Protective effects of melanoidins from black garlic on zearalenone-induced toxicity in zebrafish embryonic developmental model.

Zearalenone (ZEN), a ubiquitous mycotoxin that widely occurs in grain and foodstuff may induce serious toxic effects after accumulation in vivo. Melanoidins (MLDs) have shown multiple bio-functional properties such as antioxidant, anti-bacterial and prebiotic activities. Black garlic exhibits several advantages over fresh garlic related to health improvement. In this study, the alleviative effects of black garlic MLDs on ZEN-induced toxicity and the potential mechanisms were studied using zebrafish embryonic developmental model. The results showed that MLDs restored the ZEN-induced adverse influences on zebrafish embryonic development, including delay in hatching time, morphological abnormality and the impairment of nervous development. Further studies showed that MLDs significantly inhibited the ZEN-induced production of reactive oxygen species (ROS) and enhanced the intrinsic antioxidant ability by increasing the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) and the content of glutathione (GSH). In addition, co-exposure of MLDs significantly inhibited the ZEN-stimulated cellular apoptosis in zebrafish larvae through down-regulation of pro-apoptotic genes of bax, caspase-3 and caspase-9 and up-regulation of anti-apoptotic gene bcl-2. Moreover, MLDs inhibited the in vivo accumulation of ZEN in zebrafish larvae. To sum up, MLDs attenuated the ZEN-induced zebrafish embryonic developmental toxicity through suppression of the oxidative stress and intervention on mitochondria apoptosis pathway as well as inhibiting the absorption of ZEN in zebrafish embryos/larvae. The results suggest that black garlic MLDs have potential to be used as a functional ingredient against the adverse effects of exogenous toxins.

Garlic-derived exosome-like nanovesicles alleviate dextran sulphate sodium-induced mouse colitis via the TLR4/MyD88/NF-κB pathway and gut microbiota modulation.

Plant-derived exosome-like nanovesicles play an important role in transferring their biological cargos to recipient cells. The effect of garlic-derived exosome-like nanovesicles (GENs) against inflammatory bowel disease (IBD) remains unknown. This study aimed to investigate the effect of GENs on dextran sulphate sodium (DSS)-induced colitis in mice. A comprehensive analysis of bioactive components in GENs was performed. Data showed that GENs contained 26 lipids, 61 proteins and 127 known microRNAs (miRNAs). Han-miR3630-5p in GENs could bind to the 3' untranslated region of toll-like receptor 4 (TLR4), which led to the inhibition of TLR4 expression. Besides, GENs significantly up-regulated the expression of barrier-related proteins and inhibited the overproduction of pro-inflammatory cytokines in LPS-induced Caco-2 cells. As a result, pretreatment with GENs at 100 mg kg-1 efficiently ameliorated the inflammatory bowel behavior, intestinal histological pathological damage, and tight junction protein dysfunction induced by DSS in the colon tissue. Intake of GENs significantly down-regulated the expressions of TLR4, myeloid differentiation primary response gene 88 (MyD88), and nuclear factor kappa-B (NF-κB), which suppressed the downstream cascades and led to less secretion of pro-inflammatory cytokines induced by DSS. Furthermore, pretreatment with GENs altered the gut microbiota profile of colitis mice by recovering the relative abundance of Lachnospiraceae and reducing the relative abundance of Helicobacter. Totally, GENs had potential to protect the colon against DSS-induced damage through inhibiting the TLR4/MyD88/NF-κB signaling pathway and regulating gut microbiota. This study clarified the role of miRNAs of GENs in anti-colitis and proved that GENs had a potential application for IBD prevention.

Protective effects of cyanidin-3-O-glucoside on BPA-induced neurodevelopmental toxicity in zebrafish embryo model.

