RESUMEN
Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49fhigh cells. The disruption of the S100A enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.
Asunto(s)
Hidradenitis Supurativa , Humanos , Hidradenitis Supurativa/genética , Piel/metabolismo , Epigenómica , Epigénesis Genética , Células Madre/metabolismo , Cromatina/metabolismoRESUMEN
Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates, namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES), respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of vesicants. Murine skin exposure to these chemicals causes tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells, and apoptosis of epidermal and dermal cells. RNA sequencing analysis identified â¼346 inflammatory genes that were commonly altered by both PAO and CEES, along with the identification of cytokine signaling activation as the top canonical pathway. Activation of several proinflammatory genes and pathways is associated with phosphorylation-dependent activation of heat shock protein 90α (p-HSP90α). Topical treatment with known HSP90 inhibitors SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuated skin damage including reduction in overall skin injury and clinical scores. In addition, highly upregulated inflammatory genes Saa3, Cxcl1, Ccl7, IL-6, Nlrp3, Csf3, Chil3, etc. by both PAO and CEES were significantly diminished by treatment with HSP90 inhibitors. These drugs not only reduced PAO- or CEES-induced p-HSP90α expression but also its client proteins NLRP3 and pP38 and the expression of their target inflammatory genes. Our data confirm a critical role of HSP90 as a shared underlying molecular target of toxicity by these two distinct vesicants and provide an effective and novel medical countermeasure to suppress vesicant-induced skin injury. SIGNIFICANCE STATEMENT: Development of effective and novel mechanism-based antidotes that can simultaneously block cutaneous toxic manifestations of distinct vesicants is important and urgently needed. Due to difficulties in determining the exact nature of onsite chemical exposure, a potent drug that can suppress widespread cutaneous damage may find great utility. Thus, this study identified HSP90 as a common molecular regulator of cutaneous inflammation and injury by two distinct warfare vesicants, arsenicals and mustards, and HSP90 inhibitors afford significant protection against skin damage.
Asunto(s)
Arsenicales , Sustancias para la Guerra Química , Gas Mostaza , Humanos , Animales , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sustancias para la Guerra Química/toxicidad , Irritantes , Piel , Gas Mostaza/toxicidad , Arsenicales/metabolismo , Arsenicales/farmacologíaRESUMEN
Worldwide, more than 200 million people are estimated to be exposed to unsafe levels of arsenic. Chronic exposure to unsafe levels of groundwater arsenic is responsible for multiple human disorders, including dermal, cardiovascular, neurological, pulmonary, renal, and metabolic conditions. Consumption of rice and seafood (where high levels of arsenic are accumulated) is also responsible for human exposure to arsenic. The toxicity of arsenic compounds varies greatly and may depend on their chemical form, solubility, and concentration. Surprisingly, synthetic organoarsenicals are extremely toxic molecules which created interest in their development as chemical warfare agents (CWAs) during World War I (WWI). Among these CWAs, adamsite, Clark I, Clark II, and lewisite are of critical importance, as stockpiles of these agents still exist worldwide. In addition, unused WWII weaponized arsenicals discarded in water bodies or buried in many parts of the world continue to pose a serious threat to the environment and human health. Metabolic inhibition, oxidative stress, genotoxicity, and epigenetic alterations including micro-RNA-dependent regulation are some of the underlying mechanisms of arsenic toxicity. Mechanistic understanding of the toxicity of organoarsenicals is also critical for the development of effective therapeutic interventions. This review provides comprehensive details and a critical assessment of recently published data on various chemical forms of arsenic, their exposure, and implications on human and environmental health.
