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Sonic hedgehog (SHH) signaling pathway promotes the process of angiogenesis, contributing to the growth and progression of many human malignancies including colorectal cancer (CRC), which therefore has become a promising target for cancer chemotherapy. Hedyotis diffusa Willd (HDW), as a well-known traditional Chinese herbal medicine, has long been used in China for the clinic treatment of various cancers. Recently, we reported that HDW can inhibit colorectal cancer growth in vivo and in vitro via suppression of the STAT3 pathway. In addition, we demonstrated the anti-angiogenic activity of HDW in vitro. To further elucidate the mechanism of the tumoricidal activity of HDW, by using a CRC mouse xenograft model we evaluated the in vivo effect of the ethanol extract of HDW (EEHDW) on tumor angiogenesis, and investigated the underlying molecular mechanisms. We found that EEHDW could significantly reduce intratumoral microvessel density (MVD), indicating its activity of antitumor angiogenesis in vivo. EEHDW suppressed the activation of SHH signaling in CRC xenograft tumors since it significantly decreased the expression of key mediators of SHH pathway. EEHDW treatment inhibited the expression of the critical SHH signaling target gene VEGF-A as well as its specific receptor VEGFR2. Taken together, we propose for the first time that Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of SHH-mediated tumor angiogenesis.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that may lead to joint damage, deformity, and disability, if not treated effectively. Hedyotis diffusa Willd (HDW) and its main components have been widely used to treat a variety of tumors and inflammatory diseases. The present study utilized a network pharmacology approach, microarray data analysis and molecular docking to predict the key active ingredients and mechanisms of HDW against RA. Eleven active ingredients in HDW and 180 potential anti-RA targets were identified. The ingredients-targets-RA network showed that stigmasterol, beta-sitosterol, quercetin, kaempferol, and 2-methoxy-3-methyl-9,10-anthraquinone were key components for RA treatment. KEGG pathway results revealed that the 180 potential targets were inflammatory-related pathways with predominant enrichment of the AGE-RAGE, TNF, IL17, and PI3K-Akt signaling pathways. Screened through the PPI network and with Cytoscape software, RELA, TNF, IL6, TP53, MAPK1, AKT1, IL10, and ESR1 were identified as the hub targets in the HDW for RA treatment. Molecular docking was used to identify the binding of 5 key components and the 8 related-RA hub targets. Moreover, the results of network pharmacology were verified by vitro experiments. HDW inhibits cell proliferation in MH7A cells in a dose and time-dependent manner. RT-qPCR and WB results suggest that HDW may affect hub targets through PI3K/AKT signaling pathway, thereby exerting anti-RA effect. This study provides evidence for a clinical effect of HDW on RA and a research basis for further investigation into the active ingredients and mechanisms of HDW against RA.

Prostate cancer (PCa), a globally prevalent male malignancy, necessitates breakthroughs in treating its hormone-refractory stage. The Traditional Chinese Medicine drug pair Hedyotis Diffusae Herba – Scutellaria Barbatae Herba (HDH–SBH) shows significant antitumor value, but its multi-component synergistic mechanisms remain unclear. This study elucidated HDH-SBH’s molecular mechanisms in suppressing PCa via apoptosis pathways. Network pharmacology predicted active components (quercetin, ursolic acid, apigenin) and core targets (AKT1, BCL2, NFKB) enriched in apoptosis ( P  < 0.05). Molecular docking revealed strong binding (e.g., ursolic acid-AKT1: -7.76 kcal/mol), confirmed by stable 100 ns molecular dynamics simulations (RMSD < 5.0 Å). In vitro, HDH-SBH significantly inhibited PC-3 cell proliferation (48 h IC 50  = 1.094 mg/mL), reduced migration (36 h rate decreased by 64.2%), and induced apoptosis (rate 13.57% vs. control 4.79%). It downregulated BCL2 and p-65 protein expression ( P  < 0.05) while suppressing AKT1 phosphorylation. Thus, HDH-SBH targets the AKT1/BCL2/NFKB axis to regulate apoptosis and suppress PCa progression, providing a theoretical and experimental foundation for modernizing TCM in antitumor research.

