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1.
J Enzyme Inhib Med Chem ; 37(1): 2417-2422, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36065959

RESUMO

The α-class carbonic anhydrase (CA, EC 4.2.1.1) from the protozoan pathogen Trypanosoma cruzi, TcCA, was investigated earlier for its inhibition with anions, sulphonamides, thiols and hydroxamates, well-known classes of CA inhibitors (CAIs). Here we present the first inhibition study of this enzyme with phenols, which possess a diverse CA inhibition mechanism compared to the previously investigated compounds, which are all zinc binders. Indeed, phenols are known to anchor to the zinc coordinated water molecule within the enzyme active site. In a series of 22 diversely substituted phenols, the best inhibitors were simple phenol, pyrocatechol, salicylic acid, 3,5-difluorophenol, 3,4-dihydroxy-benzoic acid, 3,6- dihydroxy-benzoic acid, caffeic acid and its des-hydroxy analog, with KIs of 1.8 - 7.3 µM. The least effective TcCA inhibitor was 3-chloro-4-amino-phenol (KI of 47.9 µM). Although it is not yet clear whether TcCA can be considered as an anti-Chagas disease drug target, as no animal model for investigating the antiprotozoan effects is available so far, finding effective in vitro inhibitors may be a first relevant step towards new antiprotozoal agents.


Assuntos
Anidrases Carbônicas , Trypanosoma cruzi , Ácido Benzoico , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Fenóis/farmacologia , Zinco/farmacologia
2.
Sci Rep ; 12(1): 15580, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114355

RESUMO

In crush syndrome, massive muscle breakdown resulting from ischemia-reperfusion muscle injury can be a life-threatening condition that requires urgent treatment. Blood reperfusion into the ischemic muscle triggers an immediate inflammatory response, and neutrophils are the first to infiltrate and exacerbate the muscle damage. Since free zinc ion play a critical role in the immune system and the function of neutrophils is impaired by zinc depletion, we hypothesized that the administration of a zinc chelator would be effective for suppressing the inflammatory reaction at the site of ischemia-reperfusion injury and for improving of the pathology of crush syndrome. A crush syndrome model was created by using a rubber tourniquet to compress the bilateral hind limbs of mice at 8 weeks. A zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) was administered immediately after reperfusion in order to assess the anti-inflammatory effect of the chelator for neutrophils. Histopathological evaluation showed significantly less muscle breakdown and fewer neutrophil infiltration in TPEN administration group compared with control group. In addition, the expression levels of inflammatory cytokine and chemokine such as IL-6, TNFα, CXCL1, CXCL2, CXCR2, CCL2 in ischemia-reperfusion injured muscle were significantly suppressed with TPEN treatment. Less dilatation of renal tubules in histological evaluation in renal tissue and significantly better survival rate were demonstrated in TPEN treatment for ischemia-reperfusion injury in crush syndrome. The findings of our study suggest that zinc chelators contributed to the resolution of exacerbation of the inflammatory response and attenuation of muscle breakdown in the acute phase after crush syndrome. In addition, our strategy of attenuation of the acute inflammatory reaction by zinc chelators may provide a promising therapeutic strategy not only for crush syndrome, but also for other diseases driven by inflammatory reactions.


Assuntos
Síndrome de Esmagamento , Traumatismo por Reperfusão , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Quelantes/uso terapêutico , Quimiocinas , Síndrome de Esmagamento/tratamento farmacológico , Citocinas , Etilenodiaminas , Inflamação/tratamento farmacológico , Interleucina-6/uso terapêutico , Isquemia/tratamento farmacológico , Camundongos , Músculos/patologia , Infiltração de Neutrófilos , Reperfusão , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Borracha , Fator de Necrose Tumoral alfa/uso terapêutico , Zinco/farmacologia
3.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077208

RESUMO

Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress response characterized by the upregulation of amino acid transporters and synthetic enzymes and activation of stress-related pathways such as nuclear factor kB (NFkB) and other pro-apoptotic regulators, which leads to cancer cell death by apoptosis. Recently, APN inhibition has been shown to augment DR4-induced tumor cell death and thus overcome resistance to cancer treatment with DR4-ligand TRAIL, which is available as a recombinant soluble form dulanermin. This implies that APN inhibitors could serve as potential weapons for overcoming cancer treatment resistance. In this study, a series of basically substituted acetamidophenones and the semicarbazones and thiosemicarbazones derived from them were prepared, for which APN inhibitory activity was determined. In addition, a selective anti-proliferative activity against cancer cells expressing APN was demonstrated. Our semicarbazones and thiosemicarbazones are the first compounds of these structural types of Schiff bases that were reported to inhibit not only a zinc-dependent aminopeptidase of the M1 family but also a metalloenzyme.


