Antitumor effects of Cypaliuruside F from Cyclocarya paliurus on HepG2 cells.

An undescribed dammarane triterpenoid saponin Cypaliuruside F was isolated from the leaves of Cyclocarya paliurus in our preliminary study. The MTT assay, flow cytometry, cell scratch, and DAPI staining were used to detect the antitumor effects of Cypaliuruside F on HepG2 cells. Subsequently, network pharmacology and molecular docking analysis were used to analyse the key targets of Cypaliuruside F against HCC. In addition, a Western blot was performed to determine the effects of Cypaliuruside F on the expression of key proteins in HepG2 cells. The experimental results indicated that the damarane triterpenoid saponin Cypaliuruside F from Cyclocarya paliurus inhibits the proliferation of HepG2 cells by inducing apoptosis and cell cycle arrest. These changes may promote the apoptosis of HepG2 cells by inhibiting the expression of mTOR, STAT3, and Bcl-2 while activating Bax.

Value of Intrauterine Autologous Platelet-Rich Plasma Therapy on Endometrial Receptivity: A Literature Review.

Endometrial receptivity is an important factor that influences embryo implantation. Thus, it is important to identify an applicable approach to improve endometrial receptivity in women undergoing assisted reproductive technology. Recently, growing evidence has indicated that intrauterine platelet-rich plasma (PRP) infusion is an effective method to obtain a satisfactory reproductive outcome by increasing endometrial thickness and improving endometrial receptivity. Therefore, the present review aims to outline the possible mechanisms of PRP on endometrial receptivity and summarize the present literature on the effects of PRP therapy in improving endometrial receptivity.

Diagnostic performance of endorectal ultrasound combined with shear wave elastography for rectal tumors staging.

OBJECTIVE: This study aims to analyze the performance of endorectal ultrasound (ERUS) combined with shear wave elastography (SWE) for rectal tumor staging. METHODS: Forty patients with rectal tumors who had surgery were enrolled. They underwent ERUS and SWE examinations before surgery. Pathological results were used as the gold standard for tumor staging. The stiffness values of the rectal tumor, peritumoral fat, distal normal intestinal wall, and distal perirectal fat were analyzed. The diagnostic accuracy of ERUS stage, tumor SWE stage, ERUS combined with tumor SWE stage, and ERUS combined with peritumoral fat SWE stage were compared and evaluated by receiver operating characteristic (ROC) curve to select the best staging index. RESULTS: From T1 to T3 stage, the maximum elasticity (Emax) of the rectal tumor increased gradually (p < 0.05). The cut-off values of adenoma/T1 and T2, T2 and T3 tumors were 36.75 and 85.15kPa, respectively. The diagnostic coincidence rate of tumor SWE stage was higher than that of ERUS stage. Overall diagnostic accuracy of ERUS combined with peritumoral fat SWE Emax restaging was significantly higher than that of ERUS. CONCLUSIONS: ERUS combined with peritumoral fat SWE Emax for tumor restaging can effectively distinguish between stage T2 and T3 rectal tumors, which provides an effective imaging basis for clinical decisions.

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation.

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.

Compounds isolated from the pericarp of Zanthoxylum bungeanum and inhibitory activity against LPS-induced NO production in RAW264.7.

Seventeen compounds were isolated and identified from the ethyl acetate part of Zanthoxylum bungeanum Maxim., including one new compound 18-acetyloxyneocryptotanshinone (1) and 16 known compounds (2-17). Their structures were elucidated by extensive spectroscopy. The absolute configuration of 1 was confirmed by electronic circular dichroism (ECD). All compounds were evaluated for the inhibition of LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, of which 1 and 10 exhibited the most significant inhibitory effect, with IC50 of 17.29 and 10.27 µM, respectively.

Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of N-Aryl Galantamine Analogues.

A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC50 = 0.19 µM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.

Synthesis, antiproliferative and anti-MDR activities of lathyrane diterpene derivatives based on configuration inversion strategy.

A series of lathyrane-type Euphorbia diterpene derivatives featured 3R configuration (H-3ß) were synthesized from natural rich Euphorbia factor L3via modified Mitsunobu reaction based on configuration inversion strategy. The antiproliferation activity and MDR reversal ability of the lathyrane derivatives were evaluated, and the most synthesized compounds showed moderate or strong potencies. Among them, diterpenes 21 (IC50 values of 2.6, 5.2 and 13.1 µM, respectively) and 25 (IC50 values of 5.5, 8.6 and 1.3 µM, respectively) presented the strong cytotoxicity against MCF-7, 4 T1 and HepG2 cells. Meanwhile, derivative 25 exhibited excellent MDR reversal ability with the reversal fold of 16.1 higher than that of verapamil. The cellular thermal shift assay and molecular docking proved direct engagement of diterpene 25 to ABCB1, suggesting 25 could be a promising MDR modulator. Furthermore, the preliminary SARs of these diterpenes were also discussed.

