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1.
Sci Rep ; 14(1): 20386, 2024 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223189

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be renoprotective in ischemia-reperfusion (I/R) injury, with several proposed mechanisms, though additional mechanisms likely exist. This study investigated the impact of luseogliflozin on kidney fibrosis at 48 h and 1 week post I/R injury in C57BL/6 mice. Luseogliflozin attenuated kidney dysfunction and the acute tubular necrosis score on day 2 post I/R injury, and subsequent fibrosis at 1 week, as determined by Sirius red staining. Metabolomics enrichment analysis of I/R-injured kidneys revealed suppression of the glycolytic system and activation of mitochondrial function under treatment with luseogliflozin. Western blotting showed increased nutrient deprivation signaling with elevated phosphorylated AMP-activated protein kinase and Sirtuin-3 in luseogliflozin-treated kidneys. Luseogliflozin-treated kidneys displayed increased protein levels of carnitine palmitoyl transferase 1α and decreased triglyceride deposition, as determined by oil red O staining, suggesting activated fatty acid oxidation. Luseogliflozin prevented the I/R injury-induced reduction in nuclear factor erythroid 2-related factor 2 activity. Western blotting revealed increased glutathione peroxidase 4 and decreased transferrin receptor protein 1 expression. Immunostaining showed reduced 4-hydroxynonenal and malondialdehyde levels, especially in renal tubules, indicating suppressed ferroptosis. Luseogliflozin may protect the kidney from I/R injury by inhibiting ferroptosis through oxidative stress reduction.


Assuntos
Injúria Renal Aguda , Ferroptose , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Ferroptose/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Camundongos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Masculino , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Sorbitol/análogos & derivados , Sorbitol/farmacologia , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Fibrose , Modelos Animais de Doenças , Transportador 2 de Glucose-Sódio
2.
Food Chem ; 461: 140917, 2024 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-39226794

RESUMO

Natural deep eutectic solvents (NADESs) showing higher cryoprotective effects are attracting concerns, because during the storage, system browning always occurs in aldose/amino acid-based NADESs, which generated brown substances remarkably weaken the cryoprotective effects. In this study, proline/glucose-based (PG) and proline/sorbitol-based (PS) NADESs were prepared, of which storage stability, browning profile, brown substance, and cryoprotective effects were investigated. Results showed that PG at molar ratios of 1:1, 2:1, and 3:1, as well as PS at 1:1, and 2:1 can form NADESs, among which only the PG-based ones could get browning after storage. The predominant brown substance was identified as 1-deoxy-1-L-proline-d-fructose (C11H19O7N, 278 m/z), which was subsequently verified to show cytotoxicity and decrease Saccharomyces cerevisiae cells viability after cryopreservation, suggesting that the brown substance could take a negative effect on cryopreservation. This study may help to attract more concerns to the storage and cryopreservation stabilities of the NADESs in food-related applications.


Assuntos
Criopreservação , Crioprotetores , Saccharomyces cerevisiae , Solventes , Saccharomyces cerevisiae/química , Crioprotetores/farmacologia , Crioprotetores/química , Solventes/química , Prolina/química , Prolina/farmacologia , Glucose/química , Reação de Maillard , Sorbitol/química , Sorbitol/farmacologia
3.
Int J Mol Sci ; 25(16)2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39201727

RESUMO

Cataracts are the world's leading cause of blindness, and diabetes is the second leading risk factor for cataracts after old age. Despite this, no preventative treatment exists for cataracts. The altered metabolism of excess glucose during hyperglycaemia is known to be the underlying cause of diabetic cataractogenesis, resulting in localised disruptions to fibre cell morphology and cell swelling in the outer cortex of the lens. In rat models of diabetic cataracts, this damage has been shown to result from osmotic stress and oxidative stress due to the accumulation of intracellular sorbitol, the depletion of NADPH which is used to regenerate glutathione, and the generation of fructose metabolites via the polyol pathway. However, differences in lens physiology and the metabolism of glucose in the lenses of different species have prevented the translation of successful treatments in animal models into effective treatments in humans. Here, we review the stresses that arise from hyperglycaemic glucose metabolism and link these to the regionally distinct metabolic and physiological adaptations in the lens that are vulnerable to these stressors, highlighting the evidence that chronic oxidative stress together with osmotic stress underlies the aetiology of human diabetic cortical cataracts. With this information, we also highlight fundamental gaps in the knowledge that could help to inform new avenues of research if effective anti-diabetic cataract therapies are to be developed in the future.


