RESUMO
Wolf-Hirschhorn syndrome candidate 1 (WHSC1) is a transcriptional regulatory protein that encodes a histone methyltransferase to control H3K36me2 modification. WHSC1 was upregulated and associated with poor prognosis in HCC. The elevated WHSC1 likely due to the alterations of DNA methylation or RNA modification. WHSC1 perhaps form a chromatin cross talk with H3K27me3 and DNA methylation to regulate transcription factors expression in HCC. Functional analysis indicated that WHSC1 was involved in DNA damage repair, cell cycle, cellular senescence and immune regulations. Furthermore, WHSC1 was associated with the infiltrating levels of B cell, CD4+, Tregs and macrophage cells. Therefore, our findings suggested that WHSC1 might function as a promotor regulator to affect the development and progression of HCC. Thus, WHSC1 could be a potential biomarker in predicting the prognosis and therapeutic target for patients with HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Senescência Celular/genética , Dano ao DNA/genética , Histonas/genética , Histonas/metabolismo , Imunidade , Neoplasias Hepáticas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/metabolismoRESUMO
Sugarcane leaf scald is a systemic disease caused by Xanthomonas albilineans that limits sugarcane yield and quality. Previous research has shown that exogenous application of copper hydroxide to plants is effective in controlling this disease. However, long-term bactericide use causes serious "3R" problems: resistance, resurgence, and residue. It is therefore urgent to discover new methods for the improvement of bactericide efficiency and efficacy. In the present study, disease index values for leaf scald were measured in sugarcane seedlings over time to determine the effects of different concentrations of copper hydroxide, types of silicon additive, and treatment timing after inoculation with X. albilineans on controlling sugarcane leaf scald disease. Our results show copper hydroxide mixed with organosilicon additive could improve the bactericide efficiency and efficacy and reduce the growth of pathogenic bacteria, even at a reduced concentration in both laboratory and field conditions. This study provides an important practical model for controlling sugarcane leaf scald disease by reducing the concentration of bactericide and increasing its efficacy in sugarcane fields.
Assuntos
Saccharum , Xanthomonas , Saccharum/microbiologia , Folhas de Planta/microbiologiaRESUMO
Growing evidences have shown that patients recovering from stroke experience high and unremitting stress. Chronic restraint stress (CRS) has been found to exacerbate neurological impairments in an experimental focal cortical ischemia model. However, there have been no studies reporting the effect and mechanism of CRS on intracerebral hemorrhage (ICH). This study aimed to evaluate the effect of CRS on a mouse ICH model. Adult male C57BL mice were subjected to infusion of collagenase IV (to induce ICH) or saline (for sham) into the left striatum. After ICH, animals were stressed with application of CRS protocol for 21 days. Our results showed that CRS significantly exacerbated neurological deficits (Garcia test, corner turn test, and wire grip test) and the ipsilateral brain atrophy and reduced body weight gain after ICH. Immunofluorescence staining indicated that CRS exerted significant suppressive effects on neuron, astrocyte, vascular endothelial cell and pericyte and excessively activated microglia post ICH. All of the key cellular components mentioned above are involved in the neurovascular unit (NVU) remodeling in the peri-hemorrhagic region after ICH. Western blot results showed that matrix metalloproteinase (MMP)-9 and tight junction (TJ) proteins including zonula occludens-1, occludin and claudin-5 were increased after ICH, but MMP-9 protein was further up-regulated and TJ-related proteins were down-regulated by CRS. In addition, ICH-induced activation of endoplasmic reticulum stress and apoptosis were further strengthened by CRS. Collectively, CRS exacerbates neurological deficits and disrupts the remodeling of the peri-hemorrhagic NVU after ICH, which may be associated with TJ proteins degradation and excessive activation of MMP-9 and endoplasmic reticulum stress-apoptosis.LAY SUMMARYCRS exacerbates neurological deficits and disrupts the remodeling of the NVU in the recovery stage after ICH, which suggest that monitoring chronic stress levels in patients recovering from ICH may merit consideration in the future.
