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1.
Biomed Pharmacother ; 153: 113407, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076533

RESUMO

Hypertension has become one of the important diseases harmful to human health. In China, Qingda granule (QDG) has been used to treat hypertension for decades. Previous studies by our team have shown that oxidative stress may be one of the pathways through which QDG inhibits hypertension-induced organs injury. However, the specific molecular mechanism of its anti-hypotension and renal oxidative stress response were unclearly. This study investigated QDG's potential protective mechanism against hypertension-induced renal injury. Mice were infused with Angiotensin Ⅱ (Ang Ⅱ, 500 ng/kg/min) or equivalent saline solution (Control) and administered oral QDG (1.145 g/kg/day) or saline for four weeks. QDG treatment mitigated the elevated blood pressure and reduced renal pathological changes induced by Ang Ⅱ. As per the RNA sequencing results, QDG affects oxidative stress signaling. In agreement with these findings, QDG significantly attenuated the Ang Ⅱ-induced increase in Nitrogen oxides 1 (NOX1) and reactive oxygen species and the decrease in superoxide dismutase in renal tissue. Additionally, QDG significantly inhibited Interleukin 6 (IL-6), Tumor necrosis factor α (TNF-α), and Interleukin 1ß (IL-1ß) expression in renal tissues and blocked the phosphorylation of P65 (NF-κB subunit) and IκB. These results were confirmed in vitro. Overall, QDG reduced Ang Ⅱ-induced elevated blood pressure and renal injury by inhibiting oxidative stress and inflammation caused by NOX1 and NF-κB pathways. The results of this study provide an experimental basis for the clinical application of QDG, and to open up a new direction for the clinical treatment of hypertension.


Assuntos
Angiotensina II , Hipertensão , Angiotensina II/efeitos adversos , Angiotensina II/toxicidade , Animais , Medicamentos de Ervas Chinesas , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Inflamação/metabolismo , Rim/patologia , Camundongos , NF-kappa B/metabolismo , Óxidos de Nitrogênio/metabolismo , Óxidos de Nitrogênio/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos
2.
Nutrients ; 14(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36079924

RESUMO

Hyperglycemia is one of the important causes of neurodegenerative disorders and aging. Aquilaria crassna Pierre ex Lec (AC) has been widely used to relieve various health ailments. However, the neuroprotective and anti-aging effects against high glucose induction have not been investigated. This study aimed to investigate the effects of hexane extract of AC leaves (ACH) in vitro using human neuroblastoma SH-SY5Y cells and in vivo using nematode Caenorhabditis elegans. SH-SY5Y cells and C. elegans were pre-exposed with high glucose, followed by ACH treatment. To investigate neuroprotective activities, neurite outgrowth and cell cycle progression were determined in SH-SY5Y cells. In addition, C. elegans was used to determine ACH effects on antioxidant activity, longevity, and healthspan. In addition, ACH phytochemicals were analyzed and the possible active compounds were identified using a molecular docking study. ACH exerted neuroprotective effects by inducing neurite outgrowth via upregulating growth-associated protein 43 and teneurin-4 expression and normalizing cell cycle progression through the regulation of cyclin D1 and SIRT1 expression. Furthermore, ACH prolonged lifespan, improved body size, body length, and brood size, and reduced intracellular ROS accumulation in high glucose-induced C. elegans via the activation of gene expression in the DAF-16/FoxO pathway. Finally, phytochemicals of ACH were analyzed and revealed that ß-sitosterol and stigmasterol were the possible active constituents in inhibiting insulin-like growth factor 1 receptor (IGFR). The results of this study establish ACH as an alternative medicine to defend against high glucose effects on neurotoxicity and aging.


