En-bloc transurethral resection vs. conventional transurethral resection for primary non-muscle invasive bladder cancer: A meta-analysis.

INTRODUCTION: We performed a meta-analysis to evaluate the effect of en-bloc transurethral resection vs. conventional transurethral resection for primary non-muscle invasive bladder cancer. METHODS: A systematic literature search up to January 2022 was done and 28 studies included 3714 primary non-muscle invasive bladder cancer subjects at the start of the study; 1870 of them were en-bloc transurethral resection, and 1844 were conventional transurethral resection for primary non-muscle invasive bladder cancer. We calculated the odds-ratio (OR) and mean-difference (MD) with 95% confidence-intervals (CIs) to evaluate the effect of en-bloc transurethral resection compared with conventional transurethral resection for primary non-muscle invasive bladder cancer by the dichotomous or continuous methods with random or fixed-effects models. RESULTS: En-bloc transurethral resection had significantly lower twenty-four-month recurrence (OR: 0.63; 95%CI: 0.50-0.78; p < 0.001), catheterization-time (MD: -0.66; 95%CI: -1.02-[-0.29]; p < 0.001), length of hospital stay (MD: -0.95; 95%CI: -1.55-[-0.34]; p = 0.002), postoperative bladder irrigation duration (MD: -6.06; 95%CI: -9.45-[-2.67]; p < 0.001), obturator nerve reflex (OR: 0.08; 95%CI: 0.02-0.34; p = 0.03), and bladder perforation (OR: 0.14; 95%CI: 0.06-0.36: p < 0.001) and no significant difference in the 12-month-recurrence (OR: 0.79; 95%CI: 0.61-1.04; p = 0.09), the operation time (MD: 0.67; 95%CI: -1.92 to 3.25; p = 0.61), and urethral stricture (OR: 0.46; 95%CI: 0.14-1.47; p = 0.0.19) compared with conventional transurethral resection for primary non-muscle invasive bladder cancer subjects. CONCLUSIONS: En-bloc transurethral resection had a significantly lower twenty-four-month recurrence, catheterization time, length of hospital stay, postoperative bladder irrigation duration, obturator nerve reflex, bladder perforation, and no significant difference in the twelve-month recurrence, operation time, and urethral stricture compared with conventional transurethral resection for primary non-muscle invasive bladder cancer subjects. Further studies are required.

Vitamin D3 sensitizes resistant human bladder cancer cells to cisplatin by regulating Sirtuin 1 gene expression.

OBJECTIVE: Cisplatin is a standard chemotherapeutic agent for advanced bladder cancer, but its efficacy is limited due to drug resistance. Vitamin D3 may reverse cancer multidrug resistance, but the potential molecular mechanisms are still only partially known. The purpose of this study was to explore the mechanism by which vitamin D3 reverses cisplatin resistance in bladder cancer to improve therapeutic efficacy and ameliorate the prognosis of cisplatin-resistant bladder cancer. PATIENTS AND METHODS: The levels of vitamin D3 and sirtuin 1 protein were detected in cisplatin-resistant bladder cancer patients and cisplatin-sensitive patients. The cisplatin-resistant bladder cancer cell lines T24/DDP and UMUC3R were used as cell experimental models, and the migration, apoptosis, mitochondrial reactive oxygen species accumulation and autophagy of cells were assessed in the present study. RESULTS: Vitamin D3 levels were decreased, and sirtuin 1 protein levels were increased in cisplatin-resistant bladder cancer patients compared with cisplatin-sensitive bladder cancer patients. Vitamin D3 treatment markedly repressed sirtuin 1 expression, and overexpression of the sirtuin 1 gene led to mitochondrial reactive oxygen species generation, promoted the initiation of autophagosome formation and enhanced autophagic flux. Cisplatin treatment in the presence of vitamin D3 inhibited cell invasion and migration and induced apoptosis and enhancing the sirtuin 1 gene abolished the effect of vitamin D3 by regulating mitochondrial reactive oxygen species accumulation and autophagosome formation. CONCLUSIONS: These data support a mechanism wherein the sirtuin 1 gene plays a crucial role in vitamin D3 reversing cisplatin resistance in bladder cancer and may provide useful preventive and therapeutic applications in the future.

