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1.
Cancer Immunol Immunother ; 73(6): 113, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38693312

RESUMO

Senescent cells have a profound impact on the surrounding microenvironment through the secretion of numerous bioactive molecules and inflammatory factors. The induction of therapy-induced senescence by anticancer drugs is known, but how senescent tumor cells influence the tumor immune landscape, particularly neutrophil activity, is still unclear. In this study, we investigate the induction of cellular senescence in breast cancer cells and the subsequent immunomodulatory effects on neutrophils using the CDK4/6 inhibitor palbociclib, which is approved for the treatment of breast cancer and is under intense investigation for additional malignancies. Our research demonstrates that palbociclib induces a reversible form of senescence endowed with an inflammatory secretome capable of recruiting and activating neutrophils, in part through the action of interleukin-8 and acute-phase serum amyloid A1. The activation of neutrophils is accompanied by the release of neutrophil extracellular trap and the phagocytic removal of senescent tumor cells. These findings may be relevant for the success of cancer therapy as neutrophils, and neutrophil-driven inflammation can differently affect tumor progression. Our results reveal that neutrophils, as already demonstrated for macrophages and natural killer cells, can be recruited and engaged by senescent tumor cells to participate in their clearance. Understanding the interplay between senescent cells and neutrophils may lead to innovative strategies to cope with chronic or tumor-associated inflammation.


Assuntos
Neoplasias da Mama , Senescência Celular , Neutrófilos , Piperazinas , Piridinas , Humanos , Piperazinas/farmacologia , Piridinas/farmacologia , Senescência Celular/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Neutrófilos/metabolismo , Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Linhagem Celular Tumoral , Ativação de Neutrófilo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
2.
Int J Oncol ; 64(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38695241

RESUMO

Cancer remains a formidable adversary, challenging medical advancements with its dismal prognosis, low cure rates and high mortality rates. Within this intricate landscape, long non­coding RNAs (lncRNAs) emerge as pivotal players, orchestrating proliferation and migration of cancer cells. Harnessing the potential of lncRNAs as therapeutic targets and prognostic markers holds immense promise. The present comprehensive review delved into the molecular mechanisms underlying the involvement of lncRNAs in the onset and progression of the top five types of cancer. By meticulously examining lncRNAs across diverse types of cancer, it also uncovered their distinctive roles, highlighting their exclusive oncogenic effects or tumor suppressor properties. Notably, certain lncRNAs demonstrate diverse functions across different cancers, confounding the conventional understanding of their roles. Furthermore, the present study identified lncRNAs exhibiting aberrant expression patterns in numerous types of cancer, presenting them as potential indicators for cancer screening and diagnosis. Conversely, a subset of lncRNAs manifests tissue­specific expression, hinting at their specialized nature and untapped significance in diagnosing and treating specific types of cancer. The present comprehensive review not only shed light on the intricate network of lncRNAs but also paved the way for further research and clinical applications. The unraveled molecular mechanisms offer a promising avenue for targeted therapeutics and personalized medicine, combating cancer proliferation, invasion and metastasis.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Neoplasias , RNA Longo não Codificante , RNA Longo não Codificante/genética , Humanos , Neoplasias/genética , Neoplasias/patologia , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Prognóstico , Progressão da Doença
3.
Cell Genom ; 4(5): 100550, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38697125

RESUMO

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Inibidores de Poli(ADP-Ribose) Polimerases , Reparo de DNA por Recombinação , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Caseína Quinase II/genética , Caseína Quinase II/metabolismo , Masculino , Camundongos , Animais , Feminino , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Predisposição Genética para Doença
4.
Cell Genom ; 4(5): 100555, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38697121