Asunto(s)
Arsénico , Arsenicales , Sustancias para la Guerra Química , Humanos , Arsénico/toxicidad , Arsenicales/efectos adversos , Arsenicales/metabolismo , Estrés OxidativoRESUMEN
Arsenicals belong to the class of chemical warfare agents known as vesicants, which are highly reactive, toxic and cause robust inflammatory response. Cutaneous exposure to arsenicals causes a wide range of systemic organ damage, beginning with cutaneous injuries, and later manifest multi-organ damage and death. Thus, the development of suitable antidotes that can effectively block injury following exposure to these agents is of great importance. Bromodomain 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) family, plays crucial role in regulating transcription of inflammatory, proliferation and cell cycle genes. In this context, the development of potent small molecule inhibitors of BRD4 could serve as potential antidotes for arsenicals. Herein, we describe the synthesis and biological evaluation of a series of compounds.
Asunto(s)
Arsenicales , Antiinflamatorios/química , Antídotos/farmacología , Arsenicales/farmacología , Arsenicales/uso terapéutico , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis.
Asunto(s)
Ácidos Anacárdicos/farmacología , Apoptosis/efectos de los fármacos , NADH NADPH Oxidorreductasas/fisiología , Proteínas de Saccharomyces cerevisiae/fisiología , Saccharomyces cerevisiae/efectos de los fármacos , Antioxidantes/farmacología , Apoptosis/fisiología , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Metanosulfonato de Etilo/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , NADH NADPH Oxidorreductasas/genética , ARN de Hongos/biosíntesis , ARN de Hongos/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/biosíntesis , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Anacardic acid (6-pentadecylsalicylic acid), extracted from cashew nut shell liquid, is a natural phenolic lipid well known for its strong antibacterial, antioxidant, and anticancer activities. Its effect has been well studied in bacterial and mammalian systems but remains largely unexplored in fungi. The present study identifies antifungal, cytotoxic, and antioxidant activities of anacardic acid in the rice blast fungus Magnaporthe oryzae. It was found that anacardic acid causes inhibition of conidial germination and mycelial growth in this ascomycetous fungus. Phosphatidylserine externalization, chromatin condensation, DNA degradation, and loss of mitochondrial membrane potential suggest that growth inhibition of fungus is mainly caused by apoptosis-like cell death. Broad-spectrum caspase inhibitor Z-VAD-FMK treatment indicated that anacardic acid induces caspase-independent apoptosis in M. oryzae. Expression of a predicted ortholog of apoptosis-inducing factor (AIF) was upregulated during the process of apoptosis, suggesting the possibility of mitochondria dependent apoptosis via activation of apoptosis-inducing factor. Anacardic acid treatment leads to decrease in reactive oxygen species rather than increase in reactive oxygen species (ROS) accumulation normally observed during apoptosis, confirming the antioxidant properties of anacardic acid as suggested by earlier reports. Our study also shows that anacardic acid renders the fungus highly sensitive to DNA damaging agents like ethyl methanesulfonate (EMS). Treatment of rice leaves with anacardic acid prevents M. oryzae from infecting the plant without affecting the leaf, suggesting that anacardic acid can be an effective antifungal agent.
Asunto(s)
Ácidos Anacárdicos/toxicidad , Antifúngicos/toxicidad , Apoptosis , Muerte Celular , Magnaporthe/efectos de los fármacos , Magnaporthe/fisiología , Ácidos Anacárdicos/aislamiento & purificación , Anacardium/química , Antifúngicos/aislamiento & purificación , Magnaporthe/crecimiento & desarrollo , Micelio/crecimiento & desarrollo , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Hojas de la Planta/microbiologíaRESUMEN
