Advances in natural small molecules on pretranslational regulation of gluconeogenesis.

Different tissues and organs coordinate to keep glucose levels at homeostasis. However, excessive gluconeogenesis in patients with type 2 diabetes mellitus increases blood glucose and causes dysregulation of homeostasis, which easily induces various diseases. Therefore, inhibiting excessive gluconeogenesis is a potential direction to regulate the disorder of blood glucose homeostasis and treat diabetes. The process of gluconeogenesis can be pretranslationally or posttranslationally regulated, and some natural small molecules can be involved in the pretranslational phase of gluconeogenesis, regulating glucose homeostasis by inhibiting gene expression, interfering with RNA transcription, and antagonizing related proteins. This paper will classify and review the natural small molecules with pretranslational regulation of gluconeogenesis according to the action sites and signaling pathways.

High-Carbohydrate Diet Consumption Poses a More Severe Liver Cholesterol Deposition than a High-Fat and High-Calorie Diet in Mice.

In the past few decades, many researchers believed that a high-fat and high-calorie diet is the most critical factor leading to metabolic diseases. However, increasing evidence shows a high-carbohydrate and low-fat diet may also be a significant risk factor. It needs a comprehensive evaluation to prove which viewpoint is more persuasive. We systematically compared the effects of high-fat and high-calorie diets and high-carbohydrate and low-fat ones on glycolipid metabolism in mice to evaluate and compare the effects of different dietary patterns on metabolic changes in mice. Sixty 8-week-old male C57BL/6 mice were divided into four groups after acclimatization and 15% (F-15), 25% (F-25), 35% (F-35), and 45% (F-45) of their dietary energy was derived from fat for 24 weeks. The body weight, body-fat percentage, fasting blood glucose, lipid content in the serum, and triglyceride content in the livers of mice showed a significantly positive correlation with dietary oil supplementation. Interestingly, the total cholesterol content in the livers of mice in the F-15 group was significantly higher than that in other groups (p < 0.05). Compared with the F-45 group, the mRNA expression of sterol synthesis and absorption-related genes (e.g., Asgr1, mTorc1, Ucp20, Srebp2, Hmgcr, and Ldlr), liver fibrosis-related genes (e.g., Col4a1 and Adamts1) and inflammation-related genes (e.g., Il-1ß and Il-6) were significantly higher in the F-15 group. Compared with the F-45 group, the relative abundance of unclassified_f_Lachnospiraceae and Akkermansia was decreased in the F-15 group. While unclassified_f_Lachnospiraceae and Akkermansia are potentially beneficial bacteria, they have the ability to produce short-chain fatty acids and modulate cholesterol metabolism. In addition, the relative abundance of unclassified_f_Lachnospiraceae and Akkermansia was significantly positively correlated with fatty acid transporters expression and negatively correlated with that of cholesteryl acyltransferase 1 and cholesterol synthesis-related genes. In conclusion, our study delineated how a high-fat and high-calorie diet (fat supplied higher than or equal to 35%) induced obesity and hepatic lipid deposition in mice. Although the high-carbohydrate and low-fat diet did not cause weight gain in mice, it induced cholesterol deposition in the liver. The mechanism is mainly through the induction of endogenous synthesis of cholesterol in mice liver through the ASGR1-mTORC1-USP20-HMGCR signaling pathway. The appropriate oil and carbon water ratio (dietary energy supply from fat of 25%) showed the best gluco-lipid metabolic homeostasis in mice.

Target identification of anti-diabetic and anti-obesity flavonoid derivative (Fla-CN).

Fla-CN is a flavonoid derivative with anti-diabetic and anti-obesity effects; however, its biological targets are still unknown. In this study, we developed bifunctional affinity-based probes to identify the direct targets of Fla-CN. When using probe 3, we observed the co-location of probe 3 and mitochondria in both HepG2 and 3T3-L1 cells. The putative target proteomes were obtained using activity-based protein profiling (ABPP) and photo-affinity labelling. Pyruvate carboxylase, mitochondrial malate dehydrogenase, mitochondrial complex I, and F1FO-ATPase were validated as the direct targets of Fla-CN by surface plasmon resonance (SPR) and biochemical assays. It was elucidated that the Tyr651, Gln870 and Lys912 were the key amino acid residues near the binding site of pyruvate carboxylase with Fla-CN. The direct interaction of Fla-CN and the above four targets allowed elucidation of its complicated molecular mechanism, including the activation of adenosine 5-monophosphate (AMP)-activated protein kinase (AMPK), and the inhibition of gluconeogenesis. Further investigation for activation of AMPK in normal and insulin resistance (IR) HepG2 cells, indicated that Fla-CN could target insulin resistance tissues.

Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase.

In this paper, the Y188C mutant HIV-1 reverse transcriptase (Y188CM-RT) target protein was constructed by homology modeling, and new ligands based on nevirapine (NVP) skeleton were designed by means of fragment growth. The binding activity of new ligands to Y188CM-RT was evaluated by structural analysis, ADMET prediction, molecular docking, energy calculation and molecular dynamics. Results show that 10 new ligands had good absorbability, and their binding energies to Y188CM-RT were significantly higher than those of wild-type HIV-1 reverse transcriptase(wt). The binding mode explained that fragment growth contributed to larger ligands, leading to improved suitability at the docking pocket. In the way of fragment growth, the larger side chain with extensive contact at terminal is obviously better than substituted benzene ring. The enhancement of docking activity is mainly due to the new fragments such as alkyl chains and rings with amino groups at NVP terminal, resulting in a large increase in hydrophobic bonding and the new addition of hydrogen bonding or salt bonding. This study is expected to provide reference for the research on non-nucleoside reverse transcriptase inhibitors resistance and AIDS treatment.

PLCD1 Suppressed Cellular Proliferation, Invasion, and Migration via Inhibition of Wnt/ß-Catenin Signaling Pathway in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Phospholipase C delta 1 (PLCD1) has been found to be abnormally expressed in various cancers. However, the potential roles of PLCD1 in esophageal squamous cell carcinoma (ESCC) are still unknown. METHODS: Western blot and qPCR were used to explore PLCD1 expression in various ESCC cells. MTT, colony formation assays, wound-healing assay, and transwell cell invasion assay were used to examine the cell viability in vitro. Western blot, qPCR, and luciferase assays were used to investigate the effects of PLCD1 on Wnt/ß-catenin signaling pathway. The xenograft models in nude mice were established to explore the roles of PLCD1 in vivo. RESULTS: We found that the expression of PLCD1 in ESCC cells was significantly downregulated than that in normal esophageal epithelial cells. In addition, upregulation of PLCD1 decreased the capacity of TE-1 and EC18 cells in proliferation, invasion, and migration. Then, the expression of ß-catenin/p-ß-catenin, C-myc, cyclin D1, MMP9, and MMP7 was investigated. PLCD1 activity was found to be negatively associated with the expression of ß-catenin, C-myc, cyclin D1, MMP9, and MMP7. Finally, the activity of PLCD1 in inhibiting ESCC proliferation in vivo was validated. CONCLUSION: The inhibitory effects of PLCD1 on the proliferation, invasion, and migration of TE-1 and EC18 cells might be associated with inhibition of Wnt/ß-catenin signaling pathway. PLCD1 played a key role in inhibiting ESCC carcinogenesis and progression in patients with ESCC.

Phototropic Aggregation and Light-Guided Long-Distance Collective Transport of Colloidal Particles.

Phoretic swarming and collective transport of colloidal particles in response to environmental stimuli have attracted tremendous interest in a variety of fields. In this work, we investigate the light-actuated motion, aggregation, and light-guided long-distance mass transport of silica microspheres in simple spiropyran solutions under the illumination of UV spot sources. The phototactic motion is confirmed by the dependence of swarming on the illumination intensity and spiropyran concentrations, ON-OFF switching tests, pattern-masked UV sources, etc. The aggregates formed via swarming of silica spheres can chase after a moving UV source, however, relying on a critical speed of the UV source. Only when the UV source speed is below the critical value, the aggregates follow the UV spot at a constant relative speed to the light spot. Analysis on the shape of silica microsphere currents indicates that continuous illumination of the UV spot source and resultant chemical gradients are important for the formation of steady microsphere currents. Light-guided aggregation and long-distance mass transport are interesting for targeted delivery and remote-controlled enrichment of environmental hazards.

