Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression.

BACKGROUND: Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (-)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood. PURPOSE: This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements. METHODS: Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo. RESULTS: Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro. CONCLUSIONS: These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.

A combination of ß-hydroxybutyrate and citrate ameliorates disease progression in a rat model of polycystic kidney disease.

Our research has shown that interventions producing a state of ketosis are highly effective in rat, mouse, and cat models of polycystic kidney disease (PKD), preventing and partially reversing cyst growth and disease progression. The ketone ß-hydroxybutyrate (BHB) appears to underlie this effect. In addition, we have demonstrated that naturally formed microcrystals within kidney tubules trigger a renoprotective response that facilitates tubular obstruction clearance in healthy animals but, alternatively, leads to cyst formation in PKD. The administration of citrate prevents microcrystal formation and slows PKD progression. Juvenile Cy/+ rats, a nonorthologous PKD model, were supplemented from 3 to 8 wk of age with water containing titrated BHB, citrate, or in combination to find minimal effective and optimal dosages, respectively. Adult rats were given a reduced BHB/citrate combination or equimolar control K/NaCl salts from 8 to 12 wk of age. In addition, adult rats were placed in metabolic cages following BHB, citrate, and BHB/citrate administration to determine the impact on mineral, creatinine, and citrate excretion. BHB or citrate alone effectively ameliorates disease progression in juvenile rats, decreasing markers of cystic disease and, in combination, producing a synergistic effect. BHB/citrate leads to partial disease regression in adult rats with established cystic disease, inhibiting cyst formation and kidney injury. BHB/citrate confers benefits via multiple mechanisms, increases creatinine and citrate excretion, and normalizes mineral excretion. BHB and citrate are widely available and generally recognized as safe compounds and, in combination, exhibit high promise for supporting kidney health in polycystic kidney disease.NEW & NOTEWORTHY Combining ß-hydroxybutyrate (BHB) and citrate effectively slows and prevents cyst formation and expansion in young Cy/+ rats using less BHB and citrate than when used alone, demonstrating synergy. In adult rats, the combination causes a partial reversal of existing disease, reducing cyst number and cystic area, preserving glomerular health, and decreasing markers of kidney injury. Our results suggest a safe and feasible strategy for supporting kidney health in polycystic kidney disease (PKD) using a combination of BHB and citrate.

Zinc citrate-coated whey protein nanoparticles alleviate kidney damage and the disturbances in inflammatory gene expression in rats.

This work was conducted to synthesize whey protein nanoparticles (WPNPs) for the coating of zinc citrate (Zn CITR) at three levels and to study their protective role against CCl4 -induced kidney damage and inflammatory gene expression disorder in rats. Seventy male Sprague-Dawley rats were divided into seven groups and treated orally for 4 weeks as follows; the control group, the group treated twice a week with CCl4 (5 mL/kg b.w), the groups received CCl4 plus WPNPs (300 mg/kg b.w); the group received 50 mg/kg b.w of Zn CITR or the three formulas of Zn CITR-WPNPs at low, medium and high doses (LD, MD, and HD). Blood and kidney samples were collected for different assays and histological analyses. The fabricated particles were semispherical, with an average size of 160 ± 2.7, 180 ± 3.1, and 200 ± 2.6 nm and ζ potential of -126, -93, and -84 mV for ZN CITR-WPNPs (LD), Zn CITR-WPNPs (MD), and ZN CITR-WPNPs (HD), respectively. CCl4 significantly increased (p ≤ 0.05) kidney function indices, oxidative stress markers, messenger RNA expression of transforming growth factor-ß1, interleukin (IL)-1ß, IL-10, IL-6, inducible nitric oxide synthase, and tumor necrosis factor-α and significantly decreased (p ≤ 0.05) renal superoxide dismutase, catalase, and glutathione peroxidase along with the histological changes in the kidney tissues. WPNPs, Zn CITR, and Zn CITR loaded WPNPS showed a protective effect against these complications and Zn CITR-WPNPs (LD) was more effective. WPNPs can be used effectively for coating Zn CITR at a level of 7 mg/g WPNPs to be used as a supplement for the protection of the kidney against different toxicants to enhance immunity and avoid harm of excess Zn.

