Aerobic Training Increases Hippocampal Volume and Protects Cognitive Function for Type 2 Diabetes Patients with Normal Cognition.

AIM: To evaluate the effects of aerobic training on hippocampal volume and cognitive function in patients with type 2 diabetes mellitus (T2DM) with normal cognition. MATERIALS AND METHODS: One hundred patients with T2DM aged 60-75 years who met inclusion criteria were randomized into the aerobic training group (n=50) and control group (n=50). The aerobic training group received 1 year of aerobic training, while the control group maintained their lifestyle without additional exercise intervention. The primary outcomes were hippocampal volume measured by MRI and Mini-mental State Examination (MMSE) score or Montreal Cognitive Assessment scale (MoCA) scores. RESULTS: Eighty-two participants completed the study (aerobic training group, n=40; control group, n=42). There was no significant difference between the two groups at baseline (P>0.05). After one year of moderate aerobic training, increase in total and right hippocampal volume in the aerobic training group were significantly higher than in the control group (P=0.027, P=0.043, respectively). In the aerobic group, total hippocampal volume significantly increased after the intervention compared with baseline (P=0.034). The between-group difference in the change of MMSE and MoCA scores was statistically significant (P=0.015, P=0.027, respectively). Logistic regression showed strong correlations between aerobic training and increase in total hippocampal volume (OR:1.091, [95%CI 0.969, 1.228], P=0.002), improvement of MMSE scores (OR:1.127, [95%CI 1.005, 1.263], P=0.041) or MoCA scores (OR:2.564, [95%CI 2.098.2.973], P=0.045). CONCLUSIONS: One-year moderate aerobic training increased total and right hippocampal volume and protected cognitive function for T2DM patients with normal cognition. Early intervention focusing on cognition protection should be considered for T2DM patients in clinical settings.

Systematic review with meta-analysis: effects of probiotic fungi on irritable bowel syndrome.

Treatment of irritable bowel syndrome (IBS) remains challenging for clinicians. Probiotic fungi may act as candidate options for IBS treatment, but systematic evaluation of their clinical value remains scarce. This study is aimed to assess the efficacy and the safety of probiotic fungi for IBS treatment by means of systematic review and meta-analysis. PubMed, Embase, Web of Science, and the Cochrane Library, were searched up to June 2022. Randomised controlled trials recruited subjects with prescriptions of probiotic fungi were eligible. Efficacy and safety of probiotic fungi were re-evaluated. Continuous data were pooled to obtain standardised difference in means (SMD) with a 95% confidence interval. The search strategy identified 120 articles of which 7 trial assessing 883 subjects were included in the analysis. Systematic data support that Saccharomyces helps to relieve abdominal pain/discomfort (SMD = -0.205, P = 0.005), and presented potential improvements on psychological outcomes, stool form for IBS patients. It is hard to demonstrate favourable effects on other symptoms (including distension, mucus passage, sense of incomplete evacuation, urgency, straining). The incidence of mild complications ranged from 0 to 51.4%, but no serious complications were observed in the included trials. Therefore, the partial response and the relative safe of probiotic fungi for IBS treatment have been demonstrated from the existing trials. However, it is premature to eventually declare the practical effects of probiotic fungi. Conducting more high-quality and large-scale trials and real-world studies, or even developing new fungal strains, is still necessary.

A study on the characteristics of coke in the hearth of a superlarge blast furnace.

An in-depth study on the characteristics of coke in the hearths of blast furnaces is of great significance for explaining the mechanism of coke deterioration in blast furnaces. In the present work, the changes in macromorphology, degree of graphitization, and microstructure of the coke taken from different hearth locations of a 5,800 m3 superlarge blast furnace during its intermediate repair period were systematically studied. Significant differences were found between cokes obtained from the edge ("edge coke") and from the center ("center coke") of the hearth in terms of properties and degradation mechanisms. Edge coke was severely eroded by liquid metal, and only a small amount of slag was detected in the coke porosity, whereas center coke was basically free from erosion by liquid metal, and a large amount of slag was detected in the coke porosity. The degree of graphitization of edge coke was higher than that of center coke. The carburizing effect of liquid metal was the main cause of the degradation of edge coke and made it smaller or even disappear. Center coke was degraded due to the combination of two factors: slag inserted into micropores on the surface of center coke loosened the surface structure; and graphite-like flakes that appeared on the center coke surface lowered the strength and caused cracks in the surface.

