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1.
Int J Mol Sci ; 25(20)2024 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-39457060

RESUMEN

Radiation liver injury is a common complication of hepatocellular carcinoma radiotherapy. It is mainly caused by irreversible damage to the DNA of hepatocellular cells directly by radiation, which seriously interferes with metabolism and causes cell death. AdipoRon can maintain lipid metabolism and stabilize blood sugar by activating adiponectin receptor 1 (AdipoR1). However, the role of AdipoRon/AdipoR1 in the regulation of ionizing radiation (IR)-induced mitochondrial damage remains unclear. In this study, we aimed to elucidate the roles of AdipoRon/AdipoR1 in IR-induced mitochondrial damage in normal hepatocyte cells. We found that AdipoRon treatment rescued IR-induced liver damage in mice and mitochondrial damage in normal hepatocytes in vivo and in vitro. AdipoR1 deficiency exacerbated IR-induced oxidative stress, mitochondrial dynamics, and biogenesis disorder. Mechanistically, the absence of AdipoR1 inhibits the activity of adenosine monophosphate-activated protein kinase α (AMPKα), subsequently leading to disrupted mitochondrial dynamics by decreasing mitofusin (MFN) and increasing dynamin-related protein 1 (DRP1) protein expression. It also controls mitochondrial biogenesis by suppressing the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) and transcription factor A (TFAM) signaling pathway, ultimately resulting in impaired mitochondrial function. To sum up, AdipoRon/AdipoR1 maintain mitochondrial function by regulating mitochondrial dynamics and biogenesis through the AdipoR1-AMPKα signaling pathway. This study reveals the significant role of AdipoR1 in regulating IR-induced mitochondrial damage in hepatocytes and offers a novel approach to protecting against damage caused by IR.


Asunto(s)
Hepatocitos , Radiación Ionizante , Receptores de Adiponectina , Animales , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/genética , Ratones , Estrés Oxidativo/efectos de la radiación , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Dinámicas Mitocondriales/efectos de la radiación , Piperidinas/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Masculino , Ratones Endogámicos C57BL , Transducción de Señal , Hígado/metabolismo , Hígado/efectos de la radiación , Hígado/patología , Hígado/efectos de los fármacos
2.
Neuropharmacology ; 262: 110180, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39393589

RESUMEN

While motor symptoms are the most well-known manifestation of Parkinson's disease (PD), patients may also suffer from non-motor signs like cognitive impairments. The adiponectin receptor agonist AdipoRon (Adipo) has shown neuroprotective effects in preclinical studies. The objective of this study was to determine the potential benefits of chronic intranasal treatment of Adipo on motor function and cognitive performance in a hemiparkinsonian rat model caused by injecting 6-hydroxydopamine (6-OHDA) into the left forebrain bundle. After one week, PD rats were given either a vehicle or one of three dosages of Adipo (0.1, 1, and 10 µg) or levodopa (10 mg/kg orally) daily for 21 days. Recognition and spatial memory were determined using the novel object recognition test (NORT) and the Barnes maze test, respectively. The hippocampal tissues of the animals were harvested to examine oxidative stress status as well as the protein expressions of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95). In hemiparkinsonian rats, motor impairments, recognition memory, and spatial memory were all improved by chronic intranasal Adipo at 1 and 10 µg. Furthermore, we found that unilateral 6-OHDA injection elevated hippocampal oxidative stress (ROS) while concurrently reducing total antioxidant capacity (TAC), BDNF, PSD-95, and antioxidant enzymes (SOD, GPx). However, Adipo 10 µg significantly reduced these biochemical alterations in the hippocampus of 6-OHDA-lesioned rats. Chronic intranasal Adipo ameliorated spatial and recognition memory deterioration in hemiparkinsonian rats, presumably by increasing hippocampal synaptic protein levels, reducing oxidative stress, and increasing BDNF.

