Publications by authors named "Ravikumar Aalinkeel"

54 Publications

Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID.

J Neuroimmune Pharmacol 2021 Oct 2. Epub 2021 Oct 2.

Department of Medicine, Division of Allergy, Immunology & Rheumatology Jacobs School of Medicine and Biomedical Sciences, University At Buffalo, Clinical Translational Research Center, Buffalo, NY, 14203, USA.

Emerging clinical data from the current COVID-19 pandemic suggests that ~ 40% of COVID-19 patients develop neurological symptoms attributed to viral encephalitis while in COVID long haulers chronic neuro-inflammation and neuronal damage result in a syndrome described as Neuro-COVID. We hypothesize that SAR-COV2 induces mitochondrial dysfunction and activation of the mitochondrial-dependent intrinsic apoptotic pathway, resulting in microglial and neuronal apoptosis. The goal of our study was to determine the effect of SARS-COV2 on mitochondrial biogenesis and to monitor cell apoptosis in human microglia non-invasively in real time using Raman spectroscopy, providing a unique spatio-temporal information on mitochondrial function in live cells. We treated human microglia with SARS-COV2 spike protein and examined the levels of cytokines and reactive oxygen species (ROS) production, determined the effect of SARS-COV2 on mitochondrial biogenesis and examined the changes in molecular composition of phospholipids. Our results show that SARS- COV2 spike protein increases the levels of pro-inflammatory cytokines and ROS production, increases apoptosis and increases the oxygen consumption rate (OCR) in microglial cells. Increases in OCR are indicative of increased ROS production and oxidative stress suggesting that SARS-COV2 induced cell death. Raman spectroscopy yielded significant differences in phospholipids such as Phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC), which account for ~ 80% of mitochondrial membrane lipids between SARS-COV2 treated and untreated microglial cells. These data provide important mechanistic insights into SARS-COV2 induced mitochondrial dysfunction which underlies neuropathology associated with Neuro-COVID.
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http://dx.doi.org/10.1007/s11481-021-10015-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487226PMC
October 2021

Telomere Length Shortening in Microglia: Implication for Accelerated Senescence and Neurocognitive Deficits in HIV.

Vaccines (Basel) 2021 Jul 1;9(7). Epub 2021 Jul 1.

Department of Medicine, Division of Allergy, Immunology & Rheumatology, University at Buffalo's Clinical Translational Research Center, Buffalo, NY 14203, USA.

The widespread use of combination antiretroviral therapy (cART) has led to the accelerated aging of the HIV-infected population, and these patients continue to have a range of mild to moderate HIV-associated neurocognitive disorders (HAND). Infection results in altered mitochondrial function. The HIV-1 viral protein Tat significantly alters mtDNA content and enhances oxidative stress in immune cells. Microglia are the immune cells of the central nervous system (CNS) that exhibit a significant mitotic potential and are thus susceptible to telomere shortening. HIV disrupts the normal interplay between microglia and neurons, thereby inducing neurodegeneration. HIV cART contributes to the inhibition of telomerase activity and premature telomere shortening in activated peripheral blood mononuclear cells (PBMC). However, limited information is available on the effect of cART on telomere length (TL) in microglia. Although it is well established that telomere shortening induces cell senescence and contributes to the development of age-related neuro-pathologies, the effect of HIV-Tat on telomere length in human microglial cells and its potential contribution to HAND are not well understood. It is speculated that in HAND intrinsic molecular mechanisms that control energy production underlie microglia-mediated neuronal injury. TL, telomerase and mtDNA expression were quantified in microglial cells using real time PCR. Cellular energetics were measured using the Seahorse assay. The changes in mitochondrial function were examined by Raman Spectroscopy. We have also examined TL in the PBMC obtained from HIV-1 infected rapid progressors (RP) on cART and those who were cART naïve, and observed a significant decrease in telomere length in RP on cART as compared to RP's who were cART naïve. We observed a significant decrease in telomerase activity, telomere length and mitochondrial function, and an increase in oxidative stress in human microglial cells treated with HIV Tat. Neurocognitive impairment in HIV disease may in part be due to accelerated neuro-pathogenesis in microglial cells, which is attributable to increased oxidative stress and mitochondrial dysfunction.
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http://dx.doi.org/10.3390/vaccines9070721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310244PMC
July 2021

IL-17 Is a Key Regulator of Mucin-Galectin-3 Interactions in Asthma.

Int J Cell Biol 2021 9;2021:9997625. Epub 2021 Jun 9.

Division of Allergy, Immunology & Rheumatology, Department of Medicine, State University of New York at Buffalo, 875 Ellicott Street, Buffalo, NY 14203, USA.

Mucus hypersecretion and chronic airway inflammation are standard characteristics of several airway diseases, such as chronic obstructive pulmonary disease and asthma. Increased mucus secretion from increased mucin gene expression in the airway epithelium is associated with poor prognosis and mortality. We previously showed that the absence of tissue inhibitor of metalloproteinase 1 (TIMP-1) enhances lung inflammation, airway hyperreactivity, and lung remodeling in asthma in an ovalbumin (OVA) asthma model of TIMP-1 knockout (TIMPKO) mice as compared to wild-type (WT) controls and mediated by increased galectin-3 (Gal-3) levels. Additionally, we have shown that in the lung epithelial cell line A549, Gal-3 inhibition increases interleukin-17 (IL-17) levels, leading to increased mucin expression in the airway epithelium. Therefore, in the current study, we further examined the relationship between Gal-3 and the production of IL-17-axis cytokines and critical members of the mucin family in the murine TIMPKO asthma model and the lung epithelium cell line A549. While Gal-3 may regulate a Th/Th response, IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. Gal-3 and IL-17 interactions induce mucus expression in OVA-sensitized mice. We conclude that Gal-3 may play an essential role in the pathogenesis of asthma, and modulation of Gal-3 may prove helpful in the treatment of this disease.
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http://dx.doi.org/10.1155/2021/9997625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211528PMC
June 2021

A cannabidiol-loaded Mg-gallate metal-organic framework-based potential therapeutic for glioblastomas.