BACKGROUND: Adenocarcinoma in Barrett's esophagus (BE) occurs more frequently between 12 and 3 o'clock at the gastroesophageal junction (GEJ). METHODS: BE patients were prospectively recruited from December 2013 to July 2016. Expression of p53, Ki-67, cyclin-D1, COX-2 and p21 was assessed in quadrantic biopsies from the proximal and distal margins of the BE segments. Cell cycle marker association with current or subsequent dysplasia or adenocarcinoma was examined. RESULTS: 110 patients: median age 64 (IQR, 56-71) years; median BE segment length C4M6; and a median follow-up of 4.7 (IQR, 3.6-5.7) years. In total 13 (11.8%) had evidence of dysplasia or neoplasia (2.7% indefinite for dysplasia, 5.5% low grade, 1.8% high grade and 1.8% adenocarcinoma) at index endoscopy. Six (7%) developed dysplasia or neoplasia (1 low grade, 2 high grade and 3 adenocarcinoma) during follow-up. Ki-67 expression was highest at 3 o'clock, and overall was 49.6% higher in the 12-6 o'clock position compared to 6-12 o'clock [odds ratio (OR), 1.42 (95% confidence interval (CI), 1.00-2.12)]. A similar pattern was found with p21 [1.82 (1.00-3.47)]. There was increased expression of several markers in distal BE biopsies; cyclin-D1 [1.74 (1.29-2.34)]; Cyclo-oxygenase 2 [2.03 (1.48-2.78]) and p21 [2.06 (1.16-3.68)]. Expression of Ki-67 was lower in distal compared to proximal biopsies [0.58 (0.43-0.78)]. P53 expression had high specificity (93.8%) for subsequent low-grade dysplasia, high-grade dysplasia or adenocarcinoma. CONCLUSION: Increased cellular proliferation was seen at 12-6 o'clock at the GEJ. Cell-cycle marker expression was increased at the GEJ compared to the proximal BE segment. These findings mirror reflux esophagitis and suggest ongoing reflux contributes to the progression of dysplasia and malignancy in BE.
Asunto(s)
Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Humanos , Persona de Mediana Edad , Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Antígeno Ki-67/metabolismo , Proteína p53 Supresora de Tumor , Adenocarcinoma/patología , Márgenes de Escisión , Ciclinas/metabolismo , Ciclo CelularRESUMEN
Lewisite, a chemical warfare agent, causes skin blisters, erythema, edema, and inflammation, requiring mitigation strategies in case of accidental or deliberate exposure. 4-phenyl butyric acid (4-PBA), a chemical chaperone, reduces endoplasmic reticulum stress and skin inflammation. The study aimed to encapsulate 4-PBA in microsponges for effective, sustained delivery against lewisite injury. Porous microsponges in a topical gel would potentially sustain delivery and improve residence time on the skin. Microsponges were developed using the quasi-emulsion solvent diffusion method with Eudragit RS100. Optimized formulation showed 10.58%w/w drug loading was incorporated in a carboxymethylcellulose (CMC) and Carbopol gel for in vitro release and permeation testing using dermatomed human skin. A sustained release was obtained from all vehicles in the release study, and IVPT results showed that compared to the control (41.52 ± 2.54 µg/sq.cm), a sustained permeation profile with a reduced delivery was observed for microsponges in PBS (14.16 ± 1.23 µg/sq.cm) along with Carbopol 980 gel (12.55 ± 1.41 µg/sq.cm), and CMC gel (10.09 ± 1.23 µg/sq.cm) at 24 h. Optimized formulation showed significant protection against lewisite surrogate phenyl arsine oxide (PAO) challenged skin injury in Ptch1+/-/SKH-1 hairless mice at gross and molecular levels. A reduction in Draize score by 29%, a reduction in skin bifold thickness by 8%, a significant reduction in levels of IL-1ß, IL6, and GM-CSF by 54%, 30%, and 55%, respectively, and a reduction in apoptosis by 31% was observed. Thus, the translational feasibility of 4-PBA microsponges for effective, sustained delivery against lewisite skin injury is demonstrated.
RESUMEN
Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.
