RESUMO
Kopsileuconines A-D (1-4), four monoterpenoid bisindole alkaloids with unprecedented skeletons, along with their biosynthetically related precursors (5-8) were isolated from the roots of Kopsia hainanensis. Compound 1 possessed an undescribed C-6-C-5' dimerization pattern of aspidofractinine-type alkaloids. Compounds 2-4 were rhazinilam-kopsine (2) and rhazinilam-aspidofractinine type (3 and 4) bisindole alkaloids with undescribed skeletons, respectively. Their structures with absolute configurations were fully accomplished by extensive spectroscopic analysis, quantum-chemical calculations, and X-ray crystallography. A plausible biosynthetic pathway for 1-4 was proposed. Compound 2 exhibited a significant inhibitory effect against human lung cancer cell lines PC9 (EGFR mutant), with an IC50 value of 15.07 ± 1.19 µM.
RESUMO
Ten C-geranylated flavonoids, along with three known analogues, were isolated from the leaves of Artocarpus communis. The chemical structures of these compounds were unambiguously determined via comprehensive spectroscopic analysis, single-crystal X-ray diffraction experiments, and quantum chemical electronic circular dichroism calculations. Structurally, artocarones A-I (1-9) represent a group of unusual, highly modified C-geranylated flavonoids, in which the geranyl chain is cyclised with the ortho-hydroxy group of flavonoids to form various heterocyclic scaffolds. Notably, artocarones E and G-I (5 and 7-9) feature a 6H-benzo[c]chromene core that is hitherto undescribed in C-geranylated flavonoids. Artocarone J (10) is the first example of C-9-C-16 connected C-geranylated aurone. Meanwhile, the plausible biosynthetic pathways for these rare C-geranylated flavonoids were also proposed. Notably, compounds 1, 2, 4, 8, 11, and 12 exhibited promising in vitro inhibitory activities against respiratory syncytial virus and herpes simplex virus type 1.
Assuntos
Antivirais , Artocarpus , Flavonoides , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Artocarpus/química , Antivirais/química , Antivirais/farmacologia , Antivirais/isolamento & purificação , Estrutura Molecular , Herpesvirus Humano 1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Folhas de Planta/química , Relação Estrutura-Atividade , Modelos MolecularesRESUMO
Mesona chinensis is a common medicinal and edible plant in the Lingnan region of China, which has extensive pharmacological activity. However, the study of its chemical constituents is not sufficient. In this study, a variety of modern chromatographic separation techniques were used to isolate two compounds from 95% ethanol extract of the grass parts of M. chinensis. Their absolute configurations were determined by ultraviolet spectroscopy(UV), infrared spectroscopy(IR), high resolution mass spectrometry(HR-ESI-MS), 1D and 2D nuclear magnetic resonance(1D NMR and 2D NMR), and single-crystal X-ray diffraction(SC-XRD). Specifically, they were two new benzoyl-sesquiterpenes and named mesonanol A and mesonanol B, respectively. The results of the pharmacological activity evaluation showed that neither of the two new compounds showed obvious antiviral and anti-inflammatory activities.
Assuntos
Lamiaceae , Sesquiterpenos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Espectrofotometria Infravermelho , Estrutura MolecularRESUMO
A phytochemical investigation on the buds of edible medicinal plant, Eugenia carvophyllata, led to the discovery of seven new compounds, caryophones A-G (1-7), along with two biogenetically-related known ones, 2-methoxy-7-methyl-1,4-naphthalenedione (8) and eugenol (9). Compounds 1-3 represent the first examples of C-5-C-1' connected naphthoquinone-monoterpene adducts with a new carbon skeleton. Compounds 4-7 are a class of novel neolignans with unusual linkage patterns, in which the C-9 position of one phenylpropene unit coupled with the aromatic core of another phenylpropene unit. The chemical structures of the new compounds were determined based on extensive spectroscopic analysis, X-ray diffraction crystallography, and quantum-chemical calculation. Among the isolates, compounds (-)-2, 3, 6, and 9 showed significant in vitro inhibitory activities against respiratory syncytial virus (RSV)-induced nitric oxide (NO) production in RAW264.7 cells.
