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1.
Mol Biol Rep ; 51(1): 379, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38429605

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a form of kidney cancer characterized by dysregulated angiogenesis and multidrug resistance. Hypoxia-induced tumor progression plays a crucial role in ccRCC pathogenesis. Beta-hydroxybutyrate (BHB) and quercetin (QCT) have shown potential in targeting angiogenesis and drug resistance in various cancer types. This study investigates the combined effects of BHB and QCT in hypoxia-induced Caki-1 cells. METHODS: Caki-1 cells were subjected to normoxic and hypoxic conditions and treated with BHB, QCT, or a combination of both. Cell-viability was assessed using the MTT assay, and mRNA expression levels of key angiogenesis-related genes (HIF-1α/2α, VEGF, Ang-1, Ang-2, and MDR4) were quantified through real-time PCR during 24 and 48 h. RESULTS: BHB and QCT treatments, either alone or in combination, significantly reduced cell-viability in Caki-1 cells (p < 0.05). Moreover, the combined therapy demonstrated a potential effect in downregulating the expression of angiogenesis-related genes and MDR4 in hypoxia-induced cells, with a marked reduction in HIF-1α/2α, VEGF, Ang-1, and MDR4 expression (p < 0.05). The expression of Ang-2 increases significantly in presence of BHB combined QCT treatment. CONCLUSION: This study highlights the promising potential of a combination therapy involving BHB and QCT in mitigating angiogenesis and MDR4 expression in hypoxia-induced ccRCC cells. These findings support further investigation into the underlying mechanisms and warrant clinical studies to evaluate the therapeutic value of this combined treatment for ccRCC patients. This research provides new insights into addressing the challenges posed by angiogenesis and drug resistance in ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Ácido 3-Hidroxibutírico , Quercetina/farmacologia , Quercetina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Hipóxia , Resistência a Múltiplos Medicamentos
2.
Tissue Cell ; 87: 102343, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38442546

RESUMO

The hyperpermeability of intestinal epithelium is a key contributor to the occurrence and development of systemic inflammation. Although D-beta-hydroxybutyrate (BHB) exhibits various protective effects, whether it affects the permeability of intestinal epithelium in systemic inflammation has not been clarified. In this study, we investigated the effects of BHB on the intestinal epithelial permeability, the epithelial marker E-cadherin and the tight junction protein Claudin-1 in colon in the lipopolysaccharide (LPS)-induced systemic inflammation mouse model. Intraperitoneal injection of LPS was used to induce systemic inflammation and BHB was given by oral administration. The permeability of intestinal epithelium, the morphological changes of colonic epithelium, the distribution and generation of colon E-cadherin, and the Claudin-1 generation and its epithelial distribution in colon were detected. The results confirmed the intestinal epithelial hyperpermeability and inflammatory changes in colonic epithelium, with disturbed E-cadherin distribution in LPS-treated mice. Besides, colon Claudin-1 generation was decreased and its epithelial distribution in colon was weakened in LPS-treated mice. However, BHB treatments alleviated the LPS-induced hyperpermeability of intestinal epithelium, attenuated the colonic epithelial morphological changes and promoted orderly distribution of E-cadherin in colon. Furthermore, BHB up-regulated colon Claudin-1 generation and promoted its colonic epithelial distribution and content in LPS-treated mice. In conclusion, BHB may alleviate the hyperpermeability of intestinal epithelium via up-regulation of Claudin-1 in colon in LPS-treated mice.


Assuntos
Inflamação , Lipopolissacarídeos , Camundongos , Animais , Claudina-1 , Lipopolissacarídeos/toxicidade , Ácido 3-Hidroxibutírico/farmacologia , Caderinas/metabolismo
3.
Pol J Vet Sci ; 27(1): 107-116, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38511631

