Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Ameliorating effects of Acanthopanax koreanum extract and components on nicotine dependence and withdrawal symptoms.

Tobacco smoking is a serious health problem in society. While smoking rates are declining, smoking remains a serious risk to national health. Currently, there are several medications available to aid in smoking cessation. However, these medications have the disadvantages of low success rates in smoking cessation and various side effects. Therefore, natural-based smoking cessation aids are being suggested as a good alternative due to their accessibility and minimal side effects. The roots and stems of Acanthopanax koreanum (AK) Nakai, a plant that is native to Jeju Island, South Korea, have traditionally been used as tonic and sedatives. Moreover, eleutheroside B and chlorogenic acid are the main components of AK stem extract. In the present study, we investigated the effect of 70% ethanol AK extract and its components on ameliorating nicotine dependence and withdrawal symptoms by using behavioural tests in mice. In addition, alterations in the dopaminergic and DRD1-EPAC-ERK-CREB pathways were observed using dopamine ELISA and western blotting using mouse brains. Our findings demonstrate that the AK extract and its components effectively mitigated the effects of nicotine treatment in behavioural tests. Furthermore, it normalized the dopamine concentration and the expression level of nicotine acetylcholine receptor α7. Additionally, it was observed that AK extract and its components led to the normalization of DRD1, ERK and CREB expression levels. These results indicate that AK extract exhibits effects in ameliorating nicotine dependence behaviour and alleviating withdrawal symptoms. Moreover, EB and CGA are considered potential marker components of AK extract.

Fabrication of Superhydrophobic Water-Pinning Surfaces through Integration of Silica Colloids into Cellulose Nanocrystals.

The water-pinning effect is a phenomenon in which water droplets adhere to a surface and do not roll off, even when the surface is tilted or turned upside down. This effect holds great potential for applications in various areas, such as dew collection in arid regions, anti-drip function for a greenhouse, and liquid transport and control. However, creating surfaces that exhibit this effect poses challenges, necessitating materials with both hydrophobicity and high adhesive force along with a scalable, cost-effective method to produce the essential geometries that have not yet been established. To address these challenges, we propose a straightforward coating approach involving silica nanoparticles (SiO2) and cellulose nanocrystals (CNCs) to fabricate artificial water-pinning surfaces. We assessed the water-pinning ability of the coated surface through measurements of the contact angle, contact radius, and hysteresis. Remarkably, the coated surface exhibited a contact angle of approximately 153.87° and a contact radius of around 0.89 mm when a 10 µL water droplet was applied, demonstrating its resistance to rolling off, even at a tilting angle of 90°. The droplet only began to fall when its volume reached approximately 33 µL, requiring a substantial water pinning force of 323.4 µN. We also investigated the physicochemical characteristics of the SiO2@CNC coating surface, including morphology, chemical composition, and chemical structure, to unravel the underlying mechanism behind its water-pinning ability. Our proposed fabrication method offers a promising avenue for the development of functional biopolymer-based surfaces capable of precisely manipulating water droplets.

Comparison of treatment outcomes and complications of coil embolization in elderly and very elderly patients with cerebral aneurysms: a propensity score matching analysis.

PURPOSE: This single center study aims to compare the treatment outcomes and procedure-related complications of coil embolization in elderly patients (60-79 years) and very elderly patients (aged 80 years or older) with cerebral aneurysms. METHODS: Data was collected from 504 elderly patients aged 60 years or older who underwent coil embolization for intracranial aneurysms from 2018 to 2021. The study evaluated patient-related and anatomical factors and assessed various outcomes, comparing results between groups using statistical analysis and propensity score matching. RESULTS: A total of 503 cerebral aneurysms were analyzed from individuals aged 60-79 years (n = 472) and those aged 80 years or older (n = 31). The majority of the aneurysms were unruptured with an average size of 3.5 mm in height and 3.4 mm in width. The patients were compared using 1:1 propensity score matching, and no significant differences were found in factors other than age and aortic elongation. Logistic analysis revealed that being over 80 years old and having a severe aortic arch elongation were identified as risk factors for procedure-related events in both total and unruptured cases. CONCLUSIONS: The study compared coil embolization treatment for cerebral aneurysms in patients aged 60-79 and over 80, finding no significant difference in treatment outcomes except for procedure-related events. Procedure-related events were associated with severe aortic arch elongation and being over 80 years old. Coil embolization can be considered safe and effective for patients over 80, but further trials are needed for accurate conclusions.