RESUMO

The complex pathobiology of late-onset Alzheimer's disease (AD) poses significant challenges to therapeutic and preventative interventions. Despite these difficulties, genomics and related disciplines are allowing fundamental mechanistic insights to emerge with clarity, particularly with the introduction of high-resolution sequencing technologies. After all, the disrupted processes at the interface between DNA and gene expression, which we call the broken AD genome, offer detailed quantitative evidence unrestrained by preconceived notions about the disease. In addition to highlighting biological pathways beyond the classical pathology hallmarks, these advances have revitalized drug discovery efforts and are driving improvements in clinical tools. We review genetic, epigenomic, and gene expression findings related to AD pathogenesis and explore how their integration enables a better understanding of the multicellular imbalances contributing to this heterogeneous condition. The frontiers opening on the back of these research milestones promise a future of AD care that is both more personalized and predictive.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Humanos , Genoma Humano , Genômica/métodos , Animais
5.
Cell ; 187(10): 2465-2484.e22, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38701782

RESUMO

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.


Assuntos
Epigênese Genética , Bainha de Mielina , Oligodendroglia , Remielinização , Animais , Bainha de Mielina/metabolismo , Humanos , Camundongos , Remielinização/efeitos dos fármacos , Oligodendroglia/metabolismo , Sistema Nervoso Central/metabolismo , Camundongos Endogâmicos C57BL , Rejuvenescimento , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Organoides/metabolismo , Organoides/efeitos dos fármacos , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/genética , Diferenciação Celular/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Masculino , Regeneração/efeitos dos fármacos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia
6.
Life Sci ; 347: 122682, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38702025

RESUMO

Thyroid cancer is one of the most common primary endocrine malignancies worldwide, and papillary thyroid carcinoma (PTC) is the predominant histological type observed therein. Although PTC has been studied extensively, our understanding of the altered metabolism and metabolic profile of PTC tumors is limited. We identified that the content of metabolite homogentisic acid (HGA) in PTC tissues was lower than that in adjacent non-cancerous tissues. We evaluated the potential of HGA as a novel molecular marker in the diagnosis of PTC tumors, as well as its ability to indicate the degree of malignancy. Studies have further shown that HGA contributes to reactive oxygen species (ROS) associated oxidative stress, leading to toxicity and inhibition of proliferation. In addition, HGA caused an increase in p21 expression levels in PTC cells and induced G1 arrest. Moreover, we found that the low HGA content in PTC tumors was due to the low expression levels of tyrosine aminotransferase (TAT) and p-hydroxyphenylpyruvate hydroxylase (HPD), which catalyze the conversion of tyrosine to HGA. The low expression levels of TAT and HPD are strongly associated with a higher probability of PTC tumor invasion and metastasis. Our study demonstrates that HGA could be used to diagnose PTC and provides mechanisms linking altered HGA levels to the biological behavior of PTC tumors.


Assuntos
Pontos de Checagem do Ciclo Celular , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21 , Ácido Homogentísico , Espécies Reativas de Oxigênio , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/metabolismo , Ácido Homogentísico/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Estresse Oxidativo , Carcinoma Papilar/patologia , Carcinoma Papilar/metabolismo , Adulto
7.
Mayo Clin Proc ; 99(5): 716-726, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38702125

RESUMO

OBJECTIVE: To evaluate the associations between prescription opioid exposures in community-dwelling older adults and gray and white matter structure by magnetic resonance imaging. METHODS: Secondary analysis was conducted of a prospective, longitudinal population-based cohort study employing cross-sectional imaging of older adult (≥65 years) enrollees between November 1, 2004, and December 31, 2017. Gray matter outcomes included cortical thickness in 41 structures and subcortical volumes in 6 structures. White matter outcomes included fractional anisotropy in 40 tracts and global white matter hyperintensity volumes. The primary exposure was prescription opioid availability expressed as the per-year rate of opioid days preceding magnetic resonance imaging, with a secondary exposure of per-year total morphine milligram equivalents (MME). Multivariable models assessed associations between opioid exposures and brain structures. RESULTS: The study included 2185 participants; median (interquartile range) age was 80 (75 to 85) years, 47% were women, and 1246 (57%) received opioids. No significant associations were found between opioids and gray matter. Increased opioid days and MME were associated with decreased white matter fractional anisotropy in 15 (38%) and 16 (40%) regions, respectively, including the corpus callosum, posterior thalamic radiation, and anterior limb of the internal capsule, among others. Opioid days and MME were also associated with greater white matter hyperintensity volume (1.02 [95% CI, 1.002 to 1.036; P=.029] and 1.01 [1.001 to 1.024; P=.032] increase in the geometric mean, respectively). CONCLUSION: The duration and dose of prescription opioids were associated with decreased white matter integrity but not with gray matter structure. Future studies with longitudinal imaging and clinical correlation are warranted to further evaluate these relationships.


