GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model.

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD.

Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice.

Therapeutic agents that increase the Hb affinity for oxygen (O) could, in theory, lead to decreased O release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O, was used to assess the impact of increasing Hb affinity for O on brain tissue oxygenation, blood pressure, heart rate, O delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O delivery were studied during normoxia and severe hypoxic challenges.

Long-Acting IL-33 Mobilizes High-Quality Hematopoietic Stem and Progenitor Cells More Efficiently Than Granulocyte Colony-Stimulating Factor or AMD3100.

Mobilization of hematopoietic stem and progenitor cells (HSPCs) has become increasingly important for hematopoietic cell transplantation. Current mobilization approaches are insufficient because they fail to mobilize sufficient numbers of cells in a significant fraction of patients and are biased toward myeloid immune reconstitution. A novel, single drug mobilization agent that allows a more balanced (myeloid and lymphoid) reconstitution would therefore be highly favorable to improve transplantation outcome.

Non-reducible disulfide bond replacement implies that disulfide exchange is not required for hepcidin-ferroportin interaction.

Previous studies have led to opposing hypotheses about the requirement of intermolecular disulfide exchange in the binding of the iron regulatory peptide hepcidin to its receptor ferroportin. To clarify this issue, we used the diaminodiacid approach to replace the disulfide bonds in hepcidin with non-reducible thioether bonds. Our results implied that disulfide exchange is not required for the interaction between hepcidin and ferroportin.

Prophylactic treatment with a novel bioadhesive gel formulation containing aciclovir and tenofovir protects from HSV-2 infection.

Objectives: Over-the-counter access to an inexpensive, effective topical microbicide could reduce the transmission of HIV and would increase women's control over their health and eliminate the need to obtain their partners' consent for prophylaxis. Chronic infection with herpes simplex virus 2 (HSV-2), also known as human herpes virus 2, has been shown to facilitate HIV infection and speed the progression to immunodeficiency disease. Our objective is to develop a drug formulation that protects against both HSV-2 and HIV infection and adheres to the vaginal surface with extended residence time.

Associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of Wernicke's encephalopathy.

Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke's encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation.

Formulation development and evaluation of innovative two-polymer (SR-2P) bioadhesive vaginal gel.

The main objective of this investigation was to study the feasibility of developing a vaginal bioadhesive microbicide using a SRI's proprietary two-polymer gel platform (SR-2P). Several formulations were prepared with different combinations of temperature-sensitive polymer (Pluronic® F-127) and mucoadhesive polymer (Noveon® AA-1), producing gels of different characteristics. Prototype polymeric gels were evaluated for pH, osmolality, buffering capacity, and viscosity under simulated vaginal semen dilutions, and bioadhesivity using ex vivo mini pig vaginal tissues and texture analyzer.

DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation.

The Duffy antigen/receptor for chemokines, DARC, belongs to the family of atypical heptahelical chemokine receptors that do not couple to G proteins and therefore fail to transmit conventional intracellular signals. Here we show that during experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, the expression of DARC is upregulated at the blood-brain barrier. These findings are corroborated by the presence of a significantly increased number of subcortical white matter microvessels staining positive for DARC in human multiple sclerosis brains as compared to control tissue.

The skin, a novel niche for recirculating B cells.

B cells infiltrate the skin in many chronic inflammatory diseases caused by autoimmunity or infection. Despite potential contribution to disease, skin-associated B cells remain poorly characterized. Using an ovine model of granulomatous skin inflammation, we demonstrate that B cells increase in the skin and skin-draining afferent lymph during inflammation.

Nociceptin/orphanin FQ inhibition with SB612111 ameliorates dextran sodium sulfate-induced colitis.

Inflammatory bowel diseases, primarily Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract with unknown etiology. The majority of current therapeutic agents focus on controlling proinflammatory molecules. The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been described as a potential immunomodulator for inflammatory bowel diseases.

SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo.

Angiogenesis is one of the major processes controlling growth and metastasis of tumors. Angiogenesis inhibitors have been targeted for the treatment of various cancers for more than 2 decades. We have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues.

Increased CCL2 expression and macrophage/monocyte migration during microbicide-induced vaginal irritation.

Despite availability of successful prevention strategies, HIV continues to spread at alarming rates, especially among women in developing countries. Vaginal microbicides offer a promising approach for blocking transmission of HIV when condom use cannot be negotiated with male partners. A major problem in the development of vaginal microbicides is chemically induced vaginal irritation, which can enhance the risk of HIV transmission.

Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis.

Mast cells contribute importantly to both protective and pathological IgE-dependent immune responses. We show that the mast cell-expressed orphan serpentine receptor mCCRL2 is not required for expression of IgE-mediated mast cell-dependent passive cutaneous anaphylaxis but can enhance the tissue swelling and leukocyte infiltrates associated with such reactions in mice. We further identify chemerin as a natural nonsignaling protein ligand for both human and mouse CCRL2.

L-Selectin-deficient SJL and C57BL/6 mice are not resistant to experimental autoimmune encephalomyelitis.

L-selectin has been suggested to play a role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we demonstrate that L-selectin(-/-) SJL mice are susceptible to proteolipid protein (PLP)-induced EAE because the compromised antigen-specific T cell proliferation in peripheral lymph nodes is fully compensated by the T cell response raised in their spleen. Transfer of PLP-specific T cells into syngeneic recipients induced EAE independent of the presence or absence of L-selectin on PLP-specific T cells or in the recipient.

DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27.

During adaptive immune responses, dendritic cells activate T cells and endow them with specific homing properties. Mechanisms that 'imprint' specific tropisms, however, are not well defined. We show here that 1,25(OH)(2)D(3), the active form of vitamin D3, signaled T cells to express CC chemokine receptor 10, which enabled them to migrate to the skin-specific chemokine CCL27 secreted by keratinocytes of the epidermis.

Gene and protein expression profiling of the microvascular compartment in experimental autoimmune encephalomyelitis in C57Bl/6 and SJL mice.

Dysfunction of the blood-brain barrier (BBB) is a hallmark of inflammatory diseases of the central nervous system (CNS) such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The molecular mechanisms leading to BBB breakdown are not well understood. In order to find molecules involved in this process, we used oligonucleotide microarrays and proteomics to analyze gene and protein expression of the microvascular compartment isolated from brains of C57Bl/6 and SJL/N mice afflicted with EAE and the microvascular compartment isolated from healthy controls.

Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis.

Migration of autoaggressive T cells across the blood-brain barrier (BBB) is critically involved in the initiation of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The direct involvement of chemokines in this process was suggested by our recent observation that G-protein-mediated signaling is required to promote adhesion strengthening of encephalitogenic T cells on BBB endothelium in vivo. To search for chemokines present at the BBB, we performed in situ hybridizations and immunohistochemistry and found expression of the lymphoid chemokines CCL19/ELC and CCL21/SLC in venules surrounded by inflammatory cells.