Assuntos
Neoplasias , Semicarbazonas , Tiossemicarbazonas , Aminopeptidases , Antígenos CD13/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Zinco/farmacologia
4.
Int J Mol Sci ; 23(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36077451

RESUMO

This work presents the synthesis and characterization of metal-free, zinc (II), and cobalt (II) porphyrins substituted with short PEG chains. The synthesized compounds were characterized by UV-Vis, 1H and 13C NMR spectroscopy, and MALDI-TOF mass spectrometry. The origin of the absorption bands for tested compounds in the UV-Vis range was determined using a computational model based on the electron density functional theory (DFT) and its time-dependent variant (TD-DFT). The photosensitizing activity was evaluated by measuring the ability to generate singlet oxygen (ΦΔ), which reached values up to 0.54. The photodynamic activity was tested using bladder (5637), prostate (LNCaP), and melanoma (A375) cancer cell lines. In vitro experiments clearly showed the structure-activity relationship regarding types of substituents, their positions in the phenyl ring, and the variety of central metal ions on the porphyrin core. Notably, the metal-free derivative 3 and its zinc derivative 6 exerted strong cytotoxic activity toward 5637 cells, with IC50 values of 8 and 15 nM, respectively. None of the tested compounds induced a cytotoxic effect without irradiation. In conclusion, these results highlight the potential value of the tested compounds for PDT application.


Assuntos
Antineoplásicos , Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Fotoquímica , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Porfirinas/química , Zinco/farmacologia
5.
J Med Chem ; 65(18): 12346-12366, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36053318

RESUMO

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , DNA/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Zinco/farmacologia
6.
PLoS Pathog ; 18(8): e1010477, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35939512

RESUMO

Zinc is a trace metal that is essential to all forms of life, but that becomes toxic at high concentrations. Because it has both antimicrobial and anti-inflammatory properties and low toxicity to mammalian cells, zinc has been used as a therapeutic agent for centuries to treat a variety of infectious and non-infectious conditions. While the usefulness of zinc-based therapies in caries prevention is controversial, zinc is incorporated into toothpaste and mouthwash formulations to prevent gingivitis and halitosis. Despite this widespread use of zinc in oral healthcare, the mechanisms that allow Streptococcus mutans, a keystone pathogen in dental caries and prevalent etiological agent of infective endocarditis, to overcome zinc toxicity are largely unknown. Here, we discovered that S. mutans is inherently more tolerant to high zinc stress than all other species of streptococci tested, including commensal streptococci associated with oral health. Using a transcriptome approach, we uncovered several potential strategies utilized by S. mutans to overcome zinc toxicity. Among them, we identified a previously uncharacterized P-type ATPase transporter and cognate transcriptional regulator, which we named ZccE and ZccR respectively, as responsible for the remarkable high zinc tolerance of S. mutans. In addition to zinc, we found that ZccE, which was found to be unique to S. mutans strains, mediates tolerance to at least three additional metal ions, namely cadmium, cobalt, and copper. Loss of the ability to maintain zinc homeostasis when exposed to high zinc stress severely disturbed zinc:manganese ratios, leading to heightened peroxide sensitivity that was alleviated by manganese supplementation. Finally, we showed that the ability of the ΔzccE strain to stably colonize the rat tooth surface after topical zinc treatment was significantly impaired, providing proof of concept that ZccE and ZccR are suitable targets for the development of antimicrobial therapies specifically tailored to kill S. mutans.


