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Phytosterols as a natural anticancer agent: Current status and future perspective

Shahzad N, Khan W, Md S, Ali A, Saluja SS, Sharma S, et al.

Biomed Pharmacother, 2017 Apr;88:786-794.
PMID: 28157655 DOI: 10.1016/j.biopha.2017.01.068

Phytosterols are naturally occurring compounds in plants, structurally similar to cholesterol. The human diet is quite abundant in sitosterol and campesterol. Phytosterols are known to have various bioactive properties including reducing intestinal cholesterol absorption which alleviates blood LDL-cholesterol and cardiovascular problems. It is indicated that phytosterol rich diets may reduce cancer risk by 20%. Phytosterols may also affect host systems, enabling antitumor responses by improving immune response recognition of cancer, affecting the hormone dependent endocrine tumor growth, and by sterol biosynthesis modulation. Moreover, phytosterols have also exhibited properties that directly inhibit tumor growth, including reduced cell cycle progression, apoptosis induction, and tumor metastasis inhibition. The objective of this review is to summarize the current knowledge on occurrences, chemistry, pharmacokinetics and potential anticancer properties of phytosterols in vitro and in vivo. In conclusion, anticancer effects of phytosterols have strongly been suggested and support their dietary inclusion to prevent and treat cancers.
Flower extract of Allium atroviolaceum triggered apoptosis, activated caspase-3 and down-regulated antiapoptotic Bcl-2 gene in HeLa cancer cell line

Khazaei S, Ramachandran V, Abdul Hamid R, Mohd Esa N, Etemad A, Moradipoor S, et al.

Biomed Pharmacother, 2017 May;89:1216-1226.
PMID: 28320088 DOI: 10.1016/j.biopha.2017.02.082

Cervical cancer accounts for the second most frequent cancer and also third leading cause of cancer mortality (15%) among women worldwide. The major problems of chemotherapeutic treatment in cervical cancer are non-specific cytotoxicity and drug resistance. Plant-derived products, known as natural therapies, have been used for thousands of years in cancer treatment with a very low number of side effects. Allium atroviolaceum is a species in the genus Allium and Liliaceae family, which could prove to have beneficial effects on cancer treatment, although there is a lack of corresponding attention. The methanolic extract from the A.atroviolaceum flower displayed marked anticancer activity on HeLa human cervix carcinoma cells with much lower cytotoxic effects on normal cells (3T3). The A.atroviolaceum extract induced apoptosis, confirmed by cell cycle arrest at the sub-G0 (apoptosis) phase, characteristic morphological changes, evident DNA fragmentation, observed by fluorescent microscope, and early and late apoptosis detection by Annexin V. Furthermore, down-regulation of Bcl-2 and activation of caspase-9 and -3 strongly indicated that the mitochondrial pathway was involved in the apoptosis signal pathway. Moreover, combination of A.atroviolaceum extract with doxorubicin revealed a significant reduction of IC50and led to a synergistic effect. In summary, A.atroviolaceum displayed a significant anti-tumour effect through apoptosis induction in HeLa cells, suggesting that the A.atroviolaceum flower might have therapeutic potential against cervix carcinoma.
Pancreatoprotective effects of Geniotrigona thoracica stingless bee honey in streptozotocin-nicotinamide-induced male diabetic rats

Aziz MSA, Giribabu N, Rao PV, Salleh N

Biomed Pharmacother, 2017 May;89:135-145.
PMID: 28222394 DOI: 10.1016/j.biopha.2017.02.026

