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Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.
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Ansiedade/metabolismo , Comportamento Animal/fisiologia , Encefalopatias Metabólicas/metabolismo , Estresse Psicológico/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Animais , Ansiedade/genética , Ansiedade/imunologia , Ansiedade/fisiopatologia , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/fisiopatologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Dinâmica Mitocondrial/genética , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Análise de Célula Única , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Transcriptoma/genética , Xantina/metabolismoRESUMO
The granulosa cells (GCs) of birds are essential for the reproduction and maintenance of populations in nature. Atrazine (ATR) is a potent endocrine disruptor that can interfere with reproductive function in females and Diaminochlorotriazine (DACT) is the primary metabolite of ATR in the organism. Melatonin (MT) is an endogenous hormone with antioxidant properties that plays a crucial role in development of animal germ cells. However, how ATR causes mitochondrial dysfunction, abnormal secretion of steroid hormones, and whether MT prevents ATR-induced female reproductive toxicity remains unclear. Thus, the purpose of this study is to investigate the protective effect of MT against ATR-induced female reproduction. In the present study, the GCs of quail were divided into 6 groups, as follows: C (Serum-free medium), MT (10 µM MT), A250 (250 µM ATR), MA250 (10 µM MT+250 µM ATR), D200 (200 µM DACT) and MD200 (10 µM MT+200 µM DACT), and were cultured for 24 h. The results revealed that ATR prevented GCs proliferation and decreased cell differentiation. ATR caused oxidative damage and mitochondrial dysfunction, leading to disruption of steroid synthesis, which posed a severe risk to GC's function. However, MT supplements reversed these changes. Mechanistically, our study exhibited that the ROS/SIRT1/STAR axis as a target for MT to ameliorate ATR-induced mitochondrial dysfunction and steroid disorders in GCs, which provides new insights into the role of MT in ATR-induced reproductive capacity and species conservation in birds.
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Atrazina , Herbicidas , Melatonina , Doenças Mitocondriais , Animais , Feminino , Atrazina/toxicidade , Atrazina/metabolismo , Células da Granulosa/metabolismo , Herbicidas/toxicidade , Herbicidas/metabolismo , Melatonina/farmacologia , Doenças Mitocondriais/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/metabolismo , Esteroides/metabolismo , Codorniz/genética , Codorniz/metabolismoRESUMO
BACKGROUND: Locking plates are widely used in open reduction internal fixation (ORIF) for proximal humeral fracture (PHF). However, the optimal surgical treatment of unstable, displaced PHF in elderly patients remains controversial. This study aimed to compare the radiological and clinical outcomes of surgical treatment of PHF in the elderly with locking plate (LP) alone and locking plate combined with 3D printed polymethylmethacrylate (PMMA) prosthesis augmentation (LP-PA). METHODS: From May 2015 to April 2021, a total of 97 patients aged ≥ 60 years with acute unstable PHF who underwent osteosynthesis with either LP (46 patients) or LP-PA (51 patients) were retrospectively analyzed. For the LP-PA group, a customized proximal humeral prosthesis made of PMMA cement was intra-operatively fabricated by a three-dimensional (3D) printed prototype mold for the humeral medial support. Radiological outcomes were analyzed by measuring the value of neck-shaft angle (NSA) and humeral head height (HHH). The clinical outcomes were evaluated using Constant-Murley Score (CMS), Disabilities of the Arm Shoulder and Hand (DASH) score, American Shoulder and Elbow Surgeons (ASES) score, and the shoulder range of motion (ROM). Pain was measured using a visual analogue scale (VAS). RESULTS: At the one-year follow-up, all fractures healed radiologically and clinically. The mean changes of NSA and HHH over the follow-up period were markedly smaller in the LP-PA group (3.8 ± 0.9° and 1.7 ± 0.3 mm) than those in the LP group (9.7 ± 2.1° and 3.2 ± 0.6 mm, both P < 0.0001). The LP-PA group also presented lower DASH score (17.1 ± 3.6), higher ASES score (89.5 ± 11.2) and better ROM in forward elevation (142 ± 26°) and external rotation (59 ± 11°) compared to the LP group (28.9 ± 4.8 for DASH score, P < 0.0001; 82.3 ± 9.0 for ASES score, P < 0.001; 129 ± 21° for forward elevation, P = 0.008; and 52 ± 9° for external rotation, P = 0.001). There was no significant difference in overall complication rate between the two groups, although the complication rate of screw perforation was higher in the LP-PA group (P = 0.172). CONCLUSIONS: For PHF in elderly patients, the combination of LP fixation and PMMA prosthesis augmentation effectively improved humeral head support and reduction maintenance, providing satisfactory outcomes both radiologically and clinically. This technique also reduced the incidence of screw perforation associated with plate fixation alone, making it a reasonable option to ensure satisfactory clinical outcomes.
