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Background and Objectives: Obesity negatively impacts on the response of asthma patients to inhaled corticosteroids. The mechanisms underlying this impact are unknown. Objective: To demonstrate that the poor response to inhaled corticosteroids in obese asthma patients is associated with impaired anti-inflammatory activity of corticosteroids and vitamin D deficiency, both of which are improved by weight loss., Methods: The study population comprised 23 obese asthma patients (OA) (18 females; median (IQR) age 56 [51-59] years), 14 nonobese asthma patients (NOA) (11 females; 53 [43-60] years), 15 obese patients (OP) (13 females; 47 [45-60] years), and 19 healthy controls (HC) (14 females; 43 [34-56] years). Ten OA and 11 OP were evaluated at baseline (V1) and 6 months after bariatric surgery (V2). Corticosteroid response was measured using dexamethasone-induced inhibition of peripheral blood mononuclear cell (PBMC) proliferation. Lung function and serum levels of leptin, adiponectin, and vitamin D were measured at V1 and V2., Results: We found a reduced response to dexamethasone in PBMCs of OP and OA with respect to NOA and HC; this inversely correlated with the adiponectin/leptin ratio and vitamin D levels. Bariatric surgery improved corticosteroid responses in OP and OA and normalized the adiponectin/leptin ratio and vitamin D levels. Exposure of PBMCs to vitamin D potentiated the antiproliferative effects of corticosteroids. Dexamethasone and vitamin D induced similar MKP1 expression in OP and OA., Conclusion: The efficacy of weight loss to improve symptoms and lung function in OA may be due, at least in part, to the recovered anti-inflammatory effects of corticosteroids. Vitamin D deficiency may contribute to corticosteroid hyporesponsiveness in OA.

Background: In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression., Methods: PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks., Results: Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks., Discussion: After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity has become a worldwide public health problem and continues to be one of the leading causes of chronic diseases. Obesity treatment is challenged by large drug doses, high administration frequencies and severe side effects. Herein, we propose an antiobesity strategy through the local administration of Ha R Chr fiber rods loaded with chrysin and grafted with hyaluronic acid and Ats F Rk fiber fragments loaded with raspberry ketone and grafted with adipocyte target sequences (ATSs). The hyaluronic acid grafts double the uptake levels of Ha R Chr by M1 macrophages to promote phenotype transformation from M1 to M2 through upregulating CD206 and downregulating CD86 expressions. ATS-mediated targeting and sustained release of raspberry ketone from Ats F Rk increase the secretion of glycerol and adiponectin, and Oil red O staining shows much fewer lipid droplets in adipocytes. The combination treatment with Ats F Rk and the conditioned media from Ha R Chr -treated macrophages elevates adiponectin levels, suggesting that M2 macrophages may secrete anti-inflammatory factors to stimulate adipocytes to produce adiponectin. Diet-induced obese mice showed significant weight losses of inguinal (49.7%) and epididymal (32.5%) adipose tissues after Ha R Chr / Ats F Rk treatment, but no effect was observed on food intake. Ha R Chr / Ats F Rk treatment reduces adipocyte volumes, lowers serum levels of triglycerides and total cholesterol and restores adiponectin levels to those of normal mice. In the meantime, Ha R Chr / Ats F Rk treatment significantly elevates the gene expression of adiponectin and interleukin-10 and downregulates tissue necrosis factor-α expression in the inguinal adipose tissues. Thus, local injection of cell-targeting fiber rods and fragments demonstrates a feasible and effective antiobesity strategy through improving lipid metabolism and normalizing the inflammatory microenvironment.

Dyslipidemia is an imbalance of various lipids, and propolis, as a natural resinous viscos mixture made by Apis mellifera L. could improve in this condition. In this single-blind, randomized trial, 60 women with type 2 diabetes and dyslipidemia were divided into four groups: (1) the patients who did not apply the combined training and 500 mg propolis capsules supplement (Control group); (2) subjects performed combined training, including aerobic and resistance training (EXR); (3) subjects received the 500 mg propolis supplement capsules (SUPP); (4) Subjects performed combined training along with receiving the 500 mg propolis supplement capsules (EXR + SUPP). We evaluated the concentration of CTRP12, SFRP5, interleukin-6 (IL6), superoxide dismutase (SOD), malondialdehyde (MDA), adiponectin, and total antioxidant capacity (TAC) before and after the intervention. MDA, TAC, IL6, CTRP12, SFRP5 IL6, adiponectin, and lipid profile levels ameliorated in the EXR + SUPP group. We found that 8 weeks of treatment by combined exercise training and propolis supplement decreased inflammation activity and increased antioxidant defense in women with diabetic dyslipidemia.Trial registration This study was registered in the Iranian Registry of Clinical Trials; IRCT code: IRCT20211229053561N1., (© 2023. The Physiological Society of Japan.)

Purpose: To investigate the effect of metformin combined with DPP-4 inhibitor on alveolar bone density in patients with type 2 diabetes mellitus and chronic periodontitis., Methods: A total of 80 patients with type 2 diabetes mellitus and chronic periodontitis were selected and randomly divided into group A and group B by random number table, with 40 patients in each group. Group A (medication alone group): oral metformin and basic periodontal treatment; Group B (combination group): DPP-4 inhibitor (sitagliptin) was taken orally in addition to group A. Before treatment (T0) and 3 months (T1) and 6 months (T2) after treatment, alveolar bone mineral density (BDM), periodontal probing depth (PD), clinical attachment loss(CAL), probing bleeding (BOP), glycated hemoglobin (HbA1c),serum phosphorus, serum calcium, adiponectin (ADP), leptin (LEP), interleukin-6 (IL-6), C-reactive protein (HS-CRP), tumor necrosis factor (TNF-α) were detected. SPSS 23.0 software package was used for data analysis., Results: Three and 6 months after treatment, PD, CAL, BOP and HbAlc in group B were significantly lower than those in group A(P＜0.05). BDM in group B was significantly higher than that in group A (P＜0.05). Compared with group A, the levels of inflammatory cytokines (IL-6, Hs-CRP, TNF-α) and leptin in group B were significantly decreased, while the level of adiponectin was significantly increased (P＜0.05)., Conclusions: Metformin combined with DPP-4 inhibitor can increase alveolar bone density in patients with type 2 diabetes mellitus and chronic periodontitis, effectively improve periodontal clinical and serum biochemical indicators, and reduce periodontal inflammation.

