Clinical and Experimental Pharmacology and Physiology
1440-1681
0305-1870
Anh Quốc
Cơ quản chủ quản: Wiley-Blackwell Publishing Ltd , WILEY
Lĩnh vực:
PharmacologyPhysiologyPhysiology (medical)
Các bài báo tiêu biểu
Discovery of curcumin, a component of golden spice, and its miraculous biological activities Summary 1. Curcumin is the active ingredient of the dietary spice turmeric and has been consumed for medicinal purposes for thousands of years. Modern science has shown that curcumin modulates various signalling molecules, including inflammatory molecules, transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion molecules, growth factors, receptors, cell cycle regulatory proteins, chemokines, DNA, RNA and metal ions. 2. Because of this polyphenol’s potential to modulate multiple signalling molecules, it has been reported to possess pleiotropic activities. First demonstrated to have antibacterial activity in 1949, curcumin has since been shown to have anti‐inflammatory, anti‐oxidant, pro‐apoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic and antimalarial properties as well. Animal studies have suggested that curcumin may be active against a wide range of human diseases, including diabetes, obesity, neurological and psychiatric disorders and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys and gastrointestinal and cardiovascular systems. 3. Although many clinical trials evaluating the safety and efficacy of curcumin against human ailments have already been completed, others are still ongoing. Moreover, curcumin is used as a supplement in several countries, including India, Japan, the US, Thailand, China, Korea, Turkey, South Africa, Nepal and Pakistan. Although inexpensive, apparently well tolerated and potentially active, curcumin has not been approved for the treatment of any human disease. 4. In the present article, we discuss the discovery and key biological activities of curcumin, with a particular emphasis on its activities at the molecular and cellular levels, as well as in animals and humans.
Tập 39 Số 3 - Trang 283-299 - 2012
Curcumin‐loaded poly(ε‐caprolactone) nanofibres: Diabetic wound dressing with anti‐oxidant and anti‐inflammatory properties Summary
Curcumin is a naturally occurring poly‐phenolic compound with a broad range of favourable biological functions, including anti‐cancer, anti‐oxidant and anti‐inflammatory activities. The low bioavailability and in vivo stability of curcumin require the development of suitable carrier vehicles to deliver the molecule in a sustained manner at therapeutic levels. In the present study, we investigated the feasibility and potential of poly(caprolactone) (PCL) nanofibres as a delivery vehicle for curcumin for wound healing applications. By optimizing the electrospinning parameters, bead‐free curcumin‐loaded PCL nanofibres were developed. The fibres showed sustained release of curcumin for 72 h and could be made to deliver a dose much lower than the reported cytotoxic concentration while remaining bioactive. Human foreskin fibroblast cells (HFF‐1) showed more than 70% viability on curcumin‐loaded nanofibres. The anti‐oxidant activity of curcumin‐loaded nanofibres was demonstrated using an oxygen radical absorbance capacity (ORAC) assay and by the ability of the fibres to maintain the viability of HFF‐1 cells under conditions of oxidative stress. The curcumin‐loaded nanofibres also reduced inflammatory induction, as evidenced by low levels of interleukin‐6 release from mouse monocyte–macrophages seeded onto the fibres following stimulation by Escherichia coli ‐derived lipopolysaccharide. The in vivo wound healing capability of the curcumin loaded PCL nanofibres was demonstrated by an increased rate of wound closure in a streptozotocin‐induced diabetic mice model. These results demonstrate that the curcumin‐loaded PCL nanofibre matrix is bioactive and has potential as a wound dressing with anti‐oxidant and anti‐inflammatory properties.
Tập 36 Số 12 - Trang 1149-1156 - 2009
ANTISENSE OLIGONUCLEOTIDES: FROM DESIGN TO THERAPEUTIC APPLICATION
Tập 33 Số 5-6 - Trang 533-540 - 2006
CURCUMIN, THE ACTIVE PRINCIPLE OF TURMERIC (<i>CURCUMA LONGA</i>), AMELIORATES DIABETIC NEPHROPATHY IN RATS SUMMARY
Chronic hyperglycaemia in diabetes leads to the overproduction of free radicals and evidence is increasing that these contribute to the development of diabetic nephropathy. Among the spices, turmeric (Curcuma longa ) is used as a flavouring and colouring agent in the indian diet every day and is known to possess anti‐oxidant properties. The present study was designed to examine the effect of curcumin, a yellow pigment of turmeric, on renal function and oxidative stress in streptozotocin (STZ)‐induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. Four weeks after STZ injection, rats were divided into four groups, namely control rats, diabetic rats and diabetic rats treated with curcumin (15 and 30 mg/kg, p.o.) for 2 weeks. Renal function was assessed by creatinine, blood urea nitrogen, creatinine and urea clearance and urine albumin excretion. Oxidative stress was measured by renal malonaldehyde, reduced glutathione and the anti‐oxidant enzymes superoxide dismutase and catalase. Streptozotocin‐injected rats showed significant increases in blood glucose, polyuria and a decrease in bodyweight compared with age‐matched control rats. After 6 weeks, diabetic rats also exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance and proteinuria, along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti‐oxidant enzymes. Chronic treatment with curcumin significantly attenuated both renal dysfunction and oxidative stress in diabetic rats. These results provide confirmatory evidence of oxidative stress in diabetic nephropathy and point towards the possible anti‐oxidative mechanism being responsible for the nephroprotective action of curcumin.
