Sanguisorba officinalis L. suppresses non-small cell lung cancer via downregulating the PI3K/AKT/mTOR signaling pathway based on network pharmacology and experimental investigation.

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Sanguisorba officinalis L. (SOL), a traditional Chinese herbal medicine called Diyu, has been shown to have potent antitumor effects. However, the role of SOL in suppressing NSCLC remains unknown. Methods: Network pharmacology was employed for acquiring the potential targets and mechanisms of SOL in NSCLC. Based on the predictions of network pharmacology, we used CCK8 and EdU assays to investigate cell proliferation, flow cytometry to investigate apoptosis, wound healing assay to investigate cell migration, and transwell assay to investigate cell invasion in vitro. Western blot was employed for detecting the potential proteins, including signaling pathways and apoptosis. The A549-bearing athymic nude mice were employed to verify the effect on cell proliferation and apoptosis in vivo. Results: SOL significantly inhibited the proliferation, migration and invasion of NSCLC cells in a dose-dependent manner. Flow cytometry showed that the apoptotic ratio and ROS level of NSCLC cells increased significantly with increasing concentrations. AKT and the PI3K-AKT signaling pathway were analyzed as the most relevant target and pathway via network pharmacology predictions. Western blotting revealed that the expression levels of p-PI3K, p-AKT, and p-mTOR in NSCLC cells treated with SOL were significantly downregulated, while cleaved PARP-1 and caspase-3 were upregulated in a dose-dependent manner. The results in the mouse xenograft model were consistent with those in NSCLC cell lines. Conclusion: SOL downregulated the PI3K/AKT/mTOR signaling pathway to suppress NSCLC.

Farnesal-loaded pH-sensitive polymeric micelles provided effective prevention and treatment on dental caries.

BACKGROUND: Farnesol is a sesquiterpene from propolis and citrus fruit that shows promising anti-bacterial activity for caries treatment and prevention, but its hydrophobicity limits the clinical application. We aimed to develop the novel polymeric micelles (PMs) containing a kind of derivative of farnesol and a ligand of pyrophosphate (PPi) that mediated PMs to adhere tightly with the tooth enamel. RESULTS: Farnesal (Far) was derived from farnesol and successfully linked to PEG via an acid-labile hydrazone bond to form PEG-hyd-Far, which was then conjugated to PPi and loaded into PMs to form the aimed novel drug delivery system, PPi-Far-PMs. The in vitro test about the binding of PPi-Far-PMs to hydroxyapatite showed that PPi-Far-PMs could bind rapidly to hydroxyapatite and quickly release Far under the acidic conditions. Results from the mechanical testing and the micro-computed tomography indicated that PPi-Far-PMs could restore the microarchitecture of teeth with caries. Moreover, PPi-Far-PMs diminished the incidence and severity of smooth and sulcal surface caries in rats that were infected with Streptococcus mutans while being fed with a high-sucrose diet. The anti-caries efficacy of free Far can be improved significantly by PPi-Far-PMs through the effective binding of it with tooth enamel via PPi. CONCLUSIONS: This novel drug-delivery system may be useful for the treatment and prevention of dental caries as well as the targeting therapy of anti-bacterial drugs in the oral disease.

Co-Delivery of Prednisolone and Curcumin in Human Serum Albumin Nanoparticles for Effective Treatment of Rheumatoid Arthritis.

BACKGROUND: Prednisolone (PD) is extremely effective for treating rheumatoid arthritis (RA). However, it distributes nonspecifically throughout the body and its use is associated with serious side effects, which promoted us to compound it into a phytomedicine for greater efficacy and safety. METHODS: We combined PD with curcumin (CU), an effective monomer from traditional Chinese medicine, and human serum albumin (HSA) in a nanoparticulate system (N-PD/CU) to compensate for the poor bioavailability of PD and CU. N-PD/CU was prepared by high-pressure homogenization, and its characteristics were evaluated in vitro. Next, we investigated its toxicity and mechanism of anti-inflammatory to macrophages. Finally, its pharmacokinetics, biodistribution and therapeutic efficacy were assessed in rats with adjuvant-induced arthritis (AIA). RESULTS: N-PD/CU showed a narrow size distribution around 150.4 ± 2.4 nm, a polydispersity index of 0.22 ± 0.02 and drug loading efficiency (DLE) of 88.75 ± 1.82% for PD and 85.79 ± 1.43% for CU. N-PD/CU showed sustained release of both drugs in vitro. N-PD/CU had no toxicity to macrophages in vitro on concentrations between 0.1 and 1.2 µmol/mL. In activated macrophages, N-PD decreased levels of pro-inflammatory cytokines, while N-CU increased levels of anti-inflammatory IL-10, and N-PD/CU exhibited best therapeutic effect in vitro, suggesting co-delivery of PD and CU may synergistically control the course of RA. In AIA rats, N-PD/CU accumulated in inflamed joints through the effect of extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS effect) in inflammatory lesion and showed higher therapeutic efficacy than single-loaded nanoparticles, either free drug on its own, or a simple mixture of the two drugs. CONCLUSION: This codelivery system based on HSA is a promising platform for combination chemotherapy in RA.

