A generalist regulator: MYB transcription factors regulate active ingredient biosynthesis in medicinal plants.

Medicinal plants are rich in a variety of secondary metabolites with therapeutic value. However, the yields of these metabolites are generally very low, making their extraction both time- and labour-consuming. Transcription factor (TF)-targeted secondary metabolic engineering can efficiently regulate the biosynthesis and accumulation of secondary metabolites in medicinal plants. v-Myb avian myeloblastosis viral oncogene homolog (MYB) TFs are involved in regulating various morphological and developmental processes, responses to stress, and the biosynthesis of secondary metabolites in plants. This review discusses the biological functions and transcription regulation mechanisms of MYB TFs and summarises the research progress concerning MYB TFs involved in the biosynthesis of representative active components. In the transcriptional regulatory network, MYB TFs regulate multiple synthase genes to mediate active ingredient biosynthesis. This study will serve as a reference for the in-depth analysis of the MYB TF family in medicinal plants.

Difference of Esophageal Motility and Reflux Characteristics in Patients with Gastroesophageal Reflux Disease (GERD) and Chronic Cough (CC) and the Impact of Standardized Drug Therapy.

This study aimed to explore the difference between esophageal motility and reflux characteristics in patients with gastroesophageal reflux disease (GERD) and chronic cough (CC) and the effect of standardized drug therapy. Eighty-four patients diagnosed with GERD in The First People's Hospital of Hangzhou from December 2020 to December 2022 were enrolled in this study. They were divided into an observation group (Obs group, patients with GERD + CC, n = 26 cases) and a control group (control group, patients with typical GERD, n = 58 cases). Reflux symptom integral questionnaire, cough symptom integral questionnaire, high-resolution esophageal manometry (HRM), and 24-hour esophageal pH/impedance monitoring were performed. The upper esophageal sphincter pressure at resting (UESP) and distal systolic score (DCI) in the Obs group were much lower. They exhibited differences with P < .05 than those in the control group. The total numbers of proximal reflux, proximal weak acid reflux, proximal non-acid reflux, weak acid reflux, and gas-liquid mixed reflux in the Obs group were more. They showed a difference with P < .05 than those in the control group. After a standard treatment, the reflux symptom score of patients with GERD + CC was greatly lower than those of patients with typical GERD (P < .05). Ineffective esophageal motility (IEM) was dominant in patients with GERD +CC. HRM and 24-hour pH/impedance monitoring can objectively evaluate the properties of esophageal motility and reflux, respectively, which had a guiding significance for individual patient treatment.

Multi-analyte fluorescence sensing based on a post-synthetically functionalized two-dimensional Zn-MOF nanosheets featuring excited-state proton transfer process.

Covalent post-synthetic modification of metal-organic frameworks (MOFs) represents an underexplored but promising avenue for allowing the addition of specific fluorescent recognition elements to produce the novel MOF-based sensory materials with multiple-analyte detection capability. Here, an excited-state proton transfer (ESPT) active sensor 2D-Zn-NS-P was designed and constructed by covalent post-synthetic incorporation of the excited-state tautomeric 2-hydroxypyridine moiety into the ultrasonically exfoliated amino-tagged 2D Zn-MOF nanosheets (2D-Zn-NS). The water-mediated ESPT process facilitates the highly accessible active sites incorporated on the surface of 2D-Zn-NS-P to specifically respond to the presence of water in common organic solvents via fluorescence turn-on behavior, and accurate quantification of trace amount of water in acetonitrile, acetone and ethanol was established using the as-synthesized nanosheet sensor with the detection sensitivity (<0.01% v/v) superior to the conventional Karl Fischer titration. Upon exposure to Fe3+ or Cr2O72-, the intense blue emission of the aqueous colloidal dispersion of 2D-Zn-NS-P was selectively quenched even in the coexistence of common inorganic interferents. The prohibition of the water-mediated ESPT process and local emission, induced by the coordination of ESPT fluorophore with Fe3+ or by Cr2O72- competitively absorbs the excitation energy, was proposed to responsible for the fluorescence turn-off sensing of the respective analytes. The present study offers the attractive prospect to develop the ESPT-based fluorescent MOF nanosheets by covalent post-synthetic modification strategy as multi-functional sensors for detection of target analytes.

PDT-sensitized ROS-responsive dextran nanosystem for maximizing antitumor potency of multi-target drugs.

The heterogeneity of tumor microenvironment leads to uneven distribution of bio-stimuli. Thus, the multi-site delivery efficiency of responsive drug delivery systems (DDS) inner tumor was always limited. Herein, we proposed a combination strategy of photodynamic therapy (PDT) with ROS-responsive nanosystem which was constructed from dextran-phenylboronic acid pinacol ester conjugates. This combination utilized PDT to amplify and homogenize tissular oxidation level, and achieve effective multi-site response and release of multi-target drugs like gambogic acid (GA). Our research demonstrated the successful preparation of GA and protoporphyrin IX (PpIX) co-loaded nanoparticles, and the PDT-mediated spatiotemporal controlled multi-site drug release in simulated conditions. Furthermore, data from in vitro and in vivo researches on B16F10 cells, HUVEC, and B16F10-bearing C57BL/6 mice potently confirmed the enhanced multi-mechanism regulations of GA mediated by the effective and homogeneous tumoral release. This tactic based on bio-stimuli amplification and homogenization proposes a paradigm to maximize the potency of multi-target drugs.