Asunto(s)
Acetilcisteína , Antídotos , Humanos , Administración Cutánea , Piel , Sistemas de Liberación de Medicamentos , AgujasRESUMEN
Arsenical vesicants cause skin inflammation, blistering, and pain. The lack of appropriate animal models causes difficulty in defining their molecular pathogenesis. Here, Ptch1+/- /C57BL/6 mice were employed to investigate the pathobiology of the arsenicals lewisite and phenylarsine oxide (PAO). Following lewisite or PAO challenge (24 h), the skin of animals becomes grayish-white, thick, leathery, and wrinkled with increased bi-fold thickness, Draize score, and necrotic patches. In histopathology, infiltrating leukocytes (macrophages and neutrophils), epidermal-dermal separation, edema, apoptotic cells, and disruption of tight and adherens junction proteins can be visualized. PCR arrays and nanoString analyses showed significant increases in cytokines/chemokines and other proinflammatory mediators. As hair follicles (HFs), which provide an immune-privileged environment, may affect immune cell trafficking and consequent inflammatory responses, we compared the pathogenesis of these chemicals in this model to that in Ptch1+/- /SKH-1 hairless mice. Ptch1+/- /SKH-1 mice have rudimentary, whereas Ptch1+/- /C57BL/6 mice have well-developed HFs. Although no significant differences were observed in qualitative inflammatory responses between the two strains, levels of cytokines/chemokines differed. Importantly, the mechanism of inflammation was identical; both reactive oxygen species induction and consequent activation of unfolded protein response signaling were similar. These data reveal that the acute molecular pathogenesis of arsenicals in these two murine models is similar.
Asunto(s)
Arsenicales , Sustancias para la Guerra Química , Animales , Sustancias para la Guerra Química/metabolismo , Quimiocinas , Citocinas/metabolismo , Folículo Piloso/metabolismo , Folículo Piloso/patología , Inflamación/patología , Irritantes , Ratones , Ratones Pelados , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Piel/metabolismoRESUMEN
The use of chemical warfare agents is prohibited but they have been used in recent Middle Eastern conflicts. Their accidental exposure (e.g. arsenical lewisite) is also known and causes extensive painful cutaneous injury. However, their molecular pathogenesis is not understood. Here, we demonstrate that a nexus of stress granules (SGs), integrated stress, and RNA binding proteins (RBPs) Roquin and Reganse-1 play a key role. Lewisite and its prototype phenylarsine oxide (PAO) induce SG assembly in skin keratinocytes soon after exposure, which associate with various RBPs and translation-related proteins. SG disassembly was detected several hours after exposure. The dynamics of SG assembly-disassembly associates with the chemical insult and cell damage. Enhanced Roquin and Regnase-1 expression occurs when Roquin was recruited to SGs and Regnase-1 to the ribosome while in the disassembling SGs their expression is decreased with consequent induction of inflammatory mediators. SG-targeted protein translational control is regulated by the phosphorylation-dependent activation of eukaryotic initiation factors 2α (eIF2α). Treatment with integrated stress response inhibitor (ISRIB), which blocks eIF2α phosphorylation, impacted SG assembly dynamics. Topical application of ISRIB attenuated the inflammation and tissue disruption in PAO-challenged mice. Thus, the dynamic regulation of these pathways provides underpinning to cutaneous injury and identify translational therapeutic approach for these and similar debilitating chemicals.
Asunto(s)
Sustancias para la Guerra Química/farmacología , Irritantes/farmacología , Queratinocitos/efectos de los fármacos , Proteínas de Unión al ARN/genética , Ribonucleasas/genética , Gránulos de Estrés/genética , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Arsenicales/farmacología , Western Blotting , Línea Celular , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Masculino , Ratones Noqueados , Proteómica/métodos , Proteínas de Unión al ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasas/metabolismo , Piel/citología , Piel/efectos de los fármacos , Piel/metabolismo , Gránulos de Estrés/metabolismo , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Skin squamous cell carcinomas (SCCs) are a major cause of death in patients who have undergone or will undergo organ transplantation. Moreover, these neoplasms cause significant disease and economic burden and diminish patients' life quality. However, no effective treatment or intervention strategies are available. In this study, we investigated the pathologic role of 5'-cap translation, which is regulated by the formation of a ternary initiation factor complex involving eIF4E, eIF4G, and eIF4A1. We detected increased expression of phosphorylated eIF4E, eIF4G, and eIF4A1 in human and murine skin SCCs. The increase in these ternary initiation factor complex proteins was associated with enhanced eIF4E translation targets cyclin D1 and c-Myc. Conversely, small interfering RNA-mediated depletion of eIF4E in human SCC cells (A431 and SCC-13) reduced eIF4G and proteins that regulate the cell cycle and proliferation. Notably, inhibition of Raf/MAPK/extracellular signal-regulated kinase signaling decreased eIF4E and phosphorylated eIF4E accumulation and significantly diminished cell-cycle gene expression and tumor volume of A431-derived xenograft tumors. Furthermore, disrupting the eIF4E with an allosteric inhibitor of eIF4E and eIF4G binding, 4EGI-1, decreased the eIF4E/eIF4G expression and reduced the proliferation. Finally, combined inhibition of the Raf/MAPK/extracellular signal-regulated kinase axis and eIF4E impaired 5'-capâdependent translation and abrogated tumor cell proliferation. These data demonstrate that 5'-capâdependent translation is a potential therapeutic target for abrogating lethal skin SCCs in patients who have undergone or will undergo organ transplantation.
