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Bisphosphonates are considered an effective inhibitor of glutamine synthetase and thus can be used for treating tuberculosis (TB). However, its clinical benefit in TB remains unknown. We conducted a population-based cohort study by using the Taiwan National Health Insurance Research Database and TB databases of the Taiwan Centers for Disease Control. Patients with osteoporosis and a history of bone fracture from 2007 to 2014 were identified. Among them, bisphosphonate users and propensity score-matched nonusers were selected. A stratified multivariable Cox proportional hazard regression model was employed to investigate the independent predictors of TB. Among 218 908 patients with osteoporosis and bone fracture, 46 842 bisphosphonate users and 46 842 propensity score-matched nonusers were selected. Within the 2-year follow-up, 723 patients-348 in the user group and 375 in the nonuser group-developed TB. Bisphosphonate use was not an independent predictor of TB in the multivariable Cox proportional hazard model (adjusted hazard ratio, 0.86; 95%CI, 0.71-1.04); however, male sex, older age, being bedridden, and steroid use were independent risk factors. The real-world data revealed that bisphosphonate use did not protect patients with osteoporosis against TB.

Background : Previous studies have indicated that statins can reduce the severity of depressive symptoms. However, the optimal choice of statin remains unclear. Therefore, we conducted a network meta-analysis to determine the optimal statin for treating depression. Method : We performed a pairwise and network meta-analysis by searching the PubMed, Embase, and Cochrane Library databases on October 29th, 2020. Eligible studies were randomized controlled trials that reported on changes in depressive symptoms. The Cochrane Collaboration tool was used to assess risk of bias. We tested for possible inconsistency globally by using a χ2-test and locally by calculating inconsistency factors for each comparison in closed loops. The ranking probabilities of being at each possible rank for each intervention were estimated. Comparison-adjusted funnel plots were obtained to assess publication bias. Sensitivity analysis was also performed. Results : We identified 13 studies that matched our inclusion criteria. The risks of bias were mostly low. None of the global or local tests found significance. Compared with placebo, atorvastatin significantly reduced the severity of depressive symptoms (mean difference −3.46, 95% confidence interval −5.26 to −1.67). Atorvastatin had the first and second rank with probabilities of 44.9% and 39.0%, respectively. Comparison-adjusted funnel plots revealed no significant publication bias. Limitations : Low similarity of included studies and a relative large treatment effect of a single study were observed. Conclusions : In this first network meta-analysis, atorvastatin, with high intensity and a lipophilic effect, was identified as the optimal choice of statin for treating depression.

Chronic exposure to aristolochic acid (AA) leads to renal interstitial fibrosis and nephropathy. In this study, we aimed to investigate the renoprotective effects of Panax ginseng extract (GE) and ginsenoside saponin (GS) on AA-induced nephropathy (AAN) in mice. Eighty female C3H/He mice were randomly divided into eight groups, including normal, AA (3 μg/mL for 56 days), AA with GE (125, 250, or 500 mg/kg/d for 14 days), and AA with important GE ingredients, Rg1, Rb1, or Rd (5 mg/kg/d for 14 days). Compared with the AA group, renal injuries were significantly decreased in the GE (250 mg/kg/d), Rb1, and Rg1 treatment groups. Rg1 exhibited the best renoprotection among all GS-treated groups. There were 24 peaks significantly altered among normal, AA, and AA + Rg1 groups, and four mitochondrial proteins were identified, including acyl-CoA synthetase medium-chain family member 2, upregulated during skeletal muscle growth 5 (Usmg5), mitochondrial aconitase 2 (ACO2), and cytochrome c oxidase subunit Va preprotein (COX5a). We demonstrated for the first time that the AAN mechanism and renoprotective effects of Rg1 are associated with expression of mitochondrial proteins, especially ACO2, Usmg5, and COX5a.

Chronic exposure to aristolochic acid (AA) leads to renal interstitial fibrosis and nephropathy. In this study, we aimed to investigate the renoprotective effects of Panax ginseng extract (GE) and ginsenoside saponin (GS) on AA-induced nephropathy (AAN) in mice. Eighty female C3H/He mice were randomly divided into eight groups, including normal; AA (3 μg/mL for 56 days); AA with GE (125, 250, or 500 mg/kg/d for 14 days); and AA with important GE ingredients, Rg1, Rb1, or Rd (5 mg/kg/d for 14 days). Compared with the AA group, renal injuries were significantly decreased in the GE (250 mg/kg/d), Rb1, and Rg1 treatment groups. Rg1 exhibited the best renoprotection among all GS-treated groups. There were 24 peaks significantly altered among normal, AA, and AA + Rg1 groups, and four mitochondrial proteins were identified, including acyl-CoA synthetase medium-chain family member 2, upregulated during skeletal muscle growth 5 (Usmg5), mitochondrial aconitase 2 (ACO2), and cytochrome c oxidase subunit Va preprotein (COX5a). We demonstrated for the first time that the AAN mechanism and renoprotective effects of Rg1 are associated with expression of mitochondrial proteins, especially ACO2, Usmg5, and COX5a.

We have designed photodetectors based on a combination of nanocrystalline diamond (NCD) and bilayer metallic layers in a metal-semiconductor-metal (MSM) structure. The NCD films were deposited on silicon substrates which nucleated by different metallic layers (tungsten, molybdenum) and nanodiamond suspension. We found that the metallic layers not only significantly improve the nucleation density of the substrates but also reduce the surface roughness of the fabricated NCD films from 8.3 nm to 4.7 nm. Furthermore, the one-step fabrication of MSM photodetectors adopts metallic interlayers consisting of two functions (diamond nucleation site and back electrodes), which shows high detection efficiency and rapid response to UV irradiation in air ambient. The W/NCD/W structure exhibits good Ohmic contact characteristics and significant changes (∼3 orders of magnitude) in photocurrent and stable reproducibility. The achievement of this research indeed demonstrates great prospects of photodetector applications of NCD films in the future.

