RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. AIM OF THE STUDY: This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). MATERIALS AND METHODS: The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. RESULTS: In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aß accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. CONCLUSIONS: These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Camundongos , Animais , Histonas/metabolismo , Lisina/metabolismo , Lisina/uso terapêutico , Secretases da Proteína Precursora do Amiloide , Acetilação , Biogênese de Organelas , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Camundongos Transgênicos , Cognição , Processamento de Proteína Pós-Traducional , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND: The asthma of some children remains poorly controlled, with recurrent exacerbations despite treatment with inhaled corticosteroids. Aside from prior exacerbations, there are currently no reliable predictors of exacerbation-prone asthma in these children and only a limited understanding of the potential underlying mechanisms. OBJECTIVE: We sought to quantify small molecules in the plasma of children with exacerbation-prone asthma through mass spectrometry-based metabolomics. We hypothesized that the plasma metabolome of these children would differ from that of children with non-exacerbation-prone asthma. METHODS: Plasma metabolites were extracted from 4 pediatric asthma cohorts (215 total subjects, with 41 having exacerbation-prone asthma) and detected with a mass spectrometer. High-confidence annotations were retained for univariate analysis and were confirmed by a sensitivity analysis in subjects receiving high-dose inhaled corticosteroids. Metabolites that varied by cohort were excluded. MetaboAnalyst software was used to identify pathways of interest. Concentrations were calculated by reference standardization. RESULTS: We identified 32 unique, cohort-independent metabolites that differed in children with exacerbation-prone asthma compared to children with non-exacerbation-prone asthma. Comparison of metabolite concentrations to literature-reported values for healthy children revealed that most metabolites were decreased in both asthma groups, but more so in exacerbation-prone asthma. Pathway analysis identified arginine, lysine, and methionine pathways as most impacted. CONCLUSIONS: Several plasma metabolites are perturbed in children with exacerbation-prone asthma and are largely related to arginine, lysine, and methionine pathways. While validation is needed, plasma metabolites may be potential biomarkers for exacerbation-prone asthma in children.
Assuntos
Asma , Lisina , Criança , Humanos , Lisina/uso terapêutico , Metionina/uso terapêutico , Arginina , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico , RacemetioninaRESUMO
Aberrations in spinal glycinergic signaling are a feature of pain chronification. Normalizing these changes by inhibiting glycine transporter (GlyT)-2 is a promising treatment strategy. However, existing GlyT2 inhibitors (e.g., ORG25543) are limited by narrow therapeutic windows and severe dose-limiting side effects, such as convulsions, and are therefore poor candidates for clinical development. Here, intraperitoneally administered oleoyl-D-lysine, a lipid-based GlyT2 inhibitor, was characterized in mouse models of acute (hot plate), inflammatory (complete Freund's adjuvant), and chronic neuropathic (chronic constriction injury) pain. Side effects were also assessed on a numerical rating score, convulsions score, for motor incoordination (rotarod), and for respiratory depression (whole body plethysmography). Oleoyl-D-lysine produced near complete antiallodynia for chronic neuropathic pain, but no antiallodynia/analgesia in inflammatory or acute pain. No side effects were seen at the peak analgesic dose, 30 mg/kg. Mild side effects were observed at the highest dose, 100 mg/kg, on the numerical rating score, but no convulsions. These results contrasted markedly with ORG25543, which reached less than 50% reduction in allodynia score only at the lethal/near-lethal dose of 50 mg/kg. At this dose, ORG25543 caused maximal side effects on the numerical rating score and severe convulsions. Oleoyl-D-lysine (30 mg/kg) did not cause any respiratory depression, a problematic side effect of opiates. These results show the safe and effective reversal of neuropathic pain in mice by oleoyl-D-lysine and provide evidence for a distinct role of glycine in chronic pain over acute or short-term pain conditions. SIGNIFICANCE STATEMENT: Partially inhibiting glycine transporter (GlyT)-2 can alleviate chronic pain by restoring lost glycinergic function. Novel lipid-based GlyT2 inhibitor ol-D-lys is safe and effective in alleviating neuropathic pain, but not inflammatory or acute pain. Clinical application of GlyT2 inhibitors may be better suited to chronic neuropathic pain over other pain aetiologies.