Effect of Loop Electrosurgical Excision Procedure on Sexual Dysfunction in Korean Women.

BACKGROUND: The role of the cervix in female sexual functioning is controversial. The loop electrosurgical excision procedure (LEEP) induces structural changes in the cervix. This study aimed to investigate whether LEEP affected sexual dysfunction in Korean women. METHODS: A prospective cohort study enrolled 61 sexually active women with abnormal Papanicolaou smear or cervical punch biopsy results and required LEEP. The patients were assessed before and six to twelve months after LEEP using the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS). RESULTS: The prevalence of female sexual dysfunction according to FSFI scores before and after LEEP was 62.5% and 66.7%, respectively. LEEP-related changes in total FSFI and FSDS scores were not significant (P = 0.399 and P = 0.670, respectively). The frequency of sexual dysfunction in the desire, arousal, lubrication, orgasm, satisfaction, and pain subdomains of the FSFI was not significantly altered by LEEP (P > 0.05). The proportion of women experiencing sexual distress according to FSDS scores did not significantly increase after LEEP (P = 0.687). CONCLUSION: A large proportion of women with cervical dysplasia experience sexual dysfunction and distress both before and after LEEP. LEEP itself may be not associated with negative effects on female sexual function.

Development of a sorafenib-loaded solid self-nanoemulsifying drug delivery system: Formulation optimization and characterization of enhanced properties.

Sorafenib, marketed under the brand name Nexavar®, is a multiple tyrosine kinase inhibitor drug that has been actively used in the clinical setting for the treatment of several cancers. However, the low solubility and bioavailability of sorafenib constitute a significant barrier to achieving a good therapeutic outcome. We developed a sorafenib-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation composed of capmul MCM, tween 80, and tetraglycol, and demonstrated that the SNEDDS formulation could improve drug solubility with excellent self-emulsification ability. Moreover, the sorafenib-loaded SNEDDS exhibited anticancer activity against Hep3B and KB cells, which are the most commonly used hepatocellular carcinoma and oral cancer cell lines, respectively. Subsequently, to improve the storage stability and to increase the possibility of commercialization, a solid SNEDDS for sorafenib was further developed through the spray drying method using Aerosil® 200 and PVP K 30. X-ray diffraction and differential scanning calorimeter data showed that the crystallinity of the drug was markedly reduced, and the dissolution rate of the drug was further improved in formulation in simulated gastric and intestinal fluid conditions. In vivo study, the bioavailability of the orally administered formulation increases dramatically compared to the free drug. Our results highlight the use of the solid-SNEDDS formulation to enhance sorafenib's bioavailability and outlines potential translational directions for oral drug development.

A double-blind, Randomized controlled trial on glucose-lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase-4 inhibitor therapy: REFIND study.

AIMS: To compare the efficacy and safety of adding low-dose lobeglitazone (0.25 mg/day) or standard-dose lobeglitazone (0.5 mg/day) to patients with type 2 diabetes mellitus (T2DM) with inadequate glucose control on metformin and dipeptidyl peptidase (DPP4) inhibitor therapy. MATERIALS AND METHODS: In this phase 4, multicentre, double-blind, randomized controlled, non-inferiority trial, patients with T2DM insufficiently controlled by metformin and DPP4 inhibitor combination therapy were randomized to receive either low-dose or standard-dose lobeglitazone. The primary endpoint was non-inferiority of low-dose lobeglitazone in terms of glycaemic control, expressed as the difference in mean glycated haemoglobin levels at week 24 relative to baseline values and compared with standard-dose lobeglitazone, using 0.5% non-inferiority margin. RESULTS: At week 24, the mean glycated haemoglobin levels were 6.87 ± 0.54% and 6.68 ± 0.46% in low-dose and standard-dose lobeglitazone groups, respectively (p = .031). The between-group difference was 0.18% (95% confidence interval 0.017-0.345), showing non-inferiority of the low-dose lobeglitazone. Mean body weight changes were significantly greater in the standard-dose group (1.36 ± 2.23 kg) than in the low-dose group (0.50 ± 1.85 kg) at week 24. The changes in HOMA-IR, lipid profile and liver enzyme levels showed no significant difference between the groups. Overall treatment-emergent adverse events (including weight gain, oedema and hypoglycaemia) occurred more frequently in the standard-dose group. CONCLUSIONS: Adding low-dose lobeglitazone to metformin and DPP4 inhibitor combination resulted in a non-inferior glucose-lowering outcome and fewer adverse events compared with standard-dose lobeglitazone. Therefore, low-dose lobeglitazone might be one option for individualized strategy in patients with T2DM.

