20( S )-Protopanaxatriol Improves Atherosclerosis by Inhibiting Low-Density Lipoprotein Receptor Degradation in ApoE KO Mice.

ABSTRACT: Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.

Infrared spectra and electronic structural changes of DNTF under high pressure: experimental and theoretical studies.

3,4-Bis(3-nitrofurazan-4-yl)furoxan (DNTF) is a novel energetic material with an excellent performance and has attracted considerable attention. Motivated by recent theories and experiments, we had carried out experimental and theoretical studies on the high-pressure responses of vibrational characteristics, in conjunction with structural and electronic characteristics. It is found that all observed infrared spectra peaks seem to shift towards higher frequencies. And the peaks attributed to N-Oc (coordinated oxygen atom) stretching vibrations become broader due to the decrease of lattice constants and the free region of DNTF crystals with the increase of pressure, where the a-direction is more sensitive to pressure. In addition, the non-covalent interaction between adjacent DNTF molecules in the same layer changes from the van der Waals interaction to the steric effect with the increase of pressure, and that between layers also changes from the van der Waals interaction to the π-π stacking interaction. More importantly, these results highlight that the increase of pressure may lead to the stability decrease and impact the sensitivity increase of DNTF. This study can deepen the understanding of the energetic material DNTF under high pressure and is of great significance for blasting and detonation applications of DNTF.

Discovery of flavonoid-containing compound Lupalbigenin as anti-NSCLC cancer agents via suppression of EGFR and ERK1/2 pathway.

Epidermal growth factor receptor exon 20 insertions (EGFR Ex20ins) driver mutations in non-small cell lung cancer (NSCLC) is insensitive to EGFR tyrosine kinase inhibitors (TKIs). Therefore, it is necessary to develop more novel strategy to address the limitations of existing therapies targeting EGFR-mutated NSCLC. Lupalbigenin (LB), a flavonoid compound extracted from Derris scandens, has shown preclinical activity in lung cancer. However, the activity of LB in Ex20ins-driven tumors has not yet been elucidated. In this study, a series of stable BaF/3 cell-line that contains a high proportion (>90 %) of EGFR-eGFP Ex20ins were generated using an IL3-deprivation method. Ba/F3 cell models harboring dissimilar Ex20ins were used to characterize the antineoplastic mechanism of LB. Molecular docking confirmed that the LB could effectively bind to key target EGFR. The in vitro anticancer activity of LB was investigated in engineered Ba/F3 cells bearing diverse uncommon EGFR mutations. LB was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines. Mechanistic studies disclosed that LB repressed EGFR phosphorylation and downstream survival pathways in Ba/F3 cells expressing EGFR Ex20ins, resulting in caspase activation by activating the intrinsic apoptotic pathway. Further analyses showed that LB significantly induced G0/G1 cell cycle arrest and apoptosis in cells. LB also reduced the protein expression levels of CDK4, CDK6, CDK8, cyclin D1, cyclin A2, and Bcl2 and promoted the expression of cytochrome C, p27, and p53. In summary, we explored the possible potential targets of LB through network pharmacology and verified the target using in vitro experiments. Furthermore, our results demonstrated that LB showed potential anti-Ex20ins cancer activity through suppression of the EGFR and ERK1/2 signaling pathway in Ba/F3 cells bearing two to three amino acid insertion mutations. These findings suggested that LB might be valuable for further investigation as a potential candidate in the treatment of associated diseases.

Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

HPLC and LC-MS/MS-Based Quantitative Characterization of Related Substances Associated with Sotalol Hydrochloride.

In total, three related substances (RS) associated with sotalol hydrochloride (STHCl) were herein identified with a novel gradient high-performance liquid chromatography (HPLC) protocol. Further characterization of these substances was then performed via liquid chromatography-mass spectroscopy (LC-MS/MS) and nuclear magnetic resonance (NMR) approaches. For these analyses, commercial STHCl samples were used for quantitative HPLC studies and the degradation of STHCl under acidic (1M HCl), alkaline (1M NaOH), oxidative (30% H2O2), photolytic (4500 Lx), and thermal stress conditions (100 °C) was assessed. This approach revealed this drug to be resistant to acidic, alkaline, and high-temperature conditions, whereas it was susceptible to light and oxidation as confirmed through long-term experiments. The putative mechanisms governing RS formation were also explored, revealing that RS3 was derived from the manufacturing process, whereas RS2 was generated via oxidation and RS1 was generated in response to light exposure. The cytotoxicity of these RS compounds was then assessed using MTT assays and acute toxicity test. Overall, this study provides details regarding the characterization, isolation, quantification, and toxicological evaluation of STHCl and associated RS compounds together with details regarding the precise, specific, and reliable novel HPLC technique, thus providing the requisite information necessary to ensure STHCl purity and safety.

