RESUMO
OBJECTIVE: Facial paralysis (FP), which resulted from head and neck cancer resection, significantly impacts patients' quality of life. Traditional assessments rely on subjective evaluations and electromyography, whereas functional magnetic resonance imaging offers a noninvasive alternative for enhanced rehabilitation. Acupuncture has shown promise in promoting cerebral cortex reorganization, yet the precise relationship between acupuncture-induced structural and functional changes remains unclear, necessitating further investigation into therapeutic mechanisms. METHODS: Fifty-five patients afflicted with FP underwent evaluations using voxel-mirrored homotopic connectivity (VMHC) and tract-based spatial statistics and were divided into the acupuncture intervention group (n = 35) and pseudo intervention group (n = 20). Comparative analyses of metrics pre and postintervention were conducted to delineate therapy-induced modifications in acupuncture intervention. The postacupuncture effect between groups to verify the necessity of accurate positioning for the rehabilitation of FP. RESULTS: Patients with FP showed deficits in VMHC in regions of the postcentral, precentral, and parietal areas. Corpus callosum and internal capsule showed significantly increased fractional anisotropy of the white matter skeleton in tract-based spatial statistics after treatment. Comparison postintervention results between groups exhibited deficits in VMHC and increased fractional anisotropy in regions of the corpus callosum in the acupuncture intervention group. CONCLUSIONS: Early acupuncture intervention may suppress cortical hyperactivation and restore interhemispheric inhibition across the corpus callosum to inhibit maladaptive structural plasticity. Precise acupoint localization is crucial for effective therapy, highlighting the potential of postacupuncture cortical space data for refining therapeutic strategies.
RESUMO
BACKGROUND: Lower eyelid suspension, a common therapeutic procedure for facial paralysis-induced eyelid retraction, faces challenges due to high recurrence in patients lacking facial muscle function and impedes wider adoption. This research aims to explore the potential effects of restoring orbicularis oculi muscle tension through facial nerve reanimation prior to lower eyelid suspension and to define the indications for lower eyelid suspension. METHODS: The study encompassed 32 individuals with complete facial paralysis, segmented into group A (reanimation group) and group B (non-reanimation group), based on whether the orbicularis oculi muscle's tension was restored through facial nerve reconstruction prior to lower eyelid suspension. Subjective assessments of eyelid closure (the inter-eyelid gap upon gentle closure) and objective methods measures of scleral show (the distance from the pupil's center to the lower eyelid margin, MRD2) were used to provide a comprehensive analysis of long-term effectiveness. RESULTS: The group A exhibited significantly greater long-term improvement in lagophthalmos and lower eyelid ectropion. The alterations in MRD2 measured 2.66 ± 0.27 mm in the group A versus 2.08 ± 0.53 mm in the group B, denoting a statistically significant variance (p < 0.001). Moreover, while the ratio of MRD2 preoperative 6 months postoperative revealed no significant difference between groups, a significant difference emerged in 12 months postoperative (group A: 1.02 ± 0.21; group B: 1.18 ± 0.24; p < 0.05), with the values in group A closer to 1, indicative of enhanced symmetry. CONCLUSIONS: Restoring the tension in the orbicularis oculi muscle through facial nerve reconstruction prior to palmaris longus tendon sling could effectively sustain long-term outcomes of lower eyelid retraction correction and reduce the recurrence rate. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
RESUMO
Tumor-associated macrophages (TAMs) has been regarded as the most prominent component in tumor microenvironment. The correlation between TAM density and poor prognosis in Hepatocellular carcinoma (HCC) patients suggests a supportive role for TAMs in tumor progression. Here we employed a co-culture system to interrogate the molecular link between Yes-Associated Protein (YAP) and TAMs chemotaxis in HCC cells. We found that YAP activation was critical for the recruitment of TAMs towards HCC cells. Furthermore, cytokine array and quantitative RT-PCR analyses showed that IL-6 secreted by YAP-activated HCC cells might induce the TAMs recruitment. Interrupting YAP function by statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could robustly suppress the chemotaxis of TAMs. Together with our findings that the expression levels ofIL-6inhumanHCC tumors were highly correlated with the prognosis of HCC patients, the current study highlight the possibility of improving HCC treatment by targeting YAP-IL-6 mediated TAMs recruitment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Carcinoma Hepatocelular/patologia , Interleucina-6/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/patologia , Macrófagos/fisiologia , Fosfoproteínas/fisiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Progressão da Doença , Células Hep G2 , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular , Prognóstico , Fatores de Transcrição , Microambiente Tumoral , Proteínas de Sinalização YAPRESUMO
