Malignant Transformation of Warthin Tumor in the Cervical Lymph Node.

ABSTRACT: Warthin tumor is the second most common benign tumor of salivary glands. Here we present an interesting case of squamous cell carcinoma arising from the Warthin tumor in the cervical lymph node. The patient had another Warthin tumor in the parotid gland as well. Both the malignant transformation of Warthin tumor and the heterotopic occurrence of Warthin tumor in the cervical lymph node are rare. This exceptionally rare case demonstrates that the 2 rare clinical entities can occur simultaneously and affect clinical decisions.

CCL24 Signaling in the Tumor Microenvironment.

Chemokines with their network play an important role in cancer growth, metastasis, and host-tumor interactions. Of many chemokines, C-C motif chemokine ligand 24 (CCL24) has been shown to contribute to tumorigenesis as well as inflammatory diseases like asthma, allergies, and eosinophilic esophagitis. CCL24 is expressed in some tumor cells such as colon cancer, hepatocellular carcinoma, and cutaneous T cell lymphoma. CCL24 can be used as a potential biomarker in several cancers including colon cancer, non-small cell cancer, and nasopharyngeal carcinoma as the plasma level of CCL24 is increased. The various functions of CCL24 contribute to the biology of cancer by M2 macrophage polarization, angiogenesis, invasion and migration, and recruitment of eosinophils.

Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway.

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. METHODS: Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. RESULTS: Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070-3.455, P = 0.029). CONCLUSIONS: Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

Characterization of IgA Deposition in the Kidney of Patients with IgA Nephropathy and Minimal Change.

Approximately 5% of patients with IgA nephropathy (IgAN) exhibit mild mesangial lesions with acute onset nephrotic syndrome and diffuse foot process effacement representative of minimal change disease (MCD). It is not clear whether these unusual cases of IgAN with MCD (IgAN-MCD) are variant types of IgAN or coincidental deposition of IgA in patients with MCD. In a retrospective multicenter cohort study of 18 hospitals in Korea, we analyzed 46 patients with IgAN-MCD. Patients with endocapillary proliferation, segmental sclerosis, and crescent were excluded, and the clinical features and prognosis of IgAN-MCD were compared with those of pure MCD. In addition, we performed galactose-deficient IgA1 (KM55) staining to characterize IgAN-MCD. Among the 21,697 patients with glomerulonephritis enrolled in the database, 46 patients (0.21%) were diagnosed with IgAN-MCD, and 1610 patients (7.4%) with pure MCD. The 46 patients with IgAN-MCD accounted for 0.6% of primary IgAN patients (n = 7584). There was no difference in prognosis between patients with IgAN-MCD and those with only MCD. IgA and KM55 showed double positivity in all patients with IgAN-MCD (n = 4) or primary IgAN (n = 5) under double immunofluorescent staining. However, in four patients with lupus nephritis, mesangial IgA was deposited, but galactose-deficient-IgA1 (Gd-IgA1) was not. These findings suggest that IgAN-MCD is a dual glomerulopathy in which MCD was superimposed on possibly indolent IgAN. We confirmed by KM55 staining that IgAN-MCD is true IgAN, enabling better characterizations of the disease. Furthermore, IgAN-MCD shows a good prognosis when treated according to the usual MCD treatment modality.

Hippo pathway and tumoral FOXP3 expression correlate with tumor growth in squamous cell carcinoma of the lung.

BACKGROUND: Expression of FOXP3 in tumors is associated with proliferation, migration, and invasion, has been implicated in cancer prognosis, and may be related to metastatic potential. The Hippo signaling pathway is known to regulate tissue homeostasis and organ size through cell proliferation and apoptosis. We investigated tumoral FOXP3, Lats2, and YAP expression related to the Hippo pathway in squamous cell carcinoma (SCC) of the lung. METHODS: Between 1983 and 2006, 149 cases of SCC were diagnosed and surgically resected at Kyung Hee University Hospital. Immunohistochemical staining for FOXP3, YAP, and Lats2 was done. RESULTS: Tumor size was inversely correlated with tumoral FOXP3 expression (p = 0.015), Treg count (p < 0.0001), and positive Lats2 expression (p = 0.028). YAP expression was inversely correlated with lymph node metastasis (p = 0.039). Positive tumoral FOXP3 expression was significantly associated with infiltrated Treg count (p = 0.001) and positive Lats2 expression (p = 0.007). CONCLUSION: Tumoral FOXP3 has the potential to suppress tumor function in SCC of the lung. The decrease or loss of FOXP3 expression in cancer cells is thought to contribute to SCC tumorigenesis and progression in the lung. The tumor suppressor function of FOXP3 in SCC of the lung was related to Lats2 and YAP expression in the Hippo pathway.

