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1.
J Drugs Dermatol ; 23(5): e124-e126, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38709684

RESUMO

Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic medication for the treatment of various autoimmune conditions. A rare side effect of HCQ is thrombotic thrombocytopenic purpura (TTP). We present two cases of patients who developed purpura that did not meet TTP criteria following treatment with HCQ. While the etiology of HCQ-associated TTP is poorly understood, we propose a spectrum of manifestations related to HCQ, ranging from benign purpura to TTP. As multiple factors contribute to the disease, we believe that HCQ may act as a "second hit" in patients with genetic susceptibility, which also influences the variability in the severity of disease manifestations. J Drugs Dermatol. 2024;23(5):e124.     doi:10.36849/JDD.7781e.


Assuntos
Antirreumáticos , Hidroxicloroquina , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/administração & dosagem , Feminino , Antirreumáticos/efeitos adversos , Pessoa de Meia-Idade , Masculino , Adulto , Púrpura Trombocitopênica Trombótica/induzido quimicamente , Púrpura Trombocitopênica Trombótica/diagnóstico
2.
Physiol Res ; 73(2): 239-251, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38710061

RESUMO

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.


Assuntos
Animais Recém-Nascidos , Displasia Broncopulmonar , Modelos Animais de Doenças , Estresse Oxidativo , Pneumonia , Resveratrol , Animais , Resveratrol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Displasia Broncopulmonar/prevenção & controle , Displasia Broncopulmonar/metabolismo , Pneumonia/prevenção & controle , Pneumonia/metabolismo , Pneumonia/induzido quimicamente , Ratos , Hiperóxia/complicações , Hiperóxia/metabolismo , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Antioxidantes/farmacologia , Hiper-Reatividade Brônquica/prevenção & controle , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Hiper-Reatividade Brônquica/induzido quimicamente , Ratos Sprague-Dawley , Masculino
3.
Physiol Res ; 73(2): 227-237, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38710058

RESUMO

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.


Assuntos
Injúria Renal Aguda , Cisplatino , Diminazena , Lisinopril , Ratos Wistar , Valsartana , Animais , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/tratamento farmacológico , Lisinopril/farmacologia , Cisplatino/toxicidade , Valsartana/farmacologia , Masculino , Diminazena/análogos & derivados , Diminazena/farmacologia , Diminazena/uso terapêutico , Ratos , Antineoplásicos/toxicidade , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo
4.
J Int Med Res ; 52(5): 3000605241244743, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38713455

RESUMO

The world population is rapidly aging. Societal aging poses many challenges for individuals, families, nations, and the global healthcare system. Therefore, geriatric care is a crucial issue that demands our attention. In this case report, we describe a woman in her early 70s with multiple comorbidities, polypharmacy, and renal insufficiency who developed cefepime-induced encephalopathy with moderate to severe cerebral dysfunction during treatment of a urinary tract infection. The patient's consciousness level gradually improved, and no further seizures were observed following the discontinuation of cefepime for several days. This case report underscores the fact that polypharmacy and medication safety are significant concerns that are often overlooked when caring for older patients. The report also highlights the increased susceptibility of older individuals to antibiotic-associated adverse reactions during the management of infectious diseases. Therefore, optimization of antibiotic therapy for older patients is a critical issue that requires thorough investigation and consideration in geriatric care.


Assuntos
Antibacterianos , Encefalopatias , Cefepima , Polimedicação , Insuficiência Renal , Infecções Urinárias , Humanos , Cefepima/efeitos adversos , Cefepima/uso terapêutico , Feminino , Idoso , Encefalopatias/induzido quimicamente , Infecções Urinárias/tratamento farmacológico , Insuficiência Renal/induzido quimicamente , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico
5.
Rev Assoc Med Bras (1992) ; 70(4): e20230937, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716933