J Mater Chem B 2021 03;9(10):2505-2514

Department of Chemical and Biological Engineering, University at Buffalo, USA. and RENEW Institute, University at Buffalo, USA.

Cannabidiol (CBD) has been shown to slow cancer cell growth and is toxic to human glioblastoma cell lines. Thus, CBD could be an effective therapeutic for glioblastoma. In the present study, we explored the anticancer effect of cannabidiol loaded magnesium-gallate (CBD/Mg-GA) metal-organic framework (MOF) using the rat glioma brain cancer (C6) cell line. Bioactive and microporous magnesium gallate MOF was employed for simultaneous delivery of two potential anticancer agents (gallic acid and CBD) to the cancer cells. Gallic acid (GA), a polyphenolic compound, is part of the MOF framework, while CBD is loaded within the framework. Slow degradation of CBD/Mg-GA MOF in physiological fluids leads to sustained release of GA and CBD. CBD's anti-cancer actions target mitochondria, inducing their dysfunction and generation of harmful reactive oxygen species (ROS). Anticancer effects of CBD/Mg-GA include a significant increase in ROS production and a reduction in anti-inflammatory responses as reflected by a significant decrease in TNF-α expression levels. Molecular mechanisms that underlie these effects include the modulation of NF-κB expression, triggering the apoptotic cascades of glioma cells. CBD/Mg-GA MOF has potential anti-cancer, anti-inflammatory and anti-oxidant properties. Thus, the present study demonstrates that CBD/Mg-GA MOF may be a promising therapeutic for glioblastoma.
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http://dx.doi.org/10.1039/d0tb02780dDOI Listing
March 2021

A Multimodal Theranostic Nanoformulation That Dramatically Enhances Docetaxel Efficacy Against Castration Resistant Prostate Cancer.

J Pharm Sci 2020 09 11;109(9):2874-2883. Epub 2020 Jun 11.

Division of Allergy, Immunology, and Rheumatology, Department of Medicine, State University of New York at Buffalo, Clinical Translational Research Center, Buffalo, New York 14203.

In this work, a multifunctional hierarchical nanoformulation composed of biodegradable chitosan (CS) coated poly (lactic-co-glycolic acid) (PLGA) nanocarriers loaded with docetaxel (Doc) and interleukin-8 (IL-8) small interfering RNA (siRNA) electrostatically bound to upconversion nanoparticles (UCNPs), is developed to treat castration-resistant prostate cancer (CRPC). This theranostic nanoformulation facilitates simultaneous delivery of chemotherapy and gene therapy, as well as a bimodal optical and magnetic resonance imaging agent that could enable image-guided combination therapy. Poly-d-lysine coated NaYF; Yb20%, Er2%@NaYF; Gd50% [email protected] UCNPs are effective siRNA transfection agents, and Er doping provides upconversion imaging capabilities, while Gd doping enables magnetic resonance contrast enhancement. These properties are maintained upon encapsulation in PLGA-CS. PLGA-CS nanocarriers containing Doc and UCNP-siRNA are 235 ± 5 nm with a zeta potential of +17 ± 4 meV, and have a high Doc encapsulation efficiency of 57 ± 6%. Compared to free Doc, this PLGA-CS nanoformulation containing Doc and UCNP-siRNA exhibits a dramatic decrease in IC of ~14,000 fold (p < 0.001) through combination therapy in human PC-3 prostate cancer cells. This biocompatible, multimodal, theranostic nanoformulation demonstrates paradigm-shifting enhancement in anticancer activity over free Doc, with unique potential for use in image-guided combination therapy to treat CRPC.
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http://dx.doi.org/10.1016/j.xphs.2020.06.004DOI Listing
September 2020

Effect of Dolutegravir and Sertraline on the Blood Brain Barrier (BBB).

J Neuroimmune Pharmacol 2020 03 15;15(1):7-9. Epub 2020 Jan 15.

Department of Medicine, Division of Allergy, Immunology & Rheumatology, University at Buffalo, Clinical & Translational Research Center, 875 Ellicott Street, Buffalo, NY, 14203, USA.

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http://dx.doi.org/10.1007/s11481-020-09904-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141951PMC
March 2020

Assessment of Antibody Interference of Enfuvirtide (T20) Function Shows Assay Dependent Variability.

Curr HIV Res 2018 ;16(6):404-415

Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, NY, United States.

Background: During HIV infection, fusion of the viral and cellular membranes is dependent on folding of the gp41 trimer into a six-helix bundle. Fusion inhibitors, such as the antiretroviral Enfuvirtide (T20), interfere with the formation of the gp41 six-helix bundle. Recent in vitro studies reveal that the gp41 immunodominant region one targeting antibody 3D6 can block T20 interference, but the clinical and pathophysiologic significance of this finding is unclear.

Objective/method: We have previously characterized a number of antibodies that target conformational epitopes on gp41and herein characterized their ability to interfere with T20 in multiple assays and assess their prevalence in HIV infected subjects.

Results: The T20 interference by antibody 3D6 was confirmed in a CHO-HXB2 envelope/ HeLaT4+ cell culture assay. Antibodies that target an immunodominant region one epitope, as well as a gp41 discontinuous epitope, also interfered in this assay, however, not all antibodies that targeted these epitopes showed T20 interference. This response was not due to the direct binding of T20 by the antibodies and could not be replicated utilizing TZM-bl and HL2/3 cells. Notably, serum competition studies on a panel of HIV subjects demonstrate that these conformational targeting antibodies are common in the HIV population.

Conclusion: The relatively common nature of antibodies targeting these epitopes, the disparate in vitro results, and lack of reported clinical failures ascribed to such antibodies leads us to conclude that antibody interference of T20 is likely not clinically relevant. However, this warrants continued consideration with the advancement of other fusion inhibitors.
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http://dx.doi.org/10.2174/1570162X17666190228154850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710457PMC
September 2019

United States National Trends in Mortality, Length of Stay (LOS) and Associated Costs of Cognitive Impairment in HIV Population from 2005 to 2014.

AIDS Behav 2018 Oct;22(10):3198-3208

Division of Allergy Immunology & Rheumatology, Department of Medicine, 6074 Clinical and Translational Research Center, State University of New York at Buffalo, 875 Ellicott Street, Buffalo, NY, 14203, USA.