Assuntos
Anti-Inflamatórios , Eugenia , Lignanas , Naftoquinonas , Óxido Nítrico , Compostos Fitoquímicos , Camundongos , Células RAW 264.7 , Animais , Óxido Nítrico/metabolismo , Estrutura Molecular , Lignanas/farmacologia , Lignanas/isolamento & purificação , Lignanas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Naftoquinonas/farmacologia , Naftoquinonas/isolamento & purificação , Naftoquinonas/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Eugenia/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , ChinaRESUMO
Guided by 1H NMR spectroscopic experiments using the characteristic enol proton signals as probes, three pairs of new tautomeric cinnamoylphloroglucinol-monoterpene adducts (1-3) were isolated from the buds of Cleistocalyx operculatus. Their structures with absolute configurations were established by spectroscopic analysis, modified Mosher's method, and quantum chemical electronic circular dichroism calculation. Compounds 1-3 represent a novel class of cinnamoylphloroglucinol-monoterpene adducts featuring an unusual C-4-C-1' linkage between 2,2,4-trimethyl-cinnamyl-ß-triketone and modified linear monoterpenoid motifs. Notably, compounds 1-3 exhibited significant in vitro antiviral activity against respiratory syncytial virus (RSV).
Assuntos
Syzygium , Syzygium/química , Monoterpenos/química , Espectroscopia de Ressonância Magnética , Antivirais/química , Estrutura MolecularRESUMO
A synthetic strategy based on biogenetic building blocks for the collective and divergent biomimetic synthesis of cleistoperlones A-F, a cinnamoylphloroglucinol collection discovered from Cleistocalyx operculatus, has been developed. These syntheses proceeded successfully in only six to seven steps starting from commercially available 1,3,5-benzenetriol and involving oxidative activation of stable biogenetic building blocks as a crucial step. Key features of the syntheses include a unique Michael addition/ketalization/1,6-addition/enol-keto tautomerism cascade reaction for the construction of the dihydropyrano[3,2-d]xanthene tetracyclic core of cleistoperlones A and B, and a rare inverse-electron-demand hetero-Diels-Alder cycloaddition for the establishment of benzopyran ring in cleistoperlones D-F. Moreover, cleistoperlone A exhibited significant antiviral activity against acyclovir-resistant strains of herpes simplex virus type 1 (HSV-1/Blue and HSV-1/153).
Assuntos
Syzygium , Biomimética , Estereoisomerismo , Reação de Cicloadição , Antivirais/farmacologiaRESUMO
Seven new secoiridoid glycosides (1-7), together with a known analogue (8), were isolated from the fruits of Ligustrum lucidum. Their structures with absolute configurations were determined by HR-ESI-MS, 1D and 2D NMR, and electronic circular dichroism (ECD) spectroscopic analysis, as well as biogenetic consideration. Compounds 1 and 2 are the first examples of secoiridoid glycoside dimers featuring a rare rearranged oleoside-type secoiridoid moiety, and compounds 3-7 represent a new class of oleoside-type secoiridoid glycosides with unusual stereochemistry at C-1 position. A plausible biosynthetic pathway for this group of unusual secoiridoid glycosides was also proposed herein. In addition, the isolates were evaluated for their in vitro anti-inflammatory activity, and all tested compounds exhibited modest inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.
Assuntos
Glicosídeos Iridoides , Ligustrum , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Ligustrum/química , Estrutura Molecular , Frutas/química , Anti-Inflamatórios/farmacologia , Glicosídeos/farmacologia , Glicosídeos/análiseRESUMO
Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound 12n potently inhibited JAK3 kinase activity with an IC50 value of 1.2 nM and was more than 900-fold selective over JAK1, JAK2, and Tyk2. Cell-based assays revealed that 12n significantly suppressed phosphorylation of JAK3 and the downstream effectors STAT3/5 and also robustly restrained proliferation of BaF3 cells transfected with JAK3M511I activating mutation and human leukemia U937 cells harboring JAK3M511I with IC50 values of 22.9 and 20.2 nM, respectively. More importantly, 12n showed reasonable pharmacokinetic (PK) properties, and oral administration of 12n at a dose of 50 mg/kg twice daily led to tumor regression in a U937 cell inoculated xenograft mouse model. Thus, 12n represents a promising lead compound for further optimization to discover new therapeutic agents for hematological malignancies.
