Xianlian Jiedu Decoction alleviates colorectal cancer by regulating metabolic profiles, intestinal microbiota and metabolites.

BACKGROUND: Xianlian Jiedu Decoction (XLJDD) has been used for the treatment of colorectal cancer (CRC) for several decades because of the prominent efficacy of the prescription. Despite the clear clinical efficacy of XLJDD, the anti-CRC mechanism of action is still unclear. PURPOSE: The inhibitory effect and mechanism of XLJDD on CRC were investigated in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice. METHODS: The AOM/DSS-induced mice model was adopted to evaluate the efficacy after administering the different doses of XLJDD. The therapeutic effects of XLJDD in treating AOM/DSS-induced CRC were investigated through histopathology, immunofluorescence and ELISA analysis methods. In addition, metabolomics profile and 16S rRNA analysis were used to explore the effective mechanisms of XLJDD on CRC. RESULTS: The results stated that the XLJDD reduced the number of tumor growth on the inner wall of the colon and the colorectal weight/length ratio, and suppressed the disease activity index (DAI) score, meanwhile XLJDD also increased body weight, colorectal length, and overall survival rate. The treatment of XLJDD also exhibited the ability to lower the level of inflammatory cytokines in serum and reduce the expression levels of ß-catenin, COX-2, and iNOS protein in colorectal tissue. The findings suggested that XLJDD has anti-inflammatory properties and may provide relief for those suffering from inflammation-related conditions. Mechanistically, XLJDD improved gut microbiota dysbiosis and associated metabolic levels of short chain fatty acids (SCFAs), sphingolipid, and glycerophospholipid. This was achieved by reducing the abundance of Turicibacter, Clostridium_sensu_stricto_1, and the levels of sphinganine, LPCs, and PCs. Additionally, XLJDD increased the abundance of Enterorhabdus and Alistipes probiotics, as well as the content of butyric acid and isovaleric acid. CONCLUSION: The data presented in this article demonstrated that XLJDD can effectively inhibit the occurrence of colon inner wall tumors by reducing the level of inflammation and alleviating intestinal microbial flora imbalance and metabolic disorders. It provides a scientific basis for clinical prevention and treatment of CRC.

Arenobufagin enhances T-cell anti-tumor immunity in colorectal cancer by modulating HSP90ß accessibility.

BACKGROUND: Colorectal cancer (CRC) is a significant public health issue, ranking as one of the predominant cancer types globally in terms of incidence. Intriguingly, Arenobufagin (Are), a compound extracted from toad venom, has demonstrated the potential to inhibit tumor growth effectively. PURPOSE: This study aimed to explore Are's molecular targets and unravel its antitumor mechanism in CRC. Specifically, we were interested in its impact on immune checkpoint modulation and correlations with HSP90ß-STAT3-PD-L1 axis activity. METHODS: We investigated the in vivo antitumor effects of Are by constructing a colorectalcancer subcutaneous xenograft mouse model. Subsequently, we employed single-cell multi-omics technology to study the potential mechanism by which Are inhibits CRC. Utilizing target-responsive accessibility profiling (TRAP) technology, we identified heatshock protein 90ß (HSP90ß) as the direct target of Are, and confirmed this through a microscale thermophoresis experiment (MST). Further downstream mechanisms were explored through techniques such as co-immunoprecipitation, Western blotting, qPCR, and immunofluorescence. Concurrently, we arrived at the same research conclusion at the organoid level by co-cultivating with immune cells. RESULTS: We observed that Are inhibits PD-Ll expression in CRC tumor xenografts at low concentrations. Moreover, TRAP revealed that HSP90ß's accessibility significantly decreased upon Are binding. We demonstrated a decrease in the activity of the HSP90ß-STAT3-PD-Ll axis following low-concentration Are treatment in vivo. The PDO analysis showed improved enrichment of lymphocytes, particularly T cells, on the PDOs following Are treatment. CONCLUSION: Contrary to previous research focusing on the direct cytotoxicity of Are towards tumor cells, our findings indicate that it can also inhibit tumor growth at lower concentrations through the modulation of immune checkpoints. This study unveils a novel anti-tumor mechanism of Are and stimulates contemplation on the dose-response relationship of natural products, which is beneficial for the clinical translational application of Are.

