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BACKGROUND: Xerostomia is a pathological condition characterized by decreased salivation due to salivary gland dysfunction and is frequently attributed to irreversible damage as a side effect of radiation therapy. Stem cell-derived organoid therapy has garnered attention as a promising avenue for resolving this issue. However, Matrigel, a hydrogel commonly used in organoid culture, is considered inappropriate for clinical use due to its undefined composition and immunogenicity. In this study, we aimed to develop a method for culturing collagen-based human salivary gland organoids (hSGOs) suitable for clinical applications and evaluated their therapeutic effectiveness. METHODS: Human salivary gland stem cells were isolated from the salivary gland tissues and cultured in both Matrigel and collagen. We compared the gene and protein expression patterns of salivary gland-specific markers and measured amylase activity in the two types of hSGOs. To evaluate the therapeutic effects, we performed xenogeneic and allogeneic transplantation using human and mouse salivary gland organoids (hSGOs and mSGOs), respectively, in a mouse model of radiation-induced xerostomia. RESULTS: hSGOs cultured in Matrigel exhibited self-renewal capacity and differentiated into acinar and ductal cell lineages. In collagen, they maintained a comparable self-renewal ability and more closely replicated the characteristics of salivary gland tissue following differentiation. Upon xenotransplantation of collagen-based hSGOs, we observed engraftment, which was verified by detecting human-specific nucleoli and E-cadherin expression. The expression of mucins, especially MUC5B, within the transplanted hSGOs suggested a potential improvement in the salivary composition. Moreover, the allograft procedure using mSGOs led to increased salivation, validating the efficacy of our approach. CONCLUSIONS: This study showed that collagen-based hSGOs can be used appropriately in clinical settings and demonstrated the effectiveness of an allograft procedure. Our research has laid the groundwork for the future application of collagen-based hSGOs in allogeneic clinical trials.
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Organoides , Glândulas Salivares , Xerostomia , Xerostomia/terapia , Xerostomia/etiologia , Humanos , Glândulas Salivares/efeitos da radiação , Animais , Camundongos , Colágeno/metabolismo , Diferenciação Celular , Laminina/química , Proteoglicanas/metabolismo , Combinação de MedicamentosRESUMO
Recently, the incidence of Achilles tendon ruptures (ATRs) has become more common, and repair surgery using a bioabsorbable suture is generally preferred, particularly in the case of healthy patients. Sutures composed of poly(lactic-co-glycolic acid) (PLGA) are commonly used in ATR surgeries. Nevertheless, owing to the inherent limitations of PLGA, novel bioabsorbable sutures that can accelerate Achilles tendon healing are sought. Recently, several studies have demonstrated the beneficial effects of atelocollagen on tendon healing. In this study, poly(3,4-dihydroxy-L-phenylalanine) (pDOPA), a hydrophilic biomimetic material, was used to modify the hydrophobic surface of a PLGA suture (Vicryl, VC) for the stable coating of atelocollagen on its surface. The main objective was to fabricate an atelocollagen-coated VC suture and evaluate its performance in the healing of Achilles tendon using a rat model of open repair for ATR. Structural analyses of the surface-modified suture indicated that the collagen was successfully coated on the VC/pDOPA suture. Postoperative in vivo biomechanical analysis, histological evaluation, ultrastructural/morphological analyses, and western blotting confirmed that the tendons in the VC/pDOPA/Col group exhibit superior healing than those in the VC and VC/pDOPA groups after 1 and 6 weeks following the surgery. The this study suggests that atelocollagen-coated PLGA/pDOPA sutures are preferable for future medical applications, especially in the repair of ATR.
