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Continuous dynamic recrystallization (CDRX) is widely acknowledged to occur during hot forming and plays a significant role in microstructure development in alloys with moderate to high stacking fault energy. In this work, the flow stress and CDRX behaviors of the TC18 alloy subjected to hot deformation across a wide range of processing conditions are studied. It is observed that deformation leads to the formation of new low-angle grain boundaries (LAGBs). Subgrains rotate by absorbing dislocations, resulting in an increase in LAGB misorientation and the transition of some LAGBs into high-angle grain boundaries (HAGBs). The HAGBs migrate within the material, assimilating the (sub)grain boundaries. Subsequently, an internal state variable (ISV)-based CDRX model is developed, incorporating parameters such as the dislocation density, adiabatic temperature rise, subgrain rotation, LAGB area, HAGB area, and LAGB misorientation angle distribution. The values of the correlation coefficient (R), relative average absolute error (RAAE), and root-mean-square error (RMSE) between the anticipated true stress and measured stress are 0.989, 6.69%, and 4.78 MPa, respectively. The predicted outcomes demonstrate good agreement with experimental findings. The evolving trends of the subgrain boundary area under various conditions are quantitatively analyzed by assessing the changes in dynamic recovery (DRV)-eliminated dislocations and misorientation angles. Moreover, the ISV-based model accurately predicts the decreases in grain and crystallite sizes with higher strain rates and lower temperatures. The projected outcomes also indicate a transition from a stable and coarse-grained microstructure to a continuously recrystallized substructure.

Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[ 18 F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [ 18 F]Nifene, displaying similar pKa and binding affinity to nicotine. Time-activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the β2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.

Portable document format (PDF) files are widely used in file transmission, exchange, and circulation because of their platform independence, small size, good browsing quality, and the ability to place hyperlinks. However, their security issues are also more thorny. It is common to distribute printed PDF files to different groups and individuals after printing. However, most PDF watermarking algorithms currently cannot resist print-scan attacks, making it difficult to apply them in leak tracing of both paper and scanned versions of PDF documents. To tackle this issue, we propose an invisible digital watermarking technology based on modifying the edge pixels of text strokes to hide information in PDFs, which achieves high robustness to print-scan attacks. Moreover, it cannot be detected by human perception systems. This method focuses on the representation of text by embedding watermarks by changing the features of the text to ensure that changes in these features can be reflected in the scanned PDF after printing. We first segment each text line into two sub-blocks, then select the row of pixels with the most black pixels, and flip the edge pixels closest to this row. This method requires the participation of original PDF documents in detection. The experimental results show that all peak signal-to-noise ratio (PSNR) values of our proposed method exceed 32 dB, which indicates satisfactory invisibility. Meanwhile, this method can extract the hidden information with 100% accuracy under the JPEG compression attack, and has high robustness against noise attacks and print-scan attacks. In the case of no attacks, the watermark can be recovered without any loss. In terms of practical applications, our method can be applied in the practical leak tracing of official paper documents after distribution.

The dichloromethane extract of the roots of Bridelia balansae Tutcher (Phyllanthaceae) was found to show potential anticancer activity against HCT116 colorectal cancer cell. Our bioassay-guided phytochemical investigation of the roots of B. balansae led to the identification of 14 compounds including seven lignans ( 1 - 7 ), three phenylbenzene derivatives ( 8 - 10 ), two flavanone ( 11 - 12 ), and two triterpenoids ( 13 - 14 ). Among them, 4'-demethyl-4-deoxypodophyllotoxin ( 1 ) is the first aryltetralin lignan compound identified from this plant species. In addition, the stereochemistry of 1 was validated by X-ray crystallography for the first time, and its distinguished cytotoxic effect on HCT116 cells with an IC 50 value at 20 nM was induced via an apoptosis induction mechanism. Compound 1 could also significantly decrease the migration rate of HCT116 cells, indicating its potential application against cancer metastasis. The western blot analysis showed that 1 has the potential to inhibit cell proliferation and metastasis. Treatment of 1 resulted in the downregulation of matrix metalloproteinases 2 (MMP2) and p-Akt, while p21 was upregulated. Collectively, the present study on the phytochemical and biological profile of B. balansae has determined the plant as a useful source to produce promising anticancer lead compounds.

In the field of nuclear medicine, the β + -emitting 43 Sc and β - -emitting 47 Sc are promising candidates in cancer diagnosis and targeted radionuclide therapy (TRT) due to their favorable decay schema and shared pharmacokinetics as a true theranostic pair. Additionally, scandium is a group-3 transition metal (like 177 Lu) and exhibits affinity for DOTA-based chelators, which have been studied in depth, making the barrier to implementation lower for 43/47 Sc than for other proposed true theranostics. Before 43/47 Sc can see widespread pre-clinical evaluation, however, an accessible production methodology must be established and each isotope's radiolabeling and animal imaging capabilities studied with a widely utilized tracer. As such, a simple means of converting an 18 MeV biomedical cyclotron to support solid targets and produce 43 Sc via the 42 Ca(d,n) 43 Sc reaction has been devised, exhibiting reasonable yields. The Nat Ti(γ,p) 47 Sc reaction is also investigated along with the successful implementation of chemical separation and purification methods for 43/47 Sc. The conjugation of 43/47 Sc with PSMA-617 at specific activities of up to 8.94 MBq/nmol and the subsequent imaging of LNCaP-ENZaR tumor xenografts in mouse models with both 43/47 Sc-PSMA-617 are also presented.