Assuntos
Catarata , Complicações do Diabetes , Pressão Osmótica , Estresse Oxidativo , Polímeros , Catarata/metabolismo , Catarata/etiologia , Catarata/patologia , Humanos , Animais , Complicações do Diabetes/metabolismo , Polímeros/metabolismo , Cristalino/metabolismo , Cristalino/patologia , Sorbitol/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/complicações , Glucose/metabolismo
4.
Physiol Plant ; 176(4): e14465, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39126176

RESUMO

Sugar is vital for plant growth and determines fruit quality via its content and composition. This study explores the differential sugar accumulation in two plum varieties, 'Fengtangli (FTL)' and 'Siyueli (SYL)'. The result showed that 'FTL' fruit displayed higher soluble solids and sugar content at various development stages. Metabolomic analysis indicated increased sorbitol in 'FTL', linked to elevated sorbitol-6-phosphate-dehydrogenase (S6PDH) activity. Transcriptome analysis identified a key gene for sorbitol synthesis, PsS6PDH4, which was significantly higher expressed in 'FTL' than in 'SYL'. The function of the PsS6PDH4 gene was verified in strawberry, apple, and plum fruits using transient overexpression and virus-induced gene silencing techniques. The results showed that overexpression of the PsS6PDH4 gene in strawberry, apple, and plum fruits promoted the accumulation of soluble solids content and sorbitol, while inhibition of the gene reduced soluble solids content and sorbitol content. Meanwhile, analysis of the relationship between PsS6PDH4 gene expression, sorbitol, and soluble solids content in four different plum varieties revealed a significant correlation between PsS6PDH4 gene expression and soluble solids content as well as sorbitol content. This research discovered PsS6PDH4 as a crucial regulator of sugar metabolism in plum, with potential applications in improving fruit sweetness and nutritional value in various fruit species. Understanding these molecular pathways can lead to innovative approaches for enhancing fruit quality, benefiting sustainable agriculture and consumer preferences in the global fruit industry.


Assuntos
Frutas , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Prunus domestica , Sorbitol , Sorbitol/metabolismo , Prunus domestica/genética , Prunus domestica/metabolismo , Frutas/genética , Frutas/metabolismo , Frutas/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Fragaria/genética , Fragaria/metabolismo , Açúcares/metabolismo , Malus/genética , Malus/metabolismo
5.
Int J Biol Macromol ; 276(Pt 1): 133817, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39002902

RESUMO

Ultrasound technology has emerged as a promising tool for enhancing enzymatic biodiesel production, yet the cavitation effect induced can compromise enzyme stability. This study explored the efficiency of polyols in enhancing lipase stability under ultrasound conditions to further improve biodiesel yield. The incorporation of sorbitol resulted in the highest fatty acid methyl ester (FAME) content in the ultrasound-assisted biodiesel production catalyzed by Eversa® Transform 2.0 among the investigated polyols. Furthermore, sorbitol enhanced the stability of the lipase, allowing it to tolerate up to 100 % ultrasound amplitude, compared to 60 % amplitude in its absence. Enzyme activity assays revealed that sorbitol preserved 99 % of the lipase activity, in contrast to 84 % retention observed without sorbitol under an 80 % ultrasound amplitude. Circular dichroism (CD) and fluorescence spectroscopy analyses confirmed that sorbitol enhanced lipase rigidity and preserved its conformational structure under ultrasound exposure. Furthermore, employing a stepwise methanol addition strategy in ultrasound-assisted reactions with sorbitol achieved an 81.2 wt% FAME content in 8 h with only 0.2 wt% enzyme concentration. This promising result highlights the potential of sorbitol as a stabilizing agent in ultrasound-assisted enzymatic biodiesel production, offering a viable approach for enhancing biodiesel yield and enzyme stability in industrial applications.


Assuntos
Biocombustíveis , Estabilidade Enzimática , Lipase , Sorbitol , Sorbitol/química , Lipase/química , Lipase/metabolismo , Ondas Ultrassônicas , Esterificação , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo
6.
Enzyme Microb Technol ; 180: 110485, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39059288