For the enantioselective and simultaneous analysis of lactate and 3-hydroxybutyrate, a validated online two-dimensional high-performance liquid chromatography system using 4-nitro-7-piperazino-2,1,3-benzoxadiazole as a fluorescent derivatization reagent has been developed. For the reversed-phase separation in the first dimension, a Capcell Pak C18 ACR column (1.5 × 250 mm, particle size 3 μm) was used, and the target fractions were isolated by their hydrophobicity. In the second dimension, a polysaccharide-coated enantioselective column, Chiralpak AD-H (2.0 × 250 mm, 5 μm), was used. The system was validated by the calibration curve, intraday precision, interday precision, and accuracy using standards and real human samples, and satisfactory results were obtained. The present method was applied to human plasma and urine, and in the plasma, trace amounts of d-lactate (8.4 μM) and l-3-hydroxybutyrate (1.0 μM), besides high levels of l-lactate (860.9 μM) and d-3-hydroxybutyrate (59.4 μM), were successfully determined. In urine, trace levels of d-lactate (3.7 μM), d-3-hydroxybutyrate (2.3 μM), and l-3-hydroxybutyrate (3.3 μM) in addition to a relatively large amount of l-lactate (15.4 μM) were observed. The present online two-dimensional high-performance liquid chromatography system is useful for the simultaneous determination of all the lactate and 3-hydroxybutyrate enantiomers in human physiological fluids, and further clinical applications are ongoing.

Nephrotoxic serum (NTS) nephritis occurs in three stages: inflammation, early kidney damage, and severe kidney damage. We quantified the temporal changes in the enantiomers of lactate (LA) and 3-hydroxybutyrate (3HB) in serum and urine during the progression of autoimmune kidney damage in mice with NTS nephritis. Two-dimensional and three-dimensional HPLC were used to quantify the enantiomers. The serum and urinary levels of LA and 3HB enantiomers significantly changed during the progression of NTS nephritis. Specifically, d-LA was significantly higher in the serum (131.8 ± 30.6, 123.7 ± 27.2, 109.3 ± 15.6 vs. 51.2 ± 7.5 μM; p 0.05) and urine (222.2 ± 34.8, 197.4 ± 53.9, 214.8 ± 68.9 vs. 100.8 ± 37.7 μmol/g creatinine; p 0.05) of the week 0 (W0), week 1 (W1), and week 2 (W2) groups than the normal group. The l-3HB/d-3HB ratio was significantly lower in the W0, W1, and W2 groups than the normal group in serum (0.0362 ± 0.0082, 0.0346 ± 0.0065, 0.0323 ± 0.0033 vs. 0.0602 ± 0.0214; p 0.05) and urine (0.0591 ± 0.0304, 0.1524 ± 0.0365, 0.1232 ± 0.1066 vs. 0.3273 ± 0.1394; p 0.05). The changes in serum and urinary d-LA and l-3HB/d-3HB ratios were stable before severe kidney damage. In conclusion, we successfully determined the levels of LA and 3HB enantiomers in NTS nephritis by HPLC. Serum and urinary d-LA contents and l-3HB/d-3HB ratios may have potential as biomarkers of early autoimmune kidney injury.

Importance Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2; however, questions remain about which treatment is associated with the best outcomes and fewest adverse events. Objective To compare the efficacy and safety of neuraminidase inhibitors and the endonuclease inhibitor for the treatment of seasonal influenza among healthy adults and children. Data sources Medline, Embase, and the Cochrane Register of Clinical Trials were searched from inception to January 2020 (the last search was updated in October 2020). Study selection Included studies were randomized clinical trials conducted among patients of all ages with influenza treated with neuraminidase inhibitors (ie, oseltamivir, peramivir, zanamivir, or laninamivir) or an endonuclease inhibitor (ie, baloxavir) compared with other active agents or placebo. Data extraction and synthesis Two investigators identified studies and independently abstracted data. Frequentist network meta-analyses were performed; relative ranking of agents was conducted using P-score probabilities. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Data were analyzed in October 2020. Main outcomes and measures The time to alleviation of influenza symptoms (TTAS), complications of influenza, and adverse events (total adverse events, nausea, and vomiting). Results A total of 26 trials were identified that investigated antiviral drugs at high or low doses; these trials included 11 897 participants, among whom 6294 (52.9%) were men and the mean (SD) age was 32.5 (16.9) years. Of all treatments comparing with placebo in efficacy outcomes, high-quality evidence indicated that zanamivir was associated with the shortest TTAS (hazard ratio, 0.67; 95% CI, 0.58-0.77), while baloxavir was associated with the lowest risk of influenza-related complications (risk ratio [RR], 0.51; 95% CI, 0.32-0.80) based on moderate-quality evidence. In safety outcomes, baloxavir was associated with the lowest risk of total adverse events (RR, 0.84; 95% CI, 0.74-0.96) compared with placebo based on moderate-quality evidence. There was no strong evidence of associations with risk of nausea or vomiting among all comparisons, except for 75 mg oseltamivir, which was associated with greater occurrence of nausea (RR, 1.82; 95% CI, 1.38-2.41) and vomiting (RR, 1.88; 95% CI, 1.47-2.41). Conclusions and relevance In this systematic review and network meta-analysis, all 4 antiviral agents assessed were associated with shortening TTAS; zanamivir was associated with the shortest TTAS, and baloxavir was associated with reduced rate of influenza-related complications.

Background: Most Aristolochiaceae plants are prohibited due to aristolochic acid nephropathy (AAN), except Xixin ( Asarum spp. ). Xixin contains trace amounts of aristolochic acid (AA) and is widely used in Traditional Chinese Medicine. Methylglyoxal and D-lactate are regarded as biomarkers for nephrotoxicity. Thus, this study aimed to evaluate tubulointerstitial injury and interstitial renal fibrosis by determining urinary methylglyoxal and D-lactate after withdrawal of low-dose AA in a chronic mouse model. Methods: C3H/He mice in the AA group ( n =24/group) were given ad libitum access to distilled water containing 3 µg/mL AA (0.5 mg/kg/day) for 56 days and drinking water from days 57 to 84. The severity of tubulointerstitial injury and fibrosis were evaluated using the tubulointerstitial histological score (TIHS) and Masson’s trichrome staining. Urinary and serum methylglyoxal were determined by high-performance liquid chromatography (HPLC); urinary D-lactate were determined by column-switching HPLC. Results: After AA withdrawal, serum methylglyoxal in the AA group increased from day 56 (429.4±48.3 μg/L) to 84 (600.2±99.9 μg/L), and peaked on day 70 (878.3±171.8 μg/L; p Conclusions: Methylglyoxal is induced after AA-induced tubulointerstitial injury, thus methylglyoxal excretion and metabolism may be a detoxification and repair strategy. A low cumulative AA dose is the key factor that limits tubulointerstitial injury and repair. Thus, AA-containing herbs, especially Xixin, should be used at low doses for short durations (less than one month).