RESUMO

Our main aim was to investigate the predictive value of prepartum behaviors such as total daily rumination (TDR), total daily activity (TDA) and dry matter intake (DMI) as early indicators to detect cows at risk for hyperketonemia (HYK), hypoglycemia (HYG) or high non-esterified fatty acid (NEFA) status in the first (wk1) and second week (wk2) postpartum. In a case control study, 64 Holstein cows were enrolled 3 weeks before the expected time of calving and monitored until 15 days in milk (DIM). Postpartum blood samples were taken at D3 and D6 for wk1 and at D12 and D15 for wk2 to measure beta-hydroxybutyrate, NEFA and glucose concentration. Ear-mounted accelerometers were used to measure TDR and TDA. DMI and milk yield were obtained from farm records. Relationships between the average daily rate of change in prepartum TDR (ΔTDR), TDA (ΔTDA), and DMI (ΔDMI) with postpartum HYK, HYG and NEFA status in wk1 and wk2 post-partum were evaluated using linear regression models. Models were adjusted for potential confounding variables, and covariates retained in the final models were determined by backward selection. No evidence was found to support the premise that prepartum ΔTDR, ΔTDA or ΔDMI predicted postpartum HYK, HYG or NEFA status in wk1 or in wk2. Overall, prepartum ΔTDR, ΔTDA and ΔDMI were not effective predictors of HYK, HYG or NEFA status in the first 2 weeks postpartum.


Assuntos
Doenças dos Bovinos , Cetose , Feminino , Bovinos , Animais , Lactação , Dieta/veterinária , Ácidos Graxos não Esterificados , Estudos de Casos e Controles , Período Pós-Parto , Leite , Cetose/veterinária , Ácido 3-Hidroxibutírico , Biomarcadores , Doenças dos Bovinos/diagnóstico
4.
Int J Biol Macromol ; 263(Pt 1): 130188, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38373562

RESUMO

Plastic pollution is the biggest environmental concern of our time. Breakdown products like micro- and nano-plastics inevitably enter the food chain and pose unprecedented health risks. In this scenario, bio-based and biodegradable plastic alternatives have been given a momentum aiming to bridge a transition towards a more sustainable future. Polyhydroxyalkanoates (PHAs) are one of the few thermoplastic polymers synthesized 100 % via biotechnological routes which fully biodegrade in common natural environments. Poly(hydroxybutyrate-co-hydroxyhexanoate) [P(HB-co-HHx)] is a PHA copolymer with great potential for the commodity polymers industry, as its mechanical properties can be tailored through fine-tuning of its molar HHx content. We have recently developed a strategy that enables for reliable tailoring of the monomer content of P(HB-co-HHx). Nevertheless, there is often a lack of comprehensive investigation of the material properties of PHAs to evaluate whether they actually mimic the functionalities of conventional plastics. We present a detailed study of P(HB-co-HHx) copolymers with low to moderate hydroxyhexanoate content to understand how the HHx monomer content influences the thermal and mechanical properties and to link those to their abiotic degradation. By increasing the HHx fractions in the range of 2 - 14 mol%, we impart an extension of the processing window and application range as the melting temperature (Tm) and glass temperature (Tg) of the copolymers decrease from Tm 165 °C to 126 °C, Tg 4 °C to -5.9 °C, accompanied by reduced crystallinity from 54 % to 20 %. Elongation at break was increased from 5.7 % up to 703 % at 14 mol% HHx content, confirming that the range examined was sufficiently large to obtain ductile and brittle copolymers, while tensile strength was maintained throughout the studied range. Finally, accelerated abiotic degradation was shown to be slowed down with an increasing HHx fraction decreasing from 70 % to 55 % in 12 h.


Assuntos
Caproatos , Poli-Hidroxialcanoatos , Ácido 3-Hidroxibutírico/metabolismo , Hidroxibutiratos , Biotecnologia
5.
Forensic Sci Int ; 356: 111963, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38354569

