The Application of Newcastle Disease Virus (NDV): Vaccine Vectors and Tumor Therapy.

Newcastle disease virus (NDV) is an avian pathogen with an unsegmented negative-strand RNA genome that belongs to the Paramyxoviridae family. While primarily pathogenic in birds, NDV presents no threat to human health, rendering it a safe candidate for various biomedical applications. Extensive research has highlighted the potential of NDV as a vector for vaccine development and gene therapy, owing to its transcriptional modularity, low recombination rate, and lack of a DNA phase during replication. Furthermore, NDV exhibits oncolytic capabilities, efficiently eliciting antitumor immune responses, thereby positioning it as a promising therapeutic agent for cancer treatment. This article comprehensively reviews the biological characteristics of NDV, elucidates the molecular mechanisms underlying its oncolytic properties, and discusses its applications in the fields of vaccine vector development and tumor therapy.

Current Status of Poultry Recombinant Virus Vector Vaccine Development.

Inactivated and live attenuated vaccines are the mainstays of preventing viral poultry diseases. However, the development of recombinant DNA technology in recent years has enabled the generation of recombinant virus vector vaccines, which have the advantages of preventing multiple diseases simultaneously and simplifying the vaccination schedule. More importantly, some can induce a protective immune response in the presence of maternal antibodies and offer long-term immune protection. These advantages compensate for the shortcomings of traditional vaccines. This review describes the construction and characterization of primarily poultry vaccine vectors, including fowl poxvirus (FPV), fowl adenovirus (FAdV), Newcastle disease virus (NDV), Marek's disease virus (MDV), and herpesvirus of turkey (HVT). In addition, the pathogens targeted and the immunoprotective effect of different poultry recombinant virus vector vaccines are also presented. Finally, this review discusses the challenges in developing vector vaccines and proposes strategies for improving immune efficacy.

Deciphering infected cell types, hub gene networks and cell-cell communication in infectious bronchitis virus via single-cell RNA sequencing.

Infectious bronchitis virus (IBV) is a coronavirus that infects chickens, which exhibits a broad tropism for epithelial cells, infecting the tracheal mucosal epithelium, intestinal mucosal epithelium, and renal tubular epithelial cells. Utilizing single-cell RNA sequencing (scRNA-seq), we systematically examined cells in renal, bursal, and tracheal tissues following IBV infection and identified tissue-specific molecular markers expressed in distinct cell types. We evaluated the expression of viral RNA in diverse cellular populations and subsequently ascertained that distal tubules and collecting ducts within the kidney, bursal mucosal epithelial cells, and follicle-associated epithelial cells exhibit susceptibility to IBV infection through immunofluorescence. Furthermore, our findings revealed an upregulation in the transcription of proinflammatory cytokines IL18 and IL1B in renal macrophages as well as increased expression of apoptosis-related gene STAT in distal tubules and collecting duct cells upon IBV infection leading to renal damage. Cell-to-cell communication unveiled potential interactions between diverse cell types, as well as upregulated signaling pathways and key sender-receiver cell populations after IBV infection. Integrating single-cell data from all tissues, we applied weighted gene co-expression network analysis (WGCNA) to identify gene modules that are specifically expressed in different cell populations. Based on the WGCNA results, we identified seven immune-related gene modules and determined the differential expression pattern of module genes, as well as the hub genes within these modules. Our comprehensive data provides valuable insights into the pathogenesis of IBV as well as avian antiviral immunology.