Two new dammarane triterpenoid saponins from the leaves of Cyclocarya paliurus.

Two undescribed dammarane triterpenoid saponins, cypaliurusides O and P (1 and 2), were isolated from the ethanol extracts of the leaves of Cyclocarya paliurus. Bioactivity assay results showed that compound 1 has potential cytotoxic activities against selected human cancer cell lines in vitro, with IC50 values ranging from 14.55 ± 0.55 to 22.75 ± 1.54 µM. Compound 1 showed better antitumor activity against HepG2 cells with IC50 of 14.55 ± 0.55 µM. In addition, compound 2 showed no obvious antitumor activity.

Deep Learning Promotes the Screening of Natural Products with Potential Microtubule Inhibition Activity.

Natural microtubule inhibitors, such as paclitaxel and ixabepilone, are key sources of novel medications, which have a considerable influence on anti-tumor chemotherapy. Natural product chemists have been encouraged to create novel methodologies for screening the new generation of microtubule inhibitors from the enormous natural product library. There have been major advancements in the use of artificial intelligence in medication discovery recently. Deep learning algorithms, in particular, have shown promise in terms of swiftly screening effective leads from huge compound libraries and producing novel compounds with desirable features. We used a deep neural network to search for potent ß-microtubule inhibitors in natural goods. Eleutherobin, bruceine D (BD), and phorbol 12-myristate 13-acetate (PMA) are three highly effective natural compounds that have been found as ß-microtubule inhibitors. In conclusion, this paper describes the use of deep learning to screen for effective ß-microtubule inhibitors. This research also demonstrates the promising possibility of employing deep learning to develop drugs from natural products for a wider range of disorders.

Flubendazole induces mitochondrial dysfunction and DRP1-mediated mitophagy by targeting EVA1A in breast cancer.

Breast cancer is still one of the most common malignancies worldwide and remains a major clinical challenge. We previously reported that the anthelmintic drug flubendazole induced autophagy and apoptosis via upregulation of eva-1 homolog A (EVA1A) in triple-negative breast cancer (TNBC) and was repurposed as a novel anti-tumor agent. However, the detailed underlying mechanisms remain unclear and need further investigation. Here, we found that flubendazole impairs the permeability of the mitochondrial outer membrane and mitochondrial function in breast cancer. Meanwhile, flubendazole increased dynamin-related protein (DRP1) expression, leading to the accumulation of PTEN induced putative kinase 1 (PINK1) and subsequent mitochondrial translocation of Parkin, thereby promoting excessive mitophagy. The resultant excessive mitophagy contributed to mitochondrial damage and dysfunction induced by flubendazole, thus inhibiting breast cancer cells proliferation and migration. Moreover, we demonstrated that excessive DRP1-mediated mitophagy played a critical role in response to the anti-tumor effects of EVA1A in breast cancer. Taken together, our results provide new insights into the molecular mechanisms in relation to the anti-tumor activities of flubendazole, and may be conducive to its rational use in potential clinical applications.

Pd-Catalyzed Direct Diversification of Natural Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of N-Aryl Huperzine A Analogues.

The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of N-(hetero)aryl analogues (1-32) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the N-aryl-huperzine A (N-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in in vitro experiments. Three arylated huperzine A analogues (14, 19, and 30) exhibited stronger anti-AChE activity than HPA. The 5-methoxy-2-pyridyl analogue (30) displayed the most potent AChE inhibition activity, with an IC50 value of 1.5 µM, which was 7.6-fold more active than HPA. Compound 30 also exhibited better neuroprotective activity for H2O2-induced damage in SH-SY5Y cells than HPA. Structure-activity relationship analysis suggested that the electron density of the installed aromatic ring or heteroaromatic ring played a significant role in inducing the AChE inhibition activity. Overall, compound 30 showed the advantages of easy synthesis, high potency and selectivity, and improved neuroprotection, making it a potential huperzine-type lead compound for Alzheimer's disease drug development.

Anti-hepatitis B virus activity and hepatoprotective effect of des(rhamnosyl) verbascoside from Lindernia ruellioides in vitro.