The plant-colonized microbial communities have closely micro-ecological effects on host plant growth and health. There are many medicinal plants in the genus Hedyotis, but it is yet unclear about the shoot-assembled bacterial and fungal communities (SBFC) of Hedyotis plants. Hence, eight plant populations of Hedyotis diffusa (HD) and H. corymbosa (HC) were evaluated with 16S rRNA gene and ITS sequences, for comparing the types, abundance, or/and potential functions of SBFC at plant species- and population levels. In tested HD- and HC-SBFC, 682 fungal operational taxonomic units and 1,329 bacterial zero-radius operational taxonomic units were identified, with rich species compositions and varied alpha diversities. Notably, the SBFC compositions of HD and HC plant populations were exhibited with partly different types and abundances at phylum and genus levels but without significantly different beta diversities at plant species and population levels. Typically, the SBFC of HD and HC plant populations were presented with abundance-different biomarkers, such as Frankiaceae and Bryobacteraceae, and with similar micro-ecological functions of microbial metabolisms of lipids, terpenoids,and xenobiotics. Taken together, HD- and HC-SBFC possessed with varied rich compositions, conservative taxonomic structures, and similar metabolic functions, but with small-scale type and abundance differences at plant species- and population- levels.

This study aimed to evaluate the pharmacological mechanism of Hedyotis diffusa Willd against CRC (colorectal cancer) using network pharmacological analysis combined with experimental validation. The active components and potential targets of Hedyotis diffusa Willd were screened from the tax compliance management program public database using network pharmacology. The core anti-CRC targets were screened using a protein-protein interaction (PPI) network. The mRNA and protein expression of core target genes in normal colon and CRC tissues and their relationship with overall CRC survival were evaluated using The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Functional and pathway enrichment analyses of the potential targets were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The first six core targets with stable binding were molecular-docked with the active components quercetin and β-sitosterol. Finally, the results of network pharmacology were verified using in vitro experiments. In total, 149 potential targets were identified by searching for seven types of active components and the intersection of all potential and CRC targets. PPI network analysis showed that ten target genes, including tumor protein p53 (TP53) and recombinant cyclin D1 (CCND1), were pivotal genes. GO enrichment analysis involved 2043 biological processes, 52 cellular components, and 191 molecular functions. KEGG enrichment analysis indicated that the anticancer effects of H. alba were mediated by tumor necrosis factor, interleukin-17, and nuclear factor-κB (NF-κB) signaling pathways. Validation of key targets showed that the validation results for most core genes were consistent with those in this study. Molecular docking revealed that the ten core target proteins could be well combined with quercetin and β-sitosterol and the structure remained stable after binding. The results of the in vitro experiment showed that β-sitosterol inhibited proliferation and induced apoptosis in SW620 cells. This study identified a potential target plant for CRC through network pharmacology and in vitro validation.

The decline in autophagy disrupts homeostasis in skin cells, leading to oxidative stress, energy deficiency, and inflammation—all key contributors to skin photoaging. Consequently, activating autophagy has become a focal strategy for delaying skin photoaging. Natural plants are rich in functional molecules and widely used in the development of anti-photoaging cosmetics. Hedyotis diffusa (HD), as a medicinal plant, is renowned for its anti-inflammatory and anticancer properties; however, its effects on skin photoaging remain unclear. This study investigates HD’s potential to counteract skin photoaging by restoring mitochondrial autophagy in keratinocytes. We used HPLC to detect the main chemical components in HD and, using a UVB-induced photoaging model in HaCaT keratinocytes, examined the effects of HD on reactive oxygen species (ROS) levels, Ca2+ concentration, mitochondrial membrane potential (MMP), apoptosis, and the cell cycle. Cellular respiration was further evaluated with the Seahorse XFp Analyzer, and RT-PCR and Western blotting were used to analyze the impact of HD on mitochondrial autophagy-related gene expression and signaling pathways. Our findings indicate that HD promotes autophagy by modulating the PI3K/AKT/mTOR and PINK/PARK2 pathways, which stabilizes mitochondrial quality, maintains MMP and Ca2+ balance, and reduces cytochrome c release. These effects relieve cell cycle arrest and prevent apoptosis associated with an increased BAX/BCL-2 ratio. Thus, HD holds promise as an effective anti-photoaging ingredient with potential applications in the development of cosmetic products.

