Design, synthesis, and anti-oomycete activity of 3-acyloxymaltol/ethyl maltol derivatives.

Twenty 3-acyloxymaltol/ethyl maltol derivatives (7a-j and 8a-j) were synthesized and evaluated in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of twenty derivatives, more than half of the compounds 7f, 7h, 8a-h and 8j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 22.23 mg/L), and the EC50 values of 18.66, 20.32, 12.80, 16.18, 10.59, 14.98, 16.80, 10.36, 15.32, 12.64, and 13.59 mg/L, respectively. Especially, compounds 8c and 8f exhibited the best anti-oomycete activity against P. capsici with EC50 values of 10.59 and 10.36 mg/L, respectively. Overall, hydroxyl group of maltol/ethyl maltol is important active modification site.

The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency.

The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.

[Simultaneous determination of maltol and seventeen saponins in red and black ginseng by UPLC-PDA wavelength switching method].

This study developed a UPLC-PDA wavelength switching method to simultaneously determine the content of maltol and seventeen saponins in red and black ginseng and compared the quality differences of two different processed products of red and black ginseng. A Waters HSS T3 column(2. 1 mm×100 mm, 1. 8 µm) at 30 ℃ was adopted, with the mobile phase of acetonitrile(A) and water containing 0. 1% phosphoric acid(B) under gradient elution, the flow rate of 0. 3 m L·min~(-1), and the injection volume of 2 µL.The wavelength switching was set at 273 nm within 0-11 min and 203 nm within 11-60 min. The content results of multiple batches of red and black ginseng samples were analyzed by the hierarchical cluster analysis(HCA) and principal component analysis(PCA) to evaluate the quality difference. The results showed that the 18 constituents exhibited good linear relationships within certain concentration ranges, with the correlation coefficients(r) greater than 0. 999 1. The relative standard deviations(RSDs) of precision,repeatability, and stability were all less than 5. 0%. The average recoveries ranged from 95. 93% to 104. 2%, with an RSD of 1. 8%-4. 2%. The content determination results showed that the quality of red and black ginseng samples was different, and the two types of processed products were intuitively distinguished by HCA and PCA. The method is accurate, reliable, and reproducible. It can be used to determine the content of maltol and seventeen saponins in red and black ginseng and provide basic information for the quality evaluation and comprehensive utilization of red and black ginseng.

Ethyl maltol disrupt iron homeostasis in SH-SY5Y neuroblastoma cell line.

Ethyl Maltol (EM) is a commonly used flavoring compound and has been reported to bind iron and facilitate iron transport. Since EM is membrane permeable, the potential that it disrupts intracellular iron homeostasis was investigated. EM increased the labile iron pool in SH-SY5Y cells and increased iron-responsive protein activity using a reporter assay in the HEK293 cells. EM induced the expression of transferrin receptor 1 messenger RNA (mRNA) and decreased the expression of ferritin light chain protein in SH-SY5Y cells. Expression of the iron-responsive amyloid precursor protein attenuated the effects of EM on these iron-responsive genes. EM treatment decreased cell viability and increased DNA damage. EM also increased the level of phosphorylated p53 and the expression of the p53-regulated genes, p21, and 14-3-3σ. The expression of amyloid precursor protein (APP) attenuated the effects of EM on viability, DNA damage, and the p53 response. Overall, we suggest that EM decreases cell viability through a mechanism involving the p53 pathway. The attenuated responses observed in cells expressing APP suggest that the effects of EM are due to disrupting iron homeostasis.

Deferiprone and Iron-Maltol: Forty Years since Their Discovery and Insights into Their Drug Design, Development, Clinical Use and Future Prospects.

The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol-iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world's population. Detailed insights into different aspects of drug development associated with L1 and the maltol-iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.

Maltol ameliorates intervertebral disc degeneration through inhibiting PI3K/AKT/NF-κB pathway and regulating NLRP3 inflammasome-mediated pyroptosis.

