morin and Hyperuricemia

Morin, one of the most widely distributed flavonoids in plants, has been identified as a potent antihyperuricemic agent. Its poor water solubility and fast in vivo clearance, however, have limited its application in the treatment of hyperuricemia. In this study, a novel amphiphilic polymer (hydroxyethyl starch-deoxycholic acid [HES-DOCA]) was synthesized to overcome these limitations.. The optimized HES-based amphiphilic polymer contained approximately 10 DOCA groups per 100 anhydroglucose units of HES, which can spontaneously self-assemble to form spherical NPs as demonstrated by TEM images. Morin/HES-DOCA-NPs were monodispersed (polydispersity index = 0.05) with a mean diameter of 197 nm and exhibited a zeta potential of -14 mV. The use of DOCA as the polymer's hydrophobic segment enabled high drug loading efficiency (15.6%). After systemic administration, Morin/HES-DOCA-NPs exhibited significantly longer half-life and higher systemic exposure (elimination half-life and area under the plasma concentration-time curve) compared with free drug Morin. In a rat hyperuricemic model, treatment with Morin/HES-DOCA-NPs demonstrated superior therapeutic efficacy over Morin in decreasing serum uric acid level, increasing the uricosuric action, as well as attenuating hyperuricemia-associated inflammation in kidney of rats.. Collectively, these findings suggest that the novel HES-based NP formulation of Morin may have great potential for clinical treatment of hyperuricemia.

Topics: Animals; Deoxycholic Acid; Drug Carriers; Drug Delivery Systems; Flavonoids; Hydrophobic and Hydrophilic Interactions; Hyperuricemia; Kidney; Male; Microscopy, Electron, Transmission; Nanoparticles; Rats, Wistar; Solubility; Starch; Uric Acid

Fructose induces insulin resistance with kidney inflammation and injury. MicroRNAs are emerged as key regulators of insulin signaling. Morin has insulin-mimetic effect with the improvement of insulin resistance and kidney injury. This study investigated the protective mechanisms of morin against fructose-induced kidney injury, with particular focus on miR-330 expression change, inflammatory response, and insulin signaling impairment.. miR-330, sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/S1P receptor (S1PR)1/3 signaling, nuclear factor-κB (NF-κB)/NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, and insulin signaling were detected in kidney cortex of fructose-fed rats and fructose-exposed HK-2 cells, respectively. Whether miR-330 mediated inflammatory response to affect insulin signaling was examined using SphK1 inhibitor, S1PR1/3 short interfering RNA, or miR-330 mimic/inhibitor, respectively. Fructose was found to downregulate miR-330 expression to increase SphK1/S1P/S1PR1/3 signaling, and then activate NF-κB/NLRP3 inflammasome to produce IL-1β, causing insulin signaling impairment. Moreover, morin upregulated miR-330 and partly attenuated inflammatory response and insulin signaling impairment to alleviate kidney injury.. These findings suggest that morin protects against fructose-induced kidney insulin signaling impairment by upregulating miR-330 to reduce inflammatory response. Morin may be a potential therapeutic agent for the treatment of kidney injury associated with fructose-induced inflammation and insulin signaling impairment.

Topics: Animals; Cell Line; Down-Regulation; Flavonoids; Fructose; Gene Expression Regulation; Humans; Hyperuricemia; Inflammasomes; Insulin; Kidney Tubules, Proximal; Male; MicroRNAs; Nephritis; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphotransferases (Alcohol Group Acceptor); Rats, Sprague-Dawley; Signal Transduction

This study aimed to compare the biodistribution and hypouricemic efficacy of morin and morin-phospholipid complex loaded self-nanoemulsifying drug delivery systems (MPC-SNEDDS), as well as to explore their therapeutic mechanisms.. We studied the biodistribution of morin and MPC-SNEDDS after they were orally administered to rats. The hypouricemic efficacy and the therapeutic mechanisms of morin and MPC-SNEDDS were evaluated using potassium oxonate-induced hyperuricemic model in rats.. With enhanced morin concentration in liver and kidney, oral delivery of MPC-SNEDDS exhibited significantly stronger urate-lowering effect in hyperuricemic rats than morin. The hypouricemic efficacy of morin was due to reduced production of uric acid via inhibiting the mRNA expression of hepatic xanthine dehydrogenase/xanthine oxidase (XDH/XO), as well as decreased urate reabsorption via modulating the alteration of mRNA levels of glucose transporter (mGLUT9), renal organic anion transporter 1 (mOAT1) and uric acid transporter (mURAT1). MPC-SNEDDS dually inhibited mRNA expression and activity of hepatic XDH/XO and restored the dysregulation of renal mGLUT9, mOAT1 and mURAT1, contributing to its superior urate-lowering efficacy.. The results demonstrated the great potential of MPC-SNEDDS as an alternative oral strategy for active agents in treating hyperuricemia.

