Natural Products in Liver Fibrosis Management: A Five-year Review.

Liver fibrosis, characterized by the overproduction of extracellular matrix proteins within liver tissue, poses a rising global health concern. However, no approved antifibrotic drugs are currently available, highlighting the critical need for understanding the molecular mechanisms of liver fibrosis. This knowledge could not only aid in developing therapies but also enable early intervention, enhance disease prediction, and improve our understanding of the interaction between various underlying conditions and the liver. Notably, natural products used in traditional medicine systems worldwide and demonstrating diverse biochemical and pharmacological activities are increasingly recognized for their potential in treating liver fibrosis. This review aims to comprehensively understand liver fibrosis, emphasizing the molecular mechanisms and advancements in exploring natural products' antifibrotic potential over the past five years. It also acknowledges the challenges in their development and seeks to underscore their potency in enhancing patient prognosis and reducing the global burden of liver disease.

Network Pharmacology-Based Analysis on the Effects and Mechanism of the Wang-Bi Capsule for Rheumatoid Arthritis and Osteoarthritis.

Wang-Bi capsule (WB) is a traditional Chinese medicine (TCM)-based herbal formula, and it has been used in the treatment of rheumatoid arthritis (RA) in China for many years. Additionally, WB is also used as a supplement to the treatment of osteoarthritis (OA) in clinical practice. Our research aimed to reveal the therapeutic effects and underling mechanism of WB on RA and OA through computational system pharmacology analysis and experimental study. Based on network pharmacology analysis, a total of 173 bioactive compounds interacted with 417 common gene targets related to WB, RA, and OA, which mainly involved the PI3K-Akt signaling pathway. In addition, the serine-threonine protein kinase 1 (AKT1) might be a core gene protein for the action of WB, which was further emphasized by molecular docking. Moreover, the anti-inflammatory activity of WB in vitro was confirmed by reducing NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells. The anti-RA and OA effects of WB in vivo were confirmed by ameliorating the disease symptoms of collagen II-induced RA (CIA) and monosodium iodoacetate-induced OA (MIA) in rats, respectively. Furthermore, the role of the PI3K-Akt pathway in the action of WB was preliminarily verified by western blot analysis. In conclusion, our study elucidated that WB is a potentially effective strategy for the treatment of RA and OA, which might be achieved by regulating the PI3K-Akt pathway. It provides us with systematic insights into the effects and mechanism of WB on RA and OA.

[Anti-inflammatory effect, plasma effective components and therapeutic targets of Huanglian Jiedu Decoction on ulcerative colitis mice].

This paper was to investigate the effect of Huanglian Jiedu Decoction(HLJD) on ulcerative colitis(UC) in mice, and determine the effective components in plasma, and virtually screen its therapeutic target, and predict its mechanism. Sixty Balb/c mice were randomly divided into blank group, model group, mesalazine treatment group(0.3 g·kg~(-1)), and HLJD treatment groups(24.66, 12.33, 6.17 g·kg~(-1)). Excepted for the blank group, all the mice in HLJD and mesalazine treatment groups were gavage administration. All mice freely drank 2.5% DSS solution for seven days to induce UC. The disease activity index(DAI) was detected each day. At the end of the experiment, HE staining was used to observe the pathological changes in colon. The content of IL-1ß, IL-6 and TNF-α in colon were determined by ELISA. The effective components in plasma were determined by UPLC-Q-TOF-MS. The reverse docking in PharmMapper was used to screen the component targets. The disease targets of UC were collected by searching TTD, OMIM and GeneCards databases. The intersection of the component targets and disease targets was selected as the therapeutic targets. Then the therapeutic targets were imported into the STRING for GO and KEGG enrichment analysis. Discovery Studio was used to simulate the docking between the components and the targets. RESULTS:: showed that the DAI in the model group increased significantly(P<0.05), and the number of inflammatory cells and infiltration degree increased significantly compared with the blank group. The DAI in HLJD treatment group was significantly reduced(P<0.05), and the number and infiltration degree of inflammatory cells were reduced compared with the model group. The ELISA results showed that the levels of IL-1ß, IL-6 and TNF-α were increased significantly in the model group(P<0.01) compared with the blank group, and significantly down regulated in the HLJD treatment group(P<0.05) compared with the model group. After UPLC-Q-TOF-MS analyse, ten components were identified. The network pharmacology analysis showed that the action targets were significantly enriched in 129 of biological processes, such as response to organic substance, chemical and oxygen-containing compound, etc., as well as 16 of signal pathways, such as IL-17, TNF and hepatitis B signal pathways, were enriched too. The results of molecular docking showed that limonin, palmatine and berberine could bind to CASP3 and MMP9 by hydrogen bond. In conclusion, HLJD could alleviate the colonic mucosal inflammatory infiltration and mucosal damage in UC mice. The mechanism may be related to the anti-inflammatory effect on UC mice by reducing the levels of IL-1ß, IL-6 and TNF-α in colon through limonin, palmatine and berberine regulating IL-17 signal pathway and TNF signal pathway via CASP3 and MMP9 meditated.

