Recent Research Advances in Nano-Based Drug Delivery Systems for Local Anesthetics.

From a clinical perspective, local anesthetics have rather widespread application in regional blockade for surgery, postoperative analgesia, acute/chronic pain control, and even cancer treatments. However, a number of disadvantages are associated with traditional local anesthetic agents as well as routine drug delivery administration ways, such as neurotoxicity, short half-time, and non-sustained release, thereby limiting their application in clinical practice. Successful characterization of drug delivery systems (DDSs) for individual local anesthetic agents can support to achieve more efficient drug release and prolonged duration of action with reduced systemic toxicity. Different types of DDSs involving various carriers have been examined, including micromaterials, nanomaterials, and cyclodextrin. Among them, nanotechnology-based delivery approaches have significantly developed in the last decade due to the low systemic toxicity and the greater efficacy of non-conventional local anesthetics. Multiple nanosized materials, including polymeric, lipid (solid lipid nanoparticles, nanostructured lipid carriers, and nanoemulsions), metallic, inorganic non-metallic, and hybrid nanoparticles, offer a safe, localized, and long-acting solution for pain management and tumor therapy. This review provides a brief synopsis of different nano-based DDSs for local anesthetics with variable sizes and structural morphology, such as nanocapsules and nanospheres. Recent original research utilizing nanotechnology-based delivery systems is particularly discussed, and the progress and strengths of these DDSs are highlighted. A specific focus of this review is the comparison of various nano-based DDSs for local anesthetics, which can offer additional indications for their further improvement. All in all, nano-based DDSs with unique advantages provide a novel direction for the development of safer and more effective local anesthetic formulations.

Contribution of immune cells to cancer-related neuropathic pain: An updated review.

Given that the incidence of cancer is dramatically increasing nowadays, cancer-related neuropathic pain including tumor-related and therapy-related pain gradually attracts more attention from researchers, which basically behaves as a metabolic-neuro-immune disorder with worse clinical outcomes and prognosis. Among various mechanisms of neuropathic pain, the common underlying one is the activation of inflammatory responses around the injured or affected nerve(s). Innate and adaptive immune reactions following nerve injury together contribute to the regulation of pain. On the other hand, the tumor immune microenvironment involving immune cells, as exemplified by lymphocytes, macrophages, neutrophils and dendritic cells, inflammatory mediators as well as tumor metastasis have added additional characteristics for studying the initiation and maintenance of cancer-related neuropathic pain. Of interest, these immune cells in tumor microenvironment exert potent functions in promoting neuropathic pain through different signaling pathways. To this end, this review mainly focuses on the contribution of different types of immune cells to cancer-related neuropathic pain, aims to provide a comprehensive summary of how these immune cells derived from the certain tumor microenvironment participate in the pathogenesis of neuropathic pain. Furthermore, the clarification of roles of various immune cells in different tumor immune microenvironments associated with certain cancers under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction, and thereby provides more opportunities for novel approaches for the prevention and treatment of cancer-related neuropathic pain.

Clinical identification of expressed proteins in adrenal medullary hyperplasia detected with hypertension.

Background: Hypertension remains a challenging public health problem worldwide, and adrenal gland-related diseases are one class of the major causes for secondary hypertension. Among them, one relatively rare pattern is adrenal hyperplastic hypertension caused by adrenal medullary hyperplasia (AMH), leading to excessive secretion of autonomic catecholamine. Given that the pathological changes of adrenal medulla are not well correlated to the onset and even severity of secondary hypertension, the molecular basis why some AMH patients are accompanied with hypertension remains unclear and is worth exploring. Aims: For this reason, this study aims at investigating differentially expressed proteins in clinical AMH tissue, with special focus on the potential contribution of these differentially expressed proteins to AMH development, in order to have a better understanding of mechanisms how AMH leads to secondary hypertension to some extent. Methods and results: To this end, AMH specimens were successfully obtained and verified through computed tomography (CT) and haematoxylin-eosin (HE) staining. Proteomic analyses of AMH and control tissues revealed 782 kinds of differentially expressed proteins. Compared with the control tissue, there were 357 types of upregulated proteins and 425 types of downregulated proteins detected in AMH tissue. Of interest, these differentially expressed proteins were significantly enriched in 60 gene ontology terms (P < 0.05), including 28 biological process terms, 14 molecular function terms, and 18 cellular component terms. Pathway analysis further indicated that 306 proteins exert their functions in at least one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Western blotting showed enhanced expression of phenylethanolamine N- methyltransferase (PNMT), myelin protein zero (MPZ), and Ras-related protein Rab-3C (RAB3C), and reduced expression of cluster of differentiation 36 (CD36) observed in AMH tissue in comparison with controls. Conclusions: Clinical AMH specimens display a different proteomic profile compared to control tissue. Of note, PNMT, MPZ, RAB3C, and CD36 are found to differentially expressed and can be potential targets for AMH, providing a theoretical basis for mechanistic exploration of AMH along with hypertension.

