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Kakali Bhadra - One of the best experts on this subject based on the ideXlab platform.

  • therapeutic role of harmalol targeting nucleic acids biophysical perspective and in vitro cytotoxicity
    Mini-reviews in Medicinal Chemistry, 2017
    Co-Authors: Sarita Sarkar, Kakali Bhadra
    Abstract:

    BACKGROUND: Harmalol, a beta carboline Alkaloid, shows remarkable importance in the contemporary biomedical research and drug discovery programs. With time, there is emerging interest in search for better anti-cancer drugs of plant origin with high activity and lower toxicity. Most of the chemotherapeutic agents due to their non-specific target and toxicity on active healthy cells, use is often restricted, necessitating search for newer drugs having greater potentiality. OBJECTIVE: The review highlighted the interaction of harmalol with nucleic acids of different motifs as sole target biomolecules and in vitro cytotoxicity of the Alkaloid in human cancer cell lines with special emphasis on its apoptotic induction ability. METHODS: Binding study and in vitro cytotoxicity was performed using several biophysical techniques and biochemical assays, respectively. RESULTS: Data from competition dialysis, UV and fluorescence spectroscopic analysis, circular dichroism, viscometry and isothermal calorimetry shows binding and interaction of harmalol with several natural and synthetic nucleic acids, both DNA and RNA, of different motifs. Furthermore, apoptotic hallmarks like internucleosomal DNA fragmentation, membrane blebbing, cell shrinkage, chromatin condensation, change of mitochondrial membrane potential, comet tail formation and ROS (reactive oxygen species) dependent cytotoxicity being analyzed in the harmalol treated cancer cells. CONCLUSION: These results stating the therapeutic role of harmalol, will lead to the interesting knowledge on the cytotoxicity, mode, mechanism, specificity of binding and correlation between structural aspects and energetics enabling a complete set of guidelines for design of new drugs.

  • targeting different rna motifs by beta carboline Alkaloid harmalol a comparative photophysical calorimetric and molecular docking approach
    Journal of Biomolecular Structure & Dynamics, 2016
    Co-Authors: Paromita Bhattacharjee, Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    AbstractRNA has attracted recent attention for its key role in gene expression and targeting by small molecules for therapeutic intervention. This work focuses towards understanding interaction of harmalol, a DNA intercalator, with RNAs of different motifs viz. single-stranded A-form poly(A), double-stranded A-form of poly(C)·poly(G), and clover leaf tRNAphe by different spectroscopic, calorimetric, and molecular modeling techniques. Results of this study converge to suggest that (i) binding constant varied in the order poly(C)·poly(G) > tRNAphe > poly(A), (ii) non-cooperative binding of harmalol to poly(C)·poly(G) and poly(A) and cooperative binding with tRNAphe, (iii) significant structural changes of poly(C)·poly(G) and tRNAphe with concomitant induction of optical activity in the bound achiral Alkaloid molecules, while with poly(A) no induced Circular dichroism (CD) perturbation was observed, (iv) the binding was predominantly exothermic, enthalpy-driven, entropy-favored with poly(C)·poly(G), while it...