Pharmacoproteomics reveals the mechanism of Chinese dragon's blood in regulating the RSK/TSC2/mTOR/ribosome pathway in alleviation of DSS-induced acute ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese dragon's blood (CDB), a crude drug extracted from Dracaena cochinchinensis (Lour.) S.C. Chen, has been historically applied for the treatment of various diseases, including ulcerative colitis (UC). Unfortunately, the underlying molecular mechanism remains unclear. MATERIALS AND METHODS: In this paper, the effects of CDB treatment on a mouse model of acute UC and proteomic variation in colonic tissue were investigated. The acute UC model in Balb/c mice was induced by administration of 2.5% (wt/vol) dextran sulfate sodium (DSS) in drinking water for 8 days. After the mice with UC were intragastrically administered CDB and intraperitoneally injected with rapamycin (RAPA, a specific inhibitor of mTORC1), the disease activity index (DAI) and histopathological score were recorded. An isobaric tags for relative and absolute quantification (iTRAQ) based LC-MS/MS proteomic technique was adopted to identify the differentially expressed proteins (DEPs) in colonic tissue. Bioinformatics analysis was used to discover the molecular functions and pathways of the DEPs. Finally, Western blot analysis and immunohistochemistry were used to verify the protein expression. RESULTS: The results showed that CDB treatment significantly ameliorated the symptoms and intestinal damage in acute UC, while RAPA treatment led to severe symptoms and intestinal damage. A total of 489 DEPs were reversed in the control check (CK) group and the CDB group. Most DEPs were enriched in the structural constituents of ribosomes and the ribosome pathway. CDB treatment significantly upregulated the expression of the mTOR, p-mTOR and p70S6K proteins and downregulated the expression of the Akt, p-Akt, and p4EBP1 proteins. However, RAPA treatment, unlike CDB, did not return the levels of mTOR, Akt, and their phosphorylated forms to nearly normal. CONCLUSIONS: In conclusion, the dysfunction of the mTOR/ribosome pathway resulting in the inhibition of ribosome synthesis played an important role in the development of acute UC in mice, and CDB, but not RAPA, was an alternative drug for the treatment of acute UC by enhancing ribosome synthesis via the mTOR/ribosome pathway and further promoting protein synthesis.

Huanglian Jiedu Decoction ameliorates DSS-induced colitis in mice via the JAK2/STAT3 signalling pathway.

BACKGROUND: Ulcerative colitis (UC) is an intestinal disease which was characterized by intestinal inflammation, mucosal injury and fibrosis. In this paper, the effect of Huanglian Jiedu Decoction (HJD), a well-known traditional Chinese medicine with significant anti-inflammatory effect, on dextran sulphate sodium (DSS)-induced UC in mice and inhibition of JAK2/STAT3 pathway were investigated. METHODS: BALB/c mice were randomly divided into 6 groups: HJD group (high, medium and low dose), USAN group, UC group, and control group. UC in mice were induced through free access to 3% DSS solution. After being treated with HJD for 8 days, all animals were sacrifice. Pathological examination of colonic specimen was performed by H&E staining. Cytokines (TNF-α, IL-6, and IL-1ß) in colon were assayed by ELISA and immunofluorescence, MPO in colon and ATT in serum were detected by ELISA. Moreover, mice in HJD group and UC group were treated with AG490 to inhibit the expression of JAK2 protein, then the expression of JAK2 and STAT3 protein in colon was determined by western blotting and immunofluorescence staining. Furthermore, KI67 in colon was examined by immunohistochemistry, and apoptosis was detected by TUNEL staining, and collagen deposition was assayed by Masson staining after JAK2/STAT3 pathway in UC mice was inhibited by HJD. RESULTS: After mice being treated with HJD, the symptoms (weight loss and haematochezia) of UC were alleviated, and the contents of inflammatory cytokines (TNF-α, IL-6 and IL-1ß) and MPO in colon were significantly decreased. The expression of JAK2 and STAT3 protein was reduced after administration with HJD. After JAK2/STAT3 pathway being inhibited with HJD, the cell apoptosis, collagen deposition and immunoreactivity of macrophage in colon were significantly reduced, but the expression of Ki67 was markedly enhanced in both UC group and HJD group compare with control group. CONCLUSIONS: HJD treatment can alleviate intestinal mucosal damage and has the protective effect on UC by downregulating JAK2 and STAT3 expression to reduce inflammation via JAK2/STAT3 pathway.

[Effect of triptolide on iNOS and SP expressions in spinal dorsal horn and dorsal root ganglion of rats with adjuvant arthritis].