3.
Br Poult Sci ; : 1-14, 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39249992

RESUMEN

1. This study evaluated the effects and mechanisms of action of the peptide gADP3 on hepatic inflammatory injury induced by lipopolysaccharide (LPS).2. Hepatic inflammatory injury was induced in geese by intraperitoneal injection of LPS and gADP3, and the adiponectin receptor agonist AdipoRon (positive control) was used for potential amelioration. Serum inflammatory factor levels, liver function-related biochemical indicators and oxidative stress-related biochemical parameters in the liver tissues were determined. The expression levels of adiponectin and its receptors, inflammation and oxidative stress-related genes and key signalling molecules involved in adiponectin, inflammation and oxidative stress signalling pathways in liver tissues were detected.3. The peptide gADP3 alleviated inflammatory cell infiltration and hepatic inflammatory changes, reversed the decrease in serum albumin (ALB), total protein (TP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) content or activity induced by LPS and increased the activity of the antioxidant enzymes CAT (catalase), SOD (superoxide dismutase) and GSH-Px (glutathione peroxidase).4. The peptide gADP3 upregulated the expression of antioxidant enzyme-related genes GCLC, HO-1 and NQO1 in liver tissues, decreased the levels of inflammatory factors like TNF-α, IL-1ß, IL-6, IFN-γ and TGF-ß and reduced mRNA expression levels of inflammatory-related genes TNF-α, IL-1ß, iNOS and TGF-ß. Additionally, it increased the mRNA and protein expression levels of adiponectin and its receptors, as well as key molecules in the adiponectin signalling pathway like AMPK and PPARα. In addition, gADP3 reversed the changes in mRNA or protein expression of inflammatory and oxidative stress signalling pathway-related genes P38MAPK, NF-κBP65, TLR4 and Nrf2 in liver tissues caused by LPS treatment.5. In conclusion, goose-derived adiponectin peptide gADP3, similar to the adiponectin receptor agonist AdipoRon, attenuated LPS-induced hepatic inflammatory injury in geese.

4.
Artículo en Inglés | MEDLINE | ID: mdl-39292249

RESUMEN

Granulosa cells, crucial components of ovarian follicles, play a fundamental role in follicle development, hormone production, and overall reproductive health. These cells are integral to steroidogenesis, including the synthesis and secretion of key hormones such as estrogen and progesterone. Dysregulation of granulosa cells can lead to reproductive disorders, including polycystic ovary syndrome and infertility. This systematic review provides a comprehensive evaluation of AdipoRon, a synthetic agonist of adiponectin receptors AdipoR1 and AdipoR2, and its effects on ovarian function, with a particular focus on granulosa cells. Due to the absence of clinical trials, the review centers on preclinical studies to explore AdipoRon's potential therapeutic benefits and to suggest future research directions. A detailed literature search across databases such as PubMed, Scopus, Web of Science, Embase, and Google Scholar was conducted using terms related to AdipoRon and ovarian function. The review encompasses four preclinical studies involving various models: primary granulosa cells from rats, laying hens' granulosa cells, human luteinized granulosa cells, and chicken ovary follicles. Findings indicate that AdipoRon enhances glucose absorption in rat granulosa cells by stimulating glucose transporter 1 expression, modulates steroid hormone secretion in laying hens' granulosa cells, and affects cell proliferation and steroidogenesis in human luteinized granulosa cells. Additionally, AdipoRon, in conjunction with recombinant chicken adiponectin, influences ovarian follicular cell proliferation and steroidogenesis in chicken ovary follicles. This review highlights the need for further investigation into AdipoRon's long-term effects and its potential applications in reproductive health and therapy.

