Objective To examine whether polymorphisms of histone deacetylase( HDACs) and environment factors can be implicated in type 2 diabetes mellitus ( T2DM) ，and to provide evidence for the prevention and treatment of T2DM． Methods In 2017，T2DM patients and controls were selected from 17 villages in Huadu District，Guangzhou． According the Diagnostic criteria for T2DM，the case group of T2DM was matched with control group from the population diagnosed as normal by gender，age no more than 5 years old，and from the same natural village． Conditional logistic regression model was used to analyze the effect of gene and environment and their interaction on T2DM． Results The average age of 499 cases group were ( 61．53±13．08) years old，and the average age of 499 controls group were ( 61．48±13．09) years old． There were no statistic difference between two groups． Furthermore，the two groups were gender－balanced too． In conditional logistic regression model，we found that glycerin trilau- rate ( TG) abnormalities ( OR= 2．410，95% CI: 1．755－3．310，P＜0．001) and cholesterol total ( TC) ab- normalities ( OR= 1．436，95% CI: 1．046－1．972，P = 0．025) were risk factors for T2DM． The subjects carries rs72792338 TC+TT genotype ( OR= 0．526，95% CI: 0．349－0．793，P= 0．002) had lower the risk to develop T2DM． Conclusions Abnormal TG and TC are risk factors for T2DM． Rs72792338 TT and TC genotype carryings decrease the risk of T2DM．

OBJECTIVES: To investigate the protective effects and potential mechanisms of Shenhua Tablet (, SHT) on the toll-like receptors (TLRs)-mediated signaling pathways in a rat model of kidney ischemia-reperfusion injury (IRI). METHODS: Sixty male Wistar rats were randomly divided into 5 groups: sham surgery, model control, astragaloside (150 mg•kg•d), low- and high-dose SHT (1.5 and 3.0 g•kg•d, repectively) groups. One week after drug treatment, rats underwent surgery to establish the IRI models. At 24 h and 72 h after the modeling, serum creatinine (Scr) and blood urea nitrogen (BUN) were analyzed; pathological damage were scored after periodic acid-Schiffstaining. TLR2, TLR4 and myeloid differentiation factor 88 (MyD88) protein and mRNA expressions were detected by inmmunohistochemistry, Western blot and qPCR. Tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) protein expressions were detected by enzyme linked immunosorbent assay. RESULTS: Compared with the sham group, the model group exhibited severe change in renal function (Scr: 189.42±21.50, P<0.05), pathological damage (damage score: 4.50±0.55, P<0.05), and the expression levels of TLR2, TLR4, MyD88, TNF-α, IL-6 were significantly higher than other groups. Meanwhile, the levels of TLRs in model group showed upward tendency from 24 to 72 h, unparalleled with pathological and functional changes. The aforementioned parameters were alleviated to a certain extent, and, in addition to TLRs, presented the obvious downward trending from the 24 to 72 h after the intervention in the SHT and astragaloside groups relative to the model (P<0.05); in particular, the most significant mitigation of these changes was observed in the SHT-H group (P<0.05). CONCLUSION TLRs may be an important spot to treat and research in acute kidney injury. SHT could effectively mitigate renal injuries and promote recovery of IRI injuries through suppression of degeneration induced by up-regulation of TLR2 and TLR4 expression levels in the MyD88-dependent signaling pathway and exhibit some dose dependence.
Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; Kidney ; blood supply ; drug effects ; Male ; Myeloid Differentiation Factor 88 ; analysis ; genetics ; Rats ; Rats, Wistar ; Reperfusion Injury ; physiopathology ; prevention & control ; Signal Transduction ; drug effects ; Tablets ; Toll-Like Receptors ; analysis ; drug effects ; genetics

Background:Chronic kidney disease (CKD) with moderate-to-severe renal dysfunction usually exhibits an irreversible course,and available treatments for delaying the progression to end-stage renal disease are limited.This study aimed to assess the efficacy and safety of the traditional Chinese medicine,Niaoduqing particles,for delaying renal dysfunction in patients with stage 3b-4 CKD.Methods:The present study was a prospective,randomized,double-blind,placebo-controlled,multicenter clinical trial.From May 2013 to December 2013,300 CKD patients with an estimated glomerular filtration rate (eGFR) between 20 and 45 ml,min-1· 1.73 m-2,aged 18-70 years were recruited from 22 hospitals in 11 Chinese provinces.Patients were randomized in a 1∶1 ratio to either a test group,which was administered Niaoduqing particles 5 g thrice daily and 10 g before bedtime for 24 weeks,or a control group,which was administered a placebo using the same methods.The primary endpoints were changes in baseline serum creatinine (Scr) and eGFR after completion of treatment.The primary endpoints were analyzed using Student's t-test or Wilcoxon's rank-sum test.The present study reported results based on an intention-to-treat (ITT) analysis.Results:A total of 292 participants underwent the ITT analysis.At 24 weeks,the median (interquartile range) change in Scr was 1.1 (-13.0-24.1) and 11.7 (-2.6-42.9) μmol/L for the test and control groups,respectively (Z =2.642,P =0.008),and the median change in eGFR was-0.2 (-4.3-2.7) and-2.2 (-5.7-0.8) ml·min-1.1.73 m-2,respectively (Z =-2.408,P =0.016).There were no significant differences in adverse events between the groups.Conclusions:Niaoduqing particles safely and effectively delayed CKD progression in patients with stage 3b-4 CKD.This traditional Chinese medicine may be a promising alternative medication for patients with moderate-to-severe renal dysfunction.

