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1.
J Ethnopharmacol ; 330: 118264, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38692417

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Optimized New Shengmai Powder (ONSMP) is a sophisticated traditional Chinese medicinal formula renowned for bolstering vital energy, optimizing blood circulation, and mitigating fluid retention. After years of clinical application, ONSMP has shown a significant impact in improving myocardial injury and cardiac function and has a positive effect on treating heart failure. However, many unknowns exist about the molecular biological mechanisms of how ONSMP exerts its therapeutic effects, which require further research and exploration. AIM OF THE STUDY: Exploring the potential molecular biological mechanisms by which ONSMP ameliorates cardiomyocyte apoptosis and ferroptosis in ischemic heart failure (IHF). MATERIALS AND METHODS: First, we constructed a rat model of IHF by inducing acute myocardial infarction through surgery and using echocardiography, organ coefficients, markers of heart failure, antioxidant markers, and histopathological examination to assess the effects of ONSMP on cardiomyocyte apoptosis and ferroptosis in IHF rats. Next, we used bioinformatics analysis techniques to analyze the active components, signaling pathways, and core targets of ONSMP and calculated the interactions between core targets and corresponding elements. Finally, we detected the positive expression of apoptosis and ferroptosis markers and core indicators of signaling pathways by immunohistochemistry; detected the mean fluorescence intensity of core indicators of signaling pathways by immunofluorescence; detected the protein expression of signaling pathways and downstream effector molecules by western blotting; and detected the mRNA levels of p53 and downstream effector molecules by quantitative polymerase chain reaction. RESULTS: ONSMP can activate the Ser83 site of ASK by promoting the phosphorylation of the PI3K/AKT axis, thereby inhibiting the MKK3/6-p38 axis and the MKK4/7-JNK axis signaling to reduce p53 expression, and can also directly target and inhibit the activity of p53, ultimately inhibiting p53-mediated mRNA and protein increases in PUMA, SAT1, PIG3, and TFR1, as well as mRNA and protein decreases in SLC7A11, thereby inhibiting cardiomyocyte apoptosis and ferroptosis, effectively improving cardiac function and ventricular remodeling in IHF rat models. CONCLUSION: ONSMP can inhibit cardiomyocyte apoptosis and ferroptosis through the PI3K/AKT/p53 signaling pathway, delaying the development of IHF.


Asunto(s)
Apoptosis , Combinación de Medicamentos , Medicamentos Herbarios Chinos , Ferroptosis , Insuficiencia Cardíaca , Miocitos Cardíacos , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Proteína p53 Supresora de Tumor , Animales , Ferroptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Apoptosis/efectos de los fármacos , Masculino , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ratas , Fosfatidilinositol 3-Quinasa/metabolismo , Isquemia Miocárdica/tratamiento farmacológico , Modelos Animales de Enfermedad , Polvos
2.
Arch Oral Biol ; 163: 105980, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38692246

RESUMEN

OBJECTIVE: To determine the effect of hyaluronic acid (HA) degradation by hyaluronidase (HYAL) in inhibiting collagen fiber production by rat periodontal ligament cells (rPDLCs). DESIGN: Primary rPDLCs were isolated from the euthanized rats and used for in vitro experiments. The appropriate HYAL concentration was determined through CCK-8 testing for cytotoxicity detection and Alizarin red staining for mineralization detection. RT-qPCR and western blot assays were conducted to assess the effect of HYAL, with or without TGF-ß, on generation of collagen fiber constituents and expression of actin alpha 2, smooth muscle (ACTA2) of rPDLCs. RESULTS: Neither cell proliferation nor mineralization were significantly affected by treatment with 4 U/mL HYAL. HYAL (4 U/mL) alone downregulated type I collagen fiber (Col1a1 and Col1a2) and Acta2 mRNA expression; however, ACTA2 and COL1 protein levels were only downregulated by HYAL treatment after TGF-ß induction. CONCLUSIONS: Treatment of rPDLCs with HYAL can inhibit TGF-ß-induced collagen matrix formation and myofibroblast transformation.


