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1.
Proc Natl Acad Sci U S A ; 121(22): e2322935121, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38771877

RESUMEN

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.


Asunto(s)
Nanopartículas , ARN Mensajero , Especies Reactivas de Oxígeno , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Animales , Nanopartículas/química , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Interleucina-4/metabolismo , Diabetes Mellitus Experimental , Humanos , Lípidos/química , Modelos Animales de Enfermedad , Masculino , Liposomas
2.
Comb Chem High Throughput Screen ; 27(5): 786-796, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38773797

RESUMEN

OBJECTIVE: Diabetic osteoporosis (DOP) belongs to the group of diabetes-induced secondary osteoporosis and is the main cause of bone fragility and fractures in many patients with diabetes. The aim of this study was to determine whether Ziyin Bushen Fang (ZYBSF) can improve DOP by inhibiting autophagy and oxidative stress. METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats using a high-fat high-sugar diet combined with streptozotocin. Micro-CT scanning was used to quantitatively observe changes in the bone microstructure in each group. Changes in the serum metabolites of DOP rats were analyzed using UHPLC-QTOF-MS. The DOP mouse embryonic osteoblast precursor cell model (MC3T3-E1) was induced using high glucose levels. RESULTS: After ZYBSF treatment, bone microstructure significantly improved. The bone mineral density, trabecular number, and trabecular thickness in the ZYBSF-M and ZYBSF-H groups significantly increased. After ZYBSF treatment, the femur structure of the rats was relatively intact, collagen fibers were significantly increased, and osteoporosis was significantly improved. A total of 1239 metabolites were upregulated and 1527 were downregulated in the serum of T1DM and ZYBSF-treated rats. A total of 20 metabolic pathways were identified. In cellular experiments, ZYBSF reduced ROS levels and inhibited the protein expression of LC3II / I, Beclin-1, and p-ERK. CONCLUSION: ZYBSF may improve DOP by inhibiting the ROS/ERK-induced autophagy signaling pathway.


Asunto(s)
Autofagia , Medicamentos Herbarios Chinos , Osteoporosis , Estrés Oxidativo , Animales , Autofagia/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Ratas , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Ratas Sprague-Dawley , Estreptozocina , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Densidad Ósea/efectos de los fármacos
3.
Gen Physiol Biophys ; 43(3): 185-196, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38774919

RESUMEN

Ampelopsin (AMP) had a wound-healing effect in rat skin wounds with or without purulent infection. However, the role of AMP in diabetic wound healing remains poorly defined. Wounds were created on the dorsal skin of type 2 diabetic mouse model, and the histological features of wounds were examined by hematoxylin and eosin (HE) staining. Caspase-1 activity and the secretion of inflammatory cytokines were detected by enzyme-linked immunosorbent assay (ELISA). Cell viability and migration were examined through cell counting kit-8 (CCK-8) and wound healing assays, respectively. AMP facilitated wound healing in vivo. AMP notably facilitated platelet endothelial cell adhesion molecule-31 (CD31), collagen type I alpha 1 chain (COL1A1), and alpha-smooth muscle actin (α-SMA), and inhibited matrix metallopeptidase 9 (MMP9) and cyclooxygenase 2 (Cox2) expression in diabetic wounds. The inflammasome pathway was implicated in skin injury. AMP inhibited pro-inflammatory factor secretions and NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in diabetic wounds and high glucose-treated THP-1 macrophages. AMP-mediated NLRP3 inflammasome inhibition in THP-1 macrophages increased cell viability and migratory capacity in HaCaT cells. AMP facilitated diabetic wound healing and increased keratinocyte cell viability and migratory ability by inhibiting the NLRP3 inflammasome pathway in macrophages.