A comprehensive investigation of the reaction behaviorial features of coke with different CRIs in the simulated cohesive zone of a blast furnace.

The reaction characteristics and mechanism of coke with different coke reactivity indices (CRIs) in the high-temperature zone of a blast furnace should be fully understood to correctly evaluate the coke quality and optimize ironmaking. In this work, low-CRI coke (coke A) and high-CRI coke (coke B) were charged into a thermogravimetric analyzer to separately study their microstructural changes, gasification characteristics, and reaction mechanism under simulated cohesive zone conditions in a blast furnace. The results show that both coke A and coke B underwent pyrolysis, polycondensation, and graphitization during the heat treatment. The pyrolysis, polycondensation, gasification speed, and dissolution speed rates of coke B were higher than those of coke A. Direct and indirect reduction between sinter and coke occurred in the cohesive zone and had different stages. The consumption rate of coke B was faster than that of coke A during the coke-sinter reduction. The carbon molecules of coke A must absorb more energy to break away from the skeleton than those of coke B.

LC/MS-Based Global Metabolomic Identification of Serum Biomarkers Differentiating Hepatocellular Carcinoma from Chronic Hepatitis B and Liver Cirrhosis.

Chronic hepatitis B virus (CHB) infection is one of the primary risk factors associated with the development of hepatocellular carcinoma (HCC). Despite having been extensively studied, diagnosing early-stage HCC remains challenging, and diagnosed patients have a poor (3-5%) survival rate. Identifying new approaches to detect changes in the serum metabolic profiles of patients with CHB and liver cirrhosis (LC) may provide a valuable approach to better detect HCC at an early stage when it is still amenable to treatment, thereby improving patient prognosis and survival. In the present study, we, therefore, employed a liquid chromatography-mass spectrometry (LC-MS)-based approach to evaluate the serum metabolic profiles of 30 CHB patients, 29 LC patients, and 30 HCC patients. We then employed appropriate statistical methods to identify those metabolites that were best able to distinguish HCC cases from LC and CHB controls. A mass-based database was then used to putatively identify these metabolites. We then confirmed the identities of a subset of these metabolites through comparisons with the MS/MS fragmentation patterns and retention times of reference standards. The serum samples were then reanalyzed to quantify the levels of these selected metabolites and of other metabolites that have previously been identified as potential HCC biomarkers. Through this approach, we observed clear differences in the metabolite profiles of the CHB, LC, and HCC patient groups in both positive- and negative-ion modes. We found that the levels of taurodeoxy cholic acid (TCA) and 1,2-diacyl-3-ß-d-galactosyl-sn-glycerol rose with the progression from CHB to LC to HCC, whereas levels of 5-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid, and glycyrrhizic acid were gradually reduced with liver disease progression in these groups. The ROC analysis showed that taurodeoxy cholic acid (TCA), 1,2-diacyl-3-ß-d-galactosyl-sn-glycerol, 5-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid, and glycyrrhizic acid had a diagnosis performance with liver disease progression. These four metabolites have a significant correlation with alpha fetal protein (AFP) level and age. Our results highlight novel metabolic biomarkers that have the potential to be used for differentiating between CHB, LC, and HCC patients, thereby facilitating the identification and treatment of patients with early-stage HCC.

Andrographolide Protects against Aortic Banding-Induced Experimental Cardiac Hypertrophy by Inhibiting MAPKs Signaling.

