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The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin ß1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Membrana Basal , Melanócitos , Vitiligo , Vitiligo/patologia , Vitiligo/metabolismo , Melanócitos/patologia , Melanócitos/metabolismo , Membrana Basal/patologia , Membrana Basal/metabolismo , Humanos , Animais , Camundongos , Metaloproteinase 2 da Matriz/metabolismo , Fibroblastos/patologia , Fibroblastos/metabolismo , Masculino , Feminino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Acne vulgaris represents a chronic inflammatory condition, the pathogenesis of which is closely associated with the altered skin microbiome. Recent studies have implicated a profound role of Gram-negative bacteria in acne development, but there is a lack of antiacne agents targeting these bacteria. Polyphyllins are major components of Rhizoma Paridis with great anti-inflammatory potential. In this study, we aimed to evaluate the antiacne effects and the underlying mechanisms of PPH and a PPH-enriched Rhizoma Paridis extract (RPE) in treating the Gram-negative bacteria-induced acne. PPH and RPE treatments significantly suppressed the mRNA and protein expressions of interleukin (IL)-1ß and IL-6 in lipopolysaccharide (LPS)-induced RAW 264.7 and HaCaT cells, along with the intracellular reactive oxygen species (ROS) generation. Furthermore, PPH and RPE inhibited the nuclear translocation of nuclear factor kappa-B (NF-κB) P65 in LPS-induced RAW 264.7 cells. Based on molecular docking, PPH could bind to kelch-like ECH-associated protein 1 (KEAP1) protein. PPH and RPE treatments could activate nuclear factor erythroid 2-related factor 2 (NRF2) and upregulate haem oxygenase-1 (HO-1). Moreover, RPE suppressed the mitogen-activated protein kinase (MAPK) pathway. Therefore, PPH-enriched RPE showed anti-inflammatory and antioxidative effects in vitro, which is promising for alternative antiacne therapeutic.
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Acne Vulgar , Saponinas , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/efeitos adversos , Saponinas/farmacologia , Saponinas/uso terapêutico , Simulação de Acoplamento Molecular , Anti-Inflamatórios/uso terapêutico , NF-kappa B/metabolismo , Bactérias Gram-Negativas/metabolismo , Acne Vulgar/tratamento farmacológico , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Inflamação/metabolismoRESUMO
We reported four patients with coronavirus disease 2019 (COVID-19)-associated myelopathies, highlighting the delayed and atypical spinal cord magnetic resonance imaging (MRI) features and the literature review. All four patients were males, aged 37 to 72 years old. The latencies from COVID-19 to the onset of myelitis were 5, 15, 30, and 80 days. The initial symptoms were numbness and weakness of lower limbs in three cases, and back pain with weakness of lower limbs in one case. The peak symptoms included paraplegia, sphincter dysfunction, sensory disturbance level, and spastic gait. The EDSS scores were 7.5, 9.0, 9.0, and 7.5, respectively. Magnetic resonance imaging (MRI) showed delayed atypical spinal cord lesions at onset, i.e., two cases without lesions, one with linear spinal meningeal enhancement, and one with punctate lesions on T2-weighted imaging (T2WI). During the follow-up period, punctate, linear, and cloudy lesions in the lateral and posterior funiculus were seen on T2WI in the peak stage. The prominent features of spinal cord lesions were linear spinal meningeal enhancement, the mismatch of deteriorated clinical symptoms, and inapparent MRI findings. All four patients were left with an obvious disability, with two patients completely bedridden and two who could stand with support. This report highlights the recognition of COVID-19-associated myelopathy even months after initial infection, especially in patients with delayed and atypical spinal cord findings on MRI.