For the enantiomer discriminated determination of lactate (LA) and 3-hydroxybutyrate (3HB) in various complicated samples, a three-dimensional HPLC (3D-HPLC) system has been designed and developed by investigating the separation of the target analytes from unknown substances observed in the real target matrices. LA and 3HB were pre-column derivatized with 4-nitro-7-piperazino-2,1,3-benzoxadiazole for the sensitive fluorescence detection and introduced into the 3D-HPLC system composed of reversed-phase, mixed-mode and enantioselective separations. The present method was validated by calibration curves, precision and accuracy using standard solutions and human samples, and sufficient values were obtained. Using the method, the levels of d-LA, l-LA, d-3Hb and l-3HB were determined, and their concentrations were 9.9, 1004.2, 79.7 and 2.1 μM in the human plasma and 16.0, 86.6, 8.7 and 4.8 μM in the human urine, respectively. The present 3D-HPLC system could selectively determine trace amounts of the target hydroxy acid enantiomers without disturbance of the intrinsic interfering substances in complicated matrices and the applications to various disease samples are expected.

Chronic kidney disease is a worldwide problem, and Pb contamination is a potential risk factor. Since current biomarkers are not sensitive for the diagnosis of Pb-induced nephrotoxicity, novel biomarkers are needed. Metformin has both hypoglycaemic effects and reno-protection ability. However, its mechanism of action is unknown. We aimed to discover the early biomarkers for the diagnosis of low-level Pb-induced nephrotoxicity and understand the mechanism of reno-protection of metformin. Male Wistar rats were randomly divided into control, Pb, Pb + ML, Pb + MH and MH groups. Pb (250 ppm) was given daily via drinking water. Metformin (50 or 100 mg/kg/d) was orally administered. Urine was analysed by nuclear magnetic resonance (NMR)-based metabolomics coupled with multivariate statistical analysis, and potential biomarkers were subsequently quantified. The results showed that Pb-induced nephrotoxicity was closely correlated with the elevation of 5-aminolevulinic acid, d-lactate and guanidinoacetic acid in urine. After co-treatment with metformin, 5-aminolevulinic acid and d-lactate were decreased. This is the first demonstration that urinary 5-aminolevulinic acid, d-lactate and guanidinoacetic acid could be early biomarkers of low-level Pb-induced nephrotoxicity in rats. The reno-protection of metformin might be attributable to the reduction of d-lactate excretion.

Aminoglycosides are widely used to treat infections; however, their applications are limited by nephrotoxicity. With the increase of antibiotic resistance, the use of aminoglycosides is inevitable. Low-molecular-weight chitosan (LMWC) has shown renal protective effects in dialysis patients. However, no study has evaluated LMWC for preventing aminoglycoside-induced nephrotoxicity or determined the mechanisms underlying the renal protective effects. In this study, LMWC (165 or 825 mg/kg/day) or metformin (100 mg/kg/day) was orally administered for 13 days to rats with nephropathy induced by gentamicin (GM), a kind of aminoglycoside (150 mg/kg/day i.p. for 6 days). Both LMCW doses improved renal function. Serum creatinine levels improved in rats treated with 165 and 825 mg/kg/day LMWC (from 2.14 ± 0.74 mg/dL to 1.26 ± 0.46 mg/dL and 0.69 ± 0.12 mg/dL, resp.,P< 0.05). Blood urea nitrogen levels were also improved in these rats (from 73.73 ± 21.13 mg/dL to 58.70 ± 22.71 mg/dL and 28.82 ± 3.84 mg/dL, resp.,P< 0.05). Additionally, renal tissue morphology improved after LMWC treatment, and accumulation of renal methylglyoxal, a damage factor associated with carbonyl stress, was reversed. These results show that LMWC prevents GM-induced renal toxicity via a carbonyl stress-dependent pathway.

Aminoglycosides are widely used to treat infections; however, their applications are limited by nephrotoxicity. With the increase of antibiotic resistance, the use of aminoglycosides is inevitable. Low-molecular-weight chitosan (LMWC) has shown renal protective effects in dialysis patients. However, no study has evaluated LMWC for preventing aminoglycoside-induced nephrotoxicity or determined the mechanisms underlying the renal protective effects. In this study, LMWC (165 or 825 mg/kg/day) or metformin (100 mg/kg/day) was orally administered for 13 days to rats with nephropathy induced by gentamicin (GM), a kind of aminoglycoside (150 mg/kg/day i.p. for 6 days). Both LMCW doses improved renal function. Serum creatinine levels improved in rats treated with 165 and 825 mg/kg/day LMWC (from 2.14 ± 0.74 mg/dL to 1.26 ± 0.46 mg/dL and 0.69 ± 0.12 mg/dL, resp., P < 0.05). Blood urea nitrogen levels were also improved in these rats (from 73.73 ± 21.13 mg/dL to 58.70 ± 22.71 mg/dL and 28.82 ± 3.84 mg/dL, resp., P < 0.05). Additionally, renal tissue morphology improved after LMWC treatment, and accumulation of renal methylglyoxal, a damage factor associated with carbonyl stress, was reversed. These results show that LMWC prevents GM-induced renal toxicity via a carbonyl stress-dependent pathway.