RESUMO

OBJECTIVE: Anticipatory nausea and vomiting are unpleasant symptoms observed before undergoing chemotherapy sessions. Less is known about the occurrence of symptoms since the advent of the new neurokinin-1 antagonist. METHODS: This prospective cohort study was performed at a single Brazilian Institution. This study included breast cancer patients who received doxorubicin and cyclophosphamide chemotherapy and an appropriate antiemetic regimen (dexamethasone 10 mg, palonosetron 0.56 mg, and netupitant 300 mg in the D1 followed by dexamethasone 10 mg 12/12 h in D2 and D4). Patients used a diary to record nausea, vomiting, and use of rescue medication in the first two cycles of treatment. The prevalence of anticipatory nausea and vomiting was assessed before chemotherapy on day 1 of C2. RESULTS: From August 4, 2020, to August 12, 2021, 60 patients were screened, and 52 patients were enrolled. The mean age was 50.8 (28-69) years, most had stage III (53.8%), and most received chemotherapy with curative intent (94%). During the first cycle, the frequency of overall nausea and vomiting was 67.31%, and that of severe nausea and vomiting (defined as grade>4 on a 10-point visual scale or use of rescue medication) was 55.77%. Ten patients had anticipatory nausea and vomiting (19.23%). The occurrence of nausea and vomiting during C1 was the only statistically significant predictor of anticipatory nausea and vomiting (OR=16, 95%CI 2.4-670.9, p=0.0003). CONCLUSION: The prevalence of anticipatory nausea is still high in the era of neurokinin-1 antagonists, and failure of antiemetic control in C1 remains the main risk factor. All efforts should be made to control chemotherapy-induced nausea or nausea and vomiting on C1 to avoid anticipatory nausea.


Assuntos
Antieméticos , Neoplasias da Mama , Náusea , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto , Antieméticos/uso terapêutico , Idoso , Náusea/induzido quimicamente , Prevalência , Brasil/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Vômito Precoce , Vômito/induzido quimicamente , Vômito/epidemiologia , Dexametasona/uso terapêutico , Palonossetrom/uso terapêutico
6.
Rev Assoc Med Bras (1992) ; 70(4): e20230990, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716935

RESUMO

OBJECTIVE: We aimed to investigate the effect of coenzyme q10 on cyclophosphamide-induced kidney damage in rats. METHODS: A total of 30 female Wistar-Albino rats were utilized to form three groups. In group 1 (control group) (n=10), no drugs were given. In group 2 (cyclophosphamide group) (n=10), 30 mg/kg intraperitoneal cyclophosphamide was administered for 7 days. In group 3 (cyclophosphamide+coenzyme q10 group) (n=10), 30 mg/kg cyclophosphamide and 10 mg/kg coenzyme q10 were given for 7 days via intraperitoneal route. Right kidneys were removed in all groups. Blood malondialdehyde levels and activities of catalase and superoxide dismutase were measured. Histopathological damage was evaluated by examining the slides prepared from kidney tissue using a light microscope. RESULTS: Tissue damage was significantly higher in the cyclophosphamide group than in the cyclophosphamide+coenzyme q10 group (p<0.05). The malondialdehyde levels were significantly higher and the activities of superoxide dismutase and catalase were lower in the cyclophosphamide group than in the cyclophosphamide+coenzyme q10 group (p<0.05). CONCLUSION: Coenzyme q10 may be a good option to prevent cyclophosphamide-induced kidney damage.


Assuntos
Catalase , Ciclofosfamida , Malondialdeído , Ratos Wistar , Superóxido Dismutase , Ubiquinona , Animais , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ciclofosfamida/toxicidade , Ciclofosfamida/efeitos adversos , Feminino , Catalase/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Ratos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Nefropatias/patologia , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos
7.
J Int Med Res ; 52(5): 3000605241247707, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38717029

RESUMO

Lipopolysaccharide (LPS) is widely used to establish various animal models, including models of acute lung injury, cardiomyocyte damage, and acute kidney injury. Currently, there is no consensus on the diagnosis and treatment of LPS-induced disease. We herein present a case series of four patients who developed dose-dependent multi-organ injury, including acute lung injury and acute kidney injury, after inhaling LPS gas in a sealed room. These patients exhibited varying degrees of multi-organ injury characterized by inflammatory cell infiltration and secretion of proinflammatory cytokines. One patient showed progressive symptoms even with active treatment, leading to mild pulmonary fibrosis. This study emphasizes the importance of early diagnosis and treatment of significant LPS exposure and suggests personalized treatment approaches for managing LPS poisoning.


Assuntos
Lipopolissacarídeos , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Administração por Inalação , Lesão Pulmonar Aguda/induzido quimicamente , Injúria Renal Aguda/induzido quimicamente , Citocinas/metabolismo , Idoso , Relação Dose-Resposta a Droga
9.
BMC Pulm Med ; 24(1): 224, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720270

RESUMO

BACKGROUND: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms. METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway. RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and transforming growth factor-ß1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions. CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.