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Tendão do Calcâneo , Colágeno , Suturas , Cicatrização , Animais , Tendão do Calcâneo/cirurgia , Tendão do Calcâneo/efeitos dos fármacos , Tendão do Calcâneo/lesões , Ratos , Cicatrização/efeitos dos fármacos , Colágeno/química , Masculino , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Implantes Absorvíveis , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Regeneração/efeitos dos fármacos , Traumatismos dos Tendões/cirurgiaRESUMO
Cancer is a life-threatening disease when it is diagnosed at a late stage or treatment procedures fail. Inhibiting cancer cells in the tumor environment is a significant challenge for anticancer therapy. The photothermal effects of nanomaterials are being studied as a new cancer treatment. In this work, rhenium disulfide (ReS2) nanosheets were made by liquid exfoliation with gum arabic (GA) and coated with silver nanoparticles (AgNPs) to produce reactive oxygen species that destroy cancer cells. The synthesized AgNP-GA-ReS2 NPs were characterized using UV, DLS, SEM, TEM, and photothermal studies. According to the DLS findings, the NPs were about 216 nm in size and had a zeta potential of 76 mV. The TEM and SEM analyses revealed that the GA-ReS2 formed single-layered nanosheets on which the AgNPs were distributed. The photothermal effects of the AgNP-GA-ReS2 NPs at 50 µg/mL were tested with an 808 nm laser at 1.2 W cm-2, and they reached 55.8 °C after 5 min of laser irradiation. MBA-MB-231 cells were used to test the cytotoxicity of the newly designed AgNP-GA-ReS2 NPs with and without laser irradiation for 5 min. At 50 µg/mL, the AgNP-GA-ReS2 showed cytotoxicity, which was confirmed with calcein and EtBr staining. The DCFH-DA and flow cytometry analyses demonstrated that AgNP-GA-ReS2 nanosheets under NIR irradiation generated ROS with high anticancer activity, in addition to the photothermal effects.
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Nanopartículas Metálicas , Neoplasias , Rênio , Humanos , Nanopartículas Metálicas/toxicidade , Prata/farmacologiaRESUMO
Since its introduction, laparoscopic surgery has been often preferred over open surgery in obstetrics and gynecology due to its advantages, such as less bleeding, lower incidence of adhesions, reduced postoperative pain, short hospital stay, and quick return to daily life. However, in the case of complex surgeries, laparoscopy presented some limitations. Nonetheless, since the 1980s, medical robots have been introduced to overcome the technical limitations of laparoscopy and start a new age for minimally invasive surgery. In this review, we explore the indications and advantages and disadvantages of robotic surgery in the field of gynecology, and try to assess the recent trend of robotic surgery.
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Transition metal dichalcogenides (TMDs) have gained considerable attention for a broad range of applications, including cancer therapy. Production of TMD nanosheets using liquid exfoliation provides an inexpensive and facile route to achieve high yields. In this study, we developed TMD nanosheets using gum arabic as an exfoliating and stabilizing agent. Different types of TMDs, including MoS2, WS2, MoSe2, and WSe2 nanosheets, were produced using gum arabic and were characterized physicochemically. The developed gum arabic TMD nanosheets exhibited a remarkable photothermal absorption capacity in the near-infrared (NIR) region (808 nm and 1 Wâ cm-2). The drug doxorubicin was loaded on the gum arabic-MoSe2 nanosheets (Dox-G-MoSe2), and the anticancer activity was evaluated using MDA-MB-231 cells and a water-soluble tetrazolium salt (WST-1) assay, live and dead cell assays, and flow cytometry. Dox-G-MoSe2 significantly inhibited MDA-MB-231 cancer cell proliferation under the illumination of an NIR laser at 808 nm. These results indicate that Dox-G-MoSe2 is a potentially valuable biomaterial for breast cancer therapy.
