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Metastasis is one of the most significant causes for deterioration of breast cancer, contributing to the clinical failure of anti-tumour drugs. Excessive inflammatory responses intensively promote the occurrence and development of tumour, while protease-activated receptor 2 (PAR2) as a cell membrane receptor actively participates in both tumour cell functions and inflammatory responses. However, rare investigations linked PAR2-mediated inflammatory environment to tumour progression. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology is an emerging and powerful gene editing technique and can be applied for probing the new role of PAR2 in breast cancer metastasis, but it still needs the development of an efficient and safe delivery system. This work constructed anionic bovine serum albumin (BSA) nanoparticles to encapsulate CRISPR/Cas9 plasmid encoding PAR2 sgRNA and Cas9 (tBSA/Cas9-PAR2) for triggering PAR2 deficiency. tBSA/Cas9-PAR2 remarkably promoted CRISPR/Cas9 to enter and transfect both inflammatory and cancer cells, initiating precise PAR2 gene editing in vitro and in vivo. PAR2 deficiency by tBSA/Cas9-PAR2 effectively suppressed NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome signalling in inflammatory microenvironment to magnify stimulator of interferon genes (STING) signalling, reactive oxygen species (ROS) accumulation and epithelial-mesenchymal transition (EMT) reversal, consequently preventing breast cancer metastasis. Therefore, this study not only demonstrated the involvement and underlying mechanism of PAR2 in tumour progression via modulating inflammatory microenvironment, but also suggested PAR2 deficiency by tBSA/Cas9-PAR2 as an attractive therapeutic strategy candidate for breast cancer metastasis. tBSA/Cas9-PAR2 modulated inflammatory tumour microenvironment to magnify STING signalling, consequently alleviating tumour metastasis. [Display omitted] • Anionic nanoparticles delivered CRISPR/Cas9 to elicit precise gene editing of PAR2. • PAR2 deficiency alleviated breast cancer metastasis via inflammatory environment. • PAR2 deficiency mitigated NLRP3 inflammasome to magnify STING signalling. [ABSTRACT FROM AUTHOR]

Hexanucleotide repeat expansion in C9ORF72 (C9) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One of the proposed pathogenic mechanisms is the neurotoxicity arising from dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG (RAN) translation. Therefore, reducing DPR levels emerges as a potential therapeutic strategy for C9ORF72-ALS/FTD. We previously identified an RNA helicase, DEAD-box helicase 3 X-linked (DDX3X), modulates RAN translation. DDX3X overexpression decreases poly-GP accumulation in C9ORF72-ALS/FTD patient-derived induced pluripotent stem cell (iPSC)-differentiated neurons (iPSNs) and reduces the glutamate-induced neurotoxicity. In this study, we examined the in vivo efficacy of DDX3X overexpression using a mouse model. We expressed exogenous DDX3X or GFP in the central nervous system (CNS) of the C9–500 ALS/FTD BAC transgenic or non-transgenic control mice using adeno-associated virus serotype 9 (AAV9). The DPR levels were significantly reduced in the brains of DDX3X-expressing C9-BAC mice compared to the GFP control even twelve months after virus delivery. Additionally, p62 aggregation was also decreased. No neuronal loss or neuroinflammatory response were detected in the DDX3X overexpressing C9-BAC mice. This work demonstrates that DDX3X overexpression effectively reduces DPR levels in vivo without provoking neuroinflammation or neurotoxicity, suggesting the potential of increasing DDX3X expression as a therapeutic strategy for C9ORF72 - ALS/FTD. • AAV9-mediated DDX3X overexpression reduces DPR levels in C9-BAC mouse brain. • DDX3X overexpression decreases p62 inclusion in C9-BAC mice. • DDX3X overexpression does not cause neuroinflammation or neurotoxicity. [ABSTRACT FROM AUTHOR]

