The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

Objective: To evaluate the inhibitory effect of tumor vaccines in colon carcinoma model mice. Methods: Mouse bone marrow⁃derived dendritic cells（BMDCs）were stimulated by using CpG β⁃glucan nanoparticles（CNP）in vitro. The BMDCs were divided into PBS group，NP group（without CpG nanoparticles），Lysate group（MC38 cell lysate）and CpG group（CpG1826），which were determined for the expression of marker molecules on the surface by flow cytometry and for the contents of interleukin⁃6（IL⁃6）and IL⁃12p40 in the culture supernatant by ELISA. The tumor lysate nano⁃vaccine was pre⁃ pared by mixing 50 mg／mL tumor lysate（MC38 cell lysate）with 200 mg／mL CNP in a volume ratio of 1∶1，with which mice were subcutaneously immunized as Vaccine group. Vaccine group，PBS group，CNP group and Lysate group were im⁃ munized once a week，for three times in total. Mice were subcutaneously inoculated with MC38 cells，2 × 105 cells for each， in the right lower limb 1 h after the last immunization，and measured for tumor volume once every three days to plot the tumor growth curve. The ratios of CD3+ CD4+ T and CD3+ CD8+ T cells in the blood were analyzed by flow cytometry and the levels of tumor necrosis factor⁃α（TNF⁃α）and interferon γ（IFNγ）in the blood and spleen of mice were determined by ELISA. Results: CNP effectively increased the expression of CD11c+ CD80+，CD11c+ CD86+，CD11c+ MHC⁃Ⅱ+ and the secretion of IL⁃6 and IL⁃12p40 in BMDCs in vitro，which were significantly higher than those in other 4 groups（t = 4. 3 ~ 46. 2，each P < 0. 05）. Compared with that of the other three groups，the tumor volume of mice in Vaccine group decreased significantly（t =2.6~3.4，eachP <0. 05）；TherewasnosignificantdifferenceinCD3+ CD8+ TandCD3+ CD8+ Tcellratios（t = 0.5~ 1. 9，each P > 0. 05）；The content of IFNγ in blood increased significantly（t = 3. 8 ~ 4. 6，P < 0. 05），while thatof TNF⁃α showed no significant difference（t = 0. 4 ~ 2. 0，each P > 0. 05）；However，the contents of IFN γ and TNF⁃α in spleen increased significantly（t = 6. 3 ~ 13. 0，each P < 0. 001）. Conclusion The prepared nano⁃vaccine of tumor lysate improvedtheimmune level in mice and effectively inhibited the growth of colon carcinoma.

Aim To investigate the effects of daidzeinDD on the proliferation and apoptosis of non-small cell lung cancer cells,with a focus on the possible role of the p53 signaling pathway in this regard. Methods CCK-8 method and flow cytometry were used to detect the effects of soy isoflavone crude extract and DD on the viability and apoptosis of HELF and H1299 cells. Gene microarray was used to detect the changes in gene expression after treatment of H1299 cells with DD. GSEA and differential analysis were used to screen the major pathways and key genes. RT-qPCR and Western blot were performed to verify the differences in mRNA and protein expression of key genesp53 and CASP9 in the major pathways. After p53 inhibitor Pifithrin-α inhibited the expression of p53,the effect of DD on p53 mRNA and protein expression levels was examined,and the proliferative effect on H1299 cells was observed. Results Soy isoflavone crude extract and DD promoted proliferation and inhibited apoptosis of normal lung cells and inhibited proliferation and promoted apoptosis of lung cancer cells. p53 signaling pathway was significantly enriched in the DD-treated groupNES=1.78,P=0.000,and the expressions of p53 and CASP9 genes were found to be significantly up-regulated in the treated group. Compared with the control group,mRNA expression of CASP9 and p53 significantly increased in both HELF and H1299 cells treated with DDP<0.05,and p53 protein expression also increased in HELF cellsP<0.05. After inhibition of p53 expression,DD significantly increased the mRNA expression of p53 in H1299 and HELF cellsP<0.05 and also markedly increased the expression of p53 protein in H1299 cellsP<0.05,and it was observed that DD inhibited the proliferation of lung cancer cells. Conclusions DD inhibits the proliferation and promotes the apoptosis of lung cancer H1299 cells,and the mechanism mainly involves the p53 signaling pathway.

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER NCT02063100 on ClinicalTrials.gov.

