Butanolides and clerodane diterpenes from the twigs of Casearia grewiifolia and their effects on adiponectin secretion.

Three butanolides derivatives, grewiifolides A-C, and nine clerodane diterpenes, grewiifolins M-U, as well as a known sterol were isolated from the twigs of Casearia grewiifolia. The chemical structures and configurations of all isolates were established by various spectroscopic means and chemical derivatization. In a cell-based phenotypic assay using the adipogenesis model of human bone marrow mesenchymal stem cells (hBM-MSCs), grewiifolide B significantly promoted adiponectin-secretion with EC50 value of 24.8 µM. In target identification studies, butanolide derivatives were selectively bound to PPARγ with Ki values of 4.65, 0.55, and 17.8 µM, respectively. Further functional analysis and molecular modeling revealed that grewiifolide B promotes adiponectin-secretion through PPARγ full agonism.

Endoscopic anterior to psoas lumbar interbody fusion: indications, techniques, and clinical outcomes.

PURPOSE: The retrospective study aimed to report the surgical technique and clinic-radiological outcomes of endoscopic anterior to psoas interbody lumbar fusion through the retroperitoneal approach with direct and indirect decompression. METHODS: We retrospectively analyzed the results of clinical parameters of patients who underwent endoscopic anterior to psoas interbody lumbar fusion between June 2013 and June 2022. Clinical outcomes were evaluated by the visual analog scale (VAS) and Oswestry Disability Index (ODI) scores. The radiological outcomes were measured and statistically compared in disc height index (DHI), whole lumbar lordosis (WLL), pelvic Incidence (PI), pelvic tilt (PT), Segmental lordosis (SL), the sagittal vertical axis (SVA). RESULTS: A total of 35 patients were selected for the procedure ranging in age from 51 to 84 years with 17.83 ± 8.85 months follow-up. The mean operation time in lateral position for one level was 162.96 ± 35.76 min (n = 24), and 207.73 ± 66.60 min for two-level fusion. The mean endoscopic time was 32.83 ± 17.71 min per level, with a total estimated blood loss of 230.57 ± 187.22 cc. The mean postoperative VAS back, leg pain score and ODI improved significantly compared to the preoperative values; Radiological data showed significant change in WLL, SL, DHI, PI, PT, and SS; however, there is no significant difference in SVA postoperatively. Subgroup analysis for the radiographic data showed 50 mm length cage has significantly improved for the DHI, SS and SVA compare to 40 mm length cage. The subgroup analysis results showed that hypertensive patients had significantly higher proportion in the incomplete fusion group compare to complete fusion group at one-year follow-up. OUTCOMES: The endoscopic anterior to psoas interbody lumbar fusion achieves satisfactory indirect and direct decompression. This convergent technique presents an effective choice for treating lumbar instability associated with disc herniations and foraminal stenosis, thus complementing the indications for oblique lumbar interbody fusion.

The relationship between digit ratio (2D:4D) and muscular fitness: A systematic review and meta-analysis.

BACKGROUND: Digit ratio (2D:4D), a marker of prenatal testosterone exposure, is a weak negative correlate of sports/athletic/fitness performance. While numerous studies have examined the relationship between 2D:4D and physical fitness, there has never been a comprehensive study that has synthesized studies examining relationships between 2D:4D and muscular fitness. OBJECTIVES: To systematically review and meta-analyze the relationship between 2D:4D and muscular fitness measured as handgrip strength (HGS). METHODS: We systematically searched five electronic databases, reference lists, topical systematic reviews/meta-analyses, and personal libraries in November 2020. Peer-reviewed, cross-sectional studies that reported Pearson's correlation coefficients between objectively measured 2D:4D and HGS were included. We used random-effects meta-analysis to estimate the pooled correlation and the 95% confidence interval (95%CI), and moderator analyses to estimate the influence of sex and age. RESULTS: Data from 22 studies, representing 5271 individuals from 11 countries ranging in (mean) age from 10.4 to 58.0 years, were included. Overall, there was a weak negative correlation between 2D:4D and HGS (r = -0.15, 95%CI = -0.20 to -0.09), indicating that individuals with low 2D:4Ds had high HGS. We found substantial heterogeneity between studies (Q = 123.4, p < .0001; I2  = 74%), but neither sex (Q = 0.003, p = .96) nor age (Q = 0.46, p = .50) significantly moderated the pooled correlation. CONCLUSIONS: We found a weak negative relationship between 2D:4D and HGS, which showed substantial heterogeneity between studies, but was neither moderated by sex nor age. Our finding probably reflects both the long-term (organizational) and short-term (activational) benefits of testosterone.

