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Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Kumari N, Kulkarni AA, Lin X, McLean C, Ammosova T, Ivanov A, Hipolito M, Nekhai S, Nwulia E - Drug Des Devel Ther (2015)

Bottom Line: The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours.But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM).Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA ; Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.

ABSTRACT
Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 μM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.

No MeSH data available.


Related in: MedlinePlus

Effect of curcumin and curcumin A on HO-1 expression and cell cycle progression.Notes: (A) Expression of HO-1. CEM-T cells were treated with 1 μM curcumin or curcumin A. DMSO was used as vehicle control. After 24 hours treatment, RNA was extracted, reverse transcribed, and analyzed by real-time PCR for HO-1 using 18S RNA as a housekeeping control gene. (B) Effect of curcumin and curcumin A on the cell cycle progression. CEM-T cells were treated with 1 μM curcumin or curcumin A for 24 hours and then fixed with 70% ethanol, stained with propidium iodide, and analyzed by fluorescence assisted cell sorting (FACS). Data were analyzed using BD FACS Calibur software (BD Biosciences, San Jose, CA, USA). Cells accumulated in G0/G1, G2/M and S phases of cell cycle are shown. Cell cycle phases: G0, resting phase; G1, gap 1 phase; G2, gap 2 phase; M, mitosis phase, and S, synthesis phase. All results are shown as a mean of three independent measurements ± standard deviation.Abbreviations: DMSO, dimethyl sulfoxide; mRNA, messenger RNA; PCR, polymerase chain reaction; PBMCs, peripheral blood mononuclear cells.
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f5-dddt-9-5051: Effect of curcumin and curcumin A on HO-1 expression and cell cycle progression.Notes: (A) Expression of HO-1. CEM-T cells were treated with 1 μM curcumin or curcumin A. DMSO was used as vehicle control. After 24 hours treatment, RNA was extracted, reverse transcribed, and analyzed by real-time PCR for HO-1 using 18S RNA as a housekeeping control gene. (B) Effect of curcumin and curcumin A on the cell cycle progression. CEM-T cells were treated with 1 μM curcumin or curcumin A for 24 hours and then fixed with 70% ethanol, stained with propidium iodide, and analyzed by fluorescence assisted cell sorting (FACS). Data were analyzed using BD FACS Calibur software (BD Biosciences, San Jose, CA, USA). Cells accumulated in G0/G1, G2/M and S phases of cell cycle are shown. Cell cycle phases: G0, resting phase; G1, gap 1 phase; G2, gap 2 phase; M, mitosis phase, and S, synthesis phase. All results are shown as a mean of three independent measurements ± standard deviation.Abbreviations: DMSO, dimethyl sulfoxide; mRNA, messenger RNA; PCR, polymerase chain reaction; PBMCs, peripheral blood mononuclear cells.

Mentions: Previously, curcumin was shown to induce HO-1.2 Activation of HO-1 by heme was also shown to inhibit HIV-1.19 Thus we examined the effects of curcumin and curcumin A on HO-1 in primary PBMCs and also in cultured CEM-T cells. The cells were treated with 1 μM curcumin A or curcumin and HO-1 expression was analyzed by mRNA quantification with quantitative PCR using 18S RNA for normalization. Both curcumin A and curcumin induced HO-1 in CEM-T cells and PBMCs (Figure 5A). Thus, the HIV-1 inhibitory effects of curcumin and curcumin A could partly be due to the activation of HO-1.


Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Kumari N, Kulkarni AA, Lin X, McLean C, Ammosova T, Ivanov A, Hipolito M, Nekhai S, Nwulia E - Drug Des Devel Ther (2015)

Effect of curcumin and curcumin A on HO-1 expression and cell cycle progression.Notes: (A) Expression of HO-1. CEM-T cells were treated with 1 μM curcumin or curcumin A. DMSO was used as vehicle control. After 24 hours treatment, RNA was extracted, reverse transcribed, and analyzed by real-time PCR for HO-1 using 18S RNA as a housekeeping control gene. (B) Effect of curcumin and curcumin A on the cell cycle progression. CEM-T cells were treated with 1 μM curcumin or curcumin A for 24 hours and then fixed with 70% ethanol, stained with propidium iodide, and analyzed by fluorescence assisted cell sorting (FACS). Data were analyzed using BD FACS Calibur software (BD Biosciences, San Jose, CA, USA). Cells accumulated in G0/G1, G2/M and S phases of cell cycle are shown. Cell cycle phases: G0, resting phase; G1, gap 1 phase; G2, gap 2 phase; M, mitosis phase, and S, synthesis phase. All results are shown as a mean of three independent measurements ± standard deviation.Abbreviations: DMSO, dimethyl sulfoxide; mRNA, messenger RNA; PCR, polymerase chain reaction; PBMCs, peripheral blood mononuclear cells.
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Related In: Results  -  Collection

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f5-dddt-9-5051: Effect of curcumin and curcumin A on HO-1 expression and cell cycle progression.Notes: (A) Expression of HO-1. CEM-T cells were treated with 1 μM curcumin or curcumin A. DMSO was used as vehicle control. After 24 hours treatment, RNA was extracted, reverse transcribed, and analyzed by real-time PCR for HO-1 using 18S RNA as a housekeeping control gene. (B) Effect of curcumin and curcumin A on the cell cycle progression. CEM-T cells were treated with 1 μM curcumin or curcumin A for 24 hours and then fixed with 70% ethanol, stained with propidium iodide, and analyzed by fluorescence assisted cell sorting (FACS). Data were analyzed using BD FACS Calibur software (BD Biosciences, San Jose, CA, USA). Cells accumulated in G0/G1, G2/M and S phases of cell cycle are shown. Cell cycle phases: G0, resting phase; G1, gap 1 phase; G2, gap 2 phase; M, mitosis phase, and S, synthesis phase. All results are shown as a mean of three independent measurements ± standard deviation.Abbreviations: DMSO, dimethyl sulfoxide; mRNA, messenger RNA; PCR, polymerase chain reaction; PBMCs, peripheral blood mononuclear cells.
Mentions: Previously, curcumin was shown to induce HO-1.2 Activation of HO-1 by heme was also shown to inhibit HIV-1.19 Thus we examined the effects of curcumin and curcumin A on HO-1 in primary PBMCs and also in cultured CEM-T cells. The cells were treated with 1 μM curcumin A or curcumin and HO-1 expression was analyzed by mRNA quantification with quantitative PCR using 18S RNA for normalization. Both curcumin A and curcumin induced HO-1 in CEM-T cells and PBMCs (Figure 5A). Thus, the HIV-1 inhibitory effects of curcumin and curcumin A could partly be due to the activation of HO-1.

Bottom Line: The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours.But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM).Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA ; Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.

ABSTRACT
Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 μM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.

No MeSH data available.


Related in: MedlinePlus