OBJECTIVES: As one of the major causes of low back pain, intervertebral disc degeneration (IDD) has caused a huge problem for humans. Increasing evidence indicates that NLRP3 inflammasome-mediated pyroptosis of NP cells displays an important role in the progression of IDD. Maltol (MA) is a flavoring agent extracted from red ginseng. Due to its anti-inflammatory and antioxidant effects, MA has been widely considered by researchers. Therefore, we hypothesized that MA may be a potential IVD protective agent by regulating NP cells and their surrounding microenvironment. METHODS: In vitro, qRT-PCR, and Western blot were used to explore the effect of MA on the transcription and protein expression of the anabolic protein (ADAMTS5, MMP3, MMP9) catabolic protein (Aggrecan), and pro-inflammatory factor (iNOS COX-2). Next, the effects of MA on PI3K/AKT/NF-κB pathway and pyroptosis pathway were analyzed by Western blot and immunofluorescence. Molecular docking was used to investigate the relationship between PI3K and MA. Moreover, ELISA was also used to detect the effects of MA on inflammatory factors (TNF-α, PGE2, IL-1ß, and IL-18). In vivo, the effects of MA on the vertebral structure of IDD mice were studied by HE and SO staining and the effects of MA on ECM and PI3K/AKT/NF-κB and pyroptosis pathway of IDD mice were studied by immunohistochemical staining. RESULTS: MA can ameliorate intervertebral disc degeneration in vivo and in vitro. Specifically, the molecular docking results showed that the binding degree of MA and PI3K was significant. Second, in vitro studies showed that MA inhibited the degradation of ECM and inflammatory response by inhibiting the PI3K/AKT/NF-κB pathway and the pyroptosis mediated by NLRP3 inflammasome, which increased the expression of anabolic proteins, decreased the expression of catabolic proteins, and decreased the secretion of inflammatory mediators such as IL-18 and IL-1ß. In addition, according to the study results of the mouse lumbar instability model, MA also improved the tissue disorder and degradation of the intervertebral disc, reduced the loss of proteoglycan and glycosaminoglycan, and inhibited intervertebral disc inflammation, indicating that MA has a protective effect on the intervertebral disc to intervertebral disc in mice. CONCLUSIONS: Our results suggest that MA slowed IDD development through the PI3K/AKT/NF-κB signaling pathway and NLRP3 inflammasome-mediated pyroptosis, indicating that MA appeared to be a viable medication for IDD treatment.

[Hsp90 participates in the necroptosis of mouse neural cells induced by aluminum through the RIP1/RIP3/MLKL pathway].

Objective: To investigate whether heat shock protein 90 (HSP90) participates in the necroptosis of C57BL/6 mouse neurons and spatial memory impairment induced by Aluminum maltol [Al (mal) (3)] through RIP1/RIP3/MLKL pathway. Methods: In March 2022, Thirty-two C57 mice were randomly divided into control group, Low dose group, a medium dose group, and a high-dose group, with 8 mice in each group, and injected intraperitoneally with physiological saline, 20, 40, and 80, respectivelyµmol/kgAl (mal) (3) was administered, it was injected 5 days a week and discontinued 2 days for 60 days. Morris water maze test was used to test the spatial learning and memory ability of mice. Nissl staining was used to observe the pathological changes of brain tissue. The protein expression levels of RIP1, RIP3, MLKL and HSP90 in hippocampus were determined by Western blotting. Results: In the water maze experiment, compared with the control group, the number of mice crossing the platform decreased in each dose group, the difference was statistically significant (H=9.50, P=0.023), and the number of mice crossing the platform was statistically significant among each dose group (P <0.05). Compared with the control group, the number of hippocampal nerve cells in each dose group decreased, the arrangement was disordered, and the Nissellite bodies decreased. Western blotting results showed that compared with the control group, the expression level of RIP1 protein in the hippocampus of mice in high-dose group was higher, and the difference was statistically significant (P <0.05). The expression levels of RIP3, MLKL and HSP90 in hippocampal tissue of mice in medium and high dose groups were increased, and the differences were statistically significant (P<0.05). After siRNA intervention decreased the expression of HSP90 protein, the expressions of HSP90, RIP1, RIP3 and MLKL in Al (mal) (3) groups were increased, and the differences were statistically significant (P<0.05) . Conclusion: Through RIP1/RIP3/MLKL pathway, HSP90 is involved in neuronal programmed necrosis and spatial memory impairment induced by maltol aluminum in C57 mice.