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Due to the wide use of atrazine (ATR), the concern has increased regarding the negative impact of ATR on reproduction. Nevertheless, the reproductive effects caused by different exposure concentrations and the severity of toxic damage are poorly understood. In organisms, ATR is metabolized and degraded through phase II enzyme systems, and changes in cytochrome P450 (CYP) enzymes may have a regulatory role in the harm of ATR. However, less information is available on the induction of CYPs by ATR in avian organisms, and even less on its effects on the testis. Birds are exposed to ATR mainly through food residues and contaminated water, the purpose of this study was to examine reproductive toxicity by different exposure concentrations and elaborate metabolic disorders caused by ATR in European quail (Coturnix coturnix). In this study, the quail were given ATR at 50 mg/kg, 250 mg/kg and 500 mg/kg by oral gavage for 45 days, and the testicular weight coefficients, histopathology and ultrastructure of testes, primary biochemical functions, sex steroid hormones, critical protein levels in the testosterone synthesis pathway, the expression of genes involved CYPs, gonad axis and nuclear receptors expression were investigated. Altogether, testicular coefficient decreased significantly in the high-dose group (1.22%) compared with the control group (3.03%) after 45 days of ATR exposure, and ATR is a potent CYP disruptor that acts through the NXRs and steroid receptor subfamily (APND, CAR, ERND and ERα) without a dose-dependent manner. Notably, ATR interfered with the homeostasis of hormones by triggering the expression of hormones on the gonad axis (LH and E2). These results suggest that exposure to ATR can cause testicular toxicity involving accommodative disorder of phase II enzyme and testosterone synthesis in European quail.
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Atrazina , Masculino , Animais , Atrazina/toxicidade , Atrazina/metabolismo , Coturnix/metabolismo , Testículo/metabolismo , Xenobióticos/metabolismo , Codorniz/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Testosterona/metabolismoRESUMO
PURPOSE: Infected forearm nonunion remains a challenge for the hand surgeon. Autologous bone grafting within an induced membrane following implantation of a cement spacer, also known as the Masquelet technique, is a procedure used for addressing segmental bone defects. This report summarized our experience using this technique to treat the infected forearm nonunion. METHODS: We retrospectively reviewed a series of 32 patients treated for infected forearm nonunion by the 2-stage Masquelet technique between 2009 and 2018. There was an infected nonunion of the ulna in 28 patients and an infected nonunion of the radius in 4 patients. All patients had undergone an average of 2.7 procedures before presenting at our institution. Treatment involved a staged procedure in which an antibiotic-impregnated cement spacer was implanted into the bone defect following debridement without internal fixation. It was left in place for 4-6 weeks, during which time a membrane formed around the cement spacer. In the second stage, the induced membrane was incised, and the cement spacer was removed. The defect was then filled with cancellous autograft with the addition of internal fixation. Postoperative radiographs were taken for the evaluation of bone healing. The functional results of the affected forearm were evaluated for motion loss of elbow or wrist and rotation loss of forearm. RESULTS: All nonunions healed without recurrent infection or loosening of internal fixation at the time of final follow-up. All the patients showed substantial functional improvement, with excellent results in 14 patients, satisfactory results in 13, and unsatisfactory results in 5. CONCLUSIONS: The induced membrane technique is an effective solution for infected forearm nonunion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.