Asunto(s)
Inflamasomas , Queratinocitos , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Cicatrización de Heridas , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Ratones , Humanos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Masculino , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células THP-1 , Células HaCaT , Flavonoides
4.
Arch Endocrinol Metab ; 68: e230097, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38739522

RESUMEN

Objective: This study sought to investigate the regulation of long noncoding RNA (lncRNA) XIST on the microRNA (miR)-101-3p/vascular endothelial growth factor A (VEGFA) axis in neovascularization in diabetic retinopathy (DR). Materials and methods: Serum of patients with DR was extracted for the analysis of XIST, miR-101-3p, and VEGFA expression levels. High glucose (HG)-insulted HRMECs and DR model rats were treated with lentiviral vectors. MTT, transwell, and tube formation assays were performed to evaluate cell viability, migration, and angiogenesis, and ELISA was conducted to detect the levels of inflammatory cytokines. Dual-luciferase reporter, RIP, and RNA pull-down experiments were used to validate the relationships among XIST, miR-101-3p, and VEGFA. Results: XIST and VEGFA were upregulated and miR-101-3p was downregulated in serum from patients with DR. XIST knockdown inhibited proliferation, migration, vessel tube formation, and inflammatory responsein HG-treated HRMECs, whereas the above effects were nullified by miR-101-3p inhibition or VEGFA overexpression. miR-101-3p could bind to XIST and VEGFA. XIST promoted DR development in rats by regulating the miR-101-3p/VEGFA axis. Conclusion: LncRNA XIST promotes VEGFA expression by downregulating miR-101-3p, thereby stimulating angiogenesis and inflammatory response in DR.


Asunto(s)
Retinopatía Diabética , MicroARNs , Neovascularización Patológica , ARN Largo no Codificante , Factor A de Crecimiento Endotelial Vascular , ARN Largo no Codificante/genética , Retinopatía Diabética/genética , Retinopatía Diabética/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Ratas , Humanos , Masculino , Neovascularización Patológica/genética , Ratas Sprague-Dawley , Femenino , Movimiento Celular/genética , Proliferación Celular/genética , Persona de Mediana Edad , Diabetes Mellitus Experimental
5.
Drug Des Devel Ther ; 18: 1439-1457, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38707616

RESUMEN

Background: Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically. Methods: First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated. Results: Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P<0.05), alongside mitigated podocyte injury (P<0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1ß, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway. Conclusion: Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside's efficacy in DKD treatment, providing a foundation for further basic and clinical research.


Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Glucósidos , Simulación del Acoplamiento Molecular , Farmacología en Red , Fenoles , Polifenoles , Estreptozocina , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Animales , Ratas , Glucósidos/farmacología , Glucósidos/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Fenoles/farmacología , Fenoles/química , Ratas Sprague-Dawley
6.
PeerJ ; 12: e17268, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38708351

RESUMEN

Objective: To study the efficacy of PADTM Plus-based photoactivated disinfection (PAD) for treating denture stomatitis (DS) in diabetic rats by establishing a diabetic rat DS model. Methods: The diabetic rat DS model was developed by randomly selecting 2-month-old male Sprague-Dawley rats and dividing them into four groups. The palate and denture surfaces of rats in the PAD groups were incubated with 1 mg/mL toluidine blue O for 1 min each, followed by a 1-min exposure to 750-mW light-emitting diode light. The PAD-1 group received one radiation treatment, and the PAD-2 group received three radiation treatments over 5 days with a 1-day interval. The nystatin (NYS) group received treatment for 5 days with a suspension of NYS of 100,000 IU. The infection group did not receive any treatment. In each group, assessments included an inflammation score of the palate, tests for fungal load, histological evaluation, and immunohistochemical detection of interleukin-17 (IL-17) and tumor necrosis factor (TNF-α) conducted 1 and 7 days following the conclusion of treatment. Results: One day after treatment, the fungal load on the palate and dentures, as well as the mean optical density values of IL-17 and TNF-α, were found to be greater in the infection group than in the other three treatment groups (P < 0.05). On the 7th day after treatment, these values were significantly higher in the infection group than in the PAD-2 and NYS groups (P < 0.05). Importantly, there were no differences between the infection and PAD-1 groups nor between the PAD-2 and NYS groups (P > 0.05). Conclusions: PAD effectively reduced the fungal load and the expressions of IL-17 and TNF-α in the palate and denture of diabetic DS rats. The efficacy of multiple-light treatments was superior to that of single-light treatments and similar to that of NYS.