RESUMO

The post-mortem diagnosis of hypothermia is challenging to establish due to the lack of pathognomonic findings and the confounding problem that any comorbidity may account for death. A 4-year retrospective case-control study was performed to compare the vitreous glucose and beta-hydroxybutyrate (BHB) concentrations between hypothermia deaths and controls. Over the study period 34 cases of hypothermia and 39 controls were analyzed. Hypothermia deaths versus controls had higher mean vitreous glucose (2.93 mmol/L vs. 1.14 mmol/L; p < 0.0001), BHB (1.89 mmol/L vs. 1.35 mmol/L; p = 0.01), and combined glucose+BHB (4.83 mmol/L vs. 2.46 mmol/L; p < 0.0001). Receiver operating characteristic (ROC) curves showed that the best model for predicting hypothermia in all cases was a combined vitreous glucose+BHB threshold of 2.03 mmol/L (sensitivity 88.2 %; specificity 56.4 %). A sub-group analysis broken down by detectable levels of blood ethanol showed that cases of hypothermia with and without ethanol maintained higher median vitreous glucose relative to the controls (2.05 vs. 0.35 mmol/L and 2.70 vs. 0.65 mmol/L; p = 0.02), however median BHB was only significantly elevated when ethanol was absent (1.88 vs. 1.42 mmol/L; p < 0.0001). Subsequent ROC curve analysis demonstrated that a better model for predicting hypothermia was in cases when blood ethanol was absent. In those deaths vitreous BHB alone had the best area under the curve, with an optimum threshold of 1.83 mmol/L (sensitivity 83.3 %; specificity 96.3 %). This study shows that post-mortem vitreous glucose and BHB are useful ancillary studies to assist in the diagnosis of hypothermia. Ethanol however is a confounder and can alter the utility of vitreous BHB when diagnosing hypothermia in those who have consumed alcohol prior to death.


Assuntos
Glucose , Hipotermia , Humanos , Glucose/análise , Ácido 3-Hidroxibutírico/análise , Estudos Retrospectivos , Estudos de Casos e Controles , Hipotermia/diagnóstico , Etanol/análise
6.
FASEB J ; 38(4): e23487, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38345808

RESUMO

Increasing attention is being paid to the mechanistic investigation of exercise-associated chronic inflammatory disease improvement. Ulcerative colitis (UC) is one type of chronic inflammatory bowel disease with increasing incidence and prevalence worldwide. It is known that regular moderate aerobic exercise (RMAE) reduces the incidence or risk of UC, and attenuates disease progression in UC patients. However, the mechanisms of this RMAE's benefit are still under investigation. Here, we revealed that ß-hydroxybutyrate (ß-HB), a metabolite upon prolonged aerobic exercise, could contribute to RMAE preconditioning in retarding dextran sulfate sodium (DSS)-induced mouse colitis. When blocking ß-HB production, RMAE preconditioning-induced colitis amelioration was compromised, whereas supplementation of ß-HB significantly rescued impaired ß-HB production-associated defects. Meanwhile, we found that RMAE preconditioning significantly caused decreased colonic Th17/Treg ratio, which is considered to be important for colitis mitigation; and the downregulated Th17/Treg ratio was associated with ß-HB. We further demonstrated that ß-HB can directly promote the differentiation of Treg cell rather than inhibit Th17 cell generation. Furthermore, ß-HB increased forkhead box protein P3 (Foxp3) expression, the core transcriptional factor for Treg cell, by enhancing histone H3 acetylation in the promoter and conserved noncoding sequences of the Foxp3 locus. In addition, fatty acid oxidation, the key metabolic pathway required for Treg cell differentiation, was enhanced by ß-HB treatment. Lastly, administration of ß-HB without exercise significantly boosted colonic Treg cell and alleviated colitis in mice. Together, we unveiled a previously unappreciated role for exercise metabolite ß-HB in the promotion of Treg cell generation and RMAE preconditioning-associated colitis attenuation.


Assuntos
Colite Ulcerativa , Colite , Humanos , Camundongos , Animais , Linfócitos T Reguladores/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Ácido 3-Hidroxibutírico/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite Ulcerativa/metabolismo , Colo/metabolismo , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Th17/metabolismo , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
7.
Microb Cell Fact ; 23(1): 52, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360657