Long-term outcomes of anti-vascular endothelial growth factor therapy with and without posterior scleral reinforcement on myopic maculopathy in myopic choroidal neovascularization eyes.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is used for myopic choroidal neovascularization (mCNV). Patchy chorioretinal atrophy (pCRA) enlargement has been reported in mCNV cases associated with vision loss. Our aim was to compare the long-term effectiveness of anti-VEGF therapy alone versus anti-VEGF followed by posterior scleral reinforcement (PSR) in controlling myopic maculopathy in mCNV eyes. METHODS: We performed a retrospective review of the medical records of 95 high myopia patients (refractive error ≥ 6.00 diopters, axial length ≥ 26.0 mm) with mCNV. Patients were treated with anti-VEGF alone (group A) or anti-VEGF followed by PSR (group B). The following data were collected: refractive error, best corrected visual acuity (BCVA), ophthalmic fundus examination, ocular coherence tomography and ocular biometry at 12 and 24 months pre- and postoperatively. The primary outcomes were changes in pCRA and BCVA. RESULTS: In 26 eyes of 24 patients, the mean pCRA size significantly increased from baseline (0.88 ± 1.69 mm2) to 12 months (1.57 ± 2.32 mm2, t = 3.249, P = 0.003) and 24 months (2.17 ± 2.79 mm2, t = 3.965, P = 0.001) postoperatively. The increase in perilesional pCRA in group B (n = 12) was 98.2% and 94.2% smaller than that in group A (n = 14) at 12 and 24 months (Beta 0.57 [95% CI 0.01, 191 1.13], P = 0.048). In group B, 7 eyes (58.3%) gained more than 2 lines of BCVA compared with only 4 eyes (28.6%) in group A at 24 months. CONCLUSION: Anti-VEGF therapy followed by PSR achieved better outcomes than anti-VEGF therapy alone in controlling the development of myopic maculopathy in mCNV and may constitute a better treatment option by securing a better long-term VA outcome.

Machine Learning-Based Virtual Screening and Identification of the Fourth-Generation EGFR Inhibitors.

Epidermal growth factor receptor (EGFR) plays a pivotal regulatory role in treating patients with advanced nonsmall cell lung cancer (NSCLC). Following the emergence of the EGFR tertiary CIS C797S mutation, all types of inhibitors lose their inhibitory activity, necessitating the urgent development of new inhibitors. Computer systems employ machine learning methods to process substantial volumes of data and construct models that enable more accurate predictions of the outcomes of new inputs. The purpose of this article is to uncover innovative fourth-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with the aid of machine learning techniques. The paper's data set was high-dimensional and sparse, encompassing both structured and unstructured descriptors. To address this considerable challenge, we introduced a fusion framework to select critical molecule descriptors by integrating the full quadratic effect model and the Lasso model. Based on structural descriptors obtained from the full quadratic effect model, we conceived and synthesized a variety of small-molecule inhibitors. These inhibitors demonstrated potent inhibitory effects on the two mutated kinases L858R/T790M/C797S and Del19/T790M/C797S. Moreover, we applied our model to virtual screening, successfully identifying four hit compounds. We have evaluated these hit ADME characteristics and look forward to conducting activity evaluations on them in the future to discover a new generation of EGFR-TKI.

Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating ß-catenin.

KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRASG12C inhibitors have been developed to treat KRASG12C-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of ß-catenin at lysine 508, which enhances the binding between ß-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.

USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2.

RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.

A Novel Feature Engineering Method Based on Latent Representation Learning for Radiomics: Application in NSCLC Subtype Classification.

Radiomics refers to the high-throughput extraction of quantitative features from medical images, and is widely used to construct machine learning models for the prediction of clinical outcomes, while feature engineering is the most important work in radiomics. However, current feature engineering methods fail to fully and effectively utilize the heterogeneity of features when dealing with different kinds of radiomics features. In this work, latent representation learning is first presented as a novel feature engineering approach to reconstruct a set of latent space features from original shape, intensity and texture features. This proposed method projects features into a subspace called latent space, in which the latent space features are obtained by minimizing a unique hybrid loss function including a clustering-like loss and a reconstruction loss. The former one ensures the separability among each class while the latter one narrows the gap between the original features and latent space features. Experiments were performed on a multi-center non-small cell lung cancer (NSCLC) subtype classification dataset from 8 international open databases. Results showed that compared with four traditional feature engineering methods (baseline, PCA, Lasso and L2,1-norm minimization), latent representation learning could significantly improve the classification performance of various machine learning classifiers on the independent test set (all p<0.001). Further on two additional test sets, latent representation learning also showed a significant improvement in generalization performance. Our research shows that latent representation learning is a more effective feature engineering method, which has the potential to be used as a general technology in a wide range of radiomics researches.