Despite therapeutic advances, heart failure-related mortality rates remain high. Therefore, understanding the pathophysiological mechanisms involved in the remodeling process is crucial for the development of new therapeutic strategies. Andrographolide (Andr), a botanical compound, has potent cardio-protective effects due to its ability to inhibit mitogen-activated protein kinases (MAPKs). Andr has also been shown to inhibit inflammation and apoptosis, which are factors related to cardiac hypertrophy. Our aim was to evaluate the effects of Andr on cardiac hypertrophy and MAPKs activation. Thus, mice were subjected to aortic banding (AB) with/without Andr administration (25 mg/kg/day, orally). Cardiac function was accessed by echocardiography and hemodynamic parameters. Our results showed that Andr administration for 7 weeks decreased cardiac dysfunction and attenuated cardiac hypertrophy and fibrosis in AB mice. Andr treatment induced a strong reduction in the transcription of both hypertrophy (ANP, BNP, and ß-MHC) and fibrosis related genes (collagen I, collagen III, CTGF, and TGFß). In addition, cardiomyocytes treated with Andr showed a reduced hypertrophic response to angiotensin II. Andr significantly inhibited MAPKs activation in both mouse hearts and cardiomyocytes. Treatment with a combination of MAPKs activators abolished the protective effects of Andr in cardiomyocytes. Furthermore, we found that Andr also inhibited the activation of cardiac fibroblasts via the MAPKs pathway, which was confirmed by the application of MAPKs inhibitors. In conclusion, Andr was found to confer a protective effect against experimental cardiac hypertrophy in mice, suggesting its potential as a novel therapeutic drug for pathological cardiac hypertrophy.

Confined Electrochemical Deposition in Sub-15 nm Space for Preparing Nanogap Electrodes.

Electrode gaps with nanoscale separation offer great promise for molecular electronics and biosensing. Previous electrochemical methods to prepare nanogaps by depositing metal on pre-defined electrode tips have suffered from lack of control in the thickness direction and reproducible control of gap size. Here we report a new process wherein the electrochemical deposition is confined by a cavity to produce a nanogap with thickness smaller even than that of the initial electrodes. Using this process, we demonstrate controlled and reversible electrochemical deposition in a sub-15 nm space, to produce a nano-fluidic channel with finely tunable nanogap control electrodes for biosensing applications.

Repression of contexual fear memory induced by isoflurane is accompanied by reduction in histone acetylation and rescued by sodium butyrate.

BACKGROUND: Isoflurane produces amnesia in mice during contextual fear conditioning (CFC) trials. Histone acetylation is a form of chromatin modification involved in the transcriptional regulation underlying memory formation. We investigated whether isoflurane-induced repression of contextual fear memory is related to altered histone acetylation in the hippocampus, and whether it can be rescued by the histone deacetylases inhibitor sodium butyrate (SB). METHODS: Adult C57BL/6 mice were chronically given intraperitoneal injections of SB or vehicle for 28 days. Immediately before CFC training, the mice were exposed to isoflurane or air for 30 min and CFC testing was performed the next day. Hippocampal histone acetylation was analysed 1 h after CFC training. c-Fos, an immediate early gene (IEG) suggested to participate in learning and memory formation, was also investigated at the same timepoint. RESULTS: Mice exposed to isoflurane showed a reduction in freezing time during the CFC test. These mice also exhibited reduced hippocampal H3K14, H4K5, and H4K12 acetylation 1 h after CFC training, and also decreased c-Fos expression. All of these changes were attenuated in isoflurane-exposed mice that were chronically treated with SB. CONCLUSIONS: Isoflurane suppresses histone acetylation and down-regulates c-Fos gene expression in CA1 of the hippocampus after CFC training. These changes are associated with isoflurane-induced amnesia. The HDAC inhibitor SB prevented repressed contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression in response to CFC training.

Diagnosis and surgical treatment of intrahepatic hepatolithiasis combined with cholangiocarcinoma.

