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1.
Antonie Van Leeuwenhoek ; 117(1): 46, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427093

RESUMO

The fast-growing rhizobia-like strains S101T and S153, isolated from root nodules of soybean (Glycine max) in Sichuan, People's Republic of China, underwent characterization using a polyphasic taxonomy approach. The strains exhibited growth at 20-40 °C (optimum, 28 °C), pH 4.0-10.0 (optimum, pH 7.0) and up to 2.0% (w/v) NaCl (optimum, 0.01%) on Yeast Mannitol Agar plates. The 16S rRNA gene of strain S101T showed 98.4% sequence similarity to the closest type strain, Ciceribacter daejeonense L61T. Major cellular fatty acids in strain S101T included summed feature 8 (C18:1ω7c and/or C18:1ω6c) and C19:0 cyclo ω8c. The predominant quinone was ubiquinone-10. The polar lipids of strain S101T included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylmethyl ethanolamine, phosphatidyl ethanolamine, amino phospholipid, unidentified phosphoglycolipid and unidentified amino-containing lipids. The DNA G + C contents of S101T and S153 were 61.1 and 61.3 mol%, respectively. Digital DNA-DNA hybridization relatedness and average nucleotide identity values between S101T and C. daejeonense L61T were 46.2% and 91.4-92.2%, respectively. In addition, strain S101T promoted the growth of soybean and carried nitrogen fixation genes in its genome, hinting at potential applications in sustainable agriculture. We propose that strains S101T and S153 represent a novel species, named Ciceribacter sichuanensis sp. nov., with strain S101T as the type strain (= CGMCC 1.61309 T = JCM 35649 T).


Assuntos
Fosfolipídeos , Humanos , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Filogenia , DNA Bacteriano/genética , Fosfolipídeos/química , Ácidos Graxos/química , Etanolaminas , China , Técnicas de Tipagem Bacteriana
2.
Sci Rep ; 14(1): 5510, 2024 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448502

RESUMO

The aim of this study was to produce an alcohol gel hand sanitizer containing green glycerol. Crude glycerol was purified using chemical and physical treatments. The sanitizer was prepared using 71.100 g of 99.3° GL ethanol, 28.0 g H2O, 0.5 g of Carboxypolymethylene [Carbopol 940® or Carbomer], 5 drops of triethanolamine (pH 5-7), and glycerol (1.5% w/w). The thermal behavior of the ethanol, carbopol, triethanolamine, glycerol, and alcohol gels were evaluated using Thermogravimetry and Differential Thermal Analysis. The apparent viscosity was obtained using a rotary viscometer. The determination of in vitro spreadability was achieved by an adaptation of the Knorst method. The ethanol content was measured by headspace gas chromatography using a flame ionization detector. The thermal behavior of the gels was influenced by the presence of glycerol, which confirms the possible network interactions formed. The relative densities of the samples were between 0.887 and 0.890 g/cm3. No alteration of the pH of the formulation resulted from the incorporation of glycerol. The apparent viscosities of the alcohol gels were greater than 20,000 cP. No alteration in the in vitro spreadability of the gel alcohol (530.6 mm2) resulted from the addition of glycerol. Hand sanitizer was produced using glycerol from a transesterification reaction. It represents an alternative use for the glycerol being produced in biodiesel processes. The product satisfied the requirements of WHO that preconize a formulation containing 1.45% glycerol as an humectant to protect skin against dryness and dermatitis.


Assuntos
Etanolaminas , Glicerol , Higienizadores de Mão , Triglicerídeos , Etanol , Géis
3.
Malar J ; 23(1): 40, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317164