  • sequence specific binding of beta carboline Alkaloid harmalol with deoxyribonucleotides binding heterogeneity conformational thermodynamic and cytotoxic aspects
    PLOS ONE, 2014
    Co-Authors: Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    BACKGROUND: Base dependent binding of the cytotoxic Alkaloid harmalol to four synthetic polynucleotides, poly(dA).poly(dT), poly(dA-dT).poly(dA-dT), poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) was examined by various photophysical and calorimetric studies, and molecular docking. METHODOLOGY/PRINCIPAL FINDINGS: Binding data obtained from absorbance according to neighbor exclusion model indicated that the binding constant decreased in the order poly(dG-dC).poly(dG-dC)>poly(dA-dT).poly(dA-dT)>poly(dA).poly(dT)>poly(dG).poly(dC). The same trend was shown by the competition dialysis, change in fluorescence steady state intensity, stabilization against thermal denaturation, increase in the specific viscosity and perturbations in circular dichroism spectra. Among the polynucleotides, poly(dA).poly(dT) and poly(dG).poly(dC) showed positive cooperativity where as poly(dG-dC).poly(dG-dC) and poly(dA-dT).poly(dA-dT) showed non cooperative binding. Isothermal calorimetric data on the other hand showed enthalpy driven exothermic binding with a hydrophobic contribution to the binding Gibbs energy with poly(dG-dC).poly(dG-dC), and poly(dA-dT).poly(dA-dT) where as harmalol with poly(dA).poly(dT) showed entropy driven endothermic binding and with poly(dG).poly(dC) it was reported to be entropy driven exothermic binding. The study also tested the in vitro chemotherapeutic potential of harmalol in HeLa, MDA-MB-231, A549, and HepG2 cell line by MTT assay. CONCLUSIONS/SIGNIFICANCE: Studies unequivocally established that harmalol binds strongly with hetero GC polymer by mechanism of intercalation where the Alkaloid resists complete overlap to the DNA base pairs inside the intercalation cavity and showed maximum cytotoxicity on HepG2 with IC50 value of 14 µM. The results contribute to the understanding of binding, specificity, energetic, cytotoxicity and docking of harmalol-DNA complexation that will guide synthetic efforts of medicinal chemists for developing better therapeutic agents.

  • Sequence Specific Binding of Beta Carboline Alkaloid Harmalol with Deoxyribonucleotides: Binding Heterogeneity, Conformational, Thermodynamic and Cytotoxic Aspects - Figure 3
    2014
    Co-Authors: Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    (A) (Top panel) A representative figure showing the changes in the absorption spectra of harmalol upon titration with poly(dG-dC).poly(dG-dC) in 15 mM CP buffer, pH 6.8 at 25±0.5°C. Curve (1) denote absorption spectrum of harmalol (10.0 µM) treated with 5.16, 10.5, 20.2, 30.50, 35.0 and 50.0 µM (curves 2–7) of poly(dG-dC).poly(dG-dC), respectively. (Bottom panel) Scatchard plots derived from absorbance spectral data for the binding of harmalol to 20 µM of (B) hetero AT, (C) homo AT, (D) hetero GC and (E) homo GC polynucleotides. The data was fit to both cooperative and non cooperative binding model derived from McGhee-von Hippel equation [68]. The best fit values of Kb, n and ω are presented in Table 1.

Sarita Sarkar - One of the best experts on this subject based on the ideXlab platform.

  • therapeutic role of harmalol targeting nucleic acids biophysical perspective and in vitro cytotoxicity
    Mini-reviews in Medicinal Chemistry, 2017
    Co-Authors: Sarita Sarkar, Kakali Bhadra
    Abstract:

    BACKGROUND: Harmalol, a beta carboline Alkaloid, shows remarkable importance in the contemporary biomedical research and drug discovery programs. With time, there is emerging interest in search for better anti-cancer drugs of plant origin with high activity and lower toxicity. Most of the chemotherapeutic agents due to their non-specific target and toxicity on active healthy cells, use is often restricted, necessitating search for newer drugs having greater potentiality. OBJECTIVE: The review highlighted the interaction of harmalol with nucleic acids of different motifs as sole target biomolecules and in vitro cytotoxicity of the Alkaloid in human cancer cell lines with special emphasis on its apoptotic induction ability. METHODS: Binding study and in vitro cytotoxicity was performed using several biophysical techniques and biochemical assays, respectively. RESULTS: Data from competition dialysis, UV and fluorescence spectroscopic analysis, circular dichroism, viscometry and isothermal calorimetry shows binding and interaction of harmalol with several natural and synthetic nucleic acids, both DNA and RNA, of different motifs. Furthermore, apoptotic hallmarks like internucleosomal DNA fragmentation, membrane blebbing, cell shrinkage, chromatin condensation, change of mitochondrial membrane potential, comet tail formation and ROS (reactive oxygen species) dependent cytotoxicity being analyzed in the harmalol treated cancer cells. CONCLUSION: These results stating the therapeutic role of harmalol, will lead to the interesting knowledge on the cytotoxicity, mode, mechanism, specificity of binding and correlation between structural aspects and energetics enabling a complete set of guidelines for design of new drugs.

