RESUMO
PURPOSE: The quick establishment of adequate vascular access is essential for the technical success of mechanical thrombectomy (MT). Focusing on shifts in aortic arch geometry and aging-related changes, we propose an imaging parameter for predicting access difficulty using chest CT. METHODS: Patients with acute anterior circulation large-vessel occlusion who underwent MT from April 2020 to September 2021 were included in this retrospective multicenter observational study. The distance from the sternum to the ascending aorta (S-AAD) was defined as the surrogate marker of access difficulty. Access was defined as difficult when the time from femoral sheath placement to guiding catheter induction (guiding time: GT) ≥ 30â¯minutes, and the patients were dichotomized into groups with short GT (sGT: GT < 30â¯min) and long GT (lGT: GT ≥ 30â¯min). RESULTS: One hundred fifteen patients were included. There were 12 patients (10.4â¯%) in lGT group. The median (IQR) S-AAD was 11.9â¯mm (6.3, 18.3â¯mm) in sGT group and 6.6â¯mm (4.0, 10.3â¯mm) in lGT group, and a significant difference in S-AAD was observed (P = 0.026). In multivariate analyses, dyslipidemia and S-AAD < 5â¯mm were significantly associated with difficult access (OR, 5.938 [95â¯% CI, 1.468, 24.022], P = 0.012 for dyslipidemia; OR, 5.147 [95â¯% CI, 1.267, 20.917], P = 0.022 for S-AAD < 5â¯mm). CONCLUSION: S-AAD is a simple and reliable imaging parameter to predict access difficulty. This parameter may be helpful in selecting the appropriate devices and access routes in preinterventional practice.
Assuntos
Trombectomia , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Trombectomia/métodos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Idoso de 80 Anos ou mais , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgiaRESUMO
BACKGROUND: Pseudo-Kaposi sarcoma (PKS) is a rare vascular proliferative disease, caused by arteriovenous malformation (AVM) and chronic venous insufficiency. The lesions are characterized by purple or reddish-brownish papules, plaques, and nodules. Although benign, it is clinically similar to Kaposi's sarcoma (KS), a malignant disease, and must be differentiated by histopathological examination. We report a rare case of PKS with chronic limb-threatening ischemia (CLTI). CASE PRESENTATION: An 83-year-old man with diabetes mellitus (DM) presented to a local dermatology department with a complaint of a right second toe ulcer and was, thereby, referred to our department due to arterial bleeding during skin biopsy to exclude malignant diseases. Although the pulsation of dorsalis pedis artery of the affected limb was palpable, the skin perfusion pressure was only 20 and 30 mmHg on the dorsum and planter surface, respectively, indicating severe ischemia of toe and forefoot. Ultrasonography and computed tomography revealed an AVM around the right second metatarsophalangeal joint and occlusion of the right dorsalis pedis artery in the middle, indicating CLTI in the background. Pathological findings of the skin biopsy found capillary blood vessel proliferation, hemosiderin deposition, and extravascular red blood cell leakage in the dermal layer, which could be found in KS. However, CD34 was normally stained in the vascular endothelium, and human herpesvirus-8 staining was negative, resulting in the pathological diagnosis of PKS, a proliferative vascular lesion associated with AVM. The ulcer was spontaneously epithelialized, but 2 years later the ulcer recurred and infection developed, necessitating treatment for abnormal blood flow. Transarterial embolization using N-butyl 2-cyanoacrylate for the AVM controlled abnormal perfusion once; however, the procedure exacerbated perfusion of the toe, resulting in foot ulcer progression. Forefoot amputation with surgical excision of AVM was performed, and thereby, wound healing was achieved. CONCLUSION: This is a rare case of PKS with CLTI complicated with AVM. As there is currently no established consensus on the treatment of PKS, the approach to treatment strategy should be tailored to the specific condition of each patient.