Tập 33 Số 10 - Trang 940-945 - 2006
MicroRNA‐320 EXPRESSION IN MYOCARDIAL MICROVASCULAR ENDOTHELIAL CELLS AND ITS RELATIONSHIP WITH INSULIN‐LIKE GROWTH FACTOR‐1 IN TYPE 2 DIABETIC RATS SUMMARY
The aim of the present study was to determine the role of myocardial microvascular endothelial cells (MMVEC) in impaired angiogenesis of type 2 diabetic Goto‐Kakizaki (GK) rats. A microRNA (miRNA) microarray was used to assess miRNA expression in MMVEC from GK and Wistar rats. Upregulation of miRNA‐320 was observed in MMVEC from GK rats using real‐time reverse transcription–polymerase chain reaction (RT‐PCR). So far, nine miRNAs have been reported to target angiogenic factors and/or receptors, including kinase insert domain containing receptor (Flk‐1), insulin‐like growth factor 1 (IGF‐1) and insulin‐like growth factor 1 receptor (IGF‐1R). The predicted genes targeted by miR‐320 include Flk‐1, IGF‐1 and IGF‐1R. Western blot analysis and RT‐PCR were used to analyse the protein and mRNA expression, respectively, of the putative genes IGF‐1 and IGF‐1R. The expression of IGF‐1 and IGF‐1R proteins decreased significantly in diabetic MMVEC. However, the expression of IGF‐1 mRNA increased rather than decreased. The mRNA expression of IGF‐1R did not differ significantly between diabetic and control MMVEC. Transfection of an miR‐320 inhibitor into MMVEC from GK rats confirmed that miR‐320 impaired angiogenesis. The proliferation and migration of diabetic MMVEC improved after transfection of the miR‐320 inhibitor. In addition, the miR‐320 inhibitor significantly increased the expression of IGF‐1 protein, but had no effect on the expression of IGF‐1R. Eleven miRNAs were upregulated in MMVEC from GK rats compared with those in Wistar rats: let‐7e , miR‐129 , miR‐291‐5p , miR‐320 , miR‐327 , mir‐333 , miR‐363–5p , miR‐370 , miR‐494 , miR‐503 and miR‐664 . The results indicate that upregulation of miR‐320 in MMVEC from GK rats may be responsible for the inconsistency between the expression of IGF‐1 protein and mRNA and therefore related to impaired angiogenesis in diabetes. Transfection of an miR‐320 inhibitor may be a therapeutic approach for the treatment of impaired angiogenesis in diabetes.
Tập 36 Số 2 - Trang 181-188 - 2009
Fibroblast Growth Factors In The Developing Central Nervous System SUMMARY 1. It is now clear that members of the fibroblast growth factor (FGF) family have multiple roles during the formation of the central nervous system (CNS). 2. There are at least 23 members of the FGF family and, of these, 10 are expressed in the developing CNS, along with four FGF receptors (FGFR‐1–4). 3. The present review discusses the roles of these FGFs, with emphasis on FGF‐2, FGF‐8, FGF‐15 and FGF‐17. Fibroblast growth factors‐2 and ‐15 are generally expressed throughout the developing CNS, whereas FGF‐8 and FGF‐17 are tightly localized to specific regions of the developing brain and are only expressed in the embryo during the early phases of proliferation and neurogenesis. 4. Expression studies on FGFRs in the chick and mouse indicate that FGFR‐1 is most generally expressed, whereas FGFR‐2 and FGFR‐3 show highly localized but changing patterns of expression throughout CNS development. The FGFR‐4 has been localized to the developing CNS in fish but not at a detailed level, as yet, in chick or mouse. 5. A picture is emerging from these studies that particular FGFs signal through specific receptors in a highly localized manner to regulate the development of different regions of the brain. 6. This picture has been demonstrated so far for the developing cortex (FGF‐2–/– mice), the forebrain and midbrain (FGF‐8 hypomorphs) and the cerebellum (FGF‐17/FGF‐8 mutant mice). In addition, generation of mutant animals deleted for FGFR‐1 and FGFR‐2b IIIb demonstrate their importance in FGF signalling. 7. However, there are significant gaps in our knowledge of the localization of members of the FGF family and their receptors. More detailed information on the spatio‐temporal mapping of FGFs and FGFR isoforms is required in order to understand the molecular mechanisms through which FGFs signal.
