Search

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.

A pair of undescribed dihydrobenzofuran neolignan enantiomers, (+/−)-phybrenan A (1a/1b), two new benzofuran neolignans, phybrenan B and C (2 and 3), along with four known neolignans (4 − 7) were obtained from the plants of Phyllanthodendron breynioides P. T. Li. The planar structures of all isolates were demonstrated by the analysis of detailed spectroscopic evidence (NMR, HRMS, and IR), and the absolute configurations of novel neolignans were elucidated by combined calculated and experimental ECD data analysis. The neuroprotective activities of all benzofuran neolignans against sodium nitroprusside (SNP)-induced cell death were examined in rat pheochromocytoma PC12 cells. The results exhibited that three compounds (4 − 6) possessed remarkable neuroprotective activities at 10 µM, better than the positive drug edaravone. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress (ERS) is involved in the pathological process of vascular dementia (VD). GJ-4 is extracted from Gardenia jasminoides J. Ellis and has been reported to have protective roles in ischemia-related brain damage. However, the role of GJ-4 in ERS has not been elucidated. We established a VD rat model through bilateral common carotid arteries occlusion (2-VO). The rats were intragastrically administrated with GJ-4 (10, 25, and 50 mg/kg) and nimodipine (10 mg/kg). Data from a Morris water maze test showed that GJ-4 could significantly alleviate learning and memory deficits in VD rats. Nissl and cleaved caspase-3 staining revealed that GJ-4 can inhibit apoptosis and thus exert a protective role in the brain of 2-VO rats. Western blot results suggested that GJ-4 significantly reduced ERS-related protein expression and inhibited apoptosis through suppression of the PERK/eIF2 α /ATF4/CHOP signaling pathway. For in vitro studies, the oxygen-glucose deprivation (OGD) SH-SY5Y model was employed. Western blot and Hoechst 33342/PI double staining were utilized to explore the effects of crocetin, the main active metabolite of GJ-4. Like GJ-4 in vivo, crocetin in vitro also decreased ERS-related protein expression and inhibited the activation of the PERK/eIF2 α /ATF4/CHOP signaling pathway. Thus, crocetin exerted similar protective roles on OGD challenged SH-SY5Y cells in vitro. In summary, GJ-4 and crocetin reduce the ERS in the brain of VD rats and SY5Y cells subjected to OGD and inhibit neuronal apoptosis through suppression of the PERK/eIF2 α /ATF4/CHOP pathway, suggesting that GJ-4 may be useful for the treatment of VD. [ABSTRACT FROM AUTHOR]

PurposeTo develop a predictive model using machine learning for levothyroxine (L-T4) dose selection in patients with differentiated thyroid cancer (DTC) after resection and radioactive iodine (RAI) therapy and to prospectively validate the accuracy of the model in two institutions.MethodsA total of 266 DTC patients who received RAI therapy after thyroidectomy and achieved target thyroid stimulating hormone (TSH) level were included in this retrospective study. Sixteen clinical and biochemical characteristics that could potentially influence the L-T4 dose were collected; Significant features correlated with L-T4 dose were selected using machine learning random forest method, and a total of eight regression models were established to assess their performance in prediction of L-T4 dose after RAI therapy; The optimal model was validated through a two-center prospective study (n=263).ResultsSix significant clinical and biochemical features were selected, including body surface area (BSA), weight, hemoglobin (HB), height, body mass index (BMI), and age. Cross-validation showed that the support vector regression (SVR) model was with the highest accuracy (53.4%) for prediction of L-T4 dose among the established eight models. In the two-center prospective validation study, a total of 263 patients were included. The TSH targeting rate based on constructed SVR model were dramatically higher than that based on empirical administration (Rate 1 (first rate): 52.09% (137/263) vs 10.53% (28/266); Rate 2 (cumulative rate): 85.55% (225/263) vs 53.38% (142/266)). Furthermore, the model significantly shortens the time (days) to achieve target TSH level (62.61 ± 58.78 vs 115.50 ± 71.40).ConclusionsThe constructed SVR model can effectively predict the L-T4 dose for postoperative DTC after RAI therapy, thus shortening the time to achieve TSH target level and improving the quality of life for DTC patients.

