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Three new meroterpenoids (1-3) and ten known ones (4-13) were obtained from the endophytic fungus Talaromyces primulinus H21 isolated from the plant of Euphorbia sikkimensis. Their structures including their absolute configurations were elucidated by extensive analysis of spectroscopic data such as HR-ESI-MS, 1D/2D NMR, and X-ray diffraction of single crystal together with comparison of experimental ECD with calculated ECD. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 3, 9, 12, and 13 exhibited certain inhibition on NO production, with IC 50 values of 27.19, 41.55, 25.23, and 24.71 μM, respectively., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests associated with this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The metabolic or proliferative abnormalities that are characteristic of tumor cells can lead to abnormal fibrinolysis or coagulation system activity, with certain tumors exhibiting hypercoagulability or existing in a fibrinolytic state. However, the utility of biomarkers of coagulation and fibrinolysis when seeking to differentiate between benign gallbladder disease and malignant gallbladder tumors remains uncertain., Methods: This study included a total of 81 patients with benign gallbladder polyps and 94 patients with malignant gallbladder tumors. Pre-biopsy or pretreatment levels of PT, APTT, FIB, D-dimer, FDP, PLT, PIC, TAT, TM, and t-PAIC from these patients were compared using Mann-Whitney tests. The baseline data of the patients were analyzed using chi-square tests, and the diagnostic utility of these biomarkers in distinguishing between benign and malignant gallbladder lesions was evaluated using ROC curves, and Spearman correlation analysis was employed to assess the correlation between these indicators and tumor parameters., Results: The average age of malignant gallbladder tumor group was higher than benign gallbladder polyp group. And the base line analysis showed that there was a statistic difference in age, history of smoking, drinking, biliary tract disease, BMI of over weight between these two groups. In patients with malignant gallbladder tumors, FIB, D-dimer, FDP, PIC, TAT, TM, and t-PAIC levels were significantly elevated relative to those in patients affected by benign gallbladder polyp. The AUC for FIB, D-dimer, and FDP was 0.8469, 0.6514, 0.5950, while for PIC, TAT, TM, t-PAIC and four biomarker combined diagnosed was 0.8455, 0.6554, 0.7130, 0.6806, and 0.8859. Among these, TM was associated with the vascular invasion of tumor patients; TAT and t-PAIC were associated with neural invasion; D-dimer and FDP were related to the maximum tumor diameter; and FDP had a certain correlation with the tumor stage., Conclusions: In gallbladder tumor patients, conventional coagulation metrics like FIB, D-dimer, and FDP, as well as newer thrombotic indicators such as PIC, TAT, TM, and t-PAIC, were obviously increased. Correlations with tumor parameters suggested their potential as biomarkers to distinguish benign from malignant gallbladder growths., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial dynamics. Partial inhibition of this protein is protective in experimental models of neurological disorders such as Parkinson's disease and Alzheimer's disease. The protective mechanism has been attributed primarily to improved mitochondrial function. However, the observations that Drp1 inhibition reduces protein aggregation in such neurological disorders suggest the involvement of autophagy. To investigate this potential novel protective mechanism of Drp1 inhibition, a model with impaired autophagy without mitochondrial involvement is needed., Methods: We characterized the effects of manganese (Mn), which causes parkinsonian-like symptoms in humans, on autophagy and mitochondria by performing dose-response studies in two cell culture models (stable autophagy HeLa reporter cells and N27 rat immortalized dopamine neuronal cells). Mitochondrial function was assessed using the Seahorse Flux Analyzer. Autophagy flux was monitored by quantifying the number of autophagosomes and autolysosomes, as well as the levels of other autophagy proteins. To strengthen the in vitro data, multiple mouse models (autophagy reporter mice and mutant Drp1 +/- mice and their wild-type littermates) were orally treated with a low chronic Mn regimen that was previously reported to increase α-synuclein aggregation and transmission via exosomes. RNAseq, laser captured microdissection, immunofluorescence, immunoblotting, stereological cell counting, and behavioural studies were used. RESULTS IN VITRO: data demonstrate that at low non-toxic concentrations, Mn impaired autophagy flux but not mitochondrial function and morphology. In the mouse midbrain, RNAseq data further confirmed autophagy pathways were dysregulated but not mitochondrial related genes. Additionally, Mn selectively impaired autophagy in the nigral dopamine neurons but not the nearby nigral GABA neurons. In cells with a partial Drp1-knockdown and Drp1 +/- mice, Mn induced autophagic impairment was significantly prevented. Consistent with these observations, Mn increased the levels of proteinase-K resistant α-synuclein and Drp1-knockdown protected against this pathology., Conclusions: This study demonstrates that improved autophagy flux is a separate mechanism conferred by Drp1 inhibition independent of its role in mitochondrial fission. Given that impaired autophagy and mitochondrial dysfunction are two prominent features of neurodegenerative diseases, the combined protective mechanisms targeting these two pathways conferred by Drp1 inhibition make this protein an attractive therapeutic target., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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.)

