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Acanthoic acid, a diterpene isolated from the root bark of Acanthopanax koreanum Nakai, possesses diverse pharmacological activities, including anti-inflammatory, anti-diabetic, gastrointestinal protection, and cardiovascular protection. This study is the first to investigate the egg-hatching rates of Drosophila melanogaster affected by acanthoic acid. Notably, male flies supplemented with 10 µM acanthoic acid exhibited a strong increase in hatching rates compared with controls under adverse temperature conditions, suggesting a potential protective effect against environmental stressors. Molecular docking simulations revealed the binding affinities and specific interactions between acanthoic acid and proteins related to male infertility, including SHBG, ADAM17, and DNase I, with binding affinity values of -10.2, -6.8, and -5.8 kcal/mol, respectively. Following the docking studies, molecular dynamic simulations were conducted for a duration of 100 ns to examine the stability of these interactions. Additionally, a total binding energy analysis and decomposition analysis offered insights into the underlying energetic components and identified key contributing residues.
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Dorsal switch protein 1(DSP1), a mammalian homolog of HMGB1, is firstly identified as a dorsal co-repressor in 1994. DSP1 contains HMG-box domain and functions as a transcriptional regulator in Drosophila melanogaster. It plays a crucial role in embryonic development, particularly in dorsal-ventral patterning during early embryogenesis, through the regulation of gene expression. Moreover, DSP1 is implicated in various cellular processes, including cell fate determination and tissue differentiation, which are essential for embryonic development. While the function of DSP1 in embryonic development has been relatively well-studied, its role in the adult Drosophila brain remains less understood. In this study, we investigated the role of DSP1 in the brain by using neuronal-specific DSP1 overexpression flies. We observed that climbing ability and life span are decreased in DSP1-overexpressed flies. Furthermore, these flies demonstrated neuromuscular junction (NMJ) defect, reduced eye size and a decrease in tyrosine hydroxylase (TH)-positive neurons, indicating neuronal toxicity induced by DSP1 overexpression. Our data suggest that DSP1 overexpression leads to neuronal dysfunction and toxicity, positioning DSP1 as a potential therapeutic target for neurodegenerative diseases.
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Proteínas de Drosophila , Drosophila melanogaster , Degeneração Neural , Junção Neuromuscular , Neurônios , Fenótipo , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Olho/patologia , Longevidade/genética , Degeneração Neural/patologia , Degeneração Neural/genética , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Neurônios/metabolismo , Neurônios/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
In human Alzheimer's disease (AD), the aggregation of tau protein is considered a significant hallmark, along with amyloid-beta. The formation of neurofibrillary tangles due to aberrant phosphorylation of tau disrupts microtubule stability, leading to neuronal toxicity, dysfunction, and subsequent cell death. Nesfatin-1 is a neuropeptide primarily known for regulating appetite and energy homeostasis. However, the function of Nesfatin-1 in a neuroprotective role has not been investigated. In this study, we aimed to elucidate the effect of Nesfatin-1 on tau pathology using the Drosophila model system. Our findings demonstrate that Nesfatin-1 effectively mitigates the pathological phenotypes observed in Drosophila human Tau overexpression models. Nesfatin-1 overexpression rescued the neurodegenerative phenotypes in the adult fly's eye and bristle. Additionally, Nesfatin-1 improved locomotive behavior, neuromuscular junction formation, and lifespan in the hTau AD model. Moreover, Nesfatin-1 controls tauopathy by reducing the protein level of hTau. Overall, this research highlights the potential therapeutic applications of Nesfatin-1 in ameliorating the pathological features associated with Alzheimer's disease.
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Doença de Alzheimer , Modelos Animais de Doenças , Nucleobindinas , Proteínas tau , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Nucleobindinas/metabolismo , Nucleobindinas/genética , Proteínas tau/metabolismo , Proteínas tau/genética , Humanos , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Animais Geneticamente Modificados , Drosophila , Locomoção , LongevidadeRESUMO
BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.