Preparation and Characterization of the Biological Compound Effervescent Granule of Calcium Acetate.

OBJECTIVE: Calcium acetate (Ca(CH3COO)2) is commonly used in calcium supplement for medicine, which is used as an auxiliary agent to treat osteoporosis. An effervescent granule is widely used in medical industry due to its palatability. The purpose of this study is to develop a new preparation of compound effervescent granule of the biological calcium acetate (Ca(CH3COO)2 effervescent granule), overcoming the disadvantages of the previous other dosage forms of calcium and thus enhancing the therapeutic efficacy. METHODS: The biological Ca(CH3COO)2 effervescent granule was prepared by the wet granulation method. The formulation was optimized by the orthogonal experiment. The effervescent base was comprised of various amounts of citric acid and sodium bicarbonate. Other ingredients were added for optimal performance of effervescent granule. The performed Ca(CH3COO)2 effervescent granule was evaluated for the particle size, repose angle, pH value of solution, calcium acetate content and effervescence time. The in vivo effects of Ca(CH3COO)2 effervescent granule on the bone microarchitecture were investigated via Micro-CT detection, and the serum calcium level was also investigated. RESULTS: The optimized formulation of the biological Ca(CH3COO)2 effervescent granules was composed of calcium acetate, citric acid, sodium bicarbonate, PEG6000, aspartame, PVP ethanol solution, lactose and vitamin D. Our findings reveal that this biological Ca(CH3COO)2 effervescent granule exhibited prominent effect on preventing the bone-mass loss and did better in enhancing the bone microarchitecture compared to the other calcium preparations. CONCLUSION: The biological Ca(CH3COO)2 effervescent granule is a novel dosage form among so many kinds of calcium preparations. It may perform better functions in the dairy calcium supplement.

Bone-targeting drug delivery system of biomineral-binding liposomes loaded with icariin enhances the treatment for osteoporosis.

BACKGROUND: Osteoporosis is a bone-incapacitating malady and it is characterized by obvious bone mass loss and bone microarchitecture deterioration. Current treatments for osteoporosis have many limitations, including the non-obvious therapeutic effect and long-term safety issues. Icariin is a pharmacologically active flavonoid glycoside, which shows potential application in treatment of osteoporosis. But its clinical application is limited by the inherent disadvantages such as poor water solubility, first pass effect after oral administration, and low bioavailability. Moreover, due to lack of targeting ability, icariin cannot accumulate at the local diseased region to provide early protection from fractures. To solve the application problems of icariin and enhance its therapeutic effects on osteoporosis, this work aimed to design a targeting drug delivery system of biomineral-binding liposomes (BBL) mediated by pyrophosphate ions. RESULTS: Biomineral-binding liposomes enhanced the binding ability of liposomes with hydroxyapatite particles. It increased the serum level of alkaline phosphatase and reduced that of tartrate-resistant acid phosphatase 5b. Meanwhile, BBL increased the mechanical strength of femoral midshaft, preserving the trabecular bone microarchitecture. Moreover, BBL could initiate bone turnover/remodeling of rats with osteoporosis. CONCLUSIONS: This drug targeting delivery system of BBL loading with icariin showed more therapeutic advantages than the free icariin for the treatment of osteoporosis, which may be a kind of valid candidate in future osteoporosis therapy.

NEP1-40-modified human serum albumin nanoparticles enhance the therapeutic effect of methylprednisolone against spinal cord injury.

BACKGROUND: Frequent injection of high-dose methylprednisolone (MP) is used to treat spinal cord injury (SCI), but free MP is associated with various side effects and its water solubility is low, limiting potential dosing regimes and administration routes. Albumin-based nanoparticles, which can encapsulate therapeutic drugs and release cargo in a controlled pattern, show high biocompatibility and low toxicity. The Nogo protein, expressed on the surface of oligodendrocytes, can inhibit axonal growth by binding with the axonal Nogo receptor (NgR). Peptide NEP1-40, an NgR antagonist, can bind specifically to Nogo, significantly improving functional recovery and axon growth in the corticospinal tract. Therefore, we hypothesized that delivering MP within nanoparticles decorated with NEP1-40 could avoid the disadvantages of free MP and enhance its therapeutic efficacy against SCI. RESULTS: We used human serum albumin to prepare MP-loaded NPs (MP-NPs), to whose surface we conjugated NEP1-40 to form NEP1-40-MP-NPs. Transmission electron microscopy indicated successful formation of nanoparticles. NEP1-40-MP-NPs were taken up significantly better than MP-NPs by the Nogo-positive cell line RSC-96 and were associated with significantly higher Basso-Beattie-Bresnahan locomotor scores in rats recovering from SCI. Micro-computed tomography assay showed that NEP1-40-MP-NPs mitigated SCI-associated loss of bone mineral density and accelerated spinal cord repair. CONCLUSIONS: NEP1-40-MP-NPs can enhance the therapeutic effects of MP against SCI. This novel platform may also be useful for delivering other types of drugs.