Isolation, Identification and Chemical Modification of Bufadienolides from Bufo melanostictus Schneider and Their Cytotoxic Activities against Prostate Cancer Cells.

The traditional Chinese medicine toad venom (Venenum bufonis) has been extensively used to treat various diseases, including cancers, in China and other Southeast Asian countries. The major constituents of toad venom, e.g., bufadienolides and alkaloids, exhibit broad-spectrum pharmacological effects in cancers. Herein, two new bufadienolides (1 and 2), along with eleven known compounds (3-13) were successfully isolated from Bufo melanostictus Schneider. Their structures were elucidated by extensive spectroscopic data and X-ray diffraction analysis. Furthermore, four lactam derivatives were synthesized through the transformation of bufadienolides lactones. The inhibitory effects of these compounds against human prostate cancer cell lines PC-3 and DU145 were evaluated. The outcomes indicated a notable trend, with a substantial subset displaying nanomolar range IC50 values against PC-3 and DU145 cells, underscoring their pronounced cytotoxicity. Moreover, a noteworthy distinction surfaces, wherein lactones consistently outperformed their lactam counterparts, further validating their heightened potency for the treatment of prostate cancer. This study contributes significant preclinical evidence substantiating the therapeutic viability of bufadienolides and toad venom as intervention strategies for prostate cancer.

Prognostic Value of Combined Neutrophil-to-Lymphocyte Ratio and Imaging Tumor Capsule in Solitary Hepatocellular Carcinoma Patients after Narrow-Margin Hepatectomy.

BACKGROUND: The study aimed to investigate the clinical value and prognostic patterns of the neutrophil-to-lymphocyte ratio (NLR) and imaging tumor capsule (ITC) in solitary hepatocellular carcinoma (HCC) patients undergoing narrow-margin hepatectomy. METHODS: Data for solitary HCC patients treated with narrow-margin surgery were extracted from Shanghai General Hospital. Clinical features of recurrence-free survival (RFS), overall survival (OS), and early recurrence were investigated by Cox/logistic regression. The significant variables were subsequently incorporated into the nomogram pattern. Survival analysis stratified by NLR and ITC was also performed. RESULTS: The study included a cohort of 222 patients, with median RFS and OS of 24.083 and 32.283 months, respectively. Both an NLR ≥ 2.80 and incomplete ITC had a significant impact on prognosis. NLR and ITC independently affected RFS and OS, whereas alpha-fetoprotein (AFP) and ITC were identified as independent factors for early relapse. The RFS and OS nomogram, generated based on the Cox model, demonstrated good performance in validation. The combination of NLR and ITC showed greater predictive accuracy for 5-year RFS and OS. Subgroups with an NLR ≥ 2.80 and incomplete ITC had the worst prognosis. CONCLUSIONS: Both NLR and ITC significantly affected RFS, OS, and early recurrence among solitary HCC patients who underwent narrow-margin hepatectomy. The combination of NLR and ITC has the potential to guide rational clinical treatment and determine the prognosis.

Cassaine diterpenoid glycosides from the seeds of Erythrophleum fordii Oliv. and their antiviral and anti-inflammatory activities.

Seven new cassaine diterpenoids (1-7) along with four known ones (8-11) were isolated from the seeds of Erythrophleum fordii Oliv. (Leguminosae). Their chemical structures were elucidated by extensive spectroscopic data interpretation and chemical methods. Compound 1 is a rare unsymmetrical dimer, which is formed by the linking of another cassaine diterpenoid acid glycoside to the 6-hydroxyl group of the sugar unit in a cassaine amide glycoside through an ester bond. Compound 2 is a cassaine diterpenoid acid derivative featuring an unusual Z double bond at C-13 and C-15. The in vitro antiviral and anti-inflammatory activities of 1-11 were evaluated. The results showed that compounds 1, 2 and 3 showed significant antiviral activities against human respiratory syncytial virus (RSV) with IC50s of 6.3, 7.8, and 9.4 µM, respectively. Compound 9 significantly suppressed the expression of nuclear factor-kappa B (NF-κB) with an IC50 value of 2.6 µM.

Tunable Toxicity of Bufadienolides is Regulated through a Configuration Inversion Catalyzed by a Short-Chain Dehydrogenase/Reductase.