RESUMO

BACKGROUND: Among the polyhydroxyalkanoate (PHA), poly[(R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate] [P(3HB-co-3HHx)] is reported to closely resemble polypropylene and low-density polyethylene. Studies have shown that PHA synthase (PhaC) from mangrove soil (PhaCBP-M-CPF4) is an efficient PhaC for P(3HB-co-3HHx) production and N-termini of PhaCs influence its substrate specificity, dimerization, granule morphology, and molecular weights of PHA produced. This study aims to further improve PhaCBP-M-CPF4 through N-terminal truncation. RESULTS: The N-terminal truncated mutants of PhaCBP-M-CPF4 were constructed based on the information of the predicted secondary and tertiary structures using PSIPRED server and AlphaFold2 program, respectively. The N-terminal truncated PhaCBP-M-CPF4 mutants were evaluated in C. necator mutant PHB-4 based on the cell dry weight, PHA content, 3HHx molar composition, molecular weights, and granule morphology of the PHA granules. The results showed that most transformants harbouring the N-terminal truncated PhaCBP-M-CPF4 showed a reduction in PHA content and cell dry weight except for PhaCBP-M-CPF4 G8. PhaCBP-M-CPF4 G8 and A27 showed an improved weight-average molecular weight (Mw) of PHA produced due to lower expression of the truncated PhaCBP-M-CPF4. Transformants harbouring PhaCBP-M-CPF4 G8, A27, and T74 showed a reduction in the number of granules. PhaCBP-M-CPF4 G8 produced higher Mw PHA in mostly single larger PHA granules with comparable production as the full-length PhaCBP-M-CPF4. CONCLUSION: This research showed that N-terminal truncation had effects on PHA accumulation, substrate specificity, Mw, and granule morphology. This study also showed that N-terminal truncation of the amino acids that did not adopt any secondary structure can be an alternative to improve PhaCs for the production of PHA with higher Mw in mostly single larger granules.


Assuntos
Cupriavidus necator , Poli-Hidroxialcanoatos , Poli-Hidroxialcanoatos/metabolismo , Ácido 3-Hidroxibutírico , Caproatos/metabolismo , Hidroxibutiratos/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Grânulos Citoplasmáticos , Cupriavidus necator/genética , Cupriavidus necator/metabolismo
8.
ACS Sens ; 9(2): 1004-1013, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38300831

RESUMO

Ketone bodies (KBs), especially ß-hydroxybutyrate (BHB), have gained tremendous attention as potential biomarkers as their presence in bodily fluids is closely associated with health and wellness. While a variety of blood fingerstick test strips are available for self-testing of BHB, there are major needs for wearable devices capable of continuously tracking changing BHB concentrations. To address these needs, we present here the first demonstration of a wearable microneedle-based continuous ketone monitoring (CKM) in human interstitial fluid (ISF) and illustrate its ability to closely follow the intake of ketone drinks. To ensure highly stable and selective continuous detection of ISF BHB, the new enzymatic microneedle BHB sensor relies on a gold-coated platinum working electrode modified with a reagent layer containing toluidine blue O (TBO) redox mediator, ß-hydroxybutyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) cofactor, along with carbon nanotubes (CNTs), chitosan (Chit), and a poly(vinyl chloride) (PVC) outer protective layer. The skin-worn microneedle sensing device operates with a miniaturized electrochemical analyzer connected wirelessly to a mobile electronic device for capturing, processing, and displaying the data. Cytotoxicity and skin penetration studies indicate the absence of potential harmful effects. A pilot study involving multiple human subjects evaluated continuous BHB monitoring in human ISF, against gold standard BHB meter measurements, revealing the close correlation between the two methods. Such microneedle-based CKM offers considerable promise for dynamic BHB tracking toward the management of diabetic ketoacidosis and personal nutrition and wellness.


Assuntos
Nanotubos de Carbono , Dispositivos Eletrônicos Vestíveis , Humanos , Cetonas , Projetos Piloto , Corpos Cetônicos , Ácido 3-Hidroxibutírico
9.
Int J Mol Sci ; 25(3)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38338928

RESUMO

The low percentage of recyclability of the polymeric materials obtained by olefin transition metal (TM) polymerization catalysis has increased the interest in their substitution with more eco-friendly materials with reliable physical and mechanical properties. Among the variety of known biodegradable polymers, linear aliphatic polyesters produced by ring-opening polymerization (ROP) of cyclic esters occupy a prominent position. The polymer properties are highly dependent on the macromolecule microstructure, and the control of stereoselectivity is necessary for providing materials with precise and finely tuned properties. In this review, we aim to outline the main synthetic routes, the physical properties and also the applications of three commercially available biodegradable materials: Polylactic acid (PLA), Poly(Lactic-co-Glycolic Acid) (PLGA), and Poly(3-hydroxybutyrate) (P3HB), all of three easily accessible via ROP. In this framework, understanding the origin of enantioselectivity and the factors that determine it is then crucial for the development of materials with suitable thermal and mechanical properties.