BACKGROUND: The aim of the present study was to describe the clinical features and to assess surgical treatment of intrahepatic hepatolithiasis combined with cholangiocarcinoma (IHCC). METHODS: A total of 107 patients with histopathologically proven IHCC were included in the study and were divided into four groups as follows: the curative resection (CR) group, the palliative resection (PR) group, the radiofrequency ablation (RA) group, and the simple laparotomy group. Demographics, symptoms, and treatment were described and survival data were retrospectively analyzed. RESULTS: The overall survival rates were 45.4, 29.8, and 20.2% at 1, 3, and 5 years. The cumulative survival rates in the CR group at 1, 3, and 5 years were 71.1, 57.9, and 50.0%, respectively, which was significantly higher than for the other three groups (P < 0.01). The survival rates in the PR group at 1, 3, and 5 years were 50.0, 19.2, and 0%, and those in the RA group were 46.2, 8.3, and 0%. There was no statistically significant difference between the two groups. In the CR group, the cumulative survival rates of the patients with stage III tumor at 1, 3, and 5 years were 74.1, 63.0, and 59.3%, which were significantly higher than those of the patients with stage IV disease (P = 0.043). CONCLUSIONS: The prognosis of IHCC is poor. Curative resection should be considered first, and radiofrequency ablation is a good choice for the patients for whom resection is impossible.

MTTP polymorphisms and susceptibility to non-alcoholic fatty liver disease in a Han Chinese population.

BACKGROUND: The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B (ApoB)-containing lipoproteins from the liver and intestine. Previous studies showed that functional polymorphisms in the MTTP gene correspond to lower LDL levels and protect against other traits of the metabolic syndrome. AIMS: Here, we aimed to investigate whether MTTP single nucleotide polymorphisms (SNPs) and their predicted haplotypes of linkage disequilibrium blocks contribute to non-alcoholic fatty liver disease (NAFLD) susceptibility in a Han Chinese population. METHODS: Seven tag SNPs in the MTTP gene were selected and genotyped in a frequency-matched case-control study in a population from Fuzhou City, China. We enrolled 580 patients with NAFLD and 580 healthy controls. RESULTS: In the multivariate logistic regression analysis, the rs1800804 (-164 T/C) was associated with an increased risk of NAFLD, while the rs1057613 A/G and rs3805335 C/T SNPs were associated with a decreased risk of NAFLD. The cumulative effect of the rs1800804 (-164 T/C), rs1057613 and rs3805335 was estimated, and a significant increased trend in the risk of NAFLD with increasing genetic risk score was observed (adjusted P(trend) = 0.014). Furthermore, the results of haplotype analysis suggested that the haplotype GC in block 1 containing the -164 C allele was associated with an increased risk of NAFLD, while haplotype TGTTC in block 2 was associated with a decreased risk of NAFLD. CONCLUSIONS: Our data show that MTTP genetic polymorphisms influence the susceptibility to developing NAFLD independently or jointly in the Han Chinese population.

Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment.

Cortical bone, the dominant component of the human skeleton by volume, plays a key role in protecting bones from fracture. We analyzed the cortical bone effects of teriparatide treatment in postmenopausal women with osteoporosis who had previously received long-term alendronate (ALN) therapy or were treatment naïve (TN). Tetracycline-labeled paired iliac crest biopsies obtained from 29 ALN-pretreated and 16 TN women were evaluated for dynamic histomorphometric parameters of bone formation at the periosteal, endocortical and intracortical bone compartments, before and after 24months of teriparatide treatment. At baseline, the frequency of specimens without any endocortical and periosteal tetracycline labeling, and the percentage of quiescent osteons, was higher in the ALN than the TN group. Endocortical and periosteal mineralizing surface (MS/BS%), periosteal bone formation rate (BFR/BS), mineral apposition rate (MAR) and the number of intracortical forming osteons were significantly lower in the ALN-pretreated patients than in the TN group. Following teriparatide treatment, the frequency of endocortical and periosteal unlabeled biopsies decreased; in the ALN-pretreated group the percentage of quiescent osteons decreased and, in contrast, forming and resorbing osteons were increased. Teriparatide treatment resulted in significant increases of MAR in the endocortical, and MS/BS% in the periosteal compartment in the ALN-pretreated group. Most indices of bone formation remained lower in the ALN-pretreated group compared with the TN group at study end. Endocortical wall width was increased in both ALN-pretreated and TN groups. Cortical porosity and cortical thickness were significantly increased in the ALN-pretreated group after teriparatide treatment. Our results suggest that 24months of teriparatide treatment increases cortical bone formation and cortical turnover in patients who were either TN or had previous ALN therapy.

