Pericytes regulate vascular immune homeostasis in the CNS

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood–brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfb^ret/ret), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfb^ret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti–ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfb^ret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfb^ret/ret;2D2^tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

Central nervous system (CNS) vasculature possesses specific features collectively referred to as the blood–brain barrier (BBB), which localizes to endothelial cells. The BBB ensures the delivery of essential nutrients while preventing the entry of xenobiotics into the brain. In addition, brain endothelial cells restrict the invasion of leukocytes into the brain parenchyma, thus contributing to the immune privilege of the CNS. BBB function is induced by neural tissue and established by all cell types constituting the neurovascular unit (NVU). Pericytes and mural cells residing on the abluminal side of capillaries and postcapillary venules regulate several features of the BBB (1, 2). Studies on Pdgfb and Pdgfrb mouse mutants, which exhibit variable pericyte loss, have demonstrated that pericytes negatively regulate endothelial transcytosis, which, if not suppressed, leads to increased BBB permeability to plasma proteins (1, 2). In addition, pericyte-deficient vessels show abnormal astrocyte end-feet polarization (1). Thus, pericytes regulate several characteristics of the brain vasculature during development and in the adult organism (1, 2). Whether the nonpermissive properties of the brain vasculature to leukocyte trafficking in the adult organism are regulated by pericytes has not been addressed. Interestingly, increasing evidence points to the role of pericytes in leukocyte extravasation in peripheral organs such as the skin and the striated muscle and in tumors (3–5).Increased vascular permeability to plasma proteins and immune cells accompanies neurological disorders such as multiple sclerosis (MS), stroke, and Alzheimer’s disease (reviewed in refs. 6–8). In MS, a chronic inflammatory and degenerative neurological disorder (9), autoreactive lymphocytes infiltrate the CNS parenchyma, leading to focal inflammatory infiltrates, demyelination, axonal damage, and neurodegeneration. These infiltrating immune cells could induce vascular dysfunction, including permeability to plasma proteins such as fibrinogen (10–12). On the contrary, disruption of the BBB has been shown to precede the infiltration of inflammatory cells and the formation of demyelinating lesions in MS patients (13). Therefore, it is important to understand roles of different cell types and alterations in cell–cell communication at the NVU, which may facilitate entry of autoimmune T cells as well as the anatomical localization of lesions. However, knowledge about how pericytes contribute to the development of the disease is still limited.This prompted us to investigate whether pericytes, which regulate several aspects of the BBB phenotype of endothelial cells, also regulate immune cell trafficking into the CNS during homeostasis and neuroinflammation. We show that pericytes play a crucial role in the regulation of BBB features related to the restricted leukocyte trafficking into the CNS parenchyma, both under physiological and pathophysiological conditions. We show that the permissiveness to leukocyte trafficking into the CNS inversely correlates with the vessel pericyte coverage, suggesting that vascular inflammation of the CNS due to alterations in the cellular composition of the NVU can direct the spatial distribution of neuroinflammation.     

Occurrence of Insecticide Residues in Selected Crops and Natural Resources

Pesticide residue monitoring was taken up at Kothapally and Enkepally villages of Ranga Reddy district, Andhra Pradesh in food crops (rice, maize, pigeonpea), vegetables (tomato and brinjal), cotton besides soil and water during 2008–2009 seasons. Of the 80 food crop and cotton samples, only two rice grain samples (3 %) showed beta endosulfan residues and two (3 %) out of 80 soil samples of food crops and cotton showed alpha and beta endosulfan residues. Out of 75 tomato samples, 26 (35 %) were contaminated and 4 % had residues above maximum residue limit (MRLs). Out of the 50 soil samples from tomato fields, 13 (26 %) contained residues. Among the 80 brinjal samples, 46 (56 %) contained residues and 4 % of samples had residues above MRLs. Only 13 % of the soil samples from brinjal fields were contaminated. Water samples found free from residues. In general the incidence of residues was below MRL in food crops.     

Curcumin loaded zinc oxide nanoparticles for activity-enhanced antibacterial and anticancer applications

Zinc oxide nanoparticles and curcumin have been shown to be excellent antimicrobial agents and promising anticancer agents, both on their own as well as in combination. Together, they have potential as alternatives/supplements to antibiotics and traditional anticancer drugs. In this study, different morphologies of zinc oxide-grafted curcumin nanocomposites (ZNP–Cs) were synthesized and characterized using SEM, TGA, FTIR, XRD and UV-vis spectrophotometry. Antimicrobial assays were conducted against both Gram negative and Gram-positive bacterial stains. Spherical ZnO–curcumin nanoparticles (SZNP–Cs) and rod-shaped ZnO–curcumin nanoparticles showed the most promising activity against tested bacterial strains. The inhibition zones for these curcumin-loaded ZnO nanocomposites were consistently larger than their bare counterparts or pure curcumin, revealing an additve effect between the ZnO and curcumin components. The potential anticancer activity of the synthesized nanocomposites was studied on the rhabdomyosarcoma RD cell line via MTT assay, while their cytotoxic effects were tested against human embryonic kidney cells using the resazurin assay. SZNP–Cs exhibited the best balance between the two, showing the lowest toxicity against healthy cells and good anticancer activity. The results of this investigation demonstrate that the nanomatrix synthesized can act as an effective, additively-enhanced combination delivery/therapeutic agent, holding promise for anticancer therapy and other biomedical applications.

