Targeting cancer epigenetic pathways with small-molecule compounds: Therapeutic efficacy and combination therapies.

Epigenetics mainly refers to covalent modifications to DNA or histones without affecting genomes, which ultimately lead to phenotypic changes in cells or organisms. Given the abundance of regulatory targets in epigenetic pathways and their pivotal roles in tumorigenesis and drug resistance, the development of epigenetic drugs holds a great promise for the current cancer therapy. However, lack of potent, selective, and clinically tractable small-molecule compounds makes the strategy to target cancer epigenetic pathways still challenging. Therefore, this review focuses on epigenetic pathways, small molecule inhibitors targeting DNA methyltransferase (DNMT) and small molecule inhibitors targeting histone modification (the main regulatory targets are histone acetyltransferases (HAT), histone deacetylases (HDACs) and histone methyltransferases (HMTS)), as well as the combination strategies of the existing epigenetic therapeutic drugs and more new therapies to improve the efficacy, which will shed light on a new clue on discovery of more small-molecule drugs targeting cancer epigenetic pathways as promising strategies in the future.

Dioscin ameliorates intestinal ischemia/reperfusion injury via adjusting miR-351-5p/MAPK13-mediated inflammation and apoptosis.

Inflammatory reaction and cell apoptosis are two important processes in intestinal ischemia/reperfusion (II/R) injury, and exploration of effective lead compounds against II/R injury via regulating inflammation and apoptosis is critical important. In this paper, the results indicated that dioscin significantly increased cell viability, and inhibited inflammation and apoptosis caused by hypoxia-reoxygenation (H/R) injury in IEC-6 cells. in vivo II/R injury, dioscin markedly suppressed inflamma- tion and apoptosis, improved pathological changes, and depressed chiu' score in rats. Mechanistic studies indicated that dioscin notably up-regulated the expression level of MAPK13 through decreasing miR-351-5p level, and thereby decreased the expression levels of p-PKD1, NF-κB, Apaf-1, cleaved Caspase-3 and cleaved Caspase-9. Furthermore, miR-351-5p mimic and inhibitor experiments in IEC-6 cells further proved that dioscin up-regulated MAPK13 expression by decreasing miR-351-5p level to inhibit inflammation and apoptosis. Therefore, dioscin showed protective effect against II/R injury via adjusting miR-351-5/MAPK13-mediated inflammation and apoptosis. Dioscin should be considered as one potent candidate and miR-351-5/ MAPK13 should be one effective drug target for the treatment of II/R injury.

Correction to: Protective effects of dioscin against alcohol­induced liver injury.

During the course of writing and revision of this paper, the band of GAPDH.

Dioscin alleviates non-alcoholic fatty liver disease through adjusting lipid metabolism via SIRT1/AMPK signaling pathway.

Dioscin, one natural product, has active effect against non-alcoholic fatty liver disease (NAFLD) in our previous work. However, the pharmacological data are insufficient and the mechanisms have not been reported. Thus, this study aims to comprehensively investigate the effects and molecular mechanisms of dioscin against NAFLD. The primary cultured hepatocytes, AML-12 and HepG-2 cells were treated with palmic acid (PA) after dioscin treatment. The mice and rats were induced by high fat diet to establish the in vivo models of NAFLD. Dioscin obviously alleviated liver lipid accumulation symptoms and improved the levels of serum and hepatic biochemical parameters in vitro and in vivo. Further investigations revealed that dioscin significantly attenuated lipid metabolism via adjusting SIRT1/AMPK signal pathway to regulate the expression levels of SREBP-1c, CPT, FAS, SCD, FoxO1 and ATGL. In addition, suppression of SIRT1 by Nicotinamide or abrogation of AMPK by Compound C eliminated the inhibitory effects of dioscin on lipid metabolism. Therefore, our findings further demonstrated that dioscin markedly prevented NAFLD through adjusting lipid metabolism via SIRT1/AMPK signal pathway, which should be developed as a new candidate for NAFLD.

Piezoresistive effect of n-type 〈111〉-oriented Si nanowires under large tension/compression.

Small-scale samples enable us to understand changes in physical properties under larger strain due to their higher tolerance to deformation. In this study, the piezoresistive character of n-type 〈111〉-oriented Si nanowires under large strain was measured during tensile and compressive deformations. The Si nanowires were directly cut from the wafer using top-down technology and deformed while capturing their electrical properties inside a transmission electron microscope. The experimental results show that both tensile and compressive deformation enhanced their electrical transport properties. The piezoresistance coefficient is of the same order of magnitude as its bulk counterpart, but half as large, which may be attributed to a larger strain magnitude. We also studied the circulatory characteristics and influence of electron beam radiation. This study provided new physical insights into piezoresistive effects under large strain.