Topics: Animals; Drug Delivery Systems; Flavonoids; Hyperuricemia; Kidney; Liver; Male; Nanostructures; Organic Anion Transporters; Phospholipids; Rats; Rats, Wistar; Tissue Distribution; Uric Acid

Morin (2′,3,4′,5,7-pentahydroxyflavone), a plant-derived flavonoid, has beneficial effects on hyperuricemia and renal dysfunction in animals. Since the decreased renal excretion of uric acid is the hallmark of hyperuricemia, here we studied the effects of oral morin administration on renal organic ion transporters in potassium oxonate-induced hyperuricemic mice.. Hyperuricemia in mice was induced by potassium oxonate. Uric acid and creatinine concentrations in urine and serum, and fractional excretion of uric acid (FEUA) were performed to evaluate renal urate handling. Changes in expression levels of renal organic ion transporters were detected by Western blotting and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) methods.. Morin treatment significantly increased urinary uric acid/creatinine ratio and FEUA, resulting in reduction of serum uric acid levels in hyperuricemic mice. And kidney conditions were also improved after morin treatment in this model. Protein and mRNA levels of glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) were significantly decreased, and of organic anion transporter 1 (mOAT1) were remarkably increased in the kidney of morin-treated hyperuricemic mice. Morin treatment also blocked down-regulations of renal organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2) in hyperuricemic mice.. These results suggest that morin exhibits the uricosuric effects via suppressing urate reabsorption and promoting urate secretion in the kidney of hyperuricemic mice and may help to attenuate deleterious effects of hyperuricemia with renal dysfunction.

Topics: Animals; Creatinine; Down-Regulation; Flavonoids; Glucose Transport Proteins, Facilitative; Hyperuricemia; Ion Transport; Kidney; Kidney Function Tests; Male; Mice; Organic Anion Transporters; Uric Acid; Urinary Tract Physiological Phenomena

Hyperuricemia is associated with a number of pathological conditions such as gout. Lowering of elevated uric acid level in the blood could be achieved by xanthine oxidase inhibitors and inhibitors of renal urate reabsorption. Some natural compounds isolated from herbs used in traditional Chinese medicine have been previously demonstrated to possess xanthine oxidase inhibitory activities. In the present investigation, morin (3,5,7,2',4'-pentahydroxyflavone), which occurs in the twigs of Morus alba L. documented in traditional Chinese medicinal literature to treat conditions akin to gout, was demonstrated to exert potent inhibitory action on urate uptake in rat renal brush-border membrane vesicles, indicating that this compound acts on the kidney to inhibit urate reabsorption. Lineweaver-Burk transformation of the inhibition kinetics data demonstrated that the inhibition of urate uptake was of a competitive type, with a K(i) value of 17.4 microM. In addition, morin was also demonstrated to be an inhibitor of xanthine oxidase. Lineweaver-Burk analysis of the enzyme kinetics indicated that the mode of inhibition was of a mixed type, with K(i) and K(ies) values being 7.9 and 35.1 microM, respectively. Using an oxonate-induced hyperuricemic rat model, morin was indeed shown to exhibit an in vivo uricosuric action, which could explain, in part at least, the observed hypouricemic effect of morin in these rats. The potential application of this compound in the treatment of conditions associated with hyperuricemia was discussed.

Topics: Alkaline Phosphatase; Animals; Antioxidants; Creatinine; Enzyme Inhibitors; Flavonoids; Hyperuricemia; In Vitro Techniques; Kidney; Kinetics; Male; Microvilli; Oxonic Acid; Rats; Rats, Sprague-Dawley; Uric Acid; Uricosuric Agents; Xanthine Oxidase