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1.
Sci Rep ; 10(1): 14547, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32884057

RESUMO

Arcobacter-like species are found associated with many matrices, including shellfish in marine environments. The culture media and conditions play a major role in the recovery of new Arcobacter-like species. This study was aimed to develop a culture media for isolation and enhanced growth of Arcobacter-like spp. from marine and shellfish matrices. For this purpose, 14 different Arcobacter-like spp. mostly isolated from shellfish, were grown in 24 different formulations of enrichment broths. The enrichment broths consisted of five main groups based on the organic contents (fresh oyster homogenate, lyophilized oyster either alone or in combination with other standard media), combined with artificial seawater (ASW) or 2.5% NaCl. Optical density (OD420nm) measurements after every 24 h were compared with the growth in control media (Arcobacter broth) in parallel. The mean and standard deviation were calculated for each species in each broth and statistical differences (p < 0.05) among broths were calculated by ANOVA. The results indicated that shellfish-associated Arcobacter-like species growth was significantly higher in Arcobacter broth + 50% ASW and the same media supplemented with lyophilized oysters. This is the first study to have used fresh or lyophilized oyster flesh in the enrichment broth for isolation of shellfish-associated Arcobacter-like spp.

2.
Chemphyschem ; 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32725859

RESUMO

We present a theoretical study of chalcogen bonded container capsules (AX +AX ) where X=O, S, Se, and Te, and their encapsulation complexes with n-C9 H20 (n-C9 H20 @AX +AX ). Both Se and Te encapsulation complexes have significant experimental and computed binding energies, analogous to the hydrogen bonded counterparts, while the S and O capsules and their encapsulation complexes show only weak binding energies, which are attributed to different types of bonding: chalcogen S⋅⋅⋅N bonds for S-capsules and π-π stacking and weak hydrogen bonds for the O case. All AX +AX and C9 H20 @AX +AX present unusually high magnetic anisotropies in their interiors. The 1 H NMR spectra of the encapsulation complexes display the proton signals of the encapsulated n-nonane highly upfield shifted, in agreement with the available experimental data for the Se capsule. We found that different factors contribute to the observed magnetic anisotropy of the capsule's interior: for the Te capsule the most important factor is Te's large polarizability; for the O analogue the inductive effects produced by the electronegative nature of the O and N heteroatoms; and for the S and Se capsules, the polarizability of the heteroatoms combines with electric field effects.

3.
Chem Commun (Camb) ; 56(51): 6945-6948, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32436496

RESUMO

A metallo-cavitand (1-2Pd) showed unprecedented binding selectivity and sequestration of p-functionalized toluene isomers in water. The host-guest complexation was studied using 1H and COSY NMR methods and xylene-isomer complexes were examined by using DFT calculations. A liquid-liquid extraction scheme was developed for the separation of p-functionalized toluenes.

4.
Int J Med Sci ; 17(6): 815-823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218703

RESUMO

Importin-11 (Ipo11) is a novel member of the human importin family of transport receptors (karyopherins), which are known to mediate the nucleocytoplasmic transport of protein and RNA cargos. Despite its role in the transport of protein, we found that knockout of Ipo11 nuclear import factor affects normal embryonic development and govern embryo-lethal phenotypes in mice. In this study, we for the first time produced a mouse line containing null mutation in Ipo11 gene utilized by gene trapping. The Ipo11-/- embryos showed an embryonic lethal phenotype. The Ipo11-/- embryos showed a reduced size at embryonic day 10.5 (E10.5) when compared with Ipo11+/+ or Ipo11+/- embryos and died by E11.5. Whereas Ipo11+/- mice were healthy and fertile, and there was no detectable changes in embryonic lethality and phenotype when reviewed. In the X-gal staining with the Ipo11-/- or Ipo11+/- embryos, strong X-gal staining positivity was detected systematically in the whole mount embryos at E10.5, although almost no X-gal positivity was detected at E9.5, indicating that the embryos die soon after the process of Ipo11 expression started. These results indicate that Ipo11 is essential for the normal embryonic development in mice.