Economic evaluation of combined population-based screening for multiple blindness-causing eye diseases in China: a cost-effectiveness analysis.

BACKGROUND: More than 90% of vision impairment is avoidable. However, in China, a routine screening programme is currently unavailable in primary health care. With the dearth of economic evidence on screening programmes for multiple blindness-causing eye diseases, delivery options, and screening frequencies, we aimed to evaluate the costs and benefits of a population-based screening programme for multiple eye diseases in China. METHODS: We developed a decision-analytic Markov model for a cohort of individuals aged 50 years and older with a total of 30 1-year cycles. We calculated the cost-effectiveness and cost-utility of screening programmes for multiple major blindness-causing eye diseases in China, including age-related macular degeneration, glaucoma, diabetic retinopathy, cataracts, and pathological myopia, from a societal perspective (including direct and indirect costs). We analysed rural and urban settings separately by different screening delivery options (non-telemedicine [ie, face-to-face] screening, artificial intelligence [AI] telemedicine screening, and non-AI telemedicine screening) and frequencies. We calculated incremental cost-utility ratios (ICURs) using quality-adjusted life-years and incremental cost-effectiveness ratios (ICERs) in terms of the cost per blindness year avoided. One-way deterministic and simulated probabilistic sensitivity analyses were used to assess the robustness of the main outcomes. FINDINGS: Compared with no screening, non-telemedicine combined screening of multiple eye diseases satisfied the criterion for a highly cost-effective health intervention, with an ICUR of US$2494 (95% CI 1130 to 2716) and an ICER of $12 487 (8773 to 18 791) in rural settings. In urban areas, the ICUR was $624 (395 to 907), and the ICER was $7251 (4238 to 13 501). Non-AI telemedicine screening could result in fewer costs and greater gains in health benefits (ICUR $2326 [1064 to 2538] and ICER $11 766 [8200 to 18 000] in rural settings; ICUR $581 [368 to 864] and ICER $6920 [3926 to 13 231] in urban settings). AI telemedicine screening dominated no screening in rural settings, and in urban settings the ICUR was $244 (-315 to 1073) and the ICER was $2567 (-4111 to 15 389). Sensitivity analyses showed all results to be robust. By further comparison, annual AI telemedicine screening was the most cost-effective strategy in both rural and urban areas. INTERPRETATION: Combined screening of multiple eye diseases is cost-effective in both rural and urban China. AI coupled with teleophthalmology presents an opportunity to promote equity in eye health. FUNDING: National Natural Science Foundation of China.

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair.

As a multifunctional protein posttranslational modification enzyme in eukaryotic cells, Poly-ADP-ribose polymerase (PARP) acts as a DNA damage sensor, which helps to repair DNA damage through recruiting repair proteins to the DNA break sites. PARP inhibitors offer a significant clinical benefit for ovarian cancer with BRCA1/2 mutations. However, the majority of ovarian cancer patients harbor wild-type (WT) BRCA1/2 status, which narrows its clinical application. Here, we identified a small compound, SN-38, a CPT analog, which sensitizes BRCA-proficient ovarian cancer cells to PARP inhibitor treatment by inhibiting homologous recombination (HR) repair. SN-38 treatment greatly enhanced PARP inhibitor olaparib induced DNA double-strand breaks (DSBs) and DNA replication stress. Meanwhile, the combination of SN-38 and olaparib synergistically induced apoptosis in ovarian cancer. Furthermore, combination administration of SN-38 and olaparib induced synergistic antitumor efficacy in an ovarian cancer xenograft model in vivo. Therefore, our study provides a novel therapeutic strategy to optimize PARP inhibitor therapy for patients with BRCA-proficient ovarian cancer.

Pyrocatechol Alleviates Cisplatin-Induced Acute Kidney Injury by Inhibiting ROS Production.