Assuntos
Anti-Infecciosos , Cárie Dentária , ATPases do Tipo-P , Adenosina Trifosfatases , Animais , Biofilmes , Cárie Dentária/prevenção & controle , Mamíferos , Manganês/metabolismo , Ratos , Streptococcus mutans/metabolismo , Zinco/farmacologia
7.
Biomater Adv ; 136: 212792, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35929323

RESUMO

Zinc is becoming one of the leading candidate materials for biodegradable orthopedic implants owing to its attractive properties in terms of degradation behavior and mechanical properties. However, the insufficient surface bio-activities postpone its clinical application. In this study, an organic-inorganic collagen entrapped calcium/zinc phosphates coating was constructed on Zn surface to lessen Zn2+ releasing rate and to leverage the surface osteogenic and angiogenic properties. Collagen molecules were immobilized onto Zn substrate and subsequently coordinated with calcium and zinc ions to promote the CaZnP inorganic phase growth, ensuing an intertwined collagen-CaZnP hybrid system. Consequently, the hybrid coating was highly coalesced and compact. Such high quality warranted the contained Zn2+ releasing in a tolerable rate favorable for cells viability. The collagen-CaZnP coated Zn showed remarkedly stronger osteogenicity as compared to the untreated Zn, ascertained by the MC3T3-E1 osteoblast cell proliferation and differentiation assays, such as alkaline phosphatase expression and calcium nodule formation results. In addition, this hybrid coating supported human umbilical vein endothelial cells (HUVECs) migration and tube formation. The enhanced osteogenic and angiogenic properties could be ascribed to the nature of collagen and calcium/zinc phosphate components, the hybrid micro/nano-structure as well as the ability of controlling the Zn2+ release of Zn substrate into a suitable concentration range. Our strategy provides a new avenue to surface modification of biodegradable metals for bone regenerative perspective.


Assuntos
Osteogênese , Zinco , Implantes Absorvíveis , Cálcio , Colágeno/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Fosfatos/farmacologia , Zinco/farmacologia
8.
Niger J Physiol Sci ; 37(1): 49-58, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35947835

RESUMO

Impaired male reproductive function is a major complication associated with diabetes mellitus (DM). Whether or not insulin, when co-administered with zinc will reverse or ameliorate reproductive dysfunction in male diabetics is not known. This study thus sought to establish if co-administration of insulin and zinc reverses or ameliorates male reproductive dysfunction in DM better than either insulin or zinc. Five (5) normal and twenty (20) diabetic sexually mature rats were assigned into five groups of five animals each. Group A consisted of normal rats and had access to only food and water. Group B consisted of diabetic animals with no treatment and served as DM control. Groups C and D consisted of diabetic animals and received insulin and zinc respectively. Group E consisted of diabetic animals and received both insulin and zinc. All diabetic animals had free access to food and water. Insulin in all cases was given subcutaneously twice daily in the morning and evening at 1 unit and 4 units respectively. Zinc (10mg/kg) was given orally once daily. Treatments in all cases commenced two weeks after DM was confirmed. The treatment lasted ten days. Samples were thereafter collected for analyses. DM decreased sperm count, sperm motility, sperm viability, normal sperm cells, semen pH, serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone, while increasing sperm cells with defective tails. DM also impaired testicular morphology. Insulin and zinc co-administration improved sperm viability, sertoli cell count, Johnsen's score, serum FSH, LH and testosterone. Co-administration also improved semen pH towards normal. Insulin or zinc ameliorated several aspects of DM-induced male sexual dysfunction. However, the co-administration of insulin and zinc provided better results.


Assuntos
Diabetes Mellitus , Motilidade Espermática , Animais , Hormônio Foliculoestimulante , Insulina , Hormônio Luteinizante , Masculino , Ratos , Sêmen , Contagem de Espermatozoides , Testículo , Testosterona , Água , Zinco/farmacologia
9.
Int J Mol Sci ; 23(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35955445

RESUMO

Zinc levels in serum and/or tissue are reported to be altered in melanoma with unknown effects on melanoma development and biology. The purpose of this study was to examine the effects of acute chelation of free intracellular zinc pools in melanoma cell lines Bowes and A375, as well as selected melanoma tissue explants with high or low intracellular free zinc. Zinc chelating agent TPEN at the concentration of 25 µM was employed during 48 h, which significantly reduced intracellular free zinc while decreasing melanoma cell proliferation, inducing G1/S arrest and cell damage leading to mitochondrial, caspase-dependent apoptosis. Chelation of free zinc was also associated with increased generation of superoxide in cell lines but not marked lysosomal membrane damage. Conversely, melanoma explant cultures mostly displayed time-dependent loss of lysosomal membrane integrity in the presence of slowly growing superoxide levels. Loss of free zinc-dependent p53 activity was similarly disparate in individual melanoma models. Surviving melanoma cells were arrested in the cell cycle, and varying proportions of them exhibited features characteristic of premature senescence, which increased in time despite zinc reloading. The present results show that melanoma cells with varying free zinc levels respond to its acute loss in a number of individual ways, reflecting activated mechanisms including oxidative stress, lysosomal damage, and p53 activity leading to heterogenous outcomes including cell death, transient, and/or permanent cell cycle arrest and premature senescence.