Curcumin-loaded ZnO nanocomposites act as an effective, synergistically-enhanced combination delivery/therapeutic agent, holding promise for anticancer and antimicrobial therapy with reduced toxicities.     

Proceedings of the 2013 CINP Summit: Innovative Partnerships to Accelerate CNS Drug Discovery for Improved Patient Care

Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21^st century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders.Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain:

1. Code of conduct dealing with conflict of interest issues,
2. Prevention, early diagnosis, and treatment,
3. Linking science and regulation,
4. Patient involvement in trial design, definition of endpoints, etc.,
5. Novel trial design,
6. Reproduction and confirmation of data,
7. Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority),
8. Large-scale, global patient registries,
9. Editorials on nomenclature, biomarkers, and diagnostic tools, and
10. Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos, Switzerland. In this context Professor Barbara Sahakian recently made a formal presentation at the World Economic Forum (see Barbara Sahakian Blog from April 11, 2014, at https://forumblog.org/people/barbara-sahakian/)

Full details of the discussions that formed the bases for these actions are presented in the main body of this document.     

Inhibition of the Interaction Between NS3 Protease and HCV IRES With a Small Peptide: A Novel Therapeutic Strategy

Recently, we have demonstrated that the protease domain of NS3 alone can bind specifically to hepatitis C virus (HCV) internal ribosome entry site (IRES) near the initiator AUG, dislodges human La protein and inhibits translation in favor of viral RNA replication. Here, by using a computational approach, the contact points of the protease on the HCV IRES were putatively mapped. A 30-mer NS3 peptide was designed from the predicted RNA-binding region that retained RNA-binding ability and also inhibited IRES-mediated translation. This peptide was truncated to 15 mer and this also demonstrated ability to inhibit HCV RNA-directed translation as well as replication. More importantly, its activity was tested in an in vivo mouse model by encapsulating the peptide in Sendai virus virosomes followed by intravenous delivery. The study demonstrates for the first time that the HCV NS3-IRES RNA interaction can be selectively inhibited using a small peptide and reports a strategy to deliver the peptide into the liver.     

Use of Animal-Assisted Therapy in the Rehabilitation of an Assault Victim with a Concurrent Mood Disorder

Multidisciplinary mental health rehabilitation settings often encounter patients with complex comorbid medical and psychiatric issues that require integrative, multifaceted treatment strategies. Although medication and psychotherapy are typical treatment mainstays, a broader variety of therapeutic options are available, including animal-assisted therapy. Here we describe a patient who received animal-assisted therapy as a psychiatric rehabilitation tool to ameliorate his atypical depression following an assault and subsequent head injury. A review of the relevant literature highlights the therapeutic potential of animal-assisted therapy to restore and maintain patient independence and level of functioning, both of which are key treatment goals.     

Variations in atmospheric CO2 growth rates coupled with tropical temperature

Previous studies have highlighted the occurrence and intensity of El Niño–Southern Oscillation as important drivers of the interannual variability of the atmospheric CO₂ growth rate, but the underlying biogeophysical mechanisms governing such connections remain unclear. Here we show a strong and persistent coupling (r² ≈ 0.50) between interannual variations of the CO₂ growth rate and tropical land–surface air temperature during 1959 to 2011, with a 1 °C tropical temperature anomaly leading to a 3.5 ± 0.6 Petagrams of carbon per year (PgC/y) CO₂ growth-rate anomaly on average. Analysis of simulation results from Dynamic Global Vegetation Models suggests that this temperature–CO₂ coupling is contributed mainly by the additive responses of heterotrophic respiration (Rh) and net primary production (NPP) to temperature variations in tropical ecosystems. However, we find a weaker and less consistent (r² ≈ 0.25) interannual coupling between CO₂ growth rate and tropical land precipitation than diagnosed from the Dynamic Global Vegetation Models, likely resulting from the subtractive responses of tropical Rh and NPP to precipitation anomalies that partly offset each other in the net ecosystem exchange (i.e., net ecosystem exchange ≈ Rh − NPP). Variations in other climate variables (e.g., large-scale cloudiness) and natural disturbances (e.g., volcanic eruptions) may induce transient reductions in the temperature–CO₂ coupling, but the relationship is robust during the past 50 y and shows full recovery within a few years after any such major variability event. Therefore, it provides an important diagnostic tool for improved understanding of the contemporary and future global carbon cycle.