Flavonoid derivatives synthesis and anti-diabetic activities.

In high fat diet-induced obese mice, the flavonoid derivative of tiliroside, Fla-CN, has antihyperglycemic effects, can improve insulin sensitivity, ameliorate metabolic lipid disorders, and benefits certain disorders characterized by insulin resistance. Fla-CN is a novel lead compound to discovery anti-diabetic and anti-obesity drugs. The present study reported the optimization of Fla-CN to obtain a new derivative, 10b, which has improved glucose consumption at the nanomolar level (EC50 = 0.3 nM) in insulin resistant (IR) HepG2 cells. 10b also increased the glycogen content and glucose uptake, and concurrently inhibited gluconeogenesis in HepG2 cells. Western blotting showed that 10b markedly enhanced the phosphorylation of AMPK (AMP-activated protein kinase) and AS160 (protein kinase B substrate of 160 kDa) and reduced the levels of the gluconeogenesis key enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6P (glucose 6-phosphatase) in HepG2 cells. The potential molecular mechanism of 10b may be activation of the AMPK/AS160 and AMPK/PEPCK/G6P pathways. We concluded that 10b might be a valuable candidate to discover anti-diabetic drugs.

Nitrogen fertilizer application affects lodging resistance by altering secondary cell wall synthesis in japonica rice (Oryza sativa).

Stem mechanical strength is an important agricultural quantitative trait that is closely related to lodging resistance in rice, which is known to be reduced by fertilizer with higher levels of nitrogen. To understand the mechanism that regulates stem mechanical strength in response to nitrogen, we analysed stem morphology, anatomy, mechanical properties, cell wall components, and expression of cell wall-related genes, in two varieties of japonica rice, namely, Wuyunjing23 (lodging-resistant variety) and W3668 (lodging-susceptible variety). The results showed that higher nitrogen fertilizer increased the lodging index in both varieties due to a reduction in breaking strength and bending stress, and these changes were larger in W3668. Cellulose content decreased slightly under higher nitrogen fertilizer, whereas lignin content reduced remarkably. Histochemical staining revealed that high nitrogen application decreased lignin deposition in the secondary cell wall of the sclerenchyma cells and vascular bundle cells compared with the low nitrogen treatments, while it did not alter the pattern of cellulose deposition in these cells in both Wuyunjing23 and W3668. In addition, the expression of the genes involved in lignin biosynthesis, OsPAL, OsCoMT, Os4CL3, OsCCR, OsCAD2, OsCAD7, OsCesA4, and OsCesA7, were also down-regulated under higher nitrogen conditions at the early stage of culm growth. These results suggest that the genes involved in lignin biosynthesis are down-regulated by higher nitrogen fertilizer, which causes lignin deficiency in the secondary cell walls and the weakening of mechanical tissue structure. Subsequently, this results in these internodes with reduced mechanical strength and poor lodging resistance.

Dexmedetomidine versus midazolam as intranasal premedication for intravenous deep sedation in pediatric dental treatment.

Background/purpose: Optimal sedation management for pediatric dental treatment demands special focus as it's tubeless and shares a same oral space. The study was to evaluate dexmedetomidine compared to midazolam for intranasal premedication in pediatric dental treatment under intravenous deep sedation. Materials and methods: A hundred children aged 3-7 years scheduled for elective dental treatment under intravenous deep sedation anesthesia were enrolled, of whom 50 children (Group D) were intranasally premedicated with 2.0 µg/kg dexmedetomidine and the remaining 50 children (Group M) received traditional 0.2 mg/kg midazolam. Acceptance rate of venipuncture was regarded as the primary endpoint. Results: The acceptance rate of venipuncture in Group D and Group M were 76% versus 52%, respectively (P = 0.021). More children in Group M complained about bitter/sour taste than Group D (62% vs. 8%, P < 0.001). Intraoperatively, children in Group M were found to have more choking cough than Group D (30% vs. 9%, P = 0.003), and patients in Group M required more suction (18 [36%] in Group M vs. 4 [8%] in Group D, P = 0.001). There were no significant differences between the groups in the incidences of temporal hypoxemia (SpO2 ≤ 90%), however, two children in Group M experienced hypoxemia over 10 s. Conclusion: Compared to the 0.2 mg/kg midazolam, children premedicated with 2.0 µg/kg intranasal dexmedetomidine showed superior venipuncture acceptance, had less intraoperative choking cough and required fewer suction. It seems to be a good alternative to midazolam as premedication for deep sedation in pediatric dental treatment.

