The crosstalk between macrophages and bone marrow mesen chymal stem cells （BMSCs） plays a vital role in regulating tendon-bone healing. Based on the traditional Chinese medicine （TCM） theory that the kidney governs the bones and generates marrow， yin-nourishing and kidney-tonifying Chinese medicines can promote the osteogenic differentiation of BMSCs and the M1-to-M2 polarization of macrophages， thereby facilitating tendon-bone healing. A variety of related medicinal monomers （such as diosgenin and oleanolic acid）， extracts and effective fractions （such as artificial tiger bone powder and total flavonoids of Drynaria fortunei ）， as well as compound prescriptions （such as Liuwei dihuang pill， Xujin jiegu decoction and Duhuo jisheng decoction）， can modulate the crosstalk between macrophages and BMSCs by regulating the Wnt/β-catenin， nuclear factor kappa-B， phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin and transforming growth factor-β/Smad signaling pathways. They further exert anti-inflammatory， antioxidant and osteogenic effects to effectively accelerate tendon-bone healing. However， current evidence was limited to animal experiments exhibiting such as limitations insufficent alignment between animal models and clinical injury types， research focusing mostly on single signaling pathways， and unclear core active ingredients. Future studies shall optimize animal models and carry out large-sample randomized controlled trials， clarify the interactive networks of multiple signaling pathways， and isolate the core active substances of yin-nourishing and kidney-tonifying Chinese medicines， so as to advance the precise application of traditional Chinese medicines.

Objective To explore the effects of multiple intravenous tranexamic acid (Ⅳ-TXA) administrations after total knee arthroplasty (TKA) on fibrinolytic activity and inflammatory response in an enhanced recovery after surgery (ERAS) program and to assess the efficacy and safety of Ⅳ-TXA.Methods One hundred and forty-one severe knee osteoarthritis patients following primary unilateral TKA from January 2016 to April 2017 were investigated retrospectively.The patients were divided into following three groups based on the dosage of Ⅳ-TXA after surgery:40 patients received ≤3 g Ⅳ-TXA after surgery (group T1),50 patients received 4 g (group T2) and the other 51 patients received ≥5 g Ⅳ-TXA (group T3).The total blood loss (TBL),hidden blood loss (HBL),transfusion rate,maximum hemoglobin (Hb) drop,the incidence of intramuscular venous thrombosis,deep vein thrombosis (DVT) and pulmonary embolism (PE),fibrinolysis parameters [fibrin(-ogeu) degradation products (FDP),D-dimer],and inflammation markers [C-reactive protein (CRP),interleukin-6 (IL-6)] during perioperative period were evaluated.In addition,correlation analyses between the dosage of Ⅳ-TXA and fibrinolysis parameters and inflammation markers were conducted.Results The mean TBL,HBL and maximum Hb drop in group T2 (537.16±270.43 ml,431.36±271.99 ml,19.68± 10.68 g/L) and T3 (541.31±290.00 ml,439.94±290.71 ml,20.24±8.48 g/L) were lower than those in group T1 (748.22±394.34 ml,P=0.012,0.013;636.47±388.14 ml,P=0.011,0.015;25.88± 11.77 g/L,P=0.005,0.010,respectively).No patient needed transfusion in all groups.There was no statistically difference in the incidence of intramuscular venous thrombosis of lower limbs among three groups (P＞ 0.05).No episode of DVT or PE occurred in any group in two weeks after surgery.There were negative correlation between the dosage of Ⅳ-TXA and FDP at postoperative day 1 and day 3 (r=-0.191,P=0.025;r=-0.291,P=0.001) and D-dimer on postoperative day 3 (r=-0.176,P=0.048).Moreover,the CRP (r=-0.184,P=0.036) and IL-6 (r=-0.269,P=0.002) level in serum on postoperatire day 1 also showed a negative relationship with the dosage of Ⅳ-TXA after surgery.Conclusion The multiple Ⅳ-TXA (≥4 g) after surgery can further reduce the TBL,HBL and maximum Hb drop following primary TKA in ERAS program without increasing the risk of thrombotic events.Most importantly,the effect of anti-fibrinolysis will be enhanced and may have an anti-inflammatory effect with the dosage of Ⅳ-TXA increased.

The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1(neo/neo) and K14cre:SmoM2(YFP)). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.
Animals ; Carcinoma, Basal Cell ; pathology ; Cell Differentiation ; drug effects ; Embryonic Stem Cells ; cytology ; Hedgehog Proteins ; antagonists & inhibitors ; metabolism ; Mice ; Motor Neurons ; cytology ; Plants, Medicinal ; chemistry ; Receptors, G-Protein-Coupled ; antagonists & inhibitors ; metabolism ; Signal Transduction ; drug effects ; Skin Neoplasms ; pathology ; Smoothened Receptor ; Solubility ; Tartrates ; blood ; pharmacology ; Tumor Burden ; drug effects ; Veratrum ; chemistry ; Veratrum Alkaloids ; blood ; isolation & purification ; pharmacology