Major Indole Alkaloids in Evodia Rutaecarpa: The Latest Insights and Review of Their Impact on Gastrointestinal Diseases.

Evodia rutaecarpa, the near-ripe fruit of Euodia rutaecarpa (Juss.) Benth, Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang, or Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang, is a famous herbal medicine with several biological activities and therapeutic values, which has been applied for abdominalgia, abdominal distension, vomiting, and diarrhea as a complementary and alternative therapy in clinic. Indole alkaloids, particularly evodiamine (EVO), rutaecarpine (RUT), and dedhydroevodiamine (DHE), are received rising attention as the major bioactivity compounds in Evodia rutaecarpa. Therefore, this review summarizes the physicochemical properties, pharmacological activities, pharmacokinetics, and therapeutic effects on gastrointestinal diseases of these three indole alkaloids with original literature collected by PubMed, Web of Science Core Collection, and CNKI up to June 2023. Despite sharing the same parent nucleus, EVO, RUT, and DHE have different structural and chemical properties, which result in different advantages of biological effects. In their wide range of pharmacological activities, the anti-migratory activity of RUT is less effective than that of EVO, and the neuroprotection of DHE is significant. Additionally, although DHE has a higher bioavailability, EVO and RUT display better permeabilities within blood-brain barrier. These three indole alkaloids can alleviate gastrointestinal inflammatory in particular, and EVO also has outstanding anti-cancer effect, although clinical trials are still required to further support their therapeutic potential.

Tou Nong powder obstructs ulcerative colitis through the regulation of NF-κB/NLRP3/Caspase-1/GSDMD inflammasome pyroptotic pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tou Nong Powder (TNP), a classical Chinese medicinal formula originated from the Chinese Ming Dynasty, has been applied to treat skin ulcers in patients with deficient constitutions. According to theory of traditional Chinese medicine, colonic ulcers share similar pathological conditions with skin ulcers, and consequently, TNP has been applied to ulcerative colitis (UC) safely and effectively. AIM OF STUDY: To investigate whether TNP obstructs 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced enteric inflammation through regulation of NLRP3 inflammasome and attenuating enteric pyroptosis. MATERIALS AND METHODS: Network pharmacology and UPLC-Q-TOF/MS were operated to identify compounds and pharmacological potential targets. The therapeutic effects of TNP were assessed on TNBS induced colitis via general symptoms (disease activity index, colonic weight and length) and histopathological observation. The NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway regulation was investigated by Western blot and real time reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: TNP ameliorates the disease activity index, reverses the increase of colonic weight increase, alleviates colonic shortening and colonic histopathological injury. A decrease in tumor necrosis factor α (TNF-α), diamine oxidase (DAO), intercellular adhesion molecule-1 (ICAM-1), and endo-toxin (ET) were investigated in peripheral circulation. Moreover, TNP significantly obstructed the NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway. CONCLUSION: TNP displays a promising therapeutic effect on UC via suppressing NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway and reducing the expression of IL-1ß and IL-18.

Crosstalk between Depression and Breast Cancer via Hepatic Epoxide Metabolism: A Central Comorbidity Mechanism.

Breast cancer (BC) is a serious global challenge, and depression is one of the risk factors and comorbidities of BC. Recently, the research on the comorbidity of BC and depression has focused on the dysfunction of the hypothalamic-pituitary-adrenal axis and the persistent stimulation of the inflammatory response. However, the further mechanisms for comorbidity remain unclear. Epoxide metabolism has been shown to have a regulatory function in the comorbid mechanism with scattered reports. Hence, this article reviews the role of epoxide metabolism in depression and BC. The comprehensive review discloses the imbalance in epoxide metabolism and its downstream effect shared by BC and depression, including overexpression of inflammation, upregulation of toxic diols, and disturbed lipid metabolism. These downstream effects are mainly involved in the construction of the breast malignancy microenvironment through liver regulation. This finding provides new clues on the mechanism of BC and depression comorbidity, suggesting in particular a potential relationship between the liver and BC, and provides potential evidence of comorbidity for subsequent studies on the pathological mechanism.

The application of Tong-fu therapeutic method on ulcerative colitis: A systematic review and meta-analysis for efficacy and safety of rhubarb-based therapy.