RESUMO

Gram-positive Bacillus subtilis is a model organism for the biotechnology industry and has recently been characterized as weakly electroactive in both planktonic cultures and biofilms. Increasing the extracellular electron transfer (EET) rate in B. subtilis biofilms will help to develop an efficient microbial electrochemical technology (MET) and improve the bioproduction of high-value metabolites under electrofermentative conditions. In our previous work, we have shown that the addition of compatible solute precursors such as choline chloride (ChCl) to the growth medium formulation increases current output and biofilm formation in B. subtilis. In this work, we utilized a low-carbon tryptone yeast extract medium with added salts to further expose B. subtilis to salt stress and observe the osmoregulatory and/or nutritional effects of a D-sorbitol/choline chloride (ChCl) (1:1 mol mol-1) deep eutectic solvents (DESs) on the electroactivity of the formed biofilm. The results show that ChCl and D-sorbitol alleviate the osmotic stress induced by the addition of NaH2PO4 and KH2PO4 salts and boost biofilm production. This is probably due to the osmoprotective effect of ChCl, a precursor of the osmoprotectant glycine betaine, and the induction of electroactive exopolymeric substances within the B. subtilis biofilm. Since high ionic strength media are commonly used in microbial biotechnology, the combination of ChCl-containing DESs and salt stress could enhance biofilm-based electrofermentation processes that bring significant benefits for biotechnological applications.


Assuntos
Bacillus subtilis , Biofilmes , Colina , Solventes Eutéticos Profundos , Osmorregulação , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/fisiologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Colina/farmacologia , Colina/metabolismo , Solventes Eutéticos Profundos/metabolismo , Solventes Eutéticos Profundos/farmacologia , Sorbitol/farmacologia , Sorbitol/metabolismo , Meios de Cultura/química , Pressão Osmótica , Fontes de Energia Bioelétrica
7.
J Gastroenterol ; 59(9): 836-848, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39060520

RESUMO

BACKGROUND: Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, potentially exerts pleiotropic effects on the liver. However, the sufficient evidence is still lacking. We aimed to investigate the effects of luseogliflozin on hepatic steatosis, fibrosis, and cardiometabolic risk factors in diabetic patients by a pooled meta-analysis. METHODS: In this pooled meta-analysis, we enrolled diabetic patients who participated in phase III clinical trials of luseogliflozin (luseogliflozin group n = 302, placebo group n = 191). The primary outcomes were changes in fatty liver index (FLI) and Hepamet fibrosis score (HFS) after 24 weeks. The secondary outcomes were changes in cardiometabolic risk factors after 24 weeks. Statistical analysis was performed using propensity scoring analysis by the inverse probability of treatment weighting method. RESULTS: Primary outcomes: Luseogliflozin significantly decreased FLI compared to placebo after 24 weeks (adjusted coefficient - 5.423, 95%CI - 8.760 to - 2.086, P = 0.0016). There was no significant difference in changes in HFS between the two groups. However, luseogliflozin significantly decreased HFS compared to placebo in diabetic patients with ALT > 30 U/L (adjusted coefficient - 0.039, 95%CI - 0.077 to - 0.001, P = 0.0438) and with FIB-4 index > 1.3 (adjusted coefficient - 0.0453, 95%CI - 0.075 to - 0.016, P = 0.0026). Secondary outcom8es: Luseogliflozin significantly decreased HbA1c level, HOMA-IR value, BMI, and uric acids level, and increased HDL cholesterol level compared to placebo. CONCLUSIONS: This pooled meta-analysis demonstrated that 24-week treatment with luseogliflozin improved hepatic steatosis and fibrosis indexes in diabetic patients, especially those with liver injury. Furthermore, luseogliflozin improved various cardiometabolic risk factors. Thus, luseogliflozin may be useful for improving MASLD in diabetic patients.


Assuntos
Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Sorbitol , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/análogos & derivados , Sorbitol/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Fatores de Risco , Ensaios Clínicos Controlados Aleatórios como Assunto , Cirrose Hepática/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino
8.
Bioresour Technol ; 406: 131098, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38986886

RESUMO

As the highest-demand vitamin, the development of a one-step vitamin C synthesis process has been slow for a long time. In previous research, a Gluconobacter oxydans strain (GKLG9) was constructed that can directly synthesize 2-keto-L-gulonic acid (2-KLG) from glucose, but carbon source utilization remained low. Therefore, this study first identified the gene 4kas (4-keto-D-arabate synthase) to reduce the loss of extracellular carbon and inhibit the browning of fermentation broth. Then, promoter engineering was conducted to enhance the intracellular glucose transport pathway and concentrate intracellular glucose metabolism on the pentose phosphate pathway to provide more reducing power. Finally, by introducing the D-sorbitol pathway, the titer of 2-KLG was increased to 38.6 g/L within 60 h in a 5-L bioreactor, with a glucose-to-2-KLG conversion rate of about 46 %. This study is an important step in the development of single-bacterial one-step fermentation to produce 2-KLG.