  • targeting different rna motifs by beta carboline Alkaloid harmalol a comparative photophysical calorimetric and molecular docking approach
    Journal of Biomolecular Structure & Dynamics, 2016
    Co-Authors: Paromita Bhattacharjee, Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    AbstractRNA has attracted recent attention for its key role in gene expression and targeting by small molecules for therapeutic intervention. This work focuses towards understanding interaction of harmalol, a DNA intercalator, with RNAs of different motifs viz. single-stranded A-form poly(A), double-stranded A-form of poly(C)·poly(G), and clover leaf tRNAphe by different spectroscopic, calorimetric, and molecular modeling techniques. Results of this study converge to suggest that (i) binding constant varied in the order poly(C)·poly(G) > tRNAphe > poly(A), (ii) non-cooperative binding of harmalol to poly(C)·poly(G) and poly(A) and cooperative binding with tRNAphe, (iii) significant structural changes of poly(C)·poly(G) and tRNAphe with concomitant induction of optical activity in the bound achiral Alkaloid molecules, while with poly(A) no induced Circular dichroism (CD) perturbation was observed, (iv) the binding was predominantly exothermic, enthalpy-driven, entropy-favored with poly(C)·poly(G), while it...

  • sequence specific binding of beta carboline Alkaloid harmalol with deoxyribonucleotides binding heterogeneity conformational thermodynamic and cytotoxic aspects
    PLOS ONE, 2014
    Co-Authors: Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    BACKGROUND: Base dependent binding of the cytotoxic Alkaloid harmalol to four synthetic polynucleotides, poly(dA).poly(dT), poly(dA-dT).poly(dA-dT), poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) was examined by various photophysical and calorimetric studies, and molecular docking. METHODOLOGY/PRINCIPAL FINDINGS: Binding data obtained from absorbance according to neighbor exclusion model indicated that the binding constant decreased in the order poly(dG-dC).poly(dG-dC)>poly(dA-dT).poly(dA-dT)>poly(dA).poly(dT)>poly(dG).poly(dC). The same trend was shown by the competition dialysis, change in fluorescence steady state intensity, stabilization against thermal denaturation, increase in the specific viscosity and perturbations in circular dichroism spectra. Among the polynucleotides, poly(dA).poly(dT) and poly(dG).poly(dC) showed positive cooperativity where as poly(dG-dC).poly(dG-dC) and poly(dA-dT).poly(dA-dT) showed non cooperative binding. Isothermal calorimetric data on the other hand showed enthalpy driven exothermic binding with a hydrophobic contribution to the binding Gibbs energy with poly(dG-dC).poly(dG-dC), and poly(dA-dT).poly(dA-dT) where as harmalol with poly(dA).poly(dT) showed entropy driven endothermic binding and with poly(dG).poly(dC) it was reported to be entropy driven exothermic binding. The study also tested the in vitro chemotherapeutic potential of harmalol in HeLa, MDA-MB-231, A549, and HepG2 cell line by MTT assay. CONCLUSIONS/SIGNIFICANCE: Studies unequivocally established that harmalol binds strongly with hetero GC polymer by mechanism of intercalation where the Alkaloid resists complete overlap to the DNA base pairs inside the intercalation cavity and showed maximum cytotoxicity on HepG2 with IC50 value of 14 µM. The results contribute to the understanding of binding, specificity, energetic, cytotoxicity and docking of harmalol-DNA complexation that will guide synthetic efforts of medicinal chemists for developing better therapeutic agents.

