Effects of prepartum 2,4-thiazolidinedione on metabolism and performance in transition dairy cows

Thiazolidinediones (TZD) are potent synthetic ligands for peroxisome proliferator-activated receptor-γ that have been shown previously to reduce plasma nonesterified fatty acids and increase peripartal dry matter intake (DMI) in dairy cows. Data from Holstein cows (n = 36) entering their second or greater lactation were used to determine whether late prepartum administration of TZD would affect periparturient metabolism, milk production, and ovarian activity. Cows were administered 0, 2.0, or 4.0 mg of TZD/kg of BW by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples were collected daily from 22 d before expected parturition through 21 d postpartum and twice weekly from wk 4 through 9 postpartum. In response to increasing TZD dosage, plasma nonesterified fatty acid concentrations decreased linearly during the postpartum period (d 0 to +21: 348, 331, 268 ± 31 μEq/L, respectively). Plasma concentrations of glucose were highest in cows administered 4.0 mg of TZD/kg of BW during the peripartum and postpartum periods (d −7 to +7: 57.9, 57.8, 61.1 ± 0.8 mg/dL and d 0 to +21: 51.6, 49.3, 54.7 ± 1.1 mg/dL, respectively). Plasma concentrations of β-hydroxybutyrate were increased during the peripartum period by TZD administration (9.6, 9.9, 10.2 ± 0.3 mg/dL) but were not affected during the postpartum period. Plasma insulin was not affected by treatment during any time period. Postpartum liver triglyceride content was decreased linearly (11.0, 10.4, 4.2 ± 1.6%) and glycogen content was increased linearly (2.16, 2.38, 2.79 ± 0.19%) by prepartum TZD administration. Prepartum TZD administration linearly increased DMI during the peripartum period (d −7 to +7: 16.1, 17.2, 17.3 ± 0.5 kg/d). Cows administered TZD prepartum maintained higher postpartum body condition scores than control cows (wk 1 through 9: 2.77, 2.89, 3.02 ± 0.05). There was no effect of prepartum TZD on milk yield; however, yields of 3.5% fat-corrected milk (52.2, 54.6, 48.0 ± 1.6 kg/d) and most other milk components were decreased in cows that received 4.0 mg of TZD/kg of BW prepartum. Prepartum TZD administration linearly decreased the number of days to first ovulation (29.3, 28.3, 19.0 ± 3.6 d). These results suggest that prepartum administration of TZD improves metabolic health and DMI of periparturient dairy cows and may decrease reliance on body fat reserves during early lactation.     

Prepartum 2,4-thiazolidinedione alters metabolic dynamics and dry matter intake of dairy cows

Thiazolidinediones (TZD) are potent, synthetic ligands for peroxisome proliferator activated receptor-gamma (PPAR-γ) that reduce plasma nonesterified fatty acids (NEFA) and potentiate the action of insulin in peripheral tissues of several species. Holstein cows (n = 9) entering their second or greater lactation were used to determine whether late prepartum administration of TZD would affect periparturient metabolism and milk production. Cows were limit-fed a total mixed ration (TMR) during the prepartum period to provide no more than 130% of predicted energy requirements. During the postpartum period cows were fed a common TMR for ad libitum intake. Cows were administered either 2,4-TZD (4.0 mg/kg of body weight) or saline (control) by intrajugular infusion once daily from 25 d before expected parturition until parturition. Plasma samples were collected daily from 26 d before expected parturition through 7 d postpartum. Plasma NEFA concentrations decreased during the prepartum period (d −21 to −1; 70 vs. 83 ± 4 μEq/L) and tended to be decreased during the peripartum period (d −7 to d +7; 113 vs. 205 ± 32 μEq/L) due to prepartum TZD administration. Plasma concentrations of glucose were not affected by treatment; however, plasma β-hydroxybutyrate concentrations decreased in TZD-treated cows (8.6 vs. 10.7 ± 1.7 mg/dL) as parturition approached, and plasma insulin concentrations increased during the peripartum period (0.65 vs. 0.38 ± 0.07 ng/mL). Postpartum liver triglyceride and glycogen content was not affected by treatment. Prepartum TZD administration tended to increase dry matter intake during the peripartum and postpartum periods (16.6 vs. 14.6 ± 0.8 kg/d and 20.0 vs. 17.2 ± 1.2 kg/d, respectively). Milk yield for the first 30 d postpartum and milk composition measured on d 8 postpartum were not affected by treatment. There was no effect of prepartum TZD administration on insulin-dependent glucose utilization assessed using insulin challenge during either the prepartum or postpartum periods. These results suggest that administration of TZD during the late prepartum period has the potential to improve metabolic health and DMI of periparturient dairy cows and warrants further investigation.     