We evaluated national trends of in-hospital discharge rates, mortality outcomes, health care costs, length of stay in HIV patients with cognitive disorders. Neurological involvement in HIV is commonly associated with cognitive impairment termed as HIV-associated neurocognitive disorder (HAND) which includes a spectrum of neurocognitive dysfunction associated with HIV infection. Although severe and progressive neurocognitive impairment has become rare in HIV patients in the era of potent antiretroviral therapy, a majority of HIV patients have mild to moderate degree of neurocognitive impairment. Study population for this analysis was derived from the Nationwide Inpatient Sample from 2005 to 2014. Patients with ICD-9 code of HIV (042) with discharge diagnosis (Dx) listed top 1 through 5 were included in the analysis. Within this population, we identified patients with cognitive impairment using ICD-9 codes of 294 (persistent mental disorders; organic psychotic brain syndromes (chronic), 323.9 (encephalitis, myelitis, and encephalomyelitis), 331.83 (mild cognitive impairment) with Dx listed from 1 to 25. Patient variables obtained included: age, race, gender, length of stay, in-hospital mortality and insurance status. Hospital level variables included teaching status, location and region of country. SAS 9.4 software was used for data analysis. Comparisons of variables between hospitalized HIV patients with and without HAND showed significant increase in cost per hospital admissions, longer hospital stay and higher risk of mortality in patients with HAND.
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http://dx.doi.org/10.1007/s10461-018-2128-zDOI Listing
October 2018

Immunomodulatory Role of Complement Proteins in the Neuropathology Associated with Opiate Abuse and HIV-1 Co-Morbidity.

Immunol Invest 2017 Nov;46(8):816-832

b Division of Nephrology , UB Clinical and Translational Research Center , Buffalo , NY , USA.

The complement system which is a critical mediator of innate immunity plays diverse roles in the neuropathogenesis of HIV-1 infection such as clearing HIV-1 and promoting productive HIV-1 replication. In the development of HIV-1 associated neurological disorders (HAND), there may be an imbalance between complement activation and regulation, which may contribute to the neuronal damage as a consequence of HIV-1 infection. It is well recognized that opiate abuse exacerbates HIV-1 neuropathology, however, little is known about the role of complement proteins in opiate induced neuromodulation, specifically in the presence of co-morbidity such as HIV-1 infection. Complement levels are significantly increased in the HIV-1-infected brain, thus HIV-induced complement synthesis may represent an important mechanism for the pathogenesis of AIDS in the brain, but remains underexplored. Anti-HIV-1 antibodies are able to initiate complement activation in HIV-1 infected CNS cells such as microglia and astrocytes during the course of disease progression; however, this complement activation fails to clear and eradicate HIV-1 from infected cells. In addition, the antiretroviral agents used for HIV therapy cause dysregulation of lipid metabolism, endothelial, and adipocyte cell function, and activation of pro-inflammatory cytokines. We speculate that both HIV-1 and opiates trigger a cytokine-mediated pro-inflammatory stimulus that modulates the complement cascade to exacerbate the virus-induced neurological damage. We examined the expression levels of C1q, SC5b-9, C5L2, C5aR, C3aR, and C9 key members of the complement cascade both in vivo in post mortem brain frontal cortex tissue from patients with HAND who used/did not use heroin, and in vitro using human microglial cultures treated with HIV tat and/or heroin. We observed significant expression of C1q and SC5b-9 by immunofluorescence staining in both the brain cortical and hippocampal region in HAND patients who abused heroin. Additionally, we observed increased gene expression of C5aR, C3aR, and C9 in the brain tissue of both HIV-1 infected patients with HAND who abused and did not abuse heroin, as compared to HIV negative controls. Our results show a significant increase in the expression of complement proteins C9, C5L2, C5aR, and C3aR in HIV transfected microglia and an additional increase in the levels of these complement proteins in heroin-treated HIV transfected microglia. This study highlights the a) potential roles of complement proteins in the pathogenesis of HIV-1-related neurodegenerative disorders; b) the combined effect of an opiate, like heroin, and HIV viral protein like HIV tat on complement proteins in normal human microglial cells and HIV transfected microglial cells. In the context of HAND, targeting selective steps in the complement cascade could help ameliorating the HIV burden in the CNS, thus investigations of complement-related therapeutic approaches for the treatment of HAND are warranted.
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http://dx.doi.org/10.1080/08820139.2017.1371891DOI Listing
November 2017

Immunomodulatory activities of curcumin-stabilized silver nanoparticles: Efficacy as an antiretroviral therapeutic.

Immunol Invest 2017 Nov;46(8):833-846

a Department of Medicine Division of Allergy, Immunology, and Rheumatology, University at Buffalo , Clinical and Translational Research Center , NY , USA.

We synthesized and characterized curcumin-stabilized silver nanoparticles (Cur-AgNP) and found them to be 45 nm by dynamic light scattering with a maximum absorbance at 406 nm. We evaluated Cur-AgNP for immunomodulatory activities and their potential as an antiretroviral agent. The antiretroviral effects of Cur-AgNP were determined in ACH-2 cells latently infected with human immunodeficiency virus (HIV)-1. ACH-2 cells, 200,000/ml, were treated with Cur-AgNP for 24-48 h. Expression of HIV-1 LTR and p24, the pro-inflammatory cytokines, IL-1β, TNF-α, and NF-κB was quantitated. Treatment of ACH-2 cells latently infected with HIV-1 with Cur-AgNP produced no toxic effects but significantly inhibited the expression of HIV-1 LTR (-73%, P < 0.01) and p24 (-57%, P < 0.05), IL-1βα (-61%, P < 0.01), TNF-αα (-54%, P < 0.05), IL-6 (-68%, P < 0.01), and NF-κB (-79%, P < 0.0001) as compared to untreated controls. Thus, Cur-AgNP have therapeutic potential as direct antiretroviral agents, as well as having immunomodulatory activities inhibiting the expression of pro-inflammatory mediators induced by infection with HIV-1. Experimental controls, such as curcumin alone, and conventional silver nanoparticles capped with citric acid, produced no similar biological effects. We conclude that treatment of HIV-1 infected cells with Cur-AgNP significantly reduced replication of HIV by inhibition of NF-κB nuclear translocation and the downstream expression of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6. Subsequent in vivo studies with Cur-AgNP using a humanized mouse model of HIV infection are underway.
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http://dx.doi.org/10.1080/08820139.2017.1371908DOI Listing
November 2017

Role of Galectin-3 in the pathophysiology underlying allergic lung inflammation in a tissue inhibitor of metalloproteinases 1 knockout model of murine asthma.