Stingless bee honey (SLBH) has been claimed to possess multiple health benefits. Its anti-diabetic properties are however unknown. In this study, ability of SLBH from Geniotrigona thoracica stingless bee species in ameliorating pancreatic damage and in maintaining metabolic profiles were investigated in diabetic condition.
METHODS: SLBH at 1 and 2g/kg/b.w. was given orally to streptozotocin (STZ)-nicotinamide-induced male diabetic rats for 28days. Metabolic parameters (fasting blood glucose-FBG and lipid profiles-LP and serum insulin) were measured by biochemical assays. Distribution and expression level of insulin, oxidative stress marker i.e. catalase, inflammatory markers i.e. IKK-β, TNF-α, IL-1β and apoptosis marker i.e. caspase-9 in the pancreatic islets were identified and quantified respectively by immunohistochemistry. Levels of NF-κβ in pancreas were determined by enzyme-linked immunoassay (ELISA).
RESULTS: SLBH administration to diabetic male rats prevented increase in FBG, total cholesterols (TC), triglyceride (TG) and low density lipoprotein (LDL) levels. However, high density lipoprotein (HDL) and serum insulin levels in diabetic rats receiving SLBH increased. Additionally, histopathological changes and expression level of oxidative stress, inflammation and apoptosis markers in pancreatic islets of diabetic rats decreased with increased expression level of insulin in the islets. LC-MS analysis revealed the presence of several compounds in SLBH that might be responsible for these effects.
CONCLUSIONS: SLBH has great potential to be used as agent to protect the pancreas against damage and dysfunction where these could account for its anti-diabetic properties.
Polyalthia longifolia Methanolic Leaf Extracts (PLME) induce apoptosis, cell cycle arrest and mitochondrial potential depolarization by possibly modulating the redox status in hela cells

Vijayarathna S, Oon CE, Chen Y, Kanwar JR, Sasidharan S

Biomed Pharmacother, 2017 May;89:499-514.
PMID: 28249252 DOI: 10.1016/j.biopha.2017.02.075

Medicinal plants have been accepted as a gold mine, with respect to the diversity of their phytochemicals. Many medicinal plants extracts are potential anticancer agents. Polyalthia longifolia var. angustifolia Thw. (Annonaceae) is one of the most significant native medicinal plants and is found throughout Malaysia. Hence, the present study was intended to assess the anticancer properties of P. longifolia leaf methanolic extract (PLME) and its underlying mechanisms. The Annexin V/PI flow cytometry analysis showed that PLME induces apoptosis in HeLa cells in dose-dependent manner whereas the PI flow cytometric analysis for cell cycle demonstrated the accumulation of cells at sub G0/G1, G0/G1 and G2/M phases. Investigation with JC-1 flow cytometry analysis indicated increase in mitochondria membrane potential depolarisation corresponding to increase in PLME concentrations. PLME was also shown to influence intracellular reactive oxygen species (ROS) by exerting anti-oxidant (half IC50) and pro-oxidant (IC50and double IC50) affect against HeLa cells. PLME treatment also displayed DNA damage in HeLa cells in concentration depended fashion. The proteomic profiling array exposed the expression of pro-apoptotic and anti-apoptotic proteins upon PLME treatment at IC50concentration in HeLa cells. Pro-apoptotic proteins; BAX, BAD, cytochrome c, caspase-3, p21, p27 and p53 were found to be significantly up-regulated while anti-apoptotic proteins; BCL-2 and BCL-w were found to be significantly down-regulated. This investigation postulated the role of p53 into mediating apoptosis, cell cycle arrest and mitochondrial potential depolarisation by modulating the redox status of HeLa cells.
Standardized Polyalthia longifolia leaf extract (PLME) inhibits cell proliferation and promotes apoptosis: The anti-cancer study with various microscopy methods

Vijayarathna S, Chen Y, Kanwar JR, Sasidharan S

Biomed Pharmacother, 2017 Jul;91:366-377.
PMID: 28463800 DOI: 10.1016/j.biopha.2017.04.112

Over the years a number of microscopy methods have been developed to assess the changes in cells. Some non-invasive techniques such as holographic digital microscopy (HDM), which although does not destroy the cells, but helps to monitor the events that leads to initiation of apoptotic cell death. In this study, the apoptogenic property and the cytotoxic effect of P. longifolia leaf methanolic extract (PLME) against the human cervical carcinoma cells (HeLa) was studied using light microscope (LM), holographic digital microscopy (HDM), scanning electron microscope (SEM) and transmission electron microscope (TEM). The average IC50 value of PLME against HeLa cells obtained by MTT and CyQuant assay was 22.00μg/mL at 24h. However, noncancerous Vero cells tested with PLME exhibited no cytotoxicity with the IC50 value of 51.07μg/mL at 24h by using MTT assay. Cytological observations showed nuclear condensation, cell shrinkage, multinucleation, abnormalities of mitochondrial cristae, membrane blebbing, disappearance of microvilli and filopodia, narrowing of lamellipodia, holes, formation of numerous smaller vacuoles, cytoplasmic extrusions and formation of apoptotic bodies as confirmed collectively by HDM, LM, SEM and TEM. In conclusion, PLME was able to produce distinctive morphological features of HeLa cell death that corresponds to apoptosis.
Biological activities of Anastatica hierochuntica L.: A systematic review