Mini-nutrition assessment, malnutrition, and postoperative complications in elderly Chinese patients with lung cancer.

PURPOSE: To assist healthcare professionals in using the mini nutrition assessment (MNA) and its short-form (MNASF) for early identification of malnourished elderly lung cancer patients, conducting preoperative nutritional support, and improving patients' postoperative prognosis, quality of life, and survival. METHODS: The MNA with revised cut-off points to better suit the Chinese population was conducted on 103 elderly lung cancer Chinese patients aged 60 or above in the Tianjin Cancer Hospital prior to their scheduled surgery. Patient demographic data, anthropometric parameters, biochemical markers, and postoperative complications were collected and analysed. RESULTS: Of the 103 patients studied 12.6% (13/103) were malnourished, 31.1% (32/103) were at risk of malnutrition, and 56.3% (58/103) had adequate nutrition; the average MNA score was 23.6±3.7. Significant positive correlations were found between total MNA score and body mass index (BMI), mid-arm circumference (MAC), calf circumference (CC), and hemoglobin (Hb) (p<0.05), as well as between total MNA-SF score and BMI, MAC, CC, and total MNA score. Significant negative correlations occurred between total MNA-SF score and age (p<0.05). Among postoperative complications, cardiovascular diseases had the highest morbidity rate (23%), followed by respiratory diseases (22%), and cardiovascular and respiratory diseases combined (19%). No significant relationship between nutritional status with types of morbidity (p=0.235) and postoperative complications (p=0.362) was found. CONCLUSION: The MNA scale is an effective tool to preoperatively evaluate the nutritional status of elderly Chinese patients with lung cancer. These patients have poor nutritional status. Further investigations are needed to re-examine the correlation between the MNA results and postoperative complications.

Teriparatide [rhPTH (1-34)], but not strontium ranelate, demonstrated bone anabolic efficacy in mature, osteopenic, ovariectomized rats.

We compared teriparatide (TPTD) and strontium ranelate (SR) efficacy on bone formation activity in a mature rat model of estrogen-deficiency bone loss. Rats were ovariectomized (OVX) at age 6 months and permitted to lose bone for 2 months to establish osteopenia before initiation of treatment with TPTD (5 or 15 µg/kg · d sc) or SR (150 or 450 mg/kg · d oral gavage). After 3 wk, RT-PCR analyses of bone formation genes in the distal femur metaphysis showed significant elevation of collagen 1α2, osteocalcin, bone sialoprotein, alkaline phosphatase, and Runx2 gene expression at both TPTD doses, relative to OVX controls. SR had no significant effect on expression of these genes. TPTD treatment for 12 wk dose dependently increased lumbar vertebral (LV) and femoral midshaft bone mineral content (BMC) and bone mineral density over pretreatment and age-matched OVX controls. SR 150 increased BMC, and SR 450 increased BMC and bone mineral density of femoral midshaft and LV over OVX controls. There were significant dose-dependent TPTD increases of LV and femoral neck strength, and TPTD 15 also increased midshaft strength compared with pretreatment and age-matched OVX controls. SR did not enhance bone strength relative to pretreatment or age-matched OVX controls. Histomorphometry of the proximal tibial metaphysis showed dose-dependent effects of TPTD on trabecular area, number, width, and osteoblast surface, bone mineralizing surface, and bone formation rate relative to pretreatment and age-matched OVX controls, whereas SR had no effect on these parameters. These findings confirmed the bone anabolic efficacy of teriparatide, but not SR in mature, osteopenic, OVX rats.