Immunology 2018 03 7;153(3):387-396. Epub 2017 Nov 7.

Department of Medicine, University at Buffalo, State University of New York, Buffalo, NY, USA.

Asthma is a chronic inflammatory respiratory disease characterized by airway inflammation, airway hyperresponsiveness and reversible airway obstruction. Understanding the mechanisms that underlie the various endotypes of asthma could lead to novel and more personalized therapies for individuals with asthma. Using a tissue inhibitor of metalloproteinases 1 (TIMP-1) knockout murine allergic asthma model, we previously showed that TIMP-1 deficiency results in an asthma phenotype, exhibiting airway hyperreactivity, enhanced eosinophilic inflammation and T helper type 2 cytokine gene and protein expression following sensitization with ovalbumin. In the current study, we compared the expression of Galectins and other key cytokines in a murine allergic asthma model using wild-type and TIMP-1 knockout mice. We also examined the effects of Galectin-3 (Gal-3) inhibition on a non-T helper type 2 cytokine interleukin-17 (IL-17) to evaluate the relationship between Gal-3 and the IL-17 axis in allergic asthma. Our results showed a significant increase in Gal-3, IL-17 and transforming growth factor-β gene expression in lung tissue isolated from an allergic asthma murine model using TIMP-1 knockout. Gal-3 gene and protein expression levels were also significantly higher in lung tissue from an allergic asthma murine model using TIMP-1 knockout. Our data show that Gal-3 may regulate the IL-17 axis and play a pivotal role in the modulation of inflammation during experimental allergic asthma.
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http://dx.doi.org/10.1111/imm.12848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795177PMC
March 2018

Neuroprotective effects of a biodegradable poly(lactic-co-glycolic acid)-ginsenoside Rg3 nanoformulation: a potential nanotherapy for Alzheimer's disease?

J Drug Target 2018 02 17;26(2):182-193. Epub 2017 Jul 17.

a Department of Medicine, Division of Allergy, Immunology, and Rheumatology , State University of New York at Buffalo, Clinical Translational Research Center , Buffalo , NY , USA.

It is well established that overproduction and accumulation of the β-amyloid (Aβ) peptide 1-42 (Aβ(1-42)) is a trigger of the pathological cascade in Alzheimer's disease (AD) that manifests as cognitive impairment. Ginsenoside Rg3 is an important constituent of ginseng, plays an essential role in memory and improved cognition, and is known to produce antioxidant effects via the reduction of free radicals. Therefore, ginsenoside Rg3 may be a promising candidate as a neuroprotective agent for the treatment of AD. A novel nanotherapeutic strategy that enhances delivery of ginsenosides to the brain by increasing its transport across the blood brain barrier (BBB) would facilitate neuroprotection and limit the accumulation of Aβ plaques and subsequent neurodegeneration. In this current study, we formulated and characterised biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that encapsulate ginsenoside Rg3 and Thioflavin T, an Aβ diagnostic; examine its neuroprotective effects; investigate key mechanisms that may underlie its neuroprotective effects; and evaluate its ability to cross the BBB using an in vitro BBB model. Our PLGA-Rg3 NPs offers an exciting new theranostic material capable of encapsulating natural nutraceuticals for the detection and treatment of AD. In addition, this nanotechnology strategy can be adapted to treat other neurological diseases, utilising many natural therapeutic agents which are limited by their solubility and/or poor pharmacokinetics.
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http://dx.doi.org/10.1080/1061186X.2017.1354002DOI Listing
February 2018

Galectin-1 Reduces Neuroinflammation via Modulation of Nitric Oxide-Arginase Signaling in HIV-1 Transfected Microglia: a Gold Nanoparticle-Galectin-1 "Nanoplex" a Possible Neurotherapeutic?

J Neuroimmune Pharmacol 2017 03 27;12(1):133-151. Epub 2016 Dec 27.

Department of Medicine, Division of Allergy, Immunology & Rheumatology, 6074 UB's Clinical and Translational Research Center, State University of New York at Buffalo, 875 Ellicott St, Buffalo, NY, 14203, USA.

Galectins are a family of β-galactoside-binding lectins that are important modulators of homeostasis in the central nervous system (CNS). Galectin-1 is a pivotal regulator of microglia activation that alters the immune balance from neurodegeneration to neuroprotection and could have therapeutic relevance in HIV associated neurocognitive disorders (HAND). We have previously shown that galectin-1 treatment decreased oxidative stress in microglia and hypothesize that the mechanism underlying this phenomenon is the cross regulatory interactions between Nitric oxide (NO) and Arginase I activity in microglia. We induced microglial activation and examined the effect of galectin-1 on the expression of various M1/M2 microglial phenotypic markers. Since, TNF-α is associated with activation of microglial cells involved in pathogenesis of neurodegenerative diseases, we treated HIV transfected human microglial cell cultures (CHME-5/HIV) with TNF-α followed by treatment with galectin-1, to examine the galectin-1 mediated neuro-modulatory response. Our results show that treatment of CHME-5/HIV microglia with galectin-1 reduced TNF-α induced oxidative stress by ~40%, and also significantly reduced iNOS gene expression and NO production while correspondingly increasing arginase-1, cationic amino acid transporter (CAT-1) gene expression and arginase activity. Galectin-1 treatment results in shifting microglia polarization from M1 toward the beneficial M2 phenotype which may prevent neurodegeneration and promote neuroprotection. Thus, our data suggests that galectin-1 treatment reduces neuroinflammation in the CNS microenvironment via the modulation of the NO-arginase network in microglia and thus could play a neuroprotective role in HAND. Further, the therapeutic potential of galectin-1 could be enhanced by conjugation of galectin-1 onto gold nanoparticles (Au-NP), resulting in a nanogold-galectin-1 (Au-Gal-1) multivalent complex that will have more clinical translational efficacy than free galectin-1 by virtue of increasing the payload influx.
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http://dx.doi.org/10.1007/s11481-016-9723-4DOI Listing
March 2017

Neuroprotective role of galectin-1 in central nervous system pathophysiology.

