Inhibitory Effect of Astragalus Polysaccharide on Premetastatic Niche of Lung Cancer through the S1PR1-STAT3 Signaling Pathway.

As a common malignant tumor, the morbidity and mortality of lung cancer have been rising in recent years. The concept of "premetastatic niche" may lead to a revolutionary change in antitumor metastasis therapeutic strategies. Traditional Chinese medicine with multitargets and lower poisonous agents may be a potentially effective means to intervene in the "premetastatic niche (PMN)" to prevent and treat tumor metastasis. Astragalus polysaccharide (APS) is a substance with strong immune activity in Astragalus membranaceus that has excellent biological activities such as immunomodulation, anti-inflammatory, and antitumor. In this study, we constructed a tumor lung metastasis animal model to explore the intervention mechanism of APS on the premetastatic niche. We found that APS inhibited the formation of the lung premetastatic niche and inhibited the recruitment of myeloid-derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and gene expression of S1PR1, STAT3, and p-STAT3 in the S1PR1/STAT3 signaling pathway were suppressed by APS. In line with the above findings, our results confirmed that APS may inhibit the accumulation of MDSCs in the premetastatic niche through the intervention of the S1PR1-STAT3 signaling pathway to achieve the antitumor effect.

Total flavonoids of Oxytropis falcata Bunge have a positive effect on idiopathic pulmonary fibrosis by inhibiting the TGF-ß1/Smad signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with unknown etiology. Oxytropis falcata Bunge (O. falcata) is a 1-35 cm high perennial clustered herb, also known as edaxia, has viscosity and a special smell, and is mainly distributed in the western areas of China. The root of O. falcata has a diameter of 6 mm, is straight and deep, dark red and its stems are shortened, woody and multibranched. O. falcata has heat-clearing, detoxification, analgesic, anti-inflammatory, antibacterial, hemostatic and antitumor activities. Furthermore, O. falcata has excellent anti-inflammatory and analgesic effects, and it is one of the three major anti-inflammatory drugs in Tibetan medicine, known as "the king of herbs". Total flavonoids of Oxytropis falcata Bunge (FOFB) were previously extracted, and their pharmacological activities are consistent with those of the whole herb. In this study, FOFB was extracted from O. falcata by ethanol extraction, and the mechanism of FOFB on IPF was verified by in vivo and in vitro experiments. AIM OF THE STUDY: In this study, we aimed to observe the effects of FOFB on idiopathic pulmonary fibrosis. MATERIALS AND METHODS: In in vivo experiments, an IPF rat model was established by bleomycin induction. The rats were treated with FOFB (100, 200, 400 mg kg-1·d-1) for 4 weeks. Masson staining and the expression of TGF-ß, p-Smad2, p-Smad3 and Smad7 in the lung tissue of rats were detected. In in vitro experiments, we perfused normal rats with FOFB (100, 200, 400 mg kg-1·d-1) and obtained the corresponding drug-containing serum. The HFL-1 cell model induced by TGF-ß1 was used to detect the corresponding indices through intervention with drug-containing serum. The best intervention time for drug-containing serum was detected by the CCK-8 method. Changes in apoptosis, cytoskeleton and rough endoplasmic reticulum structure were detected. Finally, the expression of TGF-ß, p-Smad2, p-Smad3 and Smad7 in cells was examined. RESULTS: In vivo, Masson staining indicated that the degree of pulmonary fibrosis increased significantly, the expression of TGF-ß, p-smad2 and p-Smad3 increased significantly, and the expression of Smad7 decreased in the model group. We found that the degree of pulmonary fibrosis gradually decreased and that the inhibition of the TGF-ß/Smad signaling pathway became more obvious with increasing FOFB dose. FOFB (400 mg kg-1·d-1) significantly improved the degree of pulmonary fibrosis in rats. In in vitro experiments, the CCK-8 results showed that 120 h was the best intervention time for drug-containing serum. In the model group, there was no obvious apoptosis or changes in microfilaments and microtubules, the number of rough endoplasmic reticulum increased, and the expression of TGF-ß, p-Smad2 and p-Smad3 increased significantly, while the expression of Smad7 decreased significantly. We found that with the increase in drug-containing serum concentration, the apoptosis, cytoskeleton and degree of destruction of the rough endoplasmic reticulum in the HFL-1 cell model also increased, and the inhibition of the TGF-ß/Smad signaling pathway became more pronounced; the effect of the drug-containing serum administered with FOFB (400 mg kg-1·d-1) was the most significant. CONCLUSIONS: The results suggest that FOFB can improve the occurrence and development of IPF. The effect of FOFB on IPF may be mediated by inhibition of the TGF-ß1/Smad signaling pathway.