RESUMO

BACKGROUND: Artemisinin-based combination therapy (ACT) has been effective in the supervised treatment of uncomplicated malaria in Ghana. Since ACT usage is primarily unsupervised, this study aimed to determine the effectiveness of artemether-lumefantrine (AL) for treating malaria patients in two transmission settings in Ghana. METHODS: Eighty-four individuals with uncomplicated Plasmodium falciparum malaria were recruited from Lekma Hospital (LH) in Accra (low-transmission area; N = 28), southern Ghana, and King's Medical Centre (KMC) in Kumbungu (high-transmission area; N = 56), northern Ghana. Participants were followed up for 28 days after unsupervised treatment with AL. The presence of asexual parasites was determined by microscopic examination of Giemsa-stained blood smears. Plasmodium species identification was confirmed using species-specific primers targeting the 18S rRNA gene. Parasite recrudescence or reinfection was determined by genotyping the Pfmsp 1 and Pfmsp 2 genes. RESULTS: After AL treatment, 3.6% (2/56) of the patients from KMC were parasitaemic on day 3 compared to none from the LH patients. One patient from KMC with delayed parasite clearance on day 3 remained parasite-positive by microscopy on day 7 but was parasite-free by day 14. While none of the patients from LH experienced parasite recurrence during the 28-day follow-up, three and two patients from KMC had recurrent parasitaemia on days 21 and 28, respectively. Percentage reduction in parasite densities from day 1, 2, and 3 for participants from the KMC was 63.2%, 89.5%, and 84.5%. Parasite densities for participants from the LH reduced from 98.2%, 99.8% on day 1, and 2 to 100% on day 3. The 28-day cumulative incidence rate of treatment failure for KMC was 12.8% (95% confidence interval: 1.9-23.7%), while the per-protocol effectiveness of AL in KMC was 89.47%. All recurrent cases were assigned to recrudescence after parasite genotyping by Pfmsp 1 and Pfmsp 2. CONCLUSION: While AL is efficacious in treating uncomplicated malaria in Ghana, when taken under unsupervised conditions, it showed an 89.4% PCR-corrected cure rate in northern Ghana, which is slightly below the WHO-defined threshold.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Humanos , Combinação Arteméter e Lumefantrina/uso terapêutico , Antimaláricos/uso terapêutico , Gana , Artemisininas/uso terapêutico , Combinação de Medicamentos , Artemeter/uso terapêutico , Malária Falciparum/tratamento farmacológico , Recidiva , Parasitemia/tratamento farmacológico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Plasmodium falciparum/genética
4.
Int J Mol Sci ; 25(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338779

RESUMO

The development of drugs for the treatment of acute kidney injury (AKI) that could suppress the excessive inflammatory response in damaged kidneys is an important clinical challenge. Recently, synaptamide (N-docosahexaenoylethanolamine) has been shown to exert anti-inflammatory and neurogenic properties. The aim of this study was to investigate the anti-inflammatory effect of synaptamide in ischemic AKI. For this purpose, we analyzed the expression of inflammatory mediators and the infiltration of different leukocyte populations into the kidney after injury, evaluated the expression of the putative synaptamide receptor G-protein-coupled receptor 110 (GPR110), and isolated a population of CD11b/c+ cells mainly representing neutrophils and macrophages using cell sorting. We also evaluated the severity of AKI during synaptamide therapy and the serum metabolic profile. We demonstrated that synaptamide reduced the level of pro-inflammatory interleukins and the expression of integrin CD11a in kidney tissue after injury. We found that the administration of synaptamide increased the expression of its receptor GPR110 in both total kidney tissue and renal CD11b/c+ cells that was associated with the reduced production of pro-inflammatory interleukins in these cells. Thus, we demonstrated that synaptamide therapy mitigates the inflammatory response in kidney tissue during ischemic AKI, which can be achieved through GPR110 signaling in neutrophils and a reduction in these cells' pro-inflammatory interleukin production.


Assuntos
Injúria Renal Aguda , Etanolaminas , Receptores Acoplados a Proteínas G , Traumatismo por Reperfusão , Animais , Ratos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Anti-Inflamatórios/metabolismo , Interleucinas/metabolismo , Rim/metabolismo , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
5.
Nat Metab ; 6(2): 323-342, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38409325

RESUMO

Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.


Assuntos
Glicerol , Glicerofosfatos , Metabolismo dos Lipídeos , Humanos , Glicerol/metabolismo , Etanolaminas , Fosfatos
6.
J Environ Sci (China) ; 140: 146-156, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38331496