Influence of Occupational Socialization on the Perspectives and Practices of Adapted Physical Education Teachers.

The purpose of this study was to describe and examine the occupational socialization of nine adapted physical educators (APEs). The questions we attempted to answer were (a) What were the perspectives and practices of the APEs? and (b) What factors influenced these perspectives and practices? Data were collected through six qualitative techniques and analyzed by using analytic induction and constant comparison. At the time the study was conducted, the APEs possessed traditional or progressive teaching orientations. They had been attracted to a career as an APE through their participation in sport and physical activity and interactions with persons with disabilities. The quality of adapted physical education teacher education the APEs received varied, but high-quality adapted physical education teacher education appeared to exert a powerful influence on their values and pedagogies. The school cultures and conditions in which the APEs worked on entry into the workforce either served to support or negate their programs. We conclude the paper by providing several hypotheses regarding the influences of occupational socialization on in-service APEs' teaching.

Individually differentiated serotonergic raphe nuclei measured with brain PET/MR imaging.

PURPOSE: To measure the activity of individual raphe nuclei with fluorine 18 fluorodeoxyglucose (FDG) and carbon 11 ((11)C) 3-amino-4-(2-dimethylaminomethylphenylthio) benzonitrile (DASB) imaging using a brain positron emission tomography(PET)/magnetic resonance (MR) imaging fusion system. MATERIALS AND METHODS: The study was approved by the Institutional Review Board of Gil Medical Center, and all volunteers provided written informed consent. FDG PET, (11)C-DASB PET, and T2*-weighted MR images from seven healthy volunteers were acquired by using a PET/MR imaging fusion system. The standard uptake value ratio (SUVR) of FDG (FDG-SUVR) and nondisplaceable binding potential (BPnd) of (11)C-DASB (DASB-BPnd) were determined for each raphe nucleus. A Pearson correlation analysis was performed to show the correlation between FDG-SUVR and DASB-BPnd for the raphe nuclei. RESULTS: Each raphe nucleus could be distinguished in both FDG (identifiability ratio, 0.86; κ = 0.77) and (11)C-DASB (identifiability ratio, 0.89; κ = 0.72) images. The mean values of DASB-BPnd for each raphe nucleus from dorsal to caudal direction were 6.08 (raphe nucleus 1), 5.93 (raphe nucleus 2), 3.86 (raphe nucleus 3), 3.18 (raphe nucleus 4), and 2.74 (raphe nucleus 5); the mean FDG-SUVR values were 1.00 (raphe nucleus 1), 1.00 (raphe nucleus 2), 0.87 (raphe nucleus 3), 0.94 (raphe nucleus 4), and 0.90 (raphe nucleus 5). FDG-SUVR and DASB-BPnd for the raphe nuclei were significantly correlated (r = 0.506, P = .002). CONCLUSION: Serotonergic activity, both glucose metabolism and transporter binding potential of raphe nuclei, were measured with a brain-dedicated PET/MR imaging system and showed a significant correlation.

Neural substrates of Hanja (Logogram) and Hangul (Phonogram) character readings by functional magnetic resonance imaging.

