A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm.

Sepsis is an infection-triggered, rapidly progressive systemic inflammatory syndrome with a high mortality rate. Currently, there are no promising therapeutic strategies for managing this disease in the clinic. Heparanase plays a crucial role in the pathology of sepsis, and its inhibition can significantly relieve related symptoms. Here, a novel heparanase inhibitor CV122 is rationally designed and synthesized, and its therapeutic potential for sepsis with Lipopolysaccharide (LPS) and Cecal Ligation and Puncture (CLP)-induced sepsis mouse models are evaluated. It is found that CV122 potently inhibits heparanase activity in vitro, protects cell surface glycocalyx structure, and reduces the expression of adhesion molecules. In vivo, CV122 significantly reduces the systemic levels of proinflammatory cytokines, prevents organ damage, improves vitality, and efficiently protects mice from sepsis-induced death. Mechanistically, CV122 inhibits the activity of heparanase, reduces its expression in the lungs, and protects glycocalyx structure of lung tissue. It is also found that CV122 provides effective protection from organ damage and death caused by Crimean-Congo hemorrhagic fever virus (CCHFV) infection. These results suggest that CV122 is a potential drug candidate for sepsis therapy targeting heparanase by inhibiting cytokine storm.

Valorization of hydrothermal carbonization products by anaerobic digestion: Inhibitor identification, biomethanization potential and process intensification.

Integrating hydrothermal carbonization (HTC) and anaerobic digestion for biorefinery-oriented full utilization of wet organic wastes is a promising emerging technology. The objectives of this study were to identify the potential inhibitory substances, evaluate the biomethane potential of mixed and aqueous products and explore process intensifying strategies. The results indicated that the high HTC temperature of 240 °C resulted in a significantly low methane yield of 60 ± 5 mL/g COD and a high Short chain fatty acid (SCFAs) accumulation of 4174 ± 76 mg/L. GC-MS analysis showed that the contents of inhibitory pyrazines, pyridines and ketones in aqueous fraction at 240 °C substantially increased from 13.14%, 0.4%, 0.55% at 180 °C to 23.34%, 2.89%, 5.13%, respectively. When the aqueous products obtained from 240 °C-HTC was supplemented or pretreated by carbonaceous material, the methane yields were greatly improved and increased to 1.3-fold and 1.8-fold, respectively. These finding could provide some valuable technical information for HTC based biorefinery of organic waste.

[Application of metabolomics in neonatal clinical practice].

Metabolomics is an emerging and popular subject in the post-genome era, and a large number of studies have been noted on the application of metabolomics in health evaluation, growth and development evaluation, disease diagnosis, and therapeutic efficacy evaluation. As a special period of life, the neonatal period is characterized by rapid cell renewing, consumption of a lot of energy and materials, and changes in metabolic pathways, all of which affect the level of metabolites. However, there is still no reference standard for metabolic level and profile in neonates. This article reviews the current status of metabolic research on neonatal growth and development and common diseases and related clinical application of metabolomics, so as to provide new ideas for nutrition guidance and evaluation, selection of therapeutic regimens, and new drug research in neonates.

Aberrant elastin remodeling in the lungs of O2-exposed newborn mice; primarily results from perturbed interaction between integrins and elastin.

Excessive localization of elastin from septal tips to alveolar walls is a key feature of bronchopulmonary dysplasia (BPD). The abnormal accumulation of lung elastin, involving the structural and functional interaction of a series of proteins, remains poorly understood. To further investigate the mechanisms accounting for the abnormal accumulation of elastin in the lungs of newborn mice with BPD, we evaluate elastin distribution and its interaction with proteins involved in its aberrant localization, such as integrin αv, fibulin-5 and transforming growth factor ß1 (TGF-ß1), in lungs of newborn mice exposed to 60% O2 for 21 days. Lung histology revealed aberrant elastin production and impaired lung septation in O2-exposed lungs, while tropoelastin, integrin αv, fibulin-1, fibulin-2 and fibulin-4 gene expression were elevated. Dual staining image analysis of lung sections revealed that co-localization of integrin αv and elastin increased following O2 exposure with elastin distributed throughout the walls of air spaces rather than at septal tips. Furthermore, integrin αv appeared to be induced initially. Concurrently, increased fibulin-5 and TGF-ß1 (which may regulate elastic fiber assembly) expression was detected, which may explain the altered lung elastin deposition and defective septation that are observed during BPD. These data support the hypothesis that excessive and aberrant αv integrin expression was initially induced by hyperoxia; αv integrin then interacted with and recruited elastin. These alterations were accompanied by fibulin-5 deposition and TGF-ß1 activation, which may impede normal matrix remodeling, thereby contributing to the pathological pulmonary features of BPD.