An in vitro study of coagulation evaluation in obstetric hemorrhage for pregnancy-induced hypertension with coagulation and platelet function analyzer.

This study aimed to establish in vitro hemodilution and resupplementation assays for obstetric hemorrhage in pregnancy-induced hypertension (PIH) and to monitor the coagulation function dynamically using a coagulation and platelet function analyzer. Forty-seven singleton pregnant women were divided into normal (n = 24) and PIH (n = 23) groups. Peripheral blood samples were used to construct the assays, and the activated clotting time (ACT), clotting rate (CR), and platelet function index (PF) were measured. The results showed that the baseline ACT was higher in the PIH group (p < 0.01). Hemodilution assays showed decreased ACT and increased CR and PF, with ACT changes significantly lower in the PIH group (p < 0.05). CR changed most in both groups at lower dilution ratios (35% to 50%), while ACT changed most at a higher dilution ratio (75%). In the resupplementation assay, ACT exhibited the most significant response. The analyzer effectively detected differences between pregnant women with and without PIH. Thus, we need to pay more attention to the changes of ACT in the actual clinical application to assess the coagulation status of parturients.

Multifunctional liposomes Co-encapsulating epigallocatechin-3-gallate (EGCG) and miRNA for atherosclerosis lesion elimination.

Atherosclerosis (AS) is a chronic inflammatory disease, characterized by a lipid accumulated plaque. Anti-oxidative and anti-inflammation and lipid metabolism promoting therapeutic strategies have been applied for atherosclerosis treatment. However, the therapeutic effect of a single therapeutic method is limited. It is suggested that a combination of these two strategies could help prevent lipid accumulation caused by inflammation and oxidative stress, and also promote lipid efflux from atherosclerotic plaque, to normalize arteries to the maximum extent. Hence, a strategy involving a multifunctional liposome co-encapsulating an antioxidant and anti-inflammatory drug epigallocatechin-3-gallate (EGCG) and a lipid-efflux-promoting gene miR-223 was established. The system (lip@EGCG/miR-223) could encapsulate miR-223 in core areas of the liposomes to provide a protective effect for gene drugs. Moreover, lip@EGCG/miR-223 was smaller in size (91.28 ± 2.28 nm characterized by DLS), making it easier to target AS lesions, which have smaller vascular endothelial spaces. After being efficiently internalized into the cells, lip@EGCG/miR-223 exhibited excellent antioxidant and anti-inflammatory effects in vitro by eliminating overproduced ROS and decreasing the level of inflammatory cytokines (TNF-α, IL-1ß, and MCP-1), which was due to the effect of EGCG. Besides, the lipid-efflux-promoting protein ABCA1 was upregulated when treated with lip@EGCG/miR-223. Through the two therapies mentioned, lip@EGCG/miR-223 could effectively inhibit the formation of foam cells, which are a main component of atherosclerotic plaques. In AS model mice, after intravenous (i.v.) administration, lip@EGCG/miR-223 was effectively accumulated in atherosclerotic plaques, and the distribution of drugs in the heart and aorta compared to that in the kidney was significantly increased when compared with free drugs (the ratio was 6.27% for the free miR-223-treated group, which increased to 66.10% for the lip@EGCG/miR-223-treated group). By decreasing the inflammation level and lipid accumulation, the arterial vessels in AS were normalized, with less macrophages and micro-angiogenesis, when treated with lip@EGCG/miR-223. Overall, this study demonstrated that lip@EGCG/miR-223 could be developed as a potential system for atherosclerosis treatment by a combined treatment of antioxidant, anti-inflammatory, and lipid-efflux-promoting effects, which provides a novel strategy for the safe and efficient management of atherosclerosis.

The Role of MMP-9 and MMP-9 Inhibition in Different Types of Thyroid Carcinoma.