Neural Regen Res 2016 Jun;11(6):896-7

Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York at Buffalo, Clinical Translational Research Center, Buffalo, NY, USA.

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http://dx.doi.org/10.4103/1673-5374.184455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962575PMC
June 2016

Nanotherapy silencing the interleukin-8 gene produces regression of prostate cancer by inhibition of angiogenesis.

Immunology 2016 08;148(4):387-406

Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo and Kaleida Health, Buffalo, NY, USA.

Interleukin-8 (IL-8) is a pro-angiogenic cytokine associated with aggressive prostate cancer (CaP). We detected high levels of IL-8 in sera from patients with CaP compared with healthy controls and patients with benign prostatic hypertrophy. This study examines the role of IL-8 in the pathogenesis of metastatic prostate cancer. We developed a biocompatible, cationic polylactide (CPLA) nanocarrier to complex with and efficiently deliver IL-8 small interfering RNA (siRNA) to CaP cells in vitro and in vivo. CPLA IL-8 siRNA nanocomplexes (nanoplexes) protect siRNA from rapid degradation, are non-toxic, have a prolonged lifetime in circulation, and their net positive charge facilitates penetration of cell membranes and subsequent intracellular trafficking. Administration of CPLA IL-8 siRNA nanoplexes to immunodeficient mice bearing human CaP tumours produced significant antitumour activities with no adverse effects. Systemic (intravenous) or local intra-tumour administration of IL-8 siRNA nanoplexes resulted in significant inhibition of CaP growth. Magnetic resonance imaging and ultrasonography of experimental animals demonstrated reduction of tumour perfusion in vivo following nanoplex treatment. Staining of tumour sections for CD31 confirmed significant damage to tumour neovasculature after nanoplex therapy. These studies demonstrate the efficacy of IL-8 siRNA nanotherapy for advanced, treatment-resistant human CaP.
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http://dx.doi.org/10.1111/imm.12618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948039PMC
August 2016

Anti-angiogenic activity of PSA-derived peptides.

Prostate 2015 Sep 11;75(12):1285-99. Epub 2015 May 11.

Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York.

Background: PSA is a biomarker for diagnosis and management of prostate cancer. PSA is known to have anti-tumorigenic activities, however, the physiological role of PSA in prostate tumor progression is not well understood.

Methods: Five candidate peptides identified based upon computer modeling of the PSA crystal structure and hydrophobicity were synthesized at >95% purity. The peptides in a linear form, and a constrained form forced by a di-sulfide bond joining the two ends of the peptide, were investigated for anti-angiogenic activity in HUVEC.

Results: None of the five PSA-mimetic peptides exhibited PSA-like serine protease activity. Two of the peptides demonstrated significant anti-angiogenic activity in HUVEC based on (i) inhibition of cell migration and invasion; (ii) inhibition of tube formation in Matrigel; (iii) anti-angiogenic activity in a sprouting assay; and (iv) altered expression of pro- and anti-angiogenic growth factors. Constrained PSA-mimetic peptides had greater anti-angiogenic activity than the corresponding linearized form. Complexing of PSA with ACT eliminated PSA enzymatic activity and reduced anti-angiogenic activity. In contrast, ACT had no effect on the anti-angiogenic effects of the linear or constrained PSA-mimetic peptides. Modeling of the ACT-PSA complex demonstrated ACT sterically blocks the anti-angiogenic activity of the two bioactive peptides.

Conclusions: The interaction of a hydrophilic domain on the surface of the PSA molecule with a target on the cell membrane of prostate endothelial and epithelial cells was responsible for the anti-angiogenic or anti-tumorigenic activity of PSA: enzymatic activity was not associated with anti-angiogenic effects. Furthermore, since PSA and ACT are both expressed within the human prostate tissue microenvironment, the balance of their expression may represent a mechanism for endogenous regulation of tissue angiogenesis.
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http://dx.doi.org/10.1002/pros.23010DOI Listing
September 2015

Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug-gene co-delivery to cancer cells.

Nanoscale 2014 ;6(3):1567-72

Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.

Having unique architectural features, cationic polymeric nanocapsules (NCs) with well-defined covalently stabilized biodegradable structures were generated as potentially universal and safe therapeutic nanocarriers. These NCs were synthesized from allyl-functionalized cationic polylactide (CPLA) by highly efficient UV-induced thiol-ene interfacial cross-linking in transparent miniemulsions. With tunable nanoscopic sizes, negligible cytotoxicity and remarkable degradability, they are able to encapsulate doxorubicin (Dox) with inner cavities and bind interleukin-8 (IL-8) small interfering RNA (siRNA) with cationic shells. The Dox-encapsulated NCs can effectively bypass the P-glycoprotein (Pgp)-mediated multidrug resistance of MCF7/ADR cancer cells, thereby resulting in increased intracellular drug concentration and reduced cell viability. In vitro studies also showed that the NCs loaded with Dox, IL-8 siRNA and both agents can be readily taken up by PC3 prostate cancer cells, resulting in a significant chemotherapeutic effect and/or IL-8 gene silencing.
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http://dx.doi.org/10.1039/c3nr04804gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522154PMC
September 2014

Single nucleotide polymorphisms (SNPs) in key cytokines may modulate food allergy phenotypes.

Eur Food Res Technol 2012 Nov;235(5):971-980

Department of Medicine, University at Buffalo, 640 Ellicott Street, Room 444 Innovation Center, Buffalo Niagara Medical Campus, Buffalo, NY 14203, USA.