Assuntos
Caenorhabditis elegans , Extratos Vegetais , Thymelaeaceae , Animais , Caenorhabditis elegans/efeitos dos fármacos , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/metabolismo , Glucose/efeitos adversos , Humanos , Longevidade , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Thymelaeaceae/química
3.
Molecules ; 27(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36080247

RESUMO

Combretaceae, an immense family involving species (500) or genera (20), originates in tropical and subtropical regions. This family has evinced medicinal values such as anti-leishmanial, cytotoxic, antibacterial, antidiabetic, antiprotozoal, and antifungal properties. Conocarpus lancifolius (C. lancifolius) methanol extract (CLM) was prepared, then compound isolation performed by open column chromatography, and compound structure was determined by spectroscopic techniques (13C NMR, IR spectroscopy, 1H-NMR, mass spectrometry UV-visible, and 2D correlation techniques). Molecular docking studies of ligand were performed on transcriptional regulators 4EY7 and 2GV9 to observe possible interactions. Phytochemical screening revealed the presence of secondary metabolites including steroids, cardiac glycosides, saponins, anthraquinones, and flavonoids. The isolated compound was distinguished as lancifolamide (LFD). It showed cytotoxic activity against human breast cancer, murine lymphocytic leukemia, and normal cells, human embryonic kidney cells, and rat glioma cells with IC50 values of 0.72 µg/mL, 2.01 µg/mL, 1.55 µg/mL, and 2.40 µg/mL, respectively. Although no cytotoxic activity was noticed against human colon cancer and human lung cancer, LFD showed 24.04% inhibition against BChE and 60.30% inhibition against AChE and is therefore beneficial for Alzheimer's disease (AD). AChE and LFD interact mechanistically in a way that is optimum for neurodegenerative disorders, according to molecular docking studies. Methanol and dichloromethane extract of C. lancifolius and LFD shows antibacterial and antifungal activity against antibiotic resistance Bacillus subtilis, Streptococcus mutans, Brevibacillus laterosporus, Salmonella Typhi, Candida albicans, and Cryptococcus neoformans, respectively. LFD shows antiviral activity against HSV-1 with 26% inhibition IP. The outcomes of this study support the use of LFD for cognitive disorders and highlight its underlying mechanism, targeting AChE, DNA-POL, NF-KB, and TNF-α, etc., for the first time.


Assuntos
Inibidores da Colinesterase , Combretaceae , Herpes Simples , Herpesvirus Humano 1 , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/química , Combretaceae/química , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Metanol , Camundongos , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Ratos
4.
Molecules ; 27(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36080488

RESUMO

Ganlanye (GLY), the leaf of Canarium album (Lour.) DC., is a traditional Chinese medicinal herb for warm disease treatment. We found that its aqueous extract could inhibit the influenza A virus. To find and characterize anti-influenza virus phytochemicals from GLY, we performed (1) bioassay-guided isolation, (2) a cell and animal assay, and (3) a mechanism study. Bioassay-guided isolation was used to identify the effective components. Influenza virus-infected MDCK cell and BALB/c mouse models were employed to evaluate the anti-influenza virus activities. A MUNANA assay was performed to find the NA inhibitory effect. As a result, urolithin M5 was obtained from the crude extract of GLY. It inhibited influenza virus activities in vitro and in vivo by suppressing the viral NA activity. In the MDCK cell model, urolithin M5 could inhibit an oseltamivir-resistant strain. In a PR8-infected mouse model, 200 mg/kg/d urolithin M5 protected 50% of mice from death and improved lung edema conditions. GLY was recorded as a major traditional herb for warm disease treatment. Our study identified GLY as a potent anti-influenza herb and showed urolithin M5 as the active component. We first report the in vivo activity of urolithin M5 and support the anti-influenza application of GLY.


Assuntos
Antivirais , Burseraceae , Vírus da Influenza A Subtipo H1N1 , Neuraminidase , Animais , Antivirais/química , Burseraceae/química , Cães , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Folhas de Planta/química
6.
Science ; 377(6610): eabq4515, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-36048943

RESUMO

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.