Assuntos
Ésteres , Poliésteres , Polimerização , Ésteres/química , Poliésteres/química , Polímeros , Ácido 3-Hidroxibutírico
10.
Biomed Pharmacother ; 172: 116320, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38387134

RESUMO

BACKGROUND: Mitochondrial redox imbalance underlies the pathophysiology of type2 diabetes mellitus (T2DM), and is closely related to tissue damage and dysfunction. Studies have shown the beneficial effects of dietary strategies that elevate ß-hydroxybutyrate (BHB) levels in alleviating T2DM. Nevertheless, the role of BHB has not been clearly elucidated. METHODS: We performed a spectral study to visualize the preventive effects of BHB on blood and multiorgan mitochondrial redox imbalance in T2DM mice via using label-free resonance Raman spectroscopy (RRS), and further explored the impact of BHB therapy on the pathology of T2DM mice by histological and biochemical analyses. FINDINGS: Our data revealed that RRS-based mitochondrial redox states assay enabled clear and reliable identification of the improvement of mitochondrial redox imbalance by BHB, evidenced by the reduction of Raman peak intensity at 750 cm-1, 1128 cm-1 and 1585 cm-1 in blood, tissue as well as purified mitochondria of db/db mice and the increase of tissue mitochondrial succinic dehydrogenase (SDH) staining after BHB treatment. Exogenous supplementation of BHB was also found to attenuate T2DM pathology related to mitochondrial redox states, involving organ injury, blood glucose control, insulin resistance and systemic inflammation. INTERPRETATION: Our findings provide strong evidence for BHB as a potential therapeutic strategy targeting mitochondria for T2DM.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Análise Espectral Raman , Ácido 3-Hidroxibutírico/farmacologia , Mitocôndrias , Oxirredução , Diabetes Mellitus Tipo 2/tratamento farmacológico
11.
Brain Res ; 1827: 148758, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38199308

RESUMO

BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening neurological disease that usually has a poor prognosis. Neurogenesis is a potential therapeutic target for brain injury. Ketone metabolism also plays neuroprotective roles in many neurological disorders. OXCT1 (3-Oxoacid CoA-Transferase 1) is the rate-limiting enzyme of ketone body oxidation. In this study, we explored whether increasing ketone oxidation by upregulating OXCT1 in neurons could promote neurogenesis after SAH, and evaluated the potential mechanism involved in this process. METHODS: The ß-hydroxybutyrate content was measured using an enzymatic colorimetric assay. Adeno-associated virus targeting neurons was injected to overexpress OXCT1, and the expression and localization of proteins were evaluated by western blotting and immunofluorescence staining. Adult hippocampal neurogenesis was evaluated by dual staining with doublecortin and 5-Ethynyl-2'-Deoxyuridine. LY294002 was intracerebroventricularly administered to inhibit Akt activity. The Morris water maze and Y-maze tests were employed to assess cognitive function after SAH. RESULTS: The results showed that OXCT1 expression and hippocampal neurogenesis significantly decreased in the early stage of SAH. Overexpression of OXCT1 successfully increased hippocampal neurogenesis via activation of Akt/GSK-3ß/ß-catenin signaling and improved cognitive function, both of which were reversed by administration of LY294002. CONCLUSIONS: OXCT1 regulated hippocampal ketone body metabolism and increased neurogenesis through mechanisms mediated by the Akt/GSK-3ß/ß-catenin pathway, improving cognitive impairment after SAH.


Assuntos
Coenzima A-Transferases , Disfunção Cognitiva , Hipocampo , Neurogênese , Hemorragia Subaracnóidea , Ácido 3-Hidroxibutírico , beta Catenina , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipocampo/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos
12.
ACS Appl Bio Mater ; 7(2): 1095-1114, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38270084