5.
J Am Chem Soc ; 142(12): 5876-5883, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32125842

RESUMO

Supramolecular capsules are desirable containers for the study of molecular behavior in small spaces and offer applications in transport, catalysis, and material science. We report here the use of chalcogen bonding to form container assemblies that are stable in water. Cavitands 1-3 functionalized with 2,1,3-benzoselenadiazole walls were synthesized in good yield from resorcin[4]arenes. The solid-state single-crystal X-ray structure of 3 showed a dimeric assembly cemented together through multiple Se···N chalcogen bonds. Binding of hydrophobic and amphiphilic guests in D2O was investigated by 1H NMR methods and revealed host-guest assemblies of 1:1, 2:1, and 2:2 stoichiometries. Small guests such as n-hexane or cyclohexane assembled as 2:2 capsular complexes, larger guests like cyclohexane carboxylic acid or cyclodecane formed 1:1 cavitand complexes, and longer linear guests like n-dodecane, cyclohexane carboxylic acid anhydride, and amides created 2:1 capsular complexes. The 2:1 complex of the capsule with cyclohexane carboxylic acid anhydride was stable over 2 weeks, showing that the seam of chalcogen bonds is "waterproof". Selective uptake of cyclohexane over benzene and methyl cyclohexane over toluene was observed in aqueous solution with the capsule. Hydrophobic forces and hydrogen-bonding attractions between guest molecules such as 3-methylbutanoic acid stabilized the assemblies in the presence of the competing effects of water. The high polarizability and modest electronegativity of Se provide a capsule lining complementary to guest C-H bonds. The 2,1,3-benzoselenadiazole walls impart an unusually high magnetic anisotropy to the capsule environment, which is supported by density functional theory calculations.

6.
J Am Chem Soc ; 142(5): 2396-2403, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31913618

RESUMO

Radical reduction of alkyl halides and aerobic oxidation of alkyl aromatics are reported using water-soluble container compounds (1 and 2). The reductions involve α,ω-dihalides (4-8 and 10) with radical initiators in cavitand hosts with varied binding affinities. Product distributions lead to general guidelines for the use of dynamic supramolecular systems with fast reactions. The binding of guest substrates in the hosts must show high affinities (Ka > 103 M-1) to ensure that the reactions take place under confinement in the containers.

7.
Int J Med Sci ; 16(12): 1557-1563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839743

RESUMO

E2F3, a member of the E2F family, plays a critical role in cell cycle and proliferation by targeting downstream, retinoblastoma (RB) a tumor suppressor family protein. The purpose of this study, was to investigate the role and function of E2F3 in vivo. We examined phenotypic abnormalities, by deletion of the E2f3 gene in mice. Complete ablation of the E2F3 was fully penetrant, in the pure C57BL/6N background. The E2f3+/ - mouse embryo developed normally without fatal disorder. However, they exhibited reduced body weight, growth retardation, skeletal imperfection, and poor grip strength ability. Findings suggest that E2F3 has a pivotal role in muscle and bone development, and affect normal mouse growth.


Assuntos
Desenvolvimento Ósseo/genética , Fator de Transcrição E2F3/genética , Desenvolvimento Embrionário/genética , Músculo Esquelético/crescimento & desenvolvimento , Animais , Apoptose/genética , Peso Corporal/genética , Ciclo Celular/genética , Proliferação de Células/genética , Embrião de Mamíferos , Humanos , Camundongos , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Fenótipo
8.
Proc Natl Acad Sci U S A ; 116(36): 17648-17653, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31427538

RESUMO

We describe here the effects of metal complexation on the molecular recognition behavior of cavitands with quinoxaline walls. The nitrogen atoms of the quinoxalines are near the upper rim of the vase-like shape and treatment with Pd(II) gave 2:1 metal:cavitand derivatives. Characterization by 1H, 13C NMR spectroscopy, HR ESI-MS, and computations showed that the metals bridged adjacent quinoxaline panels and gave cavitands with C2v symmetry. Both water-soluble and organic-soluble versions were prepared and their host/guest complexes with alkanes, alcohols, acids, and diols (up to C12) were studied by 1H NMR spectroscopy. Analysis of the binding behavior indicated that the metals rigidified the walls of the receptive vase conformation and enhanced the binding of hydrophobic and even water-soluble guests, compared to related cavitands reported previously. The results demonstrated that the conformational dynamics of the cavitand were slowed by the coordination of Pd(II) and stabilized the host's complexes.

9.
Org Biomol Chem ; 17(21): 5279-5282, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31090780

RESUMO

Host-guest complexation of long chain α,ω-dibromides was evaluated in deep water-soluble cavitands 1 and 2. The bound dibromides (C7-C12) tumble rapidly on the NMR timescale and averaged signals were observed. The complexation allows mono hydrolysis of dibromides in aqueous solution. The arrangement of the products in the host-guest complex was fixed in an unsymmetrical manner that protects the guest from further reaction. Up to 93% yields of the mono-alcohols were obtained. The α,ω-dibromides formed a capsule with cavitand 2 and remained unreactive to hydrolysis.

