Neutrophil extracellular traps in central nervous system (CNS) diseases.

Excessive induction of inflammatory and immune responses is widely considered as one of vital factors contributing to the pathogenesis and progression of central nervous system (CNS) diseases. Neutrophils are well-studied members of inflammatory and immune cell family, contributing to the innate and adaptive immunity. Neutrophil-released neutrophil extracellular traps (NETs) play an important role in the regulation of various kinds of diseases, including CNS diseases. In this review, current knowledge on the biological features of NETs will be introduced. In addition, the role of NETs in several popular and well-studied CNS diseases including cerebral stroke, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and neurological cancers will be described and discussed through the reviewing of previous related studies.

T cells, NK cells, and tumor-associated macrophages in cancer immunotherapy and the current state of the art of drug delivery systems.

The immune system provides full protection for the body by specifically identifying 'self' and removing 'others'; thus protecting the body from diseases. The immune system includes innate immunity and adaptive immunity, which jointly coordinate the antitumor immune response. T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are the main tumor-killing immune cells active in three antitumor immune cycle. Cancer immunotherapy focusses on activating and strengthening immune response or eliminating suppression from tumor cells in each step of the cancer-immunity cycle; thus, it strengthens the body's immunity against tumors. In this review, the antitumor immune cycles of T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are discussed. Co-stimulatory and co-inhibitory molecules in the three activity cycles and the development of drugs and delivery systems targeting these molecules are emphasized, and the current state of the art of drug delivery systems for cancer immunotherapy are summarized.

Nicotine Suppresses Phagocytic Ability of Macrophages by Regulating the miR-296-3p-SIRPα Axis.

Phagocytic ability of macrophage is responsible for tuberculosis infection. Nicotine has been shown to attenuate the phagocytic ability of macrophage; however, the underlying mechanism remains unclear. Here, we demonstrated that nicotine increased the message RNA (mRNA) and protein expression of signal regulatory protein alpha (SIRPα) and enhanced the stability of SIRPα mRNA in macrophage. Nicotine decreased the expression of microRNA (miR)-296-3p, which directly targeted the 3'-untranslated region (3'-UTR) of SIRPα mRNA in macrophage. Furthermore, nicotine inhibited the phagocytic ability of macrophage by regulating the miR-296-3p-SIRPα axis. Moreover, nicotine decreased miR-296-3p expression via increasing c-Myc expression in macrophage. Together, we found that nicotine attenuate the phagocytic ability of macrophage by regulating the c-Myc-miR-296-3p-SIRPα signal.

NLRP3 Inflammasome in Atherosclerosis: Putting Out the Fire of Inflammation.

Atherosclerosis (AS) is a chronic inflammatory disease with thickening or hardening of the arteries, which led to the built-up of plaques in the inner lining of an artery. Among all the clarified pathogenesis, the over-activation of inflammatory reaction is one of the most acknowledged one. The nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome, as a vital and special form of inflammation and innate immunity, has been widely revealed to participate in the onset and development of AS. This review will introduce the process of the pathogenesis and progression of AS, and will describe the biological features of the NLRP3 inflammasome. Furthermore, the role of the NLRP3 inflammasome in AS and the possible mechanisms will be discussed. In addition, several kinds of agents with the effect of anti-atherosclerotic taking advantage of the NLRP3 inflammasome intervention will be described and discussed in detail, including natural compounds (baicalin, dihydromyricetin, luteolin, 5-deoxy-rutaecarpine (R3) and Salvianolic acid A, etc.), microRNAs (microRNA-30c-5p, microRNA-9, microRNA-146a-5p, microRNA-16-5p and microRNA-181a, etc.), and autophagy regulators (melatonin, dietary PUFA and arglabin, etc.). We aim to provide novel insights in the exploration of the specific mechanisms of AS and the development of new treatments of AS.

Efficacy of compound aluminum sulfate injection as a monotherapeutic regimen in non-muscle invasive bladder cancer patients: a retrospective single-arm cohort study.

