CsREV-CsTCP4-CsVND7 module shapes xylem patterns differentially between stem and leaf to enhance tea plant tolerance to drought.

Cultivating drought-tolerant tea varieties enhances both yield and quality of tea plants in northern China. However, the mechanisms underlying their drought tolerance remain largely unknown. Here we identified a key regulator called CsREV, which differentially regulates xylem patterns between leaves and stems, thereby conferring drought tolerance in tea plants. When drought occurs, upregulation of CsREV activates the CsVND7a-dependent xylem vessel differentiation. However, when drought persists, the vessel differentiation is hindered as CsVND7a is downregulated by CsTCP4a. This, combined with the CsREV-promoted secondary-cell-wall thickness of xylem vessel, leads to the enhanced curling of leaves, a characteristic closely associated with plant drought tolerance. Notably, this inhibitory effect of CsTCP4a on CsVND7a expression is absent in stems, allowing stem xylem vessels to continuously differentiate. Overall, the CsREV-CsTCP4-CsVND7 module is differentially utilized to shape the xylem patterns in leaves and stems, potentially balancing water transportation and utilization to improve tea plant drought tolerance.

Low phosphorus promotes NSP1-NSP2 heterodimerization to enhance strigolactone biosynthesis and regulate shoot and root architecture in rice.

Phosphorus is an essential macronutrient for plant development and metabolism, and plants have evolved ingenious mechanisms to overcome phosphate (Pi) starvation. However, the molecular mechanisms underlying the regulation of shoot and root architecture by low phosphorus conditions and the coordinated utilization of Pi and nitrogen remain largely unclear. Here, we show that Nodulation Signaling Pathway 1 (NSP1) and NSP2 regulate rice tiller number by promoting the biosynthesis of strigolactones (SLs), a class of phytohormones with fundamental effects on plant architecture and environmental responses. We found that NSP1 and NSP2 are induced by Oryza sativa PHOSPHATE STARVATION RESPONSE2 (OsPHR2) in response to low-Pi stress and form a complex to directly bind the promoters of SL biosynthesis genes, thus markedly increasing SL biosynthesis in rice. Interestingly, the NSP1/2-SL signaling module represses the expression of CROWN ROOTLESS 1 (CRL1), a newly identified early SL-responsive gene in roots, to restrain lateral root density under Pi deficiency. We also demonstrated that GR244DO treatment under normal conditions inhibits the expression of OsNRTs and OsAMTs to suppress nitrogen absorption but enhances the expression of OsPTs to promote Pi absorption, thus facilitating the balance between nitrogen and phosphorus uptake in rice. Importantly, we found that NSP1p:NSP1 and NSP2p:NSP2 transgenic plants show improved agronomic traits and grain yield under low- and medium-phosphorus conditions. Taken together, these results revealed a novel regulatory mechanism of SL biosynthesis and signaling in response to Pi starvation, providing genetic resources for improving plant architecture and nutrient-use efficiency in low-Pi environments.

A (Traditional Chinese Medicine) TCM-Inspired Doxorubicin Resistance Reversing Strategy: Preparation, Characterization, and Application of a Co-loaded pH-Sensitive Liposome.

In this study, nano-strategy for combined medication of active compounds from traditional Chinese medicine herbs was proposed to achieve the synergistic effects of inhibiting the doxorubicin (DOX) resistance, reducing the cardio-toxicity, and improving the treatment efficacy simultaneously. Dihydroartemisinin (DHA) and tetrandrine (TET) were co-delivered for the first time to treat DOX resistance of breast cancer with multi-pathway mechanism. Tumor micro-environment sensitivity prescription was adopted to enhance the reversal effect of DOX resistance nearly 50 times (resistance index, RI was 46.70) and uptake ability. The DHA-TET pH-sensitive liposomes (DHA-TET pH-sensitive LPs) had a good spherical structure and a uniform dispersion structure with particle size, polydispersity index (PDI), and zeta potential of 112.20 ± 4.80 nm, 0.20 ± 0.02, and - 8.63 ± 0.74 Mv, and was stable until 14 days under the storage environment of 4°C and for 6 months at room temperature environment. With the DOX resistance reversing ability increased, the inhibition effect of DHA-TET pH-sensitive LPs on both MCF-7/ADR cells and MCF-7 cells was significantly enhanced; meanwhile, the toxicity on cardiac cell (H9c2) was lowered. Ferroptosis induced by the DHA was investigated showing that the intracellular reactive oxygen species (ROS) and lipid peroxidation were increased to promote the synergistic effect through the due-loaded nano-carrier, providing a promising alternative for future clinical application.

