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Triple-negative breast cancer (TNBC) is a malignant tumor without specific therapeutic targets and a poor prognosis. Chemotherapy is currently the first-line therapeutic option for TNBC. However, due to the heterogeneity of TNBC, not all of TNBC patients are responsive to chemotherapeutic agents. Therefore, the demand for new targeted agents is critical. β -tubulin isotype III (Tubb3) is a prognostic factor associated with cancer progression, including breast cancer, and targeting Tubb3 may lead to improve TNBC disease control. Shikonin, the active compound in the roots of Lithospermun erythrorhizon suppresses the growth of various types of tumors, and its efficacy can be improved by altering its chemical structure. In this work, the anti-TNBC effect of a shikonin derivative (PMMB276) was investigated, and its mechanism was also investigated. This study combines flow cytometry, immunofluorescence staining, immunoblotting, immunoprecipitation, siRNA silencing, and the iTRAQ proteomics assay to analyze the inhibition potential of PMMB276 on TNBC. In vivo study was performed, Balb/c female murine models with or without the small molecule treatments. Herein, we screened 300 in-house synthesized analogs of shikonin against TNBC and identified a novel small molecule, PMMB276; it suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase, suggesting that it could have a tumor suppressive role in TNBC. Tubb3 was identified as the target of PMMB276 using proteomic and biological activity analyses. Meanwhile, PMMB276 regulated microtubule dynamics in vitro by inducing microtubule depolymerization and it could act as a tubulin stabilizer by a different process than that of paclitaxel. Moreover, suppressing or inhibiting Tubb3 with PMMB276 reduced the growth of breast cancer in an experimental mouse model, indicating that Tubb3 plays a significant role in TNBC progression. The findings support the therapeutic potential of PMMB276, a Tubb3 inhibitor, as a treatment for TNBC. Our findings might serve as a foundation for the utilization of shikonin and its derivatives in the development of anti-TNBC. A small novel molecule, i.e., α-lipoic acyl shikonin, modified form of a natural product (shikonin), acts as a novel inhibitor of Tubb3. [Display omitted] [ABSTRACT FROM AUTHOR]

The influence of positive microscopic margin (R1) resection on the prognosis of gastrointestinal stromal tumors (GISTs) is controversial. Tumor rupture is significantly associated with the occurrence of R1 resection and may be a confounder of R1 resection in GISTs. The present meta-analysis evaluated the real influence of R1 resection on the prognosis of GISTs by excluding the confounding effect of tumor rupture. The PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases were searched. Studies that compared R1 with negative microscopic margin (R0) resection in GIST patients and reported the time-to-event data of recurrence-free survival (RFS) or disease-free survival (DFS) were eligible for inclusion. The quality of the observational studies was assessed using the Newcastle–Ottawa scale. Of the 4896 records screened, 23 retrospective studies with 6248 participants were selected. In the overall analysis, R1 resection resulted in a significantly shorter RFS/DFS than R0 resection for GISTs (HR = 1.80, 95% CI = 1.54–2.10, P < 0.001, I2 = 14%). However, the inferior RFS/DFS vanished when tumor rupture cases were excluded (HR = 1.34, 95% CI = 0.98–1.83, P = 0.07, I2 = 33%). Sensitivity analysis by high-quality studies brought about a more robust HR of 1.15 (95% CI = 0.88–1.50, P = 0.29), with low heterogeneity (I2 = 0%). The qualities of evidence for the outcomes were high. This meta-analysis shows that R1 resection did not influence the survival outcome of GISTs. Reresection may not be necessary when positive microscopic margins exist. This analysis could provide high-quality evidence for the development of guidelines. [ABSTRACT FROM AUTHOR]

The purpose of the study was to evaluate the association between microfibrillar collagen hemostat and anastomotic leakage after anterior resection. Between March 2015 and December 2019, a total of 203 consecutive rectal cancer patients who underwent elective anterior resection were included. Patient parameters were analyzed. The relevant risk factors were identified by univariate and multivariate analysis. Propensity score matching was performed to reduce the selection bias. In total, 26 (12.8%) of the 203 study patients developed clinical anastomotic leakage. The length of hospital stay was significantly prolonged by anastomotic leakage. In univariate analysis and multivariate analysis, male sex, low tumor location, and intraoperative application of microfibrillar collagen hemostat significantly increased the risk of anastomotic leakage. Furthermore, analysis after propensity score matching confirmed the independent role of microfibrillar collagen hemostat in anastomotic leakage. In addition, the median time of anastomotic leakage occurrence from the initial operation in patients with microfibrillar collagen hemostat was 9.00 days, which was significantly later than that in patients without microfibrillar collagen hemostat. In addition to male sex and low tumor location, intraoperative application of microfibrillar collagen hemostat was demonstrated to be a significant risk factor for anastomotic leakage. This finding suggested that surgeons should be fully aware of this potential risk in anterior resection. Because of the limitation of retrospective study, however, randomized controlled trials are needed to confirm this association in the future. [ABSTRACT FROM AUTHOR]