Bisphenol A (BPA) is ubiquitous in the environment and poses a threat to wildlife and human health. It has been reported that BPA may cause the neurotoxicity during gestational and neonatal periods. Cyanidin-3-O-glucoside (C3G) is one of the most abundant anthocyanins that has shown multiple bio-functions. In this study, the protective effects and possible mechanism of C3G against BPA-induced neurodevelopment toxicity in zebrafish embryos/larvae were studied. The results showed that co-exposure of C3G (25 µg/mL) significantly attenuated BPA-induced deficit in locomotor behavior and restored the BPA-induced aberrant changes in brain morphology of zebrafish larvae. Further studies showed that the defects of central nervous development and the downregulated neurogenesis relative genes induced by BPA were significantly counteracted by co-exposure with 5 µg/mL of C3G. In addition, C3G (25 µg/mL) mitigated the decline of glutathione (GSH) content and enzymatic activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT), attenuated oxidative stress and cell apoptosis induced by BPA in zebrafish. The enhancements of the expression of genes involved in the Nrf2-ARE pathway (Nrf2, HO-1, NQO1, GCLC, and GCLM) were also observed by co-exposure of C3G. The results indicate that C3G exerts protective effects on BPA-induced neurodevelopmental toxicity through improving transcription of neurogenesis related genes, enhancing antioxidative defense system and reducing cell apoptosis by regulation of apoptotic genes in zebrafish larvae. The results suggest that anthocyanins may play important role against the exogenous toxicity for vertebrates.

Platinum-Based Two-Photon Photosensitizer Responsive to NIR Light in Tumor Hypoxia Microenvironment.

Platinum-based photosensitizers are promising anticancer agents in photodynamic therapy. The cytotoxic effects primarily arise from the production of singlet oxygen and platination of DNA. However, their efficacy is limited by drug resistance and hypoxic tumor microenvironment. A naphthalimide-modified cyclometalated platinum(II) complex PtPAN [PA = N-(2-(diethylamino)ethyl)picolinamide, N = N-(2'-ethylhexyl)-4-ethynyl-1,8-naphthalimide] is designed to conquer these problems. PtPAN generates ROS efficiently under both normoxia and hypoxia. It does not interact with DNA and shows low cytotoxicity in the dark, while it kills tumor cells via ROS under near-infrared light irradiation; moreover, it inhibits tumor growth in mice at a low light dose with negligible side effects. PtPAN is the first reported platinum-based photosensitizer that is unreactive to DNA in the dark but highly cytotoxic upon near-infrared (NIR) irradiation for oxygen-independent photodynamic therapy. Owing to its two-photon excitation property (λ = 825 nm), PtPAN may be suitable for the treatment of deep solid tumors.

Concurrent suppression of Aß aggregation and NLRP3 inflammasome activation for treating Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative illness accompanied by severe memory loss, cognitive disorders and impaired behavioral ability. Amyloid ß-peptide (Aß) aggregation and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome play crucial roles in the pathogenesis of AD. Aß plaques not only induce oxidative stress and impair neurons, but also activate the NLRP3 inflammasome, which releases inflammatory cytokine IL-1ß to trigger neuroinflammation. A bifunctional molecule, 2-[2-(benzo[d]thiazol-2-yl)phenylamino]benzoic acid (BPBA), with both Aß-targeting and inflammasome-inhibiting capabilities was designed and synthesized. BPBA inhibited self- and Cu2+- or Zn2+-induced Aß aggregation, disaggregated the already formed Aß aggregates, and reduced the neurotoxicity of Aß aggregates; it also inhibited the activation of the NLRP3 inflammasome and reduced the release of IL-1ß in vitro and vivo. Moreover, BPBA decreased the production of reactive oxygen species (ROS) and alleviated Aß-induced paralysis in transgenic C. elegans with the human Aß42 gene. BPBA exerts an anti-AD effect mainly through dissolving Aß aggregates and inhibiting NLRP3 inflammasome activation synergistically.

Cyanidin-3-O-glucoside, cyanidin, and oxidation products of cyanidin protect neuronal function through alleviating inflammation and oxidative damage.

