Biscroyunoid A, an Anti-Hepatic Fibrotic 19-nor-Clerodane Diterpenoid Dimer with a C-16-C-12' Linkage from Croton yunnanensis.

Biscroyunoid A (1), a 19-nor-clerodane diterpenoid dimer featuring a unique C-16-C-12' linkage and containing an unusual 4,7-dihydro-5H-spiro[benzofuran-6,1'-cyclohexane] motif, together with its biosynthetic precursor, croyunoid A (2), were isolated from Croton yunnanensis. Their structures were determined by spectroscopic, computational, and single-crystal X-ray diffraction methods. Compound 1 exerted an antihepatic fibrosis effect in LX-2 cells via inhibition of TGFß-Smad2/3 signaling.

Discovery of Ingenane Diterpenoids from Euphorbia hylonoma as Antiadipogenic Agents.

Thirteen new Euphorbia diterpenoids, euphylonanes A-M (1-13), and eight known ones were isolated from the whole plants of Euphorbia hylonoma. Compounds 1 and 2 are two rearranged ingenanes bearing a rare 6/6/7/3-fused ring system. Compound 3 represents the first example of a 9,10-epoxy tigliane, while 4-21 are typical ingenanes varying with substituents. Structures were elucidated using a combination of spectroscopic, computational, and chemical methods. Most ingenanes exerted a significant antiadipogenic effect in 3T3-L1 adipocytes, among which 4 was the most active with an EC50 value of 0.60 ± 0.27 µM. Mechanistic study revealed that 4 inhibited the adipogenesis and lipogenesis in adipocytes via activation of the AMPK signaling pathway.

Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from Prorocentrum lima PL11: Isolation, Structural Modification, and Mechanistic Study.

Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) (1) and OA methyl ester (2), were isolated from the cultured microalgae strain Prorocentrum lima PL11. OA can significantly activate the latent HIV but has severe toxicity. To obtain more tolerable and potent latency reversing agents (LRAs), we conducted the structural modification of OA by esterification, yielding one known compound (3) and four new derivatives (4-7). Flow cytometry-based HIV latency reversal activity screening showed that compound 7 possessed a stronger activity (EC50 = 46 ± 13.5 nM) but was less cytotoxic than OA. The preliminary structure-activity relationships (SARs) indicated that the carboxyl group in OA was essential for activity, while the esterification of carboxyl or free hydroxyls were beneficial for reducing cytotoxicity. A mechanistic study revealed that compound 7 promotes the dissociation of P-TEFb from the 7SK snRNP complex to reactivate latent HIV-1. Our study provides significant clues for OA-based HIV LRA discovery.

Crotonianoids A-C, Three Unusual Tigliane Diterpenoids from the Seeds of Croton tiglium and Their Anti-Prostate Cancer Activity.

Crotonianoids A-C (1-3), three unusual tigliane diterpenoids, were isolated from the seeds of Croton tiglium. Compound 1 is a 13,14:13,15-diseco-tigliane featuring a unique spiro[bicyclo[5.3.0]decane-2,5'-2'(3'H,4'H)-furanone] core; 2 is a 13,15-seco-tigliane incorporating a rare peroxide bridge between C-13 and C-15; and 3 is the first example of a phorbol ester with a 10R-configuration. Their structures were determined by spectroscopic, computational, and X-ray diffraction methods. Compounds 1 and 2 markedly inhibited the growth and survival of prostate cancer cell C4-2B at micromolar concentrations and induced cell apoptosis. Mechanistic study revealed that 1 and 2 could suppress androgen receptor (AR) signaling pathway by promoting the degradation of AR protein.

Tigliane and rhamnofolane glycosides from Euphorbia wallichii prevent oxidative stress-induced neuronal death in PC-12 cells.

Tigliane and rhamnofolane diterpenoids bearing glycosyl substituents are rarely found in nature. In the current study, seven new tigliane glycosides, euphorwallsides A - G (1-7), and five new rhamnofolane glycosides, euphorwallsides H - L (8-12), were isolated from the whole plants of Euphorbia wallichii. Their structures were elucidated by a combination of spectroscopic, computational, and chemical means. The aglycones of 1-5 represent a rare class of 13-deoxygenated tiglianes, while those of 8-12 represent the first examples of 4-deoxygenated rhamnofolanes. 2, 3, 5, 7, 8, and 12 showed significant neuroprotective effects on sodium nitroprusside (SNP)-induced neuronal death in pheochromocytoma cell line PC-12 at 10 µM, being more active than the clinical drug, edaravone. Mechanistic study revealed that the most active compound, 3, could inhibit reactive oxygen species (ROS) accumulation and restore the mitochondrial membrane potential via modulating the Nrf2 signaling pathway in PC-12 cells.

HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson's disease models.

Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.

Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity.

Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg-1. d-1, ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.

Homo/Hetero-Dimers of Aromatic Bisabolane Sesquiterpenoids with Neuroprotective Activity from the Fungus Aspergillus versicolor A18 from South China Sea

Chromatographic fractionation of the EtOH extracts of the marine-derived fungus Aspergillus versicolor A18 has led to the isolation of 11 homo/hetero-dimers of aromatic bisabolane sesquiterpenoids including eight diphenyl ether-coupled aromatic bisabolanes (1a/1b and 5−10) and three homodimers (2−4), together with their monomers including three aromatic bisabolanes (11−13) and two diphenyl ethers (14 and 15). Their structures and absolute configurations were elucidated by extensive spectroscopic analysis including HRESIMS, 1D/2D NMR, calculated ECD, and the optical rotatory data. Among the four new compounds, (+/−)-asperbisabol A (1a/1b), asperbisabol B (2), and asperbisabol C (3), the enantiomers 1a and 1b represent an unprecedented skeleton of diphenyl ether-coupled aromatic bisabolane sesquiterpenoids with a spiroketal core moiety. The neuroprotective effects of selected compounds against sodium nitroprusside (SNP)-induced injury were evaluated in PC12 cells by the MTT assay. Five compounds (1a, 6, and 8−10) showed remarkable neuroprotective activities at 10 µM, being more active than the positive control edaravone.

Structural Elucidation of Three 9,11-Seco Tetracyclic Triterpenoids Enables the Structural Revision of Euphorol J.

Compounds 1-3, the rare examples of 9,11-seco euphane or lanostane triterpenoids featuring an enol-hemiacetal functionality, were isolated from Euphorbia stracheyi. Their structures were elucidated by a combination of spectroscopic, computational, chemical, and single-crystal X-ray diffraction means, which enables the structure of previously published euphorol J to be revised as 1. 1-3 showed significant cytotoxicities on the breast cancer cell line MDA-MB-468 with IC50 values in the range of 2.9-3.9 µM.

Ba4GeSb2Se11: An Infrared Nonlinear Optical Crystal with a V-Shaped Se32- Group Possessing a Large Contribution to the SHG Response.

The quaternary selenide Ba4GeSb2Se11 was prepared by a high-temperature solid state reaction method. Ba4GeSb2Se11 crystallizes in an acentric orthorhombic space group Cmc21 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 [SbSe3]3- trigonal pyramid, [GeSbSe5]3- dimers, V-shaped Se32-, and the adjacent Ba2+ 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 AgGaS2 at the same particle size. Interestingly, theoretical analyses show that the central Se atom of Se32- has the largest contribution (8.1%) to d31 compared to that of other Se atoms, which may be due to its easy swing in the a-axis direction.

Presegetane diterpenoids from Euphorbia sieboldiana as a new type of anti-liver fibrosis agents that inhibit TGF-ß/Smad signaling pathway.

Seven new diterpenoids, eupholenes A-G (1-7), including two presegetanes (1 and 2), four jatrophanes (3-6), and one paraliane (7), along with 19 known analogues (8-26) were obtained by anti-liver fibrosis bioassay-guided isolation of Euphorbia sieboldiana. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, ECD calculations, and single-crystal X-ray diffractions. Euphorbesulin A (10), a presegetane diterpenoid (5/9/5 ring system), was identified as a promising anti-liver fibrosis agent that could inhibit the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), and collagen I in TGF-ß1-stimulated LX-2 cells at a micromolar level. Mechanistic study revealed that 10 suppressed liver fibrosis via inhibition of TGF-ß/Smad signaling pathway, and its potential target was TGF-ß type I receptor. These findings suggested that presegetane diterpenoid could serve as a new type of structural motif in future anti-liver fibrosis drug development.

Ba10In6Zn7S26- nZnS: An Inorganic Composite System with Interface Phase-Matching Tuned for High-Performance Infrared Nonlinear Optical Materials.

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 Ba10In6Zn7S26 (SS26) is synthesized. Further, its composite system Ba10In6Zn7S26- nZnS is synthesized by eutectic reaction. In particular, Ba10In6Zn7S26-14ZnS (SS40) shows excellent balanced NLO performance that includes a large band gap of 3.05 eV, high LIDT (13.3 × AgGaS2), large second harmonic generation (SHG) response (2.1 × AgGaS2 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.

