potent antioxidant activity. Human colon cancer cell lines (HT-29 and SW-948) showed concentration- and time-dependent cytotoxicity for CAG, as determined by optical microscopy images and WST-8 assay, with relatively low IC50 values (~100 μg/ml), while preserving biocompatibility towards normal human colon (CCD-841) and liver cells (WRL-68), with high selectivity indices (≥ 2.0) at all tested time points. Collectively, our results demonstrate effective green synthesis of CAG nanocomposite, free of additional stabilizing agents, and its bioactivity as an antioxidant and selective anti-colon cancer agent.
Fulltext Antisecretory, gastroprotective, antioxidant and anti-Helicobcter pylori activity of zerumbone from Zingiber zerumbet (L.) Smith

Sidahmed HM, Hashim NM, Abdulla MA, Ali HM, Mohan S, Abdelwahab SI, et al.

PLoS One, 2015;10(3):e0121060.
PMID: 25798602 DOI: 10.1371/journal.pone.0121060

BACKGROUND: Zingiber zerumbet Smith is a perennial herb, broadly distributed in many tropical areas. In Malaysia, it's locally known among the Malay people as "lempoyang" and its rhizomes, particularly, is widely used in traditional medicine for the treatment of peptic ulcer disease beyond other gastric disorders.
AIM OF THE STUDY: The aim of the current study is to evaluate the gastroprotective effect of zerumbone, the main bioactive compound of Zingiber zerumbet rhizome, against ethanol-induced gastric ulcer model in rats.
MATERIALS AND METHODS: Rats were pre-treated with zerumbone and subsequently exposed to acute gastric ulcer induced by absolute ethanol administration. Following treatment, gastric juice acidity, ulcer index, mucus content, histological analysis (HE and PAS), immunohistochemical localization for HSP-70, prostaglandin E2 synthesis (PGE2), non-protein sulfhydryl gastric content (NP-SH), reduced glutathione level (GSH), and malondialdehyde level (MDA) were evaluated in ethanol-induced ulcer in vivo. Ferric reducing antioxidant power assay (FRAP) and anti-H. pylori activity were investigated in vitro.
RESULTS: The results showed that the intragastric administration of zerumbone protected the gastric mucosa from the aggressive effect of ethanol-induced gastric ulcer, coincided with reduced submucosal edema and leukocyte infiltration. This observed gastroprotective effect of zerumbone was accompanied with a significant (p <0.05) effect of the compound to restore the lowered NP-SH and GSH levels, and to reduce the elevated MDA level into the gastric homogenate. Moreover, the compound induced HSP-70 up-regulation into the gastric tissue. Furthermore, zerumbone significantly (p <0.05) enhanced mucus production, showed intense PAS stain and maintained PG content near to the normal level. The compound exhibited antisecretory activity and an interesting minimum inhibitory concentration (MIC) against H. pylori strain.
CONCLUSION: The results of the present study revealed that zerumbone promotes ulcer protection, which might be attributed to the maintenance of mucus integrity, antioxidant activity, and HSP-70 induction. Zerumbone also exhibited antibacterial action against H. pylori.
Fulltext The molecular mechanism of the anticancer effect of Artonin E in MDA-MB 231 triple negative breast cancer cells

Etti IC, Abdullah R, Kadir A, Hashim NM, Yeap SK, Imam MU, et al.

PLoS One, 2017;12(8):e0182357.
PMID: 28771532 DOI: 10.1371/journal.pone.0182357

Nature has provided us with a wide spectrum of disease healing phytochemicals like Artonin E, obtained from the root bark of Artocarpus elasticus. This molecule had been predicted to be drug-like, possessing unique medicinal properties. Despite strides made in chemotherapy, prognosis of the heterogenous aggressive triple negative breast cancer is still poor. This study was conducted to investigate the mechanism of inhibition of Artonin E, a prenylated flavonoid on MDA-MB 231 triple negative breast cancer cell, with a view of mitigating the hallmarks displayed by these tumors. The anti-proliferative effect, mode of cell death and the mechanism of apoptosis induction were investigated. Artonin E, was seen to effectively relinquish MDA-MB 231 breast cancer cells of their apoptosis evading capacity, causing a half-maximal growth inhibition at low concentrations (14.3, 13.9 and 9.8 μM) after the tested time points (24, 48 and 72 hours), respectively. The mode of cell death was observed to be apoptosis with defined characteristics. Artonin E was seen to induce the activation of both extrinsic and intrinsic caspases initiators of apoptosis. It also enhanced the release of total reactive oxygen species which polarized the mitochondrial membrane, compounding the release of cytochrome c. Gene expression studies revealed the upregulation of TNF-related apoptosis inducing ligand and proapoptotic genes with down regulation of anti-apoptotic genes and proteins. A G2/M cell cycle arrest was also observed and was attributed to the observed upregulation of p21 independent of the p53 status. Interestingly, livin, a new member of the inhibitors of apoptosis was confirmed to be significantly repressed. In all, Artonin E showed the potential as a promising candidate to combat the aggressive triple negative breast cancer.
Fulltext Artonin E Induces Apoptosis via Mitochondrial Dysregulation in SKOV-3 Ovarian Cancer Cells