5.
Behav Brain Res ; 472: 115174, 2024 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-39098398

RESUMEN

Sepsis-associated encephalopathy (SAE) is a common and severe clinical feature of sepsis; however, therapeutic approaches are limited because of the unclear pathogenesis. Adiponectin receptor agonist (AdipoRon) is a small-molecule agonist of the adiponectin receptor that exhibits anti-inflammatory and memory-improving effects in various diseases. In the present study, we established lipopolysaccharide (LPS)-induced mice models of SAE and found that Adiponectin receptor 1 (AdipoR1) was significantly decreased in the hippocampus. Administration of AdipoRon improves memory impairment, mitigates synaptic damage, and alleviates neuronal death. Furthermore, AdipoRon reduces the number of microglia. More importantly, AdipoRon promotes the phosphorylation of adenosine 5 '-monophosphate activated protein kinase (pAMPK). In conclusion, AdipoRon is protective against SAE-induced memory decline and brain injury in the SAE models via activating the hippocampal adenosine 5 '-monophosphate activated protein kinase (AMPK).


Asunto(s)
Modelos Animales de Enfermedad , Hipocampo , Trastornos de la Memoria , Receptores de Adiponectina , Animales , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Lipopolisacáridos/farmacología , Trastornos de la Memoria/tratamiento farmacológico , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Piperidinas/farmacología , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/tratamiento farmacológico , Encefalopatía Asociada a la Sepsis/metabolismo
6.
Neurochem Res ; 49(11): 3030-3042, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39096412

RESUMEN

Depression and anxiety are prevalent neuropsychiatric conditions among patients with Parkinson's disease (PD), which may manifest prior to motor symptoms. As levodopa, a prominent treatment for PD motor symptoms, provides few benefits for mood-related abnormalities, tackling non-motor symptoms is particularly important. AdipoRon (Ad), an adiponectin agonist, has demonstrated neuroprotective effects by suppressing neuroinflammatory responses and activating the AMPK/Sirt-1 signaling pathway. This study looked at the potential advantages and underlying mechanisms of intranasal Ad in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). We found that Ad at doses of 1 and 10 µg for 21 days exhibited anxiolytic- and antidepressant effects in the open field (OF) test, elevated plus maze (EPM), sucrose splash test, and forced swimming test in a PD model caused by a unilateral 6-OHDA injection into the medial forebrain bundle (MFB). The Ad also lowered the levels of corticosterone in the blood, decreased inflammasome components (NLRP3, caspase 1, and IL-1ß), and increased Sirt-1 protein levels in the prefrontal cortex (PFC) of PD rats. We conclude that Ad ameliorates anxious and depressive-like behaviors in the PD rat model through stimulating the AMPK/Sirt-1 signaling and blocking the NLRP3 inflammasome pathways in the PFC.


Asunto(s)
Administración Intranasal , Ansiedad , Depresión , Oxidopamina , Ratas Sprague-Dawley , Animales , Masculino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ratas , Ansiolíticos/uso terapéutico , Ansiolíticos/administración & dosificación , Ansiolíticos/farmacología , Piperidinas/uso terapéutico , Piperidinas/farmacología , Piperidinas/administración & dosificación , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Sirtuina 1/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo
7.
Cancers (Basel) ; 16(15)2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39123363

RESUMEN

Despite the countless therapeutic advances achieved over the years, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. To this primacy contribute both non-oncogene addicted and advanced NSCLCs, in which conventional therapies are only partially effective. The adiponectin receptor agonist AdipoRon has revealed antiproliferative action in different cancers, including osteosarcoma and pancreatic cancer. Herein, we investigated its potential anticancer role in NSCLC for the first time. We proved that AdipoRon strongly inhibits viability, growth and colony formation in H1299 and A549 NSCLC cells, mainly through a slowdown in cell cycle progression. Along with the biological behaviors, a metabolic switching was observed after AdipoRon administration in NSCLC cells, consisting of higher glucose consumption and lactate accumulation. Remarkably, both 2-Deoxy Glucose and Oxamate glycolytic-interfering agents greatly enhanced AdipoRon's antiproliferative features. As a master regulator of cell metabolism, AMP-activated protein kinase (AMPK) was activated by AdipoRon. Notably, the ablation of AdipoRon-induced AMPK phosphorylation by Compound-C significantly counteracted its effectiveness. However, the engagement of other pathways should be investigated afterwards. With a focus on NSCLC, our findings further support the ability of AdipoRon in acting as an anticancer molecule, driving its endorsement as a future candidate in NSCLC therapy.

