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Public health indicator analysis plays a crucial part in colorectal cancer (CRC) recognition by leveraging epidemiological data and health metrics to recognize trends, disparities, and risk factors in diagnosis and screening. Public health officials use screening, incidence, and mortality rates to analyze current screening programs, target interventions for underserved populations, and improve early recognition and treatment results. With growing case numbers, CRC ranks second in women and third in men. The growing diagnostic workload and variability in biomarker assessment have prompted the exploration of robust machine-based models for pathology labs. Diagnosing CRC from histopathological images involves analyzing tissue samples for cancerous cellular changes. These images offer elaborate insights into tissue microstructure, aiding pathologists in examining cellular characteristics such as size, shape, and organization. Artificial Intelligence (AI) and fractals algorithms have proven advanced in the healthcare field, having the inherent ability for medical applications. The incorporation of AI in CRC diagnosis aims to improve the efficiency of pathologists, reduce diagnostic errors, and ultimately contribute to better patient outcomes through early and accurate detection of cancerous lesions. The study proposes a Golden Jackal Fractal Optimization with Deep Learning Assisted CRC Detection (GJODL-CRCD) technique on HIs. The GJODL-CRCD technique mainly examines the HIs to recognize and identify the CRC. The GJODL-CRCD method applies the Gabor filtering (GF) approach as a noise removal procedure to achieve this. Furthermore, the GJODL-CRCD technique employs the DenseNet model for learning and capturing intrinsic feature patterns from the preprocessed imageries. For hyperparameter selection of the DenseNet model, the GJODL-CRCD approach uses the GJO fractal algorithm. Finally, the GJODL-CRCD method uses the Elman Neural Network (ENN) model to identify and classify CRC. The performance evaluation of the GJODL-CRCD technique takes place on benchmark medical image data. The experimental results pointed out the betterment of the GJODL-CRCD model over other methods.

Colorectal cancer (CRC) is a form of cancer that originates in the colon (large intestine) or rectum, which are components of the digestive system. It generally begins as small, benign growths known as polyps that can form on the inner lining of the colon or rectum. In Malaysia, colorectal cancer ranks among the most prevalent cancers, especially within the Chinese and Malay communities. A study released by the Malaysian National Cancer Registry indicates that colorectal cancer is the second most common cancer type following breast cancer, impacting both genders. The occurrence of colorectal cancer in Malaysia has been consistently increasing, with approximately 15–20% of cancer cases in the nation being colorectal cancer. This type of cancer arises when cells in the body start to multiply excessively, leading to various symptoms. In this research, a novel hybrid fuzzy linear regression with symmetric parameter clustering combined with a support vector machine (FLRWSPCSVM) model is employed to predict the high-risk symptoms associated with the onset of colorectal cancer in Malaysia. The study analyzed secondary data from 180 patients diagnosed with colorectal cancer and treated in a general hospital in Kuala Lumpur, considering twenty-five independent variables with various combinations of variable types. Furthermore, the model included parameters, errors, and explanations, along with two statistical measurement errors. The findings revealed that FLRWSPCSVM identified ovarian symptoms and a history of cancer symptoms as high-risk indicators for the development of colorectal cancer, with the lowest mean square error (MSE) recorded at 100.605 and a root mean square error (RMSE) of 10.030.

Coptidis rhizoma has been used as traditional herb medicine in gastrointestinal disorders in the Eastern Asia. We investigated whether the anticancer effects of the C. rhizoma induced apoptosis on human colorectal cancer cells SNU-C4. The cytotoxic effect of C. rhizoma was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. To determine apoptotic cell death, 4,6-diamidino-2-phenylindole (DAPI) staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, reverse transcription-polymerase chain reaction (RT-PCR) and caspase-3 enzyme assay were performed. In this study, C. rhizoma treatment (100 μg/ml) revealed typical morphological apoptotic features. Additionally, C. rhizoma treatment (100 μg/ml) increased levels of BAX and CASPASE-3, and decreased levels of BCL-2. Caspase-3 enzyme activity by treatment of C. rhizoma (100 μg/ml) also significantly increased compared to the control (p<0.05). These data indicate that C. rhizoma caused cell death by apoptosis through caspase pathways on human colorectal cancer cells SNU-C4.