Exosomes are small membrane vesicles secreted by most cell types, and widely exist in cell supernatants and various body fluids. They can transmit numerous bioactive elements, such as proteins, nucleic acids, and lipids, to affect the gene expression and function of recipient cells. Mesenchymal stem cells (MSCs) have been confirmed to be a potentially promising therapy for tissue repair and regeneration. Accumulating studies demonstrated that the predominant regenerative paradigm of MSCs transplantation was the paracrine effect but not the differentiation effect. Exosomes secreted by MSCs also showed similar therapeutic effects as their parent cells and were considered to be used for cell-free regenerative medicine. However, the inefficient and limited production has hampered their development for clinical translation. In this review, we summarize potential methods to efficiently promote the yield of exosomes. We mainly focus on engineering the process of exosome biogenesis and secretion, altering the cell culture conditions, cell expansion through 3D dynamic culture and the isolation of exosomes. In addition, we also discuss the application of MSCs-derived exosomes as therapeutics in disease treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Floating catalyst chemical vapor deposition (FCCVD) has been widely used for the growth of various carbon nanotube (CNT) macrostructures, mainly including vertically aligned CNT (VACNT) arrays and none-woven CNT films. However, it is still unclear for the reason why these CNT macrostructures with largely different morphologies were received via the similar method. In this research, it revealed that the growth temperature largely affected the nucleation status of floating catalysts and thus controlled the morphologies of CNT macrostructures from VACNT arrays to none-woven CNT films. In low temperatures (below 800 °C), VACNTs were grown by bottom-up mechanism with several CNTs, but not one individual from bottom to up along the array height direction. Furthermore, VACNT arrays were only grown on some substrates that can induce iron atoms aggregating to catalyst particles with a suitable size. When increasing the growth temperature higher than 800 °C, more catalyst particles were nucleated in the gas flow, which induced the formation of none-woven CNT films composed of thin CNTs (single-walled CNTs and double-walled CNTs). This research was significative for understanding CNT growth mechanism via FCCVD process and the synthesis of different CNT macrostructures by this strategy. [ABSTRACT FROM AUTHOR]

Carbon nanotube (CNT) films have shown many promising advantages in the development of high-performance flexible supercapacitors in terms of electrode specific area, mechanical reliability under bending and stretching, electron and ionic mobility tailored for high-rate performance etc. In this review, the recent progress in the design, preparation and functionalization of CNT film based electrodes for the fabrication of high-performance flexible supercapacitors are introduced in details, including the synthesis of conductive CNT films for the electrodes of supercapacitors, and the functionalizations of CNT film with other high-capacitance materials by both mixing and in situ growth strategies for high-performance composite electrodes. Furthermore, we also discussed the assembly strategies, prototypes and electrochemical performance of flexible supercapacitors based on CNT film composite electrodes. At last, the challenges and trends of the CNT film based flexible supercapacitors are prospected as well. [ABSTRACT FROM AUTHOR]

RAD51 recombinase plays a critical role for cancer cell proliferation and survival. Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, e.g. triple negative breast cancers which are often resistant to existing therapeutics. To this end, we have designed, synthesized and evaluated a panel of new RAD51 inhibitors, denoted IBR compounds. Among these compounds, we have identified a novel small molecule RAD51 inhibitor, IBR120 , which exhibited a 4.8-fold improved growth inhibition activity in triple negative human breast cancer cell line MBA-MD-468. IBR120 also inhibited the proliferation of a broad spectrum of other cancer cell types. Approximately 10-fold difference between the IC 50 values in normal and cancer cells were observed. Moreover, IBR120 was capable of disrupting RAD51 multimerization, impairing homologous recombination repair, and inducing apoptotic cell death. Therefore, these novel RAD51 inhibitors may serve as potential candidates for the development of pharmaceutical strategies against difficult-to-treat cancers. [ABSTRACT FROM AUTHOR]

