Brandon L. Adler

Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing.

Wound healing is a complex process driven largely by the migration of a variety of distinct cell types from the wound margin into the wound zone. In this study, we identify the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a fundamental regulator of cell migration that can be targeted in vivo using nanoparticle-encapsulated small interfering RNA (siRNA) to promote wound closure and regeneration. In vitro, depletion of FL2 from mammalian tissue culture cells results in a more than twofold increase in the rate of cell movement, in part due to a significant increase in directional motility. Immunofluorescence analyses indicate that FL2 normally localizes to the cell edge, importantly to the leading edge of polarized cells, where it regulates the organization and dynamics of the microtubule cytoskeleton. To clinically translate these findings, we utilized a nanoparticle-based siRNA delivery platform to locally deplete FL2 in both murine full-thickness excisional and burn wounds. Topical application of FL2 siRNA nanoparticles to either wound type results in a significant enhancement in the rate and quality of wound closure both clinically and histologically relative to controls. Taken together, these results identify FL2 as a promising therapeutic target to promote the regeneration and repair of cutaneous wounds.

Nitric Oxide Releasing Nanoparticles prevent Propionibacterium acnes induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response

Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we utilized an established nanotechnology capable of generating/releasing nitric oxide over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, though human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1β, TNF-α, IL-8 and IL-6 from human monocytes and IL-8 and IL-6 from human keratinocytes respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 β secretion from monocytes, and neither TNF-α, nor IL-6 secretion nor inhibition by NO-np was found to be dependent on this pathway. The observed mechanism by which NO-np impacts IL-1β secretion was through inhibition of caspase-1 and IL-1β gene expression. Together, these data suggest that NO-np can effectively prevent P. acnes induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response.

Epidemiology and treatment of angiolymphoid hyperplasia with eosinophilia (ALHE): A systematic review.

BACKGROUND Current knowledge of angiolymphoid hyperplasia with eosinophilia (ALHE) derives from retrospective reports and case series, leading to a nonevidence-based treatment approach. OBJECTIVE We sought to systematically review the literature relating to cutaneous ALHE to estimate its epidemiology and treatment outcomes. METHODS A literature search of PubMed, EMBASE, Web of Science, and Google Scholar was conducted. Articles detailing cases of histologically confirmed cutaneous ALHE were included. RESULTS In all, 416 studies were included in the review, representing 908 patients. There was no sex predominance among patients with ALHE. Mean age at presentation was 37.6 years. There was a significant association between presence of multiple lesions and pruritus, along with bleeding. Surgical excision was the most commonly reported treatment for ALHE. Treatment failure was lowest for excision and pulsed dye laser. Mean disease-free survival after excision was 4.2 years. There were higher rates of recurrence postexcision with earlier age of onset, longer duration of disease, multiple lesions, bilateral lesions, pruritus, pain, and bleeding. LIMITATIONS Potential for publication bias is a limitation. CONCLUSIONS Surgical excision appears to be the most effective treatment for ALHE, albeit suboptimal. Pulsed dye and other lasers may be effective treatment options. More studies are needed to improve the treatment of ALHE.

Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy

INTRODUCTION Patients undergoing radical prostatectomy (RP) suffer from erectile dysfunction (ED) refractory to phosphodiesterase 5 inhibitors, which act downstream of cavernous nerve (CN)-mediated release of nitric oxide (NO). Direct delivery of NO to the penis could potentially circumvent this limitation. AIM This study aimed to determine if topically applied NO-releasing nanoparticles (NO-NPs) could elicit erections in a rat model of RP through increased blood flow. METHODS Twenty-six Sprague Dawley rats underwent bilateral transection of the CN. One week later, NO-NPs were applied topically to the penile shaft in dimethylsulfoxide (DMSO) gel (10 animals) or coconut oil (6 animals). Control animals were treated with empty NPs. Erectile function was determined through the intracorporal pressure/blood pressure ratio (ICP/BP). The effect of the NO-NPs on blood flow was determined using a hamster dorsal window chamber. MAIN OUTCOME MEASURES Animals were investigated for spontaneous erections, onset and duration of erectile response, and basal ICP/BP ratio. Microcirculatory blood flow was determined through measurements of arteriolar and venular diameter and red blood cell velocity. RESULTS Eight of 10 animals treated with NO-NPs suspended in DMSO gel had significant increases in basal ICP/BP, and 6 out of these 10 animals demonstrated spontaneous erections of approximately 1 minute in duration. Time to onset of spontaneous erections ranged from 5 to 37 minutes, and they occurred for at least 45 minutes. Similar results were observed with NO-NPs applied in coconut oil. No erectile response was observed in control animal models treated with empty NPs. The hamster dorsal window chamber experiment demonstrated that NO-NPs applied as a suspension in coconut oil caused a significant increase in the microcirculatory blood flow, sustained over 90 minutes. CONCLUSIONS Topically applied NO-NPs induced spontaneous erections and increased basal ICP in an animal model of RP. These effects are most likely due to increased microcirculatory blood flow. These characteristics suggest that NO-NPs would be useful in penile rehabilitation of patients following RP.

