Displaying publications 21 - 40 of 67 in total

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  1. Mokhtar SS, Vanhoutte PM, Leung SW, Suppian R, Yusof MI, Rasool AH
    Eur J Pharmacol, 2016 Feb 15;773:78-84.
    PMID: 26825543 DOI: 10.1016/j.ejphar.2016.01.013
    Diabetes is associated with endothelial dysfunction, which is characterized by impaired endothelium-dependent relaxations. The present study aimed to examine the role of nitric oxide (NO), prostacyclin and endothelium-dependent hyperpolarization (EDH), in the relaxation of ventral tail arteries of rats under diabetic conditions. Relaxations of tail arteries of control and diabetic rats were studied in wire myograph. Western blotting and immunostaining were used to determine the presence of proteins. Acetylcholine-induced relaxations were significantly smaller in arteries of diabetic compared to control rats (Rmax; 70.81 ± 2.48% versus 85.05 ± 3.15%). Incubation with the combination of non-selective cyclooxygenase (COX) inhibitor, indomethacin and potassium channel blockers, TRAM 34 and UCL 1684, demonstrated that NO-mediated relaxation was attenuated significantly in diabetic compared to control rats (Rmax; 48.47 ± 5.84% versus 68.39 ± 6.34%). EDH-type (in the presence of indomethacin and NO synthase inhibitor, LNAME) and prostacyclin-mediated (in the presence of LNAME plus TRAM 34 and UCL 1684) relaxations were not significantly reduced in arteries of diabetic compared to control rats [Rmax: (EDH; 17.81 ± 6.74% versus 34.16 ± 4.59%) (prostacyclin; 15.85 ± 3.27% versus 17.23 ± 3.75%)]. Endothelium-independent relaxations to sodium nitroprusside, salbutamol and prostacyclin were comparable in the two types of preparations. Western blotting and immunostaining indicated that diabetes diminished the expression of endothelial NO synthase (eNOS), while increasing those of COX-1 and COX-2. Thus, since acetylcholine-induced NO-mediated relaxation was impaired in diabetes because of reduced eNOS protein expression, pharmacological intervention improving NO bioavailability could be useful in the management of diabetic endothelial dysfunction.
  2. Oon CE, Strell C, Yeong KY, Östman A, Prakash J
    Eur J Pharmacol, 2015 Jun 15;757:59-67.
    PMID: 25843411 DOI: 10.1016/j.ejphar.2015.03.064
    Gemcitabine remains the standard treatment for pancreatic cancer, although most patients acquire resistance to the therapy. Up-regulated in pancreatic cancer, SIRT1 is involved in tumorigenesis and drug resistance. However the mechanism through which SIRT1 regulates drug sensitivity in cancer cells is mainly unknown. We hypothesise that inhibiting SIRT1 activity may increase sensitivity of pancreatic cancer cells to gemcitabine treatment through the regulation of apototic cell death, cell cycle, epithelial-mesenschymal-transition (EMT) and senescence. We demonstrate that gemcitabine or 6-Chloro-2,3,4,9-tetrahydro-1 H-Carbazole-1-carboxamide (EX527) SIRT1 inhibitor reduces PANC-1 cell proliferation in vitro. EX527 enhanced sensitivity of PANC-1 cells to gemcitabine treatment through increased apoptosis. However, EX527 displayed no beneficial effect either as a monotreatment or in combination with gemcitabine in the modulation of cell cycle progression. Combination treatment did not reverse the two phenomena known to affect drug sensitivity, namely EMT and senescence, which are both induced by gemcitabine. Unexpectedly, EX527 promoted PANC-1 xenograft tumour growth in SCID mice compared to control group. Dual tX527 and gemcitabine displayed no synergistic effect compared to gemcitabine alone. The study reveals that SIRT1 is involved in chemoresistance and that inhibiting SIRT1 activity with EX527 sensitised PANC-1 cells to gemcitabine treatment in vitro. Sensitisation of cells is shown to be mainly through induction of micronuclei formation as a result of DNA damage and apoptosis in vitro. However, the absence of positive combinatorial effects in vivo indicates possible effects on cells of the tumor microenvironment and suggests caution regarding the clinical relevance of tissue culture findings with EX527.