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Neoplasias da Mama , Compostos Organosselênicos , Humanos , Feminino , Goma Arábica , Molibdênio/química , Morfolinas , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Doxorrubicina/químicaRESUMO
BACKGROUND: Porto-mesenteric vein (PMV) infiltration of pancreatic cancer is classified as borderline resectable cancer. For en-bloc resectability, the probability of PMV resection and reconstruction is the most decisive factor. The purpose of this study was to compare and analyze PMV resection and reconstruction during pancreatic cancer surgery using end-to-end anastomosis (EA) and a cryopreserved allograft (AG) and to verify the effectiveness of reconstruction using an AG. METHODS: Between May 2012 and June 2021, 84 patients (65 underwent EA, and 19 received AG reconstruction) underwent pancreatic cancer surgery with PMV reconstruction. An AG is a cadaveric graft with a diameter of 8-12 mm and is obtained from a liver transplant donor. Patency after reconstruction, disease recurrence, overall survival, and perioperative factors were assessed. RESULTS: The median age was higher in EA patients (p = .022) and neoadjuvant therapy (p = .02) was more in AG patients. Upon histopathological examination, the R0 resection margin did not show a significant difference by reconstruction method. During a 36-month survival analysis, primary patency was significantly superior in EA patients (p = .004), and there was no significant difference in recurrence-free survival (p = .628) or overall survival (p = .638) rates. CONCLUSION: Compared with EA, AG reconstruction after PMV resection during pancreatic cancer surgery showed a lower primary patency, but there was no difference in recurrence-free or overall survival rates. Therefore, the use of AG can be a viable option for borderline resectable pancreatic cancer surgery if the patient is properly followed-up postoperatively.
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Neoplasias Pancreáticas , Veia Porta , Humanos , Veia Porta/patologia , Pancreaticoduodenectomia/métodos , Estudos Retrospectivos , Neoplasias Pancreáticas/cirurgia , Anastomose Cirúrgica , Aloenxertos/patologia , Aloenxertos/cirurgia , Neoplasias PancreáticasRESUMO
Cellular senescence, one of the hallmarks of aging, refers to permanent cell cycle arrest and is accelerated during the aging process. Black ginseng (BG), prepared by a repeated steaming and drying process nine times from fresh ginseng (Panax ginseng C.A. Meyer), is garnering attention for herbal medicine due to its physiological benefits against reactive oxygen species (ROS), inflammation, and oncogenesis, which are common cues to induce aging. However, which key nodules in the cellular senescence process are regulated by BG supplementation has not been elucidated yet. In this study, we investigated the effects of BG on cellular senescence using in vitro and aged mouse models. BG-treated primary mouse embryonic fibroblasts (MEFs) in which senescence was triggered by ionizing radiation (IR) expressed less senescence-associated ß-galactosidase (SA-ß-gal)-positive stained cells. In our aged mice (18 months old) study, BG supplementation (300 mg/kg) for 4 weeks altered hepatic genes involved in the aging process. Furthermore, we found BG supplementation downregulated age-related inflammatory genes, especially in the complement system. Based on this observation, we demonstrated that BG supplementation led to less activation of the canonical senescence pathway, p53-dependent p21 and p16, in multiple metabolic organs such as liver, skeletal muscle and white adipose tissue. Thus, we suggest that BG is a potential senolytic candidate that retards cellular senescence.
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BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common disorders of reproductive endocrinology affecting women of reproductive age. Our study aims to explore the feasibility of a full-scale trial to evaluate the efficacy and safety of acupuncture for PCOS. METHODS: This study is a two-armed, parallel, multi-country, multi-center, pilot randomized controlled trial (RCT) for PCOS with oligomenorrhea. We will recruit 60 women aged 20 to 40âyears with oligomenorrhea due to PCOS. The participants will be randomly assigned to acupuncture and control groups. The acupuncture group will undergo a total of 40 sessions for 16âweeks with usual care. The control group will be managed with usual care (regular meals, sufficient sleep, and appropriate exercise) only. The primary clinical outcome is mean change in menstrual frequency from baseline to 16âweeks and 32âweeks (follow-up) after the start of the trial. The secondary outcomes are menstrual period, levels of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and total testosterone, LH/FSH ratio, antral follicle count and ovarian volume, body mass index, waist hip ratio, acne severity, and health-related quality of life questionnaire scores at 16 and 32âweeks after the start of the trial. DISCUSSION: This is the first protocol for multi-country, multi-center RCTs for PCOS in Korea and China. The control group in this study will be subjected to usual care (regular meals, enough sleep, and appropriate exercise). The results of this study will provide evidence for future clinical decisions and guidelines.This trial has been registered at ClinicalTrials.gov (Identifier: NCT04509817).