RESUMO
BACKGROUND: Perioperative symptomatic carotid artery occlusion after carotid endarterectomy is a rare complication. In this study, we present a case of symptomatic acute carotid artery occlusion that occurred after carotid endarterectomy in a patient with coexistent subclavian artery steal phenomenon, which was successfully treated with subclavian artery stenting. CASE PRESENTATION: A 57-year-old East Asian female presented with stenosis in the left common carotid artery and left subclavian artery along with subclavian steal. The proximal segment of the left anterior cerebral artery was hypoplastic, and the posterior communicating arteries on both sides were well-developed. Left internal carotid artery stenosis progressed during the follow-up examination; therefore, left carotid endarterectomy was performed. On the following day, symptoms of cerebral perfusion deficiency appeared due to occlusion of the left carotid artery. The stenotic origin of the left common carotid artery and the suspected massive thrombus in the left carotid artery posed challenges to carotid revascularization. Therefore, left subclavian artery stenting for the subclavian steal phenomenon was determined to be the best option for restoring cerebral blood flow to the whole brain. Her symptoms improved after the procedure, and the postprocedural workup revealed improved cerebral blood flow. CONCLUSION: Subclavian artery stenting is safe and may be helpful in patients with cerebral perfusion deficiency caused by intractable acute carotid occlusion coexisting with the subclavian steal phenomenon. Revascularization of asymptomatic subclavian artery stenosis is generally not recommended. However, cerebral circulatory insufficiency as a comorbidity may be worth considering.
Assuntos
Estenose das Carótidas , Circulação Cerebrovascular , Endarterectomia das Carótidas , Stents , Síndrome do Roubo Subclávio , Humanos , Feminino , Síndrome do Roubo Subclávio/cirurgia , Pessoa de Meia-Idade , Estenose das Carótidas/cirurgia , Resultado do Tratamento , Artéria Subclávia/cirurgia , Complicações Pós-Operatórias/cirurgia , Complicações Pós-Operatórias/etiologiaRESUMO
Breast cancer is one of the most common cancers threatening women's health. Our previous study found that silibinin induced the death of MCF-7 and MDA-MB-231 human breast cancer cells. We noticed that silibinin-induced cell damage was accompanied by morphological changes, including the increased cell aspect ratio (cell length/width) and decreased cell area. Besides, the cytoskeleton is also destroyed in cells treated with silibinin. YAP/TAZ, a mechanical signal sensor interacted with extracellular pressure, cell adhesion area and cytoskeleton, is also closely associated with cell survival, proliferation and migration. Thus, the involvement of YAP/TAZ in the cytotoxicity of silibinin in breast cancer cells has attracted our interests. Excitingly, we find that silibinin inhibits the nuclear translocation of YAP/TAZ in MCF-7 and MDA-MB-231 cells, and reduces the mRNA expressions of YAP/TAZ target genes, ACVR1, MnSOD and ANKRD. More importantly, expression of YAP1 gene is negatively correlated with the survival of the patients with breast cancers. Molecular docking analysis reveals high probabilities for binding of silibinin to the proteins in the YAP pathways. DARTS and CETSA results confirm the binding abilities of silibinin to YAP and LATS. Inhibiting YAP pathway either by addition of verteporfin, an inhibitor of YAP/TAZ-TEAD, or by transfection of si-RNAs targeting YAP or TAZ further enhances silibinin-induced cell damage. While enhancing YAP activity by silencing LATS1/2 or overexpressing YAPS127/397A, an active form of YAP, attenuates silibinin-induced cell damage. These findings demonstrate that inhibition of the YAP/TAZ pathway contributes to cytotoxicity of silibinin in breast cancers, shedding lights on YAP/TAZ-targeted cancer therapies.
Assuntos
Neoplasias da Mama , Silibina , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células MCF-7 , Simulação de Acoplamento Molecular , Fosfoproteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silibina/farmacologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/antagonistas & inibidores , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/efeitos dos fármacos , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Verteporfina/farmacologia , Proteínas de Sinalização YAP/antagonistas & inibidores , Proteínas de Sinalização YAP/efeitos dos fármacos , Proteínas de Sinalização YAP/metabolismoRESUMO
BACKGROUND: This study aimed to clarify the relationship between primary site and lymphatic drainage pattern for malignant skin tumors in the head and neck region. Malignant melanoma and squamous cell carcinoma in the head and neck region are known to have poor prognosis because of lymph node metastasis. Nevertheless, numerous aspects of lymphatic drainage patterns remain elusive. METHODS: We statistically analyzed data of 47 patients with malignant skin tumors in the head and neck region. Information was collected on the patients' clinical characteristics, primary tumor site, and lymphatic drainage patterns. RESULTS: The parotid lymph nodes drained the greatest amount of lymph from skin tumors of the head and neck. Important lymphatic drainage pathways were the superficial cervical nodes for primary tumors in the buccal/nasal region, level IA and level IB nodes for primary tumors in the lip region, the occipital nodes, posterior auricular nodes, and level VA nodes in the parietal/occipital region, and the preauricular nodes in the auricular region. CONCLUSION: These findings have considerable significance in terms of understanding lymphatic drainage patterns for malignant skin tumors in the head and neck and may be useful for clinical decision-making and when planning treatment. Further research and clinical applications are expected to contribute to an improved prognosis in patients with cutaneous head and neck malignancies.