The two basic scripts of the Korean writing system, Hanja (the logography of the traditional Korean character) and Hangul (the more newer Korean alphabet), have been used together since the 14th century. While Hanja character has its own morphemic base, Hangul being purely phonemic without morphemic base. These two, therefore, have substantially different outcomes as a language as well as different neural responses. Based on these linguistic differences between Hanja and Hangul, we have launched two studies; first was to find differences in cortical activation when it is stimulated by Hanja and Hangul reading to support the much discussed dual-route hypothesis of logographic and phonological routes in the brain by fMRI (Experiment 1). The second objective was to evaluate how Hanja and Hangul affect comprehension, therefore, recognition memory, specifically the effects of semantic transparency and morphemic clarity on memory consolidation and then related cortical activations, using functional magnetic resonance imaging (fMRI) (Experiment 2). The first fMRI experiment indicated relatively large areas of the brain are activated by Hanja reading compared to Hangul reading. The second experiment, the recognition memory study, revealed two findings, that is there is only a small difference in recognition memory for semantic transparency, while for the morphemic clarity was much larger between Hanja and Hangul. That is the morphemic clarity has significantly more effect than semantic transparency on recognition memory when studies by fMRI in correlation with behavioral study.

Navigation-guided endoscopic lumbar decompression on foramen and lateral recess in advanced scoliosis.

An 84-year-old woman presented with left leg radiating pain for 18 months and a numeric rating scale score of 8. From examination, motoric on left knee extension was grade 4, with dysesthesia and numbness along the left anterolateral thigh. Imaging showed left L3-4 foraminal and lateral recess stenosis with severe-degree scoliosis. The patient underwent navigation-guided endoscopic transforaminal foraminotomy and lateral recess decompression on the left L3-4 level with a good outcome. Three-years' follow-up showed a well-maintained clinical outcome and coronal sagittal balance. This video explores navigation-guided endoscopic lumbar decompression for neural compression in advanced scoliosis. Further research is encouraged to establish long-term efficacy. The video can be found here: https://stream.cadmore.media/r10.3171/2024.1.FOCVID23195.

Chemical constituents from the roots of Cynanchum wilfordii with PCSK9 secretion inhibitory activities.

From the Cynanchum wilfordii roots, 32 compounds, including 5 previously undescribed (1, 4-6, 12) and 27 known (2, 3, 7-11, 13-32) compounds, were isolated, and their structures were elucidated using NMR spectroscopic data and MS data aided by ECD calculations or the modified Mosher's reaction. All isolates were tested for their inhibitory effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion. Among the isolates, compound 4, a methyl cholesterol analog, exhibited the most potent effect in reducing PCSK9 secretion, along with PCSK9 downregulation at the mRNA and protein levels via FOXO1/3 upregulation. Moreover, compound 4 attenuated statin-induced PCSK9 expression and enhanced the uptake of DiI-LDL low-density lipoprotein. Thus, compound 4 is suggested to be a potential candidate for controlling cholesterol levels.

Super-resolution track-density imaging of thalamic substructures: comparison with high-resolution anatomical magnetic resonance imaging at 7.0T.

The thalamus is one of the most important brain structures, with strong connections between subcortical and cortical areas of the brain. Most of the incoming information to the cortex passes through the thalamus. Accurate identification of substructures of the thalamus is therefore of great importance for the understanding of human brain connectivity. Direct visualization of thalamic substructures, however, is not easily achieved with currently available magnetic resonance imaging (MRI), including ultra-high field MRI such as 7.0T, mainly due to the limited contrast between the relevant structures. Recently, improvements in ultra-high field 7.0T MRI have opened the possibility of observing thalamic substructures by well-adjusted high-resolution T1 -weighted imaging. Moreover, the recently developed super-resolution track-density imaging (TDI) technique, based on results from whole-brain fiber-tracking, produces images with sub-millimeter resolution. These two methods enable us to show markedly improved anatomical detail of the substructures of the thalamus, including their detailed locations and directionality. In this study, we demonstrate the role of TDI for the visualization of the substructures of the thalamic nuclei, and relate these images to T1-weighted imaging at 7.0T MRI.

Interlayer Tailoring of Ti-6Al-4V and 17-4PH Stainless Steel Joint by Tungsten Inert Gas Welding.