Effect of Total Flavonoids of Oxytropis falcata Bunge on the Expression of p-JAK1-and p-STAT1-Related Proteins in Idiopathic Pulmonary Fibrosis.

OBJECTIVE: The study aimed to explore the effect of total flavonoids of Oxytropis falcata Bunge (FOFB) on the expression of p-JAK1/p-STAT1 and SOCS3 proteins in idiopathic pulmonary fibrosis (IPF). METHODS: Rats model with IPF was established by one-off intratracheal injection of bleomycin (BLM, 5 mg/kg). After 14 days, the same volume of low dose (100 mg/kg), medium dose (200 mg/kg), and high dose (400 mg/kg) of FOFB and prednisolone acetate (20 mg/kg) as positive control drugs, as well as normal saline, were orally administered to rats once a day for 28 consecutive days. Subsequently, the degree of fibrosis and alveolitis in rat lung tissue was observed, respectively, by HE and Masson staining. Further more, observing the ultrastructure of lung tissue by transmission electron microscopy (TEM), the detection of JAK/STAT pathway related indicators including p-JAK1, p-STAT1, and SOCS3 with immunohistochemistry and SOCS3 with real-time PCR (RT-PCR) was performed. RESULTS: Compared with the BLM group, the degree of alveolitis and fibrosis improved significantly, and the expression of p-JAK1 and p-STAT1 decreased; conversely, the expression of SOCS3 increased in the treatment group. CONCLUSION: IPF causes high expression of p-JAK1 and p-STAT1 and low expression of SOCS3. FOFB can play a role in the treatment of IPF via upregulating SOCS3 and downregulating p-JAK1 and p-STAT1.

Intervention effect of pinelliae decoction for purging stomach-fire on malignant transformation of bone marrow mesenchymal stem cells in the gastric cancer microenvironment.

OBJECTIVE: The study aimed to simulate the microenvironment of gastric cancer to promote the malignant transformation of bone marrow mesenchymal stem cells (BMSCs) and further evaluate the effect of Pinelliae Decoction for Purging Stomach-Fire and its disassembled prescriptions on BMSCs. METHODS: Transwell co-culture was performed on the human gastric cancer cell strains BGC-823 and BMSCs to simulate the microenvironment of gastric cancer. The drug-containing serum prepared by Pinelliae Decoction for Purging Stomach-Fire and its disassembled prescriptions was used, and its influence on BMSCs with malignant transformation was observed. RESULTS: BMSCs were harvested successfully from the rat bone marrow, and flow cytometer identification indicated that CD44+/CD34- cells accounted for 70.64%. The co-culture of BGC-823 cells can induce malignant transformation of BMSCs. And the drug-containing serum can induce G2 phase arrest, inhibit cell proliferation, simultaneously inhibit TERT and c-myc expression, lower the cellular ability of chemotactic migration, inhibit the tumor-forming ability of BGC-823 in nude rats and promote the tumor apoptosis. CONCLUSION: The effective components of Pinelliae Decoction for Purging Stomach-Fire in gastric cancer treatment are pinelliae and dried ginger, and the main acting mechanism is to inhibit tumor cell proliferation and chemotactic migration and promote apoptosis.