10.
J Inorg Biochem ; 194: 52-64, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30831390

RESUMO

Non-small cell lung cancer (NSCLC) is the most common cancer worldwide, which is related with poor prognosis and resistance to chemotherapy. Notably, ruthenium-based complexes have emerged as good alternative to the currently used platinum-based drugs for cancer therapy. In the present study, we synthesized a novel bis-pyrimidine based ligand 1,3-bis(2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)benzene (L) and used it in the synthesis of a dimetallic Ru(II) cymene complex [(Ru(η6-p-cymene)Cl)2(1,3-bis(2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)benzene)] (L-Ru). We checked the stability of this complex in solution state in D2O/DMSO­d6 mixture and found it to be highly stable under these conditions. We determined the anticancer activity and mechanism of action of L-Ru in human NSCLC A549 and A427 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and related biological analyses. These results revealed that L-Ru exerted a strong inhibitory effect on the cells proliferation,G0/G1-arrest, accompanied with upregulation of p53, p21, p15, cleaved Poly (ADP-ribose) polymerase (PARP) protein and downregulation of cell cycle markers. L-Ru inhibited cell migration and invasion. The mitochondria-mediated apoptosis of NSCLC induced by L-Ru was also observed followed by the increase of apoptosis regulator B-cell lymphoma 2 associated X (BAX), and activation of caspase-3/-9. The effects of L-Ru on the cell viability, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and Annexin V-positive cells apoptosis induction were remarkably attenuated. This complex induced DNA damage, cell cycle arrest and cell death via caspase-dependent apoptosis involving PARP activation and induction of p53-dependent pathway. These findings suggested that this ruthenium complex might be a potential effective chemotherapeutic agent in NSCLC therapy.

11.
Eur J Med Chem ; 164: 546-561, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30622026

RESUMO

The current study unveils ONS-donor ligand based Pt(II) complexes with unusual anticancer potency showing higher anticancer effect as compared to cisplatin. This series of Pt(II)(R-salicylaldimine)Cl (C1a-C4a) (R = 5-H, 5-CH3, F, 3-CH3O) complexes were prepared in single step in good isolated yields from commercially available materials. The chloride ancillary ligand of "a" series (C1a-C4a) was replaced with 4-picoline and "b" series of four complexes Pt(II)(R-salicylaldimine)(4-picoline)BF4 (C1b-C4b) (R = 5-H, 5-CH3, F, 3-CH3O) was obtained. All these complexes were characterized by different structure elucidation techniques. Among these, the structures of C1a, C2a, C2b and C3b were determined in solid state by single crystal X-ray analysis. We found quick aquation of "a" series of complexes in DMSO/water mixture that was well investigated by 1H NMNR, LCMS and ESI-MS, while "b" series of these complexes was quite stable over a month as described by the 1H NMNR in DMSO/D2O mixture. This ONS-donor ligand based class of Pt(II) complexes showed unusual anticancer potency in non-small cell lung cancer A549, colorectal cancer HT-29 and triple negative breast cancer MDA-MB-231 cells. These Pt(II) complexes induced PARP cleavage and significantly inhibited colony formation ability of cancer cells. Mechanistically, we found reduced aggressive growth of cancer cells by the induction of autophagic cell death via LC3-I/LC3-II expression and recruitment of LC3B to autophagosomal membrane. These complexes induced p21 expression, that suggested their potentials to suppress cell cycle progression. Significant activation of Caspase3/7-dependent apoptotic signaling was observed in cancer cells treated with these Pt(II) complexes. Morphological changes of cancer cells suggested their potentials to modulate epithelial-mesenchymal-transition (EMT) like features of cancer cells. Gel electrophoresis study revealed their interaction with plasmid DNA. Similarly, strong growth retardation effect and filamentous morphology was observed in Escherichia coli (E. coli). These ONS-donor Pt(II) complexes possessed strong anticancer effect in multiple human cancer cells via activation of multiple pathways for apoptotic and autophagic cell death.


