Arterial blood pressure is controlled by vasodilatory factors such as nitric oxide (NO) that are released from the endothelium under the influence of fluid shear stress exerted by flowing blood. ...Flow-induced endothelial release of ATP and subsequent activation of Gq/G11-coupled purinergic P2Y2 receptors have been shown to mediate fluid shear stress-induced stimulation of NO formation. However, the mechanism by which fluid shear stress initiates these processes is unclear. Here, we have shown that the endothelial mechanosensitive cation channel PIEZO1 is required for flow-induced ATP release and subsequent P2Y2/Gq/G11-mediated activation of downstream signaling that results in phosphorylation and activation of AKT and endothelial NOS. We also demonstrated that PIEZO1-dependent ATP release is mediated in part by pannexin channels. The PIEZO1 activator Yoda1 mimicked the effect of fluid shear stress on endothelial cells and induced vasorelaxation in a PIEZO1-dependent manner. Furthermore, mice with induced endothelium-specific PIEZO1 deficiency lost the ability to induce NO formation and vasodilation in response to flow and consequently developed hypertension. Together, our data demonstrate that PIEZO1 is required for the regulation of NO formation, vascular tone, and blood pressure.
Polymeric micelles (PM) system, as an efficient drug carrier, has received growing scientific attention in recent years owing to its solubilization, selective targeting, P-glycoprotein inhibition and ...altered drug internalization route and subcellular localization properties. Seven PM formulations of anti-tumor drugs being evaluated in clinical trials are reviewed in this paper, in terms of formulation study, in vitro cytotoxicity, in vivo pharmacokinetics, anti-tumor efficacy and safety as well as clinical trials, to shed new light on the discovery of novel PM formulations. In these seven PM formulations, PM system was employed to overcome the issues of low water solubility, high toxicity and (or) multidrug resistance accompanied with the conventional formulation, which greatly hampered their clinical application. Those promising preclinical and clinical results combined with rapid advancement and intense multidisciplinary collaboration enable the extension of the PM system to traditional Chinese medicine, imaging agents, gene and combination agent deliveries as well as some other administration routes, which facilitate the clinical translation of the PM drug delivery system.
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White adipose tissue (WAT) expansion in obesity occurs through enlargement of preexisting adipocytes (hypertrophy) and through formation of new adipocytes (adipogenesis). Adipogenesis results in WAT ...hyperplasia, smaller adipocytes and a metabolically more favourable form of obesity. How obesogenic WAT hyperplasia is induced remains, however, poorly understood. Here, we show that the mechanosensitive cationic channel Piezo1 mediates diet-induced adipogenesis. Mice lacking Piezo1 in mature adipocytes demonstrated defective differentiation of preadipocyte into mature adipocytes when fed a high fat diet (HFD) resulting in larger adipocytes, increased WAT inflammation and reduced insulin sensitivity. Opening of Piezo1 in mature adipocytes causes the release of the adipogenic fibroblast growth factor 1 (FGF1), which induces adipocyte precursor differentiation through activation of the FGF-receptor-1. These data identify a central feed-back mechanism by which mature adipocytes control adipogenesis during the development of obesity and suggest Piezo1-mediated adipocyte mechano-signalling as a mechanism to modulate obesity and its metabolic consequences.
Nanomaterials based on chitosan have emerged as promising carriers of therapeutic agents for drug delivery due to good biocompatibility, biodegradability, and low toxicity. Chitosan originated ...nanocarriers have been prepared by mini-emulsion, chemical or ionic gelation, coacervation/precipitation, and spray-drying methods. As alternatives to these traditional fabrication methods, self-assembled chitosan nanomaterials show significant advantages and have received growing scientific attention in recent years. Self-assembly is a spontaneous process by which organized structures with particular functions and properties could be obtained without additional complicated processing or modification steps. In this review, we focus on recent progress in the design, fabrication and physicochemical aspects of chitosan-based self-assembled nanomaterials. Their applications in drug delivery of different therapeutic agents are also discussed in details.