Assuntos
Gluconobacter oxydans , Glucose , Sorbitol , Gluconobacter oxydans/metabolismo , Gluconobacter oxydans/genética , Glucose/metabolismo , Sorbitol/metabolismo , Fermentação , Engenharia Metabólica/métodos , Reatores Biológicos , Regiões Promotoras Genéticas , Açúcares Ácidos/metabolismo , Engenharia Genética
9.
Chem Commun (Camb) ; 60(63): 8244-8247, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39011590

RESUMO

A neuroelectrode can be easily prepared using a wet-spun fiber of D-sorbitol/PEDOT:PSS. At a D-sorbitol/PEDOT:PSS weight ratio of 6, the fiber is well-modulated with suitable characters, including the morphology, crystallization, diffusion resistance (179 kΩ), and electric double-layer capacitance (2.72 µF), for sensitive recording of brain activity during somatosensory stimulation and seizures. Additionally, the fiber is highly biocompatible with the brain. This study presents a simple and controllable strategy for the chemical construction of conducting polymer-based neurosensors.


Assuntos
Encéfalo , Sorbitol , Encéfalo/fisiologia , Encéfalo/metabolismo , Animais , Sorbitol/química , Transporte de Íons , Poliestirenos/química , Tiofenos/química , Fenômenos Eletrofisiológicos , Ratos , Convulsões , Camundongos , Polímeros/química
10.
Can J Microbiol ; 70(9): 370-383, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38832648

RESUMO

Consolidated bioprocessing candidate, Clostridium thermocellum, is a cellulose hydrolysis specialist, with the ability to ferment the released sugars to produce bioethanol. C. thermocellum is generally studied with model substrates Avicel and cellobiose to understand the metabolic pathway leading to ethanol. In the present study, adaptive laboratory evolution, allowing C. thermocellum DSM 1237 to adapt to growth on glucose, fructose, and sorbitol, with the prospect that some strains will adapt their metabolism to yield more ethanol. Adaptive growth on glucose and sorbitol resulted in an approximately 1 mM and 2 mM increase in ethanol yield per millimolar glucose equivalent, respectively, accompanied by a shift in the production of the other expected fermentation end products. The increase in ethanol yield observed for sorbitol adapted cells was due to the carbon source being more reduced compared to cellobiose. Glucose and cellobiose have similar oxidation states thus the increase in ethanol yield is due to the rerouting of electrons from other reduced metabolic products excluding H2 which did not decrease in yield. There was no increase in ethanol yield observed for fructose adapted cells, but there was an unanticipated elimination of formate production, also observed in sorbitol adapted cells suggesting that fructose has regulatory implications on formate production either at the transcription or protein level.


Assuntos
Carbono , Celobiose , Clostridium thermocellum , Etanol , Fermentação , Frutose , Glucose , Clostridium thermocellum/metabolismo , Clostridium thermocellum/genética , Clostridium thermocellum/crescimento & desenvolvimento , Etanol/metabolismo , Frutose/metabolismo , Carbono/metabolismo , Glucose/metabolismo , Celobiose/metabolismo , Sorbitol/metabolismo , Adaptação Fisiológica , Formiatos/metabolismo
11.
J Pharm Sci ; 113(9): 2734-2743, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38857645

RESUMO

The detachable dissolving microneedles (DDMNs) feature an array of needles capable of being separated from the base sheet during administration. Here they were fabricated to address delivery efficiency and storage stability of insulin. The constructed insulin-DDMN is multi-layered, with 1) a hard tip cover layer; 2) a layer of regular short-acting insulin (RI) mixed with hyaluronic acid (HA) and sorbitol (Sor) which occupies the taper tip region of the needles; 3) a barrier layer situated above the RI layer; and 4) a fast-dissolving layer connecting the barrier layer to the base sheet. RI entrapped in DDMNs exhibited enhanced thermal stability; it could be stored at 40 °C for 35 days without losing significant biological activity. Differential scanning calorimetric analysis revealed that the HA-Sor matrix could improve the denaturation temperature of the RI from lower than room temperature to 186 °C. Tests in ex vivo porcine skin demonstrated RI delivery efficiency of 91±1.59 %. Experiments with diabetic rats revealed sustained release of RI, i.e., when compared to subcutaneous injection with the same RI dose, RI-DDMNs produced slower absorption of insulin into blood circulation, delayed onset of hypoglycemic effect, longer serum insulin half-life, and longer hypoglycemic duration.