Assuntos
Melanoma , Zinco , Apoptose , Linhagem Celular Tumoral , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Superóxidos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Zinco/metabolismo , Zinco/farmacologia
10.
Molecules ; 27(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35956801

RESUMO

Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin 'antipeptides'. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor 'switching' between an activated state invoking receptor dimerization/G protein coupling and an inverse agonist state mediated by an alternative/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans ('Bisartans') to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1-7). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells.


Assuntos
COVID-19 , Hipertensão , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Proto-Oncogene Mas , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2 , Zinco/farmacologia
11.
Neurosci Lett ; 788: 136837, 2022 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-35963478

RESUMO

Zinc is recognized as an important element for olfaction. Zinc nanoparticles enhance olfaction in response to odors; however, the mechanisms underlying this action remain unknown. Herein, the effect of zinc on olfactory receptors was deduced using electro-olfactogram (EOG) responses recorded from the isolated olfactory mucosae of bullfrogs (Rana catesbeiana) following the administration or chelation of zinc ions. Menthone and n-amyl acetate were used as odorants, whereas forskolin (an adenylate cyclase activator) and cholera toxin (a Gαolf activator) were used as intracellular signal transduction activators. The EOG responses provoked by the odorants and cholera toxin were suppressed by dithizone-mediated zinc ion chelation, and the EOG responses were recovered by administering non-chelated zinc. However, the EOG response to forskolin was not suppressed by dithizone. In contrast, the addition of femtomolar concentrations of zinc ions enhanced the EOG responses. The above-mentioned effects on EOG responses were examined by changing the concentration of zinc ions but not zinc nanoparticles. The results of this study suggest that Gαolf alone or both olfactory receptors and Gαolf likely require zinc ions for their activation.


Assuntos
Receptores Odorantes , Olfato , Toxina da Cólera , Colforsina/farmacologia , Ditizona , Íons , Odorantes , Mucosa Olfatória , Olfato/fisiologia , Zinco/farmacologia
12.
Biomed Pharmacother ; 154: 113600, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36037784

RESUMO

Zinc and syringic acid have metabolic and antioxidant medicinal potentials. A novel zinc(II)-syringic acid complex with improved anti-hyperglycaemic and antioxidant potential was developed. Zinc(II) was complexed with syringic acid in a 1:2 molar ratio and characterized using FT-IR, 1H NMR and LC-MS. Different experimental models were used to compare the anti-hyperglycaemic and antioxidant properties between the complex and precursors. A Zn(II)-bisyringate.2H2O complex was formed. The in vitro radical scavenging and Fe3+ reducing antioxidant, antiglycation, and α-glucosidase inhibitory activities of the complex were 1.8-5.2 folds stronger than those of the syringic acid precursor and comparable to those of the positive controls. The complex possessed an increased ability to inhibit lipid peroxidation (by 1.6-1.7 folds) and glutathione depletion (2.8-3 folds) relative to syringic acid in Chang liver cells and liver tissues isolated from rats. The complex exhibited a higher glucose uptake effect (EC50 = 20.4 and 386 µM) than its precursors (EC50 = 71.1 and 6460 µM) in L6-myotubes and psoas muscle tissues isolated from rats, respectively, which may be linked to the observed increased cellular zinc uptake potentiated by complexation. Tissue glucose uptake activity was accompanied by increased hexokinase activity, suggesting increased glucose utilization. Moreover, treatment increased tissue phospho-Akt/pan-Akt ratio. The complex had strong molecular docking scores than syringic acid with target proteins linked to diabetes. The presence of two syringic acid moieties and Zn(II) in the complex influenced its potency. The complex was not hepatotoxic and myotoxic in vitro. Zinc-syringic acid complexation may be a novel promising therapeutic approach for diabetes and oxidative complications.