Calcium-containing versus calcium-free replacement solution in regional citrate anticoagulation for continuous renal replacement therapy: a randomized controlled trial.

BACKGROUND: A simplified protocol for regional citrate anticoagulation (RCA) using a commercial calcium-containing replacement solution, without continuous calcium infusion, is more efficient for use in continuous renal replacement therapy (CRRT). We aim to design a randomized clinical trial to compare the safety and efficacy between calcium-free and calcium-containing replacement solutions in CRRT with RCA. METHODS: Of the 64 patients receiving RCA-based postdilution continuous venovenous hemodiafiltration (CVVHDF) enrolled from 2017 to 2019 in West China Hospital of Sichuan University, 35 patients were randomized to the calcium-containing group and 29 to the calcium-free replacement solution group. The primary endpoint was circuit lifespan and Kaplan-Meier survival analysis was performed. Secondary endpoints included hospital mortality, kidney function recovery rate, and complications. The amount of 4% trisodium citrate solution infusion was recorded. Serum and effluent total (tCa) and ionized (iCa) calcium concentrations were measured during CVVHDF. RESULTS: A total of 149 circuits (82 in the calcium-containing group and 67 in the calcium-free group) and 7609 circuit hours (4335 h vs. 3274 h) were included. The mean circuit lifespan was 58.1 h (95% CI 53.8-62.4 h) in the calcium-containing group vs. 55.3 h (95% CI 49.7-60.9 h, log rank P = 0.89) in the calcium-free group. The serum tCa and iCa concentrations were slightly lower in the calcium-containing group during CRRT, whereas the postfilter iCa concentration was lower in the calcium-free group. Moreover, the mean amounts of 4% trisodium citrate solution infusion were not significantly different between the groups (171.1 ±â€Š15.9 mL/h vs. 169.0 ±â€Š15.1 mL/h, P = 0.49). The mortality (14/35 [40%] vs. 13/29 [45%], P = 0.70) and kidney function recovery rates of AKI patients (19/26, 73% vs. 14/24, 58%, P = 0.27) were comparable between the calcium-containing and calcium-free group during hospitalization, respectively. Six (three in each group) patients showed signs of citrate accumulation in this study. CONCLUSIONS: When compared with calcium-free replacement solution, RCA-based CVVHDF with calcium-containing replacement solution had a similar circuit lifespan, hospital mortality and kidney outcome. Since the calcium-containing solution obviates the need for a separate venous catheter and a large dose of intravenous calcium solution preparation for continuous calcium supplementation, it is more convenient to be applied in RCA-CRRT practice. REGISTRATION: Chinese Clinical Trial Registry (www.chictr.org.cn, ChiCTR-IPR-17012629).

Renal lithiasis and inflammatory bowel diseases, an update on pediatric population.