Rahman MA, Ramli F, Karimian H, Dehghan F, Nordin N, Ali HM, et al.

PLoS One, 2016;11(3):e0151466.
PMID: 27019365 DOI: 10.1371/journal.pone.0151466

Artonin E is a prenylated flavonoid isolated from the stem bark of Artocarpus elasticus Reinw.(Moraceae). This study aimed to investigate the apoptotic mechanisms induced by artonin E in a metastatic human ovarian cancer cell line SKOV-3 in vitro. MTT assay, clonogenic assay, acridine orange and propidium iodide double staining, cell cycle and annexin V analyses were performed to explore the mode of artonin E-induced cell death at different time points. DNA laddering, activation of caspases-3, -8, and -9, multi-parametric cytotoxicity-3 analysis by high-content screening, measurement of reactive oxygen species generation, and Western blot were employed to study the pathways involved in the apoptosis. MTT results showed that artonin E inhibited the growth of SKOV-3 cells, with IC50 values of 6.5±0.5 μg/mL after 72 h treatment, and showed less toxicity toward a normal human ovarian cell line T1074, with IC50 value of 32.5±0.5 μg/mL. Results showed that artonin E induced apoptosis and cell cycle arrest at the S phase. This compound also promoted the activation of caspases-3, -8, and -9. Further investigation into the depletion of mitochondrial membrane potential and release of cytochrome c revealed that artonin E treatment induced apoptosis via regulation of the expression of pro-survival and pro-apoptotic Bcl-2 family members. The expression levels of survivin and HSP70 proteins were also down regulated in SKOV-3 cells treated with artonin E. We propose that artonin E induced an antiproliferative effect that led to S phase cell cycle arrest and apoptosis through dysregulation of mitochondrial pathways, particularly the pro- and anti-apoptosis signaling pathways.
Fulltext Anti-ulcerogenic effect of methanolic extracts from Enicosanthellum pulchrum (King) Heusden against ethanol-induced acute gastric lesion in animal models

Nordin N, Salama SM, Golbabapour S, Hajrezaie M, Hassandarvish P, Kamalidehghan B, et al.

PLoS One, 2014;9(11):e111925.
PMID: 25379712 DOI: 10.1371/journal.pone.0111925

A natural source of medicine, Enicosanthellum pulchrum is a tropical plant which belongs to the family Annonaceae. In this study, methanol extract from the leaves and stems of this species was evaluated for its gastroprotective potential against mucosal lesions induced by ethanol in rats. Seven groups of rats were assigned, groups 1 and 2 were given Tween 20 (10% v/v) orally. Group 3 was administered omeprazole 20 mg/kg (10% Tween 20) whilst the remaining groups received the leaf and stem extracts at doses of 150 and 300 mg/kg, respectively. After an additional hour, the rats in groups 2-7 received ethanol (95% v/v; 8 mL/kg) orally while group 1 received Tween 20 (10% v/v) instead. Rats were sacrificed after 1 h and their stomachs subjected to further studies. Macroscopically and histologically, group 2 rats showed extremely severe disruption of the gastric mucosa compared to rats pre-treated with the E. pulchrum extracts based on the ulcer index, where remarkable protection was noticed. Meanwhile, a significant percentage of inhibition was shown with the stem extract at 62% (150 mg/kg) and 65% (300 mg/kg), whilst the percentage with the leaf extract at doses of 150 and 300 mg/kg was 63% and 75%, respectively. An increase in mucus content, nitric oxide, glutathione, prostaglandin E2, superoxide dismutase, protein and catalase, and a decrease in malondialdehyde level compared to group 2 were also obtained. Furthermore, immunohistochemical staining of groups 4-7 exhibited down-regulation of Bax and up-regulation of Hsp70 proteins. The methanol extract from the leaves and the stems showed notable gastroprotective potential against ethanol.
Pyranocycloartobiloxanthone A, a novel gastroprotective compound from Artocarpus obtusus Jarret, against ethanol-induced acute gastric ulcer in vivo

Sidahmed HM, Hashim NM, Amir J, Abdulla MA, Hadi AH, Abdelwahab SI, et al.