Macrophages are essential for the human body in both physiological and pathological conditions, engulfing undesirable substances and participating in several processes, such as organism growth, immune regulation, and maintenance of homeostasis. Macrophages play an important role in anti-bacterial and anti-tumoral responses. Aberrance in the phagocytosis of macrophages may lead to the development of several diseases, including tumors. Tumor cells can evade the phagocytosis of macrophages, and "educate" macrophages to become pro-tumoral, resulting in the reduced phagocytosis of macrophages. Hence, harnessing the phagocytosis of macrophages is an important approach to bolster the efficacy of anti-tumor treatment. In this review, we elucidated the underlying phagocytosis mechanisms, such as the equilibrium among phagocytic signals, receptors and their respective signaling pathways, macrophage activation, as well as mitochondrial fission. We also reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism, including strategies targeting the phagocytic signals, antibody-dependent cellular phagocytosis (ADCP), and macrophage activators. We also covered recent studies of Chimeric Antigen Receptor Macrophage (CAR-M)-based anti-tumor therapy. Furthermore, we summarized the shortcomings and future applications of each strategy and look into their prospects with the hope of providing future research directions for developing the application of macrophage phagocytosis-promoting therapy.

Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.

The traditional immune checkpoint blockade therapy benefits some patients with cancer, but elicits no response in certain cancers, such as pancreatic adenocarcinoma (PAAD); thus, novel checkpoints and effective targets are required. Here, we found that there was a higher Neuropilin (NRP) expression in tumor tissues as novel immune checkpoints, which was associated with poor prognosis and pessimistic responses to immune checkpoint blockade therapy. In the tumor microenvironment of PAAD samples, NRPs were widely expressed in tumor, immune and stromal cells. The relationship of NRPs with tumor immunological features in PAAD and pan-cancer was evaluated using bioinformatics methods; it was positively correlated with the infiltration of myeloid immune cells and the expression of most immune checkpoint genes. Bioinformatics analysis, in vitro and in vivo experiments suggested that NRPs exhibit potential immune-related and immune-independent pro-tumor effects. NRPs, especially NRP1, are attractive biomarkers and therapeutic targets for cancers, particularly PAAD.

It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional β-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA β-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA β-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet β-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.

Saussurea involucrata has been reported to have potential therapeutic effects against myocardial ischemia. The pharmacological effects of oral natural medicines may be influenced by the participation of gut microbiota. In this study, we aimed to investigate the bidirectional regulation of gut microbiota and the main components of Saussurea involucrata . We first established a quantitative method for the four main components (chlorogenic acid, syringin, acanthoside B, rutin) which were chosen by fingerprint using liquid chromatography tandem mass spectrometry (LC-MS/MS), and found that gut microbiota has a strong metabolic effect on them. Meanwhile, we identified five major rat gut microbiota metabolites (M1-M5) using liquid chromatography tandem time-of-flight mass spectrometry (LC/MS n -IT-TOF). The metabolic properties of metabolites in vitro were preliminarily elucidated by LC-MS/MS for the first time. These five metabolites of Saussurea involucrata may all have potential contributions to the treatment of myocardial ischemia. Furthermore, the four main components (10 μg/mL) can significantly stimulate intestinal bacteria to produce short chain fatty acids in vitro, respectively, which can further contribute to the effect in myocardial ischemia. In this study, the therapeutic effect against myocardial ischemia of Saussurea involucrata was first reported to be related to the intestinal flora, which can be useful in understanding the effective substances of Saussurea involucrata .

Three isopimarane diterpenes [fladins B ( 1 ), C ( 2 ), and D ( 3 )] were isolated from the twigs and leaves of Chinese folk medicine, Isodon flavidus . The chemical structures were determined by the analysis of the comprehensive spectroscopic data, and the absolute configuration was confirmed by X-ray crystallographic analysis. The structures of 1 - 3 were formed from isopimaranes through the rearrangement of ring A by the bond break at C-3 and C-4 to form a new δ -lactone ring system between C-3 and C-9. This structure type represents the first discovery of a natural isopimarane diterpene with an unusual lactone moiety at C-9 and C-10. In the crystal of 1 , molecules are linked to each other by intermolecular O-H···O bonds, forming chains along the b axis. Compounds 1 - 3 were evaluated for their bioactivities against different diseases. None of these compounds displayed cytotoxic activities against HCT116 and A549 cancer cell lines, antifungal activities against Trichophyton rubrum and T. mentagrophytes , or antiviral activities against HIV entry at 20 µg/mL (62.9-66.7) µM. Compounds 1 and 3 did not show antiviral activities against Ebola entry at 20 µg/mL either; only 2 was found to show an 81% inhibitory effect against Ebola entry activity at 20 µg/mL (66.7 µM). The bioactivity evidence suggested that this type of compound could be a valuable antiviral lead for further structure modification to improve the antiviral potential.

