Efficacy and safety of Xian-Lian-Jie-Du optimization decoction as an adjuvant treatment for prevention of recurrence in patients with stage IIIB/IIIC colon cancer: study protocol for a multicentre, randomized controlled trial.

INTRODUCTION: Colon cancer remains one of the most prevalent cancers worldwide. Unfortunately, there are no recognized and effective therapeutic strategies to prevent tumor recurrence after radical resection and chemotherapy, and the disease-free survival (DFS) in patients with stage IIIB or IIIC disease remains unsatisfactory. Xian-Lian-Jie-Du optimization decoction (XLJDOD) is a Chinese herbal medicine (CHM) empirical prescription, which has been validated experimentally and clinically that could inhibit the progression of colorectal cancer and ameliorate the symptoms. The purpose of this study is to evaluate the efficacy and safety of XLJDOD in prevention of recurrence of colon cancer. METHODS: This study is a multi-center, double-blind, randomized, placebo-controlled trial conducted at 13 hospitals of China. Following the completion of surgery and adjuvant 5- fluorouracil-based chemotherapy, a total of 730 subjects with stage IIIB or IIIC colon cancer will be randomized in a 1:1 ratio to an intervention group (n = 365; XLJDOD compound granule) and a control group (n = 365; Placebo). Patients will receive 6-month treatments and be followed up with 3 monthly assessments for 2 years. The primary outcome is 2-year DFS rate and the secondary outcomes are 1, 2-year relapse rate (RR), overall survival (OS) and quality of life (QoL). Safety outcomes such as adverse events will be also assessed. A small number of subgroup analysis will be carried out to explore the heterogeneity of effects of XLJDOD. DISCUSSION: The outcomes from this randomized controlled trial will provide objective evidences to evaluate XLJDOD's role as an adjuvant treatment in colon cancer. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , identifier: NCT05709249. Registered on 31 Jan 2023.

Assessing transfer of aluminum during tea brewing and associated population health risks.

Tea is consumed widely around the world owing to its refreshing taste and potential health benefits. However, drinking tea is considered a major route for dietary aluminum exposure in areas where tea consumption is relatively large. To assess the health risk associated with drinking tea, the contamination level of aluminum was determined in 81 tea samples. The transfer rate of aluminum during tea brewing was investigated. Then based on the site-specific exposure parameters such as consumption data and body weight for six different subpopulations in Fujian, the exposure risks were estimated using a probabilistic approach. Results demonstrate that the contents of aluminum in green tea, white tea, oolong tea, and black tea were significantly different according to the one-way ANOVA analysis (p < 0.05). The transfer rate of aluminum were 32.6%, 31.6%, 26.3%, and 14% for white tea, black tea, oolong tea, and green tea, respectively. With respect to the oral reference dose, the exposure of inhabitants in Fujian to aluminum through drinking tea is under control (even at the 99th percentile).

The Modulation of Chaihu Shugan Formula on Microbiota Composition in the Simulator of the Human Intestinal Microbial Ecosystem Technology Platform and its Influence on Gut Barrier and Intestinal Immunity in Caco-2/THP1-Blue™ Cell Co-Culture Model.

The traditional Chinese medicine (TCM)-Chaihu Shugan Formula (CSF), consisting of several Chinese botanical drugs like Bupleurum, is derived from the ancient Chinese pharmacopeia. It has been used for more than thousands of years in various suboptimal health statuses and diseases induced by chronic stress based on empirical therapy. Recent studies confirm the role of CSF in the development of many diseases, including depression, stress-induced hepatic injury and tumors. However, little has been known about the mechanisms behind the health effects of CSF. Here, we investigate the influence of CSF on the modulation of the simulated colonic microbiota of five healthy donors, gut barrier integrity, and intestinal immunity by combining the simulator of the human intestinal microbial ecosystem (SHIME®) technology platform with co-culture of intestinal and immune cells. This approach revealed that CSF stimulated the production of SCFA (acetate, propionate and butyrate) across donors while significantly lowering the production of branched SCFA (bSCFA). In terms of community composition, CSF stimulated a broad spectrum of health-related Bifidobacterium species, which are potent acetate and lactate producers. At the same time, it lowered the abundance of opportunistic pathogenic Escherichia coli. Later, we explore the effect of colonic fermentation of CSF on the gut barrier and intestinal immunity in the Caco-2/THP1-blue™ cell co-culture model. Based on the study using SHIME technology platform, CSF showed protective effects on inflammation-induced intestinal epithelial barrier disruption in all donors. Also, the treatment of CSF showed pronounced anti-inflammatory properties by strongly inducing anti-inflammatory cytokines IL-6 and IL-10 and reducing pro-inflammatory cytokine TNF-α. These findings demonstrate a significant modulatory effect of CSF on intestinal gut microbiota. CSF-microbial fermentation products improved the gut barrier and controlled intestinal inflammation.