The prevalence of the debilitating chronic disease ulcerative colitis (UC) is increasing significantly. Mirabegron is a selective beta-3 adrenergic receptor (β-3 AR) agonist used to treat an overactive bladder. Previous reports have demonstrated the antidiarrheal effect of β-3AR agonists. Therefore, the current study aims to investigate the potential symptomatic effects of mirabegron on an experimental colitis model. The effects of oral administration of mirabegron (10 mg/kg) for seven days on rats receiving intra-rectal acetic acid instillation on the sixth day were examined using adult male Wistar rats. Sulfasalazine was utilized as a reference medication. Gross, microscopic, and biochemical observations of the experimental colitis were performed. The quantity and mucin content of goblet cells were found to have significantly decreased in the colitis group. In the colons of rats administered mirabegron, the number of goblet cells and the optical density of its mucin content increased. Mirabegron's ability to increase adiponectin in serum and decrease glutathione, GSTM1, and catalase in the colon may account for its protective effects. In addition, mirabegron decreased the expression of the proteins caspase-3 and NF-κB p65. It also prevented the activation of their upstream signaling receptors TLR4 and p-AKT by acetic acid administration. In conclusion, mirabegron prevented acetic acid-induced colitis in rats, possibly due to its antioxidant, anti-inflammatory, and antiapoptotic properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Anorexia nervosa (AN) is a chronic, life-threatening disease with mental and physical components that include excessive weight loss, persistent food restriction, and altered body image. It is sometimes accompanied by hyperactivity, day-night reversal, and amenorrhea. No medications have been approved specific to the treatment of AN, partially due to its unclear etiopathogenesis. Because adiponectin is an appetite-regulating cytokine released by adipose tissue, we hypothesized that it could be useful as a specific biomarker that reflects the disease state of AN, so we developed a modified AN mouse model to test this hypothesis. Twenty-eight 3-week-old female C57BL/6J mice were randomly assigned to the following groups: 1) no intervention; 2) running wheel access; 3) food restriction (FR); and 4) activity-based anorexia (ABA) that included running wheel access plus FR. After a 10-day cage adaptation period, the mice of the FR and ABA groups were given 40% of their baseline food intake until 30% weight reduction (acute FR), then the body weight was maintained for 2.5 weeks (chronic FR). Running wheel activity and the incidence of the estrous cycle were assessed. Spontaneous food restriction and the plasma adiponectin level were evaluated at the end of the acute and chronic FR phases. An increase in running wheel activity was found in the light phase, and amenorrhea was found solely in the ABA group, which indicates that this is a good model of AN. This group showed a slight decrease in spontaneous food intake accompanied with an attenuated level of normally induced plasma adiponectin at the end of the chronic FR phase. These results indicate that the plasma adiponectin level may be a useful candidate biomarker for the status or stage of AN., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kuriyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the present study, we explored the effect of curcumin/turmeric supplementation on anthropometric indices of obesity, leptin, and adiponectin. We searched PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar up to August 2022. Randomized clinical trials (RCTs) investigating the impact of curcumin/turmeric on obesity indices and adipokines were included. We applied the Cochrane quality assessment tool to evaluate the risk of bias. The registration number is CRD42022350946. Sixty eligible RCTs, with a total sample size of 3691 individuals were included for quantitative analysis. We found that supplementation with curcumin/turmeric significantly reduced body weight (WMD: -0.82 kg, 95% CI: -1.30, -0.35; p = 0.001), body mass index (WMD: -0.30 kg/m 2 , 95% CI: -0.53, -0.06, p = 0.013), waist circumference (WMD: -1.31 cm, 95% CI: -1.94, -0.69, p < 0.001), body fat percentage (WMD: -0.88%, 95% CI: -1.51, -0.25, p = 0.007), leptin (WMD = -4.46 ng/mL; 95% CI: -6.70, -2.21, p < 0.001), and increased adiponectin (WMD = 2.48 μg/mL; 95% CI: 1.34, 3.62, p < 0.001). Overall, our study shows that supplementation with curcumin/turmeric significantly improves anthropometric indices of obesity and adiposity-related adipokines (leptin and adiponectin). However, due to high between-studies heterogeneity, we should interpret the results with caution., (© 2023 John Wiley & Sons Ltd.)

Psoriasis is a chronic and immune-mediated skin condition characterized by pro-inflammatory cytokines and keratinocyte hyperproliferation. Dendritic cells, T lymphocytes, and keratinocytes represent the main cell subtypes involved in the pathogenesis of psoriasis, while the interleukin-23 (IL-23)/IL-17 pathway enhances the disease progression. Human adipose tissue is an endocrine organ, which secretes multiple proteins, known as adipokines, such as adiponectin, leptin, visfatin, or resistin. Current evidence highlights the immunomodulatory roles of adipokines, which may contribute to the progression or suppression of psoriasis. A better understanding of the complexity of psoriasis pathophysiology linked with adipokines could result in developing novel diagnostic or therapeutic strategies. This review aims to present the pathogenesis of psoriasis and the roles of adipokines in this process., Competing Interests: The authors declare no conflicts of interest.

Background and Objective: Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression., Methods: Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n = 21 for ketamine 0.5 mg/kg, 20 for ketamine 0.2 mg/kg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin [IL]-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion., Results: Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion; specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5 mg/kg and 0.2 mg/kg) ketamine., Conclusions: Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine., Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number: UMIN000016985., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: To examine the effect of adiponectin administration on acute brain injury in an experimental model of cerebral ischemia/ reperfusion (I/R) in rats., Material and Methods: The study animals were divided into the following four groups: group I, sham (did not undergo surgical intervention and did not receive drugs); group II, the I/R model (received the intervention, but did not receive drugs); group III (I/Radiponectin) (the I/R model was used, and the animals were treated with 5 mg/kg adiponectin peritoneally 30 minutes after the ischemia); and group IV (I/R-tirofiban)( the I/R model was used, and the animals were treated with 0.5 mg/kg tirofiban peritoneally 30 minutes after the ischemia)., Results: Tumor necrosis factor-? (TNF-?) and interleukin (IL)-1? levels were statistically higher in the I/R group (group II) than in other groups. In the post-hoc (Tukey) test analysis, groups I, III, and IV had significantly lower TNF-? and IL-1? levels after treatment with both tirofiban and adiponectin than group II. No statistically significant difference was found between groups III and IV in terms of TNF-? levels. However, the decreased IL-1? level was more pronounced in group IV (tirofiban) than in other groups. The mean neurologic deficit scores were statistically significantly different among the groups. In the post-hoc (Tukey) test analysis, neurologic deficit scores were statistically significantly lower in groups III and IV than in group II., Conclusion: Adiponectin has anti-inflammatory and cerebral protective effects in experimental cerebral I/R injury.

Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This meta-analysis of randomized controlled trials (RCTs) was conducted to explore the effects of flavonoid intake on adiponectin and leptin levels. The PubMed, EMBASE, and Cochrane Library databases were searched on March 1, 2021. Random-effects, subgroup, sensitivity, and meta-regression analyses were conducted on 40 publications. Flavonoid intake significantly increased circulating adiponectin (0.54 μg/ml, 95% CI [0.20, 0.88], p = .002; I 2  = 86.4%) and significantly reduced leptin levels (weighted mean difference: -0.79 ng/ml, 95% CI [-1.33, -0.25], p = .004; I 2  = 87.7%). Subgroup analysis demonstrated that flavonoid intervention produced a significant elevation in adiponectin levels only in studies that lasted more than 12 weeks, conducted in Asian regions, were parallel-designed, involved obese or overweight participants and participants with type 2 diabetes mellitus (T2DM) or cardiovascular diseases, used tea catechins, and used a dietary supplement intervention. A significantly negative effect on leptin levels was observed in studies conducted in Asian countries, with healthy participants and participants with T2DM, used whole food interventions, and involved participants with lower baseline leptin levels. In conclusion, flavonoid intake significantly increased circulating adiponectin and decreased leptin levels; however, study heterogeneity was very high. Future well-designed trials are required to address heterogeneous study designs and clarify the efficacy of plants in regulating adiponectin and leptin levels., (© 2022 John Wiley & Sons Ltd.)