The expansion of the white adipose tissue (WAT) in obesity goes along with increased mechanical, metabolic and inflammatory stress. How adipocytes resist this stress is still poorly understood. Both ...in human and mouse adipocytes, the transcriptional co-activators YAP/TAZ and YAP/TAZ target genes become activated during obesity. When fed a high-fat diet (HFD), mice lacking YAP/TAZ in white adipocytes develop severe lipodystrophy with adipocyte cell death. The pro-apoptotic factor BIM, which is downregulated in adipocytes of obese mice and humans, is strongly upregulated in YAP/TAZ-deficient adipocytes under HFD, and suppression of BIM expression reduces adipocyte apoptosis. In differentiated adipocytes, TNFα and IL-1β promote YAP/TAZ nuclear translocation via activation of RhoA-mediated actomyosin contractility and increase YAP/TAZ-mediated transcriptional regulation by activation of c-Jun N-terminal kinase (JNK) and AP-1. Our data indicate that the YAP/TAZ signaling pathway may be a target to control adipocyte cell death and compensatory adipogenesis during obesity.
Abstract MicroRNAs (miRNAs) play critical roles in modulating the oncogenic driver pathways involved in the acquisition of resistance to cancer treatments. MiR-542-3p serves as a potent tumor ...suppressor molecule by targeting tumor suppressor p53 and apoptosis inhibitor survivin. A hyaluronic acid (HA)-decorated polyethylenimine-poly( d , l -lactide-co-glycolide) (PEI-PLGA) nanoparticle system was developed in this study for targeted co-delivery of doxorubicin (DOX) and miR-542-3p for triple negative breast cancer (TNBC) therapy. This system showed an average size at 131.7 nm and high drug encapsulation efficiency, and prevented miR-542-3p degradation in the serum. HA/PEI-PLGA nanoparticles increased both drug uptake and cytotoxicity in MDA-MB-231 cells compared to MCF-7 cells, which express lower CD44 levels. Intracellular restoration of miR-542-3p further promoted TNBC cell apoptosis via activating p53 and inhibiting survivin expression. These results indicate that HA/PEI-PLGA nanoparticles have the potential to co-deliver chemotherapeutic agents and tumor suppressive miRNAs in combinatorial TNBC therapy.
The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the ...mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 receptor, and Gq/G11-mediated signaling. However, only disturbed flow leads to Piezo1- and Gq/G11-mediated integrin activation resulting in focal adhesion kinase-dependent NF-κB activation. Mice with induced endothelium-specific deficiency of Piezo1 or Gαq/Gα11 show reduced integrin activation, inflammatory signaling, and progression of atherosclerosis in atheroprone areas. Our data identify critical steps in endothelial mechanotransduction, which distinguish flow pattern-dependent activation of atheroprotective and atherogenic endothelial signaling and suggest novel therapeutic strategies to treat inflammatory vascular disorders such as atherosclerosis.
•A comprehensive indicator system is constructed to evaluate green development.•Urbanization shows nonlinear effects on urban green development.•Spatial disparities exist in the impact of ...urbanization on green development.•Green technology innovation, green life consumption and infrastructure construction form crucial mechanisms.
The process of rapid urbanization has exerted immense pressure on the ecological environment of cities. Consequently, achieving green development during urbanization has emerged as the new focal point. Based on 2011–2020 panel data of 110 cities at the prefecture level and above in the Yangtze River Economic Belt (YREB), this study aims to investigate the impact of urbanization on urban green development. Specifically, this study analyzes the spatial and temporal evolution patterns of urbanization and urban green development, and examines the spatial disparities and influencing mechanisms of urbanization on urban green development with the help of panel econometric model and mediation model. The results verify that the urbanization and urban green development levels in the YREB have generally improved, but there are significant differences across cities in terms of their aggregate level and growth rate. The relationship between urbanization and urban green development in the YREB follows a “U” shaped curve, where urbanization initially hinders green development but later facilitates it. Spatially, cities located in the middle and lower reaches, as well as urban agglomerations, benefit from location and organization advantages that amplify the effect of urbanization on urban green development. Conversely, cities in the upper reaches and non-urban agglomerations, with their advantages in late development, have the great potential to promote urban green development at a lower threshold. Moreover, Urbanization influences urban green development through non-linear mediating effects. As the level of urbanization increases, green life consumption (GLC) and green technology innovation (GTI) gradually replace infrastructure construction (IC) as the primary mechanisms driving urban green development in the YREB.
Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including anti-proliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as ...regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, beta-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints. Keywords: Cancer, Chinese herbal medicine, Natural products, Bioactive compounds, Traditional Chinese medicine
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