BACKGROUND AND AIM OF THE WORK: Historical studies have demonstrated that the prevalence of symptomatic nephrolithiasis is higher in patients with inflammatory bowel disease (IBD), compared to general population. The aim of the review was to analyze literature data in order to identify the main risk conditions described in literature and the proposed treatment. METHODS: A research on the databases PubMed, Medline, Embase and Google Scholar was performed by using the keywords "renal calculi/lithiasis/stones" and "inflammatory bowel diseases". A research on textbooks of reference for Pediatric Nephrology was also performed, with focus on secondary forms of nephrolithiasis. RESULTS: Historical studies have demonstrated that the prevalence of symptomatic nephrolithiasis is higher in patients with inflammatory bowel disease (IBD), compared to general population, typically in patients who underwent extensive small bowel resection or in those with persistent severe small bowel inflammation. In IBD, kidney stones may arise from chronic inflammation, changes in intestinal absorption due to inflammation, surgery or intestinal malabsorption. Kidney stones are more closely associated with Crohn's Disease (CD) than Ulcerative Colitis (UC) in adult patients for multiple reasons: mainly for malabsorption, but in UC intestinal resection may be an additional risk. Nephrolithiasis is often under-diagnosed and might be a rare but noticeable extra-intestinal presentation of pediatric IBD. Secondary enteric hyperoxaluria the main risk factor of UL in IBD, this has been mainly studied in CD, whether in UC has not been completely explained. In the long course of CD recurrent urolithiasis and calcium-oxalate deposition may cause severe chronic interstitial nephritis and, as a consequence, chronic kidney disease. ESRD and systemic oxalosis often develop early, especially in those patients with multiple bowel resections. Even if we consider that many additional factors are present in IBD as hypomagnesuria, acidosis, hypocitraturia, and others, the secondary hyperoxaluria seems to finally have a central role. Some medications as parenteral vitamin D, long-term and high dose steroid treatment, sulfasalazine are reported as additional risk factors. Hydration status may also play an important role in this process. Intestinal surgery is a widely described independent risk factor. Patients with ileostomy post bowel resection may have relative dehydration from liquid stool, which, added to the acidic pH from bicarbonate loss, is responsible for this process. In this acidic pH, the urinary citrate level excretion reduces. The stones most commonly seen in these patients contain uric acid or are mixed. In addition, the risk of calcium containing stones also increases with ileostomy. The treatment of UL in IBD involves correction of the basic gastrointestinal tract inflammation, restricted dietary oxalate intake, and, at times, increased calcium intake. Citrate therapy that increases both urine pH and urinary citrate could also provide an additional therapeutic benefit. Finally, patients with IBD in a pediatric study had less urologic intervention for their calculosis compared with pediatric patients without IBD.

The CLOCK trial, a double-blinded randomized controlled trial: Trisodium citrate 30% and minocycline 3 mg/mL plus EDTA 30 mg/mL are effective and safe for catheter patency maintenance among CKD 5D patients on hemodialysis.

INTRODUCTION: Poor blood flow rate (PF) is highly prevalent among CKD 5D patients with long-term central venous catheters. Heparin catheter lock solutions are commonly used to maintain catheter patency, however the incidence of PF remains high. The purpose of the CLOCK Trial was to evaluate two catheter lock solutions on reduction of PF incidence. METHODS: Seventy-five CKD 5D patients on high-efficiency hemodialysis at the Integrated Centre of Nephrology (Guarulhos, Brazil) were randomized 1:1:1 to receive a lock solution combining minocycline 3 mg/mL with the anticoagulant/chelation agent EDTA 30 mg/mL (M-EDTA) or heparin 1000 IU/mL (H) or trisodium citrate 30% (TSC) vs. Hfor 15 weeks. A total of 68 patients completed the trial in which both investigators and patients were blinded to treatment allocation. The primary end-point was the occurrence of hydraulic resistance and secondary safety end-point was adverse drug reactions related to the lock solutions. FINDINGS: At the beginning of the trial, 7 patients were excluded from this trial due to their poor catheter care. The incidence of hydraulic resistance was significantly higher among patients on H (18/23) compared to TSC (4/22) and M-EDTA (2/23) lock solutions, (P < 0.001). DISCUSSION: The CLOCK Trial suggests TSC and M-EDTA may preserve catheter patency better than H. TSC may be a better option due the lack of association with long-term antimicrobial resistance.

Effects of Potassium Magnesium Citrate Supplementation on 24-Hour Ambulatory Blood Pressure and Oxidative Stress Marker in Prehypertensive and Hypertensive Subjects.

Diet rich in fruits, vegetables, and dairy products, known as the Dietary Approaches to Stop Hypertension (DASH) diet, is known to reduce blood pressure (BP) in hypertensive patients. More recently, the DASH diet was shown to reduce oxidative stress in hypertensive and nonhypertensive humans. However, the main nutritional components responsible for these beneficial effects of the DASH diet remain unknown. Because the DASH diet is rich in potassium (K), magnesium (Mg), and alkali, we performed a randomized, double-blinded, placebo-controlled study to compare effects of potassium magnesium citrate (KMgCit), potassium chloride (KCl), and potassium citrate (KCit) to allow dissociation of the three components of K, Mg, and citrate on 24-hour ambulatory BP and urinary 8-isoprostane in hypertensive and prehypertensive subjects, using a randomized crossover design. We found that KCl supplementation for 4 weeks induced a significant reduction in nighttime SBP compared with placebo (116 ± 12 vs 121 ± 15 mm Hg, respectively, p <0.01 vs placebo), whereas KMgCit and KCit had no significant effect in the same subjects (118 ± 11 and 119 ± 13 mm Hg, respectively, p >0.1 vs placebo). In contrast, urinary 8-isoprostane was significantly reduced with KMgCit powder compared with placebo (13.5 ± 5.7 vs 21.1 ± 10.5 ng/mgCr, respectively, p <0.001), whereas KCl and KCit had no effect (21.4 ± 9.1 and 18.3 ± 8.4, respectively, p >0.1 vs placebo). In conclusion, our study demonstrated differential effects of KCl and KMgCit supplementation on BP and the oxidative stress marker in prehypertensive and hypertensive subjects. Clinical significance of the antioxidative effect of KMgCit remains to be determined in future studies.