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COVID-19 , Mielite , Doenças da Medula Espinal , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , COVID-19/complicações , COVID-19/patologia , Imageamento por Ressonância Magnética/métodos , Mielite/diagnóstico por imagem , Mielite/etiologia , Mielite/patologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Doenças da Medula Espinal/complicações , Doenças da Medula Espinal/diagnóstico por imagemRESUMO
AIMS: To investigate the independent and combined effects of physical activity (PA) and depressive symptoms on the risk of frailty in community-dwelling older adults. BACKGROUND: Older adults face a high risk of frailty which is commonly used to predict adverse health outcomes in older patients. Engaging in PA and without depressive symptoms are crucial factors to prevent frailty. It is essential to investigate the independent and combined effects of these two variables on the risk of frailty. METHODS: We included 3392 community-dwelling older adults. The FRAIL Scale was used to assess older adults' frail status (robust, prefrail and frail). Multiple logistic regression was utilized to examine the independent and combined effects of PA and depressive symptoms on the risk of prefrailty and frailty. The combined effects were visualized by marginal plots. RESULTS: The prevalence of prefrailty and frailty in older adults were 42.16% and 10.58%. Compared with the group of "Light physical activity and With depressive symptoms", "Vigorous physical activity and Without depressive symptoms" had the lowest risk of prefrailty and frailty. CONCLUSIONS: Older adults who do not engage in PA or have depressive symptoms increased the risk of frailty, but older adults with depressive symptoms could lower the risk of frailty through PA. RELEVANCE TO CLINICAL PRACTICE: It is effective to reduce the risk of frailty by directing older adults to do moderate physical activity, although they have depressive symptoms. The focus should also be on older adults with depressive symptoms, who have at least more than twice and fourfold risk of prefrailty and frailty compared to those without. IMPACT: This study offers insights for future interventions aimed at preventing frailty in older adults. REPORTING METHOD: This study adhered to the STROBE checklist. PATIENT OR PUBLIC CONTRIBUTIONS: Older adults participated in this study and completed questionnaires.
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BACKGROUND: The substantial rise in the population of older adults living with disabilities is a prominent concern, presenting a profound challenge for healthcare and social welfare systems. Community-based home care is seen as an effective approach to meet the care needs of older adults living with disabilities. OBJECTIVE: To construct a coping target checklist for home-based older adults living with disabilities and their spousal caregivers. METHODS: The initial draft was developed based on a comprehensive literature review, followed by two rounds of Delphi correspondence final version. RESULTS: A comprehensive literature review resulted in the development of 7 modules, 20 topics. After round 1, 3 items were removed, 3 sections, 1 topic and 1 objective were new additions, 16 items were modified, split or combined. Four sections, 3 sections (Individual coping target for spousal caregivers, Individual coping target for older adults living with disabilities, and Shared coping target), 7 modules, 18 topics and 49 objectives were finally identified in round 2. The content of the list tool is derived from three perspectives: self-management strategies for older adults living with disabilities, caregiving strategies for spousal caregivers, and combined. CONCLUSIONS: The coping target checklist was intended to be evidence-based and reflective of a practical direction for home-based older adults living with disabilities and their spousal caregivers living at home.
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Cuidadores , Pessoas com Deficiência , Humanos , Idoso , Lista de Checagem , Cônjuges , Capacidades de EnfrentamentoRESUMO
This qualitative study aimed to gain an understanding of what it means to live with ischemic heart disease for individuals who perceive health as beyond their control and how these individuals navigate their choices regarding adhering or not adhering to self-management behavior. Participants were recruited through purposive sampling, and semi-structured interviews were conducted. Content analysis was employed to identify themes and subthemes in the interview data. The theme, "attribution of ischemic heart disease," revealed that the participants attributed their condition to lifestyle, critical events, and the natural aging process. The theme, "experiences of self-management," highlighted the different behaviors among participants who perceived health to be beyond their control. The theme, "barriers and facilitators," identified factors such as a strong sense of responsibility toward family members, the work environment, and access to medical resources. Our study showed that despite perceiving their health to be beyond their control, some individuals may still adhere to self-management practices. Understanding factors such as "attribution" and "barriers and facilitators" can provide nurses with insights into the patients' decisions to adhere or not adhere to self-management behaviors.
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Isquemia Miocárdica , Autogestão , Humanos , Isquemia Miocárdica/complicações , Isquemia Miocárdica/terapia , Pesquisa QualitativaRESUMO
Streptomyces lividans is a potent host for the extracellular overproduction of heterologous proteins. To further improve the usability and productivity of S. lividans, a dual gene expression vector of "pTSKr duet" containing two strong constitutive promoters, scmpPc and kasOp*, was constructed. The success in the overproduction of two secretory enzymes simultaneously without interference with each other indicated that the "pTSKr duet" vector can realize the coexpression of two genes simultaneously and independently. Further, using the two-gene coexpression vector, we screened the effects of the overexpression of five factors that possibly promote secretion on the extracellular overproduction of heterologous secretory proteins. Interestingly, the coexpression of a quality control regulator (CssR) promoted the overproduction level to 1.3-fold for a stable heterologous protein of SMTG (transglutaminase from S. mobaraensis), while other four factors limited the overproduction of SMTG at different degrees.