Assuntos
Hemorragia Cerebral , Estresse Psicológico , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NeurôniosRESUMO
Traumatic brain injury (TBI) is a complex injury that can cause severe disabilities and even death. TBI can induce secondary injury cascades, including but not limited to endoplasmic reticulum (ER) stress, apoptosis and autophagy. Although the investigators has previously shown that salubrinal, the selective phosphatase inhibitor of p-eIF2α, ameliorated neurologic deficits in murine TBI model, the neuroprotective mechanisms of salubrinal need further research to warrant the preclinical value. This study was undertaken to characterize the effects of salubrinal on cell death and neurological outcomes following TBI in mice and the potential mechanisms. In the current study, ER stress-related proteins including p-eIF2α, GRP78 and CHOP showed peak expressions both in the cortex and hippocampus from day 2 to day 3 after TBI, indicating ER stress was activated in our TBI model. Immunofluorescence staining showed that CHOP co-located NeuN-positive neuron, GFAP-positive astrocyte, Iba-1-positive microglia, CD31-positive vascular endothelial cell and PDGFR-ß-positive pericyte in the cortex on day 2 after TBI, and these cells mentioned above constitute the neurovascular unit (NVU). We also found TBI-induced plasmalemma permeability, motor dysfunction, spatial learning and memory deficits and brain lesion volume were alleviated by continuous intraperitoneal administration of salubrinal post TBI. To investigate the underlying mechanisms further, we determined that salubrinal suppressed the expression of ER stress, autophagy and apoptosis related proteins on day 2 after TBI. In addition, salubrinal administration decreased the number of CHOP+/TUNEL+ and CHOP+/LC3+ cells on day 2 after TBI, detected by immunofluorescence. In conclusion, these data imply that salubrinal treatment improves morphological and functional outcomes caused by TBI in mice and these neuroprotective effects may be associated with inhibiting apoptosis, at least in part by suppressing ER stress-autophagy pathway.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Cinamatos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Tioureia/análogos & derivados , Animais , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Masculino , Camundongos , Camundongos Endogâmicos ICR , Tioureia/farmacologiaRESUMO
The purpose of this study was aimed at identifying the influence of metal cations such as Mg2+, Ca2+, Al3+ and Fe3+ on poly-phosphate (poly-P) and total phosphate (T-P) release from sewage sludge collected from wastewater treatment plant during thermal treatment at 70 degrees C for 80 min. With the addition of chelating reagent such as EDTA, release of poly-P and T-P was improved obviously during thermal treatment. Inhibitory effect of metal cations on phosphorus release was apparent by adding metal cations into sludge sample. Most of Ca, Al and Fe inside of cell could be released into the supernatant, but captured in extracellular polymeric substance (EPS); oppositely, large quantity of Mg could be released into the supernatant directly and not concentrated in EPS. Performance of sewage sludge on phosphorus release in summer and winter was different; different precipitation and temperature possibly result in this phenomenon.
Assuntos
Cátions/química , Metais/química , Polifosfatos/química , Esgotos/química , Gerenciamento de Resíduos , Biomassa , Temperatura Alta , Fósforo/químicaRESUMO
OBJECTIVE: To observe the time-course expression of calcium-calmodulin dependent protein kinase II delta (CaMK II delta) in cerebral cortex after traumatic brain injury (TBI). METHODS: The TBI rat model was established. The expression of CaMK II delta in cerebral cortex around injured area was tested by Western blotting and immunohistochemical staining. RESULTS: Western blotting revealed expression of CaMK II delta in normal rat brain cortex. It gradually increased after TBI, peaked after 3 days, and then returned to normal level. The result of immunohistochemical staining was consistent with that of Western blotting. CONCLUSION: The expression of CaMK II delta around injured area after TBI increased initially and then decreased. It could be used as a new indicator for wound age determination following TBI.
Assuntos
Lesões Encefálicas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Córtex Cerebral/metabolismo , Animais , Western Blotting , Medicina Legal , Imuno-Histoquímica , Ratos , Fatores de TempoRESUMO
Varicocele (VC) refers to expansion and tortuosity of spreading venous plexus in spermatic cord due to poor blood flow. This study aimed to investigate effects of Shugan Tongluo Qiangjing recipe (SGTL) on sperm DNA damage and oxidative stress in experimental VC (EVC) rats. EVC model was established by partial ligation of left renal vein. Spermatic vein diameter, testicular weight, sperm DNA fragmentation index (DFI) were evaluated. Telomere reverse transcriptase (TERT) expression, telomere gene transcription, and testicular tissue morphology were determined·H2O2, catalase, SOD, T-AOC were measured with colorimetry. SGTL significantly decreased spermatic vein diameter (P=0.000) and increased testicular weight (P=0.013) of rats compared those of EVC rats. SGTL maintained testicular tissue morphology in EVC rats. SGTL markedly reduced sperm DFI value in sperm of rats compared to EVC rats (P=0.000). SGTL significantly enhanced TERT expression and telomere gene transcription (P=0.028) in testis of rats compared to EVC rats. SGTL reduced H2O2 levels (P=0.001) and promoted CAT activity (P=0.016), SOD activity (P=0.049), and T-AOC activity (P=0.047) of rats, compared to EVC rats. In conclusion, SGTL could reduce pathogenic process of EVC by reducing sperm DNA damage and regulating telomere length in EVC rats, which may be related to oxidative stress regulation.