Asunto(s)
Proliferación Celular , Colágeno , Fibroblastos , Hialuronoglucosaminidasa , Miofibroblastos , Ligamento Periodontal , Factor de Crecimiento Transformador beta , Animales , Ligamento Periodontal/citología , Ligamento Periodontal/efectos de los fármacos , Ligamento Periodontal/metabolismo , Hialuronoglucosaminidasa/farmacología , Ratas , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Colágeno/metabolismo , Proliferación Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Ácido Hialurónico/farmacología , Células Cultivadas , Ratas Sprague-Dawley , Actinas/metabolismo , Western Blotting , Técnicas In Vitro , Colágeno Tipo I/metabolismo , Biomarcadores/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Masculino , ARN Mensajero/metabolismo
3.
Physiol Res ; 73(2): 239-251, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38710061

RESUMEN

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.


Asunto(s)
Animales Recién Nacidos , Displasia Broncopulmonar , Modelos Animales de Enfermedad , Estrés Oxidativo , Neumonía , Resveratrol , Animales , Resveratrol/farmacología , Estrés Oxidativo/efectos de los fármacos , Displasia Broncopulmonar/prevención & control , Displasia Broncopulmonar/metabolismo , Neumonía/prevención & control , Neumonía/metabolismo , Neumonía/inducido químicamente , Ratas , Hiperoxia/complicaciones , Hiperoxia/metabolismo , Estilbenos/farmacología , Estilbenos/uso terapéutico , Antioxidantes/farmacología , Hiperreactividad Bronquial/prevención & control , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/inducido químicamente , Ratas Sprague-Dawley , Masculino
4.
Physiol Res ; 73(2): 273-284, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38710057

RESUMEN

Lifestyle intervention encompassing nutrition and physical activity are effective strategies to prevent progressive lipid deposition in the liver. This study aimed to explore the effect of dietary change, and/or high-intensity interval training (HIIT) on hepatic lipid accumulation in high fat diet (HFD)-induced obese rats. We divided lean rats into lean control (LC) or HIIT groups (LH), and obese rats into obese normal chow diet (ND) control (ONC) or HIIT groups (ONH) and obese HFD control (OHC) or HIIT groups (OHH). We found that dietary or HIIT intervention significantly decreased body weight and the risk of dyslipidemia, prevented hepatic lipid accumulation. HIIT significantly improved mitochondrial fatty acid oxidation through upregulating mitochondrial enzyme activities, mitochondrial function and AMPK/PPARalpha/CPT1alpha pathway, as well as inhibiting hepatic de novo lipogenesis in obese HFD rats. These findings indicate that dietary alone or HIIT intervention powerfully improve intrahepatic storage of fat in diet induced obese rats. Keywords: Obesity, Exercise, Diet, Mitochondrial function, Lipid deposition.


Asunto(s)
Dieta Alta en Grasa , Entrenamiento de Intervalos de Alta Intensidad , Metabolismo de los Lípidos , Hígado , Obesidad , Ratas Sprague-Dawley , Animales , Obesidad/metabolismo , Obesidad/terapia , Masculino , Dieta Alta en Grasa/efectos adversos , Ratas , Hígado/metabolismo , Condicionamiento Físico Animal/fisiología
5.
Sci Rep ; 14(1): 10568, 2024 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-38719877

RESUMEN

Early diagnosis and treatment of pre- and early-stage osteoarthritis (OA) is important. However, the cellular and cartilaginous changes occurring during these stages remain unclear. We investigated the histological and immunohistochemical changes over time between pre- and early-stage OA in a rat model of traumatic injury. Thirty-six male rats were divided into two groups, control and OA groups, based on destabilization of the medial meniscus. Histological and immunohistochemical analyses of articular cartilage were performed on days 1, 3, 7, 10, and 14 postoperatively. Cell density of proteins associated with cartilage degradation increased from postoperative day one. On postoperative day three, histological changes, including chondrocyte death, reduced matrix staining, and superficial fibrillation, were observed. Simultaneously, a compensatory increase in matrix staining was observed. The Osteoarthritis Research Society International score increased from postoperative day seven, indicating thinner cartilage. On postoperative day 10, the positive cell density decreased, whereas histological changes progressed with fissuring and matrix loss. The proteoglycan 4-positive cell density increased on postoperative day seven. These findings will help establish an experimental model and clarify the mechanism of the onset and progression of pre- and early-stage traumatic OA.