Single nucleotide polymorphisms (SNPs) can play a direct or indirect role in phenotypic expression in food allergy pathogenesis. Our goal was to quantitate the expression of SNPs in relevant cytokines that were expressed in food allergic patients. SNPs in cytokine genes IL-4 and IL-10 are known to be important in IgE generation and regulation. We examined IL-4 (C-590T), IL-4Rα (1652A/G) and IL-10 (C-627A) SNPs using real-time PCR followed by restriction fragment length polymorphism (RFLP) analysis. Our results show that the AA, AG and GG genotypes for IL-4Rα (1652A/G) polymorphisms were statistically different in radioallergosorbent test (RAST) positive versus negative patients, and although no statistically significant differences were observed between genotypes in the IL-4 (C-590T) and IL-10 (C-627A) SNPs, we observed a significant decrease in IL-4 (C-590T) gene expression and increase in IL-4Rα (1652A/G) and IL-10 (C-627A) gene expression between RAST(+) versus RAST(-) patients, respectively. We also observed significant modulation in the protein expression of IL-4 and IL-10 in the serum samples of the RAST(+) patients as compared to the RAST(-) patients indicating that changes in SNP expression resulted in altered phenotypic response in these patients.
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http://dx.doi.org/10.1007/s00217-012-1827-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516859PMC
November 2012

Well-defined degradable cationic polylactide as nanocarrier for the delivery of siRNA to silence angiogenesis in prostate cancer.

Adv Healthc Mater 2012 Nov 26;1(6):751-61. Epub 2012 Jul 26.

Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260-4200, USA.

Well-defined tertiary amine-functionalized cationic polylactides (CPLAs) are synthesized by thiol-ene click functionalization of an allyl-functionalized polylactide, and utilized for the delivery of interleukin-8 (IL-8) siRNA via CPLA-IL-8 siRNA nanoplexes. The CPLAs possess remarkable hydrolytic degradability, and their cytotoxicity is relatively low. The CPLA-IL-8 siRNA nanoplexes can be readily taken up by prostate cancer cells, resulting in significant IL-8 gene silencing. It is found that the degradability and cytotoxicity of CPLAs, as well as the transfection efficiency of the CPLA-IL-8 siRNA nanoplexes, positively correlate with the amine mol% of CPLAs.
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http://dx.doi.org/10.1002/adhm.201200094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634581PMC
November 2012

Anti-HIV-1 nanotherapeutics: promises and challenges for the future.

Int J Nanomedicine 2012 5;7:5301-14. Epub 2012 Oct 5.

Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York at Buffalo, Buffalo Niagara Medical Campus, Buffalo, NY, USA.

The advent of highly active antiretroviral therapy (HAART) has significantly improved the prognosis for human immunodeficiency virus (HIV)-infected patients, however the adverse side effects associated with prolonged HAART therapy use continue. Although systemic viral load can be undetectable, the virus remains sequestered in anatomically privileged sites within the body. Nanotechnology-based delivery systems are being developed to target the virus within different tissue compartments and are being evaluated for their safety and efficacy. The current review outlines the various nanomaterials that are becoming increasingly used in biomedical applications by virtue of their robustness, safety, multimodality, and multifunctionality. Nanotechnology can revolutionize the field of HIV medicine by not only improving diagnosis, but also by improving delivery of antiretrovirals to targeted regions in the body and by significantly enhancing the efficacy of the currently available antiretroviral medications.
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http://dx.doi.org/10.2147/IJN.S25871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468275PMC
January 2013

Gene Silencing of Human Neuronal Cells for Drug Addiction Therapy using Anisotropic Nanocrystals.

Theranostics 2012 27;2(7):695-704. Epub 2012 Jul 27.

1. Institute for Lasers, Photonics and Biophotonics, University at Buffalo, State University of New York, Buffalo, NY 14260-4200, USA.

Theranostic platform integrating diagnostic imaging and therapeutic function into a single system has become a new direction of nanoparticle research. In the process of treatment, therapeutic efficacy is monitored. The use of theranostic nanoparticle can add an additional "layer" to keep track on the therapeutic agent such as the pharmacokinetics and biodistribution. In this report, we have developed quantum rod (QR) based formulations for the delivery of small interfering RNAs (siRNAs) to human neuronal cells. PEGlyated QRs with different surface functional groups (amine and maleimide) were designed for selectively down-regulating the dopaminergic signaling pathway which is associated with the drug abuse behavior. We have demonstrated that the DARPP-32 siRNAs were successfully delivered to dopaminergic neuronal (DAN) cells which led to drastic knockdown of specific gene expression by both the electrostatic and covalent bond conjugation regimes. The PEGlyated surface offered high biocompatibilities and negligible cytotoxicities to the QR formulations that may facilitate the in vivo applications of these nanoparticles.
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http://dx.doi.org/10.7150/thno.3459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418925PMC
October 2012

Nanoparticle based galectin-1 gene silencing, implications in methamphetamine regulation of HIV-1 infection in monocyte derived macrophages.

J Neuroimmune Pharmacol 2012 Sep 12;7(3):673-85. Epub 2012 Jun 12.

Department of Medicine, Division of Allergy, Immunology and Rheumatology, State University of New York at Buffalo, Innovation Center, 640 Ellicott Street, Buffalo, NY 14203, USA.

Galectin-1, an adhesion molecule, is expressed in macrophages and implicated in human immunodeficiency virus (HIV-1) viral adsorption. In this study, we investigated the effects of methamphetamine on galectin-1 production in human monocyte derived macrophages (MDM) and the role of galectin-1 in methamphetamine potentiation of HIV-1 infection. Herein we show that levels of galectin-1 gene and protein expression are significantly increased by methamphetamine. Furthermore, concomitant incubation of MDM with galectin-1 and methamphetamine facilitates HIV-1 infection compared to galectin-1 alone or methamphetamine alone. We utilized a nanotechnology approach that uses gold nanorod (GNR)-galectin-1 siRNA complexes (nanoplexes) to inhibit gene expression for galectin-1. Nanoplexes significantly silenced gene expression for galectin-1 and reversed the effects of methamphetamine on galectin-1 gene expression. Moreover, the effects of methamphetamine on HIV-1 infection were attenuated in the presence of the nanoplex in MDM.
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http://dx.doi.org/10.1007/s11481-012-9379-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419803PMC
September 2012

Quantum rods as nanocarriers of gene therapy.