Zin SRM, Kassim NM, Alshawsh MA, Hashim NE, Mohamed Z

Biomed Pharmacother, 2017 Jul;91:611-620.
PMID: 28486192 DOI: 10.1016/j.biopha.2017.05.011

Anastatica hierochuntica L. (A. hierochuntica) is a desert plant consumed by people across the globe to treat various medical conditions. This review is aimed at providing a summary of the scientific findings on biological activities of A. hierochuntica and suggests areas in which further research is needed. This systematic review was synthesized from the literature obtained from the following databases; PubMed, Science Direct, Web of Science, Ovid Medline, Scopus, Google Scholar and WorldCat. Previous studies have indicated that the methanolic and aqueous extracts of this plant have antioxidant, antifungal and antimicrobial activities. It was shown to have the ability to activate phagocytes and to possess microbicidal activity, thereby causing increased resistance to infection. Both methanolic and aqueous extracts of this plant were also demonstrated to have a hypoglycaemic property, whilst the methanolic extract significantly exhibited hypolipidaemic effects in diabetic rats. Moreover, the methanolic extract of A. hierochuntica has been suggested to have hepatoprotective properties. This is supported by its ability to significantly decrease transaminase and alkaline phosphatase activities in alloxan-induced diabetic rats. Besides, this desert plant exhibited anti-inflammatory, anti-melanogenic and gastroprotective activities. Even though A. hierochuntica is widely used, studies on this plant are still scarce, thus its reputed biological activities and medical benefits require critical evaluation. Before A. hierochuntica can be used clinically, further studies need to be conducted to increase our understanding of the effects of this plant, its constituents, and possible mechanisms of action.
Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy

Alam J, Jantan I, Bukhari SNA

Biomed Pharmacother, 2017 Aug;92:615-633.
PMID: 28582758 DOI: 10.1016/j.biopha.2017.05.055

An autoimmune disease is defined as a clinical syndrome resulted from an instigation of both T cell and B cell or individually, in the absence of any present infection or any sort of distinguishable cause. Clonal deletion of auto reactive cells remains the central canon of immunology for decades, keeping the role of T cell and B cell aside, which are actually the guards to recognize the entry of foreign body. According to NIH, 23.5 million Americans are all together affected by these diseases. They are rare, but with the exception of RA. Rheumatoid arthritis is chronic and systemic autoimmune response to the multiple joints with unknown ethology, progressive disability, systemic complications, early death and high socioeconomic costs. Its ancient disease with an old history found in North American tribes since 1500 BCE, but its etiology is yet to be explored. Current conventional and biological therapies used for RA are not fulfilling the need of the patients but give only partial responses. There is a lack of consistent and liable biomarkers of prognosis therapeutic response, and toxicity. Rheumatoid arthritis is characterized by hyperplasic synovium, production of cytokines, chemokines, autoantibodies like rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), osteoclastogensis, angiogenesis and systemic consequences like cardiovascular, pulmonary, psychological, and skeletal disorders. Cytokines, a diverse group of polypeptides, play critical role in the pathogenesis of RA. Their involvement in autoimmune diseases is a rapidly growing area of biological and clinical research. Among the proinflammatory cytokines, IL-1α/β and TNF-α trigger the intracellular molecular signalling pathway responsible for the pathogenesis of RA that leads to the activation of mesenchymal cell, recruitment of innate and adaptive immune system cells, activation of synoviocytes which in term activates various mediators including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), resulting in inflamed synovium, increase angiogenesis and decrease lymphangiogensis. Their current pharmacotherapy should focus on their three phases of progression i.e. prearthritis phase, transition phase and clinical phase. In this way we will be able to find a way to keep the balance between the pro and anti-inflammatory cytokines that is believe to be the dogma of pathogenesis of RA. For this we need to explore new agents, whether from synthetic or natural source to find the answers for unresolved etiology of autoimmune diseases and to provide a quality of life to the patients suffering from these diseases specifically RA.
Hepatoprotective mechanism of Lygodium microphyllum (Cav.) R.Br. through ultrastructural signaling prevention against carbon tetrachloride (CCl4)-mediated oxidative stress