Recent and Emerging Therapies for Iron Deficiency in Anemia of CKD: A Review.

Iron deficiency commonly contributes to the anemia affecting individuals with chronic kidney disease. This review describes diagnostic criteria for iron deficiency in chronic kidney disease, as well as mechanisms of functional and absolute iron deficiency and general treatment principles as delineated in the KDIGO (Kidney Disease: Improving Global Outcomes) guideline. Repletion of absolute iron deficits has progressed over time with the addition of better tolerated, more effective oral agents, including ferric citrate, ferric maltol, and sucrosomial iron. This article examines the structural characteristics and trial data enabling regulatory approval of these novel oral agents. Newer intravenous iron therapies, including ferric carboxymaltose and ferric derisomaltose, allow for fewer infusions and decreased risk of serious hypersensitivity reactions. Concerns about adverse effects such as cardiovascular events and infections are discussed. The potential risk of 6H syndrome (high FGF-23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) due to these intravenous agents is emphasized. The proposed pathophysiology of 6H syndrome and hypophosphatemia is described. Ferric pyrophosphate citrate enables administration of iron for repletion through dialysate. Relative merits, costs, and risks of various iron agents such as hypersensitivity and 6H syndrome/hypophosphatemia are summarized.

Aluminum Induced Necroptosis of PC12 Cells via TNFR1-RIP1/RIP3 Signalling Pathway.

In addition to apoptosis, it has also been reported that aluminum (Al) causes necroptosis, a new form of programmed necrosis, which has recently been discovered, in nerve cells, but its molecular mechanism is not elucidated. In order to explore the answer, in this study, we apply for this method that after PC12 cells were exposed to maltol aluminum [200 µM Al(mal)3], siRNA were used as interference technique to explore the role of Tumour necrosis factor receptor 1 (TNFR1), receptor interaction proteins 1 (RIP1) and receptor interaction proteins 3 (RIP3) in necroptosis caused by Al(mal)3. After the end of this research, we demonstrated that, initially, Al(mal)3 could trigger apoptosis and necroptosis in PC12 cells and up-regulate both mRNA and protein expressions of TNFR1, RIP1 and RIP3, also, up-regulate the phosphorylated mixed lineage kinase domain-like protein (MLKL) protein expression. Additionally, in PC12 cells treated with Al(mal)3, suppression of TNFR1 was found to enhance apoptosis and attenuate the expression of RIP1/RIP3 and phosphorylated MLKL. At last, deficiency of RIP1/RIP3 reduced the extent of necroptosis. Briefly, our results verify that the TNFR1-RIP1/RIP3 pathway could be involved in Al(mal)3 induced necroptosis.

Maltol mitigates cisplatin-evoked cardiotoxicity via inhibiting the PI3K/Akt signaling pathway in rodents in vivo and in vitro.

Our current research aims to evaluate the efficiency of a flavor enhancer, maltol (produced by heating ginseng) against cisplatin-evoked cardiotoxicity by establishing cisplatin-induced heart injury in vivo and H9C2 rat cardiomyocyte model. The cisplatin-treated mice at 3 mg/kg for four times on the 7th, 9th, 11th and 13th day, and in them appeared a serious cardiac damage accompanied with the increase in indicators of heart damage. Multiple exposure of 3 mg/kg for four times of cisplatin increased cardiac cells apoptosis with increased expression of Bax and cleaved-caspase 3, and decreased expression of Bcl-2. Interestingly, supplement of maltol at doses of 50 and 100 mg/kg for 15 days significantly suppressed the cardiac disturbance. In cultured H9C2 cells, maltol enhanced PI3K/Akt expression level during cisplatin treatment, and reduced cisplatin-induced apoptosis. Notably, inhibition of PI3K/Akt by LY294002 and HY-10249A lessened the efficacy of maltol. In mice, maltol apparently induced PI3K/Akt in heart tissues and protected against cisplatin-induced cardiotoxicity. In conclusion, maltol exerted the protective effects against cisplatin-induced cardiotoxicity, at least partially by inhibiting the activation of PI3K/Akt signaling pathways in cardiomyocytes, to ease oxidative stress, and alleviate reactive oxygen species-mediated apoptosis.

