cRNAsp12 Web Server for the Prediction of Circular RNA Secondary Structures and Stabilities.

Circular RNAs (circRNAs) are a novel class of non-coding RNA that, unlike linear RNAs, form a covalently closed loop without the 5' and 3' ends. Growing evidence shows that circular RNAs play important roles in life processes and have great potential implications in clinical and research fields. The accurate modeling of circRNAs structure and stability has far-reaching impact on our understanding of their functions and our ability to develop RNA-based therapeutics. The cRNAsp12 server offers a user-friendly web interface to predict circular RNA secondary structures and folding stabilities from the sequence. Through the helix-based landscape partitioning strategy, the server generates distinct ensembles of structures and predicts the minimal free energy structures for each ensemble with the recursive partition function calculation and backtracking algorithms. For structure predictions in the limited structural ensemble, the server also provides users with the option to set the structural constraints of forcing the base pairs and/or forcing the unpaired bases, such that only structures that meet the criteria are enumerated recursively.

Kinetic Mechanism of RNA Helix-Terminal Basepairing-A Kinetic Minima Network Analysis.

RNA functions are often kinetically controlled. The folding kinetics of RNAs involves global structural changes and local nucleotide movement, such as base flipping. The most elementary step in RNA folding is the closing and opening of a basepair. By integrating molecular dynamics simulation, master equation, and kinetic Monte Carlo simulation, we investigate the kinetics mechanism of RNA helix-terminal basepairing. The study reveals a six-state folding scheme with three dominant folding pathways of tens, hundreds, and thousands of nanoseconds of folding timescales, respectively. The overall kinetics is rate limited by the detrapping of a misfolded state with the overall folding time of 10-5 s. Moreover, the analysis examines the different roles of the various driving forces, such as the basepairing and stacking interactions and the ion binding/dissociation effects on structural changes. The results may provide useful insights for developing a basepair opening/closing rate model and further kinetics models of large RNAs.

Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells.

The aim of this study is to illuminate a novel therapeutic approach by identifying a functional binding target of salinomycin, an emerging anticancer stem cell (CSC) agent, and to help dissect the underlying action mechanisms. By utilizing integrated strategies, we identify that nucleolin (NCL) is likely a salinomycin-binding target and a critical regulator involved in human neuroblastoma (NB) CSC activity. Salinomycin markedly suppresses NB CD34 expression and reduces CD34+ cell population in an NCL-dependent manner via disruption of the interaction of NCL with CD34 promoter. The elevated levels of NCL expression in NB tumors are associated with poor patient survival. Altogether, these results indicate that NCL is likely a novel functional salinomycin-binding target that exhibits the potential to be a prognostic marker for NB therapy.

CoDockPP: A Multistage Approach for Global and Site-Specific Protein-Protein Docking.

Protein-protein docking technology is an effective approach to study the molecular mechanism of essential biological processes mediated by complex protein-protein interactions. The fast Fourier transform (FFT) correlation approach makes a good balance between the exhaustive global sampling and the computational efficiency for protein-protein docking. However, it is difficult to integrate the precise knowledge-based scoring function and site constraint information into the FFT-based approach. New docking strategies with the capability of combining both global sampling and precise scoring are strongly needed. We propose a multistage protein-protein docking strategy called CoDockPP. This program takes full advantage of the sampling efficiency of the FFT-based method to choose the valid ligand protein poses with good surface complementarity. The retained poses are transformed to the real Cartesian space for the implementation of site constraints and atomic scoring. Site constraints and a rapid table lookup scoring are applied to gradually reduce the candidate poses to a tractable number. To enhance the accuracy of docking prediction, the best fast-scoring states are expanded the local sampling points and then these neighbor poses are further evaluated by the precise knowledge-based scoring function. By testing on protein-protein docking benchmark 5.0, CoDockPP remarkably improves the success rate and hit count in both ab initio docking and site-specific docking, especially in difficult cases. The server is free and open to all users with no login requirement at http://codockpp.schanglab.org.cn .

Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/ß-catenin pathway in pancreatic cancer cells.

The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/ß-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.

Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths in the world with a 5-year survival rate of less than 6%. Currently, there is no successful therapeutic strategy for advanced pancreatic cancer, and new effective strategies are urgently needed. Recently, an arginine deprivation agent, arginine deiminase, was found to inhibit the growth of some tumor cells (i.e., hepatocellular carcinoma, melanoma, and lung cancer) deficient in argininosuccinate synthetase (ASS), an enzyme used to synthesize arginine. The purpose of this study was to evaluate the therapeutic efficacy of arginine deiminase in combination with gemcitabine, the first line chemotherapeutic drug for patients with pancreatic cancer, and to identify the mechanisms associated with its anticancer effects. METHODS: In this study, we first analyzed the expression levels of ASS in pancreatic cancer cell lines and tumor tissues using immunohistochemistry and RT-PCR. We further tested the effects of the combination regimen of arginine deiminase with gemcitabine on pancreatic cancer cell lines in vitro and in vivo. RESULTS: Clinical investigation showed that pancreatic cancers with reduced ASS expression were associated with higher survivin expression and more lymph node metastasis and local invasion. Treatment of ASS-deficient PANC-1 cells with arginine deiminase decreased their proliferation in a dose- and time-dependent manner. Furthermore, arginine deiminase potentiated the antitumor effects of gemcitabine on PANC-1 cells via multiple mechanisms including induction of cell cycle arrest in the S phase, upregulation of the expression of caspase-3 and 9, and inhibition of activation of the NF-κB survival pathway by blocking NF-κB p65 signaling via suppressing the nuclear translocation and phosphorylation (serine 536) of NF-κB p65 in vitro. Moreover, arginine deiminase can enhance antitumor activity of gemcitabine-based chemotherapy in the mouse xenograft model. CONCLUSIONS: Our results suggest that arginine deprivation by arginine deiminase, in combination with gemcitabine, may offer a novel effective treatment strategy for patients with pancreatic cancer and potentially improve the outcome of patients with pancreatic cancer.

[The radial velocity measurement accuracy of different spectral type low resolution stellar spectra at different signal-to-noise ratio].

The radial velocity of the star is very important for the study of the dynamics structure and chemistry evolution of the Milky Way, is also an useful tool for looking for variable or special objects. In the present work, we focus on calculating the radial velocity of different spectral types of low-resolution stellar spectra by adopting a template matching method, so as to provide effective and reliable reference to the different aspects of scientific research We choose high signal-to-noise ratio (SNR) spectra of different spectral type stellar from the Sloan Digital Sky Survey (SDSS), and add different noise to simulate the stellar spectra with different SNR. Then we obtain theradial velocity measurement accuracy of different spectral type stellar spectra at different SNR by employing a template matching method. Meanwhile, the radial velocity measurement accuracy of white dwarf stars is analyzed as well. We concluded that the accuracy of radial velocity measurements of early-type stars is much higher than late-type ones. For example, the 1-sigma standard error of radial velocity measurements of A-type stars is 5-8 times as large as K-type and M-type stars. We discuss the reason and suggest that the very narrow lines of late-type stars ensure the accuracy of measurement of radial velocities, while the early-type stars with very wide Balmer lines, such as A-type stars, become sensitive to noise and obtain low accuracy of radial velocities. For the spectra of white dwarfs stars, the standard error of radial velocity measurement could be over 50 km x s(-1) because of their extremely wide Balmer lines. The above conclusion will provide a good reference for stellar scientific study.

Pressure-Induced Topological Phase Transition and Large Rashba Effect in Halide Double Perovskite.

In general, hydrostatic pressure can suppress ferroelectric polarization and further reduce Rashba spin-splitting, considering the spin-orbit coupling effect. Here, we present the design of ferroelectric double perovskite Cs2SnSiI6, which exhibits the anomalous enhancement of Rashba spin-splitting parameters by pressure-induced ferroelectric topological order. The Rashba effect is nonlinear with the decrease in polarization under pressure and reaches a maximum at the pressure-induced Weyl semimetal (WSM) state between the transition from a normal insulator (NI) to a topological insulator (TI). Furthermore, we discover that controlling ferroelectric polarization with an electric field can also induce the topological transition with a large Rashba spin-splitting but under a lower critical pressure. These discoveries show a tunable gaint Rashba effect and pressure-induced topological phase transition for Cs2SnSiI6, which can promote future research on the interaction between the Rashba effect and topological order, and its application to new electronic and spintronic devices.