Cytotoxic Pregnane Steroidal Glycosides from Chonemorpha megacalyx.

Three new C21 pregnane steroids, chonemorphols A-C (1, 3, and 4), 11 new C21 steroidal glycosides, chonemorphosides A-K (2 and 5-14), and 11 known compounds (15-25) were obtained from the vines and leaves of Chonemorpha megacalyx Pierre. Their structures were established using extensive spectroscopic data. The X-ray crystallographic data of 1 and 3 permitted definition of their absolute configurations. Notably, 1 and 2 possessed an uncommon 6/5/6/5/5-fused steroidal ring system. Compound 7 displayed significant cytotoxicity against several cancer cell lines with IC50 values of 2.0-3.6 µM.

New halimane and clerodane diterpenoids from Croton cnidophyllus.

Three new halimane furanoditerpenoids (1-3) and three new clerodane furanoditerpenoids (4-6), along with seven known terpenoids including four pimarane diterpenoids (7-10) and three norisoprenoids (11-13) were isolated from the 95% EtOH extracts of the plants of Croton cnidophyllus. The 2D structures including absolute configuration of new furanoditerpenoids (1-6) were elucidated by analysis of their HRMS and NMR data as well as comparison of experimental and calculated ECD curves. Bioassay revealed that two compounds (8 and 9) possessed certain inhibitory effects against NO production stimulated by LPS, with IC50 values of 19.00 ± 1.76 and 21.61 ± 1.11 µM, respectively.

New benzofuran neolignans with neuroprotective activity from Phyllanthodendron breynioides.

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.

Gardenia jasminoides Extract GJ-4 Alleviates Memory Deficiency of Vascular Dementia in Rats through PERK-Mediated Endoplasmic Reticulum Stress Pathway.

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[Formula: see text]mg/kg) and nimodipine (10[Formula: see text]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[Formula: see text]/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[Formula: see text]/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[Formula: see text]/ATF4/CHOP pathway, suggesting that GJ-4 may be useful for the treatment of VD.

Discovery of the First Raptor (Regulatory-Associated Protein of mTOR) Inhibitor as a New Type of Antiadipogenic Agent.

Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, 1c (5/7/6 carbon ring with orthoester and chlorine functionalities). Pharmacodynamic studies verified that 1c is a potent and tolerable antiadipogenic agent in vitro and in vivo. Mechanistic studies revealed that the targeting of Raptor by 1c could block the formation of mTORC1 and then downregulate the downstream S6K1- and 4E-BP1-mediated C/EBPs/PPARγ signaling, eventually retarding adipocyte cell differentiation at the early stage. These findings suggest that Raptor can be explored as a novel therapeutic target for obesity and its related complications, and 1c as the first Raptor inhibitor may provide a new therapeutic option for these conditions.

Diversity of sesquiterpenoids from Stellera chamaejasme with neuroprotective effects.

Chromatographic fractionation of the 95% EtOH extract of the roots of Stellera chamaejasme yielded 20 sesquiterpenoids of four different types, guaiane-, carotane-, sesquicarane-, and alpiniane-types. Among them, sesquistrachanoids A-F were previously undescribed ones, whose structures including absolute configurations were elucidated by spectroscopic methods, the Mo2(OAc)4-induced ECD experiment, and analysis of experimental and calculated 1D NMR and ECD data. Sesquistrachanoid A is a 2,3-seco-guaiane-type sesquiterpenoid with a α-pyrone core and sesquistrachanoid B is the first example of 8,9-seco-guaiane-type sesquiterpenoid featured with an 1,8-δ-lactone core. Sesquistrachanoid C is a guaiane sesquiterpenoid characterized by a peroxide bridge between C-8 and C-10. All sesquiterpenoids were evaluated for their neuroprotective effects on cell damage induced by sodium nitroprusside in PC-12 cells. The bioassay results showed that six compounds at 10 µM could restore the cell viability, being comparable to that of the positive control edaravone. The mechanistic study on the most pronounced activity compound, stelleraguaianone B, demonstrated that it played a neuroprotective role by promoting the mRNA expression of antioxidant enzymes to reduce oxidative stress.

Discovery of a highly potent and orally available importin-ß1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Nuclear transporter importin-ß1 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-ß1 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-ß1, 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-ß1.

[Lymphatic filariasis in Hubei Province: from prevailing to elimination].

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.