Highlights: [•] Au–Cu and Pt–Cu nanotubes are synthesized in aqueous solution. [•] Cu nanowire is used as sacrificial template. [•] The structure of the alloy nanotubes could be tuned. [•] It is a general method for noble metal alloy nanotube synthesis. [Copyright &y& Elsevier]

Abstract: Carbon nanotube (CNT)/α-Ni(OH)2 composite paper based on CNT paper was prepared by a facile chemical bath deposition (CBD) method. α-Ni(OH)2 nanosheets were vertically grown on individual CNTs in CNT paper to form hierarchical nanowires. The loading mass of α-Ni(OH)2 in the composite paper could be 66wt%. Thus the composite paper showed much higher specific surface area than that of pristine CNT paper. This novel structure brings the composite paper an electrochemical capacitance high to 1144F/g at the current density of 0.5A/g, and maintains 585F/g at 10A/g. This composite paper could be a promising candidate for the electrodes of high-performance supercapacitors. [Copyright &y& Elsevier]

Abstract: Astragalus membranaceus (Fisch.) Bge.var.mongholicus(Bge.)Hsiao(AMB) is a common Chinese herbal medicine which is widely distributed in China. To evaluate the quality of AMB from different habitats, samples from 7 different areas in China were determined by UPLC/MS. The chemical data were dealed with several chemometric methods such as hierarchical clustering, PCA, SPCA and PLSDA using R software. The results show that these chemometric methods can fully reflect the chemical composition of different areas of AMB, especially PLS has efficient discrimination ability of classification, which makes it possible to control the quality. [Copyright &y& Elsevier]

[Display omitted] • Different classes and assembled mechanisms of amphipathic peptides are described. • Several strategies to design and stabilize amphiphilic peptides are summarized. • Several strategies to realize functional transformation are elaborated. • Several delivery systems of amphiphilic peptides are outlined. Amphiphilic self-assembling peptides are widely used in tissue and cell engineering, antimicrobials, drug-delivery systems and other biomedical fields due to their good biocompatibility, functionality, flexibility of design and synthesis, and tremendous potential as delivery carriers for drugs. Currently, the design and study of amphipathic peptides by a bottom-up method to develop new biomedical materials have become a hot topic. However, defined rules have not been established for the design and development of self-assembled peptides. Therefore, the focus of this review is to summarize and provide several rational strategies for the design and study of amphiphilic self-assembly peptides. In addition, this paper also describes the types and general self-assembling mechanism of amphipathic peptides, and outlines their applications in the delivery of hydrophobic drugs, nucleic acid drugs, peptide drugs and vaccines. Amphiphilic self-assembled peptides are expected to exploit new functional materials for drug delivery and other applications. [ABSTRACT FROM AUTHOR]

This study aimed to design and screen a dual functional fusion peptide that could penetrate the blood-brain barrier and target neuropilin 1 (NRP1) overexpressed in vascular endothelial cells for the anti-angiogenesis of glioma treatment. At the cellular level, the in vitro anti-angiogenic activity of six NRP1 targeting peptides was screened by testing the ability to inhibit the proliferation and tube formation of HUVECs. Then, the in vitro anti-angiogenic activity of two fusion peptides containing different linkers was screened by testing the ability to inhibit HUVECs proliferation, tube formation and migration. The effect of fusion peptide on VEGFR2 related signal pathway was confirmed by Western-blotting. Surface plasmon resonance technology was used to detect the affinity of the fusion peptide to NRP1. The ability of FITC-labeled peptides to penetrate cells was confirmed by cell uptake assay. By establishing an orthotopic glioma model, we evaluated the ability of FITC-labeled peptides to penetrate the blood-brain barrier and their anti-glioma growth activity in vivo. We found that NRP1 targeting peptide RP7 and linker cysteine were the most suitable key components in the fusion peptide. We also found that the fusion peptide Tat-C-RP7 we constructed had the strongest ability to penetrate the blood-brain barrier and anti-angiogenic activity in vitro and in vivo. At present, NRP1 targeting peptide as a drug delivery tool and molecular probe seems to have received more attention. We constructed a fusion peptide Tat-C-RP7 with strong anti-angiogenic activity for the treatment of glioma. • We designed a fusion peptide with good ability to penetrate the BBB and anti-angiogenesis for the treatment of gliomas. • RP7 and cysteine were the most suitable components of the fusion peptide with stronger anti-angiogenic activity. • Tat-C-RP7 has a strong affinity for NRP1 and could down-regulate the phosphorylation of VEGFR2 pathways. • The fusion peptide Tat-C-RP7 had good brain targeting properties and anti-glioma activity in vivo. [ABSTRACT FROM AUTHOR]