Background: Compound aluminum sulfate injection (CASI) originated from a Chinese traditional medicine, "Kuzhiye", and has been used in treating non-muscle invasive bladder cancer (NMIBC). Previous studies suggested that CASI was a potential monotherapeutic drug for NMIBC. However, the efficacy and safety of CASI in the treatment of NMIBC, as well as the long-term recurrence after treatment, need to be further evaluated. Methods: A multicenter retrospective single-arm cohort study was conducted. From 2006 to 2009, 101 patients (74 men and 27 women, aged 58.9±11.9 years) with T1 or benign NMIBC were enrolled. Each patient was directly injected with CASI through catheter needle into the root of NMIBC. Vital signs, electrocardiography, blood count, blood biochemistry, and urine analysis were re-examined on day 2 and day 14 after CASI injection, together with a cystoscopic examination 4 weeks after CASI treatment was performed for all patients to assess the clinical activity and safety of CASI. To study long-term efficacy, patients in center 2 were followed up for recurrence with a median follow-up time of 13.8 years. Results: For the 101 patients enrolled in this study, demographic characteristics in the 3 centers showed no significant differences. After CASI, 2 patients showed administration site-dependent, but not dose-dependent, increase in their aluminum concentration in 24 hours without obvious abnormality in blood biochemistry. The overall effective rate was 97.03%, including complete tumor necrosis in 94 patients. Treatment-related adverse events occurred in 20 patients (19.80%), including 9 drug-related and 11 cystoscopy-related adverse events (AEs). All AEs were endurable and disappeared within 2 weeks without any treatment. The maximum tolerated single dose of CASI was 21 mL. Among the 43 patients at center 2, 3 patients were excluded because they changed to other treatment regimen. As of April 2022, of the 40 patients enrolled, 22 had no recurrence and 7 relapsed. The follow-up time was 2-16.2 years. The other 11 patients were lost to follow up. Conclusions: CASI may be an effective and safe option for the treatment of NMIBC and is expected to be a potential monotherapy regimen for NMIBC.

Analysis of influencing factors on the plasma concentration of first-line anti-tuberculosis drugs-a single-center retrospective cohort study.

Background: The four most commonly used first-line anti-tuberculosis (TB) drugs in clinical practice are isoniazid (INH), rifampicin (RFP), ethambutol (EMB), and pyrazinamide (PZA). The plasma concentration of anti-TB drugs is an important factor influencing the effectiveness of TB treatment. Factors affecting blood concentration of antituberculosis drugs have not been elaborated clearly. The purpose of this study is to investigate the status of plasma concentration of anti-TB drugs, explore the factors influencing anti-TB drug plasma concentration, and guide the rational use of clinical drugs. Methods: This is a single-center retrospective cohort study. Patients with pulmonary TB received first-line anti-TB drugs in the 309th Hospital of the PLA from June 2014 to September 2018 were investigated. The primary endpoint was factors affecting the anti-tuberculosis drug plasma concentration which were determined by high performance liquid chromatography-mass spectrometry. The factors influencing plasma concentration analyzed by the multiple linear regression model. Results: A total of 205 patients were included in the study. The rates of patients with substandard 2-hour plasma concentrations of INH, RFP, EMB, and PZA were 45.8%, 54.4%, 37.7%, and 52.9%, respectively. Intravenous administration of INH (P<0.001) significantly increased plasma concentrations compared with oral administration, and its plasma concentration was negatively correlated with blood uric acid levels (P=0.001). RFP 2-hour plasma concentrations were positively correlated with serum albumin levels (P=0.04). EMB 2-hour plasma concentrations were positively correlated with age (P=0.01), dose (P<0.001), and serum creatinine levels (P<0.001). PZA 2-hour plasma concentrations were positively correlated with dose (P<0.001) and total bilirubin levels (P<0.001), and were negatively correlated with blood urea nitrogen levels (P=0.001). Conclusions: Age, gender, dose, intravenous administration, retreatment, blood uric acid level, serum albumin level, serum creatinine level, total bilirubin level, and blood urea nitrogen level were independent influencing factors of anti-TB drug plasma concentration. During anti-TB treatment, plasma concentration monitoring is essential and helpful to optimize the drug dose and carry out individualized treatment regimen.

Combining bioinformatics and biological detection to identify novel biomarkers for diagnosis and prognosis of pulmonary tuberculosis.

OBJECTIVES: To identify the novel and promising indicators for pulmonary tuberculosis (PTB) patients. METHODS: The study was carried out between June 2016 and June 2019. Three RNA sequencing or microarray datasets of TB infection were used to identify the potential genes showing a common expression trend. The expression level of screened targets was determined by reverse transcription polymerase chain reaction and ELISA using samples of whole blood and peripheral blood mononuclear cells (PBMCs) isolated from 69 PTB patients and 69 healthy volunteers. The potential of the identified targets to predict the treatment outcomes was further studied. RESULTS: Bioinformatics analysis demonstrated that a total of 91 genes were up-regulated in all the 3 datasets; among them, the expression of SLAMF8, LILRB4, and IL-10Ra was significantly increased at both the mRNA and protein levels in whole blood and PBMC samples of PTB patients compared with the healthy controls. The mortality rate increased significantly in SLAMF8 or LILRB4 high expression group compared with SLAMF8 or LILRB4 low expression group. Further, the decrease rate of bacteria in patients with SLAMF8 or LILRB4 high expression was slower than that in patients with SLAMF8 or LILRB4 low expression. CONCLUSION: This study provides a promising way to identify novel indicators for PTB. Moreover, the LILRB4 expression may play a role in predicting the outcome of treatments on PTB patients.