Assuntos
Neoplasias Hematológicas , Leucemia , Animais , Furanos/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Janus Quinase 1 , Janus Quinase 3 , Leucemia/tratamento farmacológico , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Células U937RESUMO
Lead (Pb) is one of the most widespread and highly toxic heavy metals in the environment. The design and synthesis of adsorbent materials for the selective and efficient removal of Pb2+ from aqueous solution has received much attention. Herein, the ligand 4,4'-azoxydibenzoic acid with the O- group was elaborately selected to construct a novel Pr-based MOF for Pb2+ removal. The as-prepared MOF adsorbents with high stability exhibited ultra-high selectivity for Pb2+, even in the presence of various highly concentrated competitive ions (with the ratios from 1 : 5 to 1 : 50). Also, a high uptake capacity (560.26 mg g-1) can be achieved for the MOF material, due to the availability of sufficient adsorption sites. The strong electrostatic attraction and coordination interaction between the numerous active O- sites on MOF adsorbents and Pb2+ can account for the good adsorption performance for Pb2+, which was systematically verified by zeta potential, FT-IR and XPS studies.
RESUMO
Inspired by a previously reported biomimetic synthesis study, four new naturally occurring phloroglucinol trimers 1-4 with unusual 6/5/5/6/6/6-fused hexacyclic ring systems, along with two known analogues (5 and 6) and two known biogenetically related dimers (10 and 11), were isolated from Rhodomyrtus tomentosa. Their structures and absolute configurations were unambiguously elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism calculation. By mimicking two potentially alternative biosynthetic pathways, the first asymmetric syntheses of 1-4 and the racemic syntheses of 5 and 6 were achieved in only five to six steps without the need for protecting groups. Furthermore, phloroglucinol dimers 10 and 11 exhibited significant in vitro antiviral activity against the respiratory syncytial virus.
Assuntos
Myrtaceae , Floroglucinol , Biomimética , Dicroísmo Circular , Estrutura Molecular , Myrtaceae/química , Floroglucinol/químicaRESUMO
Two-dimensional (2D) metal-organic framework (MOF) nanosheets, with largely exposed surface area and highly accessible active sites, have emerged as a novel kind of sensing material. Here, a luminescent 2D MOF nanosheet was designed and synthesized by a facile top-down strategy based on a three-dimensional (3D) layered MOF {[Zn(H2L)(H2O)2]·H2O}n (Zn-MOF; H4L = 3,5-bis(3',5'-dicarboxyphenyl)-1H-1,2,4-triazole). With a large π-conjugated system and rigid planar structure, ligand H4L was elaborately selected to construct the bulk Zn-MOF, which can be readily exfoliated into 2D nanosheets, owing to the weak interlayer interactions and easy-to-release H2O molecules in the interspaces of 2D layers. Given the great threat posed to the ecological environment by anti-inflammatory drugs and pesticides, the developed luminescent Zn-MOF nanosheets were utilized to determine these organic pollutants, achieving highly selective and sensitive detection of diclofenac sodium (DCF) and tetramethylthiuram disulfide (TMTD). Compared to the detection limits of 3D Zn-MOF (7.72 ppm for DCF, 6.01 ppm for TMTD), the obviously lower detection limits for 2D Zn-MOF nanosheets toward DCF (0.20 ppm) and TMTD (0.18 ppm) further revealed that the largely exposed surface area with rigid planar structure and ultralarge π-conjugated system greatly accelerated electron transfer, which brought about a vast improvement in response sensitivity. The remarkable quenching performance for DCF and TMTD stems from a combined effect of photoinduced electron transfer and competitive energy absorption. The possible sensing mechanism was systematically investigated by the studies of powder X-ray diffraction, UV-vis, luminescence lifetime, and density functional theory calculations.
