Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability.

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.

Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study.

BACKGROUND: Chemoprevention of colorectal adenoma and colorectal cancer remains an important public health goal. The present study aimed to investigate the clinical potential and safety of berberine for prevention of colorectal adenoma recurrence. METHODS: This double-blind, randomised, placebo-controlled trial was done in seven hospital centres across six provinces in China. Individuals aged 18-75 years who had at least one but no more than six histologically confirmed colorectal adenomas that had undergone complete polypectomy within the 6 months before recruitment were recruited and randomly assigned (1:1) to receive berberine (0·3 g twice daily) or placebo tablets via block randomisation (block size of six). Participants were to undergo a first follow-up colonoscopy 1 year after enrolment, and if no colorectal adenomas were detected, a second follow-up colonoscopy at 2 years was planned. The study continued until the last enrolled participant reached the 2-year follow-up point. All participants, investigators, endoscopists, and pathologists were blinded to treatment assignment. The primary efficacy endpoint was the recurrence of adenomas at any follow-up colonoscopy. Analysis was based on modified intention-to-treat, with the full analysis set including all randomised participants who received at least one dose of study medication and who had available efficacy data. The study is registered with ClinicalTrials.gov, number NCT02226185; the trial has ended and this report represents the final analysis. FINDINGS: Between Nov 14, 2014, and Dec 30, 2016, 553 participants were randomly assigned to the berberine group and 555 to the placebo group. The full analysis set consisted of 429 participants in the berberine group and 462 in the placebo group. 155 (36%) participants in the berberine group and 216 (47%) in the placebo group were found to have recurrent adenoma during follow-up (unadjusted relative risk ratio for recurrence 0·77, 95% CI 0·66-0·91; p=0·001). No colorectal cancers were detected during follow-up. The most common adverse event was constipation (six [1%] of 446 patients in the berberine group vs one [<0·5%] of 478 in the placebo group). No serious adverse events were reported. INTERPRETATION: Berberine 0·3 g twice daily was safe and effective in reducing the risk of recurrence of colorectal adenoma and could be an option for chemoprevention after polypectomy. FUNDING: National Natural Science Foundation of China.

Nutrients Impact the Pathogenesis and Development of Colorectal Cancer.

BACKGROUND: Colorectal cancer is a commonly diagnosed cancer and the cause of many cancer deaths worldwide. Nutrients might be crucial in the pathogenesis and development of colorectal cancer. Although a number of studies have demonstrated the potential effects of nutrients, many challenges still remain. SUMMARY: A tremendous amount of research has emerged concerning the roles of nutrients in colorectal cancer during the past decades. Here, we review the latest research progress on nutrients, including vitamins, folic acid, calcium, selenium and dietary fiber, involved in colorectal cancer prevention. KEY MESSAGE: Nutrients are commonly consumed in foods or dietary supplements. It is clear that nutrients could play an important role and influence colorectal cancer outcomes. The relationship between nutrients and colorectal risk is complex. Vitamins, folic acid, calcium, selenium and dietary fiber have been proposed as potential agents to prevent colorectal cancer. However, some studies found that these nutrients did not reduce the incidence of colorectal cancer. PRACTICAL IMPLICATIONS: The supplementary dose of nutrients, the length of time required to observe the effects and confounding factors during the study might influence the role of nutrients in the prevention of colorectal cancer. Therefore, more evidence from ongoing clinical trials with different population groups and longer follow-up periods is critical to determine the relationship between nutrients and colorectal cancer.

Consensus on the Prevention, Screening, Early Diagnosis and Treatment of Colorectal Tumors in China: Chinese Society of Gastroenterology, October 14-15, 2011, Shanghai, China.