Advances in Small Molecules of Flavonoids for the Regulation of Gluconeogenesis.

Hyperglycemia resulting from over-gluconeogenesis is a prominent feature of type 2 diabetes mellitus (T2DM). Therefore, it is very important to reduce glucose output, especially liver glucose output, and maintain blood glucose homeostasis in the treatment of T2DM. It has been found that small molecules of natural flavonoids are able to act on various targets in the gluconeogenic pathways, interfering with rate-limiting enzyme activity or regulating the cascade of hormonal signaling and affecting all levels of transcription factors by limiting the transport of non-sugar substrates. As a result, gluconeogenesis is inhibited. Literature indicated that gluconeogenesis regulated by flavonoids could be divided into two pathways, namely the pre-translational pathway and the pro-translational pathway. The pre-translational pathway mainly interferes with the signaling pathway and transcription factors in gluconeogenesis and inhibits RNA transcription and the expression of gluconeogenic genes, while the post-translational pathway mainly regulates the transport of nonglucose substrates and directly inhibits four rate-limiting enzymes. This review describes the effects of small flavonoid molecules on different targets and signaling pathways during gluconeogenesis, as well as relevant validation methods, in the hope of providing references for similar studies and promoting the development of anti-diabetic drugs.

Curcumin combining temozolomide formed localized nanogel for inhibition of postsurgical chemoresistant glioblastoma.

Aim: To investigate the use of nanoparticle (NP)-encapsulated injectable thermosensitive hydrogel-formed nanogel for inhibition of postsurgical residual temozolomide (TMZ)-resistant glioblastoma (GBM) recurrence. Materials & methods: Curcumin (Cur) was coloaded with TMZ into PEG-PLGA NPs, then NPs were further encapsulated into a thermosensitive hydrogel to form a nanogel, which was injected into the resection cavity of the GBM postsurgery. Results: The prepared nanogel displayed excellent drug-loading capacity and long-term drug release. Estimated survival characteristics demonstrated that the nanogel could play a significant role in TMZ-resistant tumor inhibition with low drug-induced toxicity. The originally designed ratio of Cur/TMZ was sustained, making it an effective therapeutic outcome. Conclusion: Cur-combined TMZ-formed nanogels can be a promising candidate for the local inhibition of GBM recurrence.

In this study, the animal model used was rats suffering residual brain tumor after resection. The selected drugs were temozolomide, a first-line chemotherapeutic drug for the clinical treatment of glioma, and curcumin, an extract from the ginger plant. With the use of temozolomide, brain glioma cells gradually develop resistance, resulting in poor efficacy of temozolomide. Therefore, the purpose of this study was to construct a drug-delivery system for temozolomide-resistant brain glioma residual tumor after surgery, namely, a temperature-sensitive gel containing drug-carrying nanopreparations ­ the so-called nanogels. This drug-delivery system can directly deliver drugs to residual tumor cells in situ after surgery. In situ drug-delivery systems can reduce the dose of drugs consumed and increase their potency compared to oral or intravenous administration.

Safety of deep intravenous propofol sedation in the dental treatment of children in the outpatient department.