Tập 28 Số 7 - Trang 493-503 - 2001
STRUCTURE AND FUNCTION OF URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASES SUMMARY 1. The uridine diphosphate (UDP)‐glucuronosyltransferases (UGT) are a family of enzymes that catalyse the covalent addition of glucuronic acid to a wide range of lipophilic chemicals. They play a major role in the detoxification of many exogenous and endogenous compounds by generating products that are more polar and, thus, more readily excreted in bile or urine. 2. Inherited deficiencies in UGT forms are deleterious, as exemplified by the debilitating effects of hyperbilirubinaemia and neurotoxicity in subjects with mutations in the enzyme that converts bilirubin to its more pola. glucuronide. 3. The UGT protein can be conceptually divided into two domains with the amino‐terminal half of the protein demonstrating greater sequence divergence between isoforms. This region apparently determines aglycone specificity. The aglycone binding site is presumed to be a ‘loose’ fit, as many structurally diverse substrates can be bound by the same UGT isoform. The carboxyl‐terminal half, which is more conserved in sequence between different isoforms, is believed to contain a binding site for the cosubstrate UDP glucuronic acid (UDPGA). 4. Uridine diphosphat. glucuronosyltransfera.se is localized to the endoplasmic reticulum (ER) and spans the membrane with a type I topology. The putative transmembrane domain is located near the carboxyl terminus of the protein such that only a small portion of the protein resides in the cytosol. This cytosolic tail is believed to contain an ER‐targeting signal. The major portion of the protein is located in the ER lumen, including the proposed substrate‐binding domains and the catalytic site. 5. The microsomal membrane impedes the access of UDPGA to the active site, resulting in latency of UGT activity in intact ER‐derived microsomes. Active transport of UDPGA is believed to occur in hepatocytes, but the transport system has not been fully characterized. Uridine diphosphate glucuronosyltransfer‐ase activity is also highly lipid dependent and the enzyme may contain regions of membrane association in addition to the transmembrane domain.
Tập 24 Số 12 - Trang 907-915 - 1997
A Short History Of Nitroglycerine And Nitric Oxide In Pharmacology And Physiology SUMMARY 1. Nitroglycerine (NG) was discovered in 1847 by Ascanio Sobrero in Turin, following work with Theophile‐Jules Pelouze. Sobrero first noted the ‘violent headache’ produced by minute quantities of NG on the tongue. 2. Constantin Hering, in 1849, tested NG in healthy volunteers, observing that headache was caused with ‘such precision’. Hering pursued NG (‘glonoine’) as a homeopathic remedy for headache, believing that its use fell within the doctrine of ‘like cures like’. 3. Alfred Nobel joined Pelouze in 1851 and recognized the potential of NG. He began manufacturing NG in Sweden, overcoming handling problems with his patent detonator. Nobel suffered acutely from angina and was later to refuse NG as a treatment. 4. During the mid‐19th century, scientists in Britain took an interest in the newly discovered amyl nitrite, recognized as a powerful vasodilator. Lauder Brunton, the father of modern pharmacology, used the compound to relieve angina in 1867, noting the pharmacological resistance to repeated doses. 5. William Murrell first used NG for angina in 1876, although NG entered the British Pharmacopoeia as a remedy for hypertension. William Martindale, the pharmaceutical chemist, prepared ‘. . . a more stable and portable preparation’: 1/100th of a grain in chocolate. 6. In the early 20th century, scientists worked on in vitro actions of nitrate‐containing compounds although little progress was made towards understanding the cellular mode of action. 7. The NG industry flourished from 1900, exposing workers to high levels of organic nitrites; the phenomena of nitrate tolerance was recognized by the onset of ‘Monday disease’ and of nitrate‐withdrawal/overcompensation by ‘Sunday Heart Attacks’. 8. Ferid Murad discovered the release of nitric oxide (NO) from NG and its action on vascular smooth muscle (in 1977). Robert Furchgott and John Zawadski recognized the importance of the endothelium in acetylcholine‐induced vasorelaxation (in 1980) and Louis Ignarro and Salvador Moncada identified endothelial‐derived relaxing factor (EDRF) as NO (in 1987). 9. Glycerol trinitrate remains the treatment of choice for relieving angina; other organic esters and inorganic nitrates are also used, but the rapid action of NG and its established efficacy make it the mainstay of angina pectoris relief.