Neurotoxicity seriously affects the normal function of the nervous system. Cyanidin-3-O-glucoside (C3G) is the most abundant anthocyanin widely distributed in plants. Using ß-amyloid (Aß) transgenic Caenorhabditis elegans and cell models, the neuroprotective effect of C3G was examined. The results showed that C3G remarkably suppressed Aß aggregation, enhanced antioxidant capacity, improved the sensitive capacity towards chemical compounds, and boosted the memory ability of C. elegans. There was no significant difference between preventive and long-term treatment groups at the same dosage of C3G. Given the rapid metabolism and oxidation of C3G in vivo, the antioxidative and anti-inflammatory activities of C3G, the metabolite cyanidin (Cy), oxidation products of Cy (OP), as well as protocatechuic acid (PCA) at the corresponding level in OP were compared by using lipopolysaccharide (LPS)-stimulated BV2 microglia cell model. The results indicated that C3G, Cy, and OP could prevent BV2 cells against LPS-induced inflammation and oxidative damage. There was no significant difference on antioxidative and anti-inflammatory activities among C3G, Cy, and OP at the same level. Notably, PCA at the corresponding concentration in OP exhibited limited antioxidative and anti-inflammatory activities. The results suggested that C3G could exert neuroprotective function through the metabolite Cy and its oxidation products by inhibiting inflammation and oxidative damage, and PCA was not the primary bioactive species in OP. PRACTICAL APPLICATION: This study confirmed the neuroprotection of cyanidin-3-O-glucoside (C3G) in transgenic Caenorhabditis elegans. C3G, its metabolite cyanidin (Cy), and oxidation products of Cy (OP) alleviated both neuroinflammation and oxidative damage. It highlighted that C3G-rich foods could exert neuroprotective potential through their oxidation products, the constitution, and existence of OP in vivo need further study.

Adverse effects of bisphenol B exposure on the thyroid and nervous system in early life stages of zebrafish.

Bisphenol B (BPB), a widely used alternative of bisphenol A (BPA), has been detected in various environmental media and foodstuffs. However, the knowledge of the health risks about BPB is still limited. In this study, the effects of BPB on thyroid hormone homeostasis and neuronal development were evaluated by exposure of embryos 2 h post-fertilization (hpf) to BPB (0, 1, 10, 100 and 1000 µg/L) until 144 hpf. The results showed that 100 and 1000 µg/L BPB exposed larvae exhibited abnormal morphologies in phenotype and brain histological patterns. Significant decline of thyroid hormone thyroxine (T4) content and elevation of 3,5,3'-triiodothyronine (T3) content, along with the up-regulated expression of tg, trhr1, dio1, dio2, thrα, thrß genes and down-regulated expression of tsh, ttr and trh genes in BPB exposed zebrafish larvae were observed. Moreover, locomotor activity of larvae was decreased, and the transcription of genes (e.g., elavl3, gap43, zn5, α-tubulin, syn2a and mbp) related to neuronal development were inhibited after exposure to BPB. The mechanism of neurotoxicity and thyroid disruption in zebrafish larvae induced by BPB were discussed.

Surmounting tumor resistance to metallodrugs by co-loading a metal complex and siRNA in nanoparticles.

Copper complexes are promising anticancer agents widely studied to overcome tumor resistance to metal-based anticancer drugs. Nevertheless, copper complexes per se encounter drug resistance from time to time. Adenosine-5'-triphosphate (ATP)-responsive nanoparticles containing a copper complex CTND and B-cell lymphoma 2 (Bcl-2) small interfering RNA (siRNA) were constructed to cope with the resistance of cancer cells to the complex. CTND and siRNA can be released from the nanoparticles in cancer cells upon reacting with intracellular ATP. The resistance of B16F10 melanoma cells to CTND was terminated by silencing the cellular Bcl-2 gene via RNA interference, and the therapeutic efficacy was significantly enhanced. The nanoparticles triggered a cellular autophagy that amplified the apoptotic signals, thus revealing a novel mechanism for antagonizing the resistance of copper complexes. In view of the extensive association of Bcl-2 protein with cancer resistance to chemotherapeutics, this strategy may be universally applicable for overcoming the ubiquitous drug resistance to metallodrugs.

DNA topoisomerases as additional targets for anticancer monofunctional platinum(ii) complexes.