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Streptomyces , Streptomyces/genética , Streptomyces lividans/genética , Vetores Genéticos , Proteínas de Bactérias/metabolismo , Transporte ProteicoRESUMO
Streptomyces lividans is an efficient host for extracellular overproduction of recombinant proteins. To enhance the overexpression strength of S. lividans, we designed several kinds of expression plasmids with different positioning of repeat promoters. The effect of repeat promoters was evaluated by measuring the accumulated amounts of a stable transglutaminase or an unstable carboxypeptidase that was secreted into the medium. Successive tandem positions of repeat promoters upstream of the normal promoter did not enhance the expression of transglutaminase. Discrete positions of repeat promoters both upstream and downstream of the normal promoter enhanced the expression of transglutaminase to 2-fold, and the downstream ones also enhanced the expression of carboxypeptidase to 1.7-fold. On the other hand, there were still some constructs of plasmids with discrete repeat promoters that did not promote the expression of the target enzymes, indicating the complexity of the mechanisms of repeat promoters working on gene expression.
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Streptomyces lividans , Streptomyces , Streptomyces lividans/genética , Streptomyces/genética , Regiões Promotoras Genéticas/genética , Plasmídeos/genética , Transglutaminases/genética , Carboxipeptidases/genética , Clonagem MolecularRESUMO
The aim of this study was to explore the chain mediation model of self-efficacy and health literacy between empowerment and quality of life among spousal caregivers of disabled elderly based on 'Marriage Binding'. From December 2020 to June 2022, the cross-sectional study was conducted in hospitals and communities, in Guangdong, Fujian, Sichuan, Hunan, Jiangxi, Guangxi and Yunnan provinces, China. Descriptive statistics were used to describe the demographic data and four main variables, including empowerment, self-efficacy, health literacy and quality of life. Spearman correlation analysis was used to analyze the correlation between the four main research variables. Multiple Linear Regression and bootstrap analysis were used to analyze the direct and indirect effects among them. Any two variables of spousal caregivers were correlated among empowerment, self-efficacy, health literacy and quality of life. Self-efficacy and health literacy can separately and sequentially mediate the relationship between empowerment and quality of life. To improve the quality of life of spousal caregivers of disabled elderly, the mediating role of self-efficacy, the mediating role of health literacy and the chain mediating role of self-efficacy and health literacy should take effect. In the future, some intervention studies should be taken to enhance the effects of those variables that may be beneficial for improving quality of life of spousal caregivers of disabled elderly.
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Letramento em Saúde , Humanos , Idoso , Qualidade de Vida , Cuidadores , Autoeficácia , Estudos Transversais , ChinaRESUMO
The stress of disability significantly impacts an individual's quality of life and that of a spouse. Health empowerment, based on the idea that individuals may be successful despite disability, may be meaningful to disabled persons and their spouse carers. This cross-sectional survey study aimed to explore the effect of health empowerment on the health-related quality of life (HRQOL) of older individuals with disabilities and their spouse carers on both a personal (actor effect) and interpersonal level (partner effect). A total of 1092 dyads of older individuals with disabilities and their spouse carers residing in communities were recruited from seven provinces in China. Two separate Actor-Partner Interdependence Model analyses were conducted to examine the impact of health empowerment on the two domains of HRQOL: the Physical Component Score (PCS) and the Mental Component Score (MCS). The results revealed that health empowerment had actor effects on the PCS and MCS of older individuals with disabilities, as well as on the PCS and MCS of their spouse carers. However, no significant partner effects of health empowerment on the PCS and MCS of either the individuals with disabilities or their spouse caregivers were observed. Empowering individuals with disabilities and their spouse carers may help them enhance their own HRQOL, both physically and mentally. However, more research is required to determine the interpersonal effect of health empowerment on the HRQOL.
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Pessoas com Deficiência , Qualidade de Vida , Humanos , Idoso , Estudos Transversais , Cuidadores , CônjugesRESUMO
We have previously reported a powerful promoter from the Streptomyces cinnamoneus TH-2 strain named "scmp" and created an expression vector of pTONA5a for expression using S. lividans. The full-length scmp promoter sequence consists of 424 bp upstream of a metalloendoprotease gene in the S. cinnamoneus TH-2 genome. The promoter works in the presence of inorganic phosphate and glucose. In this study, we present the essential region of the scmp promoter (promoter C), which lacks 358 bp of the 5' region of the full-length promoter. Promoter C was very short and contained only 63 bp. Using promoter C, we succeeded in the extracellular production of the Streptomyces enzymes of leucine aminopeptidase, ferulic acid esterase, and transglutaminase, which possessed signal peptides for secretion via the type II secretion pathway, at high levels.