  3. Ravishankar D, Albadawi DAI, Chaggar V, Patra PH, Williams HF, Salamah M, et al.
    Eur J Pharmacol, 2019 Nov 05;862:172627.
    PMID: 31461638 DOI: 10.1016/j.ejphar.2019.172627
    Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85 μM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100 μM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50 > 100 μM) but inhibited collagen induced platelet aggregation at 50 μM and 100 μM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100 μM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85 μM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor.
  4. Tew WY, Tan CS, Asmawi MZ, Yam MF
    Eur J Pharmacol, 2020 Aug 05;880:173123.
    PMID: 32335091 DOI: 10.1016/j.ejphar.2020.173123
    Morin (3,5,7,2',4'-pentahydroxyflavone) is a yellow coloured natural flavonoid found in plants of the Moraceae family. This favonoid is easily sources from readily available fruits, vegetables and eve certain beverages. Among the sources that was identified, it is clear that morin is most abundantly found in almond, old fustic, Indian guava, and Osage orange. Multiple studies have suggested that morin has multiple therapeutic actions and possess potential to be a functional potent drug. Previous studies demonstrated that morin is capable of resolving deoxycorticosterone acetate-salt-induced hypertension and possess strong vasorelaxant properties. However, the exact mechanisms remains unknown. Therefore, this study is designed to investigate the in vitro mechanism of morin-induced vasorelaxant effects. The underlying mechanisms of morin's vasorelaxant activities were evaluated on thoracic aortic rings isolated from Sprague-Dawley rats. Results from the study demonstrated morin causing vasodilatory reaction in phenylephrine and potassium chloride pre-contracted endothelium-intact aortic rings with the effect being significantly affected in endothelium-denuded aortic rings. Pre-incubation of the aortic rings with ODQ (selective cGMP-independent sGC inhibitor), indomethacin (nonselective COX inhibitor), L-NAME (endothelial nitric oxide inhibitor), propranolol (β2-adrenegic receptors blocker), and atropine (muscarinic receptors blocker) significantly reduced the vasorelaxant effect of morin. It was also found to be able to reduce the intracellular calcium level by blocking VOCC and calcium intake from the extracellular environment and the intracellular release of calcium from the sarcoplasmic reticulum. The present study showed that the vasorelaxant effect of morin potentially involves the NO/sGC, muscarinic receptors, β2-adrenegic receptors, and calcium channels.
  5. Phang CW, Gandah NA, Abd Malek SN, Karsani SA
    Eur J Pharmacol, 2019 Jun 15;853:388-399.
    PMID: 31014923 DOI: 10.1016/j.ejphar.2019.04.032
    Flavokawain C (FKC), a naturally occurring chalcone, has previously been shown to inhibit the growth of colon carcinoma HCT 116 cells through induction of apoptosis and cell cycle arrest. However, the possible underlying mechanisms of cell death as a response to FKC treatment remains unclear. In this study, we performed proteomic analysis of HCT 116 cells treated with FKC to identify proteins that change in abundance. This was followed by bioinformatic analysis to predict possible associated molecular targets or pathways involved in the observed effects of FKC. A total of 35 proteins that changed in abundance (17 increased and 18 decreased) were identified through two-dimensional gel electrophoresis followed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Using the Ingenuity Pathway Analysis (IPA), these proteins were predicted to be involved in cell death and survival, cell cycle, cellular growth and proliferation, protein synthesis, post-translational modification and amino acid metabolism by. Further analysis of the transcript levels of selected proteins using qPCR showed that some of the genes exhibited similar change of profile to that of the proteins'. Our results have provided novel insights into the potential molecular mechanisms underlying FKC-induced apoptosis or cell death in colon cancer cells.
  6. Abu Bakar MH, Sarmidi MR, Tan JS, Mohamad Rosdi MN
    Eur J Pharmacol, 2017 Mar 15;799:73-83.
