Xiaotan Sanjie decoction normalizes tumor permissive microenvironment in gastric cancer (Review).

Gastric cancer (GC) develops in a complex tissue environment, the tumor microenvironment (TME), which it relies on for persistent proliferation, migration, invasion and metastasis. Non­malignant stromal cell types within the TME are regarded as a clinical meaningful target with the lower risk of resistance and tumor relapse. Studies have revealed that the Xiaotan Sanjie decoction, which is formulated on the basis of the theory of phlegm syndrome, a Traditional Chinese Medicine concept, modulates released factors such as transforming growth factor­ß from tumor cells, immune cells, cancer­associated fibroblasts, extracellular matrix, as well as vascular endothelial growth factor involved in the process of angiogenesis within the TME. Clinical studies have also shown that the Xiaotan Sanjie decoction is associated with favorable survival and quality of life. The present review aimed to interpret the hypothesis that Xiaotan Sanjie decoction has the ability to normalize the GC tumor cells by influencing functions of stromal cells within the TME. The possible association between phlegm syndrome and the TME in GC was discussed in the present review. Overall, Xiaotan Sanjie decoction may be suitable to be added to tumor cell­directed agents or emerging immunotherapies becoming a desirable modality in the management of GC and acquire improved outcomes for patients with GC.

Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties - An overview.

ETHONOPHARMACOLOGICAL RELEVANCE: Cancer is considered to be the second leading cause of human death. It is unsatisfactory that in the past decades, the treatment for cancer has not progressed as fast as it was expected, as only 50% of newly diagnosed patients could be cured even today. The development of cancer is a multifactorial process, involving tumor cells themselves, the interactions between tumor cells and their microenvironments, as well as the interactions between tumor cells and the host's immunity. Focusing on any single goal may bring limited benefits. AIM AND METHODS OF THE STUDY: Phlegm-eliminating herbs, which can reduce phlegm and eliminate pathological metabolites, are commonly used to treat cancer in China. However, the underlying molecular targets and efficacy of herbal medicines in cancer treatment still remain unclear. In this study, we reviewed the potential anticancer mechanisms of some phlegm-eliminating herbs and their active ingredients from the articles through such scientific databases as MEDLINE, PubMed, and Google Scholar. RESULTS: We found that the anticancer mechanisms of phlegm-eliminating herbs and ingredients include inducing apoptosis, anti-proliferation, preventing tumor invasion and metastasis, and reducing resistance to chemotherapy. In addition, some phlegm-eliminating herbs and their ingredients have anti-inflammatory and anti-metabolic syndrome effects. CONCLUSIONS: We suggest that the phlegm-eliminating herbs and ingredients are potential candidates for anticancer treatment and cancer prevention by playing a comprehensive role.

Xiaotan Sanjie decoction inhibits interleukin-8-induced metastatic potency in gastric cancer.

AIM: To investigate the interaction between Xiaotan Sanjie (XTSJ) decoction and interleukin-8 (IL-8) and its effect on adhesion, migration and invasion of SGC-7901 gastric cancer cells. METHODS: SGC-7901 gastric cancer cells were exposed to serum containing XTSJ decoction and/or IL-8 (1 ng/mL). SGC-7901 cell adhesion to fibronectin, an extracellular matrix component, was detected using the Cell Counting Kit-8. Migration and invasion abilities of SGC-7901 cells were detected by scratch wound and Transwell chamber assays. Then, protein (immunofluorescence and Western blot) and mRNA levels (quantitative polymerase chain reaction) of cluster of differentiation 44 (CD44), a cell adhesion molecule, were measured in 72-h-cultured SGC-7901 cells. RESULTS: Cell adhesion was promoted by IL-8 (P = 0.001), but was inhibited by XTSJ decoction (P = 0.0001). Similarly, IL-8 promoted SGC-7901 cell invasion (P = 0.003), and XTSJ decoction inhibited cell invasion (P = 0.001). IL-8 induced SGC-7901 cell migration, but this was inhibited by XTSJ decoction. IL-8 up-regulated CD44 protein (P = 0.028) and mRNA expression (P = 0.002), whereas XTSJ decoction inhibited CD44 protein expression (P = 0.0001), but not mRNA expression (P = 0.275). An interaction between XTSJ decoction and IL-8 was confirmed in the invasion (P = 0.001) and CD44 mRNA expression of SGC-7901 cells (P = 0.010), but not in cell adhesion (P = 0.051). CONCLUSION: XTSJ decoction may inhibit adhesion, migration and invasion of gastric cancer cells, which is partly associated with down-regulation of IL-8.