Dioscin attenuates renal ischemia/reperfusion injury by inhibiting the TLR4/MyD88 signaling pathway via up-regulation of HSP70.

We previously reported the effect of dioscin against hepatic ischemia/reperfusion injury (IRI) in rats. However, little is known concerning the role of dioscin in renal IRI. In the present study, rats were subjected to IRI and dioscin was intragastrically administered for seven consecutive days before surgery. In vitro models of hypoxia/reoxygenation were developed in NRK-52E and HK-2 cells, which were prophylactically treated with or without dioscin. The results showed that dioscin significantly decreased serum BUN and Cr levels, and markedly attenuated cell injury. Mechanistic studies showed that dioscin significantly increased HSP70 levels, decreased the levels of TLR4, MyD88, TRAF6, COX-2, JNK, ERK and p38 MAPK phosphorylation, suppressed the nuclear translocation of NF-κB and HMGB1, and subsequently decreased the mRNA levels of IL-1ß, IL-6, TNF-α, ICAM-1 and IFN-γ. Moreover, HSP70 siRNA or TLR4 DNA reversed the nephroprotective effects of dioscin, while dioscin still significantly down-regulated the TLR4 signaling pathway. Furthermore, by inhibiting MyD88 with ST2825 (a MyD88 inhibitor), renal IRI was significantly attenuated, suggesting that the effect of dioscin against renal IRI depended on MyD88. Our results suggested that dioscin had a potent effect against renal IRI through suppressing the TLR4/MyD88 signaling pathway by up-regulating HSP70. These data provide new insights for investigating the natural product with the nephroprotective effect against IRI, which should be developed as a new therapeutic agent for the treatment of acute kidney injury in the future.

In-silico prediction of drug targets, biological activities, signal pathways and regulating networks of dioscin based on bioinformatics.

BACKGROUND: Inverse docking technology has been a trend of drug discovery, and bioinformatics approaches have been used to predict target proteins, biological activities, signal pathways and molecular regulating networks affected by drugs for further pharmacodynamic and mechanism studies. METHODS: In the present paper, inverse docking technology was applied to screen potential targets from potential drug target database (PDTD). Then, the corresponding gene information of the obtained drug-targets was applied to predict the related biological activities, signal pathways and processes networks of the compound by using MetaCore platform. After that, some most relevant regulating networks were considered, which included the nodes and relevant pathways of dioscin. RESULTS: 71 potential targets of dioscin from humans, 7 from rats and 8 from mice were screened, and the prediction results showed that the most likely targets of dioscin were cyclin A2, calmodulin, hemoglobin subunit beta, DNA topoisomerase I, DNA polymerase lambda, nitric oxide synthase and UDP-N-acetylhexosamine pyrophosphorylase, etc. Many diseases including experimental autoimmune encephalomyelitis of human, temporal lobe epilepsy of rat and ankylosing spondylitis of mouse, may be inhibited by dioscin through regulating immune response alternative complement pathway, G-protein signaling RhoB regulation pathway and immune response antiviral actions of interferons, etc. The most relevant networks (5 from human, 3 from rat and 5 from mouse) indicated that dioscin may be a TOP1 inhibitor, which can treat cancer though the cell cycle- transition and termination of DNA replication pathway. Dioscin can down regulate EGFR and EGF to inhibit cancer, and also has anti-inflammation activity by regulating JNK signaling pathway. CONCLUSIONS: The predictions of the possible targets, biological activities, signal pathways and relevant regulating networks of dioscin provide valuable information to guide further investigation of dioscin on pharmacodynamics and molecular mechanisms, which also suggests a practical and effective method for studies on the mechanism of other chemicals.

Potent effects of the total saponins from Dioscorea nipponica Makino against streptozotocin-induced type 2 diabetes mellitus in rats.

