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It is being brought to light that smoothened (SMO)-independent non-canonical Hedgehog signaling is associated with the pathogenesis of various cancers. Ursolic acid (UA), a pentacyclic triterpenoid present in many medicinal herbs, manifests potent effectiveness against multiple malignancies including colorectal cancer (CRC). In our previous study, UA was found to protect against CRC in vitro by suppression of canonical Hedgehog signaling cascade. Here, the influence of UA on SMO-independent non-canonical Hedgehog signaling in CRC was investigated in the present study, which demonstrated that UA hampered the proliferation and migration, induced the apoptosis of HCT-116

Lonicerae japonicae flos (LJF), known as Jin Yin Hua in Chinese, is one of the most commonly used traditional Chinese herbs and nutraceuticals. Nowadays, LJF is broadly applied in an array of afflictions, such as fever, sore throat, flu infection, cough, and arthritis, with the action mechanism to be elucidated. Here, we strove to summarize the main phytochemical components of LJF and review its updated pharmacological effects, including inhibition of inflammation, pyrexia, viruses, and bacteria, immunoregulation, and protection of the liver, nervous system, and heart, with a focus on the potential efficacy of LJF on coronavirus disease-2019 based on network pharmacology so as to fully underpin the utilization of LJF as a medicinal herb and a favorable nutraceutical in daily life.

A growing body of evidence reveals that dysregulation of Hedgehog signaling pathway and dysbiosis of gut microbiota are associated with the pathogenesis of colorectal cancer (CRC). Berberine, a botanical benzylisoquinoline alkaloid, possesses powerful activities against various malignancies including CRC, with the underlying mechanisms to be illuminated.The present study investigated the potencies of berberine on CRC and deciphered the action mechanisms in the context of Hedgehog signaling cascade and gut microbiota.The effects of berberine on the malignant phenotype, apoptosis, cell cycle and Hedgehog signaling of CRC cells were examined in vitro. In azoxymethane/dextran sulfate sodium-caused mouse CRC, the efficacies of berberine on the carcinogenesis, pathological profile, apoptosis, cell cycle and Hedgehog signaling were determined in vivo. Also, the influences of berberine on gut microbiota in CRC mice were assessed by high-throughput DNA sequencing analysis of 16S ribosomal RNA of fecal microbiome in CRC mice.In the present study, berberine was found to dampen the proliferation, migration, invasion and colony formation of CRC cells, without toxicity to normal colonic cells. Additionally, berberine induced apoptosis and arrested cell cycle at GOverall, berberine may suppress colorectal cancer, orchestrated by down-regulation of Hedgehog signaling pathway activity and modulation of gut microbiota.

As an important part of complementary and alternative medicine, traditional Chinese medicine (TCM) has been applied to treat a host of diseases for centuries. Over the years, with the incidence rate of human colorectal cancer (CRC) increasing continuously and the advantage of TCM gradually becoming more prominent, the importance of TCM in both domestic and international fields is also growing with each passing day. However, the unknowability of active ingredients, effective substances, and the underlying mechanisms of TCM against this malignant tumor greatly restricts the translation degree of clinical products and the pace of precision medicine. In this review, based on the characteristics of TCM and the oral administration of most ingredients, we herein provide beneficial information for the clinical utilization of TCM in the prevention and treatment of CRC and retrospect the current preclinical studies on the related active ingredients, as well as put forward the research mode for the discovery of active ingredients and effective substances in TCM, to provide novel insights into the research and development of innovative agents from this conventional medicine for CRC treatment and assist the realization of precision medicine.

