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The Journal of Biological Chemistry Oct 2020A sterilizing or functional cure for HIV is currently precluded by resting CD4 T cells that harbor latent but replication-competent provirus. The "shock-and-kill"...
A sterilizing or functional cure for HIV is currently precluded by resting CD4 T cells that harbor latent but replication-competent provirus. The "shock-and-kill" pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple "shock-and-kill" agents, which in turn may inform ongoing LRA combination therapy efforts.
Topics: Anthracenes; Anthralin; Drug Evaluation, Preclinical; HIV Infections; HIV-1; Humans; Jurkat Cells; Virus Latency
PubMed: 32788215
DOI: 10.1074/jbc.RA120.013031 -
JAAD Case Reports Jul 2020
PubMed: 32743037
DOI: 10.1016/j.jdcr.2020.05.022 -
Recent Patents on Inflammation &... 2020Alopecia Areata (AA) is a systemic autoimmune condition that usually starts in childhood. (Review)
Review
BACKGROUND
Alopecia Areata (AA) is a systemic autoimmune condition that usually starts in childhood.
OBJECTIVE
This article aims to review genetics, therapy, prognosis, and recent patents for AA.
METHODS
We used clinical queries and keywords "alopecia areata" AND "childhood" as a search engine. Patents were searched using the key term "alopecia areata" in Patents.google.com and freepatentsonline. com.
RESULTS
Due to an immune-mediated damage to the hair follicles, hair is lost from the scalp and other areas of the body temporarily or even permanently. Children with AA are generally healthy. Evidence of genetic association and increased predisposition for AA was found by studying families with affected members. Pathophysiologically, T- lymphocytes attack hair follicles and cause inflammation and destruction of the hair follicles and hair loss. In mild cases, there would be well-demarcated round patchy scalp hair loss. The pathognomonic "exclamation mark hairs" may be seen at the lesion periphery. In more severe cases, the hair loss may affect the whole scalp and even the whole body. The clinical course is also variable, which may range from transient episodes of recurrent patchy hair loss to an indolent gradually deteriorating severe hair loss. The treatment of AA depends on factors including patients' age, the extent of the hair loss, duration of disease, psychological impact, availability and side effect profile of the treatments. For localized patchy alopecia, topical application of corticosteroids and/or intralesional corticosteroids are the treatment of choice. Other topical treatments include minoxidil, anthralin, coal tar and immunotherapy. In severe resistant cases, systemic immunosuppressants may be considered. Although herbal medicine, acupuncture, complementary and alternative medicine may be tried on children in some Asian communities, the evidence to support these practices is lacking. To date, only a few recent patents exist in topical treatments, including Il-31, laser and herbal medications. Clinical efficacy is pending for these treatment modalities.
CONCLUSION
None of the established therapeutic options are curative. However, newer treatment modalities, including excimer laser, interleukin-31 antibodies and biologics, are evolving so that there may be significant advances in treatment in the near future. AA can be psychosocially devastating. It is important to assess the quality of life, degree of anxiety, social phobia and mood of the patients and their families. Psychological support is imperative for those who are adversely affected psychosocially.
Topics: Adrenal Cortex Hormones; Alopecia Areata; Anthralin; Child; Humans; Immunotherapy; Minoxidil; Patents as Topic
PubMed: 32723274
DOI: 10.2174/1872213X14999200728145822 -
Cell and Tissue Research Dec 2020Inflammation of the cutaneous orofacial tissue can lead to a prolonged alteration of neuronal and nonneuronal cellular functions in trigeminal nociceptive pathways. In...