Traditional Chinese Medicines as Effective Reversals of Epithelial-Mesenchymal Transition Induced-Metastasis of Colorectal Cancer: Molecular Targets and Mechanisms.

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Distant metastasis is the major cause of cancer-related mortality in patients with CRC. Epithelial-mesenchymal transition (EMT) is a critical process triggered during tumor metastasis, which is also the main impetus and the essential access within this duration. Therefore, targeting EMT-related molecular pathways has been considered a novel strategy to explore effective therapeutic agents against metastatic CRC. Traditional Chinese medicines (TCMs) with unique properties multi-target and multi-link that exert their therapeutic efficacies holistically, which could inhibit the invasion and metastasis ability of CRC cells via inhibiting the EMT process by down-regulating transforming growth factor-ß (TGF-ß)/Smads, PI3K/Akt, NF-κB, Wnt/ß-catenin, and Notch signaling pathways. The objective of this review is to summarize and assess the anti-metastatic effect of TCM-originated bioactive compounds and Chinese medicine formulas by mediating EMT-associated signaling pathways in CRC therapy, providing a foundation for further research on the exact mechanisms of action through which TCMs affect EMT transform in CRC.

Health risk assessment of 42 pesticide residues in Tieguanyin tea from Fujian, China.

The objective of this study was to evaluate the residues of 42 pesticides subject to public concern in Tieguanyin tea produced in Fujian, China. The presence of 42 pesticide residues in 90 Tieguanyin tea samples were determined. A total of 17 pesticides were detected. At least one pesticide residue was detected in 65 samples (72.2%). The detected pesticides imidacloprid, tolfenpyrad, bifenthrin, acetamiprid were found in 55.6%, 33.3%, 18.9% and 16.7% of samples, respectively. Pesticide residues in Tieguanyin tea varied significantly over the seasons and across the production regions. Based on data obtained, the health risks associated with long-term exposure to those pesticides were assessed and risks of detected pesticides were ranked. The hazard quotients (HQs) among the detected pesticides range from 5 × 10-8 for fenpropathrin to 3 × 10-4 for imidacloprid. The results demonstrated that despite a high occurrence of pesticide residues in Tieguanyin tea, residue levels observed could not be considered as a serious public health problem. The risk ranking scheme showed dicofol and thiacloprid were considered to pose a medium-risk. The suggestions for 17 detected pesticides used in Tieguanyin tea plantation were made, including those already banned from use in China (dicofol and methomyl), recommended for diminished use (thiacloprid and chlorpyrifos), and permitted use with considering the pre-harvest interval (13 other pesticides).

Perchlorate contamination of tea leaves and a corresponding probabilistic dietary risk assessment using Monte Carlo simulation.

Perchlorate is known as a thyroid disrupter. Its contamination in various tea samples was monitored, and 286 samples belonging to four types of tea leaves were analysed. The detection rate of perchlorate in tea was 99.3%. The mean concentration in different tea types decreased in order from green tea, oolong tea, white tea to black tea. A probabilistic approach was performed to evaluate the dietary exposure of perchlorate for six different subpopulations. The daily intakes (EDIs) for consumers over the age of 41 were higher than that of other subpopulations. The hazard quotient for six groups was lower than 1 even at the extreme percentile (P99). It indicates that the risk of dietary exposure to perchlorate from tea consumption for Fujian people is acceptable without considering other foodstuffs. However, the high occurrence of perchlorate in tea samples suggested that the actual source of this contaminant should be further investigated.

Occurrence of pesticides in white tea and a corresponding risk exposure assessment for the different residents in Fujian, China.

White tea has been of increasing public interest worldwide owing to its health benefits. Based on 2 years of surveillance, the long-term and cumulative chronic exposure risks of pesticide residues through white tea drinking were assessed for different subpopulations in Fujian, China. Twenty-five different pesticides were found, and 74.8% of samples contained at least one pesticide residue. The most frequently detected pesticide was bifenthrin with detection rates of 61.6%. Risk assessment was performed using both the deterministic approach and semiprobabilistic model under the best-case and the worst-case scenarios. The results demonstrated that the dietary risks were extremely low for six different subpopulations in which the risks for adults over the age of 41 were relatively higher. The risk ranking scheme indicated that isocarbophos and triazophos were considered to be of medium risk. The different use suggestions for the 25 positive pesticides are proposed to further minimize the exposure risk to consumer health. PRACTICAL APPLICATION: Tea is the second most popular nonalcoholic beverage throughout the world. Pesticides are used to improve the yield of tea. Pesticide residues in tea could be one of the exposure pathways for consumers. Monitoring residual levels and assessing the health risk assessment in tea are thus in an urge.