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Sinais Direcionadores de Proteínas , Streptomyces lividans , Regiões Promotoras Genéticas/genética , Sinais Direcionadores de Proteínas/genética , Streptomyces lividans/genética , Streptomyces lividans/metabolismo , Transglutaminases/metabolismoRESUMO
Ranunculus sceleratus L.(RS) has shown various pharmacological effects in traditional Chinese medicine. In our previous study, the positive therapeutic effect on α-naphthylisothiocyanate induced intrahepatic cholestasis in rats was obtained using TianJiu treatment with fresh RS. However, the chemical profile of RS has not been clearly clarified, which impedes the research progress on the therapeutic effect of RS. Herein, an ultra-high performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) method was developed to rapidly separate and identify multiple constituents in the 80% methanol extract of RS. A total of sixty-nine compounds (19 flavonoids, 22 organic acids, 6 coumarins, 4 lignans, 14 nitrogenous compounds, and 4 anthraquinones) were successfully characterized. A total of 12 of these compounds were unambiguously identified by standard samples. Their mass spectrometric fragmentation pathways were investigated. It is worth noting that flavonoids and lignans were identified for the first time in RS. In this study, we successfully provide the first comprehensive report on identifying major chemical constituents in RS by UHPLC-Q-Orbitrap HRMS. The obtained results enrich the RS chemical profile, paving the way for further phytochemical study, quality control, and pharmacological investigation of RS.
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Lignanas , Ranunculus , Animais , Cromatografia Líquida de Alta Pressão/métodos , Flavonoides/química , Cromatografia Gasosa-Espectrometria de Massas , Espectrometria de Massas/métodos , RatosRESUMO
A 308 nm monochromatic excimer light (MEL) is widely used to treat patients with vitiligo. However, dose optimization still needs to be clarified. This study aimed to obtain objective evidence regarding various doses of MEL irradiation, induced cell level changes in vitro, and skin level alterations in vivo. Cultured human keratinocytes were irradiated with MEL using various doses. After irradiation at low doses, stem cell factor, endothelin-1, and glycoprotein nonmetastatic melanoma protein B, factors that activate and protect melanocytes, were found to be significantly elevated in keratinocytes. After irradiation using medium and high doses, inflammatory cytokines were induced. The amount of ATP released and the level of inflammasome activation, which are known to be related to interleukin-1ß activation, were also increased. The back skin of guinea pigs and mice were irradiated with MEL at varying doses. After irradiation, an increase of epidermal melanin and epidermal melanocytes was confirmed, using the minimal erythemal dose or less. In rhododendrol-induced leukoderma guinea pigs, a much lower dose of MEL irradiation was effective, when compared with the effective dose for control guinea pigs. Our results suggest that a lower irradiation dose of MEL might be sufficient and more suitable for repigmentation in vitiligo treatment.
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Queratinócitos/metabolismo , Melanócitos/metabolismo , Pigmentação da Pele/efeitos da radiação , Terapia Ultravioleta , Vitiligo , Animais , Linhagem Celular , Feminino , Cobaias , Humanos , Camundongos , Vitiligo/metabolismo , Vitiligo/radioterapiaRESUMO
Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that plays an important role in cancer metastasis and osteoblast differentiation. In the skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in melanosome formation. In our previous study, GPNMB was also found to be expressed in skin epidermal keratinocytes. In addition, decreased GPNMB expression was observed in the epidermis of lesional skin of patients with vitiligo. However, the exact role of keratinocyte-derived GPNMB and its effect on vitiligo is still unknown. In this study, we demonstrated that GPNMB expression was also decreased in rhododendrol-induced leukoderma, as seen in vitiligo. The extracellular soluble form of GPNMB (sGPNMB) was found to protect melanocytes from cytotoxicity and the impairment of melanogenesis induced by oxidative stress. Furthermore, the effect of rGPNMB was not altered by the knockdown of CD44, which is a well-known receptor of GPNMB, but accompanied by the suppressed phosphorylation of AKT but not ERK, p38, or JNK. In addition, we found that oxidative stress decreased both transcriptional GPNMB expression and sGPNMB protein expression in human keratinocytes. Our results suggest that GPNMB might provide novel insights into the mechanisms related to the pathogenesis of vitiligo and leukoderma.