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.

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 2 (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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Euphylonoids A ( 1 ) and B ( 2 ), two highly modified jatrophane diterpenoids, were isolated from Euphorbia hylonoma . 1 represents a new 9(10→18)- abeo -8,12-cyclojatrophane skeleton containing a cage-like 3,8-dioxatricyclo[5.1.2.0 4,9 ]decane core, while 2 is a 14(13→20)- abeo -8,12-cyclojatrophane featuring an unusual 17-oxatetracyclo[12.2.1.0 1,5 .0 9,13 ]heptadecane framework. Their structural elucidation was completed by spectroscopic, chemical, computational, and single-crystal X-ray diffraction means. 2 significantly inhibited early adipogenesis in 3T3-L1 adipocytes via activating AMP-activated protein kinase signaling.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 DD1 . DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar concentrations and completely blocked tumor growth in preclinical models at an extremely low dosage. Mechanistic studies revealed that targeting of importin-β1 by DD1 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of DD1 on importin-β1 abolished this anti-CRPC effect. These findings suggest that importin-β1 is an effective therapeutic target in CRPC and that DD1 as the most potent importin-β1 inhibitor to date can be developed as therapeutics for treatment of this disease.

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. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms were related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To investigate the sexual behavior and sexual function of the male partners of breast cancer patients and their potential relationship with socio-demographic and clinical variables., Methods: In this cross-sectional study, we conducted an investigation among 196 male partners (aged 23－59 years) of breast cancer patients between May 2020 and October 2020. We completed the Male Sexual Function Questionnaire (BSFI) by online and telephone interview with the subjects and collected relevant socio-demographic and clinical variables., Results: The average age of the interviewees was (46.13 ± 7.75) years old, and the mean duration of the patients' breast cancer was (1.58 ± 0.48) years at the time of the investigation. The incidence rate of sexual dysfunction in the male partners of the patients was dramatically higher after the onset of breast cancer than before it (49.76% vs 9.68%, P < 0.01). Low libido was found to be the main type of sexual dysfunction (38.3%) among the male subjects, with an even high incidence rate among those whose wives received mastectomy (OR = 5.533, P = 0.017, 95% CI: 1.366－22.412) and radiotherapy (OR = 3.439, P < 0.044, 95% CI: 1.058－11.171) and significantly correlated with age (OR = 1.134, P = 0.001, 95% CI: 1.053－1.222)., Conclusions: Breast cancer and its treatment methods may affect the sexual function of the male partners of the patients. It is necessary for doctors to pay attention to the factors affecting the sexual function of the patients and their partners so as to take appropriate intervention measures.

Two new lathyrane diterpenoids, euphanoids A and B ( 1 and 2 ), along with five known compounds ( 3 - 7 ) were isolated from the roots of Euphorbia kansuensis . Their structures were elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by single crystal X-ray diffraction. All of the isolates were screened for the inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 1 and 2 showed pronounced inhibition on NO production with IC 50 values of 4.7 and 9.5 μM, respectively, being more active than the positive control, quercetin (IC 50 = 10.8 μM).

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-β1-stimulated LX-2 cells at a micromolar level. Mechanistic study revealed that 10 suppressed liver fibrosis via inhibition of TGF-β/Smad signaling pathway, and its potential target was TGF-β 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., (Copyright © 2021. Published by Elsevier Inc.)

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 Croton kongensis followed by the structural modification led to the construction of a small ent -kaurane diterpenoid library ( 1 - 25 ). With subsequent biological screening, 20 highly potent compounds (IC 50 s < 3 μM) were identified. Among them, 8,9-seco- ent -kaurane 6 displayed comparable activity (IC 50 s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,β-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo , 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.

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. Mechanistic study revealed that, besides inducing mitogen-activated protein kinase (MAPK)-related apoptosis, JB could trigger the paraptosis via activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and extracellular signal-regulated kinase (ERK) pathway. The excessive production of ROS could be induced by JB via inhibition of thioredoxin reductase 1 (TrxR1) and depletion of glutathione (GSH). Collectively, JB that targets thioredoxin and GSH systems to induce two distinct cell death modes may serve as a promising candidate in future anti-bladder cancer drug development., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 IC 50 values in the range of 2.9-3.9 μM.