Hesperidin, a flavanone glycoside, has shown antihypertensive, antioxidant, and anti-inflammatory effects. In the present study, the therapeutic effects of hesperidin on vascular function and remodelling, and possible underlying mechanisms involved in high-fat/high-fructose diet (HFFD)-fed rats were investigated. Male Sprague-Dawley rats were fed a high-fat diet plus 15% fructose in drinking water for 16 weeks. HFFD-fed rats were treated with hesperidin (30 mg/kg/day) or vehicle for the last 4 weeks. Treatment of HFFD-fed rats with hesperidin significantly attenuated metabolic alterations, vascular endothelial dysfunction and remodelling. Hesperidin markedly alleviated HFFD-induced oxidative stress and inflammation by decreasing plasma malondialdehyde level and aortic superoxide anion production, and by suppressing aortic tumor necrosis factor-α and interleukin-6 overexpression. Additionally, increased plasma levels of the adiponectin and nitric oxide metabolite, together with restoration of adiponectin receptor 1 (AdipoR1) and endothelial nitric oxide synthase (eNOS) protein expression, were also observed after treatment with hesperidin. These findings indicated that hesperidin alleviates HFFD-induced vascular dysfunction and remodelling in rats. The possible underlying mechanism may involve the reduction of oxidative stress and inflammation, and the restoration of AdipoR1and eNOS expression., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to this study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Previous studies have shown the existence of an acute phase response in dogs with heartworm (Dirofilaria immitis), probably caused by the vascular inflammation that occurs during the pathogenesis of this disease. In addition, it has been seen that this acute phase response persists after finishing treatment, especially in dogs with pulmonary hypertension (PH). Furthermore, echocardiographic studies have shown that PH and endarteritis appear to persist for at least 10 months after completion of adulticide treatment, suggesting that the vascular changes in these dogs may not be reversible. Therefore, the objective of this study was to evaluate the serum concentrations of different positive acute phase proteins (APP) [C reactive-protein (CRP), haptoglobin and ferritin] and negative APP (albumin and paraoxonase-1 (PON-1)), and the usefulness of the endothelin-1 (ET-1) and adiponectin, in dogs infected by D. immitis to evaluate their usefulness as diagnostic biomarkers of vascular damage and PH and their progression throughout therapy up to 7 months after the end of adulticide treatment. Twenty-five heartworm-infected dogs received adulticide treatment, and serum measurements were performed on the day of diagnosis (day 0), day of discharge (day 90), and 6 months after discharge (day 270). In addition, presence or absence of PH was also echocardiographically determined using the Right Pulmonary Artery Distensibility Index. PH was present in 44% of the dogs on day 0 and day 90, and in 48% of dogs on day 270. Alterations were observed in the concentrations of all APP throughout the study, persisting the alterations in PON-1 and ferritin on day 270. Depending on the presence or absence of PH, CRP showed significant differences throughout the study, as did ET-1. On the other hand, adiponectin did not show variations throughout the study, so it did not seem a useful marker in this disease. These results could reflect the possible persistence of vascular inflammation up to 7 months after finishing treatment, whether or not there was PH, and consolidate the study of APP as useful markers in heartworm disease. Moreover, persistent PH could be the consequent clinical manifestation in dogs with more severe vascular alterations so the study of APP, especially CRP, and ET-1 could be especially advantageous in these patients in the early evaluation of the disease, as well as for the determination of disease severity, monitoring therapeutic responses, and predicting outcomes., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine if adipocytokines are independently associated with the achievement of low disease activity (LDA) over long-term follow-up in a large rheumatoid arthritis (RA) registry., Methods: This cohort study evaluated adults with RA from the Veteran's Affairs RA Registry. Adipocytokines (adiponectin, leptin, and fibroblast growth factor [FGF]-21) and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum from enrollment. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox proportional hazard models evaluated associations between adipocytokines and rates of 1) DAS28 LDA and remission, 2) individual Boolean remission criteria and 3) initiation of a new bDMARD or tsDMARD., Results: There were 1,276 participants with a DAS28 >3.2 at enrollment. Of these, 827 achieved LDA and 598 achieved remission over 2,287 and 4,096 person-years, respectively. Patients in the highest quartile of adiponectin had lower rates LDA before and after adjustment [aHR Q4: 0.68 (0.53,0.87) p<0.001]. Those in the highest quartile of leptin and FGF-21 also had lower rates of LDA. Higher quartiles of adipocytokines were also associated with lower rates of achieving a low patient/evaluator global scores and low tender joint counts. Among 1,236 biologic-naïve participants, values above the median for adiponectin [HR: 1.67 (1.23,1.26) p = 0.001] and FGF-21 [HR: 1.27 (1.09,1.47) p = 0.002] were associated with a greater likelihood of initiating a b/tsDMARD., Conclusions: Adipocytokines may serve as prognostic biomarkers of a more severe RA disease course. Additional study is needed to determine whether adipocytokines are phenotypic markers or whether they actively promote disease progression., (Published by Elsevier Inc.)

Idiopathic pulmonary fibrosis (IPF) is a common pulmonary interstitial disease with a high mortality rate. Adiponectin (APN) is reportedly an effective therapy for fibrosis-related diseases. This study aimed to investigate the potential effects of APN on IPF. Male BALB/c mice were injected with bleomycin (BLM) and treated with different doses of APN (0.1, 0.25, and 0.5 mg/kg). The body weights of the mice were recorded. Immunohistochemical, hematoxylin and eosin, and Masson staining were performed to evaluate pulmonary histopathological changes. Enzyme-linked immunosorbent assay (ELISA) and western blotting were performed to assess tissue inflammation. The human lung fibroblasts HELF were stimulated with TGF-β1 and treated with different doses of APN (2.5, 5, and 10 μg/ml). Cell proliferation, inflammation, and fibrosis were determined by MTT assay, EdU assay, colony formation assay, ELISA, and western blotting. APN significantly attenuated BLM-induced body weight loss, alveolar destruction, and collagen fiber accumulation in mice ( p < 0.05). APN decreased the expression of α-SMA and collagen I and reduced the concentration of TNF-α, IL-6, IL-1β, and IL-18 in lung tissues ( p < 0.05). In TGF-β1-treated HELF cells, cell proliferation and colony formation were inhibited by APN ( p < 0.05). Additionally, the expression of α-SMA, collagen I, and pro-inflammatory cytokines were suppressed by APN ( p < 0.05). APN inhibited the phosphorylation of IκB and nuclear translocation of p65. In conclusion, these findings suggest that APN is an effective agent for controlling IPF progression. The antifibrotic effects of APN might be mediated via inhibiting the NF-κB signaling pathway.

Background: Sacubitril valsartan and valsartan are the first new drugs approved for angiotensin receptor neprilysin lysine inhibitors (ARNIs) in outpatients with chronic heart failure (CHF) and hypertension. Compared with enalapril, sacubitril valsartan and valsartan have been shown to reduce the mortality and morbidity of cardiovascular diseases. However, there is little actual evidence regarding the efficacy of ARNIs in hypertensive patients with CHF., Methods: From January 2019 to January 2021, 60 patients with hypertension and chronic heart failure were diagnosed and treated in our hospital. The patients were randomly divided into an observation group and a control group, with 30 cases in each group. The control group was given valsartan, the observation group was given sacubitril valsartan, and both groups were treated for six months. The endothelium-dependent vasodilation (EDD) function of the brachial artery and serum nitric oxide (NO), endothelin-1 (ET-1), carotid artery intima-media thickness, and glomerular filtration, excess rate (eGFR), and left ventricular ejection fraction (LVEF) were compared between the two groups of patients before and after treatment. The serum adiponectin (APN), matrix metalloproteinase-9 (MMP-9), and brain natriuretic peptide (BNP) levels were compared before and after treatment., Results: The total effective rate of treatment in the research group was higher than that in the control group ( P < 0.05). After treatment, the cardiac function indexes LVESD and LVEDD of the two groups of patients were lower than before treatment, and LVEF was higher than before treatment, and the improvement rate of the treatment group was better than that of the control group ( P < 0.05). After treatment, the serum APN of the two groups was higher than before treatment, the levels of MMP-9 and BNP were lower than before treatment, and the improvement rate of patients in the treatment group was better than that of patients in the control group ( P < 0.05). There was no statistically significant in the levels of EDD, NO, and ET-1 of the two groups of patients before treatment ( P < 0.05). After treatment, compared with the control group, the EDD function and NO level of the research group were significantly increased ( P < 0.05), and the level of ET-1 was significantly reduced ( P < 0.05). There was no statistically significant difference in carotid artery intima-media thickness, glomerular filtration rate, and left ventricular ejection fraction before and after treatment in the two groups ( P < 0.05)., Conclusion: In the treatment of hypertension and chronic heart failure, sacubitril valsartan can improve the clinical symptoms of patients to the greatest extent and can significantly improve the levels of LVEF, LVEDD, NT-proBNP, heart function, and other indicators. Sacubitril valsartan can increase serum APN levels, reduce MMP-9 and BNP levels, and have good clinical effects. Sacubitril valsartan has a protective effect on the vascular endothelial function of patients with hypertension and CHF. However, these results need to be confirmed in studies involving more subjects and require longer follow-up times., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Haiping Du et al.)