Assuntos
Cognição , Disfunção Cognitiva , Síndrome de Down , Hormônio Liberador de Gonadotropina , Transtornos do Olfato , Adulto , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/tratamento farmacológico , Síndrome de Down/psicologia , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/fisiologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Transtornos do Olfato/tratamento farmacológico , Transtornos do Olfato/etiologia , Transmissão Sináptica/efeitos dos fármacos , Adulto Jovem
7.
Neuroreport ; 33(13): 549-560, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36049159

RESUMO

OBJECTIVE: Bergenin (BGN) is a C-glycoside of 4-O-methylgallic acid with anti-inflammatory, antioxidant, and tissue-repairing abilities. Here, we probed the roles and mechanisms of BGN in ischemic stroke-mediated cerebral injury. METHODS: The middle cerebral artery occlusion (MCAO) model was established in mice, which were injected intraperitoneally with varying concentrations of BGN (10, 20, and 40 mg/kg). The modified neurological severity score (mNSS) and the water maze experiment were adopted to evaluate mice's neural functions (movement and memory). The brain edema was assessed by the dry and wet method. TdT-mediated dUTP nick end labeling (TUNEL)-labeled apoptotic neurons and Iba1-labeled microglia in the cortex were measured by immunohistochemistry (IHC). Quantitative reverse transcription-PCR and ELISA were implemented to determine the expression of inflammatory cytokines (TNFα, IL-1ß, and IL-6), neurotrophic factors (BDNF and VEGF), and oxidative stress factors (SOD and MDA) in brain tissues. The profiles of Sirt1, FOXO3a, Nrf2, NF-κB, and STAT6 in brain tissues were checked by western blot. RESULTS: BGN significantly improved MCAO mice's cognitive, learning, and motor functions, reduced brain edema, hampered the production of inflammatory factors and oxidative stress mediators, and suppressed neuronal apoptosis. Additionally, BGN dampened the expression of proinflammatory cytokines and upregulated neurotrophic factors and oxidative stress factors in ischemic brain tissues of MCAO mice. Meanwhile, BGN reduced the expression of inflammatory cytokines and oxidative stressors in oxygen-glucose deprivation/reoxygenation-induced BV2 microglia. Further mechanistic studies revealed that BGN concentration dependently elevated the profiles of Sirt1, FOXO3a, STAT6, and Nrf2, and abated the NF-κB phosphorylation. CONCLUSION: BGN protects against ischemic stroke in mice by boosting the Sirt1/FOXO3a pathway, suggesting its potential as a therapeutic agent for ischemic stroke.


Assuntos
Benzopiranos , Edema Encefálico , AVC Isquêmico , Fármacos Neuroprotetores , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzopiranos/farmacologia , Edema Encefálico/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/tratamento farmacológico , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Fatores de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/metabolismo
8.
Proc Natl Acad Sci U S A ; 119(37): e2123451119, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067301

RESUMO

Filaggrin (FLG), an essential structural protein for skin barrier function, is down-regulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the -343/+25 of the FLG promoter was necessary for TNFα + IFNγ-induced down-regulation of FLG promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the FLG promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNFα + IFNγ stimulation. Knockdown of FRA1 or c-JUN abrogated TNFα + IFNγ-induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNFα + IFNγ stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNFα + IFNγ on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene-induced atopic dermatitis and imiquimod-induced psoriasis. Thus, the current study demonstrates that TNFα + IFNγ stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.


Assuntos
Proteínas Filagrinas , Histona Desacetilase 1 , Queratinócitos , Proteínas Proto-Oncogênicas c-fos , Proteínas Proto-Oncogênicas c-jun , Animais , Doença Crônica , Dermatite/genética , Dermatite/metabolismo , Regulação para Baixo , Proteínas Filagrinas/genética , Proteínas Filagrinas/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Interferon gama/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
9.
Biomed Pharmacother ; 153: 113469, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076495