Gnanaraj C, Shah MD, Song TT, Iqbal M

Biomed Pharmacother, 2017 Aug;92:1010-1022.
PMID: 28609838 DOI: 10.1016/j.biopha.2017.06.014

Plants have been consumed in medicinal practices for centuries. Lygodium microphyllum (Cav.) R.Br. (Lygodiaceae), also known as Old World Climbing Fern, is a medicinal plant used by local communities in Sabah for skin and dysentery ailments. This study aims to test aqueous extract of L. microphyllum leaves for hepatoprotective and immunosuppressive activity in rats. Animal studies were carried out to evaluate hepatoprotection of aqueous extract of L. microphyllum at different doses (200, 400 and 600mg/kg b.w.) against carbon tetrachloride (CCl4)-mediated liver injury and histopathological alterations. Total phenolic content in aqueous extract of L. microphyllum leaves was 206.38±9.62mg gallic acid equivalent/g. The inhibitory concentration (IC50) for free radical scavenging activity of L. microphyllum was reached at a concentration of 65μg/ml.L. microphyllum was able to prevent the increase in levels of serum alanine aminotransferase, serum aspartate aminotransferase and hepatic malondialdehyde formation in a dose-dependent manner. Immunohistochemical results evidenced the suppression of oxidative stress markers (4-hydroxynonenal, 8-hydroxydeoxyguanosine) and pro-inflammatory cytokines (Tumor Necrosis Factor-α, Interleukin-6, Prostaglandin E2). Histopathological and hepatocyte ultrastructural alterations showed protective effects by L. microphyllum against CCl4-mediated oxidative stress. Hepatoprotective mechanism of L. microphyllum can be attributed to its antioxidative effects through protection of ultrastructural organelles.
Homology modeling and molecular docking studies on Type II diabetes complications reduced PPARγ receptor with various ligand molecules

Prabhu S, Vijayakumar S, Manogar P, Maniam GP, Govindan N

Biomed Pharmacother, 2017 Aug;92:528-535.
PMID: 28575810 DOI: 10.1016/j.biopha.2017.05.077

Peroxisome proliferator-activated receptor gamma (PPARγ), a type II nuclear receptor present in adipose tissue, colon and macrophages. It reduces the hyperglycemia associated metabolic syndromes. Particularly, type II diabetes-related cardiovascular system risk in human beings. The fatty acid storage and glucose metabolism are regulated by PPARγ activation in human body. According to recent reports commercially available PPARγ activating drugs have been causing severe side effects. At the same time, natural products have been proved to be a promising area of drug discovery. Recently, many studies have been attempted to screen and identify a potential drug candidate to activate PPARγ. Hence, in this study we have selected some of the bio-active molecules from traditional medicinal plants. Molecular docking studies have been carried out against the target, PPARγ. We Results suggested that Punigluconin has a efficient docking score and it is found to have good binding affinities than other ligands. Hence, we concluded that Punigluconin is a better drug candidate for activation of PPARγ gene expression. Further studies are necessary to confirm their efficacy and possibly it can develop as a potential drug in future.
Improvement of mitochondrial function by celastrol in palmitate-treated C2C12 myotubes via activation of PI3K-Akt signaling pathway

Abu Bakar MH, Tan JS

Biomed Pharmacother, 2017 Sep;93:903-912.
PMID: 28715871 DOI: 10.1016/j.biopha.2017.07.021

