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Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

Four new polycyclic diterpenoids euphoranes A − D (1–4), together with 12 known terpenoids (5–16) were isolated from the whole plants of Euphorbia dracunculoides. Compound 2 represents the first example of aromatic 15,16,17-trinorabietane diterpenoid in Euphorbia species, and euphorane C (3) is an unusual 17-norabietane diterpenoid. The absolute configurations of 1, 2, and 4 were determined by single crystal X-ray diffraction, while that of 3 was established with the aid of ECD and 1D NMR quantum chemical calculation. Moreover, the absolute stereochemistry of 11 was demonstrated for the first time by crystallographic data. Compounds 1–16 were screened for antiproliferative activities against five human cancer cell lines, and 3 showed significant cytotoxicity against the human leukemia K562 cells with IC50 value of 3.59 μM. Preliminary mechanistic investigation revealed that 3 could induce cell cycle arrest at G0/G1 phase and apoptosis in K562 cells.

Six new tigliane diterpenoids, euphkanoids A − F (1–6), along with 12 known diterpenoids (7–18) were isolated from the roots of Euphorbia kansuensis, a traditional Chinese medicinal plant. Their structures were elucidated by spectroscopic analysis, ECD calculation and chemical methods. Compounds 1–3 represent the unusual examples of tigliane diterpenoids with a conjugated olefinic aldehyde moiety. 1–18 and two hydrolyzed analogues (1c and 4a) were screened for the inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells. The results showed that 1–3 and 6 markedly inhibited NO production with IC50 values in the range of 4.8–11.3 μM, which were more active than the positive control quercetin (IC50 = 12.3 μM).

Summary: Background: Renal replacement therapy (RRT) is an effective rescue therapy for Type 1 cardiorenal syndrome (CRS). Previous studies have demonstrated that type 1 CRS patients with severe renal dysfunction were susceptible to sepsis, and that serum lactate has been correlated with the risk of mortality in patients with sepsis. However, the association between serum lactate level and the prognosis of type 1 CRS patients requiring RRT is unknown. Methods: An inception cohort of 500 type 1 CRS patients who received RRT in a tertiary-care referral hospital in Taiwan from August 2011 to January 2018 were enrolled. The outcomes of interest were dialysis withdrawal and 90-day mortality. The results were further externally validated using sampling data of type 1 CRS patients requiring dialysis from multiple tertiary-care centers. Findings: The 90-day mortality rate was 52.8% and the incidence rate of dialysis withdrawal was 34.8%. Lower pre-dialysis lactate was correlated with a higher rate of dialysis withdrawal and lower rate of mortality. Generalized additive model showed that 4.2 mmol/L was an adequate cut-off value of lactate to predict mortality. Taking mortality as a competing risk, Fine-Gray subdistribution hazard analysis further indicated that a low lactate level (≦ 4.2 mmol/L) was an independent predictor for the possibility of dialysis withdrawal, as also shown in external validation. The interaction of quick Sequential Organ Failure Assessment score and lactate was associated with dialysis dependence in a disease severity-dependent manner. Furthermore, the associations between hyperlactatemia and dialysis dependence were consistent in the patients with and without sepsis. Interpretation: Serum lactate level is accurate and capable of forecasting the prognosis along with qSOFA severity for clinical decision-making for treating type 1 CRS patients. Further studies are needed to validate our results. Funding: This study was supported by grants from Taiwan National Science Council [104–2314-B-002–125-MY3,106–2314-B-002–166-MY3,107–2314-B-002–026-MY3], National Taiwan University Hospital [106-FTN20,106-P02,UN106–014,106-S3582,107-S3809,107-T02,PC1246,VN109–09,109-S4634,UN109–041], Ministry of Science and Technology of the Republic of China [MOST106–2321-B-182–002,106-2314-B-182A-064,MOST107–2321-B-182–004,MOST107-2314-B-182A-138, MOST108–2321-B-182–003,MOST109–2321-B-182–001, MOST108-2314-B-182A-027], Chang Gung Memorial Hospital [CMRPG-2G0361,CMRPG-2H0161,CMRPG-2J0261, CMRPG-2K0091], and Ministry of Health and Welfare of the Republic of China [PMRPG-2L0011].