Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has ...gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,β-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.
Tumor microenvironment, such as the lowered tumor extracellular pH (pHe) and matrix metalloproteinase 2 (MMP2), has been extensively explored, which promotes the development of the ...microenvironment-responsive drug delivery system. Utilizing these unique features, an activatable cell-penetrating peptide (designated as dtACPP) that is dual-triggered by the lowered pHe and MMP2 has been constructed, and a smart nanoparticle system decorating with dtACPP has been successfully developed, which could dual-load gene drug and chemotherapeutics simultaneously. After systemic administration, dtACPP-modified nanoparticles possess passive tumor targetability via the enhanced permeability and retention effect. Then dtACPP would be activated to expose cell-penetrating peptide to drive the nanoparticles’ internalization into the intratumoral cells. As angiogenesis and tumor cells might be mutually improved in tumor growth, so combining antiangiogenesis and apoptosis is meaningful for oncotherapy. Vascular endothelial growth factor (VEGF) is significant in angiogenesis, and anti-VEGF therapy could decrease blood vessel density and delay tumor growth obviously. Chemotherapy using doxorubicin (DOX) could kill off tumor cells efficiently. Here, utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and DOX (designated as dtACPPD/shVEGF–DOX) results in effective shutdown of blood vessels and cell apoptosis within the tumor. On the premise of effective drug delivery, dtACPPD/shVEGF–DOX has demonstrated good tumor targetability, little side effects after systemic administration, and ideal antitumor efficacy.
Emerging clinical usage and pharmacological effects have been achieved in using Rehmanniae Radix either singly or in combination with other herbs to treat skeletal diseases in traditional Chinese ...medicine (TCM) in the recent years. This study is aimed to provide a comprehensive review about the historical TCM interpretation of the action of Rehmanniae Radix in osteoporosis, its usage in clinical trials and osteoporotic models, its main phytochemical constituents, and its pharmacokinetics.
Several databases included PubMed, China Knowledge Resource Integrated Database, China Science and Technology Journal Database, National Science and Technology Library and the Web of Science Database were consulted to locate the publications pertaining to Rehmanniae Radix. The initial inquiry was conducted for the presence of the following terms combinations in the abstracts: Rehmanniae Radix, Dihuang, phytochemistry, pharmacokinetics, osteoporosis, bone, osteoclast and osteoblast. About 330 research papers and reviews were consulted.
In TCM, Rehmanniae Radix exerts the anti-osteoporotic effect via regulating the functions of kidney and liver as well as improving blood circulation. 107 clinical trials are identified that used Rehmanniae Radix in combination with other herbs to treat post-menopausal, senile and secondary osteoporosis. Most of the clinical trials are characterized by high efficacy and no obvious adverse effects. However, the efficacies of these clinical trials are limited because of small patient sample size, short treatment duration and poor clinical design. In addition, TCM herbs under the clinical study are not clear because of a lack of standardization and authentication. The pharmacokinetics data demonstrate that the ingredients of Rehmanniae Radix are widely distributed after administration, and that catalpol and ajugol as well as acetoside are supposed to be the active constituents. More than 140 individual compounds have been currently isolated from this plant and reported to show pleiotropic effects on various diseases. Rehmanniae Radix displays bone protecting features in the osteoporosis models via the delicate balance between osteoclastogenesis and osteoblastogenesis through single herb extracts and its isolated compounds.
The successful inclusion of Rehmanniae Radix in clinical trials and preclinical studies for the management of osteoporosis has attracted rising attentions for identifying potential anti-osteoporotic candidates from this plant and clinical existing TCM formulas, which will further speed up anti-osteoporosis drug discovery processes. Properly designed and well controlled prospective studies are still needed to further demonstrate bone protective actions and safe use of this herb and its ingredients
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Abstract Multifunctional nanocarriers are increasingly promising for disease treatment aimed to regulate multiple pathological dysfunctions and overcome barriers in drug delivery. Here we develop a ...multifunctional nanocarrier for Alzheimer's disease (AD) treatment by achieving therapeutic gene and peptide co-delivery to brain based on PEGylated dendrigraft poly- l -lysines (DGLs) via systemic administration. The dendritic amine-rich structure of DGLs provides plenty reaction sites and positive charge for drug loading. Successful co-delivery of drugs overcoming the blood–brain barrier by brain-targeted ligand modification was demonstrated both in vitro and in vivo . The pharmacodynamics study of the system following multiple-dosing treatment was verified in transgenic AD mice. Down-regulation of the key enzyme in amyloid-β formation was achieved by delivering non-coding RNA plasmid. Simultaneous delivery of the therapeutic peptide into brain leads to reduction of neurofibrillary tangles. Meanwhile, memory loss rescue in AD mice was also observed. Taken together, the multifunctional nanocarrier provides an excellent drug co-delivery platform for brain diseases.
Abstract Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related ...apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly- l -lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood–brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo . The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system.