Objective To investigate the expression of non receptor protein tyrosine phosphatase 12 (PTPN12) in hepatocellular carcinoma (HCC) and its adjacent tissues and investigate the relationship between the expression of non receptor protein and prognosis of hepatocellular carcinoma (HCC).Methods The expresson of PTPN12 protein in HCC tissues and adjacent liver tissues was detected by immunohistochemistry.The relationship between the expression of PTPN12 protein and prognosis of primary hepatocellular carcinoma was evaluated by rank correlation and Cox proportional hazards regression model.Results Compared with the adjacent liver tissues,the expression of PTPN12 protein in HCC tissues was significantly lower (55.83％ vs 43.12％,P＜0.005).Further analysis showed that the decreased expression of PTPN12 was closely related with tumor recurrence (x2 =4.346,P=0.015).Single factor analysis showed that the decreased expression of PTPN12 in hepatocellular carcinoma and liver cancer specific survival and recurrence of hepatocellular carcinoma related (x2=5.687,P＜0.001),and multivariate Cox proportional hazards regression model analysis showed that the expression of PTPN12 in patients with liver cancer were independent prognostic factors (x2 =6.687,P＜0.05).Conclusion The expression of PTPN12 protein was down or absent in human hepatocellular carcinoma,and the expression of PTPN12 may be a biomarker for the recurrence and prognosis of HCC patients.

Objective To study the expression of adhesion molecules CD44 and ICAM-1 in BALB/c mice infected with Mycoplasma pneumoniae (MP) and elucidate the relationship between MP and infection.Methods BALB/c mouse MP model was established by MP nasal instillation,and the pathological changes of lung in MP mice were observed.The expression levels of adhesion molecules CD44 and ICAM-1 in serum and bronchoalveolar lavage fluid of mice infected with 5,8,15,20 and 30d MP were determined by ELISA.Results Compared with the model group,MP infected BALB/c mice after lung inflammation was significantly up-regulated MP,the expression in BALB/c mice infected with the serum and bronchoalveolar layage fluid in CD44 and adhesion molecule ICAM 1 (t5 d serum CD44 =53.64 ng/L,t5 d BALF CD44 =144.3 ng/L;t5 d serum ICAM-1 =73.72 ng/L,t5 d BALF ICAM-1 =165.06 ng/L,all P＜ 0.000;t8 d serum CD44 =40.86 ng/L,t8 d BALF CD44 =21.31 ng/L;t8 d serum ICAM-1 =30.57 ng/L,t8 d BALF ICAM-1 =19.61 ng/L,all P＜0.000).The Mycoplasma pneumoniae infection increased the expression levels of adhesion molecules CD44 and ICAM-1 in mice.Conclusion After MP mice were cured,the expression of CD44 and ICAM-1 was down regulated,and the up regulation of CD44 and ICAM-1 expression might be related to the severity of MP pneumonia.

More and more disputes have happened to confront us continuously since the separation of Japanese(wild) honeysuckle flower in Chinese Pharmacopoeia in 2005. The state pharmacopeia committee decided to separate Japanese(wild) honeysuckle flower into two species for japanese(wild) honeysuckle flower, but didn't define their the convincing reasons still did not provide to us as a result that two medicines are not described the differences in natural properties, efficiency and indication, usage and dosage, as well as not given a resolving methodand specific solution. It was known for us that in the history of traditional Chinese medicine（TCM）, the phenomenenphenomena of the "one drug from multi-species" and "one species for multi-drug" are very ordinary thingswere ubiquitous. Whether separation of the drug species are separated shall be decided to by clinical efficiency. Through Chinese pharmacopoeia (2015 edition) issue of Chinese Pharmacopoeia the 2015 issue of the Chinese Pharmacopoeia, we still cannot find a scientific solution for the dispute of for Japanese (wild) honeysuckle flower, perhaps because of insufficient reorganization of TCM clinical medication regularities, such as "treatment of different diseases with same drug", " treatment of the same disease with different drugs" and "treatment of the same syndrome with multi-prescriptions", and "one prescription treating multiple syndromes"; lack of in-depth analysis for multi-component TCM compounds and autonomisation of "supermolecular template" for organs and meridians; less attention to the advance of efficacy and safety evaluation technologies for multi-component TCM compounds; impacts from the medication mode of "one ingredient-one composition-one effect"; as well as insufficient research methods for bioequivalent evaluation in preclinic and clinic studies . The dispute for species combination or separation for Japanese(wild) honeysuckle flower was apparently caused by regional economy, drug biological equivalent of efficacy and safety, but arising from clinical principles for systematical syndrome treatment with TCM, or concepts in the treatment of diseases with TCM or western medicines. This paper focused on current studies on Japanese(wild) honeysuckle flower in the combination with TCM clinical medication regularities, such as "treatment of different diseases with same drug", "treatment of the same disease with different drugs" and "treatment of the same syndrome with multi-prescriptions", and "one prescription treating multiple syndromes", expounded the specific pharmacological regularity of "heterogeneous equivalence" of Japanese (wild) honeysuckle flower, and put forward methods for studying bioequivalence of Japanese(wild) honeysuckle flower, in order to solve the combination and separation of Japanese(wild) honeysuckle flower and lay a foundation for promoting the development of Chinese herbal medicine industry.