Although islet transplantation (ITx) is a promising therapy for severe diabetes mellitus, further advancements are necessary. Adiponectin, an adipokine that regulates lipid and glucose metabolism, exerts favorable effects on islets, such as reinforcement of the insulin-releasing function. This study evaluated the possibility of adiponectin use to improve ITx outcomes. We treated mouse islets with 10 µg/mL recombinant mouse adiponectin by overnight culture and then assessed the insulin-releasing, angiogenic, and adhesion functions of the islets. Furthermore, 80 syngeneic islet equivalents with or without adiponectin treatment were transplanted into the renal subcapsular space of diabetic mice. In in vitro assessment, released insulin at high glucose stimulation, insulin content, and expressions of vascular endothelial growth factor and integrin β1 were improved in adiponectin-treated islets. Furthermore, adiponectin treatment improved the therapeutic effect of ITx on blood glucose levels and promoted angiogenesis of the transplanted islets. However, the therapeutic effect was not pronounced in glucose tolerance test results. In conclusion, adiponectin treatment had preferable effects in the insulin-releasing, angiogenic, and adhesion functions of islets and contributed to the improvement of ITx. The future use of adiponectin treatment in clinical settings to improve ITx outcomes should be investigated., (© 2022. The Author(s).)

Objective: Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting., Methods: We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings., Results: Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index., Conclusions: The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets., (© 2021 John Wiley & Sons Ltd.)

Obesity and dementia are two growing problems worldwide. Obesity act as a crucial risk factor for various diseases including Alzheimer's disease (AD). Several preclinical studies showed that middle-age obesity can be act as a possible feature of mild cognitive impairment in later years. Some studies have also demonstrated that a high-fat diet causes AD pathology, including extracellular amyloid-beta accumulation, hyperphosphorylation of tau, and cognition impairment. The correlation and molecular mechanism related to obesity-associated AD needs to be better evaluated. Presently, obesity results in an altered expression of several hormones, growth factors, and adipokines. Multiple signaling pathways such as leptin, insulin, adiponectin, and glutamate are involved to regulate vital functions in the brain and act as neuroprotective mediators for AD in a normal state. In obesity, altered adiponectin (APN) level and its associated downstream pathway could result in multiple signaling pathway disruption. Presently, Adiponectin and its inducers or agonist are considered as potential therapeutics for obesity-associated AD. This review mainly focuses on the pleiotropic effects of adiponectin and its potential to treat obesity-associated AD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adiponectin (ADPN) plays an important role in cerebral ischemia-reperfusion injury. Although previous studies have confirmed that ADPN pretreatment has a protective effect on ischemic stroke, the therapeutic effect of ADPN on ischemic stroke and the underlying mechanism are still unclear. In order to clarify these questions, focal transient cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice and ADPN was administered for three times at 6 h, 24 h, and 48 h after reperfusion. Meanwhile, a virus-delivered HIF-1 α siRNA was used before ADPN administration. The infarct volume, neurological score, cellular apoptosis, and oxidative stress were assessed at 72 h after reperfusion. The long-term outcome of mice after stroke was recorded as well. The results indicated that ADPN treatment reduced the infarct volume ( P = 0.032), neurological deficits ( P = 0.047), cellular apoptosis ( P = 0.041), and oxidative responses ( P = 0.031) at 72 h after MCAO. Moreover, ADPN increased both the protein level and transcriptional activity of HIF-1 α as evidenced by the transcription levels of VEGF ( P = 0.046) and EPO ( P = 0.043) at 72 h after MCAO. However, knockdown of HIF-1 α partially reversed the antioxidant and treatment effect of ADPN after cerebral ischemia. In the observation of long-term outcome after ADPN treatment, it demonstrated that ADPN not only prevented the cerebral atrophy ( P = 0.031) and the neurological function decline ( P = 0.048), but also promoted angiogenesis ( P = 0.028) after stroke. In conclusion, our findings suggest that ADPN is effective in treatment of ischemic stroke which could be attributed to the increased antioxidant capacity regulated by HIF-1 α ., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Chan Zhang et al.)

Toll-Like Receptor 9 (TLR9) is an ancient receptor integral to the primordial functions of inflammation and metabolism. TLR9 functions to regulate homeostasis in a healthy system under acute stress. The literature supports that overactivation of TLR9 under the chronic stress of obesity is a critical driver of the pathogenesis of NASH and NASH-associated fibrosis. Research has focused on the core contributions of the parenchymal and non-parenchymal cells in the liver, adipose, and gut compartments. TLR9 is activated by endogenous circulating mitochondrial DNA (mtDNA). Chronically elevated circulating levels of mtDNA, caused by the stress of overnutrition, are observed in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and NASH. Clinical evidence is supportive of TLR9 overactivation as a driver of disease. The role of TLR9 in metabolism and energy regulation may have an underappreciated contribution in the pathogenesis of NASH. Antagonism of TLR9 in NASH and NASH-associated fibrosis could be an effective therapeutic strategy to target both the inflammatory and metabolic components of such a complex disease., Competing Interests: CS is the founder of the company Avogadro Development Corp that has research and development interests in TLR9 antagonism in NASH., (Copyright © 2021 Shepard.)

Purpose: Comparing the effect of adiponectin versus bevacizumab in decreasing corneal neovascularization., Methods: This study was conducted on 30 eyes of 30 New Zealand Albino male rabbits. Corneal neovascularization was induced by a single 7-0 silk suture 2 mm long and 1 mm in front of the limbus for 2 weeks. Rabbits were randomly divided into three groups of adiponectin (20 µg/mL), bevacizumab (5 mg/mL) and artificial tears. The treatments continued up to 14 days., Results: At the end of 14 days, the average length of vessels in rabbits treated with adiponectin, bevacizumab and control groups decreased from 2.12 ± 0.32 mm to 0.89 ± 0.46 mm (57.68% ± 19.98%) (P < 0.001), 2.30 ± 0.41 mm to 1.30 ± 0.58 mm (42.49% ± 27.17%) (P = 0.048) and from 2.12 ± 0.44 mm to 1.81 ± 0.42 mm (14.81% ± 5.64%) (P = 0.112), respectively. The length of vessels decreased 57.68% ± 19.98% and 42.49% ± 27.17% in adiponectin versus bevacizumab groups, respectively (P = 0.527). The average surface area of vessels in rabbits treated with adiponectin, bevacizumab and control groups reduced from 5.02 ± 1.50 mm 2 to 1.40 ± 0.75 mm 2 (70.64% ± 17.76%) (P < 0.001) 0.34 ± 1.1 mm 2 to 2.80 ± 1.04 mm 2 (48.24% ± 19.23%) (P = 0.039) and 5.12 ± 2.92 mm 2 to 4.4 ± 2.55 mm 2 (14.68% ± 4.19%) (P = 0.117). Mean surface area of vascularization decreased 70.64% ± 17.76% and 48.24% ± 19.23% in adiponectin versus bevacizumab, respectively (P = 0.013)., Conclusions: The results of this study suggest that topical adiponectin can decrease recent corneal neovascularization.