Assuntos
Analgésicos Opioides , Vida Independente , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Idoso , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Idoso de 80 Anos ou mais , Estudos Prospectivos , Imageamento por Ressonância Magnética/métodos , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacos , Estudos Longitudinais , Estudos Transversais
9.
Arch Endocrinol Metab ; 68: e230146, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38709151

RESUMO

Objective: After initial treatment, up to 30% of patients with papillary thyroid cancer (PTC) have incomplete response, mainly cervical lymph node (LN) disease. Previous studies have suggested that active surveillance (AS) is a possible option for these patients. Our aim was to report the results of AS in patients with PTC and cervical LN disease. Materials and methods: In this retrospective observational study, we included adult patients treated and followed for PTC, who presented with cervical LN disease and were managed with AS. Growth was defined as an increase ≥ 3mm in either diameter. Results: We included 32 patients: 27 (84.4%) women, age of 39 ± 14 years, all initially treated with total thyroidectomy, and 22 (69%) with therapeutic neck dissection. Cervical LN disease was diagnosed 1 year (0.3-12.6) after initial management, with a diameter of 9.0 mm (6.0-19.0). After a median AS of 4.3 years (0.6-14.1), 4 (12.5%) patients had LNgrowth: 2 (50%) of whom were surgically removed, 1 (25%) was effectively treated with radiotherapy, and 1 (25%) had a scheduled surgery. Tg increase was the only predictive factor of LN growth evaluated as both the delta Tg (p < 0.0366) and percentage of Tg change (p < 0.0140). None of the included patients died, had local complications due to LN growth or salvage therapy, or developed distant metastases during follow-up. Conclusion: In selected patients with PTC and suspicious cervical LNs diagnosed after initial treatment, AS is a feasible and safe strategy as it allows effective identification and treatment of the minority of patients who progress.


Assuntos
Linfonodos , Metástase Linfática , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Tireoidectomia , Conduta Expectante , Humanos , Feminino , Masculino , Adulto , Estudos Retrospectivos , Tireoidectomia/métodos , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/patologia , Linfonodos/patologia , Estudos de Viabilidade , Pescoço/cirurgia , Carcinoma Papilar/cirurgia , Carcinoma Papilar/patologia , Esvaziamento Cervical/métodos , Adulto Jovem
10.
J Drugs Dermatol ; 23(5): 376-379, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38709686

RESUMO

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous malignancy. Immunosuppression increases the risk of MCC and is associated with poor prognosis. Organ transplant recipients (OTR) have worse overall survival (OS) than patients with immunosuppression due to other causes. Treating MCC after organ transplantation is challenging, as checkpoint inhibitor immunotherapy, the standard of care for treating MCC, increases the risk of transplant rejection. This paper reviews the cases of two simultaneous pancreas-kidney transplant (SPKT) recipients with MCC and explores the role of immunosuppression in the development of MCC. Immunosuppression was discontinued and checkpoint inhibitor therapy was initiated in the first patient and considered by the second patient. In both cases, treatment failed, and the patients died shortly after developing metastatic MCC. These cases illustrate the need for improved multidisciplinary treatment regimens for MCC in OTRs. J Drugs Dermatol. 2024;23(5):376-377.     doi:10.36849/JDD.8234  .


