Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder

HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB). Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population.

Magnetic nanoformulation of azidothymidine 5’-triphosphate for targeted delivery across the blood–brain barrier

Despite significant advances in highly active antiretroviral therapy (HAART), the prevalence of neuroAIDS remains high. This is mainly attributed to inability of antiretroviral therapy (ART) to cross the blood–brain barrier (BBB), thus resulting in insufficient drug concentration within the brain. Therefore, development of an active drug targeting system is an attractive strategy to increase the efficacy and delivery of ART to the brain. We report herein development of magnetic azidothymidine 5′-triphosphate (AZTTP) liposomal nanoformulation and its ability to transmigrate across an in vitro BBB model by application of an external magnetic field. We hypothesize that this magnetically guided nanoformulation can transverse the BBB by direct transport or via monocyte-mediated transport. Magnetic AZTTP liposomes were prepared using a mixture of phosphatidyl choline and cholesterol. The average size of prepared liposomes was about 150 nm with maximum drug and magnetite loading efficiency of 54.5% and 45.3%, respectively. Further, magnetic AZTTP liposomes were checked for transmigration across an in vitro BBB model using direct or monocyte-mediated transport by application of an external magnetic field. The results show that apparent permeability of magnetic AZTTP liposomes was 3-fold higher than free AZTTP. Also, the magnetic AZTTP liposomes were efficiently taken up by monocytes and these magnetic monocytes showed enhanced transendothelial migration compared to normal/non-magnetic monocytes in presence of an external magnetic field. Thus, we anticipate that the developed magnetic nanoformulation can be used for targeting active nucleotide analog reverse transcriptase inhibitors to the brain by application of an external magnetic force and thereby eliminate the brain HIV reservoir and help to treat neuroAIDS.

Magneto-Electric Nano-Particles for Non-Invasive Brain Stimulation

This paper for the first time discusses a computational study of using magneto-electric (ME) nanoparticles to artificially stimulate the neural activity deep in the brain. The new technology provides a unique way to couple electric signals in the neural network to the magnetic dipoles in the nanoparticles with the purpose to enable a non-invasive approach. Simulations of the effect of ME nanoparticles for non-invasively stimulating the brain of a patient with Parkinson’s Disease to bring the pulsed sequences of the electric field to the levels comparable to those of healthy people show that the optimized values for the concentration of the 20-nm nanoparticles (with the magneto-electric (ME) coefficient of 100 V cm21 Oe21 in the aqueous solution) is 36106 particles/cc, and the frequency of the externally applied 300-Oe magnetic field is 80 Hz.

Conjugated Quantum Dots Inhibit the Amyloid β (1–42) Fibrillation Process

Nanoparticles have enormous potential in diagnostic and therapeutic studies. We have demonstrated that the amyloid beta mixed with and conjugated to dihydrolipoic acid- (DHLA) capped CdSe/ZnS quantum dots (QDs) of size approximately 2.5 nm can be used to reduce the fibrillation process. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) were used as tools for analysis of fibrillation. There is a significant change in morphology of fibrils when amyloid β (1–42) (Aβ (1–42)) is mixed or conjugated to the QDs. The length and the width of the fibrils vary under modified conditions. Thioflavin T (ThT) fluorescence supports the decrease in fibril formation in presence of DHLA-capped QDs.

HIV infection and drugs of abuse: role of acute phase proteins

Background HIV infection and drugs of abuse such as methamphetamine (METH), cocaine, and alcohol use have been identified as risk factors for triggering inflammation. Acute phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA) are the biomarkers of inflammation. Hence, the interactive effect of drugs of abuse with acute phase proteins in HIV-positive subjects was investigated. Methods Plasma samples were utilized from 75 subjects with METH use, cocaine use, alcohol use, and HIV-positive alone and HIV-positive METH, cocaine, and alcohol users, and age-matched control subjects. The plasma CRP and SAA levels were measured by ELISA and western blot respectively and the CD4 counts were also measured. Results Observed results indicated that the CRP and SAA levels in HIV-positive subjects who are METH, cocaine and alcohol users were significantly higher when compared with either drugs of abuse or HIV-positive alone. The CD4 counts were also dramatically reduced in HIV-positive with drugs of abuse subjects compared with only HIV-positive subjects. Conclusions These results suggest that, in HIV-positive subjects, drugs of abuse increase the levels of CRP and SAA, which may impact on the HIV infection and disease progression.