Synthesis and Anti-Oomycete Preliminary Mechanism of Sulfonate Derivatives of Ethyl Maltol.

To discover novel molecules with unique mechanism against plant pathogenic oomycetes, sixteen new sulfonate derivatives of ethyl maltol (3a-p) were synthesized by structural modification of 2-ethyl-3-hydroxy-4H-pyran-4-one, and their anti-oomycete activity against a serious agricultural disease, Phytophthora capsici Leonian was determined in this study. Among all tested compounds, derivatives 3e, 3m and 3p exhibited the most potent anti-oomycete activity against P. capsici with EC50 values of 19.40, 21.04 and 31.10 mg/L, respectively; especially 3e and 3m showed the best promising and pronounced anti-oomycete activity than zoxamide (EC50 =26.87 mg/L). The results further proved that 4-tert-butylphenylsulfonyl group, 3-nitro-4-chlorophenylsulfonyl group and 8-quinolinesulfonyl group introduced at the hydroxy position of ethyl maltol or maltol were necessary for obtaining the most potent compounds. Further mechanism studies of P. capsici treated with 3e demonstrated that this compound can affect the growth of mycelia by disrupting the integrity of the membrane, and the higher the concentration of the compound is, the greater the degree of membrane integrity damage. These important results will pave the way for further modification of ethyl maltol to develop potential new fungicides.

Maltol prevents the progression of osteoarthritis by targeting PI3K/Akt/NF-κB pathway: In vitro and in vivo studies.

Osteoarthritis (OA), a prevalent degenerative arthritis disease, principle characterized by the destruction of cartilage and associated with the inflammatory response. Maltol, a product formed during the processing of red ginseng (Panax ginseng, CA Meyer), has been reported to have the potential effect of anti-inflammatory. However, its specific mechanisms are not demonstrated. We investigated the protective effect of maltol in the progression of OA both in vitro and in vivo experiments. Human chondrocytes were pre-treated with maltol (0, 20, 40, 60 µM, 24 hours) and incubated with IL-1ß (10 ng/mL, 24 hours) in vitro. Expression of PGE2, TNF-α and NO was measured by the ELISA and Griess reaction. The expression of iNOs, COX-2, aggrecan, ADAMTS-5, MMP-13, IκB-α, p65, P-AKT, AKT, PI3K and P-PI3K was analysed by Western blotting. The expression of collagen II and p65-active protein was detected by immunofluorescence. Moreover, the serious level of OA was evaluated by histological analysis in vivo. We identified that maltol could suppress the IL-1ß-stimulated generation of PGE2 and NO. Besides, maltol not only suppressed the production of COX-2, iNOs, TNF-α, IL-6, ADAMTS-5, MMP-13, but also attenuated the degradation of collagen II and aggrecan. Furthermore, maltol remarkably suppressed the phosphorylation of PI3K/AKT and NF-κB induced by IL-1ß in human OA chondrocytes. Moreover, maltol could block the cartilage destroy in OA mice in vivo. To date, all data indicate maltol is a potential therapeutic agent by inhibiting inflammatory response via the regulation of NF-κB signalling for OA.

Oral Ferric Maltol for the Treatment of Iron-Deficiency Anemia in Patients With CKD: A Randomized Trial and Open-Label Extension.