Assuntos
Antioxidantes , Zinco , Animais , Antioxidantes/metabolismo , Ácido Gálico/análogos & derivados , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Zinco/farmacologia
13.
Nutrients ; 14(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36014770

RESUMO

Oxidative stress is an imbalance between levels of reactive oxygen species (ROS) and antioxidant enzymes. Compounds with antioxidant properties, such as coenzyme Q10 (CoQ10), can reduce cellular imbalance caused by an increase in ROS. CoQ10 participates in modulating redox homeostasis due to its antioxidant activity and its preserving mitochondrial functions. Thus, the present study demonstrated the protective effects of CoQ10 against oxidative stress and cytotoxicity induced by arsenic (As). Antioxidant capacity, formation of hydroperoxides, generation of ROS, and the effect on cellular viability of CoQ10, were investigated to determine the protective effect of CoQ10 against As and pro-oxidant compounds, such as zinc. Cell viability assays showed that CoQ10 is cytoprotective under cellular stress conditions, with potent antioxidant activity, regardless of the concentration tested. Zn, when used at higher concentrations, can increase ROS and show a pro-oxidant effect causing cell damage. The cytotoxic effect observed for As, Zn, or the combination of both could be prevented by CoQ10, without any decrease in its activity at cellular levels when combined with Zn.


Assuntos
Antioxidantes , Arsênio , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Zinco/farmacologia
14.
Int J Mol Sci ; 23(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36012318

RESUMO

Zinc- and copper-containing welding fumes can cause systemic inflammation after exposure in humans. Recent ex vivo studies have shown that the observed inflammation originates from exposed immune cells. In vitro studies identified the soluble fraction of metal particles as the main effectors. Isolated perfused mouse lungs (IPLs) were perfused and ventilated for 270 min. Lungs were instilled with saline solution (control), welding fume particle suspension (WFs) or the soluble fraction of the welding fumes (SF-WFs). Bronchoalveolar lavage fluid (BALF) and perfusate samples were analyzed for cytokine levels and lung tissue mRNA expression levels were analyzed via RT-PCR. All lungs instilled with WFs did not complete the experiments due to a fatal reduction in tidal volume. Accordingly, IL-6 and MPO levels were significantly higher in BALF of WF lungs compared to the control. IL-6 and MPO mRNA expression levels were also increased for WFs. Lungs instilled with SF-WFs only showed mild reactions in tidal volume, with BALF and mRNA expression levels not significantly differing from the control. Zinc- and copper-containing welding fume particles adversely affect IPLs when instilled, as evidenced by the fatal loss in tidal volume and increased cytokine expression and secretion. The effects are mainly caused by the particles, not by the soluble fraction.


Assuntos
Poluentes Ocupacionais do Ar , Soldagem , Poluentes Ocupacionais do Ar/toxicidade , Animais , Cobre/farmacologia , Citocinas/metabolismo , Gases/farmacologia , Inflamação/etiologia , Exposição por Inalação , Interleucina-6/genética , Interleucina-6/farmacologia , Pulmão/metabolismo , Camundongos , RNA Mensageiro/genética , Zinco/farmacologia
15.
Exp Oncol ; 44(2): 126-131, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35964643

RESUMO

Histone deacetylases, especially zinc-dependent deacetylases HDACs, are among attractive drug targets for treating cancer in recent years. AIM: To explore the expression level of HDACs in several human cancer cell lines and examine the possible association between their expression and the sensitivity/resistance to the selective- or pan-HDAC inhibitors. MATERIALS AND METHODS: The RNA expression of 11 HDACs isoforms was assayed in HeLa, HepG2, AV3, HEK293, A549, and K562 cells by semiquantitative reverse transcription-polymerase chain reaction. The sensitivity/resistance of these cell lines to the pan- or selective- HDAC inhibitors was estimated by MTS assay. RESULTS: The relative transcription of HDACs genes demonstrated that members of Class I HDAC (HDAC1, 2 and 3) and members of Class II HDAC (HDAC4, 5, 6 and 7) had slight to significant levels of expression in cell lines under study with no dominant HDAC-subtype gene transcription. pan-HDAC inhibitor demonstrated superior antitumor activity compared to HDAC isoform-selective inhibitor. CONCLUSION: The absence of the dominant HDAC-subtype gene transcription in different human cancer cell lines explains the inferior efficacy of HDAC isoform-selective inhibitors as compared to pan-HDAC inhibitors.


