Chaiqin chengqi decoction (CQCQD) is a Chinese herbal formula derived from dachengqi decoction. CQCQD has been used for the management of acute pancreatitis (AP) in the West China Hospital for more than 30 years. Although CQCQD has a well-established clinical efficacy, little is known about its bioactive ingredients, how they interact with different therapeutic targets and the pathways to produce anti-inflammatory effects. Toll-like receptor 4 (TLR4) and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pro-inflammatory signaling pathways, play a central role in AP in determining the extent of pancreatic injury and systemic inflammation. In this study, we screened the bioactive ingredients using a pharmacological sub-network analysis based on the TLR4/NLRP3 signaling pathways followed by experimental validation. The main CQCQD bioactive compounds were identified by UPLC-QTOF/MS. The TLR4/NLRP3 targets in AP for CQCQD active ingredients were confirmed through a pharmacological sub-network analysis. Mice received 7 intraperitoneal injections of cerulein (50 μg/kg; hourly) to induce AP (CER-AP), while oral gavage of CQCQD (5, 10, 15 and 20 g/kg; 3 doses, 2 hourly) was commenced at the 3rd injection of cerulein. Histopathology and biochemical indices were used for assessing AP severity, while polymerase chain reaction, Western blot and immunohistochemistry analyses were used to study the mechanisms. Identified active CQCQD compounds were further validated in freshly isolated mouse pancreatic acinar cells and cultured RAW264.7 macrophages. The main compounds from CQCQD belonged to flavonoids, iridoids, phenols, lignans, anthraquinones and corresponding glycosides. The sub-network analysis revealed that emodin, rhein, baicalin and chrysin were the compounds most relevant for directly regulating the TLR4/NLRP3-related proteins TLR4, RelA, NF-κB and TNF-α. In vivo, CQCQD attenuated the pancreatic injury and systemic inflammation of CER-AP and was associated with reduced expression of TLR4/NLRP3-related mRNAs and proteins. Emodin, rhein, baicalin and chrysin significantly diminished pancreatic acinar cell necrosis with varied effects on suppressing the expression of TLR4/NLRP3-related mRNAs. Emodin, rhein and chrysin also decreased nitric oxide production in macrophages and their combination had synergistic effects on alleviating cell death as well as expression of TLR4/NLRP3-related proteins. CQCQD attenuated the severity of AP at least in part by inhibiting the TLR4/NLRP3 pro-inflammatory pathways. Its active ingredients, emodin, baicalin, rhein and chrysin contributed to these beneficial effects.

Tectorigenin is a well-known natural flavonoid aglycone and an active component that exists in numerous plants. Growing evidence suggests that tectorigenin has multiple pharmacological effects, such as anticancer, antidiabetic, hepatoprotective, anti-inflammatory, antioxidative, antimicrobial, cardioprotective, and neuroprotective. These pharmacological properties provide the basis for the treatment of many kinds of illnesses, including several types of cancer, diabetes, hepatic fibrosis, osteoarthritis, Alzheimer’s disease, etc. The purpose of this paper is to provide a comprehensive summary and review of the sources, extraction and synthesis, pharmacological effects, toxicity, pharmacokinetics, and delivery strategy aspects of tectorigenin. Tectorigenin may exert certain cytotoxicity, which is related to the administration time and concentration. Pharmacokinetic studies have demonstrated that the main metabolic pathways in rats for tectorigenin are glucuronidation, sulfation, demethylation and methoxylation, but that it exhibits poor bioavailability. From our perspective, further research on tectorigenin should cover: exploring the pharmacological targets and mechanisms of action; finding an appropriate concentration to balance pharmacological effects and toxicity; attempting diversified delivery strategies to improve the bioavailability; and structural modification to obtain tectorigenin derivatives with higher pharmacological activity.

Chaiqinchengqi decoction, a traditional Chinese medicine, has shown promising effects in in vitro, animal and preliminary small human studies for acute pancreatitis, but evidence of clinical practice is limited. To investigate whether Chaiqinchengqi decoction could improve clinical outcomes in patients with acute pancreatitis. Prospective, pragmatic, randomized controlled trial. (Chictr.org.cn registration number: ChiCTR2000034325) METHODS: This trial was conducted at West China Hospital of Sichuan University, China. Patients with acute pancreatitis were randomly assigned to receive either Chaiqinchengqi decoction or placebo by oral and rectal enemas in addition to guideline-directed administrations using a 1:1 ratio. The intervention of Chaiqinchengqi and placebo was determined by the grading of acute gastrointestinal injury. Patients were assessed within 24 and 48 hours, and on 3, 5, and 7 days after admission, or organ failure normalized. Survivors were followed up at 1, 3, and 6 months after discharge. Primary outcome was the duration of respiratory failure to 28 days after enrollment. Secondary outcomes included other organ failure, local complications, 6-month all-cause mortality, inflammatory indicators, and related interventions. Among 248 patients enrolled, Chaiqinchengqi decoction shortened the duration of respiratory failure compared with the placebo (median [IQR], 1.0 [0.0 to 5.0] vs 3.0 [1.0-8.0] days; median difference, -1.0; 95% CI, -2.0 to 0.0, P=.001). There were significant differences in the duration of circulatory failure, the incidence of new-onset respiratory and cardiovascular and failure, the incidence of new organ failure, severity, intensive care unit need, pain visual analogue scale, pancreatitis activity scoring system, and EQ-5D-5L. Chaiqinchengqi decoction as an adjunctive therapy significantly reduced the duration of respiratory failure and improved 6-month clinical outcomes of acute pancreatitis in addition to guideline-directed treatments. Further study is needed to elucidate the mechanism of action.