Efficacy and safety of Shenbai Granules for recurrent colorectal adenoma: A multicenter randomized controlled trial.

BACKGROUND: Colorectal adenoma is benign glandular tumor of colon, the precursor of colorectal cancer. But no pharmaceutical medication is currently available to treat and prevent adenomas. PURPOSE: To evaluate efficacy of Shenbai Granules, an herbal medicine formula, in reducing the recurrence of adenomas. STUDY DESIGN: This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted by eight hospitals in China. METHODS: Patients who had received complete polypectomy and were diagnosed with adenomas within the recent 6 months were randomly assigned (1:1) to receive either Shenbai granules or placebo twice a day for 6 months. An annual colonoscopy was performed during the 2-year follow-up period. The primary outcome was the proportion of patients with at least one adenoma detected in the modified intention-to-treat (mITT) population during follow-up for 2 years. The secondary outcomes were the proportion of patients with sessile serrated lesions and other specified polypoid lesions. The data were analyzed using logistic regression. RESULTS: Among 400 randomized patients, 336 were included in the mITT population. We found significant differences between treatment and placebo groups in the proportion of patients with at least one recurrent adenoma (42.5 % vs. 58.6 %; OR, 0.47; 95 % CI, 0.29-0.74; p = 0.001) and sessile serrated lesion (1.8 % vs. 8.3 %; OR, 0.20; 95 % CI, 0.06-0.72; p = 0.01). There was no significant difference in the proportion of patients developing polypoid lesions (70.7 % vs. 77.5 %; OR, 1.43; 95 % CI, 0.88-2.34; p = 0.15) or high-risk adenomas (9.0 % vs. 13.6 %; OR, 0.63; 95 % CI, 0.32-1.25; p = 0.18). CONCLUSION: Shenbai Granules significantly reduced the recurrence of adenomas, indicating that they could be an effective option for adenomas. Future studies should investigate its effects in larger patient populations and explore its mechanism of action to provide more comprehensive evidence for the use of Shenbai Granules in adenoma treatment.

Research progress on the biological basis of Traditional Chinese Medicine syndromes of gastrointestinal cancers.

Gastrointestinal cancers account for 11.6 % of all cancers, and are the second most frequently diagnosed type of cancer worldwide. Traditional Chinese medicine (TCM), together with Western medicine or alone, has unique advantages for the prevention and treatment of cancers, including gastrointestinal cancers. Syndrome differentiation and treatment are basic characteristics of the theoretical system of TCM. TCM syndromes are the result of the differentiation of the syndrome and the basis of treatment. Genomics, transcriptomics, proteomics, metabolomics, intestinal microbiota, and serology, generated around the central law, are used to study the biological basis of TCM syndromes in gastrointestinal cancers. This review summarizes current research on the biological basis of TCM syndrome in gastrointestinal cancers and provides useful references for future research on TCM syndrome in gastrointestinal cancers.

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.

The colonic metabolism differences of main alkaloids in normal and colitis mice treated with Coptis chinensis Franch. and Sophora flavescens Ait. herbal pair using liquid chromatography-high resolution mass spectrometry method combined with chemometrics.

Coptis chinensis Franch. and Sophora flavescens Ait. is a herbal pair frequently used in treating ulcerative colitis. However, the bio-disposition profile of the major components in the inflamed gut remains unclear, which is essential to understand the pharmacological material basis of this herb pair. Here we established an integral quantitative and chemometric method to deduce the colonic metabolism differences of this herbal pair in normal and colitis mice. With this LC-MS method, a total of 41 components have been found in the Coptis chinensis Franch. and Sophora flavescens Ait. extract, and 28 metabolites were found in the colon after oral administration. Alkaloid and its phase I metabolites were the main components in the colon of normal and colitis mice. The results of principal component analysis at 6 h after oral administration showed significant colonic metabolism differences between normal and colitis mice. Heamap results showed that colitis induced significant changes in the colonic bio-disposition of this herbal pair extract. In particular, in the context of colitis, the phase I metabolism of berberine, coptisine, jatrorrhizine, palmatine,and epiberberine has been inhibited. These results may provide a basis for understanding the pharmacological material basis of Coptis chinensis Franch. and Sophora flavescens Ait. in treating ulcerative colitis.