Ischemia-reperfusion (I/R) injury is a major cause of morbidity and mortality worldwide. AMP-activated protein kinase (AMPK) is an energy sensor that regulates metabolic homeostasis. A growing body of literature has shown that AMPK activation exerts protective effects against I/R injury in heart, brain, kidney, liver, lung and intestine. In this review, we first reveal the mechanisms underlying the protective effects of AMPK activation against I/R injury in preclinical studies. We found that AMPK activation attenuates I/R injury via regulation of energy metabolism, oxidative stress, mitochondrial function, autophagy, inflammatory response, and endoplasmic reticulum stress. Then, current therapeutic strategies (e.g., metformin, adiponectin) used to ameliorate I/R injury by modulating AMPK activity are reviewed in detail. Collectively, pharmacological activation of AMPK may hold a unique therapeutic potential in the prevention and attenuation of I/R injury., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims/hypothesis: Adiponectin stimulates mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a major regulator of mitochondrial biogenesis. MOTS-c (mitochondrial open reading frame of the 12S rRNA) is a biologically active mitochondrial-derived peptide encoded by mitochondrial DNA. It influences the mechanisms of obesity and diabetes. We hypothesised that the adiponectin pathway may regulate the production and/or secretion of MOTS-c in skeletal muscle. We aimed to determine whether exercise and adiponectin affect MOTS-c to improve insulin resistance in mice., Methods: To investigate this hypothesis, we used wild-type C57BL/6 mice subjected to high-fat diet, an exercise regimen, and i.p. injection of recombinant mouse adiponectin (Acrp30) or MOTS-c, and adiponectin knockout (Adipoq -/- ) mice (C57BL/6 background) subjected to i.p. injection of Acrp30. C2C12 myotubes were also treated with sirtuin 1 (SIRT1) inhibitor, PGC-1α inhibitor, SIRT1 activator, plasmid-expressed active APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper), pcDNA-SIRT1, or siRNA against APPL1, SIRT1 or PGC-1α., Results: In Adipoq -/- mice, MOTS-c levels in the plasma and skeletal muscle were downregulated. In C2C12 myotubes, adiponectin increased the mRNA expression of MOTS-c. APPL1 protein level following adiponectin treatment positively correlated with MOTS-c protein and mRNA levels in C2C12 myotubes. SIRT1 overexpression increased the adiponectin-induced mRNA and protein expression of MOTS-c, SIRT1 and PGC-1α. Pharmacologic and genetic inhibition of PGC-1α suppressed the increases in MOTS-c mRNA and protein levels induced by SIRT1 overexpression. In mice, plasma and skeletal muscle MOTS-c levels were significantly downregulated following high-fat-diet. Exercise and i.p. Acrp30 or MOTS-c increased MOTS-c levels and adiponectin mRNA and protein expression in the plasma and skeletal muscle., Conclusions/interpretation: Our findings showed that the APPL1-SIRT1-PGC-1α pathway regulates the production and/or secretion of skeletal muscle MOTS-c by mediating adiponectin signalling. Our study provides an insight into the cellular and molecular pathways underlying the pathogenesis of diabetes and shows that MOTS-c is a potential novel therapeutic target in the treatment of diabetes. Graphical abstract.

Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by oxidative stress and inflammation in the hepatocytes. Saffron and its constituents are reported to have several properties such as anti-inflammatory and anti-diabetic effects., Materials and Methods: In a randomized double-blind placebo-controlled trial with two parallel groups including 76 eligible men and female patients with NAFLD aged 18-65, recruited from Hazrat Rasul Akram Hospital in Tehran, Iran. NAFLD was defined by a Gastroenterologist based on the American Gastrointestinal and Liver Association standards. Participants were randomly assigned to two groups receiving daily supplementation of either one tablet of 100 mg saffron (n = 38) or one placebo (n = 38) for 12 weeks. The primary outcome was high sensitive C-reactive protein (hs-CRP) and secondary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), malondialdehyde (MDA), total anti-oxidant capacity (TAC), leptin, adiponectin, anthropometric, and body composition Both groups were assigned similar diet and physical activity., Results: In the treatment group, significant decreases in hs-CRP (-1.80 ng/ml, 95% CI = -2.97, -0.63, p = .032), leptin (-0.27 ng/ml, 95% CI = -0.65, -0.10, p = .040), MDA (-1.01 ng/ml, 95% CI = -1.89, -0.14, p = .023) and significant increase in TAC (0.34 μmol/L, 95% CI = 0.08, 0.61, p = .011) were observed compared to the placebo group. However, there were no significant changes in serum alanine aminotransferase, AST, TNF-α, body composition, and anthropometric indexes (p > .05)., Conclusion: In the present study, 12 weeks of 100 mg of saffron supplementation indicated beneficial effects on serum levels of some inflammatory, oxidative stress, and adipokines biomarkers but it had no significant effect on serum concentrations of liver enzymes, anthropometric, and body composition measurements., (© 2020 John Wiley & Sons, Ltd.)

Preterm infants are at high risk for developing bronchopulmonary dysplasia and pulmonary hypertension from inflammatory lung injury. In adult models, adiponectin (APN)-an adipocyte-derived hormone-protects the lung from inflammatory injury and pulmonary vascular remodeling. Cord blood APN levels in premature infants born < 26 weeks gestation are 5% of the level in infants born at term. We previously reported the expression profile of APN and its receptors in neonatal rat lung homogenates during the first 3 weeks of postnatal development. Here, we characterize the expression profile of APN and its receptors in specific lung cells and the effects of exogenous recombinant APN (rAPN) on lipopolysaccharide-(LPS)-induced cytokine and chemokine production in total lung homogenates and specific lung cells. In vitro, rAPN added to primary cultures of pulmonary artery smooth muscle cells attenuated the expression of LPS-induced pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines. In vivo, intraperitoneal rAPN (2 mg/kg), given 4 hr prior to intrapharyngeal administration of LPS (5 mg/kg) to newborn rats at postnatal day 4, significantly reduced gene and protein expression of the pro-inflammatory cytokine IL-1ß and reduced protein expression of the chemokines monocyte chemoattractant protein (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1α) in the lung. LPS-induced histopathological changes in the lung were also decreased. Moreover, rAPN given 20 hr after intrapharyngeal LPS had a similar effect on lung inflammation. These findings suggest a role for APN in protecting the lung from inflammation during early stages of lung development., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

This study was to investigate whether recombinant globular adiponectin produced its protective effect on the testis of diabetic mice by modulating autophagy, endoplasmic reticulum stress and oxidative stress. Male mice were randomly divided into control, diabetic, diabetic treated with low and high dose of adiponectin. Mice were killed at the termination after 4 weeks and 8 weeks of adiponectin treatment. Serum levels of glucose, lipids, testosterone, insulin, LH and FSH were measured. The protein expression of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), Caspase12, Beclin1, microtubule-associated protein light chain 3 (LC3) and p62 was determined by western blotting. The mRNA expression of adiponectin receptor 1 (AdipoR1), p22phox, p47phox, nuclear factor erythroid2-related factor 2 (Nrf2), NAD(P)H-quinone oxidoreductase 1(NQO1), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) were determined by real-time fluorescence quantitative PCR. The testicular weight, the sperm number and motility, and the serum levels of testosterone and insulin were significantly decreased in diabetic mice (P < 0.05). The expression of Beclin1, LC3, Nrf2, NQO1, HO-1, SOD and AdipoR1 were significantly decreased (P < 0.05), while the expression of GRP78, CHOP, Caspase12, p62, p22phox and p47phox were notably increased in the testes of diabetic mice (P < 0.05). Adiponectin treatment significantly reversed the above-mentioned changes in the testes of diabetic mice, some of which were dose- and time-dependent (P < 0.05). These data suggested that recombinant globular adiponectin may produce the protective effect on the testes of diabetic mice by inducing autophagy and inhibiting ER stress and oxidative stress., Competing Interests: Declaration of competing interest The Author(s) declare(s) that they have no conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Adiponectin is a hormone secreted by adipose tissue, exerting many positive effects in the human body. Its action has been widely studied, placing it into the metabolic health beneficial products of the adipose tissue. Nevertheless, adiponectin has been shown to exert some extra beneficial non metabolic actions, as well. Adiponectin levels can be related to reduced incidence of cancer in obese patients. Moreover, adiponectin has been shown to be implicated in the positive fertility outcomes of women. Some new studies have also indicated that adiponectin has a potential effect in the control of appetite, which raises a question, whether adiponectin could be accredited to be useful in the endocrine evaluation of obesity. Could these additional non-metabolic actions prove its helpfulness?