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Fraturas não Consolidadas , Fraturas da Ulna , Transplante Ósseo/métodos , Antebraço , Consolidação da Fratura , Fraturas não Consolidadas/cirurgia , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Fraturas da Ulna/cirurgiaRESUMO
Pevonedistat is a potent, selective, first-in-class NEDD8 activating enzyme inhibitor. It is now under multiple clinical trials that investigate its anticancer effect against solid tumors and leukemia. ATP-binding cassette (ABC) transporters are membrane proteins that are involved in mediating multidrug resistance (MDR). In this article, we reveal that pevonedistat is a substrate of ABCG2 which decreases the therapeutic effect of pevonedistat. The cytotoxicity of pevonedistat was significantly weakened in ABCG2-overexpressing cells, and the drug resistance can be reversed by ABCG2 inhibitors. The ATPase assay suggested that pevonedistat can stimulate ABCG2 ATPase activity in a concentration-dependent manner. Pevonedistat showed little effect on the expression level or subcellular localization of ABCG2 after 72 h treatment. Furthermore, a pevonedistat resistance cell line S1-PR was established and overexpressed ABCG2. Generally, our study provides evidence that ABCG2 can be a prominent factor leading to pevonedistat-resistance. Furthermore, ABCG2 may also be utilized as a biomarker to monitor the development of pevonedistat resistance during cancer treatment.
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ciclopentanos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Pirimidinas/farmacologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Humanos , Proteínas de Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Células Tumorais CultivadasRESUMO
To explore the protective effect and mechanism of ethyl acetate extract from Bidens bipinnata on hepatocyte damage induced by endoplasmic reticulum stress. Tunicamycin was used to establish the damage model in L02 cells. Methyl thiazolyl tetrazolium(MTT) colorimetric assay was used to investigate the survival rate of ethyl acetate extract from B. bipinnata in L02 cells injury induced by endoplasmic reticulum stress; the protein expressions of endoplasmic reticulum stress-related molecule glucose regulated protein 78(GRP78), PKR-like ER kinase(PERK), eukaryotic initiation factor-2(eIF2α), activating transcription factor 4(ATF4), C/EBP homologous protein(CHOP), B-cell CLL/lymphoma 2(Bcl-2), Bal-2 associated X apoptosis regulator(Bax) were examined by Wes-tern blot. The expressions of the above proteins were also detected after endoplasmic reticulum stress inhibitor(4-phenyl butyric acid) and CHOP shRNA-mediated knockdowns were added. The expressions of GRP78, PERK, CHOP in L02 cells were observed by immunofluorescence method. The results showed that ethyl acetate extract from B. bipinnata could significantly increase the survival rate of L02 cell injury caused by endoplasmic reticulum stress in a dose and time-dependent manner(P<0.05 or P<0.01). The expression levels of GRP78, PERK, eIF2α, ATF4, CHOP and Bax in the drug treatment groups were significantly down-regulated(P<0.05 or P<0.01), while Bcl-2 was significantly up-regulated(P<0.01). After endoplasmic reticulum stress inhibitor and CHOP shRNA-mediated knockdowns were added, the expression levels of GRP78, PERK, eIF2α, ATF4, CHOP, Bax in the drug treatment groups were significantly down-regulated(P<0.01), whereas Bcl-2 was significantly up-regulated(P<0.01). Immunofluorescence results showed that the expressions of GRP78, PERK, CHOP were consistent with the Western blot method. In conclusion, ethyl acetate extract from B. bipinnata has a significant protective effect on the damage of L02 cells caused by endoplasmic reticulum stress. The mechanism may be related to the inhibition of endoplasmic reticulum stress and the down-regulation of apoptosis in cells through the PERK/eIF2α/ATF4/CHOP signaling pathway.
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Bidens , Estresse do Retículo Endoplasmático , Acetatos , Apoptose , Hepatócitos , Fator de Transcrição CHOP/genética , eIF-2 Quinase/genéticaRESUMO
BACKGROUND The incidence of hip fracture is steadily increasing. We aimed to establish a creative approach to precisely estimate the risk of hip fracture by exploring the relationship between hip fracture and bone mineral density (BMD)/femur geometry. MATERIAL AND METHODS Sixteen samples of cadaveric female proximal femora were randomly selected. Experiments were performed experimental measurement of the femoral neck BMD and geometric parameters (including neck length, neck diameter, head diameter, and neck-shaft angle). In addition, the experimental measurements contain the failure load, which represents the mechanical strength of the femoral neck, and we calculated the correlation coefficient among BMD, geometric parameters, and failure load. RESULTS Significant correlations were discovered between femoral mechanical properties and femoral neck BMD (r=0.792, r²=0.628, P<0.001), trochanteric BMD (r=0.749, r²=0.560, P=0.001), and head diameter (r=0.706, r²=0.499, P=0.002). Multiple linear regression analyses indicated that the best predictor of hip fracture was the combination of femoral neck BMD, head diameter, and neck diameter (r²=0.844, P<0.001). CONCLUSIONS The results confirmed that, compared with BMD alone, the combination of BMD and geometric parameters of proximal femur is a better estimation of hip fracture. The geometry of the proximal femur played an important role in assessing the biomechanical strength of femur. This method greatly assists in predicting the risk of hip fracture in clinical trials and will assist studies on why the incidence of hip fracture varies among races.