Two new triterpenoids, 3β-hydroxytirucall-7,25-dien-24-one (1) and 3β-acetoxytirucall-7,23,25-triene (2), along with one new sesquiterpenoid, alloaromadendrane-12α,14β-dioic acid (3), were isolated from the vines and leaves of Chonemorpha megacalyx Pierre. Their structures were established on the basis of extensive spectroscopic data. [ABSTRACT FROM AUTHOR]

Nuclear transporter importin- β 1 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- β 1 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- β 1, 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- β 1., Competing Interests: The authors declare no conflicts of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The quaternary selenide Ba 4 GeSb 2 Se 11 was prepared by a high-temperature solid state reaction method. Ba 4 GeSb 2 Se 11 crystallizes in an acentric orthorhombic space group Cmc 2 1 with the lattice constants a = 9.370(11) Å, b = 25.850(0) Å, and c = 8.798(10) Å. The compound is composed of a [SbSe 3 ] 3- trigonal pyramid, [GeSbSe 5 ] 3- dimers, V-shaped Se 3 2- , and the adjacent Ba 2+ ions. It has indirect band gap of 1.35 eV and exhibits a second harmonic generation intensity of about 0.2 times that of the benchmark compound AgGaS 2 at the same particle size. Interestingly, theoretical analyses show that the central Se atom of Se 3 2- has the largest contribution (8.1%) to d 31 compared to that of other Se atoms, which may be due to its easy swing in the a -axis direction.

Crotonpenoids A ( 1 ) and B ( 2 ), two highly modified clerodane diterpenoids featuring a new 10-(butan-2-yl)-1,6,12-trimethyltricyclo[7.2.1.0 2,7 ]dodecane skeleton, were isolated from the leaves and twigs of Croton yanhuii . Their structures including the absolute configurations were determined by spectroscopic analysis, single-crystal X-ray diffraction, and biomimetic semisynthesis. Compounds 1 and 2 exhibited an agonistic effect on pregnane X receptor at 10 μM.

Mid- and far-infrared nonlinear optical (MFIR NLO) materials are important in modern laser technologies. However, it is very challenging to develop materials that can achieve a subtle balance between the key requirements, such as large NLO response, high laser-induced damage threshold (LIDT), wide IR transparency, and phase-matching. In this work, a new wide IR transparency (0.38-15.3 μm) NLO crystal Ba 10 In 6 Zn 7 S 26 (SS26) is synthesized. Further, its composite system Ba 10 In 6 Zn 7 S 26 - nZnS is synthesized by eutectic reaction. In particular, Ba 10 In 6 Zn 7 S 26 -14ZnS (SS40) shows excellent balanced NLO performance that includes a large band gap of 3.05 eV, high LIDT (13.3 × AgGaS 2 ), large second harmonic generation (SHG) response (2.1 × AgGaS 2 at 2050 nm, 5.2 × KDP at 1064 nm), and wide optical transmission window (0.37-15.4 μm). Importantly, the phase-matching condition is realized for SS40 by interfaces formed between the crystal face (112) of matrix SS26 and the crystal face (111) of reinforcement cubic ZnS by topological chemical reaction, and the NLO performance can be tuned by different concentrations of ZnS. First-principles simulations are employed to study NLO properties of SS26 and the interfaces. This work demonstrates that SS40 is a promising MFIR NLO material, and tuning components of the composite material system is a useful way to develop new MFIR NLO materials with excellent comprehensive performance.

Lymphatic filariasis used to highly prevalent in 69 counties (cities) with 29 million people at the risk of infection in Hubei Province. There were 2 million people infected either by B. malayi or W. bancrofti that 1.6 million microfilaremia cases and 0.4 million chronic patients. The average rate of microfilaremia among population was 5.94%. Anopheles sinensis and Culex quinquefasciatus were the principal transmitting vectors. Since 1970s, with the strategy of taking elimination of infection source as a major focus, the average rate of the microfilaremia reduced to 0.048% with a village as the unit in 1988, and reached the standard of transmission interruption. With continuous surveillance for over a decade, the province reached the goal of filariasis elimination in 2001. This paper reviews the prevalence, control and elimination process of filariasis in Hubei Province since 1950s.