The development of robust and efficient methods for constructing and joining complex metal specimens with high bonding quality and durability is of paramount importance for various industries, e.g., aerospace, deep space, and automobiles. This study investigated the fabrication and characterization of two types of multilayered specimens prepared by tungsten inert gas (TIG) welding: Ti-6Al-4V/V/Cu/Monel400/17-4PH (Specimen 1) and Ti-6Al-4V/Nb/Ni-Ti/Ni-Cr/17-4PH (Specimen 2). The specimens were fabricated by depositing individual layers of each material onto a Ti-6Al-4V base plate, and subsequently welding them to the 17-4PH steel. The specimens exhibited an effective internal bonding without any cracks, accompanied by a high tensile strength, with Specimen 1 exhibiting a significantly higher tensile strength than Specimen 2. However, the substantial interlayer penetration of Fe and Ni in the Cu and Monel layers of Specimen 1 and the diffusion of Ti along the Nb and Ni-Ti layers in Specimen 2 resulted in a nonuniform elemental distribution, raising concerns about the lamination quality. This study successfully achieved elemental separation of Fe/Ti and V/Fe, which is vital for preventing the formation of detrimental intermetallic compounds, particularly in the fabrication of complex multilayered specimens, representing the prime novelty of this work. Our study highlights the potential of TIG welding for the fabrication of complex specimens with high bonding quality and durability.

Determination of Modified QuEChERS Method for Chlorothalonil Analysis in Agricultural Products Using Gas Chromatography-Mass Spectrometry (GC-MS/MS).

Chlorothalonil is an organochlorine fungicide that blocks the respiratory process of cells and persists in agricultural products because it is used extensively to prevent fungal diseases. An analytical method of chlorothalonil using the modified QuEChERS method and gas chromatography- mass spectrometry (GC-MS/MS) was developed to analyze the residue in agricultural commodities distributed in Republic of Korea. Acetonitrile, including acetic acid and formic acid, was used to compare the extraction efficiency. The extraction and purification processes were established by comparing three versions of the QuEChERS method and various dispersive solid-phase extraction (d-SPE) combinations. Ultimately, 1% formic acid in acetonitrile with QuEChERS original salts and d-SPE (PSA, C18) were selected for the extraction and clean-up procedures for method validation and establishment. Five agricultural commodities, viz., brown rice, mandarin, soybean, pepper, and potato, were examined to validate the established method, which displayed excellent linearity, with a coefficient of determination of R2 = 0.9939-0.997 in the calibration curve range of 0.002-0.1 mg/kg. The limits of detection (LOD) and quantification (LOQ) were calculated to be 0.003 mg/kg and 0.01, respectively, for the method. The LOQ value satisfied the suitable level for the Positive List System (PLS). The mean recovery of chlorothalonil was 79.3-104.1%, and the coefficient of variation was <17.9% for intra- and inter-day precision at 0.01, 0.1, and 0.5 mg/kg. The matrix effects in the five commodities were confirmed by the ion suppression effects, except for brown rice, in which a medium enhancement effect was observed at 21.4%. Chlorothalonil was detected in eight apples, one watermelon, and one cucumber. Ultimately, chlorothalonil was detected in ten agricultural products. Thus, this analytical method could be used for the routine detection of chlorothalonil in agricultural products, and the data may be used to inform and improve current food policies.

Interlaminar Endoscopic Lumbar Discectomy Versus Microscopic Lumbar Discectomy: A Preliminary Analysis of L5-S1 Lumbar Disc Herniation Outcomes in Prospective Randomized Controlled Trials.

OBJECTIVE: A preliminary report from a single institution, noninferiority, prospective randomized controlled trial is conducted to determine the effectiveness of interlaminar endoscopic lumbar discectomy (IELD) versus microscopic lumbar discectomy (MLD) for the treatment of L5-S1 lumbar disc herniation (LDH). METHODS: This prospective, noncrossover, randomized controlled trials was conducted at a single neurosurgical center. Patients with symptomatic radiculopathy or intermittent neurogenic claudication caused by LDH were enrolled from July 2016 to July 2021. The study compared the effectiveness of microscopic and full-endoscopic discectomy procedures. Outcome measures included visual analogue scale (VAS) scores for back and leg pain, Oswestry Disability Index scores, radiologic measurements, endurance time of walking, and satisfaction rate. RESULTS: Of 37 assessed patients, both IELD and MLD groups demonstrated significant improvements in VAS scores for pain over time, with no significant difference between them. For secondary outcomes, the IELD group had a shorter hospital stay and reduced blood loss but a longer operation time than the MLD group. Radiographic evaluations showed no change compared to preoperative data. Patient satisfaction and recovery rates were slightly higher for the MLD group, but both groups were comparable in most evaluations, with complications being minimal. CONCLUSION: The IELD was noninferior in improving the intensity of back and leg pain and functional disability, compared to the MLD. Additionally, the IELD showed no difference in clinical outcomes for patients in terms of radiographic results and patient satisfaction rates. The results of this research preliminarily demonstrate that the IELD could be considered an effective alternative to MLD for L5-S1 central or paracentral LDH.