RESUMO

Non-aqueous absorbents (NAAs) have attracted increasing attention for CO2 capture because of their great energy-saving potential. Primary diamines which can provide high CO2 absorption loading are promising candidates for formulating NAAs but suffer disadvantages in regenerability. In this study, a promising strategy that using tertiary amines (TAs) as proton-transfer mediators was proposed to enhance the regenerability of an aminoethylethanolamine (AEEA, diamine)/dimethyl sulfoxide (DMSO) (A/D) NAA. Surprisingly, some employed TAs such as N,N-diethylaminoethanol (DEEA), N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDETA), 3-dimethylamino-1-propanol (3DMA1P), and N,N-dimethylethanolamine (DMEA) enhanced not only the regenerability of the A/D NAA but also the CO2 absorption performance. Specifically, the CO2 absorption loading and cyclic loading were increased by about 12.7% and 15.5%-22.7%, respectively. The TA-enhanced CO2 capture mechanism was comprehensively explored via nuclear magnetic resonance technique and quantum chemical calculations. During CO2 absorption, the TA acted as an ultimate proton acceptor for AEEA-zwitterion and enabled more AEEA to form carbamate species (AEEACOO-) to store CO2, thus enhancing CO2 absorption. For CO2 desorption, the TA first provided protons directly to AEEACOO- as a proton donor; moreover, it functioned as a proton carrier and facilitated the low-energy step-wise proton transfer from protonated AEEA to AEEACOO-. Consequently, the presence of TA made it easier for AEEACOO- to obtain protons to decompose, resulting in enhanced CO2 desorption. In a word, introducing the TA as a proton-transfer mediator into the A/D NAA enhanced both the CO2 absorption performance and the regenerability, which was an efficient way to "kill two birds with one stone".


Assuntos
Dióxido de Carbono , Etanolaminas , Prótons , Aminas , Diaminas
8.
mBio ; 15(3): e0002524, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38380942

RESUMO

Nitrogen is an essential element for all living organisms, including Escherichia coli. Potential nitrogen sources are abundant in the intestine, but knowledge of those used specifically by E. coli to colonize remains limited. Here, we sought to determine the specific nitrogen sources used by E. coli to colonize the streptomycin-treated mouse intestine. We began by investigating whether nitrogen is limiting in the intestine. The NtrBC two-component system upregulates approximately 100 genes in response to nitrogen limitation. We showed that NtrBC is crucial for E. coli colonization, although most genes of the NtrBC regulon are not induced, which indicates that nitrogen is not limiting in the intestine. RNA-seq identified upregulated genes in colonized E. coli involved in transport and catabolism of seven amino acids, dipeptides and tripeptides, purines, pyrimidines, urea, and ethanolamine. Competitive colonization experiments revealed that L-serine, N-acetylneuraminic acid, N-acetylglucosamine, and di- and tripeptides serve as nitrogen sources for E. coli in the intestine. Furthermore, the colonization defect of a L-serine deaminase mutant was rescued by excess nitrogen in the drinking water but not by an excess of carbon and energy, demonstrating that L-serine serves primarily as a nitrogen source. Similar rescue experiments showed that N-acetylneuraminic acid serves as both a carbon and nitrogen source. To a minor extent, aspartate and ammonia also serve as nitrogen sources. Overall, these findings demonstrate that E. coli utilizes multiple nitrogen sources for successful colonization of the mouse intestine, the most important of which is L-serine. IMPORTANCE: While much is known about the carbon and energy sources that are used by E. coli to colonize the mammalian intestine, very little is known about the sources of nitrogen. Interrogation of colonized E. coli by RNA-seq revealed that nitrogen is not limiting, indicating an abundance of nitrogen sources in the intestine. Pathways for assimilation of nitrogen from several amino acids, dipeptides and tripeptides, purines, pyrimidines, urea, and ethanolamine were induced in mice. Competitive colonization assays confirmed that mutants lacking catabolic pathways for L-serine, N-acetylneuraminic acid, N-acetylglucosamine, and di- and tripeptides had colonization defects. Rescue experiments in mice showed that L-serine serves primarily as a nitrogen source, whereas N-acetylneuraminic acid provides both carbon and nitrogen. Of the many nitrogen assimilation mutants tested, the largest colonization defect was for an L-serine deaminase mutant, which demonstrates L-serine is the most important nitrogen source for colonized E. coli.


Assuntos
Proteínas de Escherichia coli , Escherichia coli , Camundongos , Animais , Escherichia coli/genética , Acetilglucosamina/metabolismo , Nitrogênio/metabolismo , L-Serina Desidratase/metabolismo , Intestinos , Proteínas de Escherichia coli/metabolismo , Purinas , Carbono/metabolismo , Pirimidinas/metabolismo , Aminoácidos/metabolismo , Dipeptídeos/metabolismo , Etanolaminas/metabolismo , Serina/metabolismo , Ureia/metabolismo , Ácidos Siálicos/metabolismo , Mamíferos/metabolismo
9.
Nutrients ; 16(4)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38398813