Gallic Acid Can Promote Low-Density Lipoprotein Uptake in HepG2 Cells via Increasing Low-Density Lipoprotein Receptor Accumulation.

Gallic acid (GA) is a type of polyphenolic compound that can be found in a range of fruits, vegetables, and tea. Although it has been confirmed it improves non-alcoholic fatty liver disease (NAFLD), it is still unknown whether GA can improve the occurrence of NAFLD by increasing the low-density lipoprotein receptor (LDLR) accumulation and alleviating cholesterol metabolism disorders. Therefore, the present study explored the effect of GA on LDLR and its mechanism of action. The findings indicated that the increase in LDLR accumulation in HepG2 cells induced by GA was associated with the stimulation of the epidermal growth factor receptor-extracellular regulated protein kinase (EGFR-ERK1/2) signaling pathway. When the pathway was inhibited by EGFR mab cetuximab, it was observed that the activation of the EGFR-ERK1/2 signaling pathway induced by GA was also blocked. At the same time, the accumulation of LDLR protein and the uptake of LDL were also suppressed. Additionally, GA can also promote the accumulation of forkhead box O3 (FOXO3) and suppress the accumulation of hepatocyte nuclear factor-1α (HNF1α), leading to the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) mRNA expression and protein accumulation. This ultimately results in increased LDLR protein accumulation and enhanced uptake of LDL in cells. In summary, the present study revealed the potential mechanism of GA's role in ameliorating NAFLD, with a view of providing a theoretical basis for the dietary supplementation of GA.

ATP supplementation suppresses UVB-induced photoaging in HaCaT cells via upregulation of expression of SIRT3 and SOD2.

BACKGROUND: Skin photoaging is the damage caused by excessive exposure to ultraviolet (UV) irradiation. We investigated the effect of adenosine triphosphate (ATP) supplementation on UVB-induced photoaging in HaCaT cells and its potential molecular mechanism. MATERIALS AND METHODS: The toxicity of ATP on HaCaT cells was examined by the MTT assay. The effects of ATP supplementation on the viability and apoptosis of HaCaT cells were determined by crystal-violet staining and flow cytometry, respectively. Cellular and mitochondrial ROS were stained using fluorescent dyes. Expression of Bax, B-cell lymphoma (Bcl)-2, sirtuin (SIRT)3, and superoxide dismutase (SOD)2 was measured via western blotting. RESULTS: ATP (1, 2 mM) exerted no toxic effect on the normal growth of HaCaT cells. UVB irradiation caused the apoptosis of HaCaT cells, and ATP supplementation inhibited the apoptosis induced by UVB significantly, as verified by expression of Bax and Bcl-2. UVB exposure resulted in accumulation of cellular and mitochondrial reactive oxygen species (ROS), but ATP supplementation suppressed these increases. Expression of SIRT3 and SOD2 was decreased upon exposure to UVB irradiation but, under ATP supplementation, expression of SIRT3 and SOD2 was reversed, which was consistent with the reduction in ROS level observed in ATP-treated HaCaT cells after exposure to UVB irradiation. CONCLUSIONS: ATP supplementation can suppress UVB irradiation-induced photoaging in HaCaT cells via upregulation of expression of SIRT3 and SOD2.

An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC.

Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small-molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies is often ineffective in treating cancers harboring wild-type EGFR. Given the fact that EGFR possesses a kinase-independent pro-survival function, more effective inhibition of EGFR-mediated signals is therefore necessary. In this study, we investigated the effects of using a combination of low-dose nimotuzumab and theasinensin A to evaluate whether the inhibitory effect of nimotuzumab on NCI-H441 cancer cells was enhanced. Here, theasinensin A, a novel epigallocatechin-3-gallate (EGCG) derivative, was identified and its potent anticancer activity against wild-type EGFR NSCLC was demonstrated in vitro; the anticancer activity was induced through degradation of EGFR. Mechanistic studies further revealed that theasinensin A bound directly to the EGFR extracellular domain, which decreased interaction with its ligand EGF in combination with nimotuzumab. Theasinensin A significantly promoted EGFR degradation and repressed downstream survival pathways in combination with nimotuzumab. Meanwhile, treatment with theasinensin A and nimotuzumab prevented xenograft growth, whereas the single agents had limited effect. Thus, the combination therapy of theasinensin A with nimotuzumab is a powerful candidate for treatment of wild-type EGFR cancers.

