Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling.

Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo-/- mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.

Targeting STAT3 by a small molecule suppresses pancreatic cancer progression.

Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.

Interesting new Chinese species of Leptoceridae and Odontoceridae (Insecta: Trichoptera) from several recent collecting efforts.

In contravention of Article 16.4.2 of the International Code of Zoological Nomenclature (International Trust for Zoological Nomenclature 1999), the repository for the holotypes of these species was not mentioned by Yang et al. (2020), such that the names proposed for these species are presently nomina nuda.

Interesting new Chinese species of Leptoceridae and Odontoceridae (Insecta: Trichoptera) from several recent collecting efforts.

Nine new species of caddisflies are described from southeastern and central China, including 7 species of Leptoceridae: Ceraclea (Ceraclea) megalophyllon Yang Morse sp. n., C. (Athripsodina) aerumnula Yang Morse sp. n., C. (Ath.) lamellata Yang Hu sp. n., Oecetis (Oecetis) discedens Yang Morse sp. n., Oe. (Pleurograpta) spinellosa Yang Hu sp. n., Setodes charax Yang Morse sp. n., and S. scutatus Yang Morse sp. n. Two species of Odontoceridae also are included: Phraepsyche acuminata Yang Morse sp. n. and Psilotreta longicornis Yang Morse sp. n. The male genitalia of all species and female genitalia of C. megalophylla, C. lamellata, Oecetis discedens, and Oe. spinellosa are figured.

Synthesis of Cyanoenone-Modified Diterpenoid Analogs as Novel Bmi-1-Mediated Antitumor Agents.

Bmi-1 is overexpressed in colorectal cancer (CRC) and served as a novel therapeutic target for the treatment of CRC. A series of novel cyanoenone-modified diterpenoid analogs was synthesized and investigated for their antiproliferative activity against CRC cells. The results showed that most of these compounds exhibited potent antiproliferative and Bmi-1 inhibitory activity. Among them, the most active compound 33 (SH498) showed more potent antiproliferative activity than the positive control compound PTC-209. These synthetic diterpenoid analogs were less toxic for normal human fibroblasts (HAF) than for CRC cells. Especially 33, its selectivity index (SI) between HAF and tumor cells was 7.3-13.1, which was much better than PTC-209. The polycomb repressive complex 1 (PRC1) complex, transwell migration, colony formation, cancer stem cell proliferation, and apoptosis assays of 33 were performed on CRC cell lines. The in vivo antitumor effect of 33 was also observed in HCT116 tumor-bearing mice.

New species of microcaddisflies from China (Trichoptera: Hydroptilidae).

Five new species of hydroptilids in four genera are described from China, including three new species in Hydroptilinae: Agraylea dactylina n. sp., Allotrichia rhynchophyllum n. sp., and Microptila hamatilis n. sp.; and two new species in Stactobiinae: Stactobiella mutica n. sp. and Stactobiella parallelica n. sp. New records are given for Stactobiella biramosa Martynov 1929 and Pseudoxyethira thingana (Oláh) 1989. Genera Agraylea, Allotrichia, Stactobiella, and Microptila are new to Chinese fauna.

Synthesis of novel diterpenoid analogs with in-vivo antitumor activity.

A lead compound 7 has antitumor effect, which was discovered by screening our small synthetic natural product-like compound (NPL) library. Based on the lead compound, a series of novel tricyclic diterpene analogs were synthesized and investigated for their activity against the growth of various tumor cell lines using the sulforhodamine B (SRB) assay. To our delight, most aromatic amide compounds exhibited more potent antitumor activity than the lead compound. The most active compound 19 (QW30) showed an average IC50 0.33 µM, which was 15-fold more potent than the lead compound. Most of the compounds with potent antitumor activity displayed less toxic on normal human fibroblasts (HAF) in comparison with the tumor cell lines. Especially 19, its selectivity indexes (SI) between HAF and cancer cell lines was 17.3 times better than the positive control compound podophyllotoxin. The apoptosis, colony formation and transwell migration assays of 7 and 19 were performed on T47D cell line. The in-vivo antitumor effect of 19 was also observed in T47D tumor-bearing mice without obvious toxicity.

Design, synthesis and biological evaluation of tricyclic diterpene derivatives as novel neuroprotective agents against ischemic brain injury.

