Tongxie Yaofang Regulates Expression of NKG2DL to Enhance Anti-tumor Effect of NK Cells in Colon Cancer under Chronic Stress / 中国实验方剂学杂志

ObjectiveTo observe the effect of Tongxie Yaofang on the function of tumor-related natural killer （NK） cells under chronic stress and explore the possible molecular mechanism. MethodFifty SPF-grade BABL/C male mice were randomized into normal， model， and low-， medium-， and high-dose （6.825， 13.65， and 27.3 g·kg-1， respectively） Tongxie Yaofang groups， with 10 mice in each group. Other groups except the blank group were subjected to 7 days of chronic restraint stress， and then forced swimming and tail suspension tests were carried out to evaluate the modeling performance. After the successful modeling， rats in Tongxie Yaofang groups were administrated with low-， medium-， and high-doses of Tongxie Yaofang by gavage， while those in the other groups were administrated with normal saline by gavage. After 14 days， each group of mice was inoculated with subcutaneous colon cancer to establish the model of colon cancer under chronic stress. The pathological changes of the tumor tissue in each group of mice were observed using hematoxylin-eosin （HE） staining. The content of CD49b-positive cells in the peripheral blood and tumor tissue of mice was measured by flow cytometry. Enzyme-linked immunosorbent assay （ELISA） was employed to measure the content of molecules associated with NK cell activation in the peripheral blood. Western blot was employed to determine the protein levels of major histocompatibility complex class Ⅰ polypeptide-related sequences A and B （MICA+MICB） and UL-16-binding protein 1 （ULBP1） in the tumor tissue. ResultCompared with the normal group， the model group showed a decrease in 5-hydroxytryptamine （5-HT） content and an increase in corticosterone （CORT） content in the serum （P<0.05）. Compared with the model group， Tongxie Yaofang increased the 5-HT content and decreased the CORT content （P<0.05， P<0.01）. Compared with the normal group， the modeling increased the tumor volume and weight （P<0.05）， while Tongxie Yaofang inhibited such increases with no statistical significance. The tumor cells in the model group presented neat arrangement， irregular shape， uneven size， obvious atypia， common nuclear division， and small necrotic area， and blood vessels were abundant surrounding the tumor cells. Compared with the model group， Tongxie Yaofang groups showed sparse arrangement of tumor cells， different degrees of patchy necrosis areas in the tumor， and karyorrhexis， dissolution， and nuclear debris in the necrotic part. Compared with the normal group， the model group showed reduced CD49b-positive cells in the peripheral blood and tumor tissue （P<0.01）. Compared with the model group， Tongxie Yaofang increased CD49b-positive cells （medium dose P<0.01， high dose P<0.05， P<0.01）. Compared with the normal group， the modeling lowered the serum levels of granzymes-B （Gzms-B）， perforin （PF）， interferon （IFN）-γ， and tumor necrosis factor （TNF）-α （P<0.05， P<0.01）. Compared with the model group， low-dose Tongxie Yaofang elevated the serum levels of PF， Gzms-B， and TNF-α （P<0.05， P<0.01）， and medium-dose Tongxie Yaofang elevated the serum levels of Gzms-B， PF， IFN-γ， and TNF-α （P<0.05， P<0.01）. In addition， high-dose Tongxie Yaofang elevated the serum levels of PF， IFN-γ， and TNF-α （P<0.01）. Compared with the normal group， the model group presented down-regulated protein level of ULBP1 （P<0.05）. Compared with the model group， low-， medium-， and high-dose Tongxie Yaofang up-regulated the protein level of ULBP1 （P<0.05， P<0.01）， and medium- and high-dose Tongxie Yaofang up-regulated the protein level of MICA+MICB （P<0.05， P<0.01）. ConclusionTongxie Yaofang may promote NK cell activation by up-regulating the expression of MICA+MICB and ULBP1， thereby delaying the progression of colon cancer under chronic stress.

Metástasis falángica en dedo anular derecho en paciente con antecedente de cáncer de colon etapa IV

Objetivo: Reportar un caso clínico de acrometástasis de cáncer de colon. Materiales y Métodos: Se obtiene información de la ficha clínica electrónica. Se realiza revisión de literatura, utilizando los términos "acrometastasis", "metástasis óseas", "metástasis en la mano", "metástasis en falanges". Resultados: Se presenta el caso de un paciente con antecedente de cáncer de colon sigmoides etapa IV sometido a resección de metástasis hepáticas, quimioterapia y radioterapia. Consulta por lesión ulcerada en dedo anular derecho, cuya biopsia indica metástasis de adenocarcinoma de colon. Se realiza amputación transfalángica proximal con biopsia que confirma diagnóstico. Discusión: Las metástasis en mano dan cuenta del 0,0070,2% de todas las metástasis a distancia. Se presentan como aumento de volumen doloroso de aspecto granulomatoso o asociado a ulceración con empeoramiento progresivo. El tratamiento tiene por objetivo el manejo del dolor y la preservación de la funcionalidad de la extremidad. Conclusión: El adenocarcinoma de colon, raramente, da metástasis falángicas. Corresponden a una manifestación tardía de la enfermedad con una alta tasa de mortalidad a 6 meses asociada. Se deben considerar como diagnóstico diferencial en pacientes oncológicos.

