Explore the vast range of titles available.

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here.

The high mortality rate together with an ever-growing number of annual cases have defined neoplastic disorders as “the real 21st-century disease”. Its dubious distinction also results from conventional therapy failure, which has made cancer an orphan disease. Therefore, innovative and alternative therapeutic strategies are mandatory. The ability to leverage human naturally occurring anti-tumor defenses has always represented a fascinating perspective, and the immuno blockage approval in cancer treatment represents in timeline the latest success. As a multifunctional organ, adipose tissue releases a large amount of adipokines having both carcinogenic and antitumor properties. The negative correlation between serum levels and risk for developing malignancies, as well as the huge number of existing preclinical studies, have identified adiponectin as a potential anticancer adipokine. Nevertheless, its usage in clinical has constantly clashed with the inability to reproduce a mimic synthetic compound. Between 2011 and 2013, two distinct adiponectin receptor agonists were recognized, opening new scenarios even in cancer. Here, we review the first orally active adiponectin receptor agonists AdipoRon, from the discovery to the anticancer evidence. Including our latest findings in osteosarcoma models, we summarize AdipoRon and other existing agonists state-of-art, questioning about the feasibility assessment of this strategy in cancer treatment.

Adiponectin and leptin are two abundant adipokines with different properties but both described such as potent factors regulating angiogenesis. AdipoRon is a small-molecule that, binding to AdipoRs receptors, acts as an adiponectin agonist. Here, we investigated the effects of AdipoRon and leptin on viability, migration and tube formation on a human in vitro model, the human umbilical vein endothelial cells (HUVEC) focusing on the expression of the main endothelial angiogenic factors: hypoxia-inducible factor 1-alpha (HIF-1α), C-X-C motif chemokine ligand 1 (CXCL1), vascular endothelial growth factor A (VEGF-A), matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9). Treatments with VEGF-A were used as positive control. Our data revealed that, at 24 h treatment, proliferation of HUVEC endothelial cells was not influenced by AdipoRon or leptin administration; after 48 h longer exposure time, the viability was negatively influenced by AdipoRon while leptin treatment and the combination of AdipoRon+leptin produced no effects. In addition, AdipoRon induced a significant increase in complete tubular structures together with induction of cell migration while, on the contrary, leptin did not induce tube formation and inhibited cell migration; interestingly, the co-treatment with both AdipoRon and leptin determined a significant decrease of the tubular structures and cell migration indicating that leptin antagonizes AdipoRon effects. Finally, we found that the effects induced by AdipoRon administration are accompanied by an increase in the expression of CXCL1, VEGF-A, MMP-2 and MMP-9. In conclusion, our data sustain the active role of adiponectin and leptin in linking adipose tissue with the vascular endothelium encouraging the further deepening of the role of adipokines in new vessel’s formation, to candidate them as therapeutic targets.

Adiponectin (ApN) is a hormone abundantly secreted by adipocytes and it is known to be tightly linked to the metabolic syndrome. It promotes insulin-sensitizing, fat-burning, and anti-atherosclerotic actions, thereby effectively counteracting several metabolic disorders, including type 2 diabetes, obesity, and cardiovascular diseases. ApN is also known today to possess powerful anti-inflammatory/oxidative and pro-myogenic effects on skeletal muscles exposed to acute or chronic inflammation and injury, mainly through AdipoR1 (ApN specific muscle receptor) and AMP-activated protein kinase (AMPK) pathway, but also via T-cadherin. In this review, we will report all the beneficial and protective properties that ApN can exert, specifically on the skeletal muscle as a target tissue. We will highlight its effects and mechanisms of action, first in healthy skeletal muscle including exercised muscle, and second in diseased muscle from a variety of pathological conditions. In the end, we will go over some of AdipoRs agonists that can be easily produced and administered, and which can greatly mimic ApN. These interesting and newly identified molecules could pave the way towards future therapeutic approaches to potentially prevent or combat not only skeletal muscle disorders but also a plethora of other diseases with sterile inflammation or metabolic dysfunction.

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-1β), 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.