Assuntos
Proteínas Quinases Ativadas por AMP , Estresse Oxidativo , Fibrose Pulmonar , Dióxido de Silício , Sinvastatina , Animais , Sinvastatina/farmacologia , Ratos , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/prevenção & controle , Fibrose Pulmonar/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Dióxido de Silício/toxicidade , Ratos Sprague-Dawley , Modelos Animais de Doenças , Pneumonia/induzido quimicamente , Pneumonia/prevenção & controle , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Silicose/tratamento farmacológico , Silicose/patologia , Silicose/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Transdução de Sinais/efeitos dos fármacos , NADPH Oxidases/metabolismo , Ribonucleotídeos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , NADPH Oxidase 4/metabolismo , Acetofenonas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo
10.
Immun Inflamm Dis ; 12(5): e1077, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38722267

RESUMO

BACKGROUND: Considering the antihepatitis effects of Tectorigenin (TEC), and the same adenosine mitogen-activated protein kinase (MAPK) pathway in both hepatitis and inflammatory bowel disease (IBD) models, exploring the role of TEC in IBD is contributive to develop a new treatment strategy against IBD. METHODS: The IBD mouse model was constructed by feeding with dextran sodium sulfate (DSS) and injection of TEC. Afterward, the mouse body weight, colon length, and disease activity index (DAI) were tested to assess the enteritis level. Mouse intestine lesions were detected by hematoxylin and eosin staining. Murine macrophages underwent lipopolysaccharide (LPS) induction to establish an inflammation model. Cell viability was determined by cell counting kit-8 assay. Enzyme-linked immunosorbent assay was performed to measure interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) levels. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions were quantified via quantitative reverse transcription polymerase chain reaction. Levels of MAPK pathway-related proteins (p-P38, P38, p-Jun N-terminal kinase (JNK), JNK, signal-regulated kinase (ERK), p-ERK), COX-2 and iNOS were quantitated by Western blot. RESULTS: TEC improved the inflammatory response through ameliorating weight loss, shortening colon, and increasing DAI score in IBD mouse. Expressions of intestinal inflammatory factors (IL-6, TNF-α, iNOS and COX-2) and MAPK pathway-related proteins (p-P38, p-JNK, and p-ERK) were increased both in DSS-induced mouse intestinal tissue, but TEC inhibited expressions of inflammatory factors. The same increased trend was identified in LPS-induced macrophages, but TEC improved macrophage inflammation, as evidenced by downregulation of inflammatory factors. CONCLUSION: TEC mitigates IBD and LPS-induced macrophage inflammation in mice via inhibiting MAPK signaling pathway.


Assuntos
Doenças Inflamatórias Intestinais , Isoflavonas , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases , Macrófagos , Animais , Camundongos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Modelos Animais de Doenças , Sulfato de Dextrana/toxicidade , Inflamação/tratamento farmacológico , Inflamação/imunologia , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo
11.
Int J Biol Sci ; 20(7): 2507-2531, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725846

RESUMO

Neuropeptide substance P (SP) belongs to a family of bioactive peptides and regulates many human diseases. This study aims to investigate the role and underlying mechanisms of SP in colitis. Here, activated SP-positive neurons and increased SP expression were observed in dextran sodium sulfate (DSS)-induced colitis lesions in mice. Administration of exogenous SP efficiently ameliorated the clinical symptoms, impaired intestinal barrier function, and inflammatory response. Mechanistically, SP protected mitochondria from damage caused by DSS or TNF-α exposure, preventing mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. SP can also directly prevent STING phosphorylation through the neurokinin-1 receptor (NK1R), thereby inhibiting the activation of the TBK1-IRF3 signaling pathway. Further studies revealed that SP alleviated the DSS or TNF-α-induced ferroptosis process, which was associated with repressing the cGAS-STING signaling pathway. Notably, we identified that the NK1R inhibition reversed the effects of SP on inflammation and ferroptosis via the cGAS-STING pathway. Collectively, we unveil that SP attenuates inflammation and ferroptosis via suppressing the mtDNA-cGAS-STING or directly acting on the STING pathway, contributing to improving colitis in an NK1R-dependent manner. These findings provide a novel mechanism of SP regulating ulcerative colitis (UC) disease.