Asunto(s)
Diabetes Mellitus Experimental , Desinfección , Ratas Sprague-Dawley , Estomatitis Subprotética , Animales , Masculino , Ratas , Estomatitis Subprotética/microbiología , Estomatitis Subprotética/radioterapia , Estomatitis Subprotética/tratamiento farmacológico , Desinfección/métodos , Cloruro de Tolonio/farmacología , Cloruro de Tolonio/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-17/metabolismo , Modelos Animales de Enfermedad
7.
FASEB J ; 38(9): e23638, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38713098

RESUMEN

Diabetic retinopathy (DR) is associated with ocular inflammation leading to retinal barrier breakdown, vascular leakage, macular edema, and vision loss. DR is not only a microvascular disease but also involves retinal neurodegeneration, demonstrating that pathological changes associated with neuroinflammation precede microvascular injury in early DR. Macrophage activation plays a central role in neuroinflammation. During DR, the inflammatory response depends on the polarization of retinal macrophages, triggering pro-inflammatory (M1) or anti-inflammatory (M2) activity. This study aimed to determine the role of macrophages in vascular leakage through the tight junction complexes of retinal pigment epithelium, which is the outer blood-retinal barrier (BRB). Furthermore, we aimed to assess whether interleukin-10 (IL-10), a representative M2-inducer, can decrease inflammatory macrophages and alleviate outer-BRB disruption. We found that modulation of macrophage polarization affects the structural and functional integrity of ARPE-19 cells in a co-culture system under high-glucose conditions. Furthermore, we demonstrated that intravitreal IL-10 injection induces an increase in the ratio of anti-inflammatory macrophages and effectively suppresses outer-BRB disruption and vascular leakage in a mouse model of early-stage streptozotocin-induced diabetes. Our results suggest that modulation of macrophage polarization by IL-10 administration during early-stage DR has a promising protective effect against outer-BRB disruption and vascular leakage. This finding provides valuable insights for early intervention in DR.


Asunto(s)
Barrera Hematorretinal , Diabetes Mellitus Experimental , Retinopatía Diabética , Interleucina-10 , Macrófagos , Ratones Endogámicos C57BL , Animales , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Barrera Hematorretinal/metabolismo , Barrera Hematorretinal/patología , Interleucina-10/metabolismo , Ratones , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/metabolismo , Masculino , Humanos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Estreptozocina , Activación de Macrófagos/efectos de los fármacos , Modelos Animales de Enfermedad , Polaridad Celular/efectos de los fármacos
8.
J Nanobiotechnology ; 22(1): 246, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38735970

RESUMEN

Excessive production of reactive oxygen species (ROS) and inflammation are the key problems that impede diabetic wound healing. In particular, dressings with ROS scavenging capacity play a crucial role in the process of chronic wound healing. Herein, Zr-based large-pore mesoporous metal-organic frameworks (mesoMOFs) were successfully developed for the construction of spatially organized cascade bioreactors. Natural superoxide dismutase (SOD) and an artificial enzyme were spatially organized in these hierarchical mesoMOFs, forming a cascade antioxidant defense system, and presenting efficient intracellular and extracellular ROS scavenging performance. In vivo experiments demonstrated that the SOD@HMUiO-MnTCPP nanoparticles (S@M@H NPs) significantly accelerated diabetic wound healing. Transcriptomic and western blot results further indicated that the nanocomposite could inhibit fibroblast senescence and ferroptosis as well as the stimulator of interferon genes (STING) signaling pathway activation in macrophages mediated by mitochondrial oxidative stress through ROS elimination. Thus, the biomimetic multi-enzyme cascade catalytic system with spatial ordering demonstrated a high potential for diabetic wound healing, where senescence, ferroptosis, and STING signaling pathways may be potential targets.