Objective: To report a clinical case of achrometastases of colon cancer. Materials and methods: Information is obtained from the electronic medical record. A literature review is performed, using the terms "achrometastases", "bone metastases", "hand metastases", "phalangeal metastases". Results: We present the case of a patient with a history of stage IV sigmoid colon cancer who underwent resection of liver metastases, chemotherapy and radiotherapy. Consultation due to an ulcerative lesion on the right ring finger, whose biopsy indicated colon adenocarcinoma metastases. Proximal transphalangeal amputation is performed with biopsy confirming diagnosis. Discussion: Hand metastases account for 0.007-0.2% of all distant metastases. They present as a painful increase in volume with a granulomatous appearance or associated with progressively worsening ulceration. The treatment aims to manage pain and preserve the functionality of the limb. Conclusion: Colon adenocarcinoma rarely gives phalangeal metastases. They correspond to a late manifestation of the disease with a high associated 6-month mortality rate. They should be considered as a differential diagnosis in cancer patients.

Risco aumentado de câncer colorretal em pacientes com gota tofácea crônica: um estudo populacional / Increased risk of colorectal cancer in patients with chronic tophaceous gout: a population-based study

ABSTRACT Background: Colorectal cancer is the third most common type of cancer in both men and women and ranks second as the most common cause of cancer death in the United States. Classic risk factors include tobacco smoking, high alcohol consumption, physical inactivity and excess body weight. A prospective study found that an elevated serum uric acid was associated with higher rates of cancer-associated polyps. Interestingly, other studies found an association between elevated levels of serum uric acid and other types of cancer including colorectal cancer. Objective: Our study aimed to evaluate whether patients with chronic tophaceous gout had an increased risk of developing colorectal cancer. Methods: A validated multicenter and research platform database of more than 360 hospitals from 26 different healthcare systems across the United States was utilized to construct this study. Patients aged 18 years and above were included. Individuals who have had a history of familial adenomatous polyposis, a family history of colon cancer, and those diagnosed with inflammatory bowel disease were excluded from the analysis. The risk of developing colon cancer was calculated using a multivariate regression analysis to account for potential confounders. Results: 80,927,194 individuals were screened in the database and 70,177,200 were selected in the final analysis after accounting for inclusion and exclusion criteria. Type 2 diabetics (28.57%), smokers (10.98%), obese individuals (18.71%), alcoholics (3.13%), and patients who have had a diagnosis of chronic tophaceous gout were more common in the colon cancer group compared to those without the malignancy. Using multivariate regression analysis, risk of colon cancer was calculated for male gender (OR: 1.02; 95%CI: 1.01-1.03), smokers (OR: 1.54; 95%CI: 1.52-1.56), alcoholics (OR: 1.40; 95%CI: 1.37-1.43), obese patients (OR: 1.52; 95%CI: 1.50-1.54), type 2 diabetic individuals (OR: 3.53; 95%CI: 3.50-3.57), and those who have had a diagnosis of chronic tophaceous gout (OR: 1.40; 95%CI: 2.48-3.23). Conclusion: As expected, patients with colon cancer were found to have a higher prevalence in males, obese, tobacco and alcohol users. We also demonstrated that patients with gout have a significantly higher prevalence of CRC than those who do not before and after adjusting for metabolic risk factors. In fact, uric acid was found to induce production of reactive oxygen species, thus potentially promoting tumorigenesis. It would be interesting to assess the prevalence of colon cancer in patients with gout who have a serum uric acid that is less than 7 mg/dL. This might promote a tighter control of serum uric acid levels in this population in order to decrease the risk of colon cancer.

RESUMO Contexto: O câncer colorretal é o terceiro tipo mais comum de câncer em homens e mulheres e ocupa o segundo lugar como a causa mais comum de morte por câncer nos EUA. Os fatores de risco clássicos incluem tabagismo, alto consumo de álcool, inatividade física e excesso de peso corporal. Um estudo prospectivo descobriu que um ácido úrico sérico elevado estava associado a taxas mais altas de pólipos associados ao câncer. Curiosamente, outros estudos encontraram uma associação entre níveis elevados de ácido úrico sérico e outros tipos de câncer, incluindo o câncer colorretal. Objetivo: Nosso estudo teve como objetivo avaliar se os pacientes com gota tofácea crônica tinham um risco aumentado de desenvolver câncer colorretal. Métodos: Utilizou-se um banco de dados validado multicêntrico e de plataforma de pesquisa de mais de 360 hospitais de 26 diferentes sistemas de saúde nos Estados Unidos para a construção deste estudo. Foram incluídos pacientes com 18 anos ou mais. Indivíduos com histórico de polipose adenomatosa familiar, histórico familiar de câncer de cólon e aqueles diagnosticados com doença inflamatória intestinal foram excluídos da análise. O risco de desenvolver câncer de cólon foi calculado usando uma análise de regressão multivariada para contabilizar possíveis confusões. Resultados: 80.927.194 indivíduos foram rastreados no banco de dados e 70.177.200 foram selecionados na análise final após considerar critérios de inclusão e exclusão. Diabéticos tipo 2 (28,57%), fumantes (10,98%), indivíduos obesos (18,71%), alcoólatras (3,13%) e pacientes que tiveram diagnóstico de gota tofácea crônica foram mais comuns no grupo de câncer de cólon em comparação com aqueles sem a malignidade. Usando a análise de regressão multivariada, o risco de câncer de cólon foi calculado para o sexo masculino (OR: 1,02; IC95%: 1,01-1,03), fumantes (OR: 1,54; IC95%: 1,52-1,56), alcoólatras (OR: 1,40; IC95%: 1,37-1,43), pacientes obesos (OR: 1,52; IC95%: 1,50-1,54), indivíduos diabéticos tipo 2 (OR: 3,53; IC95%: 3,50-3,57), e aqueles que tiveram diagnóstico de gota tofácea crônica (OR: 1,40; IC95%: 2,48-3,23). Conclusão: Como esperado, os pacientes com câncer de cólon foram encontrados com maior prevalência em homens, obesos, usuários de tabaco e álcool. Demonstramos também que os pacientes com gota têm uma prevalência significativamente maior de câncer colorretal do que aqueles que não a têm, antes e após o ajuste para fatores de risco metabólicos. De fato, descobriu-se que o ácido úrico induz a produção de espécies reativas de oxigênio, promovendo assim potencialmente a tumorigênese. Seria interessante avaliar a prevalência de câncer de cólon em pacientes com gota que têm um ácido úrico sérico inferior a 7 mg/dL. Isso poderia promover um controle mais rígido dos níveis de ácido úrico sérico nesta população para diminuir o risco de câncer de cólon.