    PMID: 28161417 DOI: 10.1016/j.ejphar.2017.01.043
    Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resistance and inflammation in animal disease models. Nevertheless, the specific mechanistic actions of celastrol in modulating such improvements at the cellular level remain obscure. The present study sought to explore the mechanistic roles of celastrol upon insulin resistance induced by palmitate in C3A human hepatocytes. The hepatocytes exposed to palmitate (0.75mM) for 48h exhibited reduced both basal and insulin-stimulated glucose uptake, mitochondrial dysfunction, leading to increased mitochondrial oxidative stress with diminished fatty acid oxidation. Elevated expressions of nuclear factor-kappa B p65 (NF-κB p65), c-Jun NH(2)-terminal kinase (JNK) signaling pathways and the amplified release of pro-inflammatory cytokines including IL-8, IL-6, TNF-α and CRP were observed following palmitate treatment. Consistently, palmitate reduced and augmented phosphorylated Tyrosine-612 and Serine-307 of insulin receptor substrate-1 (IRS-1) proteins, respectively in hepatocytes. However, celastrol at the optimum concentration of 30nM was able to reverse these deleterious occasions and protected the cells from mitochondrial dysfunction and insulin resistance. Importantly, we presented evidence for the first time that celastrol efficiently prevented palmitate-induced insulin resistance in hepatocytes at least, via improved mitochondrial functions and insulin signaling pathways. In summary, the present investigation underlines a conceivable mechanism to elucidate the cytoprotective potential of celastrol in attenuating mitochondrial dysfunction and inflammation against the development of hepatic insulin resistance.
  7. Chin LH, Hon CM, Chellappan DK, Chellian J, Madheswaran T, Zeeshan F, et al.
    Eur J Pharmacol, 2020 Jul 15;879:173139.
    PMID: 32343971 DOI: 10.1016/j.ejphar.2020.173139
    Chronic airway inflammatory diseases are characterized by persistent proinflammatory responses in the respiratory tract. Although, several treatment strategies are currently available, lifelong therapy is necessary for most of these diseases. In recent years, phytophenols, namely, flavonoids, derived from fruits and vegetables have been gaining tremendous interest and have been extensively studied due to their low toxicological profile. Naringenin is a bioflavonoid abundantly found in citrus fruits. This substance has shown notable therapeutic potential in various diseases due to its promising diverse biological activities. In this review, we have attempted to review the published studies from the available literature, discussing the molecular level mechanisms of naringenin in different experimental models of airway inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis and cystic fibrosis. Current evidences have proposed that the anti-inflammatory properties of naringenin play a major role in ameliorating inflammatory disease states. In addition, naringenin also possesses several other biological properties. Despite the proposed mechanisms suggesting remarkable therapeutic benefits, the clinical use of naringenin is, however, hampered by its low solubility and bioavailability. Furthermore, this review also discusses on the studies that utilise nanocarriers as a drug delivery system to address the issue of poor solubility.
  8. Mohd Nasir NA, Agarwal R, Krasilnikova A, Sheikh Abdul Kadir SH, Iezhitsa I
    Eur J Pharmacol, 2020 Nov 15;887:173431.
    PMID: 32758568 DOI: 10.1016/j.ejphar.2020.173431
    Intraocular pressure (IOP) lowering in glaucomatous eyes is currently achieved mainly by improved aqueous outflow via alternate drainage pathways. However, the focus is now shifting to trabecular meshwork (TM), the site or major pathological changes including increased extracellular matrix (ECM) deposition and reduced matrix metalloproteinases (MMPs) secretion by TM cells. Trans-resveratrol was previously shown to lower IOP and reduce ECM deposition; however, the mechanisms of action remain unclear. Therefore, we determined the effect of trans-resveratrol on MMP-2 and -9 expression by human TM cells (HTMCs) in the presence of dexamethasone and whether it also affects adenosine A1 receptors (A1AR) expression and nuclear factor kappa B (NFkB) activation. We observed that trans-resveratrol, 12.5 μM, increased MMP-2 and -9 protein expression by HTMCs despite exposure to dexamethasone (1.89- and 1.53-fold, respectively; P 
  9. Ayipo YO, Mordi MN, Mustapha M, Damodaran T
    Eur J Pharmacol, 2021 Feb 15;893:173837.