Recent evidence shows that resveratrol (RSV) may ameliorate high-glucose-induced cardiac oxidative stress, mitochondrial dysfunction and myocardial fibrosis in diabetes. However, the mechanisms by which RSV regulates mitochondrial function in diabetic cardiomyopathy have not been fully elucidated. Mitochondrial dysfunction contributes to cardiac dysfunction in diabetic patients, which is associated with dysregulation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In this study we examined whether resveratrol alleviated cardiac dysfunction in diabetes by improving mitochondrial function via SIRT1-mediated PGC-1α deacetylation. T2DM was induced in rats by a high-fat diet combined with STZ injection. Diabetic rats were orally administered RSV (50 mg·kg-1·d-1) for 16 weeks. RSV administration significantly attenuated diabetes-induced cardiac dysfunction and hypertrophy evidenced by increasing ejection fraction (EF%), fraction shortening (FS%), ratio of early diastolic peak velocity (E velocity) and late diastolic peak velocity (A velocity) of the LV inflow (E/A ratio) and reducing expression levels of pro-hypertrophic markers ANP, BNP and ß-MHC. Furthermore, manganese superoxide dismutase (SOD) activity, ATP content, mitochondrial DNA copy number, mitochondrial membrane potential and the expression of nuclear respiration factor (NRF) were all significantly increased in diabetic hearts by RSV administration, whereas the levels of malondialdehvde (MDA) and uncoupling protein 2 (UCP2) were significantly decreased. Moreover, RSV administration significantly activated SIRT1 expression and increased PGC-1α deacetylation. H9c2 cells cultured in a high glucose (HG, 30 mmol/L) condition were used for further analyzing the role of SIRT1/PGC-1α pathway in RSV regulation of mitochondrial function. RSV (20 µmol/L) caused similar beneficial effects in HG-treated H9c2 cells in vitro as in diabetic rats, but these protective effects were abolished by addition of a SIRT1 inhibitor sirtinol (25 µmol/L) or by SIRT1 siRNA transfection. In H9c2 cells, RSV-induced PGC-1α deacetylation was dependent on SIRT1, which was also abolished by a SIRT1 inhibitor and SIRT1 siRNA transfection. Our results demonstrate that resveratrol attenuates cardiac injury in diabetic rats through regulation of mitochondrial function, which is mediated partly through SIRT1 activation and increased PGC-1α deacetylation.
Assuntos
Cardiotônicos/uso terapêutico , Cardiomiopatias Diabéticas/tratamento farmacológico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Estilbenos/uso terapêutico , Acetilação/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Cardiomegalia/tratamento farmacológico , Cardiotônicos/administração & dosagem , Linhagem Celular , Masculino , Mitocôndrias/metabolismo , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Resveratrol , Estilbenos/administração & dosagem , Proteína Desacopladora 2/metabolismo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Oreocharisleveilleana Fedde was collected in Ta-pin in 1910 and published in 1911. The collected location was verified within western Luodian County, Guizhou Province, China. However, there have been no records of the species' collection for more than 100 years since then. After extensive investigations by our research team on the type locality and its surrounding areas, we found that it is widely distributed in western Luodian County and eastern Wangmo County, Guizhou Province, China. During further research on the original literature, type specimens and type locality of O.leveilleana, the taxonomic position of O.leveilleana, which was once treated as a synonym of O.auricula (S.Moore) C.B.Clarke, was found to have a taxonomic problem. Through morphological research combined with geographical distribution analysis, it has been determined that it should belong to the genus Petrocodon Hance and it is the same species as P.coccineus (C.Y.Wu ex H.W.Li) Yin Z.Wang. According to the regulations and suggestions of the 2018 "International Code of Nomenclature for Algae, Fungi, and Plants (Shenzhen Code)", we propose and confirm a new combination - Petrocodonleveilleanus (Fedde) X.X.Bai & F.Wen and treat P.coccineus as a synonym of the new combination. Due to its unique bright red flowers within Petrocodon, its original Chinese name has been retained.