Inflammation of the cutaneous orofacial tissue can lead to a prolonged alteration of neuronal and nonneuronal cellular functions in trigeminal nociceptive pathways. In this study, we investigated the effects of experimentally induced skin inflammation by dithranol (anthralin) on macrophage activation in the rat trigeminal ganglion. Tissue localization and protein expression levels of ionized calcium-binding adaptor molecule 1 (Iba1), a macrophage/microglia-specific marker, and proliferation/mitotic marker antigen identified by the monoclonal antibody Ki67 (Ki67), were quantitatively analyzed using immunohistochemistry and western blots in control, dithranol-treated, dithranol- and corticosteroid-treated, and corticosteroid-treated trigeminal ganglia. Chronic orofacial dithranol treatment elicited a strong pro-inflammatory effect in the ipsilateral trigeminal ganglion. Indeed, daily dithranol treatment of the orofacial skin for 3-5 days increased the number of macrophages and Iba1 protein expression in the maxillary subregion of the ipsilateral ganglion. In the affected ganglia, none of the Iba1-positive cells expressed Ki67. This absence of mitotically active cells suggested that the accumulation of macrophages in the ganglion was not the result of resident microglia proliferation but rather the extravasation of hematogenous monocytes from the periphery. Subsequently, when a 5-day-long anti-inflammatory corticosteroid therapy was employed on the previously dithranol-treated orofacial skin, Iba1 immunoreactivity was substantially reduced in the ipsilateral ganglion. Collectively, our findings indicate that both peripheral inflammation and subsequent anti-inflammatory therapy affect macrophage activity and thus interfere with the functioning of the affected sensory ganglion neurons.
Topics: Adrenal Cortex Hormones; Animals; Inflammation; Macrophages; Male; Rats; Skin; Trigeminal Ganglion
PubMed: 32696216
DOI: 10.1007/s00441-020-03244-3 -
Journal of Cosmetic Dermatology Sep 2020Treatment is often challenging in patients with alopecia areata. We often try topical immunotherapy to treat alopecia areata in Japan. Anthralin is sometimes used in...
BACKGROUND
Treatment is often challenging in patients with alopecia areata. We often try topical immunotherapy to treat alopecia areata in Japan. Anthralin is sometimes used in other countries.
OBJECTIVES
The aim of this study was to examine effectiveness of combination therapy with both topical immunotherapy with squaric acid dibutylester or diphenylcyclopropenone and anthralin in the treatment of refractory alopecia areata.
METHODS
We treat four patients with refractory alopecia areata by topical immunotherapy and anthralin. Two patients had alopecia areata multilocularis and the other two patients had alopecia totalis. The entire scalp was treated with weekly application of squaric acid dibutylester or diphenylcyclopropenone and daily 0.5% anthralin ointment. Patients were followed up weekly, and adverse effects were recorded.
RESULTS
One patient with multifocal patches of alopecia areata got complete hair regrowth at week 30, the other patient with multifocal patches of alopecia areata turned for the worse at week 30 and recovered at week 52. Hair regrowth was not seen in the other two patients with alopecia totalis. Localized pruritis and hyperpigmentation of the scalp were seen in two patients.
CONCLUSIONS
To treat alopecia areata unresponsive to topical immunotherapy alone, topical immunotherapy in combination with anthralin is worth a try.
Topics: Administration, Topical; Alopecia Areata; Anthralin; Humans; Immunotherapy; Japan; Treatment Outcome
PubMed: 32621407
DOI: 10.1111/jocd.13588 -
ELife Jun 2020Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic...
Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic lesions and both the c-Jun/JunB and imiquimod psoriasis mouse model allowed us to study the therapeutic mechanism of this drug. Top differentially expressed genes in the early response to dithranol belonged to keratinocyte and epidermal differentiation pathways and IL-1 family members (i.e. but not elements of the IL-17/IL-23 axis. In human psoriatic response to dithranol, rapid decrease in expression of keratinocyte differentiation regulators (e.g. involucrin, and ), antimicrobial peptides (e.g. ß-defensins like S100 proteins like ), chemotactic factors for neutrophils (e.g. ) and neutrophilic infiltration was followed with much delay by reduction in T cell infiltration. Targeting keratinocytes rather than immune cells may be an alternative approach in particular for topical anti-psoriatic treatment, an area with high need for new drugs.