Compelling evidences posited that high level of saturated fatty acid gives rise to mitochondrial dysfunction and inflammation in the development of insulin resistance in skeletal muscle. Celastrol is a pentacyclic triterpenoid derived from the root extracts of Tripterygium wilfordii that possesses potent anti-inflammatory properties in a number of animal models with metabolic diseases. However, the cellular mechanistic action of celastrol in alleviating obesity-induced insulin resistance in skeletal muscle remains largely unknown. Therefore, the present investigation evaluated the attributive properties of celastrol at different concentrations (10, 20, 30 and 40nM) on insulin resistance in C2C12 myotubes evoked by palmitate. We demonstrated that celastrol improved mitochondrial functions through significant enhancement of intracellular ATP content, mitochondrial membrane potential, citrate synthase activity and decrease of mitochondrial superoxide productions. Meanwhile, augmented mitochondrial DNA (mtDNA) content with suppressed DNA oxidative damage were observed following celastrol treatment. Celastrol significantly enhanced fatty acid oxidation rate and increased the level of tricarboxylic acid (TCA) cycle intermediates in palmitate-treated cells. Further analysis revealed that the improvement of glucose uptake activity in palmitate-loaded myotubes was partly mediated by celastrol via activation of PI3K-Akt insulin signaling pathway. Collectively, these findings provided evidence for the first time that the protection from palmitate-mediated insulin resistance in C2C12 myotubes by celastrol is likely associated with the improvement of mitochondrial functions-related metabolic activities.
Phytotherapeutic potential of natural herbal medicines for the treatment of mild-to-severe atopic dermatitis: A review of human clinical studies

Hussain Z, Thu HE, Shuid AN, Kesharwani P, Khan S, Hussain F

Biomed Pharmacother, 2017 Sep;93:596-608.
PMID: 28686974 DOI: 10.1016/j.biopha.2017.06.087

For many decades, natural herbal medicines, polyherbal formulations and/or decoctions of plant-derived materials have widely been accepted as alternative complementary therapies for the treatment, cure or prevention of a wide range of acute and chronic skin diseases including chronic herpes, prurigo, acute and chronic wounds, psoriasis and atopic dermatitis (AD). This review was aimed to summarize and critically discuss about the therapeutic viability and clinical applicability of natural herbal medicines for the treatment of AD in human. The critical analysis of the literature revealed that oral (in the form of capsules, syrup or granules) and/or topical application (alone or in conjunction with wet-wrap dressing and/or acupuncture) of natural herbal medicines exhibit remarkable potential for the treatment of mild-to-severe AD in adults, children, infants and in the pregnant women. In this review, the clinical efficacy of various herbal formulations such as Chinese herbal therapies, Korean medicines, Iranian medicines, honey, natural herbal oils (coconut oil, olive oil and mineral oil), beeswax, dodder seeds and whey for the treatment of AD has been discussed. The clinical anti-AD efficacy of these complementary therapies has been observed in terms of down-regulation in Scoring Atopic Dermatitis (SCORAD) index, erythematic intensity, Children's Dermatology Life Quality Index (CDLQI), Dermatology Life Quality Index (DLQI), pruritus and itching frequency, transepidermal water loss (TEWL) and expression of AD-mediated chemokines. Conclusively, we recognized that natural herbal medicines demonstrate remarkable clinical efficacy when used alone or in conjunction with other complementary therapies for the treatment of AD in patients of all ages as well as pregnant women.
Protective effects of ethanolic peel and pulp extracts of Citrus macroptera fruit against isoproterenol-induced myocardial infarction in rats

Paul S, Das S, Tanvir EM, Hossen MS, Saha M, Afroz R, et al.

Biomed Pharmacother, 2017 Oct;94:256-264.
PMID: 28763749 DOI: 10.1016/j.biopha.2017.07.080

Increases in the incidence of cardiovascular disease (CVD) have aroused strong interest in identifying antioxidants from natural sources for use in preventive medicine. Citrus macroptera (C. macroptera), commonly known as "Satkara", is an important herbal and medicinal plant reputed for its antioxidant, nutritious and therapeutic uses. The aim of the present study was to investigate the cardio-protective effects of ethanol extracts of C. macroptera peel and pulp against isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Male albino Wistar rats (n=36) were pre-treated with peel and pulp extracts (500mg/kg) for 45days. They received a challenge with ISO (85mg/kg) on the 44th and 45th days. Our findings indicated that subcutaneous injection of ISO induced severe myocardial injuries associated with oxidative stress, as confirmed by elevated lipid peroxidation (LPO) and decreased cellular reduced glutathione (GSH) and anti-peroxidative enzymes, including glutathione peroxidase, glutathione reductase and glutathione-S-transferase, compared with levels observed in control animals. Pre-treatment with C. macroptera peel and pulp extracts prior to ISO administration however, significantly improved many of the investigated biochemical parameters, i.e., cardiac troponin I, cardiac marker enzymes, lipid profile and oxidative stress markers. The fruit peel extract showed stronger cardio-protective effects than the pulp extract. The biochemical findings were further confirmed by histopathological examinations. Overall, the increased endogenous antioxidant enzyme activity against heightened oxidative stress in the myocardium is strongly suggestive of the cardio-protective potential of C. macroptera.
Cadmium chloride-induced testicular toxicity in male wistar rats; prophylactic effect of quercetin, and assessment of testicular recovery following cadmium chloride withdrawal

Nna VU, Ujah GA, Mohamed M, Etim KB, Igba BO, Augustine ER, et al.