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Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Biliar , Cisplatino , Desoxicitidina , Gencitabina , Humanos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Adulto , Taxa de SobrevidaRESUMO
Brain endothelial cells (BECs) play an important role in maintaining central nervous system (CNS) homeostasis through blood-brain barrier (BBB) functions. BECs express low baseline levels of adhesion receptors, which limits entry of leukocytes. However, the molecular mediators governing this phenotype remain mostly unclear. Here, we explored how infiltration of immune cells across the BBB is influenced by the scaffold protein IQ motif containing GTPase activating protein 2 (IQGAP2). In mice and zebrafish, we demonstrate that loss of Iqgap2 increases infiltration of peripheral leukocytes into the CNS under homeostatic and inflammatory conditions. Using single-cell RNA sequencing and immunohistology, we further show that BECs from mice lacking Iqgap2 exhibit a profound inflammatory signature, including extensive upregulation of adhesion receptors and antigen-processing machinery. Human tissue analyses also reveal that Alzheimer's disease is associated with reduced hippocampal IQGAP2. Overall, our results implicate IQGAP2 as an essential regulator of BBB immune privilege and immune cell entry into the CNS.
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Oats (Avena sativa L.) are used as therapeutic plants, particularly in dermatology. Despite numerous studies on their skin moisturization, anti-inflammation, and antioxidation effects, the precise molecular mechanisms of these effects are only partially understood. In this study, the efficacy of oat sprouts in the treatment of allergic contact dermatitis (ACD) was investigated, and their specific phytoconstituents and exact mechanisms of action were identified. In the in vivo ACD model, by stimulating the mitogen-activated protein kinase signaling pathway, oat sprouts increased the expression levels of proteins associated with skin barrier formation, which are produced during the differentiation of keratinocytes. In addition, in a lipopolysaccharide-induced skin irritation model using HaCaT, steroidal saponins (avenacoside B and 26-deglucoavenacoside B) and a flavonoid (isovitexin-2-o-arabinoside) of oat sprouts regulated the genetic expression of the same proteins located on the adjacent locus of human chromosomes known as the epidermal differentiation complex (EDC). Furthermore, oat sprouts showed immunomodulatory functions. These findings suggest the potential for expanding the use of oat sprouts as a treatment option for various diseases characterized by skin barrier disruption.
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Avena , Extratos Vegetais , Humanos , Avena/genética , Extratos Vegetais/farmacologia , Inflamação , Pele , Anti-Inflamatórios , Grão ComestívelRESUMO
Glucose, a primary fuel source under homeostatic conditions, is transported into cells by membrane transporters such as glucose transporter 1 (GLUT1). Due to its essential role in maintaining energy homeostasis, dysregulation of GLUT1 expression and function can adversely affect many physiological processes in the body. This has implications in a wide range of disorders such as Alzheimer's disease (AD) and several types of cancers. However, the regulatory pathways that govern GLUT1 expression, which may be altered in these diseases, are poorly characterized. To gain insight into GLUT1 regulation, we performed an arrayed CRISPR knockout screen using Caco-2 cells as a model cell line. Using an automated high content immunostaining approach to quantify GLUT1 expression, we identified more than 300 genes whose removal led to GLUT1 downregulation. Many of these genes were enriched along signaling pathways associated with G-protein coupled receptors, particularly the rhodopsin-like family. Secondary hit validation confirmed that removal of select genes, or modulation of the activity of a corresponding protein, yielded changes in GLUT1 expression. Overall, this work provides a resource and framework for understanding GLUT1 regulation in health and disease.
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Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Glucose , Humanos , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Células CACO-2 , Glucose/metabolismo , Transporte BiológicoRESUMO
Osteomyelitis caused by staphylococcal infection is a serious complication of orthopedic surgery. Staphylococcus pseudintermedius is the main causative agent of osteomyelitis in veterinary medicine. Methicillin-resistant S. pseudintermedius (MRSP) has been reported in companion animals, especially dogs. Multidrug-resistant S. pseudintermedius is an emerging pathogen and has acquired antibiotic resistance against various commercial antimicrobial agents. New antimicrobial compounds are urgently needed to address antibiotic resistance, and the development of novel agents has become an international research hotspot in recent decades. Antimicrobial compounds derived from probiotics, such as bacteriocins, are promising alternatives to classical antibiotics. In this study, the antibacterial activities of Ligilactobacillus animalis SWLA-1 and its concentrated cell-free supernatant (CCFS) were evaluated in vitro and in vivo. The CCFS of this bacterium showed no toxicity against osteoblast and myoblast cells in vitro, while significantly inhibiting the multidrug-resistant S. pseudintermedius KUVM1701GC strain in a newly established rat model. The CCFS significantly inhibited multidrug-resistant staphylococci both in vitro and in vivo. This suggests that CCFS derived from L. animalis SWLA-1 has potential as an alternative to classic antibiotics for staphylococcal infections in dogs.