Background: Tong-fu therapeutic method (TFTM) is a traditional Chinese medicine treatment method for ulcerative colitis, which is a novel treatment strategies and have purgative effect. As the most representative medicinal of TFTM, Rhubarb has been reported to have a therapeutic impact on ulcerative colitis by regulating intestinal flora, anti-inflammation, and improving intestinal microcirculation. Although rhubarb has been widely used in Chinese medicine for the treatment of ulcerative colitis, the appropriate protocol is still demanded to its rational use in clinic, which promoted to evaluate the efficacy and safety for rhubarb-based therapy on ulcerative colitis. Method: Clinical trials were searched through PubMed, Cochrane Library, Web of Science, Excerpta Medica Database, Chinese National Knowledge Infrastructure, WAN FANG Database, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database. The subgroup analyses were performed with three groups: medication, course of treatment, and route of administration. The statistical analyses were performed on Review Manager software (version 5.4.1). Results: A total of 2, 475 patients in 30 original studies were analyzed in this article. It was found that rhubarb-based therapy could increase clinical efficacy and reduce the recurrence rate. Subgroup analyses showed that rhubarb-based therapy was more effective than 5-aminosalicylic acid or sulfasalazine alone. In addition, the hypercoagulable state of ulcerative colitis could be ameliorated by decreasing platelet (PLT) and fibrinogen (FIB), and increasing prothrombin time (PT) significantly. Moreover, C-reaction protein (CRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-1ß expression were significantly reduced, while IL-10 production was increased, which mediated the alleviation of intestinal inflammation stress. Conclusion: Rhubarb-based therapy could effectively improve ulcerative colitis. Of note, the rhubarb-based medicinal formulas combined with 5-ASA or SASP are more effective than the 5-ASA or SASP alone. In addition, although rhubarb has side effect, the results of our analysis showed that rhubarb-based therapy did not exhibit significant side effects. This means it has a high safety profile in clinical use. Moreover, the use of rhubarb-based therapy is recommend to use within 1-13 weeks or 3 months via administered orally or by enema, which is contributes to ensure the curative effect and avoid its toxic and side effects. As an important case of TFTM, rhubarb-based therapy provides evidence for the practical application of TFTM.

Renshen Baidu powder protects ulcerative colitis via inhibiting the PI3K/Akt/NF-κB signaling pathway.

Ulcerative colitis is a chronic and relapsing inflammatory bowel disease without satisfactory therapy available recently. Renshen Baidu powder (RSBDP) is a classic Chinese medicinal formula used since Chinese Song dynasty and has been proven as an effective treatment of ulcerative colitis in clinics. However, the active ingredients and the molecular mechanism have not been fully disclosed. It is imperative to explore the active ingredients and the mechanism of RSBDP. In this study, the potential active components for ulcerative colitis treatment in RSBDP were determined and predicted in silicon, and its molecular mechanisms were also presented, in which the PI3K/Akt/NF-κB signaling pathway was recognized to be vital. Basically, the pharmacodynamics and mechanistic studies of RSBDP for ulcerative colitis were implemented on TNBS-induced experimental rats. The results showed that RSBDP could ameliorate the disease activity index and colon weight, as well as improve colonic shortening and colon histology. In addition, the tumor necrosis factor-α (TNF-α), diamine oxidase, intercellular adhesion molecule-1, and endotoxin in serum were also reduced. It is worth mentioning that the PI3K/Akt/NF-κB signaling pathway was inhibited after RSBDP administration via inhibiting the phosphorylation of proteins. In conclusion, RSBDP effectively ameliorates TNBS-induced colitis rats by inhibiting the PI3K/Akt/NF-κB signaling pathway.

Corrigendum: The Therapeutic Principle of Combined Strengthening Qi and Eliminating Pathogens in Treating Middle-Advanced Primary Liver Cancer: A Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.3389/fphar2021.714287.].

Targeted therapy of rheumatoid arthritis via macrophage repolarization.

The polarization of macrophages plays a critical role in the physiological and pathological progression of rheumatoid arthritis (RA). Activated M1 macrophages overexpress folate receptors in arthritic joints. Hence, we developed folic acid (FA)-modified liposomes (FA-Lips) to encapsulate triptolide (TP) (FA-Lips/TP) for the targeted therapy of RA. FA-Lips exhibited significantly higher internalization efficiency in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than liposomes (Lips) in the absence of folate. Next, an adjuvant-induced arthritis (AIA) rat model was established to explore the biodistribution profiles of FA-Lips which showed markedly selective accumulation in inflammatory paws. Moreover, FA-Lips/TP exhibited greatly improved therapeutic efficacy and low toxicity in AIA rats by targeting M1 macrophages and repolarizing macrophages from M1 to M2 subtypes. Overall, a safe FA-modified liposomal delivery system encapsulating TP was shown to achieve inflammation-targeted therapy against RA via macrophage repolarization.

The Therapeutic Principle of Combined Strengthening Qi and Eliminating Pathogens in Treating Middle-Advanced Primary Liver Cancer: A Systematic Review and Meta-Analysis.

