Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity.

Complement signaling is thought to serve as an opsonization signal to promote the phagocytosis of synapses by microglia. However, while its role in synaptic remodeling has been demonstrated in the retino-thalamic system, it remains unclear whether complement signaling mediates synaptic pruning in the brain more generally. Here we found that mice lacking the Complement receptor 3, the major microglia complement receptor, failed to show a deficit in either synaptic pruning or axon elimination in the developing mouse cortex. Instead, mice lacking Complement receptor 3 exhibited a deficit in the perinatal elimination of neurons in the cortex, a deficit that is associated with increased cortical thickness and enhanced functional connectivity in these regions in adulthood. These data demonstrate a role for complement in promoting neuronal elimination in the developing cortex.

Alopecia Areata Barbae in a Nutshell.

Beard alopecia areata, or alopecia areata barbae, (BAA) is a subset of alopecia areata, a T-cell mediated inflammatory disease that disrupts the hair follicle cycle leading to early onset of catagen. The aim of this review is to help strengthen clinicians' skills in the evaluation, diagnosis, and management of BAA. We performed a literature review according to the modified PRISMA guidelines, using a combination of relevant key words in electronic databases. According to the data from the 25 articles on BAA reviewed here, BAA mostly affects middle-aged men (mean age 31 years) who typically experience patchy hair loss in the neck region, which spreads to the scalp within 12 months. Similar to AA, BAA is associated with autoimmune diseases such as H. pylori and thyroiditis; however, BAA has no clear genetic pattern of inheritance which is observed in alopecia areata. Common dermoscopic findings in BAA include vellus white hairs and exclamation mark hairs, which may help distinguish it from other pathologies affecting facial hair. In clinical trials, the ALBAS tool offers clinicians an objective metric to evaluate BAA severity. Until recently, topical steroids have been the mainstay therapy; however, topical and oral janus kinase inhibitors are achieving improved results, with up to 75% beard regrowth in an average of 12 months.

Prevention and Treatment of Chemotherapy-Induced Alopecia: What Is Available and What Is Coming?

Millions of new cancer patients receive chemotherapy each year. In addition to killing cancer cells, chemotherapy is likely to damage rapidly proliferating healthy cells, including the hair follicle keratinocytes. Chemotherapy causes substantial thinning or loss of hair, termed chemotherapy-induced alopecia (CIA), in approximately 65% of patients. CIA is often ranked as one of the most distressing adverse effects of chemotherapy, but interventional options have been limited. To date, only scalp cooling has been cleared by the US Food and Drug Administration (FDA) to prevent CIA. However, several factors, including the high costs not always covered by insurance, preclude its broader use. Here we review the current options for CIA prevention and treatment and discuss new approaches being tested. CIA interventions include scalp cooling systems (both non-portable and portable) and topical agents to prevent hair loss, versus topical and oral minoxidil, photobiomodulation therapy (PBMT), and platelet-rich plasma (PRP) injections, among others, to stimulate hair regrowth after hair loss. Evidence-based studies are needed to develop and validate methods to prevent hair loss and/or accelerate hair regrowth in cancer patients receiving chemotherapy, which could significantly improve cancer patients' quality of life and may help improve compliance and consequently the outcome of cancer treatment.

IL-17 Expression in the Perifollicular Fibrosis in Biopsies From Lichen Planopilaris.

BACKGROUND: Lichen planopilaris (LPP) is a primary lymphocytic cicatricial alopecia for which therapy is often ineffective and there is no cure. OBJECTIVES: Looking for a new targetable molecule in the treatment of LPP, we sought to verify whether IL-17 expression is increased in scalp biopsies from patients with active scalp lesions of LPP. METHODS: Horizontal sections of hematoxylin and eosin-stained slides from 40 scalp biopsies of active LPP were retrospectively collected and stained with the monoclonal antibody against IL-17 (Abcam, Cambridge, MA; ab79056, dilution 1:100). Twenty biopsies from patients with chronic telogen effluvium served as controls because of their morphological resemblance to the normal scalp. Statistical analysis was performed using IBM SPSS Statistics for Windows (IBM Corporation, Armonk, NY). RESULTS: The main finding was the positive cytoplasmic expression of IL-17 in the perifollicular fibrosis of the affected follicles in LPP which was statistically significant compared with the controls ( P < 0.0001). The labeled cells were identified as fibroblasts based on their spindle shape and fascicular concentric arrangement in tight perifollicular distribution. Although most of the LPP specimens (n = 35; 87.5%) also revealed cytoplasmic IL-17 expression in the lichenoid inflammatory infiltrate, the results were not statistically significant ( P = 0.1351). CONCLUSION: Our immunohistochemistry results show that blocking the IL-17 inflammatory pathway may interfere with the progression of the perifollicular fibrosis and inflammation in LPP.

