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Biochemical Pharmacology (v.84, #9)
Advances in bispecific biotherapeutics for the treatment of cancer by Chad May; Puja Sapra; Hans-Peter Gerber (pp. 1105-1112).
Conventional monoclonal antibody (mAb) therapeutics interfering with cellular signaling of their respective target antigens are frequently limited in their ability to induce significant anti-tumor activities when administered as single agents in patients with solid tumors. To overcome these limitations, several new technologies are being developed to empower biotherapeutics and to improve their anti-tumor activities, while maintaining their high tumor selectivity and superior safety profiles.The various efficacy enhancement technologies developed for mAbs can be divided broadly into two categories: First, technologies that improve the intrinsic anti-tumor activities of conventional immunoglobulin mAb formats, including the enhancement of effector cell functions and modulations of target binding properties, including interference with multiple signaling pathways. The second category of empowered biologics combines complementary anti-tumor modalities independent of the IgG format, including antibody drug conjugates (ADCs). In addition, bispecific compounds designed to recruit different subsets of inflammatory cells to the tumor environment, also belong to the mechanistic complementation strategy. This approach termed redirected immune cell killing, belongs to one the most promising new biotherapeutic platforms developed in oncology.Over 20 bispecific compounds are currently being developed pre-clinically, and several compounds are undergoing early stage clinical trials. In this report, we review the progress made in the development of bispecific biotherapeutics in the context of ADCs, redirected T- and B-cell killing and targeting of multiple signaling pathways. We also discuss the status of the clinical development of this class of compounds in oncology and the promises and challenges this field is currently facing.
Keywords: Monoclonal antibody; Anticancer; Immunoglobin; IgG Bispecific
The effects of polyphenols on oxidative stress and the arachidonic acid cascade. Implications for the prevention/treatment of high prevalence diseases by M.T. Mitjavila; J.J. Moreno (pp. 1113-1122).
Redox state unbalance and the activation of the arachidonic acid (AA) cascade, contribute to the pathogenesis of cardiovascular disease (CVD) and cancer. Inflammatory cells that infiltrate the atheroma plaque or tumor are a major source of reactive oxygen species and eicosanoids. The human antioxidant defense network is complex and interlocking and there is controversy surrounding the beneficial effects of diet-derived antioxidants in vivo. However, epidemiological studies indicate that populations that consume high levels of plant-derived foods containing phenolic compounds have low rates of CVD and cancer. The molecular mechanisms for these effects are multi-faceted. They include the regulation of transcription factors and consequently the modulation of genes (cytokines, growth factors and adhesion molecules), and growth factor-receptor interactions and cell signaling cascades, which determine the expression of genes involved in cell cycle, cell survival and apoptosis, as well as adhesiveness/invasiveness and angiogenesis. The present paper also focuses on the effects of phenolic compounds on AA cascade enzymes (cyclooxygenases and lipoxygenases) and the subsequent synthesis of eicosanoids, which are involved in CVD and cancer. A better understanding of these processes could explain the beneficial effects of polyphenols on the most prevalent diseases in Western societies. This commentary shows that antioxidants under evaluation include structural modifications of low-molecular-mass polyphenols, which could lead to a valuable strategy for modulating the generation of inflammatory mediators involved in these chronic diseases.
Keywords: Abbreviations; AA; arachidonic acid; AP-1; activated protein-1; COX; cyclooxygenase; CVD; cardiovascular disease; EGCG; epigallocatechin gallate; eNOS; endothelial nitric oxide synthase; ERK; extracellular signal-regulated kinase; ET; endothelin; HDAC; histone deacetylase; HETE; hydroxyeicosatetraenoic acid; LDL; low-density lipoproteins; LOX; lipoxygenase; LT; leukotriene; MAPK; mitogen activated protein kinases; NFκB; nuclear factor κB; NO; nitric oxide; NSAID; non-steroidal anti-inflammatory drug; PG; prostaglandin; PGES; prostaglandin E; 2; synthase; PLA; 2; phospholipase A; 2; RNS; reactive nitrogen species; ROS; reactive oxygen speciesFlavonoid; Stilbene; Reactive oxygen species; Eicosanoid; Cardiovascular disease; Cancer
Selective killing of cancer cells by peptide-targeted delivery of an anti-microbial peptide by Mouldy Sioud; Anne Mobergslien (pp. 1123-1132).