Steroidal Alkaloids from the Roots of Veratrum mengtzeanum Loes. with Their Anti-Inflammatory Activities.

The phytochemical investigation of Veratrum mengtzeanum Loes. roots resulted in the isolation and characterization of two novel, namely Mengtzeanines A (1), Mengtzeanines B (2), and eight known steroidal alkaloids (3-10). Their structural properties were assessed though extensive spectroscopic techniques. All constituents 1-10 were analyzed for suppression of NO formation in LPS-induced RAW264.7 macrophages. Among them, constituent 6 (Verazine) showed inhibition against LPS-induced NO production (IC50 = 20.41 µM). Additionally, compound 6 could inhibit the secretion of IL1ß, IL6, and TNFα, and downregulate the productions of iNOS and COX2 in LPS-induced RAW264.7 macrophages. Further experiments revealed that 6 exhibited a potent anti-inflammatory level in LPS-stimulated RAW264.7 macrophages via inhibiting NF-κB, and triggering of Keap1/Nrf2/HO-1 axis, implying that compound 6 may be a promising candidate for treating inflammatory disorders.

Part-Aware Point Cloud Completion through Multi-Modal Part Segmentation.

Point cloud completion aims to generate high-resolution point clouds using incomplete point clouds as input and is the foundational task for many 3D visual applications. However, most existing methods suffer from issues related to rough localized structures. In this paper, we attribute these problems to the lack of attention to local details in the global optimization methods used for the task. Thus, we propose a new model, called PA-NET, to guide the network to pay more attention to local structures. Specifically, we first use textual embedding to assist in training a robust point assignment network, enabling the transformation of global optimization into the co-optimization of local and global aspects. Then, we design a novel plug-in module using the assignment network and introduce a new loss function to guide the network's attention towards local structures. Numerous experiments were conducted, and the quantitative results demonstrate that our method achieves novel performance on different datasets. Additionally, the visualization results show that our method efficiently resolves the issue of poor local structures in the generated point cloud.

Discovery of EGFR-Targeted Environment-Sensitive fluorescent probes for cell imaging and efficient tumor detection.

Overexpression of human epidermal growth factor receptor (EGFR) plays an important role in several signaling pathways inside and outside the cell, especially in the processes of cell proliferation, differentiation, and death in various cancers. Due to the complexity of the structure and function of EGFR, research on the fluorescence visualization of EGFR protein visualization has proved challenging. One possible strategy for designing a receptor-targeting fluorescent probe with a switching mechanism is to introduce an environment-sensitive fluorophore into the drug ligand. Based on this strategic molecular design, we introduced two environment-sensitive small molecular fluorophores, dansyl chloride (DNS) and nitrobenzoxadiazole (NBD), to replace the morpholine group of gefitinib, achieving a series of fluorescent molecular probes bearing a switching mechanism. The GN probes exhibited prominent environment sensitivity, suggesting good performance as turn-on EGFR-targeting fluorescent ligands. The representative probe GN3 specifically responded to tumor cells overexpressing EGFR, which was validated with live-cell fluorescence imaging and in vivo xenograft tumor imaging. Ligand-induced EGFR phosphorylation in A431 cells was considerably inhibited by probe GN3, demonstrating that this probe still functions as an EGFR inhibitor. Owing to the turn-on response of GN3 to EGFR in tumor cells, and the competitive replacement behavior to the EGFR inhibitor gefitinib, these probes have the potential to be used for fluorescence imaging of cells overexpressing EGFR.

Oxidized tea polyphenol (OTP-3) targets EGFR synergistic nimotuzumab at inhibition of non-small cell lung tumor growth.