Assuntos
Dor Aguda , Dor Crônica , Neuralgia , Insuficiência Respiratória , Animais , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Glicina , Hiperalgesia/tratamento farmacológico , Lipídeos , Lisina/farmacologia , Lisina/uso terapêutico , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológicoRESUMO
Lysine specific demethylase 1 (LSD1), a transcriptional corepressor or coactivator that serves as a demethylase of histone 3 lysine 4 and 9, has become a potential therapeutic target for cancer therapy. LSD1 mediates many cellular signaling pathways and regulates cancer cell proliferation, invasion, migration, and differentiation. Recent research has focused on the exploration of its pharmacological inhibitors. Natural products are a major source of compounds with abundant scaffold diversity and structural complexity, which have made a major contribution to drug discovery, particularly anticancer agents. In this review, we briefly highlight recent advances in natural LSD1 inhibitors over the past decade. We present a comprehensive review on their discovery and identification process, natural plant sources, chemical structures, anticancer effects, and structure-activity relationships, and finally provide our perspective on the development of novel natural LSD1 inhibitors for cancer therapy.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Histona Desmetilases/química , Histona Desmetilases/metabolismo , Humanos , Lisina/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
Accumulation of advanced glycation end products (AGEs) of the Maillard reaction has been implicated in the pathogenesis of diabetes and its complications. Connarus ruber has been used as a folk remedy for several diseases, including diabetes; however, its underlying mechanism has not yet been investigated. This study investigated the effects of C. ruber extract against glycation on collagen-linked AGEs in vitro and streptozotocin-induced diabetic rats (STZ-DM rats) in vivo. The antiglycation activities of C. ruber extract and aminoguanidine (AG) were examined using a collagen glycation assay kit. Nonfluorescent AGE, Nε-carboxymethyl lysine (CML), Nω-carboxymethyl arginine, and Nε-carboxyethyl lysine levels were measured via electrospray ionization-liquid chromatography-tandem mass spectrometry. The effect of the extract on the cytotoxicity of methylglyoxal (MG), a precursor of AGEs, was examined in HL60 cells. STZ-DM rats were treated with the extract for 4 wk, and the effect was assessed using biochemical markers in the serum and CML-positive cells in renal tissues. C. ruber extract dose-dependently inhibited the glycation of collagen and formation of nonfluorescent AGEs, which was comparable to AG, and it significantly attenuated MG-induced cytotoxicity in HL60 cells. Furthermore, the glycated albumin levels in STZ-DM rats decreased, the increase in serum lipid levels was reversed, and immunohistochemistry demonstrated that CML deposition in the glomerulus of STZ-DM rats significantly decreased. Although further studies are needed, C. ruber could be a potential therapeutic for preventing and progressing many pathological conditions, including diabetes.
Assuntos
Connaraceae , Diabetes Mellitus Experimental , Animais , Arginina/análise , Arginina/uso terapêutico , Colágeno , Diabetes Mellitus Experimental/tratamento farmacológico , Produtos Finais de Glicação Avançada , Guanidinas , Lipídeos , Lisina/análise , Lisina/uso terapêutico , Aldeído Pirúvico/uso terapêutico , Ratos , EstreptozocinaRESUMO
OBJECTIVES AND SETTING.: As the lethal COVID-19 pandemic enters its second year, the need for effective modalities of alleviation remains urgent. This includes modalities that can readily be used by the public to reduce disease spread and severity. Such preventive measures and early-stage treatments may temper the immediacy of demand for advanced anti-COVID measures (drugs, antibodies, vaccines) and help relieve strain also on other health system resources. DESIGN AND PARTICIPANTS.: We present results of a clinical study with a multi-component OTC "core formulation" regimen used in a multiply exposed adult population. Analysis of clinical outcome data from our sample of over 100 subjects - comprised of roughly equal sized regimen-compliant (test) and non-compliant (control) groups meeting equivalent inclusion criteria - demonstrates a strong statistical significance in favor of use of the core formulations. RESULTS.: While both groups were moderate in size, the difference between them in outcomes over the 20-week study period was large and stark: Just under 4% of the compliant test group presented flu-like symptoms, but none of the test group was COVID-positive; whereas 20% of the non-compliant control group presented flu-like symptoms, three-quarters of whom (15% overall of the control group) were COVID-positive. CONCLUSIONS.: Offering a low cost, readily implemented anti-viral approach, the study regimen may serve, at the least, as a stopgap modality and, perhaps, as a useful tool in combatting the pandemic.