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The ATP-binding cassette subfamily B member 1 (ABCB1), encoding a multidrug transporter referred to as P-glycoprotein (Pgp), plays a critical role in the efflux of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. Therefore, developing high-throughput animal models to screen for Pgp function and bioavailability of substrates and inhibitors is paramount. Here, we generated and validated a zebrafish knockout line of abcb4, a human Pgp transporter homolog. CRISPR/Cas9 genome editing technology was deployed to generate a frameshift mutation in exon 4 of zebrafish abcb4. The zebrafish abcb4 homozygous mutant exhibited elevated accumulation of fluorescent rhodamine 123, a substrate of human Pgp, in the intestine and brain area of embryos. Moreover, abcb4 knockout embryos were sensitized toward toxic compounds such as doxorubicin and vinblastine compared to the WT zebrafish. Immunostaining for zebrafish Abcb4 colocalized in the endothelial brain cells of adult zebrafish. Transcriptome profiling using Gene Set Enrichment Analysis uncovered that the 'cell cycle process,' 'mitotic cell cycles,' and 'microtubule-based process' were significantly downregulated in the abcb4 knockout brain with age. This study establishes and validates the abcb4 knockout zebrafish as an animal model to study Pgp function in vivo. Unexpectedly it reveals a potentially novel role for zebrafish abcb4 in age-related changes in the brain. The zebrafish lines generated here will provide a platform to aid in the discovery of modulators of Pgp function as well as the characterization of human mutants thereof.
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Doxorrubicina , Peixe-Zebra , Adulto , Animais , Humanos , Peixe-Zebra/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Éxons , Células EndoteliaisRESUMO
Excessive brain iron accumulation is observed early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport. Here we use iPSC-derived astrocytes and endothelial cells to investigate how early-disease levels of amyloid-ß disrupt iron transport signals secreted by astrocytes to stimulate iron transport from endothelial cells. We demonstrate that conditioned media from astrocytes treated with amyloid-ß stimulates iron transport from endothelial cells and induces changes in iron transport pathway proteins. The mechanism underlying this response begins with increased iron uptake and mitochondrial activity by the astrocytes, which in turn increases levels of apo-transferrin in the amyloid-ß conditioned astrocyte media leading to increased iron transport from endothelial cells. These novel findings offer a potential explanation for the initiation of excessive iron accumulation in early stages of Alzheimer's disease. What's more, these data provide the first example of how the mechanism of iron transport regulation by apo- and holo-transferrin becomes misappropriated in disease that can lead to iron accumulation. The clinical benefit from understanding early dysregulation in brain iron transport in AD cannot be understated. If therapeutics can target this early process, they could possibly prevent the detrimental cascade that occurs with excessive iron accumulation.
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The ATP-binding cassette subfamily B member 1 (ABCB1), encoding a multidrug transporter referred to as P-glycoprotein (Pgp), plays a critical role in the efflux of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. Therefore, developing high throughput animal models to screen for Pgp function and bioavailability of substrates and inhibitors is paramount. Here, we generated and validated a zebrafish knockout line of abcb4 , a human Pgp transporter homolog. CRISPR/Cas9 genome editing technology was deployed to generate a frameshift mutation in exon 4 of zebrafish abcb4 . The zebrafish abcb4 homozygous mutant exhibited elevated accumulation of fluorescent rhodamine 123, a substrate of human Pgp, in the intestine and brain area of embryos. Moreover, abcb4 knockout embryos were sensitized toward toxic compounds such as doxorubicin and vinblastine compared to the WT zebrafish. Immuno-staining for zebrafish Abcb4 colocalized in the endothelial brain cells of adult zebrafish. Transcriptome profiling using Gene Set Enrichment Analysis (GSEA) uncovered that the 'cell cycle process,' 'mitotic cell cycles,' and 'microtubule-based process' were significantly downregulated in the abcb4 knockout brain with age. This study establishes and validates the a bcb4 knockout zebrafish as an animal model to study Pgp function in vivo. Unexpectedly it reveals a potentially novel role for zebrafish abcb4 in age-related changes in the brain. The zebrafish lines generated here will provide a platform to aid in the discovery of modulators of Pgp function as well as the characterization of human mutants thereof.