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Fêmur/anatomia & histologia , Fraturas do Quadril/etiologia , Fraturas do Quadril/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Densidade Óssea/fisiologia , Cadáver , China , Feminino , Fêmur/fisiologia , Colo do Fêmur/anatomia & histologia , Colo do Fêmur/fisiologia , Humanos , Masculino , Osteoporose Pós-Menopausa , Ossos Pélvicos , Fatores de RiscoRESUMO
Numerous biological activities including antioxidant, antitumor, anti-inflammation, and antivirus of the natural product curcumin were reported. However, the clinical application of it was significantly limited by its instability, poor solubility, less body absorbing, and low bioavailability. This review focuses on the structure modification and antioxidant activity evaluation of curcumin. To study the structure-activity relationship (SAR), five series of curcumin analogs were synthesized and their antioxidant activity were evaluated in vitro. The results showed that electron-donating groups, especially the phenolic hydroxyl group are an essential component to improve the antioxidant activity.
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Antioxidantes , Curcumina , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Curcumina/análogos & derivados , Curcumina/síntese química , Curcumina/química , Curcumina/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Biphasic effects on cell proliferation of bisphenol A (BPA) can occur at lesser or greater exposures. Sertoli cells play a pivotal role in supporting proliferation and differentiation of germ cells. The mechanisms responsible for inverse effects of great and low concentrations of BPA on Sertoli cell proliferation need further study. METHODS: We utilized proteomic study to identify the protein expression changes of Sertoli TM4 cells treated with 10(-8)M and 10(-5)M BPA. The further mechanisms related to mitochondria, energy metabolism and oxidative stress were investigated by qRT-PCR and Western-blotting analysis. RESULTS: Proteomic studies identified 36 proteins and two major clusters of proteins including energy metabolism and oxidative stress expressed with opposite changes in Sertoli cells treated with 10(-8)M and 10(-5)M BPA, respectively, for 24h. Exposure to 10(-5)M BPA resulted in greater oxidative stress and then inhibited cell proliferation, while ROS scavenger NAC effectively blocked these effects. Exposure to 10(-8)M BPA caused higher intercellular ATP, greater activities of mitochondria, and resulted in significant proliferation of TM4 cells, while oligomycin A, an inhibitor of ATP synthase, abolished these growth advantages. CONCLUSIONS: Our study demonstrated that micromolar BPA inhibits proliferation of Sertoli cells by elevating oxidative stress while nanomolar BPA stimulates proliferation by promoting energy metabolism. GENERAL SIGNIFICANCE: Micromolar BPA inhibits cell proliferation by elevating oxidative stress while nanomolar BPA stimulates cell proliferation by promoting energy metabolism.
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Poluentes Ocupacionais do Ar/farmacologia , Compostos Benzidrílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Fenóis/farmacologia , Proteoma/biossíntese , Células de Sertoli/metabolismo , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Proteômica , Células de Sertoli/citologiaRESUMO
The accumulation of senescent cells in kidneys is considered to contribute to age-related diseases and organismal aging. Mitochondria are considered a regulator of cell senescence process. Atrazine as a triazine herbicide poses a threat to renal health by disrupting mitochondrial homeostasis. Melatonin plays a critical role in maintaining mitochondrial homeostasis. The present study aims to explore the mechanism by which melatonin alleviates atrazine-induced renal injury and whether parkin-mediated mitophagy contributes to mitigating cell senescence. The study found that the level of parkin was decreased after atrazine exposure and negatively correlated with senescent markers. Melatonin treatment increased serum melatonin levels and mitigates atrazine-induced renal tubular epithelial cell senescence. Mechanistically, melatonin maintains the integrity of mitochondrial crista structure by increasing the levels of mitochondrial contact site and cristae organizing system, mitochondrial transcription factor A (TFAM), adenosine triphosphatase family AAA domain-containing protein 3A (ATAD3A), and sorting and assembly machinery 50 (Sam50) to prevent mitochondrial DNA release and subsequent activation of cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate synthase pathway. Furthermore, melatonin activates Sirtuin 3-superoxide dismutase 2 axis to eliminate the accumulation of reactive oxygen species in the kidney. More importantly, the antisenescence role of melatonin is largely determined by the activation of parkin-dependent mitophagy. These results offer novel insights into measures against cell senescence. Parkin-mediated mitophagy is a promising drug target for alleviating renal tubular epithelial cell senescence.