Assuntos
Antineoplásicos/química , Autofagia/efeitos dos fármacos , Compostos Organoplatínicos/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Cristalografia por Raios X , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
12.
Antioxid Redox Signal ; 30(4): 560-576, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29486595

RESUMO

AIMS: Glucagon-like peptide-1 (GLP-1) increases intracellular Ca2+ concentrations, resulting in insulin secretion from pancreatic ß-cells through the sequential production of Ca2+ mobilizing messengers nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR). We previously found that NAADP activates the neuronal type of nitric oxide (NO) synthase (nNOS), the product of which, NO, activates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which, in turn, induces cADPR formation. Our aim was to explore the relationship between Ca2+ signals and gasotransmitters formation in insulin secretion in ß-cells upon GLP-1 stimulation. RESULTS: We show that NAADP-induced cGMP production by nNOS activation is dependent on carbon monoxide (CO) formation by heme oxygenase-2 (HO-2). Treatment with exogenous NO and CO amplifies cGMP formation, Ca2+ signal strength, and insulin secretion, whereas this signal is impeded when exposed to combined treatment with NO and CO. Furthermore, CO potentiates cGMP formation in a dose-dependent manner, but higher doses of CO inhibited cGMP formation. Our data with regard to zinc protoporphyrin, a HO inhibitor, and HO-2 knockdown, revealed that NO-induced cADPR formation and insulin secretion are dependent on HO-2. Consistent with this observation, the administration of NO or CO donors to type 2 diabetic mice improved glucose tolerance, but the same did not hold true when both were administered concurrently. INNOVATION: Our research reveals the role of two gas transmitters, CO and NO, for Ca2+ second messengers formation in pancreatic ß-cells. CONCLUSION: These results demonstrate that CO, the downstream regulator of NO, plays a role in bridging the gap between the Ca2+ signaling messengers during insulin secretion in pancreatic ß-cells.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Monóxido de Carbono/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Óxido Nítrico/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Knockout , Camundongos Obesos
13.
Eur J Med Chem ; 157: 1480-1490, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30282320

RESUMO

A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))2(bis-salicylaldimine)Cl2 (C1C4) were prepared. These complexes were obtained in excellent isolated yields and characterized in detail by using different spectroscopic techniques. The structure of C1 was also determined in solid state by single crystal X-ray analysis. These complexes were studied for their cytotoxic effect against three different types of human cancer cells including hepatocellular carcinoma (HepG2), non-small-cell lung cancer (A549) and breast cancer (MCF-7) cells by MTT assay. These complexes showed considerable cytotoxic effect in all the above-mentioned cell lines that was comparable to the effect of cisplatin. C1 and C2 showed moderate anticancer effect while C3 and C4 showed reasonable cytotoxicity. We found the cytotoxicity was increased in series from C1 to C4 representing the effect of ligand modification from small to bulky group at the amine functionality of the salicylaldimine. We selected C3 and C4 for mechanistic anticancer study in MCF-7 cells. The acridine orange/ethidium bromide and DAPI staining assays of MCF-7 cells treated with Ru(II) complexes showed apoptosis in cancer cells. Similarly, these complexes induced p53 protein expression in MCF-7 cells. Further, increased mRNA levels of p63, p73, PUMA, BAX and NOXA genes were observed in response to the treatment with C3 and C4, while cyclinD1, MMP3 and ID1 gene expression was significantly reduced. We found reduced invasion ability in breast cancer cells treated with C3 and C4. Taken together, we demonstrated that bis-salicylaldimine based dimetallic Ru-(p-cymene) complexes exerts anticancer effects by p53 pathway, suggesting the promising chemotherapeutic potentials of these Ru(II) complexes for the treatment of cancer. This study may further pave for their in depth in vitro or in vivo anticancer investigations.


Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Invasividade Neoplásica/prevenção & controle , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Invasividade Neoplásica/patologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Rutênio/química , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 143: 1039-1052, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29232581