BACKGROUND: Colorectal cancer (CRC) is steadily increasing in China. Colorectal adenoma (CRA) is the most important precancerous disease of CRC. Screening for colorectal tumors can aid early diagnosis. Advances in endoscopic mucosal resection and endoscopic submucosal dissection can aid the early treatment of colorectal tumors. Furthermore, because of high risk of recurrence after removal of adenomas under endoscopy, factors contributing to recurrence, the follow-up mode and the interval established, and the feasibility of application and the time of various chemical preventions should be concerned. However, a relevant consensus on the screening, early diagnosis and treatment, and prevention of colorectal tumors in China is lacking. SUMMARY: The consensus recommendations include epidemiology, pathology, screening, early diagnosis, endoscopic treatment, monitoring and follow-up, and chemoprevention of colorectal tumors in China. KEY MESSAGE: This is the first consensus on the prevention, screening, early diagnosis and treatment of CRA and CRC in China based on evidence in the literature and on local data. PRACTICAL IMPLICATIONS: Through reviewing the literature, regional data and passing the consensus by an anonymous vote, gastroenterology experts from all over China launch the consensus recommendations in Shanghai. The incidence and mortality of CRC in China has increased, and the incidence or detection rate of CRA has increased rapidly. Screening for colorectal tumors should be performed at age 50-74 years. Preliminary screening should be undertaken to find persons at high risk, followed by colonoscopy. A screening cycle of 3 years is recommended for persistent interventions. Opportunistic screening is a mode suitable for the current healthcare system and national situation. Colonoscopy combined with pathological examination is the standard method for the diagnosis of colorectal tumors. CRA removal under endoscopy can prevent CRC to some extent, but CRA has an obvious recurrence trend. The follow-up interval after the removal or surgery of colorectal tumors should be different with lesions. Primary prevention of CRA includes improved diet with more fiber, supplements containing calcium and vitamin D, supplements containing folic acid for those with low hemoglobin levels, and cessation of tobacco smoking. Non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors have been recognized to prevent recurrence after adenoma removal.

Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial.

Colorectal adenoma (CRA) is the precursor lesion of colorectal cancer (CRC). Several agents have been shown to be effective in the chemoprevention of CRA recurrence, but there has been little research on its primary prevention. Participants older than 50 years with no adenomas were recruited for our study and randomized to receive either 1 mg/day folic acid supplement or treatment without folic acid. After 3 years of follow-up, plasma folate and colonoscopy were evaluated. Seven hundred ninety-one participants (91.98%) completed the study. CRA occurred in 64 (14.88%) participants in the folic acid group and 132 (30.70%) in the control group [unadjusted risk ratio (RR), 0.49; 95% confidence interval (CI), 0.37-0.63; P < 0.01]; left-sided adenoma (unadjusted RR, 0.54; 95% CI, 0.38-0.76; P = 0.001) and advanced CRA (unadjusted RR, 0.36; 95% CI, 0.16-0.81; P = 0.01) were most common. There was no significance difference in the occurrence of three or more adenomas (unadjusted RR, 0.70; 95% CI, 0.36-1.77; P = 0.38) or right-sided adenoma (unadjusted RR, 0.55; 95% CI, 0.30-1.00; P = 0.07) between the two groups. Participants with low plasma folate may have a high risk of CRA. In conclusion, primary prevention with 1 mg/day folic acid supplementation could reduce the incidence of CRA, especially left-sided and advanced disease in those with no previous adenomas. People with differing baseline plasma folate levels should be given individualized treatment. Those with low plasma folate should be encouraged to take adequate supplements; plasma folate should be elevated to an effective therapeutic level, which may reduce the incidence of CRA.

Green tea and incidence of colorectal cancer: evidence from prospective cohort studies.

A systematic meta-analysis of prospective cohort studies on green tea consumption and colorectal cancer was performed to determine whether green tea has a chemopreventive effect against colorectal cancer. Six eligible cohort studies involving 352,275 participants and 1675 cases of colorectal cancer were identified. Combined relative risk (RR) ratios for the highest vs. lowest and increment of 1 cup/day green tea consumption levels were calculated. The combined RR of 0.90 (95% CI: 0.72-1.08) was found comparing highest vs. lowest green tea consumption levels for colorectal cancer. No significant differences by cancer-site were found, but an inverse association between green tea and incidence of colorectal cancer (RR: 0.70; 95% CI: 0.55-0.85) and colon cancer (RR: 0.69; 95% CI: 0.48-0.98) was demonstrated in Shanghai population. Singapore men had a higher risk of colorectal cancer (RR: 1.36; 95% CI: 1.06-1.74). Furthermore, an increase in green tea consumption of 1 cup/day was not associated with incidence of colorectal cancer (RR: 0.97; 95% CI: 0.91-1.03). Despite the limited evidence from Shanghai studies in support of green tea as potential chemopreventive agents against colorectal cancer, available data from prospective cohort studies are insufficient to conclude that green tea may protect against colorectal cancer.

