PDZK1 regulated by miR-145-5p protects against endothelial cell apoptosis and diabetic retinopathy by targeting mitochondrial function.

Mitochondria are a focus of biomedical research because of their role in apoptosis and diabetic retinopathy (DR) initiation and progression. However, the detailed mechanisms underlying mitochondrial disorders and endothelial dysfunction during DR remain elusive. We identified PDZ domain containing 1 (PDZK1) as a key factor linking endothelial mitochondrial dysfunction and cell apoptosis during DR progression.

eIF5A downregulated by mechanical overloading delays chondrocyte senescence and osteoarthritis by regulating the CREBBP-mediated Notch pathway.

Aims: To examine how eukaryotic translation initiation factor 5A (eIF5A) regulates osteoarthritis (OA) during mechanical overload and the specific mechanism.

Methods: Histological experiments used human bone samples and C57BL/6J mice knee samples. All cell experiments were performed using mice primary chondrocytes.

Polydatin protects against DSS-induced ulcerative colitis via Nrf2/Slc7a11/Gpx4-dependent inhibition of ferroptosis signalling activation.

Introduction: Ulcerative colitis (UC), a form of inflammatory irritable bowel disease, is characterized by a recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis.

A natural small molecule alleviates liver fibrosis by targeting apolipoprotein L2.

Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP.

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1.

Mechanical overloading can promote cartilage senescence and osteoarthritis (OA) development, but its impact on synovial macrophages and the interaction between macrophages and chondrocytes remain unknown. Here, we found that macrophages exhibited M1 polarization under mechanical overloading and secreted ectosomes that induced cartilage degradation and senescence. By performing miRNA sequencing on ectosomes, we identified highly expressed miR-350-3p as a key factor mediating the homeostatic imbalance of chondrocytes caused by M1-polarized macrophages, this result being confirmed by altering the miR-350-3p level in chondrocytes with mimics and inhibitor.

Discovery of a highly potent and orally available importin-1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Nuclear transporter importin-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-1 inhibitor to afford an improved analog -Br with better tolerability (>25 folds) and oral bioavailability.

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 IC values of 19.

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, (5/7/6 carbon ring with orthoester and chlorine functionalities).

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 Mo(OAc)-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.

Performance Analysis of a Solar Heating Ammonia Decomposition Membrane Reactor under Co-Current Sweep.

Ammonia is an excellent medium for solar thermal chemical energy storage and can also use excess heat to produce hydrogen without carbon emission. To deepen the study of ammonia decomposition in these two fields, finite-time thermodynamics is used to model a solar-heating, co-current sweeping ammonia decomposition membrane reactor. According to the needs of energy storage systems and solar hydrogen production, five performance indicators are put forward, including the heat absorption rate (HAR), ammonia conversion rate (ACR), hydrogen production rate (HPR), entropy generation rate (EGR) and energy conversion rate (ECR).

Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer.

Importins are overexpressed in many cancers and mediate the abnormal nuclear transport of oncogenic factors. The druggable potential of importins still remains unclear, largely because of the lack of potent inhibitors. Herein, the anti-castration-resistant prostate cancer (CRPC) screening of a Euphorbiaceae diterpenoid library followed by target fishing led to the identification of a highly potent importin-β1 inhibitor, daphnane diterpenoid .

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.

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

Crotonianoids A-C (-), three unusual tigliane diterpenoids, were isolated from the seeds of . Compound is a 13,14:13,15--tigliane featuring a unique spiro[bicyclo[5.3.

Jolkinolide B sensitizes bladder cancer to mTOR inhibitors via dual inhibition of Akt signaling and autophagy.

The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer.

Ilicicolin A Exerts Antitumor Effect in Castration-Resistant Prostate Cancer Via Suppressing EZH2 Signaling Pathway.

The Polycomb protein enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor antagonist employed for treatment of metastatic castration-resistant prostate cancer A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently.

Discovery of 8,9-seco--Kaurane Diterpenoids as Potential Leads for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant followed by the structural modification led to the construction of a small -kaurane diterpenoid library (-). With subsequent biological screening, 20 highly potent compounds (ICs < 3 μM) were identified.