Therapeutic effect of Jinlongshe Granule () on quality of life of stage IV gastric cancer patients using EORTC QLQ-C30: A double-blind placebo-controlled clinical trial.

OBJECTIVE: To evaluate the impact of Jinlongshe Granule (, JLSG) on quality of life (QOL) of stage IV gastric cancer patients. METHODS: This randomized, double-blind and placebo-controlled clinical trial included 50 patients with advanced gastric cancer. They were equally randomized into a JLSG group and a placebo group. Patients in both groups received routine Chinese herbal decoctions according to Chinese medicine (CM) treatment based on syndrome differentiation. Patients in JLSG group received additional JLSG, and those in the placebo group received an additional placebo. In the JLSG group, 19 patients who completed the study were used for analysis. In the placebo group, finally the data of 20 patients who completed the study were used for analysis. The treatment course was at least 3 months, and the follow-up duration was at least 6 months in 5 interviews. Repeated measurements of the subscale items and individual items in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30) obtained at the 5 interviews were compared using different patient groups, changes over time and changes within one group over time independently to observe the tendency of changes in the scores. RESULTS: Using time as the variant, there was signifificant difference in 4 functional scales (physical, role, emotional and social, P<0.05), 3 symptom scales (fatigue, nausea and vomiting and pain,P<0.05) and a global health status/QOL scale (P<0.05) and 6 single symptoms dyspnoea (P>0.05), insomnia (P<0.05), appetite loss (P<0.05), constipation (P<0.05), diarrhea (P>0.05) and financial difficulties (P<0.05). There was also signifificant difference in these items between the two groups when the placebo group and group over time were used as variants (P<0.05 or P<0.01). CONCLUSION: Additional use of JLSG on the basis of routine CM treatment could improve the somatic function, role function, emotional function, social function, cognitive function and general QOL of patients with advanced gastric cancer, and relieve the symptoms of fatigue, nausea and vomiting, pain, loss of appetite and constipation.

Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1-regulated proliferation of gastric cancer stem-like cells.

AIM: To determine the underlying mechanisms of action and influence of Xiaotan Sanjie (XTSJ) decoction on gastric cancer stem-like cells (GCSCs). METHODS: The gastric cancer cell line MKN-45 line was selected and sorted by FACS using the cancer stem cell marker CD44; the stemness of these cells was checked in our previous study. In an in vitro study, the expression of Notch-1, Hes1, Vascular endothelial growth factor (VEGF), and Ki-67 in both CD44-positive gastric cancer stem-like cells (GCSCs) and CD44-negative cells was measured by Western blot. The effect of XTSJ serum on cell viability and on the above markers was measured by MTT assay and Western blot, respectively. In an in vivo study, the ability to induce angiogenesis and maintenance of GCSCs in CD44-positive-MKN-45- and CD44-negative-engrafted mice were detected by immunohistochemical staining using markers for CD34 and CD44, respectively. The role of XTSJ decoction in regulating the expression of Notch-1, Hes1, VEGF and Ki-67 was measured by Western blot and real-time polymerase chain reaction. RESULTS: CD44(+) GCSCs showed more cell proliferation and VEGF secretion than CD44-negative cells in vitro, which were accompanied by the high expression of Notch-1 and Hes1 and positively associated with tumor growth (GCSCs vs CD44-negative cells, 2.72 ± 0.25 vs 1.46 ± 0.16, P < 0.05) and microvessel density (MVD) (GCSCs vs CD44-negative cells, 8.15 ± 0.42 vs 3.83 ± 0.49, P < 0.001) in vivo. XTSJ decoction inhibited the viability of both cell types in a dose-dependent manner in vitro. Specifically, a significant difference in the medium- (82.87% ± 6.53%) and high-dose XTSJ groups (77.43% ± 7.34%) was detected at 24 h in the CD44(+) GCSCs group compared with the saline group (95.42% ± 5.76%) and the low-dose XTSJ group (90.74% ± 6.57%) (P < 0.05). However, the efficacy of XTSJ decoction was reduced in the CD44(-) groups; significant differences were only detected in the high-dose XTSJ group at 48 h (78.57% ± 6.94%) and 72 h (72.12% ± 7.68%) when compared with the other CD44- groups (P < 0.05). Notably, these differences were highly consistent with the Notch-1, Hes1, VEGF and Ki-67 expression in these cells. Similarly, in vivo, XTSJ decoction inhibited tumor growth in a dose-dependent manner. A significant difference was observed in the medium- (1.76 ± 0.15) and high-dose XTSJ (1.33 ± 0.081) groups compared with the GCSCs control group (2.72 ± 0.25) and the low-dose XTSJ group (2.51 ± 0.25) (P < 0.05). We also detected a remarkable decrease of MVD in the medium- (7.10 ± 0.60) and high-dose XTSJ (5.99 ± 0.47) groups compared with the GCSC control group (8.15 ± 0.42) and the low-dose XTSJ group (8.14 ± 0.46) (P < 0.05). Additionally, CD44 expression was decreased in these groups [medium- (4.43 ± 0.45) and high-dose XTSJ groups (3.56 ± 0.31) vs the GCSC control (5.96 ± 0.46) and low dose XTSJ groups (5.91 ± 0.38)] (P < 0.05). The significant differences in Notch-1, Hes1, VEGF and Ki-67 expression highly mirrored the results of XTSJ decoction in inhibiting tumor growth, MVD and CD44 expression. CONCLUSION: Notch-1 may play an important role in regulating the proliferation of GCSCs; XTSJ decoction could attenuate tumor angiogenesis, at least partially, by inhibiting Notch-1.