8.
Oral Dis ; 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39177011

RESUMEN

OBJECTIVE: Estimate the impact of Adiponectin receptors agonist (AdipoRon) on dental implant osseointegration in alveolar bone and explore the possible mechanism between saliva microbiota and AdipoRon in diabetic mice. MATERIALS AND METHODS: Sixty C57BL/6 mice (male, 8 weeks old) were divided randomly into four groups according to different doses of AdipoRon: normoglycemic control group; DM control group; DM with a low dose of AdipoRon (5 mg/kg/day); and DM with a high dose of AdipoRon (50 mg/kg/day). Then, dental implants were placed in the palatal root socket in the first molar extraction mouse model. Micro-computed tomography, histology examination, immunohistochemical staining, and oral microbiota were explored to evaluate implant osseointegration. RESULTS: AdipoRon treatment at 50 mg/kg markedly promoted dental implant osseointegration in diabetic mice, but AdipoRon treatment at 5 mg/kg was not effective. Moreover, distinct differences in the oral microbiota composition were shown between the diabetic mice and diabetic mice treated with AdipoRon at 50 mg/kg. CONCLUSION: AdipoRon treatment at 50 mg/kg in diabetic mice could significantly increase dental implant osseointegration. The salivary microbiota might participate in the accelerated osseointegration progress of dental implants in AdipoRon treatment.

9.
Int Immunopharmacol ; 141: 113011, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-39213872

RESUMEN

Depression is a serious mental disorder that threatens patients' physical and mental health worldwide. The activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is essential for microglia-mediated neuroinflammation and neuronal damage in depression. Numerous pathophysiological factors, such as mitochondrial dysfunction and impaired mitophagy, have an essential role in activating the NLRP3 inflammasome. AdipoRon is a potent adiponectin receptor agonist; however, its antidepressant effects have not been thoroughly investigated. In this study, we found that AdipoRon ameliorated depression-like behavior and neuronal damage induced by chronic unpredictable mild stress (CUMS). Further research demonstrated that AdipoRon inhibited the activation of the NLRP3 inflammasome and protected hippocampal neurons from microglial cytotoxicity by promoting mitophagy, increasing the clearance of damaged mitochondria, and reducing mtROS accumulation. Importantly, inhibition of mitophagy attenuated the antidepressant and neuroprotective effects of AdipoRon. Overall, these findings indicate that AdipoRon alleviates depression by inhibiting NLRP3 inflammasome activation in microglia via improving mitophagy.


Asunto(s)
Antidepresivos , Depresión , Inflamasomas , Ratones Endogámicos C57BL , Microglía , Mitofagia , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Mitofagia/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Inflamasomas/metabolismo , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/metabolismo , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Animales de Enfermedad , Humanos , Piperidinas/farmacología , Piperidinas/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/inmunología , Células Cultivadas
10.
Curr Med Chem ; 2024 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-39206478

