Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1.7 Voltage-Gated Sodium Channel.

Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the Citrus unshiu, showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin's antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (NaV) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) NaV channels, and (iv) blunts the upregulation of Nav1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Nav1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs.

High-rise buildings: A risk factor in the COVID-19 Omicron epidemic period.

Objectives: This study aimed to investigate possible viral transmission scenarios inside a high-rise building during the Omicron phase of the COVID-19 pandemic. Study design: Cross-sectional study design. Methods: In order to determine the pathogenicity of the Omicron variant of SARS-CoV-2, demographic, vaccination and clinical data were collected from COVID-19 positive cases during an outbreak in a high-rise residential building in Shenzhen, China, in early 2022. The pattern of viral transmission inside the building was determined through field investigation and engineering analysis. The results highlight the risk of Omicron infection in high-rise residential buildings. Results: Symptoms of infection with the Omicron variant are predominantly mild. Younger age has a greater impact on the severity of disease than vaccination status. Each floor of the high-rise building investigated contained 7 apartments, numbered 01 to 07, positioned in the same layout on each floor. The drainage system included vertical pipes from the ground to the roof of the building. There were statistically significant differences in infection rates at different time points and incidence ratios between apartment numbers ending in 07 (type 07) and other apartments (P < 0.001). Households with early disease onset were concentrated in apartment type 07 and the severity of their disease was more severe. The incubation period of the outbreak was 5.21-5.31 days and the time-dependent reproduction number (Rt) was 12.08 (95% confidence interval [CI] 7.66, 18.29). Results suggest both non-contact and contact viral transmission may have contributed to the outbreak. The drainage system in the building allows aerosol regurgitation, thus indicating that the structure of the building may have led to spread of the virus from the sewage pipes. Infections in other apartments may have been as result of viral transmission in the elevators and intimate family contact. Conclusions: Results from this study suggest that Omicron transmission was likely to be via the sewage system, supplemented by contact transmission in the stairs and elevators. The environmental spread of Omicron needs to be highlighted and prevented.