[Inhibitory effect of Xiaotan Sanjie Recipe on the microsatellite instability of orthotopic transplantation tumor in MKN-45 human gastric cancer nude mice].

OBJECTIVE: To study the inhibitory effect of Xiaotan Sanjie Recipe (XSR) on the microsatellite instability of orthotopic transplantation tumor in MKN-45 human gastric cancer nude mice. METHODS: The 3rd passage subcutaneous transplantation tumor was taken as the origin of the model by using MKN-45 human gastric cancer cell lines. MKN-45 human gastric cancer nude mouse model was established using OB glue adhesive method. Then 30 nude mice were divided into the model group, the XSR group, and the chemotherapy group. Mice in the XSR group were intragastrically given XSR at the daily dose of 0.4 mL. Mice in the chemotherapy group were intragastrically given Fluorouracil at the daily dose of 0.4 mL. No intervention was given to mice in the model group. After 6 weeks of medication, the tumor weight was measured, and the tumor inhibition rate calculated. The size, the peak height, and the peak area of 5 microsatellite instability sites were detected. RESULTS: The tumor inhibition rate was 40. 84% in the XSR group. The tumor weight was significantly lower in the XSR group than in the model group (P < 0.01), showing no statistical difference when compared with the chemotherapy group (P >0.05). The incidence of high microsatellite instability (MSI-H) in the model group was 70%, and the incidence of low microsatellite instability (MSI-L) was 30%. Microsatellite stable site tended be stable after 6 weeks of XSR treatment. CONCLUSION: XSR showed inhibition on microsatellite instable orthotopic transplantation tumor in MKN-45 human gastric cancer nude mice.

Xiaotan Tongfu granules contribute to the prevention of stress ulcers.

AIM: To investigate the efficacy and potential mechanism of Xiaotan Tongfu granules (XTTF) in stress ulcers. METHODS: One hundred sixty rats were randomly divided into 4 groups (n = 10) as follows: the model group (MP group), the control group (CP group), the ranitidine group (RP group) and the XTTF granule group (XP group). Rats in the MP group received no drugs, rats in the CP group received 0.2 mL of a 0.9% sodium chloride solution via oral gavage, and rats in the RP and XP groups received the same volume of ranitidine (50 mg/kg) or XTTF granule (4.9 g/kg). The cold-restraint stress model was applied to induce stress ulcers after 7 consecutive days of drug administration. Afterwards, rats were sacrificed at 0, 3, 6 and 24 h. Gastric pH was measured by a precise pH meter; gastric emptying rate (GER) was measured by using a methylcellulose test meal; myeloperoxidase activity (MPO), macrophage migration inhibitory factor (MIF), proliferating cell nuclear antigen (PCNA), and heat shock protein 70 (HSP70) were measured by immunohistochemical staining; and mucosal cell apoptosis was measured by transferase dUTP nick end labeling. RESULTS: In the cold-restraint stress model, the development of stress ulcers peaked at 3 h and basically regressed after 24 h. Gastric lesions were significantly different in the RP and XP groups at each time point. Interestingly, although this index was much lower in the RP group than in the XP group immediately following stress induction (7.00 ± 1.10 vs 10.00 ± 1.79, P < 0.05. Concerning gastric pH, between the RP and XP groups, we detected a statistically significant difference immediately after stress induction (0 h: 4.56 ± 0.47 vs 3.34 ± 0.28, P < 0.05) but not at any of the subsequent time points. For GER, compared to the RP group, GER was remarkably elevated in the XP group because a statistically significant difference was detected (3 h: 46.84 ± 2.70 vs 61.16 ± 5.12, P < 0.05; 6 h: 60.96 ± 6.71 vs 73.41 ± 6.16, P < 0.05; 24 h: 77.47 ± 3.17 vs 91.31 ± 4.34, P < 0.05). With respect to MPO and MIF, comparisons between the RP and XP groups revealed statistically significant differences at 3 h (MPO: 18.94 ± 1.20 vs 13.51 ± 0.89, P < 0.05; MIF: 150.67 ± 9.85 vs 122.17 ± 5.67, P < 0.05) and 6 h (MPO: 13.22 ± 1.54 vs 8.83 ± 0.65, P < 0.05; MIF: 135.50 ± 9.46 vs 109.83 ± 6.40, P < 0.05). With regard to HSP70, HSP70 expression was significantly increased in the RP and XP groups at 3 and 6 h compared to the MP and CP groups. In addition, comparing the RP and XP groups also showed statistically significant differences at 3 and 6 h. The expression of PCNA was higher in the RP and XP groups 3 h after stress induction. Between these two groups, small but statistically significant differences were observed at all of the time points (3 h: 69.50 ± 21.52 vs 79.33 ± 15.68, P < 0.05; 6 h: 107.83 ± 4.40 vs 121.33 ± 5.71, P < 0.05; 24 h: 125.33 ± 5.65 vs 128.50 ± 14.49, P < 0.05) except 0 h. With regard to apoptosis, the apoptotic activity in the RP and XP groups was significantly different from that in the MP and CP groups. The XP group exhibited a higher inhibition of cell apoptosis than the RP group at 3 h (232.58 ± 24.51 vs 174.46 ± 10.35, P < 0.05) and 6 h (164.74 ± 18.31 vs 117.71 ± 12.08, P < 0.05). CONCLUSION: The Xiaotan Tongfu granule was demonstrated to be similar to ranitidine in preventing stress ulcers. It exhibited multiple underlying mechanisms and deserves further study.