RESUMO

Bacopa monnieri (Brahmi) is a well-known perennial, creeping herb of the Indian Ayurveda system; it contains numerous bioactive phytoconstituents implicated in the therapeutic management of several life-threatening diseases. This herb was used by Ancient Vedic scholars due to its pharmacological effect, especially as a nerve tonic and nootropic booster. However, to better understand the roles of Bacopa monnieri extract (BME) in neurological disorders and memory-related diseases, it is necessary to understand its active phytochemical constituents and their molecular mechanisms. Several clinical studies suggested that BME have neuroprotective effects, making it worth revising a notable herb. Here we investigated the contours of BME's phytochemistry and pharmacological features, focusing on neuronal disorders. We further analyzed the underlying molecular mechanisms in therapeutic intervention. Various clinical concerns and synergistic potential of BME were explored for their effective use in cognition and neuroprotection. The generation of reactive oxygen species increases neuroinflammation and neurotoxicity and is associated with Tau and amyloid-beta (Aß) aggregation, leading to a neurological disorder. Our findings provide deeper mechanistic insights into the neuroprotective roles of BME, which can be further implicated in the therapeutic management of neurological disorders and exerting cognitive-enhancing effects.


Assuntos
Bacopa/química , Ayurveda , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Cognição/efeitos dos fármacos , Humanos , Transtornos da Memória/tratamento farmacológico , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo
10.
Front Immunol ; 13: 974767, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059528

RESUMO

Introduction: Impairment of the innate immune function may contribute to the increased risk of bacterial and viral infections in people with HIV (PWH). In this study we aimed to investigate the induced innate immune responses in PWH prior to and after initiation of combinational antiretroviral therapy (cART). Furthermore, we aimed to investigate if the induced innate immune responses before initiation of cART were associated with CD4+ T-cell recovery one year after initiating cART. Material and method: The induced innate immune response was assessed by the TruCulture® whole blood technique in 32 PWH before cART initiation and after 1, 6 and 12 months. To mimic bacterial and viral infections we used a panel of three stimuli (lipopolysaccharide (LPS), resiquimod (R848), and polyinosinic:polycytidylic acid (Poly I:C)) to stimulate the extracellular Toll-like receptor (TLR) 4 and the intracellular TLR7/8 and TLR3, respectively. The following cytokine responses were analyzed by Luminex 200: Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-1b, IL-6, IL-8, IL-10, IL-12p40, IL17A, Interferon (IFN)-α, and IFN-γ. Results: At baseline PWH with nadir CD4+ T-cell count <350 cell/µL had lower levels of LPS-, R848-, and Poly I:C-induced IL-6 and IFN-γ, LPS- and R848-induced TNF-α and IL-12, LPS induced IL-1b, and R848-induced IL-10 than PWH with nadir CD4+ T-cell count >350 cells/µL. The majority (>50%) had induced cytokine concentrations below the reference intervals at baseline which was most pronounced for the LPS- and Poly I:C-induced responses. The induced responses in the whole population improved after 12 months of cART, and more PWH had induced cytokine concentrations within the reference intervals after 12 months. However, the majority of PWH still had LPS-induced INF-α, INF-γ and Poly I:C-induced TNF-α and IL-6 below the reference interval. The induced innate immune responses before cART initiation were not associated with the CD4+ T-cell recovery after 12 months of cART. Conclusion: The innate immune response was impaired in PWH, with a more pronounced impairment in PWH with low nadir CD4+ T-cell count. Initiation of cART improved the innate immune response, but compared to the reference intervals, some impairment remained in PWH without viral replication.


Assuntos
Fármacos Anti-HIV , Terapia Antirretroviral de Alta Atividade , Infecções por HIV , Imunidade Inata , Fármacos Anti-HIV/imunologia , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Citocinas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Interferon-alfa , Interleucina-10 , Interleucina-6 , Lipopolissacarídeos/farmacologia , Poli I-C/farmacologia , Fator de Necrose Tumoral alfa , Viroses
11.
Front Endocrinol (Lausanne) ; 13: 973058, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060954

RESUMO

Protein kinase C (PKC) is a family of serine/threonine protein kinases, the activation of which plays an important role in the development of diabetic microvascular complications. The activation of PKC under high-glucose conditions stimulates redox reactions and leads to an accumulation of redox stress. As a result, various types of cells in the microvasculature are influenced, leading to changes in blood flow, microvascular permeability, extracellular matrix accumulation, basement thickening and angiogenesis. Structural and functional disorders further exacerbate diabetic microvascular complications. Here, we review the roles of PKC in the development of diabetic microvascular complications, presenting evidence from experiments and clinical trials.