RESUMEN

INTRODUCTION: Adiponectin replacement therapy shows promising outcomes in various diseases, especially for bone-related disorders. Challenges in using the complete protein have led to alternative approaches, with AdipoRon and AdipoAI emerging as extensively researched drug candidates. Their influence on models of bone-related disorders has progressed considerably but there has been no review of their effectiveness in modulating bone metabolism and repair. METHOD: This systematic review seeks to address this knowledge gap. Based on preclinical evidence from PubMed, EMBASE, and COCHRANE, ten studies were included following PRISMA guidelines. The JBI Checklist Critical Appraisal Tool assessed the quality of this systematic review. The studies encompassed various animal models, addressing bone defects, osseointegration, diabetes-associated periodontitis, fracture repair, growth retardation, and diabetes-associated peri-implantitis. RESULT: AdipoRon and AdipoAI demonstrated effectiveness in modulating bone metabolism and repair through diverse pathways, including the activation of AdipoR1/APPL1, inhibition of F-actin ring formation, suppression of IκB-α phosphorylation, p65 nuclear translocation and Wnt5a-Ror2 signaling pathway, reduction of CCL2 secretion and expression, regulation of autophagy via LC3A/B expression, modulation of SDF-1 production, activation of the ERK-1/2 signaling pathway, modulation of bone integration-related markers and osteokines such as RANKL, BMP-2, OPG, OPN, and Runx2, inhibition of RANKL in osteoblasts, and inhibition of podosome formation via the activation of AMPK. CONCLUSION: While preclinical studies show promise, human trials are crucial to confirm the clinical safety and effectiveness of AdipoRon and AdipoAI. Caution is necessary due to potential off-target effects, especially in bone therapy with multi-target approaches. Structural biology and computational methods can help predict and understand these effects.

11.
bioRxiv ; 2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-38979340

RESUMEN

Although innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus, potentially damaging inflammation must be controlled. Adiponectin (APN) is an adipokine produced mainly in adipose tissue that exerts anti-inflammatory effects in adipose-distal tissues such as the lung. We observed 100% mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN-/- AMs exhibited an inflammatory/M1 phenotype that was associated with decreased fungal killing. Pharmacological stimulation of AMs with AdipoR agonist AdipoRon partially rescued deficient killing in APN-/- AMs that was dependent on both receptors. Finally, APN-enhanced fungal killing was associated with increased activation of the non-canonical LC3 pathway of autophagy. Thus, our study identifies a novel role for APN in LC3-mediated killing of A. fumigatus.

12.
Int Immunopharmacol ; 136: 112395, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-38833845

RESUMEN

Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11th day till the 16th and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5'AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Asma , Modelos Animales de Enfermedad , Ovalbúmina , Receptores de Adiponectina , Transducción de Señal , Animales , Asma/tratamiento farmacológico , Asma/inmunología , Asma/inducido químicamente , Asma/metabolismo , Ratones , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Ovalbúmina/inmunología , Masculino , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Citocinas/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Estrés Oxidativo/efectos de los fármacos , Adiponectina , Antiasmáticos/uso terapéutico , Antiasmáticos/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Inmunoglobulina E/sangre , Humanos , Dexametasona/uso terapéutico , Dexametasona/farmacología , Piperidinas
13.
Neurochem Res ; 49(8): 2075-2086, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38819697

RESUMEN

There is growing evidence showing that adiponectin (APN) can improve Alzheimer's disease(AD)-like pathological changes by improving insulin resistance. However, the role of AdipoRon (an Adiponectin receptor agonist) on synaptic plasticity and cognitive dysfunction in the early stages of type 2 diabetes mellitus(T2DM) remains unknown. In this study, we investigated the neuroprotective effect and the molecular mechanism underlying the effect of AdipoRon in T2DM mice. We found that AdipoRon significantly restored the cognitive deficits in T2DM mice, including shorter escape latency, more crossing times, increased distances, and percentage of time in the target quadrant. In addition, AdipoRon treatment up-regulated synaptic proteins (PSD95, SYN, GAP43, and SYP), increased the number of hippocampal synapses and attenuated synaptic damage, including the length, the number and the density of dendritic spines in CA1 and DG regions. Furthermore, AdipoRon attenuated Tau phosphorylation at multiple AD-related sites (p-tau 205, p-tau 396, p-tau 404) by promoting AdipoR expression and activating the AMPK/mTOR pathway. Our data suggests that AdipoRon exerts neuroprotective effects on the T2DM mice, which may be mediated by the activation of the AdipoR/AMPK/mTOR signaling pathway.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Receptores de Adiponectina , Sinapsis , Serina-Treonina Quinasas TOR , Proteínas tau , Animales , Receptores de Adiponectina/metabolismo , Proteínas tau/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Masculino , Fosforilación/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo
14.
Br J Pharmacol ; 181(17): 3039-3063, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38679474