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Atrazine (ATZ) is a widely used herbicide that has toxic effects on animals. Melatonin (MLT) is a natural hormone with strong antioxidant properties. However, the effect of MLT on the glucose metabolism disorder caused by ATZ is still unclear. Mice were divided into four groups randomly and given 21 days of gavage: blank control group (Con), 5 mg/kg MLT group (MLT), 170 mg/kg ATZ group (ATZ), and 170 mg/kg ATZ and 5 mg/kg MLT group (ATZ + MLT). The results show that ATZ alters mRNA levels of metabolic enzymes related to glycogen synthesis and glycolysis and increased metabolites (glycogen, lactate, and pyruvate). ATZ causes abnormalities in glucose metabolism in mouse liver, interfering with glycemia regulation ability. MLT can regulate the endoplasmic reticulum to respond to disordered glucose metabolism in mice liver. This study suggested that MLT has the power to alleviate the ATZ-induced glycogen overdeposition and glycolytic deficit.
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Atrazina , Herbicidas , Melatonina , Camundongos , Animais , Atrazina/farmacologia , Melatonina/farmacologia , Herbicidas/farmacologia , Fígado/metabolismo , Estresse do Retículo Endoplasmático , Glicogênio/metabolismo , Glucose/metabolismoRESUMO
Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical applied as a plasticizer. As an environmental toxicant, DEHP poses a serious health threat. Many studies have revealed that DEHP can cause lead to various degrees of damage to the kidney. However, the evidence of DEHP-induced renal ferroptosis has not been reported. The purpose of this work was to probe the specific role of lipophagy in DEHP-induced renal injury and to investigate the relationship between lipophagy and ferroptosis. Quail were treated with DEHP (250 mg/kg BW/day, 500 mg/kg BW/day and 750 mg/kg BW/day) for 45 days. Microstructural and ultrastructural observations showed that DEHP caused damage to glomerular and tubular cells, and autophagy with multilayer structures were observed, suggesting that DEHP can induce lipophagy. The results indicated that the iron homeostasis was abnormal and the lipid peroxidation was increased. SLC7A11 and SLC3A2 were down-regulated. PTGS2, ACSL4 and LPCAT3 were elevated. In conclusion, DEHP could induce lipid peroxidation, lead to ferroptosis, and damage renal cells. Therefore, the relationship between lipophagy and ferroptosis was elucidated, which provided a new basis for intervention and prevention of DEHP increased diseases.
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Dietilexilftalato , Ferroptose , Ácidos Ftálicos , Animais , Coturnix , Codorniz , Dietilexilftalato/toxicidade , RimRESUMO
Ischemic stroke is a devastative nervous system disease associated with high mortality and morbidity rates. Unfortunately, no clinically effective neuroprotective drugs are available now. In ischemic stroke, S100 calcium-binding protein b (S100b) binds to receptor for advanced glycation end products (Rage), leading to the neurological injury. Therefore, disruption of the interaction between S100B and Rage can rescue neuronal cells. Here, we designed a peptide, termed TAT-W61, derived from the V domain of Rage which can recognize S100b. Intriguingly, TAT-W61 can reduce the inflammatory caused by ischemic stroke through the direct binding to S100b. The further investigation demonstrated that TAT-W61 can improve pathological infarct volume and reduce the apoptotic rate. Particularly, TAT-W61 significantly improved the learning ability, memory, and motor dysfunction of the mouse in the ischemic stroke model. Our study provides a mechanistic insight into the abnormal expression of S100b and Rage in ischemic stroke and yields an invaluable candidate for the development of drugs in tackling ischemic stroke. KEY MESSAGES: S100b expression is higher in ischemic stroke, in association with a high expression of many genes, especially of Rage. S100b is directly bound to the V-domain of Rage. Blocking the binding of S100b to Rage improves the injury after ischemic stroke.