Assuntos
Neoplasias de Cabeça e Pescoço , Linfonodos , Metástase Linfática , Melanoma , Neoplasias Cutâneas , Humanos , Masculino , Neoplasias Cutâneas/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Metástase Linfática/patologia , Adulto , Melanoma/patologia , Idoso de 80 Anos ou mais , Linfonodos/patologia , Carcinoma de Células Escamosas/patologia , Prognóstico , Melanoma Maligno CutâneoRESUMO
Collagen I is a major component of extracellular matrix in human skin, and is also widely used in a variety of skin-care products. In this study, we investigated the modulatory roles of collagen I on human immortalized keratinocytes HaCaT, especially when cells were irradiated with UVB. Interestingly, the cells grown on plates coated by molecular collagen I, but not fibrillar collagen I, acquired certain resistance against UVB damages, as shown by increased survival and reduced apoptosis. The accumulation of dysfunctional mitochondria in UVB-treated cells was attenuated by molecular collagen I-coating. Interestingly, molecular collagen I rescued the loss of mitochondrial biogenesis in cells treated with UVB. Loss of PINK1/parkin-mediated mitophagy was dominant for the accumulation of dysfunctional mitochondria after UVB irradiation. Of note, cells cultured on molecular collagen I-precoated plates exhibited reserved mitophagy after UVB irradiation, as reflected by the enhanced protein level of PINK1/parkin, increased mitochondrial ubiquitin and the co-localization of lysosomes and mitochondria. Moreover, in UVB-treated cells, inhibiting mitophagy by Cyclosporin A, or by silencing PINK1 or parkin, disturbed the resolution of mitochondrial stress and reduced the protective effect of molecular collagen I, indicating that mitophagy is pivotal for the protection of collagen I against UVB damage in keratinocytes HaCaT. Collectively, this study reveals an unexpected protective role of collagen I, which facilitates mitophagy to rescue cells under UVB irradiation, providing a new direction for clinical application of collagen products.
Assuntos
Apoptose , Mitofagia , Humanos , Queratinócitos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Quinases/metabolismoRESUMO
OBJECTIVES: To evaluate the long-term outcomes of patients treated under our perfusion-based strategy and assess whether conservative treatment without surgical treatment under our strategy is acceptable. MATERIALS AND METHODS: A total of 315 adult and 137 pediatric MMD patients (follow-up period ≥ 3 years from 2001 to 2020) were included. Follow-up events in each patient group (pediatric or adult, surgically treated or conservatively treated) were evaluated and compared to each other using a log-rank test. Risk factors for stroke and nonstroke events were also investigated using a multivariate Cox proportional hazard model. RESULTS: In adult-onset patients, the stroke event rates (person-year %) were not different between surgically treated patients and conservatively treated patients (2.00 % vs. 1.59 %, p = 0.558); however, conservative patients showed a higher stroke rate than surgically treated hemispheres (0.34 %; p = 0.025) and hemorrhagic stroke was the major type (18/26, 69.2 %). Hemorrhagic onset was associated with increased risk of stroke in adults (hazard ratio (95 % confidence interval) = 2.43 (1.10-5.36)). In pediatric-onset patients, no conservatively treated patients experienced stroke; however, nonstroke events occurred more frequently than in surgically treated hemispheres (4.86 % vs. 1.71 %, p = 0.020 for transient ischemic attack; and 7.91 % vs. 1.31 %, p < 0.001 for asymptomatic progression on magnetic resonance angiography). CONCLUSIONS: In adult patients, conservatively treated patients experienced stroke more frequently, especially hemorrhagic stroke. An additive strategy to prevent stroke in hemorrhagic-onset patients without hemodynamic disturbance seems to be needed. Pediatric patients with mild hemodynamic disturbance can be safely observed without initial surgical intervention, but close follow-up for disease progression is necessary.