Aberrant activation of epidermal growth factor receptor (EGFR) plays a pivotal role in cancer initiation and progression and has gained attention as an anticancer drug target. EGFR monoclonal antibodies have been canonically used in non-small cell lung cancer (NSCLC) treatment. However, a basal level of ligand-independent EGFR signaling pro-survival properties limit the clinical efficacy of EGFR monoclonal antibodies. Therefore, targeting EGFR by inducing degraders is a promising approach towards improving therapeutic efficacy and augmenting the effect of nimotuzumab. Here we describe rational discovery of OTP-3, an oxidized (-)-Epigallocatechin gallate (EGCG) derivative that elicits potent anticancer activity in EGFR wild type NSCLC. Mechanistic studies disclosed that OTP-3 directly binds to EGFR extracellular domain decreases EGF and EGFR binding affinities by combination with nimotuzumab. Molecular docking studies revealed that OTP-3-EGFR is a very stable complex. Further analyses showed that nimotuzumab combined with OTP-3 resulted in significantly promoted EGFR degradation and repressed downstream survival pathways. Accordingly, OTP-3 combined with nimotuzumab significantly inhibits tumor growth through degrading EGFR in vivo. Thus, OTP-3 can also serve as an effective therapeutic agent in NSCLC where it can augment the effects of nimotuzumab, a valuable property for combination agents.

Nitrification Progress of Nitrogen-Rich Heterocyclic Energetic Compounds: A Review.

As a momentous energetic group, a nitro group widely exists in high-energy-density materials (HEDMs), such as trinitrotoluene (TNT), 1,3,5-triamino-2,4,6-trinitrobenzene (TATB), cyclo-1,3,5-trimethylene-2,4,6-trinitramine (RDX), etc. The nitro group has a significant effect on improving the oxygen balance and detonation performances of energetic materials (EMs). Moreover, the nitro group is a strong electron-withdrawing group, and it can increase the acidity of the acidic hydrogen-containing nitrogen-rich energetic compounds to facilitate the construction of energetic ionic salts. Thus, it is possible to design nitro-nitrogen-rich energetic compounds with adjustable properties. In this paper, the nitration methods of azoles, including imidazole, pyrazole, triazole, tetrazole, and oxadiazole, as well as azines, including pyrazine, pyridazine, triazine, and tetrazine, have been concluded. Furthermore, the prospect of the future development of nitrogen-rich heterocyclic energetic compounds has been stated, so as to provide references for researchers who are engaged in the synthesis of EMs.

Biological Effects of EGCG@MOF Zn(BTC)4 System Improves Wound Healing in Diabetes.

Tea contains high levels of the compound epigallocatechin gallate (EGCG). It is considered an important functional component in tea and has anti-cancer, antioxidant, and anti-inflammatory effects. The eight phenolic hydroxyl groups in EGCG's chemical structure are the basis for EGCG's multiple biological effects. At the same time, it also leads to poor chemical stability, rendering EGCG prone to oxidation and isomerization reactions that change its original structure and biological activity. Learning how to maintain the activity of EGCG has become an important goal in understanding the biological activity of EGCG and the research and development of tea-related products. Metal-organic frameworks (MOFs) are porous materials with a three-dimensional network structure that are composed of inorganic metals or metal clusters together with organic complexes. MOFs exploit the porous nature of the material itself. When a drug is an appropriate size, it can be wrapped into the pores by physical or chemical methods; this allows the drug to be released slowly, and MOFs can also reduce drug toxicity. In this study, we used MOF Zn(BTC)4 materials to load EGCG and investigated the sustained release effect of EGCG@MOF Zn(BTC)4 and the biological effects on wound healing in a diabetic mouse model.

Paenibacillus puerhi sp. nov., isolated from the rhizosphere soil of Pu-erh tea plants (Camellia sinensis var. assamica).

An aerobic, Gram-staining-positive, rod-shaped, endospore-forming and motile bacterial strain, designated SJY2T, was isolated from the rhizosphere soil of tea plants (Camellia sinensis var. assamica) collected in the organic tea garden of the Jingmai Pu-erh tea district in Pu'er city, Yunnan, southwest China. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate belonged to the genus Paenibacillus. The closest phylogenetic relative was Paenibacillus filicis DSM 23916T (98.1% similarity). The major fatty acids (> 10% of the total fatty acids) were anteiso-C15:0 and isoC16:0. The major respiratory quinone was MK-7 and the major polar lipid was diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylmonomethylethanolamine. The peptidoglycan contained glutamic acid, serine, alanine and meso-diaminopimelic acid. Genome sequencing revealed a genome size of 6.71 Mbp and a G + C content of 53.1%. Pairwise determined whole genome average nucleotide identity (gANI) values and digital DNA-DNA hybridization (dDDH) values suggested that strain SJY2T represents a new species, for which we propose the name Paenibacillus puerhi sp. nov. with the type strain SJY2T (= CGMCC 1.17156T = KCTC 43242T).