A preliminary research on the marine fungus Fusarium sp. XBB-9 resulted in a pair of novel bisindole alkaloid enantiomers, (+)- and (-)-fusaspoid A ( 1a / 1b ) and 12 diverse compounds. One strain many compound (OSMAC) method was used to enhance as many biosynthetic pathways as possible. The structures of the compounds were elucidated by spectroscopic analysis, and the absolute configuration of 1a was determined by X-ray single-crystal diffraction analysis. Compounds 1a and 1b were tested for cytotoxic activity against HCT-15, RKO cell lines, but were inactive. Compounds 1a and 1b were the first example of bisindole alkaloids isolated from fungus Fusarium sp. XBB-9.

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 RAW264.7 cells. However, the extensive effects of SA in human cells and in vivo and the active mechanisms are unclear. Thus, in this study, we sought to access its effects in vitro and in vivo and to investigate its mechanisms. SA was proved to inhibit the induction of proinflammatory cytokines in human cell types, including pulmonary epithelial cells and endothetial cells. It also depressed monocyte adhesion. Moreover, SA potently attenuated the acute lung inflammation in the LPS-induced mouse model shown by down-regulation of proinflammatory mediators, inhibition of polymorphonuclear neutrophil infiltration, and alleviation of related symptoms like alveolar congestion and mucus secretion. Further evaluation confirmed that SA regulated NF-κB pathway by inhibiting the IκB-α phosphorylation. And it markedly mediated Nrf2/HO-1 pathway by activating the Nrf2/HO-1 expression and promoting Nrf2 nuclear translocation. Therefore, SA could attenuate acute lung inflammation via suppressing NF-κB and activating Nrf2, which provide a theoretical basis for the potential application of SA in clinic., (© 2020 John Wiley & Sons Ltd.)

Two highly oxygenated nor -clerodane diterpenoids, crocleropenes A and B ( 1 and 2 ), together with four known compounds ( 3-6 ) were isolated from the leaves and twigs of Croton caudatus . Their structures were elucidated by combination of extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. 1 and 2 represent the first examples of nor -clerodane-3,5(10)-diene diterpenoids. Compounds 1 and 2 exhibited weak cytotoxicity in vitro against MCF-7 cancer cells with IC 50 values of 35.8 and 40.2 μM, respectively. [Formula: see text].

Eight previously undescribed diterpenoids, euphoroyleans A-H, including two cembranes, three ingenanes, two ent-atisanes, and one ent-kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana. The structures of euphoroyleans A-H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities. Among them, ingol-3,7,12-triacetate-8-benzoate, the most active MDR modulator with no obvious cytotoxicity, could enhance the efficacy of anticancer drug DOX to ca. 105 folds at 10 μM, being stronger than the positive drug verapamil. Mechanistic study revealed that ingol-3,7,12-triacetate-8-benzoate could inhibit the transport activity of P-gp rather than its expression, and the possible recognition mechanism between compounds and P-gp was predicted by molecular docking., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Long noncoding RNAs (lncRNAs) are considered critical regulators in cancers; however, the clinical significance and mechanisms of MAPKAPK5-AS1 (hereinafter referred to as MK5-AS1) in colorectal cancer (CRC) remain mostly unknown., Methods: In this study, quantitative real-time PCR (qPCR) and western blotting were utilized to detect the levels of MK5-AS1, let-7f-1-3p and MK5 (MAPK activated protein kinase 5) in CRC tissues and cell lines. The biological functions of MK5-AS1, let-7f-1-3p and MK5 in CRC cells were explored using Cell Counting Kit-8 (CCK8), colony formation and transwell assays. The potential mechanisms of MK5-AS1 were evaluated by RNA pull-down, RNA immunoprecipitation (RIP), dual luciferase reporter assay, chromatin immunoprecipitation (ChIP) and bioinformatics analysis. The effects of MK5-AS1 and MK5 on CRC were investigated by a xenotransplantation model., Results: We confirmed that MK5-AS1 was significantly increased in CRC tissues. Knockdown of MK5-AS1 suppressed cell migration and invasion in vitro and inhibited lung metastasis in mice. Mechanistically, MK5-AS1 regulated SNAI1 expression by sponging let-7f-1-3p and cis-regulated the adjacent gene MK5. Moreover, MK5-AS1 recruited RBM4 and eIF4A1 to promote the translation of MK5. Our study verified that MK5 promoted the phosphorylation of c-Jun, which activated the transcription of SNAI1 by directly binding to its promoter., Conclusions: MK5-AS1 cis-regulated the nearby gene MK5 and acted as a let-7f-1-3p sponge, playing a vital role in CRC tumorigenesis. This study could provide novel insights into molecular therapeutic targets of CRC.