Colorectal cancer remains one of the most prevalent cancer and a leading cause of cancer related death in the US. Many currently used chemotherapeutic agents are derived from botanicals. Identifying herbal sources, including those from ginseng family, to develop better anti-cancer therapies remains an essential step in advancing the treatment of the cancer. In this article, potential roles of ginseng herbs, especially American ginseng and notoginseng, in colorectal cancer therapeutics are presented. The major pharmacologically active constituents of ginsengs are ginsenosides, which can be mainly classified as protopanaxadiol and protopanaxatriol groups. Structure-activity relationship between their chemical structures and pharmacological activities are discussed. In addition, various steaming temperature and time treatment of the ginseng herbs can change ginsenoside profiles, and enhance their anti-cancer activities. This heat treatment process may increase the role of ginseng in treating colorectal cancer.

We previously reported the antiproliferative effect of panaxadiol (PD), an active compound in steamed ginseng, on human HCT-116 colorectal cancer cells, and that antioxidants might play a role in this effect. In this study, we observed that PD's antiproliferative effect was significantly enhanced by epicatechin (EC), a strong natural antioxidant in grape seed. Evidence for the synergistic antiproliferative effect was supported by the remarkable increase in the number of apoptotic cells.

In the United States, many patients, including cancer patients, concurrently take prescription drugs and herbal supplements. Co-administration of prescription medicines and herbal supplements may have negative outcomes via pharmacodynamic and pharmacokinetic herb-drug interactions. However, multiple constituents in botanicals may also yield beneficial pharmacological activities. Botanicals could possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity. Herbal medicines, such as ginseng, potentiated the effects of chemotherapeutic agents via synergistic activities, supported by cell cycle evaluations, apoptotic observations, and computer-based docking analysis. Since botanicals are nearly always administrated orally, the role of intestinal microbiota in metabolizing ginseng constituents is presented. Controlled clinical studies are warranted to verify the clinical utility of the botanicals in cancer chemoprevention.

Inflammatory bowel disease increases the risks of human colorectal cancer. In this study, the effects of Salvia miltiorrhiza extract (SME) on chemically-induced colitis in a mouse model were evaluated. Chemical composition of SME was determined by HPLC analysis. A/J mice received a single injection of AOM 7.5 mg/kg. After one week, these mice received 2.5% DSS for eight days, or DSS plus SME (25 or 50 mg/kg). DSS-induced colitis was scored with the disease activity index (DAI). Body weight and colon length were also measured. The severity of inflammatory lesions was further evaluated by colon tissue histological assessment. HPLC assay showed that the major constituents in the tested SME were danshensu, protocatechuic aldehyde, salvianolic acid D, and salvianolic acid B. In the model group, the DAI score reached its highest level on Day 8, while the SME group on both doses showed a significantly reduced DAI score (both p < 0.01). As an objective index of the severity of inflammation, colon length was significantly shorter in the model group than the vehicle group. Treatment with 25 and 50 mg/kg of SME inhibited the shortening of colon in a dose-related manner (p < 0.05 and p < 0.01, respectively). SME groups also significantly reduced weight reduction (p < 0.05). Colitis histological data supported the pharmacological observations. Thus, Salvia miltiorrhiza could be a promising candidate in preventing and treating colitis and in reducing the risks of inflammation-associated colorectal cancer.

Natural products play an important role in cancer therapeutics, and lately more attentions have been paid to the prevention of major lethal malignancies, such as colorectal cancer (CRC). After oral ingestion, botanicals' parent compounds can be converted to their metabolites by the enteric microbiome, and these metabolites may have different bioactivities and variable bioavailability. In this study, we used an active ginseng metabolite, protopanaxadiol (PPD), as an example to assess its colon cancer preventive effect by comparing its effect with the treatment effect of fluorouracil (5-FU). A xenograft tumor nude mouse model with human colon cancer cell inoculation was used. After preventive PPD or treatment 5-FU administration with the same dose (30 mg/kg), tumor growth inhibition was evaluated by both a Xenogen bioluminescence imaging technique and manual tumor size measurement. Our data showed that preventive PPD very significantly inhibited the tumor growth compared to 5-FU (p < 0.01). Our data suggest that the PPD is a promising cancer prevention agent. More studies are needed to explore the chemopreventive actions of PPD and its potential clinical utility.