RATIONALE & OBJECTIVE: Iron-deficiency anemia is common in patients with chronic kidney disease (CKD) not requiring kidney replacement therapy (KRT). We evaluated effects of oral iron replacement therapy with ferric maltol in these patients. STUDY DESIGN: Phase 3, double-blind, randomized, placebo-controlled trial (AEGIS-CKD) and open-label extension. SETTING & PARTICIPANTS: Adults with stage 3 or 4 CKD and iron-deficiency anemia at 30 US centers. INTERVENTION: Oral ferric maltol at 30mg or placebo twice daily for 16 weeks (2:1 randomization) followed by ferric maltol at 30mg twice daily for up to 36 weeks (all patients). OUTCOME: Change from baseline in hemoglobin (primary end point at week 16), ferritin, transferrin saturation, and serum iron; safety. RESULTS: 167 patients were randomized (ferric maltol, n=111; placebo, n=56). At week 16, hemoglobin had increased significantly with ferric maltol versus placebo (least-squares mean difference: 0.5±0.2 [SE] g/dL; 95% CI, 0.1-0.9; P=0.01). Ferritin, transferrin saturation, and serum iron increased with ferric maltol but declined with placebo (all P<0.05). Hemoglobin levels were sustained up to week 52 in patients continuing ferric maltol and increased in patients switching from placebo to ferric maltol. The most frequent adverse events were gastrointestinal (randomized phase: 41% vs 30% [ferric maltol vs placebo]; open-label phase: 56% vs 46%, respectively). Adverse events led to treatment withdrawal in 7 patients (6%) receiving ferric maltol and 5 patients (9%) receiving placebo during double-blind treatment, and 11 patients (9%) during the open-label extension. LIMITATIONS: Heterogeneity in baseline ferritin levels; high proportion of female participants; single-arm open-label extension. CONCLUSIONS: Ferric maltol was associated with statistically significant (week 16) and sustained (up to week 52) increases in hemoglobin and iron indices in patients with CKD and iron deficiency, and was well tolerated during treatment for up to 52 weeks. FUNDING: Funded by Shield Therapeutics (UK) Ltd. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02968368.

Ferric Maltol: A New Oral Iron Formulation for the Treatment of Iron Deficiency in Adults.

OBJECTIVE: To review the pharmacology, efficacy, and safety of ferric maltol (FM), an oral iron formulation, for iron deficiency anemia (IDA). DATA SOURCES: A MEDLINE/PubMed and EMBASE (January 1, 1985, to June 19, 2020) literature search was performed using the terms ferric maltol, accrufer, feraccru, iron maltol, ferric trimaltol, iron deficiency, iron deficiency anemia, inflammatory bowel disease, and chronic kidney disease. Additional data sources included prescribing information, abstracts, and the National Institutes of Health Clinical Trials Registry. STUDY SELECTION/DATA EXTRACTION: English language literature evaluating FM pharmacology, pharmacokinetics, efficacy, or safety in the treatment of IDA were reviewed. DATA SYNTHESIS: FM is a ferric, non-salt-based oral iron formulation demonstrating improved tolerance in patients with previous intolerance to other iron formulations. Phase 3 trials demonstrated significant improvements in anemia and serum iron parameters in patients with inflammatory bowel disease (IBD) and chronic kidney disease (CKD). Common adverse effects were gastrointestinal intolerance. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: FM is an effective and well-tolerated alternative to oral iron salts for patients with IBD or CKD and IDA. Emerging data suggest that FM is noninferior to intravenous (IV) ferric carboxymaltose in patients with IBD and IDA. Prior to selecting FM over IV iron products, consideration should be given to time to normalization of Hb, ease of administration, cost, and tolerability. CONCLUSION: FM is a relatively safe, effective oral iron therapy that may be better tolerated than other oral iron formulations. FM may be an effective alternative to IV iron in patients with IBD.

The p53/p21/p16 and PI3K/Akt signaling pathways are involved in the ameliorative effects of maltol on D-galactose-induced liver and kidney aging and injury.

Successive evidence has established that maltol, a flavor-enhancing agent, could provide resistance to oxidative stress-induced tissue injury in various animal models though its benefits for aging-induced liver and kidney injuries are still undetermined. In the present work, for demonstrating maltol's ameliorative effect and probable mechanism against aging-induced liver and kidney injuries, D-galactose (D-Gal)-induced animal in vivo and HEK293 cells in vitro models were established and results demonstrated that long-term D-Gal treatment increases the accumulation of advanced glycation end products (AGEs) in liver and kidney tissues, mitigates cell viability, and arrests the cycle. Interestingly, 4-weeks maltol treatment at 50 and 100 mg/kg activated aging-associated proteins including p53, p21, and p16 followed by inhibiting malondialdehyde (MDA)'s over-production and increasing the levels of antioxidant enzymes. Therefore, decreases in cytochrome P450 E1 (CYP2E1) and 4-hydroxydecene (4-HNE)'s immunofluorescence expression levels are confirmed. Furthermore, maltol improved oxidative stress injury by activating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. In conclusion, the purpose of the present study was to estimate the mechanistic insights into maltol's role as an antioxidant in liver and kidney cell senescence and injury, which will reflect potential of therapeutic strategy for antiaging and aging-related disease treatment.