A new tigliane-type diterpenoid from .

Five tigliane (-) and one ingenane () diterpenoids were isolated from the ethanol extract of . The structures of these compounds were identified based on analysis of their spectroscopic data. Among them, compound 12--(2,4,6,8-tetradecatetraenoyl)-13--isobutyroyl-4-deoxyphorbol () was a new tigliane.

Jolkinolide B targets thioredoxin and glutathione systems to induce ROS-mediated paraptosis and apoptosis in bladder cancer cells.

Bladder cancer is a clinically heterogeneous disease with a poor prognosis. In the current study, anti-proliferation assay of a Euphorbiaceae diterpenoid library led to the identification of an anti-bladder cancer agent Jolkinolide B (JB). JB showed significant cytotoxicity against a panel of bladder cancer cell lines and suppressed the growth of cisplatin (CDDP)-resistant bladder cancer xenografts in single or combination treatments.

Salviplenoid A from Salvia plebeia attenuates acute lung inflammation via modulating NF-κB and Nrf2 signaling pathways.

Acute lung injury (ALI) involves series of inflammatory pathologies and cause high morbidity. Salviplenoid A (SA) was a new sesquiterpenoid from the traditional inflammatory herb Salvia plebeia. In our previous study, SA exhibited antiinflammatory activity in RAW264.

Orphan nuclear receptor RORγ confers doxorubicin resistance in prostate cancer.

Prostate cancer (PCa) is a malignant tumor with an extremely high prevalence. Doxorubicin is the first-line clinical treatment for castration-resistant PCa. Clinically, relapse is almost inevitable due to the cancer cells' increasing resistance to doxorubicin.

Euphopanes A-C, three new diterpenoids from .

Three new diterpenoids, euphopanes A-C (-), including one -isopimarane (), one -abietane () and one cembrane (), along with five known compounds (-) were isolated from the roots of . Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of compounds - were determined by ECD calculations. All the isolates were screened for the cytotoxicity against three cancer cell lines (C4-2B, C42B/ENZR, and MDA-MB-231), and compounds , , and showed significant cytotoxicity against human prostate cancer cells C4-2B with IC values of 14.

Euphonoids A-G, cytotoxic diterpenoids from Euphorbia fischeriana.

Seven previously undescribed polycyclic diterpenoids, euphonoids A-G, including four ent-abietanes, two ent-atisanes, and one ent-kaurene, along with 26 known analogues were isolated from the roots of Euphorbia fischeriana. The structures of the undescribed compounds were elucidated by spectroscopic analysis, ECD calculations, and single crystal X-ray diffraction. Besides, the structure of a previously reported ent-abietane diterpenoid, fischeriabietane A, was revised.

Jatrogricaine A: a new diterpenoid with a 5/6/6/4 carbon ring system from the stems of Jatropha podagrica.

Jatrogricaine A (1), a new diterpenoid possessing a 5/6/6/4 carbon ring system, together with eight known diterpenoids (2-9) were isolated from the stems of Jatropha podagrica. Their structures were elucidated by extensive spectroscopic methods and the absolute configuration of 1 was determined by single crystal X-ray diffraction analysis. All compounds were evaluated for their anti-inflammatory activities in vitro, and compound 3 showed significant inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.

Toonapolyynes A-D, new polyynes from .

Phytochemical investigation on the leaves and twigs of has led to the isolation of four new polyynes (-) and two knowns ( and ). Their structures were determined by extensive spectroscopic analysis (MS, UV, IR, and NMR) and Mosher's method. All compounds were evaluated for their inhibitory activities against HepG2 human tumor cell line but were inactive.

Anti-inflammatory Ingenane Diterpenoids from the Roots of Euphorbia kansui.

Bioassay-guided fractionation of the ethanolic extract of the roots of led to the isolation of two new ingenane diterpenoids, euphorkans A (1: ) and B (2: ), together with 16 known analogues (3:  - 18: ). Their structures were determined by combined spectral and chemical methods. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.