Chemopreventive agents can be identified from botanicals. Recently, there has been strong support for the potential of 6-shogaol, a natural compound from dietary ginger (Zingiber officinale), in cancer chemoprevention. However, whether 6-shogaol inhibits the growth of colorectal tumors in vivo remains unknown, and the underlying anticancer mechanisms have not been well characterized. In this work, we observed that 6-shogaol (15 mg/kg) significantly inhibited colorectal tumor growth in a xenograft mouse model. We show that 6-shogaol inhibited HCT-116 and SW-480 cell proliferation with IC50 of 7.5 and 10 μM, respectively. Growth of HCT-116 cells was arrested at the G2/M phase of the cell cycle, primarily mediated by the up-regulation of p53, the CDK inhibitor p21^waf1/cip1 and GADD45α, and by the down-regulation of cdc2 and cdc25A. Using p53^-/- and p53^+/+ HCT-116 cells, we confirmed that p53/p21 was the main pathway that contributed to the G2/M cell cycle arrest by 6-shogaol. 6-Shogaol induced apoptosis, mainly through the mitochondrial pathway, and the bcl-2 family might act as a key regulator. Our results demonstrated that 6-shogaol induces cancer cell death by inducing G2/M cell cycle arrest and apoptosis. 6-Shogaol could be an active natural product in colon cancer chemoprevention.

Fruit from Vitex rotundifolia L. (VF) has been reported to initiate apoptosis in human colorectal cancer cells through the accumulation of reactive oxygen species. Since various regulatory factors are involved in the apoptotic pathway, further study of the potential mechanisms of VF associated with the induction of apoptosis may be important despite the fact that the molecular target of VF for apoptosis has already been elucidated. In this study, we showed a new potential mechanism for the relationship between VF-mediated ATF3 expression and apoptosis to better understand the apoptotic mechanism of VF in human colorectal cancer cells. VF reduced the cell viability and induced apoptosis in human colorectal cancer cells. VF treatment increased both the protein and mRNA level of ATF3 and upregulated ATF3 promoter activity. The cis-element responsible for ATF3 transcriptional activation by VF was CREB which is located between $-$147 to $-$85 of ATF3 promoter. Inhibitions of ERK1/2, p38, JNK and GSK3$\beta$ blocked VF-mediated ATF3 expression. ATF3 knockdown by ATF3 siRNA attenuated the cleavage of PARP by VF, while ATF3 overexpression increased VF-mediated cleaved PARP. ATF3 knockdown also attenuated VF-mediated cell viability and cell death. In addition, VF downregulated Bcl-2 expression at both protein and mRNA level. ATF3 knockdown by ATF3 siRNA blocked VF-mediated downregulation of Bcl-2. In conclusion, VF may activate ATF3 expression through transcriptional regulation and subsequently suppress Bcl-2 expression as an anti-apoptotic protein, which may result in the induction of apoptosis in human colorectal cancer cells.

The root of Asian ginseng (Panax ginseng C.A. Meyer) has been used for centuries in Oriental medicine to improve general well-being and to relieve various medical conditions. It is commonly understood that ginsenosides are responsible for the pharmacological activities of ginseng. Compared to the root of ginseng, studies on the berry are considerably limited. In this study, we evaluated the effects of polysaccharides from Asian ginseng berries on plasma lipid levels, chemically-induced enteric inflammation and neoplasm, and cancer chemoprevention in different experimental models. We tested two polysaccharide preparations: regular ginseng berry polysaccharide extract (GBPE) and ginseng berry polysaccharide portion (GBPP, removed MV $<20,000$). We first observed that both oral GBPE and oral GBPP significantly reduced plasma cholesterol and triglycerides levels in a dose-related manner in ob/ob mice, without obvious body weight changes. Then, in AOM/DSS-induced acute colitis mice, GBPE and GBPP significantly ameliorated the increased gut disease activity index and inhibited the reduction of the colon length. Further, the berry polysaccharides significantly suppressed chemically-induced pro-inflammatory cytokine levels. This is consistent with the observation that GBPE and GBPP attenuated tumorigenesis in mice by significantly and dose-dependently reducing tumor load. Finally, in vitro HCT-116 and HT-29 human colon cancer cells were used. While these berry preparations had better antiproliferation effects on the HCT-116 than the HT-29 cells, the GBPE had significantly stronger inhibitory effects than GBPP. The observed in vitro GBPE’s effect could contribute to the actions of its small-molecule non-polysaccharide compounds due to their direct antiproliferative activities. Results obtained from the present study suggest that ginseng berry polysaccharides may have a therapeutic role in the management of high lipid levels, enteric inflammation, and colon malignancies.