Effects of intraduodenal hydroxycitrate on glucose absorption, incretin release, and glycemia in response to intraduodenal glucose infusion in health and type 2 diabetes: A randomised controlled trial.

OBJECTIVE: Hydroxycitric acid (HCA), derived from the fruit Garcinia cambogia, reduces the rate of glucose absorption and lowers postprandial glycemia in rodents, but its effect in humans is unknown. The aim of this study was to investigate the effects of small intestinal perfusion with HCA on glucose absorption, as well as the incretin and glycemic responses to a subsequent intraduodenal glucose infusion, in both healthy individuals and patients with type 2 diabetes. METHODS: Twelve healthy participants and 8 patients with type 2 diabetes received an intraduodenal infusion of HCA (2800 mg in water) or control (water) over 60 min, followed by an intraduodenal infusion of 60 g glucose over 120 min, in a double-blind, randomized crossover design. In healthy individuals, 5 g 3-O-methylglucose (3-OMG) was co-infused with glucose as a marker of glucose absorption. Blood was sampled frequently. RESULTS: In healthy individuals, blood glucose was lower with HCA than control, both before and during the intraduodenal glucose infusion (P < 0.05 for each). Plasma glucose-dependent insulinotropic polypeptide (GIP; P = 0.01) and glucagon (P = 0.06) were higher with HCA, but there were no differences in plasma glucagon-like peptide (GLP)-1, insulin, or serum 3-OMG concentrations. In patients with type 2 diabetes, blood glucose, and plasma GIP, GLP-1, and insulin did not differ between HCA and control either before or after intraduodenal glucose, but during glucose infusion, plasma glucagon was higher with HCA (P = 0.04). CONCLUSION: In healthy individuals, small intestinal exposure to HCA resulted in a modest reduction in glycemia and stimulation of plasma GIP and glucagon, but no effect on plasma GLP-1 or insulin, or on glucose absorption. HCA had no effect on glycemia in patients with type 2 diabetes.

Prevention of renal stone disease recurrence. A systematic review of contemporary pharmaceutical options.

INTRODUCTION: Renal stone disease has a high recurrence rate. Prompt metabolic evaluation followed by appropriate medical management is of paramount importance for preventing disease recurrence. AREAS COVERED: A PubMed/Medline search was performed to identify randomized controlled studies evaluating medical treatments against renal stone recurrence. Due to the limited number of published randomized studies, non-randomized studies of significant importance were included and reported. EXPERT OPINION: Thiazides are widely used for lowering calcium levels in urine and thus preventing calcium stone formation. Citrate supplements may increase the urine citrate level and increase pH. Allopurinol has shown significant efficacy for preventing formation of calcium stones in hyperuricosuric patients. Prevention of recurrence of infection stones and cystine stones has not been widely studied. Several agents that are used today have shown efficacy outside randomized controlled studies. However, they may produce severe adverse events, which are minimizing their use.

Systematic review of stimulant and nonstimulant laxatives for the treatment of functional constipation.