Targeting of a lytic peptide to cancer cell via attachment to cancer cell-binding peptides that recognize selectively cell surface receptors.Antimicrobial peptides selectively kill bacteria while maintaining low mammalian cell cytotoxicity. However, they become cytotoxic subsequent to internalization. Here we have conjugated the lytic peptide (KLAKLAK)2 to either a cancer-cell binding peptide (LTVSPWY) selected from peptide libraries or to a gastrin-releasing peptide (GNHWAVGHLM) in order to direct the lytic peptide to cancer cells. Peptide cytotoxicity was tested in breast MCF-7 and MDA-MB-231 cancer cells. The fusion peptides were internalized by cancer cells, disintegrated the cell membrane and induced rapid killing of the cells with IC50 values as low as 4–7μM. Peptide cytotoxicity was dependent on the targeting receptor. Indeed, addition of free targeting peptide reduced cell killing. Blood lymphocytes and normal human mammary epithelial cells were less sensitive to the fusion peptides. Although most of the cells were killed by necrosis, fusion peptides branched with DNA oligonucleotides induced apoptosis as assayed by annexin V staining and activation of caspase 3. Therefore, the new designed drug peptides might provide a potent and selective anticancer therapy.
Keywords: Lytic peptides; Drug delivery; Targeted therapies; Pro-drug; Chemotherapy
Novel mithramycins abrogate the involvement of protein factors in the transcription of cell cycle control genes by Carolina Vizcaíno; Sylvia Mansilla; Luz-Elena Núñez; Carmen Méndez; José A. Salas; Francisco Morís; José Portugal (pp. 1133-1142).
The effects of mithramycin SK (MSK) and demycarosyl-3D-β-d-digitoxosyl-mithramycin SK (DIG-MSK; EC-8042), two novel analogs of the antitumor antibiotic mithramycin A, on gene transcription were examined in human HCT116 colon carcinoma cells by quantitative real-time PCR of 89 genes mainly involved in cell cycle control. Each one of the analogs down-regulated a different set of genes, while only five genes were down-regulated by both compounds. Moreover, other genes were significantly up-regulated, among them p21 WAF1 /CDKN1A which is involved in halting cells at the G1 and G2/M checkpoints. These results are rationalized in terms of MSK or DIG-MSK competition with various transcription factors for binding to consensus C/G-rich tracts encompassed in gene promoters. Changes in cell cycle distribution and protein levels after treatment with every analog were consistent with changes observed in gene expression.
Keywords: Transcription factors; Antitumor drugs; Mithramycin SK; EC-8042; Gene expression; HCT116 cells
The β-catenin/TCF complex as a novel target of resveratrol in the Wnt/β-catenin signaling pathway by Hui-Jye Chen; Le-Shiang Hsu; Yu-Ting Shia; Meng-Wei Lin; Chung-Ming Lin (pp. 1143-1153).
Wnts are secreted glycolipoproteins that play important roles in the regulation of embryonic development and tissue homeostasis. Binding of Wnt to receptors and co-receptors causes inactivation of the β-catenin destruction complex, which leads to the stabilization and nuclear translocation of β-catenin to initiate Wnt-responsive gene expression after associating with TCF in the nucleus. As its deregulation results in serious human diseases, especially cancers, the Wnt signaling pathway serves as a promising platform for screening anti-cancer drugs. Resveratrol was selected based on its ability to inhibit the β-catenin/TCF-mediated transcriptional activity. Resveratrol, a natural phytoalexin found in a variety of plants, possesses health-promoting properties including anti-aging, anti-inflammatory, anti-oxidant, anti-cancer, cardioprotective and neuroprotective activities. We found that resveratrol indeed exhibited dose-dependent suppression of Wnt signaling, reduced the expression of Wnt target genes such as cyclin D1 and conductin, and inhibited the growth of Wnt-stimulated cells and Wnt-driven colorectal cancer cells. Further studies indicated that resveratrol functions downstream of GSK3β. Treatment with resveratrol did not alter the amount of β-catenin and its distribution in the cytoplasm and nucleus, suggesting that resveratrol did not affect the accumulation and nuclear targeting of β-catenin. In contrast, co-immunoprecipitation and in vitro binding analyses substantiated that resveratrol was capable of disrupting the binding between β-catenin and TCF4, contributing to the decreased Wnt signaling. Our discoveries not only reveal a novel target of resveratrol in the Wnt signaling pathway but also show the potential of therapy with harmless resveratrol in colorectal cancer and other Wnt-related diseases.