Assuntos
Carcinoma de Célula de Merkel , Transplante de Rim , Transplante de Pâncreas , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/terapia , Carcinoma de Célula de Merkel/cirurgia , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/patologia , Transplante de Rim/efeitos adversos , Neoplasias Cutâneas/patologia , Transplante de Pâncreas/efeitos adversos , Masculino , Evolução Fatal , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Feminino , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Terapia de Imunossupressão/efeitos adversos
11.
J Drugs Dermatol ; 23(5): e132-e133, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38709690

RESUMO

Skin self-examinations play a vital role in skin cancer detection and are often aided by online resources. Available reference photos must display the full spectrum of skin tones so patients may visualize how skin lesions can appear. This study investigated the portrayal of skin tones in skin cancer-related Google Images, discovering a significant underrepresentation of darker skin tones. J Drugs Dermatol. 2024;23(5):e132-e133.     doi:10.36849/JDD.7886e.


Assuntos
Neoplasias Cutâneas , Pigmentação da Pele , Humanos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Fotografação , Autoexame/métodos , Pele/patologia , Internet , Ferramenta de Busca
13.
Physiol Res ; 73(2): 189-203, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38710051

RESUMO

This comprehensive review explores the physiological and pathophysiological significance of VPS13A, a protein encoded by the VPS13A gene. The VPS13A gene is associated with Chorea-acanthocytosis (ChAc), a rare hereditary neurodegenerative disorder. The review covers essential aspects, beginning with the genetics of VPS13A, highlighting its role in the pathogenesis of ChAc, and addressing the spectrum of genetic variants involved. It delves into the structure and function of the VPS13A protein, emphasizing its presence in various tissues and its potential involvement in protein trafficking and lipid homeostasis. Molecular functions of VPS13A in the brain tissue and other cell types or tissues with respect to their role in cytoskeletal regulation and autophagy are explored. Finally, it explores the intriguing link between VPS13A mutations, lipid imbalances, and neurodegeneration, shedding light on future research directions. Overall, this review serves as a comprehensive resource for understanding the pivotal role of VPS13A in health and disease, particularly in the context of ChAc. Key words: Chorein , Tumor, Actin, Microfilament, Gene expression, Chorea-acanthocytosis.


Assuntos
Neuroacantocitose , Proteínas de Transporte Vesicular , Humanos , Animais , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/genética , Neuroacantocitose/metabolismo , Neuroacantocitose/genética , Neuroacantocitose/fisiopatologia , Neuroacantocitose/patologia , Mutação , Metabolismo dos Lipídeos/fisiologia , Metabolismo dos Lipídeos/genética
14.
Physiol Res ; 73(2): 305-314, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38710054

RESUMO

Netrin-1 (NTN-1) plays a vital role in the progress of nervous system development and inflammatory diseases. However, the role and underlying mechanism of NTN-1 in inflammatory pain (IP) are unclear. BV2 microglia were treated with LPS to mimic the cell status under IP. Adeno-associated virus carrying the NTN-1 gene (AAV-NTN-1) was used to overexpress NTN-1. Complete Freund's Adjuvant (CFA)-induced mouse was recruited as an in vivo model. MTT and commercial kits were utilized to evaluate cell viability and cell death of BV2 cells. The mRNA expressions and secretions of cytokines were measured using the ELISA method. Also, the pyroptosis and activation of BV2 cells were investigated based on western blotting. To verify the role of Rac1/NF-kappaB signaling, isochamaejasmin (ISO) and AAV-Rac1 were presented. The results showed that NTN-1 expression was decreased in LPS-treated BV2 microglia and spinal cord tissues of CFA-injected mice. Overexpressing NTN-1 dramatically reversed cell viability and decreased cell death rate of BV2 microglia under lipopolysaccharide (LPS) stimulation, while the level of pyroptosis was inhibited. Besides, AAV-NTN-1 rescued the activation of microglia and inflammatory injury induced by LPS, decreasing IBA-1 expression, as well as iNOS, IL-1beta and IL-6 secretions. Meanwhile AAV-NTN-1 promoted the anti-inflammation response, including increases in Arg-1, IL-4 and IL-10 levels. In addition, the LPS-induced activation of Rac1/NF-kappaB signaling was depressed by NTN-1 overexpression. The same results were verified in a CFA-induced mouse model. In conclusion, NTN-1 alleviated IP by suppressing pyroptosis and promoting M2 type activation of microglia via inhibiting Rac1/NF-?B signaling, suggesting the protective role of NTN-1 in IP. Keywords: Netrin-1, Inflammatory pain, Pyroptosis, Microglia M2 activation, Rac1/NF-kappaB.