Biomed Pharmacother, 2017 Oct;94:109-123.
PMID: 28756368 DOI: 10.1016/j.biopha.2017.07.087

This study assessed the effect of quercetin (QE) on cadmium chloride (CdCl2) - induced testicular toxicity, as well as the effect of withdrawal of CdCl2 treatment on same. Thirty male Wistar rats aged 10 weeks old and weighing 270-300g were assigned into 5 groups and used for this study. Rats in groups 1-4 were administered vehicle, CdCl2 (5mg/kg bwt), CdCl2+QE (5mg/kg bwt and 20mg/kg bwt, respectively) or QE (20mg/kg bwt) orally for 4 weeks. Group 5 rats received CdCl2, with 4 weeks recovery period. Results showed that cadmium accumulated in serum, testis and epididymis, decreased body weight, testicular and epididymal weights, sperm count, motility and viability. Cadmium decreased serum concentrations of reproductive hormones, but increased testicular glucose, lactate and lactate dehydrogenase activity. Cadmium decreased testicular enzymatic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymatic (glutathione, vitamins C and E) antioxidants, and increased malondialdehyde and hydrogen peroxide. Cadmium down-regulated Bcl-2 protein, up-regulated Bax protein, increased Bax/Bcl-2 ratio and cleaved caspase-3 activity. Histopathology of the testis showed decreased Johnsen's score and Leydig cell count. These negative effects were attenuated by QE administration, while withdrawal of CdCl2 did not appreciably reverse toxicity. We conclude that QE better protected the testis from CdCl2 toxicity than withdrawal of CdCl2 administration.
Feasibility of graphene in biomedical applications

Foo ME, Gopinath SCB

Biomed Pharmacother, 2017 Oct;94:354-361.
PMID: 28772213 DOI: 10.1016/j.biopha.2017.07.122

Nanotechnology is the developing field, bringing the materials in the nanoscale level, has been applied in the interdisciplinary sciences. Different nanomaterials, such as gold, silver, zinc, copper and graphene are shown to have a wide range of applications. Among these, graphene is one of the faster upcoming two-dimensional nanomaterials utilized in various fields due to its positive features including the properties of thermal, electrical, strength and elasticity. Biomedical applications of graphene have been widely attested to be popular among academician and industrial partners for creating next generation medical systems and therapies. In this review, we selectively revealed the current applications of graphene in the interdisciplinary medical sciences.
Molecular understanding of the protective role of natural products on isoproterenol-induced myocardial infarction: A review

Wong ZW, Thanikachalam PV, Ramamurthy S

Biomed Pharmacother, 2017 Oct;94:1145-1166.
PMID: 28826162 DOI: 10.1016/j.biopha.2017.08.009

Modern medicine has been used to treat myocardial infarction, a subset of cardiovascular diseases, and have been relatively effective but not without adverse effects. Consequently, this issue has stimulated interest in the use of natural products, which may be equally effective and better tolerated. Many studies have investigated the cardioprotective effect of natural products, such as plant-derived phytochemicals, against isoproterenol (ISO)-induced myocardial damage; these have produced promising results on the basis of their antioxidant, anti-atherosclerotic, anti-apoptotic and anti-inflammatory activities. This review briefly introduces the pathophysiology of myocardial infarction (MI) and then addresses the progress of natural product research towards its treatment. We highlight the promising applications and mechanisms of action of plant extracts, phytochemicals and polyherbal formulations towards the treatment of ISO-induced myocardial damage. Most of the products displayed elevated antioxidant levels with decreased oxidative stress and lipid peroxidation, along with restoration of ionic balance and lowered expression of myocardial injury markers, pro-inflammatory cytokines, and apoptotic parameters. Likewise, lipid profiles were positively altered and histopathological improvements could be seen from, for example, the better membrane integrity, decreased necrosis, edema, infarct size, and leukocyte infiltration. This review highlights promising results towards the amelioration of ISO-induced myocardial damage, which suggest the direction for future research on natural products that could be used to treat MI.
Annona muricata leaves extracts prevent DMBA/TPA-induced skin tumorigenesis via modulating antioxidants enzymes system in ICR mice