Preparation and evaluation of dual drug-loaded nanofiber membranes based on coaxial electrostatic spinning technology.

Wound healing is a complicated process consisting of wound bleeding, inflammatory response, cell proliferation and tissue remodeling. During this long-term period, wound is vulnerable to infection by bacteria or microbes. Therefore, we prepared a novel centella total glucoside-ciprofloxacin dual-loaded coaxial nanofiber membrane (CDCNM) by using coaxial electrostatic spinning technique. To satisfy personalized therapeutic demands by adjusting release behaviors, we loaded centella total glucoside (CTG) and ciprofloxacin (CIP) into different positions of the fibers and the morphology and coaxial structure of the nanofiber membranes were analyzed by SEM and TEM. In addition, water contact angle, water absorption capacity, breathability and in vitro drug release were tested. In vitro cell experiments demonstrated that CDCNM can promote fibroblast proliferation. CDCNM demonstrated excellent antimicrobial activity through the agar flat dish diffusion method. Furthermore, rat scald experiments showed that CDCNM significantly accelerated scald healing, meanwhile immunohistochemical staining showed that CDCNM promoted the expression of CD31 and VEGF during early wound healing, which accelerated scald healing by promoting neovascularization and endothelial cell proliferation. As a topical multifunctional wound dressing, this dual drug-loaded nanofiber membrane achieved scald healing effect and continuous bacterial inhibition, which provides new ideas for existing trauma treatment tools and dual drug delivery systems.

Monolithic robust hybrid sponge with enhanced light adsorption and ultrafast photothermal heating rate for rapid oil cleaning.

It remains a significant challenge to develop a photothermal adsorbent with a heating response as fast as a joule-heating adsorbent and simultaneously possessing excellent mechanical stability and reusability for rapid oil cleaning. Here, we report a novel monolithic design to fabricate a photothermal hybrid sponge for rapid oil cleaning by integrating graphite interlayer compounds as photothermal units into the three-dimensional photothermal network of carbon nanotubes. This unique monolithic design enabled the hybrid sponge to present excellent photothermal performance: firstly, the superhydrophobic hybrid sponge has low thermal resistance resulting from the defectless surface; secondly, the photothermal units were weaved in the photothermal network, preventing detachment in the cycling and providing ultrafast photothermal heating rate. The hybrid sponge rises to 81 °C in merely 25 s under irradiation (1 Sun), superior to most photothermal oil adsorbents reported so far. This study provides a new structural design for constructing photothermal adsorbents with a fast-heating response for rapid crude oil cleaning.

Icariside II Restores Vascular Smooth Muscle Cell Contractile Phenotype by Enhancing the Focal Adhesion Signaling Pathway in the Rat Vascular Remodeling Model.