Assuntos
Angiopatias Diabéticas , Proteína Quinase C , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Diabetes Mellitus , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Humanos , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Proteína Quinase C/efeitos adversos , Proteína Quinase C/metabolismo
12.
Mol Med ; 28(1): 108, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071400

RESUMO

BACKGROUND: High-mobility group box 1 protein (HMGB1) is an ubiquitous nuclear protein that once released in the extracellular space acts as a Damage Associated Molecular Pattern and promotes inflammation. HMGB1 is significantly elevated during Pseudomonas aeruginosa infections and has a clinical relevance in respiratory diseases such as Cystic Fibrosis (CF). Salicylates are HMGB1 inhibitors. To address pharmacological inhibition of HMGB1 with small molecules, we explored the therapeutic potential of pamoic acid (PAM), a salicylate with limited ability to cross epithelial barriers. METHODS: PAM binding to HMGB1 and CXCL12 was tested by Nuclear Magnetic Resonance Spectroscopy using chemical shift perturbation methods, and inhibition of HMGB1·CXCL12-dependent chemotaxis was investigated by cell migration experiments. Aerosol delivery of PAM, with single or repeated administrations, was tested in murine models of acute and chronic P. aeruginosa pulmonary infection in C57Bl/6NCrlBR mice. PAM efficacy was evaluated by read-outs including weight loss, bacterial load and inflammatory response in lung and bronco-alveolar lavage fluid. RESULTS: Our data and three-dimensional models show that PAM is a direct ligand of both HMGB1 and CXCL12. We also showed that PAM is able to interfere with heterocomplex formation and the related chemotaxis in vitro. Importantly, PAM treatment by aerosol was effective in reducing acute and chronic airway murine inflammation and damage induced by P. aeruginosa. The results indicated that PAM reduces leukocyte recruitment in the airways, in particular neutrophils, suggesting an impaired in vivo chemotaxis. This was associated with decreased myeloperoxidase and neutrophil elastase levels. Modestly increased bacterial burdens were recorded with single administration of PAM in acute infection; however, repeated administration in chronic infection did not affect bacterial burdens, indicating that the interference of PAM with the immune system has a limited risk of pulmonary exacerbation. CONCLUSIONS: This work established the efficacy of treating inflammation in chronic respiratory diseases, including bacterial infections, by topical delivery in the lung of PAM, an inhibitor of HMGB1.


Assuntos
Quimiocina CXCL12 , Proteína HMGB1 , Naftóis , Pneumonia Bacteriana , Animais , Quimiocina CXCL12/antagonistas & inibidores , Quimiotaxia/efeitos dos fármacos , Modelos Animais de Doenças , Proteína HMGB1/antagonistas & inibidores , Inflamação/tratamento farmacológico , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Naftóis/farmacologia , Pneumonia Bacteriana/tratamento farmacológico , Pseudomonas aeruginosa/metabolismo
13.
Cardiovasc Diabetol ; 21(1): 172, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056351

RESUMO

BACKGROUND: Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes. METHODS: Trials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions. RESULTS: Geometric mean baseline hsCRP was similar across trials (range 2.7-3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70-0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67-1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6-61.8%) by change in HbA1c and BW. CONCLUSIONS: Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials. TRIAL REGISTRATIONS: ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).