OBJECTIVE: To observe the analgesic effect of triptolide (TP) of high, middle and low doses on rats with adjuvant arthritis (AA), and the expressions of inducible nitric oxide synthase (iNOS) and substance P (SP) in spinal dorsal horn and dorsal root ganglion (DRG) of corresponding sections, in order to discuss the possible mechanism for the analgesic effect of TP on rats with adjuvant arthritis. METHOD: Fifty SD rats were selected and randomly divided into the normal group (group A), the model group (group B), and TP low (group C), middle (group D), high (group E) dose groups. Except for the group A, all of the remaining groups were injected with 0.1 mL of Freund's complete adjuvant through their right rear toes to establish the model. At 14 d after the model establishment, rats in C, D and E groups were intraperitoneally injected with different doses of TP (0.1 mg x kg(-1) for the group C, 0.2 mg x kg(-1) for the group D, 0.4 mg x kg(-1) for the group E) once a day for 9 days. Then the 50% mechanical withdraw threshold (MWT) was determined. And the expressions of iNOS and SP in lumbar5 (L5) spinal dorsal horn and DRG were detected with the immunohistochemical method. RESULT: The 50% MWT of rats in the group B was significantly lower than that of the group A (P < 0.01). After being treated with TP, the Thermal withdrawal latencies of groups C, D and E were significantly higher than that of the group B (P < 0.01). TP could notably increase the MWT of AA rats, with a certain dose-effect relationship. The immunohistochemical results indicated that the iNOS and SP expressions significantly increased in the group B (P < 0.01), while the positive expression levels of iNOS and SP in groups C, D and E were significantly lower than that of the group B (P < 0.01), with a certain dose-effect relationship. CONCLUSION: TP shows a good analgesic effect on AA, and could inhibit the iNOS and SP expressions in spinal dorsal horn and DRG in rats with adjuvant arthritis, which may be one of action mechanisms for the analgesic effect of TP.

[Prospective clinical study of radix astragali and its compound prescription for treatment of ß-thalassemia in children].

OBJECTIVE: To evaluate the efficacy and safety of radix astragali and its compound prescription for treatment of ß-thalassemia in children. METHODS: This study was a randomized, controlled, double-blind clinical trial. Fifty-seven children with ß-thalassemia were randomly assigned to radix astragali, compound prescription (radix astragali+ codonopsis pilosula + tortoise plastron) and placebo control groups after stratifying the patients according to disease type (intermedia and major). The parameters of hematology and safety were assessed after 12 weeks of treatment. RESULTS: After 12 weeks of treatment, the mean Hb elevation levels in children with ß-thalassemia intermedia from the compound prescription and the radix astragali groups were 1.21±1.12 and 1.05±0.80 g/dL respectively compared with -(0.28±0.51) g/dL in the placebo control group (P<0.01). Mean Hb levels in the compound prescription and radix astragali groups were significantly higher than in the placebo control group (P<0.05). Therapy with both radix astragali and its compound prescription increased fetal hemoglobin, red blood cell, mean corpuscular hemoglobin and reticulocyte levels in children with ß-thalassemia intermedia. The total effective rates were 64% and 62% in children with ß-thalassemia intermedia from the compound prescription and radix astragali groups respectively, which was significantly higher than in the placebo control group (9%; P<0.01). Therapy with radix astragali or its compound prescription in children with ß-thalassemia major had similar but less favourable effects than the same therapy in children with ß-thalassemia intermedia. White blood cell, neutrophil, platelet and hepatic and renal functions were not adversely affected by the medicines. CONCLUSIONS: Therapy with radix astragali or its compound prescription is effective and safe in children with ß-thalassemia.

Ouabain at pathological concentrations might induce damage in human vascular endothelial cells.

AIM: To examine the time- and dose-dependent effects of ouabain on human umbilical vein endothelial cells (HUVEC) in vivo, and the changes in aortic endothelium and the different expression levels of Kv4.2 in vitro. METHODS: The proliferation of HUVEC and cell death were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, the incorporation of [3H]TdR, trypan blue staining, and lactate dehydrogenase (LDH) release. The response of endothelial cells to ouabain was explored with a complementary DNA microarray and a candidate gene was found. Ouabain-sensitive hypertensive rats were established by chronic administration of ouabain. Changes in the aortic endothelium were observed by electron microscopy, and the expression level of Kv4.2 in different animals was studied by using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Ouabain stimulated the proliferation of HUVEC at physiological concentrations (0.3-0.9 nmol/L). Ouabain at pathological concentrations (0.9-1.8 nmol/L) inhibited proliferation and induced cell death. mRNA profile analysis indicated that 340 genes were differentially expressed after ouabain treatment: 145 were upregulated, of which 6 were upregulated significantly, including KCND2 (encoding the potassium voltage-gated channel shal-related subfamily member 2). The upregulated genes were mainly related to cell metabolism and transcription. In ouabain-sensitive hypertensive rats, the aortic endothelium was damaged and Kv4.2 (coded by KCND2) was over-expressed. CONCLUSION: The physiological role of ouabain in HUVEC might involve the control of growth and metabolism. Ouabain at pathological concentrations might affect the structure and function of the vascular endothelium by modification of expression of the KCND2 gene, and participate vascular remodeling in hypertension.