The bioavailability of flavonoids is generally low after oral administration. The metabolic transformation of flavonoids by the gut microbiota may be one of the main reasons for this, although these metabolites have potential pharmacological activities. Liquiritigenin is an important dihydroflavonoid compound found in Glycyrrhiza uralensis that has a wide range of pharmacological properties, such as antitumor, antiulcer, anti-inflammatory, and anti-AIDS effects, but its mechanism of action remains unclear. This study explored the metabolites of liquiritigenin by examining gut microbiota metabolism and hepatic metabolism in vitro. Using LC-MS/MS and LC/MS n -IT-TOF techniques, three possible metabolites of liquiritigenin metabolized by the gut microbiota were identified: phloretic acid (M3), resorcinol (M4), and M5. M5 is speculated to be davidigenin, which has antitumor activity. By comparing these two metabolic pathways of liquiritigenin (the gut microbiota and liver microsomes), this study revealed that there are three main metabolites of liquiritigenin generated by intestinal bacteria, which provides a theoretical basis for the study of pharmacologically active substances in vivo.

Ebola virus disease (EVD), a disease caused by infection with Ebola virus (EBOV), is characterized by hemorrhagic fever and a high case fatality rate. With limited options for the treatment of EVD, anti-Ebola viral therapeutics need to be urgently developed. In this study, over 500 extracts of medicinal plants collected in the Lingnan region were tested against infection with Ebola-virus-pseudotyped particles (EBOVpp), leading to the discovery of Maesa perlarius as an anti-EBOV plant lead. The methanol extract (MPBE) of the stems of this plant showed an inhibitory effect against EBOVpp, with an IC 50 value of 0.52 µg/mL, which was confirmed by testing the extract against infectious EBOV in a biosafety level 4 laboratory. The bioassay-guided fractionation of MPBE resulted in three proanthocyanidins (procyanidin B2 ( 1 ), procyanidin C1 ( 2 ), and epicatechin-(4 β →8)-epicatechin-(4 β →8)-epicatechin-(4β→8)-epicatechin ( 3 )), along with two flavan-3-ols ((+)-catechin ( 4 ) and (-)-epicatechin ( 5 )). The IC 50 values of the compounds against pseudovirion-bearing EBOV-GP ranged from 0.83 to 36.0 µM, with 1 as the most potent inhibitor. The anti-EBOV activities of five synthetic derivatives together with six commercially available analogues, including EGCG ((-)-epigallocatechin-3- O -gallate ( 8 )), were further investigated. Molecular docking analysis and binding affinity measurement suggested the EBOV glycoprotein could be a potential molecular target for 1 and its related compounds.

Most dynamic stretching protocols include the gastrocnemius muscle, but soleus stretches are often neglected, which is the key powerful muscle for the push-off (concentric) of all speed movements. The purpose of this study was to examine whether the added soleus stretch in a regular stretching protocol would have greater benefits for ankle flexibility, dynamic balance and functional performance. Fourteen healthy male soccer players received each of the stretching conditions (regular stretching only (Regular), regular stretching with soleus stretching (Soleus) and no stretching (Control)) randomly on different training days, with two-day separation. The ankle flexibility, standing heel-lift balance and speed performances were assessed following each stretching intervention. The active dynamic stretches were performed for 30 s with three repetitions on each of the three (Regular) and four (Soleus) muscles. One-way ANOVA with repeated measures (or the Friedman non-parametric test) was performed to determine any significant effect with alpha = 0.05. Our findings revealed that both the Regular and Soleus stretching groups showed an increased active range of ankle motion compared to the no-stretching control (Ps < 0.05). In the heel raise balance test, both stretching groups experienced a significant increase in maximum plantarflexion strength as well as resultant anterior−posterior and medial−lateral CoP excursions compared to the no-stretching control (Ps < 0.05). In the sprinting tasks, both the Soleus and Regular stretching groups induced faster linear and curved running times (Ps < 0.05). When comparing the two stretching groups, Soleus stretching led to better ankle flexibility, maximum plantarflexion strength and curved running time (Ps < 0.05). Thus, added stretches on the soleus muscles can provide further benefits to speed performances in soccer.