As one of the most common cancer chemotherapy drugs, cisplatin is widely used in cancer management. However, cisplatin-induced nephrotoxicity occurs in patients who receive this drug. This study is aimed at developing therapeutic agents that effectively alleviate the nephrotoxic effects during cisplatin treatment. We identified a compound named pyrocatechol (PCL) from a natural product library that significantly alleviated cisplatin-induced cytotoxicity in vitro. Pyrocatechol treatment substantially ameliorated cisplatin (20 mg · kg-1) treatment-induced neuropathological indexes, including inflammatory cell infiltration and apoptosis, in vivo. Mechanistically, pyrocatechol significantly prevented oxidative stress-induced apoptosis by activating glutathione peroxidase 4 (GPX4) to reduce reactive oxygen species (ROS) accumulation in cisplatin-treated cells. In addition, pyrocatechol significantly inhibited ROS-induced JNK/P38 activation. Thus, we found that pyrocatechol prevents ROS-mediated JNK/P38 MAPK activation, apoptosis, and cytotoxicity through GPX4. Our study demonstrated that pyrocatechol is a novel therapeutic agent against cisplatin-induced kidney injury.

Changing Trends in Glaucoma Surgery Over the Past 5 Years in China.

PURPOSE: To analyze the trends of glaucoma surgery procedures over the past 5 years among hospitals across major provinces in China. MATERIALS AND METHODS: This was a retrospective observational study based on medical records. We obtained the annual numbers of commonly performed glaucoma incisional surgeries from 57 hospitals of 30 provincial regions in the Chinese Glaucoma Study Consortium (CGSC) from January 2015 to September 2019. The trend of glaucoma surgery was analyzed by Cochrane-Armitage trend test. RESULTS: Trabeculectomy, cataract extraction combined with goniosynechialysis, cataract extraction combined with trabeculectomy, and surgical peripheral iridotomy (SPI) were the top 4 surgical procedures percentages of which have the most substantial change over the course of 2015 to 2019 (all Ptrend <0.001). Numbers of trabeculectomies decreased significantly from 47.59% in 2015 to 31.21% in 2019; cataract extraction combined with goniosynechialysis increased from 12.12% to 28.48%; cataract extraction combined with trabeculectomy increased from 13.11% to 15.97%; and SPI decreased from 9.03% to 6.34%. The proportion of internal drainage surgery increased from 24.31% in 2015 to 39.29% in 2019 while external drainage surgery decreased from 69.20% to 54.64% (All Ptrend <0.001). The microinvasive glaucoma surgeries including AB-interno Canaloplasty, gonioscopy-assisted transluminal trabeculotomy, and Trabectome, increased from 0.62% to 1.40% (Ptrend<0.001). Across all study hospitals, the trends were similar, except for the Tibet Autonomous Region Eye Center, where SPI and trabeculectomy remained the most common anti-glaucoma surgeries. CONCLUSION: In the past 5 years, we observed substantial reduction in trabeculectomy, and increase in combination cataract-glaucoma procedures across major hospitals in China. The proportion of internal drainage surgery increased, while external drainage surgery decreased significantly. Detailed understanding of shifting trends in glaucoma surgeries can facilitate better health care resource allocation and training of glaucoma subspecialists in China.

Clinical outcomes of anterior tibiofibular ligament's distal fascicle transfer versus ligament reconstruction with InternalBrace™ for chronic ankle instability patients.

PURPOSE: Treatment of chronic ankle instability (CAI) for ankle sprain patients remains a challenge. If initial treatments fail, surgical stabilization techniques including ligament reconstruction should be performed. Anterior tibiofibular ligament (ATiFL) distal fascicle transfer for CAI was recently introduced. The goal of the study is to assess the 1-year clinical effectiveness of ATiFL's distal fascicle transfer versus ligament reconstruction with InternalBrace™ (Fa. Arthrex, Naples). METHODS: Between October 2019 and February 2021, 25 patients (14 males and 11 females) scheduled for ligament reconstruction treatment of CAI were enrolled after propensity score matching. Twelve underwent ligament reconstruction with InternalBrace™ (InternalBrace™ group) and thirteen underwent ATiFL's distal fascicle transfer (ATiFL's distal fascicle transfer group). We recorded the American Orthopedic Foot & Ankle Society (AOFAS) score, Visual Analogue Scale (VAS), anterior drawer test grade, patient satisfaction and complications. All results of this study were retrospectively analyzed. RESULTS: Statistically significant (p = 0.0251, independent-samples t test) differences in the AOFAS can be found between the ATiFL's distal fascicle transfer group and the InternalBrace™ group. No substantial changes in the VAS (p = 0.1778, independent-samples t test), patient satisfaction (p = 0.1800, independent-samples t test) and anterior drawer test grade (p = 0.9600, independent-samples t test) were found between the two groups. There was one patient with superficial wound infection and one patient with sural nerve injury in the InternalBrace™ group and ATiFL's distal fascicle transfer group, respectively. CONCLUSION: This is the first study that assessed a cohort of CAI patients and suggests that the ATiFL's distal fascicle transfer operation has the potential to attain good-to-excellent clinical outcomes after 1-year recovery. The AOFAS scores were significantly higher for patients with ATiFL's distal fascicle transfer, indicating that this technique may be considered a viable option for both patients and their surgeon, while long-term outcomes should be investigated in the future.