Matrix metalloproteinase-9 (MMP-9), one of the most investigated and studied biomarkers of the MMPs family, is a zinc-dependent proteolytic metalloenzyme whose primary function is degrading the extracellular matrix (ECM). It has been proved that MMP-9 expression elevates in multiple pathological conditions, including thyroid carcinoma. MMP-9 has a detectable higher level in malignant or metastatic thyroid tumor tissues than in normal or benign tissues and acts as an additional marker to distinguish different tumor stages because of its close correlations with clinical features, such as lymph node metastasis, TNM stage, tumor size and so on. Natural and non-natural MMP-9 inhibitors suppress its expression, block the progression of diseases, and play a role in therapy consequently. MMP-9 inhibitory molecules also assist in treating thyroid tumors by suppressing the proliferation, invasion, migration, metastasis, viability, adhesion, motility, epithelial-mesenchymal transition (EMT), and other risk factors of different thyroid cancer cells. In a word, discovering and designing MMP-9 inhibitors provide great therapeutic effects and promising clinical values in various types of thyroid carcinoma.

Nickel-catalyzed sulfonylative coupling of 2-chlorobenzothiazoles with sulfinates at room temperature.

An efficient nickel-catalyzed cross-coupling for the synthesis of 2-sulfonylthiazoles from readily available 2-chlorobenzothiazoles and sodium sulfinates has been developed. A variety of 2-chlorobenzothiazoles and sulfinates having a diverse range of substitution patterns can undergo the coupling process successfully at room temperature. Avoiding the use of precious catalysts and sensitive ligands, moderate to excellent yields of various 2-sulfonylthiazoles were observed.

Rethinking nanoparticulate polymer-drug conjugates for cancer theranostics.

Polymer-drug conjugates (PDCs) fabricated as nanoparticles have hogged the limelight in cancer theranostics in the past decade. Many researchers have devoted to developing novel and efficient polymeric drug delivery system since the first generation of poly(N-[2-hydroxypropyl]methacrylamide) copolymer-drug conjugates. However, none of them has been approved for chemotherapy in clinic. An ideal PDC nanoparticle for cancer theranostics should possess several properties, including prolonged circulation in blood, sufficient accumulation and internalization in tumors, and efficient drug release in target sites. To achieve these goals, it is important to rationally design the nanoparticulate PDCs based on circulation, accumulation, penetration, internalization, and drug release (CAPIR) cascade. Specifically, CAPIR cascades are divided into five steps: (1) circulation in the vascular compartment without burst release, (2) accumulation in tumors via enhanced permeability and retention effect, (3) subsequent penetration into the deep regions of tumors, (4) internalization into tumor cells, and (5) release of drugs as free molecules to exert their pharmacological effects. In this review, we focus on the development and novel approaches of nanoparticulate PDCs based on CAPIR cascade, and provide an outlook on future clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Hydrogen-rich medium ameliorates lipopolysaccharides-induced mitochondrial fission and dysfunction in human umbilical vein endothelial cells (HUVECs) via up-regulating HO-1 expression.