Asunto(s)
Cartílago Articular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunohistoquímica , Osteoartritis , Animales , Cartílago Articular/patología , Cartílago Articular/metabolismo , Masculino , Ratas , Osteoartritis/patología , Osteoartritis/metabolismo , Condrocitos/metabolismo , Condrocitos/patología , Ratas Sprague-Dawley , Proteoglicanos/metabolismo
6.
BMC Pulm Med ; 24(1): 224, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38720270

RESUMEN

BACKGROUND: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms. METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway. RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and transforming growth factor-ß1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions. CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Estrés Oxidativo , Fibrosis Pulmonar , Dióxido de Silicio , Simvastatina , Animales , Simvastatina/farmacología , Ratas , Masculino , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/prevención & control , Fibrosis Pulmonar/patología , Estrés Oxidativo/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Dióxido de Silicio/toxicidad , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Neumonía/inducido químicamente , Neumonía/prevención & control , Neumonía/tratamiento farmacológico , Neumonía/metabolismo , Neumonía/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Silicosis/tratamiento farmacológico , Silicosis/patología , Silicosis/metabolismo , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Transducción de Señal/efectos de los fármacos , NADPH Oxidasas/metabolismo , Ribonucleótidos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , NADPH Oxidasa 4/metabolismo , Acetofenonas/farmacología , Factor de Crecimiento Transformador beta1/metabolismo
7.
J Transl Med ; 22(1): 437, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38720345

RESUMEN

BACKGROUND: Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. METHODS: FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. RESULTS: The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. CONCLUSION: In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials.


Asunto(s)
Durapatita , Glucólisis , Macrófagos , Fosforilación Oxidativa , Ratas Sprague-Dawley , Animales , Durapatita/química , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Glucólisis/efectos de los fármacos , Ratas , Porcinos , Proliferación Celular/efectos de los fármacos , Masculino , Osteogénesis/efectos de los fármacos , Cráneo/patología , Cráneo/efectos de los fármacos , Ratones , Microambiente Celular/efectos de los fármacos , Células RAW 264.7 , Huesos/metabolismo , Huesos/efectos de los fármacos
8.
Int J Biol Sci ; 20(7): 2370-2387, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38725841

RESUMEN

The pathogenesis of Intervertebral Disc Degeneration (IDD) is complex and multifactorial, with cellular senescence of nucleus pulposus (NP) cells and inflammation playing major roles in the progression of IDD. The stimulator of interferon genes (STING) axis is a key mediator of inflammation during infection, cellular stress, and tissue damage. Here, we present a progressive increase in STING in senescent NP cells with the degradation disorder. The STING degradation function in normal NP cells can prevent IDD. However, the dysfunction of STING degradation through autophagy causes the accumulation and high expression of STING in senescent NP cells as well as inflammation continuous activation together significantly promotes IDD. In senescent NP cells and intervertebral discs (IVDs), we found that STING autophagy degradation was significantly lower than that of normal NP cells and IVDs when STING was activated by 2'3'-cGAMP. Also, the above phenomenon was found in STINGgt/gt, cGAS-/- mice with models of age-induced, lumbar instability-induced IDD as well as found in the rat caudal IVD puncture models. Taken together, we suggested that the promotion of STING autophagy degradation in senescent NP Cells demonstrated a potential therapeutic modality for the treatment of IDD.