Keywords: Resveratrol; Wnt; β-Catenin; TCF; Colorectal cancer
Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells by Brahma N. Singh; Dhruv Kumar; Sharmila Shankar; Rakesh K. Srivastava (pp. 1154-1163).
Regulation of autophagy and apoptosis by rottlerin. ROT can induce autophagy which leads to cell death in pancreatic CSCs. Rottlerin induces conversion of LC3-I to LC3-II, and accumulations of Atg7 and Beclin-1. Inhibition of PI3K/AKT/mTOR pathway by rottlerin or ATG7 and Beclin-1 induces apoptosis.Multiple lines of evidence support the idea that autophagy plays an essential role in the development of drug resistance, self-renewal, differentiation, and tumorigenic potentials of cancer stem cells (CSCs). Rottlerin (ROT) is widely used as a protein kinase C-delta (PKC-δ) inhibitor. Recent studies revealed that ROT induces apoptosis through engagement of mitochondria. However, it is not known whether ROT-induced apoptosis is associated with other mechanisms such as autophagy. Here we found that ROT induced autophagy followed by induction of apoptosis via inhibition of PI3K/Akt/mTOR pathway and activation of caspase cascade in human pancreatic CSCs. ROT induced a dose- and time-dependent inhibition of cell survival and induction of cytoplasmic vacuolations. The conversion of microtubule-associated protein LC3-I to LC3-II, and increased accumulations of Atg7 and Beclin-1 were also observed in CSCs treated with ROT. Prolonged exposure of CSCs to ROT eventually caused apoptosis which was associated with the suppression of phosphorylated Akt (Ser473) and mTOR (Ser2448), downregulation of XIAP, cIAP-1, Bcl-2 and Bcl-XL, induction of Bax, activation of caspase-3 and -9, and concomitant degradation of PARP. ROT-induced apoptosis was enhanced by dominant negative AKT, Akt1/2 inhibitor, and rapamycin. Our study also demonstrates that gene silencing of Atg7 and Beclin1, or cotreatment of the autophagosome inhibitor, 3-methyladenine, inhibited ROT-induced autophagy and accelerated ROT-induced apoptosis. The knockdown of PKC-δ did not block ROT-induced autophagy and cell death, suggesting these effects of ROT were exerted through PKC-δ-independent pathway. In summary, our data demonstrate that ROT can induce autophagy which leads to cell death in pancreatic CSCs.
Keywords: Abbreviations; CSCs; cancer stem cells; PARR; (ADP-ribose) polymerase (PARP); PKC-δ; protein kinase C delta; ROTT; rottlerinAutophagy; Pancreatic cancer; Apoptosis; PI3K; AKT; Rottlerin; Atg7; Beclin1
Rebuilding the balance of STAT1 and STAT3 signalings by fusaruside, a cerebroside compound, for the treatment of T-cell-mediated fulminant hepatitis in mice by Xing-Xin Wu; Yang Sun; Wen-Jie Guo; Yan-Hong Gu; Xue-Feng Wu; Ren-Xiang Tan; Qiang Xu (pp. 1164-1173).