BACKGROUND: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It has been showed that the change of mitochondrial dynamics has been proved to be one of the main causes of death in patients with severe sepsis. And hydrogen has been proved to exert its protective effects against sepsis via heme oxygenase-1 (HO-1). This study was designed to demonstrate that whether the benefit effects of hydrogen can maintain the dynamic process of mitochondrial fusion/fission to mitigate human umbilical vein endothelial cells (HUVECs) injury exposed to endotoxin through HO-1. METHODS: HUVECs cells cultured with medium which contained Lipopolysaccharides (LPS), Saline, hydrogen, Mdivi-1 (a dynamin-related protein 1 [Drp1] inhibitor) or zinc protoporphyrin IX (Znpp) (a HO-1 inhibitor) were also used in the research. Cell death and apoptosis were assessed using FITC annexin V and PI. Mitochondria were stained with Mitotracker orange and observed by confocal microscope. Oxygen consumption rate was assessed by seahorse xf24 extracellular analyzer. Mitochondrial membrane potential monitored by JC-1 dye. The expressions of Drp1 and HO-1 were tested by Western blot. The co-localization of Drp1 and mitochondria was determined by immunofluorescence. RESULTS: LPS caused a decrease in ATP content, mitochondrial membrane potential, and maximal respiration rate. At the same time, increased expression of Drp1 were observed in LPS-stimulated HUVECs, concomitantly with excessive mitochondrial fission. We found that hydrogen-rich medium can increase ATP content, mitochondrial membrane potential and maximal respiration rate, and decrease the expression of Drp1 in LPS-treated HUVECs. Meanwhile, hydrogen can ameliorate excessive mitochondrial fission caused by LPS. Furthermore, hydrogen-rich medium had a similar effect to Mdivi-1, a mitochondrial fission blocker. Both of them rescued the up-regulation of Drp1 and mitochondrial fission induced by LPS, then normalized mitochondrial shape after LPS stimulation. But after Znpp pretreatment, HO-1 expression was inhibited and the protective effects of hydrogen were abrogated. CONCLUSIONS: Hydrogen-rich medium can alleviate the LPS-induced mitochondrial fusion/fission and dysfunction in HUVECs via HO-1 up-regulation.

A pyroptosis nanotuner for cancer therapy.

Pyroptosis is a gasdermin-mediated programmed necrosis that occurs via membrane perforation and that can be exploited for biomedical applications in cancer therapy. However, inducing specific pyroptotic cancer cell death while sparing normal cells is challenging. Here, we report an acid-activatable nanophotosensitizer library that can be used to spatiotemporally target distinct stages of endosomal maturation, enabling tunable cellular pyroptosis. Specific activation of phospholipase C signalling transduction in early endosomes triggers gasdermin-E-mediated pyroptosis, which is dramatically reduced when acid-activatable nanophotosensitizers are transported into late endosomes/lysosomes. This nanotuner platform induces pyroptotic cell death with up to 40-fold tunability in various gasdermin-E-positive human cancers, resulting in enhanced anti-tumour efficacy and minimized systemic side effects. This study offers new insights into how to engineer nanomedicines with tunable pyroptosis activity through specific targeting of distinct endocytic signalling for biomedical applications.

Dissecting extracellular and intracellular distribution of nanoparticles and their contribution to therapeutic response by monochromatic ratiometric imaging.

Efficient delivery of payload to intracellular targets has been identified as the central principle for nanomedicine development, while the extracellular targets are equally important for cancer treatment. Notably, the contribution of extracellularly distributed nanoparticles to therapeutic outcome is far from being understood. Herein, we develop a pH/light dual-responsive monochromatic ratiometric imaging nanoparticle (MRIN), which functions through sequentially lighting up the intracellular and extracellular fluorescence signals by acidic endocytic pH and near-infrared light. Enabled by MRIN nanotechnology, we accurately quantify the extracellular and intracellular distribution of nanoparticles in several tumor models, which account for 65-80% and 20-35% of total tumor exposure, respectively. Given that the majority of nanoparticles are trapped in extracellular regions, we successfully dissect the contribution of extracellularly distributed nanophotosensitizer to therapeutic efficacy, thereby maximize the treatment outcome. Our study provides key strategies to precisely quantify nanocarrier microdistribtion and engineer multifunctional nanomedicines for efficient theranostics.

A pH-/Enzyme-Responsive Nanoparticle Selectively Targets Endosomal Toll-like Receptors to Potentiate Robust Cancer Vaccination.