Topoisomerases are ubiquitous enzymes and important targets for DNA-oriented anticancer drugs. Two mitochondrion-targeted monofunctional platinum(ii) complexes, [Pt(ortho-PPh3CH2Py)(NH3)2Cl](NO3)2 (OPT) and [Pt(para-PPh3CH2Py)(NH3)2Cl](NO3)2 (PPT; PPh3 = triphenylphosphonium, Py = pyridine), show significant inhibition towards the activity of DNA topoisomerases in addition to their DNA binding and mitochondrial targeting capabilities. OPT exhibits strong cytotoxicity toward the human renal clear cell carcinoma 786-O and the murine prostate cancer RM-1 cell lines. The complex could bind to the minor groove of DNA, as well as DNA topoisomerases I and IIα, thereby acting as an inhibitor of topoisomerase I/IIα and causing DNA damage. The damage was evidenced by the enhanced expression of γ-H2AX, Chk1/2 phosphorylation, p53 and cell cycle arrest in the G2/M phase. In contrast, the inhibitory effect of PPT on DNA topoisomerases was largely limited to the isolated enzymes. The results demonstrate that the cellular inhibition of the complex towards the DNA topoisomerases positively correlated with its mitochondrial accumulation. Molecular docking provided more detailed structural insights into the interactions of OPT or PPT with DNA and topoisomerase I/IIα. The binding sites of OPT and PPT in topoisomerase-DNA complexes are different from each other. Aside from previously revealed DNA and mitochondrial targets, this study discovered new evidence that DNA topoisomerases may also serve as targets of monofunctional platinum(ii) complexes. For a multispecific platinum complex, strong DNA binding ability does not necessarily lead to potent cytotoxicity as other factors including the cell types, mitochondrial accumulation, and activity of DNA topoisomerases also affect the outcome of DNA damage.

Novel mitochondrion-targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1-mediating mitophagy in HCC.

[Cu(ttpy-tpp)Br2 ]Br (abbreviated as CTB) is a novel mitochondrion-targeting copper(II) complex synthesized by our research group, which contains tri-phenyl-phosphonium (TPP) groups as its lipophilic property. In this study, we explored how CTB affects mitochondrial functions and exerts its anti-tumour activity. Multiple functional and molecular analyses including Seahorse XF Bioanalyzer Platform, Western blot, immunofluorescence analysis, co-immunoprecipitation and transmission electron microscopy were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. We discovered that CTB inhibited aerobic glycolysis and cell acidification by impairing the activity of HK2 in hepatoma cells, accompanied by dissociation of HK2 from mitochondria. The modification of HK2 not only led to the complete dissipation of mitochondrial membrane potential (MMP) but also promoted the opening of mitochondrial permeability transition pore (mPTP), contributing to the activation of mitophagy. In addition, CTB co-ordinately promoted dynamin-related protein 1 (Drp1) recruitment in mitochondria to induce mitochondrial fission. Our findings established a previously unrecognized role for copper complex in aerobic glycolysis of tumour cells, revealing the interaction between mitochondrial HK2-mediated mitophagy and Drp1-regulated mitochondrial fission.

Enhancing Cytotoxicity of a Monofunctional Platinum Complex via a Dual-DNA-Damage Approach.

Mitochondrial DNA (mtDNA) is an attractive cellular target for anticancer agents in addition to nuclear DNA (nDNA). The cationic platinum(II) complex cis-[Pt(NP)(NH3)2Cl]NO3 (PtNP, NP = N-(2-ethylpyridine)-1,8-naphthalimide) bearing the DNA-intercalating moiety NP was designed. The structure of PtNP was fully characterized by single-crystal X-ray crystallography, NMR, and HRMS. PtNP is superior to cisplatin in both in vitro and in vivo anticancer activities with low systemic toxicity. The interaction of PtNP with CT-DNA demonstrated that PtNP could effectively bind to DNA through both covalent and noncovalent double binding modes. In addition to causing significant damage to nDNA and remarkable inhibition to DNA damage repair, PtNP also distributed in mitochondria, inducing mtDNA damage and affecting the downstream transcriptional level of mitochondrion-encoded genes. In addition, PtNP disturbed the physiological processes of mitochondria by reducing the mitochondrial membrane potential and promoting the generation of reactive oxygen species. Mechanistic studies demonstrate that PtNP induced apoptosis via mitochondrial pathways by upregulating Bax and Puma and downregulating Bcl-2 proteins, leading to the release of cytochrome c and activation of caspase-3 and caspase-9. As a dual-DNA-damage agent, PtNP is able to improve the anticancer activity by damaging both nuclear and mitochondrial DNA, thus providing a new anticancer mechanism of action for the naphthalimide monofunctional platinum(II) complexes.