Assuntos
Colite , Sulfato de Dextrana , Ferroptose , Inflamação , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Nucleotidiltransferases , Transdução de Sinais , Substância P , Animais , Nucleotidiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos , Colite/metabolismo , Colite/induzido quimicamente , Substância P/metabolismo , Proteínas de Membrana/metabolismo , Ferroptose/efeitos dos fármacos , Inflamação/metabolismo , Sulfato de Dextrana/toxicidade , Masculino , Receptores da Neurocinina-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , DNA Mitocondrial/metabolismo
12.
Int J Biol Sci ; 20(7): 2491-2506, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725850

RESUMO

Colon inflammation is characterized by disturbances in the intestinal microbiota and inflammation. Melatonin (Mel) can improve colon inflammation. However, the underlying mechanism remains unclear. Recent studies suggest that m6A methylation modification may play an important role in inflammatory responses. This study aimed to explore the effects of melatonin and LPS-mediated m6A methylation on colon inflammation. Our study found that melatonin inhibits M1 macrophages, activates M2 macrophages, inhibit the secretion of pro-inflammatory factors, maintain colon homeostasis and improves colon inflammation through MTNR1B. In addition, the increased methylation level of m6A is associated with the occurrence of colon inflammation, and melatonin can also reduce the level of colon methylation to improve colon inflammation. Among them, the main methylated protein METTL3 can be inhibited by melatonin through MTNR1B. In a word, melatonin regulates m6A methylation by improving abnormal METTL3 protein level to reshape the microflora and activate macrophages to improve colon inflammation, mainly through MTNR1B.


Assuntos
Adenosina , Lipopolissacarídeos , Macrófagos , Melatonina , Melatonina/farmacologia , Melatonina/metabolismo , Animais , Camundongos , Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Metilação/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Metiltransferases/metabolismo , Metiltransferases/genética , Inflamação/metabolismo , Colo/metabolismo , Colo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Células RAW 264.7
13.
PLoS One ; 19(5): e0303060, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38723008

RESUMO

In the current study we investigated the impact of combination of rutin and vitamin A on glycated products, the glyoxalase system, oxidative markers, and inflammation in animals fed a high-fat high-fructose (HFFD) diet. Thirty rats were randomly divided into six groups (n = 5). The treatments, metformin (120 mg/kg), rutin (100 mg/kg), vitamin A (43 IU/kg), and a combination of rutin (100 mg/kg) and vitamin A (43 IU/kg) were given to relevant groups of rats along with high-fructose high-fat diet for 42 days. HbA1c, D-lactate, Glyoxylase-1, Hexokinase 2, malondialdehyde (MDA), glutathione peroxidase (GPx), catalase (CAT), nuclear transcription factor-B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8) and histological examinations were performed after 42 days. The docking simulations were conducted using Auto Dock package. The combined effects of rutin and vitamin A in treated rats significantly (p < 0.001) reduced HbA1c, hexokinase 2, and D-lactate levels while preventing cellular damage. The combination dramatically (p < 0.001) decreased MDA, CAT, and GPx in treated rats and decreased the expression of inflammatory cytokines such as IL-6 andIL-8, as well as the transcription factor NF-κB. The molecular docking investigations revealed that rutin had a strong affinity for several important biomolecules, including as NF-κB, Catalase, MDA, IL-6, hexokinase 2, and GPx. The results propose beneficial impact of rutin and vitamin A as a convincing treatment strategy to treat AGE-related disorders, such as diabetes, autism, alzheimer's, atherosclerosis.


Assuntos
Dieta Hiperlipídica , Frutose , Hiperglicemia , Inflamação , Estresse Oxidativo , Rutina , Vitamina A , Animais , Rutina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Frutose/efeitos adversos , Ratos , Dieta Hiperlipídica/efeitos adversos , Vitamina A/farmacologia , Vitamina A/metabolismo , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/induzido quimicamente , Simulação de Acoplamento Molecular , Ratos Wistar , Modelos Animais de Doenças , Glicosilação/efeitos dos fármacos , Metformina/farmacologia , Hemoglobinas Glicadas/metabolismo , NF-kappa B/metabolismo , Hexoquinase/metabolismo , Catalase/metabolismo
14.
PLoS One ; 19(5): e0302628, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38723000

RESUMO

Blood vessels permit the selective passage of molecules and immune cells between tissues and circulation. Uncontrolled inflammatory responses from an infection can increase vascular permeability and edema, which can occasionally lead to fatal organ failure. We identified mexenone as a vascular permeability blocker by testing 2,910 compounds in the Clinically Applied Compound Library using the lipopolysaccharide (LPS)-induced vascular permeability assay. Mexenone suppressed the LPS-induced downregulation of junctional proteins and phosphorylation of VE-cadherin in Bovine Aortic Endothelial Cells (BAECs). The injection of mexenone 1 hr before LPS administration completely blocked LPS-induced lung vascular permeability and acute lung injury in mice after 18hr. Our results suggest that mexenone-induced endothelial cell (EC) barrier stabilization could be effective in treating sepsis patients.