Background/Aims: Migraine is a disabling condition that severely impacts socioeconomic function and quality of life. The focus of this study was to develop a mouse model of trigeminal pain that mimics migraine. Methods: After undergoing dural cannulation surgery, mice were treated with repeated dural doses of an acidic solution to induce trigeminal pain. Results: The method elicited intermittent, head-directed wiping and scratching as well as the expression of both the c-FOS gene in the spinal trigeminal nucleus caudalis and calcitonin gene related peptide (CGRP) in the periaqueductal grey matter. Interestingly, the acid-induced trigeminal pain behaviour was inhibited by amiloride, an antagonist of acid-sensing ion channels (ASICs), but not by AMG-9810, an inhibitor of transient receptor potential cation channel V1(TRPV1). In addition, the relative mRNA and protein expression levels of ASIC1a and ASIC3 were increased in the acid-induced trigeminal nociceptive pathways. Furthermore, blocking CaMKII with KN-93 significantly reduced the acid-induced trigeminal pain behaviour and c-FOS gene expression. Conclusion: The data suggested that chronic intermittent administration of an acidic solution to mice resulted in trigeminal hypersensitivity and that dural acid-induced trigeminal pain behaviour in mice may mechanistically mimic migraine. The observations here identify an entirely novel treatment strategy for migraine. [ABSTRACT FROM AUTHOR]

The remarkable nonlinearity between the viscosity and temperature significantly reduces the extrusion formability of Nylon-66. The conventional extrusion methods, which obtain extrusion profiles with high precision through first extrusion and then sizing in calibrator, are unable to realize the extrusion of Nylon-66, especially for GF/Nylon-66 composite. In this paper, a one-step extrusion method, which realizes the fast sizing of extruded parts by taking advantages of the crystallization of GF/Nylon-66 melt, was proposed based on the viscosity change features and crystallization behavior of GF/Nylon-66 around its melting temperature ( T ). Thus, the sizing and cooling processes using standardized dies in conventional extrusion methods can be eliminated. In this study, the one-step extrusion process of GF/Nylon-66 was investigated from three aspects including the extrusion rheological performance, the equilibrium property of extrusion flow and crystallization sizing behavior, based on finite element simulations and experiments. The results revealed that the melt flow property can be improved by increasing temperature and shear rate. The rheological constitutive equation can precisely describe the rheological performance of materials under different temperatures and shear rates. Increasing melt temperature and screw speed will reduce the melt flow equilibrium. With the melt temperature at neck ring mold being the peak crystallizing temperature and screw speed being appropriate, an optimized dynamic balance among the melt flow property, the flow equilibrium performance and the crystallization sizing capability can be achieved. Thus, the extrusion molding of GF/Nylon-66 can be implemented via one-step extrusion. The method proposed can realize the extrusion molding of GF/Nylon-66 with improved efficiency and reduced cost. [ABSTRACT FROM AUTHOR]

Herlyn-Werner-Wunderlich syndrome (HWWS) is a müllerian duct anomaly typically associated with a uterus didelphys with two cervices and two vaginas, one of which is obstructed. A remarkable case of HWWS with contralateral duplex kidneys and duplication of ureters is described, which, to our knowledge, is a rarely reported variant to date. For this congenital anomaly, a strong suspicion and knowledge of HWWS are essential for a precise diagnosis. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The interleukin-1 receptor antagonist (IL-1Ra), having the potential of treating cancers, has been used for treating rheumatoid arthritis in clinic. To improve its therapeutic efficacy and patient compliance, IL-1Ra was often needed to prepare a long efficacy formulation using all kinds of method for protein stabilization. In this study, we reported a novel freezing-induced PEG water solution phase/dextran water solution phase separation method to prepare the IL-1Ra-loaded dextran microparticles to address stability of IL-1Ra in preparation process for all kinds of formulation, namely: first IL-1Ra was dissolved in water together with dextran and polyethylene glycol, and then by a freezing process during which dextran is separated out as the dispersed phase with IL-1Ra partitioned in dextran microparticles preferentially. The frozen sample was then lyophilized to powder and washed with dichloromethane to remove the PEG continuous phase. Once IL-Ra was loaded in the dextran microparticles, 1–5μm in diameter, the dextran microparticles gained resistance to oil/water interfaces without IL-Ra aggregation and activity loss. The bioactivity from dextran microparticles in vitro is preserved highly (above 98%), while bioactivity from IL-1Ra-loaded dextran microparticles using the control method of water-in-oil-in-water (W/O/W) method is only 70.5% by inhibiting melanoma B16 cell proliferation. The dextran microparticles may be used further to prepare different formulations according to clinic needs. [Copyright &y& Elsevier]