RESUMEN

BACKGROUND AND PURPOSE: Amyloid-ß (Aß) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aß. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aß and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aß clearance remain unclear. EXPERIMENTAL APPROACH: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process. KEY RESULTS: AdipoRon promotes Aß clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aß deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD. CONCLUSION AND IMPLICATIONS: AdipoRon promotes the clearance of Aß by enhancing autophagy through the AdipoR1/AMPK-dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Autofagia , Ratones Transgénicos , Sirtuina 1 , Sirtuina 1/metabolismo , Sirtuina 1/antagonistas & inhibidores , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Animales , Autofagia/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Ratones , Piperidinas/farmacología , Humanos , Línea Celular , Ratones Endogámicos C57BL , Receptores de Adiponectina/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Masculino
15.
Curr Med Chem ; 31(28): 4534-4548, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38361349

RESUMEN

BACKGROUND: Cholangiocarcinoma (CCA) has a poor prognosis and only limited palliative treatment options. The deficiency of adiponectin and adenosine monophosphate-activated protein kinase (AMPK) signaling was reported in several malignancies, but the alteration of these proteins in CCA is still unclear. OBJECTIVES: This study aimed to assess the role of adiponectin and AMPK signaling in CCA. Furthermore, AdipoRon, a novel adiponectin receptor (AdipoR) agonist, was evaluated in vitro and in vivo as a new anti-tumor therapy for CCA. METHODS: The expression of AdipoR1 and p-AMPKα in human tissue microarrays (TMAs) was evaluated by immunohistochemistry staining (IHC). The effect of 2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide (AdipoRon) was investigated in vitro with proliferation, crystal violet, migration, invasion, colony formation, senescence, cell cycle and apoptosis assays and in vivo using a CCA engineered mouse model (AlbCre/LSL-KRASG12D/p53L/L). RT-qPCR and western blot methods were applied to study molecular alterations in murine tissues. RESULTS: AdipoR1 and p-AMPKα were impaired in human CCA tissues, compared to adjacent non-tumor tissue. There was a positive correlation between the AdipoR1 and p-AMPKα levels in CCA tissues. Treatment with AdipoRon inhibited proliferation, migration, invasion and colony formation and induced apoptosis in a time- and dose-dependent manner in vitro (p<0.05). In addition, AdipoRon reduced the number of CCA and tumor volume, prolonged survival, and decreased metastasis and ascites in the treated group compared to the control group (p<0.05). CONCLUSIONS: AdipoR1 and p-AMPKα are impaired in CCA tissues, and AdipoRon effectively inhibits CCA in vitro and in vivo. Thus, AdipoRon may be considered as a potential anti-tumor therapy in CCA.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Apoptosis , Neoplasias de los Conductos Biliares , Proliferación Celular , Colangiocarcinoma , Receptores de Adiponectina , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/agonistas , Humanos , Animales , Proteínas Quinasas Activadas por AMP/metabolismo , Ratones , Proliferación Celular/efectos de los fármacos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Apoptosis/efectos de los fármacos , Piperidinas/farmacología , Piperidinas/química , Piperidinas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales
16.
J Adv Res ; 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38382593

RESUMEN

INTRODUCTION: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis. OBJECTIVES: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model. METHODS: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods. RESULTS: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively. CONCLUSIONS: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