Nitrostilbenes: Synthesis and Biological Evaluation as Potential Anti-Influenza Virus Agents.

Resveratrol (RSV) is a natural stilbene polyphenolic compound found in several plant species. It is characterized by antioxidant properties, and its role in controlling viral replication has been demonstrated for different viral infections. Despite its promising antiviral properties, RSV biological activity is limited by its low bioavailability and high metabolic rate. In this study, we optimized its structure by synthesizing new RSV derivatives that maintained the phenolic scaffold and contained different substitution patterns and evaluated their potential anti-influenza virus activity. The results showed that viral protein synthesis decreased 24 h post infection; particularly, the nitro-containing compounds strongly reduced viral replication. The molecules did not exert their antioxidant properties during infection; in fact, they were not able to rescue the virus-induced drop in GSH content or improve the antioxidant response mediated by the Nrf2 transcription factor and G6PD enzyme. Similar to what has already been reported for RSV, they interfered with the nuclear-cytoplasmic traffic of viral nucleoprotein, probably inhibiting cellular kinases involved in the regulation of specific steps of the virus life cycle. Overall, the data indicate that more lipophilic RSV derivatives have improved antiviral efficacy compared with RSV and open the way for new cell-targeted antiviral strategies.

Drugs targeting epithelial-mesenchymal transition molecules for treatment of lichen planopilaris.

Primary cicatricial alopecia (PCA), also known as scarring alopecia, comprises a diverse group of hair disorders that cause permanent destruction of the pilosebaceous unit, resulting in disappearance of the follicular ostia. Lichen planopilaris (LPP) is a subtype of primary lymphocytic cicatricial alopecia. There is an urgent need to identify novel molecules that successfully target specific pathogenic pathways in LPP to inhibit and reverse disease progression. Recent studies into LPP pathogenesis have discovered that follicular stem cells undergo epithelial-mesenchymal transition (EMT). We sought to identify drugs that target molecules involved in EMT to repurpose these drugs for treatment of LPP. We identified 8 molecules and 15 drugs that target these EMT molecules. Only four of these drugs (pioglitazone, tofacitinib, barcitinib and apremilast) have been reported in individual cases or case series of patients with LPP and controlled studies are missing. We describe each drug and mechanism of action target EMT in detail. Although previous studies have demonstrated the efficacy of EMT inhibitors in anticancer therapy, there are, to our knowledge, no studies using EMT-attenuating drugs for the treatment of LPP. The treatment molecules discussed in this paper provide a new platform for clinical studies and controlled trials in LPP.

Role of HSV-1 in Alzheimer's disease pathogenesis: A challenge for novel preventive/therapeutic strategies.

Herpes simplex virus-1 (HSV-1) is a ubiquitous DNA virus able to establish a life-long latent infection in host sensory ganglia. Following periodic reactivations, the neovirions usually target the site of primary infection causing recurrent diseases in susceptible individuals. However, reactivated HSV-1 may also reach the brain resulting in severe herpetic encephalitis or in asymptomatic infections. These have been reportedly linked to neurodegenerative disorders, such as Alzheimer's disease (AD), suggesting antiviral preventive or/therapeutic treatments as possible strategies to counteract AD onset and progression. Here, we provide an overview of the AD-like mechanisms driven by HSV-1-infection in neurons and discuss the ongoing trials repurposing anti-herpetic drugs to treat AD as well as preventive strategies aimed at blocking virus infection.

A folliculocentric perspective of dandruff pathogenesis: Could a troublesome condition be caused by changes to a natural secretory mechanism?

Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under-investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune-modulatory properties, including the creation of an immunoinhibitory, immune-privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance of yeast and bacterial species, along with increasing proinflammatory sebum by-products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune-microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs.

Papuloerythroderma of Ofuji.