Alzheimer’s disease (AD) remains a leading cause of cognitive decline and mortality worldwide, characterized by neurodegeneration, synaptic deficiencies, and neuroinflammation. Despite advancements in early detection, diagnosis, and treatment, AD presents substantial challenges due to its complex pathology, heterogeneity, and the limited efficacy of current therapies. Consequently, there is a pressing need for novel therapeutic agents to target the multifaceted aspects of AD pathology, enhance current treatments, and minimize adverse effects. AdipoRon, an adiponectin receptor agonist, has garnered interest for its potential neuroprotective effects, including reducing neuroinflammation, improving mitochondrial function, and mitigating tau hyperphosphorylation. This review aimed to evaluate the effects of AdipoRon-based adiponectin replacement therapy against AD, using a comprehensive approach grounded in the PICO framework—Population, Intervention, Comparison, and Outcomes. A total of six studies were reviewed, including in vitro and in vivo investigations examining AdipoRon’s impact on various AD models. These studies involved different cell lines and transgenic mouse models, assessing various outcomes such as cognitive function, neuroinflammation, tau phosphorylation, synaptic deficiencies, and relevant molecular pathways. By synthesizing data from these studies, our review thoroughly explains AdipoRon’s neuroprotective effects, mechanisms of action, and potential as a therapeutic agent for AD. This analysis aims to highlight the current state of knowledge, identify gaps in the research, and suggest directions for future studies and clinical applications.

Aims/hypothesisChronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist.MethodsWild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration.ResultsIn HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1β (51%, p < 0.001) and TGFβ (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-κB-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNFα (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1β, IL-18, IL-6 and IL-10.Conclusions/interpretationAdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. Methods: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. Results: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. Conclusions: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.

The potential benefits of adiponectin replacement therapy extend to numerous human diseases, with current research showing particular interest in its effectiveness against specific cancer forms, especially hormone-related. However, limitations in the pharmacological use of the intact protein have led to a focus on alternative options. AdipoRon is an extensively studied non-peptidic drug candidate for adiponectin replacement therapy. While researchers have explored the efficacy and therapeutic applications of AdipoRon in various disease conditions, their effects against cancer models advanced more, with no review regarding AdipoRon’s efficacy against hormone-related cancers being published. The present systematic review aims to fill this gap. Preclinical evidence was compiled from PubMed, EMBASE, COCHRANE, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the manuscript’s quality assessment was conducted using the Joanna Briggs Institute (JBI) Checklist Critical Appraisal Tool for Systematic Reviews’ Quality. The included nine studies incorporated various cell and animal models of the pancreas, gynaecological system, and osteosarcoma cancers. AdipoRon demonstrated effectiveness against pancreatic cancer by activating p44/42 MAPK, mitochondrial dysfunction, and AMPK-mediated inhibition of ACC1. In gynaecological cancers, it exhibited promising anticancer effects through the activation of AMPK, potential inhibition of mTOR, and modulation of the SET1B/BOD1/AdipoR1 signaling cascade. Against osteosarcoma, AdipoRon worked by perturbing ERK1/2 signaling and reducing p70S6K phosphorylation. AdipoRon shows promise in preclinical studies, but human trials are crucial for clinical safety and effectiveness. Caution is needed due to potential off-target effects, especially in cancer therapy with multi-target approaches. Structural biology and computational methods can help predict these effects.

Adiponectin, a hormone secreted by adipocytes, has anti-inflammatory effects and is involved in various physiological and pathological processes such as obesity, inflammatory diseases, and cartilage diseases. However, the function of adiponectin in intervertebral disc (IVD) degeneration is not well understood. This study aimed to elucidate the effects of AdipoRon, an agonist of adiponectin receptor, on human IVD nucleus pulposus (NP) cells, using a three-dimensional in vitro culturing system. This study also aimed to elucidate the effects of AdipoRon on rat tail IVD tissues using an in vivo puncture-induced IVD degeneration model. Analysis using quantitative polymerase chain reaction demonstrated the downregulation of gene expression of proinflammatory and catabolic factors by interleukin (IL)-1β (10 ng/mL) in human IVD NP cells treated with AdipoRon (2 μM). Furthermore, western blotting showed AdipoRon-induced suppression of p65 phosphorylation (p < 0.01) under IL-1β stimulation in the adenosine monophosphate-activated protein kinase (AMPK) pathway. Intradiscal administration of AdipoRon was effective in alleviating the radiologic height loss induced by annular puncture of rat tail IVD, histomorphological degeneration, production of extracellular matrix catabolic factors, and expression of proinflammatory cytokines. Therefore, AdipoRon could be a new therapeutic candidate for alleviating the early stage of IVD degeneration.