Background/purpose: Intravenous sedation with propofol in the dental treatment offers an alternative to inhalation sedation or general anesthesia. The aim of this study was to evaluate the safety and identify risk factors for intraoperative complications. Materials and methods: Uncooperative children who could not complete dental treatment under non-pharmacological behavior management or mild-to-moderate sedation in the outpatient pediatric department were selected. Details and time of dental treatment; intraoperative vital signs data, including blood pressure, heart rate, respiratory rate, pulse oxygen saturation (SpO2), end-tidal carbon dioxide, and electrocardiogram; and incidence of intraoperative and postoperative complications were recorded. Results: Overall, 344 children were selected, with 342 completing dental treatment. The dental treatment time was 20-155 (median, 85; interquartile range, 70-100) min. The number of treated teeth was at least 1 and at most 13 (median, 6; interquartile range, 5-8). Among 342 children, 35 (10.2%) had their treatment interrupted temporarily due to choking cough. No serious complications occurred; the incidence rate of minor complications was 47/342 (13.7%). Tachycardia was observed in 5/342 (1.5%) cases, oxygen desaturation (SpO2 < 95%) in 18, and hypoxemia (SpO2 ≤ 90%) in 25. The treatment duration was significant longer in cases with than without complications (P < 0.05), and children coughing during treatment were more likely to have complications (P < 0.05). Postoperative restlessness occurred in six children, but there was no vomiting, aspiration, or respiratory obstruction. Conclusion: Decreased oxygen saturation is the most common complications. Cough during treatment and longer treatment duration were risk factors for complications.

Photo-assisted "co-movement catalysis": CoFe2O4/CNS heterojunction based portable electrochemical sensor for simultaneous detection of Pb2+ and Cd2+ in natural water.

Heavy metal ions (HMIs) seriously threaten human health even under trace conditions. Therefore, accurate, efficient and simultaneous detection of multiple HMIs is of great significance. Here, a strategy of "co-movement catalysis" based on photo-assisted electrochemical catalysis is proposed by constructing a flexible electrochemical sensor with CoFe2O4/CNS heterojunction-modified nickel foam as the working electrode for simultaneous detection of HMIs. Regarding photo-assisted catalysis, CoFe2O4/CNS nanocomposites formed a p-n type heterojunction, effectively separating photo-generated electron-hole pairs and reducing photo-generated carriers' recombination rate, leading to the catalytic reaction of photogenerated electrons and holes with HMIs and atoms to improve the efficiency of preconcentration and stripping, further amplifying the electrochemical signal. Regarding electrochemical catalysis, the CoFe2O4 spinel contains variable valence transition metal ions Fe2+/Fe3+ and Co2+/Co3+, which can reduce and oxidize HMIs circularly, further enhancing the sensor's sensitivity. The portable sensor based on "co-movement catalysis" exhibited sensitive detection performance. The linear range is 0.100-10.0 µM for Pb2+ and 1.00-10.0 µM for Cd2+, with the detection limit of 0.0310 µM for Pb2+ and 0.219 µM for Cd2+, respectively. The recovery rate of the sensor to natural water samples is between 96% and 105%, which proves its development potential in environmental monitoring.

SNX-2112 Induces Apoptosis and Inhibits Proliferation, Invasion, and Migration of Non-Small Cell Lung Cancer by Downregulating Epithelial-Mesenchymal Transition via the Wnt/ß-Catenin Signaling Pathway.

Lung cancer is the most frequent malignant tumor, and non-small cell lung cancer (NSCLC) is responsible for substantial mortality worldwide. The small molecule SNX-2112 was recently shown to critically effect the proliferation and apoptosis of tumor cells. Nevertheless, the precise mechanism by which SNX-2112 affects NSCLC remains poorly understood. Therefore, we investigated the function of SNX-2112 in NSCLC. We verified that SNX-2112 promoted apoptosis and suppressed the proliferation, invasion, and migration of A549 and H520 NSCLC cells in vitro. We further verified the potential mechanism of SNX-2112 in NSCLC. The changes in the protein levels demonstrated that SNX-2112 inhibited the epithelial-mesenchymal transition (EMT) (increased E-cadherin and decreased N-cadherin and vimentin) and the Wnt/ß-catenin signaling pathway (glycogen synthase kinase (GSK) 3ß and phosphorylated (p)-ß-catenin increased, ß-catenin and p-GSK3ß decreased) in NSCLC cells. These results were verified by rescue experiments using a Wnt/ß-catenin pathway agonist. We also established a tumor xenograft model and confirmed that SNX-2112 reduced tumor growth and proliferation and enhanced necrosis and apoptosis in a NSCLC model in vivo. In conclusion, the current study is the first to discover the mechanism of SNX-2112 in NSCLC. SNX-2112 induced apoptosis and also inhibited the proliferation, invasion, and migration of NSCLC cells by downregulating EMT via the Wnt/ß-catenin signaling pathway.