α-hederin regulates glucose metabolism in intestinal epithelial cells by increasing SNX10 expression.

BACKGROUND: Sorting nexin 10 (SNX10) has recently been identified as a critical regulator of colorectal carcinogenesis, whose deletion promoted cell proliferation and survival in human CRC cells, and promoted colorectal tumor growth and upregulated amino-acid metabolism in mice. However, what happens when silencing SNX10 in normal human intestinal epithelial cells (IECs) remains unknown, and no drugs targeting SNX10 have been reported. Here, we first investigated the biological function and underlying mechanisms of SNX10 in normal human IECs, and found that α-hederin, a pentacyclic triterpenoid saponin, has a regulatory effect on SNX10 expression. PURPOSE: This study aimed to explore the function of SNX10 in IECs to provide a new target for the prevention and treatment of malignant transformation and the intervention mechanism of α-hederin for further development of potential novel agents targeting SNX10. METHODS: The transfection approach was used to construct SNX10 stable knockdown cells. Cell proliferation was detected by CCK8, clone formation, EdU, flow cytometry, and wound healing assays. Enzyme activity assays for glucose metabolism, qRT-PCR, western blotting, and immunofluorescence staining were performed to investigate the protein expression of signaling pathways. RESULTS: Silencing SNX10 promoted cell proliferation and cycle transition in IECs and increased the activity of key enzymes involved in glucose metabolism. Moreover, DEPDC5 expression was significantly decreased following SNX10 knockdown, followed by activation of the mTORC1 pathway. α-hederin reversed the accelerated cell proliferation, cycle progression, and glucose metabolic activity, as well as the activated mTORC1 pathway caused by SNX10 knockdown, by notably increasing SNX10 expression in a dose-dependent manner. CONCLUSION: We first reported that knockdown of SNX10 in normal human IECs promoted cell proliferation and activated glucose metabolism by activating the mTORC1 pathway. Meanwhile, we first found that α-hederin down-regulated glucose metabolism activity and slowed cell proliferation by increasing SNX10 expression in IECs.

[Guidelines for prevention and treatment of colorectal adenoma with integrated Chinese and western medicine].

The Guidelines for prevention and treatment of colorectal adenoma with integrated Chinese and western medicine are put forward by Nanjing University of Chinese Medicine and approved by China Association of Chinese Medicine. According to the formulation processes and methods of relevant clinical practice guidelines, the experts in clinical medicine and methodology were organized to discuss the key problems to be addressed in the clinical prevention and treatment of colorectal adenoma(CRA) and provided answers following the evidence-based medicine method, so as to provide guidance for clinical decision-making. CRA is the major precancerous disease of colorectal cancer. Although the prevention and treatment with integrated Chinese and western medicine have been applied to the clinical practice of CRA, there is still a lack of high-quality guidelines. Four basic questions, 15 clinical questions, and 10 outcome indicators were determined by literature research and Delphi questionnaire. The relevant randomized controlled trial(RCT) was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, Web of Science, and 2 clinical trial registries, and finally several RCTs meeting the inclusion criteria were included. The data extracted from the RCT was imported into RevMan 5.3 for evidence synthesis, and the evidence was evaluated based on the Grading of Recommendations, Assessment, Development, and Evaluations(GRADE). The final recommendations were formed by the nominal group method based on the evidence summary table. The guidelines involve the diagnosis, screening, treatment with integrated Chinese and western medicine, prevention, and follow-up of colorectal adenoma, providing options for the clinical prevention and treatment of CRA.

Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8 T cells via inhibiting MHC-I degradation.

BACKGROUND: The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus, has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear. METHODS: The antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated. RESULTS: We found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8+ T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8+ T cells in xenograft mice and colorectal cancer organoids. CONCLUSION: Our data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.

Synergistic antitumor effects of compound-composed optimal formula from Aidi injection on hepatocellular carcinoma and colorectal cancer.