Assuntos
Dano ao DNA , Medicamentos de Ervas Chinesas , Estresse Oxidativo , Espermatozoides , Telômero , Varicocele , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Varicocele/patologia , Varicocele/metabolismo , Telômero/efeitos dos fármacos , Telômero/metabolismo , Dano ao DNA/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Testículo/metabolismo , Testículo/efeitos dos fármacos , Testículo/patologia , Ratos Sprague-DawleyRESUMO
OBJECTIVES: To evaluate changes in health outcomes between years 2 and 3 after discharge following COVID-19 and to identify risk factors for poor health 3-year post-discharge. DESIGN: This is a multicentre observational cohort study. SETTING: This study was conducted in two centres from Wuhan, China. PARTICIPANTS: Eligibility screening has been performed in 3988 discharged laboratory-confirmed adult COVID-19 patients. Exclusion criteria were refusal to participate, inability to contact and death before follow-up. The WHO COVID-19 guidelines on defining disease severity were adopted. RESULTS: 1594 patients participated in the 1-year, 2-year and 3-year follow-ups, including 796 (49.9%) male patients, and 422 (26.5%) patients were classified in the severe disease group. 3 years after discharge, 182 (11.4%) patients still complained of at least one symptom. The most common symptoms were fatigue, myalgia, chest tightness, cough, anxiety, shortness of breath and expectoration. Fatigue or myalgia, the most common symptom cluster, frequently coexisted with chest symptoms and anxiety. Symptom persistence between years 2 and 3 was reported in 70 patients (4.4%) for which intensive care unit (ICU) admission was a risk factor (p=0.038). Of the 1586 patients who completed the chronic obstructive pulmonary disease assessment test (CAT), 97 (6.1%) scored ≥10, with older age being associated with CAT ≥10 (p=0.007). CONCLUSIONS: Between years 2 and 3 after SARS-CoV-2 infection, most patients returned to an asymptomatic state, and only a few were still symptomatic. ICU admission was a risk factor for symptom persistence.
Assuntos
COVID-19 , Alta do Paciente , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Masculino , Feminino , China/epidemiologia , Pessoa de Meia-Idade , Alta do Paciente/estatística & dados numéricos , Adulto , Idoso , Fatores de Risco , Estudos de Coortes , Índice de Gravidade de Doença , Unidades de Terapia Intensiva/estatística & dados numéricosRESUMO
Background: Existing evidence on the association between sedentary behavior (SB) and cognitive function remains inconclusive. Therefore, this study investigated the association between SB and the risk of cognitive decline (CD) or mild cognitive impairment (MCI) in the elderly. Methods: A comprehensive search was independently conducted by two researchers (XC and GQ) in seven electronic databases, including Medline (via PubMed), China Biology Medicine, Embase, Web of Science, China National Knowledge Infrastructure, Wanfang database, and VIP database for Chinese technical periodicals, covering studies published from the inception of database to June 2023. Studies that investigated the relationship between SB and the risk of CD or MCI in the elderly were included. The quality of the literature was assessed using the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality (AHRQ) assessment tools. The combined effect size analysis, subgroup analysis, and publication bias assessment were performed using STATA 14.0. Results: A total of 13 cross-sectional and 6 cohort studies involving 81,791 individuals were included, comprising 17 high-quality studies and 2 medium-quality studies. We found that SB was significantly associated with an increased risk of CD [odds ratio (OR) = 1.69, 95% confidence intervals (CI): 1.47-1.94] or MCI (OR = 1.34, 95% CI: 1.14-1.56) among the elderly. Subgroup analysis stratified according to comorbidity, lifestyle, family structure, publication year, and region showed statistical differences between groups, and the consistency of the results revealed the sources of the heterogeneity. Conclusion: This meta-analysis showed that SB is positively associated with the risk of CD or MCI in the elderly, providing a higher level of evidence for the promotion of healthy behaviors by clinicians and health policymakers. Due to the number and quality of the included articles, more high-quality longitudinal studies are needed to further confirm our findings.