A Prospective Study of Intraocular Pressure Spike and Failure After Gonioscopy-Assisted Transluminal Trabeculotomy in Juvenile Open-Angle Glaucoma: A Prospective Study of GATT in JOAG.

PURPOSE: To identify risk factors for surgical failure after gonioscopy-assisted transluminal trabeculotomy (GATT) in juvenile open-angle glaucoma (JOAG). DESIGN: Prospective, interventional case series. METHODS: GATT was the initial surgery in 70 eyes of 70 patients with JOAG. Surgical success was defined as a postoperative intraocular pressure (IOP) of ≤21 mm Hg with at least a 20% reduction from preoperative IOP, with or without the use of antiglaucoma medication (qualified and complete success, respectively) at each postoperative visit. IOP spike was defined as IOP >30 mm Hg and an increase of at least 10 mm Hg from IOP before the spike, and then reduced to ≤21 mm Hg. RESULTS: The median age at the time of surgery was 19.3 years (range, 4.9-37.5 years) with a visual field mean deviation of -17.4 ± 10.6 dB. Mean IOP decreased from 31.3 ± 9.5 mm Hg preoperatively to 15.8 ± 2.7 at 12 months postoperatively. The complete and qualified success rates were 74.3% and 91.4%, respectively. An IOP spike occurred in 52 eyes (74%), with a median spike duration of 3.5 days (range, 1-21 days). Longer duration of IOP spike (P = .009) and older age at the time of surgery (P = .025) were both associated with worse surgical outcomes. Advanced disease was associated with prolonged IOP spike (P = .007). CONCLUSIONS: GATT provided excellent outcomes in patients with severe JOAG. Older age and longer duration of postoperative IOP spike are risk factors for failure. Severe cases are more likely to have longer durations of IOP spike. Frequent IOP monitoring during the early postoperative period is needed to detect IOP spikes in these patients.

The Entry and Egress of Monocytes in Atherosclerosis: A Biochemical and Biomechanical Driven Process.

In accordance with "the response to injury" theory, the entry of monocytes into the intima guided by inflammation signals, taking up cholesterol and transforming into foam cells, and egress from plaques determines the progression of atherosclerosis. Multiple cytokines and receptors have been reported to be involved in monocyte recruitment such as CCL2/CCR2, CCL5/CCR5, and CX3CL1/CX3CR1, and the egress of macrophages from the plaque like CCR7/CCL19/CCL21. Interestingly, some neural guidance molecules such as Netrin-1 and Semaphorin 3E have been demonstrated to show an inhibitory effect on monocyte migration. During the processes of monocytes recruitment and migration, factors affecting the biomechanical properties (e.g., the membrane fluidity, the deformability, and stiffness) of the monocytes, like cholesterol, amyloid-ß peptide (Aß), and lipopolysaccharides (LPS), as well as the biomechanical environment that the monocytes are exposed, like the extracellular matrix stiffness, mechanical stretch, blood flow, and hypertension, were discussed in the latter section. Till now, several small interfering RNAs (siRNAs), monoclonal antibodies, and antagonists for CCR2 have been designed and shown promising efficiency on atherosclerosis therapy. Seeking more possible biochemical factors that are chemotactic or can affect the biomechanical properties of monocytes, and uncovering the underlying mechanism, will be helpful in future studies.

mTORC2 regulates ribonucleotide reductase to promote DNA replication and gemcitabine resistance in non-small cell lung cancer.