RESUMO

Two series of homoleptic Pt(II)(hydrazone)Cl (C1a-C5a) and heteroleptic Pt(II)(hydrazone)(4-picoline). BF4 (C1b-C5b) complexes were prepared and characterized by 1H, 13C, 19F NMR and HR ESI-MS. Structure of C2b was confirmed by single crystal X-ray analysis. These complexes were studied for their in vitro anticancer activities in human multiple cancer cells including breast (MCF-7), liver (HepG2), lung (H460), colon (HCT116) and cervical (Hela) cancers. C1a-C5a and C1b-C5b showed considerable anticancer effect. The overall anticancer effect of all these complexes was higher in liver (HepG2) and lung (H460) cancer cell lines and the effect of C2b and C3b was observed to be the highest among these 10 complexes. Therefore, we selected C2b and C3b to study their in vitro anticancer mechanism in HepG2 and H460 cancer cells. C2b and C3b changed cancer cell morphology and inhibited cell migration. The anticancer mechanistic studies demonstrated that C2b and C3b induced cell apoptosis, as evidenced by DAPI and AO/EB staining and flow cytometry analyses. Moreover, qRT-PCR and western blotting analysis showed that H460 and HepG2 cells treated with C2b and C3b significantly increased the expression of p53, p63, p21, p15, Bax and decreased Bcl-2 and c-Myc levels. The DNA binding property of these complexes was investigated by gel electrophoresis using pBR322 plasmid DNA. Taken together, the results obtained from the present study demonstrated the potentials of this new class of Pt(II) complexes in reduction of cell viability, suppression of cell migration and acceleration of apoptosis in different cancer cells.


Assuntos
Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Compostos Organoplatínicos/farmacologia , Picolinas/farmacologia , Platina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/química , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Picolinas/química , Platina/química , Relação Estrutura-Atividade
15.
Eur J Pharmacol ; 814: 302-312, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28865678

RESUMO

Cisplatin is an effective chemotherapeutic agent indicated in cancer chemotherapy. However, its clinical use is associated with peripheral neuropathy that invariably impairs patient quality of life. Gabapentin (GBP) is an effective analgesic for neuropathic pain conditions but its clinical efficacy in cisplatin-induced neuropathic pain (CINP) is limited, in addition to generating unwanted side-effects. In this study, a gabapentin-salicylaldehyde derivative [gabapentsal (GPS)] was synthesized and evaluated to explore any potential benefit in comparison with GBP in a rat model of CIPN. Administration of cisplatin (3.0mg/kg/week, i.p.) for five consecutive weeks generated reproducible mechanical-allodynia (decreased paw withdrawal threshold to von Frey filament application; PWT, g) and thermal hypoalgesia (increased nociceptive reaction latency in the hot plate paradigm; s). Treatment with GBP or its derivative on the 37th day of the experimental protocol, dose dependently attenuated cisplatin-induced nocifensive behaviors. Accordingly, doses of GBP (50-100mg/kg, i.p.) and GPS (25-100mg/kg, i.p.) suppressed the expression of CINP by normalizing the PWT and hot plate response latency 1h and 3h post administration. In the rotarod paradigm, GBP at all doses markedly impaired motor performance, whilst GPS was devoid of motor incoordination except at the highest dose, when a mild impairment occurred. Salicylaldehyde alone had no effect on CINP or rotarod performance and neither was there any synergism when coadministered with GBP. These findings suggest that both GBP and GPS have beneficial effects in the neuropathic pain model though GPS may be potentially more useful in the management of CINP.


Assuntos
Aldeídos/química , Aminas/química , Aminas/farmacologia , Cisplatino/efeitos adversos , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacologia , Hiperalgesia/tratamento farmacológico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacologia , Aldeídos/farmacologia , Aminas/uso terapêutico , Animais , Ácidos Cicloexanocarboxílicos/uso terapêutico , Interações Medicamentosas , Feminino , Gabapentina , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Qualidade de Vida , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Ácido gama-Aminobutírico/uso terapêutico
16.
Arch Pharm (Weinheim) ; 350(6)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28498506

RESUMO

A novel pregabalin derivative named as pregsal ((S,E)-3-(((2-hydroxybenzylidene)amino)methyl)-5-methylhexanoic acid) was synthesized by a simple imination reaction between pregabalin and salicylaldehyde and was evaluated in the in vivo testing paradigms. The compound was characterized by UV, IR, 1 H, 13 C NMR, HR ESI-MS, and elemental analysis. It was screened (30, 50, 75, and 100 mg/kg) for antinociceptive, anti-inflammatory, and antipyretic activities in relation to pregabalin. The synthesized compound significantly attenuated the tonic acetic acid-induced nociceptive pain (30 mg/kg (P < 0.05), 50 mg/kg (P < 0.01), 75 and 100 mg/kg (P < 0.001)), and thermal-induced hyperalgesia (P < 0.001). These activities were succinctly antagonized (P < 0.05, P < 0.01, P < 0.001) by naloxone and pentylenetetrazole, implicating the involvement of opioidergic and GABAergic mechanisms. The compound also inhibited the temporal inflammatory response and alleviated the yeast-induced pyrexia (P < 0.05, P < 0.01, and P < 0.001). These findings suggest that the synthesized compound possessed prospective pain, inflammation, and pyrexia relieving propensities and therefore may serve as a potential drug candidate for the therapeutic management of chronic pain conditions.