Acidic Microenvironment Determines Antibiotic Susceptibility and Biofilm Formation of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is the most prevalent bacterial species that contribute to cystic fibrosis (CF) respiratory failure. The impaired function of CF transmembrane conductance regulator leads to abnormal epithelial Cl-/HCO3 - transport and acidification of airway surface liquid. However, it remains unclear why the CF lung is most commonly infected by Pseudomonas aeruginosa versus other pathogens. We carried out studies to investigate if lower pH helps Pseudomonas aeruginosa adapt and thrive in the CF-like acidic lung environment. Our results revealed that Pseudomonas aeruginosa generally forms more biofilm, induces antibiotic resistance faster in acidic conditions, and can be reversed by returning the acidic environment to physiologically neutral conditions. Pseudomonas aeruginosa appears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronic Pseudomonas aeruginosa infection and colonization.

Antimicrobial and Anti-Inflammatory Activity of Apple Polyphenol Phloretin on Respiratory Pathogens Associated With Chronic Obstructive Pulmonary Disease.

Bacterial infections contribute to accelerated progression and severity of chronic obstructive pulmonary disease (COPD). Apples have been associated with reduced symptoms of COPD and disease development due to their polyphenolic content. We examined if phloretin, an apple polyphenol, could inhibit bacterial growth and inflammation induced by the main pathogens associated with COPD. Phloretin displayed bacteriostatic and anti-biofilm activity against nontypeable Haemophilus influenzae (NTHi), Moraxella catarrhalis, Streptococcus pneumoniae, and to a lesser extent, Pseudomonas aeruginosa. In vitro, phloretin inhibited NTHi adherence to NCI-H292 cells, a respiratory epithelial cell line. Phloretin also exhibited anti-inflammatory activity in COPD pathogen-induced RAW 264.7 macrophages and human bronchial epithelial cells derived from normal and COPD diseased lungs. In mice, NTHi bacterial load and chemokine (C-X-C motif) ligand 1 (CXCL1), a neutrophil chemoattractant, was attenuated by a diet supplemented with phloretin. Our data suggests that phloretin is a promising antimicrobial and anti-inflammatory nutraceutical for reducing bacterial-induced injury in COPD.

Pulmonary Inflammation and KRAS Mutation in Lung Cancer.

Chronic lung infection and lung cancer are two of the most important pulmonary diseases. Respiratory infection and its associated inflammation have been increasingly investigated for their role in increasing the risk of respiratory diseases including chronic obstructive pulmonary disease (COPD) and lung cancer. Kirsten rat sarcoma viral oncogene (KRAS) is one of the most important regulators of cell proliferation, differentiation, and survival. KRAS mutations are among the most common drivers of cancer. Lung cancer harboring KRAS mutations accounted for ~25% of the incidence but the relationship between KRAS mutation and inflammation remains unclear. In this chapter, we will describe the roles of KRAS mutation in lung cancer and how elevated inflammatory responses may increase KRAS mutation rate and create a vicious cycle of chronic inflammation and KRAS mutation that likely results in persistent potentiation for KRAS-associated lung tumorigenesis. We will discuss in this chapter regarding the studies of KRAS gene mutations in specimens from lung cancer patients and in animal models for investigating the role of inflammation in increasing the risk of lung tumorigenesis driven primarily by oncogenic KRAS.