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Excessive brain iron accumulation is observed in early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport. Here we use iPSC-derived astrocytes and endothelial cells to investigate how early-disease levels of amyloid-ß disrupt iron transport signals secreted by astrocytes to stimulate iron transport from endothelial cells. We demonstrate that conditioned media from astrocytes treated with amyloid-ß stimulates iron transport from endothelial cells and induces changes in iron transport pathway protein levels. The mechanism underlying this response begins with increased iron uptake and mitochondrial activity by the astrocytes which in turn increases levels of apo-transferrin in the amyloid-ß conditioned astrocyte media leading to increased iron transport from endothelial cells. These novel findings offer a potential explanation for the initiation of excessive iron accumulation in early stages of Alzheimer's disease. What's more, these data provide the first example of how the mechanism of iron transport regulation by apo- and holo-transferrin becomes misappropriated in disease to detrimental ends. The clinical benefit from understanding early dysregulation in brain iron transport in AD cannot be understated. If therapeutics can target this early process, they could possibly prevent the detrimental cascade that occurs with excessive iron accumulation. Significance Statement: Excessive brain iron accumulation is hallmark pathology of Alzheimer's disease that occurs early in the disease staging and before widespread proteinopathy deposition. This overabundance of brain iron has been implicated to contribute to disease progression, thus understandingthe mechanism of early iron accumulation has significant therapeutic potential to slow to halt disease progression. Here, we show that in response to low levels of amyloid-ß exposure, astrocytes increase their mitochondrial activity and iron uptake, resulting in iron deficient conditions. Elevated levels of apo (iron free)-transferrin stimulate iron release from endothelial cells. These data are the first to propose a mechanism for the initiation of iron accumulation and the misappropriation of iron transport signaling leading to dysfunctional brain iron homeostasis and resultant disease pathology.
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Fluorescent RNA-based biosensors are useful tools for real-time detection of molecules in living cells. These biosensors typically consist of a chromophore-binding aptamer and a target-binding aptamer, whereby the chromophore-binding aptamer is destabilized until a target is captured, which causes a conformational change to permit chromophore binding and an increase in fluorescence. The target-binding region is typically fabricated using known riboswitch motifs, which are already known to have target specificity and undergo structural changes upon binding. However, known riboswitches only exist for a limited number of molecules, significantly constraining biosensor design. To overcome this challenge, we designed a framework for producing mammalian cell-compatible biosensors using aptamers selected from a large random library by Capture-SELEX. As a proof-of-concept, we generated and characterized a fluorescent RNA biosensor against L-dopa, the precursor of several neurotransmitters. Overall, we suggest that this approach will have utility for generating RNA biosensors that can reliably detect custom targets in mammalian cells.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Animais , RNA/química , Aptâmeros de Nucleotídeos/química , Técnica de Seleção de Aptâmeros , Biblioteca Gênica , Corantes , Mamíferos/genética , Mamíferos/metabolismoRESUMO
Tendons are responsible for transmitting mechanical forces from muscles to bones for body locomotion and joint stability. However, tendons are frequently damaged with high mechanical forces. Various methods have been utilized for repairing damaged tendons, including sutures, soft tissue anchors, and biological grafts. However, tendons experience a higher rate of retear post-surgery due to their low cellularity and vascularity. Surgically sutured tendons are vulnerable to reinjury due to their inferior functionality when compared with native tendons. Surgical treatment using biological grafts also has complications such as joint stiffness, re-rupture, and donor-site morbidity. Therefore, current research is focused on developing novel materials that can facilitate the regeneration of tendons with histological and mechanical characteristics similar to those of intact tendons. With respect to the complications in association with the surgical treatment of tendon injuries, electrospinning may be an alternative for tendon tissue engineering. Electrospinning is an effective method for fabrication of polymeric fibers with diameters ranging from nanometers to micrometers. Thus, this method produces nanofibrous membranes with an extremely high surface area-to-volume ratio, which is similar to the extracellular matrix structure, making them suitable candidates for application in tissue engineering. Moreover, it is possible to fabricate nanofibers with specific orientations that are similar to those of the native tendon tissue using an adequate collector. To increase the hydrophilicity of the electrospun nanofibers, natural polymers in addition to synthetic polymers are used concurrently. Therefore, in this study, aligned nanofibers composed of poly-d,l-lactide-co-glycolide (PLGA) and small intestine submucosa (SIS) were fabricated using electrospinning with rotating mandrel. The diameter of aligned PLGA/SIS nanofibers was 568.44 ± 135.594 nm, which closely resembles that of native collagen fibrils. Compared to the results of the control group, the mechanical strength exhibited by the aligned nanofibers was anisotropic in terms of break strain, ultimate tensile strength, and elastic modulus. Elongated cellular behavior was observed in the aligned PLGA/SIS nanofibers using confocal laser scanning microscopy, indicating that the aligned nanofibers were highly effective with regard to tendon tissue engineering. In conclusion, considering its mechanical properties and cellular behavior, aligned PLGA/SIS is a promising candidate for tendon tissue engineering.