Assuntos
Aldeídos/farmacologia , Febre/tratamento farmacológico , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Pregabalina/farmacologia , Aldeídos/administração & dosagem , Animais , Feminino , Febre/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pregabalina/administração & dosagem , Saccharomyces cerevisiae/química
17.
Eur J Med Chem ; 131: 263-274, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28334655

RESUMO

Morpholine and methylpiperazine are among the most important structural parts of different drugs including organic chemotherapeutic agents. In the current study we incorporated these entities as co-ligand and a series of structurally related mono- and di-metallic square planner Pt(II) complexes (Pt(II)(salicylaldimine)(morpholine)Cl C1a-C3a, Pt(II)(salicylaldimine) (methylpiperazine)Cl C1b-C3b, di-metallic Pt(II)2(bis-salicylaldimine)(morpholine)2Cl2C4a and Pt(II)2(bis-salicylaldimine)(methylpiperazine)2Cl2C4b were prepared. These complexes were characterized by 1H, 13C, 19F, 2D NOESY NMR, HR ESI-MS and elemental analyses, while structures of C2a, C3a and C4b were determined by single crystal X-ray analysis. All these complexes were studied for their in vitro cytotoxic effect on breast (MCF-7), liver (HepG2) and lung (A549) cancer cell lines. All these complexes showed considerable cytotoxic effect on these tested cancer cell lines comparable to cisplatin. Moreover three complexes C1a, C4a and C1b were studied in details. Time- and dose-dependent study was performed for C1a, C4a and C1b. These complexes induced the expression of p53 that suppresses cancer cell growth. Induction of PUMA gene and repression of MYC oncogene suggested that these complexes targeted different genes to suppress cancer progression. TUNEL assay showed induction of apoptosis and invasion analysis showed reduction in invasion ability of breast cancer cells treated with C1a, C4a or C1b. Importantly, these novel complexes suppressed the expression of EMT and metastasis promoter genes. Similarly these complexes induced autophagy by enhancing the expression of autophagy related genes such as beclin, atg-5 and atg-7. The E. coli growth retardation study showed stronger growth inhibitory effects and subsequently resulted in filamentous morphology of bacterial cells. Gel electrophoresis study proved the interaction of these complexes with DNA. All these analysis revealed anticancer potencies of this class of complexes.


Assuntos
Antineoplásicos/farmacologia , Escherichia coli/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Piperazinas/química , Piperazinas/farmacologia , Platina/química , Platina/farmacologia , Salicilatos/química , Salicilatos/farmacologia , Relação Estrutura-Atividade
18.
Talanta ; 164: 307-313, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28107934

RESUMO

Salicylaldehyde based hydrazones 2-((2-methyl-2-(pyridin-2-yl)hydrazono)methyl)phenol (SMPH), 4-methyl-2-((2-methyl-2-(pyridin-2-yl)hydrazono)methyl)phenol (MSMPH) and 4-fluoro-2-((2-methyl-2-(pyridin-2-yl)hydrazono)methyl)phenol (FSMPH) were prepared and structurally characterized. These hydrazones exhibited fluorescence "turn on" response toward Al3+ in dimethyl formamide/water (DMF/H2O) (1: 1) mixture. SMPH showed enhanced emission (70 folds) as compared to MSMPH (46 folds) and FSMPH (28 folds) upon the addition of 3 equivalents of Al3+. Similarly a red shift was observed in the emission wavelength of hydrazone/Al3+ mixture from non-substituted (SMPH) to fluoro-substituted (FSMPH) and in turn to methyl-substituted (MSMPH). They also showed high selectivity towards Al3+ over the other common metal ions. Among the tested metal ions only copper interfered and quenched the fluorescence completely. Further SMPH was investigated spectroscopically in details for Al3+ detection. The binding phenomenon of SMPH was analyzed by 1H NMR and HR-ESI-MS. Mass analysis showed a 1: 1 complex formation of SMPH with Al3+. Job's plot also confirmed their 1: 1 interaction. SMPH showed a good tolerance for Al3+ detection in acidic to neutral pH, ranges 3-8. The limit of detection (LOD) for Al3+ was observed to be 1.5×10-7M. Moreover SMPH and MSMPH were studied for living cells imaging in MCF-7 (Michigan Cancer Foundation-7) cells. These analyses also revealed the importance of these hydrazones in monitoring Al3+ in living cells.