GLO1 Contributes to the Drug Resistance of Escherichia coli Through Inducing PER Type of Extended-Spectrum ß-Lactamases.

Background: Escherichia coli-associated antimicrobial resistance (AMR) issue so far needs urgent considerations. This study aims to screen the potent genes associated with extended-spectrum ß-lactamases (ESBLs) in drug-resistant Escherichia coli and elucidate the specific drug-resistant mechanism. Methods: Clinical ESBLs-EC samples were obtained based on the microbial identification, and the whole genome was sequenced. In combination with the significantly enriched pathways, several differently expressed genes were screened and verified by RT-PCR. Furthermore, through knocking out glyoxalase 1 (GLO1) gene and transfecting overexpressed plasmids, the potential relationship between GLO1 and ESBLs was then investigated. Lastly, the concentrations of ß-lactamases in bacteria and supernatant from different groups were examined by enzyme-linked immunosorbent assay (ELISA). Results: After successful isolation and identification of ESBLs-EC, the whole genome and eighteen differential metabolic pathways were analyzed to select differently expressed genes, including add, deoD, guaD, speG, GLO1, VNN1, etc. RT-PCR results showed that there were no differences in these genes between the standard bacteria and susceptible Escherichia coli. Remarkably, the relative levels of four genes including speG, Hdac10, GLO1 and Ppcdc were significantly increased in ESBLs-EC in comparison with susceptible strains, whereas other gene expression was decreased. Further experiments utilizing gene knockout and overexpression strains confirmed the role of GLO1. At last, a total of 10 subtypes of ß-lactamases were studied using ELISA, including BES-, CTX-M1-, CTX-M2-, OXA1-, OXA2-, OXA10-, PER-, SHV-, TEM-, and VEB-ESBLs, and results demonstrated that GLO1 gene expression only affected PER-ß-lactamases but had no effects on other ß-lactamases. Conclusion: SpeG, Hdac10, GLO1 and Ppcdc might be associated with the drug-resistant mechanism of Escherichia coli. Of note, this study firstly addressed the role of GLO1 in the drug resistance of ESBLs-EC, and this effect may be mediated by increasing PER-ß-lactamases.

Proteomics and metabolomics analysis reveal potential mechanism of extended-spectrum ß-lactamase production in Escherichia coli.