Targeting Energy Metabolism by a Platinum(IV) Prodrug as an Alternative Pathway for Cancer Suppression.

Cancer is characterized by abnormal cellular energy metabolism, which preferentially switches to aerobic glycolysis rather than oxidative phosphorylation as a means of glucose metabolism. Many key enzymes involved in the abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV) complexes are potential anticancer prodrugs and kinetically more inert than the platinum(II) counterparts, which offer an opportunity to be modified by functional ligands for activation or targeted delivery. A novel platinum(IV) complex, c, c, t-[Pt(NH3)2Cl2(C10H15N2O3S)(C2HO2Cl2)] (DPB), was designed to explore the effects of axial ligands on the reactivity and bioactivity of the complex as well as on tumor energy metabolism. The complex was characterized by electrospray ionization mass spectrometry and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy. The introduction of dichloroacetate (DCA) markedly increases the lipophilicity, reactivity, and cytotoxicity of the complex and blocks the growth of cancer cells having active glycolysis, and the introduction of biotin (C10H16N2O3S) enhances the tumor-targeting potential of the complex. The cytotoxicity of DPB is increased dramatically in a variety of cancer cell lines as compared with the platinum(IV) complex PB without the DCA group. DPB alters the mitochondrial membrane potential and disrupts the mitochondrial morphology. The levels of mitochondrial and cellular reactive oxygen species are also decreased. Furthermore, the mitochondrial function of tumor cells was impaired by DPB, leading to the inhibition of both glycolysis and glucose oxidation and finally to the death of cancer cells via a mitochondria-mediated apoptotic pathway. These findings demonstrate that DPB suppresses cancer cells mainly through altering metabolic pathways and highlight the importance of dual-targeting for the efficacy of anticancer drugs.

Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism.

Mitochondria are potential therapeutic targets for anticancer drugs. A series of mitochondrion-targeted monofunctional platinum complexes, [Pt(ortho-PPh3CH2Py)(NH3)2Cl](NO3)2 (OPT), [Pt(meta-PPh3CH2Py)(NH3)2Cl](NO3)2 (MPT), and [Pt(para-PPh3CH2Py)(NH3)2Cl](NO3)2 (PPT) (PPh3 = triphenylphosphonium, Py = pyridine), are studied in this article. The antitumor activity and mechanism of action have been investigated in vitro and in vivo as well as on molecular levels. OPT exhibits higher efficacy than cisplatin against A549 lung cancer cells; furthermore, it shows a strong inhibition towards the growth of non-small-cell lung cancer in nude mice. The DNA binding ability of these complexes follows an order of PPT > OPT > MPT. Cellular uptake and distribution studies show that OPT accumulates mainly in mitochondria, while MPT and PPT accumulate more preferentially in nuclei than in mitochondria. As a result, OPT induces remarkable changes in the ultrastructure and membrane of mitochondria, leading to more radical mitochondrial dysfunctions than cisplatin. The release of cytochrome c from mitochondria is more evident for cells treated with OPT than with cisplatin, though the apoptosis of A549 cells induced by OPT is similar to that induced by cisplatin. Disruption to mitochondrial oxidative phosphorylation and glycolysis is involved in the antitumor mechanism of these compounds. The results indicate that in addition to DNA binding, bioenergetic pathways also play crucial roles in the antitumor activity of mitochondrion-targeted monofunctional platinum complexes.

Inhibiting Aß toxicity in Alzheimer's disease by a pyridine amine derivative.

Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid ß-peptide (Aß) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced Aß aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the Aß-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C. elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of Aß toxicity. PAT also inhibits the activity of acetylcholinesterase in C. elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both in vitro and in vivo studies demonstrate that PAT is effective in counteracting Aß toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.

DNA cleavage, DNA/HSA binding study, and antiproliferative activity of a phenolate-bridged binuclear copper(II) complex.