Assuntos
Alumínio/análise , Alumínio/química , Técnicas de Química Analítica/instrumentação , Corantes Fluorescentes/química , Hidrazonas/química , Limite de Detecção , Imagem Molecular/métodos , Aldeídos/química , Sobrevivência Celular , Corantes Fluorescentes/síntese química , Humanos , Hidrazonas/síntese química , Células MCF-7 , Espectrometria de Fluorescência
19.
Eur J Med Chem ; 125: 1064-1075, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27810593

RESUMO

Novel phenylenediamine bridged mixed ligands dimetallic square planner Pt(II) complex (L-Pt-Py) was synthesized from simple commercially available precursors in good yield and characterized by 1H, 13C, 2D NOESY NMR and high resolution mass spectrometry (HR-ESI-MS). The stability of L-Pt-Py was checked by 1H NMR in mixed DMSO-d6/D2O solvents. L-Pt-Py showed considerable in vitro cytotoxicity in lung (A549), breast (MCF-7) and liver (HepG2) cancer cell lines and strong in vivo growth inhibition in Escherichia coli (E. coli). These results were compared to the well-known market available platinum anticancer drug cisplatin. L-Pt-Py has strong ability to suppress the growth of multiple cancer cells. Mechanistically, it enhanced p53 protein expression and regulated p53-dependent genes expression such as p21, PUMA, MYC and hTERT. The TUNEL assay showed that L-Pt-Py induced cell death in cancer cells. Inhibition of caspase signaling with caspase inhibitor Z-VAD-FMK suggested that cell death induced by this complex was caspase-dependent. Importantly, L-Pt-Py has the ability to suppress the invasion and migration of human lung and luminal-like breast cancer cells. Similarly L-Pt-Py suppressed the expression of several matrix metalloproteinases (MMPs) such as MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9 to inhibit lung and breast cancer cell metastasis. L-Pt-Py showed stronger inhibitory effects on bacterial growth and also resulted in filamentous morphology of bacterial cells. The gel electrophoresis study of DNA migration revealed the strong interaction of L-Pt-Py with DNA. Taken altogether, L-Pt-Py was highly stable and the in vitro and in vivo biological study results corroborated this complex to be effective anticancer agent.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Descoberta de Drogas , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/metabolismo , Humanos , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacologia , Metaloproteinases da Matriz/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fenilenodiaminas/química , Fenilenodiaminas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
20.
Jundishapur J Microbiol ; 9(7): e31824, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27679701

RESUMO

BACKGROUND: The distribution pattern of phase-variable genes varies from strain to strain and from region to region. The present study was carried out to investigate the distribution pattern of phase-variable genes within Pakistan-based Helicobacter pylori strains and to analyze and compare them with strains prevalent in other parts of the world. OBJECTIVES: To determine the distribution pattern of phase-variable genes in H. pylori strains circulating in Pakistan. PATIENTS AND METHODS: Biopsy samples were collected from 85 symptomatic patients suffering from various upper gastrointestinal tract symptoms. The biopsy specimens were chopped, then inoculated on H. pylori-specific media and incubated in a Campylobacter Gas Generating kit. Positive isolates were further confirmed via staining and biochemical procedures. Primers were designed for five phase-variable genes using OligoCalc, an oligonucleotide properties calculator (version 3.26) according to parameters stipulated in the literature. Polymerase chain reaction (PCR) was performed on all positive isolates to determine the presence or absence of phase-variable genes. RESULTS: On culturing, the prevalence of H. pylori infections in the samples was 44.7%. The prevalence was higher in females than in males, and it increased with age. PCR amplification revealed that the hsdR gene was present in 79% of samples, while the mod and ß-subunit genes were present in 16% and 30% of samples, respectively. The streptococcal M protein gene was found in 79%, while the fliP gene was prevalent in 56%. CONCLUSIONS: The distribution patterns of phase-variable genes in Pakistani H. pylori strains were found to be somewhat different. The dominant prevalence of the hsdR gene was an interesting finding, considering its role in bacterial defense in both micro- and macroenvironments.

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