RESUMO

BACKGROUND: Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator which is naturally produced in the body and found in certain foods. The aim of this study was to assess the effect of a bioavailable formulated form of PEA (Levagen+®) on serum BDNF levels and parameters of cognitive function in healthy adults. METHODS: A randomised double-blinded placebo-controlled cross-over trial was implemented to measure the effects of a 6-week 700 mg/day course of formulated PEA supplementation versus a placebo. Participants (n = 39) completed pre- and post-assessments of a lab-based cognitive test. Serum samples were collected to measure BDNF concentrations using an immunoassay. RESULTS: A significant increase in serum BDNF levels was found following PEA supplementation compared with the placebo (p = 0. 0057, d = 0.62). The cognition test battery demonstrated improved memory with PEA supplementation through better first success (p = 0.142, d = 0.54) and fewer errors (p = 0.0287; d = -0.47) on the Paired Associates Learning test. CONCLUSION: This was the first study to report a direct beneficial effect of Levagen+® PEA supplementation on memory improvement as well as corresponding increases in circulating neurotrophic marker levels. This suggests that formulated PEA holds promise as an innovative and practical intervention for cognitive health enhancement.


Assuntos
Amidas , Fator Neurotrófico Derivado do Encéfalo , Cognição , Etanolaminas , Ácidos Palmíticos , Adulto , Humanos , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego
10.
Int J Mol Sci ; 25(3)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38338728

RESUMO

Plant FLOWERING LOCUS T-Like (FTL) genes often redundantly duplicate on chromosomes and functionally diverge to modulate reproductive traits. Rice harbors thirteen FTL genes, the functions of which are still not clear, except for the Hd3a and RFT genes. Here, we identified the molecular detail of OsFTL12 in rice reproductive stage. OsFTL12 encoding protein contained PEBP domain and localized into the nucleus, which transcripts specifically expressed in the shoot and leaf blade with high abundance. Further GUS-staining results show the OsFTL12 promoter activity highly expressed in the leaf and stem. OsFTL12 knock-out concurrently exhibited early flowering phenotype under the short- and long-day conditions as compared with wild-type and over-expression plants, which independently regulates flowering without an involved Hd1/Hd3a and Ehd1/RFT pathway. Further, an AT-hook protein OsATH1 was identified to act as upstream regulator of OsFTL12, as the knock-out OsATH1 elevated the OsFTL12 expression by modifying Histone H3 acetylation abundance. According to the dissection of OsFTL12 molecular functions, our study expanded the roles intellectual function of OsFTL12 in the mediating of a rice heading date.


Assuntos
Flores , Oryza , Flores/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Fotoperíodo , Etanolaminas/metabolismo , Regulação da Expressão Gênica de Plantas
11.
Malar J ; 23(1): 61, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418982

RESUMO

BACKGROUND: Children are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine-artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM). METHODS: An integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum, body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population). PA was administered once daily for 3 days; two trials included the comparator artemether-lumefantrine (AL). PCR-adjusted day 28 adequate clinical and parasitological response (ACPR) was evaluated. Real-world PA granules safety and effectiveness was also considered. RESULTS: In the integrated safety analysis, 63.9% (95% CI 60.2, 67.4; 426/667) of patients had adverse events following PA and 62.0% (95% CI 56.9, 66.9; 222/358) with AL. Vomiting was more common with PA (7.8% [95% CI 6.0, 10.1; 52/667]) than AL (3.4% [95% CI 1.9, 5.8; 12/358]), relative risk 2.3 (95% CI 1.3, 4.3; P = 0.004), occurring mainly following the first PA dose (6.7%, 45/667), without affecting re-dosing or adherence. Prolonged QT interval occurred less frequently with PA (3.1% [95% CI 2.1, 4.8; 21/667]) than AL (8.1% [95% CI 5.7, 11.4; 29/358]), relative risk 0.39 (95% CI 0.22, 0.67; P = 0.0007). In CANTAM, adverse events were reported for 17.7% (95% CI 16.3, 19.2; 460/2599) of patients, most commonly vomiting (5.4% [95% CI 4.6, 6.4; 141/2599]), mainly following the first dose, (4.5% [117/2599]), with all patients successfully re-dosed, and pyrexia (5.4% [95% CI 4.6, 6.3; 140/2599]). In the two comparative clinical trials, Day 28 ACPR in the per-protocol population for PA was 97.1% (95% CI 94.6, 98.6; 329/339) and 100% (95% CI 99.3, 100; 514/514) versus 98.8% (95% CI 95.7, 99.9; 165/167) and 98.4% (95% CI 95.5, 99.7; 188/191) for AL, respectively. In CANTAM, PA clinical effectiveness was 98.0% (95% CI 97.3, 98.5; 2273/2320). CONCLUSIONS: Anti-malarial treatment with PA paediatric granules administered once daily for 3 days was well tolerated in children and displayed good clinical efficacy in clinical trials, with effectiveness confirmed in a real-world study. Trial registration Clinicaltrials.gov: SP-C-003-05: identifier NCT00331136; SP-C-007-07: identifier NCT0541385; SP-C-021-15: identifier NCT03201770. Pan African Clinical Trials Registry: SP-C-013-11: identifier PACTR201105000286876.