Quantifying RNA structures and interactions with a unified reduced chain representation model.

RNA is a pivotal molecule that plays critical roles in various cellular processes. Quantifying RNA structures and interactions is essential to understanding RNA function and developing RNA-based therapeutics. Using a unified five-bead model and a non-redundant database, this paper investigates the structural features and interactions of five commonly occurring RNA motifs, i.e., double-stranded helices, hairpin loops, internal/bulge loops, multi-branched junctions, and single-stranded terminal tails. Analyzing detailed distributions of RNA local structural features and base-base interactions reveals a preference for helical structures in both local backbone structures and base orientations. The interactions between adjacent bases exhibit motif-specific and sequence-dependent characteristics, reflecting the distinct topological constraints imposed by different loop-helix connection modes and the varying pairing and stacking interactions among different sequences. These findings shed light on the stability of RNA helices, emphasizing their significance in providing dominant base pairing and stacking interactions for RNA structures and stability. The four non-helix motifs encompass unpaired nucleotide loops and exhibit diverse base-base interactions, contributing to the structural diversity observed in RNA. Overall, the complexity of RNA structure arises from the intricate interplay of base-base interactions.

Neural networks prediction of the protein-ligand binding affinity with circular fingerprints.

BACKGROUND: Protein-ligand binding affinity is of significant importance in structure-based drug design. Recently, the development of machine learning techniques has provided an efficient and accurate way to predict binding affinity. However, the prediction performance largely depends on how molecules are represented. OBJECTIVE: Different molecular descriptors are designed to capture different features. The study aims to identify the optimal circular fingerprints for predicting protein-ligand binding affinity with matched neural network architectures. METHODS: Extended-connectivity fingerprints (ECFP) and protein-ligand extended connectivity fingerprints (PLEC) encode circular atomic and bonding connectivity environments with the preference for intra- and inter-molecular features, respectively. Densely-connected neural networks are employed to map the circular fingerprints of protein-ligand complexes to binding affinitiesRESULTS:The performance of neural networks is sensitive to the parameters used for ECFP and PLEC fingerprints. The R2_score of the evaluated ECFP and PLEC fingerprints reaches 0.52 and 0.49, higher than that of the improperly set ECFP and PLEC fingerprints with R2_score of 0.45 and 0.38, respectively. Additionally, compared to the predictions from the standalone fingerprints, the ECFP+PLEC conjoint ones slightly improve the prediction accuracy with R2_score of approximately 0.55. CONCLUSION: Both intra- and inter-molecular structural features encoded in the circular fingerprints contribute to the protein-ligand binding affinity. Optimizing the parameters of ECFP and PLEC can enhance performance. The conjoint fingerprint scheme can be generally extended to other molecular descriptors for enhanced feature engineering and improved predictive performance.

Anaerobic digestion of different organic wastes for biogas production and its operational control performed by the modified ADM1.

Anaerobic digestion (AD) of different organic wastes for biogas production under variable operating conditions was simulated with a steady-state implementation of the modified IWA Anaerobic Digestion Model No. 1 (ADM1), and an input-output feedback control system using the model as a test platform was developed. The main aim of this study was to compare the characteristics of organic wastes in the AD processes and manage to keep the processes stable based on the results of simulation. The two important operating factors, solid retention time (SRT) and organic loading rate (OLR) (or the ratio of input flows for co-digestion), were investigated. Anaerobic digestion of biowaste was characterized with lower biogas production and instability of the processes, especially at OLR 2.5 kgCOD/m(3)·d or more, although longer SRT could increase the biogas production. Moreover, the co-substrate composed of biowaste and corn silage would lead to instability of the processes and much lower biogas production. Biowaste was, however, preferable to be co-digested with manures of living stock or sewage sludge. Manure could contribute to the stability of the AD processes, and its co-substrates with organic wastes rich in carbohydrates such as biowaste and corn silage would improve the biogas production and the proportion of methane. Longer SRTs would improve the biogas production from manure as well as its co-substrates except the co-substrate with biowaste as the production was not distinctly raised. The test of the developed input-output feedback control system showed that the control system could reject a realistic set of random disturbances and keep the AD processes stable under the desired operational conditions with a minimal use of measurement facilities.