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Terapia por Acupuntura , Acupuntura , Síndrome do Ovário Policístico , Terapia por Acupuntura/métodos , Adulto , Feminino , Humanos , Oligomenorreia/etiologia , Oligomenorreia/terapia , Projetos Piloto , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/terapia , Adulto JovemRESUMO
BACKGROUND: Endometrial cancer is the most common gynecological cancer in developed countries. Treatment-related lymphedema negatively affects the quality of life and function of patients. This study investigated the cumulative incidence and risk factors of, and utilization of health care resources for, lymphedema in patients with endometrial cancer. METHODS: We conducted a nationwide, retrospective cohort study of women with endometrial cancer who underwent cancer-direct treatment using the Korean National Health Insurance Service (NHIS) database. Patients were categorized by age, region, income, and treatment modality. Cox proportional hazards regression models were used to analyze the incidence and risk factors of lymphedema. We also analyzed utilization of health care resources for lymphedema using diagnostic and treatment claim codes. RESULTS: A total of 19,027 patients with endometrial cancer were evaluated between January 2004 and December 2017. Among them, 2493 (13.1%) developed lymphedema. Age (<40 years, adjusted odds ratio [aOR] = 1 vs. 40-59 years, aOR = 1.413; 95% confidence interval (CI) 1.203-1.66 vs. 60+ years, aOR = 1.472; 95% CI 1.239-1.748) and multimodal treatment (surgery only, aOR = 1 vs. surgery + radiation + chemotherapy, aOR = 2.571; 95% CI 2.27-2.912) are considered to be possible risk factors for lymphedema in patients with endometrial cancer (p < 0.001). The utilization of health care resources for the treatment of lymphedema has increased over the years. CONCLUSIONS: Lymphedema is a common complication affecting women with endometrial cancer and leads to an increase in national healthcare costs. Post-treatment surveillance of lymphedema, especially in high-risk groups, is needed.
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Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.
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Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/química , Inibidores Enzimáticos/química , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases.
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Antifúngicos/farmacologia , Reabsorção Óssea/tratamento farmacológico , Ciclopirox/farmacologia , Osteoclastos/citologia , Osteogênese , Ovariectomia/efeitos adversos , Substâncias Protetoras/farmacologia , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Diferenciação Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Ligante RANK/genética , Ligante RANK/metabolismoRESUMO
RATIONALE: Primary signet ring cell carcinoma of the uterine cervix is extremely rare and the clinical characteristics and prognosis are not well known and there are no specific guidelines for treatment. PATIENT CONCERNS: A 43-year-old woman was referred to our hospital for abnormal uterine bleeding lasting 1âmonth. DIAGNOSES: Histological examination revealed a signet ring cell carcinoma of the uterine cervix. After evaluation of extragenital origin, the patient was diagnosed International Federation of Gynecology and Obstetrics stage IIIC1 primary signet ring cell carcinoma or the uterine cervix. INTERVENTION: The patient was prescribed concomitant chemo-radiation followed by intracavitary brachytherapy. OUTCOMES: She showed no evidence of disease after treatment but, it recurred after 7 months of last treatment. LESSONS: Different approaches to diagnosis and treatment of this rare disease are needed and molecular pathological studies related to the onset of the disease are required.