Efficacy of Allograft Versus Bioactive Glass-Ceramic Cage in Anterior Cervical Discectomy and Fusion: A Randomized Controlled Study.

STUDY DESIGN: A randomized controlled trial. OBJECTIVE: The aim of this study is to compare the efficacy of allografts and bioactive glass-ceramic (BG) cages for anterior cervical discectomy and fusion (ACDF) in treating cervical degenerative disc disease. METHODS: We conducted a single-center, randomized controlled trial between August 2017 and August 2022. Participants were randomized into two groups, and consecutive patients requiring ACDF were randomly assigned to receive either the allograft cage or the BG cage. The surgical outcomes measured included pain levels, neck disability, surgical details, and radiological assessments. RESULTS: Of the 45 assessed, 40 participants were included, with 18 in the allograft cage group and 22 in the BG cage group. By the 12-month follow-up, both groups exhibited significant improvements in pain levels and disability scores, with no notable intergroup differences. Over 85% of patients in both groups were satisfied with their outcomes. Radiological assessments revealed stability in the cervical spine with both cage types post intervention. Although both materials showed a trend toward increased subsidence over time, the difference between them was not statistically significant. Fusion rates were comparable between the groups at 12 months, with BG cage showing a slightly higher early fusion rate at 6 months. No significant differences were observed between the two groups in terms of complications. CONCLUSIONS: Both allograft and BG cages are effective in ACDF surgeries for cervical degenerative disc disease, with both contributing to substantial postoperative improvements. Differences in disc height, interspinous motion, and subsidence were not significant in the last follow-up, indicating both materials' suitability for clinical use. Future research with a larger cohort and longer follow-up is needed to confirm these preliminary findings.

Oral Ingestion of AP Collagen Peptide Leads to Systemic Absorption of Gly-Pro-Hyp, Alleviating H2O2-Induced Dermal Fibroblast Aging.

Collagen-derived dipeptides and tripeptides have various physiological activities. In this study, we compared the plasma kinetics of free Hyp, peptide-derived Hyp, Pro-Hyp, cyclo(Pro-Hyp), Hyp-Gly, Gly-Pro-Hyp, and Gly-Pro-Ala after ingestion of four different collagen samples: AP collagen peptide (APCP), general collagen peptide, collagen, and APCP and γ-aminobutyric acid (GABA) combination. Each peptide was measured by high-performance liquid chromatography and triple quadrupole mass spectrometer. We found that, among all the peptides that were analyzed, only Gly-Pro-Hyp was significantly increased after ingestion of APCP compared with that of general collagen peptides and collagen. In addition, ingestion of the APCP and GABA combination improved the absorption efficiency of Gly-Pro-Ala. Finally, we reveal that Gly-Pro-Hyp was effective for preventing H2O2-induced reduction in extracellular matrix (ECM)-related genes, COL1A, elastin, and fibronectin, in dermal fibroblasts. Taken together, APCP significantly enhances the absorption of Gly-Pro-Hyp, which might act as an ECM-associated signaling factor in dermal fibroblasts, and the APCP and GABA combination promotes Gly-Pro-Ala absorption. Clinical Trial Registration number: UMIN000047972.

Simultaneous Screening of 322 Residual Pesticides in Fruits and Vegetables Using GC-MS/MS and Deterministic Health Risk Assessments.