Md Roduan MR, Hamid RA, Sulaiman H, Mohtarrudin N

Biomed Pharmacother, 2017 Oct;94:481-488.
PMID: 28779710 DOI: 10.1016/j.biopha.2017.07.133

Annona muricata, locally known as soursop has been reported to exhibit antiproliferative activities against various cancer cell lines. In this current study, we have investigated the antitumor promotion of various fractions of Annona muricata leaves (AML); hexane (AMLH), dichloromethane (AMLD) and methanol (AMLM) fraction respectively on 7, 12-dimethylbenz[α]anthracene (DMBA) induced and 12-0-tetradecaboylphorbol-13-acetate (TPA) promoted skin tumorigenesis in mice via morphological assessment, biochemical analysis and histopathological evaluation. The results of the study revealed significant inhibition in tumor incidence, tumor burden and tumor volume in the groups received AMLH and AMLD, respectively, and suppressive effects in group received AMLM compared with carcinogen control group at week 21. Superoxide dismutase, catalase, and lipid peroxidation levels were returned to near normal by administration of AML to DMBA/TPA-induced mice. The above findings were supported by histopathological studies, in which the extensive epidermal hyperplasia in carcinogen control group was restored to normal in AML treated groups. Whilst, annonacin, a major annaonaceous acetogenin was found to be the highest in AMLH and AMLD. From the present study, it can be inferred that AML supressed DMBA/TPA-induced skin tumor and this antitumor-promoting activity may be linked to the antioxidant/free radical-scavenging constituents of the extract and annonacin contained in the extracts.
Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats

Ismail N, Ismail M, Azmi NH, Bakar MFA, Yida Z, Abdullah MA, et al.

Biomed Pharmacother, 2017 Nov;95:780-788.
PMID: 28892789 DOI: 10.1016/j.biopha.2017.08.074

Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis. Despite the neuropharmacological attributes of black cumin seed (Nigella sativa) extracts and its main active compound, thymoquinone (TQ), limited records are available in relation to AD research. Nanoemulsion (NE) is exploited as drug delivery systems due to their capacity of solubilising non-polar active compounds and is widely examined for brain targeting. Herewith, the effects of thymoquinone-rich fraction nanoemulsion (TQRFNE), thymoquinone nanoemulsion (TQNE) and their counterparts' conventional emulsion in response to high fat/cholesterol diet (HFCD)-induced rats were investigated. Particularly, the Aβ generation; APP processing, β-secretase 1 (BACE1), γ-secretases of presenilin 1 (PSEN1) and presenilin 2 (PSEN2), Aβ degradation; insulin degrading enzyme (IDE), Aβ transportation; low density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) were measured in brain tissues. TQRFNE reduced the brain Aβ fragment length 1-40 and 1-42 (Aβ40 and Aβ42) levels, which would attenuate the AD pathogenesis. This reduction could be due to the modulation of β- and γ-secretase enzyme activity, and the Aβ degradation and transportation in/out of the brain. The findings show the mechanistic actions of TQRFNE in response to high fat and high cholesterol diet associated to Aβ generation, degradation and transportation in the rat's brain tissue.
Prophetic medicine as potential functional food elements in the intervention of cancer: A review

Sheikh BY, Sarker MMR, Kamarudin MNA, Ismail A

Biomed Pharmacother, 2017 Nov;95:614-648.
PMID: 28888208 DOI: 10.1016/j.biopha.2017.08.043