Assuntos
Revascularização Cerebral , Acidente Vascular Cerebral Hemorrágico , Doença de Moyamoya , Acidente Vascular Cerebral , Adulto , Humanos , Criança , Doença de Moyamoya/complicações , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/cirurgia , Seguimentos , Acidente Vascular Cerebral Hemorrágico/complicações , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/complicações , Prognóstico , Perfusão/efeitos adversos , Revascularização Cerebral/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Ferroptosis, an iron-dependent cell death, is caused by lipid peroxidation. Noteworthily, accumulation of iron and lipid peroxidation are found in the proximity of the neuritic plaque, a hallmark of Alzheimer's disease (AD), but the relationship between ferroptosis and neuroinflammation in AD is unclear. Silibinin, extracted from the Silybum marianum, is possibly developed as an agent for AD treatment from its neuroprotective effect, but the effect of silibinin on sporadic AD that accounts for more than 95% of AD remains unclear. To determine whether silibinin alleviates the pathogenesis of sporadic AD and investigate the underlying mechanisms, STZ-treated HT22 murine hippocampal neurons and intracerebroventricular injection of streptozotocin (ICV-STZ) rats, a sporadic AD model, were used in this study. Results show that silibinin not only promotes survival of STZ-treated HT22 cells, but also ameliorates the cognitive impairment and anxiety/depression-like behavior of ICV-STZ rats. We here demonstrate that silibinin evidently inhibits the protein level of p53 as well as upregulates the protein level of cystine/glutamate antiporter SLC7A11 and ferroptosis inhibitor GPX4, but not p21, leading to the protection against STZ-induced ferroptotic damage. Immunofluorescent staining also shows that accumulation of lipid peroxidation induced by ferroptotic damage leads to increased fluorescence of 8-oxo-deoxyguanosine (8-OHDG), a maker of oxidized DNA. The oxidized DNA then leaks to the cytoplasm and upregulates the expression of the stimulator of interferon gene (STING), which triggers the production of IFN-ß and other inflammatory cascades including NF-κB/TNFα and NLRP3/caspase 1/IL-1ß. However, the treatment with silibinin blocks the above pathological changes. Moreover, in HT22 cells with/without STZ treatment, GPX4-knockdown increases the protein level of STING, indicating that the ferroptotic damage leads to the activation of STING signaling pathway. These results imply that silibinin exerts neuroprotective effect on an STZ-induced sporadic AD model by downregulating ferroptotic damage and thus the downstream STING-mediated neuroinflammation.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Ratos , Camundongos , Animais , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Silibina/farmacologia , Silibina/uso terapêutico , Regulação para Baixo , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estreptozocina/efeitos adversos , Modelos Animais de DoençasRESUMO
Type 2 diabetes (T2DM) is induced by the abundance of glucose and lipids, which causes glucolipotoxicity to the pancreatic ß-cells. Silibinin is a natural flavonoid possessing the regulatory activity on insulin production and therapeutic activity in diabetic mice; however, its effect on glucolipotoxicity is not fully explained. This in vitro study investigates the effects of silibinin on palmitic acid (PA) and high glucose (HG)-induced cell loss and ferroptosis of rat insulinoma INS-1 cells. In the cells treated with PA and HG, expressions of glucose transporter 4 (Glut4) and carnitine acyltransferase I (CPT1) for ß-oxidation of fatty acids are reduced. Mitochondria are the metabolic organelles for glucose and fatty acids. The mitochondrial membrane potential (MMP) and ATP production were decreased, while the ROS level was elevated in the cells treated with PA and HG, indicating an induction of mitochondrial disorder. Cell loss was partially rescued by ferroptosis inhibition, suggesting an involvement of ferroptosis in the cells treated with PA and HG. More importantly, the increases in total iron, lipid ROS, MDA and COX-2, and the decrease in ferroptosis inhibitory molecules GSH, GPX4 and FSP1 appeared in the cells treated with PA and HG, confirming the occurrence of ferroptosis. Moreover, PINK1/parkin-mediated mitophagy, a vital process for selective elimination of damaged mitochondria, was blocked. Interestingly, silibinin rescued the mitochondria, restricted the ferroptosis and restored the mitophagy. By using the pharmacological stimulator and inhibitor of mitophagy, and si-RNA transfection to silence PINK1 expression, silibinin's protective effect against ferroptosis caused by PA and HG treatment was found to depend on mitophagy. Collectively, our current study reveals the new mechanisms for the protection of silibinin against the injury of INS-1 cells treated with PA and HG, elucidates the participation of ferroptosis in glucolipotoxicity, highlighting the involvement of mitophagy in defense against ferroptotic cell death.