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An 11-year-old castrated male Shih Tzu was referred for lethargy and melena. The hematocrit level was 18.8% (normal range: 36-56%), indicating severe anemia. Abdominal ultrasound revealed a round-to-oval-shaped mass in the stomach. Computed tomography (CT) revealed an intraluminal mass (17 × 12 × 15 mm) cranial to the pyloric antrum. After obtaining informed consent from the owner, exploratory laparotomy and subsequent gastrostomy were performed, showing an ulcerated mass potentially responsible for the severe anemia. A lump of hair was firmly attached to the ulcerated surface of the mass. After complete removal of the mass, the anemia resolved spontaneously. Histological examination revealed that the mass was a gastric hyperplastic polyp. At the 6-month follow-up, the dog was healthy with a normal hematocrit level. Gastric hyperplastic polyps are tumor-like lesions arising from the mucosal surface of the stomach, and projecting into the lumen. They can appear in any part of the stomach, and are usually found incidentally during gastric endoscopy or necropsy. The clinical signs include chronic occult blood loss, abdominal pain, and gastric tract obstruction. Gastric polyps causing acute blood loss anemia have rarely been reported in human medicine. To our knowledge, this is the first report describing a gastric hyperplastic polyp that caused severe anemia because of acute blood loss in a dog.
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A 7-year-old spayed female domestic shorthair cat presented with a swollen right forelimb and mild lameness. On physical examination, the mass was palpable in the right humeral region, and the cat exhibited pain on palpation. Radiography revealed an expansile osteolytic lesion at the proximal end of the right humerus. Computed tomography (CT) revealed an expansile bony mass on the proximal end of the right humerus and a mild periosteal reaction around the acromion of the scapula. Amputation of the right forelimb, including the scapula and removal of the axillary lymph node, were strongly recommended to the owner, but were declined. Four months after the initial presentation, the cat presented with a dramatically swollen right forelimb and progressive lameness. CT was performed again. In addition to osteolytic changes in the mass, vascular development had occurred at the cranioproximal region. The right forelimb, including the scapula and ipsilateral lymph nodes, was removed. The cat died during the postoperative recovery period. Based on clinical, diagnostic imaging, and histological findings, the final diagnosis was aneurysmal bone cyst. To the best of our knowledge, this is the first case of an aneurysmal bone cyst in the humerus of a cat.
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Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation of astrocytes to reactive states can be protective or harmful to BBB function. Here, using a human induced pluripotent stem cell (iPSC)-derived BBB co-culture model, we show that tumor necrosis factor (TNF) transitions astrocytes to an inflammatory reactive state that causes BBB dysfunction through activation of STAT3 and increased expression of SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, we correlated astrocytic STAT3 activation to vascular inflammation in postmortem human tissue. Further, in murine brain organotypic cultures, astrocyte-specific silencing of Serpina3n reduced vascular inflammation after TNF challenge. Last, treatment with recombinant Serpina3n in both ex vivo explant cultures and in vivo was sufficient to induce BBB dysfunction-related molecular changes. Overall, our results define the TNF-STAT3-α1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction.
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Barreira Hematoencefálica , Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Camundongos , Barreira Hematoencefálica/metabolismo , Astrócitos/metabolismo , alfa 1-Antiquimotripsina/metabolismo , Células Cultivadas , Células-Tronco Pluripotentes Induzidas/metabolismo , Inflamação/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
Here we show that intradermal injection of keratin promotes hair growth in mice, which results from extracellular interaction of keratin with hair forming cells. Extracellular application of keratin induces condensation of dermal papilla cells and the generation of a P-cadherin-expressing cell population (hair germ) from outer root sheath cells via keratin-mediated microenvironmental changes. Exogenous keratin-mediated hair growth is reflected by the finding that keratin exposure from transforming growth factor beta 2 (TGFß2)-induced apoptotic outer root sheath cells appears to be critical for dermal papilla cell condensation and P-cadherin-expressing hair germ formation. Immunodepletion or downregulation of keratin released from or expressed in TGFß2-induced apoptotic outer root sheath cells negatively influences dermal papilla cell condensation and hair germ formation. Our pilot study provides an evidence on initiating hair regeneration and insight into the biological function of keratin exposed from apoptotic epithelial cells in tissue regeneration and development.