RESUMO
Owing to the serious clinical side effects of intravenous Taxol, an oral chemotherapeutic strategy is expected to be promising for paclitaxel (PTX) delivery. However, its poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity need to be overcome. A triglyceride (TG)-like prodrug strategy facilitates oral drug delivery by bypassing liver metabolism. However, the effect of fatty acids (FAs) in sn-1,3 on the oral absorption of prodrugs remains unclear. Herein, a series of TG-mimetic prodrugs of PTX is explored with different carbon chain lengths and degrees of unsaturation of FAs at the sn-1,3 position in an attempt to enhance oral antitumor effect and to guide the design of TG-like prodrugs. Interestingly, the different FA lengths exhibit great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to fourfold differences in plasma pharmacokinetics. The prodrug with long-chain FAs shows a more effective antitumor effect, whereas the degree of unsaturation has a negligible impact. The findings illustrate how FAs structures affect the oral delivery efficiency of TG-like PTX prodrugs and thus provide a theoretical basis for their rational design.
Assuntos
Pró-Fármacos , Pró-Fármacos/química , Paclitaxel/química , Ácidos Graxos , Sistemas de Liberação de Medicamentos , TriglicerídeosRESUMO
Traumatic brain injury (TBI) results in neuronal apoptosis, autophagic cell death and necroptosis. Necroptosis is a newly discovered caspases-independent programmed necrosis pathway which can be triggered by activation of death receptor. Previous works identified that necrostatin-1 (NEC-1), a specific necroptosis inhibitor, could reduce tissue damage and functional impairment through inhibiting of necroptosis process following TBI. However, the role of NEC-1 on apoptosis and autophagy after TBI is still not very clear. In this study, the amount of TBI-induced neural cell deaths were counted by PI labeling method as previously described. The expression of autophagic pathway associated proteins (Beclin-1, LC3-II, and P62) and apoptotic pathway associated proteins (Bcl-2 and caspase-3) were also respectively assessed by immunoblotting. The data showed that mice pretreated with NEC-1 reduced the amount of PI-positive cells from 12 to 48 h after TBI. Immunoblotting results showed that NEC-1 suppressed TBI-induced Beclin-1 and LC3-II activation which maintained p62 at high level. NEC-1 pretreatment also reversed TBI-induced Bcl-2 expression and caspase-3 activation, as well as the ratio of Beclin-1/Bcl-2. Both 3-MA and NEC-1 suppressed TBI-induced caspase-3 activation and LC3-II formation, Z-VAD only inhibited caspase-3 activation but increased LC3-II expression at 24 h post-TBI. All these results revealed that multiple cell death pathways participated in the development of TBI, and NEC-1 inhibited apoptosis and autophagy simultaneously. These coactions may further explain how can NEC-1 reduce TBI-induced tissue damage and functional deficits and reflect the interrelationship among necrosis, apoptosis and autophagy.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Lesões Encefálicas/patologia , Imidazóis/farmacologia , Indóis/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Western Blotting , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Corantes , Ativação Enzimática , Imidazóis/antagonistas & inibidores , Indóis/antagonistas & inibidores , Injeções Intraventriculares , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Associadas aos Microtúbulos/genética , Oligopeptídeos/farmacologia , Propídio , Proteínas Proto-Oncogênicas c-bcl-2/biossínteseRESUMO
Plasmalemma permeability plays an important role in the secondary neuronal death induced by traumatic brain injury (TBI). Previous works showed that Poloxamer 188 (P188) could restore the intactness of the plasma membrane and play a cytoprotective action. However, the roles of P188 in blood-brain barrier (BBB) integrity and TBI-induced neural cell death are still not clear. In this study, mice were induced TBI by controlled cortical impact (CCI), and cerebral water content was measured to explore the profile of brain edema after CCI. Further, the regimen of P188 in mouse CCI models was optimized. The neurological test and BBB integrity assessment were performed, and the numbers of TBI-induced neural cell death were counted by propidium iodide (PI) labeling. The expression of apoptotic pathway associated proteins (Bax, cyt-c, caspase-8, caspase-9, caspase-3, P53) and aquaporin-4 (AQP4) was assessed by RT-PCR or immunoblotting. The data showed that the brain edema peaked at 24 h after TBI in untreated animals. Tail intravenous injection of P188 (4 mg/ml, 100 µl) 30 min before TBI or within 30 min after TBI could attenuate TBI-induced brain edema. P188 pre-treatment restored BBB integrity, suppressed TBI-induced neural cell death, and improved neurological function. TBI induced an up-regulation of Bax, cyt-c, caspase-8, caspase-9, caspase-3, and the expression of p53 was down-regulated by P188 pre-treatment. AQP4 mainly located on endothelial cells and astrocytes, and its expression was also regulated by P188 pretreatment. All these results revealed that P188 attenuates TBI-induced brain edema by resealing BBB and regulating AQP4 expression, and suppressed apoptosis through extrinsic or intrinsic pathway. Plasmalemma permeability may be a potential target for TBI treatment.