The development of efficient methods for evaluating pesticide residues is essential in order to ensure the safety and quality of agricultural products since the Republic of Korea implemented the Positive List System (PLS). The objective of this research was to establish a method for the simultaneous analysis of 322 pesticide residues in fruits and vegetables (such as coffee, potato, corn, and chili pepper), using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) approach in combination with gas chromatography-tandem mass spectrometry (GC-MS/MS). This study introduces a robust, high-throughput GC-MS/MS method for screening the target pesticide residues in agricultural products, achieving the PLS criterion of 0.01 mg/kg LOQ. Despite some compounds not aligning with the CODEX recovery guideline, sufficient reproducibility was confirmed, attesting to the method's applicability in qualitative analyses. A health risk assessment conducted using estimated daily intake/acceptable daily intake ratios indicated low risks associated with product consumption (<0.035391%), thereby confirming their safety. This efficient method holds significant implications for the safe distribution of agricultural products, including during import inspections.

Glucose metabolism of the midline nuclei raphe in the brainstem observed by PET-MRI fusion imaging.

UNLABELLED: The brainstem contains various important monoaminergic neuronal centers, including the raphe nuclei which contain serotonergic neurons. The raphe nuclei, however, are not easily identifiable and located by conventional neuroimaging. METHODS: Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) were performed in seven healthy subjects using a new PET-MRI, which consists of a high-resolution research tomograph (HRRT) PET and 7.0 T-MRI. Glucose metabolism of raphe nuclei was semiquantitatively measured and identified along the midline brainstem region in vivo. RESULTS: Midline nuclei clustered in four groups appeared to be the raphe nuclei and could be clearly visualized; specifically, we identified the groups as the dorsal raphe, raphe reticularis centralis superior, raphe pontis, and raphe magnus group. CONCLUSION: FDG imaging of the midline raphe nuclei in vivo could potentially be an important tool for investigating brain diseases as well as conducting functional brain studies in the context of sleep disorders, depression, and neurodegenerative disease.

Low molecular weight (1 kDa) polyethylene glycol conjugation markedly enhances the hypoglycemic effects of intranasally administered exendin-4 in type 2 diabetic db/db mice.

An intranasally active glucagon-like peptide-1 (GLP-1) formulation would have great advantages over conventional injectable therapies for the treatment of diabetic patients. The purpose of this study was to investigate the biological potentials of PEGylated exendin-4 (PEG-Ex4) analogs administered intranasally and the effects of polyethylene glycol (PEG) molecular weight (1, 2, 5 kDa) on nasal absorption. Initially, PEGEx4 analogs were site-specifically PEGylated to Lys²7-amine, and their bioactivities and stabilities were studied in vitro. The hypoglycemic effects and pharmacokinetics of these analogs after nasal administration were evaluated in type 2 diabetic animal models. PEG-Ex4 analogs had 3.1-, 3.8-, and 5.9-fold increased stabilities in rat nasal homogenates than Ex4. However, Lys²7-PEG(1k)-Ex4 was found to have well-preserved bioactivities (83.3% potency vs. Ex4), and other analogs were found to have much lower bioactivities than Lys²7-PEG(1k)-Ex4. In particular, the in vivo pharmacokinetic parameters of Lys²7-PEG(1k)-Ex4 in intranasally administered rats were significantly improved by PEGylation. Area under the curve (AUC) values of Lys²7-PEG(1k)-Ex4 were 33.6-fold higher and circulating t(1/2) values was 27.1-fold higher than Ex4. But, other analogs were not effectively absorbed via the intranasal route, because the higher molecular weight PEG (over 2 kDa) limited intranasal absorption. Finally, in vivo hypoglycemic experiment showed that Lys²7-PEG(2k)-, Lys²7-PEG(5k)-Ex4 had significantly lower hypoglycemic efficacies than Lys²7-PEG(1k)-Ex4, probably because of their lower intrinsic bioactivities and intranasal absorptions. Taken together, our findings suggest that the site-specific conjugation of appropriately sized PEG (1 kDa) substitution onto peptides like Ex4 offers two advantages for deliveryvia the intranasal route, namely, increased stability and extended circulating half-life.

Ginseng Berry Extract Prevents Atherogenesis via Anti-Inflammatory Action by Upregulating Phase II Gene Expression.