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Controle de Doenças Transmissíveis , Suplementos Nutricionais , Pandemias , Adulto , COVID-19/virologia , Cinchona , Feminino , Humanos , Ionóforos/uso terapêutico , Lisina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Medicamentos sem Prescrição , Quercetina/uso terapêutico , SARS-CoV-2 , Índice de Gravidade de Doença , Resultado do Tratamento , Vitaminas/uso terapêutico , Zinco/uso terapêuticoRESUMO
OBJECTIVES: Positively charged amino acids (AA) such as arginine/lysine are coinfused with radiolabeled somatostatin analogs to reduce rates of nephrotoxicity. In the phase 3 NETTER-1 trial, commercial AA formulations were used in association with 177Lu-DOTA-0-Tyr3-Octreotate (DOTATATE). These formulations were also used in an early-access program (EAP) before regulatory approval of 177Lu-DOTATATE. Our program transitioned to compounded l-arginine 2.5%/l-lysine 2.5% in 0.9% NaCl after commercial approval of 177Lu-DOTATATE. We sought to compare rates of nausea/vomiting with arginine/lysine versus commercial parenteral AA formulations. METHODS: Rates of nausea/vomiting of all 20 EAP patients who received commercial AAs (15% Clinisol) were compared with the first 29 patients to receive 177Lu-DOTATATE after commercial approval and coinfused with arginine/lysine. Other parameters reviewed included infusion rates, need for PRN nausea medications, and other toxicities. RESULTS: Seventeen percent of patients who received compounded arginine/lysine experienced nausea, compared with 100% of patients in the EAP group (P < 0.0001). Infusion-related reactions occurred in 3% of the arginine/lysine cohort versus 35% in the EAP group. Infusion durations were substantially shorter in the arginine/lysine cohort (reduced by 61%). CONCLUSIONS: Coinfusions of arginine/lysine with radiolabeled somatostatin analogs result in substantially lower rates of nausea/vomiting compared with commercial AA formulations designed for parenteral nutrition.
Assuntos
Aminoácidos/uso terapêutico , Náusea/diagnóstico , Tumores Neuroendócrinos/terapia , Octreotida/análogos & derivados , Compostos Organometálicos/uso terapêutico , Nutrição Parenteral/métodos , Vômito/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/administração & dosagem , Aminoácidos/efeitos adversos , Arginina/administração & dosagem , Arginina/efeitos adversos , Arginina/uso terapêutico , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Humanos , Bombas de Infusão , Lisina/administração & dosagem , Lisina/efeitos adversos , Lisina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Octreotida/administração & dosagem , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Nutrição Parenteral/efeitos adversos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Peptídeos/química , Estudos Retrospectivos , Vômito/etiologiaRESUMO
A captive loggerhead turtle (Caretta caretta) of unknown sex, 3 years of age, presented with bilateral mucoid secretions, severe chemosis, conjunctival hyperemia, and globe retraction. The animal was evaluated ophthalmologically and systemically, and hematological, microbiological, and conjunctival cytological and biopsy samples were collected for complementary diagnosis. The histopathological examination showed amphophilic intranuclear inclusions associated with severe inflammatory infiltrate. The diagnosis of Chelonid alphaherpesvirus 5 (ChAHV 5) was confirmed with end point PCR. Following systemic treatment with L-lysine, acyclovir and vitamin A, the ocular signs resolved. No amphophilic intranuclear inclusions were seen in a follow-up biopsy 5 months later, and there has been no recurrence of clinical ophthalmic signs during a 4-year follow-up. It is suggested that ChAHV 5 be considered as a differential diagnosis in captive marine turtles that present for conjunctival disease other than fibropapillomatosis.