Chronic inflammation-driven colorectal cancer (CRC) is critically mediated by interleukin-17A (IL-17A)-dependent immune responses and nuclear factor-κB (NF-κB) signaling, which promote immune cell infiltration and tumor progression. In this study, the anti-tumor efficacy and molecular mechanisms of a standardized extract of Hedyotis diffusa Willd. (HD) and its constituent, ferulic acid (FA), were investigated using an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated CRC mouse model. HD and FA treatment markedly alleviated colitis, reduced tumor number and size, improved survival, and attenuated histopathological damage. Transcriptomic analysis revealed significant modulation of immune-related pathways, with prominent suppression of IL-17A and NF-κB signaling. Molecular docking demonstrated binding of FA to IL-17A at Pro59 and Arg101, suggesting potential disruption of the IL-17A/IL-17RA interaction. Consistently, both HD and FA reduced immune cell infiltration, downregulated IL-17A production, and inhibited NF-κB activation in colonic tissues. Collectively, these findings demonstrated that HD exerted protective effects against inflammation-associated CRC through targeting the IL-17A/IL-17RA axis and downstream NF-κB signaling, providing mechanistic insight into IL-17A-centered immunomodulation in colorectal tumorigenesis.

Introduction Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti‐GCa effects in experimental models, are currently being investigated. Method The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5‐fluracil were applied onto AGS, SC‐M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web‐based GCa cohort for Ar expression association with prognosis was performed. Result The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5‐FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer‐suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor‐suppressing index (TSI) score of 90% over a 6‐week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements. Ursolic acid (UA) has been discovered to inhibit gastric cancer without identified target. This article defined UA as is aromatase silencer, of which turn off aromatase expression rather than suppressing enzymatic activity.

Hedyotis diffusa Willd (HD) and Scutellaria barbata D.Don (SB) are widely used traditional Chinese herbs with detoxifying properties and anti-tumor activities. The HD-SB pairing demonstrated significant anti-tumor efficacy in cancer, however, the synergistic potential of HD-SB with cisplatin in the treatment of cancer remains poorly understood. The current work aimed to uncover the synergistic effect of HD-SB with cisplatin on ovarian cancer. In the present study, the combination of HD-SB and cisplatin exhibited a pronounced inhibitory effect on the proliferation, migration and invasion, while promoting effect on apoptosis of ovarian cancer cells. Moreover, the interaction between drug compounds and disease targets contained 277 nodes and 1395 edges, the highlighting active ingredients were quercetin, luteolin, wogonin. Among the PPI network, the top targets were TP53, STAT3, SRC, AKT1, HSP90AA1, ESR1, EGFR, TNF, PIK3R1, IL6, PIK3CA, PIK3CB. Furthermore, GO enrichemnt analysis revealed that the target intersection mainly involved in biological process, cellular component and molecular function, KEGG analysis revealed that the target intersection mainly contained the pathways in cancer, PI3K/AKT signaling pathway, proteoglycans in cancer, MAPK signaling pathway. Ultimately, the molecular docking revealed that quercetin, luteolin and wogonin exhibited significant affinity with AKT1 and PIK3CA. Mechanistically, HD-SB enhance the anti-tumor effect of cisplatin on ovarian cancer via PI3K/AKT pathway. Taken together, our study revealed that the combination of HD-SB exhibited an enhanced capacity to improve cisplatin sensitivity in ovarian cancer cells through the PI3K/AKT pathway. HD-SB in combination with cisplatin could be a potential therapeutic strategy for the treatment of ovarian cancer patients.

Protective effect of Hedyotis diffusa (H. diffusa) Willd against lipopolysaccharide (LPS)-induced renal inflammation was evaluated by the productions of cytokines and chemokine, and the bioactive constituents of H. diffusa were detected by the ultra-fast liquid chromatography -diode array detector-quadrupole-time of flight mass spectrometry (UFLC-DAD-Q-TOF-MS/MS) method. As the results showed, water extract of H. diffusa (equal to 5.0 g/kg body weight) obviously protected renal tissues, significantly suppressed the productions of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1, as well as significantly promoted the production of IL-10 in serum and renal tissues. According the chemical profiles of H. diffusa, flavonoids, iridoid glycosides and anthraquinones were greatly detected in serum from H. diffusa extract treatment mice. Two main chemotypes, including eight flavonoids and four iridoid glycosides were found in renal tissues from H. diffusa extract treatment mice. The results demonstrated that water extract of H. diffusa had protective effect on renal inflammation, which possibly resulted from the bioactive constituents consisting of flavonoids, iridoids and anthraquinones.