Effects of blood pathological changes before TAI on pregnancy of dairy cows with anestrus and estrus / [Efeitos de mudanças patológicas de plasma antes de (TAI) na gestação de vacas em anestro e estro]

The objective of this study was to investigate the influence of plasma pathological changes before timed artificial insemination (TAI) on pregnancy of cows. The contents of estrogen (E2), progesterone (P4), glucose (Glu), selenium (Se), brain-derived neurotrophic factor (BDNF), and histamine (HIS) in plasma of 48 Holstein cows were measured before TAI. According to the estrus detection, the cows were divided into estrus (E) and anestrus (A) groups. After pregnancy testing at 28 d after TAI, two groups of E and A were divided into positive pregnancy of E group (EP+), negative pregnancy of E group (EP-), positive pregnancy of A group (AP+), and negative pregnancy of A group (AP-). The contents of E2, P4, Glu, Se, BDNF and hIS significantly differed among the four groups (P<0.01). The ROC analysis was used to determine the risk of negative pregnancy test (-) after TAI was increased when plasma E2 was less than 46.45 pmol/L in cows before TAI. The changes in E2, P4,hIS, Glu, and BDNF in the blood of natural estrus and natural anestrus cows affected the pregnancy after TAI. the level of E2 in plasma may be used to assess the risk of negative pregnancy after TAI.(AU)

O objetivo do presente estudo foi investigar a influência de mudanças patológicas de plasma antes de inseminação artificial (TAI) na gestação de vacas. O conteúdo de estrogênio (E2), progesterona (P4), glucose (Glu), selênio (Se), fator neurotrófico derivado do cérebro (BDNF), e histamina (HIS) no plasma de 48 vacas Holstein foi medido antes de TAI. De acordo com a detecção de estro, as vacas foram divididas em dois grupos: estro (E) e anestro (A). Após teste de gestação 28 d após TAI, dois grupos de E e A foram formados em gestação positiva do grupo E (EP+), gestação negativa do grupo E (EP-), gestação positiva do grupo A (AP+), e gestação negativa do grupo A (AP-). Os valores de E2, P4, Glu, Se, BDNF e hIS foram significativamente diferentes entre os quatro grupos (P<0,01). A análise ROC foi utilizada para determinar o risco de teste de gestação negativo (-) após aumento de TAI quando plasma E2 estava abaixo de 46,45 pmol/L em vacas antes de TAI. Alterações em E2, P4,hIS, Glu e BDNF no sangue de estro natural e anestro natural em vacas afetou a gestação após TAI. O nível de E2 no plasma pode ser usado para avaliar o risco de gestação negativa após TAI.(AU)

Toll interacting protein protects bronchial epithelial cells from bleomycin-induced apoptosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by altered epithelial cell phenotypes, which are associated with myofibroblast accumulation in the lung. Atypical alveolar epithelial cells in IPF express molecular markers of airway epithelium. Polymorphisms within and around Toll interacting protein (TOLLIP) are associated with the susceptibility to IPF and mortality. However, the functional role of TOLLIP in IPF is unknown. Using lung tissues from IPF and control subjects, we showed that expression of TOLLIP gene in the lung parenchyma is globally lower in IPF compared to controls. Lung cells expressing significant levels of TOLLIP include macrophages, alveolar type II, and basal cells. TOLLIP protein expression is lower in the parenchyma of IPF lungs but is expressed in the atypical epithelial cells of the distal fibrotic regions. Using overexpression and silencing approaches, we demonstrate that TOLLIP protects cells from bleomycin-induced apoptosis using primary bronchial epithelial cells and BEAS-2B cells. The protective effects are mediated by reducing mitochondrial reactive oxygen species (ROS) levels and upregulating autophagy. Therefore, global downregulation of the TOLLIP gene in IPF lungs may predispose injured lung epithelial cells to apoptosis and to the development of IPF.

A Rare Mutation in SPLUNC1 Affects Bacterial Adherence and Invasion in Meningococcal Disease.

BACKGROUND: Neisseria meningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD), but the contributions of rare variants other than those in the complement system have not been determined. METHODS: We identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-Threatening Infectious Disease Study. Candidate genetic variants were identified by whole-exome sequencing of 2 patients with familial IMD. Candidate variants were further validated by in vitro assays. RESULTS: Exomes of 2 siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other nonfamilial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defense protein expressed in the nasopharyngeal epithelia; however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 protein inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant recombinant SPLUNC1 (p.G22E) showed reduced antibiofilm activity, increased meningococcal adhesion, and increased invasion of cells, compared with wild-type SPLUNC1. CONCLUSIONS: A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.