ß2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway.

BACKGROUND: Smoking and stress, pancreatic cancer (PanCa) risk factors, stimulate nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and catecholamines production respectively. NNK and catecholamine bind the ß-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that ß-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by ß2-adrenergic antagonist, we hypothesize that blockage of the ß2-adrenoceptor could induce G1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells. RESULTS: The ß1 and ß2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The ß2-adrenergic antagonist ICI118,551 significantly induced G1/S phase arrest and apoptosis compared with the ß1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. ß2-adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the ß2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells. CONCLUSIONS: The blockage of ß2-adrenoceptor markedly induced PanCa cells to arrest at G1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of ß2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the ß2-adrenoceptor antagonist induced G1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.

Does the board's on-site decision inhibit over-investment.

It is an effective expansion of the research on the Board of Directors to do the research based on different board meeting forms and their effects sampling A-share companies listed in 2007-2017, the article empirically tests the impact of the times of board meetings, the proportion of on-site board meetings on listed companies' over-investment. Consequently and significantly, the times of board meetings is positively correlated with over-investment, while the proportion of on-site board meetings is negatively correlated with over-investment. That is, the on-site meeting for the Board decision-making will better inhibit the enterprises' over-investment behaviors. Further research shows that when there is a controlling shareholder in the company or in a dual position, the on-site board meeting no longer has a significant inhibitory effect on over-investment. By research on the independence of the Board of Directors, it is found that when selecting on-site board decision-making, the existence of independent directors has an over-investment suppression effect, and the higher the proportion of independent directors, the more obvious the inhibitory effect is. The samples are divided into state-owned enterprises and private enterprises, the study found that when choosing on-site board meetings, state-owned enterprises have a greater inhibitory effect on over-investment than private enterprises. The findings of this study will enrich the research of the board meeting and provide a new testing method for the relevant research of the Board of Directors.

Study on the Mechanism of Periplaneta americana Extract to Accelerate Wound Healing after Diabetic Anal Fistula Operation Based on Network Pharmacology.

OBJECTIVE: Using network pharmacology research methods to explore the healing mechanism of American cockroach extract to accelerate wound healing after diabetic anal fistula surgery. METHOD: The main chemical constituents of extracts from Periplaneta americana were collected by literature retrieval. Chemical composition and targets related to diabetic anal fistula wound could be predicted based on PubChem, Swiss Target Prediction, OMIM, and GeneCards databases, and the putative targets of Periplaneta americana extraction (PAE) for diabetic anal fistula wound were obtained by Venn diagram. These common targets were predicted using the String database for protein-protein interaction (PPI) network and then screening key genes through Cytohubba. Meanwhile, the above targets were analyzed using the DAVID database for gene ontology (GO) enrichment analyses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) path enrichment analyses. RESULTS: A total of 12 chemical components of PAE were obtained by literature retrieval, and 61 therapeutic targets that may accelerate the healing of diabetic anal fistula wounds were predicted by the database. According to PPI network analysis, PAE accelerates wound healing after diabetic anal fistula surgery which may be related to proteins such as AKT1, VEGFA, EGFR, CASP3, STAT3, MAPK1, TNF, JUN, ESR1, and MMP9. GO analysis results show that targets of PAE to promote wound healing were mainly involved in biological processes such as cell proliferation, macrophage differentiation, angiogenesis, and response to hypoxia. KEGG analysis showed that the target genes were mainly concentrated in the PI3K-Akt signaling pathway, HIF-1 signaling pathway, and estrogen signaling pathway. CONCLUSION: Periplaneta americana extract regulates multiple targets and multiple pathways to promote wound healing after diabetic anal fistula surgery. PI3K-Akt signaling pathway, HIF-1 signaling pathway, and sex hormone signaling pathway may be key pathways in the process of Periplaneta americana extract promoting wound healing.

SMARCB1 Gene Mutation Predisposes to Earlier Development of Glioblastoma: A Case Report of Familial GBM.