Ribonucleotide reductase (RNR) is the key enzyme that catalyzes the production of deoxyribonucleotides (dNTPs) for DNA replication and it is also essential for cancer cell proliferation. As the RNR inhibitor, Gemcitabine is widely used in cancer therapies, however, resistance limits its therapeutic efficacy and curative potential. Here, we identified that mTORC2 is a main driver of gemcitabine resistance in non-small cell lung cancers (NSCLC). Pharmacological or genetic inhibition of mTORC2 greatly enhanced gemcitabine induced cytotoxicity and DNA damage. Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. Targeting mTORC2 retarded DNA replication fork progression and improved therapeutic efficacy of gemcitabine in NSCLC xenograft model in vivo. Thus, these results identified a mechanism through mTORC2 regulating RNR activity and DNA replication, conferring gemcitabine resistance to cancer cells.

Smart Responsive Quercetin-Conjugated Glycol Chitosan Prodrug Micelles for Treatment of Inflammatory Bowel Diseases.

The incidence and progression of inflammatory bowel disease are closely related to oxidative stress caused by excessive production of reactive oxygen species (ROS). To develop an efficacious and safe nanotherapy against inflammatory bowel diseases (IBD), we designed a novel pH/ROS dual-responsive prodrug micelle GC-B-Que as an inflammatory-targeted drug, which was comprised by active quercetin (Que) covalently linked to biocompatible glycol chitosan (GC) by aryl boronic ester as a responsive linker. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. Time-dependent NMR spectra traced the changes in the polymer structure in the presence of H2O2, confirming the release of the drug. The in vitro drug release studies indicated a low release rate (<20 wt %) in physiological conditions, but nearly complete release (>95 wt % after 72 h incubation) in a pH 5.8 medium containing 10 µM H2O2, exhibiting a pH/ROS dual-responsive property and sustained release behavior. Importantly, the negligible drug release in a simulated gastric environment in 1 h allowed us to perform intragastric administration, which has potential to achieve the oral delivery by mature enteric-coating modification in future. Further in vivo activities and biodistribution experiments found that the GC-B-Que micelles tended to accumulate in intestinal inflammation sites and showed better therapeutic efficacy than the free drugs (quercetin and mesalazine) in a colitis mice model. Typical inflammatory cytokines including TNF-α, IL-6, and iNOS were significantly suppressed by GC-B-Que micelle treatment. Our work promoted inflammatory-targeted delivery and intestinal drug accumulation for active single drug quercetin and improved the therapeutic effect of IBD. The current study also provided an alternative strategy for designing a smart responsive nanocarrier for a catechol-based drug to better achieve the target drug delivery.

Effects of recombinant Lactobacillus casei on growth performance, immune response and disease resistance in crucian carp, Carassius auratus.

In the present study, we constructed two recombinant Lactobacillus casei (L. casei) Lc-pPG-1-AcrV (surface-displayed) and Lc-pPG-2-AcrV (secretory) constitutively expressing AcrV protein of Aeromonas veronii (A. veronii). Expression of recombinant AcrV protein was verified by western blot and immunofluorescence technique. Compared with PBS group, the final weight (FW), weight gain (WG) and specific growth rate (SGR) of fish fed Lc-pPG-1-AcrV, Lc-pPG-2-AcrV and Lc-pPG diets after 56 days observed significantly increase (p < 0.05), while the feed conversion ratio (FCR) showed a significantly decrease (p < 0.05). The recombinant L. casei strains were orally administrated to crucian carp, and significant increased (p < 0.05) the immunoglobulin M (IgM), elevated the acid phosphatase (ACP), alkaline phosphatase (AKP), lysozyme (LZM) and superoxide dismutase (SOD) activity in serum. Moreover, leukocytes phagocytosis percentage and index of the recombinant L. casei were both enhanced. The results demonstrated that the recombinant L. casei could elicit systemic immune responses and increase the serum immunological index. The Interleukin-10 (IL-10), Interleukin-1ß (IL-1ß), interferon-γ (IFN-γ) and Tumor Necrosis Factor-α (TNF-α) levels in liver, spleen, kidney and intestine have up regulated significantly in tissues (p < 0.05), suggesting that the recombinant L. casei has the ability to induce expression of cytokines and enhance the innate immune response. Higher survival rates were exhibited that crucian carp immunized with Lc-pPG-1-AcrV (67.5%) and Lc-pPG-2-AcrV (52.5%) after challenge with A. veronii. In conclusion, these two recombinant L. casei vaccine were effective in improving crucian carp growth, immunity response and disease resistance. The recombinant L. casei strains may be a promising candidate for the development of an oral vaccine against A. veronii.