Assuntos
Alphaherpesvirinae , Conjuntivite Viral/veterinária , Infecções por Herpesviridae/veterinária , Tartarugas , Animais , Conjuntivite Viral/diagnóstico , Conjuntivite Viral/tratamento farmacológico , Conjuntivite Viral/patologia , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/virologia , Lisina/uso terapêutico , Reação em Cadeia da Polimerase/veterináriaRESUMO
BACKGROUND AND AIMS: Diabetes is a leading cause of morbidity and mortality worldwide. Recent studies have demonstrated that nutraceutical products have beneficial effects in diabetes. Present study aims to investigate whether a product (Lysulin™) containing amino acid lysine, micronutrient zinc and vitamin C will have beneficial effects in pre-diabetes. METHODS: A randomized, double-blind, placebo-controlled trial was conducted for a period of 6 months. The two parallel groups (1:1) were Lysulin™ (Interventional group-IG) and placebo (control group-CG). Evaluations were done at baseline, 1, 3 and 6 months. Primary outcome was defined as change in glycaemic control measured by HbA1c from baseline. Other outcomes included change in; fasting plasma glucose (FPG), 2-h OGTT plasma glucose and lipid profile from baseline. Three multiple regression analyses were performed, where change in FPG, 2-h OGTT, and HbA1c post intervention from baseline respectively were the continuous dependent variable with other independent variables. RESULTS: One hundred and ten participants were recruited, 50% (n = 55) were males and mean age (±SD) was 46.7 ± 9.9 years. A significantly higher percentage of participants in CG (25.4%, n = 14) developed diabetes in comparison to IG (7.3%, n = 4) (p = 0.018). FPG, 2-h OGTT and HbA1c significantly reduced in the IG only. Both total cholesterol and LDL cholesterol decreased significantly from baseline only in the IG. In all three regression models the best predictor of respective dependent variable was Lysulin™ treatment. CONCLUSIONS: Lysulin™ improved glycaemic control, with reduced progression to diabetes, in those with pre-diabetes. Treatment also showed a beneficial reduction in total and LDL cholesterol levels. TRIAL REGISTRATION: Sri Lanka Clinical Trials Registry, identifier: SLCTR/2018/022 (http://slctr.lk/trials/1290). Registered on 13th July 2018; Study protocol version 2.0 (23rd March 2018).
Assuntos
Ácido Ascórbico/uso terapêutico , Suplementos Nutricionais , Hipoglicemiantes/uso terapêutico , Lisina/uso terapêutico , Estado Pré-Diabético/tratamento farmacológico , Zinco/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Glicemia/análise , Método Duplo-Cego , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , PrognósticoRESUMO
Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.
Assuntos
Imageamento por Ressonância Magnética Multiparamétrica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Próstata , Neoplasias da Próstata , Idoso , Meios de Contraste/uso terapêutico , Humanos , Lisina/análogos & derivados , Lisina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Próstata/química , Próstata/diagnóstico por imagem , Próstata/patologia , Neoplasias da Próstata/química , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Sensibilidade e Especificidade , Ureia/análogos & derivados , Ureia/uso terapêuticoRESUMO
The present study investigated the effectiveness of a Carisolv III + 0.5% sodium hypochlorite (NaOCl)-based root canal irrigant for smear layer removal.Forty maxillary incisors were randomly divided into 4 groups (nâ=â10 per group). The canals in group A (experimental) were prepared with 0.5% NaOCl, and Carisolv III and 0.5% NaOCl was used for the final washing; groups B and C (positive controls) used 2% and 5.25% NaOCl, respectively; and group D (negative control) used phosphate-buffered saline (PBS). Ethylenediaminetetraacetic acid (EDTA) was used for all of the groups. A 5-point scoring scale and scanning electron microscopy were used to evaluate the effectiveness of the irrigants. The canals were consistently cleaner in the coronal and middle thirds than in the apical thirds (Pâ<â.05).For cleaning the root canals, 5.25% NaOCl was more effective than 2% NaOCl, 0.5% NaOClâ+âCarisolv III, and phosphate-buffered saline , respectively (Pâ<â.05). The 2% NaOCl solution showed similar results to 0.5% NaOClâ+âCarisolv III (Pâ>â.05). The combination of 5.25% NaOCl and 17% EDTA remains the most effective irrigant for removal of the root canal smear layer.A combination of Carisolv IIIâ+â0.5% NaOCl (with 17% EDTA) showed a cleaning ability similar to that of 2% NaOCl (with 17% EDTA).