Asunto(s)
Inflamación , Estructuras Metalorgánicas , Especies Reactivas de Oxígeno , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Animales , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Ratones , Superóxido Dismutasa/metabolismo , Porosidad , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células RAW 264.7 , Masculino , Ferroptosis/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Diabetes Mellitus Experimental , Nanopartículas/química , Humanos , Antioxidantes/farmacología , Nanocompuestos/química , Proteínas de la Membrana
9.
FASEB J ; 38(10): e23668, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38742811

RESUMEN

Podocyte injury plays a critical role in the progression of diabetic kidney disease (DKD), but the underlying cellular and molecular mechanisms remain poorly understanding. MicroRNAs (miRNAs) can disrupt gene expression by inducing translation inhibition and mRNA degradation, and recent evidence has shown that miRNAs may play a key role in many kidney diseases. In this study, we identified miR-4645-3p by global transcriptome expression profiling as one of the major downregulated miRNAs in high glucose-cultured podocytes. Moreover, whether DKD patients or STZ-induced diabetic mice, expression of miR-4645-3p was also significantly decreased in kidney. In the podocytes cultured by normal glucose, inhibition of miR-4645-3p expression promoted mitochondrial damage and podocyte apoptosis. In the podocytes cultured by high glucose (30 mM glucose), overexpression of miR-4645-3p significantly attenuated mitochondrial dysfunction and podocyte apoptosis induced by high glucose. Furthermore, we found that miR-4645-3p exerted protective roles by targeting Cdk5 inhibition. In vitro, miR-4645-3p obviously antagonized podocyte injury by inhibiting overexpression of Cdk5. In vivo of diabetic mice, podocyte injury, proteinuria, and impaired renal function were all effectively ameliorated by treatment with exogenous miR-4645-3p. Collectively, these findings demonstrate that miR-4645-3p can attenuate podocyte injury and mitochondrial dysfunction in DKD by targeting Cdk5. Sustaining the expression of miR-4645-3p in podocytes may be a novel strategy to treat DKD.


Asunto(s)
Quinasa 5 Dependiente de la Ciclina , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Ratones Endogámicos C57BL , MicroARNs , Mitocondrias , Podocitos , Podocitos/metabolismo , Podocitos/patología , Animales , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/genética , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Mitocondrias/metabolismo , Masculino , Humanos , Diabetes Mellitus Experimental/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Quinasa 5 Dependiente de la Ciclina/genética , Apoptosis , Glucosa
10.
ACS Appl Mater Interfaces ; 16(19): 24351-24371, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38690969

RESUMEN

Chronic nonhealing wounds are serious complications of diabetes with a high morbidity, and they can lead to disability or death. Conventional drug therapy is ineffective for diabetic wound healing because of the complex environment of diabetic wounds and the depth of drug penetration. Here, we developed a self-healing, dual-layer, drug-carrying microneedle (SDDMN) for diabetic wound healing. This SDDMN can realize transdermal drug delivery and broad-spectrum sterilization without drug resistance and meets the multiple needs of the diabetic wound healing process. Quaternary ammonium chitosan cografted with dihydrocaffeic acid (Da) and l-arginine and oxidized hyaluronic acid-dopamine are the main parts of the self-healing hydrogel patch. Methacrylated poly(vinyl alcohol) (methacrylated PVA) and phenylboronic acid (PBA) were used as the main part of the MN, and gallium porphyrin modified with 3-amino-1,2 propanediol (POGa) and insulin were encapsulated at its tip. Under hyperglycaemic conditions, the PBA moiety in the MN reversibly formed a glucose-boronic acid complex that promoted the rapid release of POGa and insulin. POGa is disguised as hemoglobin through a Trojan-horse strategy, which is then taken up by bacteria, allowing it to target bacteria and infected lesions. Based on the synergistic properties of these components, SDDMN-POGa patches exhibited an excellent biocompatibility, slow drug release, and antimicrobial properties. Thus, these patches provide a potential therapeutic approach for the treatment of diabetic wounds.