Asunto(s)
Autofagia , Senescencia Celular , Degeneración del Disco Intervertebral , Proteínas de la Membrana , Núcleo Pulposo , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Núcleo Pulposo/metabolismo , Animales , Autofagia/fisiología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Senescencia Celular/fisiología , Ratas , Masculino , Ratas Sprague-Dawley , Humanos , Ratones Endogámicos C57BL
9.
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
10.
Sci Rep ; 14(1): 10647, 2024 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724510

RESUMEN

This study aimed to evaluate the safety of Moringa by comparing the effects of different gavage doses of Moringa. The general behavior, body weight, food intake, blood indexes, serum biochemical indexes, and histopathology of rats were used to determine the safety threshold and to provide a reference for the further development and use of Moringa as animal feed. 40 Sprague Dawley rats were selected and given transoral gavage for 28 consecutive days. The T1, T2 and T3 groups were observed for general behavior, body weight, and food intake. Blood and serum biochemical indices were quantified, and histopathology was performed to evaluate the effect and safety of Moringa. The results of the toxicological test showed that (1) Only T1 groups experienced diarrhea. (2) The body weight and food intake of rats in each group were normal compared with the control group. (3) The hematological and serum biochemical indices of rats in the T1 group were significantly different from those of CK but were in the normal range; (4) The results of microscopic examination of the heart, liver, spleen, lung, and kidney of rats in each group were normal, but inflammation occurred in stomach and jejunum of rats in the T1 group, but not in the ileum. The gastrointestinal tract of rats in the T2 and T3 groups were normal. (5) No abnormal death occurred in any of the treatment groups.The results of this study revealed that gavage of Moringa homogenate at a dose of 6 g/kg BW can cause diarrhea in rats. Although there is no pathological effect on weight, food intake, blood and serum biochemical indicators in rats, there are pathological textures in the gastrointestinal tissue caused by diarrhea. Therefore, the safety threshold of Moringa homogenate should be ≤ 3 g/kg BW.


Asunto(s)
Peso Corporal , Moringa oleifera , Ratas Sprague-Dawley , Animales , Moringa oleifera/química , Ratas , Masculino , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Alimentación Animal/análisis , Diarrea/inducido químicamente , Diarrea/veterinaria
11.
Sci Rep ; 14(1): 10650, 2024 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724532

RESUMEN

Avoiding fatigue is a long-standing challenge in both healthy and diseased individuals. Establishing objective standard markers of fatigue is essential to evaluate conditions in spatiotemporally different locations and individuals and identify agents to fight against fatigue. Herein, we introduced a novel method for evaluating fatigue using nervous system markers (including dopamine, adrenaline, and noradrenaline), various cytokine levels (such as interleukin [IL]-1ß, tumor necrosis factor [TNF]-α, IL-10, IL-2, IL-5 and IL-17A), and oxidative stress markers (such as diacron-reactive oxygen metabolites [d-ROMs] and biological antioxidant potential [BAP]) in a rat fatigue model. Using this method, the anti-fatigue effects of methyl dihydrojasmonate (MDJ) and linalool, the fragrance/flavor compounds used in various products, were assessed. Our method evaluated the anti-fatigue effects of the aforementioned compounds based on the changes in levels of the nerves system markers, cytokines, and oxidative stress markers. MDJ exerted more potent anti-fatigue effects than linalool. In conclusion, the reported method could serve as a useful tool for fatigue studies and these compounds may act as effective therapeutic agents for abrogating fatigue symptoms.


Asunto(s)
Monoterpenos Acíclicos , Citocinas , Modelos Animales de Enfermedad , Fatiga , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Monoterpenos Acíclicos/farmacología , Ratas , Fatiga/tratamiento farmacológico , Fatiga/metabolismo , Citocinas/metabolismo , Masculino , Ciclopentanos/farmacología , Antioxidantes/farmacología , Biomarcadores , Monoterpenos/farmacología , Oxilipinas/farmacología , Ratas Sprague-Dawley
12.
BMC Nephrol ; 25(1): 156, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724923