A Nonsecosteroidal Vitamin D Receptor Modulator Ameliorates Experimental Autoimmune Encephalomyelitis without Causing Hypercalcemia.

Vitamin D receptor (VDR) agonists are currently the agents of choice for the treatment of psoriasis, a skin inflammatory indication that is believed to involve an autoimmune component. 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D(3)], the biologically active metabolite of vitamin D, has shown efficacy in animal autoimmune disease models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. However, the side effect of 1,25-(OH)(2)D(3) and its synthetic secosteroidal analogs is hypercalcemia, which is a major impediment in their clinical development for autoimmune diseases. Hypercalcemia develops as a result of the action of VDR agonists on the intestine. Here, we describe the identification of a VDR modulator (VDRM) compound A that was transcriptionally less active in intestinal cells and as a result exhibited less calcemic activity in vivo than 1,25-(OH)(2)D(3). Cytokine analysis indicated that the VDRM not only modulated the T-helper cell balance from Th1 to Th2 effector function but also inhibited Th17 differentiation. Finally, we demonstrate that the oral administration of compound A inhibited the induction and progress of experimental autoimmune encephalomyelitis in mice without causing hypercalcemia.

Comparative effects of teriparatide and strontium ranelate in the periosteum of iliac crest biopsies in postmenopausal women with osteoporosis.

The periosteum contains osteogenic cells that regulate the outer shape of bone and contribute to determine its cortical thickness, size and position. We assessed the effects of subcutaneous injections of teriparatide (TPTD, 20µg/day) or oral strontium ranelate (SrR, 2g/day) in postmenopausal women with osteoporosis on new bone formation activity at the periosteal and endosteal bone surfaces using dynamic histomorphometric measurements. Evaluable tetracycline-labeled transiliac crest bone biopsies were analyzed from 27 patients in the TPTD group, and 22 in the SrR group after six months of treatment. Measurements were conducted on the thicker and thinner cortices separately, and comparisons between the thicker, thinner and combined cortices were carried out. At the combined periosteal cortex, the mineralization surface as a percent of bone surface (MS/BS%) was greater for TPTD (mean±SE: 8.08±1.22%) than SrR (3.22±1.05%) (p<0.005). The difference in mineral apposition rate (MAR) between TPTD (0.35±0.06µm/day) and SrR (0.14±0.06µm/day) was also significant (p<0.05), while that of bone formation rate per bone surface (BFR/BS) between TPTD (0.014±0.004 mm(3)/mm(2)/year) and SrR (0.004±0.003 mm(3)/mm(2)/year) was not (p=0.057). Statistically significant differences between the two treatments were also observed for MS/BS%, BFR/BS, MAR and the double-labeled perimeter in the periosteum of the thicker, but not thinner, iliac crest cortices. The comparison between the thicker and thinner cortices of both periosteal and endosteal surfaces showed statistically significant differences for MAR and the double-labeled perimeter for TPTD treated women. There were no statistically significant differences in any bone formation dynamic measurements between the two cortices in the SrR group. In conclusion, most of the bone formation and mineralization variables were significantly higher for TPTD- than SrR-treated women at both the periosteal and endosteal combined cortices. The response to TPTD for dynamic bone formation measurements in the periosteal surface was greater for the thicker than thinner cortex, but this difference was not significant in SrR treated patients. This may reflect a greater ability of TPTD to enhance responsiveness of bone to the mechanical loading environment. These effects on bone formation may underlie the improvement in bone quality in patients with osteoporosis treated with TPTD.

