A DFX-based iron nanochelator for cancer therapy.

Iron as an essential element, is involved in various cellular functions and maintaining cell viability, cancer cell is more dependent on iron than normal cell due to its chief characteristic of hyper-proliferation. Despite that some of the iron chelators exhibited potent and broad antitumor activity, severe systemic toxicities have limited their clinical application. Polyaminoacids, as both drug-delivery platform and therapeutic agents, have attracted great interests owing to their different medical applications and biocompatibility. Herein, we have developed a novel iron nanochelator PL-DFX, which composed of deferasirox and hyperbranched polylysine. PL-DFX has higher cytotoxicity than DFX and this effect can be partially reversed by Fe2+ supplementation. PL-DFX also inhibited migration and invasion of cancer cells, interfere with iron metabolism, induce phase G1/S arrest and depolarize mitochondria membrane potential. Additionally, the anti-tumor potency of PL-DFX was also supported by organoids derived from clinical specimens. In this study, DFX-based iron nanochelator has provided a promising and prospective strategy for cancer therapy via iron metabolism disruption.

Ailanthus Altissima-derived Ailanthone enhances Gastric Cancer Cell Apoptosis by Inducing the Repression of Base Excision Repair by Downregulating p23 Expression.

Chemotherapy plays an irreplaceable role in the treatment of GC, but currently available chemotherapeutic drugs are not ideal. The application of medicinal plants is an important direction for new drug discovery. Through drug screening of GC organoids, we determined that ailanthone has an anticancer effect on GC cells in vitro and in vivo. We also found that AIL can induce DNA damage and apoptosis in GC cells. Further transcriptome sequencing of PDX tissue indicated that AIL inhibited the expression of XRCC1, which plays an important role in DNA damage repair, and the results were also confirmed by western blotting. In addition, we found that AIL inhibited the expression of P23 and that inhibition of P23 decreased the expression of XRCC1, indicating that AIL can regulate XRCC1 via P23. The results of coimmunoprecipitation showed that AIL can inhibit the binding of P23 and XRCC1 to HSP90. These findings indicate that AIL can induce DNA damage and apoptosis in GC cells. Meanwhile, AIL can decrease XRCC1 activity by downregulating P23 expression to inhibit DNA damage repair. The present study sheds light on the potential application of new drugs isolated from natural medicinal plants for GC therapy.

Mechanism and Basis of Traditional Chinese Medicine Against Obesity: Prevention and Treatment Strategies.

In the last few decades, the incidences of obesity and related metabolic disorders worldwide have increased dramatically. Major pathophysiology of obesity is termed "lipotoxicity" in modern western medicine (MWM) or "dampness-heat" in traditional Chinese medicine (TCM). "Dampness-heat" is a very common and critically important syndrome to guild clinical treatment in TCM. However, the pathogenesis of obesity in TCM is not fully clarified, especially by MWM theories compared to TCM. In this review, the mechanism underlying the action of TCM in the treatment of obesity and related metabolic disorders was thoroughly discussed, and prevention and treatment strategies were proposed accordingly. Hypoxia and inflammation caused by lipotoxicity exist in obesity and are key pathophysiological characteristics of "dampness-heat" syndrome in TCM. "Dampness-heat" is prevalent in chronic low-grade systemic inflammation, prone to insulin resistance (IR), and causes variant metabolic disorders. In particular, the MWM theories of hypoxia and inflammation were applied to explain the "dampness-heat" syndrome of TCM, and we summarized and proposed the pathological path of obesity: lipotoxicity, hypoxia or chronic low-grade inflammation, IR, and metabolic disorders. This provides significant enrichment to the scientific connotation of TCM theories and promotes the modernization of TCM.

Gegen Qinlian Decoction abates nonalcoholic steatohepatitis associated liver injuries via anti-oxidative stress and anti-inflammatory response involved inhibition of toll-like receptor 4 signaling pathways.

Gegen Qilian Decoction (GGQLD) is a well-established classic Chinese medicine prescription in treating nonalcoholic steatohepatitis (NASH). However, the molecular mechanism of GGQLD action on NASH is still not clear. This study aimed to assess the anti-NASH effect of GGQLD, and to explore its molecular mechanisms in vivo and in vitro. In HFD-fed rats, GGQLD decreased significantly serum triglyceride (TG), cholesterol (CHO), total bile acid (TBA), low-density lipoprotein (LDL), free fatty acid (FFA) and lipopolysaccharide (LPS) levels, increased levels of differentially expressed proteins (DEPs) Ahcy, Gpx1, Mat1a, GNMT, and reduced the expression of ALDOB. In RAW264.7 macrophages, GGQLD reduced the expression levels of inflammatory factors TNF-α and IL-6 mRNA, and diminished NASH by increasing differentially expressed genes (DEGs) CBS, Mat1a, Hnf4α and Pparα to reduce oxidative stress or lipid metabolism. The results of DEGs verification also showed that GGQLD up-regulated expressions of Hnf4α, Pparα and Cbs genes. In HepG2 cells, GGQLD decreased IL-6 levels and intracellular TG content, and inhibited FFA-induced expression of toll-like receptor 4 (TLR4). In summary, GGQLD abates NASH associated liver injuries via anti-oxidative stress and anti-inflammatory response involved inhibition of TLR4 signal pathways. These findings provide new insights into the anti-NASH therapy by GGQLD.