A phytochemical investigation of the leaves of the medicinal plant Isodon rubescens led to the isolation of the two new degraded abietane lactone diterpenoids rubesanolides F ( 1 ) and G ( 2 ). Their structures were elucidated based on the analyses of the HRESIMS and 1D/2D NMR spectral data, and their absolute configurations were determined by ECD spectrum calculations and X-ray single crystal diffraction methods. Compounds 1 and 2 , with a unique γ-lactone subgroup between C-8 and C-20, were found to form a carbonyl carbon at C-13 by removal of the isopropyl group in an abietane diterpene skeleton. Rubesanolide G ( 2 ) is a rare case of abietane that possesses a cis -fused configuration between rings B and C. The two isolates were evaluated for their biological activities against two cancer cell lines (A549 and HL60), three fungal strains ( Candida alba , Aspergillus niger and Rhizopus nigricans ) and three bacterial strains ( Escherichia coli , Staphylococcus aureus and Bacillus subtilis ).

Cyclopeptides or cyclic peptides are polypeptides formed by ring closing of terminal amino acids. A large number of natural cyclopeptides have been reported to be highly effective against different cancer cells, some of which are renowned for their clinical uses. Compared to linear peptides, cyclopeptides have absolute advantages of structural rigidity, biochemical stability, binding affinity as well as membrane permeability, which contribute greatly to their anticancer potency. Therefore, the discovery and development of natural cyclopeptides as anticancer agents remains attractive to academic researchers and pharmaceutical companies. Herein, we provide an overview of anticancer cyclopeptides that were discovered in the past 20 years. The present review mainly focuses on the anticancer efficacies, mechanisms of action and chemical structures of cyclopeptides with natural origins. Additionally, studies of the structure-activity relationship, total synthetic strategies as well as bioactivities of natural cyclopeptides are also included in this article. In conclusion, due to their characteristic structural features, natural cyclopeptides have great potential to be developed as anticancer agents. Indeed, they can also serve as excellent scaffolds for the synthesis of novel derivatives for combating cancerous pathologies.

In host-parasitoid interactions, antagonistic relationship drives parasitoids to vary in virulence in facing different hosts, which makes these systems excellent models for stress-induced evolutionary studies. Venom compositions varied between two strains of Tetrastichus brontispae , Tb-Bl and Tb-On. Tb-Bl targets Brontispa longissima pupae as hosts, and Tb-On is a sub-population of Tb-Bl, which has been experimentally adapted to a new host, Octodonta nipae . Aiming to examine variation in parasitoid virulence of the two strains toward two hosts, we used reciprocal injection experiments to compare effect of venom/ovarian fluids from the two strains on cytotoxicity, inhibition of immunity and fat body lysis of the two hosts. We found that Tb-Onvenom was more virulent towards plasmatocyte spreading, granulocyte function and phenoloxidase activity than Tb-Blvenom. Tb-Blovary was able to suppress encapsulation and phagocytosis in both hosts; however, Tb-Onovary inhibition targeted only B. longissima . Our data suggest that the venom undergoes rapid evolution when facing different hosts, and that the wasp has good evolutionary plasticity.

Intracellular calcium dynamics play essential roles in the proper functioning of cellular activities. It is a well known important chemosensing and mechanosensing process regulated by the spatio-temporal microenvironment. Nevertheless, how spatio-temporal biochemical and biomechanical stimuli affect calcium dynamics is not fully understood and the underlying regulation mechanism remains missing. Herein, based on a developed microfluidic generator of biochemical and biomechanical signals, we theoretically analyzed the generation of spatio-temporal ATP and shear stress signals within the microfluidic platform and investigated the effect of spatial combination of ATP and shear stress stimuli on the intracellular calcium dynamics. The simulation results demonstrate the capacity and flexibility of the microfluidic system in generating spatio-temporal ATP and shear stress. Along the transverse direction of the microchannel, dynamic ATP signals of distinct amplitudes coupled with identical shear stress are created, which induce the spatio-temporal diversity in calcium responses. Interestingly, to the multiple combinations of stimuli, the intracellular calcium dynamics reveal two main modes: unimodal and oscillatory modes, showing significant dependence on the features of the spatio-temporal ATP and shear stress stimuli. The present study provides essential information for controlling calcium dynamics by regulating spatio-temporal biochemical and biomechanical stimuli, which shows the potential in directing cellular activities and understanding the occurrence and development of disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) and its interaction with many metabolic pathways raises global public health concerns. This study aimed to determine the therapeutic effects of Pyrroloquinoline quinone (PQQ, provided by PQQ.Na 2 ) on MAFLD in a chick model and primary chicken hepatocytes with a focus on lipid metabolism, anti-oxidative capacity, and mitochondrial biogenesis. The MAFLD chick model was established on laying hens by feeding them a high-energy low-protein (HELP) diet. Primary hepatocytes isolated from the liver of laying hens were induced for steatosis by free fatty acids (FFA) and for oxidative stress by hydrogen peroxide (H 2 O 2 ). In the MAFLD chick model, the dietary supplementation of PQQ conspicuously ameliorated the negative effects of the HELP diet on liver biological functions, suppressed the progression of MAFLD mainly through enhanced lipid metabolism and protection of liver from oxidative injury. In the steatosis and oxidative stress cell models, PQQ functions in the improvement of the lipid metabolism and hepatocytes tolerance to fatty degradation and oxidative damage by enhancing mitochondrial biogenesis and then increasing the anti-oxidative activity and anti-apoptosis capacity. At both the cellular and individual levels, PQQ was demonstrated to exert protective effects of hepatocyte and liver from fat accumulation through the improvement of mitochondrial biogenesis and maintenance of redox homeostasis. The key findings of the present study provide an in-depth knowledge on the ameliorative effects of PQQ on the progression of fatty liver and its mechanism of action, thus providing a theoretical basis for the application of PQQ, as an effective nutrient, into the prevention of MAFLD., Competing Interests: The authors declare no competing interests.