Toll-like receptor (TLR) agonists are potent immune-stimulators that hold great potential in vaccine adjuvants as well as cancer immunotherapy. However, TLR agonists in free form are prone to be eliminated quickly by the circulatory system and cause systemic inflammation side effects. It remains a challenge to achieve precise release of TLR7/8 agonist in the native form at the receptor site in the endosomal compartments while keeping stable encapsulation and inactive in nontarget environment. Here, we report a pH-/enzyme-responsive TLR7/8 agonist-conjugated nanovaccine (TNV), which responds intelligently to the acidic environment and cathepsin B in the endosome, precisely releases TLR7/8 agonist to activate its receptor signaling at the endosomal membrane, stimulates DCs maturation, and provokes specific cellular immunity. In vivo experiments demonstrate outstanding prophylactic and therapeutic efficacy of TNV in mouse melanoma and colon cancer. The endosome-targeted responsive nanoparticle strategy provides a potential delivery toolbox of adjuvants to advance the development of tumor nanovaccines.

High concentration of hydrogen gas alleviates Lipopolysaccharide-induced lung injury via activating Nrf2 signaling pathway in mice.

BACKGROUND AND AIMS: The lung is the first organ to fail in sepsis. Our previous studies have proven that 2% molecular hydrogen (H2) inhalation remain a protective effect on a septic animal model via its anti-inflammatory and anti-apoptosis properties. This current research aims to observe the therapeutic effect of high concentration hydrogen (67%, HCH) on lipopolysaccharide (LPS) induced acute lung injury (ALI), and further investgate the role of Nrf2 signaling pathway. METHODS: ALI model was induced by LPS areosol inhalation. HCH were treated for 1 h at 1 and 6 h after modelling. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 4 and 24 h after the exposure of LPS. The histological scores, wet/dry weight ratios, myeloperoxidase (MPO) activity, protein content and cytokine levels in BALF, apoptosis condition of lung cells, expression of Nrf2 and NF-κB were assessed in both wild type and Nrf2-knockout mice. RESULTS: HCH Inhalation significantly alleviated LPS-induced pathological alterations of lung, and reduced the protein concentration, the wet/dry weight ratio, and the MPO activity of lung tissue. HCH Inhalation improved LPS-induced increasement in caspase-3 activity and the number of TUNEL-positive cells. HCH inhalation attenuated the LPS induced increased total cell content and polymorphonuclear granulocyte content, and pro-inflammatory cytokines, Nrf2 and NF-κB expression. HCH could not produce protective effct in Nrf2-knockout mice. CONCLUSION: HCH can effectively alleviate LPS-induced ALI, which may be related to activation of Nrf2 signaling pathway and inhibition of inflammatory response and cell apoptosis mediated by NF-κB.

Hydrogen alleviates cell damage and acute lung injury in sepsis via PINK1/Parkin-mediated mitophagy.

BACKGROUND: Multiple organ failure (MOF) is the main cause of early death in septic shock. Lungs are among the organs that are affected in MOF, resulting in acute lung injury. Inflammation is an important factor that causes immune cell dysfunction in the pathogenesis of sepsis. Autophagy is involved in the process of inflammation and also occurs in response to cell and tissue injury in several diseases. We previously demonstrated that hydrogen alleviated the inflammation-induced cell injury and organ damage in septic mice. AIM: The focus of the present study was to elucidate whether mitophagy mediates the inflammatory response or oxidative injury in sepsis in vitro and in vivo. Furthermore, we evaluated the role of mitophagy in the protective effects of hydrogen against cell injury or organ dysfunction in sepsis. METHOD: RAW 264.7 macrophages induced by lipopolysaccharide (LPS) were used as an in vitro model for inflammation, and cecal ligation and puncture (CLP)-induced acute lung injury mice were used as an in vivo model for sepsis. The key protein associated with mitophagy, PTEN-induced putative kinase 1 (PINK1), was knocked down by PINK1 shRNA transfection in RAW 264.7 macrophages or mice. RESULTS: Hydrogen ameliorated cell injury and enhanced mitophagy in macrophages stimulated by LPS. PINK1 was required for the mitigation of the cell impairment in LPS-stimulated macrophages by hydrogen treatment. PINK1 knockdown abrogated the beneficial effects of hydrogen on mitophagy in LPS-stimulated macrophages. Hydrogen inhibited acute lung injury in CLP mice via activation of PINK1-mediated mitophagy. CONCLUSION: These results suggest that PINK1-mediated mitophagy plays a key role in the protective effects of hydrogen against cell injury in LPS-induced inflammation and CLP-induced acute lung injury.