Phytomedicine, 2013 Jul 15;20(10):834-43.
PMID: 23570997 DOI: 10.1016/j.phymed.2013.03.002

Pyranocycloartobiloxanthone A (PA), a xanthone derived from the Artocarpus obtusus Jarret, belongs to the Moraceae family which is native to the tropical forest of Malaysia. In this study, the efficacy of PA as a gastroprotective compound was examined against ethanol-induced ulcer model in rats. The rats were pretreated with PA and subsequently exposed to acute gastric lesions induced by absolute ethanol. The ulcer index, gastric juice acidity, mucus content, histological analysis, glutathione (GSH) levels, malondialdehyde level (MDA), nitric oxide (NO) and non-protein sulfhydryl group (NP-SH) contents were evaluated in vivo. The activities of PA as anti-Helicobacter pylori, cyclooxygenase-2 (COX-2) inhibitor and free radical scavenger were also investigated in vitro. The results showed that the oral administration of PA protects gastric mucosa from ethanol-induced gastric lesions. PA pretreatment significantly (p<0.05) restored the depleted GSH, NP-SH and NO levels in the gastric homogenate. Moreover, PA significantly (p<0.05) reduced the elevated MDA level due to ethanol administration. The gastroprotective effect of PA was associated with an over expression of HSP70 and suppression of Bax proteins in the ulcerated tissue. In addition, PA exhibited a potent FRAP value and significant COX-2 inhibition. It also showed a significant minimum inhibitory concentration (MIC) against H. pylori bacterium. The efficacy of PA was accomplished safely without the presence of any toxicological parameters. The results of the present study indicate that the gastroprotective effect of PA might contribute to the antioxidant and anti-inflammatory properties as well as the anti-apoptotic mechanism and antibacterial action against Helicobacter pylori.
Involvement of NF-κB and Bcl2/Bax signaling pathways in the apoptosis of MCF7 cells induced by a xanthone compound Pyranocycloartobiloxanthone A

Mohan S, Abdelwahab SI, Kamalidehghan B, Syam S, May KS, Harmal NS, et al.

Phytomedicine, 2012 Aug 15;19(11):1007-15.
PMID: 22739412 DOI: 10.1016/j.phymed.2012.05.012

The plant Artocarpus obtusus is a tropical plant that belongs to the family Moraceae. In the present study a xanthone compound Pyranocycloartobiloxanthone A (PA) was isolated from this plant and the apoptosis mechanism was investigated. PA induced cytotoxicity was observed using MTT assay. High content screening (HCS) was used to observe the nuclear condensation, cell permeability, mitochondrial membrane potential (MMP) and cytochrome c release. Reactive oxygen species formation was investigated on treated cells by using fluorescent analysis. Human apoptosis proteome profiler assays were performed to investigate the mechanism of cell death. In addition mRNA levels of Bax and Bcl2 were also checked using RT-PCR. Caspase 3/7, 8 and 9 were measured for their induction while treatment. The involvement of NF-κB was analyzed using HCS assay. The results showed that PA possesses the characteristics of selectively inducing cell death of tumor cells as no inhibition was observed in non-tumorigenic cells even at 30 μg/ml. Treatment of MCF7 cells with PA induced apoptosis with cell death-transducing signals, that regulate the MMP by down-regulation of Bcl2 and up-regulation of Bax, triggering the cytochrome c release from mitochondria to cytosol. The release of cytochrome c triggered the activation of caspases-9, then activates downstream executioner caspase-3/7 and consequently cleaved specific substrates leading to apoptotic changes. This form of apoptosis was found closely associated with the extrinsic pathway caspase (caspase-8) and inhibition of translocation of NF-κB from cytoplasm to nucleus. The results demonstrated that PA induced apoptosis of MCF7 cells through NF-κB and Bcl2/Bax signaling pathways with the involvement of caspases.
Cleistopholine isolated from Enicosanthellum pulchrum exhibits apoptogenic properties in human ovarian cancer cells

Nordin N, Majid NA, Mohan S, Dehghan F, Karimian H, Rahman MA, et al.