Glioblastoma (GBM) is the most aggressive adult brain tumor. While GBM typically occurs sporadically, familial GBM can be associated with certain hereditary disorders and isolated familial GBMs in the absence of syndrome are rare. Relevant hereditary factors have remained elusive in these cases. Understanding specific genetic abnormality may potentially lead to better treatment strategies in these patients. Here, we analyzed GBM tissue from our patient and 2 afflicted family members, with next generation sequencing to better understand the genetic alterations associated with this disease development. DNA was extracted and sequenced and the data were then analyzed. Results revealed 2 common mutations in afflicted family members; PDGFRA and HRAS. In addition, both siblings showed a mutation of the SMARCB1 gene. The sister of our patient exhibited a homozygous mutation, while our patient had heterozygous mutation of this gene in the tumor tissue. This result suggests that mutation of SMARCB1, either alone or in the presence of PDGFRA and HRAS mutations, is associated with earlier onset GBM.

Propagation of Pathological α-Synuclein from the Urogenital Tract to the Brain Initiates MSA-like Syndrome.

The neuropathological feature of multiple system atrophy (MSA), a fatal adult-onset disorder without effective therapy, is the accumulation of pathological α-synuclein (α-Syn) in the central nervous system (CNS). Here we show that pathological α-Syn exists in nerve terminals in detrusor and external urethral sphincter (EUS) of patients with MSA. Furthermore, α-Syn-preformed fibrils (PFFs) injected in the EUS or detrusor in TgM83+/- mice initiated the transmission of pathological α-Syn from the urogenital tract to brain via micturition reflex pathways, and these mice developed widespread phosphorylated α-Syn inclusion pathology together with phenotypes. In addition, urinary dysfunction and denervation-reinnervation of external anal sphincter were detected earlier in the mouse models with α-Syn PFFs inoculation before the behavioral manifestations. These results suggest that pathological α-Syn spreading through the micturition reflex pathways retrogradely from the urogenital tract to CNS may lead to urinary dysfunction in patients with MSA, which is different from the etiology of idiopathic Parkinson disease.

Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action.

BACKGROUND: Breast cancer is the second leading cause of cancer related deaths among females worldwide. Berbamine (BER), a kind of bis-benzylisoquinoline alkaloid, has been used to treat clinical patients with inflammation and cancer for many years in China. The purpose of this study is to investigate the activity of BER against highly-metastatic human breast cancer and its molecular mechanisms of action. RESULTS: In our study, we found that BER inhibits growth of highly-metastatic human breast cancer cell lines MDA-MB-231 and MDA-MB-435S cells dose-dependently and time-dependently. The sera from BER-treated rats suppress the growth of MDA-MB-231 cells. BER shows synergistic effects with some existing anticancer agents such as trichostatin A (TSA, the histone deacetylase inhibitor), celecoxib (the inhibitor of COX-2), and carmofur against the growth of MDA-MB-231 cells. BER also displays the strong activity of inducing apoptosis in both estrogen receptor-negative MDA-MB-231 cells and estrogen receptor-alpha-positive MCF-7 breast cancer cells, but not in normal human mammary epithelial cell line MCF10A. BER down-regulates anti-apoptotic protein Bcl-2 levels and up-regulates pro-apoptotic protein Bax expressions in MDA-MB-231 and MDA-MB-435S cells. BER also has synergistic effects with anticancer agents trichostatin A, celecoxib and/or carmofur on reducing Bcl-2/Bax ratios and VEGF secretions in MDA-MB-231 cells. In addition, BER significantly suppresses cell migration and invasion, as well as decreases pro-MMP-9/pro-MMP-2 activation in breast cancer cells. Furthermore, BER suppresses Akt and nuclear factor kappaB signaling by reducing the phosphorylation of c-Met and Akt, and inhibiting their downstream targets such as nuclear factor kappaB p-65, Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2 on protein and/or mRNA levels in breast cancer cells. CONCLUSION: Our findings have showed that BER suppresses the growth, migration and invasion in highly-metastatic human breast cancer cells by possibly inhibiting Akt and NF-kappaB signaling with their upstream target c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2. BER has synergistic effects with anticancer agents trichostatin A, celecoxib and carmofur on inhibiting the growth of MDA-MB-231 cells and reducing the ratio of Bcl-2/Bax and/or VEGF expressions in the cancer cells. These findings suggest that BER may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer and other cancers.