RESUMEN

BACKGROUND: Islet transplantation is an effective treatment for diabetes or even its complications. Aim of this study is to investigate efficacy of biomaterial treated islet transplantation on treating diabetic nephropathy. METHODS: Male rats were randomly divided into 6 groups; Control, diabetic control, diabetic transplanted with untreated islets, with platelet rich plasma treated islets, with pancreatic islets homogenate treated islets, or with these biomaterials combination treated islets. Islets cultured with biomaterials and transplanted to diabetic rats. After 60 days, biochemical, oxidative stress, and stereological parameters were assessed. RESULTS: Serum albumin and BUN concentration, decreased and increased respectively, Oxidative stress of kidney impaired, kidney weight, volume of kidney, cortex, medulla, glomerulus, proximal and distal tubules, collecting ducts, vessels, inflammatory, necrotic and fibrotic tissue in diabetic group increased compared to control group (p < 0.001). In treated groups, especially pancreatic islets homogenate treated islets transplanting animals, there was significant changes in kidney weight, and volume of kidney, proximal and distal tubules, Henle's loop and collecting ducts compared with diabetic group (p = 0.013 to p < 0.001). Combination treated islets animals showed significant increase in vessel volume compared to diabetic group (p < 0.001). Necrotic and fibrotic tissue significantly decreased in islets treated than untreated islet animals, it was higher in pancreatic islets homogenate, and combination treated islets groups (p = 0.001). CONCLUSIONS: Biomaterials treated islets transplanting could improve diabetic nephropathy. Improvement of oxidative stress followed by controlling glucose level, and effects of growth factors presenting in biomaterials can be considered as capable underlying mechanism of ameliorating inflammatory, necrotic and fibrotic tissue volume.


Asunto(s)
Materiales Biocompatibles , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Trasplante de Islotes Pancreáticos , Animales , Masculino , Ratas , Nefropatías Diabéticas/patología , Trasplante de Islotes Pancreáticos/métodos , Materiales Biocompatibles/uso terapéutico , Islotes Pancreáticos/patología , Estrés Oxidativo , Ratas Sprague-Dawley , Resultado del Tratamiento
13.
J Nanobiotechnology ; 22(1): 221, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724958

RESUMEN

Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.


Asunto(s)
Flavonoides , Macrófagos , Estructuras Metalorgánicas , Osteoartritis , Especies Reactivas de Oxígeno , Estructuras Metalorgánicas/química , Osteoartritis/tratamiento farmacológico , Animales , Flavonoides/farmacología , Flavonoides/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , Células RAW 264.7 , Antioxidantes/farmacología , Antioxidantes/química , Sistemas de Liberación de Medicamentos/métodos , Ácido Fólico/química , Masculino , Ratas , Lipopolisacáridos/farmacología , Ratas Sprague-Dawley
14.
BMC Musculoskelet Disord ; 25(1): 331, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38725009

RESUMEN

BACKGROUND: The development of neuropathic pain (NP) is one of the reasons why the pain is difficult to treat, and microglial activation plays an important role in NP. Recently, platelet-rich plasma (PRP) has emerged as a novel therapeutic method for knee osteoarthritis (KOA). However, it's unclarified whether PRP has analgesic effects on NP induced by KOA and the underlying mechanisms unknown. PURPOSE: To observe the analgesic effects of PRP on NP induced by KOA and explore the potential mechanisms of PRP in alleviating NP. METHODS: KOA was induced in male rats with intra-articular injections of monosodium iodoacetate (MIA) on day 0. The rats received PRP or NS (normal saline) treatment at days 15, 17, and 19 after modeling. The Von Frey and Hargreaves tests were applied to assess the pain-related behaviors at different time points. After euthanizing the rats with deep anesthesia at days 28 and 42, the corresponding tissues were taken for subsequent experiments. The expression of activating transcription factor 3 (ATF3) in dorsal root ganglia (DRG) and ionized-calcium-binding adapter molecule-1(Iba-1) in the spinal dorsal horn (SDH) was detected by immunohistochemical staining. In addition, the knee histological assessment was performed by hematoxylin-eosin (HE) staining. RESULTS: The results indicated that injection of MIA induced mechanical allodynia and thermal hyperalgesia, which could be reversed by PRP treatment. PRP downregulated the expression of ATF3 within the DRG and Iba-1 within the SDH. Furthermore, an inhibitory effect on cartilage degeneration was observed in the MIA + PRP group only on day 28. CONCLUSION: These results indicate that PRP intra-articular injection therapy may be a potential therapeutic agent for relieving NP induced by KOA. This effect could be attributed to downregulation of microglial activation and reduction in nerve injury.