Methylglyoxal (MGO) is highly cytotoxic and its levels are elevated in diabetes, nephropathy and atherosclerosis. However, it has never been studied in liver disease. For this reason, we aimed to assess the levels of MGO and its metabolite d-lactate in an early hepatitis model. Wistar rats were administered CCl4 (0.75 mL/kg, i.p.) to induce hepatitis. In either CCl4 -treated or untreated rats, alanine transaminase and aspartate transaminase levels did not change over the course of the study, indicating that significant liver damage did not occur following CCl4 treatment. However, the levels of MGO and d-lactate were higher in the livers of CCl4 -treated animals than in untreated animals (MGO: 128.2 ± 18.8 and 248.1 ± 64.9 μg/g protein, p < 0.01; d-lactate: 0.860 ± 0.040 and 1.293 ± 0.078 μmol/g protein, respectively p < 0.01). Furthermore, in untreated and treated animals, serum d-lactate levels were 57.65 ± 2.59 and 92.16 ± 16.69 μm and urine d-lactate levels were 1.060 ± 0.007 and 1.555 ± 0.366 μmol/mg UCr, respectively (p < 0.01). These data show that in this model of early-stage liver damage, the levels of MGO and its metabolite d-lactate are elevated and that d-lactate could be useful as a reference marker for the early stage of hepatitis.

Hydrogen-free diamond-like carbon (DLC) films have been deposited on polyimide (PI) substrate at room temperature using the sputtering with a novel nanodiamond target. Also, argon plasma pretreatment procedure for PI substrate was optimized to improve the adhesion and characteristics of the as-prepared DLC film. The deposited DLC film on the PI substrate pretreated with −400 V of bias voltage was found to possess the highest sp3 bonding fraction of 53%, the pencil hardness of 3H, and the optical transmittance of 82%, respectively. The research work demonstrates prosperous applications of DLC films in the protective coating for commercialized optoelectronic devices.

Atorvastatin (ATO) inhibits the synthesis of nonsteroidal isoprenoid compounds and possesses a pleiotropic effect. However, the detailed mechanism of ATO in preventing gentamicin (GM)-induced renal injury remains obscure. Although underlying multifaceted mechanisms involving GM-induced nephrotoxicity were well known, further work on elucidating the essential mechanism was needed. Using a fluorogenic derivatization-liquid chromatography tandem mass spectrometry proteomic method (FD-LC-MS/MS method), we investigated the effects and mechanisms of ATO treatment on GM-induced nephrotoxicity in rats. Consequently, 49 differentially expressed proteins were identified. The most significant mechanisms of nephrotoxicity caused by GM were mitochondrial dysfunction, fatty acid metabolism and oxidative stress. Their upstream regulator was found to be PPARα. The proteins involved in GM nephrotoxicity were sodium-hydrogen exchanger regulatory factor (SLC9A3R1), cathepsin V (CTSV), macrophage migration inhibitory factor (MIF) and RhoGDP dissociation inhibitor alpha (ARHGDIA). After ATO intervention, we observed a reversed enrichment pattern of their expression, especially in CTSV and SLC9A3R1 (P-value

In this study, we investigated the role of carbonyl stress in gentamicin (GM)-induced renal injury in rats. Carbonyl stress is represented by methylglyoxal (MGO) and its downstream advanced glycation end products, such as N ɛ -(carboxyethyl)lysine (CEL). GM (150 mg /kg/day, i.p.) administration for 6 days significantly increased blood urea nitrogen (BUN) levels from 24.06 ± 0.55 to 85.04 ± 21.31 mg/dL and decreased creatinine clearance rate (Ccr) from 10.68 ± 0.76 to 2.53 ± 1.11 ml/min/kg B.W.; biopsy showed tubular injury. The kidney levels of MGO and CEL increased significantly from 9.56 ± 1.94 to 79.13 ± 17.96 μg/g of protein and from 0.03 ± 0.00 to 0.06 ± 0.00 μmol/μg of protein, respectively. Therefore, MGO and CEL appeared to be associated with GM-induced renal damage. Co-administration of metformin (50 or 100 mg/kg/day) and GM for 13 days effectively reversed GM-induced renal damage. The kidney levels of MGO and CEL decreased significantly from 24.95 ± 7.74 to 22.98 ± 17.74 μg/g of protein and from 0.04 ± 0.01 to 0.03 ± 0.01 μmol/μg of protein (both vs. the GM group), respectively. The identification of this new pathway may help prevent GM-induced nephrotoxicity.

Urinary d-lactate is highly correlated to diabetic nephropathy – a progressive kidney disease in renal glomeruli. In this study, we used a C3H/3e mouse model to investigate the relationship between urinary d-lactate and aristolochic acid nephropathy where the glomerular structure is not affected. The nephropathy was induced using intravenous injections of aristolochic acid at a dosage of 10 mg/kg per day for 5 days and was characterized biochemically and histologically. The urinary excretions of proteins, N-acetyl-β-d-glucosaminidase and serum creatinine were determined and connected to histological conventional findings. Urinary d-lactate was analyzed using column-switching high-performance liquid chromatography with fluorescence detection. The results showed a remarkable increase of urinary markers, including of urinary proteins and N-acetyl-β-d-glucosaminidase, and the histological examination confirmed a diagnosis of acute tubule necrosis. The ratio of d-lactate to creatinine in the urine of aristolochic acid-treated mice was approximately 36 times greater than that of the mice in the control group (p

Background Kawasaki disease (KD) is an autoimmune disease that is associated with systemic vasculitis and other cardiovascular disorders. Recent studies have shown that the calcium sensor, stromal interaction molecule 1 (STIM1), is a key molecule that modulates functioning of the immune system. In this study, the association of STIM1 polymorphisms with KD was investigated. Methods The Han Chinese in Beijing reference population sample from the haplotype map database was analyzed and four tagging single nucleotide polymorphisms (SNPs; rs2304891, rs3750996, rs1561876, and rs3750994) located in the coding region of the STIM1 gene, with a minor allele frequency of 10% or more, were selected. TaqMan allelic discrimination assay was performed for genotyping 381 patients with KD. Results By using a recessive model, our data demonstrated that the rs2304891 SNP in the STIM1 gene was significantly associated with coronary artery dilation in KD patients. However, there was no association between the assessed STIM1 SNPs and intravenous immunoglobulin treatment or the incidence of aneurysm. Conclusion The present results show that a genetic polymorphism in the STIM1 gene (rs2304891) might be associated with coronary artery dilation, but not with resistance to intravenous immunoglobulin treatment or aneurysm formation, in the Taiwanese population.