The paper, based on the previous publication as special impact of Chinese medicine theories on supramolcular chemistry, aims to analyze the natural origination for the Chinese medicine and to explain the special impact of "Qi chromatography" reaction on "imprinting templates" in supramolcular host of human being with Chinese medicine, in order to reveal the CM's properties of "medical element" with "imprinting templates" autonomisation generally took place in natural supramolecules, and also to discover that the CM's pharmacology are satisfied with its own approaches different form western pharmacology. It was decided, for CM's pharmacology guided by CM's theories, to "Qi chromatography" relations between the CM's ingredient groups and the meridian zang-fu viscera. The supramolcular chemistry played an all-through role in procession of making macro-regularities and special presentation on behavior of "Qi chromatography" impulse owning to the matching action of all kinds of ingredients on the meridian zang-fu viscera with similar "imprinting templates". The CM's pharmacology were guided by CM's theories, owing to its interpretation of supramolecular chemistry. The pharmacology was achieved to construct up completely on base of classical chemical single molecular bonds whereas the CM's pharmacology be configured to big building by way of "imprinting templates" as multi-weak bonds among "supramolecular society". CM's pharmacology was supramolcular pharmacology dealt with "molecular society" on the base of western pharmacology, and employed to double research approaches both math-physical quantitative representation on macroscope and qualitative analyses in microscope.
Animals ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Humans ; Meridians ; Molecular Imprinting ; Qi

In this paper, based on the special influence of supramolecular chemistry on the basic theory of Chinese medicines ( CM) , the authors further analyzed the history of meridian tropism and natural origins of CM organisms and explained CM ingredients and the universal regularity of the automatic action of the supramolecular "imprinting templates" hole channel structure. After entering human bodies, CMs, as the aggregation of supramolecular "imprinting templates" , automatically seek supramolecular subjects that are matched with their "imprinting templates" in human meridians and organs for the purpose of self-recognition, self-organization, self-assembly and self-replication, so as to generate specific efficacy in meridians and organs, which is reflected as the meridian tropism phenomena at macro level. This regularity can be studied by in vitro and in vivo experimental studies. In vitro methods are mostly supra molecular structure analysis and kinetic and thermodynamic parameter calculation; Whereas in vivo methods are dominated by the analysis on object component distribution, chromatopharmacodynamic parameters and network chromatopharmacodynamic parameters; Particularly, the acupoint-medicine method can simplify to study the supramolecular subject-object relations. Consequently, CM's'meridian tropism reveals the universal regularity for interactions of macromolecular and micromolecular "imprinting templates" of subjects and objects in natural organisms. As the first barrier for the material base of the CM theory and breakthrough in the modernization of the basic CM theory, meridian tropism plays an important role in studies on basic theories of the basic CM theory.
Acupuncture Points ; Drug Therapy ; Drugs, Chinese Herbal ; chemistry ; Humans ; Medicine, Chinese Traditional ; Meridians

The paper aimed to elucidate the specific impact of supramolecular chemistry on the Chinese medicine theories (CMT) in their modernization, after had summarized up the research status of supramolecular chemistry and analyzed the possible supramolecular forms of Chinese medicine (CM), as well as considered the problems in modernization of CM theories. On comparison of the classical chemistry that delt with chemical bonds among atoms, the supramolecular chemistry was rather concerned with varietes of weak noncovalent bonds intermolecules, and reflected the macro-apparent chemical properties of each molecules, and was the most appropriate chemical theories to explain the CMT and microcosmic materials. The molecules in the human body and Chinese material medica (CMM) formed supramolecules by way of self-assembly, self-organization, self-recognition and self-replication, with themselves or with complexation, composition, chelation, inclusion, neutralization etc. Meridian and Zang-fu viscera in CMT might be a space channel structure continuously consisted of unique molecules cavity that was imprinted with the supramolecularly template inside and outside of cells, through which the molecules in CMM interacted with the meridian and Zang-fu viscera. When small molecules in human body imprinted with macromolecules in meridian and Zang-fu viscera, in other words, they migrated along within imprinting channels of meridian and Zang-fu viscera on behavior of "Qi chromatography" impulsed by the heart beat, finally showed up on macroscopic the anisotropy of tissue and organ, as described namely as visceral manifestation in Chinese medical science. When small molecules in CMM interacted with imprinting channel on meridian and Zang-fu viscera, the natural properties and efficacy regularities of CMM was reflected on macroscopic. Therefore, the special representation forms of basic CMT is based on the macroscopic expression of "Qi chromatography" abided by imprinting effect regularities, and on whether the imprinted template of small molecules matched with cavity template of macromolecules in meridian and Zang-fu viscera, only is the adequate representation of supramolecular chemistry for them. The CMM materials is the mixture including single molecules and supramolecules. The compatibility for CM prescriptions can significantly change the function rules. Therefore in the study of basic CMT, we should pay special attention to the laws of supramolecular chemistry. It is the most essential differences of the CMT from the modern medicine which established by the laws of single molecular theories.
Chemistry, Pharmaceutical ; Drug Therapy ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Humans ; Meridians ; Nanotechnology