Topological analysis of the gp41 MPER on lipid bilayers relevant to the metastable HIV-1 envelope prefusion state.

The membrane proximal external region (MPER) of HIV-1 envelope glycoprotein (gp) 41 is an attractive vaccine target for elicitation of broadly neutralizing antibodies (bNAbs) by vaccination. However, current details regarding the quaternary structural organization of the MPER within the native prefusion trimer [(gp120/41)3] are elusive and even contradictory, hindering rational MPER immunogen design. To better understand the structural topology of the MPER on the lipid bilayer, the adjacent transmembrane domain (TMD) was appended (MPER-TMD) and studied. Membrane insertion of the MPER-TMD was sensitive both to the TMD sequence and cytoplasmic residues. Antigen binding of MPER-specific bNAbs, in particular 10E8 and DH511.2_K3, was significantly impacted by the presence of the TMD. Furthermore, MPER-TMD assembly into 10-nm diameter nanodiscs revealed a heterogeneous membrane array comprised largely of monomers and dimers, as enumerated by bNAb Fab binding using single-particle electron microscopy analysis, arguing against preferential trimeric association of native MPER and TMD protein segments. Moreover, introduction of isoleucine mutations in the C-terminal heptad repeat to induce an extended MPER α-helical bundle structure yielded an antigenicity profile of cell surface-arrayed Env variants inconsistent with that found in the native prefusion state. In line with these observations, electron paramagnetic resonance analysis suggested that 10E8 inhibits viral membrane fusion by lifting the MPER N-terminal region out of the viral membrane, mandating the exposure of residues that would be occluded by MPER trimerization. Collectively, our data suggest that the MPER is not a stable trimer, but rather a dynamic segment adapted for structural changes accompanying fusion.

The dopaminergic alterations induced by 4-F-PCP and 4-Keto-PCP may enhance their drug-induced rewarding and reinforcing effects: Implications for abuse.

Novel psychoactive substances remain the popular recreational drugs of use over the years. They continue to bypass government restrictions due to their synthesis and modifications. Recent additions to the lists are the 4-F-PCP and 4-Keto-PCP, analogs of the drug phencyclidine (PCP) known to induce adverse effects and abuse potential. However, studies on the abuse potential of 4-F-PCP and 4-Keto-PCP remain scarce. The rewarding and reinforcing effects of the drugs were assessed using conditioned place preference (CPP), self-administration, and locomotor sensitization tests. Dopamine (DA) receptor antagonists (SCH23390 and haloperidol) were administered during CPP to evaluate the involvement of the mesolimbic dopaminergic system. DA-related protein expression in the nucleus accumbens (NAcc) and ventral tegmental area (VTA) was measured. Additionally, phosphorylated cyclic-adenosine monophosphate-activated protein (AMP) response element-binding (p-CREB) protein, deltaFosB (∆FosB), and brain-derived neurotrophic factor (BDNF) protein levels in the NAcc were measured to assess the addiction neural plasticity effect of the drugs. Both 4-F-PCP and 4-Keto-PCP-induced CPP and self-administration; however, only 4-F-PCP elicited locomotor sensitization. Treatment with DA receptor antagonists (SH23390 and haloperidol) inhibited the 4-F- and 4-Keto-induced CPP. Both substances altered the levels of DA receptor D1 (DRD1), thyroxine hydroxylase (TH), DA receptor D2 (DRD2), p-CREB, ∆FosB, and BDNF. The results suggest that 4-F-PCP and 4-Keto-PCP may induce abuse potential in rodents via alterations in dopaminergic system accompanied by addiction neural plasticity.