Asunto(s)
Ácidos Borónicos , Diabetes Mellitus Experimental , Glucosa , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Animales , Ácidos Borónicos/química , Glucosa/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Agujas , Insulina/administración & dosificación , Ratones , Quitosano/química , Alcohol Polivinílico/química , Ratas , Ácido Hialurónico/química , Masculino , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacología , Sistemas de Liberación de Medicamentos , Ratas Sprague-Dawley , Humanos , Hidrogeles/química
11.
Biochem Biophys Res Commun ; 716: 150002, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38697011

RESUMEN

Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34+ and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity.


Asunto(s)
Diabetes Mellitus Experimental , Células Progenitoras Endoteliales , Péptidos Similares al Glucagón , Glucosa , Fragmentos Fc de Inmunoglobulinas , Dinámicas Mitocondriales , Proteínas Recombinantes de Fusión , Sirtuina 1 , Animales , Fragmentos Fc de Inmunoglobulinas/farmacología , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Sirtuina 1/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Células Progenitoras Endoteliales/efectos de los fármacos , Células Progenitoras Endoteliales/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Masculino , Ratones , Glucosa/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Ratones Endogámicos C57BL , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Hipoglucemiantes/farmacología , Humanos , Isquemia/metabolismo , Isquemia/tratamiento farmacológico , Isquemia/patología
12.
ACS Appl Mater Interfaces ; 16(19): 24221-24234, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38709623

RESUMEN

Clinical studies have continually referred to the involvement of drug carrier having dramatic negative influences on the biocompatibility, biodegradability, and loading efficacy of hydrogel. To overcome this deficiency, researchers have proposed to directly self-assemble natural herbal small molecules into a hydrogel without any structural modification. However, it is still a formidable challenge due to the high requirements on the structure of natural molecules, leading to a rarity of this type of hydrogel. Mangiferin (MF) is a natural polyphenol of C-glucoside xanthone with various positive health benefits, including the treatment of diabetic wounds, but its poor hydrosolubility and low bioavailability significantly restrict the clinical application. Inspired by these, with heating/cooling treatment, a carrier-free hydrogel (MF-gel) is developed by assembling the natural herbal molecule mangiferin, which is mainly governed through hydrogen bonds and intermolecular π-π stacking interactions. The as-prepared hydrogel has injectable and self-healing properties and shows excellent biocompatibility, continuous release ability, and reversible stimuli-responsive performances. All of the superiorities enable the MF-based hydrogel to serve as a potential wound dressing for treating diabetic wounds, which was further confirmed by both the vitro and vivo studies. In vitro, the MF-gel could promote the migration of healing-related cells from peripheral as well as the angiogenesis and displays the capacity of mediating inflammation response by scavenging the intracellular ROS. In vivo, the MF-gel accelerates wound contraction and healing via inflammatory adjustment, collagen deposition, and angiogenesis. This study provides a facile and effective method for diabetic wound management and emphasizes the direct self-assembly hydrogel from natural herbal small molecule.


Asunto(s)
Hidrogeles , Cicatrización de Heridas , Xantonas , Xantonas/química , Xantonas/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Humanos , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Ratas , Masculino
13.
Sci Rep ; 14(1): 10855, 2024 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740782

RESUMEN

Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease that can compromise the functioning of various organs, including the salivary glands (SG). The purinergic system is one of the most important inflammatory pathways in T2DM condition, and P2X7R and P2X4R are the primary purinergic receptors in SG that regulate inflammatory homeostasis. This study aimed to evaluate P2X7R and P2X4R expression, and morphological changes in the submandibular gland (SMG) in T2DM. Twenty-four 5-week-old mice were randomly assigned to control (CON) and diabetes mellitus (DM) groups (n = 12 each). Body weight, diet, and blood glucose levels were monitored weekly. The histomorphology of the SMG and the expression of the P2X7R, and P2X7R was evaluated by immunohistochemistry (IHC) staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) at 11 and 13 weeks of age. Our findings indicate a significant increase in food consumption, body weight, and blood glucose levels in the DM group. Although a significant increase in P2X7R and P2X4R expression was observed in the DM groups, the receptor location remained unchanged. We also observed a significant increase in the acinar area in the DM13w group, and a significant decrease in the ductal area in the DM11w and DM13w groups. Targeting purinergic receptors may offer novel therapeutic methods for diabetic complications.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dieta Alta en Grasa , Receptores Purinérgicos P2X4 , Receptores Purinérgicos P2X7 , Glándula Submandibular , Animales , Glándula Submandibular/metabolismo , Glándula Submandibular/patología , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X4/genética , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Dieta Alta en Grasa/efectos adversos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Masculino , Glucemia/metabolismo , Peso Corporal , Estreptozocina , Ratones Endogámicos C57BL
14.
Front Endocrinol (Lausanne) ; 15: 1388361, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38745946