Substance P Improves Renal Ischemia Reperfusion Injury Through Modulating Immune Response.

Substance P (SP), an injury-inducible messenger that mobilizes bone marrow stem cells and modulates the immune response, has been suggested as a novel target for therapeutic agents. We evaluated the role of SP as an immune cell modulator during the progression of renal ischemic/reperfusion injury (IRI). Unilateral IRI induced the transient expression of endogenous SP and the infiltration of CCR7+ M1 macrophages in injured kidneys. However, SP altered the intrarenal macrophage polarization from CCR7+ M1 macrophages to CD206+ M2 macrophages in injured kidneys. SP also modulated bone marrow-derived neutrophils and mesenchymal stromal cells after IRI. SP treatment for 4 weeks starting one week after unilateral IRI significantly preserved kidney size and length and normal tubular structures and alleviated necrotic tubules, inflammation, apoptosis, and tubulointerstitial fibrosis. The beneficial effects of SP were accompanied by attenuation of intrarenal recruitment of CD4, CD8, and CD20 cells and abnormal angiogenesis. The immunomodulatory effect of SP suggested that SP could be a promising therapeutic target for preventing the progression of acute kidney injury to chronic kidney disease.

Recurrent breast amyloidosis associated with Sjögren's syndrome: A case report with description of the radiologic-pathologic correlation.

We describe the case of a 41-year-old woman with primary Sjögren's syndrome (SS) who presented multiple recurrences of breast amyloidosis. Each recurrence of breast amyloidosis showed different sonographic features, potentially mimicking malignancy. We briefly discuss the possible cause of this variability in imaging features based on the radiologic-histologic correlation.

The expression of C-MYC in gastric adenocarcinoma is associated with PD-L1 and FOXP3 expression: C-MYC overexpression is a good prognostic factor.

BACKGROUND: C-MYC appears to initiate and maintain tumorigenesis through modulation of immune regulatory molecules such as PD-L1. The aim of our research was to evaluate the clinical implication of C-MYC expression in gastric adenocarcinoma in relation to the expression of the immune regulatory molecules PD-L1 and FOXP3. METHODS: Tissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected at Kyung Hee University Hospital at Gangdong from 2006 to 2012. Immunohistochemical staining for C-MYC, PD-L1, CD8 and FOXP3 was done. RESULTS: C-MYC overexpression showed a significant correlation with smaller tumor size, lower T category, lower N category, lower recurrence rate, and less lymphatic invasion. And C-MYC overexpression was negatively correlated with PD-L1 expression. The tumoral FOXP3 was positively correlated with C-MYC overexpression and Tregs count. PD-L1 expression was positively correlated with Tregs, CD8 + T cells, and tumor infiltrating lymphocytes (TIL). Tregs count was positively correlated with CD8 + T cells and TIL. CD8 + T cells was positively correlated with TIL. CONCLUSION: We discovered that the immune regulatory effect of C-MYC and PD-L1, and the tumor suppressor function of tumoral FOXP3 had a significant influence on the tumor microenvironment (Tregs, CD8 + T cells, and tumor infiltrating lymphocytes) in a complex manner. The C-MYC overexpression is a good prognostic factor in gastric adenocarcinoma.

Alterations in Lipid Profile of the Aging Kidney Identified by MALDI Imaging Mass Spectrometry.

During aging, the kidney undergoes functional and physiological changes that are closely affiliated with chronic kidney disease (CKD). There is increasing evidence supporting the role of lipid or lipid-derived mediators in the pathogenesis of CKD and other aging-related diseases. To understand the role of lipids in various metabolic processes during kidney aging, we conducted matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) analysis in kidneys harvested from young (2 months old, n = 3) and old mice (24 months old, n = 3). MALDI-IMS analysis showed an increase in ceramide level and a decrease in sphingomyelin (SM) and phosphatidylcholine (PC) levels in kidneys of old mice. The increased expression of cPLA2 and SMPD1 protein in aged kidney was confirmed by immunohistochemistry and Western blot analysis. Our MALDI-IMS data showed the altered distribution of lipids in aged kidney as indicative of aging-related functional changes of the kidney. Combined analysis of MALDI-IMS and IHC confirmed lipidomic changes and expression levels of responsible enzymes as well as morphological changes.