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ferroptose , Animais , Ratos , Glucose/farmacologia , Mitofagia , Ácido Palmítico/farmacologia , Proteínas Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Silibina/farmacologia , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Ultraviolet B (UVB) irradiation causes skin inflammation and apoptosis. Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in skin damages, little is known about the roles of mitochondrial dynamics in these processes. UVB irradiation increases abnormal mitochondrial content but decreases mitochondrial volume in immortalized human keratinocyte HaCaT cells. UVB irradiation resulted in marked upregulation of mitochondrial fission protein dynamin-related protein 1 (DRP1) and downregulation of mitochondrial outer membrane fusion proteins 1 and 2 (MFN1 and MFN2) in HaCaT cells. Mitochondrial dynamics was discovered to be crucial for NLRP3 inflammasome and cGAS-STING pathway activation, as well as the induction of apoptosis. Inhibition of mitochondrial fission by treatments with a DRP1 inhibitor, mdivi-1, or with DRP1-targeted siRNA, efficiently prevented UVB-induced NLRP3/cGAS-STING mediated pro-inflammatory pathways or apoptosis in the HaCaT cells, whereas inhibition of mitochondrial fusion with MFN1and 2 siRNA increased these pro-inflammatory pathways or apoptosis. The enhanced mitochondrial fission and reduced fusion caused the up-regulation of reactive oxygen species (ROS). Application of an antioxidant, N-acetyl-l-cysteine (NAC), which scavenges excessive ROS, attenuated inflammatory responses through suppressing NLRP3 inflammasome and cGAS-STING pathway activation, and rescued cells from apoptosis caused by UVB-irradiation. Together, our findings revealed the regulation of NLRP3/cGAS-STING inflammatory pathways and apoptosis by mitochondrial fission/fusion dynamics in UVB-irradiated HaCaT cells, providing a new strategy for the therapy of UVB skin injury.
Assuntos
Dinâmica Mitocondrial , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Células HaCaT/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Queratinócitos/metabolismo , Apoptose/efeitos da radiação , Nucleotidiltransferases/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
Ultraviolet B (UVB) irradiation causes skin damages. In this study, we focus on the involvement of mitochondrial disorders in UVB injury. Surprisingly, UVB irradiation increases the amounts of mitochondria in human immortalized keratinocytes HaCaT. However, further analysis shows that ATP levels decreased by UVB treatment in accordance with the collapse of mitochondrial membrane potential (MMP), suggesting an accumulation of dysfunctional mitochondria in UVB-irradiated HaCaT cells. Mitophagy, mainly mediated by PINK1 and parkin, is critical for the elimination of damaged mitochondria. Western blot results show that the levels of both PINK1 and parkin are decreased in UVB-irradiated cells, indicating the impairment of mitophagy. Silencing the expression of PINK1 or parkin by transfection of siRNA shows essentially the same damage to the cells as UVB irradiation does, including increased mitochondrial amount, decreased MMP and ATP production, and enhanced apoptosis, evidencing that repression of PINK1/parkin-mediated mitophagy plays a primary cause of UVB-caused cells damages. We previously found that HaCaT cells exposed to UVB showed activation of the cGAS-STING pathway and apoptosis. Here, silencing PINK1 or parkin also increases the protein levels of cGAS and STING, facilitates nuclear accumulation of NF-κB, and promotes the transcription of IFNß, suggesting for the activation of STING pathway. Mitophagy impairment either by UVB-irradiation or by PINK1/parkin silencing initiates caspase-3-mediated apoptosis, as shown by the activation of caspase-3 and cleavage of PARP, as well as the increase of Hoechst-positive stained cells and Annexin V-positive cells. Further studies find that Bax-mediated permeabilization of mitochondrial membrane is critical for cell apoptosis, as well as the cytosolic leakage of mtDNA in UVB-treated cells, which results in cGAS-STING activation, and these processes are negatively-regulated by PINK1/parkin-mediated mitophagy. This study reveals the involvement of dysfunctional mitochondria due to impaired mitophagy in the damaging effect of UVB irradiation on HaCaT cells. Restoring the mitophagy has the potential to be developed as a new strategy to protect skin from UVB damages.