Lead (Pb) is an environmental pollutant associated with several diseases, such as nephrotoxicity. Methylglyoxal (MG) is a reactive dicarbonyl compound formed during glycolysis and reported to increase in kidney damage. Metformin is used as an MG scavenger in the clinic. In this study, we investigated the mechanism of Pb-induced renal injury and the effect of metformin on Pb-induced nephrotoxicity. Eighteen Wistar rats were randomly divided into three groups: control, Pb, and Pb + metformin groups. Pb (250 ppm) was administered in drinking water, and 50 mg/kg of metformin was co-administered orally. After 28 days, the levels of MG and its metabolite d-lactate in urine, serum and renal tissues were examined. The elevation of renal MG (56.86 ± 17.47 vs 36.40 ± 5.69, p 0.01) and urinary d-lactate (0.68 ± 0.28 vs 0.32 ± 0.13, p 0.01) was observed in Pb-exposed rats compared with those in control rats. After co-treatment with metformin, these phenomena were attenuated. In the present study, it was demonstrated for the first time that urinary d-lactate might serve as the candidate marker for Pb-induced nephrotoxicity in the clinic, and metformin might be a new therapeutic candidate for Pb poisoning.

Background Cantharidin isolated from the blister beetle is used as a traditional Chinese medicine. The anticancer activity of thiadizolyl and some known N-substituted thiazolyl of cantharidin has been reported. We obtained a novel type of cantharidinimides for testing their cytotoxicity in human carcinoma cell lines. The structural modification of cantharidin to cantharidinimide might lead to the discovery of a novel class of antitumor compounds. Methods We synthesized more than 34 cantharidinimide derivatives from heating the cantharidin (compound 1) to ca. 200°Cin toluene and triethylamine along with primary amine, aniline derivatives, and aminopyridines, respectively. These imide derivatives contain aryl, pyridyl, azolyl, thiadiazolyl, diaminophenyl, aminosulfanyl, sulfamethoxazolyl, or sulfadiazine cantharidinimides (compounds 2-34). All of these synthetic compounds were tested for their capability to suppress growth of the human carcinoma cell lines such as HepG2, HL-60, 59T, HONE-1, DLD-1, SCM-1 NUGC, and Hep3B cells. Results The 3-(4, 5-dimethylthiazol-2-yl)2, 5-diphenyltetrazolium bromide (MTT) viability assay was used to evaluate the cytotoxic effect of newly synthesized cantharidinimides against the previously mentioned carcinoma cell lines. The current results indicate that compounds 2, 3, 4, 6, 8, 11, 12, 13, 14, 15, 17, 29, 30, and 31 were somehow effective and some of them were more potent than the parent compound cantharidin. Compounds 4, 13, 14, and 15, which were thiazol- and thiadiazol-containing cantharidinimides, caused cytotoxic effects on 59T, SCM-1, HONE-1, Hep3B, and NUGC human carcinoma cell lines. Compounds 11 and 16 with a planar side chain had medium cytotoxicity on hepatoma cell lines. Compounds 6 and 8 were bromine-containing aromatic cantharidinimide that produced significant cytotoxic effects on HONE-I and NUGC in high concentrations, but only compound 6 inhibited the growth of 59T and SCM-1 cell lines. Conclusions The current results indicate that the cytotoxic effects on several cancer cells were produced by many different structural domains of the cantharidinimide compounds. The current in vitro results suggest that decreasing electron negativity on the substituent-donating group might increase their cytotoxicity to cancer cells.

The surfaces of implantable biomaterials improving biocompatibility and bioinertness are critical for new application of bioimplantable devices. Diamond-like carbon (DLC) film is a promising biomaterial with use for coating bioimplantable devices because of its good biocompatibility, bioinertness, and mechanical properties. In this study, concurrent improvement in biocompatibility and bioinertness of DLC films has been achieved using N-incorporation technique. The N doping degree was found to play an important role in affecting the biocompatibility and bioinertness of N-doped DLC films. The results indicated that the N-doped DLC films deposited at N(2) concentration of 5% could help to create suitable condition of surface/structure/adhesion combination of DLC films in the both affinity of the L929 mouse fibroblasts and electrochemical inertness in the Hank's balanced salt solutions (simulating human body fluids). N doping supports the attachment and proliferation of cells and prevents the permeation of electrolyte solutions, thereby simultaneity improved the biocompatibility and bioinertness of DLC films. This finding is useful for the fabrication and encapsulation of in vivo devices without induced immune response in the human body.

SummaryObjectiveThe aim of this study was to evaluate the reversible factors that could possibly affect outcomes of anti-tuberculosis (anti-TB) treatment.MethodsA retrospective observational nested case–control study was performed to evaluate the association of patient and clinical factors with anti-TB therapy outcomes as defined by the World Health Organization (WHO).ResultsTo examine the impact of a variety of factors on the outcomes of anti-TB treatment, a total of 302 TB patients were included in the study. Univariate analysis revealed that age, gender, concurrent hypertension, asthma/chronic obstructive pulmonary disease, or liver disease, worsened baseline blood urea nitrogen or creatinine, ethambutol 20 cigarettes per day) was significantly associated with a decreased odds of cure or treatment completion (odds ratio 0.23, 95% confidence interval 0.05–0.98, p=0.047).ConclusionsAs smoking significantly inhibits the effectiveness of TB treatment, the integration of smoking cessation into TB treatment programs is strongly advocated to reduce the dual global burden of smoking and TB.