BACKGROUND: Traditional Chinese medicine formula (TCMF) possesses unique advantages in the prevention and treatment of malignant tumors such as hepatocellular carcinoma (HCC) and colorectal cancer (CRC). However, the unclear chemical composition and mechanism lead to its unstable efficacy and adverse reactions occurring frequently, especially injection. We previously proposed the research idea and strategy for compound-composed Chinese medicine formula (CCMF). PURPOSE: A demonstration study was performed through screening of the compound-composed optimal formula (COF) from Aidi injection, confirmation of the synergistic effect, and exploration of the related mechanism in the treatment of HCC and CRC. METHOD: The feedback system control (FSC) technique was applied to screening of COF. CCK-8 and calcein-AM/PI assays were performed to evaluate cell proliferation. Cell apoptosis was assessed using flow cytometry and DAPI staining. JC-1 probe and mitochondrial staining were employed to detect mitochondrial membrane potential (MMP) and the release of cytochrome c into cytoplasm, respective. Quantitative proteomics, drug affinity responsive target stability (DARTS) assay, bioinformatics, and molecular docking were carried out to explore the targets of the compounds and the synergistic mechanism involved. RESULTS: COF was obtained from Aidi injection, which comprises cantharidin (CAN): calycosin-7-O-ß-D-glucoside (CAG): ginsenoside Rc: ginsenoside Rd = 1:12:12:8 (molar ratio). The monarch drug CAN in combination with minister medicines consisting of CAG, Rc and Rd (abbr. TD) displayed evidently synergistic effect, which inhibited cell viability, increased dead cell number, induced apoptosis, reduced MMP, promoted cytochrome c leakage of HCC and CRC cells, and suppressed the increases of tumor volume and weight in HCC and CRC bearing nude mice. TD probably antagonized CAN enhanced activity of the ubiquitin proteasome system (UPS) to depress the degradation of cytotoxic proteins through binding to ubiquitin proteasome, thus exerting the synergistic effect with CAN activated protein phosphatase 2A (PP2A) to activate the mitochondrial apoptosis pathway. In addition, the CAN enhanced protein expression of UPS was also observed for the first time. CONCLUSION: CAN and TD exert synergism through activation of PP2A and inhibition of UPS. It makes sense to elucidate the scientific nature of the compatibility theory of TCMF based on CCMF, which will be an important research direction of the modernization of traditional Chinese medicines.

Flavonoids from Scutellaria barbata D. Don exert antitumor activity in colorectal cancer through inhibited autophagy and promoted apoptosis via ATF4/sestrin2 pathway.

PURPOSE: Scutellaria barbata D. Don (SB), mainly containing flavonoids, has been frequently used for cancer treatment. However, little research has investigated the antitumor activity of flavonoids from SB (FSB). The current study aimed to assess the antitumor effect of TFSB and elucidate the probable underlying mechanism in vivo and in vitro. STUDY DESIGN: FSB was prepared, and its chemical composition was characterized by HPLC-MS. Colorectal HCT116 cells were treated with various concentration of FSB. The viability, proliferation, apoptosis, migration, and autophagy of HCT116 cells were studied, as were further confirmed in tumor xenografts. METHODS: Cell viability and proliferation were respectively examined by MTT and EdU staining. ROS was determined with DCFH-DA, and cell apoptosis was detected using flow cytometry. Transwell and wound-healing assays were performed to evaluate cell migration. Immunofluorescence was employed to evaluate sestrin2 and ATF4 level. The protein expressions of p-AMPK, p-ULK1, p-mTOR, 4E-BP1, LC3-I/II, cleaved-caspase-3, Bax, and bcl-2 were investigated by western blot. ATF4 was overexpressed in experiments to explore the role of ATF4/sestrin2 pathway in FSB-mediated efficacy. RESULTS: FSB clearly reduced the cell viability, promoted ROS generation, and induced apoptosis in HCT116 cells by down-regulated Bcl-2, and increased cleaved-caspase-3 and Bax. Furthermore, FSB significantly inhibited migration of colorectal cells in a dose-dependent manner. Further mechanistic study indicated that FSB upregulated p-mTOR protein level, and reduced p-AMPK, p-ULK1, p-mTOR, p-4E-BP1 and LC3-I/II expression, which were major autophagy-related genes. In addition, FSB could cause downregulation of endogenous mTOR inhibitor sestrin2 and ATF4 expression. Transient overexpression of ATF4 resulted in mTOR and sestrin2 inhibition, and significantly compromised the effects of FSB on apoptosis and autophagy in HCT116 cells. CONCLUSION: Our results reveal, for the first time, that FSB exerts antitumor activity through autophagy inhibition and apoptosis induction via ATF4/sestrin2 pathway in colorectal cancer cells. Scutellaria barbata D. Don may have great potential in the application for the prevention and treatment of human colorectal cancer.