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Carcinoma de Células em Anel de Sinete , Colo do Útero , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Neoplasias do Colo do Útero , Esfregaço Vaginal/métodos , Adulto , Antineoplásicos/administração & dosagem , Biópsia/métodos , Braquiterapia/métodos , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/fisiopatologia , Carcinoma de Células em Anel de Sinete/terapia , Colo do Útero/diagnóstico por imagem , Colo do Útero/patologia , Evolução Fatal , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Papillomaviridae/isolamento & purificação , Retratamento/métodos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/fisiopatologia , Neoplasias do Colo do Útero/terapia , Hemorragia Uterina/diagnóstico , Hemorragia Uterina/etiologiaRESUMO
The genome of the radiation-resistant bacterium Deinococcus geothermalis contains 19 types of insertion sequences (ISs), including 93 total transposases (Tpases) in 73 full-length ISs from the main chromosome and 2 mega plasmids. In this study, 68 ISs from the D. geothermalis genome were extracted to implicate the earlier genome before its mutation by transposition of ISs. The total size of eliminated ISs from genome was 78.85 kb. From these in silico corrections of mutation by the ISs, we have become aware of some bioinformatics factualness as follows: (1) can reassemble the disrupted genes if the exact IS region was eliminated, (2) can configure the schematic clustering of major DDE type Tpases, (3) can determine IS integration order across multiple hot spots, and (4) can compare genetic relativeness by the partial synteny analysis between D. geothermalis and Deinococcus strain S9. Recently, we found that several IS elements actively transferred to other genomic sites under hydrogen peroxide-induced oxidative stress conditions, resulting in the inactivation of functional genes. Therefore, the single species genome's mobilome study provides significant support to define bacterial genome plasticity and molecular evolution from past and present progressive transposition events.
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Psiguadial B (8), and its fluoro- (8a), chloro- (8b), and bromo- (8c) derivatives were synthesized using a sodium acetate-catalyzed single step coupling of three components: ß-caryophyllene (5), diformylphloroglucinol (11), and benzaldehyde (12). These compounds efficiently and dose-dependently decreased H2O2-induced cell death, a quantitative marker of cell death, in primary cultures of mouse cortical neurons. Psiguadial B also decreased neuronal death and accumulation of ROS induced by FeCl2 in cortical cultures. The in vitro effects of these compounds in lipopolysaccharide (LPS)-induced expression of nitric oxide (NO), and TNF-α and IL-6 by suppressing the NF-κB pathway in immune cells demonstrated their antioxidative and anti-inflammatory activity. The present findings warrant further research on the development of psiguadial B-based neuroprotective agents for the treatment of neurodegenerative diseases, acute brain injuries and immunological disorders.
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Anti-Inflamatórios/química , Antioxidantes/química , Fármacos Neuroprotetores/química , Terpenos/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Compostos Ferrosos/farmacologia , Halogenação , Peróxido de Hidrogênio/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , Psidium/química , Psidium/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Mitochondria are the major source of intercellular bioenergy in the form of ATP. They are necessary for cell survival and play many essential roles such as maintaining calcium homeostasis, body temperature, regulation of metabolism and apoptosis. Mitochondrial dysfunction has been observed in variety of diseases such as cardiovascular disease, aging, type 2 diabetes, cancer and degenerative brain disease. In other words, the interpretation and regulation of mitochondrial signals has the potential to be applied as a treatment for various diseases caused by mitochondrial disorders. In recent years, mitochondrial transplantation has increasingly been a topic of interest as an innovative strategy for the treatment of mitochondrial diseases by augmentation and replacement of mitochondria. In this review, we focus on diseases that are associated with mitochondrial dysfunction and highlight studies related to the rescue of tissue-specific mitochondrial disorders. We firmly believe that mitochondrial transplantation is an optimistic therapeutic approach in finding a potentially valuable treatment for a variety of mitochondrial diseases.
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Mitocôndrias/transplante , Doenças Mitocondriais/terapia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/terapia , Humanos , Hepatopatias/metabolismo , Hepatopatias/patologia , Hepatopatias/terapia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Dinâmica Mitocondrial , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/terapiaRESUMO
Estrogen-related receptor gamma (ERRγ) is the NR3B subgroup of associated transcription factors. In this report, a new generation of a potent and selective ERRγ inverse agonist (25) with good biocompatibility was proposed. We also explored the potential of the newly developed compound 25 in the PDTC model to expand the original indications from ATC. In addition, an X-ray crystallographic study of the ligand and ERRγ co-complex showed that 25 completely binds to the target protein (PDB 6KNR). Its medicinal chemistry, including a distinctive structural study to in vivo results, denotes that 25 may be directed towards the development of a pivotal treatment for ERRγ-related cancers.
