C-Reactive Protein-Albumin Ratio (CAR): A More Promising Inflammation-Based Prognostic Marker for Patients Undergoing Curative Hepatectomy for Hepatocellular Carcinoma.

Background: Systemic inflammatory response is a hallmark of cancer and plays a significant role in the development and progression of various malignant tumors. This research aimed to estimate the prognostic function of the C-reactive protein-albumin ratio (CAR) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC) and compare it with other inflammation-based prognostic scores, including the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, monocyte-lymphocyte ratio, systemic immune inflammation index, prognostic index, Glasgow prognostic score, and modified Glasgow prognostic score. Methods: Retrospective analysis was conducted on data from 1039 HCC cases who underwent curative liver resection. The prognostic performance of CAR was compared with other scores using the area under the time-dependent receiver operating characteristic (t-ROC) curve. Multivariable Cox regression analyses were performed to confirm independent predictors for disease-free survival (DFS) and overall survival (OS). Results: The area under the t-ROC curve for CAR in the evaluation of DFS and OS was significantly greater than that of other scores and alpha-fetoprotein (AFP). Patients were stratified based on the optimal cut-off value of CAR, and the data revealed that both DFS and OS were remarkably worse in the high-CAR set compared to the low-CAR set. Multivariable Cox analysis demonstrated that CAR was an independent prognostic parameters for assessing DFS and OS. Regardless of AFP levels, all patients were subsequently divided into significantly different subgroups of DFS and OS based on CAR risk stratification. Similar results were observed when applying CAR risk stratification to other scoring systems. CAR also showed good clinical applicability in patients with different clinical features. Conclusion: CAR is a more effective inflammation-based prognostic marker than other scores and AFP in predicting DFS as well as OS among patients with HCC after curative hepatectomy.

Cinnamaldehyde and Doxorubicin Co-Loaded Graphene Oxide Wrapped Mesoporous Silica Nanoparticles for Enhanced MCF-7 Cell Apoptosis.

BACKGROUND: Combined chemotherapy is often affected by the different physicochemical properties of chemotherapeutic drugs, which should be improved by the reasonable design of co-loaded preparations. PURPOSE: A kind of simple but practical graphene oxide (GO) wrapped mesoporous silica nanoparticles (MSN) modified with hyaluronic acid (MSN@GO-HA) were developed for the co-delivery of cinnamaldehyde (CA) and doxorubicin (DOX), in order to enhance their combined treatment on tumor cells and reduce their application defects. METHODS: The MSNCA@GODOX-HA was constructed by MSNCA (loading CA via physical diffusion) and GODOX-HA (modified with HA and loading DOX via π-π stacking) through the electrostatic adsorption, followed by the physicochemical characterization, serum stability and in vitro release study. Cytotoxicity on different cells was detected, followed by the tumor cell uptake tests. The intracellular reactive oxygen species (ROS) changes, mitochondrial functions and activities of caspase-3/-9 in MCF-7 cells were also evaluated, respectively. RESULTS: The MSNCA@GODOX-HA nanoparticles kept stable in FBS solution and achieved pH-responsive release behavior, which was beneficial to increase the accumulation of CA and DOX in tumor cells to enhance the treatment. MSNCA@GODOX-HA exerted higher cytotoxicity to MCF-7 human breast cancer cells than H9c2 cardiac myocyte cells, which were not only attributed to the active targeting to tumor cells by HA, but also related with the activation of intrinsic apoptotic pathway in MCF-7 cells induced by CA, which was mediated by the specific ROS signal amplification and the interference with mitochondrial function. Moreover, the efficacy of DOX was also enhanced by the above process. CONCLUSION: The establishment of the MSNCA@GODOX-HA nanoparticles played a role in promoting strengths and restricting shortcomings of CA and DOX, thereby exerting their function and achieving efficient treatment against cancer.

Antitumor Activity and Mechanism Study of Riluzole and Its Derivatives.

To explore novel antitumor agents with high efficiency and low toxicity, riluzole alkyl derivatives (4a-4i) were synthesized. Their anti-proliferative activities against HeLa, HepG2, SP2/0, and MCF-7 cancer cell lines were assessed by the CCK-8 assay and compared with human normal liver (LO2) cells. Most of them showed potent cytotoxic effects against four human tumor cell lines and low toxic to LO2 cells. In particular, 2-(N-ethylamine)-6-trifluoromethoxy- benzothiazole (4a) showed a IC50 value of 7.76 µmol/L in HeLa cells and was found to be nontoxic to LO2 cells up to 65 µmol/L. Furthermore, flow cytometry indicated that 4a could induce remarkable early apoptosis and G2/M cell cycle arrest in HeLa cells. It also impaired the migration ability of HeLa cells in wound healing assays. Western blot results demonstrated that 4a suppressed Bcl-2 protein expression but increased the level of Bax in HeLa cells, and elevated the Bax/Bcl-2 expression ratio. These new findings suggest that 4a exhibited beneficially anti-cervical cancer effect on HeLa cells by inducing HeLa cell apoptosis.

Radix Dipsaci total saponins stimulate MC3T3-E1 cell differentiation via the bone morphogenetic protein-2/MAPK/Smad-dependent Runx2 pathway.