Fusaruside, a natural cerebroside compound, attenuates Con A-induced T-cell dependent hepatitis through regulating the balance of STAT1 and STAT3 signalings.Dysregulation of signal transducer and activator of transcription (STAT) signaling is usually associated with intricate immune diseases and rebuilding the balance of STAT1 and STAT3 signaling is being explored as a useful approach for the treatment of these diseases. However, few chemicals have been reported to rebuild the balance of these two signalings for immune hepatitis therapy. In the present study, we found that fusaruside, a new kind of cerebroside isolated from an endophytic fungus Fusarium sp. IFB-121 in Quercus variabilis, significantly ameliorated concanavalin A (Con A)-induced T-cell-mediated fulminant hepatitis in mice, which was closely associated with the improvement of histopathological parameters, inhibition of activation of liver CD4+ T cells and NKT cells, regulation of balance of Th1/Th2/Th17/Treg cytokines and protection of hepatocyte from apoptosis. Moreover, T-cell proliferation and activation was also notably inhibited by fusaruside in vitro. Furthermore, the protective effect of fusaruside was attributable to a novel regulatory mechanism through down-regulating STAT1 activation and T-bet expression in liver CD4+ T cells and up-regulating STAT3 activation and Bcl-XL expression in hepatocytes. In conclusion, fusaruside exhibited its capability against T-cell-mediated liver injury in vivo, through rebuilding the balance of STAT1 and STAT3 signalings. These results suggest that fusaruside is potentially useful for the treatment of T-cell-mediated human liver disorders.
Keywords: Key words; Fusaruside; Concanavalin A; Liver injury; STAT1; STAT3
Evidence for ligand-specific conformations of the histamine H2-receptor in human eosinophils and neutrophils by Till M. Reher; Irena Brunskole; Detlef Neumann; Roland Seifert (pp. 1174-1185).
In this paper, we show dissociations in the effects of H2R agonists and antagonists in native cells versus recombinant systems. These data support the concept of ligand-specific receptor conformations.The histamine H2-receptor (H2R) couples to GS-proteins and induces adenylyl cyclase-mediated cAMP accumulation. In human neutrophils and eosinophils, the H2R reduces chemotactic peptide-stimulated superoxide anion (O2−) formation. However, pharmacological characterization of the H2R in these cells is far from being complete. The aim of this study was to provide a comprehensive profiling of the H2R in neutrophils and eosinophils. Histamine inhibited O2− formation in human neutrophils more effectively than in eosinophils. H2R agonists mimicked the effects of histamine and H2R antagonists blocked the effects of histamine. We noticed multiple discrepancies in the potencies and efficacies of H2R agonists with respect to cAMP accumulation and inhibition of O2− formation in both cell types. There were also differences in the antagonist profiles between cAMP accumulation and inhibition of O2− formation in neutrophils. Moreover, the pharmacological profile of the recombinant H2R did not match the H2R profile in native cells. The H2R sequence identified in human neutrophils corresponds to the published H2R sequence, excluding the exclusive expression of a new H2R isoform as explanation for the differences. Very likely, the differences between ligands are explained by the existence of ligand-specific receptor conformations with unique affinities, potencies and efficacies. Thus, our data provide evidence for the notion that the concept of ligand-specific receptor conformations can be extended from recombinant systems to native cells.
Keywords: Histamine H; 2; -receptor; Eosinophil; Neutrophil; Ligand-specific receptor conformation; Functional selectivityAbbreviations; AM; amthamine; cAMP; cyclic 3′–5′ adenosine monophosphate; DI; dimaprit; FAM; famotidine; HA; histamine; H; 2; R; histamine H; 2; -receptor; IM; impromidine; O; 2; −; superoxide anion; PLC; phospholipase C; ROS; reactive oxygen species; THIO; thioperamide; TIO; tiotidine; 5-MHA; 5-methylhistamine; ZOL; zolantadine
Concerted actions of the catechol O-methyltransferase and the cytosolic sulfotransferase SULT1A3 in the metabolism of catecholic drugs by Katsuhisa Kurogi; Adnan Alazizi; Ming-Yih Liu; Yoichi Sakakibara; Masahito Suiko; Takuya Sugahara; Ming-Cheh Liu (pp. 1186-1195).