Computer-assisted engineering of programmed drug releasing multilayer nanomedicine via indomethacin-mediated ternary complex for therapy against a multidrug resistant tumor.

Nanomedicine with programmed drug release can give full play to the synergistic effect of multi-component system in complicated tumor environment. However, the construction of these programmed drug delivery systems often depends on the sophisticated materials design and synthesis. In this study, we successfully designed an indomethacin (IND)-mediated ternary complex system based on a PEG cleavable polyethyleneimine (PEI), indomethacin (IND) and benzene ring containing chemotherapeutic drugs (such as paclitaxel (PTX), doxorubicin and docetaxel). Based on the difference of hydrophobicity in these components, these components were one-pot self-assembled into drug-loaded IND mediated PEGylation cleavable nanoassemblies (IPCNs) in multilayer structure. In drug-loaded IPCNs, PEG fragments, PEI/IND, and chemotherapeutic drug were respectively distributed from the out layer to core of nanomedicine. When drug-loaded IPCNs reached tumor site through EPR effect, the PEG fragment would firstly responsively release to the acidic tumor microenvironment to expose the intermediate layer of drug-loaded IPCNs that composed by mixture of PEI and IND for increasing the surface potential to promote the uptake by tumor cells. After entering cells, IND would be released faster than chemotherapeutic drug encapsulated in core to efficiently inhibit the expression of multidrug resistance protein 1 to reverse MDR of tumor cells before chemotherapeutic drug releasing. Contributed by the staged responsively releasing of PEG fragments, IND and encapsulated chemotherapeutic drug, the drug-loaded IPCNs exhibited a superior antitumor efficacy against A549/MDR tumor cells both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: The way to develop programmed released drug delivery system is commonly relied on complicated material design and synthesis. Herein, under the computer-assist design, we successfully designed a ternary complex derived from indomethacin (IND), paclitaxel (PTX) and a pH-responsive PEGylated polyethyleneimine (PEG-s-PEI), and employed this ternary complex to successfully prepare a high drug loading and multilayer structured nanomedicine of PTX (PTX IPCNs). Contribute by the different location of PTX, IND and PEG-s-PEI in PTX IPCNs, PEG fragments, IND and PTX molecules could programmed release after reaching tumor for perfectly realizing the synergistic anti-tumor effect of tumor targeting, reversal of MDR and chemotherapy. Based on a fusion of these multiple mechanisms, PTX IPCNs showed a superior antitumor efficacy in mice loading A549/MDR tumor.

Downregulation of miR-218 by nicotine promotes cell proliferation through targeting CDK6 in non-small cell lung cancer.

BACKGROUND: Nicotine, an important component of tobacco, is a major risk factor of lung cancer, but the mechanism through which nicotine promotes lung cancer development remains unclear. METHODS: Eighty patients with lung cancer were enrolled in this study, 34 of whom did not smoke and the others did. The expression of miR-218 and CDK6 messenger RNA (mRNA) was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A luciferase reporter system was used to identify the direct target of miR-218. The protein expression of CDK6 was analyzed by using Western blotting. Cell proliferation was analyzed using an approach of calculation of cell number under a microscope. RESULTS: Nicotine decreased miR-218 expression in non-small cell lung cancer (NSCLC) cells and promoted proliferation of NSCLC cells. Smoking patients with NSCLC had lower expression of miR-218 in tumor compared with NSCLC patients who did not smoke. We found that miR-218 directly targeted the CDK6 mRNA 3'untranslated region and inhibited its expression in NSCLC cells and also observed a negative correlation between the expression of miR-218 and CDK6 mRNA in lung cancer tissues. Furthermore, miR-218- or nicotine-induced proliferative effects of NSCLC cells were rescued by the recovery of the expression level of CDK6. CONCLUSION: Nicotine promotes proliferation of NSCLC cells through regulating the miR-218/CDK6 axis, which may be a potential therapeutic target for lung cancer.

ING5 inhibits lung cancer invasion and epithelial-mesenchymal transition by inhibiting the WNT/ß-catenin pathway.