[Professor Wei Pin-kang's experience in treating chemotherapy induced nausea and vomiting: an analysis of herbal medication].

OBJECTIVE: To summarize the herbal medication by Professor WEI Pin-kang's prescriptions in treating chemotherapy induced nausea and vomiting (CINV). METHODS: On the basis of outpatient and inpatients' medical records concerning CINV from case-database (keywords: chemotherapy and vomiting), data of 143 patients and 143 effective prescriptions were collected. The herbs and those category, nature, flavor and meridian distribution were summarized by frequency method using SPSS 13.0 Software. The couple herbs were analyzed by hierarchical cluster analysis. RESULTS: A total of 144 herbs were used (2 353 frequencies). Six groups of herbs [ frequency >5%, cumulative relative frequency (CRF) 58.89%] were used frequently as follow: the herbs for regulating qi (17.81%), resolving phlegm (13.51%), invigorating qi (8.07%), relieving food retention (7.44%), calming Gan to stop endogenous wind (7.05%), and warming the interior (5.01%). The most frequently used herbs ( >20 frequencies, CRF 77.31%) had 31 species as follow: the herbs for regulating qi (6 species), calming Gan to stop endogenous wind (4 species), resolving phlegm (3 species), external application (2 species), invigorating qi (2 species), warming the interior (2 species), activating blood and removing blood stasis (2 species), promoting diuresis and resolving dampness (1 species), purgation (1 species), invigorating blood (1 species), relieving exterior syndrome with pungent-warm property (1 species), relieving exterior syndrome with pungent-cool property (1 species), astringent (1 species), resolving dampness with aromatic property (1 species), calming the mind (1 species), eliminating heat and dampness (1 species), relieving food retention (1 species). Frequency of Rhizoma Pinelliae was 127 including Rhizoma Pinelliae (processed with ginger) 83 (65.35%). Frequency of prepared Radix et Rhizoma Rhei was 85 (95.51% of Prea- praed Rhizoma Rhei). These herbs were mostly of warm nature (43.99%). The total frequency of herb-nature was 3 677 and the pungent (34.76%), bitter (32.06%) and sweet herbs (18.22%) were most frequently used (CRF 85.04%). The total frequency of meridian distribution was 6 627 and these herbs were mostly attributed to Pi, Wei, Gan, and Fei meridians (CRF 71.34%). The most frequently used couple-herbs included Rhizoma Pinelliae and Rhizoma Atisaematis, Fructus Aurantii Immaturus and Submature Bitter Orange, Flos Caryophylli and Calyx Kaki, Rhizoma Coptidis and Os Sepiae, Rumulus Ginnamomi and Radix Paeoniae, Fructus Citri Sarcodactylis and Fructus Citri, aloeswood and toad skin, scorpion and centipede, earth worm and Gekko Swinhoana, bupleurum root and curcumae, fossilia ossis mastodi and oyster, large head atractylodes and poria, and so on. CONCLUSIONS: Professor WEI Pin-kang regarded the therapy of dissolving phlegm and regulating Wei as the fundamental treatment of CINV. He emphasized gastrointestinal metabolic disorders induced by phlegm and stagnation related to chemotherapeutics. He laid equal emphasis on regulating qi, dissolving phlegm, and removing stagnation.

