Aloe polymeric acemannan inhibits the cytokine storm in mouse pneumonia models by modulating macrophage metabolism.

The cytokine storm is highly associated with inflammatory-type disease severity and patients' survival. Plant polysaccharides, the main natural phytomedicine source, have a great potential to be an effective drug to treat cytokine storm. Herein we found that a polymeric acemannan (ABPA1) isolated from Aloe Vera Barbadensis extract C (AVBEC) exerted prominent inhibitory effects on inflammation-induced cytokine storm. The results displayed that ABPA1 effectively suppressed LPS-induced proinflammatory cytokines release in vitro. Moreover, ABPA1 treatment alleviated the cytokine storm and tissue damage in LPS- and IAV-induced mouse pneumonia models, and altered the phenotypic balance of macrophages in lung tissues. Functionally, ABPA1 enhanced macrophage M2 polarization and phagocytosis in RAW264.7 cells and inhibited LPS-induced M1 polarization. Mechanistically, ABPA1 enhanced mitochondrial metabolism and OXPHOS through activated PI3K/Akt/GSK-3ß signalling pathway. Overall, our findings suggest that ABPA1 may modulate macrophage activation and mitochondrial metabolism by targeting PI3K/Akt/GSK-3ß signalling pathway, thereby alleviating cytokine storm and inflammation.

The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, we report that esterification of the 5'-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5'-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.

Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models.

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.

Chinese tree shrew: a permissive model for in vitro and in vivo replication of human adenovirus species B.

Human adenovirus (HAdV) species B can cause severe acute respiratory diseases. However, the researches to combat this infection have been hampered by the lack of an animal model permissive to the virus. Here, we report in vitro and in vivo HAdV species B infections of tree shrews, the closest relative of primates. HAdV-3, -7, -14, and -55 efficiently replicated in primary cell cultures. After intranasal inoculation of tree shrews with HAdV-55, the viral replication in the oropharyngeal region remained high until day 5 post-infection and was still detected until day 12. HAdV-55 in the lung or turbinate bone tissues reached the highest levels between days 3 and 5 post-infection, which indicated viral replication in the upper and lower respiratory tracts. HAdV-55 infection caused severe interstitial pneumonia in the animal. IL-8, IL-10, IL-17A, and IFN-γ expression in the peripheral blood mononuclear cells from infected animals was up-regulated. The pre-vaccination with HAdV-55 cleared the virus faster in the respiratory tract, mitigated lung pathological changes. Finally, HAdV-55 infection was propagated among tree shrews. Our study demonstrated that the tree shrew is a permissive animal model for HAdV species B infection and may serve as a valuable platform for testing multiple anti-viral treatments.

Exosomal miR-22-3p from human umbilical cord blood-derived mesenchymal stem cells protects against lipopolysaccharid-induced acute lung injury.

BACKGROUND: Mesenchymal stem cells (MSCs) are widely applied in various clinical disorders, including acute lung injury (ALI). We aimed to investigate the effects of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs)-derived exosomal microRNA-22-3p (miR-22-3p) on lipopolysaccharid (LPS)-induced ALI via regulating frizzled class receptor 6 (FZD6). METHODS: Rat lung cells were selected to construct the LPS-induced ALI cell model. The LPS-treated cells were transfected with restored miR-22-3p and depleted FZD6 for investigating their roles in ALI. Human UCB-MSCs were cultured and exosomes were extracted. Rat lung cells were co-cultured with exosomes that had been transfected with restored miR-22-3p and upregulated FZD6 to detect their roles in inflammatory reaction, oxidative stress, cell proliferation activity and apoptosis. The ALI rat model was established through LPS inhalation and the rats were respectively treated. Then, the pathology, apoptosis and expression of the NF-κB signaling pathway-related factors in rat lung tissues were determined. RESULTS: miR-22-3p expression was reduced and FZD6 expression was enhanced in LPS-treated rat lung cells while exosomes raised miR-22-3p expression and decreased FZD6 expression. In LPS-treated cells, up-regulating miR-22-3p or depleting FZD6 reduced inflammatory reaction and oxidative stress response, raised rat lung cell proliferation activity and inhibited cell apoptosis rate. In the in vivo ALI model, exosomes suppressed pathological changes, apoptosis and NF-κB expression in LPS-treated rats. Upregulated miR-22-3p further attenuated ALI. CONCLUSION: Our study highlights the potential of UCB-MSC-exosomal miR-22-3p in preventing ALI. This study may provide further insights into ALI therapy.