A novel phenolate-bridged binuclear copper(II) complex, [Cu 2II (L-3H)Cl] (1, where L = 2,6-bis[((2-hydroxybenzyl)(2-pyridylmethyl)amino)methyl]-4-methylphenol), have been synthesized and characterized. The antiproliferative activity of the complex has been tested in vitro against the human cervical cancer cell line HeLa, human non-small-cell lung cancer cell line A-549, the human breast cancer cell line MCF-7, and the human hepatic cell line LO2. The results show the complex has the low micromolar range (9.4-11.2 µM) of IC50 values towards the three cancer cell lines, which is markedly comparable to those of cisplatin. However 1 exhibited 10.6-fold less toxicity than cisplatin toward normal cells LO2, suggesting that complex 1 had high selectivity between tumor cells and normal cells. The interactions with DNA were investigated by UV-Vis absorption, fluorescence, circular dichroism, and gel electrophoresis. The results show that the copper(II) complex could strongly bind to DNA mainly by the groove binding mode and efficiently cleave the pBR322 plasmid DNA into its nicked and linear forms in the presence of excessive ascorbic acid. In addition, the evaluation of the protein binding ability shows that complex 1 could bind to human serum albumin (HSA) with a moderate binding affinity and quench the intrinsic fluorescence of HSA.

Inhibition of metal-induced amyloid ß-peptide aggregation by a blood-brain barrier permeable silica-cyclen nanochelator.

Alzheimer's disease (AD) is a neurodegenerative malady associated with amyloid ß-peptide (Aß) aggregation in the brain. Metal ions play important roles in Aß aggregation and neurotoxicity. Metal chelators are potential therapeutic agents for AD because they could sequester metal ions from the Aß aggregates and reverse the aggregation. The blood-brain barrier (BBB) is a major obstacle for drug delivery to AD patients. Herein, a nanoscale silica-cyclen composite combining cyclen as the metal chelator and silica nanoparticles as a carrier was reported. Silica-cyclen was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) and dynamic light scattering (DLS). The inhibitory effect of the silica-cyclen nanochelator on Zn2+- or Cu2+-induced Aß aggregation was investigated by using a BCA protein assay and TEM. Similar to cyclen, silica-cyclen can effectively inhibit the Aß aggregation and reduce the generation of reactive oxygen species induced by the Cu-Aß40 complex, thereby lessening the metal-induced Aß toxicity against PC12 cells. In vivo studies indicate that the silica-cyclen nanochelator can cross the BBB, which may provide inspiration for the construction of novel Aß inhibitors.

Alleviation of symptoms of Alzheimer's disease by diminishing Aß neurotoxicity and neuroinflammation.

Alzheimer's disease (AD) is one of the most prevailing neurodegenerative illnesses in the elderly. Accumulation of amyloid-ß peptide (Aß) and inflammation play critical roles in the pathogenesis and development of AD. Multi-target drugs may interdict the progress of AD through a synergistic mechanism. A neuromodulator, 2-((1H-benzo[d]imidazole-2-yl)methoxy)benzoic acid (BIBA), consisting of an Aß-targeting group and a derivative of anti-inflammatory aspirin was designed as a potential anti-AD agent. BIBA exhibits a remarkable inhibitory effect on the self- and metal-induced Aß aggregations and shows outstanding anti-inflammatory activity simultaneously. The neurotoxicity of Aß aggregates is attenuated, and the production of pro-inflammatory cytokines (PICs), such as IL-6, IL-1ß and TNF-α, in microglia stimulated by lipopolysaccharide (LPS) or Aß is reduced. Owing to the synergy between the inhibition of Aß oligomerization and downregulation of PICs, BIBA markedly prolongs the lifespan and relieves the Aß-induced paralysis of Aß-transgenic Caenorhabditis elegans, thus showing the potential to ameliorate the symptoms of AD through inhibiting Aß neurotoxicity and deactivating microglia. These findings demonstrate that both Aß aggregation and neuroinflammation are therapeutic targets for anti-AD drugs, and dual-functional agents that integrate anti-Aß and anti-inflammatory capabilities have great advantages over the traditional single-target agents for AD treatment.

Impact of Mitochondrion-Targeting Group on the Reactivity and Cytostatic Pathway of Platinum(IV) Complexes.