Assuntos
Ácido Glutâmico/uso terapêutico , Leucina/uso terapêutico , Lisina/uso terapêutico , Irrigantes do Canal Radicular/uso terapêutico , Tratamento do Canal Radicular/métodos , Hipoclorito de Sódio/uso terapêutico , Adulto , Cavidade Pulpar/cirurgia , Feminino , Humanos , Técnicas In Vitro , Incisivo/cirurgia , Masculino , Pessoa de Meia-IdadeRESUMO
The priority pathogen list published by the World Health Organization (WHO) has categorized carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa as the top two critical pathogens, and hence, the development of novel antibacterial strategies to tackle such bacteria is highly necessary. Toward this aim, herein we report the efficacy of the combination of a lysine-based membrane-active small molecule, D-LANA-14 (d-lysine conjugated aliphatic norspermidine analogue bearing tetradecanoyl chain) and the obsolete/inactive antibiotics (such as tetracycline and rifampicin) to combat these superbugs. The combination of D-LANA-14 and the antibiotics tetracycline or rifampicin showed not only synergistic activity against growing planktonic cells of meropenem-resistant A. baumannii and P. aeruginosa clinical isolates but was also able to disrupt their established biofilms. More importantly, this synergistic effect was retained under the in vivo scenario, wherein the combination showed excellent efficacy in mice model of burn-wound infection with a drastic reduction of bacterial burden. A combined treatment of D-LANA-14 (40 mg/kg) and rifampicin (40 mg/kg) showed 4.9 log and 4.0 log reduction in A. baumannii and P. aeruginosa viability, respectively. On the contrary, individual treatment of D-LANA-14 decreased bacterial burden by 2.3 log (A. baumannii) and 1.3 log (P. aeruginosa) and rifampicin reduced about 3.0 log (A. baumannii) and 1.6 log (P. aeruginosa). Owing to the membrane-active nature imparted by D-LANA-14, bacteria could not develop resistance against the combined treatment, whereas a high-level of resistance development was observed against the last resort Gram-negative antibiotic, colistin. Taken together, the results therefore indicate a great potential of this novel combination to be developed as therapeutic regimen to combat infections caused by critical Gram-negative pathogens.
Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Lisina/química , Pseudomonas aeruginosa/efeitos dos fármacos , Rifampina/uso terapêutico , Tetraciclina/uso terapêutico , Infecções por Acinetobacter/tratamento farmacológico , Animais , Antibacterianos/uso terapêutico , Carga Bacteriana , Membrana Externa Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Queimaduras/tratamento farmacológico , Queimaduras/microbiologia , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Lisina/análogos & derivados , Lisina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologiaRESUMO
BACKGROUND AND OBJECTIVES: The efficacy of commonly prescribed analgesic and adjuvant drugs for the management of patients with radiculopathy has not been well established. Oral steroids are commonly used to treat sciatica or radiculopathy due to a herniated disk but the effect remains controversial. L-lysine aescinate showed superiority over placebo or baseline therapy with NSAIDs alone in treating sciatica, but have not been evaluated in an appropriately powered clinical trial. MATERIALS AND METHODS: Randomized, double-blind clinical trial conducted in two health centers in collaboration with Uzhhorod Natioanl University in Ukraine. Adults (N = 90) with acute radicular pain and a herniated disk confirmed by MRI were eligible. Participants were randomly assigned to three groups (N = 30 in each) to receive a baseline therapy with lornoxicam (16 mg per day) and adjunctive 5-day course of IV dexamethasone (first group: 8 mg per day/40 mg total) or 0,1% solution of L-lysine aescinate (5 mL and 10 mL for group 2 and 3 respectively). Primary outcomes were Visual Analogue Scale changes and the straight leg raise angle at 15th and 30th day. RESULTS: The level of pain improvement at 15th days after initiation of therapy with dexamethasone or solution of L-lysine aescinate at doses of 5 or 10 mL was not significantly different. The lowest levels of pain were achieved in patients who received the L-lysine aescinate 10 mL, but the range of decrease in pain was slightly greater in the group administered dexamethasone. CONCLUSIONS: Among patients with acute radiculopathy due to a herniated lumbar disk a short course of IV dexamethasone or L-lysine aescinate resulted in pain improvement at 15th and 30th day. Dexamethasone may be preferable if a longer-term analgesic effect is needed. Taking into account side effects of dexamethasone, a solution of L-lysine aescinate can be used to relieve pain symptoms.