This study investigated the effects of low molecular weight chitosan (LMWC) on the renal functions for aristolochic acid (AA)-induced renal lesions in C3H/He mice. Commercial crab shell chitosan (molecular mass of ∼1100 kDa) was hydrolysed using bamboo chitosanase at pH 3.5 and 50 °C for 18 h. LMWC (with molecular mass of ∼29 kDa) was isolated from the hydrolysate through 50% methanol fractionation. The levels of urinary microalbumin, urinary-N-acetyl-beta- d -glucosaminidase, serum creatinine, and blood urea nitrogen were higher in the AA induced mice than those in the control group, while the rate for creatinine clearance was lower in the AA induced mice. Oral administration of LMWC could suppress the elevation of urinary and blood nitrogen concentrations induced by AA treatment. Renal histopathological examination revealed that AA-induced renal alterations were reverted effectively by the treatment of LMWC at three tested doses, especially at the moderate dose of 500 mg/kg BW.

This study employed a new light source, a light-emitting diode (LED), for fluorescence detection of high-performance liquid chromatography to measure the concentration of trace constituents in biological fluids. Using l-3-hydroxybutyrate ( l-3HB) as a tested trace compound, the function of the new system was compared with that of the current commercially available model. A detailed schematic diagram of the path of the detection rays in the LED detector is given. A voltage-stabilizer for the drive circuit was designed with an input of 10 V and an output of 8 V, and another voltage regulator was used to maintain a constant 8 V. Then the regulator was used to set the output voltage for the LED at 2.8 V by two external resistors. Replacing the xenon lamp with LED, this system provided higher photon density and a narrow spectrum at a wavelength of 491 nm. At room temperature (22.1°C), the average temperature of six places in the chamber of LED detector was 22.1°C compared with 51.1°C in the xenon detector. The spectra of the excitation light sources were measured. Compared with the xenon lamp, approximately 1.32 times higher excitation intensity was obtained by the LED source. The accuracy of detection of l-3HB in 50 μL of rat serum was 99.85–100.85%, and the intra-day and inter-day precision values were within 8.99 and 13.90%, respectively. The limit of detection of l-3HB was approximately 0.73 µM (signal-to-noise ratio 3). The sensitivity of the proposed LED detector was comparable to that of traditional fluorescence detectors using xenon arc lamps; however, the cost and operating temperature of LED lamps were far lower. This assay system could be further used to detect trace constituents in various samples. Copyright © 2011 John Wiley & Sons, Ltd.

This work was supported by the Ministry of Education and Science of Spain (Project CTM2006-11991) and FEDER funds.

Arylamine N-acetyltransferase-2 (NAT2) displays extensive genetic polymorphisms that affect the rates of acetylation of drugs and toxic compounds such as amine carcinogens. The association of NAT2 polymorphisms with adult brain tumors has been unclear. To investigate whether the NAT2 genotype is a risk factor of brain tumors, we determined the frequencies of three common polymorphisms in the NAT2 gene, NAT2*5 (T341C), NAT2*6 (G590A), and NAT2*7(G857A), in brain tumor patients and in age- and gender-matched control subjects (n = 27 in each group). Genotyping was carried out using PCR-RFLP and subjects were phenotyped as a fast or slow acetylator based on the genotypes. The odds ratio of NAT2*7 allele frequency was significantly higher in patients with brain tumor than in controls (odds ratio, 6.786; 95% confidence interval, 2.06-22.37; P = 0.003); in the mean time, NAT2*4/*7 genotype was significantly more common in the patient group than in controls (odds ratio, 6.19; 95% confidence interval, 1.68-22.79; P = 0.0039). The tumors in the patients with NAT2*7 allele tended to be high-grade astrocytoma or glioblastoma multiforme (P = 0.016). In conclusion, these data suggest that the presence of NAT2*7 allele might be a potential risk factor for the development of brain tumors in Taiwan. (Cancer Epidemiol Biomarkers Prev 2008;17(3):661–5)

The activity of lipoprotein lipase (LPL), an enzyme responsible for lipoprotein metabolism, would vary in diseases and metabolic disorders. For determination of LPL activity, a highly sensitive high performance liquid chromatography (HPLC) method using a fluorescent reagent, 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ) was applied to determinate the oleic acid (OA) generated from triolein by LPL activity without multiple solvents extraction step. We studied the optimal conditons of the reaction including the effect of emulsifiers, deproteinizing solvents, and the concentration of bovine serum albumin (BSA). Ten millimolar concentrations of triolein, 5% of BSA, 1% of Gum arabic (GA), and acetonitrile showed the optimum conditions for measuring the LPL activity. The accuracy values for the determination of LPL activity in 10 µL of rat post heparin plasma were 108.73 ∼ 114.36%, and the intra- and inter-day precision values were within 1.28% and 2.91%, respectively. The limit of detection was about 4.53 nM (signal-to-noise ratio 3). The proposed method was applied to determination of LPL activity in post heparin plasma of normal and streptozotocininduced diabetic rats associated with 52.3% reduction. The established assay system could be used for determining LPL activity in different physiological and pathological conditions to clarify the relationship between LPL activity and diabetes mellitus. Copyright © 2008 John Wiley & Sons, Ltd.

Methylglyoxal (MG) can cause protein glycation, resulting in cell damage and dysfunction. Accumulation of MG and its downstream metabolite Nε-(carboxyethyl)lysine (CEL) has been identified in several variations of nephropathy, including diabetic, hypertensive, and gentamicin-induced nephropathies. In this study, we investigated the effects of low-molecular-weight chitosan (lmw-chitosan) on MG-induced carbonyl stress in aristolochic acid-induced nephropathy. We used a buffer to investigate whether MG could be scavenged by lmw-chitosan in vitro. In addition, we also used a mouse model of aristolochic acid-induced nephropathy, which exhibits 12-fold greater accumulation of MG in the kidneys than that found in control animals, to examine whether lmw-chitosan could decrease MG levels in vivo. Examination of the binding of lmw-chitosan with MG in vitro demonstrated that the concentration of lmw-chitosan necessary to achieve 50% inhibition was 4.60 µg mL−1. Treatment with lmw-chitosan (500 mg kg−1 day−1 orally) for 14 days significantly decreased renal MG accumulation from 212.86 ± 24.34 to 86.15 ± 33.79 µg g−1 protein (p