OBJECTIVETo study the prevention effect of salidroside on contrast-induced-nephropathy (CIN) and its underlying mechanism.

METHODSA total of 24 Wistar rats were randomly divided into 4 groups with 6 in each group. Rats were firstly administrated with normal saline (control and model groups), N-acetylcysteine (NAC, NAC group) and salidroside (salidroside group) for 7 days before model establishment in each group, respectively. Histopathological analysis was performed by periodic acid-Schiff (PAS) staining. Oxidative stress related parameters including superoxide dismutase (SOD) and methane dicarboxylic aldehyde (MDA), nitric oxide (NO), angiotensin II (Ang II), 8-hydroxy-2'-deoxyguanosine (8-OHdG), mRNA and protein levels of endothelial nitric oxide synthase (eNOS), and nitric oxide synthase (NOS) activity were measured.

RESULTSCompared with the control group, the levels of MDA, Ang II and 8-OHdG were all significantly increased and levels of SOD, NO, and eNOS mRNA and protein were decreased significantly in the model group (P<0.05). Meanwhile, the NOS activity was also significantly decreased in the model group (P<0.05). In addition, the levels of these parameters were all improved in the NAC (P<0.05) and salidroside groups and no significant different was found between these two groups (P>0.05).

CONCLUSIONSalidroside can be the potential substitute of NAC to prevent CIN. The underlying mechanism may be associated with oxidative stress damage caused by contrast agents.

Acetylcysteine ; pharmacology ; Animals ; Contrast Media ; adverse effects ; Cytoprotection ; drug effects ; Glucosides ; pharmacology ; Kidney ; drug effects ; pathology ; Kidney Diseases ; chemically induced ; prevention & control ; Oxidative Stress ; drug effects ; Phenols ; pharmacology ; Rats ; Rats, Wistar ; Signal Transduction ; drug effects

OBJECTIVETo observe the effect of Compound Shenhua Tablet (, SHT) on the sodium-potassium- exchanging adenosinetriphosphatase (Na(+)-K(+)-ATPase) in the renal tubular epithelial cells of rats with acute ischemic reperfusion and to investigate the mechanisms underlying the effects of SHT on renal ischemic reperfusion injury (RIRI).

METHODSFifty male Wistar rats were randomly divided into the sham surgery group, model group, astragaloside group [150 mg/(kg·d)], SHT low-dose group [1.5 g/(kg·d)] and SHT high-dose group [3.0 g/(kg·d)], with 10 rats in each group. After 1 week of continuous intragastric drug administration, surgery was performed to establish the model. At either 24 or 72 h after the surgery, 5 rats in each group were sacrificed, blood biochemistry, renal pathology, immunoblot and immunohistochemical examinations were performed, and double immunofluorescence staining was observed under a laser confocal microscope.

RESULTSCompared with the sham surgery group, the serum creatinine (SCr) and blood urea nitrogen (BUN) levels were significantly increased, Na(+)-K(+)-ATPase protein level was decreased, and kidney injury molecule-1 (KIM-1) protein level was increased in the model group after the surgery (P<0.01 or P<0.05). Compared with the model group, the SCr, BUN, pathological scores, Na(+)-K(+)-ATPase, and the KIM-1 protein level of the three treatment groups were significantly improved at 72 h after the surgery (P<0.05 or P<0.01). And the SCr, BUN of the SHT low- and high-dose groups, and the pathological scores of the SHT high-dose group were significantly lower than those of the astragaloside group (P<0.05). The localizations of Na(+)-K(+)-ATPase and megalin of the model group were disrupted, with the distribution areas overlapping with each other and alternately arranged. The severity of the disruption was slightly milder in three treatment groups compared with that of the model group. The results of immunofluorescence staining showed that the SHT high-dose group had a superior effect as compared with the astragaloside group and the SHT low-dose group.

CONCLUSIONSThe SHT effectively alleviated RIRI caused by ischemic reperfusion, promoted the recovery of the polarity of renal tubular epithelial cells, and protected the renal tubules. The therapeutic effects of SHT were superior to those of astragaloside as a single agent.