Vascular smooth muscle cell (VSMC) phenotypic transition represents the fundamental pathophysiological alteration in the vascular remodeling process during the initiation and progression of cardiovascular diseases. Recent studies have revealed that Icariside II (ICS-II), a flavonol glycoside derived from the traditional Chinese medicine Herba Epimedii, exhibited therapeutic effects in various cardiovascular diseases. However, the therapeutic efficacy and underlying mechanisms of ICS-II regarding VSMC phenotypic transition were unknown. In this study, we investigated the therapeutic effects of ICS-Ⅱ on vascular remodeling with a rat's balloon injury model in vivo. The label-free proteomic analysis was further implemented to identify the differentially expressed proteins (DEPs) after ICS-II intervention. Gene ontology and the pathway enrichment analysis were performed based on DEPs. Moreover, platelet-derived growth factor (PDGF-BB)-induced primary rat VSMC was implemented to verify the restoration effects of ICS-II on the VSMC contractile phenotype. Results showed that ICS-II could effectively attenuate the vascular remodeling process, promote SMA-α protein expression, and inhibit OPN expression in vivo. The proteomic analysis identified 145 differentially expressed proteins after ICS-II intervention. Further, the bioinformatics analysis indicated that the focal adhesion signaling pathway was enriched in the ICS-II group. In vitro studies showed that ICS-II suppressed VSMC proliferation and migration, and promoted VSMC contractile phenotype by modulating the focal adhesion signaling pathway. Taken together, our results suggest that ICS-II attenuates the vascular remodeling process and restores the VSMC contractile phenotype by promoting the focal adhesion pathway.

Icariside II Attenuates Vascular Remodeling Via Wnt7b/CCND1 Axis.

ABSTRACT: Angioplasty often fails due to the abnormal proliferation of vascular smooth muscle cells (VSMCs). Success rates of angioplasty may increase following the administration of an agent that effectively ameliorates aberrant vascular remodeling. Icariside II (ICS-II) is a natural flavonol glycoside extract from the Chinese herbal medicine Epimedii that possesses several medicinal qualities that are beneficial in humans. Nevertheless, the role of ICS-II in addressing aberrant vascular remodeling have yet to be clarified. The current investigation studies the molecular effects of ICS-Ⅱ on balloon-inflicted neointimal hyperplasia in rats in vivo and on platelet-derived growth factor-induced vascular proliferation in primary rat aortic smooth muscle cells (VSMCs) in vitro. ICS-II was found to be as effective as rapamycin, the positive control used in this study. ICS-II inhibited neointimal formation in injured rat carotid arteries and notably reduced the expression of Wnt7b. ICS-Ⅱ significantly counteracted platelet-derived growth factor-induced VSMCs proliferation. Cell cycle analysis showed that ICS-II triggered cell cycle arrest during the G1/S transition. Western blot analysis further indicated that this cell cycle arrest was likely through Wnt7b suppression that led to CCND1 inhibition. In conclusion, our findings demonstrate that ICS-II possesses significant antiproliferative qualities that counteracts aberrant vascular neointimal hyperplasia. This phenomenon most likely occurs due to the suppression of the Wnt7b/CCND1 axis.

Reduced antioxidant and anti-inflammatory effects of propofol at high-dose on morbidly obese patients.

This study was aimed to investigate differences in antioxidant and anti-inflammatory effects of propofol at two commonly used dosing schedules on morbidly obese patients. Twenty-two morbidly obese patients were randomly divided into two groups, namely, TBW (dosing based on total body weight) and LBW (dosing based on lean body weight) groups. Three biomarkers, i.e. superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) were measured as indicators of the level of oxidation stress reaction. Pro-inflammatory cytokines including Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were used to describe the degree of inflammation. Plasma levels of SOD, MDA and NO were increased and reached a peak value 0.5h after anesthesia induction, but the increase was smaller in the LBW group compared with the TBW group. Besides, plasma concentrations of IL-6 and IL-8 were also increased and attained a peak level 0.5h after anesthesia induction, but the increase was higher in the TBW group compared with the LBW group. The LBW-based dosing of propofol had more potent antioxidant and anti-inflammatory effects than the TBW-based dosing during anesthesia induction period on morbidly obese patients. This study provided a dosing recommendation of propofol for morbidly obese patients.

Effects of walnut intake on blood pressure: A systematic review and meta-analysis of randomized controlled trials.