Assuntos
Barreira Hematoencefálica , Edema Encefálico/prevenção & controle , Lesões Encefálicas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Poloxâmero/uso terapêutico , Animais , Sequência de Bases , Western Blotting , Lesões Encefálicas/fisiopatologia , Primers do DNA , Imunofluorescência , Masculino , Aprendizagem em Labirinto , Camundongos , Poloxâmero/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: To investigate the ameliorative effect of urine-derived stem cells (USCs) conditioned medium on the aging retinal pigment epithelial (RPE) cells and explore the underlying mechanism. METHODS: The RPE cells were cultured, and aging RPE models were prepared by D-galactose treatment and identified by ß-Galactosidase staining. USCs were primarily cultured and identified by immunofluorescence staining. The proliferation and cell cycle of RPE cells in USCs conditioned medium (with USCs removal) were detected by CCK-8 assay and flow cytometry. Gene sequencing was applied to analyze the genetic variation with or without medium treatment. Bioinformatics analysis was used to investigate the biological functions of up- and downregulated differentially expressed genes after medium treatment. RESULTS: The cell morphology of aging RPE cells treated with the USCs medium were improved significantly and resembled normal RPE cells. In addition, the number of RPE cells increased with USCs medium, and the number of aging cells was significantly reduced after treatment with USCs medium. Moreover, the apoptosis rate of RPE cells was much lower in USCs medium group. The proportion of G1-phase RPE cells was significantly smaller and the proportion of S-phase RPE cells was significantly higher in the USCs medium group. It was found that there were 423 genes upregulated and 64 genes downregulated between the normal RPE cells and aging RPE cells, and 90 genes upregulated and 75 genes downregulated between the aging RPE cells and aging RPE cells cultured in USCs medium. CONCLUSIONS: Our data confirmed that the USCs could positively ameliorate the aging progression of RPE cells by regulating multiple gene network.
Assuntos
Células Epiteliais , Células-Tronco , Meios de Cultivo Condicionados/farmacologia , Pigmentos da Retina/metabolismo , Células Cultivadas , Epitélio Pigmentado da RetinaRESUMO
Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.
Assuntos
Pró-Fármacos , Administração Oral , Animais , Disponibilidade Biológica , Docetaxel/farmacologia , Cães , Absorção Intestinal , Intestinos , Ratos , Triglicerídeos/metabolismoRESUMO
Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity. Here, we show that the loss of CD147 on T cells prevents thymic senescence, resulting in slowed shrinkage of the thymus with age and increased production of naive T cells. This phenotype is the result of slowing of the epithelial-mesenchymal transition (EMT) process in thymic epithelial cells (TECs), which eventually leads to reduced adipocyte accumulation. In an in vitro coculture system, we found that TGFß is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-Smad2/FoxC2 signaling. Moreover, CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs. In the presence of TGFß, Annexin A2 and E-cadherin colocalize on TECs. However, CD147 on T cells competitively binds to Annexin A2 on TECs, leading to the isolation of E-cadherin. Then, the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase, the phosphorylation of which was induced by TGFß, and finally, p-E-cadherin is degraded. Thus, in the thymus, the interaction between T cells and TECs contributes to thymic involution with age. In this study, we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFß and/or CD147 may serve as a strategy to hinder age-related thymic involution.