Assuntos
Deslocamento do Disco Intervertebral/complicações , Lisina/normas , Manejo da Dor/normas , Radiculopatia/tratamento farmacológico , Adulto , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Deslocamento do Disco Intervertebral/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Dor Lombar/etiologia , Lisina/farmacologia , Lisina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Manejo da Dor/estatística & dados numéricos , Medição da Dor/métodos , Radiculopatia/etiologia , Resultado do Tratamento , UcrâniaRESUMO
Sepsis is a severe, life-threatening condition caused primarily by the cellular response to infection. Sepsis leads to increased tissue damage and mortality in patients in the intensive care unit. L-Lysine is an essential amino acid required for protein biosynthesis and is abundant in lamb, pork, eggs, red meat, fish oil, cheese, beans, peas, and soy. The present study investigates the protective effect of L-lysine against sepsis-induced acute lung injury (ALI) in a lipopolysaccharide-induced mouse model. In the present study, mice were divided into sham, control, 5â¯mg/kg body weight L-lysine, and 10â¯mg/kg body weight L-lysine treatment groups. At the end of the treatment period, we determined the levels of oxidative and inflammatory markers, myeloperoxidase (MPO) and catalase activities, total cell count, the wet/dry ratio of lung tissue, and total protein content. The effects of L-lysine on the cellular architecture of lung tissue were also evaluated. L-Lysine treatment significantly reduced the magnitude of lipid peroxidation; total protein content; wet/dry ratio of lung tissue; tumor necrosis factor alpha, interleukin-8, and macrophage inhibitory factor levels; MPO activity; and total cell, neutrophil, and lymphocyte counts. It also increased the levels of reduced glutathione and the activities of glutathione peroxidase, superoxide dismutase, and catalase. A normal cellular architecture was noted in mice in the sham group, whereas proinflammatory changes such as edema and neutrophilic infiltration were detected in mice in the control group. L-lysine significantly ameliorated these proinflammatory changes. Taking all these data together, it is suggested that the L-lysine was effective against sepsis-induced ALI.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lisina/uso terapêutico , Sepse/complicações , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/patologia , Animais , Contagem de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lisina/farmacologia , Camundongos , Tamanho do Órgão , Peroxidase/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Sepsis is a severe, life-threatening condition primarily caused by the cellular response to infection. Sepsis leads to increased tissue damage and mortality in patients in the intensive care unit. L-Lysine is an essential amino acid required for protein biosynthesis and is abundant in lamb, pork, eggs, red meat, fish oil, cheese, beans, peas, and soy. Male albino rats were divided into sham, control, 10-mg/kg bwt L-lysine, and 20-mg/kg bwt L-lysine groups. At the end of treatment, we determined the levels of oxidative and inflammatory markers, myeloperoxidase (MPO) and catalase activities, total cell count, the wet/dry ratio of lung tissue, and total protein content. Furthermore, the effect of L-lysine on the cellular architecture of lung tissue was evaluated. L-Lysine significantly reduced the magnitude of lipid peroxidation; total protein content; wet/dry ratio of lung tissue; tumor necrosis factor-alpha, interleukin-8, and macrophage inhibitory factor levels; MPO activity; and total cell, neutrophil, and lymphocyte counts, and it increased the reduced glutathione levels and the glutathione peroxidase, superoxide dismutase, and catalase activities. A normal cellular architecture was noted in rats in the sham group, whereas proinflammatory changes, such as edema and neutrophilic infiltration, were detected in rats in the control group. L-lysine significantly ameliorated these proinflammatory changes. Thus, L-lysine has the potential for the treatment of sepsis-induced CLI.
Assuntos
Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lisina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Sepse/complicações , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Contagem de Células , Doença Crônica , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/patologia , Lisina/farmacologia , Masculino , Peroxidase/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Sepse/patologia , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: To evaluate the effect of red propolis and L-lysine on angiogenesis and tumor growth in a new model of hamster cheek pouch inoculated with Walker 256 tumor cells. METHODS: The study consisted of two experiments with four groups each (total: 57 hamsters). In the experiment 1, the animals were inoculated with Walker tumor cells, followed by administration of test substances (red propolis 200mg/5mL/kg or L-lysine 150mg/kg) or control substances (gum arabic 5mL/kg or water 5mL/kg) for 10 days. The animals in the experiment 2 received red propolis, L-lysine, gum arabic or water at the same doses, for 33 days prior to inoculation of Walker tumor cells, followed by 10 days of treatment with the same substances. Based on single-plane images, angiogenesis was quantified (mean vascular area), in percentage, and tumor area (mm2) and perimeter (mm). RESULTS: In the experiment 1, compared to animals receiving water, the mean vascular area expressed in percentage was significantly smaller in animal treated with propolis (p<0.05) and L-lysine (p<0.001). CONCLUSION: Both red propolis and L-lysine inhibited tumor angiogenesis in the new hamster cheek pouch model when administered after tumor inoculation.