Four new tetracyclic triterpenoids (1-4) were isolated from the leaves and twigs of Jatropha gossypiifolia. Their structures were elucidated by MS and NMR data analysis, together with the Mo 2 (OAc) 4 -induced CD data. Jagabeoeuphols A-C (1-3) are rare 19(10 → 9)abeo-euphane-type triterpenoids possessing a Δ 5(10) group and a 7,8-epoxide moiety, and jagoseuphone A (4) is a typical euphane-type triterpenoid. The inhibitory effects of 1-4 on nitric oxide production induced by lipopolysaccharide in RAW264.7 cells were evaluated, and 4 exhibited moderate inhibitory activity with an IC 50 value of 20.1 μM., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Thirteen new jatrophane diterpenoids, euphoresulanes A-M (1-13), and seven known analogues (14-20) were isolated from the whole plants of Euphorbia esula. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of 1, 6, and 10 were confirmed by single crystal X-ray diffraction. Compounds 1-20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent cancer cell line HepG2/ADR, and 1, 2, 4, 6, and 8 exhibited comparable activity to the positive drugs. Euphoresulane H (8), the most active MDR modulator, could enhance the efficacy of anticancer drug adriamycin to ca. 33 folds at 5 μM. The structure-activity relationship (SAR) study revealed that the acyloxy substitution at C-9 is essential to the activity and presence of H-2 was favorable., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The phytochemical investigation of the roots of Croton crassifolius led to the isolation of 16 new halimane furanoditerpenoids, crohalifuranes A-P ( 1 - 16 ), along with 15 known analogues, 17 - 31 . The new structures including their absolute configurations were elucidated by NMR and MS data analysis, comparison of experimental and calculated electronic circular dichroism data, single-crystal X-ray diffraction data, and chemical methods. Crohalifuranes A ( 1 ) and B ( 2 ) are tetranor - and 19- nor -halimane diterpenoids featuring a rare decahydroacenaphthene core, respectively, which might be derived from the accompanying crassifoliusin A by loss of the furan ring or the C-19 substituent. Crohalifurane C ( 3 ) represents the first example of a 20- nor -halimane diterpenoid, and crohalifurane D ( 4 ) is characterized by an unusual 6,20-δ-lactone moiety. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide in RAW264.7 cells, and 2 and 23 exhibited moderate inhibition on NO production with IC 50 values of 17.2 ± 1.3 and 23.7 ± 1.4 μM, respectively.

Jatrofolianes A ( 1 ) and B ( 2 ), which are two highly modified lathyrane diterpenoids, were isolated from Jatropha gossypiifolia . 1 incorporates an unusual transannular 1,3-dioxolane moiety, forming a unique 5/6/5/8/3 ring system, while 2 possesses a new 10,11:13,14-diseco-lathyrane skeleton with a 12-membered macrocyclic lactone ring. Their structures were determined by spectroscopic analysis, quantum chemical calculations, and single-crystal X-ray diffraction. 2 showed significant multidrug resistance (MDR) reversal activity to cancer cells HepG2/ADR and HCT-15/5-FU at 10 μM.