Assuntos
Histona Desacetilases , Neoplasias , Células HEK293 , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Neoplasias/genética , Isoformas de Proteínas/genética , Zinco/farmacologia
16.
Biochem Biophys Res Commun ; 626: 1-7, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-35963044

RESUMO

Zinc stimulates intestinal iron absorption via induction of divalent metal ion transporter (DMT1) and hephaestin (HEPH). While the increase in DMT1 is mediated via a PI3K/IPR2 axis, the mechanisms of Zn-induced HEPH expression downstream of PI3K remain elusive. In the current study we probed the role of Caudal-related homeobox transcription factor-2 (CDX2) on Zn-induced HEPH expression. Zn treatment of Caco-2 cells increased CDX2 phosphorylation and HEPH protein and mRNA expression. siRNA-silencing of CDX2 inhibited Zn-induced HEPH expression. LY294002, an antagonist of PI3K inhibited Zn-induced phosphorylation of CDX2, and downstream HEPH expression. These results suggest that increased expression of HEPH in intestinal cells following Zn treatment is mediated via a PI3K-CDX2 pathway.


Assuntos
Proteínas de Membrana/metabolismo , Fosfatidilinositol 3-Quinases , Zinco , Fator de Transcrição CDX2 , Células CACO-2 , Humanos , Ferro/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Zinco/farmacologia
17.
Colloids Surf B Biointerfaces ; 218: 112798, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36030726

RESUMO

Magnesium (Mg) alloys are potential materials for orthopedic fixation devices but rapid degradation of the materials restricts wider clinical applications. Herein, zinc-incorporated calcium phosphate (Ca-Zn-P) coatings are prepared on the Zn-pretreated WE43 Mg alloy by a hydrothermal technique under relatively stable and favorable conditions. The hydrothermal coating consists of a compact bottom layer of CaZn2(PO4)2∙2 H2O and ZnO granular crystals and a jagged upper layer of CaHPO4. The Zn coating reduces the corrosion current density of WE43 to (3.49 ± 1.60) × 10-5 A cm-2, whereas the Ca-Zn-P/Zn composite coating further reduces it by 3 orders of magnitude in the simulated body fluid (SBF). The charge transfer resistances of the Zn-coated and Ca-Zn-P/Zn-coated alloys increase by 49 and 7176 times to 835 and 1.22 × 105 Ω cm2, respectively. The 7-day immersion results reveal that the Zn coating cannot provide long-term protection to WE43 in SBF because of the formation of galvanic couples between the Zn coating and WE43. In contrast, Ca-Zn-P/Zn-coated WE43 remains intact after soaking for 7 days and furthermore, the Ca-Zn-P coating self-repairs and continues to grow despite dissolution. The compact and adherent Ca-Zn-P bottom layer plays a major role in mitigating corrosion of WE43 by hindering penetration of the aggressive medium and charge transfer of the corrosion reactions resulting in only slight corrosion of the Zn layer. Biologically, the Zn coating reduces attachment and proliferation of MC3T3-E1 pre-osteoblasts on WE43, but the composite coating fosters cell adhesion and proliferation which stems from the good biocompatibility of the hydrothermal layer and relatively stable surface conditions avoiding severe corrosion.


Assuntos
Magnésio , Óxido de Zinco , Ligas/química , Ligas/farmacologia , Fosfatos de Cálcio , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Corrosão , Magnésio/química , Magnésio/farmacologia , Teste de Materiais , Zinco/química , Zinco/farmacologia
18.
Biomater Adv ; 140: 213051, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35914326

RESUMO

Functional calcium phosphate biomaterials can be designed as carriers of a balanced mixture of biologically relevant ions able to target critical processes in bone regeneration. They hold the potential to use mechanisms very similar to growth factors naturally produced during fracture healing, while circumventing some of their drawbacks. Here we present a novel phase of carbonated-apatite containing Mg2+, Sr2+, Zn2+ and Ga3+ ions (HApMgSrZnGa). While all dopants decrease the crystallinity, Ga3+ limits crystal growth and enables the formation of a nanosized apatite phase with enhanced specific surface area. Coexistence of the ions enhances degradability and controls solubility of low crystalline, distorted, multi-doped apatite structure, controlled by Ga3+ ions accumulated at the surface. Consequently, HApMgSrZnGa supports the viability of human mesenchymal stromal cells (MSCs) and induces their stimulation along the osteogenic lineage. In addition, the co-released ions has a synergistic antimicrobial effect, particularly within the HApMgSrZnGa-Au(arg) composite with Au(arg) as contact-based antimicrobial. The activity is stable up to two months in vitro. Osteogenic nature and antimicrobial activity, combined in a single biomaterial, are suggesting a well-balanced, multi-doped apatite design applicable as future option in bone regeneration and tissue engineering.