Although clinically approved hepatitis B virus (HBV) polymerase inhibitors (lamivudine-3TC, entecavir, etc.) serve as effective therapeutics, the virus can easily generate resistance to them. Therefore, the treatment of HBV infection remains a public health problem. Numerous studies have shown that natural products have prospective anti-HBV activity. The purpose of this study was to isolate and extract des(rhamnosyl) verbascoside from Lindernia ruellioides (Colsm.) Pennell and explore its anti-HBV and hepatoprotective effects. Anti-HBV activity was evaluated in HepG2.2.15 cells, a human hepatocellular carcinoma cell line with HBV-stable infection, and its protective effect was evaluated in HL-7702 cells, a normal human liver cell line. HepG2.2.15 cells maintained normal growth morphology within the selected concentration range of des(rhamnosyl) verbascoside. It also inhibited the expression of HBV antigens and HBV DNA in a dose- and time-dependent manner in vitro. Further, western blot experiments showed that it could downregulate HBV X protein (HBx) expression in a dose-dependent manner. In the H2 O2 -induced hepatocyte injury model, the cell-survival rate of the HL-7702 cells with the highest drug dose reached 85.25%, which was significantly improved compared with that of the model group. Most of the cells returned to normal morphology, showing polygonal or fusiform structures. Thus, it may be stated that des(rhamnosyl) verbascoside exhibits anti-HBV activity and hepatoprotective effects in vitro and may exert an anti-HBV effect via antigen inhibition, HBV DNA secretion, and HBx protein expression.

Iron-Catalyzed Skeletal Conversion of Lathyrane to Premyrsinane Euphorbia Diterpenes and Their Cytotoxic Activities.

Two new premyrsinane-type diterpenes (2 and 3) as diastereomers were synthesized from lathyrane-type diterpene euphorbia factor L3 (1) for the first time via an efficient Fe(acac)3-catalyzed skeleton conversion process. This conversion features a biogenetically inspired strategy that relies on a concise reductive olefin coupling involving intramolecular Michael addition with free radicals. The structures of 2 and 3 were elucidated by a combination of the interpretation of their spectroscopic data and single-crystal X-ray diffraction analysis. The premyrsinane diterpenes 2 and 3 exhibited cytotoxic activity against the 4T1 breast cancer cell line, while the parent compound euphorbia factor L3 (1) was inactive. The current results not only confirmed the biogenetic relationship between lathyranes and premyrsinanes for the first time but also suggested a novel method for the preparation of naturally rare premyrsinane diterpenes with high bioactivity from the more abundant natural lathyrane diterpenes.

Bioactive dammarane triterpenoid saponins from the leaves of Cyclocarya paliurus.

Thirteen undescribed dammarane triterpenoid saponins (cypaliurusides A-M), including eleven seco-dammarane type triterpenoids, were isolated from Cyclocarya paliurus. Each of these compounds has the unique feature of having a monosaccharide attached to C-11, rather than C-12, compared to the same type of saponins found in this plant. The structures of them were determined by comprehensive analysis of 1D, 2D NMR and HRESIMS data. Cypaliuruside J showed significant α-glucosidase inhibitory effect with IC50 value of 2.22 ± 0.13 µM. In addition, Cypaliurusides F and K exhibited modest cytotoxic activities against selected human cancer cell lines in vitro, with IC50 values ranging from 4.61 ± 0.13 to 15.23 ± 3.88 µM.

An unexpected Lewis acid-mediated structural conversion of a Euphorbia Diterpene: From a Lathyrane skeleton to diterpene pseudo-alkaloids.

Three types of new Euphorbia diterpene pseudo-alkaloids possessing 5/6/7/3 (1), 5/6/6/4 (2-5), and 5/7/7/4 (6-7) fused ring skeletons were obtained through an unexpected BF3·Et2O/CH3CN-mediated structural conversion and amination of lathyrane diterpene (Euphorbia factor L1), in which the solution acetonitrile had been introduced into the Euphorbia diterpene as a nitrogen source and tandem amination/oxirane-opening (cyclopropane-opening)/oxa-Michael addition reaction was involved in the conversion. The structures of new Euphorbia diterpene pseudo-alkaloids were elucidated by a combination of spectroscopic data and single crystal X-ray diffraction analysis. The basic skeletons of Euphorbia diterpene pseudo-alkaloids 1 and 2-5 could fall into the structural types of euphoractine B and euphoractine A diterpenes, respectively, suggesting the possible biogenetic pathway relationship between lathyrane diterpene with euphoractines A and B types diterpenes. Pseudo-alkaloids 1-7 did not show any potential cytotoxicity against several tumor cell lines.