Knockdown of PTEN promotes colon cancer progression and induces M2 macrophage polarization in the colon cancer cell environment

Objective: This article aims to study the effect of phosphate and tension homolog deleted on chromosome ten (PTEN) knockdown on colon cancer progression and macrophage polarization in the cancer environment. Materials and Methods and Results: The expression of PTEN in colon cancer tissues and colon cancer cells was significantly lower than in precancerous tissues or CCD-18Co cells, and the decrease was most evident in SW620 cells. The expressions of phosphate (p)-p38, c-Jun N-terminal kinase (JNK), activator protein 1 (AP-1), B-cell lymphoma-2 (Bcl-2) protein in colon cancer tissues and cells were significantly higher than in precancerous tissues or CCD-18Co cells (P-values < 0.05). Bcl-2-associated X (Bax) and Caspase-3 expressions in colon cancer tissues and cells were significantly lower than in precancerous tissues or CCD-18Co cells (P-values < 0.05). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was applied to measure cell viability. Transwell evaluated the cell migration and invasion ability. Si-PTEN improved the proliferation, migration, and invasion of SW620 cells (P-values < 0.05). The expression levels of arginase-1 (Arg-1), CD163, CD206 in colon cancer tissues were significantly higher than in precancerous tissues (P-values < 0.05). The cell cycle, the number of M1 and M2 double-positive cells were assessed by flow cytometry. Si-PTEN reduced the expression of tumor necrosis factor-alpha (TNF-?), interleukin-1beta (IL-1?), and inducible nitric oxide synthase (iNOS), which upregulated the expression of Arg-1, CD206, CD163, p-p38, JNK, and AP-1 (P-values < 0.05). Conclusion: Si-PTEN promoted colon cancer progression and induced the polarization of M2 tumor-associated macrophages in the colon cancer cell environment.

Silenced ANP32A inhibits the growth, invasion and migration of colorectal cancer in vitro via the inactivation of AKT pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of ANP32A silencing on invasion and migration of colon cancer cells and the influence of the activity of AKT signaling pathway on this effect.@*METHODS@#Colorectal cancer HCT116 and SW480 were transfected with a small interfering RNA targeting ANP32A via a lentiviral vector. At 24, 48 and 72 h after the transfection, the changes in cell proliferation and AKT activity in the cells were detected using MTT assay and Western blotting, respectively. HCT116 and SW480 cells were treated with the AKT agonist SC79 or its inhibitor MK2206 for 24, 48, 72 and 96 h, and the changes in cell migration and invasion ability were analyzed using Transwell chamber assay and cell proliferation was assessed using MTT assay. The effects of SC79 and MK2206 on migration and invasion abilities of HCT116 and SW480 cells with or without ANP32A silencing were examined using wound healing and Transwell chamber assays, and the changes in the expression of metadherin (MTDH), a factor associated with cells invasion and migration, was detected with Western blotting.@*RESULTS@#Lentivirus-mediated ANP32A silencing significantly down-regulated the activity of AKT and inhibited the proliferation of both HCT116 and SW480 cells (P < 0.01). The application of AKT inhibitor MK2206 obviously inhibited the proliferation, invasion and migration of the colorectal cancer cells (P < 0.05), while the AKT agonist SC79 significantly promoted the invasion and migration of the cells (P < 0.01). In HCT116 and SW480 cells with ANP32A silencing, treatment with MK2206 strongly enhanced the inhibitory effects of ANP32A silencing on cell invasion and migration (P < 0.05) and the expression of MTDH, while SC79 partially reversed these inhibitory effects (P < 0.01).@*CONCLUSION@#ANP32A silencing inhibits invasion and migration of colorectal cancer cells possibly by inhibiting the activation of the AKT signaling pathway.

Aerobic glycolysis in colon cancer is repressed by naringin via the HIF1Α pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Metabolic reprogramming is a common phenomenon in cancer, with aerobic glycolysis being one of its important characteristics. Hypoxia-inducible factor-1α (HIF1Α) is thought to play an important role in aerobic glycolysis. Meanwhile, naringin is a natural flavanone glycoside derived from grapefruits and many other citrus fruits. In this work, we identified glycolytic genes related to HIF1Α by analyzing the colon cancer database. The analysis of extracellular acidification rate and cell function verified the regulatory effects of HIF1Α overexpression on glycolysis, and the proliferation and migration of colon cancer cells. Moreover, naringin was used as an inhibitor of colon cancer cells to illustrate its effect on HIF1Α function. The results showed that the HIF1Α and enolase 2 (ENO2) levels in colon cancer tissues were highly correlated, and their high expression indicated a poor prognosis for colon cancer patients. Mechanistically, HIF1Α directly binds to the DNA promoter region and upregulates the transcription of ENO2; ectopic expression of ENO2 increased aerobic glycolysis in colon cancer cells. Most importantly, we found that the appropriate concentration of naringin inhibited the transcriptional activity of HIF1Α, which in turn decreased aerobic glycolysis in colon cancer cells. Generally, naringin reduces glycolysis in colon cancer cells by reducing the transcriptional activity of HIF1Α and the proliferation and invasion of colon cancer cells. This study helps to elucidate the relationship between colon cancer progression and glucose metabolism, and demonstrates the efficacy of naringin in the treatment of colon cancer.