The impact of walnuts on blood pressure (BP) is not a well-established fact. Although several studies have assessed the effects of walnut consumption on BP, results are conflicting. Thus, we examined the effects of walnut doses and length of supplementation on BP. Biomedical databases were searched for published trials that compared walnut-enhanced diet to control diet. Eighteen trials met eligibility criteria (n = 1,799). Overall, walnut consumption neither did alter SBP (weighted mean difference [WMD]: 0.08 mmHg; 95% CI: -0.69, 0.85) nor DBP (WMD: 0.08 CI: -0.26, 0.42). In subgroup analyses, walnut ingestion ≤40 g was statistically correlated with reduction in SBP (WMD: -0.53 mmHg, 95% CI: -0.79, -0.26) and DBP (WMD: -0.191 mmHg, 95% CI: -0.384, -0.034). Moreover, the length of intervention ≥8 weeks was linked to a significant reduction in SBP (WMD: -1.18 mmHg, 95% CI: -1.30, -1.06). Following dose-response evaluation, walnut intake significantly changed SBP (p = .015) and DBP (p = .026) through a nonlinear fashion at walnut dose up to 40 g/d. Nevertheless, these statistical results cannot be translated into clinical practice, once the changes expressed as WMD are slight taking into consideration the absolute values of BP categories. In conclusion, this meta-analysis does not support walnut consumption as a BP-lowering strategy.

Strategies for targeting the cardiac sarcomere: avenues for novel drug discovery.

Introduction: Heart failure remains one of the largest clinical challenges in the United States. Researchers have continually searched for more effective heart failure treatments that target the cardiac sarcomere but have found few successes despite numerous expensive cardiovascular clinical trials. Among many reasons, the high failure rate of cardiovascular clinical trials may be partly due to incomplete characterization of a drug candidate's complex interaction with cardiac physiology.Areas covered: In this review, the authors address the issue of preclinical cardiovascular studies of sarcomere-targeting heart failure therapies. The authors consider inherent tradeoffs made between mechanistic transparency and physiological fidelity for several relevant preclinical techniques at the atomic, molecular, heart muscle fiber, whole heart, and whole-organism levels. Thus, the authors suggest a comprehensive, bottom-up approach to preclinical cardiovascular studies that fosters scientific rigor and hypothesis-driven drug discovery.Expert opinion: In the authors' opinion, the implementation of hypothesis-driven drug discovery practices, such as the bottom-up approach to preclinical cardiovascular studies, will be imperative for the successful development of novel heart failure treatments. However, additional changes to clinical definitions of heart failure and current drug discovery culture must accompany the bottom-up approach to maximize the effectiveness of hypothesis-driven drug discovery.

Comparison of long-term ceramic membrane bioreactors without and with in-situ ozonation in wastewater treatment: Membrane fouling, effluent quality and microbial community.

The comparison of long-term ceramic membrane bioreactors (MBRs) without and with in-situ ozonation was investigated in this study in terms of membrane fouling, activated sludge, effluent quality and microbial community in wastewater treatment. The optimal dosage of in-situ ozonation for long-term MBR operation was firstly determined as 5 mg/L (0.66 mg-ozone/g-mixed liquor suspended solid (MLSS)) with the optimal filterability of mixed liquor. During the long-term filtration experiment, MBR-ozone with in-situ ozonation demonstrated its significantly alleviated ceramic membrane fouling performance compared with MBR-control without in-situ ozonation as a result of the enhanced filterability of mixed liquor and organic foulants removal from membrane surface by in-situ ozonation oxidation. Furthermore, ozonation was beneficial to phosphorus removal and the total phosphorus (TP) concentration in effluent of MBR-control (0.82 ±â€¯0.63 mg/L) was >2-fold higher than that of MBR-ozone (0.29 ±â€¯0.41 mg/L). The improved phosphorus removal performance by ozonation was due to the increased abundance of phosphate accumulating bacteria of Candidatus Accumulibacter in activated sludge. However, ozonation was detrimental to nitrogen removal mainly as a result of the inhibition of denitrification with the decreased relative abundance of denitrification genus of Dechloromonas in activated sludge. Overall, ceramic MBR with in-situ ozonation had not only significantly alleviated membrane fouling but also remarkably improved phosphorus removal performance.

