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TOPIC: To provide an overview on the incidence of Acanthamoeba Keratitis (AK). CLINICAL RELEVANCE: Although being a major and sight-threatening cause of infectious keratitis in the population, a comprehensive assessment of the incidence of this condition is lacking. METHODS: Incidence of AK was computed as the number of AK eyes, per healthcare center, per year (annualized-center-incidence, or ACI). Two meta-analytical ratios were also calculated: a) the ratio of AK eyes to the count of non-viral microbial keratitis (MK) eyes; b) the ratio of AK eyes to the overall population (i.e., the total number of subjects of a nation or region, as indicated by the authors in each study). Center was defined as the healthcare facility (e.g., Hospital, Private Practice, Clinic) where the study took place. Actual and projected estimates of the number of AK eyes in years were calculated multiplying the ratio of AK to the total population and the corresponding present and projected population estimates (age range: 15 to 70), sourced from the United Nations (UN) Population Prospects. RESULTS: Overall, 105 articles were included, published between 1987 and 2022. The total number of eyes identified was 91,951, with 5,660 affected by AK and 86,291 by non-viral MK. The median ACI was 1.9 new AK eyes per healthcare center per year (95%CI of the median: 1.5 to 2.6), with no statistically significant differences observed among continents. The ratio of AK eyes to the total number of MK eyes was 1.52% (95%CI: 1.02% to 2.24%), while the ratio of AK in relation to the entire population was estimated at 0.0002% (95%CI: 0.0001 to 0.0006), or 2.34 eyes per 1,000,000 subjects (95%CI: 0.98 to 5.55 per 1.000.000 subjects). The projected increase in the numbers of AK eyes indicates a rise of +18.5% (15,356 AK eyes) in 2053 and +25.5% (16,253 AK eyes) in 2073, compared to the baseline of 2023 (12,954 AK eyes) CONCLUSION: AK emerged as a relatively low-incident disorder, and no significant differences in terms of its incidence were found among different continents.
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The transcription factor p63, belonging to the p53 family, is considered the master regulator of epidermal differentiation, skin, and in general of the differentiation of ectodermal tissues. Mutations in TP63 gene cause several rare ectodermal dysplasia disorders that refers to epidermal structural abnormalities and ocular surface disease, such as Ectrodactyly Ectodermal Dysplasia Clefting (EEC) syndrome. In this review, we discuss the key roles of p63 in keratinocytes and corneal epithelial differentiation, highlighting the function of the ΔNp63α isoform in driving limbal stem cell and epithelial stem cells commitment. We have summarized the specific ocular phenotypes observed in the TP63-mutation derived EEC syndrome, discussing the current and novel therapeutic strategies for the management of the ocular manifestations in EEC syndrome.
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Fenda Labial , Fissura Palatina , Displasia Ectodérmica , Fenda Labial/tratamento farmacológico , Fissura Palatina/tratamento farmacológico , Displasia Ectodérmica/tratamento farmacológico , Displasia Ectodérmica/genética , Humanos , Fatores de Transcrição/química , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: The present study aims to determine hydrogen sulfide (H2S) concentrations of the aqueous humor from patients with diabetic retinopathy (DR) to compare its levels in the anterior segments, also to investigate its effect on the retinal microvascular endothelial cells under high glucose condition. METHODS: AH samples were collected from patients with proliferative diabetic retinopathy (n = 11), non-proliferative diabetic retinopathy (n = 12) and diabetic patients without DR as controls (n = 12). There were 5 patients with PDR received intraocular anti-VEGF injection (Lucentis). Cultured RF/6A cells were grouped into control group, mannitol group, high glucose group and NaHS co-administrated high glucose group. Concentrations of H2S were detected by chemical assay. Cell apoptosis was evaluated by flow cytometry. RESULTS: A significantly higher H2S level was observed in AH samples of PDR patients among other groups. The H2S level of DR group was higher than that of control group. Decreased H2S levels in the AH of post-injected PDR patients were observed compared with their AH samples before the anti-VEGF injection. In cell culture, low concentration of NaHS can reverse high-glucose-induced apoptosis of RF/6A cells. CONCLUSION: Our study revealed increased H2S levels in the anterior segments of different DR patients. The anti-VEGF injection reduced the H2S level in AH from PDR patients. The study suggested that H2S may serve as a biomarker in the progression of PDR. On the other hand, the H2S donor exerted a protective effect on retinal vascular endothelial cells against high-glucose-induced apoptosis.