Puerhibacterium puerhi gen. nov., sp. nov., a novel member of the family Promicromonosporaceae, isolated from Pu-erh tea pile-fermentation.

A Gram-staining positive aerobic bacterium, designated TLY-12T, was isolated from the Pu-erh tea pile-fermentation process in Pu'er city, Yunnan, China. Strain TLY-12T grew at 15-37 °C (optimum, 30 °C), pH 6.0-11.0 (optimum, pH 9.0) and 0-9.0% (w/v) NaCl (optimum, 3.0%). The major cellular fatty acids were anteiso-C15:0, C16:0 and iso-C16:0. The respiratory quinone were menaquinones MK-9 (H2) and MK-9 (H4). The polar lipids were phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylinositol (PI), phosphoglycolipid (PGL), glycolipid (GL) and an unidentified phospholipid (PL). The peptidoglycan contained glutamic acid, aspartic acid, alanine and lysine, with the last named being the diagnostic diamino acid. Whole-cell sugars of the isolate were ribose, galactose and glucose. Phylogenetic analyses of 16S rRNA gene showed that this strain belonged to the family Promicromonosporaceae, and was most closely related to Isoptericola cucumis DSM 101603 T, which gave sequence similarity of 97.9%. Genome sequencing revealed a genome size of 3.91 Mbp and a G + C content of 75.0%. Average nucleotide identity and digital DNA-DNA hybridization values were all below the species threshold of described Promicromonosporaceae species. Genome phylogenetic analysis showed that strain TLY-12T formed a separate evolutionary branch, and was parallel to other related genera of Promicromonosporaceae. Based on the phylogenetic, phenotypic, chemotaxonomic and genome pairwise data, strain TLY-12T is considered to represent a novel species in a new genus in the family Promicromonosporaceae, for which the name Puerhibacterium puerhi gen. nov, sp. nov. is proposed. The type strain is TLY-12T (= CGMCC 1.17157T = KCTC 49467T).

Proliferation of MDA-MB-231 can be suppressed by dimeric-epigallocatechin gallate through competitive inhibition of amphiregulin-epidermal growth factor receptor signaling.

Triple-negative breast cancer (TNBC) is highly aggressive, with high rates of early relapse and very poor overall prognosis. Amphiregulin (AREG) is the most abundant epidermal growth factor receptor (EGFR) agonist in MDA-MB-231 TNBC cells, whose proliferation can be inhibited by (-)-epigallocatechin gallate (EGCG), a constituent of green tea that is prone to oxidative polymerization. The effect of dimeric-EGCG, a dimer of oxidized and polymerized EGCG, on MDA-MB-231 cell the proliferation warrants further exploration. In the present study, MTT, flow cytometry, migration scratch, transwell, western blotting, and surface plasmon resonance assays were used to evaluate the effect of dimeric-EGCG on MDA-MB-231 cells and explore the underlying mechanism. MDA-MB-231 cell proliferation and migration were significantly inhibited by dimeric-EGCG at concentrations as low as 10 µM. Levels of EGFR and p44/42 MAPK phosphorylation in MDA-MB-231 cells were significantly reduced by treatment with 10 µM dimeric-EGCG (P < 0.01). In addition, the levels of phosphorylation induced by exogenous AREG were also inhibited by dimeric-EGCG (P < 0.01); however, no significant effects of dimeric-EGCG were observed on epidermal growth factor or transforming growth factor-alpha signaling. Surface plasmon resonance analysis demonstrated that 10 µM dimeric-EGCG bound directly to the extracellular domain of EGFR, competitively inhibiting the binding of AREG to EGFR. These results suggest a novel mechanism underlying the inhibitory effect of dimeric-EGCG on MDA-MB-231 cells, with potential application in the development of drugs for the treatment of TNBC.