Helix-Based RNA Landscape Partition and Alternative Secondary Structure Determination.

RNA is a versatile macromolecule with the ability to fold into and interconvert between multiple functional conformations. The elucidation of the RNA folding landscape, especially the knowledge of alternative structures, is critical to uncover the physical mechanism of RNA functions. Here, we introduce a helix-based strategy for RNA folding landscape partition and alternative secondary structure determination. The benchmark test of 27 RNAs involving alternative stable structures shows that the model has the ability to divide the whole landscape into distinct partitions at the secondary structure level and predict the representative structures for each partition. Furthermore, the predicted structures and equilibrium populations of metastable conformations for the 2'dG-sensing riboswitch reveal the allosteric conformational switch on transcript length, which is consistent with the experimental study, indicating the importance of metastable states for RNA-based gene regulation. The model delivers a starting point for the landscape-based strategy toward the RNA folding mechanism and functions.

Resveratrol enhances the chemotherapeutic response and reverses the stemness induced by gemcitabine in pancreatic cancer cells via targeting SREBP1.

OBJECTIVES: Gemcitabine is a standard treatment for advanced pancreatic cancer patients but can cause chemoresistance during treatment. The chemoresistant cells have features of cancer stem cells (CSCs). Resveratrol has been reported to overcome the resistance induced by gemcitabine. However, the mechanism by which resveratrol enhances chemosensitivity remains elusive. Here, we explored the mechanism by which resveratrol enhanced chemosensitivity and the role of sterol regulatory element binding protein 1 (SREBP1) in gemcitabine-induced stemness. MATERIALS AND METHODS: The pancreatic cancer cell lines MiaPaCa-2 and Panc-1 were treated under different conditions. Methyl thiazolyl tetrazolium and colony formation assays were performed to evaluate effects on proliferation. Flow cytometry was conducted to detect apoptosis. Oil red O staining was performed to examine lipid synthesis. The sphere formation assay was applied to investigate the stemness of cancer cells. Immunohistochemistry was performed on tumour tissue obtained from treated KPC mice. RESULTS: Resveratrol enhanced the sensitivity of gemcitabine and inhibited lipid synthesis via SREBP1. Knockdown of SREBP1 limited the sphere formation ability and suppressed the expression of CSC markers. Furthermore, suppression of SREBP1 induced by resveratrol reversed the gemcitabine-induced stemness. These results were validated in a KPC mouse model. CONCLUSIONS: Our data provide evidence that resveratrol reverses the stemness induced by gemcitabine by targeting SREBP1 both in vitro and in vivo. Thus, resveratrol can be an effective chemotherapy sensitizer, and SREBP1 may be a rational therapeutic target.

Ginkgo biloba extract improves coronary artery circulation in patients with coronary artery disease: contribution of plasma nitric oxide and endothelin-1.

In patients with coronary artery disease (CAD), coronary blood flow is usually impaired due to imbalanced vasoactive substances such as nitric oxide (NO) and endothelin-1 (ET-1). The study was designed to test the effects of Ginkgo biloba extract (GBE) on the distal left anterior descending coronary artery (LAD) blood flow and plasma NO and ET-1 levels. Eighty CAD patients were randomly assigned to GBE (n = 42) and control (n = 38) groups. The LAD blood flow was assessed non-invasively using Doppler echocardiography at baseline and after 2 weeks. GBE treatment demonstrated a significant improvement in maximal diastolic peak velocity (MDPV), maximal systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI) compared with controls (14.61 +/- 4.51% vs 0.67 +/- 2.66%, 9.03 +/- 4.81% vs 0.34 +/- 2.67% and 14.69 +/- 5.08% vs 0.68 +/- 3.00%, respectively, p < 0.01). NO was increased by 12.42% (p < 0.01), whereas ET-1 was decreased by 5.82% (p < 0.01). The NO/ET-1 ratio was increased by 19.47% (p < 0.01). A linear correlation was confirmed between the percentage change in LAD blood flow and in NO, ET-1 or NO/ET-1 ratio following GBE treatment. The results suggest that GBE treatment in CAD patients led to an increase of LAD blood flow, which might at least be related partly to the restoration of the delicate equilibrium between NO and ET-1.