Assuntos
Antimaláricos , Artemisininas , Artesunato , Malária Falciparum , Malária , Naftiridinas , Criança , Humanos , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/efeitos adversos , Malária Falciparum/tratamento farmacológico , Artemeter/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Malária/tratamento farmacológico , Combinação de Medicamentos , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Etanolaminas/uso terapêutico
12.
BMC Med ; 22(1): 33, 2024 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273283

RESUMO

BACKGROUND: The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. METHODS: Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. RESULTS: Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. CONCLUSIONS: Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.


Assuntos
Amidas , Etanolaminas , Cinurenina , Ácidos Palmíticos , Triptofano , Humanos , Triptofano/metabolismo , Cinurenina/metabolismo , Depressão/diagnóstico , Endocanabinoides , Serotonina , Biomarcadores
13.
ACS Infect Dis ; 10(2): 377-383, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38252850

RESUMO

Shigellosis poses an ongoing global public health threat. The presence and length of the O-antigen in lipopolysaccharide play critical roles in Shigella pathogenesis. The plasmid-mediated opt gene encodes a phosphoethanolamine (PEtN) transferase that catalyzes the addition of PEtN to the O-antigen of Shigella flexneri serotype X and Y strains, converting them into serotype Xv and Yv strains, respectively. Since 2002, these modified strains have become prevalent in China. Here we demonstrate that PEtN-mediated O-antigen modification in S. flexneri increase the severity of corneal infection in guinea pigs without any adaptive cost. This heightened virulence is associated with epithelial cell adhesion and invasion, as well as an enhanced inflammatory response of macrophage. Notably, PEtN addition allow S. flexneri to attenuate the binding of complement C3 and better resist phagocytosis, potentially contributing to the retention of S. flexneri in the host environment.


Assuntos
Etanolaminas , Antígenos O , Shigella flexneri , Animais , Cobaias , Antígenos O/genética , Antígenos O/metabolismo , Sorotipagem , Plasmídeos , Shigella flexneri/genética , Shigella flexneri/metabolismo
14.
Drug Metab Dispos ; 52(4): 305-311, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38262704

RESUMO

Tree shrews are a nonprimate species used in a range of biomedical studies. Recent genome analysis of tree shrews found that the sequence identities and the numbers of genes of cytochrome P450 (CYP or P450), an important family of drug-metabolizing enzymes, are similar to those of humans. However, tree shrew P450s have not yet been sufficiently identified and analyzed. In this study, novel CYP2D8a and CYP2D8b cDNAs were isolated from tree shrew liver and were characterized, along with human CYP2D6, dog CYP2D15, and pig CYP2D25. The amino acid sequences of these tree shrew CYP2Ds were 75%-78% identical to human CYP2D6, and phylogenetic analysis showed that they were more closely related to human CYP2D6 than rat CYP2Ds, similar to dog and pig CYP2Ds. For tree shrew CYP2D8b, two additional transcripts were isolated that contained different patterns of deletion. The gene and genome structures of CYP2Ds are generally similar in dogs, humans, pigs, and tree shrews. Tree shrew CYP2D8a mRNA was most abundantly expressed in liver, among the tissue types analyzed, similar to dog CYP2D15 and pig CYP2D25 mRNAs. Tree shrew CYP2D8b mRNA was also expressed in liver, but at a level 7.3-fold lower than CYP2D8a mRNA. Liver microsomes and recombinant protein of both tree shrew CYP2Ds metabolized bufuralol and dextromethorphan, selective substrates of human CYP2D6, but the activity level of CYP2D8a greatly exceeded that of CYP2D8b. These results suggest that tree shrew CYP2D8a and CYP2D8b are functional drug-metabolizing enzymes, of which CYP2D8a is the major CYP2D in liver. SIGNIFICANCE STATEMENT: Novel tree shrew CYP2D8a and CYP2D8b cDNAs were isolated from liver. Their amino acid sequences were 75%-78% identical to human CYP2D6. For CYP2D8b, two additional transcripts contained different patterns of deletion. Tree shrew CYP2D8a mRNA was abundantly expressed in liver, similar to dog CYP2D15 and pig CYP2D25 mRNAs. Recombinant tree shrew CYP2Ds catalyzed the oxidation of bufuralol and dextromethorphan. Tree shrew CYP2D8a and CYP2D8b are functional drug-metabolizing enzymes, of which CYP2D8a is the major CYP2D in liver.