Thiazolidinedione-based PI3Kα inhibitors: an analysis of biochemical and virtual screening methods

A series of synthesized and commercially available compounds were assessed against PI3Kα for in vitro inhibitory activity and the results compared to binding calculated in silico. Using published crystal structures of PI3Kγ and PI3Kδ co-crystallized with inhibitors as a template, docking was able to identify the majority of potent inhibitors from a decoy set of 1000 compounds. On the other hand, PI3Kα in the apo-form, modeled by induced fit docking, or built as a homology model gave only poor results. A PI3Kα homology model derived from a ligand-bound PI3Kδ crystal structure was developed that has a good ability to identify active compounds. The docking results identified binding poses for active compounds that differ from those identified to date and can contribute to our understanding of structure-activity relationships for PI3K inhibitors.     

From Antidiabetic to Antifungal: Discovery of Highly Potent Triazole–Thiazolidinedione Hybrids as Novel Antifungal Agents

In an attempt to discover a new generation of triazole antifungal agents, a series of triazole–thiazolidinedione hybrids were designed and synthesized by molecular hybridization of the antifungal agent fluconazole and rosiglitazone (an antidiabetic). Most of the target compounds showed good to excellent inhibitory activity against a variety of clinically important fungal pathogens. In particular, compounds (Z)‐5‐(2,4‐dichlorobenzylidene)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)thiazolidine‐2,4‐dione) ( 15 c ), (Z)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(furan‐3‐ylmethylene)thiazolidine‐2,4‐dione ( 15 j ), and (Z)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(furan‐3‐ylmethylene)thiazolidine‐2,4‐dione ( 15 r ) were highly active against Candida albicans, with MIC₈₀ values in the range of 0.03–0.15 μM . Moreover, compounds 15 j and 15 r were found to be effective against four fluconazole‐resistant clinical isolates; these two compounds are particularly promising antifungal leads for further optimization. Molecular docking studies revealed that the hydrogen bonding interactions between thiazolidinedione and CYP51 from C. albicans are important for antifungal activity. This study also demonstrates the effectiveness of molecular hybridization in antifungal drug discovery.     

Effects of plane of nutrition and 2,4-thiazolidinedione on insulin responses and adipose tissue gene expression in dairy cattle during late gestation

Specific mechanisms by which dry period dietary energy affects transition cow metabolism have been intensively investigated but those of thiazolidinedione (TZD) administration have not. We hypothesized that effects of both are mediated via changes in insulin, glucose, or fatty acid metabolism. The objective of this experiment was to determine the effects of the insulin-sensitizing agent TZD and dietary energy level on glucose and fatty acid metabolism during late gestation in dairy cows. Multiparous Holstein cows (n = 32) approximately 50 d before expected calving date were dried-off and assigned to 1 of 2 dietary energy levels for 3 wk (high: 1.52 Mcal/kg of NE_L, or low: 1.34 Mcal/kg of NE_L) and treated daily during the final 14 d with 4.0 mg of TZD/kg of body weight (BW) or saline in a completely randomized design. Cows fed the low energy diet had lower dry matter intake (12.8 vs. 16.1 kg/d) and higher plasma nonesterified fatty acid (NEFA) concentrations (103.3 vs. 82.4 μEq/L) compared with cows fed the high energy diet. Cows administered TZD had higher plasma glucose concentrations (62.5 vs. 59.6 mg/dL) than saline controls and cows fed the high energy diet had higher plasma insulin concentrations (35.1 vs. 25.3 μU/mL) compared with those fed the low energy diet. After 2 wk of TZD treatment, all cows were subjected to an intravenous glucose tolerance test (GTT; 0.25 g of dextrose/kg of BW) followed 110 min later by an insulin challenge (IC; 1.0 μg of insulin/kg of BW). Differences in plasma glucose response to GTT were minimal based on diet; however, cows fed the low energy diet had more negative NEFA areas under the curve (AUC; −4,838 vs. −2,137 μEq/L × min over 90 min) and greater rates of NEFA decrease (1.35 vs. 0.63%/min) during GTT, suggesting differential responses of tissue glucose and fatty acid metabolism in response to dietary energy level. During IC, the TZD-treated cows tended to have more negative glucose AUC (−45.0 vs. −12.1 mg/dL × min over 15 min) than controls, suggesting that TZD-treated cows had greater responses to insulin. Limited interactions were observed between dietary and TZD treatments in all response variables measured. Adipose tissue biopsies performed on the final day of treatment suggested higher expression of peroxisome proliferator-activated receptor-γ (0.71 vs. 0.50 relative expression) and lipoprotein lipase (0.71 vs. 0.40 relative expression) in cows fed the high energy diet as measured by quantitative real-time PCR. These results indicate that energy level and insulin-sensitizing agents affect glucose and lipid metabolism during the dry period.     