Acute Disease ; Animals ; Blood Urea Nitrogen ; Cell Adhesion Molecules ; metabolism ; Chromatography, Liquid ; Creatinine ; blood ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Fluorescent Antibody Technique ; Immunoblotting ; Kidney Function Tests ; Kidney Tubules ; blood supply ; drug effects ; enzymology ; pathology ; Low Density Lipoprotein Receptor-Related Protein-2 ; metabolism ; Male ; Rats ; Rats, Wistar ; Reperfusion Injury ; drug therapy ; enzymology ; pathology ; Saponins ; analysis ; Sodium-Potassium-Exchanging ATPase ; metabolism ; Staining and Labeling ; Tablets

OBJECTIVETo investigate the impact of a traditional Chinese medicinal compound known as Fufang Shenhua Tablet (SHP) on the expression of Toll-like receptors (TLRs) during renal ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) in rats.

METHODSA total of 28 Wistar rats were randomly divided into five groups: (1) pseudo-operation control group, (2) ischemia-reperfusion model group, (3) Astragaloside group, (4) high-dose SHP group, and (5) low-dose SHP group. There were four rats in the pseudo-operation group and six rats in each of the other groups. The accepted ischemia-reperfusion model was established after a 7-day gavage intervention, and pathological changes and renal function were observed, using an enzyme-linked immunosorbent assay (ELISA) to detect interleukin 8 (IL-8) and interferon gamma (IFN-γ) levels, as well as immunohistochemical staining to detect altered levels of TLR2 and TLR4 expression in renal tissue.

RESULTSAfter 24 h, renal pathological damage and the expression levels of serum creatinine (Scr), IL-8, IFN-γ, TLR2, and TLR4 were significantly higher in the model group as compared with the pseudo-operation group (P<0.05). In addition, at 24 h the above indicators decreased significantly in the Astragaloside group, high-dose SHP group and low-dose SHP group as compared with the ischemia-reperfusion model group (P< 0.05). TLR2 and TLR4 expression levels were significantly reduced in the SHP treatment and Astragaloside group as compared with the pseudo-operation group (P<0.05). Further, the high-dose SHP group showed significantly less renal damage score and decreased levels of TLR expression than those of low-dose SHP group and Astragaloside group (all P<0.05).

CONCLUSIONSHP can alleviate the renal structural and functional damage caused by IRI-induced AKI in rats by reducing the damage of renal pathology, which may reduce inflammatory cytokine levels by downregulating the expression of TLRs in renal tissue in a dose-dependent manner.

Acute Kidney Injury ; etiology ; metabolism ; Animals ; Drugs, Chinese Herbal ; pharmacology ; Enzyme-Linked Immunosorbent Assay ; Immunohistochemistry ; Interferon-gamma ; blood ; Interleukin-8 ; blood ; Kidney Tubules ; drug effects ; metabolism ; Male ; Rats ; Rats, Wistar ; Reperfusion Injury ; complications ; Tablets ; Toll-Like Receptor 2 ; metabolism ; Toll-Like Receptor 4 ; metabolism

BACKGROUNDIntegrin-linked kinase (ILK) dysregulation is involved in the progression of diabetic nephropathy (DN). The aim of this study was to investigate the effects of angiotensin II receptor blocker (ARB), irbesartan, on ILK expression and podocyte injury in DN.

METHODSDN was induced by the combined feeding of high-sucrose, high-fat diet and intra-peritoneal injection of low dose of streptozotocin (35 mg/kg) in spontaneously hypertensive rats. Diabetic rats were treated with irbesartan (50 mg×kg(-1)×d(-1)) by gavage for 8 weeks. The renal morphologic changes and podocyte injury were investigated by light and electron microscopy, and the ILK expression was evaluated by real-time RT-PCR and Western blotting analysis.

RESULTSDiabetic rats exhibited with the similar clinical feature of type 2 DN. Morphologically, they were characterized by expansion of mesangial matrix, loss of podocyte and podocyte injury. Impressively, compared to controls, the ILK expression in diabetic rats were upregulated, which were positively correlated with both podocyte injury and albuminuria. Irbesartan significantly prevented ILK overexpression, along with the amelioration of podocyte injury and albuminuria.

CONCLUSIONSILK plays an important role in mediating podocyte injury in DN; irbesartan inhibits ILK upregulation and attenuates podocyte injury, which might offer a new insight into the role of ARB in preventing DN progression.