Bronchial epithelium repair by Esculentin-1a-derived antimicrobial peptides: involvement of metalloproteinase-9 and interleukin-8, and evaluation of peptides' immunogenicity.

The airway epithelium is seriously damaged upon pulmonary Pseudomonas aeruginosa infection, especially in cystic fibrosis (CF) sufferers. Therefore, the discovery of novel anti-infective agents accelerating healing of infected injured tissues is crucial. The antipseudomonal peptides esculentin-1a(1-21)NH2 and its diastereomer Esc(1-21)-1c (Esc peptides) hold promise in this respect. In fact, they stimulate airway epithelial wound repair, but no mechanistic insights are available. Here we demonstrated that this process occurs through promotion of cell migration by an indirect activation of epidermal growth factor receptor mediated by metalloproteinases. Furthermore, we showed an increased expression of metalloproteinase 9, at both gene and protein levels, in peptide-treated bronchial epithelial cells with a functional or mutated form of CF transmembrane conductance regulator. In addition, the two peptides counteracted the inhibitory effect of Pseudomonas lipopolysaccharide (mimicking an infection condition) on the wound healing activity of the airway epithelium, and they enhanced the production of interleukin-8 from both types of cells. Finally, no immunogenicity was discovered for Esc peptides, suggesting their potential safety for clinical usage. Besides representing a step forward in understanding the molecular mechanism underlying the peptide-induced wound healing activity, these studies have contributed to highlight Esc peptides as valuable therapeutics with multiple functions.

15-Lipoxygenase 1 in nasal polyps promotes CCL26/eotaxin 3 expression through extracellular signal-regulated kinase activation.

BACKGROUND: 15-Lipoxygenase 1 (15LO1) is expressed in airway epithelial cells in patients with type 2-high asthma in association with eosinophilia. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also associated with type 2 inflammation and eosinophilia. CCL26/eotaxin 3 has been reported to be regulated by 15LO1 in lower airway epithelial cells. However, its relation to 15LO1 in patients with CRSwNP or mechanisms for its activation are unclear. OBJECTIVE: We sought to evaluate 15LO1 and CCL26 expression in nasal epithelial cells (NECs) from patients with CRSwNP and healthy control subjects (HCs) and determine whether 15LO1 regulates CCL26 in NECs through extracellular signal-regulated kinase (ERK) activation. METHODS: 15LO1, CCL26, and phosphorylated ERK were evaluated in NECs from patients with CRSwNP and HCs. 15LO1/CCL26 and CCL26/cytokeratin 5 were colocalized by means of immunofluorescence. IL-13-stimulated NECs were cultured at an air-liquid interface with or without 15-lipoxygenase 1 gene (ALOX15) Dicer-substrate short interfering RNAs (DsiRNA) transfection, a specific 15LO1 enzymatic inhibitor, and 2 ERK inhibitors. Expression of 15LO1 and CCL26 mRNA and protein was analyzed by using quantitative RT-PCR, Western blotting, and ELISA. RESULTS: 15LO1 expression was increased in nasal polyp (NP) epithelial cells compared with middle turbinate epithelial cells from patients with CRSwNP and HCs. 15LO1 expression correlated with CCL26 expression and colocalized with CCL26 expression in basal cells of the middle turbinate and NPs from patients with CRSwNP. In primary NECs in vitro, IL-13 induced 15LO1 and CCL26 expression. 15LO1 knockdown and inhibition decreased IL-13-induced ERK phosphorylation and CCL26 expression. ERK inhibition (alone) similarly decreased IL-13-induced CCL26. Phosphorylated ERK expression was increased in NECs from CRSwNP subjects and positively correlated with both 15LO1 and CCL26 expression. CONCLUSIONS: 15LO1 expression is increased in NP epithelial cells and contributes to CCL26 expression through ERK activation. 15LO1 could be considered a novel therapeutic target for CRSwNP.