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Segmento Anterior do Olho/metabolismo , Retinopatia Diabética/metabolismo , Sulfeto de Hidrogênio/metabolismo , Humor Aquoso/metabolismo , Biomarcadores/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Optoelectronic devices, such as light-emitting diodes, have been demonstrated as one of the most demanded forthcoming display and lighting technologies because of their low cost, low power consumption, high brightness, and high contrast. The improvement of device performance relies on advances in precisely designing novelty functional materials, including light-emitting materials, hosts, hole/electron transport materials, and yet which is a time-consuming, laborious and resource-intensive task. Recently, machine learning (ML) has shown great prospects to accelerate material discovery and property enhancement. This review will summarize the workflow of ML in optoelectronic materials discovery, including data collection, feature engineering, model selection, model evaluation and model application. We highlight multiple recent applications of machine-learned potentials in various optoelectronic functional materials, ranging from semiconductor quantum dots (QDs) or perovskite QDs, organic molecules to carbon-based nanomaterials. We furthermore discuss the current challenges to fully realize the potential of ML-assisted materials design for optoelectronics applications. It is anticipated that this review will provide critical insights to inspire new exciting discoveries on ML-guided of high-performance optoelectronic devices with a combined effort from different disciplines.
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The significant features of carbon dots (CDs), such as bright and tunable photoluminescence, high thermal stability, and low toxicity, endow them with tremendous potential for application in next generation optoelectronics. Despite great progress achieved in the design of high-performance CDs so far, the practical applications in solid-state lighting and displays have been retarded by the aggregation-caused quenching (ACQ) effect ascribed to direct π-π interactions. This review provides a comprehensive overview of the recent progress made in solid-state CD emitters, including their synthesis, optical properties and applications in light-emitting diodes (LEDs). Their triplet-excited-state-involved properties, as well as their recent advances in phosphor-converted LEDs and electroluminescent LEDs, are mainly reviewed here. Finally, the prospects and challenges of solid-state CD-based LEDs are discussed with an eye on future development. We hope that this review will provide critical insights to inspire new exciting discoveries on solid-state CDs from both fundamental and practical standpoints so that the realization of their potential in optoelectronic areas can be facilitated.
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Glucocorticoid (GC) is essential for maintaining immune homeostasis. While GC is known to regulate the expression of genes related to inflammation in immune cells, the effects of GC, especially in the presence of inflammation, on non-immune cells remain largely unexplored. In particular, the impact of GC on inflammatory cytokine-induced immune modulatory responses of tissue stromal cells is unknown, though it has been widely used to modulate tissue injuries. Here we found that GC could enhance the expression of TSG6, a vital tissue repair effector molecule, in IFNγ and TNFα treated human umbilical cord (UC)-MSCs. NF-κB activation was found to be required for GC-augmented TSG6 upregulation. STAT3, but not STAT1, was also found to be required for the TSG6 upregulation in MSCs exposed to IFNγ, TNFα and GC. Moreover, the phosphorylation (activation) of STAT3 was attenuated when NF-κB was knocked down. Importantly, human UC-MSCs pretreated with a cocktail containing GC, IFNγ, and TNFα could significantly enhance the therapeutic effect of human UC-MSCs in an acute lung injury mouse model, as reflected by reduced infiltration of immune cells and down-regulation of iNOS in macrophages in the lung. Together, the findings reveal a novel link between GR, NF-κB and STAT3 in regulating the immunomodulatory and regenerative properties of MSCs, providing novel information for the understanding and treatment of inflammatory conditions.
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Células-Tronco Mesenquimais , NF-kappa B , Camundongos , Animais , Humanos , NF-kappa B/metabolismo , Citocinas/metabolismo , Glucocorticoides/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
Carbon dots (CDs), as emerging carbon nanomaterials, have been regarded as promising alternatives for electroluminescent light-emitting diodes (LEDs) owing to their distinct characteristics, such as low toxicity, tuneable photoluminescence, and good photostability. In the last few years, despite remarkable progress achieved in CD-based LEDs, their device performance is still inferior to that of well-developed organic, heavy-metal-based QDs, and perovskite LEDs. To better exploit LED applications and boost device performance, in this review, a comprehensive overview of currently explored CDs is presented, focusing on their key optical characteristics, which are closely related to the structural design of CDs from their carbon core to surface modifications, and to macroscopic structural engineering, including the embedding of CDs in the matrix or spatial arrangement of CDs. The design of CD-based LEDs for display and lighting applications based on the fluorescence, phosphorescence, and delayed fluorescence emission of CDs is also highlighted. Finally, it is concluded with a discussion regarding the key challenges and plausible prospects in this field. It is hoped that this review inspires more extensive research on CDs from a new perspective and promotes practical applications of CD-based LEDs in multiple directions of current and future research.