Tumor interstitial fluid and gastric cancer metastasis: an experimental study to verify the hypothesis of "tumor-phlegm microenvironment".

OBJECTIVE: To extract tumor interstitial fluid (TIF) from MKN-45 gastric cancer which is similar to "muddy phlegm" in Chinese medicine and observe influences of MKN-45 tumor interstitial fluid (MKN-45 TIF) intervention on metastasis of gastric cancer and on the expressions of vascular endothelial growth factor (VEGF), kinase insert domain containing receptor (KDR), epithelial-cadherin (E-cad), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1) and telomerase genes and proteins in primary tumor tissue. METHODS: An MKN-45 tumor-bearing model was established in 50 nude mice. The modeled animals were equally randomized to 5 groups: the simple tumor-bearing group (model group), the normal saline (NS) via tail vein injection (i.v.) group (NS i.v. group), MKN-45 TIF i.v. group (TIF i.v. group), NS intraperitoneal injection (i.p.) group (NS i.p. group), and MKN-45 TIF i.p. group (TIF i.p. group). The TIF and NS intervention groups received injection (i.p. or i.v.) of MKN-45 TIF or NS twice a week, 0.2 mL at a time. After 8 weeks, the primary tumors were removed, weighed and HE stained to observe tumor metastasis. The primary tumor tissues were analyzed by immunohistochemistry and real-time quantitative PCR to detect expressions of VEGF, KDR, E-cad, COX-2, ICAM-1, and telomerase genes and proteins in different groups. RESULTS: There were significant differences in tumor weight between TIF intervention groups and the model and NS intervention groups. Tumor metastasis was observed in all 5 groups, but the tumor metastasis rate in TIF intervention groups was significantly higher than those in the model and NS intervention groups. The gene and protein expressions of gastric cancer-related factors VEGF, KDR, COX-2, ICAM-1 and telomerase were unregulated while the gene and protein expressions of E-cad were downregulated in TIF intervention groups. CONCLUSIONS: TIF promotes tumor growth, invasion and metastasis of gastric cancer. These findings provide preliminary experimental clues for verifying the hypothesis of "tumor-phlegm microenvironment".

A chinese herbal formula to improve general psychological status in posttraumatic stress disorder: a randomized placebo-controlled trial on sichuan earthquake survivors.

Introduction. Posttraumatic stress disorder (PTSD) is accompanied by poor general psychological status (GPS). In the present study, we investigated the effects of a Chinese herbal formula on GPS in earthquake survivors with PTSD. Methods. A randomized, double-blind, placebo-controlled trial compared a Chinese herbal formula, Xiao-Tan-Jie-Yu-Fang (XTJYF), to placebo in 2008 Sichuan earthquake survivors with PTSD. Patients were randomized into XTJYF (n = 123) and placebo (n = 122) groups. Baseline-to-end-point score changes in the three global indices of the Symptom Checklist-90-Revised (SCL-90-R) and rates of response in the SCL global severity index (GSI) were the primary endpoints. A subanalysis of the nine SCL factors and the sleep quality score were secondary endpoints. Results and Discussion. Compared to placebo, the XTJYF group was significantly improved in all three SCL global indices (P = 0.001~0.028). More patients in the XTJYF group reported "much improved" than the placebo group (P = 0.001). The XTJYF group performed significantly better than control in five out of nine SCL factors (somatization, obsessive-compulsive behavior, depression, anxiety, and hostility (P = 0.001~0.036)), and in sleep quality score (P < 0.001). XTJYF produced no serious adverse events. These findings suggest that XTJYF may be an effective and safe treatment option for improving GPS in patients with PTSD.

[Eight therapies of resolving phlegm and dispersing nodules in treatment of gastric cancer: experience from Professor Wei Pin-kang].

Professor Wei Pin-kang developed phlegm theory for gastric cancer. He adopted the therapy of resolving phlegm and dispersing nodules as the fundamental therapy for gastric cancer. As the symptoms may vary due to the changes of etiology and pathogenesis at different stages of gastric cancer, he further formulated eight therapies based on the fundamental therapy, namely, resolving phlegm and regulating stomach, resolving phlegm and removing stagnancy, resolving phlegm and clearing heat toxin, resolving phlegm and relieving qi depression, resolving phlegm and dredging collaterals, resolving phlegm and removing blood stasis, resolving phlegm and promoting diuresis, and resolving phlegm to soften abdominal mass. These therapies showed satisfactory effects following the principle of simultaneous treatment of disease and symptoms.