Trichophyton rubrum is Inhibited by Free and Nanoparticle Encapsulated Curcumin by Induction of Nitrosative Stress after Photodynamic Activation

Antimicrobial photodynamic inhibition (aPI) utilizes radical stress generated from the excitation of a photosensitizer (PS) with light to destroy pathogens. Its use against Trichophyton rubrum, a dermatophytic fungus with increasing incidence and resistance, has not been well characterized. Our aim was to evaluate the mechanism of action of aPI against T. rubrum using curcumin as the PS in both free and nanoparticle (curc-np) form. Nanocarriers stabilize curcumin and allow for enhanced solubility and PS delivery. Curcumin aPI, at optimal conditions of 10 μg/mL of PS with 10 J/cm2 of blue light (417 ± 5 nm), completely inhibited fungal growth (p<0.0001) via induction of reactive oxygen (ROS) and nitrogen species (RNS), which was associated with fungal death by apoptosis. Interestingly, only scavengers of RNS impeded aPI efficacy, suggesting that curcumin acts potently via a nitrosative pathway. The curc-np induced greater NO• expression and enhanced apoptosis of fungal cells, highlighting curc-np aPI as a potential treatment for T. rubrum skin infections.

Silver Sulfadiazine Retards Wound Healing in Mice via Alterations in Cytokine Expression

Methods: Thermal burns were induced on the dorsal surface of BALB/c mice; mice were split into two groups: untreated control (n=56) and SSD-treated (n=46) (50μL of 1% SSD cream per wound daily). Daily photographs and Image J software were used to asses change in wound area relative to day 0. Histologic samples were stained using hematoxylin and eosin (H&E), Masson’s trichrome, ionized calcium-binding adapter molecule-1(IBA-1) and myeloperoxidase (MPO) to visualize morphology, collagen deposition, macrophages and neutrophils respectively. Burn wounds were harvested for cytokine analysis (n= 10 wounds, 5 animals per group) and tissue samples were analyzed in duplicate for cytokine expression using Mouse Cytokine Antibody Array and cytokine signal intensity was measured using Quantity One Software.

Acinetobacter baumannii Emerging as a Multidrug-Resistant Skin and Soft-Tissue Pathogen: Parallels to Methicillin-Resistant Staphylococcus aureus

Acinetobacter baumannii Emerging as a Multidrug-Resistant Skin and Soft-Tissue Pathogen: Parallels to Methicillin-Resistant Staphylococcus aureus Over the last 30 years, the gram-negative coccobacillus Acinetobacter baumannii has risen to microbiologic notoriety for its ability to successfully evade nearly all available antibiotics. It is now a well-established source of nosocomial bacteremia and pneumonia, known to cause hospital outbreaks, particularly in the intensive care unit. Less often it represents a source of nosocomial skin and soft-tissue infection (SSTI) in the setting of war wounds, surgical sites, and burns.1 Most reports of A baumannii infection, both nosocomial and community-acquired (CA) SSTI, involve cellulitis of peau d’orange appearance with overlying vesicles that, when untreated, progress to necrotizing fasciitis with coalescent bullae.2 The condition is uncommon and has been reported solely in compromised hosts.3 To our knowledge, A baumannii has never been reported as a cause of CA-SSTI in a healthy patient. However, unpublished and anecdotal cases of increasingly drug-resistant A baumannii presenting as SSTI in healthy patients are known to exist. Molecular typing experiments reveal community and nosocomial A baumannii isolates to be genetically distinct, existing as separate reservoirs with unique virulence and resistance patterns. Until recently, multidrug resistance was considered a hospital-based phenomenon.4 We report herein the case of a healthy woman with CA multidrugresistant A baumannii.

