Synthesis of C3'-Foused Aryl/Penta-1,4-dien-3-one/Amine Hybrids as HSP90 C-Terminal Inhibitors.

24 C3'-focused hybrids of aryl/penta-1,4-dien-3-one/amine (APDA) were designed and synthesized. Of these hybrids, 2n demonstrated improved antiproliferative effects on HER2-positive breast cancer cells (SKBr3 and BT474) and triple-negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) with IC50 values ranging from 7.45 to 10.75 µM, but less toxicity to normal breast cells MCF-10A than the first generation of hybrid 1. Additionally, 2n retained its ability to inhibit HSP90 C-terminus, leading to the degradation of HSP90 client proteins HER2, EGFR, pAKT, AKT, and CDK4, without inducing a heat-shock response. Notably, 2n also demonstrated improved thermostability compared to 1 and maintained in vitro metabolic stability in simulated intestinal fluid. These findings will provide a scientific basis for developing HSP90 C-terminal inhibitors in the future.

A silicon-containing aryl/penta-1,4-dien-3-one/amine hybrid exhibits antiproliferative effects on breast cancer cells by targeting the HSP90 C-terminus without inducing heat-shock response.

A pharmacophore-hybridized strategy based on previously reported HSP90 C-terminal inhibitors was utilized to prepare 32 aryl/penta-1,4-dien-3-one/amine hybrids. Among them, a silicon-containing compound 1z exhibited remarkable broad-spectrum antiproliferative effects on various human breast cancer cell lines. Through fluorescence polarization and AlphaScreen-based assays, we demonstrated that 1z specifically inhibited the HSP90 C-terminus without affecting HSP90 N-terminus. Furthermore, 1z effectively inhibited the HSP90 C-terminus without inducing heat-shock response (HSR), leading to the degradation of its client proteins HER2, pAKT, AKT, and CDK4, causing G1 arrest of MCF-7 and SKBr3 cells, and ultimately contributing to apoptosis of these cells through caspase-3, caspase-8, and caspase-9 activation. Additionally, the penta-1,4-dien-3-one linker in the hybrid, a large bulky lipophilic substitution in the aryl fragment at the 3'-site, and the presence of N-methylpiperazine as the amine fragment were identified as crucial factors that significantly contributed to the observed antiproliferative activity through structure-activity relationship (SAR) analysis. Lastly, we found that 1z exhibited superior thermostability compared to vibsanin B derivatives and good in vitro metabolic stability in simulated intestinal fluid, representing one of the few reported silicon-containing HSP90 C-terminal inhibitors.

Evaluating tacrolimus treatment in idiopathic membranous nephropathy in a cohort of 408 patients.

BACKGROUND: The KDIGO Clinical Practice Guidelines for Glomerulonephritis recommended tacrolimus as an alternative regimen for the initial therapy for Idiopathic membranous nephropathy (IMN), however, large observational studies evaluating tacrolimus treatment in IMN remains rare. METHODS: A total of 408 consecutive IMN patients with nephrotic syndrome who were treated with tacrolimus in Jinling Hospital were included. The effectiveness and safety of tacrolimus treatment in IMN were analyzed in this study. RESULTS: The cumulative partial or complete remission after tacrolimus therapy were 50%, 63% and 67% at 6, 12 and 24 months, respectively, and the cumulative complete remission rates were 4%, 13% and 23%, respectively. Multivariate logistic analysis showed that higher tacrolimus exposure during induction treatment, female gender, higher eGFR and no history of previous immunosuppressive therapy were independently associated with higher probability of remission. A relapse occurred in 101 of the 271 (37.3%) patients with partial or complete remission, and 18 of the 95 (18.9%) patients with complete remission. Tapering duration of tacrolimus and complete remission versus partial remission status were independent factors associated with risk of relapse. A decline in eGFR was the most frequent adverse event during tacrolimus treatment. During tacrolimus treatment, a ≥40% decrease in eGFR was observed in 43 (10.5%) patients. CONCLUSIONS: Low dose tacrolimus is effective for IMN, with a total remission rate of 66% whereas with a rather high rate of relapse. However, the safety of tacrolimus treatment needs to be further validated in large randomized clinical trials.

[Analysis of chemical speciation of heavy metals in L07-11 profile sediments of "Big Ear" Region of Lop Nor Lake].