Drug Deliv 2012 May;19(4):220-31

Department of Medicine, Division of Allergy, Immunology and Rheumatology, University at Buffalo, The State University of New York and Kaleida Health, Buffalo, New York 14203, USA.

Both antisense oligonucleotides (ASODN) and small interfering RNA (siRNA) have enormous potential to selectively silence specific cancer-related genes and could therefore be developed to be important therapeutic anti-cancer drugs. The use of nanotechnology may allow for significant advancement of the therapeutic potential of ASODN and siRNA, due to improved pharmacokinetics, bio-distribution and tissue specific targeted therapy. In this mini-review, we have discussed the advantages of using a nanocarrier such as a multimodal quantum rod (QR) complexed with siRNA for gene delivery. Comparisons are made between ASODN and siRNA therapeutic efficacies in the context of cancer and the enormous application potential of nanotechnology in oncotherapy is discussed. We have shown that a QR-interleukin-8 (IL-8) siRNA nanoplex can effectively silence IL-8 gene expression in the PC-3 prostate cancer cells with no significant toxicity. Thus, nanocarriers such as QRs can help translate the potent effects of ASODN/siRNA into a clinically viable anti-cancer therapy. Drug delivery for cancer therapy, with the aid of nanotechnology is one of the major translational aspects of nanomedicine, and efficient delivery of chemotherapy drugs and gene therapy drugs or their co-delivery continue to be a major focus of nanomedicine research.
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http://dx.doi.org/10.3109/10717544.2012.690001DOI Listing
May 2012

Nanoparticle-mediated targeted delivery of antiretrovirals to the brain.

Methods Enzymol 2012 ;509:41-60

Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York at Buffalo, Innovation Center, Buffalo, New York, USA.

Nanotechnology offers a new platform for therapeutic delivery of antiretrovirals to the central nervous system (CNS) where human immunodeficiency virus (HIV-1) is sequestered in patients with HIV-1-associated neurological disorders (HAND). HAND is a spectrum of neurocognitive disorders that continue to persist in HIV-1-infected patients in spite of successful highly active antiretroviral therapy (HAART). Nanoformulated antiretroviral drugs offer multifunctionality, that is, the ability to package multiple diagnostic and therapeutic agents within the same nanocomposite, along with the added provisions of site-directed delivery, delivery across the blood-brain barrier (BBB), and controlled release of therapeutics. We have stably incorporated the antiretroviral drug, Amprenavir, within a transferrin (Tf)-conjugated quantum dot (QD), and evaluated the transversing ability of this Tf-QD-Amprenavir nanoplex across an in vitro BBB model and analyzed its antiviral efficacy in HIV-1-infected monocytes. We describe methods for synthesis of the Tf-QD-Amprenavir nanoplex and approaches to evaluate both its BBB transversing capability and antiviral efficacy.
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http://dx.doi.org/10.1016/B978-0-12-391858-1.00003-4DOI Listing
August 2012

Morphine and galectin-1 modulate HIV-1 infection of human monocyte-derived macrophages.

J Immunol 2012 Apr 19;188(8):3757-65. Epub 2012 Mar 19.

Division of Allergy, Immunology, and Rheumatology, Department of Medicine, State University of New York at Buffalo, Buffalo, NY 14203, USA.

Morphine is a widely abused, addictive drug that modulates immune function. Macrophages are a primary reservoir of HIV-1; therefore, they play a role in the development of this disease, as well as impact the overall course of disease progression. Galectin-1 is a member of a family of β-galactoside-binding lectins that are soluble adhesion molecules and that mediate direct cell-pathogen interactions during HIV-1 viral adhesion. Because the drug abuse epidemic and the HIV-1 epidemic are closely interrelated, we propose that increased expression of galectin-1 induced by morphine may modulate HIV-1 infection of human monocyte-derived macrophages (MDMs). In this article, we show that galectin-1 gene and protein expression are potentiated by incubation with morphine. Confirming previous studies, morphine alone or galectin-1 alone enhance HIV-1 infection of MDMs. Concomitant incubation with exogenous galectin-1 and morphine potentiated HIV-1 infection of MDMs. We used a nanotechnology approach that uses gold nanorod-galectin-1 small interfering RNA complexes (nanoplexes) to inhibit gene expression for galectin-1. We found that nanoplexes silenced gene expression for galectin-1, and they reversed the effects of morphine on galectin-1 expression. Furthermore, the effects of morphine on HIV-1 infection were reduced in the presence of the nanoplex.
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http://dx.doi.org/10.4049/jimmunol.1102276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324598PMC
April 2012

Proteomic Approach to Evaluate Mechanisms That Contribute to Food Allergenicity: Comparative 2D-DIGE Analysis of Radioallergosorbent Test Positive and Negative Patients.

Int J Proteomics 2011 19;2011:673618. Epub 2011 Sep 19.

Division of Allergy, Immunology, and Rheumatology, Department of Medicine, University at Buffalo, 640 Ellicott Street, Room 444 Innovation Center, Buffalo Niagara Medical Campus, 640 Ellicott Street, Buffalo, NY 14203, USA.

Proteomic profiles of RAST(+) subjects with severe food allergies and RAST(-) subjects were compared using 2D-DIGE analysis to obtain candidate biomarkers specific to food allergies. Our analysis highlighted 52 proteins that were differentially expressed between the RAST(+) and RAST(-) groups of which 37 were successfully identified that include chondroitin sulfates, zinc finger proteins, C-type lectins, retinoic acid binding proteins, heat shock proteins, myosin, cytokines, mast cell expressed proteins, and MAP kinases. Biological network analysis tool Metacore revealed that most of these regulated proteins play a role in immune tolerance, hypersensitivity and modulate cytokine patterns inducing a Th2 response that typically results in IgE-mediated allergic response which has a direct or indirect biological link to food allergy. Identifying unique biomarkers associated with certain allergic phenotypes and potentially cross-reactive proteins through bioinformatics analyses will provide enormous insight into the mechanisms that underlie allergic response in patients with food allergies.
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http://dx.doi.org/10.1155/2011/673618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195815PMC
November 2011

Suppression of MMP-9 expression in brain microvascular endothelial cells (BMVEC) using a gold nanorod (GNR)-siRNA nanoplex.