RESUMO

Peripheral nerve injury poses a threat to the mobility and sensitivity of a nerve, thereby leading to permanent function loss due to the low regenerative capacity of mature neurons. To date, the most widely clinically applied approach to bridging nerve injuries is autologous nerve grafting, which faces challenges such as donor site morbidity, donor shortages, and the necessity of a second surgery. An effective therapeutic strategy is urgently needed worldwide to overcome the current limitations. Herein, a magnetic nerve guidance conduit (NGC) based on biocompatible biodegradable poly(3-hydroxybutyrate) (PHB) and 8 wt % of magnetite nanoparticles modified by citric acid (Fe3O4-CA) was fabricated by electrospinning. The crystalline structure of NGCs was studied by X-ray diffraction, which indicated an enlarged ß-phase of PHB in the composite conduit compared to a pure PHB conduit. Tensile tests revealed greater ductility of PHB/Fe3O4-CA: the composite conduit has Young's modulus of 221 ± 52 MPa and an elongation at break of 28.6 ± 2.9%, comparable to clinical materials. Saturation magnetization (σs) of Fe3O4-CA and PHB/Fe3O4-CA is 61.88 ± 0.29 and 7.44 ± 0.07 emu/g, respectively. The water contact angle of the PHB/Fe3O4-CA conduit is lower as compared to pure PHB, while surface free energy (σ) is significantly higher, which was attributed to higher surface roughness and an amorphous phase as well as possible PHB/Fe3O4-CA interface interactions. In vitro, the conduits supported the proliferation of rat mesenchymal stem cells (rMSCs) and SH-SY5Y cells in a low-frequency magnetic field (0.67 Hz, 68 mT). In vivo, the conduits were used to bridge damaged sciatic nerves in rats; pure PHB and composite PHB/Fe3O4-CA conduits did not cause acute inflammation and performed a barrier function, which promotes nerve regeneration. Thus, these conduits are promising as implants for the regeneration of peripheral nerves.


Assuntos
Nanopartículas de Magnetita , Neuroblastoma , Traumatismos dos Nervos Periféricos , Poli-Hidroxibutiratos , Ratos , Humanos , Animais , Traumatismos dos Nervos Periféricos/terapia , Ácido 3-Hidroxibutírico/farmacologia , Materiais Biocompatíveis/farmacologia , Nanopartículas de Magnetita/uso terapêutico , Hidroxibutiratos/farmacologia , Regeneração Nervosa/fisiologia
13.
J Diabetes Complications ; 38(2): 108652, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38190779

RESUMO

BACKGROUND: Diabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease. AIM: To investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism. METHODS: DKD model was established using high-fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low-dose of canagliflozin, 4) high-dose of canagliflozin and 5) ß-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed. RESULTS: Canagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. ß-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice. CONCLUSION: Canagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Masculino , Camundongos , Ácido 3-Hidroxibutírico/uso terapêutico , Aminoácidos , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/etiologia , Rim/patologia , Camundongos Endogâmicos C57BL , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
14.
Int J Biol Macromol ; 259(Pt 1): 129248, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38191108

RESUMO

Marine biological resources, serving as a renewable and sustainable reservoir, holds significant import for the utilization of composite material. Hence, we produced bamboo fiber/poly(3-hydroxybutyrate) (BF/PHB) biocomposites with exceptional performance and economic viability, drawing inspiration from the resilience of crustacean shells. Polyaminoethyl modified chitin (PAECT) was synthesized using the alkali freeze-thaw method and introduced into the interface between BF and PHB to improve interfacial adhesion. The resulting chitin fibers, characterized by their intertwined helical chains, constructed a flexible mesh structure on the BF surface through an electrostatic self-assembly approach. The interwoven PAECT filaments infiltrated the dual-phase structure, acting as a promoter of interfacial compatibility, while the flexible chitin network provided a greater capacity for deformation accommodation. Consequently, both impact and tensile strength of the BF/PHB composites were notably enhanced. Additionally, this flexible layer ameliorated the thermal stability and crystalline properties of the composites. This investigation aimed to leverage the distinctive helical configuration of chitin to facilitate the advancement of bio-reinforced composites.


Assuntos
Quitina , Poliésteres , Poli-Hidroxibutiratos , Poliésteres/química , Ácido 3-Hidroxibutírico , Resistência à Tração
15.
Int J Biol Macromol ; 260(Pt 1): 129407, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38224805

RESUMO

The utilization of 3D printing has become increasingly common in the construction of composite scaffolds. In this study, magnetic mesoporous bioactive glass (MMBG) was incorporated into polyhydroxybutyrate (PHB) to construct extrusion-based 3D printed scaffold. After fabrication of the PHB/MMBG composite scaffolds, they were coated with chitosan (Cs) and chitosan/multi-walled carbon nanotubes (Cs/MWCNTs) solutions utilizing deep coating method. FTIR was conducted to confirm the presence of Cs and MWCNTs on the scaffolds' surface. The findings of mechanical analysis illustrated that presence of Cs/MWCNTs on the composite scaffolds increases compressive young modulus significantly, from 16.5 to 42.2 MPa. According to hydrophilicity evaluation, not only MMBG led to decrease the contact angle of pure PHB but also scaffolds surface modification utilization of Cs and MWCNTs, the contact angle decreased significantly from 82.34° to 54.15°. Furthermore, investigation of cell viability, cell metabolism and inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) and transforming growth factor-beta (TGF-ß) proved that the scaffolds not only do not stimulate the immune system, but also polarize macrophage cells from M1 phase to M2 phase. The present study highlights the suitability of 3D printed scaffold PHB/MMBG with Cs/MWCNTs coating for bone tissue engineering.