S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction.

OBJECTIVE: Thoracic aortic dissection (TAD) is a fatal disease that leads to aortic rupture and sudden death. However, little is known about the effect and molecular mechanism of S-nitrosylation (SNO) modifications in TAD formation. Approach and Results: SNO levels were higher in aortic tissues from TAD patients than in those from healthy controls, and PLS3 (plastin-3) SNO was identified by liquid chromatography-tandem mass spectrometry analysis. Furthermore, tail vein administration of endothelial-specific adeno-associated viruses of mutant PLS3-C566A (denitrosylated form) suppressed the development of TAD in mice, but the wild-type PLS3 (S-nitrosylated form) virus did not. Mechanistically, Ang II (angiotensin II)-induced PLS3 SNO enhanced the association of PLS3 with both plectin and cofilin via an iNOS (inducible nitric oxide synthase)-dependent pathway in endothelial cells. The formation of PLS3/plectin/cofilin complex promoted cell migration and tube formation but weakened adherens junction formation in Ang II-treated endothelial cells. Interestingly, denitrosylated form of PLS3 partially mitigated Ang II-induced PLS3/plectin/cofilin complex formation and cell junction disruption. Additionally, the inhibition of iNOS attenuated PLS3 SNO and the association of PLS3 with plectin and cofilin, thereby modulating endothelial barrier function. CONCLUSIONS: Our data indicate that protein SNO modification in endothelial cells modulates the progression of aortic aneurysm and dissection. The iNOS-mediated SNO of PLS3 at the Cys566 site promoted its interaction with cofilin and plectin, thus contributing to endothelial barrier disruption and pathological angiogenesis in TAD.

Oral Administration of Lactobacillus Casei Expressing Flagellin A Protein Confers Effective Protection against Aeromonas Veronii in Common Carp, Cyprinus Carpio.

Aeromonas veronii is a pathogen capable of infecting humans, livestock and aquatic animals, resulting in serious economic losses. In this study, two recombinant Lactobacillus casei expressing flagellin A (FlaA) of A. veronii, Lc-pPG-1-FlaA (surface-displayed) and Lc-pPG-2-FlaA (secretory) were constructed. The immune responses in fish administered with recombinant L. casei were evaluated. The two recombinant L. casei were orally administered to common carp, which stimulated high serum IgM and induced higher ACP, AKP, SOD and LYZ activity. Using qRT-PCR, the expression of IL-10, IL-8, IL-1ß, TNF-α and IFN-γ in the tissue of fish immunized with recombinant L. casei was significantly (p < 0.05) upregulated, which indicated that recombinant L. casei could activate the innate immune system to trigger the cell immune response and inflammatory response. Furthermore, recombinant L. casei was able to survive the intestinal environment and colonize in intestine mucosal. The study showed that after being challenged by A. veronii, fish administered with Lc-pPG-1-FlaA (70%) and Lc-pPG-2-FlaA (50%) had higher survival rates compared to Lc-pPG and PBS, indicating that recombinant L. casei might prevent A. veronii infection by activating the immune system to trigger immune responses. We demonstrated that flagellin as an antigen of vaccine, is acceptable for preventing A. veronii infection in fish. The recombinant L. casei expressing FlaA may be a novel mucosal vaccine for treating and controlling A. veronii.