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AVC Isquêmico , Camundongos , Animais , Receptor para Produtos Finais de Glicação Avançada , AVC Isquêmico/patologia , Neurônios , Peptídeos/farmacologia , Subunidade beta da Proteína Ligante de Cálcio S100/farmacologiaRESUMO
Atrazine (ATR) is a widely used herbicide worldwide that can cause kidney damage in humans and animals by accumulation in water and soil. Lycopene (LYC), a carotenoid with numerous biological activities, plays an important role in kidney protection due to its potent antioxidant and anti-inflammatory effects. The current study sought to investigate the role of interactions between mtDNA and the cGAS-STING signaling pathway in LYC mitigating PANoptosis and inflammation in kidneys induced by ATR exposure. In our research, 350 mice were orally administered LYC (5 mg/kg BW/day) and ATR (50 or 200 mg/kg BW/day) for 21 days. Our results reveal that ATR exposure induces a decrease in mtDNA stability, resulting in the release of mtDNA into the cytoplasm through the mPTP pore and the BAX pore and the mobilization of the cGAS-STING pathway, thereby inducing renal PANoptosis and inflammation. LYC can inhibit the above changes caused by ATR. In conclusion, LYC inhibited ATR exposure-induced histopathological changes, renal PANoptosis, and inflammation by inhibiting the cGAS-STING pathway. Our results demonstrate the positive role of LYC in ATR-induced renal injury and provide a new therapeutic target for treating renal diseases in the clinic.
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Atrazina , DNA Mitocondrial , Rim , Licopeno , Proteínas de Membrana , Substâncias Protetoras , Animais , Camundongos , Atrazina/toxicidade , Rim/efeitos dos fármacos , Rim/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Licopeno/farmacologia , Licopeno/administração & dosagem , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Masculino , Substâncias Protetoras/farmacologia , Substâncias Protetoras/administração & dosagem , Humanos , Herbicidas , Nefropatias/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Nefropatias/genética , Nefropatias/tratamento farmacológico , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Ischemic stroke ranks among the leading causes of death and disability in humans and is accompanied by motor and cognitive impairment. However, the precise mechanisms underlying injury after stroke and effective treatment strategies require further investigation. Peroxiredoxin-1 (PRDX1) triggers an extensive inflammatory cascade that plays a pivotal role in the pathology of ischemic stroke, resulting in severe brain damage from activated microglia. In the present study, we used molecular dynamics simulation and nuclear magnetic resonance to detect the interaction between PRDX1 and a specific interfering peptide. We used behavioral, morphological, and molecular experimental methods to demonstrate the effect of PRDX1-peptide on cerebral ischemia-reperfusion (I/R) in mice and to investigate the related mechanism. We found that PRDX1-peptide bound specifically to PRDX1 and improved motor and cognitive functions in I/R mice. In addition, pretreatment with PRDX1-peptide reduced the infarct area and decreased the number of apoptotic cells in the penumbra. Furthermore, PRDX1-peptide inhibited microglial activation and downregulated proinflammatory cytokines including IL-1ß, IL-6, and TNF-α through inhibition of the TLR4/NF-κB signaling pathway, thereby attenuating ischemic brain injury. Our findings clarify the precise mechanism underlying PRDX1-induced inflammation after ischemic stroke and suggest that the PRDX1-peptide can significantly alleviate the postischemic inflammatory response by interfering with PRDX1 amino acids 70-90 and thereby inhibiting the TLR4/NF-κB signaling pathway. Our study provides a theoretical basis for a new therapeutic strategy to treat ischemic stroke.
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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.