• TLR4 was activated on the membrane of mononuclear macrophage after PHP treatment. • After PHP treatment, the intestinal mucosa was more complete. • The contents of ScFA increased after PHP treatment. • The type and abundance of intestinal flora in colitis mice were changed after PHP treatment. Radix Pseudostellariae , the root of Pseudostellaria heterophylla (Miq.) Pax , has historically been used as medicine food homology plant for thousand years in China. Herein, PHP, a water soluble polysaccharides from Radix Pseudostellariae , was isolated and identified by HPGPC, GC–MS, FT-IR, and scanning electron microscopy. Results showed that PHP (Mw = 1.07 × 104 kDa) mainly consisted of rhamnose, galacturonic acid, glucose, galactose, arabinose, fucose in a molar ratio of 0.055:0.208:0.306:0.055:0.753:0.594:0.014. It contained nine types of linkages, including → 6)-Gal p (A)-(1→, →6)-Gal p -(1→, →3)-Ara p -(1→, Gal p -(1→, →3)-Rha p -(1→, Glu p -(1→, →3)-Ara f -(1→, →2,3,4)-Man p -(1 → and → 3,4)-Fuc p -(1→. Morphology analysis showed that PHP took flakes with irregular size and properties. It significantly activated TLR4 in vivo. In DSS induced mouse-acute-colitis molds, PHP90-3a improved and the colon length was on ulcerative in mice. the production of IL-1β and TNF-α were decreased. The intestinal mucosa was more complete, there were much more goblet cells, and the infiltration of lymphocytes and neutrophils was significantly decreased. The content of SCFA increased, whereas acetic acid, propionic acid and butyric acid increased. 16S RNA sequencing and OTUs cluster analysis revealed that Bacteroides and Pseudomonas were the dominant intestinal flora. The analysis of community thermogram showed that the abundance ratio of Pseudomonas and Bacteroides (F/B) was significantly lower than the dominant group and significantly inhibited the levels of Verrucomicrobia and Akkermansia. Altogether, the data suggested that the anti-inflammatory activity might be implicated with the activation of TLR4 signal pathways, reducing IL-1β and TNF-α, and the regulation of mucosal immunity and the composition of intestinal flora. [ABSTRACT FROM AUTHOR]

Abstract: We have developed an air-stable soluble polyethylene glycol bound ruthenium catalyst which performs efficient ring-closing metathesis in organic solvents as well as in aqueous media. [ABSTRACT FROM AUTHOR]