Longitudinal in vivo analysis of the region-specific efficacy of parathyroid hormone in a rat cortical defect model.

PTH has been shown to enhance fracture repair; however, exactly when and where PTH acts in this process remains to be elucidated. Therefore, we conducted a longitudinal, region-specific analysis of bone regeneration in mature, osteopenic rats using a cortical defect model. Six-month-old rats were ovariectomized, and allowed to lose bone for 2 months, before being subjected to bilateral 2-mm circular defects in their femoral diaphyses. They were then treated for 5 wk with hPTH1-38 at doses of 0, 3, 10, or 30 microg/kg . d and scanned weekly by in vivo quantitative computed tomography. Quantitative computed tomography analyses showed temporal, dose-dependent increases in mineralization in the defects, intramedullary (IM) spaces, and whole diaphyses at the defect sites. Histomorphometry confirmed PTH stimulation of primarily woven bone in the defects and IM spaces, but not the periosteum. After necropsy, biomechanical testing identified an increase in strength at the highest PTH dose. Serum procollagen type I N-terminal propeptide concentration showed a transient increase due to drilling, but procollagen type I N-terminal propeptide also increased with PTH treatment, whereas tartrate-resistant acid phosphatase unexpectedly decreased. Analyses of lumber vertebra confirmed systemic efficacy of PTH at a nonfracture site. In summary, PTH dose dependently induced new bone formation within defects, at endocortical surfaces, and in IM spaces, resulting in faster and greater bone healing, as well as efficacy at other skeletal sites. The effects of PTH were kinetic, region specific, and most apparent at high doses that may not be entirely clinically relevant; therefore, clinical studies are necessary to clarify the therapeutic utility of PTH in bone healing.

Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators.

Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine. In order to discover VDR ligands with less hypercalcemia liability, we sought to identify tissue-selective VDR modulators (VDRMs) that act as agonists in some cell types and lack activity in others. Here, we describe LY2108491 and LY2109866 as nonsecosteroidal VDRMs that function as potent agonists in keratinocytes, osteoblasts, and peripheral blood mononuclear cells but show poor activity in intestinal cells. Finally, these nonsecosteroidal VDRMs were less calcemic in vivo, and LY2108491 exhibited more than 270-fold improved therapeutic index over the naturally occurring VDR ligand 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in an in vivo preclinical surrogate model of psoriasis.

Teriparatide [PTH(1-34)] strengthens the proximal femur of ovariectomized nonhuman primates despite increasing porosity.

UNLABELLED: OVX monkeys treated for 18 months with 1 or 5 microg/kg/d teriparatide [PTH (1-34)] had significantly stronger proximal femora relative to ovariectomized controls. Teriparatide enhancement of cortical area, cortical width, and trabecular bone volume seemed to more than compensate for the dose-dependent increase in cortical porosity. Beneficial effects of teriparatide treatment on the proximal femur persisted beyond the treatment period and may extend to the marrow. INTRODUCTION: We conducted a detailed quantitative analysis of the effects of teriparatide on the proximal femur of ovariectomized monkeys. Teriparatide increased bone mass, enhanced structural architecture, and strengthened the hip, despite increasing cortical porosity. MATERIALS AND METHODS: Monkeys were treated with vehicle (sham or OVX controls), 1 microg/kg/day teriparatide [parathyroid hormone (1-34); PTH1], or 5 microg/kg/day teriparatide (PTH5) for 18 months or for 12 months followed by 6 months of treatment withdrawal (PTH1W and PTH5W, respectively). Excised proximal femora were analyzed by microCT, conventional histomorphometry, and biomechanics. RESULTS AND CONCLUSIONS: The femoral neck showed significant reduction in trabecular bone volume (BV/TV) for OVX compared with sham, whereas PTH1 BV/TV was restored to sham levels and PTH5 BV/TV was greater than sham and OVX. The withdrawal groups had BV/TVs intermediate between sham and OVX. PTH1 had trabecular number (Tb.N) greater than OVX, and PTH5 Tb.N was greater than sham and OVX. The withdrawal groups had Tb.Ns intermediate between sham and OVX. No differences between groups were observed for trabecular orientation or trabecular thickness. Teriparatide dose-dependently increased bone formation rate and activation frequency in the femoral neck. Cellular composition analyses suggested a tendency of ovariectomy to increase adiposity of marrow by 100%, whereas PTH tended to reduce adipocyte number and increase osteoblast number compared with OVX. Analyses of the cortex showed dose-dependent elevation of cortical porosity, which was consistent with enhanced bone turnover with treatment. Cortical porosity was reduced after withdrawal of teriparatide, because PTH1W cortical porosity was lower than OVX, whereas PTH5W cortical porosity was intermediate between sham and OVX. Increased cortical porosity did not weaken the proximal femora. Biomechanics showed that ovariectomy weakened proximal femora compared with sham, but PTH1, PTH5, and PTH1W were stronger than OVX and not different from sham. PTH5W strength was intermediate between sham and OVX. Therefore, teriparatide had beneficial effects on the proximal femur, despite increasing cortical porosity. Cortical porosity did not adversely affect the mechanical integrity of the proximal femora, because enhanced cortical area and trabecular bone volume more than compensated for the porosity. Much of the beneficial effects of teriparatide were retained after 6 months withdrawal from treatment. PTH effects on the femoral neck were not limited to bone but may include inhibition of OVX-stimulated adiposity of the marrow.