  • Sequence Specific Binding of Beta Carboline Alkaloid Harmalol with Deoxyribonucleotides: Binding Heterogeneity, Conformational, Thermodynamic and Cytotoxic Aspects - Figure 3
    2014
    Co-Authors: Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    (A) (Top panel) A representative figure showing the changes in the absorption spectra of harmalol upon titration with poly(dG-dC).poly(dG-dC) in 15 mM CP buffer, pH 6.8 at 25±0.5°C. Curve (1) denote absorption spectrum of harmalol (10.0 µM) treated with 5.16, 10.5, 20.2, 30.50, 35.0 and 50.0 µM (curves 2–7) of poly(dG-dC).poly(dG-dC), respectively. (Bottom panel) Scatchard plots derived from absorbance spectral data for the binding of harmalol to 20 µM of (B) hetero AT, (C) homo AT, (D) hetero GC and (E) homo GC polynucleotides. The data was fit to both cooperative and non cooperative binding model derived from McGhee-von Hippel equation [68]. The best fit values of Kb, n and ω are presented in Table 1.

Prateek Pandya - One of the best experts on this subject based on the ideXlab platform.

  • targeting different rna motifs by beta carboline Alkaloid harmalol a comparative photophysical calorimetric and molecular docking approach
    Journal of Biomolecular Structure & Dynamics, 2016
    Co-Authors: Paromita Bhattacharjee, Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    AbstractRNA has attracted recent attention for its key role in gene expression and targeting by small molecules for therapeutic intervention. This work focuses towards understanding interaction of harmalol, a DNA intercalator, with RNAs of different motifs viz. single-stranded A-form poly(A), double-stranded A-form of poly(C)·poly(G), and clover leaf tRNAphe by different spectroscopic, calorimetric, and molecular modeling techniques. Results of this study converge to suggest that (i) binding constant varied in the order poly(C)·poly(G) > tRNAphe > poly(A), (ii) non-cooperative binding of harmalol to poly(C)·poly(G) and poly(A) and cooperative binding with tRNAphe, (iii) significant structural changes of poly(C)·poly(G) and tRNAphe with concomitant induction of optical activity in the bound achiral Alkaloid molecules, while with poly(A) no induced Circular dichroism (CD) perturbation was observed, (iv) the binding was predominantly exothermic, enthalpy-driven, entropy-favored with poly(C)·poly(G), while it...

  • sequence specific binding of beta carboline Alkaloid harmalol with deoxyribonucleotides binding heterogeneity conformational thermodynamic and cytotoxic aspects
    PLOS ONE, 2014
    Co-Authors: Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    BACKGROUND: Base dependent binding of the cytotoxic Alkaloid harmalol to four synthetic polynucleotides, poly(dA).poly(dT), poly(dA-dT).poly(dA-dT), poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) was examined by various photophysical and calorimetric studies, and molecular docking. METHODOLOGY/PRINCIPAL FINDINGS: Binding data obtained from absorbance according to neighbor exclusion model indicated that the binding constant decreased in the order poly(dG-dC).poly(dG-dC)>poly(dA-dT).poly(dA-dT)>poly(dA).poly(dT)>poly(dG).poly(dC). The same trend was shown by the competition dialysis, change in fluorescence steady state intensity, stabilization against thermal denaturation, increase in the specific viscosity and perturbations in circular dichroism spectra. Among the polynucleotides, poly(dA).poly(dT) and poly(dG).poly(dC) showed positive cooperativity where as poly(dG-dC).poly(dG-dC) and poly(dA-dT).poly(dA-dT) showed non cooperative binding. Isothermal calorimetric data on the other hand showed enthalpy driven exothermic binding with a hydrophobic contribution to the binding Gibbs energy with poly(dG-dC).poly(dG-dC), and poly(dA-dT).poly(dA-dT) where as harmalol with poly(dA).poly(dT) showed entropy driven endothermic binding and with poly(dG).poly(dC) it was reported to be entropy driven exothermic binding. The study also tested the in vitro chemotherapeutic potential of harmalol in HeLa, MDA-MB-231, A549, and HepG2 cell line by MTT assay. CONCLUSIONS/SIGNIFICANCE: Studies unequivocally established that harmalol binds strongly with hetero GC polymer by mechanism of intercalation where the Alkaloid resists complete overlap to the DNA base pairs inside the intercalation cavity and showed maximum cytotoxicity on HepG2 with IC50 value of 14 µM. The results contribute to the understanding of binding, specificity, energetic, cytotoxicity and docking of harmalol-DNA complexation that will guide synthetic efforts of medicinal chemists for developing better therapeutic agents.