The radiation intensity of observed auroras in the far-ultraviolet (FUV) band varies dramatically with location for aerospace applications, requiring a photon counting imaging apparatus with a wide dynamic range. However, combining high spatial resolution imaging with high event rates is technically challenging. We developed an FUV photon counting imaging system for aurora observation. Our system mainly consists of a microchannel plate (MCP) stack readout using a wedge strip anode (WSA) with charge induction and high-speed electronics, such as a charge sensitive amplifier (CSA) and pulse shaper. Moreover, we constructed an anode readout model and a time response model for readout circuits to investigate the counting error in high counting rate applications. This system supports global rates of 500 kilo counts, 0.610 dark counts s -1 cm -2 at an ambient temperature of 300 K and 111 µm spatial resolution at 400 kilo counts s -1 (kcps). We demonstrate an obvious photon count loss at incident intensities close to the counting capacity of the system. To preserve image quality, the response time should be improved and some noise performance may be sacrificed. Finally, we also describe the correlation between counting rate and imaging resolution, which further guides the design of space observation instruments.

External secretions, composed of a variety of chemical components, are among the most important traits that endow insects with the ability to defend themselves against predators, parasites, or other adversities, especially pathogens. Thus, these exudates play a crucial role in external immunity. Red palm weevil larvae are prolific in this regard, producing large quantities of p-benzoquinone, which is present in their oral secretion. Benzoquinone with antimicrobial activity has been proven to be an active ingredient and key factor for external immunity in a previous study. To obtain a better understanding of the genetic and molecular basis of external immune secretions, we identify genes necessary for p-benzoquinone synthesis. Three novel ARSB genes, namely, RfARSB-0311 , RfARSB-11581 , and RfARSB-14322 , are screened, isolated, and molecularly characterized on the basis of transcriptome data. To determine whether these genes are highly and specifically expressed in the secretory gland, we perform tissue/organ-specific expression profile analysis. The functions of these genes are further determined by examining the antimicrobial activity of the secretions and quantification of p-benzoquinone after RNAi. All the results reveal that the ARSB gene family can regulate the secretory volume of p-benzoquinone by participating in the biosynthesis of quinones, thus altering the host's external immune inhibitory efficiency.

Since the first discovery in 1961, more than 1300 ent -kaurane diterpenoids have been isolated and identified from different plant sources, mainly the genus Isodon . Chemically, they consist of a perhydrophenanthrene subunit and a cyclopentane ring. A large number of reports describe the anticancer potential and mechanism of action of ent -kaurane compounds in a series of cancer cell lines. Oridonin is one of the prime anticancer ent -kaurane diterpenoids that is currently in a phase-I clinical trial in China. In this review, we have extensively summarized the anticancer activities of ent -kaurane diterpenoids according to their plant sources, mechanistic pathways, and biological targets. Literature analysis found that anticancer effect of ent -kauranes are mainly mediated through regulation of apoptosis, cell cycle arrest, autophagy, and metastasis. Induction of apoptosis is associated with modulation of BCL-2, BAX, PARP, cytochrome c, and cleaved caspase-3, -8, and -9, while cell cycle arrest is controlled by cyclin D1, c-Myc, p21, p53, and CDK-2 and -4. The most common metastatic target proteins of ent -kauranes are MMP-2, MMP-9, VEGF, and VEGFR whereas LC-II and mTOR are key regulators to induce autophagy.