Hydrogen sulfide attenuates renal I/R­induced activation of the inflammatory response and apoptosis via regulating Nrf2­mediated NLRP3 signaling pathway inhibition.

Renal ischemia/reperfusion (I/R) injury can lead to acute renal failure, delayed graft function and graft rejection. Nucleotide­binding oligomerization domain NOD­like receptor containing pyrin domain 3 (NLRP3)­mediated inflammation participates in the development of renal injury. Nrf2 accelerates NLRP3 signaling pathway activation and further regulates the inflammatory response. In addition, hydrogen sulfide serves a protective role in renal injury; however, the detailed underlying mechanism remains poorly understood. The present study investigated whether Nrf2 and NLRP3 pathway participate in hydrogen sulfide­regulated renal I/R­induced activation of the inflammatory response and apoptosis. Wild­type and Nrf2­knockout (KO) mice underwent surgery to induce renal I/R via clamping of the bilateral renal pedicles. A total of 20 mg/kg MCC950 (an NLRP3 inhibitor) was injected intraperitoneally daily for 14 days prior to surgery. Renal tissue and blood were collected from the I/R model mice to analyze NLRP3 and Nrf2 mRNA expression levels, NLRP3, PYD and CARD domain containing, caspase­1, IL­1ß, Nrf2 and heme oxygenase 1 protein expression levels, cell apoptosis, the secretion of tumor necrosis factor­α, IL­1ß and IL­6 cytokines and renal histopathology and function. Renal I/R activated the NLRP3 and Nrf2 signaling pathways. Conversely, MCC950 treatment inhibited activation of the NLRP3 signaling pathway, and prevented I/R­induced renal injury, release of cytokines and apoptosis in renal I/R model mice. Sodium hydrosulfide (NaHS) not only alleviated upregulation of NLRP3 protein expression levels, but also relieved renal injury, release of cytokines and cell apoptosis induced by renal I/R in wild­type mice, but not in Nrf2­KO mice. NaHS alleviated NLRP3 inflammasome activation, renal injury, the inflammatory response and cell apoptosis via the Nrf2 signaling pathway in renal I/R model mice.

Dexmedetomidine protects against burn-induced intestinal barrier injury via the MLCK/p-MLC signalling pathway.

BACKGROUND: Evidence suggests that sedative dexmedetomidine can prevent intestinal dysfunction. However, the specific mechanisms of its protective effects against burn-induced intestinal barrier injury remain unclear. We aimed to explore the possible positive effects of dexmedetomidine on burn-induced intestinal barrier injury and the effects the myosin light chain kinase (MLCK)/phosphorylated myosin light chain (p-MLC) signalling pathway in an experimental model of burn injury. METHODS: In this study, the plasma concentration of fluorescein isothiocyanate-labelled dextran (FITC-dextran) was measured. Histological changes were evaluated using haematoxylin and eosin (HE) staining. Tight junction proteins were evaluated by western blot and immunofluorescence analyses to assess the structural integrity of intestinal tight junctions. The level of inflammation was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The results shows that the increase in intestinal permeability caused by burn injury is accompanied by histological damage to the intestine, decreases in the expression of the tight junction proteins Zonula Occludens-1 (ZO-1) and Occludin, increases in inflammatory cytokine levels and elevation of both MLCK protein expression and MLC phosphorylation. After dexmedetomidine treatment, the burn-induced changes were ameliorated. CONCLUSIONS: In conclusion, dexmedetomidine exerted an anti-inflammatory effect and protected tight junction complexes against burn­induced intestinal barrier damage by inhibiting the MLCK/p-MLC signalling pathways.