Papuloerythroderma of Ofuji (PEO) is a rare skin condition first described in 1984 and characterized by diffuse erythroderma composed of papules coalescing into plaques with sparing of skin folds, known as the deck-chair sign. The disease is almost exclusively seen in the elderly and affects men more frequently than women. Common laboratory findings include peripheral and tissue eosinophilia, elevated levels of immunoglobulin E, and lymphopenia. The diagnosis entails exclusion of potentially causative pathologies, including drug intake, atopy, malignancy, and infection. These factors have frequently been found in association with PEO, but their role in the etiopathogenesis of the disease is poorly understood. A dysregulated immune system, with particular involvement of T-helper (Th)2 and Th22 cells, seems to be important in the development of PEO. Controversy exists as to whether PEO exists as an independent entity or as a clinical pattern of a variety of distinct conditions. Treatment necessitates first addressing any coexisting circumstances that may have a causal relationship with PEO. In idiopathic cases, topical and oral corticosteroids, ultraviolet light therapies, and immunosuppressive/immunomodulating therapies have been used with variable results. Future studies are needed to further understand the disease process and to establish guidelines for diagnostic workup and treatment.

A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia?

Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-ß and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies.

Recent Insight on the Management of Lupus Erythematosus Alopecia.

Lupus erythematosus (LE) is a chronic autoimmune condition with a wide spectrum of clinical presentations. Alopecias, both non-scarring and scarring, frequently occur in the context of LE and can assume several different patterns. Furthermore, alopecia occurring with LE may be considered LE-specific if LE-specific features are present on histology; otherwise, alopecia is considered non-LE-specific. Non-scarring alopecia is highly specific to systemic LE (SLE), and therefore has been regarded as a criterion for the diagnosis of SLE. Variants of cutaneous LE (CLE), including acute, subacute, and chronic forms, are also capable of causing hair loss, and chronic CLE is an important cause of primary cicatricial alopecia. Other types of hair loss not specific to LE, including telogen effluvium, alopecia areata, and anagen effluvium, may also occur in a patient with lupus. Lupus alopecia may be difficult to treat, particularly in cases that have progressed to scarring. The article summarizes the types of lupus alopecia and recent insight regarding their management. Data regarding the management of lupus alopecia are sparse and limited to case reports, and therefore, many studies including in this review report the efficacy of treatments on CLE as a broader entity. In general, for patients with non-scarring alopecia in SLE, management is aimed at controlling SLE activity with subsequent hair regrowth. Topical medications can be used to expedite recovery. Prompt treatment is crucial in the case of chronic CLE due to potential for scarring and irreversible damage. First-line therapies for CLE include topical corticosteroids and oral antimalarials, with or without oral corticosteroids as bridging therapy. Second and third-line systemic treatments for CLE include methotrexate, retinoids, dapsone, mycophenolate mofetil, and mycophenolate acid. Additional topical and systemic medications as well as physical modalities used for the treatment of lupus alopecia and CLE are discussed herein.

Understanding Hormonal Therapies: Overview for the Dermatologist Focused on Hair.

Hormones have an intimate relationship with hair growth. Hormonal replacement therapy is used to treat menopausal symptoms and to provide protection from chronic diseases for which postmenopausal women may be at risk. Additionally, hormonal therapies are prescribed for contraception and treatment of acne. Considering the widespread use of such therapies, there is a demand for further understanding of their implications in hair disorders. This article reviews the specific properties of current estrogen- and progesterone-containing hormonal treatments and their implications for the patient with hair loss. The complexity of the task comes from the paucity of data and discrepancy in the literature on the effect of the specific hormonal-receptor activities.

Increased Association between Previous Pregnancies and Use of Chemical Relaxers in 74 Women with Central Centrifugal Cicatricial Alopecia.

BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is a type of scarring alopecia exclusively seen in women of African descent. The etiology is unknown and epidemiologic studies including data on comorbidities in patients with CCCA are limited. Our primary objective was to identify possible etiologic and lifestyle associations in patients with CCCA. MATERIALS AND METHODS: A retrospective chart review was conducted for patients diagnosed with CCCA between January 1, 2013, and January 1, 2018, at a university dermatology outpatient clinic. Controls consisted of age-, sex-, and race-matched African-American women diagnosed with other hair loss conditions. Data from 74 cases and 96 controls were collected and analyzed via logistic regression. In addition, a phone survey was conducted in the CCCA cohort asking specific questions related to their condition and quality of life. RESULTS: A significant relationship was found between CCCA and previous pregnancies as well as the use of chemical relaxers: patients with CCCA were 11.71 times more likely to have had a previous pregnancy (P < 0.001) and 12.37 times more likely to have used chemical relaxers in the past (P < 0.001). Association with uterine fibroids was found not statistically significant (P > 0.05). CONCLUSION: We identified an association between previous pregnancies and use of chemical relaxers in patients diagnosed with CCCA when compared to controls. These findings may help to plan prospective studies aiming at establishing a more concrete link between hormones and CCCA.