Venom injected into the host plays vital roles in facilitating successful parasitization and development for parasitoid wasps, especially those devoid of polydnavirus, and the abundant venom proteins appear to be most likely involved in parasitization success. Previously, we found the four most abundant venom proteins, including 4-coumarate:CoA ligase-like 4 (4CL4-like), in the Tetrastichus brontispae (Hymenoptera: Eulophidae) venom apparatus. In this study, we cloned, expressed T. brontispae 4CL4-like (Tb4CL4-like) in Escherichia coli , and investigated its immunosuppressive properties. The deduced amino acid sequence for Tb4CL4-like shares high identity at conserved amino acids associated with the acyl-activating enzyme (AAE) consensus motif but shows only <40% identity with the members in the AAE superfamily. mRNA abundance analysis indicated that Tb4CL4-like was transcribed mainly in the venom apparatus. Recombinant Tb4CL4-like inhibited Octodonta nipae (Coleoptera: Chrysomelidae) pupal cellular encapsulation and spreading by targeting the hemocyte cytoskeleton and reduced the hemocyte-mediated phagocytosis of E. coli in vivo. Moreover, Tb4CL4-like exhibited greater affinity to palmitic acid and linolenic acid based on the molecular docking assay and is hypothesized to be involved in fatty acid metabolism. In conclusion, our results suggest that Tb4CL4-like may be an immunity-related AAE protein that is involved in the regulation of host immunity through fatty acid metabolism-derived signaling pathways.

MicroRNAs (miRNAs) are important negative regulators of genes involved in physiological and pathological processes in plants and animals. It is worth exploring whether plant miRNAs play a cross-kingdom regulatory role in animals. Herein, we found that plant MIR167e-5p regulates the proliferation of enterocytes in vitro. A porcine jejunum epithelial cell line (IPEC-J2) and a human colon carcinoma cell line (Caco-2) were treated with 0, 10, 20, and 40 pmol of synthetic 2'- O -methylated plant MIR167e-5p, followed by a treatment with 20 pmol of MIR167e-5p for 0, 24, 48, and 72 h. The cells were counted, and IPEC-J2 cell viability was determined by the MTT and EdU assays at different time points. The results showed that MIR167e-5p significantly inhibited the proliferation of enterocytes in a dose- and time-dependent manner. Bioinformatics prediction and a luciferase reporter assay indicated that MIR167e-5p targets β-catenin. In IPEC-J2 and Caco-2 cells, MIR167e-5p suppressed proliferation by downregulating β-catenin mRNA and protein levels. MIR167e-5p relieved this inhibition. Similar results were achieved for the β-catenin downstream target gene c-Myc and the proliferation-associated gene PCNA. This research demonstrates that plant MIR167e-5p can inhibit enterocyte proliferation by targeting the β-catenin pathway. More importantly, plant miRNAs may be a new class of bioactive molecules for epigenetic regulation in humans and animals.

Natural products, explicitly medicinal plants, are an important source of inspiration of antitumor drugs, because they contain astounding amounts of small molecules that possess diversifying chemical entities. For instance, Isodon (formerly Rabdosia ), a genus of the Lamiaceae (formerly Labiatae) family, has been reported as a rich source of natural diterpenes. In the current study, we evaluated the in vitro anti-proliferative property of flexicaulin A (FA), an Isodon diterpenoid with an ent -kaurane structure, in human carcinoma cells, by means of cell viability assay, flow cytometric assessment, quantitative polymerase chain reaction array, Western blotting analysis, and staining experiments. Subsequently, we validated the in vivo antitumor efficacy of FA in a xenograft mouse model of colorectal carcinoma. From our experimental results, FA appears to be a potent antitumor molecule, since it significantly attenuated the proliferation of human colorectal carcinoma cells in vitro and restricted the growth of corresponsive xenograft tumors in vivo without causing any adverse effects. Regarding its molecular mechanism, FA considerably elevated the expression level of p21 and induced cell cycle arrest in the human colorectal carcinoma cells. While executing a non-apoptotic mechanism, we believe the antitumor potential of FA opens up new horizons for the therapy of colorectal malignancy.

The biomechanical properties of single cells show great potential for early disease diagnosis and effective treatments. In this study, a microfluidic device was developed for quantifying the mechanical properties of a single cell. Micropipette aspiration was integrated into a microfluidic device that mimics a classical Wheatstone bridge circuit. This technique allows us not only to effectively alter the flow direction for single-cell trapping, but also to precisely control the pressure exerted on the aspirated cells, analogous to the feature of the Wheatstone bridge that can precisely control bridge voltage and current. By combining the micropipette aspiration technique into the microfluidic device, we can effectively trap the microparticles and Hela cells as well as measure the deformability of cells. The Young's modulus of Hela cells was evaluated to be 387 ± 77 Pa, which is consistent with previous micropipette aspiration studies. The simplicity, precision, and usability of our device show good potential for biomechanical trials in clinical diagnosis and cell biology research.