Antibacterial Properties and Efficacy of a Novel SPLUNC1-Derived Antimicrobial Peptide, α4-Short, in a Murine Model of Respiratory Infection.

Multidrug resistance (MDR) by bacterial pathogens constitutes a global health crisis, and resistance to treatment displayed by biofilm-associated infections (e.g., cystic fibrosis, surgical sites, and medical implants) only exacerbates a problem that is already difficult to overcome. Antimicrobial peptides (AMPs) are a promising class of therapeutics that may be useful in the battle against antibiotic resistance, although certain limitations have hindered their clinical development. The goal of this study was to examine the therapeutic potential of novel AMPs derived from the multifunctional respiratory host defense protein SPLUNC1. Using standard growth inhibition and antibiofilm assays, we demonstrated that a novel structurally optimized AMP, α4-short, was highly effective against the most common group of MDR bacteria while showing broad-spectrum bactericidal and antibiofilm activities. With negligible hemolysis and toxicity to white blood cells, the new peptide also demonstrated in vivo efficacy when delivered directly into the airway in a murine model of Pseudomonas aeruginosa-induced respiratory infection. The data warrant further exploration of SPLUNC1-derived AMPs with optimized structures to assess the potential application to difficult-to-cure biofilm-associated infections.IMPORTANCE The rise of superbugs underscores the urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs) have the ability to kill superbugs regardless of resistance to traditional antibiotics. However, AMPs often display a lack of efficacy in vivo. Sequence optimization and engineering are promising but may result in increased host toxicity. We report here the optimization of a novel AMP (α4-short) derived from the multifunctional respiratory protein SPLUNC1. The AMP α4-short demonstrated broad-spectrum activity against superbugs as well as in vivo efficacy in the P. aeruginosa pneumonia model. Further exploration for clinical development is warranted.

The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium.

Bacterial permeability family member A1 (BPIFA1), also known as short palate, lung, and nasal epithelium clone 1 (SPLUNC1), is a protein involved in the antiinflammatory response. The goal of this study was to determine whether BPIFA1 expression in asthmatic airways is regulated by genetic variations, altering epithelial responses to type 2 cytokines (e.g., IL-13). Nasal epithelial cells from patients with mild to severe asthma were collected from the National Heart, Lung, and Blood Institute Severe Asthma Research Program centers, genotyped for rs750064, and measured for BPIFA1. To determine the function of rs750064, cells were cultured at air-liquid interface and treated with IL-13 with or without recombinant human BPIFA1 (rhBPIFA1). Noncultured nasal cells with the rs750064 CC genotype had significantly less BPIFA1 mRNA expression than the CT and TT genotypes. Cultured CC versus CT and TT cells without stimulation maintained less BPIFA1 expression. With IL-13 treatment, CC genotype cells secreted more eotaxin-3 than CT and TT genotype cells. Also, rhBPIFA1 reduced IL-13-mediated eotaxin-3. BPIFA1 mRNA levels negatively correlated with serum IgE and fractional exhaled nitric oxide. Baseline FEV1% levels were lower in the asthma patients with the CC genotype (n = 1,016). Our data suggest that less BPIFA1 in asthma patients with the CC allele may predispose them to greater eosinophilic inflammation, which could be attenuated by rhBPIFA1 protein therapy.

[Observation on pollinosis with vegetable food allergy].