Assuntos
Inflamação , Microglia , NF-kappa B , Netrina-1 , Neuropeptídeos , Piroptose , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP , Animais , Piroptose/fisiologia , Piroptose/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Netrina-1/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , NF-kappa B/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Dor/metabolismo , Linhagem Celular , Lipopolissacarídeos
15.
Physiol Res ; 73(2): 253-263, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38710055

RESUMO

Up to now, there's a limited number of studies on the relationship between PINK1/Park2 pathway and mitophagy in NAFLD. To investigate the effect of Park2-mediated mitophagy on non-alcoholic fatty liver disease (NAFLD). Oleic acid was used for the establishment of NAFLD model. Oil red-dyed lipid drops and mitochondrial alternations were observed by transmission electron microscopy. Enzymatic kit was used to test lipid content. The levels of IL-8 and TNF-alpha were determined by ELISA. Lenti-Park2 and Park2-siRNA were designed to upregulate and downregulate Park2 expression, respectively. The changing expression of PINK and Park2 was detected by RT-qPCR and Western blot. Immunofluorescence staining was applied to measure the amount of LC3. Successful NAFLD modeling was featured by enhanced lipid accumulation, as well as the elevated total cholesterol (TC), triglyceride (TG), TNF-alpha and IL-8 levels. Mitochondria in NAFLD model were morphologically and functionally damaged. Park2 expression was upregulated by lenti-Park2 and downregulated through Park2-siRNA. The PINK1 expression showed the same trend as Park2 expression. Immunofluorescence staining demonstrated that the when Park2 was overexpressed, more LC3 protein on mitochondrial autophagosome membrane was detected, whereas Park2 knockdown impeded LC3' locating on the membrane. The transmission electron microscopy image exhibited that the extent of damage to the mitochondrial in NAFLD model was revered by enhanced Park2 expression but further exacerbated by reduced Park2 expression. Park2-mediated mitophagy could relive NAFLD and may be a novel therapeutic target for NAFLD treatment. Keywords: Non-alcoholic Fatty Liver Disease (NAFLD), Mitophagy, PINK1/Park2, Park2, PINK1.


Assuntos
Mitofagia , Hepatopatia Gordurosa não Alcoólica , Proteínas Quinases , Ubiquitina-Proteína Ligases , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Mitofagia/fisiologia , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Animais , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Masculino , Humanos , Camundongos
16.
Physiol Res ; 73(2): 285-294, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38710059