Etomidate is a general anesthetic that has shown good hemodynamic stability without significant cardiovascular or respiratory depression. Despite several kinds of dosage forms having been reported for this drug, formulation types are very limited in clinical practice, and brain-targeted formulations for this central nervous system (CNS) drug have been rarely reported. Moreover, studies on the biocompatibility, toxicity, and anesthetic effects of the etomidate preparations in vivo were inadequate. The present study was to develop lactoferrin-modified liposomal etomidate (Eto-lip-LF) for enhanced drug distribution in the brain and improved anesthetic effects. Eto-lip-LF had good stability for storage and hemocompatibility for intravenous injection. Compared with the non-lactoferrin-containing liposomes, the lactoferrin-modified liposomes had notably enhanced brain-targeting ability in vivo, which was probably realized by the binding of transferrin with the transferrin and lactoferrin receptors highly distributed in the brain. Eto-lip-LF had a therapeutic index of about 25.3, higher than that of many other general anesthetics. Moreover, compared with the commercial etomidate emulsion, Eto-lip-LF could better achieve rapid onset of general anesthesia and rapid recovery from anesthesia, probably due to the enhanced drug delivery to the brain. The above results demonstrated the potential of this lactoferrin-modified liposomal etomidate to become an alternative preparation for clinical general anesthesia. [ABSTRACT FROM AUTHOR]

Inflammatory diseases have become increasingly prevalent throughout the world. Coronavirus disease 2019 (COVID‐19), which has recently become pandemic, also exhibits hyperinflammation and cytokine release syndrome. To address inflammation‐related diseases, numerous molecular targets have been explored in preclinical studies and clinical trials. Among them, the protease‐activated receptors (PARs) that belong to G protein‐coupled receptors are one of the most popular classes of drug targets, participating in inflammatory signalling and diseases. PARs activation can trigger downstream intracellular signalling to modulate a variety of inflammatory responses in multiple systems, including nervous, respiratory, digestive, circulatory, urinary and immune systems. Importantly, there are the Yin‐Yang effects, comprising anti‐ and pro‐inflammatory roles, of PARs activation in different types of inflammations, and these are context‐dependent. Alternatively, it was recently revealed that PARs not only modulate inflammatory‐related tumour progression, but also participate in inflammatory cytokine release related to COVID‐19 via direct interaction with severe acute respiratory syndrome coronavirus 2 protein, suggesting that PARs also participate in other diseases via inflammatory responses. In this review, we renew and discuss the findings of PARs as molecular targets for treating inflammatory diseases, highlighting the novel roles of PARs and facilitating a better understanding of their designated values in the specific inflammatory environment. [ABSTRACT FROM AUTHOR]

Background: Surgery is a potential trigger of Guillain-Barré syndrome (GBS), a disorder which leads to an autoimmune-mediated attack of peripheral nerves. The present study was designed to explore clinical features of post-surgical GBS compared with those of general GBS in order to provide better clinical advice to patients undergoing surgery.Methods: The medical records of GBS patients who were seen at 31 tertiary hospitals in southern China between January 1, 2013 and September 30, 2016 were retrospectively analyzed. Post-surgical GBS was defined as symptoms of GBS within 6 weeks after surgery. Clinical features of post-surgical GBS are described and are compared with general GBS.Results: Among the 1001 GBS patient cases examined in this study, 45 (4.5%) patient cases exhibited symptoms of GBS within 6 weeks of undergoing surgery. Within this group, 36 (80.0%) patients developed initial symptoms of limb weakness. The average interval between surgery and symptom onset was 13.31 days. The most common type of surgery which triggered GBS was orthopedic surgery, followed by neurological surgery. Compared to general GBS, post-surgical GBS was characterized by a higher proportion of severe patients (Hughes functional grading scale (HFGS) score ≥ 3) upon admission and at nadir, higher HFGS scores at discharge, and longer hospital stays. Post-surgical GBS patients also had a significantly higher frequency of the acute motor axonal neuropathy subtype (37.9 vs. 14.2, respectively; P = 0.001).Conclusion: Surgery is probably a potential trigger factor for GBS, especially orthopedic surgery. Infections secondary to surgery may play a role. The possibility of preceding (post-operative) infections was not excluded in this study. Clinical presentation of post-surgical GBS is characterized by a more severe course and poorer prognosis, and should be closely monitored.Trial Registration: chicTR-RRc-17,014,152 . [ABSTRACT FROM AUTHOR]