Characterization of the chemical constituents and in vivo metabolic profile of Scutellaria barbata D. Don by ultra high performance liquid chromatography with high-resolution mass spectrometry.

Scutellaria barbata D. Don (S. barbata) is one of the most frequently used anticancer herb medicine in China. Mechanistic understanding of the biological activities of S. barbata is hindered by limited knowledge regarding its components and metabolic profile. In this study, ultra-high-performance liquid chromatography coupled with high resolution mass spectrometry (quadrupole time-of-flight mass spectrometry) was used to identify the chemical constituents in S. barbata and their metabolic profiles in rats. By applying cleavage rules and comparison with reference substances, 89 components were identified in S. barbata, which included 45 flavonoids, 28 diterpenoids, 10 phenolics, and 6 others. A total of 110 compounds, including 32 prototype compounds and 78 metabolites, were identified or tentatively characterized in vivo. Methylation, sulfonation, and glucuronidation were the main metabolic pathways, which could be attributed to the fact that several of the compounds in S. barbata have phenolic hydroxyl groups. This is the first systematic study on the chemical constituents and in vivo metabolic profile of S. barbata. The analytical method features a quick and comprehensive dissection of the chemical composition and metabolic profile of S. barbata and provides a basis for exploring its various biological activities.

[Multi-index components of Scutellariae Barbatae Herba according to UHPLC-QTRAP-MS coupled with chemometrics].

The present study developed an ultra-fast liquid chromatography coupled with triple quadrupole-linear ion trap composite mass spectrometry(UHPLC-QTRAP-MS) to simultaneously determine the content of potential active components in Scutellariae Barbatae Herba and also to provide a reference approach for screening out the differential quality control components among different batches of Scutellariae Barbatae Herba. Chromatographic separations were conducted on a Thermo Acclaim~(TM) RSLC 120 C_(18) column(3.0 mm×100 mm, 2.2 µm) in a gradient program. The mobile phase consisted of 0.1% aqueous formic acid and acetonitrile, and the column temperature was maintained at 40 ℃. The flow rate was 0.4 mL·min~(-1) and the injection volume was 2 µL. The targeted compounds were monitored in the multiple reaction monitoring(MRM) mode. The acquired data were processed by hierarchical cluster analysis(HCA) and partial least square discriminant analysis(PLS-DA). Sixteen compounds all showed good linear relationship within the corresponding linear ranges and the R~2 values were all higher than 0.993 2. The RSDs of precision, repeatability, and stability were less than or equal to 3.7%. Mean recovery rates were in the range of 95.67% and 104.8% with RSDs≤3.2%. According to HCA and PLS-DA, all samples were clustered into four categories. Scutellarin, acteoside, scutellarein, and scutebarbatine X(VIP>1) were considered as differential chemical markers in the four categories. In conclusion, the developed method can be used for the simulta-neous determination of the multiple components and quality control of Scutellariae Barbatae Herba.