Detection of major loci associated with the variation of 18 important agronomic traits between Solanum pimpinellifolium and cultivated tomatoes.

Wild species can be used to improve various agronomic traits in cultivars; however, a limited understanding of the genetic basis underlying the morphological differences between wild and cultivated species hinders the integration of beneficial traits from wild species. In the present study, we generated and sequenced recombinant inbred lines (RILs, 201 F10 lines) derived from a cross between Solanum pimpinellifolium and Solanum lycopersicum tomatoes. Based on a high-resolution recombination bin map to uncover major loci determining the phenotypic variance between wild and cultivated tomatoes, 104 significantly associated loci were identified for 18 agronomic traits. On average, these loci explained ~39% of the phenotypic variance of the RILs. We further generated near-isogenic lines (NILs) for four identified loci, and the lines exhibited significant differences for the associated traits. We found that two loci could improve the flower number and inflorescence architecture in the cultivar following introgression of the wild-species alleles. These findings allowed us to construct a trait-locus network to help explain the correlations among different traits based on the pleiotropic or linked loci. Our results provide insights into the morphological changes between wild and cultivated tomatoes, and will help to identify key genes governing important agronomic traits for the molecular selection of elite tomato varieties.

Graphdiyne Nanosheet-Based Drug Delivery Platform for Photothermal/Chemotherapy Combination Treatment of Cancer.

Nowadays, two-dimensional (2D) materials have attracted extensive attention as cancer drug delivery platforms owing to their unparalleled physicochemical properties and superior specific surface area. Graphdiyne (GDY) is a novel 2D carbon material. Compared with graphene, GDY not only has benzene rings composed of sp2-hybridized carbon atoms but also has acetylene units composed of sp-hybridized carbon atoms; therefore, it possesses multiple conjugated electronic structures. Herein, we used doxorubicin (DOX) as a model drug to develop a GDY nanosheet-based drug delivery platform for a photothermal/chemotherapy combination in living mice. With a high photothermal conversion ability and drug loading efficiency, GDY/DOX under 808 nm laser irradiation showed a much higher cancer inhibition rate compared with solo therapy both in vitro and in vivo. Furthermore, GDY exhibited great biocompatibility and no obvious side effects, as shown by histopathological examination and serum biochemical analysis. For the first time, our work demonstrated a successful example of GDY for efficient photothermal/chemotherapy and suggests both safety and great promise for GDY in cancer treatment.

Dual-Mode Imaging-Guided Synergistic Chemo- and Magnetohyperthermia Therapy in a Versatile Nanoplatform To Eliminate Cancer Stem Cells.

Cancer stem cells (CSCs) have been identified as a new target for therapy in diverse cancers. Traditional therapies usually kill the bulk of cancer cells, but are often unable to effectively eliminate CSCs, which may lead to drug resistance and cancer relapse. Herein, we propose a novel strategy: fabricating multifunctional magnetic Fe3O4@PPr@HA hybrid nanoparticles and loading it with the Notch signaling pathway inhibitor N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycinet-butylester (DAPT) to eliminate CSCs. Hyaluronic acid ligands greatly enhance the accumulation of the hybrid nanoparticles in the tumor site and in the CSCs. Both hyaluronase in the tumor microenvironment and the magnetic hyperthermia effect of the inner magnetic core can accelerate the release of DAPT. This controlled release of DAPT in the tumor site further enhances the ability of the combination of chemo- and magnetohyperthermia therapy to eliminate cancer stem cells. With the help of polypyrrole-mediated photoacoustic and Fe3O4-mediated magnetic resonance imaging, the drug release can be precisely monitored in vivo. This versatile nanoplatform enables effective elimination of the cancer stem cells and monitoring of the drugs.