Assuntos
Diabetes Mellitus Experimental , Estabilidade de Medicamentos , Hipoglicemiantes , Agulhas , Animais , Ratos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/sangue , Suínos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/química , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/instrumentação , Ratos Sprague-Dawley , Insulina de Ação Curta/administração & dosagem , Insulina de Ação Curta/farmacocinética , Insulina de Ação Prolongada/administração & dosagem , Insulina de Ação Prolongada/farmacocinética , Masculino , Ácido Hialurônico/química , Ácido Hialurônico/administração & dosagem , Temperatura , Administração Cutânea , Pele/metabolismo , Insulina/administração & dosagem , Insulina/farmacocinética , Sorbitol/química , Microinjeções/métodos , Microinjeções/instrumentação , Injeções Subcutâneas , Preparações de Ação Retardada
12.
Viruses ; 16(6)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38932234

RESUMO

The thermostability of vaccines, particularly enveloped viral vectored vaccines, remains a challenge to their delivery wherever needed. The freeze-drying of viral vectored vaccines is a promising approach but remains challenging due to the water removal process from the outer and inner parts of the virus. In the case of enveloped viruses, freeze-drying induces increased stress on the envelope, which often leads to the inactivation of the virus. In this study, we designed a method to freeze-dry a recombinant vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike glycoprotein. Since the envelope of VSV is composed of 50% lipids and 50% protein, the formulation study focused on both the protein and lipid portions of the vector. Formulations were prepared primarily using sucrose, trehalose, and sorbitol as cryoprotectants; mannitol as a lyoprotectant; and histidine as a buffer. Initially, the infectivity of rVSV-SARS-CoV-2 and the cake stability were investigated at different final moisture content levels. High recovery of the infectious viral titer (~0.5 to 1 log loss) was found at 3-6% moisture content, with no deterioration in the freeze-dried cakes. To further minimize infectious viral titer loss, the composition and concentration of the excipients were studied. An increase from 5 to 10% in both the cryoprotectants and lyoprotectant, together with the addition of 0.5% gelatin, resulted in the improved recovery of the infectious virus titer and stable cake formation. Moreover, the secondary drying temperature of the freeze-drying process showed a significant impact on the infectivity of rVSV-SARS-CoV-2. The infectivity of the vector declined drastically when the temperature was raised above 20 °C. Throughout a long-term stability study, formulations containing 10% sugar (sucrose/trehalose), 10% mannitol, 0.5% gelatin, and 10 mM histidine showed satisfactory stability for six months at 2-8 °C. The development of this freeze-drying process and the optimized formulation minimize the need for a costly cold chain distribution system.


Assuntos
Vacinas contra COVID-19 , Crioprotetores , Liofilização , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Liofilização/métodos , SARS-CoV-2/imunologia , SARS-CoV-2/química , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/química , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Crioprotetores/química , Crioprotetores/farmacologia , Trealose/química , COVID-19/prevenção & controle , COVID-19/virologia , Animais , Humanos , Manitol/química , Sacarose/química , Células Vero , Chlorocebus aethiops , Sorbitol/química , Estabilidade de Medicamentos , Histidina/química , Vírus da Estomatite Vesicular Indiana/genética , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia
13.
Sultan Qaboos Univ Med J ; 24(2): 243-249, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38828248

RESUMO

Objectives: This study aimed to evaluate the safety and efficacy of remogliflozin compared to vildagliptin as an add-on drug to metformin in type 2 diabetes mellitus (T2DM) treatment. Metformin is considered a first-line drug in T2DM. However, as the disease progresses with heightened insulin resistance and declining ß-cell function, the use of metformin alone is often inadequate to achieve optimum glucose levels. Methods: This prospective, randomised study was conducted at Maulana Azad Medical College and Associated Hospital in New Delhi, India, between February 2020 to January 2021. This study recruited 60 T2DM patients aged 35-70 years with glycated haemoglobin (HbA1c) >6.5% taking metformin at a daily dosage of 1,500-3,000 mg for ≥3 months. Patients were randomly assigned in a 1:1 ratio to receive either vildagliptin (50 mg) or remogliflozin (100 mg) twice daily for 90 days. The primary endpoint was a change in HbA1c levels from baseline to the end of 90 days whereas secondary endpoints were changes in lipid profile and weight. Results: The decrement in mean HbA1c levels was significantly higher in the remogliflozin group than in the vildagliptin group (-8.1% versus -2.4%; P <0.001). In addition, more significant weight loss was found in remogliflozin-treated patients (-5.2% versus -0.6%; P <0.01). Both treatments were well tolerated throughout the study. Conclusion: Compared to vildagliptin, remoglilflozin was significantly more effective in glycaemic control and weight loss in patients with T2DM and can therefore be considered as an add-on drug in T2DM not adequately controlled by metformin monotherapy.