S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology

UNLABELLED Nitric oxide (NO), an essential agent of the innate immune system, exhibits multi-mechanistic antimicrobial activity. Previously, NO-releasing nanoparticles (NO-np) demonstrated increased antimicrobial activity when combined with glutathione (GSH) due to formation of S-nitrosoglutathione (GSNO), a transnitrosylating agent. To capitalize on this finding, we incorporated the thiol-containing ACE-inhibitor, captopril, with NO-np to form SNO-CAP-np, nanoparticles that both release NO and form S-nitrosocaptopril. In the presence of GSH, SNO-CAP-np demonstrated increased transnitrosylation activity compared to NO-np, as exhibited by increased GSNO formation. Escherichia coli and methicillin-resistant Staphylococcus aureus were highly susceptible to SNO-CAP-np in a dose-dependent fashion, with E. coli being most susceptible, and SNO-CAP-np were nontoxic in zebrafish embryos at translatable concentrations. Given SNO-CAP-nps increased transnitrosylation activity and increased E. coli susceptibility compared to NO-np, transnitrosylation rather than free NO is likely responsible for overcoming E. colis resistance mechanisms and ultimately killing the pathogen. FROM THE CLINICAL EDITOR This team of authors incorporated the thiol-containing ACE-inhibitor, captopril, into a nitric oxide releasing nanoparticle system, generating nanoparticles that both release NO and form S-nitrosocaptopril, with pronounced toxic effects on MRSA and E. coli in the presented model system.

Nitric oxide therapy for dermatologic disease

Nitric oxide (NO) plays an important role in the maintenance and regulation of the skin and the integrity of its environment. Derangement of NO production is implicated in the etiology of a multitude of dermatologic diseases, indicating future therapeutic directions. In an era of increasing resistance rates to available antibiotics and subpar development of new agents, NO is promising as a prospective topical broad-spectrum antimicrobial agent with small likelihood of resistance development. Because the greatest strides have been made in the setting of infectious disease and skin and soft-tissue infection, this will be a major focus of this article. In addition, we will review NOs role in skin regulation and dysregulation, immune function, the various topical release systems that have been devised and tested, NOs relation to UV radiation and skin pigmentation, and finally, its potential applications as a cosmeceutical.

Biafine topical emulsion accelerates excisional and burn wound healing in mice

Macrophages play a fundamental role in wound healing; therefore, employing a strategy that enhances macrophage recruitment would be ideal. It was previously suggested that the mechanism by which Biafine® topical emulsion improves wound healing is via enhanced macrophage infiltration into the wound bed. The purpose of this study was to confirm this observation through gross and histologic assessments of wound healing using murine full-thickness excisional and burn wound models, and compare to common standards, Vaseline and silver sulfadiazine (SSD). Full-thickness excisional and burn wounds were created on two groups of 60 mice. In the excisional arm, mice were divided into untreated control, Biafine, and Vaseline groups. In the burn arm, mice were divided into untreated control, Biafine, and SSD groups. Daily treatments were administered and healing was measured over time. Wound tissue was excised and stained to appropriately visualize morphology, collagen, macrophages, and neutrophils. Collagen deposition was measured and cell counts were performed. Biafine enhanced wound healing in murine full-thickness excisional and burn wounds compared to control, and surpassed Vaseline and SSD in respective wound types. Biafine treatment accelerated wound closure clinically, with greater epidermal/dermal maturity, granulation tissue formation, and collagen quality and arrangement compared to other groups histologically. Biafine application was associated with greater macrophage and lower neutrophil infiltration at earlier stages of healing when compared to other study groups. In conclusion, Biafine can be considered an alternative topical therapy for full-thickness excisional and burn wounds, owing to its advantageous biologically based wound healing properties.