Assuntos
DNA Mitocondrial , Mitofagia , Humanos , DNA Mitocondrial/metabolismo , Caspase 3/metabolismo , Mitocôndrias/metabolismo , Queratinócitos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Quinases/genética , Trifosfato de Adenosina/metabolismoRESUMO
BACKGROUND: Over-activation of N-methyl-D-aspartate receptors (NMDARs) is involved in sporadic Alzheimer's disease. Silibinin, a natural flavonoid gained from the seeds of Silybum marianum, exerts neuroprotective effects on sporadic AD models, but its impacts on NMDARs remain unknown. PURPOSE: To study silibinin's regulatory effects on NMDARs pathway in sporadic AD models. METHODS: MTT assay, western blotting, confocal microscopy, flow cytometry, RT-PCR, and siRNA transfection etc. were used for cellular and molecular studies. The direct interactions between silibinin and NMDAR subunits were evaluated by computational molecular docking, drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA). Y maze test, novel objects recognition test and Morris water maze test were conducted to examine the learning and memory ability of rats. RESULTS: An in vitro AD model was established by treating HT22 murine hippocampal neurons with streptozotocin (STZ), as evidenced by the amyloid ß (Aß) deposition and hyperphosphorylation of tau proteins. Silibinin shows protection of neurons against STZ-induced cell damage. It is noteworthy that STZ-induced cellular calcium influx is inhibited by silibinin-treatment, indicating the possible modulation of calcium channels. Studies on NMDARs, the most widely distributed calcium channel, by using molecular docking, DARTS and CESTA, reveal that the GluN2B subunit, but not GluN2A, is the potential target of silibinin. Further studies using the pharmacological agonist (NMDA) and the GluN2B-specific inhibitor (Ifenprodil) or siRNA, indicate that the protection by silibinin treatment from STZ-induced cytotoxicity is medicated through interference with GluN2B-containing NMDARs, followed by the upregulation of CaMKIIα/ BDNF/ TrkB signaling pathway and improved levels of synaptic proteins (SYP and PSD-95). The results in vivo using rats intracerebroventricularly injected with STZ (ICV-STZ), a well-established sporadic AD model, confirm that silibinin improves learning and memory ability in association with modulation of the GluN2B/CaMKIIα/ BDNF/TrkB signaling pathway. CONCLUSION: Inhibiting over-activation of GluN2B-containing NMDARs is involved in the neuroprotective effect of silibinin on STZ-induced sporadic AD models.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Ratos , Camundongos , Animais , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Peptídeos beta-Amiloides/metabolismo , Silibina/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estreptozocina , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Simulação de Acoplamento Molecular , Modelos Animais de DoençasRESUMO
The recommended treatment strategy for stage 3 bisphosphonate-related osteonecrosis of the jaw (BRONJ) is currently rigid plate fixation without bone reconstruction. However, a recent systematic review indicated the utility of microsurgical reconstruction after resection of BRONJ. Several types of flaps have been described but their applications are controversial. Here we present a detailed reconstruction plan for obtaining better outcomes in patients with maxillary and mandibular BRONJ. Given that progressive maxillary BRONJ is often invasive to the skin, including the eyelid, leading to functional loss such as leakage of discharge and ectropion, several revision surgeries are needed to increase the volume in the defect after the free flap transfer. For progressive mandibular BRONJ, hemi-mandibulectomy to subtotal mandibulectomy with an adequate margin from the necrotic bone is necessary, followed by a well-designed fibular free flap.