Angiotensin Receptor Antagonists ; therapeutic use ; Animals ; Biphenyl Compounds ; therapeutic use ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Enzyme Activation ; drug effects ; Male ; Podocytes ; drug effects ; Protein-Serine-Threonine Kinases ; metabolism ; Rats ; Rats, Inbred SHR ; Tetrazoles ; therapeutic use

In order to search for novel inhibitors of Na+/H+ exchanger isoform-1 (NHE-1), nine feruloylagmatine analogues were designed and synthesized from ferulic acid and agmatine. The structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR and mass spectra, among which compounds 5f-5i were novel compounds. The results of preliminary pharmacological test showed that some of the compounds possessed strong NHE-1 inhibitory activity, among which compounds 5a, 5b and 6c were more potent than cariporide in NHE-1 inhibition.
Agmatine ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Cardiotonic Agents ; chemical synthesis ; chemistry ; pharmacology ; Drug Design ; Female ; Male ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Sodium-Hydrogen Exchangers ; antagonists & inhibitors ; Structure-Activity Relationship

Objective The choice of surgical approaches for salvage surgery based on the location and invasion of recurrent and residual lesions of nasopharyngeal carcinoma (NPC),surgical results,complications,and survival were assessed.Methods Thirty-seven cases with recurrent and residual lesions of NPC underwent salvage surgery between March 1991 and January 2005 were analysed retrospectively.Of 37 patients,23 were men and 14 women,with a median age of 46.5 years (26 -57 years) ;4 were at stage Ⅰ,10 at stage Ⅱ,14 at stage Ⅲ,and 9 at stage Ⅳ; 5 cases were with cervical metastasis,including 3 cases of N1 and 2 cases N2.All recurrent and residual lesions of NPC were determined by biopsy.On the location and invasion of recurrent and residual lesions of NPC,8 cases underwent endoscopic resection of lesions,12 cases of the palate nasopharyngectomy,5 cases of maxillary swing,4 cases of maxillary swing plus preronal approach,2 cases of lateral rhinotomy plus coronalflap approach,and 6 cases transfacial plus nasal pyramid swing approach.Five cases with cervical metastasis received neck dissection in addition to the operations for recurrent and residual lesions of NPC. Postoperatively 31 cases received radiotherapy with dosage of 60 Gy,among them 15 cases with concurrent chemoradiation therapy,and 6 cases with clear surgical margin did not received radiotherapy or chemotherapy. The cases were followed up for 12 - 72 months,with a median of 45 months.Results Total resection for the recurrent and residual lesions of NPC acounted for 91.8% (34/37) and subtotal resection for 8.2% (3/37). The accidence of perioperative complications was 24.3% (9/37). The 3- and 5-year overall disease-free survival rates (DFSR) were 62.1% and 43.3%,respectively. The 3- and 5-year overall survival rates (OSR) were 72.9% and 51.3%,respectively.The 5 year DFSR of cases at stage Ⅰ - Ⅳ were 100%,40%,28% and 11% (χ2 =10.0,P ＜0.01＝,respectively.The 5 year OSR were 100%,70%,35% and 28% (χ2 = 11.5,P ＜0.01),respectively.Conclusions Salvage surgery is a justified treatment for the recurren and residual lesions of NPC,by which some patients with recurren and residual lesions of NPC can be salvaged.

OBJECTIVETo investigate the frequency of JAK2V617F mutation in Chinese patients with chronic myeloproliferative neoplasms (MPN) and to study the relationship between JAK2V617F mutation and clinical characteristics.

METHODSJAK2V617F mutation was screened by allele-specific polymerase chain reaction (AS-PCR).

RESULTSJAK2V617F mutation was detected in 277 of the 412 patients with MPN. The frequency of JAK2V617F mutation was similar among essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloproliferative disorders-unclassified (MPD-U) (P > 0.05), but it was significantly lower than that in polycythemia vera (PV) (P < 0.05). The presence of JAK2V617F was found to be significantly correlative with advanced age at diagnosis (P < 0.01) and with higher hemoglobin levels and higher leukocyte counts (P < 0.05). Significant difference was found in complication of vascular events between JAK2V617 positive and negative patients (P < 0.05). JAK2V617F positive MPD-U patients were more prone to progress into typical MPN compared with JAK2V617F negative MPD-U patients. The association between abnormal karyotype and JAK2V617F was not found in cytogenetical analysis of 301 patients.

CONCLUSIONThe presence of JAK2V617F in MPD-U is associated with the disease development. There is a correlation between JAK2V617F mutation in MPN and advanced age, higher leukocyte counts, hemoglobin level and vascular events.

Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; Hemoglobins ; metabolism ; Humans ; Janus Kinase 2 ; genetics ; Leukocyte Count ; Male ; Middle Aged ; Mutation ; Myeloproliferative Disorders ; blood ; complications ; genetics ; Polycythemia Vera ; blood ; complications ; genetics ; Primary Myelofibrosis ; blood ; complications ; genetics ; Thrombocythemia, Essential ; blood ; complications ; genetics ; Thrombosis ; etiology ; Young Adult