Although Arctii Fructus (AF) has been shown to have various pharmacological effects, there have been no studies concerning the inhibitory effects of AF on the metastatic properties of colorectal cancer (CRC). The aim of this study was to investigate whether AF could suppress CRC progression by inhibiting cell growth, epithelial-mesenchymal transition (EMT), migration, and the invasion ability of CRC cells. AF decreased proliferation of CRC cells by inducing cell cycle arrest and apoptosis via extrinsic and intrinsic apoptotic pathways. Regarding metastatic properties, AF inhibited EMT by increasing the expression of the epithelial marker, E-cadherin, and decreasing the expression of the mesenchymal marker, N-cadherin, in CT26 cells. Moreover, AF decreased the migration and invasion of CT26 cells by inhibiting matrix metalloproteinase-2 (MMP-2) and MMP-9 activity. We confirmed that the decreased invasion ability and MMP-9 activity by AF treatment involved AMP-activated protein kinase (AMPK) activation. Collectively, this study demonstrates that AF inhibits the proliferation and metastatic properties of CRC cells.

Oplopanax elatus (Nakai) Nakai is an oriental herb, the polyyne-enriched fraction of which (PEFO) showed anticolorectal cancer (anti-CRC) effects. Other concomitant components, which are inevitably bio-transformed by gut microbiota after oral administration, might be interfere with the pharmacodynamics of polyynes. However, the influence of human gut microbiota on molecules from O. elatus possessing anticancer activity are yet unknown. In this study, the compounds in PEFO and PEFO incubated with human gut microbiota were analyzed and tentatively identified by HPLC-DAD-QTOF-MS. Two main polyynes ((3$S,$8$S)$-falcarindiol and oplopandiol) were not significantly decomposed, but some new unknown molecules were discovered during incubation. However, the antiproliferative effects of PEFO incubated with human gut microbiota for 72 h (PEFO I) were much lower than that of PEFO on HCT-116, SW-480, and HT-29 cells. Furthermore, PEFO possessed better anti-CRC activity in vivo, and significantly induced apoptosis of the CRC cells, which was associated with activation of caspase-3 according to the Western-blot results ($P<0.05$). These results suggest anticolorectal cancer activity of polyynes might be antagonized by some bio-converted metabolites after incubation with human gut microbiota. Therefore, it might be better for CRC prevention if the polyynes could be orally administrated as purified compounds.

The intestinal tract plays an essential role in protecting tissues from the invasion of external harmful substances due to impaired barrier function. Furthermore, it participates in immunomodulation by intestinal microorganisms, which is important in health. When the intestinal tract is destroyed, it can lose its protective function, resulting in multiple systemic complications. In severe cases, it may lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Thus far, there are no curative therapies for intestinal mucosal barrier injury, other than a few drugs that can relieve symptoms. Thus, the development of novel curative agents for gastrointestinal diseases remains a challenge. Ursolic acid (UA) and its isomer, Oleanolic acid (OA), are pentacyclic triterpene acid compounds. Both their aglycone and glycoside forms have anti-oxidative, anti-inflammatory, anti-ulcer, antibacterial, antiviral, antihypertensive, anti-obesity, anticancer, antidiabetic, cardio protective, hepatoprotective, and anti-neurodegenerative properties in living organisms. In recent years, several studies have shown that UA and OA can reduce the risk of intestinal pathological injury, alleviate intestinal dysfunction, and restore intestinal barrier function. The present study evaluated the beneficial effects of UA and OA on intestinal damage and diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC).

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.

Combining innocuous natural products with cytotoxic agents may enhance the effectiveness of chemotherapy. Tangeretin is a citrus flavonoid that has antineoplastic properties, but its mechanism of action is still unknown. Here, we used a high throughput-screening (HTS) platform to screen for drugs that may synergize with tangeretin and confirmed the top hits against colorectal cancer (CRC) cells in vitro and in vivo. 5-Fluorouracil (5-FU) and PI3K/Akt inhibitors have come out as top hits that show a strong synergy effect with tangeretin by HTS. We further confirmed the synergistic effect of tangeretin with 5-FU against CRC cells in vitro and in vivo. Since 5-FU can increase microRNA-21 (miR-21) expression and activate PI3K/Akt signaling, we addressed if tangeretin acted at this level. In 5-FU treated cells, tangeretin inhibited miR-21 induction, rescued the expression of the target PTEN, reduced Akt activation, and induced autophagy. Together, our data indicated that a natural product, such as tangeretin, can modulate miR-21 expression and that this pathway might be a potential therapeutic target for CRC. Combining tangeretin with 5-FU may be useful in the clinic, since 5-FU is the current first line drug for treating CRC.