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Queratinócitos/efeitos dos fármacos , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Glicoproteínas de Membrana/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Skin is a major target of oxidative stress. Increasing evidence suggests that oxidative stress is the cause of melanocyte disappearance in vitiligo, which is an acquired pigmentary skin disorder characterized by patches of skin that have lost pigmentation. New herbal extracts with antioxidant activity are therefore being studied. 6-Shogaol (6-SG), an active compound from ginger, is capable of attenuating oxidative stress-induced ageing and neurotoxicity. Subsequently, to investigate whether 6-SG could protect melanocytes from oxidative stress, cultured human primary epidermal melanocytes (HEMn-MPs) were treated with hydrogen peroxide (H2O2) in the presence or absence of 6-SG. The 6-SG exhibited protective effects against H2O2-induced cell death by reducing oxidative stress. In addition, the 6-SG treatment activated the Nrf2-antioxidant response element signaling pathway by upregulating the mRNA expression of the antioxidant enzyme heme oxygenase 1 (HO-1), and protein expression of Nrf2, NAD(P)H: quinine oxidoreductase 1 (Nqo1), and HO-1. Furthermore, the 6-SG also displayed protective effects on melanocytes against Rhododendrol-induced oxidative stress. We concluded that 6-SG protects melanocytes against oxidative stress in vitro, and its protective effect is associated with the activation of the Nrf2-antioxidant response element signaling pathway. 6-SG, therefore, has potential for use in the prevention of melanocyte loss in the early stages of vitiligo or other pigmentary disorders.
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Elementos de Resposta Antioxidante/genética , Catecóis/farmacologia , Citoproteção , Melanócitos/metabolismo , Melanócitos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais , Butanóis , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção/efeitos dos fármacos , Epiderme/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Recém-Nascido , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genéticaRESUMO
As the outermost barrier of the body, skin is a major target of oxidative stress. In the brain, estrogen has been reported synthesized locally and protects neurons from oxidative stress. Here, we explored whether estrogen is also locally synthesized in the skin to protect from oxidative stress and whether aberrant local estrogen synthesis is involved in skin disorders. Enzymes and estrogen receptor expression in skin cells were examined first by quantitative real-time PCR and Western blot analyses. Interestingly, the estrogen synthesis enzyme was mainly localized in epidermal keratinocytes and estrogen receptors were mainly expressed in melanocytes among 13 kinds of cultured human skin cells. The most abundant estrogen synthesis enzyme expressed in the epidermis was 17ß-hydroxysteroid dehydrogenase 1 (HSD17ß1) localized in keratinocytes, and the most dominant estrogen receptor expressed in the epidermis was G protein-coupled estrogen receptor 1 (GPER1) in melanocytes. To investigate whether keratinocyte-derived estradiol could protect melanocytes from oxidative stress, cultured human primary epidermal melanocytes (HEMn-MPs) were treated with H2O2 in the presence or absence of 17ß estradiol or co-cultured with HSD17ß1 siRNA-transfected keratinocytes. Keratinocyte-derived estradiol exhibited protective effects against H2O2-induced cell death. Further, reduced expression of HSD17ß1 in the epidermis of skin from vitiligo patients was observed compared to the skin from healthy donors or in the normal portions of the skin in vitiligo patients. Our results suggest a possible new target for interventions that may be used in combination with current therapies for patients with vitiligo.
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Suscetibilidade a Doenças , Epiderme/metabolismo , Estrogênios/metabolismo , Melanócitos/metabolismo , Estresse Oxidativo , Vitiligo/etiologia , Vitiligo/metabolismo , Contagem de Células , Morte Celular , Células Epidérmicas/metabolismo , Estradiol Desidrogenases/genética , Estradiol Desidrogenases/metabolismo , Expressão Gênica , Humanos , Queratinócitos/metabolismo , Melaninas/biossíntese , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismoAssuntos
Nevo , Esclerose Tuberosa , Humanos , Esclerose Tuberosa/complicações , Estudos Retrospectivos , PacientesRESUMO
Tuberculosis (TB) is one of the biggest infectious disease killers caused by Mycobacterium tuberculosis (MTB). Studying the protein-protein interactions (PPIs) between MTB and human can deepen our understanding of the pathogenesis of TB and offer new clues to the treatment against MTB infection, but the experimentally validated interactions are especially scarce in this regard. Herein we proposed an integrated framework that combined template-, domain-domain interaction-, and machine learning-based methods to predict MTB-human PPIs. As a result, we established a network composed of 13â¯758 PPIs including 451 MTB proteins and 3167 human proteins ( http://liulab.hzau.edu.cn/MTB/ ). Compared to known human targets of various pathogens, our predicted human targets show a similar tendency in terms of the network topological properties and enrichment in important functional genes. Additionally, these human targets largely have longer sequence lengths, more protein domains, more disordered residues, lower evolutionary rates, and older protein ages. Functional analysis demonstrates that these proteins show strong preferences toward the phosphorylation, kinase activity, and signaling transduction processes and the disease and immune related pathways. Dissecting the cross-talk among top-ranked pathways suggests that the cancer pathway may serve as a bridge in MTB infection. Triplet analysis illustrates that the paired targets interacting with the same partner are adjacent to each other in the intraspecies network and tend to share similar expression patterns. Finally, we identified 36 potential anti-MTB human targets by integrating known drug target information and molecular properties of proteins.