Assuntos
Quitosana , Nanocompostos , Nanotubos de Carbono , Tecidos Suporte , Ácido 3-Hidroxibutírico , Porosidade , Engenharia Tecidual/métodos , Regeneração Óssea , Poliésteres/farmacologia , Impressão Tridimensional , Fenômenos Magnéticos
16.
Int J Biol Macromol ; 260(Pt 2): 129521, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38246453

RESUMO

Poly (3-hydroxybutyrate) (PHB) is undoubtedly a potential substitute for petroleum-based non-biodegradable food packaging materials due to its renewability, high crystallinity, biocompatibility, and biodegradability. Nonetheless, PHB exhibits certain shortcomings, including low flexibility, moderate gas barrier properties, and negligible antimicrobial and antioxidant activities, which limit its direct application in food packaging. Loading essential oils can increase flexibility and induce antimicrobial and antioxidant activities in biopolymers but at the cost of reduced tensile strength. In contrast, nanofiller reinforcement can increase the tensile strength and barrier properties of such biopolymers. Therefore, to harness the synergistic effects of essential oil and nanofiller, PHB-based films incorporated with 5 wt% grapeseed oil (GS) and varying concentrations (0.1-1 wt%) of MgO nanoparticles (MgO NPs) were prepared in this study following simple sonication-assisted solution casting technique. Physicochemical, tensile, microstructural, optical, barrier, antimicrobial, and antioxidant properties were then evaluated for the prepared composite films. FESEM analysis of the PHB-based films with 5 wt% GS and 0.7 wt% MgO NPs (PHB/5GS/0.7MgO) confirmed its compact morphology without any aggregates, pores, or phase separation. In comparison with pristine PHB, the PHB/5GS/0.7MgO films demonstrated higher tensile strength (by 1.4-fold) and flexibility (by 30-fold), along with 79 and 90 % reduction in water vapor and oxygen transmission, respectively. In addition, PHB/5GS/0.7MgO showed good UV-blocking properties, 65.25 ± 0.98 % antioxidant activity, and completely inhibited the growth of Staphylococcus aureus and Escherichia coli. Moreover, PHB/5GS/0.7MgO films proved beneficial effects in terms of extending the shelf-life of white button mushrooms up to 6 days at ambient room conditions.


Assuntos
Agaricus , Anti-Infecciosos , Nanopartículas , Óleos Voláteis , Ácido 3-Hidroxibutírico , Óxido de Magnésio , Antioxidantes/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Embalagem de Alimentos/métodos , Biopolímeros , Óleos Voláteis/farmacologia , Expectativa de Vida
17.
PLoS One ; 19(1): e0296523, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38166036

RESUMO

PURPOSE: Ketogenic diets may positively influence cancer through pleiotropic mechanisms, but only a few small and short-term studies have addressed feasibility and efficacy in cancer patients. The primary goals of this study were to evaluate the feasibility and the sustained metabolic effects of a personalized well-formulated ketogenic diet (WFKD) designed to achieve consistent blood beta-hydroxybutyrate (ßHB) >0.5 mM in women diagnosed with stage IV metastatic breast cancer (MBC) undergoing chemotherapy. METHODS: Women (n = 20) were enrolled in a six month, two-phase, single-arm WFKD intervention (NCT03535701). Phase I was a highly-supervised, ad libitum, personalized WFKD, where women were provided with ketogenic-appropriate food daily for three months. Phase II transitioned women to a self-administered WFKD with ongoing coaching for an additional three months. Fasting capillary ßHB and glucose were collected daily; weight, body composition, plasma insulin, and insulin resistance were collected at baseline, three and six months. RESULTS: Capillary ßHB indicated women achieved nutritional ketosis (Phase I mean: 0.8 mM (n = 15); Phase II mean: 0.7 mM (n = 9)). Body weight decreased 10% after three months, primarily from body fat. Fasting plasma glucose, plasma insulin, and insulin resistance also decreased significantly after three months (p < 0.01), an effect that persisted at six months. CONCLUSIONS: Women diagnosed with MBC undergoing chemotherapy can safely achieve and maintain nutritional ketosis, while improving body composition and insulin resistance, out to six months.