The aim of the present paper was to investigate the effects and possible mechanisms of the total saponins from Dioscorea nipponica Makino (TSDN) against type 2 diabetes mellitus. Streptozotocin (STZ) with high-fat diet induced type 2 diabetes mellitus (T2DM) rats were treated with TSDN. Some biochemical parameters, target proteins and genes were investigated. The results showed that TSDN decreased the levels of food/water intake, fasting blood glucose and serum lipid parameters, ameliorated oral glucose and insulin tolerance test levels, markedly increased body weight and serum insulin, reduced excess free radicals and affected ossification and renal protection. Histopathological examination indicated that TSDN increased liver glycogen, decreased the production of lipid vacuoles and lightened liver damage. Further investigation showed that TSDN down-regulated the protein expressions of NF-κB, GRP78, ATF6, eIF2 and the levels of MAPK phosphorylation and up-regulated the protein expressions of IRS-1, GLUT-4, p-Akt and p-AMPK. In addition, TSDN obviously decreased the gene expressions of TNF-a, IL-6, PEPCK, G6Pase, GSK-3ß and GSK-3ß activity, and increased the gene expressions of PFK, PK and GK activity. These findings show the anti-diabetic activity of total saponins from D. nipponica Makino, which should be developed as a new potent drug for treatment of diabetes mellitus in future.

Protective effects of dioscin against alcohol-induced liver injury.

Our previous studies have shown that dioscin has protective effect against liver injury. However, the action of the compound against ethanol-induced liver injury is still unknown. In the present paper, ethanol-induced acute and chronic liver damage rat models were used, and the results showed that dioscin significantly alleviated liver steatosis, reduced the levels of alanine aminotransferase, aspartate aminotransferase, total triglyceride (TG), total cholesterol and malondialdehyde, and increased the levels of high-density lipoprotein, superoxide dismutase, glutathione and glutathione peroxidase. Transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays showed that dioscin prevented mitochondrial ultrastructural alterations and apoptosis caused by ethanol. In addition, dioscin significantly inhibited ethanol-induced cytochrome P450 2E1 activation, down-regulated the levels of mitogen-activated protein kinases phosphorylation, inhibited the expressions of nuclear factor kappa B, glucose regulated protein 78, activating transcription factor 6 and alpha subunit of translation initiation factor 2 to attenuate oxidative damage, decreased the expressions of tumor necrosis factor alpha and interleukin-6, and down-regulated the expressions of apoptosis-related proteins including p53, caspase-3, caspase-9, poly (ADP-ribose)-polymerase and cytokeratin-18. Further investigation indicated that dioscin markedly increased the expressions of peroxisome proliferators-activated receptor α and its target genes including medium-chain acyl-CoA dehydrogenase, carnitine palmitoyl-CoA transferase I and acyl-CoA oxidase to advance fatty acid ß-oxidation, up-regulated the expressions of acyl-CoA synthetase long-chain family member 1, acyl-CoA synthetase long-chain family member 5, alpha-aminoadipic semialdehyde dehydrogenase and acyl-CoA dehydrogenase to promote fatty acid metabolism, and down-regulated the expressions of glycerol-3-phosphate acyltransferase, diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 to accelerate TG synthesis. However, dioscin had no effects on the expressions of sterol regulatory element-binding protein-1c, fatty acid synthase, acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase 1 associated with fatty acid synthesis. In conclusion, dioscin shows excellent protective effect against ethanol-induced liver injury through ameliorating ethanol-induced oxidative stress, mitochondrial function, inflammatory cytokine production, apoptosis and liver steatosis, which should be developed as a new drug for the treatment of ethanol-induced liver injury in the future.

Analgesic treatment for refractory cancer pain caused by gastric cancer bone metastasis: A case report and literature review.

RATIONALE: Patients with bone metastasis-associated cancer pain often experience a complex mix of pain types. Consequently, the use of multimodal combination therapy is essential. While monitoring for common adverse reactions in pain treatment, it is also crucial to be vigilant for the rare but serious serotonin syndrome. PATIENT CONCERNS: A 53-year-old female with metastatic gastric cancer was hospitalized due to severe, uncontrolled thoracic and cervical pain. During the titration of her cancer pain medication, she developed serotonin syndrome. DIAGNOSES: He was diagnosed with refractory cancer pain and serotonin syndrome. INTERVENTIONS: The complete process of cancer pain medication in a patient with gastric cancer and bone metastasis was analyzed, with a primary focus on the selection of analgesic medications, adjustment of opioid dosages, and prevention and treatment of medication-associated adverse reactions. OUTCOMES: The patient's cancer pain was well controlled, with the prompt management of adverse reactions. Furthermore, by adjusting the medication regimen, intolerable adverse reactions were prevented. LESSONS: In clinical settings, personalized analgesic regimens must be developed for patients with cancer pain to enhance patient compliance with medication, prevent the occurrence of severe adverse reactions, and improve the overall quality of life of patients with cancer. Healthcare professionals should pay increased attention to ADRs associated with opioid medications, whereas pharmacists should assist them in promptly identifying ADRs.

Data-independent acquisition-based global phosphoproteomics reveal the diverse roles of casein kinase 1 in plant development.