Assuntos
Citocromo P-450 CYP2D6 , Dextrometorfano , Etanolaminas , Humanos , Ratos , Suínos , Animais , Cães , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/metabolismo , Tupaia/genética , Tupaia/metabolismo , Tupaiidae/genética , Tupaiidae/metabolismo , Filogenia , Musaranhos/genética , Musaranhos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-38181883

RESUMO

AIM: Sjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS. METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites. CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.


Assuntos
Síndrome de Sjogren-Larsson , Humanos , Síndrome de Sjogren-Larsson/diagnóstico , Síndrome de Sjogren-Larsson/metabolismo , Lipidômica , Pele/metabolismo , Etanolaminas , Lipídeos
16.
J Allergy Clin Immunol Pract ; 12(2): 385-395.e4, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38040117

RESUMO

BACKGROUND: Digital health tools have been shown to help address challenges in asthma control, including inhaler technique, treatment adherence, and short-acting ß2-agonist overuse. The maintenance and reliever Digihaler System (DS) comprises 2 Digihaler inhalers (fluticasone propionate/salmeterol and albuterol) with an associated patient App and web-based Dashboard. Clinicians can review patients' inhaler use and Digihaler inhalation parameter data to support clinical decision-making. OBJECTIVE: CONNECT2 evaluated asthma control in participants using the DS versus standard-of-care (SoC) maintenance and reliever inhalers. METHODS: Participants (13 years or older) with uncontrolled asthma (Asthma Control Test [ACT] score <19) were randomized 4:3 (open-label) to the DS (n = 210) or SoC (n = 181) for 24 weeks. The primary endpoint was the proportion of patients achieving well-controlled asthma (ie, an ACT score ≥20 or increase from baseline of ≥3 units at week 24). RESULTS: There was an 88.7% probability that participants using the DS would have greater odds of achieving improvement in asthma control compared with SoC after 24 weeks. The mean odds ratio (95% credible interval) for DS versus SoC was 1.35 (0.846-2.038), indicating a 35% higher odds of improved asthma control with the DS. The DS group had more clinician-participant interactions versus SoC, mainly addressing a poor inhaler technique. DS participants' maintenance treatment adherence was good (month 1: 79.2%; month 6: 68.6%); reliever use decreased by 38.2% versus baseline. App and Dashboard usability was rated "good." CONCLUSION: The positive results in asthma control in this study after 24 weeks demonstrate the effectiveness of the DS in asthma management.


Assuntos
Antiasmáticos , Asma , Humanos , Budesonida/uso terapêutico , Fumarato de Formoterol/uso terapêutico , Etanolaminas/uso terapêutico , Antiasmáticos/uso terapêutico , Combinação de Medicamentos , Asma/tratamento farmacológico , Albuterol/uso terapêutico , Administração por Inalação , Broncodilatadores/uso terapêutico
17.
J Biochem ; 175(3): 299-312, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38030385

RESUMO

Extracellular vesicles (EVs) are important mediators of intercellular communication. However, the methods available for distinguishing the heterogeneity of secreted EVs and isolating and purifying them are limited. This study introduced a HiBiT-tag to detect various EV markers, including CD63, CD9, Epidermal Growth Factor Receptor (EGFR), Flotilin1, and Syndecan-1, and investigated whether these marker-containing vesicles were capable of binding to differently charged column carriers. Four column carriers, Diethylaminoethyl (DEAE), Capto Adhere, Blue and Heparin, showed affinity for CD63 containing EVs, but their elution patterns varied. Furthermore, we observed that the elution patterns of the EV markers differed among vesicles with distinct surface charges when a DEAE column was used. This suggests that the incorporation of EV markers varied between these vesicles. The markers showed different subcellular localizations, indicating that the site of vesicle formation may contribute to the production of vesicles with varying charges and marker incorporation. These findings may have implications for the development of methods to purify homogeneous EVs, which could be useful in EV-mediated drug delivery systems.