Combination effect of curcumin with docetaxel on the PI3K/AKT/mTOR pathway to induce autophagy and apoptosis in esophageal squamous cell carcinoma.

BACKGROUND: Docetaxel (DTX) is widely used to treat many malignant tumors but has many adverse effects. Curcumin (CUR) also has effects on a variety of tumor cells and can reduce the toxicity and side effects of chemotherapy drugs and the occurrence of drug resistance. However, the combination of CUR and DTX for treating esophageal cancer has not been reported. METHODS: Human esophageal squamous cell carcinoma (ESCC) KYSE150 and KYSE510 cells were treated with CUR or DTX alone or both drugs and cancer cell viability was detected by CCK8, apoptosis, scratch-healing and migration assays. Electron microscopy and Western blots were used. In vivo experiments were used observe anti-tumor effects. RESULTS: CUR combined with DTX significantly inhibited the viability and migration of esophageal cancer cells (P<0.01) and further promoted the apoptosis of cancer cells. In addition, CUR induced autophagy in esophageal cancer cells when combined with DTX. DTX combined with CUR may induce apoptosis and autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. The compound 3-methyladenine (3MA) inhibited the autophagy induced by DTX and CUR (DC), further accelerated apoptosis and inhibited the proliferation of esophageal cancer cells when combined with DC. CONCLUSION: CUR combined with DTX induced apoptosis and autophagy of ESCC and probably worked through the PI3K/AKT/mTOR signaling pathway. The combination of the autophagy inhibitor, CUR and DTX may become a new treatment strategy for esophageal cancer.

Chitosan-based nanoparticle co-delivery of docetaxel and curcumin ameliorates anti-tumor chemoimmunotherapy in lung cancer.

The application of traditional chemotherapy drugs for lung cancer has obvious limitations, such as toxic side effects, uncontrolled drug-release, poor bioavailability, and drug-resistance. Thus, to address the limitations of free drugs and improve treatment effects, we developed novel T7 peptide-modified nanoparticles (T7-CMCS-BAPE, CBT) based on carboxymethyl chitosan (CMCS), which is capable of targeted binding to the transferrin receptor (TfR) expressed on lung cancer cells and precisely regulating drug-release according to the pH value and reactive oxygen species (ROS) level. The results showed that the drug-loading content of docetaxel (DTX) and curcumin (CUR) was approximately 7.82% and 6.48%, respectively. Good biosafety was obtained even when the concentration was as high as 500 µg/mL. More importantly, the T7-CMCS-BAPE-DTX/CUR (CBT-DC) complexes exhibited better in vitro and in vivo anti-tumor effects than DTX monotherapy and other nanocarriers loaded with DTX and CUR alone. Furthermore, we determined that CBT-DC can ameliorate the immunosuppressive micro-environment to promote the inhibition of tumor growth. Collectively, the current findings help lay the foundation for combinatorial lung cancer treatment.

Circ-HMGA2 (hsa_circ_0027446) promotes the metastasis and epithelial-mesenchymal transition of lung adenocarcinoma cells through the miR-1236-3p/ZEB1 axis.

Lung adenocarcinoma (LUAD) has high incidence and mortality rates worldwide; however, its detailed molecular pathology remains unclear. Although circRNAs have gradually been identified as molecules that are differentially expressed in tumors and play key roles in tumor progression, their role in LUAD is poorly understood. Through microarray analysis, we obtained the circRNA expression profile of LUAD and found that circ-HMGA2 (hsa_circ_0027446), a novel RNA, is highly expressed in LUAD. The high expression of circ-HMGA2 was further verified in 36 paired LUAD and adjacent normal tissues. Functionally, circ-HMGA2 promoted LUAD cell metastasis in vitro and in vivo. The luciferase reporter assay and FISH results showed that circ-HMGA2 interacts with miR-1236-3p and that miR-1236-3p interacts with ZEB1. In addition, miR-1236-3p was expressed at low levels in LUAD, inhibited LUAD cell metastasis, and suppressed the function of circ-HMGA2. ZEB1 is an EMT-promoting transcription factor. The PCR and WB analysis results showed that circ-HMGA2 promotes both ZEB1 expression and EMT. MiR-1236-3p had the opposite effect, reversing the promotive effect of circ-HMGA2 on EMT. In summary, circ-HMGA2 promotes LUAD cell metastasis through the miR-1236-3p/EMT axis, indicating that it could be a therapeutic target in LUAD.

FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-ß and miR-182-5p.

The mesenchymal transcription factor forkhead box F2 (FOXF2) is a critical regulator of embryogenesis and tissue homeostasis. Our previous studies demonstrated that FOXF2 is ectopically expressed in basal-like breast cancer (BLBC) cells and that FOXF2 deficiency promotes the epithelial-mesenchymal transition and aggressiveness of BLBC cells. In this study, we found that FOXF2 controls transforming growth factor-beta (TGF-ß)/SMAD signaling pathway activation through transrepression of TGF-ß-coding genes in BLBC cells. FOXF2-deficient BLBC cells adopt a myofibroblast-/cancer-associated fibroblast (CAF)-like phenotype, and tend to metastasize to visceral organs by increasing autocrine TGF-ß signaling and conferring aggressiveness to neighboring cells by increasing paracrine TGF-ß signaling. In turn, TGF-ß silences FOXF2 expression through upregulating miR-182-5p, a posttranscriptional regulator of FOXF2 and inducer of metastasis. In addition to mediating a reciprocal repression loop between FOXF2 and TGF-ß through direct transrepression by SMAD3, miR-182-5p forms a reciprocal repression loop with FOXF2 that directly transrepresses MIR182 expression. Therefore, FOXF2 deficiency accelerates the visceral metastasis of BLBC through unrestricted increases in autocrine and paracrine TGF-ß signaling, and miR-182-5p expression. Our findings provide novel mechanisms underlying the roles of TGF-ß, miR-182-5p, and FOXF2 in accelerating BLBC dissemination and metastasis, and may facilitate the development of therapeutic strategies for aggressive BLBC.

The synthesis and anti-metastatic effects of optical isomers of ionone alkaloid 9-(N,N-dimethyl)-4,7-megastigmedien-3-one.

Ionone alkaloid 9-(N,N-dimethyl)-4,7-megastigmedien-3-one (compound 1) is a new anti-metastatic natural product. However, it was previously reported as optical isomers mixture. Herein, the optical isomers (6a-6d) of compound 1 were synthesized. The absolute configurations of 6a-6d were determined by ECD experiments and calculated spectra with time-dependent density functional theory (TDDFT). The anti-metastatic effects of the optical isomers were examined by transwell assay. These results revealed that compound 6a had potential anti-metastatic activity with an IC50 value of 0.512 ±â€¯0.093 µM.

Impact of low-temperature, overcast and rainy weather during the reproductive growth stage on lodging resistance of rice.

The objectives of this study were to explore the mechanism by which the lodging resistance of the rice population during the late growth period responds to low-temperature, overcast and rainy weather during the reproductive growth stage. Field experiments were conducted using indica rice Yliangyou2 (lodging-resistance variety), IIyou084 (lodging-susceptible variety) and japonica rice Wuyunjing23 (lodging-resistance variety) and W3668 (lodging- susceptible variety) in 2013 (high temperature and strong radiation during the rice reproductive growth stage), 2012 and 2014 (low temperature and weak radiation during rice reproductive growth stage). The results showed that the length of the basal internodes and the height of the gravitational centres were greater in plants grown in 2014. Dry weight of basal culms, culm diameter, lignin content and total content of structural carbohydrates (lignin and cellulose) in basal internodes were reduced in these plants, causing a significant reduction in the bending stress and lodging resistance of the rice stems. Low-temperature, overcast and rainy weather had a greater effect on lodging resistance in indica rice compared with japonica rice. This was reflected in a greater reduction in the lignin content of the indica rice stems, which yielded a significantly lower breaking strength and bending stress.