Amounting scientific evidences have revealed the antitumor, antimetastatic, antiangiogenic, antiproliferative, chemopreventive and neo-adjuvant efficacy of Prophetic Medicine in various in vitro, in vivo and clinical cancer models. Prophetic Medicine includes plants, dietary materials or spices that were used as remedy recipes and nutrition by the great Prophet Mohammed (peace be upon him) to treat various ailments. Prophetic medicine is the total authentic Hadith narrated by the Prophet (PBUH) in relation to medicine, whether Qur'anic verses or honourable Prophetic Hadith. The ability of functional foods from Prophetic Medicine to modulate various signalling pathways and multidrug resistance conferring proteins with low side-effects exemplify their great potential as neo-adjuvants and/or chemotherapeutics. The present review aims to provide the collective in vitro, in vivo, clinical and epidemiology information of Prophetic Medicines, and their bioactive constituents and molecular mechanisms as potential functional foods for the management of cancer.
Marantodes pumilum (Kacip fatimah) enhances in-vitro glucose uptake in 3T3-L1 adipocyte cells and reduces pancreatic complications in streptozotocin-nicotinamide induced male diabetic rats

Adam SH, Giribabu N, Bakar NMA, Salleh N

Biomed Pharmacother, 2017 Dec;96:716-726.
PMID: 29040959 DOI: 10.1016/j.biopha.2017.10.042

Marontades pumilum is claimed to have beneficial effects in the treatment of diabetes mellitus (DM), however the underlying mechanisms were not fully identified. In this study, we hypothesized that M. pumilum could help to enhance cellular glucose uptake and reduces pancreatic complications, which contributed towards its beneficial effects in DM.
METHODS: Two parameters were measured (i) rate of glucose uptake by 3T3-L1 adipocyte cells in-vitro (ii) degree of pancreatic destruction in streptozotocin-nicotinamide induced male diabetic rats receiving M. pumilum aqueous extract (M.P) (250 and 500mg/kg/day) as reflected by levels of pancreatic oxidative stress, inflammation and apoptosis. In the meantime, phyto-chemical compounds in M.P were also identified by using LC-MS.
RESULTS: M.P was found able to enhance glucose uptake by 3T3-L1 adipocyte cells in-vitro while its administration to the male diabetic rats causes decreased in the fasting blood glucose (FBG), glycated haemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) levels but causes increased in insulin and high-density lipoprotein (HDL) levels, to near normal. Levels of oxidative stress in the pancreas as reflected by levels of lipid peroxidation product (LPO) decreased while levels of anti-oxidantive enzymes (SOD, CAT and GPx) in pancreas increased. Additionally, levels of inflammation as reflected by NF-κB p65, Ikkβ and TNF-α levels decreased while apoptosis levels as reflected by caspase-9 and Bax levels decreased. Anti-apoptosis marker, Bcl-2 levels in pancreas increased.
CONCLUSIONS: The ability of M.P to enhance glucose uptake and reduces pancreatic complications could account for its beneficial effects in treating DM.
Parkia speciosa empty pod prevents hypertension and cardiac damage in rats given N(G)-nitro-l-arginine methyl ester

Kamisah Y, Zuhair JSF, Juliana AH, Jaarin K

Biomed Pharmacother, 2017 Dec;96:291-298.
PMID: 28992471 DOI: 10.1016/j.biopha.2017.09.095

Parkia speciosa Hassk is a plant found abundantly in Southeast Asia region. Its seeds with or without pods and roots have been used in traditional medicine in this region to treat hypertension. Therefore, we aimed to investigate the potential effect of the plant empty pod extract on hypertension development and changes in heart induced by N(G)-nitro-l-arginine methyl ester (l-NAME) administration in rats. Twenty-four male Sprague Dawley rats were divided into four groups. Groups 1 to 3 were given l-NAME (25mg/kg, intraperitoneally) for 8 weeks. Groups 2 and 3 were also given Parkia speciosa empty pods methanolic extract (800mg/kg, orally) and nicardipine (3mg/kg, orally), concurrently with l-NAME. The last group served as the control. l-NAME reduced plasma nitric oxide level and therefore, increased systolic blood pressure, angiotensin-converting enzyme and NADPH oxidase activities as well as lipid peroxidation in the heart. Parkia speciosa extract and nicardipine treatments had significantly prevented the elevations of blood pressure, angiotensin-converting enzyme, NADPH oxidase activities and lipid peroxidation in the heart induced by the l-NAME. Parkia speciosa extract but not nicardipine prevented the reduction in plasma nitric oxide level caused by l-NAME. In conclusion, Parkia speciosa empty pods methanolic extract has a potential to prevent the development of hypertension possibly by preventing the loss of plasma nitric oxide, as well as has cardioprotective effects by reducing angiotensin-converting enzyme activity and oxidative stress in the heart in rats administered l-NAME.

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