Immunol Invest 2012 24;41(4):337-55. Epub 2011 Aug 24.

Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University at Buffalo, The State University of New York, Innovation Center, Buffalo, New York 14203, USA.

Inhibition of Matrix metalloproteinase-9 (MMP-9) activity using delivery of short interfering RNA (siRNA) molecules to brain microvascular endothelial cells (BMVECs) that constitute the BBB may have a significant impact on reducing the BBB permeability. Gold nano rods (GNRs) can electrostatically bind with MMP-9 siRNA to form a nanoplex and the uptake of this nanoplex by BMVEC cells can result in suppression of MMP-9 expression. The current study explores if this GNR-MMP-9 siRNA nanoplex gene silencing modulates the expression of tight junction (TJ) proteins in the BMVEC. The endothelial TJ's of the BBB play a critical role in controlling cellular traffic into the central nervous system. We hypothesize that silencing of the MMP-9 gene expression in BMVEC will increase the expression of TJ proteins thereby decrease endothelial permeability. Our results showed a significant increase in the gene and protein expression of TJ proteins: ZO-1, Occludin and Claudin-5 in BMVEC cells that were transfected with the GNRs-siRNA-MMP-9 nanoplex suggesting that BBB disruption, which results from loss of TJ function due to MMP-9 activation during neuroinflammation can be prevented by silencing MMP-9 expression.
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http://dx.doi.org/10.3109/08820139.2011.604863DOI Listing
July 2012

Nanotherapeutics Using an HIV-1 Poly A and Transactivator of the HIV-1 LTR-(TAR-) Specific siRNA.

Patholog Res Int 2011 10;2011:719139. Epub 2011 May 10.

Division of Allergy, Immunology, and Rheumatology, Department of Medicine, University at Buffalo, The State University of New York, 640 Ellicott Street, Room 444 Innovation Center, Buffalo, NY 14203, USA.

HIV-1 replication can be efficiently inhibited by intracellular expression of an siRNA targeting the viral RNA. We used a well-validated siRNA (si510) which targets the poly A/TAR (transactivator of the HIV-1 LTR) site and suppresses viral replication. Nanotechnology holds much potential for impact in the field of HIV-1 therapeutics, and nanoparticles such as quantum rods (QRs) can be easily functionalized to incorporate siRNA forming stable nanoplexes that can be used for gene silencing. We evaluated the efficacy of the QR-si510 HIV-1 siRNA nanoplex in suppressing viral replication in the HIV-1-infected monocytic cell line THP-1 by measuring p24 antigen levels and gene expression levels of HIV-1 LTR. Our results suggest that the QR-si510 HIV-1 siRNA nanoplex is not only effective in delivering siRNA, but also in suppressing HIV-1 viral replication for a longer time period. HIV-1 nanotherapeutics can thus enhance systemic bioavailability and offer multifunctionality.
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http://dx.doi.org/10.4061/2011/719139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108557PMC
July 2011

Enzymatic activity of free-prostate-specific antigen (f-PSA) is not required for some of its physiological activities.

Prostate 2011 Nov 28;71(15):1680-90. Epub 2011 Mar 28.

Department of Molecular & Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Background: Prostate specific antigen (PSA) is a well known biomarker for early diagnosis and management of prostate cancer. Furthermore, PSA has been documented to have anti-angiogenic and anti-tumorigenic activities in both in vitro and in vivo studies. However, little is known about the molecular mechanism(s) involved in regulation of these processes, in particular the role of the serine-protease enzymatic activity of PSA.

Methods: Enzymatic activity of PSA isolated directly from seminal plasma was inhibited specifically (>95%) by incubation with zinc2+ . Human umbilical vein endothelial cells (HUVEC) were utilized to compare/contrast the physiological effects of enzymatically active versus inactive PSA.

Results: Equimolar concentrations of enzymatically active PSA and PSA enzymatically inactivated by incubation with Zn2+ had similar physiological effects on HUVEC, including inhibiting the gene expression of pro-angiogenic growth factors, like VEGF and bFGF, and up-regulation of expression of the anti-angiogenic growth factor IFN-γ; suppression of mRNA expression for markers of blood vessel development, like FAK, FLT, KDR, TWIST-1; P-38; inhibition of endothelial tube formation in the in vitro Matrigel Tube Formation Assay; and inhibition of endothelial cell invasion and migration properties.

Discussion: Our data provides compelling evidence that the transcriptional regulatory and the anti-angiogenic activities of human PSA are independent of the innate enzymatic activity.
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http://dx.doi.org/10.1002/pros.21385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498389PMC
November 2011

Methamphetamine and HIV-1 gp120 effects on lipopolysaccharide stimulated matrix metalloproteinase-9 production by human monocyte-derived macrophages.

Immunol Invest 2011 22;40(5):481-97. Epub 2011 Mar 22.

Departments of Medicine, Division of Allergy, Immunology and Rheumatology, State University of New York at Buffalo, Innovation Center, USA.

Monocytes/macrophages are a primary source of human immunodeficiency virus (HIV-1) in the central nervous system (CNS). Macrophages infected with HIV-1 produce a plethora of factors, including matrix metalloproteinase-9 (MMP-9) that may contribute to the development of HIV-1-associated neurocognitive disorders (HAND). MMP-9 plays a pivotal role in the turnover of the extracellular matrix (ECM) and functions to remodel cellular architecture. We have investigated the role of methamphetamine and HIV-1 gp120 in the regulation of lipopolysaccaride (LPS) induced-MMP-9 production in monocyte-derived macrophages (MDM). Here, we show that LPS-induced MMP-9 gene expression and protein secretion are potentiated by incubation with methamphetamine alone and gp120 alone. Further, concomitant incubation with gp120 and methamphetamine potentiated LPS-induced MMP-9 expression and biological activity in MDM. Collectively methamphetamine and gp120 effects on MMPs may modulate remodeling of the extracellular environment enhancing migration of monocytes/macrophages to the CNS.
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http://dx.doi.org/10.3109/08820139.2011.559499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110539PMC
September 2011
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