Gadolinium(III)-Chelated Silica Nanospheres Integrating Chemotherapy and Photothermal Therapy for Cancer Treatment and Magnetic Resonance Imaging.

The combination of therapy and diagnosis has been emerging as a promising strategy for cancer treatment. To realize chemotherapy, photothermal therapy, and magnetic resonance imaging (MRI) in one system, we have synthesized a new magnetic nanoparticle (Gd@SiO2-DOX/ICG-PDC) integrating doxorubicin (DOX), indocyanine green (ICG), and gadolinium(III)-chelated silica nanospheres (Gd@SiO2) with a poly(diallyldimethylammonium chloride) (PDC) coating. PDC coating serves as a polymer layer to protect from quick release of drugs from the nanocarriers and increase cellular uptake. The DOX release from Gd@SiO2-DOX/ICG-PDC depends on pH and temperature. The process will be accelerated in the acidic condition than in a neutral pH 7.4. Meanwhile, upon laser irradiation, the photothermal effects promote DOX release and improve the therapeutic efficacy compared to either DOX-loaded Gd@SiO2 or ICG-loaded Gd@SiO2. Moreover, MRI results show that the Gd@SiO2-PDC nanoparticles are safe T1-type MRI contrast agents for imaging. The Gd@SiO2-PDC nanoparticles loaded with DOX and ICG can thus act as a promising theranostic platform for multimodal cancer treatment.

DWARF27, an iron-containing protein required for the biosynthesis of strigolactones, regulates rice tiller bud outgrowth.

Tillering in rice (Oryza sativa) is one of the most important agronomic traits that determine grain yields. Previous studies on rice tillering mutants have shown that the outgrowth of tiller buds in rice is regulated by a carotenoid-derived MAX/RMS/D (more axillary branching) pathway, which may be conserved in higher plants. Strigolactones, a group of terpenoid lactones, have been recently identified as products of the MAX/RMS/D pathway that inhibits axillary bud outgrowth. We report here the molecular genetic characterization of d27, a classic rice mutant exhibiting increased tillers and reduced plant height. D27 encodes a novel iron-containing protein that localizes in chloroplasts and is expressed mainly in vascular cells of shoots and roots. The phenotype of d27 is correlated with enhanced polar auxin transport. The phenotypes of the d27 d10 double mutant are similar to those of d10, a mutant defective in the ortholog of MAX4/RMS1 in rice. In addition, 2'-epi-5-deoxystrigol, an identified strigolactone in root exudates of rice seedlings, was undetectable in d27, and the phenotypes of d27 could be rescued by supplementation with GR24, a synthetic strigolactone analog. Our results demonstrate that D27 is involved in the MAX/RMS/D pathway, in which D27 acts as a new member participating in the biosynthesis of strigolactones.

Silencing of phosphoethanolamine N-methyltransferase results in temperature-sensitive male sterility and salt hypersensitivity in Arabidopsis.

S-Adenosyl-L-methionine:phosphoethanolamine N-methyltransferase (PEAMT; EC 2.1.1.103) catalyzes the key step in choline (Cho) biosynthesis, the N-methylation of phosphoethanolamine. Cho is a vital precursor of the membrane phospholipid phosphatidylcholine, which accounts for 40 to 60% of lipids in nonplastid plant membranes. Certain plants use Cho to produce the osmoprotectant glycine betaine, which confers resistance to salinity, drought, and other stresses. An Arabidopsis mutant, t365, in which the PEAMT gene is silenced, was identified using a new sense/antisense RNA expression system. t365 mutant plants displayed multiple morphological phenotypes, including pale-green leaves, early senescence, and temperature-sensitive male sterility. Moreover, t365 mutant plants produced much less Cho and were hypersensitive to salinity. These results demonstrate that Cho biosynthesis not only plays an important role in plant growth and development but also contributes to tolerance to environmental stresses. The temperature-sensitive male sterility caused by PEAMT silencing may have a potential application in agriculture for engineering temperature-sensitive male sterility in important crop plants.