Tập 27 Số 4 - Trang 313-319 - 2000
Proceedings of the Australian Physiological and Pharmacological Society Symposium: The Hypothalamus HYPOTHALAMIC PARAVENTRICULAR NUCLEUS AND CARDIOVASCULAR REGULATION SUMMARY 1. The hypothalamic paraventricular nucleus (PVN) is an important integrative site within the brain composed of magnocellular and parvocellular neurons. It is known to influence sympathetic nerve activity. 2. The parvocellular PVN contains neurons that project to the intermediolateral cell column of the thoraco–lumbar spinal cord (IML). This defines the PVN as an autonomic ‘premotor nucleus’, one of only five present within the brain. 3. Another projection arising from the PVN is a prominent innervation of the pressor region of the rostral ventrolateral medulla (RVLM), also a premotor nucleus. The distribution of the PVN neurons projecting to the RVLM is similar to that of the PVN neurons that project to the IML. 4. It has been found that up to 30% of spinally projecting neurons in the PVN also send collaterals to the RVLM. Thus, there are neurons in the PVN that can: (i) directly influence sympathetic nerve activity (via PVN–IML connections); (ii) indirectly influence sympathetic nerve activity (via PVN–RVLM connections); and (iii) both directly and indirectly influence sympathetic nerve activity (via neurons with collaterals to the IML and RVLM). 5. In the rat, results of studies using the protein Fos to identify activated neurons in the brain suggest that neurons in the PVN with projections to the IML or RVLM may be activated by decreases in blood volume. 6. In conclusion, the PVN can influence sympathetic nerve activity. Within the PVN are neurons with anatomical connections that enable them to affect sympathetic nerve activity either directly, indirectly or via both mechanisms (via collaterals). Studies that have examined the role of specific subgroups within the PVN suggest that PVN neurons with connections to the IML or to the RVLM may play a role in the reflex changes in sympathetic nerve activity that are involved in blood volume regulation.
Tập 28 Số 1-2 - Trang 95-99 - 2001
Pathological responses of rat skeletal muscle to a single subcutaneous injection of a toxin isolated from the venom of the Australian tiger snake, <i>Notechis scutatus scutatus</i> SUMMARY 1. The pathology of mammalian skeletal muscle following a single subcutaneous injection of a purified toxin from the venom of the Australian tiger snake, Notechis scutatus scutatus , has been investigated. 2. The toxin was injected into the antero‐lateral aspect of one hind limb of rats and the effects of the injection on the histology, histo‐chemistry and physiology of the extensor digitorum longus muscles were studied. 3. The muscles underwent degenerative necrosis, with oedema and the infiltration of lymphocytes, polymorphs and macrophages within 12–24 h after the injection. 4. Three days after injection, the oedema had subsided and the necrotic fibres had been completely destroyed by phagocytes. Small uninucleate cells, with basophilic cytoplasm and vesicular nuclei were present at this stage; on the basis of these criteria they were identified as regenerating myoblasts. 5. By 5 days the myoblasts had fused to form myotubes, but differentiation of the myotubes into histochemically distinct muscle fibre types did not commence until around 7 days after the injection. 6. Regeneration and differentiation was virtually complete by 21 days after injection. 7. Between 3 and 5 days, many of the fibres were sensitive to acetylcholine, and muscle fibre action potentials were resistant to tetrodotoxin. Miniature end‐plate potentials were of low amplitude and frequency; they may have been absent from many fibres. 8. By 7–10 days, the proportion of fibres with tetrodotoxin‐resistant action potentials was declining, and acetylcholine sensitivity was less marked; miniature end‐plate potentials, though of normal amplitude, were of reduced frequency. The fibres were virtually normal by 14–21 days. 9. It is considered likely that these physiological properties were recorded from regenerating muscle fibres that reached maturity by 28 days; the possibility that they were recorded from functionally denervated fibres is discussed. 10. The rapid rate of regeneration and differentiation of the toxin‐damaged muscle was sustained only if the peripheral nerve supply was left intact. 11. Preliminary results suggested that mitochondria‐rich fibres were preferentially damaged by the toxin, and that the toxin is less active in vitro than in vivo. These problems are currently being investigated. 12. It is concluded that the toxin has a direct myotoxic effect on muscles; the relationship of this effect to the previously described neurotoxic effect is also currently under investigation.
Tập 2 Số 5 - Trang 383-404 - 1975