  • Sequence Specific Binding of Beta Carboline Alkaloid Harmalol with Deoxyribonucleotides: Binding Heterogeneity, Conformational, Thermodynamic and Cytotoxic Aspects - Figure 3
    2014
    Co-Authors: Sarita Sarkar, Prateek Pandya, Kakali Bhadra
    Abstract:

    (A) (Top panel) A representative figure showing the changes in the absorption spectra of harmalol upon titration with poly(dG-dC).poly(dG-dC) in 15 mM CP buffer, pH 6.8 at 25±0.5°C. Curve (1) denote absorption spectrum of harmalol (10.0 µM) treated with 5.16, 10.5, 20.2, 30.50, 35.0 and 50.0 µM (curves 2–7) of poly(dG-dC).poly(dG-dC), respectively. (Bottom panel) Scatchard plots derived from absorbance spectral data for the binding of harmalol to 20 µM of (B) hetero AT, (C) homo AT, (D) hetero GC and (E) homo GC polynucleotides. The data was fit to both cooperative and non cooperative binding model derived from McGhee-von Hippel equation [68]. The best fit values of Kb, n and ω are presented in Table 1.

Santo Davide Ferrara - One of the best experts on this subject based on the ideXlab platform.

  • A case of Beta-Carboline Alkaloid intoxication following ingestion of Peganum harmala seed extract.
    Forensic science international, 2008
    Co-Authors: Giampietro Frison, Donata Favretto, Giorgio Fazzin, Flavio Zancanaro, Santo Davide Ferrara
    Abstract:

    Beta-Carboline Alkaloids harmine, harmaline, and tetrahydroharmine can stimulate the central nervous system by inhibiting the metabolism of amine neurotransmitters, or by direct interaction with specific receptors; they are found in numerous plants, including Peganum harmala, Passiflora incarnata and Banisteriopsis caapi, and in the entheogen preparation Ayahuasca, which is traditionally brewed using B. caapi to enhance the activity of amine hallucinogenic drugs. The ingestion of plant preparations containing Beta-Carboline Alkaloids may result in toxic effects, namely visual and auditory hallucinations, locomotor ataxia, nausea, vomiting, confusion and agitation. We report a case of intoxication following intentional ingestion of P. harmala seed infusion; P. harmala seeds were bought over the Internet. The harmala Alkaloids were identified by gas chromatography-mass spectrometry in the seed extract and the patient's urine. This is, to our knowledge, the first case of P. harmala intoxication corroborated by toxicological findings.

Rehen, Stevens K. - One of the best experts on this subject based on the ideXlab platform.

  • Harmine stimulates proliferation of human neural progenitors
    'PeerJ', 2021
    Co-Authors: Dakic Vanja, Macier, Renata De Moraes, Drummond Hannah, Nascimento, Juliana M., Trindade Pablo, Rehen, Stevens K.
    Abstract:

    Harmine is the Beta-Carboline Alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo4CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO CARLOS CHAGAS FILHO DE AMPARO À PESQUISA DO ESTADO DO RIO DE JANEIRO - FAPERJFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPFunding Authority for Studies and Projects (FINEP); Brazilian Development Bank (BNDES