In this study, ten clinical susceptible strains and ten clinical ESBL-EC (extended-spectrum ß-lactamase-producing Escherichia coli) were screened and obtained by microbial identification using ITEK® 2 Compact. TMT (Tandem Mass Tag) proteomics analysis discovered 1553 DEPs (differentially expressed proteins) between ESBL-EC and non-ESBL-EC. In addition, an untargeted metabolomics assay by using UHPLC-MS (ultra-high-performance liquid chromatography-mass spectrometry) was applied to compare the differential profiles of metabolites between ß-lactam antibiotic-sensitive E. coli and multidrug-resistant ESBL-producing E. coli strains. The PCA (principal component analysis) score plots and OPLS-DA (orthogonal projections to latent structures discriminant analysis) plots clearly discriminated ESBL-EC and non-ESBL-EC, and volcano analysis presented 606 and 459 altered metabolites between ESBL-EC vs. non-ESBL-EC in positive and negative ion modes, respectively. Interestingly, the bioinformatics analysis demonstrated that the purine metabolism pathway was enriched in ESBL-EC. These results suggest that the existence of extended-spectrum ß-lactamase affects the metabolite and protein profiles of E. coli. The correlation analysis of metabolomics and proteomics data established a correlation between DEPs and differential metabolites in the purine metabolism pathway. Moreover, three metabolite candidates in the purine metabolism pathway were validated by the UPLC-MRM-MS (ultra-performance liquid chromatography multiple reaction monitoring mass spectrometry) method. Our data suggest that these DEPs and differential metabolites may play important roles in the antibiotic resistance of ESBL-EC. Our study can provide scientific data for the mechanism study of antibiotic resistance of ESBL-EC at the metabolite and protein levels and targeting modulators to these pathways may be effective for treatment of ESBL-EC strains.

ITRAQ-based proteomic analysis reveals possible target-related proteins in human adrenocortical adenomas.

BACKGROUND: Adrenocortical adenomas (ACAs) can lead to the autonomous secretion of aldosterone responsible for primary aldosteronism (PA), which is the most common form of secondary arterial hypertension. However, the authentic fundamental mechanisms underlying ACAs remain unclear. OBJECTIVE: Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics and bioinformatics analyses from etiological studies of ACAs were performed to screen the differentially expressed proteins (DEPs) and investigate the relevant mechanisms of their occurrence and development. Results could help determine therapeutic targets of clinical significance. METHODS: In the present study, iTRAQ-based proteomics was applied to analyze ACA tissue samples from normal adrenal cortex tissues adjacent to the tumor. Using proteins extracted from a panel of four pairs of ACA samples, we identified some upregulated proteins and other downregulated proteins in all four pairs of ACA samples compared with adjacent normal tissue. Subsequently, we predicted protein-protein interaction networks of three DEPs to determine the authentic functional factors in ACA. RESULTS: A total of 753 DEPs were identified, including 347 upregulated and 406 downregulated proteins. The expression of three upregulated proteins (E2F3, KRT6A, and ALDH1A2) was validated by Western blot in 24 ACA samples. Our data suggested that some DEPs might be important hallmarks during the development of ACA. CONCLUSIONS: This study is the first proteomic research to investigate alterations in protein levels and affected pathways in ACA using the iTRAQ technique. Thus, this study not only provides a comprehensive dataset on overall protein changes but also sheds light on its potential molecular mechanism in human ACAs.

Warming infusion improves perioperative outcomes of elderly patients who underwent bilateral hip replacement.

BACKGROUND: This prospective, randomized, and controlled study was performed to determine the benefits of prewarmed infusion in elderly patients who underwent bilateral hip replacement. METHODS: Between September 2015 and April 2016, elderly patients who underwent bilateral hips replacement that met the inclusion and exclusion criteria were included in this study. After inclusion, patients were randomized into one of the study groups: in the control group, patients received an infusion of fluid kept at room temperature (22-23°C); in the warming infusion group, patients received an infusion of fluid warmed using an infusion fluid heating apparatus (35°C). Postoperative outcomes, including recovery time, length of hospital stay, visual analogue scale (VAS) score, and postoperative complications rate of patients from both groups, were compared. RESULTS: A total of 64 patients were included in our study (71.2 ±â€Š7.6 years, 53.1% males), with 32 patients in the control group and 32 patients in warming infusion group. No significant difference was found in terms of demographic data and intraoperative blood transfusion rate between 2 groups (P > 0.05). Patients receiving a prewarmed infusion had a significantly shorter time to spontaneous breath, eye opening, consciousness recovery, and extubation than the control group (P < 0.05). In addition, significant differences were found in Steward score and VAS score between 2 groups (P < 0.05). Moreover, warming infusion group also showed an obviously decreased incidence of shivering and postoperative cognitive dysfunction (P < 0.05). CONCLUSION: A prewarmed infusion could reduce the incidence of perioperative hypothermia and improve outcomes in the elderly during bilateral hip replacement.