Asunto(s)
Regulación hacia Abajo , Microglía , Neuralgia , Osteoartritis de la Rodilla , Plasma Rico en Plaquetas , Ratas Sprague-Dawley , Animales , Masculino , Neuralgia/terapia , Neuralgia/metabolismo , Microglía/metabolismo , Ratas , Osteoartritis de la Rodilla/terapia , Factor de Transcripción Activador 3/metabolismo , Ganglios Espinales/metabolismo , Modelos Animales de Enfermedad , Inyecciones Intraarticulares , Proteínas de Unión al Calcio/metabolismo , Ácido Yodoacético/toxicidad , Proteínas de Microfilamentos
15.
Cells ; 13(9)2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38727268

RESUMEN

Treatment strategies for steatohepatitis are of special interest given the high prevalence of obesity and fatty liver disease worldwide. This study aimed to investigate the potential therapeutic mechanism of L-carnitine (LC) and Ginkgo biloba leaf extract (GB) supplementation in ameliorating the adverse effects of hyperlipidemia and hepatosteatosis induced by a high-cholesterol diet (HCD) in an animal model. The study involved 50 rats divided into five groups, including a control group, a group receiving only an HCD, and three groups receiving an HCD along with either LC (300 mg LC/kg bw), GB (100 mg GB/kg bw), or both. After eight weeks, various parameters related to lipid and glucose metabolism, antioxidant capacity, histopathology, immune reactivity, and liver ultrastructure were measured. LC + GB supplementation reduced serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, glucose, insulin, HOMA-IR, alanine transaminase, and aspartate transaminase levels and increased high-density lipoprotein cholesterol levels compared with those in the HCD group. Additionally, treatment with both supplements improved antioxidant ability and reduced lipid peroxidation. The histological examination confirmed that the combination therapy reduced liver steatosis and fibrosis while also improving the appearance of cell organelles in the ultrastructural hepatocytes. Finally, the immunohistochemical analysis indicated that cotreatment with LC + GB upregulated the immune expression of GLP-1 and ß-Cat in liver sections that were similar to those of the control animals. Mono-treatment with LC or GB alone substantially but not completely protected the liver tissue, while the combined use of LC and GB may be more effective in treating liver damage caused by high cholesterol than either supplement alone by regulating hepatic oxidative stress and the protein expression of GLP-1 and ß-Cat.


Asunto(s)
Carnitina , Suplementos Dietéticos , Dislipidemias , Ginkgo biloba , Hígado , Extractos Vegetales , Animales , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Carnitina/farmacología , Masculino , Ratas , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Dislipidemias/tratamiento farmacológico , Dislipidemias/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/patología , Hígado Graso/metabolismo , Ratas Sprague-Dawley , Metabolismo de los Lípidos/efectos de los fármacos , Antioxidantes/farmacología , Dieta Alta en Grasa/efectos adversos , Extracto de Ginkgo
16.
Cells ; 13(9)2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38727297

RESUMEN

Spinal fusion, a common surgery performed for degenerative lumbar conditions, often uses recombinant human bone morphogenetic protein 2 (rhBMP-2) that is associated with adverse effects. Mesenchymal stromal/stem cells (MSCs) and their extracellular vesicles (EVs), particularly exosomes, have demonstrated efficacy in bone and cartilage repair. However, the efficacy of MSC exosomes in spinal fusion remains to be ascertained. This study investigates the fusion efficacy of MSC exosomes delivered via an absorbable collagen sponge packed in a poly Ɛ-caprolactone tricalcium phosphate (PCL-TCP) scaffold in a rat posterolateral spinal fusion model. Herein, it is shown that a single implantation of exosome-supplemented collagen sponge packed in PCL-TCP scaffold enhanced spinal fusion and improved mechanical stability by inducing bone formation and bridging between the transverse processes, as evidenced by significant improvements in fusion score and rate, bone structural parameters, histology, stiffness, and range of motion. This study demonstrates for the first time that MSC exosomes promote bone formation to enhance spinal fusion and mechanical stability in a rat model, supporting its translational potential for application in spinal fusion.