Objective: To investigate the incidence of plant food allergy in patients with pollinosis and the effect of food allergens on the clinical symptoms of pollinosis patients. Method: A total of 40 patients with pollinosis and food allergy attended to the allergy Department of Duolun People's Hospital of Inner Mongolia were accepted skin prick test of inhaled allergens while the rhino conjunctivitis quality of life questionnaire(RQLQ) were also completed. The patients were divided into A and B groups randomly. Patients in group A were required for avoiding allergic plant foods intake but not them in group B. The two groups of patients with RQLQ, VAS and clinical symptom scores were statistically analyzed by P<0.05, the difference was statistically significant. Result: Forty cases were allergic to Artemisia. The most common allergic plant foods was peach, which accounted for 47.5%. Twenty-four patients were allergic to multiple foods simultaneously. Seventeen cases of pollinosis were preceded by food allergy, and 23 cases of food allergy were preceded by pollinosis. The mean values of RQLQ, VAS and symptom scores in group A were 81.44±14.31, 6.02±1.39, 10.60±3.68, respectively. The mean values of group B patients after 1 years were 100.73±21.66, 8.30±1.00, 13.45±3.51, the difference was statistically significant (P<0.01). The patients in group A complained that the symptoms were better than before. The mean values of RQLQ, VAS and symptom scores before intervention were 105.2±26.69, 7.00±1.71, 14.83±3.66, with significant difference (P<0.01). There was no significant improvement in the symptoms of Group B patients (P>0.05). Conclusion: Patients with pollinosis are often associated with food allergies. Reducing the intake of allergic plant foods should help alleviate symptoms.

Enhanced biofilm prevention activity of a SPLUNC1-derived antimicrobial peptide against Staphylococcus aureus.

SPLUNC1 is a multifunctional protein of the airway with antimicrobial properties. We previously reported that it displayed antibiofilm activities against P. aeruginosa. The goal of this study was to determine whether (1) the antibiofilm property is broad (including S. aureus, another prevalent organism in cystic fibrosis); (2) the α4 region is responsible for such activity; and (3), if so, this motif could be structurally optimized as an antimicrobial peptide with enhanced activities. We used S. aureus biofilm-prevention assays to determine bacterial biomass in the presence of SPLUNC1 and SPLUNC1Δα4 recombinant proteins, or SPLUNC1-derived peptides (α4 and α4M1), using the well-established crystal-violet biofilm detection assay. The SPLUNC1Δα4 showed markedly reduced biofilm prevention compared to the parent protein. Surprisingly, the 30-residue long α4 motif alone demonstrated minimal biofilm prevention activities. However, structural optimization of the α4 motif resulted in a modified peptide (α4M1) with significantly enhanced antibiofilm properties against methicillin-sensitive (MSSA) and-resistant (MRSA) S. aureus, including six different clinical strains of MRSA and the well-known USA300. Hemolytic activity was undetectable at up to 100µM for the peptides. The data warrant further investigation of α4-derived AMPs to explore the potential application of antimicrobial peptides to combat bacterial biofilm-related infections.

[The relationship between optical coherence tomography performance and visual acuity of acute retinal necrosis].

Objective: To analyze the relationship between optical coherence tomography(OCT) performance and visual acuity of patients with acute retinal necrosis (ARN). Methods: Retrospective analysis was performed on the patients diagnosed with ARN at the ophthalmology department of Peking union hospital during October 2011 and May 2016. Fourteen patients (15 eyes), 9 males and 5 females, whose anterior and posterior inflammation disappeared and the retinal necrosis lesion in the fundus of the eye subsided were included. The mean age was (41.6±12.2) years. All patients underwent careful examinations including best corrected visual acuity (BCVA), slit-lamp microscope, indirect ophthalmoscope, color fundus picture, fundus fluorescein angiography (FFA) and OCT (results of their last consultations). Results: BCVA: 8 eyes were increased, 2 eyes were unchanged and 5 eyes were decreased at the last visit; light perception (LP) 1 eye, finger count (FC) 1 eye, 3 eyes of 0.01 to 0.1, 6 eyes of 0.15 to 0.25. The inflammatory reaction in the anterior segment of 14 eyes disappeared, while the inflammatory reaction of the remaining 1 eye was relieved. The fundus lesions of all 15 eyes disappeared. According to OCT results: five eyes (5/15) exhibited normal macula area, among the 5 eyes, 4 eyes are of 0.15 to 0.25 visual acuity, and 1 eye is of 0.5 visual acuity;macular epiretinal membrane is present in three eyes (3/15), of which the visual acuity is 0.02, 0.25 and 0.3 respectively macula edema is present in three eyes (3/15), among the 3 eyes, 1 eye (visual acuity of 0.01)showed thickening of neurosensory retina, cystoid change of fovea and several fluid dark areas, the other 2 eyes (visual acuity of 0.02 and 0.5 respectively) showed small diffuse fluid dark area in the neurosensory retina;atrophy of neurosensory retina and absence of IS/OS was found in four eyes (4/15), among the 4 eyes, the visual acuity of 3 is below 0.01, and the other 1 eye is of 0.08 visual acuity. Conclusions: The OCT performance of stationary phase of ARN tends to be positively correlated with the visual acuity of patients. The prognosis of visual acuity of the patients whose OCT results showed atrophy of neurosensory retina and absence of IS/OS is poor. (Chin J Ophthalmol, 2018, 54: 369-374).