17.
J Neural Eng ; 21(1)2024 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-38359460

RESUMEN

Objective.Abundant lipid-laden macrophages are found at the injury site after spinal cord injury (SCI). These cells have been suggested to be pro-inflammatory and neurotoxic. AdipoRon, an adiponectin receptor agonist, has been shown to promote myelin lipid efflux from mouse macrophage foam cells. While it is an attractive therapeutic strategy, systemic administration of AdipoRon is likely to exert off-target effects. In addition, the pathophysiology after SCI in mice is different from that in humans, whereas rat and human SCI share similar functional and histological outcomes. In this study, we evaluated the effects of AdipoRon on rat macrophage foam cells and developed a drug delivery system capable of providing sustained local release of AdipoRon to the injured spinal cord.Approach.Rat macrophages were treated with myelin debris to generate anin vitromodel of SCI foam cells, and the effects of AdipoRon treatment on myelin uptake and efflux were studied. AdipoRon was then loaded into and released from microparticles made from dextran sulfate and fibrinogen for sustained release.Main results.AdipoRon treatment not only significantly promotes efflux of metabolized myelin lipids, but also inhibits uptake of myelin debris. Myelin debris alone does not appear to be inflammatory, but myelin debris treatment potentiates inflammation when administered along with pro-inflammatory lipopolysaccharide (LPS) and interferon-γ. AdipoRon significantly attenuated myelin lipid-induced potentiation of inflammation. Bioactive AdipoRon can be released in therapeutic doses from microparticles.Significance.These data suggest that AdipoRon is a promising therapeutic capable of reducing lipid accumulation via targeting both myelin lipid uptake and efflux, which potentially addresses chronic inflammation following SCI. Furthermore, we developed microparticle-based drug delivery systems for local delivery of AdipoRon to avoid deleterious side effects. This is the first study to release AdipoRon from drug delivery systems designed to reduce lipid accumulation and inflammation in reactive macrophages after SCI.


Asunto(s)
Vaina de Mielina , Piperidinas , Traumatismos de la Médula Espinal , Ratas , Ratones , Humanos , Animales , Macrófagos/metabolismo , Macrófagos/patología , Inflamación/patología , Lípidos/farmacología
18.
J Transl Med ; 22(1): 2, 2024 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-38166990

RESUMEN

BACKGROUND: Diabetes mellitus (DM) is a progressive disease that involves multiple organs due to increased blood glucose, and diabetic retinopathy (DR) is the main complication of DM in the eyes and causes irreversible vision loss. In the pathogenesis of diabetic vascular disease, oxidative stress caused by hyperglycemia plays an important role in Müller cell impairment. In recent years, AdipoRon, an adiponectin analog that demonstrated important physiological functions in obesity, diabetes, inflammation, and cardiovascular diseases, demonstrated cellular protection from apoptosis and reduced inflammatory damage through a receptor-dependent mechanism. Here, we investigated how AdipoRon reduced oxidative stress and apoptosis in Müller glia in a high glucose environment. RESULTS: By binding to adiponectin receptor 1 on Müller glia, AdipoRon activated 5' adenosine monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase phosphorylation downstream, thereby alleviating oxidative stress and eventual apoptosis of cells and tissues. Transcriptome sequencing revealed that AdipoRon promoted the synthesis and expression of early growth response factor 4 (EGR4) and inhibited the cellular protective effects of AdipoRon in a high-glucose environment by reducing the expression of EGR4. This indicated that AdipoRon played a protective role through the EGR4 and classical AMPK pathways. CONCLUSIONS: This provides a new target for the early treatment of DR.


Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Proteínas Quinasas Activadas por AMP/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismo , Glucosa , Fosforilación , Receptores de Adiponectina/metabolismo , Animales , Ratones
19.
Cell Biochem Biophys ; 82(2): 687-695, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38243102