New Era in the Treatment of Iron Deficiency Anaemia Using Trimaltol Iron and Other Lipophilic Iron Chelator Complexes: Historical Perspectives of Discovery and Future Applications.

The trimaltol iron complex (International Non-proprietary Name: ferric maltol) was originally designed, synthesised, and screened in vitro and in vivo in 1980-1981 by Kontoghiorghes G.J. following his discovery of the novel alpha-ketohydroxyheteroaromatic (KHP) class of iron chelators (1978-1981), which were intended for clinical use, including the treatment of iron deficiency anaemia (IDA). Iron deficiency anaemia is a global health problem affecting about one-third of the world's population. Many (and different) ferrous and ferric iron complex formulations are widely available and sold worldwide over the counter for the treatment of IDA. Almost all such complexes suffer from instability in the acidic environment of the stomach and competition from other dietary molecules or drugs. Natural and synthetic lipophilic KHP chelators, including maltol, have been shown in in vitro and in vivo studies to form stable iron complexes, to transfer iron across cell membranes, and to increase iron absorption in animals. Trimaltol iron, sold as Feraccru or Accrufer, was recently approved for clinical use in IDA patients in many countries, including the USA and in EU countries, and was shown to be effective and safe, with a better therapeutic index in comparison to other iron formulations. Similar properties of increased iron absorption were also shown by lipophilic iron complexes of 8-hydroxyquinoline, tropolone, 2-hydroxy-4-methoxypyridine-1-oxide, and related analogues. The interactions of the KHP iron complexes with natural chelators, drugs, metal ions, proteins, and other molecules appear to affect the pharmacological and metabolic effects of both iron and the KHP chelators. A new era in the treatment of IDA and other possible clinical applications, such as theranostic and anticancer formulations and metal radiotracers in diagnostic medicine, are envisaged from the introduction of maltol, KHP, and similar lipophilic chelators.

Flavored e-liquids increase cytoplasmic Ca2+ levels in airway epithelia.

E-cigarettes are noncombustible, electronic nicotine-delivery devices that aerosolize an e-liquid, i.e., nicotine, in a propylene glycol-vegetable glycerin vehicle that also contains flavors. While the effects of nicotine are relatively well understood, more information regarding the potential biological effects of the other e-liquid constituents is needed. This is a serious concern, because e-liquids are available in >7,000 distinct flavors. We previously demonstrated that many e-liquids affect cell growth/viability through an unknown mechanism. Since Ca2+ is a ubiquitous second messenger that regulates cell growth, we characterized the effects of e-liquids on cellular Ca2+ homeostasis. To better understand the extent of this effect, we screened e-liquids for their ability to alter cytosolic Ca2+ levels and found that 42 of 100 flavored e-liquids elicited a cellular Ca2+ response. Banana Pudding (BP) e-liquid, a representative e-liquid from this group, caused phospholipase C activation, endoplasmic reticulum (ER) Ca2+ release, store-operated Ca2+ entry (SOCE), and protein kinase C (PKCα) phosphorylation. However, longer exposures to BP e-liquid depleted ER Ca2+ stores and inhibited SOCE, suggesting that this e-liquid may alter Ca2+ homeostasis by short- and long-term mechanisms. Since dysregulation of Ca2+ signaling can cause chronic inflammation, ER stress, and abnormal cell growth, flavored e-cigarette products that can elicit cell Ca2+ responses should be further screened for potential toxicity.

Binding mechanism of maltol with catalase investigated by spectroscopy, molecular docking, and enzyme activity assay.