[Effects of Banxia Xiexin Decoction Containing Serum on Proliferation, Invasion and Metastasis of Gastric Cancer Peritoneal Metastasis Cell Line GC9811-P].

Objective To observe the effects of Banxia Xiexin Decoction (BXD) containing ser- um on proliferation, invasion and metastasis of in vitro human gastric cancer peritoneum cell strain GC9811-P (which has high metastatic potential). Methods BXD containing serum was prepared. GC9811-P cells were inoculated in the E-Plate 96 and CIM Plate 16, and then 0, 25, 50, 100 µL/mL BXD containing serums were added respectively. Meanwhile, GC9811-P cells were stained by Diff-Quik stai- ning method. Inhibition of BXD containing serum on cell index (CI) for proliferation of GC9811-P cells, invasion and metastasis were observed by real time cellular analysis (RTCA) and Diff-Quik staining method. Results BXD containing serum could obviously inhibit the proliferation of GC9811-P cells. The Cl approximated to 0 after 70 h. Most stained Diff-Quik cells died. Cell migration curve showed that 25, 50, 100 µL/mL BXD containing serums could obviously inhibit the capacities for cell migration of GC9811-P cells in concentration dependent manner. The number of migration cells was reduced more obviously, as com- pared with 0 µL/mL BXD containing serum (P <0. 05). Conclusion BXD containing serums could inhibit the proliferation, invasion and metastasis of GC9811-P cells, which might be associated with blocking peritoneal metastasis of gastric cancer.

Sodium tanshinone IIA sulfonate attenuates radiation-induced fibrosis damage in cardiac fibroblasts.

The main pathological change in radiation-induced heart disease is fibrosis. Emerging evidence has indicated that sodium tanshinone IIA sulfonate (STS) was used for treating fibrosis diseases. The present study was undertaken to characterize the effect of STS on radiation-induced cardiac fibrosis (RICF) on cultured cardiac fibroblasts (CFs). CFs were irradiated with 1 or 2 Gy X-rays, and the expression of TGF-ß1 and collagen I (Col-1) increased, indicating that low-dose X-rays promoted fibrosis damage effect. The fibrosis damage was accompanied by morphologic changes in the endoplasmic reticulum (ER), as well as an increase in the expression of the ER stress-related molecules, GRP78 and CHOP. Administration of STS reduced ROS production and decreased the expression of Col-1, TGF-ß1, p-Smad2/3, GRP78, and CHOP in irradiated CFs, thus weakening the radiation-induced fibrosis damage and ER stress. Radiation-induced fibrosis damage was observed on a cellular level. The involvement of ER stress in radiation-induced fibrosis damage was demonstrated for the first time. STS attenuated the fibrosis damage effect in CFs and this effect may be related to its antioxidant action, and also related to its inhibition of ER stress and TGF-ß1-Smad pathway. These results suggest that STS shows a good prospect in clinical prevention and treatment of RICF.

[Influence of single leaf Asarum himalaicum on renal function of rabbits].

OBJECTIVE: To study the influence of single leaf Asarum himalaicum on the renal function of rabbits. METHODS: Rabbits were divided into three groups. Asarum himalaicum, Asarum heterotropoides and normal saline were intravenously administered to the rabbits of one group respectively. The urine volume per minute, urine pH, urine glucose, protein and red blood cells, BUN, SCr, TXB2, 6-keto-PGF1alpha, TXB2/6-keto-PGF1alpha, endothelin, p-aminohippuric acid clearance rate and phenolsulfonphthalein excretion rate were tested before and after the administration. RESULTS: A certain dosage of single leaf Asarum himalaicum caused acute renal failure in rabbits. The indices tested were significantly different between rabbits administered Asarum himalaicum and normal saline. As compared with the rabbits administered Asarum heterotropoides, the results of indices tested decreased, but without statistical significance, except for SCr. CONCLUSION: The single leaf Asarum himalaicum can cause renal damage to rabbits. Its renal toxicity is lower that that of Asarum heterotropoides.