Summary The transcription factor IRF3 is phosphorylated in response to viral infection, and it subsequently forms a homodimer and translocates into the nucleus to induce the transcription of genes important for antiviral immunity, such as type I interferons (IFNs). This multistep process is essential for host defense against viral infection, but its regulation remains elusive. Here, we report that the EF-hand protein calmodulin-like 6 (CALML6) directly bound to the phosphorylated serine-rich (SR) region of IRF3 and impaired its dimerization and nuclear translocation. Enforced CALML6 expression suppressed viral infection-induced production of IFN-β and expression of IFN-stimulated genes (ISGs), whereas CALML6 deficiency had the opposite effect. In addition, impaired IFN-β and ISG expression in bone-marrow-derived macrophages and tissues of CALML6 transgenic mice promoted viral replication. These findings identify a phosphorylation-dependent negative feedback loop that maintains the homeostasis of antiviral innate immunity. Graphical Abstract Highlights • CALML6 attenuates type I interferon signaling in vitro and in vivo • CALML6 binds to phosphorylated IRF3 and sequesters it in the cytosol • CALML6 facilitates the replication of both DNA and RNA viruses Wang et al. report that the EF-hand protein CALML6 binds to the phosphorylated serine-rich region of IRF3 to impair IRF3 dimerization and nuclear translocation, thereby attenuating the transcription of type I interferons. This work identifies a negative feedback regulatory loop that maintains homeostasis during antiviral innate immunity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The main problem addressed in this study is the anti-inflammatory effects of Magnolol-a natural extract and the main bioactive component from Magnolia. • U937 LO-2 cells culture and DSS-treated experimental mice were utilized to analyze inflammatory cytokines, proteins activation in MAPK, NF-κB signal pathways regulation, the phagocytosis immunoregulatory effects in vitro and in vivo with that permits analysis of Magnolol contributors to the inflammatory bowel diseases. • By studying living human cell lines, we identified Magnolol previously unknown contributions of enhancement of phagocytosis, specific pro-inflammatory factors IL-6 and IL-1β significantly depression, p-JNK, p-P38, p-IκBα and p-P65 were down-regulation. • We provide experimental evidence to show that Magnolol as a drug could be used to improve human inflammatory bowel disease and gain new insights into the mechanisms involved phagocytosis immunoregulatory effects, MAPK and NF-κB signal pathways. Abstract Magnolol is a natural extract and the main bioactive component from Chinese medicine-Magnolia. We speculate that it's functional action might be associated with the anti-inflammatory effects of magnolol. Herein, the main purpose was to elucidate the phagocytic immune function and anti-inflammatory activities associated. The toxicity of magnolol on U937 and LO-2 cells was assayed by MTT, flow cytometry and laser scanning confocal microscope was utilized to detect the phagocytosis effect on U937 cells, C57BL/6 mice and the follow-up hematoxylin-eosin staining methods were used to evaluate its bioactivity in vivo. The results showed that magnolol had dose dependent effects on enhancement of phagocytosis ability and significantly inhibited the NO production at the concentration range from10 to 40 μM. Furthermore, Magnolol significantly reduced the gene expression and protein release of IL-1β and TNF-α. However, the p-ERK1/2 in MAPK signaling pathway was not significantly affected by magnolol, whereas p-JNK and p-P38 were down-regulated. Magnolol also inhibited the expression of p-IκBα and p-P65 of NF-κB signaling pathways. The loss of body weight and the shorter length of colon were significantly improved in DSS-treated colitis C57BL/6 mice after the administration of magnolol. The cytokines of pro-inflammatory factors TNF-α, IL-6 and IL-1β attenuated significantly in a concentration dependent manner. The histopathological manifestations of 5–20 mg/kg after the treatment magnolol were markedly improved in the DSS-treated mice. These findings showed that magnolol exerted an anti-inflammatory effect through immunoregulatory phagocytosis, MAPK and NF-κB signaling pathways. Our results provide experimental evidence and theory basis for research on anti-inflammatory effects for magnolol as a potentially anti-inflammatory drug candidate. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the association between the number of nodes harvested and the rate of node positivity, and to evaluate the effect of carbon nanoparticles (CNPs) in improving lymph node detection and staging accuracy in patients who received neoadjuvant chemoradiotherapy (NCRT) followed by curative resection.Study Design: Between September 2008 and June 2014, 152 consecutive rectal cancer patients treated with NCRT and curative resection were included. Forty-five patients underwent preoperative submucosal injection of CNPs (CNP group); the other patients underwent surgery only (control group). The relationship between the number of lymph nodes harvested and the rate of node positivity was investigated. A comparison of the number of harvested lymph nodes and the node positivity rate between the 2 groups was also performed. The lymph nodes in the CNP group were analyzed in detail.Results: The rate of node positivity increased gradually from 8.6% in patients with 1 to 5 nodes assessed to 37.8% in patients with 17 to 44 nodes assessed. The number of lymph nodes harvested was an independent risk factor for node positivity (p = 0.036). The mean number of lymph nodes retrieved in the CNP group was more than in the control group (21.1 vs 8.0, p = 0.000). The percentage of patients with positive lymph nodes was lower than in the control group (19.6% vs 35.6%, p = 0.037). In the CNP group, of 58 metastatic lymph nodes, 45 (77.6%) were dyed. Of 37 metastatic lymph nodes smaller than 5 mm, 33 (89.2%) were dyed.Conclusions: More precise oncologic prognosis assessment was provided for patients with rectal cancer after NCRT by increasing the number of lymph nodes counted using a dye-tracing method, indicating that the use of CNPs is beneficial. [ABSTRACT FROM AUTHOR]

Abstract: Buckypapers, the thin sheets made from an aggregate of carbon nanotubes (CNTs), have demonstrated promising electrical and thermal conductivities. However, the high in-plane to perpendicular anisotropy makes its application as thermal interface materials difficult. In order to increase the perpendicular electrical and thermal conductivities, copper nanowires (Cu NWs) were introduced into buckypapers. The Cu NWs stuck into the empty spaces between CNTs, connected them perpendicularly, and even induced a certain perpendicular CNT alignment. The electrical conductivity increased continuously with increasing the Cu content, while the smallest anisotropy was observed at the 50wt.% Cu filling because an in-plane Cu network formed and improved much more the in-plane conductivity above this filling. On the contrary, as CNTs are more thermally conducting than Cu, the loading of Cu NWs over 50wt.% decreased the thermal conductivity. Our measurement showed a high perpendicular conductivity of 10.1W/mK at the 50wt.% loading, more than quadruple and double as compared with the ones for a pure buckypaper and the one filled with 67–75wt.% Cu NWs. [Copyright &y& Elsevier]