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Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Agonismo Inverso de Drogas , Radioisótopos do Iodo/uso terapêutico , Receptores de Estrogênio/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Receptores de Estrogênio/química , Receptores de Estrogênio/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
Alport syndrome (AS) is a rare genetic disorder that causes progressive nephritis and is more common among males. Studies have reported an association between thyroid antibodies and hypothyroidism in patients with AS, but the relevance of this relationship is under debate. Prolonged untreated hypothyroidism induces short stature, abnormal pubertal development, and various other symptoms. However, children with long-standing hypothyroidism rarely present with signs of precocious puberty, or Van Wyk-Grumbach syndrome (VWGS). We report the case of a boy, 8 years and 4 months old, who had VWGS caused by prolonged untreated congenital hypothyroidism and AS. The boy had repeated gross hematuria and proteinuria and was diagnosed with AS by renal biopsy and genetic testing. He had normal renal function but severe growth retardation and hypothyroidism. Obesity, bone age delay, hyperlipidemia, and abnormal increased testicle size were also present due to prolonged untreated hypothyroidism. His thyroid antibody titer elevation was unclear, although ultrasonography and thyroid scanning showed a decrease in thyroid volume. We diagnosed the patient with congenital hypothyroidism caused by thyroid dysgenesis. VWGS was diagnosed due to hypothyroidism, delayed bone age, and pseudoprecocious puberty. To the best of our knowledge, this is the first report of a prepubertal Korean boy with prolonged untreated congenital hypothyroidism complicated by VWGS in AS.
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Monocytes are important cellular effectors of innate immune defense. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. The expansion of intermediate CD14+CD16+ monocytes has been reported in chronic inflammatory diseases including rheumatoid arthritis (RA). However, the mechanism underlying induction of CD16 and its role in monocytes remains poorly understood. Here, we demonstrate that activated platelets are important for induction of CD16 on classical CD14+CD16- monocytes by soluble factors such as cytokines. Cytokine neutralization and signaling inhibition assays reveal that sequential involvement of platelet-derived TGF-ß and monocyte-derived IL-6 contribute to CD16 induction on CD14+CD16- monocytes. Activated platelet-induced CD16 on monocytes participates in antibody-dependent cellular phagocytosis (ADCP) and its level is positively correlated with phagocytic activity. CD14+CD16- monocytes treated with activated platelets preferentially differentiate into M2 macrophages, likely the M2c subset expressing CD163 and MerTK. Lastly, the amount of sCD62P, a marker of activated platelets, is significantly elevated in plasma of RA patients and positively correlates with clinical parameters of RA. Our findings suggest an important role of activated platelets in modulating phenotypical and functional features of human monocytes. This knowledge increases understanding of the immunological role of CD14+CD16+ cells in chronic inflammatory diseases.
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Artrite Reumatoide/metabolismo , Plaquetas/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Fagocitose , Ativação Plaquetária , Receptores de IgG/metabolismo , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Plaquetas/imunologia , Estudos de Casos e Controles , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Selectina-P/metabolismo , Fenótipo , Receptores de Superfície Celular/metabolismo , Receptores de IgG/genética , Transdução de Sinais , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismoRESUMO
Structure-based targeting of fluorescent dyes is essential for their use as imaging agents for disease diagnosis. Here, we describe the development of the benzoquinolizinium compound Medical fluorophore 1 (MF1) as a novel biomedical imaging agent that allows the visualization of inflammation by virtue of its unique chemical structure. Lipopolysaccharide treatment stimulated the uptake of MF1 by bone marrow-derived macrophages, with no adverse effects on cell proliferation. In vivo fluorescence lifetime imaging revealed the accumulation of MF1 in carrageenan-induced acute inflammatory lesions in mice, which peaked at 6 h. MF1-based imaging also allowed monitoring of the response to the anti-inflammatory drugs dexamethasone and sulfasalazine. Thus, MF1 can be used to diagnose diseases characterized by inflammation as well as treatment efficacy.