Twenty new ingol diterpenoids, euphornans A-T (1-20), representing a rare class of C-19-oxidated and H-2, H-3 β-oriented ingols, were isolated from the seeds of Euphorbia marginata. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, ECD analysis, and single crystal X-ray diffraction. Compounds 1-20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent MDR cancer cell line HepG2/ADR, and 11, 14, and 18 were identified as potent MDR modulators that could enhance the efficacy of anticancer drug adriamycin to ca. 20 folds at 5 μM. The Pgp inhibition mechanism and brief structure-activity relationships (SARs) of these compounds were also discussed., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Targeting alpha-synuclein (α-syn) as a therapeutic strategy for Parkinson's disease (PD) has been intensively pursued largely due to its well-recognized pathogenic role. Since its discovery as the first familial link to PD over two decades ago, this protein has been associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and impaired autophagic flux. We report here that blocking dynamin-related protein 1 (Drp1) improved both mitochondrial function and autophagic flux in experimental models of α-syn. Using rat dopaminergic neuronal cells with inducible wild-type human α-syn, we observed excessive mitochondrial fragmentation and increased Drp1 levels 48 h after gene induction. Functionally, these cells exhibited lower mitochondrial membrane potential, reduced ATP production rate and mitochondrial spare respiratory capacity, as well as increased levels of mitochondrial reactive oxygen species. To evaluate the protective role of Drp1 inhibition, we used three complementary approaches: gene silencing mediated by siRNA, overexpression of Drp1-dominant negative and the small molecule mitochondrial division inhibitor-1 (mdivi-1). Both morphological and functional defects induced by α-syn were attenuated by these strategies. Importantly, Drp1 inhibition reduced proteinase K-resistant α-syn aggregates. Based on that observation, we investigated the involvement of autophagy. Through a combination of stable autophagy reporter cells and immunoreactivity for LC3 and p62 in neuronal cells with either α-syn overexpression or treatment of human α-syn preformed fibrils (PFF), we observed that Drp1 inhibition abolished autophagic impairment induced by α-syn. Consistent with its role in improving autophagy function, Drp1 inhibition reduced exosome release and spread of α-syn pathology from neurons to neurons and from microglia to neurons. In summary, this study highlights new insights that Drp1 inhibition confers neuroprotection through both mitochondrial and autophagy-lysosomal pathways, further strengthening the therapeutic potential of targeting Drp1.

Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson's disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1). We show here that mdivi-1 reduced neurodegeneration, α-syn aggregates and normalized motor function. Mechanistically, mdivi-1 reduced mitochondrial fragmentation, mitochondrial dysfunction and oxidative stress. These in vivo results support the negative role of mutant α-syn in mitochondrial function and indicate that mdivi-1 has a high therapeutic potential for PD.

Mitochondrial dysfunction has been reported in both familial and sporadic Parkinson's disease (PD). However, effective therapy targeting this pathway is currently inadequate. Recent studies suggest that manipulating the processes of mitochondrial fission and fusion has considerable potential for treating human diseases. To determine the therapeutic impact of targeting these pathways on PD, we used two complementary mouse models of mitochondrial impairments as seen in PD. We show here that blocking mitochondrial fission is neuroprotective in the PTEN-induced putative kinase-1 deletion (PINK1(-/-)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models. Specifically, we show that inhibition of the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) using gene-based and small-molecule approaches attenuates neurotoxicity and restores pre-existing striatal dopamine release deficits in these animal models. These results suggest Drp1 inhibition as a potential treatment for PD.

Ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) based on solidification of the floating organic solvent droplets (SFO) combined with HPLC was used for determination of five fungicides in fruit juice samples. 1-Dodecanol, which has a low density and low toxicity, was used as the extraction solvent in UA-DLLME. The solidification of floating organic droplets facilitates the transfer of analytes from the aqueous phase to the organic phase. This method was easy, quick, inexpensive, precise, and linear over a wide range. Under the optimized conditions, the enrichment factors for a 5 mL fruit juice sample were 25 to 56, and the LODs for the five fungicides ranged from 5 to 50 microg/L. The average recoveries ranged from 71.8 to 118.2% with RSDs of 0.9 to 13.9%. Application of the DLLME-SFO technique allows successful separation and preconcentration of the fungicides at a low concentration level in fruit juice samples.

Objective: To investigate the relationship between the resistance of methotrexate (MTX) enantiomer and the gene expression levels of folylpolyglutamate synthetase (FPGS)., Methods: The cell lines of MTX enantiomer resistance from 15 - 55 µmol/L were obtained when the A549 cell lines were exposed intermittently and progressively to an incremental dose of each MTX enantiomer. The resistant index of MTX resistance cell lines were detected by MTT. The gene expressions of FPGS in cytoplasm and mitochondria were detected by real-time quantitative polymerase chain reaction (PCR)., Results: The resistance indice of D-(-)-MTX resistant cell lines were higher than those of L-(+)-MTX resistant cells (32.7 ± 9.3 vs 11.5 ± 2.9, P < 0.05). The resistant indice of L-(+)-MTX/A549 were from 5 to 15, which mean the middle resistance. The resistant indice of D-(-)-MTX/A549 were more than 15, which mean the severe resistance. The expression of mFPGS had difference between resistant cell lines of L-(+) and D-(-)-MTX except at 15 µmol/L MTX (at 25 µmol/L, 1.3 ± 0.7 vs. 2.3 ± 0.9; at 35 µmol/L, 1.1 ± 0.9 vs. 2.6 ± 0.3; at 45 µmol/L, 1.0 ± 1.0 vs. 1.4 ± 0.8; at 55 µmol/L, 0.2 ± 0.1 vs. 1.0 ± 0.2; all P < 0.05). The expressions of cFPGS had no difference between resistant cell lines of L-(+) and D-(-)-MTX at 15 µmol/L MTX, while at 25 - 55 µmol/L, the cFPGS levels and resistance indice of D-(-)-MTX/A549 resistant cell lines showed a highly negative correlation (r = -0.95, P < 0.05)., Conclusion: There may be a different mechanism between the first time treatment with 15 µmol/L dosage and the continual treatment with more than 25 µmol/L dosage in A549 cell lines. There had higher resistant index in D-(-)-MTX/A549 cell line than in L-(+)-MTX/A549 cell line. The results indicated that the difference in chirality should be considered in clinical treatment with MTX.