Assuntos
Células Endoteliais , Lipopolissacarídeos , Sepse , Animais , Sepse/tratamento farmacológico , Sepse/induzido quimicamente , Sepse/metabolismo , Camundongos , Bovinos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Masculino , Caderinas/metabolismo , Camundongos Endogâmicos C57BL , Antígenos CD/metabolismo
15.
PLoS One ; 19(5): e0302990, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38723006

RESUMO

The aim of this study is to determine the prevalence of taste alterations (TAs) during chemotherapy and their association with nutritional status and malnutrition. In addition to the associated factors with TA, including sociodemographic health-related factors and clinical status, and to investigate coping strategies to manage TA. A multicenter cross-sectional design study was conducted on 120 cancer patients aged at least 18 who had been undergoing at least one round of chemotherapy. TAs were evaluated using the chemotherapy-induced taste alteration scale (CiTAS), the malnutrition universal screening tool (MUST) was used for nutritional screening, the antineoplastic side effects scale (ASES) was used for subjective assessment of chemotherapy side effects, and the Charlson comorbidity index (CCI) was used for comorbidity assessment. SPSS21 software was used to analyze the data, and the independent T-test and one-way ANOVA test were used to determine the association between TAs and a variety of related variables. The prevalence of TAs was 98.3%. Among participants, 48.3% were at low risk of malnutrition, 20% at medium risk, and 31.7% at high risk. Malnutrition risk was associated with taste disorders (p<0.05). Patients' age, gender, educational level, and physical status were associated with TAs (p<0.05). Type of cancer, chemotherapy regimen, and number of chemotherapy cycles were also associated with TAs (p<0.05). A variety of antineoplastic side effects were associated with TAs (p<0.05), including nausea, vomiting, dry mouth, sore mouth and throat, excessive thirst, swallowing difficulty, appetite changes, weight loss, dizziness, lack of energy, disturbed sleep, anxiety, and difficulty concentrating. TAs were associated with an increased number of comorbidities, and individuals with diabetes, pulmonary diseases, and hypertension were associated with TAs (P<0.05). Patients in this study rarely practice self-management strategies to cope with TAs. A high prevalence (98.3%) of TAs in cancer patients receiving chemotherapy was found, and it was linked to a variety of negative outcomes. Chemotherapy-induced TAs are an underestimated side effect that requires more attention from patients and health care providers.


Assuntos
Antineoplásicos , Neoplasias , Estado Nutricional , Distúrbios do Paladar , Humanos , Masculino , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Estudos Transversais , Pessoa de Meia-Idade , Distúrbios do Paladar/induzido quimicamente , Distúrbios do Paladar/epidemiologia , Idoso , Antineoplásicos/efeitos adversos , Adulto , Desnutrição/epidemiologia , Desnutrição/induzido quimicamente , Prevalência , Paladar/efeitos dos fármacos
16.
Sci Rep ; 14(1): 10647, 2024 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724510

RESUMO

This study aimed to evaluate the safety of Moringa by comparing the effects of different gavage doses of Moringa. The general behavior, body weight, food intake, blood indexes, serum biochemical indexes, and histopathology of rats were used to determine the safety threshold and to provide a reference for the further development and use of Moringa as animal feed. 40 Sprague Dawley rats were selected and given transoral gavage for 28 consecutive days. The T1, T2 and T3 groups were observed for general behavior, body weight, and food intake. Blood and serum biochemical indices were quantified, and histopathology was performed to evaluate the effect and safety of Moringa. The results of the toxicological test showed that (1) Only T1 groups experienced diarrhea. (2) The body weight and food intake of rats in each group were normal compared with the control group. (3) The hematological and serum biochemical indices of rats in the T1 group were significantly different from those of CK but were in the normal range; (4) The results of microscopic examination of the heart, liver, spleen, lung, and kidney of rats in each group were normal, but inflammation occurred in stomach and jejunum of rats in the T1 group, but not in the ileum. The gastrointestinal tract of rats in the T2 and T3 groups were normal. (5) No abnormal death occurred in any of the treatment groups.The results of this study revealed that gavage of Moringa homogenate at a dose of 6 g/kg BW can cause diarrhea in rats. Although there is no pathological effect on weight, food intake, blood and serum biochemical indicators in rats, there are pathological textures in the gastrointestinal tissue caused by diarrhea. Therefore, the safety threshold of Moringa homogenate should be ≤ 3 g/kg BW.