Catecholic drugs had been reported to be metabolized through conjugation reactions, particularly methylation and sulfation. Whether and how these two Phase II conjugation reactions may occur in a concerted manner, however, remained unclear. The current study was designed to investigate the methylation and/or sulfation of five catecholic drugs. Analysis of the spent media of HepG2 cells metabolically labeled with [35S]sulfate in the presence of individual catecholic drugs revealed the presence of two [35S]sulfated metabolites for dopamine, epinephrine, isoproterenol, and isoetharine, but only one [35S]sulfated metabolite for apomorphine. Further analyses using tropolone, a catechol O-methyltransferase (COMT) inhibitor, indicated that one of the two [35S]sulfated metabolites of dopamine, epinephrine, isoproterenol, and isoetharine was a doubly conjugated (methylated and sulfated) product, since its level decreased proportionately with increasing concentrations of tropolone added to the labeling media. Moreover, while the inhibition of methylation resulted in a decrease of the total amount of [35S]sulfated metabolites, sulfation appeared to be capable of compensating the suppressed methylation in the metabolism of these four catecholic drugs. A two-stage enzymatic assay showed the sequential methylation and sulfation of dopamine, epinephrine, isoproterenol, and isoetharine mediated by, respectively, the COMT and the cytosolic sulfotransferase SULT1A3. Collectively, the results from the present study implied the concerted actions of the COMT and SULT1A3 in the metabolism of catecholic drugs.
Keywords: Methylation; Sulfation; COMTs; SULTs; Catecholic drugs
Metabolic activation by human arylacetamide deacetylase, CYP2E1, and CYP1A2 causes phenacetin-induced methemoglobinemia by Yuki Kobayashi; Tatsuki Fukami; Ryota Higuchi; Miki Nakajima; Tsuyoshi Yokoi (pp. 1196-1206).
Phenacetin has been used as an analgesic antipyretic but has now been withdrawn from the market due to adverse effects such as methemoglobinemia and renal failure. It has been suggested that metabolic activation causes these adverse effects; yet, the precise mechanisms remain unknown. We previously demonstrated that human arylacetamide deacetylase (AADAC) was the principal enzyme catalyzing the hydrolysis of phenacetin. In this study, we assessed whether AADAC was involved in phenacetin-induced methemoglobinemia. A high methemoglobin (Met-Hb) level in the blood was detected 1h after administration of phenacetin (250mg/kg, p.o.) to male C57BL/6 mice. Pre-administration of tri- o-tolylphosphate, a general esterase inhibitor, was found to decrease the levels of Met-Hb and the plasma concentration of p-phenetidine, a hydrolyzed metabolite of phenacetin. An in vitro study using red blood cells revealed that incubation of phenacetin or p-phenetidine with human liver microsomes (HLM) increased the formation of Met-Hb. To identify the enzymes involved in the formation of Met-Hb, we used recombinant enzymes and HLM treated with inhibitors in the measurement of the formation of Met-Hb. High levels of Met-Hb were observed following incubation of human AADAC with either cytochrome P450 (CYP) 1A2 or CYP2E1. Furthermore, the increased Met-Hb formation by the incubation of HLM with phenacetin was significantly inhibited to 25.1±0.7% of control by eserine, a potent AADAC inhibitor. In conclusion, we found that the hydrolysis by AADAC and subsequent metabolism by CYP1A2 and CYP2E1 play predominant roles in phenacetin-induced methemoglobinemia.
Keywords: Arylacetamide deacetylase; Cytochrome P450; Phenacetin; MethemoglobinemiaAbbreviations; AADAC; arylacetamide deacetylase; APAP; acetaminophen; BNPP; bis-(; p; -nitrophenyl)phosphate; CES; carboxylesterase; CYP; cytochrome P450; FMO; flavin-containing monooxygenase; HLM; human liver microsomes; i.p.; intraperitoneal; MLM; mouse liver microsomes; PNPA; p; -nitrophenyl acetate; p.o.; per os; RT-PCR; reverse transcription-polymerase chain reaction; TOTP; tri-; o; -tolyl phosphate
A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate by Yohei Miyamoto; Yasunori Iwao; Katsumi Mera; Hiroshi Watanabe; Daisuke Kadowaki; Yu Ishima; Victor Tuan Giam Chuang; Keizo Sato; Masaki Otagiri; Toru Maruyama (pp. 1207-1214).