Maltol is a flavor additive that is widely used in the daily diet of humans, and its biosafety attention is concomitantly increasing. Catalase (CAT) is an antioxidant enzyme to maintain homeostasis in the tissue's environment of human body and protect cells from oxidative damages. The adverse effects of maltol to CAT activity within mouse hepatocytes as well as the structural and functional changes of CAT on molecular level were investigated by multiple spectroscopy techniques, enzyme activity experiments, and molecular docking. Results suggested that when the maltol concentrations reached to 8 × 10-5 mol L-1 , the viability of hepatocytes decreased to 93%, and CAT activity was stimulated by maltol to 111% than the control group after exposure for 24 hours. Changes in CAT activity on molecular level were consistent with those on cellular level. The fluorescence quenching of CAT by maltol was static with the forming of maltol-CAT complex. Moreover, ultraviolet-visible (UV-visible) absorption, synchronous fluorescence, and circular dichroism (CD) spectra reflected that the presence of maltol caused conformational change of CAT and made the CAT molecule skeleton loose and increased α-helix of CAT. Maltol mainly bound with CAT through hydrogen bond, and binding site that is near the heme ring in the enzyme activity center did not interact with its main amino acid residues. This study explores the combination between maltol and CAT, providing references for evaluating health damages caused by maltol.

Adamantyl pyran-4-one derivatives and their in vitro antiproliferative activity.

Pyran-4-one (maltol, kojic acid and chlorokojic acid 1) esters of adamantan-1-ylacetic acid were prepared through efficient synthetic routes in good yields and evaluated for their in vitro antiproliferative activity on four cancer cell lines: K562 (chronic myelogenous leukemia), HeLa (cervical cancer), Caco-2 (colorectal adenocarcinoma) and NCI-H358 (bronchioalveolar carcinoma). The results indicate that the presence and the position of the adamantyl acyl group or chlorine atom are the necessary requirement for antitumor activity of pyranone systems. Derivatives of kojic acid with either free (compounds 1 and 8) or acylated 5-OH group (compounds 2 and 9) have shown good-to-moderate activity (IC50 values ranging from 13.1 to 43.0 µM) on all cell lines. Adamantyl kojic acid derivative 5 with a free OH group on the position 2 showed activity only on the K562 cell line. It seems that removal of halogen or adamantyl unit from position 2 elicits antileukemic activity, as observed in compound 5. The positive influence of the adamantyl unit was also observed on a 3-OH acylated derivative of maltol I which was also selectively active on the same cell line. 5-O-benzylated adamantyl compounds 6 and 7 and unmodified starting pyranones were found to be inactive. Antibacterial activity of compounds was also evaluated on S. aureus ATCC 13709, M. catarrhalis ATCC 23246, E. faecalis ATCC29212 and E. coli TolC-Tn10, but no activity was observed (MIC values 128-256 µg/mL).

Purification and characterization of molybdenum-containing aldehyde dehydrogenase that oxidizes benzyl maltol derivative from Pseudomonas nitroreducens SB32154.

Maltol derivatives are used in a variety of fields due to their metal-chelating abilities. In the previous study, it was found that cytochrome P450 monooxygenase, P450nov, which has the ability to effectively convert the 2-methyl group in a maltol derivative, transformed 3-benzyloxy-2-methyl-4-pyrone (BMAL) to 2-(hydroxymethyl)-3-(phenylmethoxy)-4H-pyran-4-one (BMAL-OH) and slightly to 3-benzyloxy-4-oxo-4 H-pyran-2-carboxaldehyde (BMAL-CHO). We isolated Pseudomonas nitroreducens SB32154 with the ability to convert BMAL-CHO to BMAL-COOH from soil. The enzyme responsible for aldehyde oxidation, a BMAL-CHO dehydrogenase, was purified from P. nitroreducens SB32154 and characterized. The purified BMAL-CHO dehydrogenase was found to be a xanthine oxidase family enzyme with unique structure of heterodimer composed of 75 and 15 kDa subunits containing a molybdenum cofactor and [Fe-S] clusters, respectively. The enzyme showed broad substrate specificity toward benzaldehyde derivatives. Furthermore, one-pot conversion of BMAL to BMAL-COOH via BMAL-CHO by the combination of the BMAL-CHO dehydrogenase with P450nov was achieved.