BACKGROUND: ING5 is the last member of the Inhibitor of Growth (ING) candidate tumor suppressor family that has been implicated in multiple cellular functions, including cell cycle regulation, apoptosis, and chromatin remodeling. Our previous study showed that ING5 overexpression inhibits lung cancer aggressiveness and epithelial-mesenchymal transition (EMT), with unknown mechanisms. METHODS: Western blotting was used to detect total and phosphorylated levels of ß-catenin and EMT-related proteins. Immunofluorescent staining was used to observe E-cadherin expression. Proliferation and colony formation, wound healing, and Transwell migration and invasion assays were performed to study the proliferative and invasive abilities of cancer cells. RESULTS: ING5 overexpression promotes phosphorylation of ß-catenin at Ser33/37, leading to a decreased ß-catenin protein level. Small hairpin RNA-mediated ING5 knockdown significantly increased the ß-catenin level and inhibited phosphorylation of ß-catenin S33/37. Treatment with the WNT/ß-catenin inhibitor XAV939 inhibited ING5-knockdown promoted proliferation, colony formation, migration, and invasion of lung cancer A549 cells, with increased phosphorylation of ß-catenin S33/37 and a decreased ß-catenin level. XAV939 also impaired ING5-knockdown-induced EMT, as indicated by upregulated expression of the EMT marker E-cadherin, an epithelial marker; and decreased expression of N-cadherin, a mesenchymal marker, and EMT-related transcription factors, including Snail, Slug, Twist, and Smad3. Furthermore, XAV939 could inhibit the activation of both IL-6/STAT3 and PI3K/Akt signaling pathways. CONCLUSION: ING5 inhibits lung cancer invasion and EMT by inhibiting the WNT/ß-catenin pathway.

Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells.

BACKGROUND: Triclosan is a widely applied antimicrobial agent which affects the endocrine system and homeostasis; it may also promote the cirrhosis and hepatocellular carcinoma (HCC) growth in a mice model. The exact roles of triclosan in regulating human hepatocellular carcinoma development and treatment remain unknown. METHODS: MHCC97-H, a highly aggressive HCC cell line, was treated with indicated concentration of triclosan or sorafenib. The expression of drug-resistance genes was examined by qPCR. The clearance or metabolism of sorafenib was determined by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS). MTT assay was used to examine the MHCC97-H cell proliferation. Nude mice were used to exam the anti-tumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H cells. RESULTS: In the present study, triclosan could induce the expression of drug-resistance genes in MHCC97-H cells (a highly aggressive HCC cell line), accelerate the clearance of sorafenib, and attenuate the anti-proliferation effect of this molecular targeted agent in MHCC97-H cells. Triclosan decreased the antitumor effect of sorafenib on subcutaneous and intrahepatic growth of MHCC97-H in nude mice. CONCLUSION: By discovering the fact that triclosan treatment enhances sorafenib resistance in HCC cells, this work suggests exposure of triclosan is detrimental to HCC patients during chemotherapy.

Smart pH-sensitive nanoassemblies with cleavable PEGylation for tumor targeted drug delivery.

A new acidly sensitive PEGylated polyethylenimine linked by Schiff base (PEG-s-PEI) was designed to render pH-sensitive PEGylation nanoassemblies through multiple interactions with indomethacin and docetaxel (DTX). DTX nanoassemblies driven by PEG-s-PEI thus formulated exhibited an excellent pH-sensitivity PEGylation cleavage performance at extracellular pH of tumor microenvironment, compared to normal tissues, thereby long circulated in blood but were highly phagocytosed by tumor cells. Consequently, this smart pH-sensitive PEGylation cleavage provided an efficient strategy to target tumor microenvironment, in turn afforded superior therapeutic outcome in anti-tumor activity.

Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial.

INTRODUCTION: Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS AND ANALYSIS: This study will be a multicentred, prospective, double-blind, randomised parallel controlled trial for hypertensive CKD patients in China. Patients will be randomised to one of two treatment groups: a combination of benidipine 4-8 mg/day and fosinopril 20 mg/day; or a combination of HCTZ 12.5-25 mg/day and fosinopril 20 mg/day. Patients will be followed up for 24 months after a month's fosinopril run-in. There will be dose-titration after 1 and 2 months. The primary endpoint is changes in estimated glomerular filtration rate (eGFR) from baseline to month 24. Secondary endpoints include changes in home blood pressure (BP), ambulatory BP, proteinuria, urinary albumin/creatinine ratio, and composite renal events in 24 months. Inclusion criteria are: age 18-80 years, non-dialysis CKD patients with eGFR >30 mL/min/1.73 m2, home BP >130 mm Hg systolic or BP >80 mm Hg diastolic at the screening and randomisation, and 24 hour proteinuria <3.5 g. Principal exclusions are hypertensive crisis, transplantation, cancer, severe diabetes complications, hyperkalaemia and severe allergy. The required sample size was 511 patients for detecting a difference in the change of eGFR (one sided α=0.025, power 1-ß=0.90). ETHICS AND DISSEMINATION: BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02646397.