A uremic toxin, CMPF induces cell damage through a generation of its radical intermediate in renal proximal tubular cell.3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a furan fatty acid uremic toxin (UT) and a substrate for organic ion transporters, contributes to the accumulation of CMPF in renal tubular cells. Although oxidative stress induced by UTs has been proposed as a mechanism of its toxicity in chronic kidney disease, little information is available regarding the redox property of CMPF and its relation to renal cell damage. The findings herein show that CMPF enhances the production of reactive oxygen species (ROS) in HK-2 cells in the presence of angiotensin II (A-II), an inducer of O2−. When iron is also present, CMPF and A-II induce the Fenton reaction, resulting in a further increase in ROS production. Such CMPF-induced oxidative stress increases TGF-β1secretion in HK-2 cells, and a positive correlation between CMPF-induced ROS production and the secretion of active TGF-β1 was observed. CMPF caused a reduction in cell viability which was negatively correlated with intracellular ROS production. These negative effects of CMPF in HK-2 cells were completely suppressed by probenecid, an inhibitor of organic anion transport. Interestingly, in vitro ROS assays indicate that CMPF directly interacts with superoxide anion radicals (O2−) and peroxy radicals (LOO) to produce CMPF radicals. The subsequent interaction of CMPF radicals with dissolved oxygen leads to the overproduction of O2−. Based on these findings, we conclude that CMPF, which accumulates in the renal cells, appears to play a prominent role as a pro-oxidant which subsequently leads to renal cellular damage via the overproduction of O2−.
Keywords: Abbreviations; CMPF; 3-carboxy-4-methyl-5-propyl-2-furanpropionate; UTs; uremic toxins; OATs; organic anion transporters; O; 2; −; superoxide anion radical; LOO; peroxy radical; ROS; reactive oxygen species; TGF; transforming growth factor; A-II; angiotensin II; CKD; chronic kidney disease; X/XO; xanthine/xanthine oxidase; Hb/; t; -Bu; hemoglobin/; t; -butyl hydroperoxide; HK-2 cells; human renal proximal tubular epithelial cells; Cu, Zn-SOD; Cu, Zn-superoxide disumutase; ALP; allopurinol; IS; indoxyl sulfate; HA; hippurate; CL; chemiluminescence; EPR; electron paramagnetic resonance; HNA; human nonmercaptalbumin; HMA; human mercaptalbumin; AGE; advanced glycation end product; NAC; N-acetylcysteine3-Carboxy-4-methyl-5-propyl-2-furanpropionate; Uremic toxin; Oxidative stress; Chronic kidney disease; Reactive oxygen species
Covalent inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by the carbamates JZL184 and URB597 by J. Allen Crow; Victoria Bittles; Abdolsamad Borazjani; Philip M. Potter; Matthew K. Ross (pp. 1215-1222).
Carboxylesterase type 1 (CES1) and CES2 are serine hydrolases located in the liver and small intestine. CES1 and CES2 actively participate in the metabolism of several pharmaceuticals. Recently, carbamate compounds were developed to inhibit members of the serine hydrolase family via covalent modification of the active site serine. URB597 and JZL184 inhibit fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively; however, carboxylesterases in liver have been identified as a major off-target. We report the kinetic rate constants for inhibition of human recombinant CES1 and CES2 by URB597 and JZL184. Bimolecular rate constants ( kinact/ Ki) for inhibition of CES1 by JZL184 and URB597 were similar [3.9 (±0.2)×103M−1s−1 and 4.5 (±1.3)×103M−1s−1, respectively]. However, kinact/ Ki for inhibition of CES2 by JZL184 and URB597 were significantly different [2.3 (±1.3)×102M−1s−1 and 3.9 (±1.0)×103M−1s−1, respectively]. Rates of inhibition of CES1 and CES2 by URB597 were similar; however, CES1 and MAGL were more potently inhibited by JZL184 than CES2. We also determined kinetic constants for spontaneous reactivation of CES1 carbamoylated by either JZL184 or URB597 and CES1 diethylphosphorylated by paraoxon. The reactivation rate was significantly slower (4.5×) for CES1 inhibited by JZL184 than CES1 inhibited by URB597. Half-life of reactivation for CES1 carbamoylated by JZL184 was 49±15h, which is faster than carboxylesterase turnover in HepG2 cells. Together, the results define the kinetics of inhibition for a class of drugs that target hydrolytic enzymes involved in drug and lipid metabolism.
Keywords: Carboxylesterase; Monoacylglycerol lipase; Carbamate; Bimolecular rate constant; Reactivation; Drug–drug interactions