The aim of the present study was to determine the cytotoxic effects of a series of novel dehydroepiandrosterone derivatives containing triazole at the C 16 position on human cancer cells. The cancer cells used in the present study were A549, Hela, HepG-2, BEL7402, MCF-7, and HCT116. Several of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound was ( E )-3-hydroxy-16-((1-(4-iodophenyl)-1 H -1,2,3-triazole-4-yl)methylene)-10,13-dimet-hyl-1,3,4,7,8,9,10,11,12,13,15,16-dodecahydro-2 H -cyclopenta[a]phenanthren-17(14)-one (compound 2n ), which showed considerably high antiproliferative activity in the HepG-2 cell line, with an IC 50 value of 9.10 µM, and considerably high activity against the MCF-7 cell line, with an IC 50 value of 9.18 µM. Flow cytometry assays demonstrated that compound 2n exerted antiproliferative effects by arresting cells in the G2 phase of the cell cycle and inducing apoptosis.

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum . As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled &ldquo;Antimalarial activity of plant metabolites&rdquo; by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

The sol-gel method is a simple and facile wet chemical process for fabricating advanced materials with high homogeneity, high purity, and excellent chemical reactivity at a relatively low temperature. By adjusting the processing parameters, the sol-gel technique can be used to prepare hollow sphere and 1D structural materials that exhibit a wide application in the fields of catalyst, drug or gene carriers, photoactive, sensors and Li-ion batteries. This feature article reviewed the development of the preparation of hollow sphere and 1D structural materials using the sol-gel method. The effects of calcination temperature, soaking time, pH value, surfactant, etc., on the preparation of hollow sphere and 1D structural materials were summarized, and their formation mechanisms were generalized. Finally, possible future research directions of the sol-gel technique were outlined., Competing Interests: The authors declare no conflict of interest.

Our previous study showed that the anticonvulsant Q808 might be effective against seizures induced by maximal electroshock, pentylenetetrazole (PTZ), isoniazid (ISO), thiosemicarbazide (THIO), and 3-mercaptopropionic acid (3-MP). In the present study, we explored the possible mechanism of action of Q808. Results obtained with high-performance liquid chromatography (HPLC) suggest that Q808 may affect neurotransmitter content in the brain, by specifically increasing GABA content in the rat hippocampus at doses of 40 mg/kg and 80 mg/kg, and by reducing the content of glutamate and glutamine in the rat thalamus at a dose of 80 mg/kg. Intriguingly, there were no changes in the neurotransmitter content in the cortex in response to Q808. In vitro brain slice electrophysiological studies showed that 10 -5 M Q808 enhanced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in corn cells of the CA1 area of the hippocampus, and had no effect on the amplitude of sIPSCs, the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), or γ-aminobutyric acid (GABA) receptor-mediated currents in primary cultured hippocampal neurons. These findings suggest that the antiepileptic activity of Q808 may be due to its ability to increase the amount of GABA between synapses, without affecting the function of GABA receptors., Competing Interests: All the authors have no conflicts of interest.

Two novel series of 3,4-dihydroisoquinolin with heterocycle derivatives ( 4a - t and 9a - e ) were synthesized and evaluated for their anticonvulsant activity using maximal electroshock (MES) test and pentylenetetrazole (PTZ)-induced seizure test. All compounds were characterized by IR, ¹H-NMR, 13 C-NMR, and mass spectral data. Among them, 9-(exyloxy)-5,6-dihydro-[1,2,4]triazolo[3,4- a ]isoquinolin-3(2 H )-one ( 9a ) showed significant anticonvulsant activity in MES tests with an ED 50 value of 63.31 mg/kg and it showed wide margins of safety with protective index (PI > 7.9). It showed much higher anticonvulsant activity than that of valproate. It also demonstrated potent activity against PTZ-induced seizures. A docking study of compound 9a in the benzodiazepine (BZD)-binding site of γ-aminobutyric acid A (GABA A ) receptor confirmed possible binding of compound 9a with the BZD receptors.

The International Cooperative Biodiversity Groups (ICBG) Program based at the University of Illinois at Chicago (UIC) is a program aimed to address the interdependent issues of inventory and conservation of biodiversity, drug discovery and sustained economic growth in both developing and developed countries. It is an interdisciplinary program involving the extensive synergies and collaborative efforts of botanists, chemists and biologists in the countries of Vietnam, Laos and the USA. The UIC-ICBG drug discovery efforts over the past 18 years have resulted in the collection of a cumulative total of more than 5500 plant samples (representing more than 2000 species), that were evaluated for their potential biological effects against cancer, HIV, bird flu, tuberculosis and malaria. The bioassay-guided fractionation and separation of the bioactive plant leads resulted in the isolation of approximately 300 compounds of varying degrees of structural complexity and/or biological activity. The present paper summarizes the significant drug discovery achievements made by the UIC-ICBG team of multidisciplinary collaborators in the project over the period of 1998-2012 and the projects carried on in the subsequent years by involving the researchers in Hong Kong.