Diterpenoid alkaloids from Aconitum anthoroideum that offer protection against MPP+-Induced apoptosis of SH-SY5Y cells and acetylcholinesterase inhibitory activity.

Nine unprecedented diterpenoid alkaloid, including a diterpenoid alkaloid featuring a diterpenoid moiety, anthoroidine A; one bisditerpenoid alkaloid joined with a carbon-carbon single bond, anthoroidine B; three racemulosine-type C20-diterpenoid alkaloids, anthoroidines C-E; one hetidine-type C20-diterpenoid alkaloid, anthoroidine F; and three hetisine-type C20-diterpenoid alkaloids, anthoroidines G-I, together with ten known diterpenoid alkaloids were isolated from Aconitum anthoroideum DC. Their structures were established via detailed spectroscopic analyses. Most of the isolated compounds along with five known diterpenoid alkaloids obtained in a previous study were screened for neuroprotective activities and acetylcholinesterase inhibitory effects. Nominine showed potent protective activity against MPP+-induced apoptosis in SH-SY5Y cells, with a rescue rate of 34.4% (50 µM). Rotundifosine F showed a significant inhibitory activity against AChE (IC50 = 0.3 µM). The structure-activity relationship of these alkaloids is also briefly discussed.

Evaluation of thyroid nodules with coexistent Hashimoto's thyroiditis according to various ultrasound-based risk stratification systems：A retrospective research.

PURPOSES: To investigate the efficiency of Thyroid Imaging Reporting and Data System (TI-RADS) proposed by KWAK, the American College of Radiology, and the 2015 American Thyroid Association (ATA) guidelines for thyroid nodules with Hashimoto's thyroiditis (HT) and to determine whether HT influence the diagnostic performance of these risk-stratification systems. METHODS: A total of 101 nodules with HT and 101 nodules with non-HT were retrospectively analyzed by ultrasound-based diagnostic classifications and compared with histopathological results. The areas under the receiver operating characteristic curve (AUCs) were calculated for comparative analysis. RESULTS: In the HT group, KWAK TI-RADS has the best sensitivity (91.67%), while ACR TI-RADS has the highest specificity (82.93%) and accuracy (81.19%). The AUCs of ACR TI-RADS, ATA guidelines, and KWAK TI-RADS were 0.844, 0.782, and 0.830, respectively. In the non-HT group, the sensitivity and specificity of three risk-stratification systems had no significant difference. The AUCs of ACR TI-RADS, ATA guidelines, and KWAK TI-RADS were 0.872, 0.839, and 0.874, respectively. No significant difference was found in diagnostic effectiveness of the same systems with both contexts. CONCLUSIONS: ACR TI-RADS performed the most effective for thyroid nodules in HT, whereas KWAK TI-RADS was the best for those in non-HT. Both of TI-RADS (ACR and KWAK) provided higher diagnostic effectiveness than ATA guidelines in HT or in non-HT. Moreover, HT could not affect the diagnostic performance of these risk-stratification systems.

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer.

Background: Triple-negative breast cancer (TNBC) is one of the most prevalent neoplastic diseases worldwide, but efficacious treatments for this pathological condition are still challenging. The lack of an effective targeted therapy also leads to a poor prognosis for patients affected by TNBC. In the present study, we repurposed the distinctive inhibitory effects of flubendazole, a traditional anthelmintic drug, towards the putative modulation of proliferation and migration of TNBC in vitro and in vivo. Methods: According to a series of experimental approaches, including immunofluorescence (IF), immunoblotting (IB), siRNA and GFP-mRFP-LC3 plasmid transfection, respectively, we have found that flubendazole is capable of inducing autophagic cell death and apoptosis, thus exerting some anti-proliferative and anti-migration activity in TNBC cells. The therapeutic effects of flubendazole were evaluated by xenograft mouse models, followed by immunohistochemistry (IHC), IF and IB. Changes in the gene expression profiles of flubendazole-treated TNBC cells were analyzed by RNA sequencing (RNA-seq) and validated by IB. The potential binding mode of flubendazole and EVA1A was predicted by molecular docking and demonstrated by site-directed mutagenesis. Results: We have presently found that flubendazole exhibits a considerable anti-proliferative activity in vitro and in vivo. Mechanistically, the induction of autophagic cell death appears to be pivotal for flubendazole-mediated growth inhibition of TNBC cells, whereas blocking autophagy was able to improve the survival rate and migration ability of flubendazole-treated TNBC cells. Specifically, RNA-seq analysis showed that flubendazole treatment could promote the up-regulation of EVA1A. Flubendazole may regulate autophagy and apoptosis by targeting EVA1A, thus affecting the mechanisms of TNBC proliferation and migration. Furthermore, Thr113 may be the key amino acid residues for the binding of flubendazole to EVA1A. Conclusion: Our results provide novel insights towards the putative anti-cancer efficacy of flubendazole. Furthermore, here we show that flubendazole could serve as a potential therapeutic drug in TNBC. Altogether, this study highlights the possibility of this repurposed autophagic inducer for future cancer treatments.