Inhibitory Effect and Mechanism of Sishenwan-containing Serum on Aerobic Glycolysis in Human Colon Cancer Cells / 中国实验方剂学杂志

ObjectiveTo explore the effect and mechanism of Sishenwan-containing serum on aerobic glycolysis in human colon cancer HCT116 cells. MethodCell counting kit-8 （CCK-8） was used to detect the cell viability of colon cancer HCT116 cells after treatment with Sishenwan-containing serum （2.5%， 5%， and 10%） for 24， 48， 72 h. The concentration of lactic acid， the content of intracellular glucose， and the activity of hexokinase （HK） and fructose-6-phosphate kinase （PFK） in the cell culture medium were detected by the micro-method. The content of glucose transporter 1 （GluT1） mRNA was detected by Real-time quantitative polymerase chain reaction （Real-time PCR）. The protein expression of GluT1 and methyltransferase-like 3 （MettL3） was detected by Western blot. The expression of GluT1 in cells was detected by immunofluorescence and the level of N6-methyladenosine （m6A） RNA methylation was detected by colorimetry. ResultCompared with the normal serum， 2.5%， 5%， and 10% Sishenwan-containing serum had no significant effect on the viability of HCT116 cells at 24 h， while 10% Sishenwan-containing serum showed a significant inhibitory effect on the viability of HCT116 cells at 48 h （P<0.05）. Hence， 10% Sishenwan-containing serum was used in subsequent experiments， and the intervention time was 48 h. Compared with the normal serum， 10% Sishenwan-containing serum could reduce lactate production （P<0.05）， down-regulate glucose uptake （P<0.05）， and blunt the activities of HK and PFK， the key rate-limiting enzymes of glycolysis （P<0.05）. Meanwhile， 10% Sishenwan-containing serum could decrease the expression of GluT1 protein （P<0.01） and mRNA （P<0.05） and reduce the proportion of cells expressing GluT1 （P<0.01）. Compared with the normal serum， Sishenwan-containing serum also decreased the protein content of MettL3 （P<0.05） and the methylation level of m6A RNA （P<0.01）. ConclusionSishenwan can inhibit glycolysis in colon cancer cells， and its inhibitory mechanism may be related to reducing MettL3 overexpression， inhibiting m6A RNA methylation， and down-regulating GluT1 and the activities of intracellular aerobic glycolysis-related enzymes such as HK and PFK.

Causal Relationship Between Acromegaly and Colon Cancer: A Two-sample Mendelian Randomization Study / 肿瘤防治研究

Objective To determine the causal relationship between acromegaly and colon cancer by using two-sample Mendelian randomization. Methods Genetic loci closely related to acromegaly in the whole genome-wide association study (GWAS) were selected as tool variables, and the genetic data of colon cancer from different GWASs were analyzed by two-sample Mendelian randomization (MR).The inverse variance weighting method (IVW) of the random effect model was used for analysis, and MR-weighted median and MR-Egger methods were used to supplement the analysis. Results were presented as OR values. Results Four SNPs closely related to acromegaly were obtained as tool variables, and the multiplicity test of tool variables showed that P=0.59.Three methods were used to estimate causal effects.The IVW analysis were OR=1.00(0.99-1.001) and P=0.42;the MR-Egger analysis results were OR=1.00(0.99-1.001) and P=0.42;and the Weighted median analysis results were OR=1.00(1.00-1.001) and P=0.03.The sensitivity test showed that the confidence interval of the tool variable SNP passed through 0, indicating the robustness of the MR results. Conclusion Acromegaly is not an independent risk factor for colon cancer.

Research on the anti-tumor effect of nordihydroguaiaretic acid targeting MyD88 / 药学学报

This study mainly explores the role of myeloid differentiation primary response protein 88 (MyD88) in tumorigenesis and development, to identify active compounds targeting MyD88. CRISPR/Cas9 system and xenograft tumor model were used to detect the effect of MyD88 deletion on tumor growth, and the experimental animal ethics review number was PZSHUTCM200828006. Microscale thermophoresis technology (MST) was used to identify compounds directly bind to MyD88 and further detect the impact of candidate small molecules on cell proliferation. Results showed that depletion of MyD88 significantly inhibited xenograft tumor growth of colon cancer, pancreatic cancer and skin cancer and the activity of NF-κB signaling pathway. MST showed that nordihydroguaiaretic acid (NDGA) bound to MyD88, with the binding dissociation constant Kd of 14.61 µmol·L-1. NDGA inhibited NF-κB reporting system activation and phosphorylation of p65, the key factor in NF-κB signal pathway. In addition, the results of colony formation assay showed that NDGA suppressed the proliferation of tumor cells. The above results show that, MyD88 is a potential therapeutic target for colon cancer, pancreatic cancer and skin cancer, NDGA directly binds to MyD88 and inhibits the activity of NF-κB signaling pathway, as well as inhibits the proliferation of pancreatic cancer, skin cancer and colon cancer cells.