    PMID: 33359647 DOI: 10.1016/j.ejphar.2020.173837
    Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. β-Carboline (βC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the βC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that βC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.
  10. Ramanunny AK, Wadhwa S, Gulati M, Singh SK, Kapoor B, Dureja H, et al.
    Eur J Pharmacol, 2021 Jan 05;890:173691.
    PMID: 33129787 DOI: 10.1016/j.ejphar.2020.173691
    Skin diseases are the fourth leading non-fatal skin conditions that act as a burden and affect the world economy globally. This condition affects the quality of a patient's life and has a pronounced impact on both their physical and mental state. Treatment of these skin conditions with conventional approaches shows a lack of efficacy, long treatment duration, recurrence of conditions, systemic side effects, etc., due to improper drug delivery. However, these pitfalls can be overcome with the applications of nanomedicine-based approaches that provide efficient site-specific drug delivery at the target site. These nanomedicine-based strategies are evolved as potential treatment opportunities in the form of nanocarriers such as polymeric and lipidic nanocarriers, nanoemulsions along with emerging others viz. carbon nanotubes for dermatological treatment. The current review focuses on challenges faced by the existing conventional treatments along with the topical therapeutic perspective of nanocarriers in treating various skin diseases. A total of 213 articles have been reviewed and the application of different nanocarriers in treating various skin diseases has been explained in detail through case studies of previously published research works. The toxicity related aspects of nanocarriers are also discussed.
  11. Izzati Mat Rani NN, Alzubaidi ZM, Azhari H, Mustapa F, Iqbal Mohd Amin MC
    Eur J Pharmacol, 2021 Jun 05;900:174009.
    PMID: 33722591 DOI: 10.1016/j.ejphar.2021.174009
    Over the years, extensive studies on erythrocytes, also known as red blood cells (RBCs), as a mechanism for drug delivery, have been explored mainly because the cell itself is the most abundant and has astonishing properties such as a long life span of 100-120 days, low immunogenicity, good biocompatibility, and flexibility. There are various types of RBC-based systems for drug delivery, including those that are genetically engineered, non-genetically engineered RBCs, as well as employing erythrocyte as nanocarriers for drug loading. Although promising, these systems are still in an early development stage. In this review, we aimed to highlight the development of biomimicking RBC-based drug and vaccine delivery systems, as well as the loading methods with illustrative examples. Drug-erythrocyte associations will also be discussed and highlighted in this review. We have highlighted the possibility of exploiting erythrocytes for the sustained delivery of drugs and vaccines, encapsulation of these biological agents within the erythrocyte or coupling to the surface of carrier erythrocytes, and provided insights on genetically- and non-genetically engineered erythrocytes-based strategies. Erythrocytes have been known as effective cellular carriers for therapeutic moieties for several years. Herein, we outline various loading methods that can be used to reap the benefits of these natural carriers. It has been shown that drugs and vaccines can be delivered via erythrocytes but it is important to select appropriate methods for increasing the drug encapsulated or conjugated on the surface of the erythrocyte membrane. The outlined examples will guide the selection of the most effective method as well as the impact of using erythrocytes as delivery systems for drugs and vaccines.
  12. Faghfouri AH, Zarezadeh M, Tavakoli-Rouzbehani OM, Radkhah N, Faghfuri E, Kord-Varkaneh H, et al.
    Eur J Pharmacol, 2020 Oct 05;884:173368.