BACKGROUND: Constipation is an uncomfortable and common condition that affects many, irrespective of age. Since 1500 BC and before, health care practitioners have provided treatments and prevention strategies to patients for chronic constipation despite the significant variation in both medical and personal perceptions of the condition. OBJECTIVE: To review relevant research evidence from clinical studies investigating the efficacy and safety of commercially available pharmacological laxatives in Canada, with emphasis on studies adopting the Rome criteria for defining functional constipation. SEARCH METHODS: PubMed, Medline, Embase and Evidence-Based Medicine Reviews databases were searched for blinded or randomized clinical trials and meta-analyses assessing the efficacy of nonstimulant and stimulant laxatives for the treatment of functional constipation. RESULTS: A total of 19 clinical studies and four meta-analyses were retrieved and abstracted regarding study design, participants, interventions and outcomes. The majority of studies focused on polyethylene glycol compared with placebo. Both nonstimulant and stimulant laxatives provided better relief of constipation symptoms than placebo according to both objective and subjective measures. Only one study compared the efficacy of a nonstimulant versus a stimulant laxative, while only two reported changes in quality of life. All studies reported minor side effects due to laxative use, regardless of treatment duration, which ranged from one week to one year. Laxatives were well tolerated by both adults and children.

[Urinary calculi and infection]. / Calcolosi urinaria e infezione.

Infection urinary stones resulting from urease-producing bacteria are composed by struvite and/or carbonate apatite. Bacterial urease splits urea and promotes the formation of ammonia and carbon dioxide leading to urine alkalinization and formation of phosphate salts. Proteus species are urease-producers, whereas a limited number of strains of other Gram negative and positive species may produce urease. Ureaplasma urealyticum and Corynebacterium urealyticum are urease-producers that are not isolated by conventional urine cultures, but require specific tests for identification. Primary treatment requires surgical removal of stones as complete as possible. Extracorporeal and endoscopic treatments are usually preferred, while open surgery is actually limited to few selected cases. Residual stones or fragments should be treated by chemolysis via ureteral catheter or nephrostomy or administration of citrate salts in order to achieve a stone-free renal unit. Postoperatively, recurrent urinary tract infection should be treated with appropriate antibiotic treatment although long-term antibiotic prophylaxis can cause resistance. Urinary acidification has been proposed for the prophylaxis of infection stones, but long-term acidification is difficult to achieve in urine infected by urease-producing bacteria. Urease inhibitors lead to prevention and/or dissolution of stones and encrustations in patients with infection by urea-splitting bacteria, but their use is limited by their toxicity. The administration of citrate salts involves an increase of the value of nucleation pH (pHn), that is the pH value at which calcium and magnesium phosphate crystallization occurs, in a greater way than the corresponding increase in the urinary pH due to its alkalinizing effect and resulting in a reduction of the risk of struvite crystallization. In conclusion prevention of the recurrence of infection stones can be achieved by an integrated approach tailored on the single patient. Complete clearance of the stone must be achieved by primary surgical procedure and residual fragments should be extensively treated. In the case of persistent infection, conservative measures, such as acidification and urease inhibitors or citrate administration, should be adopted to minimize its effect on urinary saturation with respect to struvite.

Continuous veno-venous hemofiltration using a phosphate-containing replacement fluid in the setting of regional citrate anticoagulation.

PURPOSE: The need for prolonged anticoagulation and the occurrence of hypophosphatemia are well known drawbacks of continuous renal replacement therapies (CRRT). The aim was to evaluate the effects on acid-base status and serum phosphate of a regional citrate anticoagulation (RCA) protocol for continuous veno-venous hemofiltration (CVVH) combining the use of citrate with a phosphate-containing replacement fluid. METHODS: In a small cohort of heart surgery patients undergoing CRRT for acute kidney injury, we adopted an RCA-CVVH protocol based on a commercially available citrate solution (18 mmol/l) combined with a recently introduced phosphate-containing replacement fluid (HCO3 -30 mmol/l, phosphate 1.2), aimed at preventing phosphate depletion. RESULTS: In 10 high bleeding-risk patients, the RCA-CVVH protocol provided an adequate circuit lifetime (46.8 ± 30.3 h) despite the adoption of a low citrate dose and a higher than usual target circuit Ca2+ (≤0.5 mmol/l). Acid-base status was adequately maintained without the need for additional interventions on RCA-CVVH parameters and without indirect sign of citrate accumulation [(pH 7.43 (7.41-7.47), bicarbonate 24.4 mmol/l (23.2-25.6), BE 0 (-1.5 to 1.1), calcium ratio 1.97 (1.82-2.01); median (IQR)]. Serum phosphate was steadily maintained in a narrow range throughout RCA-CVVH days [1.1 mmol/l (0.9-1.4)]. A low amount of phosphorus supplementation (0.9 ± 2 g/day) was required in only 30% of patients. CONCLUSIONS: Although needing further evaluation, the proposed RCA-CVVH protocol ensured a safe and effective RCA without electrolyte and/or acid-base derangements. CRRT-induced hypophosphatemia was prevented in most of the patients by the adoption of a phosphate-containing replacement solution, minimizing phosphate supplementation needs.

Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin.

Cellular metabolic alterations are now well described as implicated in cancer and some strategies are currently developed to target these different pathways. In previous papers, we demonstrated that a combination of molecules (namely alpha-lipoic acid and hydroxycitrate, i.e. Metabloc™) targeting the cancer metabolism markedly decreased tumor cell growth in mice. In this work, we demonstrate that the addition of capsaicin further delays tumor growth in mice in a dose dependant manner. This is true for the three animal model tested: lung (LLC) cancer, bladder cancer (MBT-2) and melanoma B16F10. There was no apparent side effect of this ternary combination. The addition of a fourth drug (octreotide) is even more effective resulting in tumor regression in mice bearing LLC cancer. These four compounds are all known to target the cellular metabolism not its DNA. The efficacy, the apparent lack of toxicity, the long clinical track records of these medications in human medicine, all points toward the need for a clinical trial. The dramatic efficacy of treatment suggests that cancer may simply be a disease of dysregulated cellular metabolism.

Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia extracts in humans.

Several studies have shown that Garcinia cambogia plays an important role in the regulation of endogenous lipid biosynthesis. This effect is specially attributed to (-)-hydroxycitric acid (HCA) inhibiting the enzyme ATP-dependent citrate lyase, which catalyzes the cleavage of citrate to oxaloacetate and acetyl-CoA. Although several studies have found that the administration of G. cambogia extracts is associated with body weight and fat loss in both experimental animals and humans, we should be cautious when interpreting the results as other randomized, placebo-controlled clinical trials have not reported the same outcomes. Furthermore, most studies in humans have been conducted on small samples and mainly in the short term. None of them have shown whether these effects persist beyond 12 weeks of intervention. Therefore, there is still little evidence to support the potential effectiveness and long-term benefits of G. cambogia extracts. With regard to toxicity and safety, it is important to note that except in rare cases, studies conducted in experimental animals have not reported increased mortality or significant toxicity. Furthermore, at the doses usually administered, no differences have been reported in terms of side effects or adverse events (those studied) in humans between individuals treated with G. cambogia and controls.

[Pharmacotherapy for preventing calcium containing stone formation].

Many urinary tract stones consist of calcium, and has high relapse rate. Accordingly, it is very important to prevent calcium-containing stone formation. This paper describes about effects and mechanisms for Xanthine oxidase inhibitor, citrate formulation, magnesium formulation, thiazides, vitamin B(6), extract of Quercus salicina Blume and chorei-to (medical herb) . Recent new drugs and the elucidation of new metabolic pathways may lead to the development of prevention of urolithiasis.

Anti-diabetic properties of chromium citrate complex in alloxan-induced diabetic rats.

The chromium citrate complex [CrCIT] was synthesized and its structure was determined by infrared, UV-visible and atomic absorption spectroscopy, elemental and thermodynamic analysis. Anti-diabetic activity, oxidative DNA damage capacity and acute oral toxicity of [CrCIT] were investigated and compared with that of chromium trichloride hexahydrate. [CrCIT] was synthesized in a single step reaction by chelating chromium(III) with citric acid in aqueous solution. The molecular formula of [CrCIT] was inferred as CrC(6)H(5)O(7)·4H(2)O. The anti-diabetic activity of the complex [CrCIT] was assessed in alloxan-diabetic rats by daily oral gavage for 3 weeks. The biological activity results showed that the complex at the dose of 0.25-0.75 mg Cr/kg body weight could decrease the blood glucose level and increase liver glycogen level in alloxan-diabetic rats. [CrCIT] had more beneficial influences on the improvement of controlling blood glucose, serum lipid and liver glycogen levels compared with CrCl(3)·6H(2)O. Furthermore, [CrCIT] did not cause oxidative DNA damage under physiologically relevant conditions, and [CrCIT] did not produce any hazardous symptoms or deaths in acute oral toxicity test, showing the LD(50) value for female and male rats were higher than 15.1 g/kg body weight. The results suggested that [CrCIT] might represent a novel and proper chromium supplement with potential therapeutic value to control blood glucose in diabetes.