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Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Tuberculose Pulmonar/tratamento farmacológico , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Aprendizado de Máquina , Terapia de Alvo Molecular/métodos , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Fosforilação , Transdução de Sinais , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologiaRESUMO
BACKGROUND Regorafenib (RGF) is the drug of choice for treating hepatic carcinoma (HCC), but the drug has drawbacks due to resistance and associated adverse effects. Thus, it becomes crucial to understand the causal 'map' of the resistance conferred by RGF, so that its clinical potency can be amplified, resulting in enhanced efficacy with reduced adverse effects. Metformin (MTF) has been reported to target NLK (Nemo-like kinase) to inhibit non-small lung cancer cells. Based on the literature, the present investigation was carried out to reveal the effect of RGF and MTF, with an expectation that MTF can synergize therapeutic potential as well reduce chances of resistance. MATERIAL AND METHODS Protein expression of hypoxia inducible factors (HIF)-2α, 30 kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK were assessed by Western blot analysis. RGF and MTF were exposed to MHCC97H cell and proliferation was quantified by assay of cell viability. Gene silencing and chromatin immunoprecipitation assay were done to reveal the relationship between TIP30 and HIF-2α. The impact of RGF and MTF together on postoperative recurrence and lung metastasis of hepatocellular carcinoma was investigated using tumor engrafted mice after administration of MTF and RGF once daily for 35 days. Immunohistochemistry was used to reveal CD31, Ki67, and TUNEL. RESULTS The results suggested MTF-RGF combination lowered expression of HIF-2α gene silencing and suggested increased TIP30 after reduction of HIF-2α. The chromatin immunoprecipitation study indicated that under hypoxia, HIF-2α could bind with TIP30 promoter. Cell number quantification (CCK8), viable cell count, and apoptosis data (using Annexin V-FITC) indicated co-administration of RGF and MTF reduced cell proliferation, encouraging cell apoptosis, and reduced epithelial-mesenchymal transition course. Thus, in orthotopic mice, the RGF-MTF combination exhibited substantial reduction of HCC in lung metastasis and postoperative relapse. CONCLUSIONS MTF can enhance the potential of RGF and inhibit the recurrence and metastasis of HCC after postoperative liver section by regulating the levels of TIP30 and HIF-2α.
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Carcinoma Hepatocelular/tratamento farmacológico , Metformina/farmacologia , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Acetiltransferases/efeitos dos fármacos , Acetiltransferases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/genética , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepatectomia , Humanos , Hipóxia/metabolismo , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/genética , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismoRESUMO
Depression has been associated with a low-grade chronic inflammatory state, suggesting a potential therapeutic role for anti-inflammatory agents. Fisetin is a naturally occurring flavonoid in strawberries that has anti-inflammatory activities, but whether fisetin has antidepressant effects is unknown. In this study, we exposed mice to spatial restraint for 2 weeks with or without treatment with fisetin. Immobility time in the forced swimming and tail suspension test after this restraint increased in the untreated group, but this increase did not occur in the fisetin group. We administered fisetin to Abelson helper integration site-1 (Ahi1) knockout mice, which have depressive phenotypes. We found that fisetin attenuated the depressive phenotype of these Ahi1 knockout mice. We further investigated the potential mechanism of fisetin's antidepressant effects. Because TrkB is a critical signaling pathway in the mechanisms of depression, we examined whether phosphorylated TrkB was involved in the antidepressant effects of fisetin. We found that fisetin increased phosphorylated TrkB level without altering total TrkB; this increase was attenuated by K252a, a specific TrkB inhibitor. Taken together, our results demonstrated that fisetin may have therapeutic potential for treating depression and that this antidepressant effect may be mediated by the activation of the TrkB signaling pathway.