RESUMO
Excessive physical exercise (overtraining, OT) charactered by long-term and excessive training results in the damage of multiple vital tissues including hippocampus which plays a critical role in learning and memory. A combination of dasatinib (D) plus quercetin (Q) (D+Q) belongs to senolytic drugs which selectively kill senescent cells in vitro and vivo. In this study, the rats that suffered a five-week excessive swimming training were subjected to the oral administration of D+Q. D+Q alleviated the decline in exercise performance of OT rats during the swimming training, and prevented learning and memory deficits in Morris water maze, Y-maze and novel object recognition tests after excessive swimming training. Analytical results by SA-ß-gal staining and western blotting showed that D+Q significantly reduced senescent cells with repressed expression of senescence-related proteins, p53 and p21, in hippocampus. Nissl and immunohistochemical staining showed that D+Q significantly attenuated neuronal loss caused by apoptosis. Interestingly, we observed elevated level of cleaved caspase 3, an apoptosis executor protein, in p21 positive hippocampus cells by D+Q treatment in immunofluorescent staining, suggesting that senescent cells were induced to apoptosis in D+Q-treated rats. The positive control drug, silibinin, showed similar protective effect against OT, but did not induce the apoptosis of senescent cells, suggesting a difference in the protective mechanisms. These results indicated that D+Q alleviates overtraining-induced deficits in learning and memory through elimination of senescent cells and reduction of apoptotic cell number.
Assuntos
Apoptose , Quercetina , Ratos , Animais , Quercetina/farmacologia , Dasatinibe/farmacologia , Dasatinibe/metabolismo , Aprendizagem em Labirinto , Senescência Celular , Hipocampo/metabolismoRESUMO
PURPOSE: Severe lymphedema is difficult to treat because of the associated extensive scar formation. Therefore, preventing scar formation might alleviate the severity of lymphedema following lymphadenectomy. In this study, we evaluated the usefulness of flap transfer, performed immediately after lymphadenectomy, for preventing scar formation. METHODS: Twenty-three patients with subcutaneous malignancy in a lower extremity, who underwent inguino-pelvic lymphadenectomy, were divided into groups based on whether flap transfer was performed. The severity of lymphedema was categorized according to the ratio of the circumference of the affected extremity to that of the unaffected extremity, as mild (< 20% increase in volume), moderate (20-40%), or severe (> 40%). RESULTS: In the 18 patients who underwent lymphadenectomy without flap transfer, lymphedema was classified as mild in 7, moderate in 7, and severe in 4. In the five patients who underwent lymphadenectomy with flap transfer, lymphedema was classified as mild in 4 and moderate in 1. This difference between the groups did not reach significance. CONCLUSIONS: The findings of this study suggest that flap transfer may help prevent scar formation and contribute to the restoration of lymph flow after lymphadenectomy.
Assuntos
Cicatriz , Linfedema , Humanos , Excisão de Linfonodo/efeitos adversos , Linfedema/etiologia , Linfedema/prevenção & controle , Linfedema/cirurgia , Extremidade Inferior/cirurgia , Linfonodos/cirurgia , Linfonodos/patologiaRESUMO
The extracellular matrix (ECM) regulates cell behavior through signal transduction and provides a suitable place for cell survival. As one of the major components of the extracellular matrix, type I collagen is involved in regulating cell migration, proliferation and differentiation. We present a system in which 3T3-L1 preadipocyte cells are induced for adipogenic differentiation on type I collagen coated dishes. Our previous study has found that type I collagen inhibits adipogenic differentiation via YAP activation. Here we further reveal that type I collagen inactivates autophagy by up-regulating mTOR activity via the YAP pathway. Under collagen-coating conditions, co-localization of lysosomes with mTOR was increased and the level of downstream protein p-S6K was elevated, accompanied by a decrease in the level of autophagy. Autophagy is negatively correlated with adipogenesis under type I collagen coating. Through the YAP-autophagy axis, type I collagen improves glycolipid metabolism accompanied by increased mitochondrial content, enhanced glucose uptake, reduced release of free fatty acids (FFAs) and decreased intracellular lipid accumulation. Our findings provide insight into the strategy for dealing with obesity: Type I collagen or the drugs with inhibitory effects on autophagy or YAP, have a potential to accelerate the energy metabolism of adipose tissue, so as to better maintain the homeostasis of glucose and lipids in the body, which can be used for achieving weight loss.