RESUMO
BACKGROUND: Facial palsy, often resulting from trauma or iatrogenic treatments, leads to significant esthetic and functional impairment. Surgical interventions, such as masseteric-to-facial nerve transfer combined with static suspension, are frequently recommended to restore facial nerve function and symmetry. METHODS: This study examines how Botulinum Toxin A (BoNT-A) treatment on the unaffected side affects facial symmetry and brain connectivity in patients with severe oral commissure droop from facial nerve damage. Patients were divided into two groups: one received BoNT-A injections on the unaffected side, and the other did not. RESULTS: Our findings revealed that BoNT-A treatment not only improved facial symmetry but also induced significant modifications in brain functional network connectivity. These modifications extended beyond the sensorimotor network, involving high-level cognitive processes, and exhibited a significant correlation with the degree of facial asymmetry. CONCLUSIONS: These results provide valuable insights into the mechanisms underlying the positive effects of BoNT-A intervention on motor recovery and brain plasticity in facial palsy patients. Furthermore, the study emphasizes the importance of a multidisciplinary approach to facial palsy rehabilitation. Understanding these intricate interactions between facial symmetry restoration and brain network adaptations may pave the way for more effective treatments and improved quality of life for individuals dealing with facial palsy.
RESUMO
OBJECTIVE: To evaluate the effect of Notoginseng Radix on hepatic expression of transforming growth factor beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in rats with alcoholic liver disease (ALD), in order to discuss its protective effect on alcoholic cirrhosis. METHOD: Fifty SD male rats were divided into the normal control group, the model group, the high-dose and low-dose Notoginseng Radix groups (3.0, 12.0 g x kg(-1)) and the magnesium isoglycyrrhizinate group (24 mg x kg(-1)), with 10 rats in each group. Apart from the control group, other groups were administered with ethanol-cornoil-pyrazole for 14 weeks to establish the alcoholic liver disease model. During the establishment of the model, the high-dose and low-dose Notoginseng Radix groups were administered with 12 g x kg(-1) x d(-1) Notoginseng Radix for 14 weeks, once everyday. Efforts were made to detect liver function, pathology with Masson staining, and the expressions of TGF-beta1, Smad3, Smad7 and CTGF mRNA. RESULT: Compared with the rats in model group, rats in Notoginseng Radix groups showed significant reduction in liver ALT, AST, collagen fiber deposition, and TGF-beta1, Smad3 and CTGF mRNA expressions in liver tissues, with the increase in the expression quantity of Smad7 mRNA. There were differences between the Notoginseng Radix groups. No significant difference was observed between the high-dose Notoginseng Radix group and the magnesium isoglycyrrhizinate group. CONCLUSION: Notoginseng Radix can affect TGF-beta1/Smads signaling pathway and reduce the expression of CTGF.
Assuntos
Fator de Crescimento do Tecido Conjuntivo/genética , Medicamentos de Ervas Chinesas/administração & dosagem , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/genética , Panax notoginseng/química , Proteína Smad3/genética , Proteína Smad7/genética , Fator de Crescimento Transformador beta1/genética , Animais , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Hepatopatias Alcoólicas/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
One-stage combined dynamic reanimation with static suspension has obvious advantages of improving facial symmetry. In clinical observation, patients with different levels of oral commissure drooping achieve different symmetry outcomes, despite undergoing the same surgical procedure. Patients with slight asymmetry obtain better outcomes than those with severe asymmetry. The mechanisms influencing postoperative outcomes have not been systematically explored. We retrospectively analyzed 44 patients performed with masseteric-to-facial nerve transfer combined with static suspension. Patients were divided into two groups according to the level of oral commissure drooping: slight-asymmetry group (n = 24) and severe-asymmetry group (n = 20). Static and dynamic symmetry were assessed with FACE-gram software pre and postoperatively. The symmetry of the oral commissures at rest and during smiling significantly improved postoperatively in all patients. The differences of the bilateral oral commissure positions were significantly smaller in slight-asymmetry group than that in severe-asymmetry group (p<0.001), indicating that slight-asymmetry group achieved better symmetry. Furthermore, these differences were caused by the oral commissures position on the unaffected side, both pre and postoperatively (p<0.001), but not the paralyzed side's (p>0.05). In conclusion, masseteric-to-facial nerve transfer combined with static suspension achieved dynamic and static symmetry in patients with different levels of asymmetry. Patients with slight asymmetry obtained better postoperative symmetry than those with severe asymmetry. Postoperative facial asymmetry might be influenced by the hypertonicity of facial muscles on the unaffected side.