Radix Dipsaci total saponins (RTS) are primary active components of Radix Dipsaci, which is administered orally for the treatment of osteoporosis according to Chinese Medicine. RTS have also been shown to reduce the risk of bone fractures in rats. However, the detailed molecular mechanisms underlying their action remain elusive. In the present study, the ability of RTS to increase alkaline phosphatase activity, osteocalcin levels and the degree of mineralization was investigated in MC3T3­E1 mouse osteoblast precursor cells. In addition, the associated molecular mechanism was detected. The results revealed that RTS exerted an effect on osteoblastic maturation and differentiation. Induction of differentiation by RTS was associated with an increase in the expression levels of bone morphogenetic protein­2 (BMP­2), phosphorylated (P)­Smad1/5/8, P­ERK1/2, P­p38 and Runt­related transcription factor 2 (Runx2). Blocking BMP­2 expression with noggin significantly reduced the levels of osteoblastic differentiation and subsequently attenuated the expression levels of P­Smad1/5/8, P­ERK1/2, P­p38 and Runx2. This indicated that RTS induced osteoblastic differentiation through BMP­2/mitogen­activated protein kinase/Smad1/5/8­dependent Runx2 signaling pathways and that it may be a promising agent for enhancing bone formation.

The importance of the prenyl group in the activities of osthole in enhancing bone formation and inhibiting bone resorption in vitro.

Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt-related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-κB ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects.

Preparation of amifostine polylactide-co-glycolide microspheres and its irradiation protective to mouse through oral administration.

The objectives of this study were to prepare the amifostine polylactide-co-glycolide (PLGA) microsphere and investigate its irradiation protective to mouse through oral administration. Amifostine-loaded PLGA microsphere was formulated using a modified double emulsion-solvent evaporation technique. The microsphere particle was spherical with a mean diameter of 2.8 ± 0.1 µm. Release data of amifostine PLGA microsphere was tested in phosphate-buffered saline at 37°C using a dialysis method and its release profiles was biphasic, showing a relatively large burst effect (50%) over the first 6 h, followed by a slower release phase, which sustained with 80% amifostine released in 48 h and almost 100% release till 6 days (144 h). A diffusion-controlled release model (Higuchi equation, R² = 0.9725) was obtained for amifostine releasing from PLGA microsphere. The radiation experiment was performed by applied cobalt-60 γ-radiation source. One hour before γ-radiation exposure, the mouse was orally given free amifostine and PLGA microsphere, respectively. The irradiation effects, such as blood cell concentration, superoxidase dismutase (SOD) activity and malondialdehyde (MDA) level were monitored. The results indicated that amifostine PLGA microsphere was more irradiation protective to mouse than that of free amifostine under the same oral administration route.

Synthesis and in vivo bioactivity of lipophilic alendronate derivatives against osteoporosis.

New lipophilic alendronate amidated derivatives anchored alkyl chains (C(n)H(2n+1), n = 12, 14, 16, 18) had been obtained through the reaction of alendronate with carboxylic acid under anhydrous condition. The physicochemical parameters, such as the solubility and partition coefficient P(o/w) in n-octanol/water, were determined through calculation by performing reversion phase high-performance liquid chromatography (RP-HPLC). The results showed that the derivatives had improved lipophilicity compared with alendronate. The in vivo bioactivities of the derivatives were investigated using the hindlimb unloading growing rats' model. The results showed that the derivatives had in vivo bioactivity against hindlimb unloading growing rats' bone loss, which indicated that the lipophilic derivative would be a promising new potent bisphosphates for treatment of the osteoporosis.

[Construction and evaluation of non-specific targeting cationic polymer lipid liposomes].

A new class of dendrimer polylysine poly(ethylene glycol)-lipid was designed and synthesized. The cationic polymer liposomes were prepared by the lipid film-extrusion and post-insertion two methods with these dendrimer polylysine poly(ethylene glycol)-lipid and other lipids. The structural properties of obtained cationic polymer liposomes were studied by laser light scattering and fluorescence spectrometer. It was demonstrated that the nano sized liposomes with different density of surface cationic charges can be prepared by either lipid film-extrusion or post-insertion methods, but post-insertion process did not affect drug loading, did not influence drug loading capacity and did not induce liposomal morphology and particle size. The density of positive charge does not affect the size and distribution of different liposomes size and distribution. It was the better choice for manufacture because post-insertion method did not cause early release of drug and size changes. Cell binding experiments show that cationic polymer liposomes, especially dendrimer polymer liposomes had higher local charge density, and therefore have dramatic non specific cell targeting ability.

[Acid-sensitive polymer liposomes prepared by poly(2-ethylacrylic acid) alkylamide derivatives].

Poly (2-ethylacrylic acid) (PEAA) alkylamide derivatives were synthesized for constructing pH-sensitive liposomes by partially modification of carboxylic groups of PEAA with chemical reaction. These lipid derivatives of PEAA were synthesized by partially modification of carboxylic groups of PEAA with alkylamines. The acid-sensitive polymer associated liposomes were obtained by the method of polymer self-insertion in aqueous solutions through inserting hydrophobic lipid anchors of the polymer PEAA derivatives into the outer layer of vesicles. Factor effects on polymer insertion into liposomes were evaluated and the pH-sensitivity of the polymer associated liposomes was studied by calcein release assay. The PEAA-assoeiated-liposomes were prepared successfully by the methods of self-insertion. The PEAA-associated-liposomes are shown to be stable at neutral pH. (1) There was no correlate of anchor density of PEAA with length of the alkyl chain, but was positively correlated with the degree of PEAA modification. (2) Polymer insertion increased with initial ratio of polymer to lipid. (3) Unerting hydrophobic lipidr acidic conditions the associated polymer induces membrane disruption and fusion. (4) The PEAA-associated-liposomes shown pH-sensitive drug release property under acidic conditions. The anchored-poly (ethylacrylic acid) lipid derivatives can be useful in developing a potential pH sensitive drug delivery system.