Phytomedicine, 2016 Apr 15;23(4):406-16.
PMID: 27002411 DOI: 10.1016/j.phymed.2016.02.016

Cleistopholine is a natural alkaloid present in plants with numerous biological activities. However, cleistopholine has yet to be isolated using modern techniques and the mechanism by which this alkaloid induces apoptosis in cancer cells remains to be elucidated.
Tannic acid enhances cisplatin effect on cell proliferation and apoptosis of human osteosarcoma cell line (U2OS)

Kasiram MZ, Hapidin H, Abdullah H, Hashim NM, Azlina A, Sulong S

Pharmacol Rep, 2022 Feb;74(1):175-188.
PMID: 34652600 DOI: 10.1007/s43440-021-00330-3

BACKGROUND: The increase in cases of chemoresistance of cisplatin for osteosarcoma treatment has called for the need to establish a new treatment regime. Tannic acid (TA) possesses a potent antiproliferative effect against various cancers. Therefore, this study investigated the effect of TA combined with cisplatin on human osteosarcoma cell lines (U2OS).
METHODS: MTT assay was used to determine the half-maximal inhibitory concentration (IC50), while the combination index (CI) value was utilized to analyze the interaction within each combination. The antiproliferative effect of the treatment was evaluated by trypan blue exclusion assay. The morphological changes of cells were observed under a phase-contrast inverted microscope. The nuclear morphology and percentage of apoptosis cells were evaluated by using the Hoechst 33258 staining and annexin V/PI assay, respectively.
RESULTS: The U2OS cells showed cytotoxic effect when treated with TA and cisplatin, with IC50 at 4.47 µg/mL and 16.25 µg/mL, respectively. The TA demonstrated no significant inhibition effect on the normal human fetal osteoblast cells (hFOB 1.19); yet, interestingly, a potent proliferative effect was indicated. Synergistic interaction was triggered when TA was combined with cisplatin at percentage ratios of 90:10 and 85:15. Meanwhile, antagonistic interaction was induced in the combination at percentage ratios of 75:25 and 50:50. On the other hand, a significant antiproliferative effect with prominent morphological alteration was detected in the cells treated with a combination of TA and cisplatin at the percentage ratio of 90:10. Additionally, combination-treated cells demonstrated the highest percentage of apoptosis cells, with distinct chromosomal condensation, nuclear fragmentation, reduction of nuclear volume, and notable apoptotic body.
CONCLUSION: Therefore, there is a high potential for the inclusion of TA in the cisplatin-based chemotherapeutic regimen of osteosarcoma.
In vitro evaluation of osteoprotegerin in chitosan for potential bone defect applications

Jayash SN, Hashim NM, Misran M, Baharuddin NA

PeerJ, 2016;4:e2229.
PMID: 27635307 DOI: 10.7717/peerj.2229

The receptor activator of nuclear factor kappa-B (RANK)/RANK ligand/osteoprotegerin (OPG) system plays a critical role in bone remodelling by regulating osteoclast formation and activity. OPG has been used systemically in the treatment of bone diseases. In searching for more effective and safer treatment for bone diseases, we investigated newly formulated OPG-chitosan complexes, which is prepared as a local application for its osteogenic potential to remediate bone defects.
Fulltext Local application of osteoprotegerin-chitosan gel in critical-sized defects in a rabbit model

Jayash SN, Hashim NM, Misran M, Baharuddin NA

PeerJ, 2017;5:e3513.
PMID: 28674665 DOI: 10.7717/peerj.3513

BACKGROUND: Osteoprotegerin (OPG) is used for the systemic treatment of bone diseases, although it has many side effects. The aim of this study was to investigate a newly formulated OPG-chitosan gel for local application to repair bone defects. Recent studies have reported that immunodetection of osteopontin (OPN) and osteocalcin (OC) can be used to characterise osteogenesis and new bone formation.
METHODS: The osteogenic potential of the OPG-chitosan gel was evaluated in rabbits. Critical-sized defects were created in the calvarial bone, which were either left unfilled (control; group I), or filled with chitosan gel (group II) or OPG-chitosan gel (group III), with rabbits sacrificed at 6 and 12 weeks. Bone samples from the surgical area were decalcified and treated with routine histological and immunohistochemical protocols using OC, OPN, and cathepsin K (osteoclast marker) antibodies. The toxicity of the OPG-chitosan gel was evaluated by biochemical assays (liver and kidney function tests).
RESULTS: The mean bone growth in defects filled with the OPG-chitosan gel was significantly higher than those filled with the chitosan gel or the unfilled group (p

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