Effect of Quality Control Program in Surgical Management of Early Cervical Cancer.

BACKGROUND: Regular assessments of clinical performance in gynecologic cancer surgery is important for the safety of patients. We evaluated the effects of quality control (QC) program on the treatment pattern and clinical outcomes of early cervical cancer. METHODS: Medical records of cervical cancer patients who received operation in our institution from January 2007 to December 2018 were retrospectively reviewed. Cases were divided into 2 groups, before and after the initiation of QC program, group 1 (2007-2013) and group 2 (2014-2018), based on the operation date. Two groups were compared in clinicopathologic variables, surgical methods, operative details, adjuvant treatments, recurrence and survival. RESULTS: A total of 305 cervical cancer patients were included in the analysis, 210 in group 1 and 95 in group 2. In group 2, minimally invasive surgery (MIS) was more frequently performed (60.0% vs. 76.8%, P = 0.004), especially in earlier stages (stage IA, 72.6% vs. 100.0%; stage IB, 52.2% vs. 69.5%). However, the median tumor size treated by MIS was decreased in stage IB (20 mm vs. 17 mm, P = 0.015). Frequency of adjuvant treatment was also reduced in stage IB (56.5% vs. 37.3%, P = 0.016). Recurrence within 3 years, 3-year disease free survival and overall survival did not show significant difference; however, 3-year recurrence after MIS was significantly reduced in stage IB. CONCLUSION: QC program enforced stricter patient selection criteria for MIS and positively affected clinical outcomes in cervical cancer patients who underwent surgery. Systemic monitoring should be considered for patient safety.

Disparities between Uptake of Germline BRCA1/2 Gene Tests and Implementation of Post-test Management Strategies in Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients.

BACKGROUND: To assess the rate of germline BRCA gene tests in epithelial ovarian cancer (EOC) patients and uptake of post-test risk management strategies in BRCA1/2-mutated patients. METHODS: Institutional databases were searched to identify patients who were diagnosed with epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) between 2009 and 2019 in two academic hospitals. Retrospective review on medical records was performed to collect clinico-pathologic variables, including performance of germline BRCA gene test and its results, as well as conduct of breast cancer screening tests and cascade testing. If annual mammography +/- breast ultrasonography was performed, it was considered that regular breast cancer surveillance was done. RESULTS: A total of 840 women with EOC were identified during the study period. Of these, 454 patients (54.0%) received BRCA gene testing and 106 patients (106/454, 23.3%) were positive for BRCA1/2 mutations. The rate of BRCA tests has markedly increased from 25.8% in 2009-2012 to 62.7% in 2017-2019. Among the 93 patients with BRCA1/2 mutation without previous personal breast cancer history, 20 patients (21.5%) received annual mammography with or without breast ultrasonography for regular surveillance. Among the 106 BRCA1/2-mutated EOC patients, cascade testing on family members was performed only in 13 patients (12.3%). CONCLUSION: Although BRCA1/2 gene tests have been substantially expanded, the uptake of post-test risk management strategies, including breast cancer screening for BRCA1/2-mutated patients and cascade testing for family members, has remained low. Strategies to increase its uptake and education about the importance of post-test risk managements are needed.

The FGFR Family Inhibitor AZD4547 Exerts an Antitumor Effect in Ovarian Cancer Cells.

The dysregulation of fibroblast growth factor (FGF) signaling has been implicated in tumorigenesis, tumor progression, angiogenesis, and chemoresistance. The small-molecule AZD4547 is a potent inhibitor of FGF receptors. This study was performed to investigate the antitumor effects and determine the mechanistic details of AZD4547 in ovarian cancer cells. AZD4547 markedly inhibited the proliferation and increased the apoptosis of ovarian cancer cells. AZD4547 also suppressed the migration and invasion of ovarian cancer cells under nontoxic conditions. Furthermore, it attenuated the formation of spheroids and the self-renewal capacities of ovarian cancer stem cells and exerted an antiangiogenic effect. It also suppressed in vivo tumor growth in mice. Collectively, this study demonstrated the antitumor effect of AZD4547 in ovarian cancer cells and suggests that it is a promising agent for ovarian cancer therapy.