Understanding Ten-Eleven Translocation-2 in Hematological and Nervous Systems

I proposed the study of two distinct aspects of Ten-Eleven Translocation 2 (TET2) protein for understanding specific functions in different body systems. In Part I, I characterized the molecular mechanisms of Tet2 in the hematological system. As the second member of Ten-Eleven Translocation protein family, TET2 is frequently mutated in leukemic patients. Previous studies have shown that the TET2 mutations frequently occur in 20% myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), 10% T-cell lymphoma leukemia and 2% B-cell lymphoma leukemia. Genetic mouse models also display distinct phenotypes of various types of hematological malignancies. I performed 5-hydroxymethylcytosine (5hmC) chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) of hematopoietic stem/progenitor cells to determine whether the deletion of Tet2 can affect the abundance of 5hmC at myeloid, T-cell and B-cell specific gene transcription start sites, which ultimately result in various hematological malignancies. Subsequent Exome sequencing (Exome-Seq) showed that disease-specific genes are mutated in different types of tumors, which suggests that TET2 may protect the genome from being mutated. The direct interaction between TET2 and Mutator S Homolog 6 (MSH6) protein suggests TET2 is involved in DNA mismatch repair. Finally, in vivo mismatch repair studies show that the loss of Tet2 causes a mutator phenotype. Taken together, my data indicate that TET2 binds to MSH6 to protect genome integrity. In Part II, I intended to better understand the role of Tet2 in the nervous system. 5-hydroxymethylcytosine regulates epigenetic modification during neurodevelopment and aging. Thus, Tet2 may play a critical role in regulating adult neurogenesis. To examine the physiological significance of Tet2 in the nervous system, I first showed that the deletion of Tet2 reduces the 5hmC levels in neural stem cells. Mice lacking Tet2 show abnormal hippocampal neurogenesis along with 5hmC alternations at different gene promoters and corresponding gene expression downregulation. Through the luciferase reporter assay, two neural factors Neurogenic differentiation 1 (NeuroD1) and Glial fibrillary acidic protein (Gfap) were down-regulated in Tet2 knockout cells. My results suggest that Tet2 regulates neural stem/progenitor cell proliferation and differentiation in adult brain.

Molecular diversity, cultivation, and improved detection by fluorescent in situ hybridization of a dominant group of human gut bacteria related to Roseburia spp. or Eubacterium rectale

Peer reviewed

Molecular diversity, cultivation, and improved detection by fluorescent in situ hybridization of a dominant group of human gut bacteria related to Roseburia spp. or Eubacterium rectale

Peer reviewed

Immobilized kidney 28 KDa endostatin-related (KES28KDa) fragment promotes endothelial cell survival

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Erection induced by Tx2-6 toxin of Phoneutria nigriventer spider: expression profile of genes in the nitric oxide pathway of penile tissue of mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ontogenia del sistema digestivo y caracterización de la actividad enzimática de las larvas de chita Anisotremus scapularis (Tschudi, 1846)