噻唑烷二酮类药物吡格列酮盐酸盐的合成研究

以5-乙基-2-羟乙基吡啶为起始原料,经过缩合、还原、重氮化、环化、水解和成盐六步反应,合成了噻唑烷二酮类药物吡格列酮盐酸盐,总收率32%。通过红外光谱、核磁共振谱和元素分析等确定了其化学结构。     

Effects of prepartum 2,4-thiazolidinedione on insulin sensitivity, plasma concentrations of tumor necrosis factor-α and leptin, and adipose tissue gene expression

Administration of peroxisome proliferator-activated receptor gamma (PPARγ) ligands, thiazolidinediones (TZD), to prepartum dairy cattle has been shown to improve dry matter intake and decrease circulating nonesterified fatty acids (NEFA) around the time of calving. The objective of this work was to elucidate mechanisms of TZD action in transition dairy cattle by investigating changes in plasma leptin, tumor necrosis factor-α (TNFα), the revised quantitative insulin sensitivity check index (RQUICKI), and adipose tissue gene expression of leptin, PPARγ, lipoprotein lipase (LPL), and fatty acid synthase (FAS). Multiparous Holstein cows (n = 40) were administered 0, 2.0, or 4.0 mg of TZD/kg of body weight (BW) by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples collected daily from 22 d before expected parturition through 21 d postpartum were analyzed for glucose, NEFA, and insulin. Plasma samples collected on d −14, −3, −1, 1, 3, 7, 14, and 49 relative to parturition were also analyzed for leptin and TNFα. Adipose tissue was collected on d 7 before expected parturition from a subset of cows, and gene expression was examined via quantitative real-time PCR. A tendency for a treatment by time effect on plasma leptin prepartum was observed such that values were similar on d −14 but cows receiving 2.0 mg/kg of BW of TZD tended to have lower circulating leptin as calving approached. Postpartum leptin tended to be increased linearly (2.3, 2.4, and 2.5 ± 0.1 ng/mL for 0, 2.0, and 4.0 mg/kg treatments, respectively) in cows that received TZD prepartum. Plasma TNFα increased linearly (2.6, 3.7, and 4.0 ± 0.1 pg/mL) in response to TZD treatment and decreased through the first week postpartum. Calculation of RQUICKI 1/[log(glucose) + log(insulin) + log(NEFA)] suggested altered insulin sensitivity in cows administered TZD that may depend on day relative to calving. Administration of TZD increased adipose tissue expression of PPARγ mRNA (11.0, 13.3, and 12.8 ± 1.9). Administration of TZD had a quadratic effect on gene expression of leptin (16.2, 10.7, and 17.4 ± 1.6) and no effect on LPL expression, and expression of FAS was lower for TZD-treated cows than for controls (8.2, 4.2, and 6.1 ± 1.8, respectively). Results imply altered expression and plasma concentrations of leptin, increased plasma TNFα concentrations, and increased expression of PPARγ in adipose tissue as potential mechanisms for the effects of TZD administration on transition dairy cattle.     

Interaction between peroxisome proliferator-activated receptor γ and its agonists: docking study of oximes having 5-benzyl-2,4-thiazolidinedione

The molecular modelling of oximes having 5-benzyl-2,4-thiazolidinedione moieties, agonists of the peroxisome proliferator-activated receptor γ (PPARγ), was performed with respect to their structures complexed with the ligand binding domain of PPARγ. For each ligand molecule, the 5-benzyl-2,4-thiazolidinedione head group was used as an anchor and the conformation of the rest of the molecule was searched for the most energetically favorable interaction with the receptor by systematic conformation search and manual modelling. Although both tail-up and tail-down configurations, which have been observed in the crystal structure of eicosapentaenoic acid when complexed with PPARδ, appeared among the lowest energy structures for most of the compounds, potent agonists were found to adopt a configuration similar to that of rosiglitazone when bound to PPARγ, according to the crystal structure. The structure–activity relationships were analyzed based on the receptor–ligand interaction. The alkyl group and the aromatic ring of the tail group of the ligands had hydrophobic interactions with the receptor, and these interactions were found to be essential for the strong activity.     

罗格列酮的合成

以2—氯吡啶和2—甲氨基乙醇为原料，经过威廉森成醚反应、缩合反应、催化氢化反应合成得到了噻唑烷二酮类胰岛素增敏剂罗格列酮。在此过程中改进了合成中间体4—[2—(甲基—2—吡啶氨基)乙氧基]苯甲醛的威廉森成醚反应条件；简化了中间体的纯化方法；优化了5—{4—[2—(甲基—2—吡啶氨基)—乙氧基]—亚苄基}—噻唑烷—2，4—二酮的催化氢化反应条件。实验结果表明，该合成路线具有反应条件温和、收率高且操作简便。