Cyclic Peptide Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Design, Synthesis, and In Vivo Treatment of Acute Lung Injury.

Directly blocking the Keap1-Nrf2 pathway is a promising strategy for the mitigation of acute lung injury (ALI). Peptide Keap1-Nrf2 inhibitors have been reported to have a high Keap1 binding affinity. However, these inhibitors showed weak activity in cells and/or animals. In this study, we designed a series of linear peptides from an Nrf2-based 9-mer Ac-LDEETGEFL-NH2. To improve the cellular activity, we further designed cyclic peptides based on the crystal complex of Keap1 with a linear peptide. Among them, cyclic 9-mer ZC9 targeting Keap1 showed a better affinity (KD2 = 51 nM). Specifically, it exhibited an acceptable water solubility (>38 mg/mL), better cell permeability, cell activity, and metabolic stability (serum t1/2 > 24 h). In the in vitro LPS-induced oxidative damages and ALI model, ZC9 showed significant dose-response reversal activity without apparent toxicity. In conclusion, our results suggested ZC9 as a lead cyclic peptide targeting the Keap1-Nrf2 pathway for ALI clinical treatment.

Hyperbaric oxygen combined with hydrogen-rich saline protects against acute lung injury.

Background: This study sought to investigate therapeutic effects of hydrogen-rich saline (HRS) combined with hyperbaric oxygen (HBO2) in an experimental rat model of acute lung injury (ALI). Method: Forty male Sprague-Dawley rats were randomly divided into sham, LPS, LPS + HBO2, LPS + HRS, and LPS + HBO2 + HRS groups. After an intratracheal injection of LPS-induced ALI, the rats were given a single-agent HBO2 or HRS or HBO2 + HRS treatment. The treatments were continued for three days in this experimental rat model of ALI. At the end of experiment, the lung pathological, inflammatory factors, and cell apoptosis in the pulmonary tissue were detected by Tunel method and cell apoptosis rate was calculated accordingly. Results: In the groups treated with HBO2 + HRS, pulmonary pathological data, wet-dry weight ratio, and inflammatory factors of pulmonary tissues and alveolar lavage fluid were significantly superior to those of the sham group (p≺0.05). Cell apoptosis detection revealed that no single agent treatment of HRS or HBO2, or combination treatment, could alleviate all cell apoptosis. HRS combined with HBO2 treatment was superior to single treatment (p≺0.05). Conclusion: HRS or HBO2 single treatment could decrease inflammatory cytokines release in lung tissue, reduce the accumulation of oxidative products and alleviate apoptosis of pulmonary cells, then lead to positive therapeutic effects on ALI induced by LPS. Furthermore, HBO2 combined with HRS treatment presented a synergy effect on cell apoptosis decrease and a decline in inflammatory cytokine release and related inflammatory product generation, compared with a single treatment.

Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are serious and devastating pulmonary manifestations of acute systemic inflammation with high morbidity and mortality worldwide. Currently, there are no specific effective treatments for ALI/ARDS. RIPK1, which contributes to necroptosis and inflammation, is confirmed to be a promising strategy for the treatment of ALI. Herein, 23 benzothiazole derivatives were designed to specifically target RIPK1, and SZM-1209 showed high anti-necroptotic activity (EC50 = 22.4 nM) and kinase selectivity on RIPK1 over RIPK3 (Kd,RIPK1 = 85 nM, Kd,RIPK3 > 10,000 nM). In a mTNF-α-induced systemic inflammatory response syndrome (SIRS) model, SZM-1209 could completely reverse mouse deaths with significant anti-inflammatory effects. Furthermore, in a NNK short-term intratracheal exposure-induced ALI model, SZM-1209 significantly alleviated ALI by reducing pulmonary edema and pathological damage. Collectively, activities of SZM-1209 against RIPK1, necroptosis, SIRS, and ALI warranted further investigation of optimized benzothiazoles as promising lead structures against ALI-related diseases.

A Novel Combined Model for Predicting Humidity in Sheep Housing Facilities.

Accurately predicting humidity changes in sheep barns is important to ensure the healthy growth of the animals and to improve the economic returns of sheep farming. In this study, to address the limitations of conventional methods in establishing accurate mathematical models of dynamic changes in humidity in sheep barns, we propose a method to predict humidity in sheep barns based on a machine learning model combining a light gradient boosting machine with gray wolf optimization and support-vector regression (LightGBM-CGWO-SVR). Influencing factors with a high contribution to humidity were extracted using LightGBM to reduce the complexity of the model. To avoid the local extremum problem, the CGWO algorithm was used to optimize the required hyperparameters in SVR and determine the optimal hyperparameter combination. The combined algorithm was applied to predict the humidity of an intensive sheep-breeding facility in Manas, Xinjiang, China, in real time for the next 10 min. The experimental results indicated that the proposed LightGBM-CGWO-SVR model outperformed eight existing models used for comparison on all evaluation metrics. It achieved minimum values of 0.0662, 0.2284, 0.0521, and 0.0083 in terms of mean absolute error, root mean square error, mean squared error, and normalized root mean square error, respectively, and a maximum value of 0.9973 in terms of the R2 index.

Lung cancer coexisting with Papiliotrema flavescens infection diagnosed by next-generation sequencing: a case report.

BACKGROUND: Papiliotrema flavescens is a rare environmental yeast, which has been isolated from air, trees, kernels of wheat and corn, fermenting soya sauce, and cerebrospinal fluid of patient with AIDS. Additionally, it is also reported to cause subcutaneous infection in a dog. In this case, we describe primary lung adenocarcinoma coexisting with Papiliotrema flavescens infection in a female patient diagnosed by next-generation sequencing (NGS) technique, which is the first such reported case. CASE PRESENTATION: The patient was a 52-year-old female with recurrent cough for 3 months. Chest CT examination revealed a ground glass nodule of 17 * 23 * 18 mm in the right upper lung, and 3 new pulmonary nodules appeared around it 2 months later. The patient underwent right upper lobe lobectomy and pathology confirmed that the primary 2-cm-lesion in the right upper lobe was invasive lung adenocarcinoma, and two of the three surrounding lung nodules were pathologically suggestive of pulmonary fungal infection (not known in specific fungal types). Hence, the patient received empirical anti-fungal treatments with fluconazole 400 mg/day for a week and follow-up CT scanning showed no tumor progression and no relapse of fungal infection. The specific pathogen was eventually identified as Papiliotrema flavescens by the next-generation sequencing of pathogen. DISCUSSION AND CONCLUSION: We first reported that lung cancer coexisting with Papiliotrema flavescens infection in a female patient. The diagnosis of lung cancer with typical CT imaging features is relatively simple, while the diagnosis of lung cancer coexisting with rare fungal infection is challenging. NGS technique is an effective supplementary technique for clinical diagnosis of bacterial or fungal infectious diseases, enabling precise clinical decision-making and appropriate treatment. In this case, the lung cancer may result in a degree of immune suppression, at least locally, resulting in the formation of pulmonary fungal nodular lesions around the tumor.