Assuntos
Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hipoglicemiantes , Metformina , Vildagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Vildagliptina/farmacologia , Vildagliptina/uso terapêutico , Metformina/uso terapêutico , Metformina/farmacologia , Pessoa de Meia-Idade , Masculino , Feminino , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Estudos Prospectivos , Idoso , Adulto , Quimioterapia Combinada/métodos , Índia , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Resultado do Tratamento , Glicemia/análise , Glicemia/efeitos dos fármacos , Sorbitol/análogos & derivados , Sorbitol/uso terapêutico , Sorbitol/farmacologia , Sorbitol/efeitos adversos , Sorbitol/administração & dosagem , Pirazóis
14.
Int J Biol Macromol ; 274(Pt 1): 133236, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38897511

RESUMO

Nucleating agents, especially those with small particle sizes, are preferred to boost the nucleation density and crystallinity of poly(lactic acid) (PLA) due to its weak crystallization capability. Organophilicly modified nanofillers hardly alter the nucleation and crystallinity of non-isothermally crystallized PLA. Herein, nano-silica adsorbed trace D-sorbitol (m-SiO2) as a heterogeneous nucleating agent was melt-mixed with poly(L-lactic acid) (PLLA), and the isothermal and non-isothermal crystallization behavior, as well as crystallization kinetics, were investigated. Transmission electron microscopy (TEM) revealed that m-SiO2 was uniformly dispersed in the PLA matrix as 100-300 nm clusters. Differential scanning calorimetry (DSC) and polarized optical microscopy (POM) showed that the nucleation rate and density of the non-isothermally crystallized PLLA/m-SiO2 composites were significantly improved. Despite the fact that m-SiO2 does not raise the overall non-isothermal crystallization rate, the crystallization temperature and crystallinity of the PLLA/3%m-SiO2 composite increased from 97.2 °C and 6.8 % for neat PLLA to 108.2 °C and 48.6 % (10 °C/min cooling rate), respectively. The Avrami exponent n of isothermal crystallization remains unchanged, while the crystallization rate increases dramatically. Both isothermal and non-isothermal crystallization have increased activation energies. The heat deflection temperature increased from 59 °C of neat PLLA to 152 °C with a 50 % increase in impact strength.


Assuntos
Cristalização , Poliésteres , Dióxido de Silício , Sorbitol , Poliésteres/química , Dióxido de Silício/química , Sorbitol/química , Nanopartículas/química , Varredura Diferencial de Calorimetria , Cinética , Temperatura
15.
Mediators Inflamm ; 2024: 7524314, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725539

RESUMO

Objective: Microfold cells (M cells) are specific intestinal epithelial cells for monitoring and transcytosis of antigens, microorganisms, and pathogens in the intestine. However, the mechanism for M-cell development remained elusive. Materials and Methods: Real-time polymerase chain reaction, immunofluorescence, and western blotting were performed to analyze the effect of sorbitol-regulated M-cell differentiation in vivo and in vitro, and luciferase and chromatin Immunoprecipitation were used to reveal the mechanism through which sorbitol-modulated M-cell differentiation. Results: Herein, in comparison to the mannitol group (control group), we found that intestinal M-cell development was inhibited in response to sorbitol treatment as evidenced by impaired enteroids accompanying with decreased early differentiation marker Annexin 5, Marcksl1, Spib, sox8, and mature M-cell marker glycoprotein 2 expression, which was attributed to downregulation of receptor activator of nuclear factor kappa-В ligand (RANKL) expression in vivo and in vitro. Mechanically, in the M-cell model, sorbitol stimulation caused a significant upregulation of phosphodiesterase 4 (PDE4) phosphorylation, leading to decreased protein kinase A (PKA)/cAMP-response element binding protein (CREB) activation, which further resulted in CREB retention in cytosolic and attenuated CREB binds to RANKL promoter to inhibit RANKL expression. Interestingly, endogenous PKA interacted with CREB, and this interaction was destroyed by sorbitol stimulation. Most importantly, inhibition of PDE4 by dipyridamole could rescue the inhibitory effect of sorbitol on intestinal enteroids and M-cell differentiation and mature in vivo and in vitro. Conclusion: These findings suggested that sorbitol suppressed intestinal enteroids and M-cell differentiation and matured through PDE4-mediated RANKL expression; targeting to inhibit PDE4 was sufficient to induce M-cell development.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Células M , Ligante RANK , Sorbitol , Animais , Masculino , Camundongos , Diferenciação Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Mucosa Intestinal/metabolismo , Células M/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ligante RANK/metabolismo , Sorbitol/farmacologia
16.
Sci Rep ; 14(1): 12461, 2024 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816376