Disseminated Primary Pulmonary Choriocarcinoma Successfully Treated by Chemotherapy: A Case Report and Literature Review.

Primary pulmonary choriocarcinoma (PPC) is frequently fatal due to difficulties in diagnosis. Few cases of PPC are bilateral and involve exceptionally large nodules. Here, we report an unusual case of PPC involving disseminated bilateral nodules, which was misdiagnosed as tuberculosis, but successfully treated using chemotherapy. A review of 65 cases revealed six cases of bilateral disease, including the present one. Patients treated with surgery, chemotherapy, or a combination of both showed similar treatment outcomes; however, chemotherapy may be the preferred option. Despite its rarity, PPC should be included in the differential diagnosis for all lung nodules to enable early detection.

Efficacy and safety of evogliptin treatment in patients with type 2 diabetes: A multicentre, active-controlled, randomized, double-blind study with open-label extension (the EVERGREEN study).

AIM: To investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes. MATERIALS AND METHODS: In this 12-week, multicentre, randomized, double-blind, active-controlled, and 12-week open-label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%-10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92). RESULTS: After 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was -0.85% and -0.75%, respectively. The between-group difference was -0.10% (95% CI: -0.32 to 0.11), showing non-inferiority based on a non-inferiority margin of 0.4%. The change in MAGE was -24.6 mg/dL in the evogliptin group and -16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by -0.94%, with HbA1c values of <7.0% in 80.2% of the patients. The incidence and types of adverse events were comparable between the two groups for 24 weeks. CONCLUSION: In this study, the glucose-lowering efficacy of evogliptin was non-inferior to linagliptin. It was maintained at week 24 with a 0.94% reduction in HbA1c. Evogliptin therapy improved glycaemic variability without causing any serious adverse events in patients with type 2 diabetes.

25B-NBOMe, a novel N-2-methoxybenzyl-phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential.

An increasing number of N-2-methoxybenzyl-phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B-NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self-administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD1 ), dopamine D2 (DRD2 ), and serotonin 2A (5-HT2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B-NBOMe-mediated effects. We also examined the effects of 25B-NBOMe on the expression of dopamine-related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p-CREB), deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5-HT2A receptors in the 25B-NBOMe-induced head twitch response (HTR). We also examined the effects of 25B-NBOMe on brain wave activity using electroencephalography. 25B-NBOMe elicited CPP and SA. SCH and HAL blocked 25B-NBOMe-induced CPP, whereas KS did not. Moreover, 25B-NBOMe altered the DRD1 , DRD2 , and dopamine transporter expression and increased dopamine levels. It also induced changes in p-CREB, ΔFosB, and BDNF expression. 25B-NBOMe induced HTR and increased 5-HT2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B-NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B-NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential.

SPSB1 enhances ovarian cancer cell survival by destabilizing p21.

SPRY domain-containing SOCS box protein 1 (SPSB1) is an E3 ligase adaptor protein with unknown functions in cancer cells. In this study, we found that SPSB1 knockdown markedly decreased the viability and migration of ovarian cancer cells, while ectopic SPSB1 overexpression in IL-3-dependent Ba/F3 cells significantly increased their proliferation rate compared with empty vector-transfected cells. SPSB1 knockdown significantly elevated p21 protein and mRNA levels and induced apoptosis in ovarian cancer cells, as evidenced by increased levels of cleaved PARP and decreased levels of Bcl-2. Notably, mechanistic investigations revealed that SPSB1 accelerated p21 destabilization by directly interacting with p21 and promoting its ubiquitin-mediated proteasomal degradation. Taken together, our findings provide novel insights into the role of SPSB1 in ovarian cancer cells.

The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice.