[Effects of ethanol extract of Rhizome Pinelliae Preparata on intracellular pH value of human gastric adenocarcinoma cells].

OBJECTIVE: To observe the effects of ethanol extract of Rhizome Pinelliae Preparata on the intracellular pH value of human gastric cancer SGC7901 cells. METHODS: After coculturing SGC7901 cells with ethanol extract of Rhizome Pinelliae Preparata (1, 0.5, 0.25 and 0.125 mg/mL), cell viability was evaluated by chromatometry with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining. Intracellular pH value of SGC7901 cells was measured in the monolayer by using the pH-sensitive fluorescent probe 2,7-bis-(2-carboxyethyl)-5-carboxyfluorescein-acetoxymethyl ester. The extracellular pH value of culture medium was measured by a pH211 Calibration Check Microprocessor pH Meter. Half-inhibitory concentration (IC(50)) of ethanol extract culture to SGC7901 cells was decided by the MTT method and expressions of vacuolar-H(+)-ATPase (V-ATPase) and Na(+)/H(+) exchanger isoform 1 (NHE1) mRNAs were examined by the method of fluorescence quantitative-polymerase chain reaction after 72 h of drug treatment. RESULTS: Ethanol extract of Rhizome Pinelliae Preparata at different concentrations significantly inhibited the proliferation of SGC7901 cells, lowered the intracellular pH values and heightened the extracellular pH values. The IC(50) of 72 h culture was 0.5mg/mL and it inhibited the expressions of V-ATPase and NHE1 mRNAs. CONCLUSION: Ethanol extract of Rhizome Pinelliae Preparata can lower down the intracellular pH value of SGC7901 cells. The mechanism may be related to inhibiting the expressions of V-ATPase and NHE1 mRNAs.

[The phlegm theory of gastric cancer].

Based on years of ancient literature research and clinical experience, Professor Pin-kang Wei developed the phlegm theory of gastric cancer. In light of the properties of gastric cancer and the method of differentiating syndromes within the traditional Chinese medicine (TCM) paradigm, it is believed that gastric cancer is closely related with phlegm. Much ancient literature regarding the relationship between phlegm and gastric cancer was reviewed to explain the rationale and academic inheritance of the phlegm theory. In this theory, gastric cancer is regarded as a form of phlegm stagnation and consists of phlegm core, phlegm collateral and phlegm contamination. In order to explain the mechanism of development, recurrence and metastasis of gastric cancer, phlegm contamination is regarded as the most fundamental cause and pathogenesis of gastric cancer. The therapy of resolving phlegm and dispersing nodules is suggested for the fundamental treatment of gastric cancer.

[Effects of xiaotan sanjie recipe on vasculogenic mimicry of human gastric cancer xenografts in nude mice].

OBJECTIVE: To study the effect of Xiaotan Sanjie Recipe (XTSJD) and its mechanism on vasculogenic mimicry (VM) of human gastric cancer xenografts in nude mice. METHODS: The tumor-bearing mice model was established by subcutaneous inoculating with xenografts of human gastric cancer into the right armpit of 30 BALB/c nude mice. After modeling, the tumor-bearing mice were randomly divided into the normal saline group, the XTSJD group, and the doxycycline hyclate (DH) group, 10 in each. And the mice were administered with corresponding medicine by gastrogavage for 4 weeks. Then all mice were killed by cervical dislocation. The tumor mass were weighed and the tumor inhibition rate calculated. The amount of VM in tumor was counted. Expressions of matrix metalloproteinase (MMP) -2 and MMP-9 were tested using immunohistochemical method. RESULTS: Tumor weight in the XTSJD group and the OH group decreased significantly when compared with the NS group (P<0.01). The amount of VM in the XTSJD group (24.50+/-3.03) and the OH group (14.70+/-1.34) was significantly less than that in the NS group (33.10+/-2.64) (P<0.01). The positive expressions of MMP-2 and MMP-9 in the XTSJD group and the OH group was significantly lower than that in the NS group (P <0.01). CONCLUSION: XTSJD could inhibit the formation of VM in xenografted tumor of nude mice. The mechanism might be correlated with the down-regulation of MMP-2 and MMP-9 expressions.

[Effect of xiaotan sanjie recipe on expressions of VEGF-C and VEGFR-3 in nude mice with transplanted human gastric adenocarcinoma cell MKN-45].