Assuntos
Gálio , Estrôncio , Apatitas , Materiais Biocompatíveis/farmacologia , Humanos , Íons , Magnésio/farmacologia , Estrôncio/farmacologia , Engenharia Tecidual , Zinco/farmacologia
19.
ACS Infect Dis ; 8(9): 1920-1934, 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-35997625

RESUMO

Histatin-5 (Hist-5) is a polycationic, histidine-rich antimicrobial peptide with potent antifungal activity against the opportunistic fungal pathogen Candida albicans. Hist-5 can bind metals in vitro, and metals have been shown to alter the fungicidal activity of the peptide. Previous reports on the effect of Zn2+ on Hist-5 activity have been varied and seemingly contradictory. Here, we present data elucidating the dynamic role Zn2+ plays as an inhibitory switch to regulate Hist-5 fungicidal activity. A novel fluorescently labeled Hist-5 peptide (Hist-5*) was developed to visualize changes in internalization and localization of the peptide as a function of metal availability in the growth medium. Hist-5* was verified for use as a model peptide and retained antifungal activity and mode of action similar to native Hist-5. Cellular growth assays showed that Zn2+ had a concentration-dependent inhibitory effect on Hist-5 antifungal activity. Imaging by confocal microscopy revealed that equimolar concentrations of Zn2+ kept the peptide localized along the cell periphery rather than internalizing, thus preventing cytotoxicity and membrane disruption. However, the Zn-induced decrease in Hist-5 activity and uptake was rescued by decreasing the Zn2+ availability upon addition of a metal chelator EDTA or S100A12, a Zn-binding protein involved in the innate immune response. These results lead us to suggest a model wherein commensal C. albicans may exist in harmony with Hist-5 at concentrations of Zn2+ that inhibit peptide internalization and antifungal activity. Activation of host immune processes that initiate Zn-sequestering mechanisms of nutritional immunity could trigger Hist-5 internalization and cell killing.


Assuntos
Antifúngicos , Candida albicans , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Quelantes/farmacologia , Histatinas/metabolismo , Histatinas/farmacologia , Peptídeos/farmacologia , Zinco/metabolismo , Zinco/farmacologia
20.
Food Funct ; 13(17): 9143-9152, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35959699

RESUMO

Zinc supplementation prior to heat shock increases HSP70 (heat shock protein 70) expression, which has cytoprotective effects in tissue cells during inflammation. Effects of zinc deficiency in this regard have been discussed controversially. Whether zinc modulates the expression of HSP70 in the human immune system as well and thus affects cell survival during heat stress is so far largely unknown. Therefore, we investigated the effect of alterations in the cellular zinc status on HSP70 expression and on cellular survival in human monocytes and lymphocytes. Three cell lines (Jurkat, THP-1, and Ramos) and enriched primary human monocytes and lymphocytes from young subjects were subjected to zinc deficiency or supplementation and subsequently heat shock at 42 °C. HSP70 mRNA expression was analyzed by real-time PCR, whereas HSP70 protein expression was analyzed by western blotting. In all cells other than Ramos cells, zinc supplementation and deficiency augmented heat shock-induced HSP70 expression. Further experiments in primary monocytes and lymphocytes indicated that this may be explained by the enhanced phosphorylation of HSF1 (Heat shock factor 1) at Ser326, which plays a significant role in HSP70 induction, as observed in zinc deficient and supplemented cells. While zinc supplementation had negligible effects on cell viability, acute zinc deficiency further increased cell death, induced by heat shock. Our results emphasize the importance of an optimal cellular zinc status. Moreover, we present a possible mechanism behind zinc's influence on HSP70 expression in human leukocytes. Our data form the basis for further in vivo and ex vivo studies to investigate how the zinc status may affect cellular damage in transient high temperature situations.


Assuntos
Proteínas de Ligação a DNA , Zinco , Proteínas de Ligação a DNA/genética , Suplementos Nutricionais , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Resposta ao Choque Térmico , Humanos , Linfócitos/metabolismo , Fosforilação , Serina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Zinco/metabolismo , Zinco/farmacologia
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