In this study, a new method based on immobilized metal affinity chromatography (IMAC) combined with ultrafiltration-ultra performance liquid chromatography-mass spectrometry (UF-UPLC-MS) was developed for discovering ligands for xanthine oxidase (XO) in Gnaphalium hypoleucum DC., a folk medicine used in China for the treatment of gout. By IMAC, the high flavonoid content of G. hypoleucum could be determined rapidly and efficiently. UF-UPLC-MS was used to select the bound xanthine oxidase ligands in the mixture and identify them. Finally, two flavonoids, luteolin-4'-O-glucoside and luteolin, were successfully screened and identified as the candidate XO inhibitors of G. hypoleucum. They were evaluated in vitro for XO inhibitory activity and their interaction mechanism was studied coupled with molecular simulations. The results were in favor of the hypothesis that the flavonoids of G. hypoleucum might be the active content for gout treatment by inhibiting XO.

New benztriazoles with a mercapto-triazole and other heterocycle substituents were synthesized and evaluated for their anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and rotarod neurotoxicity (TOX) tests. Among the compounds studied, compound 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((3-fluorobenzyl) oxy)benzo[d]thiazol-2-yl)acetamide (5i) and 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((4-fluorobenzyl)oxy) benzo[d] thiazol-2-yl)acetmide (5j) were the most potent, with an ED50 value of 50.8 mg/kg and 54.8 mg/kg in the MES test and 76.0 mg/kg and 52.8 mg/kg in the scPTZ seizures test, respectively. They also showed lower neurotoxicity and, therefore a higher protective index. In particular, compound 5j showed high protective index (PI) values of 8.96 in the MES test and 9.30 in the scPTZ test, which were better than those of the standard drugs used as positive controls in this study.

Rhizoma Atractylodes macrocephala polysaccharides (RAMP) have been reported to have a variety of important biological activities. In this study, an ultrasonic-assisted enzymatic extraction (UAEE) was employed to obtain the highest extraction yield and strongest antioxidant activity of RAMP and optimized by a multi-response optimization process. A three-level four-factor Box-Behnken design (BBD) was performed as response surface methodology (RSM) with desirability function (DF) to attain the optimal extraction parameters. The DPPH scavenging percentage was used to represent the antioxidant ability of RAMP. The maximum D value (0.328), along with the maximum yield (59.92%) and DPPH scavenging percentage (13.28%) were achieved at 90.54 min, 57.99 °C, 1.95% cellulase and 225.29 W. These values were further validated and found to be in good agreement with the predicted values. Compared to the other extraction methods, both the yield and scavenging percentage of RAMP obtained by UAEE was favorable and the method appeared to be time-saving and of high efficiency. These results demostrated that UAEE is an appropriate and effective extraction technique. Moreover, RSM with DF approach has been proved to be adequate for the design and optimization of the extraction parameters for RAMP. This work has a wide range of implications for the design and operation of polysaccharide extraction processes.

Henrin A (1), a new ent-kaurane diterpene, was isolated from the leaves of Pteris henryi. The chemical structure was elucidated by analysis of the spectroscopic data including one-dimensional (1D) and two-dimensional (2D) NMR spectra, and was further confirmed by X-ray crystallographic analysis. The compound was evaluated for its biological activities against a panel of cancer cell lines, dental bacterial biofilm formation, and HIV. It displayed anti-HIV potential with an IC50 value of 9.1 µM (SI = 12.2).

This work concerns the design and synthesis of novel, substituted 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a-p prepared from 3-amino-2-thiophenecarboxylic acid methyl ester. The final compounds were screened for their in vivo anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. Neurotoxicity (NT) was tested using a rotarod test. The structure-anticonvulsant activity relationship analysis revealed that the most effective structural motif involves a substituted phenol, especially when substituted with a single chlorine, fluorine or trifluoromethyl group (at the meta-position), or two chlorine atoms. These molecules possessed high activity according to the MES and scPTZ models. Quantitative assessment of the compounds after intraperitoneal administration in mice showed that the most active compound was 5-[3-(trifluoromethyl)phenoxy]thieno[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidine (5o) with ED50 values of 11.5 mg/kg (MES) and 58.9 mg/kg (scPTZ). Furthermore, compound 5o was more effective in the MES and scPTZ tests than the well-known anticonvulsant drugs carbamazepine and ethosuximide.

Five new norditerpene endoperoxides, named diacarperoxides H-L (1-5), and a new norditerpene diol, called diacardiol B (6), were isolated from the South China Sea sponge, Diacarnus megaspinorhabdosa. Their structures, including conformations and absolute configurations, were determined by using spectroscopic analyses, computational approaches and chemical degradation. Diacarperoxides H-J (1-3) showed some interesting stereochemical issues, as well as antimalarial activity.

A new scalarane sesterterpene, phyllofolactone M (1), and a new sterol, (24E)-5alpha,6alpha-epoxystigmasta-7,24(28)-dien-3beta-ol (3), together with a known sesterterpene, phyllofolactone B (2), were isolated from the South China Sea sponge Phyllospongia foliascens. Their structures were elucidated by spectroscopic analysis and comparison with known compounds. In addition, previous NMR data assignments for the known sesterterpene phyllofolactone B (2) were revised.