As playa is the typical characteristic in "Big Ear" Region of Lop Nor Lake, it is significant for enriching playa heavy metal earth environmental chemical data by analyzing species distribution of heavy metal among this district. In this thesis, heavy metal Cd, Pb, Ni, Cu in L07-11 Profile Sediments of "Big Ears" Region of Lop Nor Lake are considered as research objects. Tessier sequential extraction and Graphite furnace atomic absorption method (GF-990) are used to discuss and analyze five forms of Cd, Pb, Ni, Cu among sediments. The results show that the content of Cd, Pb, Ni and Cu is in the range from 1.10~2.54, 9.18~20.02, 9.88~17.15, 4.43~21.11 mg · kg(-1), respectively. The value of organic matter range from 8.71-54.72 g · kg(-1). The order of the bioavailable state in heavy metals is Cd>Pb>Cu>Ni. Pb and Cd mainly exist in exchangeable form including water-soluble, and that Ni is in residual form, and that Cu is mostly in Fe-Mn oxide bound iron-manganese oxides or in residual form. Among surface sediments, effective content of heavy metal is more than 80%. Except Cu, the content of heavy metal Cd, Pb, Ni in exchangeable form is more than 60%. Heavy metal Cd and Pb has higher secondary release potential. The content of heavy metal and organic material has some correlation.

Heart-type fatty acid binding protein is associated with proteinuria in obesity.

RATIONALE: Lipid metabolism contributes to the formation of obesity-related glomerulopathy (ORG). Heart-type fatty acid binding protein (H-FABP or FABP3) is involved in lipid metabolism and was predicted to relate to renal lesions in obesity. METHODS: A total of 28 patients with ORG were investigated, and renal tissue from 7 kidney donors served as controls. Db/db mice with albuminuria were treated with Simvastatin for 12 weeks. RESULTS: Immunohistochemistry demonstrated the H-FABP staining in glomerular and tubular areas of patients with ORG, and the percentage of H-FABP in the glomerular area was significantly higher than in controls (15.8±1.62 versus 4.51±0.56%, P<0.001). Moreover, H-FABP expression correlated with proteinuria, high-density lipoprotein (HDL) cholesterol, waist circumference and the homeostatic model assessment - insulin resistance (HOMA-IR) among patients with ORG. Enhanced expression of H-FABP was also detected in the db/db mice, and expression increased from 8 to 20 weeks of age and was weakly related to increased albuminuria (r = 0.433; P = 0.020). Furthermore, H-FABP was co-localized with synaptopodin and demonstrated a podocyte pattern distribution. After Simvastation treatment, the urine albumin levels decreased with lipid levels and H-FABP expression in the glomeruli. The expression of H-FABP was related to Simvastatin treatment, albuminuria and triglycerides, while it was only linked with triglycerides and albuminuria (r = 0.643, P = 0.036). CONCLUSIONS: This study confirmed an association of H-FABP with the pathogenesis of clinical and experimental ORG, and suggests that such a process might be related to podocytes and lipid dysmetabolism.

[Speciation analysis of Cd in PM10 and PM2.5 during heating period in Urumqi].

PM2.5 and PM10 samples were collected on campus of Xinjiang Agricultural University during Dec. 14-28, 2009, and the speciation of Cd in PM10 and PM2.5 and its health risk index was analyzed. The results showed that the pollution caused by PM10 and PM2.5 was severe here during the heating period; Cd in PM10 and PM2.5 was of concentration 3.642 and 1.964 ng x m(-3) respectively, mainly in the form of residue; however, Cd in PM2.5 had a higher bioavailability than that in PM10. The carcinogenic risk of Cd in PM10 and PM2.5 was 6.56 x 10(-6) and 3.46 x 10(-6) respectively, which were both acceptable.

[Analysis of Cd pollution & spatial variability characteristics of typical agricultural soils in suburbs of Urumqi City, Xinjiang].

Cd content in agricultural soils from 4 townships in north suburb and 2 townships in south suburb of Urumqi City was determined with graphite furnace (GF-990) atomic absorption spectrometry, and the spatial variability of Cd content there was analyzed with geo-statistics method. The result indicates that Cd content from the sampling points in north suburb exceeds the stipulated standard and falls into medium or strong spatial variability with nugget value > 75%, which explains a weak self-correlation among those variable spaces under mainly the impact of random factors of external pollution such as local fertilization level, irrigation and cultivation etc. Cd content from the sampling points in north suburb does not exceed the stipulated standard but approaches to the critical warning value with nugget value at 50.2%, which falls into medium self-correlation among those variable spaces. Spatial variability characteristics of Cd distribution in suburban agricultural soils of Urumqi City, Xinjiang were studied in this paper for providing scientific basic data to source analysis and control of Cd pollution in the far mLands there.