Compound Taxus chinensis Capsule Combined with Chemotherapy for Non-Small-Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Compound Taxus chinensis capsule (CTCC), an antitumor Chinese patent medicine, has been commonly prescribed as an adjunctive agent to chemotherapy for the management of non-small-cell lung cancer (NSCLC); however, the effects of CTCC added to chemotherapy for NSCLC patients have never been comprehensively evaluated or summarized. PURPOSE: To assess the synergistic effects of CTCC and chemotherapy on NSCLC. Study Design. Evidence-based study, systematic review, and quantitative meta-analysis. METHODS: This systematic review and meta-analysis was implemented in accordance with the PRISMA (Preferred Reported Items for Systematic Review and Meta-Analysis) guidelines. Eight databases including China National Knowledge Infrastructure, SINOMED, China Biomedical Literature Database, Wanfang Database, VIP, PubMed, Cochrane Library, and EMBASE were searched for relevant RCTs from their inception until May 24, 2021, and hand-searching was also carried out to identify additional studies. All randomized controlled trials (RCTs) that compared CTCC combined with chemotherapy versus chemotherapy alone were included in our study. The Cochrane Risk-of-Bias tool was used to determine the risk of bias and methodological quality of the included RCTs. Review Manager 5.3 software was used for comprehensive analysis. The primary outcome measure for this study was the disease control rate (DCR), and the secondary outcomes included the objective response rate (ORR), adverse reactions, and quality of life (QOL). RESULTS: Six RCTs with a total sample size of 410 were finally included. The pooled data showed that, compared with chemotherapy alone, CTCC combined with chemotherapy significantly improved DCR (RR = 1.15, 95% CI: 1.06-1.25, P = 0.006), ORR (RR = 1.38, 95% CI: 1.18-1.63, P < 0.00001), and QOL (MD = 8.69, 95% CI: 7.26-10.13, P < 0.006) and reduced the incidence of total adverse reactions (RR = 0.48, 95% CI: 0.38-0.60, P < 0.00001). The subgroup analyses indicated that CTCC plus chemotherapy significantly improved gastrointestinal reactions (P = 0.004), leukopenia (P = 0.0009), thrombocytopenia (P = 0.01), rash (P = 0.002), and fever (P = 0.007). CONCLUSION: Based on the available evidence, compared with chemotherapy alone, CTCC used as an adjunctive agent to chemotherapy for NSCLC can improve the clinical efficacy and quality of life and decrease the likelihood of adverse reactions, suggesting that CTCC might be an effective and safe adjunctive medicine to chemotherapy for NSCLC. However, considering the relatively small sample size and the inherent imperfections of the included randomized controlled trials, more high-quality clinical trials with longer follow-up time are needed to further assess the efficacy and safety of this combined treatment regimen.

Arsenene Nanodots with Selective Killing Effects and their Low-Dose Combination with ß-Elemene for Cancer Therapy.

Arsenical drugs have achieved hallmark success in treating patients with acute promyelocytic leukemia, but expanding their clinical utility to solid tumors has proven difficult with the contradiction between the therapeutic efficacy and the systemic toxicity. Here, leveraging efforts from materials science, biocompatible PEGylated arsenene nanodots (AsNDs@PEG) with high monoelemental arsenic purity that can selectively and effectively treat solid tumors are synthesized. The intrinsic selective killing effect of AsNDs@PEG is closely related to high oxidative stress in tumor cells, which leads to an activated valence-change of arsenic (from less toxic As0 to severely toxic oxidation states), followed by decreased superoxide dismutase activity and massive reactive oxygen species (ROS) production. These effects occur selectively within cancer cells, causing mitochondrial damage, cell-cycle arrest, and DNA damage. Moreover, AsNDs@PEG when applied in a multi-drug combination strategy with ß-elemene, a plant-derived anticancer drug, achieves synergistic antitumor outcomes, and its newly discovered on-demand photothermal properties facilitate the elimination of the tumors without recurrence, potentially further expanding its clinical utility. In line of the practicability for a large-scale fabrication and negligible systemic toxicity of AsNDs@PEG (even at high doses and with repetitive administration), a new-concept arsenical drug with high therapeutic efficacy for selective solid tumor therapy is provided.

Study on efficacy and safety of Huangqi Guizhi Wuwu decoction treatment for oxaliplatin induced peripheral neurotoxicity: A protocol for a randomized, controlled, double-blind, multicenter trial.