Prevention of ESKAPE pathogen biofilm formation by antimicrobial peptides WLBU2 and LL37.

OBJECTIVES: Bacterial biofilm-dependent infections (e.g. cystic fibrosis, surgical sites, and medical implants) are associated with enhanced drug-resistance and are thus difficult to eradicate. The goal of this study was to systematically compare three distinct classes of antimicrobial peptides (AMPs) that include the clinically used antibiotic colistin, the natural AMP LL37, the engineered cationic-AMP WLBU2, and four commonly used antibiotics with different bactericidal mechanisms (tobramycin, ciprofloxacin, ceftazidime, and vancomycin) for biofilm prevention properties. METHODS: Using biofilm-prevention assays, we detected bacterial biomass post-attachment in subinhibitory concentrations (1/3 of the minimum inhibitory concentration [MIC]) for each AMP by the crystal violet method, to distinguish the commonly known bactericidal activity from potentially distinct mechanisms of biofilm prevention. Biofilm regulatory gene expression was assessed using RT-qPCR for correlation with biofilm growth inhibition. RESULTS: Commonly used antibiotics at 1x MIC showed modest ESKAPE biofilm prevention while 1/3 MIC of AMPs demonstrated up to 90% biofilm prevention. WLBU2 was generally more effective in preventing bacterial attachment than colistin and LL37. Changes in bacterial biofilm regulatory gene expression were consistent with biofilm prevention. CONCLUSION: The data warrant further exploration of AMPs with optimized structures to fill a knowledge gap on the potential application of AMPs for difficult-to-cure bacterial biofilm-related infections.

Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of Pseudomonas aeruginosa pneumonia.

OBJECTIVES: Pseudomonas aeruginosa is a common cause of pneumonia in patients with cystic fibrosis with the property to generate multidrug resistance against clinically used antibiotics. Antimicrobial peptides (AMPs) are a diverse group of effector molecules of the innate immune system that protect the host against pathogens. However, the lack of activity in common biological matrices has hampered efforts towards clinical development. In this study, we evaluated the therapeutic potential of the engineered AMP WLBU2 via direct airway delivery in a murine model of P. aeruginosa infection. METHODS: The human AMPs LL37 and WLBU2 were compared for (i) antibiofilm activity using P. aeruginosa on polarized human bronchial epithelial cells, and (ii) efficacy in P. aeruginosa pneumonia in mice using intratracheal instillation of bacteria and AMPs. RESULTS: WLBU2 (16 µM) prevents biofilm formation by up to 3-log compared with 1-log reduction by LL37. With a single dose of 1 µg (0.05 mg/kg) delivered intratracheally, the initial effect of LL37 was moderate and transitory, as bacterial load and inflammatory cytokines increased at 24 h with observed signs of disease such as lethargy and hypothermia, consistent with moribund state requiring euthanasia. In sharp contrast, WLBU2 reduced bacterial burden (by 2 logs) and bacteria-induced inflammation (leucocytic infiltrates, cytokine and chemokine gene expression) at 6 h and 24 h post-exposure, with no observed signs of disease or host toxicity. CONCLUSION: These promising results now establish a much lower minimum therapeutic dose of WLBU2 (a net gain of 80-fold) compared with the previously reported 4 mg/kg systemic minimum therapeutic dose, with significant implications for clinical development.