The anti-diabetic activities, gut microbiota composition, the anti-inflammatory effects of Scutellaria-coptis herb couple against insulin resistance-model of diabetes involving the toll-like receptor 4 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria-coptis herb couple (SC) is one of the well-known herb couples in many traditional Chinese compound formulas used for the treatment of diabetes mellitus (DM), which has been used to treat DM for thousands of years in China. AIM OF THE STUDY: Few studies have confirmed in detail the anti-diabetic activities of SC in vivo and in vitro. The present investigations aimed to evaluate the anti-diabetic activity of SC in type 2 diabetic KK-Ay mice and in RAW264.7 macrophages to understand its possible mechanism. MATERIALS AND METHODS: High-performance liquid chromatography with ultraviolet detection (HPLC-UV) and LC-LTQ-Orbitrap Pro mass spectrometry were used to analyze the active ingredients of SC extracts and control the quality. A type 2 diabetic KK-Ay mice model was established by high-fat diet. Body weight, fasting blood glucose levels, fasting blood insulin levels, glycosylated hemoglobin and glycosylated serum protein were measured. The effects of SC on total cholesterol (TC), high-density lipoprotein (HDL) and triglyceride (TG) levels were examined. The lipopolysaccharide (LPS), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) levels were measured. Gut microbial communities were assayed by polymerase chain reaction (PCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) methods. The expressions of Toll-like receptor 4 (TLR4) and MyD88 protein in the colons were measured by western blot. In RAW264.7 macrophages, IL-6, TNF-α, TLR4 and MyD88 protein levels were measured by enzyme-linked immunosorbent assay (ELISA) kits or western blot, and the mRNA expression of IL-6, TNF-α and TLR4 was examined by the real time PCR. RESULTS: The present results showed that the SC significantly increased blood HDL and significantly reduced fasting blood glucose, fasting blood insulin, glycosylated hemoglobin, glycosylated serum protein, TC, TG, LPS, IL-6 and TNF-α levels (P < 0.05 or P < 0.01) in type-2 diabetic KK-Ay mice. Furthermore, SC could regulate the structure of intestinal flora. Additionally, the expressions of TLR4 and MyD88 protein in the colons were significantly decreased in the model group (P < 0.05 or P < 0.01). However, SC had no significant effect on weight gain. In RAW264.7 macrophages, SC containing serum (SC-CS) (5%, 10% and 20%) significantly decreased IL-6, TNF-α, TLR4 and MyD88 protein levels and the mRNA expression of IL-6, TNF-α and TLR4 (P < 0.05 or P < 0.01). CONCLUSIONS: The anti-diabetic effects of SC were attributed to its regulation of intestinal flora and anti-inflammation involving the TLR4 signaling pathway. These findings provide a new insight into the anti-diabetic application for SC in clinical settings and display the potential of SC in the treatment of DM.

Interaction of baicalin with berberine for glucose uptake in 3T3-L1 adipocytes and HepG2 hepatocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Baicalin and berberine are important coexisting constituents of the combination of Radix Scutellariae and Rhizoma Coptidis, known as scutellaria-coptis herb couple (SC), which has heat clearing and detoxifying effects. The aims of the present study were to investigate the effects of the combination of baicalin+berberine on glucose uptake in 3T3-L1 adipocytes or HepG2 cells. MATERIALS AND METHODS: Insulin-resistant adipocytes and hepatocytes models were established. Glucose consumption was assayed to evaluate the effects of berberine, baicalin, and berberine+baicalin on glucose uptake, and the interaction of baicalin with berberine for glucose uptake was evaluated in 3T3-L1 adipocytes or HepG2 cells. Moreover, the effects of baicalin on the dose-effect relationship of berberine for glucose uptake was also evaluated in 3T3-L1 adipocytes. RESULTS: The results of the present study demonstrated that berberine increased glucose consumption in 3T3-L1 adipocytes and HepG2 hepatocytes in a dose-dependent manner. In contrast, statistical analyses indicated that baicalin (in doses up to 100µmol/L) produced no obvious effect. The effect of berberine+baicalin on glucose uptake was better than that of berberine or baicalin alone, which indicated that berberine and baicalin had the trend of synergetic effect on glucose uptake. Furthermore, these results showed that the synergistic effect occurred in a specific dose range, while the antagonistic effect was present in another dose range in the presence of 10µmol/L baicalin. Interestingly, the entire dose-response curves of berberine shifted down in the presence of 100µmol/L baicalin, and baicalin antagonised the effect of berberine on glucose uptake in 3T3-L1 adipocytes. CONCLUSIONS: The results of the present study showed that berberine dose-dependently increased glucose consumption in 3T3-L1 adipocytes and HepG2 hepatocytes. Furthermore, interaction of baicalin with berberine was additive at low doses of baicalin and antagonistic at higher baicalin doses. Thus, it is possible that baicalin is a partial agonist. These results provided a basis for the study of the TCM compatibility mechanism and a new insight into the application for Gegen Qinlian Decoction (GGQLD) or SC in the clinic.