Assuntos
Envelhecimento , Células Epiteliais/fisiologia , Transição Epitelial-Mesenquimal , Linfócitos T/metabolismo , Timo/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/fisiologia , Transdução de Sinais , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/genéticaRESUMO
The purpose of this study was to investigate whether the ERK signaling pathway was involved in ameliorating chronic myofascial hyperalgesia from contused gastrocnemius muscle in rats. We established an animal model associated with myofascial pain syndrome and described the mechanism of muscle pain in an animal model. Changes in the mechanical pain threshold were observed 0.5, 1, 2, 3, 4, 5, 8, 12, 18, and 24 h after ERK inhibitor injection around myofascial trigger points (MTrPs) of the gastrocnemius muscle in rats. Morphological changes in gastrocnemius muscle cells were observed by hematoxylin and eosin (H&E) staining. ERK signaling pathway activation was detected through immunohistochemistry and Western blotting. The main morphological characteristics of injured muscle fibers around MTrPs include gathered circular or elliptical shapes of different sizes in the cross-section and continuous inflated and tapering fibers in the longitudinal section. After intramuscular injection of U0126 (ERK inhibitor), the mechanical pain threshold significantly increased. The reduction in mechanical hyperalgesia was accompanied by reduced ERK protein phosphorylation, myosin light chain kinase (MLCK) protein, p-MLC protein expression, and the cross-sectional area of skeletal muscle cells around MTrPs. An ERK inhibitor contributed to the attenuation of mechanical hyperalgesia in the rat myofascial pain model, and the increase in pain threshold may be related to MLCK downregulation and other related contraction-associated proteins by ERK.
Assuntos
Sistema de Sinalização das MAP Quinases , Mialgia/enzimologia , Pontos-Gatilho/patologia , Animais , Hiperalgesia/complicações , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Células Musculares/efeitos dos fármacos , Células Musculares/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Mialgia/complicações , Mialgia/patologia , Mialgia/fisiopatologia , Síndromes da Dor Miofascial/complicações , Síndromes da Dor Miofascial/patologia , Síndromes da Dor Miofascial/fisiopatologia , Quinase de Cadeia Leve de Miosina/metabolismo , Limiar da Dor/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-DawleyRESUMO
Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family and an extracellular ligand for the orphan IL-1 receptor ST2. Accumulated evidence shows that the IL-33/ST2 axis plays a crucial role in the pathogenesis of central nervous system (CNS) diseases and injury, including traumatic brain injury (TBI). However, the roles and molecular mechanisms of the IL-33/ST2 axis after TBI remain poorly understood. In this study, we investigated the role of IL-33/ST2 signaling in mouse TBI-induced brain edema and neurobehavioral deficits, and further exploited underlying mechanisms, using salubrinal (SAL), the endoplasmic reticulum (ER) stress inhibitor and anti-ST2L. The increase in IL-33 level and the decrease in ST2L level at injured cortex were first observed at 24 h post-TBI. By immunofluorescent double-labeled staining, IL-33 co-localized in GFAP-positive astrocytes, and Olig-2-positive oligodendrocytes, and predominantly presented in their nucleus. Additionally, TBI-induced brain water content, motor function outcome, and spatial learning and memory deficits were alleviated by IL-33 treatment. Moreover, IL-33 and SAL alone, or their combination prevented TBI-induced the increase of IL-1ß and TNF-α levels, suppressed the up-regulation of ER stress, apoptosis and autophagy after TBI. However, anti-ST2L treatment could significantly invert the above effects of IL-33. Together, these data demonstrate that IL-33/ST2 signaling mitigates TBI-induced brain edema, motor function outcome, spatial learning and memory deficits, at least in part, by a mechanism involving suppressing autophagy, ER stress, apoptosis and neuroinflammation.