[Research on the relevance of earthworms inducing soil Cd2+ absorbed by perennial ryegrass].

Through the method of simulating the heavy metal pollution in farmland, the graphite oven (GF-990) atomic absorption was used for analyzing the regulations of the earthworms inducing the soil Cd2+ absorbed by the perennial ryegrass. The result indicated: (1) under the circumstance of the soil Cd2+ density of 3-6 mg x kg(-1), the positive relevance appeared extremely remarkably that the contents of Cd2+ in underground portions of the perennial ryegrass relate to the earthworm quantity (r = 0.883 2-0.986 2), but in the portion above ground the positive relevance did not appear extremely remarkably (r = 0.345 5-0.325 4); And the negative relevance appeared remarkably that the contents of Cd2+ in the soil relate to the earthworm quantity (r = -0.588 7(-) -0.678 4). (2) Under the conditions of isometric number of earthworms, the more the density of Cd2+ in the soil, the more the increase of Cd2+ in both portions under and above ground of perennial ryegrass. (3) Under the same soil environment, the negative relevance appeared that the number of earthworms relates to the contents of Cd2+ in the earthworms (r = -0.982 0(-) -0.991 6).

[Comparative analysis of endogenous hormones between two species of Ammopiptanthus seedlings around germination and under Pb2+ stress].

The changes in three endogenous hormones, phytohormones gibberrelic acid (GA3), indoles-3-acid (IAA) and abscisic acid (ABA), were studied around germination and under tress of different density of Pb2+ between two species of Ammopiptanathus. It was found that (1) around germination, in Xinjiang Ammopiptanthus the rate IAA decreased 77.80%, and the rate of ABA decreased 98.90%; and in Mongolia Ammopiptanthus the rate of IAA decreased 75.80%, the rate of ABA decreased 66.20%, and the GA3 contents in both had no big change. (2) With the increase in Pb2+ concentration (20-1 500 mg x L(-1)), the IAA decreased significantly; and only under the high density (more than 1 000 mg x L(-1)) of Pb2+, the GA3 was affected by it; the ABA did not change regularly. So the three endogenous hormone levels of Mongolia Ammopiptanthus were higher than those of Xinjiang Ammopiptanthus. (3) the distributions of Pb2+ in Ammopiptanthus seedlings are the root > stems > leaves. (4) the stress of high concentration of Pb2+ damages irreversibly the leaf cells of Ammopiptanthus. This study can provide the basis of reference data for further research on the growth characteristics, resilience and the mechanism of specific broad-leaved evergreen shrubs-Ammopiptanthus in desertification area.

Triptolide reduces proteinuria in experimental membranous nephropathy and protects against C5b-9-induced podocyte injury in vitro.

Membranous nephropathy is a major cause of nephrotic syndrome in adults where podocyte injuries were found to mediate the development of proteinuria. Triptolide, a major active component of Tripterygium wilfordii Hook F, has potent immunosuppressive, anti-inflammatory and antiproteinuric effects. To study its antiproteinuric properties, we established an experimental rat model of passive Heymann nephritis and a C5b-9 injury model of podocytes in vitro. Treatment or pretreatment with triptolide markedly reduced established proteinuria as well as the titer of circulating rat anti-rabbit IgG antibodies in these nephritic rats, accompanied by a reduction in glomerular C5b-9 deposits. Expression of desmin, a marker of podocyte injury, diminished after triptolide treatment, whereas quantitative analysis of mean foot process width showed that effacement of foot processes was substantially reversed. In in vitro studies we found that triptolide deactivated NADPH oxidase, suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase, and restored RhoA signaling activity. Triptolide did not interfere with the formation of C5b-9 on the membrane of podocytes. Thus, triptolide reduces established heavy proteinuria and podocyte injuries in rats with passive Heymann nephritis, and protects podocytes from C5b-9-mediated injury.

Mercury-induced membranous nephropathy: clinical and pathological features.