RESUMO

Contaminated lake water and fish can be sources of bacterial pathogens of public health concern, including pathogenic E. coli. Within Ethiopia, specifically, Central Oromia, raw fish consumption is a common practice. Although there are few reports on occurrence of E. coli O157 in fish destined for human consumption and children under five years, information on the transmission pathways of E. coli O157 and other sorbitol non-fermenting (SN-F) E. coli from water-to-fish-to-human, and their virulence factors and antimicrobial resistant determinants along the fish supply chain is lacking. The study aimed to investigate the occurrence, molecular characteristics, and antimicrobial susceptibility of E. coli O157 and other SN-F E. coli strains in fish, lake water and humans in central Oromia, Ethiopia. A total of 750 samples (450 fish samples, 150 water samples, 150 human stool samples) were collected from five lakes and three health facilities. The samples were processed following the standard protocol recommended by European Food Safety Authority and Kirby-Bauer disc diffusion method for detection of the bacteria, and antimicrobial susceptibility tests, respectively. Molecular characterization of presumptive isolates was performed using Whole-Genome Sequencing (WGS) for serotyping, determination of virulence factors, antimicrobial resistance traits, and genetic linkage of the isolates. Overall, 3.9% (29/750) of the samples had SN-F E. coli; of which 6.7% (n = 10), 1.8% (n = 8) and 7.3% (n = 11) were retrieved from water, fish, and diarrheic human patients, respectively. The WGS confirmed that all the isolates were SN-F non-O157: H7 E. coli strains. We reported two new E. coli strains with unknown O-antigen from fish and human samples. All the strains have multiple virulence factors and one or more genes encoding for them. Genetic relatedness was observed among strains from the same sources (water, fish, and humans). Most isolates were resistant to ampicillin (100%), tetracycline (100%), cefotaxime (100%), ceftazidime (100%), meropenem (100%), nalidixic acid (93.1%) and sulfamethoxazole/trimethoprim (79.3%). Majority of the strains were resistant to chloramphenicol (58.6%) and ciprofloxacin (48.3%), while small fraction showed resistance to azithromycin (3.45%). Isolates had an overall MDR profile of 87.5%. Majority, (62.1%; n = 18) of the strains had acquired MDR traits. Genes encoding for mutational resistance and Extended-spectrum beta-lactamases (ESBL) were also detected. In conclusion, our study revealed the occurrence of virulent and MDR SN-F E. coli strains in water, fish, and humans. Although no genetic relatedness was observed among strains from various sources, the genomic clustering among strains from the same sources strongly suggests the potential risk of transmission along the supply chain at the human-fish-environment interface if strict hygienic fish production is not in place. Further robust genetic study of the new strains with unknown O-antigens, and the epidemiology of SN-F E. coli is required to elucidate the molecular profile and public health implications of the pathogens.


Assuntos
Escherichia coli , Peixes , Lagos , Sorbitol , Humanos , Etiópia/epidemiologia , Animais , Lagos/microbiologia , Sorbitol/farmacologia , Peixes/microbiologia , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Escherichia coli/patogenicidade , Testes de Sensibilidade Microbiana , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/epidemiologia , Antibacterianos/farmacologia , Fatores de Virulência/genética , Sequenciamento Completo do Genoma , Microbiologia da Água , Farmacorresistência Bacteriana/genética , Microbiologia de Alimentos , Fezes/microbiologia , Escherichia coli O157/genética , Escherichia coli O157/efeitos dos fármacos , Escherichia coli O157/isolamento & purificação , Escherichia coli O157/patogenicidade
17.
Sci Rep ; 14(1): 11285, 2024 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760389

RESUMO

Feeding behaviors are determined by two main factors. One is the internal state, such as hunger or previous experiences; the other is external factors, such as sensory stimulation. During starvation, animals must balance food-seeking behavior with energy conservation. The fruit fly, Drosophila melanogaster, serves as a useful model for studying food selectivity and various behaviors related to food intake. However, few studies have directly connected food selectivity with other behaviors, such as locomotor activity and sleep. In this study, we report that flies exhibited a preference for specific positions and spent more time in the proximity of sweet sugars, such as sucrose and sucralose, but not non-sweet and nutritious sugars like xylitol and sorbitol. On the other hand, prolonged exposure to sorbitol increased the staying time of flies in the proximity of sorbitol. Additionally, after starvation, flies immediately exhibited a position preference in the proximity of sorbitol. These findings suggest that flies prefer the proximity of sweet food, and starvation alters their preference for nutritious food, which may be beneficial for their survival.