Assuntos
Estruturas MetalorgânicasRESUMO
A phytochemical investigation on the roots of medicinal plant Eurycoma longifolia resulted in the isolation of 10 new highly oxygenated C20 quassinoids longifolactones GâP (1-10), along with four known ones (11-14). Their chemical structures and absolute configurations were unambiguously elucidated on the basis of comprehensive spectroscopic analysis and X-ray crystallographic data. Notably, compound 1 is a rare pentacyclic C20 quassinoid featuring a densely functionalized 2,5-dioxatricyclo[5.2.2.04,8]undecane core. Compound 4 represents the first example of quassinoids containing a 14,15-epoxy functionality, and 7 features an unusual α-oriented hydroxyl group at C-14. All isolated compounds were evaluated for their anti-proliferation activities on human leukemia cells. Among the isolates, compounds 5, 12, 13, and 14 potently inhibited the in vitro proliferation of K562 and HL-60 cells with IC50 values ranging from 2.90 to 8.20 µM.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Eurycoma/química , Leucemia/tratamento farmacológico , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Quassinas/farmacologia , Proliferação de Células , Células HL-60 , Humanos , Células K562 , Leucemia/patologiaRESUMO
Based on the typical HPLC-UV-MS profiles and characteristic 1H NMR signals, twelve new phloroglucinol-derived lipids (1-12), featuring a long linear aliphatic side chain, together with three known ones (13-15) were isolated from the ethanol extract of the leaves of Syzygium cumini. Their structures were elucidated on the basis of extensive NMR spectroscopic analyses and mass spectrometric data. Compounds 1-5 characterize an enolizable ß,ß'-tricarbonyl motif with a cyclohexa-3,5-dien-1-one core that is hitherto undescribed in phloroglucinol-derived lipids. Compounds 4 and 10-12 are novel phloroglucinol-derived lipids containing an uncommon methylene interrupted trans double bond in their polyunsaturated aliphatic side chains. A polyketide biogenetic pathway for those phloroglucinol-derived lipids was also proposed. In addition, the isolates were evaluated for their neuroprotective activities against oxygen-glucose deprivation and reoxygenation (OGD/R)-induced Neuro-2a cell injury. Notably, compounds 1, 5, and 10-12 significantly improved viability of Neuro-2a cells after OGD/R damage.
Assuntos
Lipídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Floroglucinol/química , Syzygium/química , Animais , Linhagem Celular , China , Lipídeos/isolamento & purificação , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/químicaRESUMO
The phytochemical study of the aerial part of Mesona chinensis led to the isolation of five new caffeic acid oligomers (1-5), as well as four known analogues (6-9). The structures of the new compounds including their absolute configurations were elucidated by comprehensive spectroscopic analysis, chemical method, and quantum-chemical electronic circular dichroism (ECD) calculation. Among the isolates, compound 7 showed significant in vitro antiviral activity on respiratory syncytial virus (RSV).
Assuntos
Antivirais/farmacologia , Ácidos Cafeicos/farmacologia , Lamiaceae/química , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Antivirais/isolamento & purificação , Ácidos Cafeicos/isolamento & purificação , Linhagem Celular Tumoral , China , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/químicaRESUMO
Two novel phloroglucinol-terpenoid adducts (1 and 2), featuring a rare 2,2,4-trimethyl-cinnamyl-ß-triketone unit, were isolated from the buds of Cleistocalyx operculatus. Their structures with absolute configurations were established by spectroscopic analyses, single-crystal X-ray diffraction, and quantum chemical calculations. Structurally, compound 1 represents a new carbon skeleton possessing a densely functionalized tricyclo[11.3.1.03;8]heptadecane bridged ring system with an unusual bridgehead enol. Compounds 1 and 2 exhibited significant in vitro antiviral activities against respiratory syncytial virus (RSV).
Assuntos
Antivirais/farmacologia , Floroglucinol/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Syzygium , Terpenos/farmacologia , Antivirais/química , Linhagem Celular , Glicoproteínas/metabolismo , Humanos , Estrutura Molecular , Floroglucinol/química , Vírus Sinciciais Respiratórios/metabolismo , Terpenos/química , Proteínas Virais/metabolismoRESUMO
Guided by 1H NMR spectroscopic experiments using the aromatic protons as probes, 11 macrocyclic diterpenes (1-11) were isolated from the aerial parts of Euphorbia helioscopia. Their full three-dimensional structures, including absolute configurations, were established unambiguously by spectroscopic analysis and single-crystal X-ray crystallographic experiments. Among the isolated compounds, compound 1 is the third member thus far of a rare class of Euphorbia diterpenes featuring an unusual 5/10 fused ring system, and 2-4 are new jatrophane diterpenes. Based on the NMR data of the jatrophane diterpenes obtained in this study as well as those with crystallographic structures reported in the literature, the correlations of the chemical shifts of the relevant carbons and the configurations of C-2, C-13, and C-14 of their flexible macrocyclic ring were considered. Moreover, the anti-inflammatory activities of 1-11 were investigated by monitoring their inhibitory effects on nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells. Compound 1 showed an IC50 of 7.4 ± 0.6 µM, which might be related to the regulation of the NF-κB signaling pathway by suppressing the translocation of the p65 subunit and the consequent reduction of IL-6 and TNF-α secretions.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Diterpenos/isolamento & purificação , Euphorbia/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cristalografia por Raios X , Diterpenos/química , Diterpenos/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , NF-kappa B/fisiologia , Componentes Aéreos da Planta/química , Células RAW 264.7RESUMO
A new meroterpenoid, tomentodione E (1), along with four known ones (2-5) were isolated from the leaves of Rhodomyrtus tomentosa. Their structures were elucidated based on extensive spectroscopic data as well as computational methods. Compound 1 represents the first example of meroterpenoid possessing a sec-pentyl syncarpic acid motif coupled with a caryophyllene. Compounds 1-4 were evaluated for their in vitro antiviral activity against respiratory syncytial virus (RSV) with cytopathic effect (CPE) reduction assay, and 2 showed potent in vitro anti-RSV effect.