BACKGROUND: Oxaliplatin can cause severe peripheral neurotoxicity, which is an important reason for clinical oxaliplatin reduction and cessation of treatment. Oxaliplatin induced peripheral neurotoxicity (OIPN) can cause paresthesia and dysesthesia, even affect the quality life of patients. So far, there are no recognized and effective measures to prevent OIPN. Huangqi Guizhi Wuwu decoction is a classical prescription of ancient Chinese medicine recorded in "the synopsis of the Golden Chamber," which can be used in the treatment of various neurotoxicity. However, there is a lack of large-scale and high-quality clinical studies on the prevention of OIPN by Huangqi Guizhi Wuwu decoction. The purpose of this study is to evaluate the efficacy and safety of Huangqi Guizhi Wuwu decoction on preventing OIPN. METHODS/DESIGN: This study is a randomized, controlled, double-blind, and multicenter clinical trial. Three hundred sixty patients will be randomly assigned into Huangqi Guizhi Wuwu decoction group and Huangqi Guizhi Wuwu decoction mimetic agent group. Patients will receive chemotherapy with FOLFOX of 8 cycles of 3 weeks with Traditional Chinese Medicine (TCM) for 6 months and 1-year follow-up. The primary outcome measure is the differences in the incidence of chronic neurotoxicity of grade 2 and above during and after treatment. The secondary outcome measure is the improvement in other symptoms associated with chemotherapy. Four methods will be used to evaluate the efficacy of neurotoxicity, including oxaliplatin specific toxicity grading standard (Levi classification); CTCAE4.02 version; EORTC QLQ-CIPN20 scale, EORTC QLQ C30 scale, and EORTC QLQ-CR29 scale are used at the same time; Electromyography. DISCUSSION: This study will provide objective evidences to evaluate the efficacy and safety of Huangqi Guizhi Wuwu Decoction on preventing OIPN. TRIAL REGISTRATION: Clinical Trials.gov (Identifier: NCT04261920).

Identification of the absorbed components and metabolites of Xiao-Ai-Jie-Du decoction and their distribution in rats using ultra high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

Xiao-Ai-Jie-Du decoction (XAJDD), a traditional Chinese medicine formula, has long been used for the treatment of hepatocarcinoma, gastric cancer and colorectal cancer. It is composed of six herbal medicines, including Scutellariae Barbatae Herba, Pseudostellariae Radix, Ophiopogonis Radix, Cremastrae Pseudobulbus, Curcumae Rhizoma and Akebiae Fructus. Despite the in-depth study on its pharmacological effects on cancer prevention and treatment, the comprehensive analysis of the chemical components and the absorbed bioactive constituents are not well studied. Thus, an ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was established to detect and identify the chemical constituents in XAJDD. The absorbed components and metabolites after oral administration of XAJDD in rats were also studied. In total, 102 components were identified or tentatively characterized in XAJDD, including 30 flavonoids, 19 triterpenoids, 12 organic acids, 9 steroidal saponins, 9 cyclic peptides, 7 phenanthrenes, 5 amino acids, 3 alkaloids and 8 other compounds. After analysing the metabolites in rat plasma and urine after oral administration of XAJDD, a total of 70 compounds were identified, including 15 primary components and 55 metabolites, and metabolic pathways, including hydrogenation, hydroxylation, methylation, sulfonation, and glucuronidation were evaluated. Among these, methylation and glucuronidation were the main metabolic pathways. In conclusion, the developed UHPLC-Q-TOF-MS method with high sensitivity and resolution is suitable for identifying and characterizing the chemical constituents of XAJDD in vitro and characterizing the primary components and their metabolites in vivo; moreover, the results will provide essential data for further studying the relationship between the chemical components and pharmacological activity of XAJDD.

Traditional Chinese medicine (Xiaoai Jiedu Decoction) as an adjuvant treatment for prevention new colorectal adenomatous polyp occurrence in post-polypectomy: Study protocol for a randomized controlled trial.