Assuntos
Drosophila melanogaster , Comportamento Alimentar , Açúcares , Animais , Drosophila melanogaster/fisiologia , Comportamento Alimentar/fisiologia , Inanição , Preferências Alimentares/fisiologia , Sorbitol/farmacologia , Sacarose/metabolismo
18.
J Dent ; 146: 105069, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38762077

RESUMO

OBJECTIVES: This study aimed to systematically review the effect of sugar substitute consumption on caries prevention in permanent teeth among children and adolescents. DATA: Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing the clinical effect of sugar substitutes (both high- and low-intensity sweeteners) in preventing caries in permanent teeth among children and adolescents aged 6-19 were included. SOURCES: A systematic search was conducted in three databases (PubMed, Web of Science and Embase) without any restrictions on publication year. STUDY SELECTION: The initial search found 1,859 items, and finally, 15 studies (11 RCTs and 4 CCTs) with a total of 6325 participants (age: 6-18 years) were included. The Cochrane risk-of-bias assessment tools were used for quality assessment. Most (80%, 12/15) were graded as having a 'moderate' or 'high' risk of bias. All trials investigated sugar alcohol, which is a low-intensity sweetener. Xylitol was the most commonly investigated (73.3%, 11/15), followed by sorbitol (46.7%, 7/15), and erythritol (13.3%, 2/15). Results of the meta-analysis showed that both xylitol (standardized mean difference [SMD]: -0.50, 95% confidence interval [CI] -0.85 to -0.16, P = 0.005) and sorbitol (SMD: -0.10, 95% CI: -0.19 to -0.01, P = 0.03) had a significant effect in preventing dental caries compared to no treatment/placebo. No clinical trials on high-intensity sweeteners such as aspartame and saccharin were found. CONCLUSION: The consumption of xylitol or sorbitol is potentially effective in preventing caries in permanent teeth among children and adolescents. No clinical evidence is available regarding the role of high-intensity sweeteners in caries prevention. CLINICAL SIGNIFICANCE: The use of xylitol or sorbitol as sugar substitutes has a beneficial effect in preventing dental caries among children and adolescents.


Assuntos
Cárie Dentária , Dentição Permanente , Sorbitol , Edulcorantes , Xilitol , Humanos , Cárie Dentária/prevenção & controle , Adolescente , Criança , Xilitol/uso terapêutico , Sorbitol/uso terapêutico , Edulcorantes/uso terapêutico , Eritritol/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Kidney Int ; 106(3): 408-418, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38801992

RESUMO

The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, and 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Taxa de Filtração Glomerular , Glomérulos Renais , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Masculino , Ratos , Antagonistas do Receptor A1 de Adenosina/farmacologia , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/irrigação sanguínea , Ratos Zucker , Sistema Renina-Angiotensina/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivados , Xantinas/farmacologia
20.
PLoS One ; 19(5): e0295735, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38696486

RESUMO

The stability of monoclonal antibodies (mAbs) is vital for their therapeutic success. Sorbitol, a common mAb stabilizer used to prevent aggregation, was evaluated for any potential adverse effects on the chemical stability of mAb X. An LC-MS/MS based analysis focusing on the post-translational modifications (PTMs) of mAb X was conducted on samples that had undergone accelerated aging at 40°C. Along with PTMs that are known to affect mAbs' structure function and stability (such as deamidation and oxidation), a novel mAb PTM was discovered, the esterification of glutamic acid by sorbitol. Incubation of mAb X with a 1:1 ratio of unlabeled sorbitol and isotopically labeled sorbitol (13C6) further corroborated that the modification was the consequence of the esterification of glutamic acid by sorbitol. Levels of esterification varied across glutamic acid residues and correlated with incubation time and sorbitol concentration. After 4 weeks of accelerated stability with isotopically labeled sorbitol, it was found that 16% of the total mAb possesses an esterified glutamic acid. No esterification was observed at aspartic acid sites despite the free carboxylic acid side chain. This study unveils a unique modification of mAbs, emphasizing its potential significance for formulation and drug development.


Assuntos
Anticorpos Monoclonais , Ácido Glutâmico , Sorbitol , Anticorpos Monoclonais/química , Estabilidade de Medicamentos , Esterificação , Ácido Glutâmico/química , Espectrometria de Massa com Cromatografia Líquida/métodos , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Sorbitol/química , Espectrometria de Massas em Tandem/métodos
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