Colorectal cancer (CRC) is the third most common cancer worldwide. The main obstacle in treating advanced CRC is tumor recurrence and metastasis due to chemoresistance. S-phase kinase associated protein 2 (Skp2), an E3 ligase, is highly associated with tumor resistance and a poor prognosis. The results of immunoblotting, immunohistochemical staining, ubiquitination analysis, and co-immunoprecipitation (co-IP) assay revealed that the plant curcuma, curcumol, is a novel Skp2 inhibitor for CRC treatment. Curcumol inhibits aerobic glycolysis in CRC by inducing Skp2 degradation. Co-immunoprecipitation results showed that curcumol enhanced the interaction between cadherin-1 (Cdh1) and Skp2 and led to the ubiquitination and degradation of Skp2. Curcumol exhibited significant antitumor effects against CRC, such as increased intrinsic apoptosis and decreased tumorigenic properties, both in vivo and in vitro. Furthermore, curcumol overcame 5-fluorouracil (5-Fu) resistance in CRC and induced apoptosis in 5-Fu-resistant CRC cells. The present data revealed a novel antitumor mechanism of glycolytic regulation by curcumol, suggesting that curcumol may be a potential chemical candidate for treating 5-Fu-resistant CRC.

Colorectal cancer is the third leading cause of cancer-related death worldwide. Hence, there is a need to identify new therapeutic agents to improve the current repertoire of therapeutic drugs. Wogonin, a flavonoid from the herbal medicine Scutellaria baicalensis, has unique antitumor activity. Our study aimed to further explore the inhibitory effects of wogonin on colorectal cancer and its specific mechanism. The results showed that wogonin significantly inhibited the proliferation of colorectal cancer cells as well as their ability to invade and metastasize. We detected phosphorylation of tumor-associated signaling pathways using a phosphorylated protein microarray and found that wogonin intervention significantly inhibited the phosphorylation level of the AKT protein in colorectal cancer cells. Through in vitro and in vivo experiments, it was confirmed that wogonin exerted its antitumor effects against colorectal cancer by inhibiting phosphorylation in the AKT pathway. Our discovery of wogonin as an inhibitor of AKT phosphorylation provides new opportunities for the pharmacological treatment of colorectal cancer.

Colorectal cancer, characterized by its high incidence, concealed early symptoms, and poor prognosis at advanced stages, ranks as the third leading cause of cancer-related deaths worldwide. Astragalus membranaceus (AM) refers to the dried roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao and Astragalus membranaceus (Fisch.) Bge. In the theory of Traditional Chinese Medicine (TCM), it is believed to have the functions of tonifying qi and lifting yang, as well as generating body fluids and nourishing blood. It can effectively treat cancer caused by the deficiency of vital energy and susceptibility to external diseases. Modern research has confirmed that the active components of AM, including Astragalus polysaccharides, flavonoids (formononetin and calycosin), Astragalus saponins (Astragaloside I and Astragaloside III), and Astragalus nanovesicles, are effective in the treatment of colorectal cancer. The mechanisms mainly involve inducing apoptosis, inhibiting tumor angiogenesis and the metastasis of cancer cells, regulating the cell cycle and tumor microenvironment, and reversing drug resistance. Moreover, it offers a synergistic enhancement when used in combination with chemotherapy, radiotherapy, targeted therapy, or surgical treatment. AM also has great potential in treating colorectal cancer when combined with other herbs. This review summarizes the relevant research findings on the treatment of colorectal cancer with AM, as well as its main pharmacological effects and molecular mechanisms, aiming to provide guidance for the development of new drugs, and offer direction for the conduct of more related research and promoting the development and application of AM.

Colorectal cancers are the third most common type of cancer. They originate from intestinal crypts, glands that descend from the intestinal lumen into the underlying connective tissue. Normal crypts are thought to exist in a dynamic equilibrium where the rate of cell production at the base of a crypt is matched by that of loss at the top. Understanding how genetic alterations accumulate and proceed to disrupt this dynamic equilibrium is fundamental to understanding the origins of colorectal cancer. Colorectal cancer emerges from the interaction of biological processes that span several spatial scales, from mutations that cause inappropriate intracellular responses to changes at the cell/tissue level, such as uncontrolled proliferation and altered motility and adhesion. Multiscale mathematical modelling can provide insight into the spatiotemporal organisation of such a complex, highly regulated and dynamic system. Moreover, the aforementioned challenges are inherent to the multiscale modelling of biological tissue more generally. In this review we describe the mathematical approaches that have been applied to investigate multiscale aspects of crypt behavior, highlighting a number of model predictions that have since been validated experimentally. We also discuss some of the key mathematical and computational challenges associated with the multiscale modelling approach. We conclude by discussing recent efforts to derive coarse-grained descriptions of such models, which may offer one way of reducing the computational cost of simulation by leveraging well-established tools of mathematical analysis to address key problems in multiscale modelling.