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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
OBJECTIVE: To analyze the clinical outcomes of mini-plate combined with wireforms in the treatment of Type C distal radial fractures with marginal articular fragments. METHODS: This retrospective study included a total of 10 cases, including 5 males and 5 females, with 6 cases involving the left side and 4 cases involving the right side, of Type C distal radial fractures with marginal articular fragments. The age of the patients ranged from 35 to 67 years old. All patients underwent surgical treatment utilizing mini-plate combined with wireforms for internal fixation. RESULTS: The follow-up period ranged from 6 to 18 months. Complete fracture healing was observed in all cases, with healing times ranging from 10 to 16 weeks. During the entire follow-up period, patients reported high levels of satisfaction with the treatment outcomes, and there were no incidences of incision infection, chronic wrist pain, or wrist traumatic arthritis. At the final follow-up assessment, the Mayo score for the wrist joint ranged from 85 to 95, with 7 cases rated as excellent and 3 cases as good. CONCLUSION: Mini-plate combined with wireforms proves to be an effective fixation method for Type C distal radial fractures with marginal articular fragments. The early initiation of wrist joint exercises, strong fixation, maintenance of proper reduction, minimal complications, and high rates of excellent and good outcomes demonstrate the reliability and efficacy of this treatment approach.
Assuntos
Fraturas do Rádio , Fraturas do Punho , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Reprodutibilidade dos Testes , Fraturas do Rádio/cirurgia , Fixação Interna de Fraturas/métodos , Resultado do Tratamento , Articulação do Punho , Placas Ósseas , Amplitude de Movimento ArticularRESUMO
Di-(2-ethylhexyl) phthalate (DEHP) is an environmental toxicant that is widely used in the whole world as a plasticizer that can enhance plastic properties. A number of reserarches have demonstrated that DEHP could cause varying degrees of damage to the normal function of nerve. The research aimed to investigate the mechanism of DEHP-induced cerebellar toxicity. In present study, we set DEHP-caused cerebellar injury models of quail and implied that DEHP induced cerebellar dysplasia by abnormity of Purkinje cell and reduction of cerebellar granule cell. Furthermore, the mitochondrial damage was confirmed by the swelling, cristae reduction, membrane rupture of mitochondria or even the occurrence of autophagic vacuole. To clarified DEHP-induced mitochondrial damage in cerebellum, we examined the relevant genes of mitochondrial biogenesis, mitochondrial dynamics, oxidative damage, the pathways related to Nrf2 and PINK1/Parkin in cerebellum. Based on data, it appeared that DEHP treatment had a damaging effect on the cerebellum and led to mitophagy as well as oxidative stress. In conclusion, the research indicated that DEHP-actuated mitochondrial injury has a directly relationship with mitophagy. DEHP-actuated reduced mitochondrial biogenesis and dysregulation of mitochondrial dynamics. The increase of oxidative stress damaged mitochondria, and the redundant ROS in damaged mitochondria that gave rise to cerebellar harm.
Assuntos
Dietilexilftalato , Sirtuína 1/metabolismo , Mitocôndrias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Transdução de Sinais , Cerebelo/metabolismo , Proteínas Quinases/metabolismoRESUMO
OBJECTIVE: Inferior pole fractures of patella are notorious fractures where it is difficult to obtain rigid internal fixation by conventional methods. The objective of the study was to introduce the Hand Plating System (HPS), which was a novel surgical technique for inferior pole fractures of patella, and to report the radiological and clinical outcomes following the application of the surgical technique. METHODS: The study was designed as a retrospective cohort study. Between July 2017 and December 2018, 30 patients who were diagnosed with inferior pole fracture of the patella without additional orthopaedic injuries were enrolled in this case series. After X-ray and 3D-CT examinations, all patients underwent open reduction and internal fixation by HPS with or without supplementary cannulated screw and lag screw stabilization. The bony union time, final range of motion (ROM), Bostman score, visual analog scale (VAS), and complications were measured as the clinical outcomes under a minimum of 12 months of follow-up. RESULTS: All of the operations went well with the mean operative time of 76.2 ± 15.3 min. Bony union achieved in all the cases at an average of 9.5 ± 1.4 weeks after surgery. There was no loss of reduction, fixative failure, or surgical implant removal during follow-up. The average range of motion 1 year postoperatively was 0°-123.3°. The mean Bostman Score at the last follow-up was 26.8 ± 2.1 with the satisfactory rate of 100%. The pain feeling during walking as measured by VAS averaged at 0.9 ± 1.3. No complications developed except for one case of poor incision healing, which healed eventually after surgical debridement. CONCLUSIONS: HPS was demonstrated as a secure fixation and as a kind of tension band for inferior pole fractures of the patella. Satisfactory recovery of knee function and low complication rate, including no need for hardware removal, could be expected.