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Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.
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Mesenchymal stem/stromal cells (MSCs) possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders. This capacity is not innate but is activated or 'licensed' by inflammatory cytokines. The licensing mechanism remains unclear. Here, we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity. In response to stimulation by inflammatory cytokines, MSCs exhibited a dramatic increase in the consumption of glucose, which was accompanied by an enhanced use of nicotinamide adenine dinucleotide (NAD+) and increased expression of nicotinamide phosphoribosyltransferase (NAMPT), a central enzyme in the salvage pathway for NAD+ production. When NAD+ synthesis was blocked by inhibiting or depleting NAMPT, the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated. Consequently, when NAD+ metabolism in MSCs was perturbed, their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury. Further analysis revealed that NAMPT-driven production of NAD+ was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs. Furthermore, the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle, which led to hypoxia-inducible factor 1α (HIF-1α) stabilization and subsequently increased the transcription of key glycolytic genes, thereby persistently maintaining glycolytic flux. This study demonstrated that unlike its proinflammatory role in immune cells, NAD+ metabolism governs the anti-inflammatory function of MSCs during inflammation.
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Células-Tronco Mesenquimais , NAD , Camundongos , Animais , NAD/metabolismo , Glicólise , Ciclo do Ácido Cítrico , Citocinas/metabolismo , Células-Tronco Mesenquimais/metabolismoRESUMO
Triple-negative breast cancer (TNBC) is the most aggressive subtype of mammary carcinoma. Here, we describe a case of an 81-year-old female diagnosed with ductal triple negative breast cancer with a germline pathogenic variant in BReast CAncer gene2 (BRCA2). Genetic testing also revealed the presence of four somatic mutations in the ephrin type-A receptor 3 (EphA3), TP53, BRCA1-associated protein (BAP1), and MYB genes. The BRCA2, TP53, and BAP1 gene mutations are highly predictive of a defective homologous recombination repair system and subsequent chromosomal instability in this patient. Coherently, the patient displayed a strong homologous recombination deficiency signature and high tumor mutational burden status, which are generally associated with increased probability of immune neoantigens formation and presentation, and with tumor immunogenicity. Analysis of immune checkpoint revealed high expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), programmed death 1 (PD1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), suggesting that the patient might likely benefit from immunotherapies. Altogether, these findings support an unveiled link between BRCA2 inactivation, HR deficiency and increased expression of immune checkpoints in TNBC. This clinical case highlights the importance of screening TNBC patients for genetic mutations and TMB biomarkers in order to predict the potential efficacy of immunotherapy.
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Mesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.
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Células-Tronco Mesenquimais , Diferenciação Celular/genética , Citocinas/metabolismo , HumanosRESUMO
BACKGROUND: Mesenchymal stem/stromal cells (MSCs) acquire immunosuppressive capacity only in an inflammatory microenvironment. This can be recapitulated in vitro by treating MSCs with inflammatory cytokines TNFα and IFNγ, which induce indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene-6 (TSG-6). However, the signaling pathways downstream of the cytokines remain to be elucidated. METHODS: Inflammatory bowel disease (IBD) mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. Human UC-MSCs were pretreated with TNF-α and IFN-γ for 24 h and were then infused intravenously at day 2 of DSS administration. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay. Real-time PCR and Western blot were used to examine the mRNA level and protein expression. MSCs overexpressing constitutive active AKT or dominant negative AKT were generated and were analyzed. The glycolysis level of the MSCs was measured using Extracellular Flux Analyzer. 2-NBDG was used to monitor the uptake of glucose by MSCs. RESULTS: TNFα and IFNγ treatment led to rapid consumption of glucose and metabolic skewing toward glycolysis in MSCs, which was required for the therapeutic efficacy of MSCs on IBD. Blockade of glycolysis in MSCs inhibited the expression of immunomodulatory molecules, IDO and TSG-6, as well as the therapeutic effect on IBD. Moreover, PI3K-AKT signaling axis was rapidly activated and was required for the skewing toward glycolysis induced by TNFα and IFNγ. MSCs expressing dominant negative AKT were compromised in their therapeutic efficacy on IBD. CONCLUSION: The glycolysis-dependent anti-inflammatory property of MSCs conferred by inflammatory cytokines is mediated by PI3K-AKT signaling pathway.