RESUMEN

Introduction: The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome. Methods: Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas. Results: Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon. Discussion: This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.


Asunto(s)
Modelos Animales de Enfermedad , Síndrome Metabólico , Obesidad , Ratas Sprague-Dawley , Tacrolimus , Animales , Tacrolimus/farmacología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Síndrome Metabólico/inducido químicamente , Obesidad/metabolismo , Obesidad/patología , Ratas , Masculino , Inmunosupresores/efectos adversos , Inmunosupresores/farmacología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/efectos de los fármacos , Fenotipo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/metabolismo , Resistencia a la Insulina , Dieta Alta en Grasa/efectos adversos
15.
Mol Med ; 30(1): 58, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38720283

RESUMEN

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Exenatida , Receptor del Péptido 1 Similar al Glucagón , Mitofagia , Transducción de Señal , Calcificación Vascular , Animales , Mitofagia/efectos de los fármacos , Calcificación Vascular/etiología , Calcificación Vascular/metabolismo , Calcificación Vascular/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Ratones , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Masculino , Proteínas Quinasas Activadas por AMP/metabolismo , Humanos , Exenatida/farmacología , Exenatida/uso terapéutico , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(4): 675-681, 2024 Apr 20.
Artículo en Chino | MEDLINE | ID: mdl-38708500

RESUMEN

OBJECTIVE: To investigate the role of irisin in exercise-induced improvement of renal function in type 2 diabetic rats. METHODS: Forty male SD rats aged 4-6 weeks were randomized into normal control group, type 2 diabetes mellitus model group, diabetic exercise (DE) group and diabetic irisin (DI) group (n=8). The rats in DE group were trained with treadmill running for 8 weeks, and those in DI group were given scheduled irisin injections for 8 weeks. After the treatments, blood biochemical parameters of the rats were examined, and renal histopathology was observed with HE, Masson and PAS staining. Western blotting was used to detect the protein expression levels in the rats'kidneys. RESULTS: The diabetic rats showed significantly increased levels of fasting insulin, total cholesterol, triglyceride, serum creatinine and blood urea nitrogen with lowered serum irisin level (all P < 0.05). Compared with those in DM group, total cholesterol, triglyceride, serum creatinine and blood urea nitrogen levels were decreased and serum irisin levels were increased in both DE and DI groups (all P < 0.05). The rats in DM group showed obvious structural disorders and collagen fiber deposition in the kidneys, which were significantly improved in DE group and DI group. Both regular exercises and irisin injections significantly ameliorated the reduction of FNDC5, LC3-II/I, Atg7, Beclin-1, p-AMPK, AMPK and SIRT1 protein expressions and lowered of p62 protein expression in the kidneys of the diabetic rats (all P < 0.05). CONCLUSION: Both exercise and exogenous irisin treatment improve nephropathy in type 2 diabetic rats possibly due to irisin-mediated activation of the AMPK/SIRT1 pathway in the kidneys to promote renal autophagy.