Assuntos
Paralisia Facial , Transferência de Nervo , Procedimentos de Cirurgia Plástica , Nervo Facial/cirurgia , Paralisia Facial/cirurgia , Humanos , Nervo Mandibular/cirurgia , Transferência de Nervo/métodos , Procedimentos de Cirurgia Plástica/métodos , Estudos Retrospectivos , Sorriso/fisiologiaRESUMO
Facial asymmetry is the major complaint of patients with unilateral facial nerve lesions. Frustratingly, although patients experience the same etiology, the extent of oral commissure asymmetry is highly heterogeneous. Emerging evidence indicates that cerebral plasticity has a large impact on clinical severity by promoting or impeding the progressive adaption of brain function. However, the precise link between cerebral plasticity and oral asymmetry has not yet been identified. In the present study, we performed functional magnetic resonance imaging on patients with unilateral facial nerve transections to acquire in vivo neural activity. We then identified the regions of interest corresponding to oral movement control using a smiling motor paradigm. Next, we established three local networks: the ipsilesional (left) intrahemispheric, contralesional (right) intrahemispheric, and interhemispheric networks. The functional connectivity of each pair of nodes within each network was then calculated. After thresholding for sparsity, we analyzed the mean intensity of each network connection between patients and controls by averaging the functional connectivity. For the objective assessment of facial deflection, oral asymmetry was calculated using FACEgram software. There was decreased connectivity in the contralesional network but increased connectivity in the ipsilesional and interhemispheric networks in patients with facial nerve lesions. In addition, connectivity in the ipsilesional network was significantly correlated with the extent of oral asymmetry. Our results suggest that motor deafferentation of unilateral facial nerve leads to the upregulated ipsilesional hemispheric connections, and results in positive interhemispheric inhibition effects to the contralesional hemisphere. Our findings provide preliminary information about the possible cortical etiology of facial asymmetry, and deliver valuable clues regarding spatial information, which will likely be useful for the development of therapeutic interventions.
RESUMO
Primulinasilaniae X.X.Bai & F.Wen, a new species of Primulina Hance (Gesneriaceae) from the limestone area of Wangmo County, Guizhou Province, is described and illustrated. The new species is similar to P.spiradiclioides Z.B.Xin & F.Wen, but can be easily distinguished from the latter by a combination of characteristics, especially in the lateral veins of its leaf and floral shape and tube. At present, three populations in one locality of this new taxon were found, totaling about 600 mature individuals. According to the IUCN Red List Categories and Criteria (Version 3.1), the species is provisionally assessed as Vulnerable [VU D1].
RESUMO
FeOOH on the real catalytic interface for the oxygen evolution reaction (OER) is chemically unstable to dissolve in alkaline media. Herein, based on the perspective of the dynamically stable interface, we purposely design the well-dispersed nanorod arrays of CoMoO4 as a host on activated iron foam (IF) to realize the optimal redeposition of FeOOH, constructing a self-sacrificial template rich in the FeOOH surface. Notably, at long-time oxidation potential, the precatalyst FeOOH-CoMoO4 can realize MoO42- dissolution and redeposition of Co oxyhydroxides on FeOOH host simultaneously, constructing a dynamically stable Fe(Co)OOH interface. The introduction of CoOOH improves conductivity and provides synergistic effect with FeOOH to lower the energy barrier for OER and maintain long-time stability, eventually exhibiting a low overpotential of 298 mV to reach the current density of 100 mA cm-2 and high stability over 60 h. This work demonstrates the feasibility of manipulating metal dissolution-redeposition process for a dynamically stable interface.