    PMID: 32726657 DOI: 10.1016/j.ejphar.2020.173368
    Prolonged inflammation could be considered as the leading cause of chronic diseases such as cardiovascular disorders, type two diabetes, and obesity. N-acetylcysteine (NAC) is considered an antioxidant. The present meta-analysis aims to determine the efficacy of NAC in alleviating inflammation and oxidative stress. PubMed-Medline, SCOPUS, Web of Science and Embase databases and Google Scholar were searched up to Nov 2019. Random effect analysis was used to perform meta-analysis. Subgroup analyses were carried out to find heterogeneity sources. Meta-regression analysis was used to explore linear relationship between effect size and variables. Trim and fill analysis were performed in case of the presence of publication bias. Quality assessment was performed using Cochrane Collaboration's tool. A total of 28 studies were included in meta-analysis. NAC significantly decreased malondialdehyde (MDA) (SMD = -1.44 μmol/L; 95% CI: -2.05, -0.84; P 
  13. Abu Bakar MH, Shariff KA, Tan JS, Lee LK
    Eur J Pharmacol, 2020 Sep 15;883:173371.
    PMID: 32712089 DOI: 10.1016/j.ejphar.2020.173371
    Accumulating evidence indicates that adipose tissue inflammation and mitochondrial dysfunction in skeletal muscle are inextricably linked to obesity and insulin resistance. Celastrol, a bioactive compound derived from the root of Tripterygium wilfordii exhibits a number of attributive properties to attenuate metabolic dysfunction in various cellular and animal disease models. However, the underlying therapeutic mechanisms of celastrol in the obesogenic environment in vivo remain elusive. Therefore, the current study investigated the metabolic effects of celastrol on insulin sensitivity, inflammatory response in adipose tissue and mitochondrial functions in skeletal muscle of the high fat diet (HFD)-induced obese rats. Our study revealed that celastrol supplementation at 3 mg/kg/day for 8 weeks significantly reduced the final body weight and enhanced insulin sensitivity of the HFD-fed rats. Celastrol noticeably improved insulin-stimulated glucose uptake activity and increased expression of plasma membrane GLUT4 protein in skeletal muscle. Moreover, celastrol-treated HFD-fed rats showed attenuated inflammatory responses via decreased NF-κB activity and diminished mRNA expression responsible for classically activated macrophage (M1) polarization in adipose tissues. Significant improvement of muscle mitochondrial functions and enhanced antioxidant defense machinery via restoration of mitochondrial complexes I + III linked activity were effectively exhibited by celastrol treatment. Mechanistically, celastrol stimulated mitochondrial biogenesis attributed by upregulation of the adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways. Together, these results further demonstrate heretofore the conceivable therapeutic mechanisms of celastrol in vivo against HFD-induced obesity mediated through attenuation of inflammatory response in adipose tissue and enhanced mitochondrial functions in skeletal muscle.
  14. Singh P, Charles S, Madhavan T, Munusamy-Ramanujam G, Saraswathi NT, Arasu MV, et al.
    Eur J Pharmacol, 2021 Jan 15;891:173697.
    PMID: 33144068 DOI: 10.1016/j.ejphar.2020.173697
    We investigated the role of protein arginine methylation (PAM) in estrogen receptor (ER)-positive breast cancer cells through pharmacological intervention. Tamoxifen (TAM) or adenosine dialdehyde (ADOX), independently, triggered cell cycle arrest and down-regulated PAM, as reduced protein arginine methyltransferase1 (PRMT1) mRNA and asymmetric dimethylarginine (ADMA) levels. Synergistic effect of these compounds elicited potent anti-cancer effect. However, reduction in ADMA was not proportionate with the compound-induced down-regulation of PRMT1 mRNA. We hypothesized that the disproportionate effect is due to the influence of the compounds on other methyltransferases, which catalyze the arginine dimethylation reaction and the diversity in the degree of drug-protein interaction among these methyltransferases. In silico analyses revealed that independently, ADOX or TAM, binds with phosphatidylethanolamine-methyltransferase (PEMT) or betaine homocysteine-methyl transferase (BHMT); and that the binding affinity of ADOX with PEMT or BHMT is prominent than TAM. These observations suggest that in breast cancer, synergistic effect of ADOX + TAM elicits impressive protective function by regulating PAM; and plausibly, restoration of normal enzyme activities of methyltransferases catalyzing arginine dimethylation could have clinical benefits.