Asunto(s)
Carcinoma de Células Escamosas/genética , Factor 4E Eucariótico de Iniciación/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , ARN Interferente Pequeño/farmacología , Neoplasias Cutáneas/genética , Regulación Alostérica/efectos de los fármacos , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Ciclina D1/genética , Factor 4A Eucariótico de Iniciación/metabolismo , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Factor 4G Eucariótico de Iniciación/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Iniciación de la Cadena Peptídica Traduccional/efectos de los fármacos , Fosforilación , Proteínas Proto-Oncogénicas c-myc/genética , Caperuzas de ARN/metabolismo , ARN Interferente Pequeño/uso terapéutico , Piel/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lewisite and many other similar arsenicals are warfare vesicants developed and weaponized for use in World Wars I and II. These chemicals, when exposed to the skin and other epithelial tissues, cause rapid severe inflammation and systemic damage. Here, we show that topically applied arsenicals in a murine model produce significant acute kidney injury (AKI), as determined by an increase in the AKI biomarkers NGAL and KIM-1. An increase in reactive oxygen species and ER stress proteins, such as ATF4 and CHOP, correlated with the induction of these AKI biomarkers. Also, TUNEL staining of CHOP-positive renal tubular cells suggests CHOP mediates apoptosis in these cells. A systemic inflammatory response characterized by a significant elevation in inflammatory mediators, such as IL-6, IFN-α, and COX-2, in the kidney could be the underlying cause of AKI. The mechanism of arsenical-mediated inflammation involves activation of AMPK/Nrf2 signaling pathways, which regulate heme oxygenase-1 (HO-1). Indeed, HO-1 induction with cobalt protoporphyrin (CoPP) treatment in arsenical-treated HEK293 cells afforded cytoprotection by attenuating CHOP-associated apoptosis and cytokine mRNA levels. These results demonstrate that topical exposure to arsenicals causes AKI and that HO-1 activation may serve a protective role in this setting.
Asunto(s)
Lesión Renal Aguda , Apoptosis/efectos de los fármacos , Arsenicales , Sustancias para la Guerra Química/envenenamiento , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Factor de Transcripción Activador 4/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Animales , Biomarcadores/metabolismo , Ciclooxigenasa 2/metabolismo , Activación Enzimática/efectos de los fármacos , Células HEK293 , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Humanos , Interleucina-6/metabolismo , Ratones , Ratones Pelados , Factor 2 Relacionado con NF-E2/metabolismo , Factor de Transcripción CHOP/metabolismoRESUMEN
Gynecomastia is the most common cause of breast enlargement in males. Trichophyton rubrum is a common dermatophyte, is responsible for a variety of infections, and may rarely manifest as a dermatophytic pseudomycetoma. We report the case of a 52-year-old man who presented with progressive bilateral breast enlargement. This is the first reported case of bilateral breast pseudomycetoma due to T. rubrum. Long-term antifungal therapy with itraconazole was successful.