The effects of current treatment strategies for ischemic stroke are weakened by ischemia-reperfusion (I/R) injury. Effective treatments targeting I/R injury are still insufficient. Adiponectin (APN), a fat-derived hormone, has a wide range of antioxidative and anti-inflammatory effects. However, the application of APN to the central nervous system is restricted by its limited blood-brain barrier permeability. Therefore, an adiponectin peptide (APNp) was chemically synthesized on the basis of the functional area in the APN structure. The present study was carried out to explore the effect and the underlying mechanism of APNp on I/R injury. A transient middle cerebral artery occlusion (tMCAO) model with C57BL/6 J mice was used, and an in vitro oxygen-glucose deprivation and reintroduction (OGD-R) model with primary astrocytes was induced. The results showed that APNp decreased the cerebral infarction volume, alleviated brain edema, improved neurological function and had antioxidative, anti-inflammatory, and antiapoptotic effects against cerebral I/R injury. In addition, APNp upregulated the phosphorylation of AMPK and GSK-3β, promoted the nuclear translocation of Nrf2 and increased the expression of Trx1. The protective effect of APNp was abolished by compound C, a selective AMPK inhibitor, and PX-12, a selective Trx inhibitor. Moreover, APNp decreased the protein level of TXNIP and suppressed the activation of the NLRP3 inflammasome in astrocytes, which were also reversed by compound C and PX-12. These findings suggest that APNp, as a potential substitute for adiponectin, has a great potential for clinical application in the treatment of acute brain ischemia., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The main aim of the study was to assess changes in adiponectin and fibroblast growth factor 21 (FGF21) levels in pregnant women with intrahepatic cholestasis during ursodeoxycholic acid (UDCA) therapy. The study included 40 pregnant women with intrahepatic cholestasis (ICP) treated with UDCA. In the pregnant ICP group, material for further analysis was collected three times: before the first dose of drug T1, 4 weeks after the first dose of drug T2, 8 weeks after the first dose of drug T3, and 1 day after delivery T4 (P < .05). Regarding changes in the adiponectin concentration profile, three statistical significance (P < .05) was found: before the first dose and 8 weeks of treatment and 1 day after delivery, as well as between 4 and 8 weeks of UDCA acid therapy. In the fourth and eighth weeks of treatment, adiponectin levels reached a higher concentration than before the first dose of UDCA, but a decrease was observed 1 day after delivery. It has been confirmed that UDCA therapy has an impact on the dynamics of changes in adiponectin and FGF21 levels as well as indicators characterizing liver function., (© 2020 Wiley Periodicals LLC.)

Keloids, benign cutaneous overgrowths of dermal fibroblasts, are caused by pathologic scarring of wounds during healing. Current surgical and therapeutic modalities are unsatisfactory. Although adiponectin has shown an antifibrotic effect, its large size and insolubility limit its potential use in keloid treatment. We investigated the effect of a smaller and more stable adiponectin-based peptide (ADP355) on transforming growth factor β1 (TGF-β1)-induced fibrosis in a primary culture of keloid fibroblasts prepared from clinically obtained keloid samples. Xenograft of keloid tissues on athymic nude mice was used to investigate the effect of intralesional injection of ADP355. ADP355 significantly attenuated the TGF-β1-induced expression of procollagen type 1 in keloid fibroblasts ( p < 0.05). Moreover, it inhibited the TGF-β1-induced phosphorylation of SMAD3 and ERK, while amplifying the phosphorylation of AMP-activated protein kinase ( p < 0.05). Knockdown of adiponectin receptor 1 reversed the attenuation of procollagen expression in ADP355-treated TGF-β1-induced fibrosis ( p < 0.05 ). ADP355 also significantly reduced the gross weight and procollagen expression of keloid tissues in xenograft mice compared to control animals. These results demonstrate the therapeutic potential of the adiponectin peptide ADP355 for keloids.

The present study sought to investigate the correlation between adipose cytokines (visfatin, leptin and adiponectin) and markers of multiple myeloma bone disease, and to determine the effects and mechanism of action of adiponectin on the differentiation and maturation of osteoclasts in multiple myeloma (MM). The levels of visfatin, leptin and adiponectin were measured. Their association with the indices of myeloma tumor load and bone disease were analyzed. Reverse transcription‑quantitative PCR was used to detect the expression of receptor activator of nuclear factor‑κB ligand (RANKL), osteoclast associated Ig‑like receptor (OSCAR), tartrate‑resistant acid phosphatase (TRAP) and Cathepsin K genes. Flow cytometry was used to detect the expression of adiponectin receptor 1 (AdipoR1) and the phosphorylation of the mechanistic target of rapamycin kinase (mTOR) pathway‑associated proteins mTOR and eukaryotic translation initiation factor 4E‑binding protein (4EBP1). There were no significant correlations among leptin, visfatin and the indexes of myeloma tumor load and bone disease. Serum adiponectin levels were significantly lower in patients with newly diagnosed multiple myeloma compared with healthy volunteers (12.37±3.13 vs. 13.80±0.95; P<0.05). The number of mature osteoclasts in the adiponectin group was lower compared with in the control group. Adiponectin also inhibited the mRNA expression of the osteoclast‑associated factors RANKL, OSCAR, TRAP and Cathepsin K. Comparison between the non‑adiponectin group and the adiponectin group revealed that adiponectin increased the expression of AdipoR1 on the surface of osteoclast precursor cells (26.21±4.27% vs. 29.86±6.23%; P<0.05) and reduced the expression of phosphorylated (p‑)mTOR (7.89±1.00% vs. 5.91±1.26%; P<0.05) and p‑4EBP1 (26.78±5.00% vs. 22.49±4.24%; P<0.05). The p‑mTOR and p‑4EBP1 levels in the adiponectin + MHY1485 (an mTOR signaling pathway‑specific agonist) group were significantly higher compared with those in the adiponectin group. It was revealed that adiponectin may inhibit osteoclast differentiation and maturation via the mTOR pathway. In conclusion, adiponectin inhibits the differentiation and maturation of osteoclasts by increasing the expression of AdipoR1 and reducing the phosphorylation levels of mTOR and 4EBP1 in patients with MM.