Bufadienolides are toxic components widely found in amphibious toads that exhibit a wide range of biological activities. Guided by UPLC-QTOF-MS analysis, several 3-epi-bufadienolides with unique structures were isolated from the bile of the Asiatic toad, Bufo gargarizans. However, the enzymatic machinery of this epimerization in toads and its significance in chemical ecology remains poorly understood. Herein, we firstly compared the toxicities of two typical bufadienolides, bufalin (featuring a 14ß-hydroxyl) and resibufogenin (containing a 14, 15-epoxy group), with their corresponding 3-epi isomers in a zebrafish model. The results of the toxicology assays showed that the ratio of maximum non-toxic concentrations of these two pairs of compounds are 256 and 96 times, respectively, thereby indicating that 3-hydroxyl epimerization leads to a significant decrease in toxicity. Aiming to investigate the biotransformation of 3-epi bufadienolides in toads, we applied liver lysate to transform bufalin and found that it could stereoselectively catalyze the conversion of bufalin into its 3α-hydroxyl epimer. Following this, we cloned and characterized a short-chain dehydrogenase/reductase, HSE-1, from the toad liver cDNA library and verified its 3(ß→α)-hydroxysteroid epimerization activity. To the best of our knowledge, this is the first hydroxyl epimerase identified from amphibians that regulates the toxicity of animal-derived natural products.

Cassaine diterpenoids from the seeds of Erythrophleum fordii Oliv. and their antiangiogenic activity.

Fourteen undescribed cassaine diterpenoids along with nine known ones were isolated from the seeds of Erythrophleum fordii Oliv. (Leguminosae). In addition, subsequent structural modification yielded ten derivatives. Their chemical structures were established by extensive spectroscopic methods and acid hydrolysis. All the diterpenoids were screened for their antiangiogenic activity using the human umbilical vein endothelial cell (HUVEC) model. Five compounds were active, of which three possessed excellent activity as their effect was better than that of the positive control (SU5416). The structure-activity relationship analysis revealed that the side chain at C-13 was the key part affecting the inhibitory effect. Further study demonstrated that 3ß-hydroxynorerythrosuamine-3-O-ß-D-glucopyranoside and the formate of 3ß-hydroxynorerythrosuamine-3-O-ß-D-glucopyranoside significantly inhibited a series of angiogenic processes including proliferation, migration and capillary-like structure formation of endothelial cells. These findings may provide a new type of antiangiogenic agent for future cancer drug development.

Multiobjective optimization on cooperative control of autonomous emergency steering and occupant restraint system for enhancing occupant safety.

Occupant safety remains one of the most challenging and significant design considerations in the automotive and transportation industry. Nevertheless, independently developed active or passive safety systems may lead to unsatisfactory protective performance under the critical driving scenarios. This study aimed to conduct multiobjective optimization of the cooperative controls between autonomous emergency steering (AES) and occupant restraint system (ORS) to explore the potential occupant injury reduction capability as well as mechanisms subjected to a frontal collision. First, a multiple simulation approach comprising PreScan/Simulink, LS-DYNA, Madymo was used to correlate the control parameters of the safety systems and occupant injuries quantitatively. Then the control parameters of AES and ORS were selected as the design variables after sensitivity analysis, and injury responses of the sampling points were extracted by the multiple simulation approach. Surrogate models and multiobjective optimization algorithm were used to determine the optimum design in cooperative controls of AES and ORS maneuvers, from which in-depth effect mechanisms that contributed to the improvement of occupant protection were identified. Compared to the baseline design, the optimum control parameters of AES-ORS integration substantially decreased the occupant injuries of the head, chest and neck, and consequently led to a reduction of 33.02% in the overall injury risk. This study is anticipated to demonstrate a new design approach for the control system, thereby enhancing occupant safety.

Bufadienolides from the Eggs of the Toad Bufo bufo gargarizans and Their Antimelanoma Activities.

Toads produce potent toxins, named bufadienolides, to defend against their predators. Pharmacological research has revealed that bufadienolides are potential anticancer drugs. In this research, we reported nine bufadienolides from the eggs of the toad Bufo bufo gargarizans, including two new compounds (1 and 3). The chemical structures of 1 and 3, as well as of one previously reported semisynthesized compound (2), were elucidated on the basis of extensive spectroscopic data interpretation, chemical methods, and X-ray diffraction analysis. Compound 1 is an unusual 19-norbufadienolide with rearranged A/B rings. A biological test revealed that compounds 2 and 4-8 showed potent cytotoxic activities toward human melanoma cell line SK-MEL-1 with IC50 values less than 1.0 µM. A preliminary mechanism investigation revealed that the most potent compound, 8, could induce apoptosis via PARP cleavage, while 5 and 6 significantly suppressed angiogenesis in zebrafish. Furthermore, an in vivo biological study showed that 5, 6, and 8 inhibit SK-MEL-1 cell growth significantly.