Cooperative Self-Assembled Nanoparticle Induces Sequential Immunogenic Cell Death and Toll-Like Receptor Activation for Synergistic Chemo-immunotherapy.

Anticancer immunotherapy is hampered by poor immunogenicity and a profoundly immunosuppressive microenvironment in solid tumors and lymph nodes. Herein, sequential pH/redox-responsive nanoparticles (SRNs) are engineered to activate the immune microenvironment of tumor sites and lymph nodes. The two-modular SRNs could sequentially respond to the acidic tumor microenvironment and endosome compartments of dendritic cells (DCs) to precisely deliver doxorubicin (DOX) and imidazoquinolines (IMDQs). In the tumor microenvironment, released DOX triggers immunogenic cell death. In sentinel lymph nodes, the IMDQ nanoparticle module is dissociated in the acidic endosome compartment to specifically stimulate toll-like receptor 7/8 for DC maturation. Thus, the orchestrated nanoparticle system could enhance the infiltration of CD8α+ T cells in tumors and provoke a strong antitumor immune response toward primary and abscopal tumors in B16-OVA and CT26 tumor-bearing mice models. The cooperative self-assembled nanoparticle strategy provides a potential candidate of nanomedicine to advance the synergistic cancer chemo-immunotherapy.

pH-Amplified CRET Nanoparticles for In Vivo Imaging of Tumor Metastatic Lymph Nodes.

Noninvasive imaging strategies have been extensively investigated for in vivo mapping of sentinel lymph nodes (SLNs). However, the current imaging strategies fail to accurately assess tumor metastatic status in SLNs with high sensitivity. Here we report pH-amplified self-illuminating near-infrared nanoparticles, which integrate chemiluminescence resonance energy transfer (CRET) and signal amplification strategy, enabling accurate identification of metastatic SLNs. After draining into lymph nodes, the nanoparticles were phagocytosed and dissociated in acidic phagosomes of inflammatory macrophages to emit near-infrared luminescent light. Using these nanoparticles, we successfully differentiated tumor metastatic lymph nodes from benign ones. These nanoparticles also exhibited excellent imaging capability for early detection of metastatic SLNs in diverse animal tumor models with small tumor volume (100-200 mm3 ).

Precise Monitoring of Singlet Oxygen in Specific Endocytic Organelles by Super-pH-Resolved Nanosensors.

Singlet oxygen (1O2) plays a vital role in pathophysiological processes and is the dominant executor of photodynamic therapy (PDT). Several small molecular probes have been designed to detect singlet oxygen for the evaluation of PDT efficacy. However, little attention was paid to the precise visualization of the 1O2 signal at the subcellular organelle level in living biological systems. Herein, a super-pH-resolved (SPR) nanosensor was developed to specifically illuminate 1O2 in endocytic organelles through encoding the cell-impermeant singlet oxygen sensor green (SOSG) into pH-sensitive micelles. The acid-activatable SPR-SOSG achieved more than 10-fold amplification of the 1O2 signal, leading to extremely higher sensitivity of singlet oxygen detection in specific endocytic organelles of living cells and animals, as compared with the nonactivatable nanoprobe and the commercially available 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe. Hence, the SPR-SOSG nanoplatform provides a promising tool to evaluate the efficacy and mechanism of nanocarrier-based photodynamic therapy.

Quantitative imaging of intracellular nanoparticle exposure enables prediction of nanotherapeutic efficacy.

Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.

P2X4 receptor in the dorsal horn contributes to BDNF/TrkB and AMPA receptor activation in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.