La chita Anisotremus scapularis es un pez marino que habita las costas de Perú, es muy valorado para el consumo humano directo, y, es considerada una especie con potencial acuícola. El cultivo larval en muchas especies de peces marinos se considera como uno de los cuellos de botella para el desarrollo de la tecnología de cultivo a escala comercial, este es el caso de la chita. Como primer alimento y durante los primeros días de vida de las larvas se les suministra presas vivas, y posteriormente, cuando poseen un sistema digestivo más desarrollado, se les suministra alimento balanceado. Sin embargo, los alimentos vivos más empleados no satisfacen los requerimientos nutricionales de las larvas convirtiéndose en un punto crítico. Es por ello, que en los últimos años diversas investigaciones han concentrado sus esfuerzos en la sustitución del alimento vivo por alimento balanceado; no obstante, esto exige un buen conocimiento de la organización y funcionalidad del sistema digestivo. En este sentido, en el presente trabajo se investigan algunos aspectos de la fisiología nutricional de las larvas de chita durante los primeros 30 días de vida. Las larvas fueron cultivadas a partir de huevos obtenidos de desoves naturales de un lote de reproductores mantenidos en cautiverio en el Laboratorio de Cultivo de Peces del Instituto del Mar del Perú (IMARPE). El estudio del crecimiento en longitud, los análisis histológicos y la caracterización enzimática se realizaron a partir de muestras de larvas colectadas a los 0, 1, 2, 3, 4, 6, 8, 10, 14, 18, 22, 26 y 30 días después de la eclosión (DDE). Para los análisis histológicos, las larvas fueron sometidas a un proceso de deshidratación e inclusión en parafina, y teñidos utilizando la técnica de hematoxilina-eosina. La cuantificación de las enzimas digestivas de la chita, proteasas totales (ácidas y alcalinas), tripsina, leucina aminopeptidasa, lipasas dependientes de sales biliares y alfa-amilasa se llevó a cabo con técnicas espectrofotométricas. Al momento de la eclosión, las larvas poseen un tubo digestivo recto e histológicamente indiferenciado ubicado dorsalmente con respecto al saco vitelino, que se caracteriza por poseer una gota de aceite. Entre los 2 y 4 DDE, se observaron los mayores cambios en el desarrollo del sistema digestivo, entre los más importantes están la diferenciación de la bucofaringe, esófago e intestino, plegamiento de la mucosa intestinal, la formación de las microvellosidades en los enterocitos y el desarrollo de sus glándulas anexas, hígado y páncreas, los cuales permitieron la ingestión, digestión y absorción de los primeros alimentos exógenos ingeridos por las larvas. El mayor cambio que se observó en días posteriores fue la observación de un estómago en desarrollo, con la diferenciación de las glándulas gástricas (26 DDE). Las enzimas digestivas analizadas, fueron detectadas desde el momento de la eclosión de las larvas, antes de la apertura de la boca, y se incrementaron con la edad de los organismos. En general, se observó incrementos en la actividad total de las enzimas digestivas a partir de los 8 y 10 DDE o a los 4 mm de longitud total (LT), particularmente con aumentos más marcados en la actividad de las lipasas y de la leucina aminopeptidasa. Para la actividad de proteasas alcalinas totales, tripsina y alfa-amilasa, los aumentos fueron evidentes a partir de los 22 DDE o entre 6 y 7 mm de LT. La actividad de las proteasas ácidas se evidenció e incrementó a partir del 26 DDE o a los 9 mm de LT. En cuanto los patrones de actividad específica, en general, se observaron incrementos súbitos de la actividad que se relacionan con los periodos de transición de la alimentación endógena a exógena (3-6 DDE), y con el cambio de alimentación de rotíferos a metanauplios de Artemia (26 DDE). También, exceptuando la actividad de la leucina aminopeptidasa, se observaron estos incrementos súbitos antes de la primera alimentación. Con base al análisis histológico y bioquímico de las larvas de chita, se recomienda iniciar el destete a los 26 DDE.

Survey on the digenean and monogenean helminthes of clupeidae (teleosts) from southern part of Caspian Sea

The helminthes parasites fauna of 313 specimens of Caspian herrings (Clupeonella cultriventris, Clupeonella engrauliformis, Clupeonella grimmi) caught from catching localities situated in southeast of Caspian Sea Were investigated during winter 2008 until autumn 2009. A total of 3 helminthes species were found. They were including Pseudopentagramma symmetrica from intestine (mid gut, hind gut and cecae) Bunocotyle cingulata in intestine, Mazocreas alosae the only monogenean with Marine origin in the gills of infected specimens. In addition to two zoonotic species including Contracecum sp. and Anisakis sp. in digestive system, muscle and ovary and an Acanthocephal, Corynosoma strumosum in intestine which were previously reported. We can conclude that the main characteristic of the helminthes parasites community of Clupeidae species studied is the dominance of the endoparasites species due mainly to the digenean Pseudopentagramma symmetrica and Bunocotyle cingulata and the relative scarcity of ectohelminthes fauna. In this paper the latest data of helminthes fauna and community ecology of digenean of Clupeidae species are presented and the community structure of Pseudopentagramma symmetrica is discussed.