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In this study, the polysaccharide from Polygonatum sibiricum (PSP) was evaluated for the immunomodulatory activity by the cyclophosphamide (Cy)-induced immunosuppressed-model in vivo. The PSP has been analyzed in order to identify a variety of chemical properties such as monosaccharide compositions and structural confirmation. The results show that the main components of PSP were galactose and rhamnose. The PSP could significantly stimulate neutral red phagocytosis of RAW264.7 macrophages. Compared with the cyclophosphamide group, PSP accelerated recovery of spleen and thymus indexes, and enhanced T cell and B cell proliferation responses as well as peritoneal macrophage phagocytosis. In addition, PSP treatment restored the levels of IL-2, TNF-α, IL-8 and IL-10 in the serum of the Cy-treated mice in a dose-dependent manner. Therefore, PSP played an important role in the protection against immunosuppression in the Cy-treated mice and could be used as a potential immunostimulant agent.

Diallyl trisulfide (DATS), a natural agent derived from garlic, has been tested for its antigastric cancer activities in various preliminary studies. However, more systematic pharmacodymatic (PD) and mechanistic evaluations are clearly needed. The aim of this study was to investigate the antitumor effects of DATS in the treatment of human gastric cancer cell SGC-7901 both in vitro and in vivo using widely recommended study procedures. DATS suppressed cancer cells proliferation and induced cell cycle arrest accompanied by an increase in the expressions of cyclin A2 and cyclin B1 in SGC-7901 cancer cells. DATS also caused an increase in apoptotic cell death, which involved in accumulations of bax, p53, and cytochrome C and reduction of Bcl-2 expressions. Besides, activation of JNK, ERK and p38 phosphorylation in DATS-treated cells suggested that mitogen-activated protein kinase (MAPKs) pathways were involved in DATS-induced apoptosis. Meanwhile, DATS significantly inhibited tumor growth and promoted tumor apoptosis in a xenograft model of gastric cancer cell SGC-7901. DATS inhibited tumor migration and invasion by modulating MMP9 and E-cadherin protein expressions. In addition, DATS treatment evidently increased the cytokine secretions of IL-12, TNF-α and IFN-γ (p

Diallyl trisulfide (DATS), a garlic organosulfide, has shown excellent chemopreventive potential. Cisplatin (DDP) is widely used to treat solid malignant tumors, but causing serious side effects. In the current study, we attempted to elucidate the chemopreventive mechanisms of DATS in human gastric cancer BGC-823 cells in vitro, and to investigate whether DATS could enhance the anti-tumor efficacy of DDP and improve quality of life in BGC-823 xenograft mice in vivo. Treatment with DATS (25–400 μmol/L) dose-dependently inhibited the viability of BGC-823 cells in vitro with an IC50 of 115.2±4.3 μmol/L after 24 h drug exposure. DATS (50–200 μmol/L) induced cell cycle arrest at G2/M phase in BGC-823 cells, which correlated with significant accumulation of cyclin A2 and B1. DATS also induced BGC-823 cell apoptosis, which was accompanied by the modulation of Bcl-2 family members and caspase cascade activation. In BGC-823 xenograft mice, administration of DATS (20–40 mg·kg−1·d−1, ip) dose-dependently inhibited tumor growth and markedly reduced the number of Ki-67 positive cells in tumors. Interestingly, combined administration of DATS (30 mg·kg−1·d−1, ip) with DDP (5 mg/kg, every 5 d, ip) exhibited enhanced anti-tumor activity with fewer side effects. We showed that treatment of BGC-823 cells with DATS in vitro and in vivo significantly activated kinases such as p38 and JNK/MAPK and attenuated the Nrf2/Akt pathway. This study provides evidence that DATS exerts anticancer effects and enhances the antitumor efficacy of DDP, making it a novel candidate for adjuvant therapy for gastric cancer.

Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p

Ethnopharmacological relevance Traditional Chinese medicine Yifei Tongluo Granules has been employed clinically with the combination of chemotherapy agents to treat patients with multidrug-resistant tuberculosis. However, the mechanisms underlying the therapeutic potential have not been well elucidated. The present study was employed to verify immunomodulatory effect and to investigate the underlying mechanisms which have not been explored. Materials and methods The study samples of total extracts (FB-E) and polysaccharides (FB-P) were prepared by the extraction of the Yifei Tongluo Granules using appropriate techniques. A simple immunodeficient mice model was established by challenging Balb/c mice with cyclophosphamide in order to avoid the handling of tuberculosis viruses. The in vivo study was thus designed to systematically elucidate the immuno-enhancement effects of Yifei Tongluo Granules extracts in immunosuppressed mice induced by cyclophosphamide. Balb/c mice were orally ingested once daily with the low and high doses of two different extracts for ten consecutive days, respectively, accompanied by intraperitoneal injection of cyclophosphamide (60 mg/kg) on days 1–3 and 10. Results Compared with the model group, the treatment of immunodeficient mice with the low and high doses of the extracts FB-E or FB-P enhanced spleen and thymus indices, T- and B-cell proliferation as well as increased the activities of splenic natural killer, lymphokine activated killer, cytotoxic T lymphocyte cells and peritoneal macrophage phagocytosis. In addition, the FB-E or FB-P treatment balanced the ratio of Th1/Th2 and up-regulated the CD4+/CD8+ ratio in the serum. Conclusions These results demonstrate, for the first time, that the treatment of the cyclophosphamide-challenged mice with the Yifei Tongluo Granules extracts resulted in accelerated recovery of immunosuppression, sugguesting that the immunomodulation might be the mechanism for the observed clinical benefits of Yifei Tongluo Granules. Our findings provide preliminary mechanistic study evidences for clinical application of Yifei Tongluo Granules in patients with immunodeficient diseases such as tuberculosis.

The 70 kD heat shock proteins (Hsp70s) are ubiquitous and highly conserved molecular chaperones essential for cellular protein folding and proteostasis. Each Hsp70 has two functional domains: a nucleotide-binding domain (NBD) that binds and hydrolyzes ATP, and a substrate-binding domain (SBD) that binds extended polypeptides. NBD and SBD interact little when in ADP; however, ATP binding allosterically couples the polypeptide- and ATP-binding sites. ATP binding promotes polypeptide release; polypeptide rebinding stimulates ATP hydrolysis. This allosteric coupling was poorly understood. To explore the molecular mechanism of this essential ATP-induced allosteric coupling, we solved a crystal structure of an intact Hsp70 from E. coli in complex with ATP at 1.96 A resolution. NBD-ATP adopts a unique conformation, forming extensive interfaces with a radically changed SBD that has its α-helical lid displaced and the polypeptide-binding pocket of its β-subdomain flipped open. Our biochemical analysis inspired by this structure provides a long-sought mechanistic explanation of how ATP binding allosterically opens the polypeptide-binding site.

Direct estimation of the number of channels on a membrane path is important for channel biophysics. It is a classical question and has been addressed elegantly by previous studies. Especially, pioneering researchers took the advantage of fluctuations in membrane conductance caused by ion channels opening and closing. The number of channels, the single-channel current, and the probability of the channel opening can be obtained using the method of non-stationary or stationary fluctuation analysis. Here, we developed a method to count the number of channels by simultaneous electrical recording of channel opening and optical recording of the fluorescence from the green fluorescent protein(GFP) tagged to the channel. Based on the number of channels and the macroscopic current, we first tuned this method using the cyclic-nucleotide gated (CNG) channel, of which the single channel conductance and open probability are well characterized. Then we applied the I-F relationship to the hyperpolarization-activated, cAMP-regulated HCN channel, of which the estimation of single channel conductance has been controversial. We estimated that the number of channels on a piece of membrane patch could read 10,000 to 20,000 and the single channel conductance for mHCN2 channel is about 1.82 pico Siemens.