Asunto(s)
Exosomas , Células Madre Mesenquimatosas , Ratas Sprague-Dawley , Fusión Vertebral , Animales , Exosomas/metabolismo , Exosomas/trasplante , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Fusión Vertebral/métodos , Ratas , Osteogénesis/efectos de los fármacos , Fosfatos de Calcio/farmacología , Masculino , Humanos , Andamios del Tejido/química , Proteína Morfogenética Ósea 2/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos
17.
Cells ; 13(9)2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38727301

RESUMEN

Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, can progress to cirrhosis and increases the risk of liver cancer. Hepatic stellate cells (HSCs) play a pivotal role in fibrosis progression, transitioning from a quiescent to activated state upon liver injury, wherein they proliferate, migrate, and produce ECM. Calcium signaling, involving the inositol 1,4,5-trisphosphate receptor (IP3R), regulates HSC activation. This study investigated the efficacy of a novel IP3R inhibitor, desmethylxestospongin B (dmXeB), in preventing HSC activation. Freshly isolated rat HSCs were activated in vitro in the presence of varying dmXeB concentrations. The dmXeB effectively inhibited HSC proliferation, migration, and expression of fibrosis markers without toxicity to the primary rat hepatocytes or human liver organoids. Furthermore, dmXeB preserved the quiescent phenotype of HSCs marked by retained vitamin A storage. Mechanistically, dmXeB suppressed mitochondrial respiration in activated HSCs while enhancing glycolytic activity. Notably, methyl pyruvate, dimethyl α-ketoglutarate, and nucleoside supplementation all individually restored HSC proliferation despite dmXeB treatment. Overall, dmXeB demonstrates promising anti-fibrotic effects by inhibiting HSC activation via IP3R antagonism without adverse effects on other liver cells. These findings highlight dmXeB as a potential therapeutic agent for liver fibrosis treatment, offering a targeted approach to mitigate liver fibrosis progression and its associated complications.


Asunto(s)
Proliferación Celular , Células Estrelladas Hepáticas , Receptores de Inositol 1,4,5-Trifosfato , Cirrosis Hepática , Animales , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inhibidores , Ratas , Humanos , Proliferación Celular/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Movimiento Celular/efectos de los fármacos
18.
Elife ; 132024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38727716

RESUMEN

PHOX2B is a transcription factor essential for the development of different classes of neurons in the central and peripheral nervous system. Heterozygous mutations in the PHOX2B coding region are responsible for the occurrence of Congenital Central Hypoventilation Syndrome (CCHS), a rare neurological disorder characterised by inadequate chemosensitivity and life-threatening sleep-related hypoventilation. Animal studies suggest that chemoreflex defects are caused in part by the improper development or function of PHOX2B expressing neurons in the retrotrapezoid nucleus (RTN), a central hub for CO2 chemosensitivity. Although the function of PHOX2B in rodents during development is well established, its role in the adult respiratory network remains unknown. In this study, we investigated whether reduction in PHOX2B expression in chemosensitive neuromedin-B (NMB) expressing neurons in the RTN altered respiratory function. Four weeks following local RTN injection of a lentiviral vector expressing the short hairpin RNA (shRNA) targeting Phox2b mRNA, a reduction of PHOX2B expression was observed in Nmb neurons compared to both naive rats and rats injected with the non-target shRNA. PHOX2B knockdown did not affect breathing in room air or under hypoxia, but ventilation was significantly impaired during hypercapnia. PHOX2B knockdown did not alter Nmb expression but it was associated with reduced expression of both Task2 and Gpr4, two CO2/pH sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function.