BACKGROUND: Colorectal Adenomatous Polyp (CAP) was one precursor of colorectal cancer (CRC) and having a high chance of developing into CRC. There was a lack of conclusive chemoprevention evidences to prevention new CAP occurrence in post-polypectomy. Xiaoai Jiedu Decoction, Chinese National Medical Professor (Zhou Zhongying)'s experience formula, has been used to treat new CAP occurrence in post-polypectomy from the 20th century in China. However, clinical research of Xiaoai Jiedu Decoction in the treatment of CAP recurrence was lack. We design this study to evaluate the efficacy and safety of Xiaoai Jiedu Decoction in the treatment of new CAP occurrence in post-polypectomy on colonoscopy. METHODS/DESIGN: A randomized, controlled, blind and multicenter trial to evaluate the efficacy and safety of Xiaoai Jiedu Decoction is proposed. CAP patients (after complete polypectomy under colonoscopy) will be randomly assigned into Xiaoai Jiedu Decoction group and Xiaoai Jiedu Decoction mimetic agent group. Patients will receive 6-course treatments and a 2-year follow-up. Follow-up colonoscopy will be anticipated to perform in 1 and 2 years after the baseline examinations. The primary outcome measure is the new CAP occurrence in 1 and 2 years. The secondary outcome measure is the occurrence of advanced adenoma in 1 and 2 years. DISCUSSION: This study will provide objective evidences to evaluate the efficacy and safety of Xiaoai Jiedu Decoction as an adjuvant treatment for new CAP occurrence in post-polypectomy. TRIAL REGISTRATION: NCT03616444.

2-Hydroxy-3-methylanthraquinone inhibits lung carcinoma cells through modulation of IL-6-induced JAK2/STAT3 pathway.

BACKGROUND: 2-hydroxy-3-methylanthraquinone (HMA), an anthraquinone monomer in traditional Chinese medicine Hedyotis diffusa, has been reported to inhibit the growth of several types of cancer, but its effect on lung cancer has not been adequately investigated. HYPOTHESIS/PURPOSE: This study aimed to test the hypothesis that HMA inhibit the growth, migration, and invasion of lung cancer cells in part via downregulation of interleukin (IL)-6-induced JAK2/STAT3 pathway. METHODS: Growth and apoptosis of lung cancer cells were quantitated by CCK-8 assay and Annexin V-FITC/PI flow cytometric analysis, respectively. Migration and invasion of A549 cells were determined by wound-healing assay and transwell invasion assay, respectively. The effect of HMA on cytokines expression in A549 cells was evaluated by the cytokine antibody array assay. Gene expression and protein levels of related molecular markers were quantitated by real time-PCR and Western blot analysis, respectively. RESULTS: HMA significantly inhibited IL-6-stimulated growth and colony formation of A549 cells, increased the number of apoptotic cells, and inhibited invasion associated with downregulation of expression of IL-6-induced MMP-1, MMP-2, and MMP-9 genes. IL-6 increased the levels of tyrosine phosphorylation of JAK2 and STAT3 in A549 cells, which was reversed by HMA treatment. In addition, HMA reduced the expression of a series of inflammation-related cytokines in A549 cells supernatant, including IL-6, G-CSF, IL-6R, IL-8, MCP-1, RANTES, TNF-α. CONCLUSION: These results suggest that HMA may inhibit the growth and invasion of lung cancer cells in part via downregulation of IL-6-induced JAK2/STAT3 pathway.

Traditional Chinese medicine as targeted treatment for epithelial-mesenchymal transition-induced cancer progression.

The epithelial-mesenchymal transition (EMT) program, which loosens cell-cell adhesion complexes, endows cells with enhanced migratory and invasive properties. Furthermore, this process facilitates both the development of drug resistance and immunosuppression by tumor cells, which preclude the successful treatment of cancer. Recent research has demonstrated that many signaling pathways are involved in EMT progression. In addition, cancer stem cells (CSCs), vasculogenic mimicry (VM) and the tumor-related immune microenvironment all play important roles in tumor formation. However, there are few reports on the relationships between EMT and these factors. In addition, in recent years, traditional Chinese medicine (TCM) has developed a unique system for treating cancer. In this review, we summarize the crucial signaling pathways associated with the EMT process in cancer patients and discuss the interconnections between EMT and other molecular factors (such as CSCs, VM, and the tumor-related immune microenvironment). We attempt to identify common regulators that might be potential therapeutic targets to thereby optimize tumor treatment. In addition, we outline recent research on TCM approaches that target EMT and thereby provide a foundation for further research on the exact mechanisms by which TCMs affect EMT in cancer.