Assuntos
Adipócitos , Adipogenia , Colágeno Tipo I , Metabolismo dos Lipídeos , Serina-Treonina Quinases TOR , Proteínas de Sinalização YAP , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Animais , Autofagia/genética , Autofagia/fisiologia , Diferenciação Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipídeos , Camundongos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Sinalização YAP/genética , Proteínas de Sinalização YAP/metabolismoRESUMO
Alcoholic liver disease has become one of the main causes of liver injury, and its prevention and cure are important medical tasks. Silibinin, a natural flavonoid glycoside, is a conventional hepatic protectant. This study elucidates the modulation of ferroptosis in silibinin's protective effects on ethanol- or acetaldehyde-induced liver cell damage by using human carcinomatous liver HepG2 cells and immortalized liver HL7702 cells. Our results show that ferroptosis is induced in the cells treated with ethanol or acetaldehyde, as evidenced by the increased ROS stress and iron level. Silibinin resolves the oxidative stress and reduces iron level. Ferroptosis induced by ethanol- or acetaldehyde involving nuclear receptor co-activator 4 (NCOA4)-dependent autophagic degradation of ferritin, a protein for storing iron is rescued by silibinin. PINK1 and Parkin-mediated mitophagy is arrested in ethanol- or acetaldehyde-treated cells but reversed by silibinin. Ferritin degradation and ROS level are further increased when PINK1 or Parkin is silenced in the cells treated with ethanol or acetaldehyde. Collectively, our study reveals that silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in two liver cell lines, HepG2 and HL7702 cells, providing new therapeutic strategies for alcoholic liver injury.
Assuntos
Acetaldeído , Ferroptose , Acetaldeído/toxicidade , Linhagem Celular , Etanol/toxicidade , Ferritinas , Humanos , Ferro , Fígado , Proteínas Quinases , Espécies Reativas de Oxigênio , Silibina/farmacologia , Ubiquitina-Proteína LigasesRESUMO
Japanese encephalitis virus (JEV), a mosquito-borne virus, causes severe clinical symptoms in humans in the Asian-Pacific region, where it circulates in a primary transmission cycle among Culex tritaeniorhynchus mosquitoes, domestic swine (Sus scrofa domesticus), and wading birds. We report here an anomalous result that mosquito-borne JEV was detected in unfed host-questing ticks collected from the field in Japan. JEV genomic RNA was detected in four pools of Haemaphysalis flava nymphs collected in November and December 2019, and March 2020, when Cx. tritaeniorhynchus adults were not presumed to be active. Moreover, JEV antigenomic RNA was detected in some JEV-positive tick samples, suggesting virus replication in ticks. However, taken together with no infectious virus isolated, the possibility that the antigenomic RNA was derived from the undigested bloodmeal source in ticks cannot be ruled out. Thus, the role of the ticks as a natural reservoir for JEV remains to be confirmed.
RESUMO
INTRODUCTION: Rectourethral fistula (RUF) after prostatectomy is a rare complication; however, when it occurs it is likely to be intractable and treatment requires surgical closure of the fistula. Several approaches to fistula closure have been reported, but there is no established treatment. CASE PRESENTATION: The patient was a 66-year-old man who had undergone robot-assisted laparoscopic radical prostatectomy for prostate cancer. On the 16th postoperative day, RUF was diagnosed. Cystostomy, laparoscopic ileostomy and transanal fistula closure were performed, and conservative treatment was continued for 5 months; however, the RUF remained, so the patient underwent fistula closure with a gracilis muscle flap using both transperineal and laparoscopic manipulation. Because it was a high fistula, the RUF was difficult to fill with a transperineal approach alone; however, in combination with laparoscopic manipulation, the appropriate filling of the fistula was possible. CLINICAL DISCUSSION: Although few reports have described the use of the laparoscopic transabdominal approach in combination with a transperineal gracilis muscle flap, the advantages of this technique are that the superior part of the fistula can be dissected, the flap can be filled more securely than with a transperineal approach alone, and transabdominal manipulation can be performed in a less invasive manner. In addition, by coordinating perineal and laparoscopic manipulation, we were able to close the fistula without organ damage by safe dissection. CONCLUSION: The laparoscopic approach is useful for RUF closure because it allows the interposition of the flap to reliably fill the space between the bladder and the rectum.