OBJECTIVE: To observe the mechanism of Xiaotan Sanjie Recipe (XSR) in inhibiting lymphatic metastasis of gastric carcinoma by observing its effects on the expressions of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 in nude mice with transplanted human gastric adenocarcinoma cell MKN-45. METHODS: Thirty mice were made into MKN-45 tumor model and randomly divided into three groups treated with saline, 5-Fu, and XSR, respectively. Gene and protein expressions of VEGF-C and VEGFR-3 in the tumor tissue were detected by RT-PCR, and the lymphatic microvessel density (LMVD) in tumor was measured with immunohistochemistry. RESULTS: Compared with the group treated with saline, the mRNA and protein expressions of VEGF-C and VEGFR-3 as well as LMVD level were significantly lower (P < 0.05 or P < 0.01) in the group treated with XSR. There was no significantly statistic difference between the group of XSR and 5-Fu on the indices mentioned above (P > 0.05). CONCLUSION: By down-regulating the mRNA and protein expressions of VEGF-C and VEGFR-3 might be one of possible mechanisms for XSR in preventing and curing the lymphatic metastasis of gastric carcinoma.

Tumor interstitial fluid and postoperative recurrence of tumors: An experimental study for verifying hypothesis of "tumor-phlegm microenvironment".

OBJECTIVE: To explore a method of extracting tumor interstitial fluid (TIF) which is similar to muddy phlegm in Chinese medicine (CM), interleukin-8 (IL-8) in concentration was taken as the representative of the content of TIF, analyzed in the extracted TIF and the original tumor tissue, and examined to see whether TIF has an interfering effect on tumor recurrence. METHODS: Tumor tissue was ground, centrifuged, and filtered for intercellular substances. Tumor-bearing Kunming S180 mice were raised for 21 days and then the tumors were removed to observe the influence of intervention with TIF, normal saline (NS) and a blank control on tumor recurrence. RESULTS: The content of IL-8 in the filtered and unfiltered tumor tissue was not significantly different (P>0.05). Postoperative tumor recurrence in TIF intervention group was significantly higher than that in the NS intervention and control groups (60%, 12/20 vs. 20%, 4/20. vs. 15%, 3/20, χ(2) =11.058, P<0.01). Tumor cells grew vigorously and infiltrated to muscular tissue in TIF intervention group. Large numbers of tumor cells were seen necrotic in the NS intervention group, and small numbers of tumor cells were seen necrotic in the blank control group. CONCLUSIONS: TIF can be effectively extracted by the means described. It does not contain tumor cells, but its contents such as IL-8 may stimulate tumor cell growth and promote postoperative tumor recurrence, which provided preliminary experimental basis for hypothesis of "tumor-phlegm microenvironment".

[Relationship between expressions of estrogen and progesterone receptors and syndrome types of gastric carcinoma].

OBJECTIVE: To explore the relationship between expressions of estrogen (ER) and progesterone (PR) receptors and syndromes of traditional Chinese medicine (TCM) in gastric carcinoma and to establish prognostic indicators for gastric carcinoma. METHODS: A total of 72 patients with gastric carcinoma were divided into six groups according to TCM syndrome differentiation. Specimens were collected after operation and ER and PR protein expressions were detected by EnVision immunohistochemical method. RESULTS: The common syndromes in female patients with gastric carcinoma were disharmony between liver and stomach, yin impairment due to stomach heat, and insufficiency of both qi and blood; while in males, interior retention of stagnant toxin, interior retention of phlegm and dampness, and deficiency-cold in spleen and stomach were common. Different TCM syndromes were related with gender (P<0.01), pathology (P<0.01), cell differentiation (P<0.05), infiltration depth (P<0.01), lymphaden metastasis (P<0.05), distant metastasis (P<0.05), and TNM stage (P<0.01). Deficiency and excess syndromes were associated with gender (P<0.05), pathology (P<0.05), tumor location (P<0.01) and TNM stage (P<0.05). The deficiency syndromes were common in female patients. The total positive rates of ER and PR expressions were 8.33% and 37.5% respectively. There was a significant difference in PR expression among different TCM syndromes (P<0.01). PR expression was significantly higher in the syndrome of yin deficiency due to stomach heat than in the other syndromes. The PR expressions in deficiency syndromes were significantly higher than those in excess syndromes (P<0.01). No correlation was found between ER expression and different TCM syndromes. CONCLUSION: There is a correlation between PR expression and different TCM syndromes in gastric carcinoma.

Syndrome characteristics of traditional Chinese medicine: summary of a clinical survey in 767 patients with gastric cancer.