Backgrounds: Asthma is characterized as inflammatory disorder in the respiratory system with increasing tendency. Most of the asthma patients suffered from the disease since childhood. Thus, developing novel therapeutic targets of childhood asthma is necessary. Here, we conducted the present study to investigate the effects of CTRP9 (C1q tumor necrosis factor-related protein 9), a newly identified anti-inflammatory factor, on asthma., Methods: Sixty asthmatic children (30 moderate and 30 mild) were recruited. The mRNA level of CTRP9 in peripheral blood mononuclear cells (PBMCs) and protein level of CTRP9 in serum and induced sputum (IS) samples from asthma patients and healthy controls (HCs) were measured by qPCR and ELISA, respectively. The anti-inflammatory effects of CTRP9 was determined in vitro and potential therapeutic effect on asthma was evaluated in mouse model., Results: The mRNA and protein levels of CTRP9 was significantly down-regulated in asthmatics than HCs. Furthermore, the expression level of CTRP9 was negatively correlated with the expression of TNF-α, IL-1β, and IL-6 in PBMCs. The CTRP9 significantly suppressed the expression of pro-inflammatory factors in PBMCs and sputum cells from asthma patients in vitro. And delivering CTRP9 into mouse model of asthma showed disease alleviation., Conclusion: Our data here indicated that CTRP9 may alleviate airway inflammation and remodeling in asthma., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Patients with diabetes are vulnerable to myocardial I/R (ischaemia/reperfusion) injury, but are not responsive to IPO (ischaemic post-conditioning). We hypothesized that decreased cardiac Adiponectin (APN) is responsible for the loss of diabetic heart sensitivity to IPO cardioprotecton., Methods: Diabetic rats were subjected to I/R injury (30 min of LAD occlusion followed by 120 min of reperfusion). Myocardial infarct area was determined by TTC staining. Cardiac function was monitored by a microcatheter. ANP, 15-F2t-isoprostane, nitrotyrosine and MDA were measured by assay kits. Levels of p-Akt, total-Akt and GAPDH were determined by Western Blot., Results: Diabetic rats subjected to myocardial IR exhibited severe myocardial infarction and oxidative stress injury, lower APN in the plasma and cardiac p-Akt expression ( P <0.05). IPO significantly attenuated myocardial injury and up-regulated plasma APN content and cardiac p-Akt expression in non-diabetic rats but not in diabetic rats. Linear correlation analysis showed that the expression of adiponectin was positively correlated with p-Akt and negatively correlated with myocardial infarction area ( P <0.01)., Conclusion: Protective effect of IPO was tightly correlated with the expression of adiponectin, exacerbation of I/R injury and ineffectiveness of IPO was partially due to the decline of adiponectin and inactivation of Akt in diabetes mellitus.

Purpose: To evaluate the efficacy of adiponectin (APN)-derived short peptides (ADPs) 355 compared with globular APN in a mouse model of experimental dry eye (EDE) and corneal alkali burn. Methods: EDE and chemical burn were induced in C57BL/6 mice by desiccating stress and application of NaOH, respectively. Eye drops consisting of 0.01% globular APN, 0.01% ADPs, 0.1% ADPs, or balanced salt solution (BSS) were applied. Tear volume, tear film break-up time, and corneal staining scores were measured. Concentrations of interleukin (IL)-1β, interferon (IFN)-γ, IL-6, CXCL-9, and CXCL-10 using multiplex immunobead assay were evaluated, and flow cytometry were performed. Corneal epithelial defects and haze degree were analyzed, and enzyme-linked immunosorbent assay for IL-1β and transforming growth factor (TGF)-β levels were observed. Results: All treatment groups showed an improvement in clinical parameters and CD4+CCR5+ T cell and CD11b+ cell infiltrations in the conjunctiva (all P  < 0.05). Both ADPs groups had significantly decreased concentrations of IL-1β, IFN-γ, IL-6, CXCL-9, and CXCL-10 in the conjunctiva than the EDE or BSS group. Significantly improved parameters of epithelial defect, degree of haze, and concentrations of IL-1β and TGF-β were observed in all treatment groups. However, no significant differences were noted in clinical or experimental parameters among treatment groups. Conclusion: Topical ADPs could effectively improve clinical signs and inflammation of ocular surface in the EDE or alkali burn, and its efficacy and potency were similar to those of globular APN.

Depression is the most devastating mental disorder and one of the leading contributors to the global medical burden. Current antidepressant prescriptions present drawbacks, including treatment resistance, delayed onset of treatment response, and side effects. The rapid and long-lasting antidepressant effect of ketamine has brought hope to treatment-resistant major depressive disorder patients. However, ketamine has undesirable addictive properties and is a drug of abuse. There is an urgent need, therefore, to develop novel pharmacological interventions that could be as effective as ketamine, but without its side effects. Adiponectin, a pleiotropic adipocyte-secreted hormone, has insulin-sensitizing and neurotrophic properties. It can cross the blood-brain barrier and target multiple brain regions where the adiponectin receptors are detected. Emerging evidence has suggested that adiponectin and the adiponectin receptor agonist, AdipoRon, could promote adult neurogenesis, dendritic and spine remodeling, and synaptic plasticity in the hippocampus, resulting in antidepressant effects in adult mice. By summarizing the most recent clinical and animal studies, this review provides a timely insight on how modulating the adiponergic system in the hippocampus could be a potential therapeutic target for an effective and fast-acting antidepressant response.

Adiponectin, an adipokine derived from the adipose tissue, manifests anti-inflammatory effects in the metabolically active organs and is, therefore, beneficial in various metabolic diseases associated with inflammation. However, the role of adiponectin in alleviating the hypothalamic inflammation connected to the pathogenesis of obesity has not yet been clearly interrogated. Here, we identified that the systemic administration of adiponectin suppresses the activation of microglia and thereby reverses the hypothalamic inflammation during short-term exposure to a high-fat diet. Additionally, we show that adiponectin induces anti-inflammatory effects in the microglial cell line subjected to an exogenous treatment with a saturated free fatty acid. In conclusion, the current study suggests that adiponectin suppresses the saturated free fatty acid-triggered the hypothalamic inflammation by modulating the microglial activation and thus maintains energy homeostasis.

Given the enormous impact of HCC on the patients' quality of life and healthcare economics, the current study was conducted to investigate the potential ability of adiponectin to reverse established HCC and to investigate the underlying mechanisms which control the chemotherapeutic and hepatoprotective effects. HCC was induced in Male Sprague Dawely rats by I.P. injection of thioacetamide(200 mg/kg) 3 times/week for 14 weeks.HCC development was confirmed by histopathological examination and assessment of serum levels of α-fetoprotein (AFP). Adiponectin was administered (5 μg/kg, I.P.) starting from week 13 of the experiment and for further 4 weeks. Adiponectinadministration revealed a significant antitumor activity with significant improvement in liver functions and oxidative status. Nevertheless, pathological features as cirrhosis, dysplastic changes, and tumoral nodules were significantly attenuated with significant enhancement in hepatic caspase-3 immunostaining. Mechanistically, adiponectin administration was associated with significant restoration of p53 activity; which increased by 133%, with a reduction in HCC-induced expression of-JNK which decreased by 53%as well as a significant enhancement of hepatic TRAIL and caspase-8 activities which increased by 27% and 20% respectively. In conclusion; Adiponectin can be proposed as a promising therapy for HCC. Adiponectin's tumoricidal activity can be partially mediated by blocking HCC-induced reduction in p53 expression as well as reactivation of TRAIL signaling and induction of apoptotic pathway providing more protection for the body against the tumor., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of the IgG and/or IgM isotypes of the antiphospholipid antibodies, thrombosis and/or recurrent pregnancy losses. Various markers of inflammation are associated with clinical and/or laboratory features of APS. Adiponectin (Ad) is a member of the adipocytokines that exert its roles by binding to its receptors (AdR). Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists induced Ad production. The aged Pparg null-mice represented the first animal model that spontaneously develops APS and this model emphasized the importance of PPAR-gamma signaling in the development of APS. Recombinant Ad (rAd) application was beneficial for the improvement of glucose, insulin and lipid levels in mice. Orally active AdR agonist exerted similar effects to Ad in mice. Due to the re-occurrence of thrombotic episodes in APS patients (despite life-long anticoagulation), administration of PPAR-gamma agonists, rAd, or AdR agonists should be further tested in experimental models of APS, which eventually, will provide more data for novel therapeutic strategies that will ameliorate clinical manifestations of the APS.