Endocan as a marker of microvascular inflammation in kidney transplant recipients.

Endocan is a water-soluble proteoglycan exclusively secreted by vascular endothelium. Endocan levels may be elevated in kidney transplant recipients experiencing antibody-mediated rejection (ABMR), which is characterized by vascular inflammation in transplanted kidney. We evaluated the clinical relevance of endocan as markers of microvascular inflammation in patients who underwent kidney transplantation. Plasma and urinary endocan levels were measured in 203 kidney transplant recipients and were compared across different etiologies of allograft dysfunction and various pathologic scores. Both plasma and urinary endocan levels were significantly higher in patients with acute ABMR than those in patients with normal pathology, acute tubular necrosis (ATN), acute pyelonephritis, BK virus associated nephropathy (BKVN), and T-cell mediated rejection (TCMR). Patients with chronic active ABMR also exhibited significantly higher plasma and urinary endocan levels than patients with long-term graft survival. Scores of glomerulitis and peritubular capillaritis, which are typical features of microvascular inflammation, were significantly elevated in patients with higher plasma and/or urinary endocan levels. Furthermore, plasma and urinary endocan levels could effectively discriminate ABMR from ATN, BKVN, and TCMR. Finally, patients exhibiting high urinary and plasma endocan levels in acute ABMR group showed significantly worse renal survival. Altogether, plasma and urinary endocan levels may serve as potential markers of microvascular inflammation in kidney transplant recipients.

Lower Sympathetic Nervous System Density and ß-adrenoreceptor Expression Are Involved in Gastric Cancer Progression.

BACKGROUND/AIM: Identifying the role of the sympathetic nervous system (SNS) in tumor progression is among the most important challenges in cancer research. This study aimed to investigate the role of the SNS and ß-adrenoreceptor in gastric cancer progression. MATERIALS AND METHODS: The density of SNS was quantified by immunohistochemical staining for tyrosine hydroxylase in 115 surgically-resected gastric cancer specimens. Immunostaining for ß1- and ß2-adrenoreceptor was also performed to examine the ß-adrenoreceptor expression status in gastric cancer. Then the association of protein expression status with histological grade, pathological tumor stage (pT), and pathological node stage of gastric cancer was investigated. RESULTS: The SNS density of pT4 tumors was significantly lower than that of pT1-3 tumors. The SNS density was positively correlated with ß1-adrenoreceptor expression status. In addition, lower ß1-adrenoreceptor expression was significantly associated with increased lymph node metastasis. Reduced ß2-adrenoreceptor staining proportion was significantly associated with worse histological grade. Furthermore, the proportion of ß2-adrenoreceptor staining was significantly lower in tumors with diffuse-type histology, than those with intestinal-type histology. CONCLUSION: A lower SNS density and ß-adrenoreceptor expression was associated with an aggressive oncogenic behavior including worse histological grade, advanced pT, and increased lymph node metastasis. SNS and ß-adrenergic pathway are involved in the negative regulation of gastric cancer progression.

ALDH1 and tumor infiltrating lymphocytes as predictors for neoadjuvant chemotherapy response in breast cancer.

Many studies have reported that Aldehyde dehydrogenase 1 (ALDH1) and tumor-infiltrating lymphocytes (TIL) are related to breast cancer prognosis. However, the clinical significance of ALDH1 and tumor-infiltrating immune cells in breast cancer has not been fully investigated in patients who received neoadjuvant chemotherapy (NAC). We studied the significance of the expression of ALDH1 and the population of TIL for predicting the prognosis and chemotherapeutic response of patients with breast cancer who had received NAC. Forty patients who underwent NAC were enrolled in this study. ALDH1 and TIL (T cells and tumor associated macrophages) were evaluated before and after NAC. The influences of ALDH1 expression status and TIL populations on both prognosis and chemotherapeutic response were evaluated. ALDH1 positivity was related to estrogen receptor (p = 0.026) and progesterone receptor negativity (p = 0.025). Positive change of ALDH1 after NAC tended to be associated with a poor NAC response (p = 0.078). Patients with more CD8+ T cells before NAC and fewer CD68 (+) macrophages after NAC tended to have better OS, respectively (p = 0.086, p = 0.096). The chemotherapeutic response and prognosis of patients with breast cancer who received NAC are thought to be determined by the tumor microenvironment. Further research with more patients and a longer study period is needed.

Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease is associated with insulin resistance. Compound K (CK) is the final metabolite of panaxadiol ginsenosides that have been shown to exert antidiabetic effects. However, the molecular mechanism of the antidiabetic effects in the liver have not been elucidated; further, whether CK has beneficial effects in hepatosteatosis remains unclear. Therefore, we evaluated the effect of CK on hepatosteatosis as well as its mechanism in high-fat diet (HFD)-fed type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: Twenty-four-week-old male OLETF rats were assigned to four groups: control (saline), CK 10 mg/kg, CK 25 mg/kg, or metformin 300 mg/kg (positive control); all treatments were administered orally for 12 weeks. RESULTS: Fasting glucose levels of the CK25 group were significantly lower than those of the control group during the 12 weeks. The results of the oral glucose tolerance test showed that both the glucose concentration after glucose loading and the fasting insulin levels of the CK25 group were significantly lower than those of the control. Hepatosteatosis was significantly improved by CK25. CK25 and metformin significantly increased the phosphorylation of hepatic adenosine monophosphate-activated protein kinase (AMPK). CK25 significantly inhibited the expression of sterol regulatory element-binding protein-1c and fatty acid synthase, while upregulating that of peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1. CONCLUSIONS: CK improved glucose intolerance and hepatosteatosis in HFD-fed OLETF rats through AMPK activation, which has dual mode of action that involves decreasing the synthesis of fatty acids and increasing fatty acid oxidation.

Tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma: the tumor suppressor function of tumoral FOXP3 is related with the P21 expression in gastric adenocarcinoma.

The function and contribution of tumoral FOXP3 in gastric cancer development remain poorly understood. Thus, we studied the expression of tumoral FOXP3 and its relationship with the well-known tumor suppressor proteins P21 and P53 in gastric adenocarcinoma. The tissue microarray was constructed from 182 cases of gastric adenocarcinoma. The immunohistochemistry was performed on 4-µm tissue sections from each tissue microarray block. We found that positive tumoral FOXP3 expression was significantly correlated with a lower T category, a lower N category, a lower recurrence rate, and less lymphatic invasion. Furthermore, the survival analysis revealed that the tumoral FOXP3-positive group had significantly increased overall survival and disease-free survival rates compared with the tumoral FOXP3-negative group. Additionally, P21 expression showed a significant positive correlation with tumoral FOXP3 expression in gastric adenocarcinoma cells. Taken together, these findings demonstrate that tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma through increased expression of the tumor suppression protein P21.

Prognostic value of putative cancer stem cell markers (CD24, CD44, CD133, and ALDH1) in human papillary thyroid carcinoma.

We hypothesized that cancer stem cells (CSCs) are responsible for the poor outcome and aggressive clinicopathological factors. We surveyed the expression of selected CSC markers that are specifically expressed in thyroid papillary carcinoma (PTC). A total of 80 patients with PTC from 2011 to 2012 were enrolled. We selected CD24, CD44, CD133, and dehydrogenase 1 (ALDH1), as they have been suggested to be candidate CSC markers. Expression of these markers was investigated by immunohistochemical (IHC) staining. IHC staining for CD24, CD44, CD133 and ALDH1 was evaluated according to staining intensity and proportion. The intensity and proportion scores were multiplied together for a total score, which was either 0-2 (negative) or 3-7 (positive). IHC for CD133 in PTC was positive in 49 (61.3%) patients, and CD24 was positive in 28 (35.0%). Seventy-eight (97.5%) patients were CD44 positive and 79 (98.8%) were ALDH1 positive. When we assessed the relationship between CSC markers and clinicopathological factors in PTC, CD24 expression was inversely correlated with multifocality (p=0.045; odds ratio [OR], 0.370; 95% confidence interval [CI], 0.138-0.991) and CD44 expression was significantly correlated with a BRAF mutation (p=0.001; OR, 7.091; 95% CI, 4.101-12.262). However, CD133 and ALDH1 were not associated with any of the clinicopathological parameters. CD24 expression was inversely correlated with multifocality, and CD44 expression was significantly correlated with a BRAF mutation. Therefore, CD24 and CD44 are related to clinicopathological aggressive features and important for determining surgical extent in patients with PTC.

Predictor of abnormal gallbladder ejection fraction in patients with atypical biliary pain: Histopathological point of view.