BACKGROUND AND OBJECTIVES: Long-term contact with mercury may induce membranous nephropathy (MN); however, the clinical pathologic features and pathogenesis of mercury-induced MN have not been investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The present study retrospectively evaluated 11 cases of mercury-induced MN to analyze its causes and its clinical and pathologic features. RESULTS: A total of 10 women and 1 man ages 15 to 45 years were enrolled in the present study. Mercury exposure was caused by mercury-containing pills (five patients), skin lightening cream (four patients), hair-dyeing agents (one patient), and mercury vapor (one patient). The duration of contact with mercury ranged from 2 to 60 months, and the urinary mercury concentrations were 1.5 to 50 times higher than reference values. All patients presented with proteinuria and normal renal function; three had nephrotic syndrome. Light microscopy revealed thickened glomerular basement membrane and mildly proliferative mesangial cells. Acute tubulointerstitial injury occurred in three patients. The immunofluorescence findings showed granular deposits of IgG and C3 along the glomerular capillary wall, mostly accompanied by deposits of C4 and C1q. IgG1 and IgG4 (predominantly IgG1) deposits were observed along the glomerular capillary loops. Nine patients reached complete remission in follow-up after withdrawal from mercury exposure. CONCLUSIONS: Deposits of IgG1 subclasses in renal tissues indicated that the pathogenesis of mercury-induced MN differs from that of idiopathic MN. It is important that clinicians are aware that mercury exposure should be considered a possible cause of membranous nephropathy.

[Analysis of the microelements contents in melons and fruits of Xinjiang].

Through the atom absorption and emission spectrum analysis, it is detected 8 trace elements contents in eleven species of melons and fruits in Xinjiang. On comparative analysis with biological standard of China, it is found that the zinc quantity in apples is 66.75 mg x kg(-1), the strontium quantity in jujubes is 8.62 mg x kg(-1) and Chinese-date contains strontium 8.62 mg x kg(-1) in Hetian area; and that in the Kuerle area the pomegranate is potassium 687 mg x kg, in Hami Territory Chinese-date contains manganese, zinc, strontium, calcium, iron, potassium and nickel, all of them are more over the national biological standard. The contents of copper in eleven species of melons and fruits are lower than the biological standard of China The average contents of 8 kind microelement in the pomegranate of Kuerle, in the apples of Hetian, the Chinese-date of Hami are very high (respectively to be 91.82, 121.5 and 275.3 mg x kg(-1)), and in the watermelon of Wujiaqu, the pericarp (54.19 mg x kg(-1)) take place higher than in the pulp (48.69 mg x kg(-1)) by 1.11 times. The result can provides the conference for studies of melons and fruits foodstuff studies in Xinjiang.

Triptolide protects podocytes from puromycin aminonucleoside induced injury in vivo and in vitro.

Extracts of Tripterygium wilfordii Hook F have been used to treat glomerulonephritis for more than 30 years in China with dramatic antiproteinuric effects. Triptolide, a diterpene triepoxide, is one of the major active components of these extracts. To clarify its antiproteinuric effects we induced podocyte injury by puromycin aminonucleoside. Triptolide effectively reduced the proteinuria induced by puromycin in nephrotic rats without reducing the glomerular filtration rate. The antiproteinuric effect was associated with improvement in the foot process effacement, a decrease in the podocyte injury marker desmin as well as the restoration of nephrin and podocin expression and distribution. In cultured mouse podocytes triptolide pretreatment prevented the puromycin-induced disruption of the actin cytoskeleton and microfilament-associated synaptopodin while protecting nephrin and podocin expression. Triptolide suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase activation while restoring RhoA signaling activity. These results show that triptolide ameliorates puromycin aminonucleoside-mediated podocyte injury in vivo and in vitro.

[The corn seedlings are affected by the heavy metal Pb2+].

The corn seedlings in hydroponic culture are treated with the lead acetate solutions of various concentrations, the content of Pb2+ in the roots, stems and leafs of the corns at 10th day, 20th day and 30th day is measured. The analyzing conclusions are that the contents of Pb2+ in the corns display a sequence of root>leaf>stem, the contains of chlorophyll in corns fall off, the raising of Pb2+ in solutions, the membrane penetrability of the corns increased along a sequence of root>leaf>stem, and the harmful rate of Pb2+ display a sequence of root>leaf>stem in corns. The data of the study gives some references for the further researches of the crops, relating the endurance and the distributing of corns with Pb2+.