Assuntos
Proteína C-Reativa , Diabetes Mellitus Tipo 2 , Peptídeos Semelhantes ao Glucagon , Peso Corporal , Proteína C-Reativa/análise , Proteína C-Reativa/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/farmacologia , Hemoglobina A Glicada/análise , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/tratamento farmacológico , Resultado do Tratamento
14.
Redox Rep ; 27(1): 177-185, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36047349

RESUMO

OBJECTIVES: This study aimed to evaluate the potential mitigating effect of fisetin on monosodium glutamate (MSG)-induced testicular toxicity and investigate the possible involvement of silent mating type information regulation 2 homolog 1 (SIRT1) in this effect. METHODS: Forty male rats were divided into normal control, fisetin-treated, MSG-treated, and fisetin + MSG-treated groups. Testosterone, GnRH, FSH, and LH were measured in plasma, as well as SIRT1 and phosphorylated AMP-activated protein kinase (pAMPK) levels in testicular tissues using ELISA. Hydrogen peroxide (H2O2), nitric oxide (NO), and reduced glutathione (GSH) were measured colorimetrically, while Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression was relatively quantified using RT-PCR in testicular tissues. RESULTS: After 30 days, fisetin could ameliorate MSG-induced testicular toxicity by acting centrally on the hypothalamic-pituitary-gonadal axis, increasing plasma levels of GnRH, FSH, LH, and testosterone. Peripheral actions of fisetin on the testis were indicated as it increased testicular SIRT1 and pAMPK. Furthermore, it antagonized glutamate-induced oxidative stress by significantly lowering H2O2, NO, and relative NOX4 expression while significantly increasing reduced GSH levels. It also improved the architecture of the seminiferous tubules, reduced sperm abnormality, and increased sperm count. DISCUSSION: Fisetin ameliorates MSG-induced testicular toxicity via central and peripheral mechanisms making it a promising therapeutic target for male infertility.


Assuntos
Flavonóis , Sirtuína 1 , Testículo , Animais , Flavonóis/farmacologia , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Estresse Oxidativo , Ratos , Sêmen/metabolismo , Sirtuína 1/metabolismo , Glutamato de Sódio/toxicidade , Testículo/efeitos dos fármacos , Testosterona/metabolismo
15.
Oxid Med Cell Longev ; 2022: 4212331, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36062191

RESUMO

Herein, the molecular pathogenic pathways implicated in renal injury triggered by amikacin (AK), together with the alleviating actions of ß-caryophyllene (BCP), were investigated. Adult male Wistar rats (n = 32) were disseminated to the four following groups (n = 8/group): normal group, positive control animals (PC) that received AK intraperitoneal injections for 14 days (500 mg/kg/day), and rats that received AK simultaneously with small (200 mg/kg/day) and high doses (400 mg/kg/day) of BCP. The PC renal tissues revealed abnormal histology alongside increased apoptosis and significantly elevated serum creatinine and urea with marked proteinuria and oliguria relative to the normal rats. Moreover, renal tissues from the PC animals also showed substantial upregulations in NF-κB/TGF-ß/KIM-1, whilst Nrf2/AMPK/AKT/PCNA declined, at the gene and protein levels in comparison to the normal rats. Additionally, the levels of markers of oxidative stress (MDA/H2O2/protein adducts) and inflammation (TNF-α/IL-1ß/IL-6/IL-18/TLR/HSP25) were substantially higher in the PC renal specimens, whereas the antioxidants (GSH/GPx/SOD1/CAT) and interleukin-10 decreased, relative to the NC group. Both BCP protocols improved the biochemical markers of renal functions, alleviated renal histopathology and apoptosis, and decreased NF-κB/TGF-ß/KIM-1 alongside the concentrations of oxidative stress and proinflammatory markers, whilst promoting Nrf2/AMPK/AKT/IL-10/PCNA and the targeted antioxidants. However, the improving effects in the high-dose regimen were markedly stronger than those observed in animals treated with low dose of BCP. In conclusion, the present report is the first to connect NF-κB/TGF-ß/KIM-1 proinflammatory and Nrf2/AMPK/AKT antioxidative stress pathways with the pathogenesis of AK-induced nephrotoxicity. Additionally, the current report is the first to disclose alleviating activities for BCP against AK-triggered nephrotoxicity by modulating multiple antioxidative stress with anti-inflammatory molecular pathways.