Platinum(IV) complexes are prodrugs of cisplatin with multiple potential advantages over platinum(II) drugs. Mitochondria play pivotal roles in producing energy and inducing death of cancer cells. Two platinum(IV) complexes, namely, c,c,t-[Pt(NH3)2Cl2(OH)(OCOCH2CH2CH2CH2PPh3)]Br and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2CH2CH2PPh3)2]Br2, were designed to explore the effect of mitochondrion-targeting group(s) on the bioactivity and cytotoxicity of platinum(IV) complexes. The complexes were characterized by electrospray ionization mass spectrometry, reverse-phase high-performance liquid chromatography, and multinuclear (1H, 13C, 31P, and 195Pt) NMR spectroscopy. The introduction of triphenylphosphonium targeting group(s) markedly influences the reactivity and cytotoxicity of the Pt(IV) complexes. The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin. The lipophilicity of the Pt(IV) complexes is enhanced by the targeting group(s), while their reactivity to DNA is decreased. As a result, the mitochondrial morphology and adenosine triphosphate producing ability are impaired, which constitutes an alternative pathway to inhibit cancer cells. This study shows that both the reactivity of platinum(IV) center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted Pt(IV) complexes. For targeting groups with pharmacological activities, their intrinsic function could enrich the anticancer mechanism of Pt(IV) complexes.

A Potential Bone-Targeting Hypotoxic Platinum(II) Complex with an Unusual Cytostatic Mechanism toward Osteosarcoma Cells.

Osteosarcoma (OS) is the most common primary pediatric bone tumor lethal to children and adolescents. Chemotherapeutic agents such as cisplatin are not effective for OS because of their poor accessibility to this cancer and severe systemic toxicity. In this study, a lipophilic platinum(II) complex bearing a bisphosphonate bone-targeting moiety, cis-[PtL(NH3)2Cl]NO3 {BPP; L = tetraethyl [2-(pyridin-2-yl)ethane-1,1-diyl]bisphosphonate}, was prepared and characterized by NMR, electrospray ionization mass spectrometry, and single-crystal X-ray crystallography. The cytotoxicity of BPP toward OS cell lines U2OS and MG-63 was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. BPP exhibits moderate inhibition against U2OS cells through a mechanism involving both DNA binding and a mevalonate pathway. The acute toxicity of BPP to mice is 7-fold lower than that of cisplatin. The relative low systemic toxicity may result from the steric hindrance of the ligand, which blocks BPP approaching the bases of DNA. The results suggest that incorporating bisphosphonates into a platinum complex not only enhances its bone-targeting property but also minimizes its reactivity toward DNA and thereby lowers the systematic toxicity of the complex. The diminished cytotoxicity of BPP could be compensated for by increasing the therapeutic dose with marginal harm. This strategy provides a new possibility for overcoming the ineffectiveness and systemic toxicity of platinum drugs in the treatment of OS.

Redox-triggered mitoxantrone prodrug micelles for overcoming multidrug-resistant breast cancer.

Multidrug resistance (MDR) severely hinders the efficient chemotherapeutic treatments of cancer. d-α-Tocopherol polyethylene 1000 succinate (TPGS) based drug delivery system holds the potential of re-sensitizing resistant cancer cells. In this study, a TPGS prodrug containing both TPGS and mitoxantrone (MTO) via a disulphide bond was synthesised and assembled into micelle (TSMm) with a monodispersed diameter of 46.50 ± 1.12 nm. The disulphide bonds within the micelles could be cleaved in response to a high concentration of intracellular glutathione (GSH) after entering the tumour cells, leading a rapid release of MTO. In vitro cytotoxicity study showed TSMm significantly inhibited the growth of resistant breast tumour cells MDA-MB-231/MDR comparing to either free MTO or disulphide-free prodrug micelle (TCMm). In addition, TSMm could sustain favourable intracellular retention and cause the depletion of ATP activity, leading to the preferential transportation of MTO into the nucleus and the reversal of MDR. In vivo imaging also verified that TSMm was specifically targeted to the tumour regions at 24 h post injection. Finally, TSMm has significantly stronger antitumor activity in xenograft nude mice with negligible side effects. Hence, TSMm can serve as promising prodrug candidates to strengthen the reversal of MDR in tumours with less side effects.