RESUMEN

Hepatocellular carcinoma (HCC) is the second lethal cancer. Short overall survival, low five-year survival rate, and unimproved treatment efficacy urge the need to improve HCC prognosis. Adiponectin is key protector against cancer and hepatic abnormalities. Hypoadiponectinemia occurs in and promotes carcinogenesis and hepatic diseases. Adiponectin reactivation by different methods showed impressive effect against cancer and hepatic diseases. Recently, AdipoRon, an adiponectin receptor agonist, can interact with both Adiponectin receptors. AdipoRon showed promising anti-cancer effect in some cancers, but no study on HCC yet. The in vitro effect of AdipoRon on HCC was investigated by cell viability, migration, invasion, colony formation and apoptosis assays. The signalling alteration was determined by RT-qPCR and Western blot. The effect of treatment was interpreted by comparison between treatments and control. The difference between two cell lines was relatively compared. Our results showed significant in vitro anti-cancer effect of AdipoRon via AMPK- and dose-dependent manner. Huh7 cells showed a lower level of AdipoR1/2 and a superior proliferation and aggressiveness, compared to Hep3B. In addition, Huh7 cells were more sensitive to AdipoRon treatment (lower IC50, less cell growth, migration, invasion and colonies upon AdipoRon treatment) than Hep3B cells. In conclusion, AdipoRon effectively inhibited HCC growth and invasiveness in vitro. The deficient expression of adiponectin receptors affects efficacy of AdipoRon and aggressiveness of HCC cells.


Asunto(s)
Apoptosis , Carcinoma Hepatocelular , Movimiento Celular , Proliferación Celular , Neoplasias Hepáticas , Receptores de Adiponectina , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/agonistas , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Transducción de Señal/efectos de los fármacos
20.
Pharmacol Rep ; 76(1): 112-126, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38236555

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of death globally. Multiple factors may contribute to the pathogenesis of CRC, including the abnormalities in the functioning of the endogenous opioid system (EOS) or adiponectin-related signaling. The aim of our study was to evaluate if differences in the expression of opioid receptors (ORs) influence the development of CRC and if modulation of adiponectin receptors using AdipoRon, a selective AdipoR1 receptor agonist, affects colorectal carcinogenesis. METHODS: Naltrexone, an opioid receptor antagonist, was injected intraperitoneally every second day for 2 weeks, at the dose of 1 mg/kg in healthy Balb/C mice to induce changes in ORs expression. CRC was induced by a single intraperitoneal injection of azoxymethane (AOM) and the addition of dextran sodium sulfate (DSS) into drinking water in three-week cycles. The development of CRC was assessed using macro- and microscopic scoring and molecular analysis (RT qPCR, ELISA) after 14 weeks. RESULTS: Naltrexone significantly increased the mRNA expression of Oprm1, Oprd1, and Oprk1 in the mouse colon and in the brain (non-significantly). The pretreatment of mice with naltrexone aggravated the course of CRC (as indicated by tumor area, colon thickness, and spleen weight). The level of circulatory adiponectin was lowered in mice with CRC and increased in the colon as compared with healthy mice. The ß-endorphin level was increased in the plasma of mice with CRC and decreased in the colon as compared to healthy mice. AdipoRon, AdipoR1 agonist, worsened the CRC development, and pretreatment with naltrexone enhanced this negative effect in mice. CRC did not affect the expression of the Adipor1 gene, but the Adipor1 level was increased in mice pretreated with naltrexone (AOM/DSS and healthy mice). AdipoRon did not influence the expression of opioid receptors at the mRNA level in the colon of mice with CRC. The mRNA expression of Ptgs2, Il6, Nos2, Il1b, Il18, Gsdmd, and Rela was increased in mice with CRC as compared to the healthy colon. AdipoRon significantly decreased mRNA expression of Ptgs2, Il6, Il1b, and Il18 as compared to CRC mice. CONCLUSION: EOS and adiponectin-related signaling may play a role in the pathogenesis of CRC and these systems may present some additivity during carcinogenesis.


Asunto(s)
Neoplasias Asociadas a Colitis , Colitis , Neoplasias Colorrectales , Ratones , Animales , Interleucina-18 , Analgésicos Opioides/efectos adversos , Interleucina-6 , Adipoquinas , Naltrexona/farmacología , Adiponectina/efectos adversos , Ciclooxigenasa 2 , Carcinogénesis , Azoximetano/toxicidad , Modelos Animales de Enfermedad , Receptores Opioides/genética , ARN Mensajero , Sulfato de Dextran , Neoplasias Colorrectales/genética , Ratones Endogámicos C57BL , Colitis/inducido químicamente
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