Asunto(s)
Autofagia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Fibronectinas , Riñón , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Sirtuina 1 , Animales , Fibronectinas/metabolismo , Masculino , Ratas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Riñón/metabolismo , Sirtuina 1/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/terapia , Beclina-1/metabolismo , Creatinina/sangre , Nitrógeno de la Urea Sanguínea , Insulina , Triglicéridos/metabolismo , Triglicéridos/sangre , Colesterol/sangre , Proteínas Quinasas Activadas por AMP/metabolismo
17.
BMC Med Genomics ; 17(1): 122, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38711057

RESUMEN

OBJECTIVE: There is increasing evidence that type 2 diabetes mellitus (T2DM) is an independent risk factor for the occur of tendinopathy. Therefore, this study is the first to explore the dynamic changes of the "gene profile" of supraspinatus tendon in rats at different time points after T2DM induction through transcriptomics, providing potential molecular markers for exploring the pathogenesis of diabetic tendinopathy. METHODS: A total of 40 Sprague-Dawley rats were randomly divided into normal (NG, n = 10) and T2DM groups (T2DM, n = 30) and subdivided into three groups according to the duration of diabetes: T2DM-4w, T2DM-8w, and T2DM-12w groups; the duration was calculated from the time point of T2DM rat model establishment. The three comparison groups were set up in this study, T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG. Differentially expressed genes (DEGs) in 3 comparison groups were screened. The intersection of the three comparison groups' DEGs was defined as key genes that changed consistently in the supraspinatus tendon after diabetes induction. Cluster analysis, gene ontology (GO) functional annotation analysis and Kyoto encyclopedia of genes and genomes (KEGG) functional annotation and enrichment analysis were performed for DEGs. RESULTS: T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG detected 519 (251 up-regulated and 268 down-regulated), 459 (342 up-regulated and 117 down-regulated) and 328 (255 up-regulated and 73 down-regulated) DEGs, respectively. 103 key genes of sustained changes in the supraspinatus tendon following induction of diabetes, which are the first identified biomarkers of the supraspinatus tendon as it progresses through the course of diabetes.The GO analysis results showed that the most significant enrichment in biological processes was calcium ion transmembrane import into cytosol (3 DEGs). The most significant enrichment in cellular component was extracellular matrix (9 DEGs). The most significant enrichment in molecular function was glutamate-gated calcium ion channel activity (3 DEGs). The results of KEGG pathway enrichment analysis showed that there were 17 major pathways (p < 0.05) that diabetes affected supratinusculus tendinopathy, including cAMP signaling pathway and Calcium signaling pathway. CONCLUSIONS: Transcriptomics reveals dynamic changes in the"gene profiles"of rat supraspinatus tendon at three different time points after diabetes induction. The 103 DEGs identified in this study may provide potential molecular markers for exploring the pathogenesis of diabetic tendinopathy, and the 17 major pathways enriched in KEGG may provide new ideas for exploring the pathogenesis of diabetic tendinopathy.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratas Sprague-Dawley , Animales , Ratas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Perfilación de la Expresión Génica , Transcriptoma , Factores de Tiempo , Tendones/metabolismo , Tendones/patología , Manguito de los Rotadores/patología , Manguito de los Rotadores/metabolismo
18.
BMC Res Notes ; 17(1): 128, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38711110

RESUMEN

The elemental composition of chemical elements can vary between healthy and diseased tissues, providing essential insights into metabolic processes in physiological and diseased states. This study aimed to evaluate the calcium (Ca) and phosphorus (P) levels in the bones of rats with/without streptozotocin-induced diabetes and/or exposure to infrasound. X-ray fluorescence spectroscopy was used to determine the concentrations of Ca and P in Wistar rat tibiae samples.The results showed a significant decrease in bone P concentration in streptozotocin-induced diabetic rats compared to untreated animals. Similarly, the Ca/P ratio was higher in the streptozotocin-induced diabetic group. No significant differences were observed in bone Ca concentration between the studied groups or between animals exposed and not exposed to infrasound.Moreover, streptozotocin-induced diabetic rats had lower bone P concentration but unaltered bone Ca concentration compared to untreated rats. Infrasound exposure did not impact bone Ca or P levels. The reduced bone P concentration may be associated with an increased risk of bone fractures in diabetes.