Direct electrochemistry and thermal stability of hemoglobin (Hb) immobilized on a nanometer-sized zirconium dioxide (ZrO2) modified pyrolytic graphite (PG) electrode were studied. The immobilized Hb displayed a couple of stable and well-defined redox peaks with an electron transfer rate constant of (7.90±0.93) s−1 and a formal potential of −0.361 V (−0.12 V versus NHE) in 0.1 M pH 7.0 PBS. Both nanometer-sized ZrO2 and dimethyl sulfoxide (DMSO) could accelerate the electron transfer between Hb and the electrode. Spectroscopy analysis of the Hb/ZrO2/DMSO film showed that the immobilized Hb could retain its natural structure. This modified electrode showed a high thermal stability up to 74 °C and an electrocatalytic activity to the reduction of hydrogen peroxide (H2O2) without the aid of an electron mediator. The electrocatalytic response showed a linear dependence on the H2O2 concentration ranging from 1.5 to 30.2 μM with a detection limit of 0.14 μM at 3σ. The apparent Michaelis–Menten constant KMapp for H2O2 sensor was estimated to be (0.31±0.02) mM, showing a high affinity. [Copyright &y& Elsevier]

• Two novel MET exon 14 variants was identified in Ia NSCLC patients. • MET exon 14 skipping was confirmed via DNA-based and RNA-based assays. • The new variants was defined as MET exon 14 skipping analogs. • Annotation for novel MET exon 14 alterations by DNA-NGS requires RNA-level evidence. MET exon 14 skipping (MET ex14) is a validated oncogenic driver in lung cancer and MET tyrosine kinase inhibitors are now available as effective clinical treatments. The majority of known MET ex14 alterations are typical donor/acceptor splicing or ubiquitination site mutations. Herein, two new MET ex14 variants were detected in two patients with lung adenocarcinoma by targeted next generation sequencing (NGS). Reverse transcription (RT)-based analysis confirmed that these mutations led to MET exon 14 skipping. Our analysis provided evidence for possible targeted therapy options for patients carrying these MET mutations or similar MET ex14 analogs. [ABSTRACT FROM AUTHOR]

Honey-processed Astragalus is a dosage form of Radix Astragali processed with honey, which exhibits better efficacy of tonifying Qi than the raw product. Polysaccharides are its main water-soluble active components. This work was designed to study the structural differences of homogeneous honey-processed Astragalus polysaccharides (HAPS3a) and Astragalus polysaccharides (APS3a) and their effects on colitis mice. The results showed that HAPS3a (Mw = 2463.5 kDa) and APS3a (Mw = 3373.2 kDa) differed in molecular weight, monosaccharide compositions, glycosidic bonds and degree of branching (DB). Notably, the molar ratios of galactose and galacturonic acid in HAPS3a were 22.66% and 33.24%, while those in APS3a were 11.87% and 49.55%, respectively. The uronic acid residues 1,4-β-Gal p A and 1,6-α-Glc p A of the backbone in APS3a were converted into the corresponding neutral residues in HAPS3a after honey processing. The different DB of HAPS3a (15.35%) and APS3a (25.13%) suggested that the chain conformation became smoother. The anti-inflammatory effects on colitis mice revealed that HAPS3a exhibited better effects than APS3a by protecting intestinal mucosa, regulating the expression of cytokines and influencing microbiota diversity. Taken together, the differences in anti-inflammatory activity might be related to structural differences caused by honey processing. Our findings have laid a foundation for the processing mechanism of Astragalus. [ABSTRACT FROM AUTHOR]

Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis, but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity, we proposed a "two-step approach" that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC 50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC 50 = 4.56 μmol/L) and the positive control gefitinib (IC 50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK. Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes, thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5 , a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation. [Display omitted] • A synergistic effect of PKM2 activation and PDK1 inhibition was first demonstrated. • A series of PKM2/PDK1 dual-target shikonin thioether derivatives were developed. • The most active compound E5 significantly inhibit tumor growth in vitro and in vivo. • The most active compound E5 enhance the sensitivity of H1975 cells to gefitinib. [ABSTRACT FROM AUTHOR]