Casein kinase 1 (CK1) is serine/threonine protein kinase highly conserved among eukaryotes, and regulates multiple developmental and signaling events through phosphorylation of target proteins. Arabidopsis early flowering 1 (EL1)-like (AELs) are plant-specific CK1s with varied functions, but identification and validation of their substrates is a major bottleneck in elucidating their physiological roles. Here, we conducted a quantitative phosphoproteomic analysis in data-independent acquisition mode to systematically identify CK1 substrates. We extracted proteins from seedlings overexpressing individual AEL genes (AEL1/2/3/4-OE) or lacking AEL function (all ael single mutants and two triple mutants) to identify the high-confidence phosphopeptides with significantly altered abundance compared to wild-type Col-0. Among these, we selected 3985 phosphopeptides with higher abundance in AEL-OE lines or lower abundance in ael mutants compared with Col-0 as AEL-upregulated phosphopeptides, and defined 1032 phosphoproteins. Eight CK1s substrate motifs were enriched among AEL-upregulated phosphopeptides and verified, which allowed us to predict additional candidate substrates and functions of CK1s. We functionally characterized a newly identified substrate C3H17, a CCCH-type zinc finger transcription factor, through biochemical and genetic analyses, revealing a role for AEL-promoted C3H17 protein stability and transactivation activity in regulating embryogenesis. As CK1s are highly conserved across eukaryotes, we searched the rice, mouse, and human protein databases using newly identified CK1 substrate motifs, yielding many more candidate substrates than currently known, largely expanding our understanding of the common and distinct functions exerted by CK1s in Arabidopsis and humans, facilitating future mechanistic studies of CK1-mediated phosphorylation in different species.

Soy protein isolate-based active films functionalized with Zanthoxylum bungeanum by-products: Effects on barrier, mechanical, antioxidant and cherry tomato preservation performance.

In this work, soy protein isolate (SPI)-based films enriched with naturally sourced Zanthoxylum bungeanum leaf extract (ZBLE) were prepared. Different ZBLE contents (0, 1, 3, 5, and 7 % w/w SPI) were incorporated into the SPI matrix to investigate the effect of ZBLE on various properties of the obtained films. ZBLE exhibited excellent compatibility with SPI in terms of tensile strength, water barrier properties, UV-light resistance capability, and antioxidant activities. The films with 5 % ZBLE addition presented the most comprehensive performance. The release of total phenolic compounds in two different aqueous food simulants was analyzed. Furthermore, the films were employed to preserve fresh cherry tomatoes at 25 ± 1 °C for 18 days. The changes in the physicochemical properties (mass loss rate, decay rate, and vitamin C content) of cherry tomatoes revealed that the addition of ZBLE to films significantly extended the storage time. Therefore, the SPI/ZBLE composite film has the potential as an eco-friendly active packaging material for food preservation.

Dual-binding domain electrochemiluminescence biosensing platform with self-checking function for sensitive detection of synthetic cathinone in e-cigarettes.

Current single signal electrochemiluminescence (ECL) sensors are susceptible to false positive or false negative phenomena due to experimental conditions. Therefore, sensors with "self-checking" function are attracting democratic attention. In quick succession, a highly sensitive single-cathode dual ECL signal aptasensor with self-checking function to improve the shortcomings mentioned above was designed. This aptasensor used In-based metal-organic framework (MIL-68) as load and stabilizer to effectively attenuate the aggregation-induced quenching (ACQ) effect of porphyrin derivatives (Sn-TCPP) while improve ECL stability. The introduction of cooperative-binding split-aptamers" (CBSAs) aptamers increased the specificity of the aptasensor and its unique double-binding domains detection accelerated the detection efficiency. When analyzing 3,4-methylenedioxypyrovalerone (MDPV), we could calculate two concentrations based on the strength of ECL 1 and ECL 2. If the concentrations are the same, the result would be obtained; if not, it should be retested. Depending on the above operation, the results achieve self-check. It was found that the designed aptasensor could quantify the concentration of MDPV between 1.0 × 10-12 g/L and 1.0 × 10-6 g/L with the limit of detection (LOD) of 1.4 × 10-13 g/L and 2.0 × 10-13 g/L, respectively (3 σ/slope). This study not only improves the detection technology of MDPV, but also explores the dual-signal detection of porphyrin for the first time and enriches the definition of self-checking sensor.

Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.