The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain-related studies showed that P2X4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model. The study simulated the remifentanil infusion and surgical incision during general anesthesia. The mRNA and protein expression level of P2X4R in rats with RIH model increased from 2 h to 48 h after the surgery. The administration of P2X4R inhibitors prevented the occurrence of RIH, resulting in a reduction in mechanical and thermal pain. Moreover, P2X4R was involved in RIH in male and female rats, indicating no sex-specific difference. P2X4R also increased the expression of AMPA receptor subunit GluA1 in a brain-derived neurotrophic factor (BDNF) / tyrosine receptor kinase B (TrkB) dependent manner. The results from whole-cell patch-clamp recording suggested that P2X4R also regulated AMPA receptor-mediated miniature excitatory postsynaptic currents and participated in the synaptic plasticity of spinal dorsal horn neurons. In summary, P2X4R was involved in AMPAR expression, electrophysiological function, and synaptic plasticity of spinal dorsal horn neurons through BDNF/TrkB signaling. This might be the mechanism underlying RIH, and hence inhibition of P2X4R might be a potential treatment strategy.

Sequential Modulations of Tumor Vasculature and Stromal Barriers Augment the Active Targeting Efficacy of Antibody-Modified Nanophotosensitizer in Desmoplastic Ovarian Carcinoma.

Active-targeted nanoparticles are attractive carriers due to their potentials to facilitate specific delivery of drugs into tumor cells while sparing normal cells. However, the therapeutic outcomes of active-targeted nanomedicines are hampered by the multiple physiological barriers in the tumor microenvironment (TME). Herein, an epidermal growth factor receptor-targeted ultra-pH-sensitive nanophotosensitizer is fabricated, and the regulation of the TME to augment the active targeting ability and therapeutic efficacy is pinpointed. The results reveal that tumor vasculature normalization with thalidomide indiscriminately enhance the tumor accumulation of passive and active targeted nanoparticles, both of which are sequestered in the stromal bed of tumor mass. Whereas, photoablation of stromal cells located in perivascular regions significantly improves the accessibility of antibody-modified nanophotosensitizer to receptor-overexpressed cancer cells. After sequential regulation of TME, the antitumor efficacy of antibody-modified nanophotosensitizer is drastically enhanced through synergistic enhancements of tumor accumulation and cancer cell accessibility of active-targeted nanoparticles. The study offers deep insights about the intratumoral barriers that hinder the active-targeted nanoparticles delivery, and provides a basis for developing more effective strategies to accelerate the clinical translation of active-targeted nanomedicines.

Effect of Equal Channel Angular Pressing on the Dynamic Softening Behavior of Ti-6Al-4V Alloy in the Hot Deformation Process.

To investigate the effect of equal channel angular pressing (ECAP) on the deformation of Ti-6Al-4V alloy at a higher temperature, hot compression tests were conducted on alloys having two different initial microstructures (the original alloy (Pre-ECAP) and ECAP-deformed alloy (Post-ECAP)). Post-ECAP, the alloy showed a higher degree of dynamic softening during the hot deformation process due to its finer grain size and higher distortion energy. The flow stress of Post-ECAP alloy was higher than the Pre-ECAP alloy at 500 °C when ε˙= 0.003 s-1. However, the stress of the Post-ECAP alloy decreased rapidly with increasing temperature and strain rate, until the stress value was much lower than that of Pre-ECAP at 700 °C when ε˙= 0.03 s-1. The value of the dynamic softening coefficient revealed that the dynamic softening behavior of Post-ECAP was more pronounced than that of Pre-ECAP in the hot compression deformation process. The main dynamic softening mechanism of Pre-ECAP is dynamic recovery, while the dynamic recrystallization process plays a more important role in the deformation process of Post-ECAP alloy. The microstructures observation results showed that dynamic recrystallization was more likely to occur to Post-ECAP alloys under the same deformation condition. Almost fully dynamic recrystallization had occurred in the deformation process of Post-ECAP at 700 °C and a strain rate of ε˙= 0.01 s-1. The grains of Post-ECAP alloys were further refined. The Post-ECAP alloy exhibits better plastic deformation at temperatures higher than 600 °C due to its significant dynamic recrystallization.