RESUMO
BACKGROUND: Mycoplasma pneumoniae pneumonia is generally a self-limiting disease, but it can develop into severe Mycoplasma pneumoniae pneumonia (SMPP). Immunologic mechanisms are thought to play an important role in the pathogenesis of SMPP. Therefore, the use of systemic glucocorticoids may have beneficial effects. However, to date, the use of glucocorticoid therapy in SMPP is limited to small case series, and the glucocorticoid dosage for children with SMPP has not been established. METHODS: Here, we used a meta-analysis method to collect data from randomized control trials of different doses of methylprednisolone in SMPP to assess the safety and efficacy of treatment with low- versus high-dose methylprednisolone in children with SMPP. RESULTS: We included 13 Chinese randomized control trials that included 1049 children. The high- and low-dose groups were comprised of 524 and 525 children, respectively. The high-dose group was significantly more effective than the low-dose group in clinical efficacy [risk ratio = 1.30, 95% confidence interval (CI) (1.23, 1.38), P < 0.05]. In addition, compared with low-dose methylprednisolone, high-dose methylprednisolone significantly shortened hospital stays and antipyretic therapy, pulmonary rales disappearance, cough disappearance and pulmonary shadow absorption times. There was no significant difference in adverse events between the high- and low-dose groups: risk ratio= 0.85, 95% CI (0.53, 1.36), P > 0.05. CONCLUSIONS: We conclude that high-dose methylprednisolone is effective in the treatment of SMPP without increasing the incidence of adverse reactions.
Assuntos
Anti-Inflamatórios/administração & dosagem , Metilprednisolona/administração & dosagem , Mycoplasma pneumoniae/efeitos dos fármacos , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/microbiologia , Anti-Inflamatórios/efeitos adversos , Criança , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Tempo de Internação , Metilprednisolona/efeitos adversos , Pneumonia por Mycoplasma/diagnóstico , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Avaliação de Sintomas , Resultado do TratamentoRESUMO
In situ electrochemical activation as a new pretreating method to adjust electrocatalytic performance attracts extensive attention. However, the activation mechanisms of electrocatalysts are still ambiguous. Herein, we propose a facile modulation strategy of in situ cathodic activation of FePx based on W-incorporation (W-FePx/IF) for the hydrogen evolution reaction (HER). The activated W-FeOx with obvious surface reconstruction demonstrates the role of W-incorporation for driving the cathodic activation of FePx, which suggests the larger surface area and more active sites. In fact, W incorporation can not only accelerate the cathodic activation process but also act as the adsorption sites for Had to form the synergistic effect with FeOx for water dissociation. The obtained W-FeOx/IF exhibits greatly enhanced HER activity featuring decreased overpotential from 237.7 to 154.0 mV at 100 mA cm-2, which may be ascribed to W-FeOx with double catalytic active sites after cathodic activation. Additionally, the modulation effects of cathodic activation can be exactly achieved by changing electrochemical parameters such as CV cycles. W-FeOx/IF also shows excellent long-term stability for at least 100 h at 100 mA cm-2. This modulation engineering based on metal doping is expected to provide inspiration for the understanding of the cathodic activation process for efficient electrocatalysts.
RESUMO
OBJECTIVE: To determine the reversal effect of aloe emodin liposomes (AE-L) on cisplatin resistance human lung adenocarcinoma cell line A549/DDP. METHOD: The un-cytotoxic and cytotoxic concentration of AE-L, and un-cytotoxic concentration of E-L were determined by MTT. The sensitivity of cisplatin were determined by MTT assay in above 3 groups. The intracellular concentration of cisplatin was detected by inductively coupled plasma mass spectrometry (ICP-MS). RESULT: The maximum non-toxic concentration group of AE-L (2.0 mg x L(-1)) increased the sensitivity of cisplatin in A549/DDP, decreased IC50 of cisplatin in A549/DDP from 16.81 mg x L(-1) to 5.86 mg x L(-1), and the hyp-cytotoxic concentration (7.0 mg x L(-1) ) group's IC50 decreased to 4.34 mg x L(-1); AE-L groups significantly increased intracellular concentration of cisplatin in A549/DDP cells. CONCLUSION: The results showed that aloe emodin can reverse multidrug resistance (MDR) of A549/DDP cells and the mechanism might be associated with the increase of intracellular concentration of cisplatin.