A two-dimensional chiral high-performance liquid chromatography system was established for simultaneous detection of lactate (LA) and 3-hydroxybutyrate (3HB) enantiomers in human clinical samples. d-LA is increased upon kidney damage but 3HB protected against kidney injury. Therefore, determining the concentrations of D,L-LA and D,L-3HB simultaneously would be useful for evaluating pathological conditions. LA and 3HB were pre-column-derivatized with the fluorescent reagent 4-(N-chloroformylmethyl-N-methylamino)-7-nitro-2,1,3-benzoxadiazole (NBD-COCl) at 60 °C for 15 min and separated in the first dimension with a capillary monolithic octadecylsilane column. The mobile phase consisted of 13% acetonitrile and 0.05% tirfluoroacetic acid in water. Chiralpak QD-AX and KSAACSP-001S enantioselective columns were used in the second dimension to separate LA and 3HB enantiomers, respectively. Mobile phases were mixed solutions of methanol and acetonitrile containing formic acid. The separation factors were 1.14 and 1.08, respectively. The detection limit of LA and 3HB enantiomers was 10 fmol/injection. This method was applied to human clinical samples; intra- and inter-day relative standard deviations of LA and 3HB enantiomers were, respectively, 1.04-3.25% and 1.61-5.12% in plasma, 9.19-11.2% and 4.60-5.89% in urine, and 7.12-8.90% and 2.86-6.97% in saliva. This novel analytical method is a powerful tool for investigating variations in LA and 3HB enantiomers under disease conditions.

Our new constructed LCM system with a near field fiber probe heated the thermoplastic polymer film which placed above the tissue section by focusing laser beam (810 nm), and this method improved the resolution of the dissection capture. In this study, we designed a new cap with a hole, which made the fiber probe exert close melting, and the optimal conditions of making the thermoplastic film adhere on the cap were also studied. We used a copolymer with ethylene vinyl acetate (EVA) as the main material of the film and 0.001 M infrared naphthalocyanine dye dissolved in toluene were added and mixed for spin coating. The thermoplastic film was coated on a release agent sprayed substrate, and the new cap was placed on the substrate then put into the oven at 80 for one hour. After cooling to the room temperature, we got the thermoplastic film on the cap, and we investigated the effect of different thickness of the thermoplastic film. By using the LCM system with near-field fiber probe, the melted spots have successfully formed on the films, and the results showed that the melted size is related to the thickness of the film. According to the results of this study, the fiber probe was workable on the hollow cap with thermoplastic film, and these provided the further development of the new LCM system in nano-captures.

A highly sensitive method for the fluorimetric determination of d- lactate in urine of normal and diabetic rats was developed using column-switching high-performance liquid chromatography (HPLC) with an octadecylsilica (ODS) column connected to a chiral column, an amylose tris(3,5-dimethylphenylcarbamate) coated on silica gel (Chiralpak AD-RH). During the separation step on the ODS column, the peak fraction of the ( d + l )-lactate derivative with a fluorescence reagent, 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ), was introduced directly to the chiral column by changing the flow of the eluent via a six-port valve. The d- lactate derivative was separated enantiomerically from the l -lactate derivative, and the enantiomeric ratio was determined from the chromatogram. The accuracy values for the determination of d- lactate in 20 μL of rat urine were 96.93–104.85%, and the intra- and inter-day precision values were within 0.80 and 14.44%, respectively. The detection limit for d- lactate was approximately 10 nM (with a signal-to-noise ratio of 3). The proposed HPLC method was applied to the urine of normal and diabetic rats induced by intraperitoneal administration of streptozotocin, and significant increases in d- lactate excreted into the urine were observed in diabetic rats compared to normal rats. In diabetic rats, d- lactate concentrations showed a rising tendency from the seventh day and then remained stable from the 28th day after induction, suggesting that urinary d- lactate may be used as an indicator to determine the diabetic stage and the level of kidney damage.

Diabetic nephropathy (DN) has become the major cause of end-stage renal disease. Early detection of disease risk, to enable intervention before advanced renal damage occurs, is an important goal. Microalbuminuria has been used to monitor renal damage in clinical settings for years. In this study, we divided patients with diabetes into different groups based on their microalbumin values to elucidate the relationship between urinary D-lactate and corresponding microalbumin values. Group DM1 comprised of patients with an albumin-to-creatinine ratio (ACR) of less than 30 μg albumin/mg creatinine (normal range); Group DM2 comprised of patients with an ACR of 30-299 μg albumin/mg creatinine (microalbuminuria); and Group DM3 comprised of patients with an ACR of ≥300 μg albumin/mg creatinine (macroalbuminuria). The urinary D-lactate concentration of patients with diabetes was determined by pre-column fluorescence derivatization with 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ), and the accuracy (recovery) and precision (relative standard deviation; RSD) were validated. The measured values showed an accuracy that was in the acceptable range (91.59-112.96%), with an RSD in the range of 3.13-13.21%. The urinary D-lactate levels of the 3 diabetic groups (groups DM1, DM2, and DM3) were significantly higher than those of healthy subjects (78.31 ± 22.13, 92.47 ± 21.98, and 47.29 ± 17.51 vs. 6.28 ± 2.39 nmol/mg creatinine, respectively; p

Methylglyoxal (MGO), a byproduct of sugar and lipid metabolic processes, is a major glycating agent. This metabolite reacts with basic residues of proteins and promotes the formation of advanced glycation end products (AGEs). Although MGO and AGEs are widely discussed in the context of diabetes, until recently, MGO was thought to result from insufficient blood sugar control. A new report reveals that plasma MGO, and not blood sugar, distinguishes diabetic patients with no pain from those with pain. This ability brings to MGO a new applicability to disease diagnosis. Diseases with normal sugar conditions, such as hypertension, sepsis, and renal disease, are increasingly recognized as MGO-related. We review the role of MGO in drug-induced nephropathy, induction of hypertension by oral administration, and as a biomarker of sepsis. We also discuss the measurement of MGO and its stable metabolite d-lactate. The metabolism and pathogenic mechanisms of MGO need investigation in diverse disease models. Whether MGO can be considered as an individual pathological factor will be an interesting topic.