Drug addiction is a chronic and relapsing brain disorder, influenced by complex interactions between endogenous and exogenous factors. Per2, a circadian gene, plays a role in drug addiction. Previous studies using Per2-knockout mice have shown a role for Per2 in cocaine, morphine and alcohol addiction. In the present study, we investigated the role of Per2 in methamphetamine (METH) addiction using Per2-overexpression and knockout mice. We observed locomotor sensitization responses to METH administration, and rewarding effects using a conditioned place preference test. In addition, we measured expression levels of dopamine and dopamine-related genes (monoamine oxidase A, DA receptor 1, DA receptor 2, DA active transporter, tyrosine hydroxylase and cAMP response element-binding protein 1) in the striatum of the mice after repeated METH treatments, using qRT-PCR. Per2-overexpressed mice showed decreased locomotor sensitization and rewarding effects of METH compared to the wildtype mice, whereas the opposite was observed in Per2 knockout mice. Both types of transgenic mice showed altered expression levels of dopamine-related genes after repeated METH administration. Specifically, we observed lower dopamine levels in Per2-overexpressed mice and higher levels in Per2-knockout mice. Taken together, Per2 expression levels may influence the addictive effects of METH through the dopaminergic system in the striatum of mice.

Metabolic changes in urine and serum during progression of diabetic kidney disease in a mouse model.

Diabetic kidney disease (DKD) involves various pathogenic processes during progression to end stage renal disease, and activated metabolic pathways might be changing based on major pathophysiologic mechanisms as DKD progresses. In this study, nuclear magnetic resonance spectroscopy (NMR)-based metabolic profiling was performed in db/db mice to suggest potential biomarkers for early detection and its progression. We compared concentrations of serum and urinary metabolites between db/m and db/db mice at 8 or 20 weeks of age and investigated whether changes between 8 and 20 weeks in each group were significant. The metabolic profiles demonstrated significantly increased urine levels of glucose and tricarboxylic acid cycle intermediates at both 8 and 20 weeks of age in db/db mice. These intermediates also exhibited strong positive associations with urinary albumin excretion, suggesting that they may be potential biomarkers for early diagnosis. On the contrary, branched chain amino acid and homocysteine-methionine metabolism were activated early in the disease, whereas ketone and fatty acid metabolism were significantly changed in the late phase of the disease. We demonstrated phase-specific alterations in metabolites during progression of DKD. This study provides insights into perturbed mechanisms during evolution of the disease and identifies potential novel biomarkers for DKD.

Thyroidectomy stimulates glucagon-like peptide-1 secretion and attenuates hepatic steatosis in high-fat fed rats.

Thyroid hormones (THs) as a therapeutic intervention to treat obesity has been tried but the effect of THs on body weight and the mechanistic details of which are far from clear. This study was designed to determine and elucidate the mechanistic details of metabolic action of THs in high-fat diet (HFD) fed Sprague Dawley (SD) rats. Rats were made surgically hypothyroid (thyroidectomy, Thx). Body weights and food and water intake profoundly decreased in HFD fed thyroidectomized group (HN Thx). Results showed that delayed insulin response, increased total cholesterol, high-density lipoprotein, and low-density lipoprotein in HN Thx. Unexpectedly, however, Thx reduced serum and hepatic triglyceride concentrations. Further studies revealed that Thx dramatically increased circulating GLP-1 as well as increased expressions of GLP-1 in small intestine. Diminished hepatic expressions of lipogenic genes, were observed in HN Thx group. Beta-catenin and glutamine synthetase, a known target of ß-catenin, were up-regulated in the liver of HN Thx group. The expressions of gluconeogenic genes G6P and PCK were reduced in the liver of HN Thx group. The results may suggest that surgery-induced hypothyroidism increases GLP-1, the actions of which may in part be responsible for the reduction in water intake, appetite and hepatic steatosis.

Unique binding mode of Evogliptin with human dipeptidyl peptidase IV.

Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl) piperazine-2-one)) is a highly potent selective inhibitor of dipeptidyl peptidase IV (DPP4) that was approved for the treatment of type 2 diabetes in South Korea. In this study, we report the crystal structures of Evogliptin, DA-12166, and DA-12228 (S,R diastereomer of Evogliptin) complexed to human DPP4. Analysis of both the structures and inhibitory activities suggests that the binding of the trifluorophenyl moiety in the S1 pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S2 extensive subsite, and that the multiple hydrogen bonds made by the (R)-ß-amine group in the S2 pocket and the contacts made by the (R)-tert-butyl group with Arg125 contribute to the high potency observed for Evogliptin.