Background Shikonin is one of the major phytochemical components of Lithospermum erythrorhizon (Purple Cromwell), which is a type of medicinal herb broadly utilized in traditional Chinese medicine. It is well established that shikonin possesses remarkable therapeutic actions on various diseases, with the underlying mechanisms, pharmacokinetics and toxicological effects elusive. Also, the clinical trial and pharmaceutical study of shikonin remain to be comprehensively delineated. Purpose The present review aimed to systematically summarize the updated knowledge regarding the therapeutic actions, pharmacokinetics, toxicological effects, clinical trial and pharmaceutical study of shikonin. Methods The information contained in this review article were retrieved from some authoritative databases including Web of Science, PubMed, Google scholar, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database and so on, till August 2021. Results Shikonin exerts multiple therapeutic efficacies, such as anti-inflammation, anti-cancer, cardiovascular protection, anti-microbiomes, analgesia, anti-obesity, brain protection, and so on, mainly by regulating the NF-κB, PI3K/Akt/MAPKs, Akt/mTOR, TGF-β, GSK3β, TLR4/Akt signaling pathways, NLRP3 inflammasome, reactive oxygen stress, Bax/Bcl-2, etc. In terms of pharmacokinetics, shikonin has an unfavorable oral bioavailability, 64.6% of the binding rate of plasma protein, and enhances some metabolic enzymes, particularly including cytochrome P450. In regard to the toxicological effects, shikonin may potentially cause nephrotoxicity and skin allergy. The above pharmacodynamics and pharmacokinetics of shikonin have been validated by few clinical trials. In addition, pharmaceutical innovation of shikonin with novel drug delivery system such as nanoparticles, liposomes, microemulsions, nanogel, cyclodextrin complexes, micelles and polymers are beneficial to the development of shikonin-based drugs. Conclusions Shikonin is a promising phytochemical for drug candidates. Extensive and intensive explorations on shikonin are warranted to expedite the utilization of shikonin-based drugs in the clinical setting.

Based on the study and research on the pathogenesis of colorectal cancer, the types and functions of gut microbiota, and its role in guiding and regulating the occurrence and development of diseases, we have explored the mechanism of traditional Chinese medicine in the treatment of colorectal cancer by regulating the gut microbiota. Genetic variation, abnormal responses of innate and adaptive immunity, mucosal barrier dysfunction, imbalance of intestinal microbial colonization, personal and environmental risk factors are the main pathogenesis of colorectal cancer. The gut microbiota mainly includes Sclerotium (including Clostridium, Enterococcus, Lactobacillus and Ruminococcus) and Bacteroides (including Bacteroides and Prevotella), which have biological antagonism, nutrition for the organism, metabolic abilities, immune stimulation, and ability to shape cancer genes functions to body. The gut microbiota can be related to the health of the host. Current studies have shown that Chinese herbal compound, single medicinal materials, and monomer components can treat colorectal cancer by regulating the gut microbiota, such as Xiaoyaosan can increase the abundance of Bacteroides, Lactobacillus, and Proteus and decrease the abundance of Desulfovibrio and Rickerella. Therefore, studying the regulation and mechanism of gut microbiota on colorectal cancer is of great benefit to disease treatment.

Background: This study was aimed to investigate the effect of Scutellarin on apoptosis of human colorectal cancer SW480 cells and azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse, and clarify its mechanism. Methods: 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) and cell migration assay were performed to detect the viability and proliferation of SW480 cells that treated with different concentrations of Scutellarin. Hoechst33342 Staining to determine apoptosis, detecting Caspase-3 and Caspase-9 activities after administration of different concentrations of Scutellarin. AOM/DSS mouse were administrated with Scutellarin; immunohistochemistry and western blot was employed to detect the effect on the expression of BCL2-Associated X (Bax) and B-cell lymphoma-2 (Bcl-2) proteins, and the message Ribonucleic Acid (mRNA) levels of Bax, Bcl-2, Caspase-3and Caspase-9 were assessed with quantitative reverse transcription polymerase chain reaction (qRT-PCR). The data was analyzed by one-way analysis of variance (ANOVA) with SPSS19.0 software, expressed as mean ± standard deviation (x ± s). Results: Scutellarin could inhibit the proliferation of SW480 cells after treatment with different concentrations of Scutellarin, while the chromatin condensation and nucleus showed more intense blue fluorescence. Moreover, Scutellarin could significantly increase the activities of Caspase-3 and Caspase-9 as well as different concentrations of Scutellarin could significantly down-regulate the expression of apoptosis related protein Bcl-2 and up-regulate the expression of Bax protein. When compared with the solvent control group, the relative expression levels of the related gene Bcl-2 were down-regulated by different concentrations of Scutellarin, while the Bax, Caspase-3 and Caspase-9 genes were up-regulated. Conclusion: Scutellarin can inhibit the in vitro activity of colon cancer SW480 cells, promote Bax expression, inhibit Bcl-2 expression, and up-regulate the activities of apoptotic enzymes Caspase-3 and Caspase-9 to induce apoptosis in vivo and in vitro, suggesting that it has a certain therapeutic effect on colon cancer.