[Current research of sympathetic ophthalmia].

Sympathetic ophthalmia (SO) is a rare, bilateral, non-necrotizing, granulomatous uveitis that usually occurs after open ocular injury or intraocular surgery. The pathophysiology is not clearly understood, but generally SO is an immediate hypersensitivity mediated by T lymphocytes which are related to ocular tissue antigens. The main histopathological features are granulation tissues composed of lymphocytes, macrophages and multinucleated giant cells. The clinical manifestations are different from person to person, which might be mild or severe. Although it could be presented with anterior uveitis, intermediate uveitis and posterior uveitis, panuveitis is the most common sign. The ophthalmic examinations, such as fundus fluorescein angiography, optical coherence tomography and B-scan, could be used to observe the patients' conditions and monitor the therapeutic effect. The main treatment of SO is medical therapy with corticosteroids, immunomodulators and biomodulators. Topical drug administration, including intravitreal injection of triamcinolone acetonide and implantation of a fluocinolone acetonide implant, can be considered. There is controversy about whether enucleation or evisceration is more appropriate and when the procedure should be done. The prognosis of SO could be poor. SO is liable to deteriorate and may lead to blindness. This article reviews the etiology, mechanisms, histopathology, clinical characteristics, diagnosis and treatment of SO. (Chin J Ophthalmol, 2017, 53:778-782).

In vivo therapeutic efficacy of frog skin-derived peptides against Pseudomonas aeruginosa-induced pulmonary infection.

Pseudomonas aeruginosa is an opportunistic and frequently drug-resistant pulmonary pathogen especially in cystic fibrosis sufferers. Recently, the frog skin-derived antimicrobial peptide (AMP) Esc(1-21) and its diastereomer Esc(1-21)-1c were found to possess potent in vitro antipseudomonal activity. Here, they were first shown to preserve the barrier integrity of airway epithelial cells better than the human AMP LL-37. Furthermore, Esc(1-21)-1c was more efficacious than Esc(1-21) and LL-37 in protecting host from pulmonary bacterial infection after a single intra-tracheal instillation at a very low dosage of 0.1 mg/kg. The protection was evidenced by 2-log reduction of lung bacterial burden and was accompanied by less leukocytes recruitment and attenuated inflammatory response. In addition, the diastereomer was more efficient in reducing the systemic dissemination of bacterial cells. Importantly, in contrast to what reported for other AMPs, the peptide was administered at 2 hours after bacterial challenge to better reflect the real life infectious conditions. To the best of our knowledge, this is also the first study investigating the effect of AMPs on airway-epithelia associated genes upon administration to infected lungs. Overall, our data highly support advanced preclinical studies for the development of Esc(1-21)-1c as an efficacious therapeutic alternative against pulmonary P. aeruginosa infections.

Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications.

In the last several decades, there have been significant advances in anticancer therapy. However, the development of resistance to cancer drugs and the lack of specificity related to actively dividing cells leading to toxic side effects have undermined these achievements. As a result, there is considerable interest in alternative drugs with novel antitumor mechanisms. In addition to the recent approach using immunotherapy, an effective but much cheaper therapeutic option of pharmaceutical drugs would still provide the best choice for cancer patients as the first line treatment. Ribosomally synthesized cationic antimicrobial peptides (AMPs) or host defense peptides (HDP) display broad-spectrum activity against bacteria based on electrostatic interactions with negatively charged lipids on the bacterial surface. Because of increased proportions of phosphatidylserine (negatively charged) on the surface of cancer cells compared to normal cells, cationic amphipathic peptides could be an effective source of anticancer agents that are both selective and refractory to current resistance mechanisms. We reviewed herein the prospect for AMP application to cancer treatment, with a focus on modes of action of cationic AMPs.