Evaluation of anti-tumor effect of a novel manganese adjuvant collaborated with tumor antigens / 中国生物制品学杂志

@#ObjectiveTo investigate the anti-tumor effect of agonist MnCl_2of a novel cyclic guanosine monophosphate-adenosine monophosphate synthase(c GAS)/stimulator of interferon genes(STING)pathway collaborated with tumor cell lysate(Lysate)and the neo-antigen 10K-Adpgk of mouse colon cancer MC38 cell line.MethodsBone marrow-derived dendritic cells(BMDCs)were extracted from mouse bone marrow and divided into three groups:PBS,1 μmol/L MnCl_2and 10 μmol/L MnCl_2,which were analyzed for the maturation by flow cytometry,determined for the concentration of IL-6 in supernatant by ELISA,and detected for the transcription levels of IL-6,IFN-α,IFN β and CXCL9 genes by q PCR.Mouse tumor model was established by using MC38 cell line.When the tumor volume reached 100 mm3,the mice were randomly divided into two groups for administration,PBS,Lysate,MnCl_2,10K-Adpgk,Lysate + MnCl_2group and Lysate +10K-Adpgk + MnCl_2combined treatment group,which were administered subcutaneously through the tail for 3 times,with each interval of 1 week,and measured for the tumor volume every 2 days.One week after the last dose,serum samples were collected and determined for the concentrations of IFNγ and TNFα by ELISA.The tumor and spleen were isolated.The proportions of tumor infiltrating T cells and T cells in peripheral blood mononuclear cells(PBMCs)and the ratio of T cells to memory T cells in spleen were detected by flow cytometry,and the proportion of antigen specific T cells in spleen was detected by ELISPOT.Results10 μmol/L MnCl_2stimulated the maturation of BMDCs and activated the subsequent immune process.The tumor volumes of mice in the combined treatment group were considerably smaller than those in PBS group,the contents of IFNγ and TNF-α in serum were higher than those in other groups,and the proportions of tumor infiltrating T cells,T cells in PBMCs and ratio of T cells to memory T cells in spleen were also significantly higher than those in PBS group.Combined therapy caused strong antigen-specific T cell immune response.ConclusionThe addition of the novel adjuvant MnCl_2significantly enhanced the treatment effect of tumor cell lysate and neo-antigen,which provided an experimental basis for the development of the combination tumor treatment method based on MnCl_2and tumor antigens.

Medication rules of famous Beijing TCM doctor Wang Pei in the treatment of colon cancer based on data mining / 国际中医中药杂志

Objective:To explore the medication rules of Professor Wang Pei in the treatment of colon cancer.Methods:The medical records of Professor Wang Pei's outpatient treatment for colon cancer were collected, entered into the Traditional Chinese Medicine Inheritance Computing Platform V3.0, and the laws of the prescription's nature, flavor, meridian, drug frequency, drug combination, association rules, and cluster analysis were explored.Results:A total of 65 prescriptions were collected, including 150 Chinese materia medica. The medicinal properties of these Chinese materia medica are mainly warm, cold and flat, the tastes were mainly sweet, bitter and pungent, and the meridians were mainly liver, spleen and kidney meridians. Dampness category and blood circulation promoting and blood stasis category were mainly used, and the most frequently used drugs include Poria, Polyporus, Scutellariae Barbatae Herba, Astragali Radix, Curcumae Rhizoma, and the pairs of Polyporus- Poria, Astragali Radix- Astragali Radix Praeparata cum Melle, Scutellariae Barbatae Herba- Curcumae Rhizoma. Twenty nine high-related drug pairs were obtained from association rules, including Polyporus- Astragali Radix Praeparata cum Melle- Astragali Radix, Poria- Scutellariae Barbatae Herba- Polyporus, Scutellariae Barbatae Herba- Curcumae Rhizoma- Polyporus. The cluster analysis showed the combination of 6 types of medicines mainly focuses on strengthening the spleen and removing dampness, nourishing qi and promoting blood, clearing heat and detoxifying, and astringing the intestines to stop bleeding. Conclusion:Professor Wang Pei mostly discusses the treatment of colon cancer from "spleen dampness, rectification deficiency, heat toxin, blood stasis, bleeding", and the treatment is "invigorating the spleen and removing dampness, invigorating Qi and strengthening the body, clearing away heat and detoxifying, promoting blood circulation and removing blood stasis, and astringent intestines to stop bleeding", which is in line with the thought of Traditional Chinese Medicine treatment of tumors, strengthening the righteousness and eliminating pathogenic factors, and and can be used for clinical reference.