Efficacy of progesterone on threatened miscarriage: an updated meta-analysis of randomized trials.

PURPOSE: The efficacy of progesterone supplementation in the treatment of threatened miscarriage is controversial. This meta-analysis was to evaluate the correlation between progesterone and improving pregnancy outcomes in women with threatened miscarriage. METHODS: We searched PubMed, EMBASE, and the Cochrane Library for relevant randomized controlled trials (RCTs) to demonstrate the efficacy of progesterone on the threatened miscarriage pregnancy. The outcomes were miscarriage, preterm birth, and live birth. RESULTS: Nine RCTs comparing 4907 patients were included in this study. Compared with placebo or no treatment, progesterone supplementation had a relationship with a reduction in the rate of miscarriage [RR 0.70 95% Cl (0.52, 0.94)]. There was no significant difference between progesterone supplementation and placebo or no treatment in preterm birth [RR 0.87 95% Cl (0.52, 1.47) and live birth (RR 1.02 95% Cl (0.98, 1.07)]. CONCLUSION: Progesterone supplementation did not significantly improve the incidence of preterm and live birth, so progesterone treatment of threatened miscarriage may be unhelpful.

Triterpene saponins from the seeds of Erythrophleum fordii and their cytotoxic activities.

Erythrosides A-G, seven undescribed oleanane-type triterpenoid saponins, were isolated from the seeds of Erythrophleum fordii. Their structures with absolute configurations were determined by extensive spectroscopic analysis including one-dimensional [1D] and two-dimensional [2D] nuclear magnetic resonance [NMR], high-resolution electrospray ionization mass spectroscopy [HR-ESI-MS] analysis, and chemical methods. Erythrosides A-G featured a diverse oligosaccharide chain containing 4-6 pentoses or hexoses at C-3 and a monoterpenic acid or a (E)-cinnamic acid unit at the C-21 position. Of particular interest, erythrosides A-C, E and F contained a rare alpha xylose in their sugar chains. The bioassay results indicated that erythrosides A-C showed moderate cytotoxic activities against human lung cancer cell line PC9 with IC50 values of 13.14, 16.67 and 17.59 µM, respectively (the positive control, Taxol, IC50 = 0.60 nM).

Carbon Composite Networks with Ultrathin Skin Layers of Graphene Film for Exceptional Electromagnetic Interference Shielding.

Natural cotton was selected as a cheap and renewable carbon source to fabricate novel carbon networks with porous three-dimensional conductive frameworks composed of numerous unique hollow carbon fibers by pyrolysis, and outstanding electromagnetic interference (EMI) shielding effectiveness (SE) of ∼26.9-46.9 dB was observed for the samples (∼0.3 mm in thickness) with density of ∼0.14-0.06 g/cm3. Moreover, the combination of cotton-derived carbon networks with graphene through the construction of a sandwich configuration, where graphene sheets were dispersed inhomogeneously on both sides of carbon networks, was further developed and the resultant carbon composite networks with ultrathin skin layers of graphene film in thickness of only ∼2 µm possessed higher EMI SE of ∼48.5-87.0 dB than that (∼33.7-55.6 dB) of pure carbon networks in thickness of ∼0.3-0.7 mm, possibly due to the enhanced EM reflection and absorption of EM waves penetrating the material. The SE increment of ∼26-41% was also observed in the sandwiched samples in comparison with the counterparts with homogeneous graphene dispersion, demonstrating a very promising configuration for the significant SE enhancement.

Cassaine diterpenoids from the seeds of Erythrophleum fordii and their cytotoxic activities.

Six new cassaine diterpenoids (1, 3-7), along with three known ones (2, 8-9) were isolated from the seeds of Erythrophleum fordii. Their structures were elucidated by extensive spectroscopic methods and acid hydrolysis. Compound 2 was tested to be the most potent one and showed more sensitive activities on MCF-7 and A549 cancer cells with IC50 values of 3.66 ±â€¯1.20 and 2.87 ±â€¯0.46 µM, respectively. Furthermore, compound 2 reduced the number of cell colonies significantly in a dose-dependent manner in the colony formation assay and triggered apoptosis of MCF-7 cell.