Public-private partnerships (PPPs) have been widely applied in infrastructure development around the world. However, reasonable concessionary items are critical to compromise interest conflicts ...between government agencies and sponsors to ensure project success. A broad literature review centering on PPP transaction structuring revealed two significant research gaps: (1) a lack of attention to the ‘availability payment only’ (APO) funding method and (2) negligence of the public side’s perspective in determining concessionary items. The research objective was to develop a methodological framework for determining concessionary items in APO PPP projects while considering the interests of the public side. This study proposed a value-for-money (VFM) and social values integrated framework which accommodates discounted cash flow (DCF) analysis, bargaining game modeling, and multi-objectives decision-making (MODM). This framework enables a decision-making process based on both an indifferent feasible interval of concessionary items under a discount rate agreed upon by both parties and an optimal set of concessionary items. Additionally, results of a sensitivity analysis indicated that project construction profit can significantly affect feasible and optimal concession items, and the optimal concession period is less sensitive to changes in risk allocation. The application of proposed model indicated that this paper successfully provides a methodology for determining a feasible interval and an optimal concession items group tailored to APO PPP projects. This study paves the way towards a platform for the public and private partners to jointly and quickly come up with sound PPP concessional items in light of the win-win principle, particularly under the APO funding mechanism.
Herba Epimedii (HEP) known as YinYangHuo in Chinese is the dried leaf of the Epimediium, and has been historically used in combination with other herbs to treat skeletal diseases in traditional ...Chinese medicine (TCM). Here, we review the historical TCM interpretation of the action of HEP, its use in clinical trials, its main phytochemical constituents and its pharmacological findings. 85 clinical trials were identified which used HEP in TCM prescriptions with other herbs to treat primary and secondary osteoporosis from 2005 to now. More than 60 individual compounds were isolated and characterized from HEP and studied in various animal and cell models. HEP and its constituents exhibited a variety of anti-resorptive and bone formation-stimulating effects, which target different pathways in the bone remodeling cycle. These compounds may provide new perspectives in alternative treatment regimes and reveal novel chemical scaffolds for the development of anti-osteoporotic drugs. These approaches are also useful for guiding our research to employ an integrative therapeutic approach to treat complex diseases such as osteoporosis diseases which could be superior to the conventional single target - single drug approach.
Abstract A tumor targeting nanoparticle system has been successfully developed to response to the lowered tumor extracellular pH (pHe) and upregulated matrix metalloproteinase 2 (MMP2) in the tumor ...microenvironment. The nanoparticles are modified with activatable cell-penetrating peptide (designated as dt ACPP) that's dual-triggered by the lowered pHe and MMP2. In dt ACPP, the internalization function of cell-penetrating peptide (CPP) is quenched by a pH-sensitive masking peptide, linking by a MMP2 substrate. The masking peptide is negatively charged to quench the cationic CPP well after systemic administration. Hence, dt ACPP-modified nanoparticles possesses passive tumor targetability via the enhanced permeability and retention (EPR) effect. Once reaching the tumor microenvironment, the pre-existing attraction would be eliminated due to the lowered pHe, accompanying the linker cleaved by MMP2, dt ACPP would be activated to expose CPP to drive the nanoparticles' internalization into the intratumoral cells. The studies of plasmid DNA loading, toxicity assessment, cellular uptake, tumor targeting delivery, and gene transfection demonstrate that dt ACPP-modified nanoparticle system is a potential candidate for tumor targeting gene delivery.
Triple‐negative breast cancer (TNBC) is a basal‐like cancer which is considered to be more intrusive, have a poorer prognosis and chemoresistance. TNBC is characterized by the presence of epithelial ...to mesenchymal transition (EMT) that plays a major role in the progression of the cancer. In the present study, we first use a classic prescription of Chinese medicine Fangjihuangqi Decoction to treat TGFβ1‐induced MDA‐MB‐231 cells in vitro. Our data showed that TGFβ1‐induced MDA‐MB‐231 cell morphology change, promoted MDA‐MB 231 invasion, increased Vimentin expression, and decreased E‐cadherin expression. Further, Fangjihuangqi Decoction‐medicated serum (FHS) treated both MDA‐MB 231 cells and TGFβ1‐induced MDA‐MB‐231 cells. Results showed that Fangjihuangqi Decoction could inhibit cell proliferation, reduce cell invasion, increase E‐cadherin expression, and decrease EMT markers. Secondly, we established a xenograft tumor zebrafish model to assess Fangjihuangqi Decoction inhibition of cancer cell proliferation and invasion. Our results indicated that Fangjihuangqi Decoction could inhibit tumor growth, restrain the sprouts number of tumor neovascularization, and reduce the length of tumor neoplastic lymphatics by increasing E‐cadherin expression and decreasing EMT markers in TNBC xenograft tumor zebrafish model. Overall, our studies provide evidences that Fangjihuangqi Decoction could inhibit TNBC, reverse EMT, and contribute to antimetastasis by increasing E‐cadherin expression and decreasing EMT markers, which provide an experimental basis for clinical application of Fangjihuangqi Decoction on TNBC treatment.
Fangjihuangqi Decoction could inhibit MDA‐MB‐231 cell invasion in vitro and decrease tumor growth and metastasis in triple‐negative breast cancer xenografts tumor model zebrafish
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