A Mixed Protonic-Electronic Conductor Base on the Host-Guest Architecture of 2D Metal-Organic Layers and Inorganic Layers.

The key to designing and fabricating highly efficient mixed protonic-electronic conductors materials (MPECs) is to integrate the mixed conductive active sites into a single structure, to break through the shortcomings of traditional physical blending. Herein, based on the host-guest interaction, an MPEC is consisted of 2D metal-organic layers and hydrogen-bonded inorganic layers by the assembly methods of layered intercalation. Noticeably, the 2D intercalated materials (≈1.3 nm) exhibit the proton conductivity and electron conductivity, which are 2.02 × 10-5 and 3.84 × 10-4 S cm-1 at 100 °C and 99% relative humidity, much higher than these of pure 2D metal-organic layers (>>1.0 × 10-10 and 2.01×10-8 S cm-1 ), respectively. Furthermore, combining accurate structural information and theoretical calculations reveals that the inserted hydrogen-bonded inorganic layers provide the proton source and a networks of hydrogen-bonds leading to efficient proton transport, meanwhile reducing the bandgap of hybrid architecture and increasing the band electron delocalization of the metal-organic layer to greatly elevate the electron transport of intrinsic 2D metal-organic frameworks.

An engineered nanoplatform cascade to relieve extracellular acidity and enhance resistance-free chemotherapy.

Tumor extracellular acidity and chemoresistance are regarded as the main obstacles to achieving optimal chemotherapeutic efficacy in tumor therapy. Herein, a new kind of acid-cascade P-S-Z nanoparticles (NPs) is developed to relieve extracellular acidosis and enhance chemotherapy without causing drug resistance. The P-S-Z NPs selectively accumulate in tumors and then regulate the release of S-Z NPs containing syrosingopine (Syr) and acid-activated prodrug ZMC1-Pt depending on the extracellular acidity. Benefiting from their small size and positive surface charge, S-Z NPs are easily internalized by tumor cells in deep tumor tissue, facilitating the release of Syr to inhibit lactic acid excretion and ultimately enhance cell acidosis. The prolonged intracellular acidosis not only inhibits tumor cell proliferation, but also continuously triggers the activation of ZMC1-Pt prodrug, a platinum-based chemotherapeutic drug that effectively eliminates cancer cells and restores wild-type p53 function to prevent tumor chemoresistance. As a proof of concept, this is a promising strategy to transfer the adverse effect of intracellular acidosis to facilitate chemotherapy. This well-designed delivery system effectively kills tumor cells without causing significant tumor drug resistance, thus opening a new window to treat cancer.

A pHe sensitive nanodrug for collaborative penetration and inhibition of metastatic tumors.

Current chemotherapies for metastatic tumors are seriously restricted by limited drug infiltration and deficient disturbance of metastasis-associated complex pathways involving tumor cell autocrine as well as paracrine loops in the microenvironment (TME). Of note, cancer-associated fibroblasts (CAFs) play a predominant role in shaping TME favoring drug resistance and metastasis. Herein, we constructed a tumor extracellular pH (pHe) sensitive methotrexate-chitosan conjugate (MTX-GC-DEAP) and co-assembled it with quercetin (QUE) to achieve co-delivered nanodrugs (MTX-GC-DEAP/QUE). The pHe sensitive protonation and disassembly enabled MTX-GC-DEAP/QUE for stroma-specific delivery of QUE and positive-charged MTX-GC-DEAP molecular conjugates, thereby achieving deep tumor penetration via the combination of QUE-mediated CAF inactivation and adsorption-mediated transcytosis. On the basis of significantly promoted drug availability, a strengthened "omnidirectional" inhibition of pre-metastatic initiation was generated both in vitro and in vivo from the CAF inactivation-mediated reversion of metastasis-promoting environments as well as the inhibition of epithelial-mesenchymal transition, local and blood vessel invasion via QUE-mediated direct regulation on tumor cells. Our tailor-designed versatile nanodrug provides a deep insight into potentiating multi-faceted penetration of multi-mechanism-based regulating agents for intensive metastasis inhibition.

Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient transmembrane internalization and controlled release for penetrated "full-line" inhibition of pre-metastatic initiation.

Metastatic breast cancer is a major cause of cancer-related mortality worldwide. The tumor-specific penetration and triggered drug release for "full-line" inhibition of pre-metastatic initiation are of essential importance in improving mortality rates. Here, a crosslinked, redox-sensitive amphiphilic conjugate (cHLC) was constructed with a combination of features, including hyaluronic acid (HA)-mediated tumor active targeting, lipoic acid (LA) core-crosslinking based bio-stability and reducibility, and lipid raft anchoring-promoted HA-mediated endocytosis through cholesterol (CHO) modification for the penetrated co-delivery of paclitaxel (PTX) and the multi-targeted anti-metastatic agent, silibinin (SB). Resultantly, the nanodrug (cHLC/(PTX + SB)) demonstrated enhanced tumor cytoplasm-selective rapid drug delivery in a 4T1 model both in vitro and in vivo. The released SB efficiently sensitized cells to PTX treatment and inhibited the whole process of pre-metastatic initiation including epithelial-to-mesenchymal transition (EMT), local and blood vessel invasion. The exquisite design of this delivery system provides a deep insight into enhancing focus accessibility of multi-targeted drugs for an efficient inhibition of tumor metastasis.