• Archives of Pharmacal Research
• /
• 제29권12호
• /
• pp.1164-1170
• /
• 2006

A triptolide-lysozyme (TP-LZM) conjugate was synthesized to achieve renal specific delivery and to reduce the side effects of triptolide. Triptolide was coupled to lysozyme through succinic via an ester bond with an average coupling degree of 1 mol triptolide per 1 mol lysozyme. The lysozyme can specifically accumulate in the proximal tubular cells of the kidney, making it a potential carrier for targeting drugs to the kidney. The structure of triptolide succinate (TPS) was confirmed by IR, $^{1}H-NMR$, MS and UV. The concentrations of triptolide in various samples were determined by reversed-phase high-performance liquid chromatography (HPLC). In this study, the physicochemical and stability profiles of TP-LZM under various conditions were investgated the stability and releasing profiles of triptolide-lysozyme (TP-LZM) under various conditions. In vitro release trails showed triptolide-lysozyme was relatively stable in plasma (less than 30% of free triptolide released) and could release triptolide quickly in lysosome (more than 80% of free triptolide released) at $37^{\circ}C$ for 24 h. In addition, the biological activities of the conjugate on normal rat kidney proximal tubular cells (NRK52E) were also tested. The conjugate can effectively reduce NO production in the medium of NRK52E induced by lipopolysaccharide (LPS) but with much lower toxicity. These studies suggest the possibility to promote curative effect and reduce its extra-renal toxicity of triptolide by TP-LZM conjugate.

• Biomolecules & Therapeutics
• /
• 제25권1호
• /
• pp.80-90
• /
• 2017

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, $S1P_{1-5}$. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn's disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

• Asian Pacific Journal of Cancer Prevention
• /
• 제13권12호
• /
• pp.6463-6468
• /
• 2012

Purpose: To evaluated the effect of the gambogic acid (GA), one of the effective components of Garcinia, in combination with a new multi-targeted oral medication, sunitinib (SU) on renal cancer cell proliferation in vitro and on tumor growth in vivo. Methods: After treatment with GA or SU, either alone or in combination, MTT and FACS analysis were used to examine cell viability and cycle distribution of the renal carcinoma cell lines 786-0 and Caki-1. Western blotting was employed to examine the expression of proteins related to the cell cycle and vascular formation. Furthermore, a xenograft model was applied to study the antitumor efficacy of SU or GA alone or in combination, with immunohistochemistry to detect expression of proteins related to xenograft growth and angiogenesis. Western blotting was used to examine NF-${\kappa}B$ signaling pathway elements in xenografts. Results: Treatment of 786-0 and Caki-1 cells with GA or SU resulted in decreased tumor cell proliferation, especially with joint use. Cells accumulated more strongly in the sub-G1 phase after joint treatment with GA and SU than treatment of GA and SU alone. Western blotting arrays showed 1 protein significantly upregulated, 2 proteins downregulated, and 2 proteins unchanged. Moreover, combined use of GA and SU inhibited the growth and angiogenesis of xenografts generated from Caki-1 significantly. Immunohistochemistry arrays showed downregulation of the expression of proteins promoting xenograft growth and angiogenesis, and Western blotting showed inhibition of the NF-${\kappa}B$ signaling pathway after treatment by GA alone and in combination with SU in xenografts. Conclusions: Our results show that the joint use of GA and SU can provide greater antitumor efficacy compared to either drug alone and thus may offer a new treatment strategy for renal cell carcinoma.

• 약학회지
• /
• 제36권6호
• /
• pp.591-597
• /
• 1992

The organ distribution of $[^3H]$-methotrexate-lactosaminated bovine serum albumin conjugates ($[^3H]$-MTX-LBSA) was investigated to examine their role as a liver-specific anticancer drug. Synthesis of lactosaminated bovine serum albumin(LBSA) with BSA, lactose and sodium cyanoborohydride through reductive amination was followed by its conjugation with methotrexate (MTX) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), thereby synthesizing [$[^3H]$-MTX-LBSA conjugates. Organ distribution and plasma elimination profiles were studied in male Wistar rats after intravenous injection of [$[^3H]$-MTX-LBSA conjugates. The fates of $[^3H]$-MTX and the $[^3H]$-MTX-BSA conjugates´fates were also investigated for comparison. The results showed that the plasma level of $[^3H]$-MTX-LBSA conjugates declined more rapidly than those of $[^3H]$-MTX-BSA and their liver concentration was significantly higher than those of other treatment (p<0.01). In addition, their uptake compared to the amount taken up by the liver (1 : 33.1 at 10 min, 1 : 24.1 at 120 min). All these suggested that MTX-LBSA conjugate is one of the drug delivery system (DDS) that is advanced in concentrating MTX in the liver and minimizing the renal toxicity of MTX.