Assuntos
Antraquinonas/química , Antraquinonas/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipossomos , Adenocarcinoma/patologia , Animais , Antraquinonas/efeitos adversos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Dose Letal Mediana , Neoplasias Pulmonares/patologiaRESUMO
The traditional synthesis for bimetallic-based electrocatalysts is challengeable for fine composition and elemental distribution because of the uncontrollable growth speed of nanostructures utilizing metal salt precursors. Herein, a unique electrochemical corrosion engineering strategy is developed via electrochemically transforming metal solid substrates (iron foil and nickel foam) into a highly active Ni-Fe oxide film for oxygen evolution, rather than directly utilizing metal ion precursors. This synthesis involves electrochemical corrosion of a Fe foil in an aqueous electrolyte along with electrochemical passivation of Ni foam (NF). The released trace Fe ions gradually incorporate into passivated NF surfaces to construct Ni-Fe oxide film and crucially improve composition distribution in the catalyst film. As a result, the resulted film with an ultralow mass loading (0.22 mg cm-2) delivers large current densities of 500 mA cm-2 at overpotential of only 270 mV in 6.0 M KOH at 60 °C, outperforming many reported NiFe catalysts requiring much higher mass loadings. More interestingly, the as-prepared catalyst almost reaches the standard (500 mA cm-2 within the overpotential of 300 mV) in commercial water electrolysis with long-term stability for at least 10 h. This work may provide a unique synthesis strategy for nonprecious transition-metal catalysts for desirable water splitting and can be expanded to many other electrocatalysis systems.
RESUMO
A 66-year-old male patient with a 10-year course of Parkinson's disease (PD) was admitted for hallucination lasting a half a month. After treatment with levodopa/carbidopa, selegiline, and piribedil, the patient's motor symptoms were improved while no significant effects were observed on psychotic symptoms. A clinical pharmacist analyzed the pharmacologic and pharmacokinetic characteristics of selegiline and piribedil, summarized the scheme of PD with psychotic symptoms in the literature, and discovered that selegiline might potentiate psychotic side effects of piribedil, while the use of levodopa/carbidopa cannot be ruled out either. Finally, the clinical pharmacist proposed to reduce the dosage of levodopa/carbidopa, increase the dosage of selegiline and quetiapine, and discontinue piribedil. The clinician accepted this suggestion. After the adjustment of medication, the patient's motor symptoms were absolutely improved and the psychotic symptoms were notably improved. This case study suggests that long-term treatment with levodopa/carbidopa and piribedil, along with the progression of the disease itself, could contribute to the emergence of psychotic symptoms in PD. Additionally, selegiline could potentiate psychotic side effects of piribedil. Neurology clinical pharmacists should work alongside neurology clinicians at the bedside to optimize pharmacotherapy, improve patient safety, and contribute to scholarly efforts.
RESUMO
Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Hepáticas/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/efeitos dos fármacos , Atorvastatina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos Nus , Niacinamida/farmacologia , Fosfoproteínas/genética , Prognóstico , Transporte Proteico/efeitos dos fármacos , Sorafenibe , Fatores de Transcrição , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAPRESUMO
Nuclear factor-kappa B (NF-kappaB) regulates the expression of various genes, several genes involved in inflammation and tumorigenesis, including those of the liver. A role for NF-kappaB has been implicated in the pathogenesis of hepatocellular carcinoma. This transcription factor can regulate hTERT gene transcription. Expression of hTERT was found to be at high levels in hepatocellular carcinoma. However, positive effects of NF-kappaB on hTERT protein synthesis in HepG(2) cells are unknown. In this study, we show that LPS (specific binding to TLR4 to activate NF-kappaB) was positive for NF-kappaB p65 mRNA expression and activation, and also up-regulated hTERT mRNA and protein expressions at 36h in a dose-dependent manner. In contrast, MG-132 (blocking the activity of 26S proteasome and thereby preventing nuclear translocation of NF-kappaB) significantly inhibited activation of NF-kappaB and mRNA expression. And also reduced the expression of hTERT at both mRNA and protein levels at 36h in a dose-dependent manner. Furthermore, dexamethasone inhibited LPS-induced activation of NF-kappaB and expression of the hTERT in HepG(2) cells. These findings suggest that NF-kappaB may modulate hTERT mRNA level, importantly, in protein level in HepG(2) cells and dexamethasone inhibits LPS-induced hTERT via blocking NF-kappaB.