Topics: Animals; Anthralin; Chemokines, CXC; Dermatologic Agents; Interleukin-1; Keratinocytes; Mice; Neutrophils; Pore Forming Cytotoxic Proteins; Psoriasis; Serpins; Signal Transduction; Skin
PubMed: 32484435
DOI: 10.7554/eLife.56991 -
Current Drug Research Reviews 2020Dithranol (DTH) is a well-known moiety that has long been used promisingly to impede and treat skin disorders, particularly psoriasis. Nowadays, a rekindled interest in... (Review)
Review
OBJECTIVE
Dithranol (DTH) is a well-known moiety that has long been used promisingly to impede and treat skin disorders, particularly psoriasis. Nowadays, a rekindled interest in the use of DTH for this disorder has been observed. Side effects associated with conventional topical formulations of this moiety have aroused the interest of the scientific community in investigating novel cargos of DTH for psoriasis management.
RESULTS
Previous research has evidenced the anti-inflammatory and anti-proliferating potential of DTH. Numerous studies have indicated that DTH inhibits polymorphonuclear (PMN) leucocyte, modulates epidermal cell receptors and promotes anti-psoriatic action. However, some deterrent factors like poor solubility, stability, toxicity, staining and skin irritation hamper its use as a potential therapeutic agent. With the adoption of novel drug delivery technologies, the above mentioned inherent limitations of DTH have been compensated to reestablish this drug moiety.
CONCLUSION
This article reviews novel drug delivery aspects, safety concerns, clinical evidence, current status, and future opportunities of DTH in the management of psoriasis. Further, it will update researchers on this promising drug moiety, which is free from systemic adverse responses in comparison to other therapeutic molecules like steroids, for psoriasis treatment.
Topics: Administration, Cutaneous; Animals; Anthralin; Dermatologic Agents; Drug Delivery Systems; Humans; Psoriasis; Solubility
PubMed: 32484107
DOI: 10.2174/2589977512666200525154954 -
Journal of Cosmetic Dermatology Jan 2021Among alopecia areata (AA) treatments, contact irritants (anthralin) and topical immunotherapies (diphenylcyclopropenone) have been successfully used. Chemoexfoliation... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Among alopecia areata (AA) treatments, contact irritants (anthralin) and topical immunotherapies (diphenylcyclopropenone) have been successfully used. Chemoexfoliation can potentially be utilized, acting as irritants and consecutively immunomodulators. Peels via therapeutic wounding provoke growth factors and cytokines that may induce hair regrowth.
AIM
To evaluate and compare trichloroacetic acid (TCA) 35% and phenol 88% peels effectiveness and tolerability in patchy AA.
PATIENTS/METHODS
This comparative, randomized, double-blind study included 20 patients with multifocal patchy AA. In each patient, 2 patches were selected and randomized into group I (20 patches: TCA 35%) and group II (20 patches: phenol 88%). A session was performed every 3 weeks for 9 weeks. Response was assessed by two blinded observers as regards percentage of clinical improvement, severity of alopecia tool (SALT), and trichoscopic scaled scores for dystrophic and terminal hairs, respectively. Patients were scheduled for follow-up visits over 6 months past treatment cessation.
RESULTS
A total of 19 patients completed the study and showed significant reduction in SALT score. TCA- and phenol-treated patches demonstrated significant improvement in the percentage of clinical improvement, trichoscopic scale of dystrophic and terminal hairs. However, TCA was superior to phenol as it showed significant more reduction in trichoscopic score of dystrophic hairs and significant higher increase in terminal hairs. Phenol yielded significant higher discomfort than TCA. No relapse was detected.
CONCLUSIONS
Trichloroacetic acid 35% and phenol 88% peels can be considered effective therapeutic modalities for patchy AA. TCA 35% represents a treatment of choice in terms of the efficacy and tolerability.
Topics: Alopecia Areata; Dermoscopy; Humans; Phenol; Phenols; Trichloroacetic Acid
PubMed: 32436287
DOI: 10.1111/jocd.13465 -
Pharmaceutics May 2020To enhance anthralin efficacy against psoriasis and reduce its notorious side effects, it was loaded into various liposomal and ethosomal preparations. The nanocarriers...