Assuntos
Rim , Fator 2 Relacionado a NF-E2 , NF-kappa B , Sesquiterpenos Policíclicos , Proteínas Quinases Ativadas por AMP/metabolismo , Amicacina/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Peróxido de Hidrogênio/farmacologia , Rim/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Sesquiterpenos Policíclicos/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Fator de Crescimento Transformador beta
16.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 38(3): 252-257, 2022 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-36062795

RESUMO

Objective: To evaluate the effects of antiretrovirals on cardiovascular function and some biochemical indexes in gestational female rats. Methods: Nineteen 9-week-old female and six 10-week-old male SD rats were divided into normal control group (CON) and highly active antiretroviral therapy group (HARRT), 9/10 female rats and 3 male rats were combined into one cage, totally 2 cages. Female rats in CON group were intragastrically given with normal saline (NS, 10 ml/kg) every morning and evening, while female rats in HARRT group were treated with equal volume antiretrovirals (AZT 31.25 mg/kg + 3TC 15.63 mg/kg + LPV/r (41.67/10.42) mg/kg) for 3 months. The body weight and survival rate of female rats were recorded. Echocardiography and multichannel physiological recorder were used to detect arterial blood pressure and cardiac hemodynamic parameters. The levels of blood glucose, blood lipids, myocardial enzymes and liver enzymes were detected by corresponding kits. Myocardial collagen fibers were observed by Masson staining and the ultrastructure of myocardial cells were observed by transmission electron microscopy. Results: All female rats in CON group survived (9/9), while only 6 rats in HARRT group survived (6/10). Compared with CON group, the body weight of female rats in HAART group was decreased significantly(P<0.01); the levels of left ventricular end diastolic diameter (LVDd), interventricular septal thickness (IVST), thickness of left ventricular posterior wall (LVPWT) , left atrial diameter (LAD) and arterial diastolic pressure were increased significantly (P<0.05); the level of LVP+dP/dtmax was decreased (P<0.01). The levels of triglyceride, creatine kinase, and glutamic oxaloacetic transaminase were decreased (P<0.05 or P<0.01), while the level of glucose was increased (P<0.05). The collagen fibers were increased in myocardial tissue, and ultrastructure of myocardial cells was abnormal. Conclusion: Antiretrovirals during gestation can cause cardiovascular diseases in female rats.


Assuntos
Antirretrovirais , Cardiotoxicidade , Miócitos Cardíacos , Animais , Antirretrovirais/efeitos adversos , Peso Corporal , Colágeno , Feminino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/ultraestrutura , Gravidez , Ratos , Ratos Sprague-Dawley
17.
Eur J Dermatol ; 32(3): 305-311, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36065535

RESUMO

Short- and long-term exposure to atmospheric pollution has significant health effects. The skin is the organ directly in contact with pollutants and is responsible for protection of the organism. Particulate matter (PM) such as polycyclic aromatic hydrocarbons (PAHs) are the basis of certain pulmonary as well as dermatological complications. Pollution exacerbates certain illnesses such as atopic dermatitis and cancer, and it may also participate in delaying wound healing and in the occurrence of chronic ailments such as diabetes. The aryl hydrocarbon receptor (AhR) transcription factor, at the core of these responses to pollutants, is expressed by all cells of the skin. The AhR is subject to tight regulation that depends on its ligand. Pollutants act in a deleterious manner via the AhR, influencing the behaviour of keratinocytes as well as fibroblasts. Natural ligands, on the other hand, allow the noxious effects of pollution to be countered. This non-systematic review of the literature shows that modulation of AhR appears to be an excellent therapeutic approach to improve or stop the cutaneous problems linked to pollution.