RESUMO
Interleukin-33 (IL-33) is a recently identified member of the IL-1 family that exerts biologic functions by binding to a heterodimer composed of IL-1 receptor-related protein ST2L and IL-1RAcP. However, the role of IL-33 and whether IL-33 accounts for inflammation, apoptotic, and autophagic neuropathology after intracerebral hemorrhage (ICH) are not clear. Here, we established a mouse ICH model in this study, to determine the role of IL-33 and explore the underlying mechanism. Male mice were subjected to an infusion of type IV collagenase/saline into the left striatum to induce ICH/sham model. IL-33, soluble ST2 (sST2), or saline were also administered by a single intracerebroventricular (i.c.v.) injection, respectively. The results showed that the expression level of IL-33 markedly decreased within 6 h and reached the valleys at 6 and 72 h after ICH vs. sham group. In parallel, ST2L (a transmembrane form receptor of IL-33) significantly increased within 6 h and reached the peaks at 6 h and 24 h after ICH vs. sham group. In addition, administration of IL-33 alleviated cerebral water contents, reduced the number of PI- and TUNEL-positive cells, and improved neurological function after ICH. Moreover, IL-33 treatment apparently suppressed the expression of pro-inflammation cytokines IL-1ß and TNF-α, evidently increased Bcl-2 but decreased cleaved-caspase-3, and obviously decreased the levels of autophagy-associated proteins LC3-II and Beclin-1 but maintained P62 at high level after ICH. On the contrary, treatment with sST2, a decoy receptor of IL-33, exacerbated ICH-induced brain damage and neurological dysfunction by promoting apoptosis, and enhancing autophagic activity. In conclusion, IL-33 provides neuroprotection through suppressing inflammation, apoptotic, and autophagic activation in collagenase-induced ICH model.
Assuntos
Apoptose , Autofagia , Hemorragia Cerebral/tratamento farmacológico , Interleucina-33/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Edema Encefálico/patologia , Caspase 3/metabolismo , Colagenases/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Interleucina-33/uso terapêutico , Masculino , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Interleucina-1/metabolismo , Fatores de TempoRESUMO
Mitochondria dysfunction, an enormous potential crisis, has attracted increasing attention. Disturbed regulation of mitochondrial dynamics, the balance of mitochondrial fusion and fission, has been implicated in neurodegenerative diseases, such as Parkinson׳s disease and cerebral ischemia/reperfusion. However the role of mitochondrial dynamics in traumatic brain injury (TBI) has not been illuminated. The aim of the present study was to investigate the role of Mdivi-1, a small molecule inhibitor of a key mitochondrial fission protein dynamin-related protein 1 (Drp1), in TBI-induced cell death and functional outcome deficits. Protein expression of Drp1 was first investigated. Outcome parameters consist of motor test, Morris water maze, brain edema and lesion volume. Cell death was detected by propidium iodide (PI) labeling, and mitochondrial morphology was assessed using transmission electron microscopy. In addition, the expression of apoptosis-related proteins cytochrome c (cyt-c) and caspase-3 was investigated. Our findings showed that up-regulation of Drp1 expression started at 1h post-TBI and peaked at 24 h, but inhibition of Drp1 by Mdivi-1 significantly alleviated TBI-induced behavioral deficits and brain edema, reduced morphological change of mitochondria, and decreased TBI-induced cell death together with lesion volume. Moreover, treatment with Mdivi-1 remarkably inhibited TBI-induced the release of cyt-c from mitochondria to cytoplasm, and activation of caspase-3 at 24 h after TBI. Taken together, these data imply that inhibition of Drp1 may help attenuate TBI-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis.
Assuntos
Lesões Encefálicas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Quinazolinonas/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Citocromos c/metabolismo , Modelos Animais de Doenças , Dinaminas/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Atividade Motora/efeitos dos fármacos , Distribuição Aleatória , Recuperação de Função Fisiológica/fisiologiaRESUMO
Based on 3S technique, this paper examined the responses of ecosystem service values (ESVs) to the landscape pattern change in the typical Karst area of northwest Guangxi, China in 1985, 1990, 2000 and 2005. The ESVs in the study area had close relations to landscape area, fragmentation degree, complexity of patch shape, areas of critical type, patch connectivity, and patch richness. It was linearly positively correlated with landscape area and had curvilinear positive correlations with patch index (LPI), contagion index (CONTAG), aggregative index (AI), effective mesh (MESH), proportion of like adjacencies (PLADJ), and tended to be increased with increasing patch area and patch connectivity of critical landscape type. The ESVs had curvilinear negative correlations with division index (DIVISION), split index (SPLIT), and patch richness (PRD), and decreased with increasing patch fragmentation and shrinking patch size. Therefore, it would be important to protect the critical landscape types such as woodland, shrub, and grassland, and to increase the patch size and connectivity to 'avoid further fragmentation. Moreover, it would be necessary to reduce the frequency and severity of disturbances to ensure the ESVs growth and the sustainable development of the study area.