  15. Benchoula K, Arya A, Parhar IS, Hwa WE
    Eur J Pharmacol, 2021 Jan 15;891:173758.
    PMID: 33249079 DOI: 10.1016/j.ejphar.2020.173758
    Glucose production and the consumption of high levels of carbohydrate increase the chance of insulin resistance, especially in cases of obesity. Therefore, maintaining a balanced glucose homeostasis might form a strategy to prevent or cure diabetes and obesity. The activation and inhibition of glucose production is complicated due to the presence of many interfering pathways. These pathways can be viewed at the downstream level because they activate certain transcription factors, which include the Forkhead-O1 (FoxO1). This has been identified as a significant agent in the pancreas, liver, and adipose tissue, which is significant in the regulation of lipids and glucose. The objective of this review is to discuss the intersecting portrayal of FoxO1 and its parallel cross-talk which highlights obesity-induced insulin susceptibility in the discovery of a targeted remedy. The review also analyses current progress and provides a blueprint on therapeutics, small molecules, and extracts/phytochemicals which are explored at the pre-clinical level.
  16. Chen Y, Li H, Ye Z, Găman MA, Tan SC, Zhu F
    Eur J Pharmacol, 2020 Nov 05;886:173458.
    PMID: 32763300 DOI: 10.1016/j.ejphar.2020.173458
    Metformin administration has been reported to influence the carotid intima-media thickness (CIMT) in humans. However, since previously conducted studies have yielded inconsistent results, the exact effect of metformin on CIMT remains unclear. Causes that could lead to inconsistency in reported research could be the duration and dose of the intervention, as well as the sample size. To address this inconsistency, we conducted a systematic review and meta-analysis to evaluate the influence of metformin on CIMT in human subjects. We identified eligible studies by searching several electronic databases (EMBASE, PubMed-MEDLINE, Web of Science and Google Scholar) up to December 12, 2019. Data were pooled using the random-effects model. Combining data from 1087 participants (9 studies), our meta-analysis revealed that the administration of metformin resulted in a significant reduction in CIMT (WMD = -0.049 mm; 95% CI: -0.095, -0.004). Stratified analyses showed that an intervention lasting ≥12 months (WMD: -0.084 mm, 95% CI: -0.145, -0.024) and an intake of metformin ≤1500 mg/day (WMD: -0.081 mm, 95% CI: -0.132, -0.029) resulted in a significantly greater reduction in CIMT. However, an intervention duration of less than 12 months and an intake of metformin ˃1500 mg/day yielded no significant effects on CIMT. The results of the current study confirm that metformin administration is associated with a significant reduction in CIMT. Taking into account that CIMT reflects the burden of atherosclerosis, the clinical utility of metformin might also be related to its anti-atherogenic effects.
  17. Afzal S, Sattar MA, Johns EJ, Eseyin OA
    Eur J Pharmacol, 2021 Sep 15;907:174218.
    PMID: 34111396 DOI: 10.1016/j.ejphar.2021.174218
    Oxidative stress causes hypoadiponectemia and reactive oxygen species production. This study investigates the pathophysiological role and potential effects of adiponectin with partial and full peroxisome proliferator-activated receptor-gamma agonists on modulation of metabolic dysregulation and oxidative stress in diabetic model of Wistar Kyoto rats (WKY). Forty two male WKY rats were randomized equally into 7 groups (n = 6), Group I serve as control, group II as WKY diabetic control, groups III, IV and V treated with irbesartan (30 mg/kg), pioglitazone (10 mg/kg) and adiponectin (2.5 μg/kg), groups VI and VII were co-treated as: irbesartan + adiponectin, pioglitazone + adiponectin, respectively. Streptozotocin @ 40 mg/kg was administered intraperitoneally to induce diabetes. Plasma adiponectin, metabolic indices, pulse wave velocity, oxidative stress and antioxidant enzymatic activities were measured. Streptozotocin induced WKYs expressed hyperglycaemia, hypertriglyceridemia, hypercholesterolemia, hypoadiponectemia, increased arterial stiffness and decreased antioxidant enzymatic levels (P<0.05). Treatment with adiponectin or pioglitazone alone showed improvements in metabolic indices, antioxidant enzymes, and abrogated arterial stiffness, attenuated generation of reactive oxygen species and dyslipidaemic effects of streptozotocin better as compared to irbesartan sets of treatment (all P<0.05). Co-treatment of adiponectin with pioglitazone significantly amplified the improvement in plasma triglycerides, adiponectin concentration, pulse wave velocity and antioxidant enzymatic activities indicating synergistic effects of adiponectin with full PPAR-γ agonist.