Plasma CPU-86017 concentrations regarding suppression of ouabain-induced cardiac arrhythmias and decrease of heart rate in guinea pigs.

AIM: To determine the effective plasma levels of CPU-86017 which could suppress the cardiac arrhythmias induced by i.v. ouabain in guinea pigs. METHODS: The cardiac arrhythmias and the heart rate were monitored by ECG traces. Blood samples were collected to determine plasma levels using HPLC assay. TXB2 and 6-keto-PGF1 alpha were measured in plasma. RESULTS: The plasma concentrations of CPU-86017 which were effective to suppress ventricular fibrillation (VF) and heart rate were 0.13-0.23 mg/L and 0.13-0.31 mg/L, respectively. A reduction of TXB2 levels and an elevation of 6-keto-PGF1 alpha levels were observed after CPU-86017 i.v. administration. CONCLUSION: The arrhythmia-suppressing and heart rate-slowing effect of CPU-86017 followed a linear relationship with its concentrations in plasma.

Growth hormone requirement for a normal human adipocyte glucose carrier function.

One of the most prominent actions of insulin is stimulation of the glucose carrier in different cell types, especially adipose cells. However, the exact mechanism of the mode of action of insulin, between receptor binding and stimulation of glucose transport, is not understood in detail. We have shown earlier, that GH plays an important role in the control of the insulin-sensitive glucose carrier system in rat fat cells. In this study, we measured glucose transport in fat cells of normal probands, GH-deficient (GHD) and GH-treated GHD patients. From sc fat tissue biopsies of three GHD patients, fat cells were isolated after digestion with collagenase. In normal fat cells, basal glucose transport was slow (t/2 = 2.5 min) and stimulated by insulin (t/2 = 0.8 min), as expected. In fat cells of GHD patients glucose transport was maximal already in the basal state (t/2 = 0.8 min) without an additional effect of insulin. After GH administration during several months to GHD patients, glucose transport was again slow in the basal state (t/2 = 3.2 min) and could be stimulated by insulin (t/2 = 0.7 min). These results confirm our earlier findings in rat adipocytes for human adipocytes: GH in vivo is responsible for a glucose transport-limiting factor in the plasma membrane that restricts basal glucose transport and is acutely inhibited by insulin resulting in enhanced glucose transport. These results demonstrate the physiological importance of GH for a normal function of the insulin transmembrane signaling system in fat tissue and indicate a possible benefit of GH administration in adult GHD patients.