Asunto(s)
Ginecomastia/diagnóstico , Tiña/diagnóstico , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Diagnóstico Diferencial , Ginecomastia/tratamiento farmacológico , Ginecomastia/patología , Humanos , Itraconazol/administración & dosificación , Itraconazol/uso terapéutico , Masculino , Persona de Mediana Edad , Tiña/tratamiento farmacológico , Tiña/patología , Trichophyton/aislamiento & purificaciónRESUMEN
An unusual case of congenital benign hibernoma, in the submandibular region, in a 2.5 years old girl, is reported, who presented with a progressively increasing neck swelling. A CAT scan of neck revealed a superficial and deep low density mass. Surgical excision revealed a benign hibernoma. A 3-year follow-up shows no recurrence.
Asunto(s)
Neoplasias de Cabeza y Cuello , Lipoma , Neoplasias de los Tejidos Blandos , Preescolar , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Lipoma/diagnóstico por imagen , Lipoma/patología , Lipoma/cirugía , Cuello/diagnóstico por imagen , Cuello/patología , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/cirugía , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
Castleman's disease is a rare disorder of unknown etiology and different clinical manifestations, occurring in young adults (usually prior to age 30 years). In this case report we present one such case who was a 16 years old male with abdominal pain, weight loss, cervical lymph adenopathy and hepatosplenomegaly. Lymph node biopsy revealed hyaline-vascular type of Castleman's disease. He was put on chemotherapy but was lost to follow-up.
Asunto(s)
Enfermedad de Castleman/diagnóstico , Adolescente , Humanos , MasculinoRESUMEN
Solid and cystic papillary epithelial neoplasms of the pancreas are uncommon tumors occurring predominantly in young women. These tumors have excellent prognosis and after complete surgical resection, more that 95% patients are cured. Occasionally, they invade the surrounding pancreatic parenchyma. These tumors can recur even many years after resection, so long-term follow up is essential. Very few cases metastasize. We present a case of a middle aged woman with metastases to liver and omentum.
Asunto(s)
Cistoadenoma Papilar/patología , Neoplasias Hepáticas/secundario , Neoplasias Pancreáticas/patología , Neoplasias Peritoneales/secundario , Adulto , Cistoadenoma Papilar/diagnóstico por imagen , Cistoadenoma Papilar/tratamiento farmacológico , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Epiplón , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Peritoneales/diagnóstico por imagen , Neoplasias Peritoneales/tratamiento farmacológico , Tomografía Computarizada por Rayos XRESUMEN
Sarcoidosis is a chronic granulomatous multi-system disease with a clinical picture often mimicking tuberculosis. We present a case of a patient who presented with a clinical picture akin to both of these granulomatous disorders and was started on anti-tuberculous regimen despite the lack of any solid evidence pointing towards tuberculosis. As a result her clinical condition continued to deteriorate for months until finally a bronchoscopic biopsy established her disease process as sarcoidosis. She was then started on systemic corticosteroid therapy for sarcoidosis and during the ensuing period has shown marked improvement in her clinical picture with near normalization of the biochemical and radiographic parameters of her pathology. This case illustrates the need for vigilant interpretation of the clinical scenario in patients such as these where a misdiagnosis may lead to significant patient distress as well as weighing down on the economic and health resources.
Asunto(s)
Tos/diagnóstico , Sarcoidosis Pulmonar/diagnóstico , Pérdida de Peso , Enfermedad Crónica , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Sarcoidosis Pulmonar/fisiopatología , Tuberculosis Pulmonar/diagnósticoRESUMEN
Associating systemic lupus erythematosus (SLE), with an initial presentation of hemolytic uremic syndrome (HUS) is rare. We report a case of 21-year old Afghani female admitted to our hospital with an initial complaint of high grade fever and diffuse maculopapular rash and swelling of lower limbs. Diagnosis of atypical HUS was established according to the clinical triad of HUS without a veriotoxin-producing organism in her stool and the pathological finding compatible to thrombotic microangiopathy. In addition, her symptoms fulfilled the 1982 revised criteria for the classification of SLE. After pulse methylprednisolone, cyclophosphamide and plasmapheresis therapies, her laboratory findings and general condition improved. Unfortunately she was lost to follow up as she decided to return back to Afghanistan.