Assuntos
Peso Corporal , Moringa oleifera , Ratos Sprague-Dawley , Animais , Moringa oleifera/química , Ratos , Masculino , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Ração Animal/análise , Diarreia/induzido quimicamente , Diarreia/veterinária
17.
Nat Commun ; 15(1): 3912, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724509

RESUMO

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.


Assuntos
Inibidores do Fator Xa , Fator Xa , Hemorragia , Hemostasia , Pirazóis , Piridonas , Piridonas/farmacologia , Pirazóis/farmacologia , Fator Xa/metabolismo , Animais , Hemorragia/tratamento farmacológico , Hemorragia/induzido quimicamente , Humanos , Inibidores do Fator Xa/farmacologia , Hemostasia/efeitos dos fármacos , Camundongos , Pirazolonas , Proteínas Recombinantes , Masculino , Anticoagulantes/farmacologia , Anticoagulantes/efeitos adversos
18.
J Headache Pain ; 25(1): 74, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38724948

RESUMO

BACKGROUND: Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM. METHODS: A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated. RESULTS: Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE. CONCLUSION: EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.


Assuntos
Sensibilização do Sistema Nervoso Central , Modelos Animais de Doenças , Hiperalgesia , Transtornos de Enxaqueca , Nitroglicerina , Animais , Nitroglicerina/toxicidade , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/metabolismo , Hiperalgesia/induzido quimicamente , Feminino , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Sensibilização do Sistema Nervoso Central/fisiologia , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Meio Ambiente , Camundongos Endogâmicos C57BL
19.
J Neuroinflammation ; 21(1): 123, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38725082

RESUMO

BACKGROUND: Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes. CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.


Assuntos
Encefalopatia Hepática , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Falência Hepática Aguda , Camundongos Knockout , Tioacetamida , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Tioacetamida/toxicidade , Camundongos , Encefalopatia Hepática/patologia , Encefalopatia Hepática/genética , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Falência Hepática Aguda/genética , Masculino , Camundongos Endogâmicos C57BL
20.
PLoS One ; 19(5): e0300980, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38728311

RESUMO

In this cross-sectional study, we determined the relative impact of long-term occupational exposure to pesticides on physical performance and perception of tiredness. Experimental data was collected in locus from agricultural communities and included surveys to assess the duration of exposure to pesticides, social status, habitual physical activity levels, presence of common mental disorders (CMD), and self-reported tiredness. Plasmatic cholinesterase (PChE), body composition and traditional functional performance tests (Handgrip strength-HGS; Time up and go-TUG; and Sit-to-stand-STS) were obtained. From the 127 individuals tested, cluster analysis yielded 80 individuals divided in Direct Exposed (n = 37) and Indirect Exposed (n = 43); Tired (n = 16), and Not Tired (n = 64). PChE values were within the reference values (5209.64-13943.53 U/L). Pesticide exposure had no influence on PChE levels, CMD or fatigue (p > 0.05), while Self-reported tiredness had (p < 0.05). Principal Component Analyses showed that HGS; STS and TUG (i.e., physical performance variables) are negatively influenced by two independent factors: pesticide exposure and self-reported tiredness. We conclude that chronic pesticide exposure and tiredness can negatively impact physical performance, independently, without clinically significant changes in PChE levels that is a biomarker used to track pesticide intoxication. Functional physical tests can be a useful tool to identify chronic pesticide exposure, and help with the limitations of commonly used parameters (i.e. PChE and CMD). Self-reported tiredness is a confounding variable.


Assuntos
Biomarcadores , Exposição Ocupacional , Praguicidas , Humanos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Masculino , Adulto , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Biomarcadores/sangue , Fadiga/induzido quimicamente , Força da Mão , Colinesterases/sangue , Desempenho Físico Funcional
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