Design of drug-like hepsin inhibitors against prostate cancer and kidney stones

Hepsin, a transmembrane serine protease abundant in renal endothelial cells, is a promising therapeutic target against several cancers, particularly prostate cancer. It is involved in the release and polymerization of uromodulin in the urine, which plays a role in kidney stone formation. In this work, we design new potential hepsin inhibitors for high activity, improved specificity towards hepsin, and promising ADMET properties. The ligands were developed through a novel hierarchical pipeline. This pipeline explicitly accounts for off-target binding to the related serine proteases matriptase and HGFA (human hepatocyte growth factor activator). We completed the pipeline incorporating ADMET properties of the candidate inhibitors into custom multi-objective optimization functions. The ligands designed show excellent prospects for targeting hepsin the blood stream and the urine and thus enable key experimental studies. The computational pipeline proposed is remarkably cost-efficient and can be easily adapted for designing inhibitors against new drug targets.

Effects of Tamm-Horsfall protein on kidney stone formation / 医学研究生学报

Objective Tamm-Horsfall protein (THP) may play a role in kidney stone formation.The article aimed to conduct a preliminary study on the role of THP in kidney stone formation by investigating the changes of THP in rat urine, pathological changes of renal tissue and the formation of calcium salt crystals after establishing CNPs rat model of kidney stones.Methods Stone samples of 40 patients from February to June 2015 in our department were collected to establish the model of CNPs-induced kidney stone in rats and prepare CNPs suspension.48 SD rats were randomly divided into experimental group (group A) and blank control group (group B).Group A were injected with CNPs and the same amount of sterile saline injection in the group B.The urine of rats was collected after injection at 3h, 6h, 12h, 24h, 1w, 2w, 4w and 8w.ELISA were applied to detect THP levels in the urine.Then the rats were killed to take the kidney tissue.HE staining was used to investigate the pathological changes of the cells and evaluate the formation of the calcium salt crystals.Results THP levels in group A at 24h, 1w, 2w, 4w and 8w ([166.03±3.02], [173.50±1.78], [174.55±2.05], [176.54±2.45], [177.11±1.76]pg/mL) were significantly higher than that at 3h(165.89±2.23pg/mL)(P<0.05), which was the same case in comparison with those of group B ([157.65±2.22], [156.54±1.43], [159.45±3.21], [158.63±2.98], [157.33±2.05]pg/mL).Compared with the calcium salt crystal score at 6h (1 point), the scores at 3,6,12,24h (average score 2 points) increased.At 2w the score increased significantly to 3 points and reached the top score(6.7points) at 8w, which was of significant difference.The score of calcium salt crystals was in positive correlation with THP content (r=0.843,P<0.05).Conclusion THP in urine may contribute to the aggregation of calcium salt crystals and the formation of kidney stones.

Familial Juvenile Hyperuricemic Nephropathy and Uromodulin Gene Mutation

Familial Juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal dominant disorder, characterized by early onset of hyperuricemia, gout and progressive kidney disease. Hyperuricemia prior to renal impairment and decreased fractional excretion of uric acid are hallmarks of FJHN. Renal dysfunction gradually appears early in life and results in end-stage renal disease usually between the ages of 20 and 70 years. FJHN is mostly caused by mutations in the uromodulin gene located at 16p12. The course of FJHN is highly variable. Treatment includes management for hyperuricemia, gout and progressive kidney disease. Individuals with gout have been usually treated with allopurinol. But controversy exists as to whether uric acid lowering therapy prevents the progression of chronic kidney disease.

A Case of Familial Juvenile Hyperuricemic Nephropathy with Novel Uromodulin Gene Mutation, a Novel Heterozygous Missense Mutation in Korea

Familial Juvenile hyperuricemic nephropathy (FJHN, OMIM #162000) is a rare autosomal dominant disorder characterized by hyperuricemia with renal uric acid under-excretion, gout and chronic kidney disease. In most but not all families with FJHN, genetic studies have revealed mutations in the uromodulin (UMOD) gene located on chromosome 16p11-p13. We here described a novel heterozygous missense mutation (c.1382C>A causing p.Ala461Glu) in an affected 16-year-old male with hyperuricemia, gout and chronic kidney disease. His father was also affected and the UMOD mutation was found to segregate with the disease. There has been only one case report of Korean family with FJHN, which has not been diagnosed by genetic study. This is the first report of genetically diagnosed FJHN in Korea.

Identification and Clinical Analysis of Tamm-Horsfall Detection of RBC in Urine to Diabetic Nephropathy Hematuria / 医疗卫生装备

70% for 9 patients;the positive rate was between 30-70% for 4 patients;the positive rate 0.05). Conclusion Tamm-Horsfall detection of RBC in urine could be used as one of the Identification indicators for DN hematuria, and it can provide a basis for diagnosis and treatment of DN.

The Comparison of the Urine RBC Phase Contrast Microscopy and Immunoperoxidase Stain in Differentiation of Hematuria / 대한신장학회잡지

Differentiation of renal(RH) and non-renal(NRH) hematuria is important in the diagnosis and treatment of the patients with hematuria. Recently, urine RBC immunoperoxidase(IPx) staining method was developed, but there was no report on the usefulness of IPx in Korea. We validated the usefulness of IPx by comparing with the PCM. Both PCM and IPx were performed at the same time in 26 patients with RH confirmed by renal biopsy and 23 patients with NRH confirmed by radiologic and/or pathologic studies who were admitted to Chungbuk National University Hospital from January 1996 to December 1996. The age of RH and NRH group were 36.6+/-15.0 and 56.5+/-22.2 years. 35.7+/-30.4% of urine RBC were stained by IPx in RH group and only 1.6+/-4.4% were stained in NRH group(P<0.001). 23.4+/-29.9% of urine RBC by PCM were counted as dysmorphic RBC in RH group and 5.7+/-13.6% were counted in NRH group(P<0.05). At the cut-off value of 20%, the sensitivity and specificity of IPx were 57.7% and 100%. At the cut-off value of 30%, those of PCM were 30.9% and 95.7%, respectively. When comparing overall test performance by calculating AUCs of ROC(receiver operating characteristics) curve, IPx was better than PCM. IPx was better than PCM in localizing the origin of hematuria. The NRH might be excluded when IPx(+) cells are more than 20% of total urine RBC.

Evaluation of renal tubular function with fasting plasma homocysteine level in type 2 diabetic patients / 中华内分泌代谢杂志

Type 2 diabetic patients with the decline of urinary Tamm-Horsfall protein excretory rate showed the increment of fasting plasma homocysteine levels, suggesting that the damage of synthetic function of renal tubule may participate in the increment of homocysteine levels.

Changes of Tamm-Horsfall protein in the urine and blood of severely burn patients / 第三军医大学学报

Tamm-Horsfall protein(THP)was determined with radioimmunoassay in the urine and blood samples of 59 burn patients.It was found that urine and blood THP was significantly decreased postburn and the degree of decresing was correlated with the extent of the burnt body surface and the severity of renal damage.The changes of THP occurred earlier than those of the routine parameters for renal damage such as BUN or Cr.It is suggested that THP determination can be used as an index for the early damage of the Henle's loop and the distal convoluted tubules after burn injury.