RESUMO

This study aimed to determine whether electrical stimulation-based twitch exercise is effective in inhibiting the progression of immobilization-induced muscle fibrosis. 19 Wistar rats were randomly divided into a control group (n=6), an immobilization group (n=6; with immobilization only), and a Belt group (n=7; with immobilization and twitch exercise through the belt electrode device, beginning 2 weeks after immobilization). The bilateral soleus muscles were harvested after the experimental period. The right soleus muscles were used for histological analysis, and the left soleus muscles were used for biochemical and molecular biological analysis. As a result, in the picrosirius red images, the perimysium and endomysium were thicker in both the immobilization and Belt groups compared to the control group. However, the perimysium and endomysium thickening were suppressed in the Belt group. The hydroxyproline content and alpha-SMA, TGF-beta1, and HIF-1alpha mRNA expressions were significantly higher in the immobilization and belt groups than in the control group. These expressions were significantly lower in the Belt group than in the immobilization group. The capillary-to-myofiber ratio and the mRNA expressions of VEGF and PGC-1alpha were significantly lower in the immobilization and belt groups than in the control group, these were significantly higher in the Belt group than in the immobilization group. From these results, Electrical stimulation-based twitch exercise using the belt electrode device may prevent the progression of immobilization-induced muscle fibrosis caused by downregulating PGC-1alpha/VEGF pathway, we surmised that this intervention strategy might be effective against the progression of muscle contracture. Keywords: Immobilization, Skeletal muscle, Fibrosis, Electrical stimulation-based twitch exercise, PGC-1alpha/VEGF pathway.


Assuntos
Regulação para Baixo , Fibrose , Músculo Esquelético , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Condicionamento Físico Animal , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular , Animais , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Masculino , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Ratos , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/fisiologia , Estimulação Elétrica , Terapia por Estimulação Elétrica/métodos , Progressão da Doença , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/prevenção & controle , Doenças Musculares/etiologia
17.
Physiol Res ; 73(2): 227-237, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38710058

RESUMO

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.


Assuntos
Injúria Renal Aguda , Cisplatino , Diminazena , Lisinopril , Ratos Wistar , Valsartana , Animais , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/tratamento farmacológico , Lisinopril/farmacologia , Cisplatino/toxicidade , Valsartana/farmacologia , Masculino , Diminazena/análogos & derivados , Diminazena/farmacologia , Diminazena/uso terapêutico , Ratos , Antineoplásicos/toxicidade , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo
18.
Int J Immunopathol Pharmacol ; 38: 3946320241240706, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38712735

RESUMO

Introduction: Bladder cancer represents a significant public health concern with diverse genetic alterations influencing disease onset, progression, and therapy response. In this study, we explore the multifaceted role of Solute Carrier Family 31 Member 1 (SLC31A1) in bladder cancer, a pivotal gene involved in copper homeostasis. Methods: Our research involved analyzing the SLC31A1 gene expression via RT-qPCR, promoter methylation via targeted bisulfite sequencing, and mutational status via Next Generation Sequencing (NGS) using the clinical samples sourced by the local bladder cancer patients. Later on, The Cancer Genome Atlas (TCGA) datasets were utilized for validation purposes. Moreover, prognostic significance, gene enrichment terms, and therapeutic drugs of SLC31A1 were also explored using KM Plotter, DAVID, and DrugBank databases. Results: We observed that SLC31A1 was significantly up-regulated at both the mRNA and protein levels in bladder cancer tissue samples, suggesting its potential involvement in bladder cancer development and progression. Furthermore, our investigation into the methylation status revealed that SLC31A1 was significantly hypomethylated in bladder cancer tissues, which may contribute to its overexpression. The ROC analysis of the SLC31A1 gene indicated promising diagnostic potential, emphasizing its relevance in distinguishing bladder cancer patients from normal individuals. However, it is crucial to consider other factors such as cancer stage, metastasis, and recurrence for a more accurate evaluation in the clinical context. Interestingly, mutational analysis of SLC31A1 demonstrated only benign mutations, indicating their unknown role in the SLC31A1 disruption. In addition to its diagnostic value, high SLC31A1 expression was associated with poorer overall survival (OS) in bladder cancer patients, shedding light on its prognostic relevance. Gene enrichment analysis indicated that SLC31A1 could influence metabolic and copper-related processes, further underscoring its role in bladder cancer. Lastly, we explored the DrugBank database to identify potential therapeutic agents capable of reducing SLC31A1 expression. Our findings unveiled six important drugs with the potential to target SLC31A1 as a treatment strategy. Conclusion: Our comprehensive investigation highlights SLC31A1 as a promising biomarker for bladder cancer development, progression, and therapy.