[Curcumin mediates IL-6/STAT3 signaling pathway to repair intestinal mucosal injury induced by 5-FU chemotherapy for colon cancer].

This study aims to investigate the potential mechanism of curcumin in mediating interleukin-6(IL-6)/signal transducer and activator of transcription 3(STAT3) signaling pathway to repair intestinal mucosal injury induced by 5-fluorouracil(5-FU) chemotherapy for colon cancer. SD rats were intraperitoneally injected with 60 mg·kg~(-1)·d~(-1) 5-FU for 4 days to establish a model of intestinal mucosal injury. Then the rats were randomly divided into model group(equal volume of normal saline), curcumin low, medium and high dose groups(50, 100, 200 mg·kg~(-1)), and normal SD rats were used as control group(equal volume of normal saline). Each group received gavage administration for 4 consecutive days, and the changes of body weight and feces were recorded every day. After administration, blood was collected from the heart, and jejunum tissues were collected. The levels of serum interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) were detected by ELISA, and at the same time, the concentration of Evans blue(EB) in jejunum was measured. Hematoxylin-eosin(HE) staining was used to observe the pathological state of jejunum, and the length of jejunum villi and the depth of crypt were measured. The positive expression levels of claudin, occludin and ZO-1 were detected by immunohistochemistry. Western blot was used to detect the protein expression of IL-6, p-STAT3, E-cadherin, vimentin and N-cadherin in jejunum tissues. The results showed that, curcumin significantly increased body weight and fecal weight(P<0.05 or P<0.01), decreased fecal score, EB concentration, IL-1ß and TNF-α levels(P<0.05 or P<0.01) in rats. In addition, curcumin maintained the integrity of mucosal surface and villi structure of jejunum to a large extent, and reduced pathological changes in a dose-dependent manner. Meanwhile, curcumin could increase the positive expression of occludin, claudin and ZO-1(P<0.05 or P<0.01), repair intestinal barrier function, downregulate the protein expression of IL-6, p-STAT3, vimentin and N-cadherin in jejunum tissues(P<0.05 or P<0.01), and upregulate the protein expression of E-cadherin(P<0.05). Therefore, curcumin could repair the intestinal mucosal injury induced by 5-FU chemotherapy for colon cancer, and the mechanism may be related to the inhibition of IL-6/STAT3 signal and the inhibition of epithelial-mesenchymal transition(EMT) process.

Prevention of oxaliplatin-related neurotoxicity by ω-3 PUFAs: A double-blind randomized study of patients receiving oxaliplatin combined with capecitabine for colon cancer.

BACKGROUND: Peripheral neurotoxicity (PN) is a frequent side effect of oxaliplatin treatment, and also is its dose-limiting toxicity. Studies have confirmed that ω-3 polyunsaturated fatty acids (ω-3 PUFAs) had a neuroprotective effect. However, the efficacy of ω-3 PUFAs on the prevention of oxaliplatin-related neurotoxicity remains unclear. We assessed the effect of ω-3 PUFAs on the neurotoxicity in colon cancer patients treated by oxaliplatin combined with capecitabine. METHODS: In a randomized, double-blind, placebo-controlled study, 179 patients with colon cancer receiving oxaliplatin combined with capecitabine were recruited, and randomly assigned to take ω-3 PUFAs, 640 mg t.i.d during chemotherapy and 1 month after the end of the treatment or placebo. All patients were treated with chemotherapy for 6 treatment cycles. The incidence and severity of PN were evaluated, and the nerve conduction was measured before the onset of chemotherapy and 1 month after treatment. In addition, the quality of life was also accessed using Chinese version of European organization for research and treatment of cancer quality of life questionnaire. RESULTS: The incidence of PN in the ω-3 PUFAs group and placebo group was 52.22% and 69.66%, respectively (P = .017). In addition, there was a significant difference in the severity of PN between the 2 groups (P = .017). In terms of motor and sensory nerve conduction, the sensory action potentials amplitude of sural nerve in the ω-3 PUFAs group and placebo group after chemotherapy treatment were (15.01 ±â€Š3.14) and (13.00 ±â€Š3.63) µ V respectively, suggesting there was a significant difference in the 2 groups (P = .000). In addition, the mean score of the global health-status/quality of life was obviously higher in the ω-3 PUFAs group than that in the placebo group. CONCLUSION: ω-3 PUFAs seem to reduce the incidence and severity of oxaliplatin-related neurotoxicity, and improve the quality of patients' life, indicating it is expected to be a potential drug for the treatment of oxaliplatin-related neurotoxicity.

A Holistic View of Berberine Inhibiting Intestinal Carcinogenesis in Conventional Mice Based on Microbiome-Metabolomics Analysis.