Ginseng berry possesses higher ginsenoside content than its root, which has been traditionally used in herbal medicine for many human diseases, including atherosclerosis. We here examined the antiatherogenic effects of the Korean ginseng berry extract (KGBE) and investigated its underlying mechanism of action in vitro and in vivo. Administration of KGBE decreased atherosclerotic lesions, which was inversely correlated with the expression levels of phase II genes to include heme oxygenase-1 (HO-1) and glutamine-cysteine ligase (GCL). Furthermore, KGBE administration suppressed NF-κB-mediated expression of atherogenic inflammatory genes (TNF-α, IL-1ß, iNOS, COX-2, ICAM-1, and VCAM-1), without altering serum cholesterol levels, in ApoE(-/-) mice fed a high fat-diet. Treatment with KGBE increased phase II gene expression and suppressed lipopolysaccharide-induced reactive oxygen species production, NF-κB activation, and inflammatory gene expression in primary macrophages. Importantly, these cellular events were blocked by selective inhibitors of HO-1 and GCL. In addition, these inhibitors reversed the suppressive effect of KGBE on TNF-α-mediated induction of ICAM-1 and VCAM-1, resulting in decreased interaction between endothelial cells and monocytes. These results suggest that KGBE ameliorates atherosclerosis by inhibiting NF-κB-mediated expression of atherogenic genes via upregulation of phase II enzymes and thus has therapeutic or preventive potential for atherosclerosis.

Mono-PEGylated dimeric exendin-4 as high receptor binding and long-acting conjugates for type 2 anti-diabetes therapeutics.

Dimerization is viewed as the most effective means of increasing receptor binding affinity, and both dimerization and PEGylation effectively prolong the life spans of short-lived peptides and proteins in vivo by delaying excretion via the renal route. Here, we describe the high binding affinities of two long-acting exendin-4 (Ex4) conjugates, dimerized Ex4 (Di-Ex4) and PEGylated Di-Ex-4 (PEG-Di-Ex4). Di-Ex4 and PEG-Di-Ex4 were prepared using cysteine and amine residue specific coupling reactions using Ex4-Cys, bisMal-NH(2), and activated PEG. The Ex4 conjugates produced were of high purity (>98.5%), as determined by size-exclusion chromatography and MALDI-TOF mass spectrometry. The receptor binding affinity of Di-Ex4 on RIN-m5F cells was 3.5-fold higher than that of Ex4, and the in vivo antihyperglycemic efficacy of Di-Ex4 was also greater than that of native Ex4 in type 2 diabetic db/db mice. Furthermore, Di-Ex4 and PEG-Di-Ex4 were found to have greater blood circulating t(1/2) and AUC(inf) values than native Ex4 by 2.7- and 13.7-fold, and by 4.0- and 17.3-fold, respectively. Accordingly, hypoglycemic durations were greatly increased to 15.0 and 40.1 h, respectively, at a dose of 25 nmol/kg (native Ex4 7.3 h). The results of this study show that combined dimerization and PEGylation are effective when applied to Ex4, and suggest that PEG-Di-Ex4 has considerable potential as a type 2 anti-diabetic agent.

Direct visualization of Parkinson's disease by in vivo human brain imaging using 7.0T magnetic resonance imaging.

Parkinson's disease (PD) is a neurodegenerative disorder resulting from progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. Therefore, imaging of the SN has been regarded to hold greatest potential for use in the diagnosis of PD. At the 7.0T magnetic resonance imaging (MRI), it is now possible to delineate clearly the shapes and boundaries of the SN. We scanned eight early and two advanced PD patients, along with nine age-matched control subjects, using a 7.0T MRI in an attempt to directly visualize the SN and quantify the differences in shape and boundaries of SN between PD subjects in comparison with the normal control subjects. In the normal controls, the boundaries between the SN and crus cerebri appear smooth, and clean "arch" shapes that stretch ventrally from posterior to anterior. In contrast, these smooth and clean arch-like boundaries were lost in PD subjects. The measured correlation analyses show that, in PD patients, there is age-dependent correlation and substantially stronger UPDRS motor score-dependent correlation. These results suggest that, by using 7.0T MRI, it appears possible to use these visible and distinctive changes in morphology as a diagnostic marker of PD.