Assuntos
Neoplasias da Mama , Dieta Cetogênica , Resistência à Insulina , Insulinas , Cetose , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Estudos de Viabilidade , Ácido 3-Hidroxibutírico
18.
Nutrients ; 16(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38201992

RESUMO

This study aimed to determine the impact of various fast-interrupting shakes on markers of glycemic control including glucose, ß-hydroxybutyrate (BHB), insulin, glucagon, GLP-1, and GIP. Twenty-seven sedentary adults (twelve female, fifteen male) with overweight or obesity completed this study. One condition consisted of a 38-h water-only fast, and the other two conditions repeated this, but the fasts were interrupted at 24 h by either a high carbohydrate/low fat (HC/LF) shake or an isovolumetric and isocaloric low carbohydrate/high fat (LC/HF) shake. The water-only fast resulted in 135.3% more BHB compared to the HC/LF condition (p < 0.01) and 69.6% more compared to the LC/HF condition (p < 0.01). The LC/HF condition exhibited a 38.8% higher BHB level than the HC/LF condition (p < 0.01). The area under the curve for glucose was 14.2% higher in the HC/LF condition than in the water condition (p < 0.01) and 6.9% higher compared to the LC/HF condition (p < 0.01), with the LC/HF condition yielding 7.8% more glucose than the water condition (p < 0.01). At the 25-h mark, insulin and glucose-dependent insulinotropic polypeptide (GIP) were significantly elevated in the HC/LF condition compared to the LC/HF condition (p < 0.01 and p = 0.02, respectively) and compared to the water condition (p < 0.01). Furthermore, insulin, GLP-1, and GIP were increased in the LC/HF condition compared to the water condition at 25 h (p < 0.01, p = 0.015, and p < 0.01, respectively). By the 38-h time point, no differences were observed among the conditions for any of the analyzed hormones. While a LC/HF shake does not mimic a fast completely, it does preserve some of the metabolic changes including elevated BHB and glucagon, and decreased glucose and insulin compared to a HC/LF shake, implying a potential for improved metabolic health.


Assuntos
Glucagon , Controle Glicêmico , Adulto , Humanos , Feminino , Masculino , Estudos Cross-Over , Insulina , Glucose , Biomarcadores , Ácido 3-Hidroxibutírico , Polipeptídeo Inibidor Gástrico , Peptídeo 1 Semelhante ao Glucagon , Fatores de Transcrição , Tremor , Água
19.
Am J Physiol Cell Physiol ; 326(3): C707-C711, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38189135

RESUMO

Ketone bodies are short-chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important nonmetabolic functions of the most abundant ketone body, ß-hydroxybutyrate (BHB). Notably, many of these functions, including limiting specific sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells. Likewise, dietary manipulations like caloric restriction or ketogenic diet feeding have been associated with lowered inflammation, improved health outcomes, and improved host defense against infection. However, the underlying mechanisms of the broad benefits of ketosis remain incompletely understood. In this Perspective, we contextualize the current state of the field of nonmetabolic functions of ketone bodies specifically in the immune system and speculate on the molecular explanations and broader physiological significance.


Assuntos
Corpos Cetônicos , Cetose , Humanos , Ácido 3-Hidroxibutírico , Sistema Imunitário , Inflamação
20.
Clin Exp Immunol ; 216(1): 89-103, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38195093

RESUMO

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1ß, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1ß, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time.


Assuntos
Diabetes Mellitus Tipo 2 , Interleucina-10 , Adulto , Humanos , Ácido 3-Hidroxibutírico/farmacologia , Ácido 3-Hidroxibutírico/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cetonas/uso terapêutico , Fator de Necrose Tumoral alfa , Lipopolissacarídeos , Inflamação/tratamento farmacológico , Citocinas , Anti-Inflamatórios/uso terapêutico , Interleucina-1beta , Imunidade
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