In the title complex, [Ni(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)]·4H(2)O, the Ni(II) ion is coordinated in a slightly distorted octa-hedral environment formed by two bis-chelating H(2)pimda (H(3)pimda is 2-propyl-1H-4,5-dicarb-oxy-lic acid) ligands and two coordinated water mol-ecules. In the crystal structure, a three-dimensional framework is formed by inter-molecular O-H⋯O and N-H⋯O hydrogen bonds involving the solvent water mol-ecules, coordinated water mol-ecules, carboxyl-ate O atoms and the protonated N atoms of the H(2)pimda ligands. The propyl groups of each H(2)pimda ligand are disordered over two sets of sites with refined occupancies of 0.50 (2):0.50 (2) and 0.762 (11):0.238 (11). In one water solvent mol-ecule, one of the H atoms was refined as disordered over two sites of equal occupancy.

In the mononuclear title compound, [Ni(C(8)H(7)O(2))(2)(C(3)H(4)N(2))(2)(H(2)O)], the Ni(II) atom is coordinated by three carboxylate O atoms (from a bidentate 4-methyl-benzoate ligand and a monodentate 4-methyl-benzoate ligand), two N atoms (from two imidazole ligands) and a water mol-ecule in an octa-hedral geometry. Inter-molecular O-H⋯O hydrogen-bonding inter-actions lead to infinite chains, which are further self-assembled into a supra-molecular network through inter-molecular N-H⋯O hydrogen-bonding inter-actions and π-π stacking [centroid-centroid distance = 3.717 (2) Å].

In the title coordination polymer, {[Ba(C(7)H(2)N(2)O(7))(H(2)O)(2)]·H(2)O}(n), the Ba(II) atom is ten-coordinated by seven O atoms from four 3,5-dinitro-salicylatate ligands, two μ(2)-bridging aqua ligands and one water mol-ecule. The coordination mode is best described as a bicapped square-anti-prismatic geometry. The 3,5-dinitrosalicylatate ligands bridge three Ba atoms. Centrosymmetrically related dinuclear barium units, with a Ba⋯Ba separation of 4.767 (5) Å, form infinite chains, which are further self-assembled into a supra-molecular network through inter-molecular O-H⋯O hydrogen-bonding inter-actions between O atoms of 3,5-dinitro-salicylatate ligands and water mol-ecules.

The title complex, [Co(C(8)H(12)N(2)O(3))(2)(C(3)H(4)N(2))(2)], whose structure was first determined by Wang & Craven [(1971). J. Chem. Soc. D, pp. 290-291], has been redetermined with improved precision. A crystallographic twofold rotation axis passes through the Co atom, which is tetrahedrally coordinated by two N atoms from two barbital ligands and two N atoms from two imidazole ligands. The mol-ecules are self-assembled via inter-molecular N-H⋯O hydrogen-bonding inter-actions into a supra-molecular network.

A deleterious gene achieves a population balance between the opposing forces of selection and mutation. In this paper we explore the nature of this stochastic balance when the surrounding normal population is not at equilibrium. Assuming that new mutations occur according to a Poisson process and thereafter evolve by the rules of a continuous time branching process, we derive explicit formulas and recurrence relations determining the probability distribution of the current number of mutant individuals. In fact, we compute expectations for a variety of interesting random variables for genetic models involving autosomal dominant and X-linked diseases. We can also handle haplotype information on linked markers. This feature will be especially helpful in understanding the linkage disequilibrium strategy of positional cloning in population isolates. In the presence of exponential growth of the normal population, our formulas reduce to the evaluation of certain Laplace transforms.