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Lisina/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Própole/uso terapêutico , Animais , Antioxidantes , Carcinoma 256 de Walker/irrigação sanguínea , Bochecha , Cricetinae , Feminino , Mesocricetus , Modelos Animais , Neoplasias Bucais/irrigação sanguínea , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/tratamento farmacológico , Resultado do Tratamento , Aumento de PesoRESUMO
Photodynamic therapy (PDT) is a well-established treatment of cancer in which cell toxic reactive oxygen species, including singlet oxygen (1O2), are produced by a photosensitiser drug following irradiation of a specific wavelength. Visible light is commonly used as the excitation source in PDT, although these wavelengths do have limited tissue penetration. In this research, upconverting nanoparticles (UCNPs) functionalised with the photosensitiser Rose Bengal (RB) have been designed and synthesised for PDT of breast cancer cells. The use of UCNPs shifts the required excitation wavelength for the production of 1O2 to near infrared light (NIR) thus allowing deeper tissue penetration. The system was designed to maximise the production of 1O2via efficient Förster resonance energy transfer (FRET) from the UCNPs to the photosensitiser. Highly luminescent NaYF4:Yb,Er,Gd@NaYF4 core-shell UCNPs were synthesised that exhibited two main anti-Stokes emission bands at 541 and 652 nm following 980 nm irradiation. RB was chosen as the photosensitiser since its absorption band overlaps with the green emission of the UCNPs. To achieve efficient energy transfer from the nanoparticles to the photosensitiser, the functionalised UCNPs included a short l-lysine linker to attach the RB to the nanocore yielding RB-lysine functionalised UCNPs. The efficient FRET from the UCNPs to the RB was confirmed by luminescence lifetime measurements. The light emitted by the UCNPs at 541 nm, following excitation at 980 nm, generates the 1O2via the RB. Multi-photon and confocal laser scanning microscopies confirmed the internalisation of the RB-lysine-UCNPs by SK-BR-3 breast cancer cells. Cell viability studies revealed that the RB-lysine-UCNPs induced low dark toxicity in cells prior to PDT treatment. Importantly, following irradiation at 980 nm, high levels of cell death were observed in cells loaded with the RB-lysine-UCNPs. Cell death following PDT treatment was also confirmed using propidium iodide and confocal microscopy. The high drug loading capacity (160 RB/nanoparticle) of the UCNPs, the efficient FRET from the UCNPs to the photosensitiser, the high level of accumulation inside the cells and their PDT cell kill suggest that the RB-lysine-UCNPs are promising for NIR PDT and hence suitable for the treatment of deep-lying cancer tumours.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Corantes Fluorescentes/farmacologia , Nanopartículas , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Endocitose , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/uso terapêutico , Humanos , Lisina/química , Lisina/farmacologia , Lisina/uso terapêutico , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Rosa Bengala/química , Rosa Bengala/farmacologia , Rosa Bengala/uso terapêutico , Oxigênio SingleteRESUMO
ABSTRACT Objective: To evaluate the effect of red propolis and L-lysine on angiogenesis and tumor growth in a new model of hamster cheek pouch inoculated with Walker 256 tumor cells. Methods: The study consisted of two experiments with four groups each (total: 57 hamsters). In the experiment 1, the animals were inoculated with Walker tumor cells, followed by administration of test substances (red propolis 200mg/5mL/kg or L-lysine 150mg/kg) or control substances (gum arabic 5mL/kg or water 5mL/kg) for 10 days. The animals in the experiment 2 received red propolis, L-lysine, gum arabic or water at the same doses, for 33 days prior to inoculation of Walker tumor cells, followed by 10 days of treatment with the same substances. Based on single-plane images, angiogenesis was quantified (mean vascular area), in percentage, and tumor area (mm2) and perimeter (mm). Results: In the experiment 1, compared to animals receiving water, the mean vascular area expressed in percentage was significantly smaller in animal treated with propolis (p<0.05) and L-lysine (p<0.001). Conclusion: Both red propolis and L-lysine inhibited tumor angiogenesis in the new hamster cheek pouch model when administered after tumor inoculation.
