# Mechanisms of Novel Herbal Therapies for Sepsis.

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $418,750

## Abstract

Project Abstract
Despite recent advances in antibiotic therapy and intensive care, sepsis remains the most common cause of
death in the intensive care unit, annually claiming >225,000 victims in the U.S. alone. The pathogenesis of
sepsis remains obscure, but is partly attributable to dys-regulated inflammation propagated by “early”
cytokines (e.g., TNF and IL-1β), but sustained by “intermediate” (e.g., SAA) and “late” (e.g., HMGB1) mediators.
We recently discovered that LPS and SAA upregulated the expression of connexin 43 (Cx43) and/or pannexin
1 (Panx1) hemichannels to facilitate ATP-dependent PKR activation and HMGB1 release, but did not know
whether LPS and SAA also induced procathepsin L (pCTS-L) secretion to mediate lethal bacterial infections
(LBI). Our preliminary data indicated that LPS and SAA induced a marked expression and secretion of pCTS-
L in both murine macrophage and human monocyte cultures. Consequently, pCTS-L was not detectable in the
circulation of healthy animals or human subjects, but significantly elevated in the blood of septic animals and
patients. Highly purified recombinant pCTS-L stimulated primary human monocytes to release various
chemokines, as well as pro- (e.g., TNF and IL-1β) and anti-inflammatory cytokines (e.g., IL-10) in vitro, and
exacerbated endotoxemic lethality in vivo. In contrast, pCTS-L-neutralizing antibodies significantly rescued
mice from lethal sepsis, suggesting pCTS-L as another late mediator of LBI. Meanwhile, a semi-high
throughput screening of a NatProduct Collection of 800 natural products and a US Drug Collection of 1360
bioactive compounds led to the finding of a few lead compounds [including lanosterol (LAN) and progesterone
(PRO)] with striking structural resemblance and similar pCTS-L-inhibiting activities. Although LAN is an
abundant secondary metabolite in some medicinal plants including wolfberry and aveloz, it also serves as a
substrate for the synthesis of PRO in animals and humans. These exciting findings prompted the current
proposal to investigate a novel role of pCTS-L in LBI, as well as intricate mechanisms by which a natural
product, LAN, and its derivative, PRO, inhibit pCTS-L-induced inflammation. The experiments outlined in
Aim 1 will test the hypothesis that pCTS-L systemically accumulates in the circulation of septic patients and
correlates with other surrogate markers of sepsis. In Aim 2, we will test the hypothesis that alterations of
pCTS-L levels (by supplementation of pCTS-L or genetic knockout) or activities (by use of neutralizing IgGs or
natural inhibitor LAN or PRO) divergently influence the outcomes of LBI. The experiments outlined in Aim 3
will test the hypothesis that LAN and/or PRO inhibit the pCTS-L-induced inflammation through impairing the
TLR4/ RAGE-dependent hemichannel and PKR activation in vitro, and confer protection against LBI partly by
attenuating systemic inflammation and associated dysregulated coagulation in vivo. Collectively, this project
wil...

## Key facts

- **NIH application ID:** 10058673
- **Project number:** 2R01AT005076-09A1
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Haichao Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 2
- **Project period:** 2010-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058673

## Citation

> US National Institutes of Health, RePORTER application 10058673, Mechanisms of Novel Herbal Therapies for Sepsis. (2R01AT005076-09A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10058673. Licensed CC0.

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