Efficacy of adjuvant XELOX and FOLFOX6 chemotherapy after D2 dissection for gastric cancer.

AIM: To compare the efficacy of capecitabine and oxaliplatin (XELOX) with 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX6) in gastric cancer patients after D2 dissection. METHODS: Between May 2004 and June 2010, patients in our gastric cancer database who underwent D2 dissection for gastric cancer at the First Affiliated Hospital of Sun Yat-Sen University were retrospectively analyzed. A total of 896 patients were enrolled into this study according to the established inclusion and exclusion criteria. Of these patients, 214 received the XELOX regimen, 48 received FOLFOX6 therapy and 634 patients underwent surgery only without chemotherapy. Overall survival was compared among the three groups using Cox regression and propensity score matched-pair analyses. RESULTS: Patients in the XELOX and FOLFOX6 groups were younger at the time of treatment (median age 55.2 years; 51.2 years vs 58.9 years), had more undifferentiated tumors (70.1%; 70.8% vs 61.4%), and more lymph node metastases (80.8%; 83.3% vs 57.7%), respectively. Overall 5-year survival was 57.3% in the XELOX group which was higher than that (47.5%) in the surgery only group (P = 0.062) and that (34.5%) in the FOLFOX6 group (P = 0.022). Multivariate analysis showed that XELOX therapy was an independent prognostic factor (hazard ratio = 0.564, P < 0.001). After propensity score adjustment, XELOX significantly increased overall 5-year survival compared to surgery only (58.2% vs 44.2%, P = 0.025) but not compared to FOLFOX6 therapy (48.5% vs 42.7%, P = 0.685). The incidence of grade 3/4 adverse reactions was similar between the XELOX and FOLFOX6 groups, and more patients suffered from hand-foot syndrome in the XELOX group (P = 0.018). CONCLUSION: Adjuvant XELOX therapy is associated with better survival in patients after D2 dissection, but does not result in a greater survival benefit compared with FOLFOX6 therapy.

Anti-diabetic activities of Gegen Qinlian Decoction in high-fat diet combined with streptozotocin-induced diabetic rats and in 3T3-L1 adipocytes.

Gegen Qinlian Decoction (GGQLD) is one of the well-known traditional Chinese medicines. Recently, it was reported that GGQLD had good clinical effects on type 2 diabetes mellitus. However, few studies have confirmed in detail the anti-diabetic activities of GGQLD in vivo and in vitro. In the present study, we investigated the anti-diabetic effects of GGQLD in high-fat diet combined with streptozotocin-induced diabetic rats and in 3T3-L1 adipocytes. The present results suggested GGQLD (4.95, 11.55 and 18.15 g/kg) decreased significantly fasting blood glucose, glycosylated serum protein, and glycosylated hemoglobin of diabetic rats (p<0.05), and GGQLD (4.95 and 18.15 g/kg) decreased significantly fasting serum insulin levels of diabetic rats (p<0.05); in 3T3-L1 adipocytes, Gegen Qinlian Decoction-containing serum (GGQLD-CS) (4%, 8% and 16%) enhanced glucose consumption, triglyceride (TG) content, adiponectin protein concentration and the mRNA expression of adiponectin. Adiponectin contributes to the regulation of lipid and glucose metabolism, and can play a critical role in the development of diabetes mellitus; the mechanisms of action of GGQLD might be related to augmentation of adiponectin protein concentration and up-regulation of the mRNA expression of adiponectin. However, the multi-target mechanisms of action of GGQLD need to be clarified further. The present study further validated the beneficial effects of GGQLD as an anti-diabetic agent. These findings provide a new insight into the anti-diabetic application for GGQLD in clinic and display the potential of GGQLD as a new drug candidate for the treatment of diabetes mellitus.