Asunto(s)
Calcio , Diabetes Mellitus Experimental , Fósforo , Ratas Wistar , Estreptozocina , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Fósforo/metabolismo , Calcio/metabolismo , Ratas , Masculino , Espectrometría por Rayos X , Tibia/metabolismo , Sonido/efectos adversos , Huesos/metabolismo , Intolerancia a la Glucosa/metabolismo
19.
J Nanobiotechnology ; 22(1): 232, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38720301

RESUMEN

Diabetic wounds pose a challenge to healing due to increased bacterial susceptibility and poor vascularization. Effective healing requires simultaneous bacterial and biofilm elimination and angiogenesis stimulation. In this study, we incorporated polyaniline (PANI) and S-Nitrosoglutathione (GSNO) into a polyvinyl alcohol, chitosan, and hydroxypropyltrimethyl ammonium chloride chitosan (PVA/CS/HTCC) matrix, creating a versatile wound dressing membrane through electrospinning. The dressing combines the advantages of photothermal antibacterial therapy and nitric oxide gas therapy, exhibiting enduring and effective bactericidal activity and biofilm disruption against methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Furthermore, the membrane's PTT effect and NO release exhibit significant synergistic activation, enabling a nanodetonator-like burst release of NO through NIR irradiation to disintegrate biofilms. Importantly, the nanofiber sustained a uniform release of nitric oxide, thereby catalyzing angiogenesis and advancing cellular migration. Ultimately, the employment of this membrane dressing culminated in the efficacious amelioration of diabetic-infected wounds in Sprague-Dawley rats, achieving wound closure within a concise duration of 14 days. Upon applying NIR irradiation to the PVA-CS-HTCC-PANI-GSNO nanofiber membrane, it swiftly eradicates bacteria and biofilm within 5 min, enhancing its inherent antibacterial and anti-biofilm properties through the powerful synergistic action of PTT and NO therapy. It also promotes angiogenesis, exhibits excellent biocompatibility, and is easy to use, highlighting its potential in treating diabetic wounds.


Asunto(s)
Antibacterianos , Vendajes , Biopelículas , Óxido Nítrico , Terapia Fototérmica , Ratas Sprague-Dawley , Cicatrización de Heridas , Animales , Cicatrización de Heridas/efectos de los fármacos , Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Ratas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/uso terapéutico , Biopelículas/efectos de los fármacos , Terapia Fototérmica/métodos , Masculino , Quitosano/química , Quitosano/farmacología , Nanofibras/química , Escherichia coli/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Staphylococcus aureus/efectos de los fármacos , Alcohol Polivinílico/química , Alcohol Polivinílico/farmacología , S-Nitrosoglutatión/farmacología , S-Nitrosoglutatión/química
20.
Nat Commun ; 15(1): 3904, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724502

RESUMEN

Chronic wounds are a major complication in patients with diabetes. Here, we identify a therapeutic circRNA and load it into small extracellular vesicles (sEVs) to treat diabetic wounds in preclinical models. We show that circCDK13 can stimulate the proliferation and migration of human dermal fibroblasts and human epidermal keratinocytes by interacting with insulin-like growth factor 2 mRNA binding protein 3 in an N6-Methyladenosine-dependent manner to enhance CD44 and c-MYC expression. We engineered sEVs that overexpress circCDK13 and show that local subcutaneous injection into male db/db diabetic mouse wounds and wounds of streptozotocin-induced type I male diabetic rats could accelerate wound healing and skin appendage regeneration. Our study demonstrates that the delivery of circCDK13 in sEVs may present an option for diabetic wound treatment.


Asunto(s)
Proliferación Celular , Diabetes Mellitus Experimental , Vesículas Extracelulares , Fibroblastos , Queratinocitos , ARN Circular , Cicatrización de Heridas , Animales , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Cicatrización de Heridas/efectos de los fármacos , Humanos , Masculino , Ratones , Ratas , Fibroblastos/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Queratinocitos/metabolismo , Movimiento Celular , Piel/metabolismo , Receptores de Hialuranos/metabolismo , Receptores de Hialuranos/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética
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