Yangyin Huayu Jiedu Preseription Regulates Autophagy and Apoptosis of Colon Cancer Cells in Hypoxic Environment Through PI3K/Akt Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect of different oxygen concentration on the proliferation and autophagy of colon cancer cells and to explore the effect of Yangyin Huayu Jiedu Preseription （YHJP） on autophagy and apoptosis of colon cancer cells under hypoxia based on phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway. MethodHCT-116 cells were divided into normoxia group， 1% O2 group， and 5% O2 group. Cell viability was detected by cell proliferation assay （MTS）， and autophagy was observed based on monodansylcadaverine （MDC） staining. HCT-116 cells were treated with YHJP in 5% O2 microenvironment. The cells were divided into normal group， blank serum group， and low-， medium-， high-dose YHJP groups （5%， 15%， 25% serum containing YHJP）. Cell inhibition rate in each group was calculated by MTS， and changes in the rate of autophagy were detected based on MDC staining. Annexin V-fluorescein isothiocyanate （FITC）/propidium iodide （PI） was employed to detect the apoptosis rate of each group. Western blotting was applied to measure the expression of autophagy proteins microtubule-associated protein 1 light chain 3 （LC3Ⅱ/Ⅰ）， yeast Atg6 homolog （Beclin-1）， ubiquitin-binding scaffold protein p62 （p62）， apoptosis-related proteins B-cell lymphoma-2 （Bcl-2）， Bcl-2/adenovirus E1B interacting protein 3 （BNIP-3）， and Bcl-2 associated X protein （Bax）， cleaved cysteine-aspartic acid protease-3 （Caspase-3）， hypoxia-inducible factor-1α （HIF-1α） and pathway proteins PI3K， phosphorylated （p）-PI3K， Akt， and p-Akt. ResultCell survival rates of the 1% O2 and 5% O2 groups were increased compared with that in the normoxia group， particularly the 5% O2 group （P<0.01）. The fluorescence intensity for autophagy in 1% O2 and 5% O2 groups was significantly increased compared with that in the normoxia group， especially the 5% O2 group. In the presence of 5% O2， compared with the blank serum group， medium-dose and high-dose YHJP groups showed high cell inhibition rate， low autophagy rate， high apoptosis rate （P<0.01）， and low expression of Beclin-1 protein （P<0.05）. Compared with low-dose YHJP group， high-dose YHJP group demonstrated low expression of Beclin-1 protein （P<0.05）. Compared with the blank serum group， the three YHJP groups had low expression of LC3Ⅱ/Ⅰ protein （P<0.05， P<0.01）. Compared with the blank serum group， medium-dose and high-dose YHJP groups showed high expression of p62 protein （P<0.01）. Compared with low-dose YHJP group， high-dose YHJP group showed high expression of p62 protein （P<0.05）. Compared with the blank serum group， high-dose YHJP increased the expression of BNIP-3 and Bax and decreased the expression of Bcl-2 （P<0.01）. The expression of Bax protein in the high-dose YHJP group was increased compared with that in the low-dose YHJP group （P<0.05）. The expression of HIF-1α in the medium-dose and high-dose YHJP groups was decreased （P<0.01） and the expression of p-PI3K/PI3K and p-Akt/Akt in the high-dose YHJP group was increased （P<0.05， P<0.01） compared with that in the blank serum group. The expression of p-Akt/Akt was higher in the high-dose YHJP group than in the medium-dose YHJP （P<0.05）. ConclusionHypoxic microenvironment can significantly promote autophagy and proliferation of colon cancer cells. YHJP can significantly inhibit autophagy and proliferation and promote apoptosis of colon cancer cells in 5% O2 environment by up-regulating the PI3K/Akt signaling pathway.

Effects of Substrate Stiffness on Epithelial-Mesenchymal Transition of Colon Cancer Cells under Simulated Hypoxia Environment / 医用生物力学

Objective To explore the effects from the synergy of substrate stiffness and hypoxia on epithelial mesenchymal transition (EMT) of colon cancer cells SW480 by simulating the microenvironment of human colon cancer tissues. Methods Polyvinyl alcohol gels with different stiffness ( 4. 5, 20, 40 kPa) were prepared to simulate the stiffness of each part of colon cancer tissues. The morphological change of cells on substrate with different stiffness was detected under simulated hypoxia ( CoCl2 ) environment. The expression of hypoxia inducible factor (HIF-1α), and EMT markers E-cadherin, Vimentin, Snail 1 were detected by Western blot. The mRNA expression of E-cadherin, Vimentin, Snail 1, matrix metalloproteinase-2 ( MMP-2), and MMP-9 was detected by quantitative real-time PCR ( qRT-PCR). Results Under simulated hypoxia environment, with the increase of substrate stiffness, the SW480 cells spreading area increased, and transformed from round shape into irregular polygon. The EMT of SW480 could be enhanced through up-regulating expression of Vimentin, Snail 1, MMP-2, MMP-9, and down-regulating expression of E-cadherin. Conclusions This study is important for exploring the synergistic effect of substrate stiffness and hypoxia on the EMT of colon cancer cells as well as the molecular mechanism.

NKD1 promotes glucose uptake in colon cancer cells by activating YWHAE transcription / 南方医科大学学报

OBJECTIVE@#Bo investigate the regulatory relationship between NKD1 and YWHAE and the mechanism of NKD1 for promoting tumor cell proliferation.@*METHODS@#HCT116 cells transfected with pcDNA3.0-NKD1 plasmid, SW620 cells transfected with NKD1 siRNA, HCT116 cells with stable NKD1 overexpression (HCT116-NKD1 cells), SW620 cells with nkd1knockout (SW620-nkd1-/- cells), and SW620-nkd1-/- cells transfected with pcDNA3.0-YWHAE plasmid were examined for changes in mRNA and protein expression levels of YWHAE using qRT-PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assay was used to detect the binding of NKD1 to the promoter region of YWHAE gene. The regulatory effect of NKD1 on YWHAE gene promoter activity was analyzed by dual-luciferase reporter gene assay, and the interaction between NKD1 and YWHAE was analyzed with immunofluorescence assay. The regulatory effect of NKD1 on glucose uptake was examined in the tumor cells.@*RESULTS@#In HCT116 cells, overexpression of NKD1 significantly enhanced the expression of YWHAE at both the mRNA and protein levels, while NKD1 knockout decreased its expression in SW620 cells (P < 0.001). ChIP assay showed that NKD1 protein was capable of binding to the YWHAE promoter sequence; dual luciferase reporter gene assay showed that NKD1 overexpression (or knockdown) in the colon cancer cells significantly enhanced (or reduced) the transcriptional activity of YWHAE promoter (P < 0.05). Immunofluorescence assay demonstrated the binding of NKD1 and YWHAE proteins in colon cancer cells. NKD1 knockout significantly reduced glucose uptake in colon cancer cells (P < 0.01), while YWHAE overexpression restored the glucose uptake in NKD1-knockout cells (P < 0.05).@*CONCLUSION@#NKD1 protein activates the transcriptional activity of YWHAE gene to promote glucose uptake in colon cancer cells.

