Background: Oxymatrine, an isolated extract from traditional Chinese herb Sophora Flavescens Ait, has been traditionally used for therapy of anti-hepatitis B virus, anti-inflammation and anti-anaphylaxis. The present study was to investigate the anti-cancer effect of oxymatrine on human pancreatic cancer PANC-1 cells, and its possible molecular mechanism. Methods: The effect of oxymatrine on the viability and apoptosis was examined by methyl thiazolyl tetrazolium and flow cytometry analysis. The expression of Bax, Bcl-2, Bcl-x (L/S), Bid, Bad, HIAP-1, HIAP-2, XIAP, NAIP, Livin and Survivin genes was accessed by RT-PCR. The levels of cytochrome c and caspase 3 protein were assessed by Western blotting. Results: Oxymatrine inhibited cell viability and induced apoptosis of PANC-1 cells in a time- and dose-dependent manner. This was accompanied by down-regulated expression of Livin and Survivin genes while the Bax/Bcl-2 ratio was upregulated. Furthermore, oxymatrine treatment led to the release of cytochrome c and activation of caspase-3 proteins. Conclusion: Oxymatrine can induce apoptotic cell death of human pancreatic cancer, which might be attributed to the regulation of Bcl-2 and IAP families, release of mitochondrial cytochrome c and activation of caspase-3.

Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants.

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS‐CoV‐2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS‐CoV‐2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169 ⁺ expressing monocytes in the peripheral blood. Systemic levels of pro‐inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro‐inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus‐specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS‐CoV‐2 was observed in asymptomatic patients. In addition, asymptomatic COVID‐19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro‐inflammatory and more protective immune responses against SARS‐CoV‐2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID‐19.

The SARS‐CoV‐2 Delta (B.1.617.2) variant is capable of infecting vaccinated persons. An open question remains as to whether deficiencies in specific vaccine‐elicited immune responses result in susceptibility to vaccine breakthrough infection. We investigated 55 vaccine breakthrough infection cases (mostly Delta) in Singapore, comparing them against 86 vaccinated close contacts who did not contract infection. Vaccine breakthrough cases showed lower memory B cell frequencies against SARS‐CoV‐2 receptor‐binding domain (RBD). Compared to plasma antibodies, antibodies secreted by memory B cells retained a higher fraction of neutralizing properties against the Delta variant. Inflammatory cytokines including IL‐1β and TNF were lower in vaccine breakthrough infections than primary infection of similar disease severity, underscoring the usefulness of vaccination in preventing inflammation. This report highlights the importance of memory B cells against vaccine breakthrough and suggests that lower memory B cell levels may be a correlate of risk for Delta vaccine breakthrough infection.

The changing landscape of SARS-CoV-2 Spike protein is linked to the emergence of variants, immune-escape and reduced efficacy of the existing repertoire of anti-viral antibodies. The functional activity of neutralizing antibodies is linked to their quaternary changes occurring as a result of antibody-Spike trimer interactions. Here, we reveal the conformational dynamics and allosteric perturbations linked to binding of novel human antibodies and the viral Spike protein. We identified epitope hotspots, and associated changes in Spike dynamics that distinguish weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan-Hu-1, Delta, and Omicron variants on differences in the antibody-induced conformational changes in Spike and illustrate how these render certain antibodies ineffective. Antibodies with similar binding affinities may induce destabilizing or stabilizing allosteric effects on Spike, with implications for neutralization efficacy. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19 and may assist in designing effective antiviral strategies.