Colorectal cancer (CRC) is one of malignant afflictions burdening people worldwide, mainly caused by shortages of effective medical intervention and poorly mechanistic understanding of the pathogenesis of CRC. Non-coding RNAs (ncRNAs) are a type of heterogeneous transcripts without the capability of coding protein, but have the potency of regulating protein-coding gene expression. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic contents are delivered to cellular lysosomes for degradation, resulting in the turnover of cellular components and producing energy for cell functions. A growing body of evidence reveals that ncRNAs, autophagy, and the crosstalks of ncRNAs and autophagy play intricate roles in the initiation, progression, metastasis, recurrence and therapeutic resistance of CRC, which confer ncRNAs and autophagy to serve as clinical biomarkers and therapeutic targets for CRC. In this review, we sought to delineate the complicated roles of ncRNAs, mainly including miRNAs, lncRNAs and circRNAs, in the pathogenesis of CRC, particularly focus on the regulatory role of ncRNAs in CRC-related autophagy, attempting to shed light on the complex pathological mechanisms, involving ncRNAs and autophagy, responsible for CRC tumorigenesis and development, so as to underpin the ncRNAs- and autophagy-based therapeutic strategies for CRC in clinical setting.

Colitis-associated colorectal cancer (CAC) is a specific type of colorectal cancer (CRC) and mainly develops from long-term intestinal inflammation. Mounting evidence reveals that activated Hedgehog signaling pathway plays a vital role in the pathogenesis of CRC. Scutellarin is a type of phytochemical flavonoid with a powerful efficacy on various malignancies, including CRC.Here, we studied the therapeutic effect of scutellarin on CRC and its direct regulating targets.The CAC model in mice was established by azomethane oxide (AOM) and sodium dextran sulfate (DSS), followed by detection of the efficacies of scutellarin on the carcinogenesis, apoptosis, inflammation, Hedgehog signaling cascade and complicated inflammatory networks in CAC tissues of mice. In CRC SW480 cells, the effects of scutellarin on malignant phenotype, apoptosis and Hedgehog signaling were examined. In TNF-α-stimulated IEC-6 intestinal epithelial cells, the actions of scutellarin on inflammatory response and Hedgehog signals were assessed as well.Scutellarin significantly ameliorated AOM/DSS-caused CAC in mice and induced apoptosis in CAC tissues of mice, by inhibiting NF-κB (nuclear factor kappa B) -mediated inflammation and Hedgehog signaling axis. RNA-seq and transcriptome analysis indicated that scutellarin regulated complicated inflammatory networks in mouse CAC. Also, scutellarin suppressed the proliferation, migration, colony formation, and induced apoptosis of SW480 cells by down-regulation of Hedgehog signaling pathway activity. Additionally, scutellarin lessened NF-κB-mediated inflammatory response in TNF-α-stimulated IEC-6 cells, by attenuating Hedgehog signaling cascade.Scutellarin potently ameliorates CAC by suppressing Hedgehog signaling pathway activity, underpinning the promising application of scutellarin to CRC in clinical settings.

Dysregulated Wnt/β-catenin signaling pathway plays a critical role in the pathogenesis of colorectal cancer (CRC). Scutellarin, a flavonoid compound in Scutellaria barbata, has been reported to suppress CRC, with the action mechanism elusive. In this study, Scutellarin was found to inhibit the carcinogenesis of colitis-associated cancer (CAC) in mice caused by azoxymethane/dextran sulfate sodium, with alleviation of pathologic symptoms. Besides, Scutellarin attenuated mouse serum concentrations of TNF-α and IL-6, heightened Bax expression and diminished B-cell lymphoma-2 (Bcl-2) level in CAC tissues of mice, through down-regulating Wnt/β-catenin signaling cascade. In CRC HT-29 cells, Scutellarin retarded the proliferation and migration, induced apoptosis, with boosted Bax expression and decreased Bcl-2 level, which may be attributed to its repression of Wnt/β-catenin signals in HT-29 cells. Our findings demonstrate that Scutellarin may ameliorate colitis-associated colorectal cancer by weakening Wnt/β-catenin signaling cascade.