  18. Rengarajan T, Yaacob NS
    Eur J Pharmacol, 2016 Oct 15;789:8-16.
    PMID: 27377217 DOI: 10.1016/j.ejphar.2016.07.001
    Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer.
  19. Yam MF, Tan CS, Ahmad M, Shibao R
    Eur J Pharmacol, 2016 Oct 15;789:27-36.
    PMID: 27370961 DOI: 10.1016/j.ejphar.2016.06.047
    Previous studies demonstrated that eupatorin content in Orthosiphon stamineus fractions correlated with their vasorelaxation activity. Even with previous studies, there is still very little information on the vasorelaxation effect of eupatorin, and not many scientific studies had been carried out. Therefore, the present study was designed to investigate the vasorelaxation activity and mechanism of action of eupatorin. The vasorelaxation activity and the underlying mechanisms of eupatorin was evaluated on thoracic aortic rings isolated from Sprague Dawley rats. Eupatorin caused the relaxation of aortic rings pre-contracted with phenylephrine with and without endothelium (pD2=6.66±0.13, EMAX=99.72±6.39%; pD2=6.10±0.22, EMAX=65.78±8.01%), and also the relaxation of endothelium-intact aortic rings pre-contracted with potassium chloride (pD2=6.20±0.30, EMAX=71.89±12.25%). In the presence of Nω-nitro-l-arginine methyl ester (pD2<4.60, EMAX=24.91±6.39%), methylene blue (pD2=6.05±0.38, EMAX=66.79±9.69%), ODQ (pD25.84±0.32, EMAX=60.47±9.6%), indomethacin (pD2=6.27±0.21, EMAX=76.03±9.45%), tetraethylammonium (pD2=6.09±0.35, EMAX=69.35±11.31%), 4-aminopyridine (pD2=6.34±0.12, EMAX=76±6.1%), barium chloride (pD2=6.47±0.14, EMAX=79.61±10.02%), atropine (pD2=6.36±0.29, EMAX=86.47±12.95%) and propranolol (pD2=6.49±0.26, EMAX=83.2±12.01%), relaxation stimulated by eupatorin was significantly reduced. Eupatorin was also found to be active in reducing Ca(2+) release from sarcoplasmic reticulum and in blocking calcium channels. The present study demonstrates the vasorelaxation effect of eupatorin involving NO/sGC/cGMP and indomethacin pathways, calcium and potassium channels, and muscarinic and beta-adrenergic receptors.
  20. De Blasio MJ, Ramalingam A, Cao AH, Prakoso D, Ye JM, Pickering R, et al.
    Eur J Pharmacol, 2017 Jul 15;807:12-20.
    PMID: 28438648 DOI: 10.1016/j.ejphar.2017.04.026
    Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47phox), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGFβ1, TGFβ-R2, pSMAD3, α-SMA) and pro-inflammatory cytokines (TNFα, MCP-1, ANX-A1, FPR2) expression. In addition, the diabetes-induced renal ER stress, evidenced by increased expression of GRP-78 chaperone and stress-associated markers ATF4, TRB3, as well as XBP1s, phospho-p38 mitogen-activated protein kinase (MAPK) and 3-nitrotyrosination, were all attenuated by tempol and ramipril. These observations suggest that antioxidant approaches that blunt NADPH upregulation may attenuate diabetic nephropathy, at least in part by negatively regulating ER stress and inflammation, and hence ameliorating kidney damage.
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