Assuntos
Dermatite Atópica , Poluentes Ambientais , Receptores de Hidrocarboneto Arílico , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Dermatite Atópica/metabolismo , Poluentes Ambientais/toxicidade , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Receptores de Hidrocarboneto Arílico/fisiologia , Pele/efeitos dos fármacos , Pele/metabolismo
18.
Clin Lab ; 68(9)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36125160

RESUMO

BACKGROUND: The anti-CD38 antibody daratumumab is a common multiple myeloma treatment. As the erythrocyte's membrane expresses CD38, Daratumumab-treated samples show agglutination in serological pre-transfusion tests, hindering detection of erythrocyte alloantibodies. Dithiothreitol interferes with erythrocyte antigens, affecting investigation of unexpected antibodies. DARAEx®, an anti-CD38 neutralizing agent, overcomes daratumumab-induced effects, without dithiothreitol's interferences. DARAEx® is applied only in Biorad columns. This study aimed to provide a DARAEx® protocol for application with the Grifols platform. METHODS: We introduced a modified DARAEx® protocol (AssutaBB protocol) and performed antibody screenings on samples from nineteen daratumumab-treated patients. RESULTS: The AssutaBB protocol provided antibody screen results for all patients, exactly as established in the default manufacturing protocol. Eleven patients presented natural negative antibody screens; eight presented positive K/E antibodies. CONCLUSIONS: AssutaBB allows the use of the more widespread Grifols platform in daratumumab-treated patients.


Assuntos
Anticorpos Monoclonais , Antineoplásicos , Eritrócitos , Mieloma Múltiplo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ditiotreitol/farmacologia , Eritrócitos/efeitos dos fármacos , Humanos , Isoanticorpos , Mieloma Múltiplo/tratamento farmacológico
20.
BMC Med ; 20(1): 288, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36064525

RESUMO

BACKGROUND: Beta-blocker (BB) and calcium channel blocker (CCB) antihypertensive drugs are commonly used in pregnancy. However, data on their relative impact on maternal and foetal outcomes are limited. We leveraged genetic variants mimicking BB and CCB antihypertensive drugs to investigate their effects on risk of pre-eclampsia, gestational diabetes and birthweight using the Mendelian randomization paradigm. METHODS: Genetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs) associated with SBP (p < 5 × 10-8) in BB and CCB drug target gene regions were selected as proxies for drug target perturbation. Genetic association estimates for the outcomes were extracted from GWASs on 4743 cases and 136,325 controls (women without a hypertensive disorder in pregnancy) for pre-eclampsia or eclampsia, 7676 cases and 130,424 controls (women without any pregnancy-related morbidity) for gestational diabetes, and 155,202 women (who have given birth at least once) for birthweight of the first child. All studies were in European ancestry populations. Mendelian randomization estimates were generated using the two-sample inverse-variance weighted model. RESULTS: Although not reaching the conventional threshold for statistical significance, genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per 10 mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p = 0.08) and increased risk of gestational diabetes (OR per 10 mmHg SBP reduction 2.01, 95%CI 0.91-4.42, p = 0.08), and significantly associated with lower birthweight of first child (beta per 10 mmHg SBP reduction - 0.27, 95%CI - 0.39 to - 0.15, p = 1.90 × 10-5). Genetically-proxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR 0.62, 95%CI 0.43-0.89, p = 9.33 × 10-3), and was not associated with gestational diabetes (OR 1.05, 95% CI 0.76-1.45, p = 0.76) or changes in birthweight of first child (beta per 10 mmHg SBP reduction 0.02, 95%CI - 0.04-0.07, p = 0.54). CONCLUSIONS: While BB and CCB antihypertensive drugs may both be efficacious for lowering blood pressure in pregnancy, this genetic evidence suggests that BB use may lower birthweight. Conversely, CCB use may reduce risk of pre-eclampsia and eclampsia without impacting gestational diabetes risk or birthweight. These data support further study on the effects of BBs on birthweight.


Assuntos
Antagonistas Adrenérgicos beta , Anti-Hipertensivos , Bloqueadores dos Canais de Cálcio , Diabetes Gestacional , Hipertensão , Pré-Eclâmpsia , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Peso ao Nascer/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Criança , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/genética , Eclampsia/epidemiologia , Eclampsia/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/genética , Análise da Randomização Mendeliana , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/genética , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética
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