• The Korean Journal of Physiology and Pharmacology
• /
• 제20권3호
• /
• pp.261-268
• /
• 2016

$Foxp3^+$ $CD25^+CD4^+$ regulatory T (Treg) cells are crucial for the maintenance of immunological self-tolerance and are abundant in tumors. Most of these cells are chemo-attracted to tumor tissues and suppress anti-tumor responses inside the tumor. Currently, several cancer immunotherapies targeting Treg cells are being clinically tested. Cisplatin is one of the most potent chemotherapy drugs widely used for cancer treatment. While cisplatin is a powerful drug for the treatment of multiple cancers, there are obstacles that limit its use, such as renal dysfunction and the development of cisplatin-resistant cancer cells after its use. To minimize these barriers, combinatorial therapies of cisplatin with other drugs have been developed and have proven to be more effective to treat cancer. In the present study, we evaluated the effect of the combination therapy using methyl gallate with cisplatin in EL4 murine lymphoma bearing C57BL/6 mice. The combinatorial therapy of methyl gallate and cisplatin showed stronger anti-cancer effects than methyl gallate or cisplatin as single treatments. In Treg cell-depleted mice, however, the effect of methyl gallate vanished. It was found that methyl gallate treatment inhibited Treg cell migration into the tumor regardless of cisplatin treatment. Additionally, in both the normal and cisplatin-treated tumor-bearing mice, there was no renal toxicity attributed to methyl gallate treatment. These findings suggest that methyl gallate treatment could be useful as an adjuvant method accompanied with cisplatin therapy.

• 대한약침학회지
• /
• 제27권1호
• /
• pp.1-13
• /
• 2024

Background: Diabetic nephropathy (DN) is one of the major complications of chronic hyperglycaemia affecting normal kidney functioning. The ayurvedic medicine curcumin (CUR) is pharmaceutically accepted for its vast biological effects. Objectives: The Curcuma-derived diferuloylmethane compound CUR, loaded on Poly (lactide-co-glycolic) acid (PLGA) nanoparticles was utilized to combat DN-induced renal apoptosis by selectively targeting and modulating Bcl2. Methods: Upon in silico molecular docking and screening study CUR was selected as the core phytocompound for nanoparticle formulation. PLGA-nano-encapsulated-curcumin (NCUR) were synthesized following standard solvent displacement method. The NCUR were characterized for shape, size and other physico-chemical properties by Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Fourier-Transform Infrared (FTIR) Spectroscopy studies. For in vivo validation of nephro-protective effects, Mus musculus were pre-treated with CUR at a dose of 50 mg/kg b.w. and NCUR at a dose of 25 mg/kg b.w. (dose 1), 12.5 mg/kg b.w (dose 2) followed by alloxan administration (100 mg/kg b.w) and serum glucose levels, histopathology and immunofluorescence study were conducted. Results: The in silico study revealed a strong affinity of CUR towards Bcl2 (dock score -10.94 Kcal/mol). The synthesized NCUR were of even shape, devoid of cracks and holes with mean size of ~80 nm having -7.53 mV zeta potential. Dose 1 efficiently improved serum glucose levels, tissue-specific expression of Bcl2 and reduced glomerular space and glomerular sclerosis in comparison to hyperglycaemic group. Conclusion: This study essentially validates the potential of NCUR to inhibit DN by reducing blood glucose level and mitigating glomerular apoptosis by selectively promoting Bcl2 protein expression in kidney tissue.

• Asian Pacific Journal of Cancer Prevention
• /
• 제16권18호
• /
• pp.8637-8644
• /
• 2016

Background: Malignant serous effusions (MSE) are one complication in patients with advanced cancer. Endostar is a new anti-tumor drug targeting vessels which exerts potent inhibition of neovascularization. This study aimed to systematically evaluate the efficacy and safety of intraperitoneal perfusion therapy of Endostar combined with platinum chemotherapy for malignant serous effusions (MSE). Materials and Methods: Randomized controlled trials (RCTs) on intraperitoneal perfusion therapy of Endostar combined with platinum chemotherapy for malignant serous effusions were searched in the electronic data of PubMed, EMBASE, Web of Science, CNKI, VIP, CBM and WanFang. The quality of RCTs was evaluated by two independent researchers and a meta-analysis was performed using RevMan 5.3 software. Results: The total of 25 RCTs included in the meta-analysis covered 1,253 patients, and all literature quality was evaluated as "B" grade. The meta-analysis showed that Endostar combined with platinum had an advantage over platinum alone in terms of response rate of effusions (76% vs 48%, RR=1.63, 95%CI: 1.50-1.78, P<0.00001) and improvement rate in quality of life (69% vs 44%, RR=1.57, 95%CI: 1.42-1.74, P<0.00001). As for safety, there was no significant difference between the two groups in the incidences of nausea and vomiting (35% vs 34%, RR=1.01, 95%CI: 0.87-1.18, P=0.88), leucopenia (38% vs 38%, RR=1, 95%CI: 0.87-1.15, P=0.99), and renal impairment (18% vs 20%, RR=0.86, 95%CI: 0.43-1.74, P=0.68). Conclusions: Endostar combined with platinum by intraperitoneal perfusion is effective for malignant serous effusions, and patient quality of life is significantly improved without the incidence of adverse reactions being obviously increased.