Cholescintigraphy has traditionally been used as a tool to select patients with biliary pain for elective cholecystectomy. However, atypical biliary pain presents a clinical challenge and there is no literature evaluating the factors of the gallbladder (GB) wall related to abnormal ejection fraction of cholescintigraphy in such patients. Therefore, we aimed to evaluate characteristics of the GB wall in patients with abnormal gallbladder ejection fraction (GBEF) on cholescintigraphy and atypical biliary pain. Patients who underwent cholescintigraphy for atypical biliary pain and subsequent cholecystectomy were initially recruited for this study. Medical records and pathologic findings of these patients were retrospectively reviewed. Parameters that were significant on univariate analysis, including factors of GB wall and cholescintigraphy, were subsequently tested by multivariate analysis to identify independent predictors for abnormal GBEF. Abnormal or low GBEF was defined as GBEF <35%. A total of 41 adult patients were divided into a low GBEF (n = 15) and a high GBEF group (n = 26) based on the cutoff value of 35%. In univariate analysis mean muscle thickness, muscle to total layer ratio, and muscle to fibrosis layer ratio were significantly higher in the low GBEF group than in the high GBEF group. In multivariate analysis, the muscle to fibrosis layer ratio was found to be an independent risk factor for abnormal GBEF (odds ratio = 3.514, 95% confidence interval = 1.058-11.673, P = .04). The fibrosis to total layer ratio was negatively correlated with GBEF in the low GBEF group (r = -0.657, P < .01). Muscle to fibrosis layer ratio was significantly associated with decreased GBEF. The fibrosis thickness ratio also seems to play an important role in patients with decreased GBEF.

Distinctive interrelation of p53 with SCO2, COX, and TIGAR in human gastric cancer.

PURPOSE: p53, widely known as a tumor-suppressing gene, has recently been reported to regulate glucose metabolism in human cancers through the synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase complex (COX), and TP53-induced glycolysis and apoptosis regulator (TIGAR). In this study, we investigated the interrelations of the aforementioned proteins, particularly in human gastric cancer, with cancer progression, other clinicopathological parameters, and patient outcomes. MATERIALS AND METHODS: One hundred and ten cases of primary gastric cancer occurring from June 2006 to June 2009 were investigated and classified into two groups according to the intensity of immunohistochemical staining for p53, SCO2, COX, and TIGAR. The clinicopathological data were organized and analyzed based on electronic medical records. RESULTS: In accordance with previous reports, the expression of p53 showed an inverse correlation with the expression of TIGAR (p=0.032) in gastric cancer cells. However, the expression of SCO2 and COX were not shown to be associated with the regulatory role of p53, unlike TIGAR expression. Nevertheless, a significantly high recurrence rate was found in a patient group with high COX expression (p=0.012). CONCLUSIONS: This study demonstrated that a high p53 expression could be associated with the promotion of glycolysis in gastric cancer via the modulation of TIGAR expression. In addition, a high COX expression appeared to be interrelated with poor prognosis of gastric cancer. However, further studies regarding the underlying molecular interactions are required to provide more evidence to propose a novel mechanism that explains our findings in gastric cancer.

The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes.

OBJECTIVE: Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes. METHODS: Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation. RESULTS: Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis. CONCLUSION: Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes.

Suppression of GLTSCR2 expression in renal cell carcinomas.

Nucleolar protein PICT-1/GLTSCR2 (GLTSCR2) has both tumor suppressive and oncogenic activities, depending on the types of cancer tissue and its expression level. The role of GLTSCR2 in renal cell carcinoma (RCC) has not yet been addressed. The aims of this study were to evaluate GLTSCR2 expression in RCC tissue and to determine pathological significance of GLTSCR2 in terms of tumor grade. RCC and adjacent normal tissue from 84 different patients was retrieved from nephrectomy specimens. The expression level of GLTSCR2 in RCC tissues was determined via immunohistochemical staining and invasion was determined using transwell chambers with Matrigel-coated membranes. The expression of GLTSCR2 was suppressed in about 80% of the carcinoma specimens compared to noncancerous renal tissue and inversely correlated with Fuhrman nuclear grade (r=-0.40, p<0.05). Knockdown of GLTSCR2 expression increased the invasiveness of SNU267 RCC cells. The expression of GLTSCR2 was suppressed in RCCs and its downregulation accentuated the malignant phenotype.