Comparison of Supersonic Shear Wave Imaging-Derived Renal Parenchyma Stiffness Between Diabetes Mellitus Patients With and Without Diabetic Kidney Disease.

This study aims to evaluate the difference in renal parenchyma stiffness assessed by measuring Young's modulus (YM) using a supersonic shear wave imaging (SSI) technique among healthy patients and patients with type 2 diabetes mellitus (DM) with and without diabetic kidney disease (DKD). We analyzed the correlations of YM with clinical information and conventional ultrasound parameters. All patients (N = 124) were divided into three groups: (i) healthy patients (patients without kidney disease or type 2 DM, N = 31); (ii) patients with type 2 DM without kidney disease (N = 38); and (iii) patients with DKD (N = 55). Conventional and SSI ultrasound examinations were performed in all individuals for both kidneys. Then, we recorded renal length, width, parenchyma thickness, interlobar arterial resistive index (RI) and values of mean, mininum and maximum YM. The mean values of these parameters for the left and right kidneys were calculated for statistical analysis. Statistical significance was considered at p < 0.05. Among all ultrasound parameters, the mean YM demonstrated the largest area under the receiver operating characteristic (ROC) curve (0.860). The areas under the ROC curve (AUCs) for renal length, width, parenchyma thickness, interlobar arterial RI, minimum YM and maximum YM were 0.493, 0.616, 0.507, 0.733, 0.848 and 0.794, respectively. The corresponding cutoff value of mean YM was 31.73 kPa, with a sensitivity of 85.5% and a specificity of 71.0%. The mean YM in patients with type 2 DM without kidney disease (31.44 ± 3.83 kPa) was significantly higher than that in the healthy group (26.45 ± 4.32 kPa) and lower than that in the DKD group (37.60 ± 6.56 kPa). Patients with type 2 DM without kidney disease were considered as stage 0 of DKD. Thus, the mean YM in the control group was significantly lower than that in the stage 0, 2, 3, 4 and 5 subgroups. The mean YM in the stage 0-2 subgroups was lower than that in the stage 5 group, and the mean YM in the stage 0 group was lower than that in the stage 4 group. In the DKD group, the mean YM had a positive correlation with cystine-c (r = 0.634), urea (r = 0.596), creatine (r = 0.690), uric acid (r = 0.263), albumin/creatinine ratio (r = 0.428) and the presence or absence of diabetic retinopathy (r = 0.354). The mean YM also had a negative correlation with the estimated glomerular filtration rate (r = -0.657). SSI is a non-invasive method with which to diagnose DKD and has a performance superior to that of conventional ultrasound. In addition, SSI may provide a secondary index for the staging of DKD and the monitoring of renal damage in type 2 DM patients.

Palladium-Catalyzed Synthesis and Anticancer Activity of Paclitaxel-Dehydroepiandrosterone Hybrids.

According to the activity-structure relationship of the C-13 side chain in paclitaxel or docetaxel, eighteen novel paclitaxel-dehydroepiandrosterone (DHEA) hybrids were designed and synthesized by Pd(II)-catalyzed Suzuki-Miyaura cross-coupling of 17-trifluoromethanesulfonic enolate-DHEA with different aryl boronic acids. The in vitro anticancer activity of the hybrids against a human liver cancer cell line (HepG-2) was evaluated by MTT assay, showing that most of these hybrids possessed moderate antiproliferative activity against the HepG-2 cancer cell line. Among these hybrids, three ones (7b, 7g, and 7i) with ortho-substituents in the phenyl group of the D-ring of DHEA analogues exhibited moderate anticancer activity. The optimal compound 7i showed superior anticancer activity against the HepG-2 cell line with an IC50 value of 26.39 µM.