Asunto(s)
Dióxido de Carbono , Proteínas de Homeodominio , Factores de Transcripción , Animales , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Dióxido de Carbono/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratas , Técnicas de Silenciamiento del Gen , Masculino , Hipoventilación/genética , Hipoventilación/congénito , Hipoventilación/metabolismo , Células Quimiorreceptoras/metabolismo , Ratas Sprague-Dawley , Apnea Central del Sueño/genética , Apnea Central del Sueño/metabolismo , Neuronas/metabolismo , Neuronas/fisiología
19.
PLoS One ; 19(5): e0303235, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38728287

RESUMEN

Excitotoxicity represents the primary cause of neuronal death following spinal cord injury (SCI). While autophagy plays a critical and intricate role in SCI, the specific mechanism underlying the relationship between excitotoxicity and autophagy in SCI has been largely overlooked. In this study, we isolated primary spinal cord neurons from neonatal rats and induced excitotoxic neuronal injury by high concentrations of glutamic acid, mimicking an excitotoxic injury model. Subsequently, we performed transcriptome sequencing. Leveraging machine learning algorithms, including weighted correlation network analysis (WGCNA), random forest analysis (RF), and least absolute shrinkage and selection operator analysis (LASSO), we conducted a comprehensive investigation into key genes associated with spinal cord neuron injury. We also utilized protein-protein interaction network (PPI) analysis to identify pivotal proteins regulating key gene expression and analyzed key genes from public datasets (GSE2599, GSE20907, GSE45006, and GSE174549). Our findings revealed that six genes-Anxa2, S100a10, Ccng1, Timp1, Hspb1, and Lgals3-were significantly upregulated not only in vitro in neurons subjected to excitotoxic injury but also in rats with subacute SCI. Furthermore, Hspb1 and Lgals3 were closely linked to neuronal autophagy induced by excitotoxicity. Our findings contribute to a better understanding of excitotoxicity and autophagy, offering potential targets and a theoretical foundation for SCI diagnosis and treatment.


Asunto(s)
Autofagia , Galectina 3 , Aprendizaje Automático , Neuronas , Animales , Neuronas/metabolismo , Ratas , Galectina 3/metabolismo , Galectina 3/genética , Ratas Sprague-Dawley , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/genética , Mapas de Interacción de Proteínas , Ácido Glutámico/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética
20.
PLoS One ; 19(5): e0302015, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38728332

RESUMEN

Nature has proven to be a treasure resource of bioactive metabolites. In this regard, Tamarix aphylla (F. Tamaricaceae) leaves crude extract was investigated for its gastroprotective effect against indomethacin-induced damage to the gastric mucosa. Additionally, phytochemical investigation of the methanolic extract afforded eight flavonoids' derivatives (1-8). On pharmacology networking study, the isolated compounds identified 123 unique targets where only 45 targets were related to peptic ulcer conditions, these 45 targets include 11 targets specifically correlate to gastric ulcer. The protein-protein interaction defined the PTGS2 gene as one of the highly interacted genes and the complete pharmacology network defined the PTGS2 gene as the most represented gene. The top KEGG signaling pathways according to fold enrichment analysis was the EGFR tyrosine kinase inhibitor resistance pathway. As a result, these findings highlighted the significance of using T. aphylla leaves crude extract as an anti-gastric ulcer candidate, which provides a safer option to chemical antisecretory medicines, which are infamous for their negative side effects. Our findings have illuminated the potent anti-inflammatory and antioxidant effects of T. aphylla, which are likely mediated by suppressing IL-1ß, IL-6, TNF-α, and MAPK signaling pathways, without compromising gastric acidity.


Asunto(s)
Indometacina , Sistema de Señalización de MAP Quinasas , Estrés Oxidativo , Extractos Vegetales , Úlcera Gástrica , Tamaricaceae , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Animales , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Indometacina/efectos adversos , Indometacina/toxicidad , Ratas , Tamaricaceae/química , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Hojas de la Planta/química , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/inducido químicamente , Ratas Sprague-Dawley , Farmacología en Red , Mucosa Gástrica/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Antiulcerosos/farmacología , Antiulcerosos/uso terapéutico , Antiulcerosos/química , Flavonoides/farmacología , Flavonoides/química
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