Massilia puerhi sp. nov., isolated from soil of Pu-erh tea cellar.

A Gram-reaction-negative, yellow-pigmented, non-spore-forming rod, aerobic, motile bacterium, designated SJY3T, was isolated from soil samples collected from a Pu-erh tea cellar in Bolian Pu-erh tea estate Co. Ltd. in Pu'er city, Yunnan, south-west China. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate belonged to the genus Massilia. The closest phylogenetic relative was Massilia arenae CICC 24458T (99.5 %), followed by M. timonae CCUG45783T (97.9 %), M. oculi CCUG43427AT (97.8 %), and M. aurea DSM 18055T (97.8 %). The major fatty acids were C16 : 0 and C16 : 1 ω7c and/or C16 : 1 ω6c. The major respiratory quinone was ubiquinone Q-8 and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. Genome sequencing revealed a genome size of 5.97 M bp and a G+C content of 65.4 mol%. Pairwise determined whole genome average nucleotide identity (gANI) values and digital DNA-DNA hybridization (dDDH) values were all below the threshold. Although the 16S rRNA gene similarity of stain SJY3T and Massilia arenae CICC 24458T was more than 99 %, the gANI, dDDH values and genomic tree clearly indicated that they were not of the same species. In summary, strain SJY3T represents a new species, for which we propose the name Massilia puerhi sp. nov. with the type strain SJY3T (=CGMCC 1.17158T=KCTC 82193T).

Demethyleneberberine promotes apoptosis and suppresses TGF-ß/Smads induced EMT in the colon cancer cells HCT-116.

Colorectal cancer (CRC) is one of the most common malignant tumours in the world. Recent reports have revealed natural products displayed inhibition on colon cancer potential by suppressing transforming growth factor-ß/Smads induced epidermal-mesenchymal transition (EMT). In this article, 12 kinds of natural berberine analogues were screened for their effects on the inhibition of the colon cancer cells, the results showed that demethyleneberberine (DM-BBR) exhibited an interesting and potential effect on inducing the apoptosis of HCT-116 cells with drug concentrations of 6, 12 and 18 µM. Particularly, DM-BBR reversed the EMT process by inhibiting the expression of p-Smad2 and p-Smad3 in the transforming growth factor-ß/Smads signal pathway, up-regulated pro-apoptotic protein cleaved caspase-9, and blocked cell cycle at the S phase and increasing the expression of cyclin proteins P27 and P21. Taken together, these findings suggested that DM-BBR could promote apoptosis and suppress TGF-ß/Smads induced EMT in the colon cancer cells HCT-116.

Inhibition of the notch signaling pathway overcomes resistance of cervical cancer cells to paclitaxel through retardation of the epithelial-mesenchymal transition process.

Use of paclitaxel as monotherapy or in combination with other therapeutic agents is a widely employed front-line chemotherapeutic strategy for cervical cancer. However, previous reports have shown that approximately 70% of the patients with cervical cancer develop resistance to paclitaxel. Epithelial-mesenchymal transition (EMT) contributes to the occurrence of chemoresistance in several types of cancer, including cervical cancer. Identification of the critical signaling pathway that regulates the EMT process may provide a novel strategy for avoiding or delaying the emergence of paclitaxel resistance during the treatment of cervical cancer. Herein, we established a paclitaxel-resistant cervical cancer cell line (HeLa-229PTR cells) by culturing parental HeLa-229 cells with increasing concentrations of paclitaxel. We observed elevated expression of Notch1 in HeLa-229PTR cells compared with their parental HeLa-229 cells, indicating its potential involvement in the EMT phenotype of the paclitaxel-resistant cells. Furthermore, silencing of the NOTCH1 gene, as well as treatment with a γ-secretase inhibitor (DAPT) partially reversed the EMT phenotype and significantly enhanced the sensitivity of HeLa-229PTR cells to paclitaxel. Moreover, we found that DAPT could significantly inhibit invasiveness, reduce colony formation activity, and promote apoptosis of HeLa-229PTR cells. Taken together, these results indicated that HeLa-229PTR cells develop the EMT phenotype partly through activation of Notch1 signaling. Thus, inhibition of Notch1 signaling can be a strategy for the reversal of the EMT phenotype and may increase the sensitivity of cervical cancer cells to treatment with paclitaxel.