The astrocyte-targeted therapy by Bushi for the neuropathic pain in mice.

BACKGROUND: There is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required. METHODS/PRINCIPAL FINDINGS: Using Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an "early induction phase" and subsequent "late maintenance phase". We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1ß- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro. CONCLUSIONS: Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, therefore, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain.

Therapeutic effects of potassium sodium hydrogen citrate on melamine-induced urinary calculi in China.

BACKGROUND: In 2008, a sharp increase of the number of children diagnosed with urinary calculi was observed in China, 9433 children were diagnosed as having melamine-induced urinary calculi at outpatient clinic in Beijing Children's Hospital. This study examined the therapeutic efficacy of potassium sodium hydrogen citrate (PSHC) used to treat melamine-induced urinary stones in Chinese children who consumed melamine-containing infant formula. METHODS: Seventy-two infants and children (average age (18.2 +/- 7.7) months) who were diagnosed with urinary calculi were randomly divided into three treatment groups using the SAS Plan program. Group 1 was given a low dose (1 g/d) of PSHC, group 2 was given high dose of PSHC (2 g/d) and group 3 was given no PSHC (control group). The dose of drug was adjusted according to the baseline urinary pH. This study analyzed the influence of the dose of PSHC, the age of patients, stone size and position, and urinary pH on the level of efficacy of PSHC (cured, effectively treated or not cured). RESULTS: After 1 - 6 months of therapy, 19 patients from group 1, five patients from group 2 and six patients from group 3 were cured. Five patients from group 1, five patients from group 2 and four patients from group 3 were effectively treated. There were significant differences in therapeutic efficacy between the two treatment doses after 3 and 6 months as measured by the increase in the successful expulsion rate and time of melamine-induced urinary calculi. After 6 months the mean time of expulsion of urinary calculi in groups 1 and 2 was significantly shorter than in the control group. CONCLUSIONS: PSHC can significantly increase the successful expulsion rate and time of melamine-induced urinary calculi. The therapeutic efficacy is affected by PSHC dose, treatment duration, calculi position, and urinary pH. There is no relationship between the therapeutic efficacy and the stone size or patient age.

Influence of root-surface conditioning with acid and chelating agents on clot stabilization.

OBJECTIVE: To compare the adhesion and maturation of blood components on chemically conditioned root surfaces. METHOD AND MATERIALS: Clinical root samples of human teeth were obtained (n = 150) and manually scaled. Five groups of 30 samples were treated as follows: (1) saline solution irrigation (control); (2) 24% EDTA gel; (3) 25% citric acid solution; (4) tetracycline solution (50 mg/mL); and (5) 30% sodium citrate solution. After these treatments, 15 samples of each group received a blood drop and were analyzed by SEM. The remaining 15 had their surface morphology evaluated for collagen fibrils exposure by SEM. Photomicrographs were analyzed according to the score of adhesion of blood components. Kruskal-Wallis and Dunn multiple comparison tests were employed. RESULTS: The control group was characterized by the absence of blood elements on the surface. The best result was observed in the citric acid group, which had a dense fibrin network with blood elements adhered. The EDTA group showed a moderate fibrin network formation. In contrast, a scarce fibrin network and a few cells were present in the tetracycline samples, and an absence of blood elements was found on sodium citrate specimens. The citric acid group was statistically different from the control group (P < .01). No differences were found among the control, EDTA, tetracycline, and sodium citrate groups (P > .05). CONCLUSION: Under these experimental conditions, citric acid is indicated to stabilize clots on the root surface, which act as a scaffold for connective tissue cell development.