Folic acid supplementary reduce the incidence of adenocarcinoma in a mouse model of colorectal cancer: microarray gene expression profile.

BACKGROUND: Whether Folic acid is a potential drug that may prevent the progression of colorectal carcinoma and when to use are important healthy issues we focus on. Our study is to examine the effect of folic acid on the development of the CRC and the optimal time folic acid should be provided in a mouse-ICR model induced by 1, 2-Dimethylhydrazine. Also, we investigated the gene expression profile of this model related to folic acid. METHOD: Female ICR mouse (n=130) were divided into 7 groups either with the treatment of 1, 2-Dimethylhydrazine (20 mg/kg bodyweight) weekly or folic acid (8 mg/kg bodyweight) twice a week for 12 or 24 weeks. Using a 4 x 44 K Agilent whole genome oligo microarray assay, different gene expression among groups (NS, DMH, FA2, FA3) were identified and selected genes were validated by real-time polymerase chain reaction. RESULTS: Animals with a supplementary of folic acid showed a significant decrease in the incidence, the maximum diameter and multiplicity of adenocarcinomas (P<0.05). Furthermore, there were fewer adenomas or adenocarcinomas developed in the group of folic acid supplementation in pre-adenoma stage compared to group of post-adenoma stage. Meanwhile, about 1070 genes that were changed by 1, 2-Dimethylhydrazine can be reversed by folic acid and 172 differentially genes were identified between the groups of pre- and post- adenoma stage using microarray gene expression analysis. CONCLUSION: Our study demonstrated that folic acid supplementary was significantly associated with the decrease risk of CRC. And the subgroup of providing folic acid without precancerous lesions was more effective than that with precancerous lesions.

Folate and fiber in the prevention of colorectal cancer: between shadows and the light.

Colorectal cancer (CRC) is one of the most common malignancies and causes of cancer deaths throughout the world. Endoscopy has its functional and financial limitations; therefore, chemoprevention might be crucial in reducing the incidence of CRC. Although a number of studies have demonstrated the potential chemopreventive effects of folate (or folic acid), many challenges still remain. The relationship between folate intake and CRC risk is a complex association that might depend on many factors including gender, age, alcohol consumption, and smoking, all of which interfere with folate metabolism. The supplementary dose of fiber, the length of time required to observe the effects, and confounding factors exposed during the trial might also influence these findings. Therefore, more evidence from clinical studies is needed regarding the mechanisms that underlie the actions of bioactive food components in minimizing the risk of CRC.

Folic acid and sodium butyrate prevent tumorigenesis in a mouse model of colorectal cancer.

Colorectal cancer is a leading cause of morbidity and mortality worldwide, and its incidence has been increasing in recent years. The role of epigenetic modifications, including DNA methylation and histone modifications, has only recently been investigated. In this study, the effects of epigenetic agents such as folic acid (FA) and sodium butyrate (NaBu) on the development of colorectal cancer induced by 1,2-dimethylhydrazine (DMH) using ICR mice was examined. Of the mice treated in a chemopreventive manner with epigenetic agents, FA and NaBu, 15-50% developed colorectal cancer at 24 weeks compared with a 95% incidence of colorectal cancer in DMH-treated control mice. Folate deficiency can alter cytosine methylation in DNA leading to inappropriate activation of the proto-oncogene c-myc. We detected lower levels of p21(WAF1) gene expression in colorectal cancer samples, as well as significantly lower levels of acetylated histone H3, compared with samples from corresponding normal colorectal mucosa. In contrast, administration of NaBu increased levels of p21(WAF1) mRNA and p21(WAF1) protein, and was associated with an accumulation of histone acetylation. In summary, our results show that FA and NaBu reduce the incidence of colorectal cancer induced by DMH-induced in ICR mice, and therefore we hypothesize that targeting epigenetic targets should be further investigated for the prevention of colorectal cancer in humans.