To enhance anthralin efficacy against psoriasis and reduce its notorious side effects, it was loaded into various liposomal and ethosomal preparations. The nanocarriers were characterized for drug encapsulation efficiency, size, morphology and compatibility between various components. Optimum formulations were dispersed in various gel bases and drug release kinetics were studied. Clinical efficacy and safety of liposomal and ethosomal PluronicF-127 gels were evaluated in patients having psoriasis (clinicaltrials.gov identifier is NCT03348462). Safety was assessed by recording various adverse events. Drug encapsulation efficiency ≥97.2% and ≥77% were obtained for liposomes and ethosomes, respectively. Particle sizes of 116 to 199 nm and 146 to 381 nm were observed for liposomes and ethosomes, respectively. Fourier-Transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) studies confirmed the absence of interaction between anthralin and various nanocarrier components. Tested gel bases showed excellent ability to sustain drug release. At baseline, the patients had a median Psoriasis Area and Severity Index (PASI) of 3.4 for liposomes and 3.6 for ethosomes without significant difference. After treatment, mean PASI change was -68.66% and -81.84% for liposomes and ethosomes, respectively with a significant difference in favor of ethosomes. No adverse effects were detected in both groups. Anthralin ethosomes could be considered as a potential treatment of psoriasis.
PubMed: 32403379
DOI: 10.3390/pharmaceutics12050446 -
International Journal of Nanomedicine 2020Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative...
PURPOSE
Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative strategies eradicating ROS may serve as effective and easy treatment options for psoriasis, while nanozymes with intrinsic antioxidant enzyme-like activity have not been explored for psoriasis treatment. The aim of this study is to fabricate β-cyclodextrins (β-CDs)-modified ceria nanoparticles (β-CDs/CeO NPs) with drug-loaded and multimimic-enzyme activities for combinational psoriasis therapy.
METHODS
The β-CDs/CeO NPs were synthesized by a hydrothermal method using unmodified β-CDs as a protecting agent. The structure, size and morphology were analyzed by dynamic light scattering, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. Considering the superoxide dismutase (SOD)- and catalase-mimetic activities, the in vitro antioxidant activity of the β-CDs/CeO2 NPs was investigated. After dithranol (DIT) was loaded, the drug-loading capacity and release profile were determined by UV-visible light spectrophotometer and high-performance liquid chromatography. The anti-psoriatic efficacy was studied in the imiquimod (IMQ)-induced mouse model on the basis of morphological evaluation, psoriasis area and severity index calculation (PASI), and inflammatory cytokine expression.
RESULTS
The average particle size of the blank β-CDs/CeO NPs was 60.89±0.32 nm with a polydispersity index (PDI) of 0.12, whereas that of the DIT-loaded NPs was 79.38±1.06 nm with a PDI of 0.27. TEM results showed the as-prepared NPs formed a uniform quasi-spherical shape with low polydispersity. XPS indicates synthesized NPs have a mixed Ce/Ce valence state. FTIR spectroscopy confirmed the presence of β-CDs and DIT in the NPs. Inhibition of superoxide anion rate by NPs could be reached to 79.4% in the presence of 200 µg/mL, and elimination of HO efficiency reached about 50% in the presence of 40 µg/mL, demonstrating excellent superoxide dismutase- and catalase-mimicking activities, thereby providing remarkable cryoprotection against ROS-mediated damage. Furthermore, β-CDs on the surface endowed the NPs with drug-loading function via host-guest interactions. The entrapment efficiency and drug loading of DIT are 94.7% and 3.48%, respectively. The in vitro drug release curves revealed a suitable release capability of DIT@β-CDs/CeO NPs under physiological conditions. In IMQ-induced psoriatic model, the DIT@β-CDs/CeO NPs exhibited excellent therapeutic effect.
CONCLUSION
This study may pave the way for the application of nanozyme β-CDs/CeO NPs as a powerful tool for psoriasis therapy.
Topics: Animals; Catalase; Cell Line; Cell Survival; Cerium; Combined Modality Therapy; Free Radical Scavengers; Hydrodynamics; Imiquimod; Male; Mice, Inbred BALB C; Nanoparticles; Particle Size; Photoelectron Spectroscopy; Psoriasis; Reactive Oxygen Species; Skin; Spectroscopy, Fourier Transform Infrared; Superoxide Dismutase; Tumor Necrosis Factor-alpha; beta-Cyclodextrins
PubMed: 32368038
DOI: 10.2147/IJN.S246783