Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness.Autophagy plays a critical role in ischemic brain injury,but its role in hypo-baric hypoxia(HH)remains unknown.Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain,and is partially responsible for HH-induced oxidative stress,neuronal loss,and brain damage.The autophagic agonist rapamycin only promotes the initiation of autophagy.By proteome analysis,a screen showed that protein dynamin2(DNM2)potentially regulates autophagic flux.Overexpression of DNM2 significantly increased the formation of autolysosomes,thus maintaining autophagic flux in combination with rapamycin.Furthermore,the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure.These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication.Meplazumab is a humanized anti-CD147 IgG_(2) monoclonal antibody,which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019(COVID-19)patients.Here,we conducted a randomized,double-blinded,placebo-controlled phase 1 trial to evaluate the safety,tolerability,and pharmacokinetics of meplazumab in healthy subjects,and an open-labeled,concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients.In phase 1 study,59 subjects were enrolled and assigned to eight cohorts,and no serious treatment-emergent adverse event(TEAE)or TEAE grade≥3 was observed.The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics.No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort.The biodistribution study indicated that meplazumab reached lung tissue and maintained>14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32.In the exploratory phase 2 study,17 COVID-19 patients were enrolled,and 11 hospitalized patients were involved as concurrent control.The meplazumab treatment significantly improved the discharged(P=0.005)and case severity(P=0.021),and reduced the time to virus negative(P=0.045)in comparison to the control group.These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

CD 147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

Major gaps in understanding the molecular mechanisms of colorectal cancer(CRC)progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders.Trefoil factor 3(TFF3)has been reported to be involved in CRC progression and intestinal mucosal repair;however,how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood.Here,we found that the upregulated TFF3 in CRC predicted a worse overall survival rate.TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis.CD147,a membrane protein,was identified as a binding partner for TFF3.Via binding to CD147,TFF3 enhanced CD147-CD44s interaction,resulting in signal transducer and activator of transcription 3(STAT3)activation and prostaglandin G/H synthase 2(PTGS2)expression,which were indispensable for TFF3-induced migration,proliferation,and invasion.PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype(PTGER4)and contributed to TFF3-stimulated CRC progression.Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression.The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor.Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice.Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression,which widens and deepens the understanding of the molecular function of trefoil factors.