Assuntos
Antivirais/isolamento & purificação , Myrtaceae/química , Folhas de Planta/química , Terpenos/isolamento & purificação , Terpenos/farmacologia , Antivirais/química , Antivirais/farmacologia , Glicosídeos/química , Estrutura Molecular , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Terpenos/químicaRESUMO
To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC)-UV method. Clofarabine toxicity in all groups fluctuated in accordance with circadian rhythms in vivo. The toxicity of clofarabine in mice in the rest phase was more severe than the active one, indicated by more severe liver damage, immunodepression, higher mortality rate, and lower LD50. No significant pharmacokinetic parameter changes were observed between the night and daytime treatment groups. These findings suggest the dosing-time dependent toxicity of clofarabine synchronizes with the circadian rhythm of mice, which might provide new therapeutic strategies in further clinical application.
Assuntos
Nucleotídeos de Adenina/farmacocinética , Nucleotídeos de Adenina/toxicidade , Arabinonucleosídeos/farmacocinética , Arabinonucleosídeos/toxicidade , Nucleotídeos de Adenina/sangue , Animais , Arabinonucleosídeos/sangue , Peso Corporal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Clofarabina , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Especificidade de Órgãos/efeitos dos fármacos , Fatores de Tempo , Testes de Toxicidade AgudaRESUMO
Altered transforming growth factor-ß (TGF-ß) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-ß1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-ß1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.
Assuntos
Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/metabolismo , Neoplasias Pulmonares/genética , Profilinas/genética , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Epigênese Genética , Citometria de Fluxo , Imunofluorescência , Células HEK293 , Humanos , Imuno-Histoquímica , Imunoprecipitação , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Microscopia Confocal , Metástase Neoplásica , Transplante de Neoplasias , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Action potential (AP) contours vary considerably between the fibers of normal adult and aged left atria. The underlying ionic and molecular mechanisms that mediate these differences remain unknown. The aim of the present study was to investigate whether the L-type calcium current (ICa.L) and the L-type Ca2+ channel of the left atria may be altered with age to contribute to atrial fibrillation (AF). Two groups of mongrel dogs (normal adults, 2-2.5 years old and older dogs, >8 years old) were used in this study. The inducibility of AF was quantitated using the cumulative window of vulnerability (WOV). A whole-cell patch-clamp was used to record APs and ICa.L in left atrial (LA) cells obtained from the two groups of dogs. Protein and mRNA expression levels of the a1C (Cav1.2) subunit of the L-type calcium channel were assessed using western blotting and quantitative PCR (qPCR), respectively. Although the resting potential, AP amplitude and did not differ with age, the plateau potential was more negative and the APD90 was longer in the aged cells compared with that in normal adult cells. Aged LA cells exhibited lower peak ICa.L current densities than normal adult LA cells (P<0.05). In addition, the Cav1.2 mRNA and protein expression levels in LA cells were decreased in the aged group compared with those in the normal adult group. The lower AP plateau potential and the decreased ICa.L of LA cells in aged dogs may contribute to the slow and discontinuous conduction of the left atria. Furthermore, the reduction of the expression levels of Cav1.2 with age may be the molecular mechanism that mediates the decline in ICa.L with increasing age.