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Colite , Doenças Inflamatórias Intestinais , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Anti-Inflamatórios/metabolismo , Colite/induzido quimicamente , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Água Potável , Glucose/metabolismo , Glicólise , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Interferon gama/metabolismo , Interferon gama/farmacologia , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Skeletal muscle has an extraordinary regenerative capacity reflecting the rapid activation and effective differentiation of muscle stem cells (MuSCs). In the course of muscle regeneration, MuSCs are reprogrammed by immune cells. In turn, MuSCs confer immune cells anti-inflammatory properties to resolve inflammation and facilitate tissue repair. Indeed, MuSCs can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory ability, including effects primed by interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). At the molecular level, the tryptophan metabolites, kynurenine or kynurenic acid, produced by indoleamine 2,3-dioxygenase (IDO), augment the expression of TNF-stimulated gene 6 (TSG6) through the activation of the aryl hydrocarbon receptor (AHR). In addition, insulin growth factor 2 (IGF2) produced by MuSCs can endow maturing macrophages oxidative phosphorylation (OXPHOS)-dependent anti-inflammatory functions. Herein, we summarize the current understanding of the immunomodulatory characteristics of MuSCs and the issues related to their potential applications in pathological conditions, including COVID-19.
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COVID-19/terapia , Sistema Imunitário/fisiologia , Músculos/fisiologia , Regeneração/fisiologia , Células-Tronco/citologia , Animais , COVID-19/imunologia , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Proliferação de Células , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação , Fator de Crescimento Insulin-Like II/metabolismo , Interferon gama/metabolismo , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Macrófagos/metabolismo , Camundongos , Músculos/metabolismo , Fosforilação Oxidativa , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Glucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.
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Glucocorticoides/efeitos adversos , Osteoporose/induzido quimicamente , Osteoporose/imunologia , Linfócitos T/imunologia , Animais , Apoptose/imunologia , Quimiocinas/imunologia , Dexametasona/efeitos adversos , Dexametasona/farmacologia , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Osteoporose/metabolismo , Osteoporose/patologia , Ligante RANK/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
The dome-shaped cornea is a transparent, non-vascularized, and epithelialized highly organized tissue. Physical and chemical injuries may trigger corneal wound healing (CWH) response and result in neovascularization that impairs the visual function. CWH involves not only migration, proliferation, and differentiation of the cells in different layers of cornea, but also the mobilization of immune cells. We demonstrated here that human adipose-derived mesenchymal stromal cells (ADSCs) could effectively inhibit neovascularization during ethanol-induced injury in mouse cornea. Importantly, we found that while neutrophils are essential for CWH, excessive and prolonged neutrophil retention during the granulation stage contributes to neovascularization. ADSCs were found to promote the clearance of neutrophils in the cornea during the granulation stage, likely via increasing the reverse transendothelial cell migration of CXCR4high neutrophils from cornea to the lung. Our results demonstrate that ADSCs are effective in treating CWH-induced neovascularization and modulation of neutrophil clearance could be novel strategies for better vision recovery after injury.
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Córnea/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cicatrização/fisiologia , Animais , Diferenciação Celular , China , Lesões da Córnea/metabolismo , Lesões da Córnea/terapia , Feminino , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Pele/citologia , Cicatrização/efeitos dos fármacosRESUMO
Hydrogen sulfide (H2S) serves as a gasotransmitter in the regulation of organ development and maintenance of homeostasis in tissues. Its abnormal levels are associated with multiple human diseases, such as neurodegenerative disease, myocardial injury, and ophthalmic diseases. Excessive exposure to H2S could lead to cellular toxicity, orchestrate pathological process, and increase the risk of various diseases. Interestingly, under physiological status, H2S plays a critical role in maintaining cellular physiology and limiting damages to tissues. In mammalian species, the generation of H2S is catalyzed by cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), 3-mercapto-methylthio pyruvate aminotransferase (3MST) and cysteine aminotransferase (CAT). These enzymes are found inside the mammalian eyeballs at different locations. Their aberrant expression and the accumulation of substrates and intermediates can change the level of H2S by orders of magnitude, causing abnormal structures or functions in the eyes. Detailed investigations have demonstrated that H2S donors' administration could regulate intraocular pressure, protect retinal cells, inhibit oxidative stress and alleviate inflammation by modulating the function of intra or extracellular proteins in ocular tissues. Thus, several slow-releasing H2S donors have been shown to be promising drugs for treating multiple diseases. In this review, we discuss the biological function of H2S metabolism and its application in ophthalmic diseases.