Nomogram for Predicting Early Death in Patients with Metastatic Colon Cancer Based on SEER Database / 肿瘤防治研究

Objective To construct a Nomogram model that can accurately predict early death of metastatic colon cancer (mCC). Methods A total of 6 669 patients from the SEER database were identified using inclusion and exclusion criteria. Multivariate logistic regression was used to identify risk factors for early mortality and to construct a Nomogram. The predictive performance of the Nomogram was evaluated by C-index, calibration curve, and decision curve analysis (DCA). Results Primary tumor location, differentiation grade, T stage, M stage, bone metastases, brain metastases, CEA, tumor size, age and marital status were independent factors for early death in patients with mCC. A Nomogram was constructed based on these variables. The C-index and the calibration curve of the Nomogram showed the good predictive ability of the nomogram. DCA showed that the Nomogram had a superior clinical net benefit in predicting early death compared with TNM stage. Conclusion The developed Nomogram has good predictive ability and can help guide clinicians to identify patients with high-risk mCC for individualized diagnosis and treatment.

Mechanism of Huangqintang in Treatment of Ulcerative Colitis and Related Colon Cancer： A Review / 中国实验方剂学杂志

Ulcerative colitis （UC） is a chronic intestinal disease with unknown etiology， with main symptoms of abdominal pain， diarrhea， mucus， pus， and blood in the stool. It can be accompanied by various complications and has a high risk of developing to colon cancer. In recent years， the incidence of UC and related colon cancer has been increasing， which seriously affects human health and quality of life. The operation， immunosuppressant， etc. are the main approaches in the modern clinical treatment of UC and related colon cancer， but these methods all have different toxic and side effects， and the therapeutic effect is not ideal. For many years， traditional Chinese medicine （TCM） has attracted much attention in the treatment of UC and related colon cancer due to its slightly toxic side effects and remarkable curative efficacy. Huangqintang， derived from the Shang Han Lun （伤寒论）， is composed of Scutellariae Radix， Paeoniae Radix Alba， Glycyrrhizae Radix et Rhizoma， and Jujubae Fructus with the functions of clearing heat， checking diarrhea， harmonizing the middle， and relieving pain， and has a significant effect on the treatment of UC. Huangqintang has complex compositions and plays roles with multiple targets and pathways. According to the literature and the research results of this research group for many years， it was found that the mechanism of Huangqintang in the treatment of UC and related colon cancer was presumably related to the protection of the intestinal mucosal barrier， inhibition of inflammatory response， promotion of mitophagy， inhibition of oxidative stress， regulation of intestinal flora， cell cycle， and gene expression， suppression of cell proliferation， and promotion of apoptosis. To provide theoretical references for an in-depth study of the mechanism and clinical use of Huangqintang， this paper reviewed the research advances in recent years.

Astragali Radix-Curcumae Rhizoma combination inhibits proliferation, migration, and invasion of colon cancer HT-29 cells by regulating EMT / 中国中药杂志

This study aims to investigate the effect of Astragali Radix-Curcumae Rhizoma(AC) combination on the proliferation, migration, and invasion of colon cancer HT-29 cells based on epithelial-mesenchymal transition(EMT). HT-29 cells were respectively treated with 0, 3, 6 and 12 g·kg~(-1) AC-containing serum for 48 h. The survival and growth of cells were measured by thiazole blue(MTT) colorimetry, and the proliferation, migration, and invasion of cells were detected by 5-ethynyl-2'-deoxyuridine(EdU) test and Transwell assay. Cell apoptosis was examined by flow cytometry. The BALB/c nude mouse model of subcutaneous colon cancer xenograft was established, and then model mice were classified into blank control group, 6 g·kg~(-1) AC group, and 12 g·kg~(-1) AC group. The tumor weight and volume of mice were recorded, and the histopathological morphology of the tumor was observed based on hematoxylin-eosin(HE) staining. The expression of apoptosis-associated proteins B-cell lymphoma-2-associated X protein(Bax), cysteine-aspartic acid protease-3(caspase-3), and cleaved caspase-3, and EMT-associated proteins E-cadherin, MMP9, MMP2 and vimentin in HT-29 cells and mouse tumor tissues after the treatment of AC was determined by Western blot. The results showed that cell survival rate and the number of cells at proliferation stage decreased compared with those in the blank control group. The number of migrating and invading cells reduced and the number of apoptotic cells increased in the administration groups compared with those in the blank control group. As for the in vivo experiment, compared with the blank control group, the administration groups had small tumors with low mass and shrinkage of cells and karyopycnosis in the tumor tissue, indicating that the AC combination may improve EMT. In addition, the expression of Bcl2 and E-cadherin increased and the expression of Bax, caspase-3, cleaved caspase-3, MMP9, MMP2, and vimentin decreased in HT-29 cells and tumor tissues in each administration group. In summary, the AC combination can significantly inhibit the proliferation, invasion, migration, and EMT of HT-29 cells in vivo and in vitro and promote the apoptosis of colon cancer cells.