Berberine (BBR) has been reported that it has effects on inhibiting colorectal cancer (CRC). However, the mechanism of BBR on CRC also remains largely unknown. Herein, we investigated the therapeutic effects of BBR on CRC from the perspective of gut microbiota and metabolic alterations, which can provide a holistic view to understand the effects of BBR on CRC. First, azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse was used as CRC animal model, then the degree of colorectal carcinogenesis in AOM/DSS mice with or without BBR administration was measured. The composition and abundance of gut microbiota was investigated by using 16S rRNA. Meanwhile, feces samples were analyzed with 1H NMR spectroscopy to investigate the metabolic alterations. As a result, BBR significantly reduced intestinal tumor development with lower macroscopic polyps and ki-67 expression of intestinal tissue, and better colonic morphology in mice. Moreover, BBR altered the composition of gut microbiota in AOM/DSS mice obviously, which were characterized by a decrease of Actinobacteria and Verrucomicrobia significantly at the phylum level. At the genus level, it was able to suppress pathogenic species, such as f_Erysipelotrichaceae, Alistipes, and elevate some short-chain fatty acids (SCFA)-producing bacteria, including Alloprevotella, Flavonifractor, and Oscillibacter. Metabolic data further revealed that BBR induced metabolic changes in feces focus on regulating glycometabolism, SCFA metabolism and amino acid metabolism, which also provides evidence for alteration of the microbiota because these feces metabolites are the products of interactions between the host and the microbial community. This study showed that BBR induced alterations in microbiota and metabolic in AOM/DSS mice, which might providing new insight into the inhibition effects of BBR on CRC.

Curcumin may reverse 5-fluorouracil resistance on colonic cancer cells by regulating TET1-NKD-Wnt signal pathway to inhibit the EMT progress.

BACKGROUND AND PURPOSE: Colorectal cancer is a kind of gastrointestinal tumor with rising morbidity and mortality. 5-fluorouracil is one of the most effective chemotherapy drugs for the treatment of CRC. However, clinical data reported dramatic resistance on the treatment for CRC with 5-fluorouracil. Present study aims to explore the anti-resistant effect of curcumin and its mechanism. METHODS: MTT assay was used to evaluate the proliferation of rHCT-116 cells. Flow cytometry was used to determine the apoptosis and cell cycle of rHCT-116 cells. Western Blot was performed to detect the expression level of TET1, NKD2, E-cadherin, Vimentin, ß-catenin, TCF4 and Axin in transfected rHCT-116 cells. RESULTS: 5-fluorouracil resistant HCT-116 cells were successfully established. Curcumin was found to be effective in the inhibition of proliferation, inducement of apoptosis and block of G0/G1 phase on 5-fluorouracil treated HCT-116 cells. The expression of TET1 and NKD2 was greatly inhibited by high dosage of curcumin. The WNT signal pathway and EMT progress were suppressed in rHCT-116 cells by high dosage of curcumin. The inhibitory effects of curcumin on WNT signal pathway and EMT progress were verified to be consistent with Pax-6, TET1 and NKD2. CONCLUSION: Curcumin might exert anti-resistant effect of 5-FU on HCT-116 cells by regulating the TET1-NKD2-WNT signal pathway to inhibit the EMT progress.

ω-3 polyunsaturated fatty acids inhibit the proliferation of the lung adenocarcinoma cell line A549 in vitro.

ω-3 polyunsaturated fatty acids (n-3 PUFA), in particular the marine-derived forms eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been demonstrated to affect cancer cell replication, the cell cycle and cell death. Epidemiological studies have also suggested diets rich in n-3 PUFA were inversely correlated with the development of cancer. In the present study, we explored the effects of DHA and EPA on the proliferation activity and apoptosis of the human lung adenocarcinoma cell line A549. A methyl thiazolyl tetrazolium (MTT) assay was used to detect cell proliferation, apoptosis was detected by flow cytometry and morphological analysis was determined by fluorescence microscopy and transmission electron microscopy. A549 cells were treated with different doses of DHA (40, 45, 50 and 55 µg/ml) or EPA (45, 50, 55 and 60 µg/ml) for 24, 48 and 72 h. The results demonstrated that DHA and EPA significantly suppressed the proliferation of A549 cells and induced apoptosis of A549 cells in a dose- and time-dependent manner. The apoptotic phenomenon was also confirmed by fluorescence microscopy and transmission electron microscopy. Furthermore, compared with the control, the formation of autophagosomes was clearly enhanced in DHA­ or EPA-treated cells. In conclusion, DHA and EPA inhibited the proliferation of A549 cells and induced cell apoptosis and autophagy, which may provide new safe and effective options for the treatment of lung cancer in the future.