Assuntos
Transportador de Cobre 1 , Metilação de DNA , Progressão da Doença , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Transportador de Cobre 1/genética , Transportador de Cobre 1/metabolismo , Regulação Neoplásica da Expressão Gênica , Masculino , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regiões Promotoras Genéticas , Mutação , Pessoa de Meia-Idade , Prognóstico , Idoso , Regulação para Cima
19.
J Int Med Res ; 52(5): 3000605241252115, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38713460

RESUMO

OBJECTIVE: To assess the predictive value of the serum lipid profile for initial intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) in patients with Kawasaki disease (KD). METHODS: This retrospective cohort study enrolled patients with KD and divided them into IVIG-responsive and IVIG-resistant groups. They were also stratified based on the presence of CALs (CALs and non-CALs groups). Clinical, echocardiographic and biochemical values were evaluated. A subgroup analysis was performed on complete and incomplete KD. Predictors of initial IVIG resistance and CALs were determined by multivariate logistic regression analysis. RESULTS: A total of 649 KD patients were enrolled: 151 had CALs and 76 had initial IVIG resistance. Low-density lipoprotein cholesterol (LDL-C) was significantly lower in the IVIG-resistant group than in the IVIG-responsive group. LDL-C and apolipoprotein (Apo) B were significantly lower in the CALs group compared with the non-CALs group. Multivariate logistic regression failed to identify the serum lipid profile (LDL-C, Apo A or Apo B) as an independent risk factor for initial IVIG resistance or CALs in KD patients. CONCLUSION: KD patients might have dyslipidaemia in the acute phase, but the serum lipid profile might not be suitable as a single predictor for initial IVIG resistance or CALs.


Assuntos
Doença da Artéria Coronariana , Imunoglobulinas Intravenosas , Síndrome de Linfonodos Mucocutâneos , Humanos , Síndrome de Linfonodos Mucocutâneos/sangue , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Feminino , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/imunologia , Pré-Escolar , Estudos Retrospectivos , Lactente , LDL-Colesterol/sangue , Resistência a Medicamentos , Lipídeos/sangue , Criança , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Fatores de Risco , Apolipoproteínas B/sangue , Prognóstico
20.
J Int Med Res ; 52(5): 3000605241248884, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38713457

RESUMO

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare, benign condition affecting young Oriental-Asian females. It is characterized by fever and tender cervical lymphadenopathy with an unclear aetiology, and in most longitudinal reviews, KFD occurs before systemic lupus erythematosus (SLE). Herein, the case of a 28-year-old Kuwaiti female without any relevant past medical history, who was simultaneously diagnosed with KFD and SLE following an Ebstein-Barr virus infection, is reported. The patient was treated with oral prednisolone, hydroxychloroquine, cyclosporin, and belimumab and her response was clinically and biochemically favourable. Although KFD is prevalent in Asian populations, it may affect all races. Early diagnosis of KFD is difficult, particularly when simultaneously diagnosed with SLE, but crucial to preventing inappropriate therapy. Clinicians need to know about this rare disease, especially when patients present with fever and swollen lymph nodes, due to a risk of misdiagnosis with tuberculosis or lymphoma, as these are more often thought to be the cause of such symptoms.


Assuntos
Linfadenite Histiocítica Necrosante , Lúpus Eritematoso Sistêmico , Humanos , Linfadenite Histiocítica Necrosante/diagnóstico , Linfadenite Histiocítica Necrosante/tratamento farmacológico , Linfadenite Histiocítica Necrosante/patologia , Feminino , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Árabes , Prednisolona/uso terapêutico , Prednisolona/administração & dosagem
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