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T-cell costimulation and coinhibition generated by engagement of the B7 family and their receptor CD28 family are of central importance in regulating the T-cell response, making these pathways very attractive therapeutic targets. Here we describe HERV-H LTR-associating protein 2 (HHLA2) as a member of the B7 family that shares 10-18% amino acid identity and 23-33% similarity to other human B7 proteins and phylogenetically forms a subfamily with B7x and B7-H3 within the family. HHLA2 is expressed in humans but not in mice, which is unique within the B7 and CD28 families. HHLA2 protein is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation with LPS and IFN-γ. HHLA2 does not interact with other known members of the CD28 family or the B7 family, but does bind a putative receptor that is constitutively expressed not only on resting and activated CD4 and CD8 T cells but also on antigen-presenting cells. HHLA2 inhibits proliferation of both CD4 and CD8 T cells in the presence of T-cell receptor signaling. In addition, HHLA2 significantly reduces cytokine production by T cells including IFN-γ, TNF-α, IL-5, IL-10, IL-13, IL-17A, and IL-22. Thus, we have identified a unique B7 pathway that is able to inhibit human CD4 and CD8 T-cell proliferation and cytokine production. This unique human T-cell coinhibitory pathway may afford unique strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may help to design better vaccines. [ABSTRACT FROM AUTHOR]

Platelet-producing megakaryocytes (MKs) primarily reside in the bone marrow, where they duplicate their DNA content with each cell cycle resulting in polyploid cells with an intricate demarcation membrane system. While key elements of the cytoskeletal reorganizations during proplatelet formation have been identified, what initiates the release of platelets into vessel sinusoids remains largely elusive. Using a cell cycle indicator, we observed a unique phenomenon, during which amplified centrosomes in MKs underwent clustering following mitosis, closely followed by proplatelet formation, which exclusively occurred in G1 of interphase. Forced cell cycle arrest in G1 increased proplatelet formation not only in vitro but also in vivo following short-term starvation of mice. We identified that inhibition of the centrosomal protein kinesin family member C1 (KIFC1) impaired clustering and subsequent proplatelet formation, while KIFC1-deficient mice exhibited reduced platelet counts. In summary, we identified KIFC1- and cell cycle-mediated centrosome clustering as an important initiator of proplatelet formation from MKs. [ABSTRACT FROM AUTHOR]

Shaving is an ubiquitous practice, and cutaneous irritation and inflammation are common sequelae, which may be worsened by underlying skin conditions or poor hair removal techniques. Moisturizing shaving creams and aftershaves are available to help maintain or restore the epidermal barrier; however, many continue to suffer from post-shave redness, itching, and pain. To reduce post-shave inflammation, some products have included botanical and other natural ingredients, which are often favored by consumers. We evaluated Bensal HP, an ointment containing 3% oak bark extract, 3% salicylic acid, and 6% benzoic acid, which has documented anti-inflammatory and antimicrobial properties, in a murine model of shave irritation to determine whether it would be useful in this clinical setting. Shaving dermatitis was simulated using a depilatory agent and electric clippers, and the shaved area was photographed and treated with Bensal HP daily for four days. Compared to untreated controls, mice treated with Bensal HP experienced a visible reduction in skin irritation and inflammation. These findings were mirrored on histology, as Bensal HP-treated areas demonstrated increased epidermal integrity and decreased dermal inflammatory infiltrate compared to untreated skin. Using immunohistochemistry, fewer neutrophils and macrophages were noted, and cytokine analysis also revealed decreased IL-6 in Bensal HP-treated skin at 24 and 96 hours after shaving. These results highlight the potential of Bensal HP as an anti-inflammatory treatment for shave irritation. Given the product's application against a variety of inflammatory and infectious skin disorders, its use against shave irritation may also improve comorbid skin conditions, such as pseudofolliculitis barbae. , , J Drugs Dermatol. 2016;15(7):836-840.

Natural ingredients are of increasing interest within the field of dermatology. Bensal HP, an ointment containing 3% oak bark extract, 3% salicylic acid, and 6% benzoic acid, is believed to be efficacious against a variety of inflammatory and infectious dermatidites. Here we evaluate Bensal HP's ability to influence wound healing, which has yet to be studied in this setting. Bensal HP applied to burn wounds on the dorsal surface of BALB/c mice significantly attenuated wound expansion in the first few days post-injury as compared to controls. Histological analysis mirrored these findings with accelerated maturation of the wound bed and increased collagen deposition by the end of the study period. Cytokine analysis revealed decreased IL-6 and TNFα secretion in the Bensal HP-treated burns as compared to controls. Similarly, excisional wounds treated with Bensal HP demonstrated comparable wound healing as compared to controls with positive histologic features and increased collagen deposition. Furthermore, IL-6 production was attenuated in the Bensal-HP treated wounds at day 3, with no differences appreciated in IL-6 at day 7 or in TNFα at either time point. While Bensal-HP represents a therapeutic strategy to enhance the histologic and immunologic milieu in burn and excisional wounds, further study is needed to fully elucidate the full potential of this treatment.

Background: The treatment of cutaneous wounds in the clinical setting continues to be a clinical challenge and economic burden, with burn wounds being especially formidable. Direct mechanical injury coupled with the transfer of thermal energy leads to tissue necrosis, pro-inflammatory cytokine release and the eventual expansion of an initial wound. Our current therapeutic armamentarium falls short of options to help prevent wound expansion, and therefore new modalities are required. Nitrosating substances such as RSNOs have been proven to be effective in promoting wound closure due to their ability to modulate inflammation, cytokine production and vascular function., Objective: We aim to evaluate the efficacy of n-actetylcysteine s-nitrosothiol nanoparticles (NAC-SNO-np) on thermal burn wounds and associated expansion., Methods: A multi-burn model was utilized to induce three burn wounds on the dorsal surface of BALB/c mice, allowing for evaluation of the burn itself and peripheral tissue. Wounds were excised and processed for histology and immunohistochemistry on day 7 following wounding., Results: Following treatment with NAC-SNO-np, burn wound expansion was attenuated and wound healing was accelerated. Histological analysis revealed increased collagen deposition as well as increased macrophage and decreased neutrophil infiltration into the wound bed., Conclusion: NAC-SNO-np represents a platform that harnesses the nitrosative properties of NAC-SNO in order to accelerate the transition from inflammatory to proliferative wound healing. Further studies are needed in order to translate to the clinical setting.