Background: The combination of strengthening Qi and eliminating pathogens is an available therapeutic principle in traditional Chinese medicine (TCM) for primary liver cancer (PLC) at middle-advanced stage. However, there is a lack of reasonable evidence to support the proper application of this therapeutic principle. This meta-analysis aims to evaluate the efficacy and safety of Chinese medicinal formulas (CMFs), including two subgroup analyses of the principle of strengthening Qi and eliminating pathogens. Method: Clinical trials were obtained through searching of EMBASE, Web of Science, PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, and two clinical trial registries. The randomized controlled trials with the combination of CMFs and transcatheter arterial chemoembolization (TACE) in the experiment group were acceptable, in contrast to the TACE alone in the control group. The statistics analysis was performed on Review Manager 5.4. Results: A total of eligible 24 trials were accessed in this work. Overall, CMFs could improve the survival duration of 6 months, 1 year, and 2 years, Karnofsky Performance Status, tumor objective response rate (ORR), AFP, and symptom. In the subgroup analysis, trials complying with the principle of single strengthening Qi did not show any significant difference in increasing tumor ORR. Meanwhile, the principle of combined strengthening Qi and eliminating pathogens was uncertain in improving symptoms and 1-year and 2-year survival time. In addition, the outcome indexes of ALT and AST were heterogeneous. In last, the total occurrence of adverse events could not be reduced via using CMFs. Patients treated with CMFs exhibited liver injury, fever, and white blood cell decline, with mild events occurring more frequently and severe events occurring less. Conclusion: CMFs are an effective treatment method to cure PLC at the middle-advanced stage. Adopting the principle of single strengthening Qi presents better efficacy in the long term by prolonging the survival duration. Following the principle of combined strengthening Qi and eliminating pathogens could be more beneficial to patients in short term by lessening the tumor size. CMFs have the advantage of reducing certain serious adverse events.

Houttuynia cordata Thunb: An Ethnopharmacological Review.

Houttuynia cordata Thunb (H. cordata; Saururaceae) is widely distributed in Asian regions. It plays an important role in traditional health care and disease treatment, as its aboveground stems and leaves have a long medicinal history in China and are used in the treatment of pneumonia and lung abscess. In clinical treatment, it can usually be combined with other drugs to treat dysentery, cold, fever, and mumps; additionally, H. cordata is an edible plant. This review summarizes detailed information on the phytochemistry and pharmacological effects of H. cordata. By searching the keywords "H. cordata and lung", "H. cordata and heart", "H. cordata and liver", and "H. cordata and inflammation" in PubMed, Web of Science and ScienceDirect, we screened out articles with high correlation in the past ten years, sorted out the research contents, disease models and research methods of the articles, and provided a new perspective on the therapeutic effects of H. cordata. A variety of its chemical constituents are characteristic of medicinal plants, the chemical constituents were isolated from H. cordata, including volatile oils, alkaloids, flavonoids, and phenolic acids. Flavonoids and volatile oils are the main active components. In pharmacological studies, H. cordata showed organ protective activity, such as reducing the release of inflammatory factors to alleviate lung injury. Moreover, H. cordata regulates immunity, enhances the immune barriers of the vagina, oral cavity, and intestinal tract, and combined with the antibacterial and antiviral activity of its extract, effectively reduces pathogen infection. Furthermore, experiments in vivo and in vitro showed significant anti-inflammatory activity, and its chemical derivatives exert potential therapeutic activity against rheumatoid arthritis. Antitumour action is also an important pharmacological activity of H. cordata, and studies have shown that H. cordata has a notable effect on lung tumour, liver tumour, colon tumour, and breast tumour. This review categorizes the biological activities of H. cordata according to modern research papers, and provides insights into disease prevention and treatment of H. cordata.

Tou Nong San Attenuates Inflammation in TNBS-IBD Model by Inhibiting NF-κB Signaling Pathway.

The incidence of inflammatory bowel disease (IBD), which predominantly comprises Crohn's disease and ulcerative colitis, is increasing worldwide. However, the treatment of IBD still faces great challenges. The involved NF-κB is the main signaling pathway in human IBD and thus is a prime target. There is abundant evidence that Tou Nong San (TNS), which is a traditional Chinese medicinal decoction used for treating sores and carbuncles, has a positive effect on the inflammation. This study investigated the effects of oral administration of TNS on colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and the underlying mechanism(s). Quality control of the major compounds in TNS was performed by high-performance liquid chromatography, and six chemical constituents were identified in aqueous extracts. TNS led to improvements in weight loss and water and food intake in rats. The macroscopic and microscopic scores of rat tissues greatly decreased. Protein and mRNA levels of proinflammatory cytokines, including interleukin-17 (IL-17), tumour necrosis factor-α, IL-1ß, and IL6, involved in the NF-κB signaling pathway were greatly reduced. The results suggest that the anti-inflammatory effect of TNS is associated with the regulation of the NF-κB signaling pathway, which contributes to the network pharmacological effect of TNS on human IBD in clinical practice.