Assuntos
Etanolaminas , Vesículas Extracelulares , Vesículas Extracelulares/metabolismo , Comunicação Celular , Transporte Biológico
18.
Ann Allergy Asthma Immunol ; 132(2): 229-239.e3, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37879568

RESUMO

BACKGROUND: The management of mild asthma has lacked an over-the-counter (OTC) option aside from inhaled epinephrine, which is available in the United States. However, inhaled epinephrine use without an inhaled corticosteroid may increase the risk of asthma death. OBJECTIVE: To compare the cost-effectiveness of OTC as-needed budesonide-formoterol as a plausible alternative to inhaled epinephrine. METHODS: We developed a probabilistic Markov model to compare OTC as-needed budesonide-formoterol inhaler use vs inhaled epinephrine use in adults with mild asthma from a US societal perspective over a lifetime horizon, with a 3% annual discount rate (2022 US dollars). Inputs were derived from the SYmbicort Given as-needed in Mild Asthma (SYGMA) trials, published literature, and commercial costs. Outcomes were quality-adjusted life-years (QALY), costs, incremental net monetary benefit (INMB), severe asthma exacerbations, well-controlled asthma days, and asthma-related deaths. Microsimulation was used to evaluate underinsured Americans living with mild asthma (n = 5,250,000). RESULTS: Inhaled epinephrine was dominated (with lower QALYs gains at a higher cost) by both as-needed budesonide-formoterol (INMB, $15,541 at a willingness-to-pay of $100,000 per QALY) and the no-OTC inhaler option (INMB, $1023). Adults using as-needed budesonide-formoterol had 145 more well-controlled asthma days, 2.79 fewer severe exacerbations, and an absolute risk reduction of 0.23% for asthma-related death compared with inhaled epinephrine over a patient lifetime. As-needed budesonide-formoterol remained dominant in all sensitivity and scenario analyses, with a 100% probability of being cost-effective compared with inhaled epinephrine in probabilistic sensitivity analysis. CONCLUSION: If made available, OTC as-needed budesonide-formoterol for treating mild asthma in underinsured adults without HCP management improves asthma outcomes, prevents fatalities, and is cost-saving.


Assuntos
Asma , Combinação Budesonida e Fumarato de Formoterol , Adulto , Humanos , Combinação Budesonida e Fumarato de Formoterol/uso terapêutico , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Análise Custo-Benefício , Fumarato de Formoterol/uso terapêutico , Etanolaminas/uso terapêutico , Asma/tratamento farmacológico , Epinefrina/uso terapêutico , Combinação de Medicamentos , Administração por Inalação
20.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166908, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37793464

RESUMO

Metabolic disorders such as type 2 diabetes, fatty liver disease, hyperlipidemia, and obesity commonly co-occur but clinical treatment options do not effectively target all disorders. Calorie restriction, semaglutide, rosiglitazone, and mitochondrial uncouplers have all demonstrated efficacy against one or more obesity-related metabolic disorders, but it currently remains unclear which therapeutic strategy best targets the combination of hyperglycaemia, liver fat, hypertriglyceridemia, and adiposity. Herein we performed a head-to-head comparison of 5 treatment interventions in the female db/db mouse model of severe metabolic disease. Treatments included ∼60 % calorie restriction (CR), semaglutide, rosiglitazone, BAM15, and niclosamide ethanolamine (NEN). Results showed that BAM15 and CR improved body weight and liver steatosis to levels superior to semaglutide, NEN, and rosiglitazone, while BAM15, semaglutide, and rosiglitazone improved glucose tolerance better than CR and NEN. BAM15, CR, semaglutide, and rosiglitazone all had efficacy against hypertriglyceridaemia. These data provide a comprehensive head-to-head comparison of several key treatment strategies for metabolic disease and highlight the efficacy of mitochondrial uncoupling to correct multiple facets of the metabolic disease milieu in female db/db mice.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Feminino , Niclosamida/uso terapêutico , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Etanolamina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Restrição Calórica , Etanolaminas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo
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