Cholesterol is an essential component of cell membranes and helps to maintain their structure and function. Abnormal cholesterol metabolism has been linked to the development and progression of tumors. Changes in cholesterol metabolism triggered by internal or external stimuli can promote tumor growth. During metastasis, tumor cells require large amounts of cholesterol to support their growth and colonization of new organs. Recent research has shown that cholesterol metabolism is reprogrammed during tumor development, and this can also affect the anti-tumor activity of immune cells in the surrounding environment. However, identifying the specific targets in cholesterol metabolism that regulate cancer progression and the tumor microenvironment is still a challenge. Additionally, exploring the potential of combining statin drugs with other therapies for different types of cancer could be a worthwhile avenue for future drug development. In this review, we focus on the molecular mechanisms of cholesterol and its derivatives in cell metabolism and the tumor microenvironment, and discuss specific targets and relevant therapeutic agents that inhibit aspects of cholesterol homeostasis.

Preparative purification of five bioactive components from Agrimonia pilosa Ledeb by high-speed counter-current chromatography.

High-speed counter-current chromatography (HSCCC) coupled with ultraviolet (UV) detection or evaporative light-scattering detection was successfully applied for preparative separation of five bioactive compounds from Agrimonia pilosa Ledeb. In preliminary process, D101 macroporous resin was used to separate the crude extract of the plant and four fractions (20, 40, 50, and 60% aqueous ethanol elutions) were produced. Then, these fractions were directly subjected to HSCCC purification. Five chemicals including taxifolin-3-glucoside (6.4 mg), quercetin-3-rhamnoside (13.0 mg), tiliroside (14.7 mg), agrimonolide (21.4 mg), and tormentic acid (29.8 mg) with the purities of 94.24, 95.37, 97.42, 95.29, and 96.34% were separated from each 200 mg prepared fraction. The purities were analyzed by high-performance liquid chromatography, and the chemical structures of the products were identified by UV detection, mass spectrometry, nuclear magnetic resonance, and the standards. This paper used a simple method to separate five bioactive compounds from A. pilosa Ledeb, and it could provide a new idea for the purification of bioactive compounds from other medicinal plants.

Subchronic toxicity study of the total flavonoids from Rosa laevigata Michx fruit in rats.

The total flavonoids (TFs) from Rosa laevigata Michx fruit showed hepatoprotective and antioxidant activities. However, the safety of this natural product has not been investigated. In the present paper, a 90-day subchronic toxicity study was conducted, and the tested TFs was orally administered to rats at the doses of 500, 1000 and 2000mg/kg/day. The toxicity of the TFs was evaluated on base of ophthalmic examination, body weight, feed/water consumption, urinalysis, hematology, clinical biochemistry and pathology. No toxic signs of the TFs at the doses of 500 and 1000mg/kg/day were observed. However, decreased PLT was found in the 2000mg/kg/day groups and increased intercellular space of myocardial cells was observed in the male 2000mg/kg/day group compared with control. A significant increase in the relative cardiac weight was observed in the male 1000 and 2000mg/kg/day groups. And the significant decrease in the absolute and relative weight of adrenals in the female 1000 and 2000mg/kg groups was happened. The TFs could cause mild side effects at the dose of 1000mg/kg/day in males and females. Thus, the dose of 500mg/kg/day for male and female were selected as the no-observed-adverse-effect level (NOAEL). The present study provides useful data for subsequent researches and new drug exploration of the TFs from R. laevigata Michx fruit.

1-Chloro-1H-1,2,3-benzotriazole.

The title compound, C6H4ClN3, is essentially planar, with a maximum deviation of 0.007 (3) Å. In the crystal, a short contact of 2.818 (3) Šis observed between N and Cl atoms of adjacent mol-ecules.

Unravelling the roles of Autophagy in OSCC: A renewed perspective from mechanisms to potential applications.

Oral squamous cell carcinoma (OSCC) is associated with a low survival rate and a high disability rate, making it a serious health burden, particularly in Southeast Asian countries. Therefore, improvements in the diagnosis, treatment, and prognosis prediction of OSCC are highly warranted. Autophagy has a significant impact on cancer development. Studies on autophagy in various human cancers have made outstanding contributions; however, the relationship between autophagy and OSCC remains to be explored. This review highlights the roles of autophagy in OSCC and discusses the relationship between autophagy and Epithelial-mesenchymal transition. Considering the lack of OSCC biomarkers, we focus on the studies involving OSCC-related bioinformatics analysis and molecular targets. Based on some classical targets, we summarize several key autophagy-related biomarkers with a considerable potential for clinical application, which may become the hotspot of OSCC research. In conclusion, we elaborate on the interrelationship between autophagy and OSCC and highlight the shortcomings of current studies to provide insights into the potential clinical strategies.