Lead compound 7 has neuroprotective effects, and it was discovered by screening a small synthetic natural product-like (NPL) library. Based on the lead, a series of tricyclic diterpene derivatives was designed and synthesized, and their neuroprotective effects were further evaluated against glutamate-, oxygen and glucose deprivation (OGD)- and nutrient deprivation-induced neuronal injury using cell-based assays. To our delight, most of these synthetic compounds exhibited increased neuroprotective effects and blood-brain barrier (BBB) permeability without cellular toxicity. The most potent compound, compound 30, showed significantly improved neuroprotection against neuronal injury in primary neurons. Furthermore, compound 30 exhibited remarkable neuroprotection in transient middle cerebral artery occlusion (tMCAO) rats by reducing their infarct sizes and neurological deficit scores. A mechanistic exploration using in vitro and in vivo experiments showed that the neuroprotection of these compounds was at least partly mediated by improving the levels of glutathione (GSH), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein. Therefore, these tricyclic diterpene derivatives could be used as promising leads for the development of a new type of neuroprotective agents against ischemic brain injury.

The genus Nyctiophylax Brauer in China (Trichoptera, Polycentropodidae).

Currently, 8 species of the genus Nyctiophylax Brauer are known from China. Examination of material collected from Guangdong, Guangxi, Jiangxi and Sichuan Provinces during 2004-2005 has revealed 4 new species and 2 new records of this genus, bringing the number of Chinese Nyctiophylax species to 14. Newly described species include: Nyctiophylax (Paranyctiophylax) crinalis n. sp., N. (P.) dactylatus n. sp., N. (P.) orbicularis n. sp., and N. (P.) macrorrhinus n. sp. Nyctiophylax (Paranyctiophylax) sagax Mey and N. (N.) amphonion Malicky & Chantaramongkol are newly recorded for the Chinese fauna, which are re-illustrated and re-described for clear comparisons. The additional collection sites for the previously described species are provided. 

New species of Plectrocnemia and Nyctiophylax (Trichoptera, Polycentropodidae) from China.

Four new species of genus Plectrocnemia and 4 new species of genus Nyctiophylax are described, namely: Plectrocnemia verticalissp. n.; Plectrocnemia acuminatasp. n.; Plectrocnemia cryptoparameresp. n.; Plectrocnemia qianshanensissp. n.; Nyctiophylax (Nyctiophylax) senticosussp. n.; Nyctiophylax (Paranyctiophylax) gracilissp. n.; Nyctiophylax (Paranyctiophylax) pungenssp. n.; and Nyctiophylax (Paranyctiophylax) auriculatussp. n.

[Stream health assessment using a benthic-index of biotic integrity in Xitiaoxi Stream, Zhejiang Province, China].

Stream macro-invertebrate assemblages were collected from 64 stream sites in Xitiaoxi Stream, Anji County, Zhejiang Province, China. Thirty-six candidate metrics were evaluated stepwise by distributing range analysis, discriminatory power analysis, and Pearson's correlation analysis. The B-IBI was composed of seven metrics: total taxa, EPT taxa, Coleoptera %, three dominant taxa, Hydropsychidae (Trichoptera) %, filterers %, and Biotic Index (BI). The ratio scoring method was used to transform the value of each metric into a uniform score. A variability coefficient method and an entropy method were used to calculate the weight value of each metric of the B-IBI. The measurement accuracy of the health criteria for the B-IBI derived from all sample data was better than that from only reference data. The entropy method had a higher accuracy (92.9%) than the sum total score method (85.7%) and the variability coefficient method (78.5%) in discriminating stressed and reference sites. The B-IBI health criteria for Xitiaoxi Stream were: B-IBI > 0.69 = healthy, 0.52 - 0.68 = sub-healthy, 0.35-0.51 = good-fair, 0.18-0.34 = fair, B-IBI < 0.17 = poor. The Pearson's correlation analysis between B-IBI and chemical-physical variables showed that the B-IBI strongly corresponded with the habitat quality index (r = 0.62, p < 0.01), water temperature (r = -0.64, p < 0.01), and altitude (r = 0.64, p < 0.01). Our results suggest that the B-IBI is a good indicator in stream health assessment and should be used in water resource management in China.