RESUMO Objetivo: Avaliar o efeito da própolis vermelha e da L-lisina na angiogênese e no crescimento tumoral em novo modelo de bolsa jugal de hamster inoculada com células de tumor de Walker 256. Métodos: O estudo consistiu em dois experimentos com quatro grupos cada (total: 57 hamsters). No experimento 1, os animais foram inoculados com células de tumor de Walker, tendo em seguida administradas as substâncias teste (própolis vermelha 200mg/5mL/kg ou L-lisina 150mg/kg) ou controle (goma arábica 5mL/kg ou água 5mL/kg) por 10 dias. Os animais do experimento 2 receberam própolis vermelha, L-lisina, goma arábica ou água nas mesmas doses, por 33 dias antes do inóculo das células de tumor de Walker, seguido por 10 dias de tratamento com as mesmas substâncias. Baseado em imagens em plano único, foram quantificados a angiogênese (área vascular média), em termos percentuais, e a área (mm2) e o perímetro (mm) do tumor. Resultados: Comparada aos animais que receberam água, a área vascular média, expressa em percentagem, foi significativamente menor nos animais tratados com própolis (p<0,05) e com L-lisina (p<0,001). Conclusão: Tanto a própolis vermelha quanto a L-lisina inibiram a angiogênese no novo modelo de bolsa jugal de hamsters, quando administradas após a inoculação do tumor.
Assuntos
Própole/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Lisina/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/irrigação sanguínea , Neoplasias Bucais/tratamento farmacológico , Carcinoma 256 de Walker/irrigação sanguínea , Aumento de Peso , Bochecha , Cricetinae , Mesocricetus , Resultado do Tratamento , Modelos Animais , AntioxidantesRESUMO
BACKGROUND: Diet is suggested to participate in the etiology of inflammatory bowel diseases (IBD). Repeated exposure to Maillard reaction products (MRPs), molecules resulting from reduction reactions between amino acids and sugars during food heating, has been reported to be either potentially detrimental or beneficial to health. AIMS: The aim of this study is to determine the effect of repeated oral ingestion of N ε-carboxymethyllysine (CML), an advanced MRP, on the onset of two models of experimental IBD and on the gut microbiota composition of mice. METHODS: Mice received either saline (control) or N ε-carboxymethyllysine daily for 21 days. For the last week of treatment, each group was split into subgroups, receiving dextran sulfate sodium salt (DSS) or trinitrobenzenesulfonic acid (TNBS) to induce colitis. Intensity of inflammation was quantified, and cecal microbiota characterized by bacterial 16S ribosomal RNA (rRNA) amplicon sequencing. RESULTS: Daily oral administration of N ε-carboxymethyllysine did not induce intestinal inflammation and had limited impact on gut microbiota composition (Bacteroidaceae increase, Lachnospiraceae decrease). DSS and TNBS administration resulted in expected moderate experimental colitis with a shift of Bacteroidetes/Firmicutes ratio and a significant Proteobacteria increase but with distinct profiles: different Proteobacteria taxa for DSS, but mainly Enterobacteriaceae for TNBS. While N ε-carboxymethyllysine exposure failed to prevent the inflammatory response, it allowed maintenance of healthy gut microbiota profiles in mice treated with DSS (but not TNBS). CONCLUSIONS: Repeated oral exposure to CML limits dysbiosis in experimental colitis. IBD patients may modulate their microbiota profile by regulating the level and type of dietary MRP consumption.
Assuntos
Colite/microbiologia , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Produtos Finais de Glicação Avançada/uso terapêutico , Lisina/análogos & derivados , Administração Oral , Animais , Colite/complicações , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Disbiose/etiologia , Ingestão de Alimentos/efeitos dos fármacos , Produtos Finais de Glicação Avançada/farmacologia , Lisina/farmacologia , Lisina/uso terapêutico , Masculino , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacosRESUMO
Mesotherapy, or intradermal therapy, is a therapeutic approach that is gaining popularity, but there is still a significant lack of information on its mechanisms of action or the pharmacokinetics of the therapeutic regimens. This retrospective study on 220 records compared the short-term and long-term effects of mesotherapy using a mixture of drugs versus normal saline solution in the treatment of patients with chronic spinal pain (CSP). At the end of treatment, outcome measures showed a significant improvement (P<0.003) in both groups, which persisted at the follow-up assessments. At 12 weeks of follow-up, the improvement was significantly greater in patients treated with the drug cocktail than with the saline solution (P<0.05). Mesotherapy was effective in patients affected by CSP, with high patient satisfaction reported irrespective of the agent used. Considering the risks and costs of drugs, normal saline solution appears to be the best agent in cost-benefit terms for treating localized pain by mesotherapy in CSP.