KCNK9 mediates the inhibitory effects of genistein on hepatic metastasis from colon cancer

ABSTRACT Objective: The tyrosine-protein kinase inhibitor, genistein, can inhibit cell malignant transformation and has an antitumor effect on various types of cancer. It has been shown that both genistein and KNCK9 can inhibit colon cancer. This research aimed to investigate the suppressive effects of genistein on colon cancer cells and the association between the application of genistein and KCNK9 expression level. Methods: The Cancer Genome Atlas (TCGA) database was used to study the correlation between the KCNK9 expression level and the prognosis of colon cancer patients. HT29 and SW480 colon cancer cell lines were cultured to examine the inhibitory effects of KCNK9 and genistein on colon cancer in vitro, and a mouse model of colon cancer with liver metastasis was established to verify the inhibitory effect of genistein in vivo. Results: KCNK9 was overexpressed in colon cancer cells and was associated with a shorter Overall Survival (OS), a shorter Disease-Specific Survival (DFS), and a shorter Progression-Free Interval (PFI) of colon cancer patients. In vitro experiments showed that downregulation of KCNK9 or genistein application could suppress cell proliferation, migration, and invasion abilities, induce cell cycle quiescence, promote cell apoptosis, and reduce epithelialmesenchymal transition of the colon cancer cell line. In vivo experiments revealed that silencing of KCNK9 or application of genistein could inhibit hepatic metastasis from colon cancer. Additionally, genistein could inhibit KCNK9 expression, thereby attenuating Wnt/β-catenin signaling pathway. Conclusion: Genistein inhibited the occurrence and progression of colon cancer through Wnt/β-catenin signaling pathway that could be mediated by KCNK9.

Short-term outcomes of laparoscopic-assisted colectomy versus open colectomy in patients with colonic carcinoma: a prospective randomized study

Introduction: The second most common cause of cancer-related mortality is colorectal cancer, and laparoscopic-assisted colectomy (LAC) has gained popularity among surgeons as an alternative to the conventional approach, which is open colecrtomy (OC). The differences between LAC and OC in terms of short-term outcomes have not been well documented, and the aim of the present work is to compare the short-term outcomes of both procedures. Materials and Methods: The present prospective study comprised 164 participants submitted to LAC (n = 82) and OC (n = 82) at the Helwan and Zagazig University hospitals between January 2018 and January 2022. We collected and analyzed demographic data, surgical data, and the short-term outcomes. Results: The LAC group had a significantly lower estimated amount of blood loss, shorter hospital stay, lower rates of incisional surgical site infection, and fewer cases of burst abdomen postoperatively, but with a considerably longer operative time (30.3 minutes) than the OC group. Conclusions: Our findings show that LAC is favorable option to OC, with superior outcomes. (AU)

Enfoque interdisciplinario en el manejo del cáncer de colon / The Interdisciplinary Approach in Colon Cancer Management

Introducción: El modelo interdisciplinario en el ámbito oncológico ha permitido la vinculación entre diferentes disciplinas lo que permite aportar soluciones para elevar la calidad de vida de los enfermos y proporcionan una atención de excelencia. Objetivo: Explorar la evidencia científica sobre la colaboración interdisciplinar en el tratamiento del cáncer de colon. Métodos: Se realizó una investigación de tipo sistemática. Se ejecutó una búsqueda digital en las bases de datos de Web of Science, Lilacs, SciELO, Latindex, Elsevier, PubMed, Medline y Google de publicaciones actualizadas en inglés y español. Desarrollo: El enfoque interdisciplinario en el tratamiento de las enfermedades oncológicas, entre ellas el cáncer de colon, se ha descrito desde hace algún tiempo. El diseño permite vincular diferentes especialidades en las interconsultas y en el propio acto quirúrgico, lo que redunda en la formulación de problemas de investigación que requieren para su solución el intercambio de conocimientos y tecnologías de una especialidad a otra, permite aportar soluciones para elevar la calidad de vida de los enfermos y proporciona una atención de excelencia. Conclusiones: El cáncer es una enfermedad que requiere una atención para el paciente, no solo dentro de la esfera biológica; también psicológica, social y espiritual. Los equipos interdisciplinares, formados por profesionales de distintas disciplinas, son una herramienta que puede ayudar, en gran medida, a conseguir una mejor atención(AU)

Introduction: The interdisciplinary model in the oncological field has permitted connection between different disciplines, allowing to offer solutions for raising the quality of life of patients and provide excellent care. Objective: To explore the scientific evidence on interdisciplinary collaboration in the treatment of colon cancer. Methods: A systematic research was carried out. A digital search was carried out in the Web of Science, Lilacs, SciELO, Latindex, Elsevier, PubMed, Medline and Google databases, in view of identifying updated publications in English and Spanish. Development: The interdisciplinary approach in the treatment of oncologic diseases, including colon cancer, has been described for some time. The design allows connecting different specialties during interconsultation or the surgical act itself, which results in the formulation of research problems that require, for their solution, the exchange of knowledge and technologies from one specialty to another, allowing to offer solutions for raising the quality of life of patients and provide excellent care. Conclusions: Cancer is a disease that requires care for the patient, not only within the biological sphere, but also in the psychological, social and spiritual aspect. Interdisciplinary teams, made up of professionals from different disciplines, are a tool that can help, to a great extent, achieve better care(AU)