OBJECTIVE: The present study is a summary of syndrome types of gastric cancer in order of priority based on clinical practical situations, routine clinical syndrome differentiation and a large-sample clinical survey in 767 patients with gastric cancer. METHODS: Based on the six-type classification of gastric cancer in a previous study, a bedside syndrome differentiation diagnosis was made simultaneously by two attending doctors of traditional Chinese medicine (TCM to avoid possible diagnostic bias. A clinical differentiation survey form designed under the direction of epidemiologists was filled out by patients with gastric cancer in multiple centers, and the results were digitally valued and statistically analyzed. RESULTS: The symptoms and signs in each syndrome type of gastric cancer were ranked in order of priority as follows: distended pain, stringy pulse, eructation, mood-related pain, susceptibility to anger, acid regurgitation, hiccup, fullness sensation or distension after eating just a little, dizziness, thin pulse, abdominal enlargement, obstruction sensation after eating, moving pain, and uneven pulse in disharmony between liver and stomach; dark red tongue with little fur or a smooth surface, burning pain, rapid pulse, associated burning heat in anus, dry mouth, fissured tongue, thin pulse, tidal fever in the afternoon, nausea and vomiting, and night sweating in impairment of yin due to stomach heat; slender tongue fur, obstruction after eating, slow pulse, moderate pulse, rapid and irregular pulse, normal mood, abdominal pain, diarrhea, cold extremities, lower-extremity edema, cold intolerance, pale complexion, dizziness, emaciation, hiccup, silence, nausea, uneven pulse, acid regurgitation, fullness sensation or distension after eating just a little, vomiting, and constipation in deficiency-cold in spleen and stomach; uneven pulse, stabbing pain, tortuous sublingual vein, blue or purplish tongue, fixed pain, tarry stool or dark red stool, vomiting of dark red fluid, pale complexion, dry mouth without desire to drink, stringy pulse, white tongue fur, nausea, thin tongue fur, colic pain, hiccup, dizziness, acid regurgitation, bitter taste in mouth, slow pulse, rapid and irregular pulse, thin pulse, and pain relief by pressing in interior retention of toxin stagnation; slippery pulse, greasy and thick tongue fur, dry mouth without desire to drink, vomiting of bilious fluid, nausea, bitter taste in mouth, fullness sensation or distension after eating just a little, colic pain, and hiccup in stagnation of phlegm-dampness; abdominal pain relief by pressing, map-like tongue, thin pulse, weakness, yellowish complexion, dizziness, spontaneous sweating, fissured tongue, epigastric discomfort, night sweating, emaciation, cold intolerance, constipation, nausea, and dry tongue in deficiency of both qi and blood. CONCLUSION: The summarized syndrome types of gastric cancer from this study are consistent with the clinical situations and would prove to be more referential for TCM syndrome differentiation diagnosis and treatment of gastric cancer.

[Discussion of the correlation between phlegm and tumor microenvironment].

An abnormal microenvironment which is not fit for the living of normal cells is induced and maintained due to rapid growth, abnormal energy metabolism and self-regulation of specific proteins of the tumor cells. At the same time, the abnormal microenvironment is the guarantee of the neoplastic transformation, proliferation, invasion and metastasis of tumor cells. The microenvironment mainly consists of interstitial cells and their components. There are correlations between the physiological role of body fluid and the physiological functions of microenvironment. Phlegm is the product of abnormal body fluid metabolism. So to discuss the correlations of them may contribute to clarifying the material base of phlegm and will further give new insight for integrated traditional Chinese and Western medicine in cancer research.

[Effects of Xiaotan Sanjie Decoction-containing serum on proliferation and apoptosis of human gastric cancer cells MKN-45].

OBJECTIVE: To observe the effects of serum containing Xiaotan Sanjie Decoction, a compound traditional Chinese herbal medicine, on proliferation and apoptosis of human gastric cancer cell line MKN-45. METHODS: After coculturing MKN-45 cells with low-, medium- and high-dose Xiaotan Sanjie Decoction-containing serum, inverted microscope was utilized to observe morphological changes and counting chamber was used to count the MKN-45 cells; the proliferation of MKN-45 cells was determined by cell counting kit 8; Annexin V-fluorescein isothiocyanate/propidium iodide double label method was used to detect apoptosis rate of MKN-45 cells. RESULTS: Xiaotan Sanjie Decoction-containing serum significantly inhibited the proliferation of MKN-45 cells. The typical morphological changes of apoptotic MKN-45 cells were observed after treating with Xiaotan Sanjie Decoction-containing serum. The cell apoptosis was also observed by flow cytometry and the apoptosis rates of medium- and high-dose Xiaotan Sanjie Decoction-containing serum groups were higher than that of low-dose group. CONCLUSION: Xiaotan Sanjie Decoction-containing serum can inhibit the MKN-45 cell proliferation and induce cell apoptosis, which provides an experimental evidence for its treatment of human gastric cancer.