[Display omitted] Dihydromyricetin (DHM) is an important natural flavonoid. However, most of DHM preparations have shown shortcomings such as low drug loading, poor drug stability, and/or large fluctuations in blood concentration. This study aimed to develop a gastric floating tablet with a double-layered structure for zero-order controlled release of DHM (DHM@GF-DLT). The final product DHM@GF-DLT showed a high average cumulative drug release at 24 h that best fit the zero-order model, and had a good floating ability in the stomach of the rabbit with a gastric retention time of over 24 h. The FTIR, DSC, and XRPD analyses indicated the good compatibility among the drug and the excipients in DHM@GF-DLT. The pharmacokinetic study revealed that DHM@GF-DLT could prolong the retention time of DHM, reduce the fluctuation of blood drug concentration, and enhance the bioavailability of DHM. The pharmacodynamic studies demonstrated that DHM@GF-DLT had a potent and long-term therapeutic effect on systemic inflammation in rabbits. Therefore, DHM@GF-DLT had the potential to serve as a promising anti-inflammatory agent and may develop into a once-a-day preparation, which was favorable to maintain a steady blood drug concentration and a long-term drug efficacy. Our research provided a promising development strategy for DHM and other natural products with a similar structure to DHM for improving their bioavailability and therapeutic effect. [ABSTRACT FROM AUTHOR]

Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor γ- (PPARγ-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARγ agonists, selective PPARγ modulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5′-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers. [ABSTRACT FROM AUTHOR]

Osimertinib, as the third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), is a first-line molecularly targeted drug for non-small cell lung cancer (NSCLC). However, the emergence of therapeutic resistance to osimertinib markedly impairs its efficiency and efficacy, leading to the failure of clinical applications. Novel molecular targets and drugs are urgently needed for reversing osimertinib resistance in NSCLC. Protease-activated receptor 2 (PAR2) that belongs to a subfamily of G protein-coupled receptors can stimulate the transactivation of EGFR to regulate multiple cellular signalling, actively participating in tumour progression. This study firstly discovered that PAR2 expression was notably enhanced when NSCLC cells became resistant to osimertinib. A PAR2 inhibitor facilitated osimertinib to attenuate EGFR transactivation, ERK phosphorylation, EMT and PD-L1 expression which were associated to osimertinib resistance. The combination of the PAR2 inhibitor and osimertinib also notably blocked cell viability, migration, 3D sphere formation and in vivo tumour growth whereas osimertinib itself lost such inhibitory effects in osimertinib-resistant NSCLC cells. Importantly, this reversal effect of PAR2 blockade was uncovered to depend on ERK-mediated EMT and PD-L1, since inhibition of β-arrestin or ERK, which could be modulated by PAR2, sensitized osimertinib to prevent EMT, PD-L1 expression and consequently overcame osimertinib resistance. Thus, this study demonstrated that PAR2 antagonism could limit ERK-mediated EMT and immune checkpoints, consequently attenuating EGFR transactivation and reactivate osimertinib. It suggested that PAR2 may be a novel drug target for osimertinib resistance, and PAR2 inhibition may be a promising strategy candidate for reversing EGFR-TKI resistance in NSCLC. • Targeting PAR2 overcame osimertinib resistance in NSCLCs. • PAR2 inhibition reactivated osimertinib to attenuate in vivo NSCLC tumour growth. • PAR2 modulated osimertinib resistance via ERK-mediated EMT and PD-L1. [ABSTRACT FROM AUTHOR]

A chemical investigation of the extract of the marine-sponge-associated fungus P. colombiensis resulted in the isolation of eight chlorinated benzophenone derivatives, named, pestalone (1), pestalachlorides A-C, E, and F (2 - 6), pestalalactone (7), and pestalalactone atropisomer (8). The structures of these compounds were identified by spectroscopic analysis (MS, 1D/2D NMR) and comparison with the previously reported data. Compounds (1 – 8) were isolated from this species for the first time. Moreover, compounds (1 – 8) had not been reported from any other genus , and the chemotaxonomic signifcance of eight chlorinated benzophenone derivatives (1 – 8) was also discussed. • Chlorinated benzophenone derivatives (1-8) were isolated from the marine-sponge-associated fungus pestalotiopsis colombiensis. Compounds (1 – 8) were isolated from this species for the first time. Chlorinated benzophenone derivatives (1 – 8) could be used as chemotaxonomic markers for the genus of pestalotiopsis. [ABSTRACT FROM AUTHOR]