Aristolochic acid (AA) causes interstitial renal fibrosis, which called aristolochic acid nephropathy (AAN). There is no specific indicator for diagnosing AAN, so this study was to investigate the biomarkers for AAN using a proteomics method. The C3H/He female mice were given ad libitum AA-distilled water (0.5 mg/kg/day) and distilled water for 56 days in the AA and normal groups, respectively. The AA-induced proteins in the kidney were investigated using a proteomics study, including fluorogenic derivatization with 7-chloro-N-[2-(dimethylamino)ethyl]-2,1,3- benzoxadiazole-4-sulfonamide (DAABD-Cl), and followed by high performance liquid chromatography analysis and liquid chromatography tandem mass spectrometry (FD-LC-MS/MS) with a MASCOT database searching system. There were two altered proteins, thrombospondin type 1 (TSP1) and G protein-coupled receptor 87 (GPR87), in the kidney of AA-group mice on day 56. GPR87, tumorigenesis-related protein, was newly reported in the current study. The renal interstitial fibrosis was certainly induced in the AA-group mice under the observation of histological examination. Based on the results of histological examination and proteomics study, this model might be applied to AAN studies in the future. TSP1 might be a novel biomarker for AAN, and the further role of GPR87 leading to AA-induced tumorigenesis should be researched in future studies.

Free D-amino acid content in some archaea was investigated and D-forms of several amino acids were found in them. In the acidothermophilic archaeon, Thermoplasma acidophilum, the proportion of D-aspartate (D-Asp) to total Asp was as high as 39.7%. Crude extracts of Thermoplasma acidophilum had Asp-specific racemase activity that was pyridoxal 5'-phosphate (PLP)-dependent. The relative insensitivity to a SH-modifying reagent distinguished this activity from those of the PLP-independent Asp racemases found in other hyperthermophilic archaea (Matsumoto, M., et al., J. Bacteriol. 181, 6560-6563 1999). Thus, high levels of d-Asp should be produced by a new type(s) of Asp-specific racemase in Thermoplasma acidophilum, although the function of d-Asp in this archaeon remains unknown.

A highly sensitive method for the determination of D-lactic acid and 3-hydroxybutyric acid (3-HB) in rat plasma was developed using high-performance liquid chromatography with octadecylsilica (ODS) connected to a chiral column. At first, (D + L)-lactic acid and 3-HB in the plasma were derivatized with a fluorescent reagent, 4-nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ), separated on the ODS column and determined fluorimetrically at 547 nm with 491 nm of excitation wavelength. During the separation step on the ODS, the peak fraction of (D + L)-lactate derivative was introduced directly to a phenylcarbamoylated beta-cyclodextrin chiral column by changing the flow of the eluent via a six-port valve. Then, D-lactate derivative was separated enantiomerically from the L-lactate derivative, and the enantiomeric ratio was determined from the chromatogram. Intra- and inter-day accuracy values for the determination of D-lactic acid in 10 microL of rat plasma were 97.8-109.2 and 98.4-109.9%, and those for 3-HB were 99.8-108.4 and 99.8-103.8%, respectively. The intra- and inter-day precision values were within 4.6 and 5.1% for D-lactic acid, and 2.7 and 2.4% for 3-HB, respectively. The detection limits for D-lactic acid and 3-HB were approximately 2.0 and 0.04 microM, respectively (signal-to-noise ratio 3). The proposed method was applied to the plasma of diabetic rats induced by intraperitoneal administration of streptozotocin, and the significant increases of both D-lactic acid and 3-HB concentrations were observed in the diabetic rats as compared to the normal rats.

Large amounts of D-aspartate (D-Asp) are present in the rat adrenal and pituitary glands. D-Asp is thought to be synthesized in the mammalian body and also accumulates in various tissues following intraperitoneal or intravenous administration. This report examines the origins of D-Asp in the adrenal and pituitary glands. We administered D-Asp to male rats intraperitoneally and immunolocalized this exogenous D-Asp in adrenal and pituitary tissue, using an anti-D-Asp antiserum which was previously developed in our laboratory. D-Asp levels in the rat adrenal gland have been shown to undergo a transient increase at 3 weeks of age and to decrease rapidly thereafter. We found that in the adrenal gland, exogenous D-Asp administered intraperitoneally was incorporated into the same region of the adrenal cortex in which endogenous D-Asp was present. By Northern and Western blot analysis and immunohistochemistry of glutamate (Glu) transporter, we also found that expression of the Glu transporter (GLAST), which has an affinity for D-Asp, transiently increased at 3 weeks of age and that localization patterns of the Glu transporter within the tissue were almost coincident with those of endogenous D-Asp. These observations suggest that D-Asp in the adrenal cortex of 3-week-old male rats is primarily acquired by uptake from the vascular system. We have previously shown that D-Asp is specifically localized in prolactin (PRL)-containing cells in the anterior lobe of the adult rat pituitary gland. Here we report that in the pituitary gland, exogenous D-Asp accumulated in endothelial cells, but not in PRL-containing cells. Northern and Western blot analysis and immunohistochemistry of Glu transporter revealed that developmental changes in the Glu transporter (GLAST) expression did not correlate with tissue levels of D-Asp and that the Glu transporter was not expressed in PRL-containing cells. These observations suggest that, in contrast to the adrenal gland, most of the D-Asp in the pituitary gland of adult male rats originates inside the gland itself.

d-Aspartate increases human chorionic gonadotropin-induced testosterone production in purified rat Leydig cells. l-Aspartate, d-,l-glutamate or d-,l-asparagine could not substitute for d-aspartate and this effect was independent of glutamate receptor activation. Testosterone production was enhanced only in cells cultured with d-aspartate for more than 3 h. The increased production of testosterone was well correlated with the amounts of d-aspartate incorporated into the Leydig cells, and l-cysteine sulfinic acid, an inhibitor of d-aspartate uptake, suppressed both testosterone production and intracellular d-aspartate levels. d-Aspartate therefore is presumably taken up into cells to increase steroidogenesis. Intracellular d-aspartate probably acts on cholesterol translocation into the inner mitochondrial membrane, the rate-limiting process in steroidogenesis.