IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms.

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

Stimulation of the Internal Ribosome Entry Site (IRES)-Dependent Translation of Enterovirus 71 by DDX3X RNA Helicase and Viral 2A and 3C Proteases.

The translation of enterovirus 71 (EV71) is mediated by an internal ribosome entry site (IRES)-dependent manner. EV71 IRES comprises five highly structured domains (domains II-VI) in the 5'-untranslated region of the viral mRNA. A conserved AUG triplet residing in domain VI is proposed to be the ribosome entry site. It is thus envisaged that the highly structured conformation of domain VI may actually reduce the accessibility of the AUG triplet to the ribosome. This study identified a DEAD-box family RNA helicase, DDX3X, that positively regulated the EV71 IRES-dependent translation. The helicase activity of DDX3X was required for the stimulation of EV71 IRES activity; however, DDX3X was no longer important for the IRES activity when the secondary structure of domain VI was destabilized. DDX3X interacted with the truncated eIF4G which bound specifically to domain V. Thus, we proposed that DDX3X might bind to domain VI or a region nearby via the interaction with the truncated eIF4G, and subsequently unwound the secondary structure of domain VI to facilitate ribosome entry. Additionally, we demonstrated that the viral 2Apro and 3Cpro enhanced the IRES-dependent translation via their protease activities. Together, these results indicate that DDX3X is an important RNA helicase involved in EV71 IRES-dependent translation and that IRES translation is enhanced by viral infection, partly mediated by viral protease activity.

Effect of Tianma Gouteng Decoction with subtractive ingredients and its active constituents on memory acquisition.

Accumulating evidence indicates that the high blood pressure (BP) is a potent risk factor for dementia in the elderly. In line with this theory, we had found the mixture of Chinese herbs (TGD) which were traditionally used to treat hypertension, could enhance the cognitive function. The aim of this study was to decrease the number of herbs used from 11 (TGD) to 4 herbs (TGDS) and further to search the active constituents. After administering a dose of 10 g/kg of TGDS0 to ICR mice, no cholinergic symptoms of lacrimation, salivation, emesis, eyeclosure, increased respiration and fibrillation were observed. All the mice survived without any deaths after 24 hours and 7 days. No changes were observed in control and experimental groups on locomotor activity (no stimulant or sedative effects). It was also revealed that TGDS could prolong the step-through latency at the dose of 1.0 and 2.5 g/kg on passive avoidance tasks in mice. This result was the same as the previous study. The active constituents which enhanced the memory acquisition were discovered in the butanol layer and ethyl acetate layer after the extraction.

Traditional Chinese herbs against hypertension enhance memory acquisition.

Recent findings of a link between high blood pressure (BP) and dementia have given new prospects. The aim of this study is to analyze a mixture of Chinese herbs, Tianma Gouteng Decoction (TGD), which was traditionally used to treat hypertension, and investigate its relation to ameliorating cognitive impairment. We discovered that TGD also had properties involving enhancement of memory acquisition (learning) skills in mice, but not memory consolidation. It was observed that TGD could prolong the step-through latency at doses of 1.0 and 2.5 g/kg on passive avoidance task in mice. TGD could be developed further to treat mice with amnesia, which was induced by scopolamine at the same dose under long-term (8 days) administration.