Accumulating evidence demonstrates the beneficial effects of physical exercise on pain conditions; however, the underlying mechanisms are not understood thoroughly. The purpose of the present study was to investigate the effects of regular swimming exercise on neuroma pain and the possible roles of adipokines (leptin and adiponectin) in the pain behaviors modulated by exercise. The results showed that 5 weeks of regular swimming exercise relieved pain behaviors in a rat model of neuroma pain and normalized the dysregulation of circulating leptin and adiponectin in plasma induced by nerve injury. Moreover, regular swimming exercise reversed the altered expressions of leptin receptor and adiponectin receptor 1 in neuroma. In addition, the administration of exogenous leptin to the neuroma site dampened the effects of regular swimming exercise on neuroma pain and adiponectin administration alleviated the neuroma pain in the non-exercised neuroma rats. These findings indicate that leptin and adiponectin might be involved in mediating the beneficial effects of exercise on neuroma pain. PERSPECTIVE: Perspective: Identifying which endogenous processes are activated by specific exercise regimes would likely reveal novel therapeutic targets for the treatment of neuropathic pain. The current study suggests that adipokines might be involved in pain behaviors modulated by exercise and thus presents them as potential targets for pain management., (Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Lipodystrophy is a group of clinically heterogeneous, inherited or acquired, disorders characterized by complete or partial absence of subcutaneous adipose tissue that may occur simultaneously with the pathological, ectopic, accumulation of fat in other regions of the body, including the liver. Fatty liver adds significantly to hepatic and extra-hepatic morbidity in patients with lipodystrophy. Lipodystrophy is strongly associated with severe insulin resistance and related comorbidities, such as hyperglycemia, hyperlipidemia and nonalcoholic fatty liver disease (NAFLD), but other hepatic diseases may co-exist in some types of lipodystrophy, including autoimmune hepatitis in acquired lipodystrophies, or viral hepatitis in human immunodeficiency virus (HIV)-associated lipodystrophy. The aim of this review is to summarize evidence linking lipodystrophy with hepatic disease and to provide a special focus on potential therapeutic perspectives of leptin replacement therapy and adiponectin upregulation in lipodystrophy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Angiotensin II type 1 receptor autoantibodies (AT1-AA) cause endothelial-dependent smooth muscle relaxation disorder. It is well understood that impairment of the NO-cGMP signaling pathway is one of the mechanisms of endothelial-dependent smooth muscle relaxation disorder. However, it is still unclear whether AT1-AA induces endothelial-dependent smooth muscle relaxation disorder via the impairment of the NO-cGMP signaling pathway. In addition, adiponectin exerts vascular endothelial protection through the NO-cGMP signaling pathway. Therefore, the purpose of this investigation was to assess the mechanism of vascular endothelial-dependent smooth muscle relaxation disorder induced by AT1-AA and the role of adiponectin in attenuating this dysregulation. Serum endothelin-1 (ET-1), adiponectin and AT1-AA were detected by enzyme-linked immunosorbent assay. In preeclamptic patients, there was an increased level of AT1-AA, which was positively correlated with ET-1 and negatively correlated with adiponectin, as elevated levels of ET-1 suggested endothelial injury. AT1-AA-positive animal models were actively immunized with the second extracellular loop of the angiotensin II type 1 receptor (AT1R-ECII) for eight weeks. In thoracic aortas of AT1-AA positive rats, ET-1 was elevated, endothelium-dependent vasodilation was decreased. Paradoxically, as the upstream element of the NO-cGMP signaling pathway, NO production was not decreased but increased, and the ratio of p-VASP/VASP, an established biochemical endpoint of NO-cGMP signaling pathway, was reduced. Moreover, the levels of nitrotyrosine and gp91phox which indicate the presence of peroxynitrite (ONOO - ) and superoxide anion (O 2 · - ) were increased. Pretreatment with the ONOO - scavenger FeTMPyP or O 2 · - scavenger Tempol normalized vasorelaxation. Key enzymes responsible for NO synthesis were also assessed. iNOS protein expression was increased, but p-eNOS(Ser1177)/eNOS was reduced. Preincubation with the iNOS inhibitor 1400 W or eNOS agonist nebivolol restored vasorelaxation. Further experiments showed levels of p-AMPKα (Thr172)/AMPKα, which controls iNOS expression and eNOS activity, to have been reduced. Furthermore, levels of the upstream component of AMPK, adiponectin, was reduced in sera of AT1-AA positive rats and supplementation of adiponectin significantly decreased ET-1 contents, improved endothelial-dependent vasodilation, reduced NO production, elevated p-VASP/VASP, inhibited protein expression of nitrotyrosine and gp91phox, reduced iNOS overexpression, and increased eNOS phosphorylation at Ser1177 in the thoracic aorta of AT1-AA positive rats. These results established that impairment NO-cGMP pathway may aggravate the endothelial-dependent smooth muscle relaxation disorder in AT1-AA positive rats and adiponectin improved endothelial-dependent smooth muscle relaxation disorder by enhancing NO-cGMP pathway. This discovery may shed a novel light on clinical treatment of vascular diseases associated with AT1-AA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Targeting neuronal apoptosis after intracerebral hemorrhage (ICH) may be an important therapeutic strategy for ICH patients. Emerging evidence indicates that C1q/TNF-Related Protein 9 (CTRP9), a newly discovered adiponectin receptor agonist, exerts neuroprotection in cerebrovascular disease. The aim of this study was to investigate the anti-apoptotic role of CTRP9 after experimental ICH and to explore the underlying molecular mechanisms. ICH was induced in mice via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administrated intranasally at 1 h after ICH. To elucidate the underlying mechanisms, adiponectin receptor1 small interfering ribonucleic acid (AdipoR1 siRNA) and selective PI3 K inhibitor LY294002 were administered prior to rCTRP9 treatment. Western blots, neurofunctional assessments, immunofluorescence staining, and Fluoro-Jade C (FJC) staining experiments were performed. Administration of rCTRP9 significantly improved both short- and long-term neurofunctional behavior after ICH. RCTRP9 treatment significantly increased the expression of AdipoR1, PI3 K, p-Akt, and Bcl-2, while at the same time was found to decrease the expression of Bax in the brain, which was reversed by inhibition of AdipoR1 and PI3 K. The neuroprotective effect of rCTRP9 after ICH was mediated by attenuation of neuronal apoptosis via the AdipoR1/PI3K/Akt signaling pathway; therefore, rCTRP9 should be further evaluated as a potential therapeutic agent for ICH patients.

The metabolic burden caused by hyperglycemia can result in direct and immediate metabolic injuries, such as oxidative stress and tissue inflammation, in the kidney. Furthermore, chronic hyperglycemia can lead to substantial structural changes such as formation of advanced glycation end-products, glomerular and tubular hypertrophy, and tissue fibrosis. Glomerular hypertrophy renders podocytes vulnerable to increased glomerular filtration, leading to podocyte instability and loss. Thus, prevention of glomerular hypertrophy and attenuation of glomerular hyperfiltration may have therapeutic potential for diabetic nephropathy (DN). Adiponectin is an adipokine that improves insulin sensitivity in obesity-related metabolic disorders, including diabetes, but its efficacy is unknown. Moreover, the recently developed adiponectin receptor agonist, AdipoRon, shows therapeutic potential for DN. In this review, we focus on the role of glomerular hypertrophy in the pathogenesis of DN and discuss the role of adiponectin in its prevention.

Adiponectin (APN) is an adipocytokine, secreted from adipose tissue and has anti-inflammatory, anti-ageing, and antidiabetic properties. Hyperglycaemia can damage the renal cells, and mammalian target of rapamycin (mTOR), along with Sirtuin 1 (SIRT1), have an important role in kidney cell response to hyperglycaemia. Therefore, understanding the relationship between adiponectin, mTOR, and SIRT1 proteins is beneficial for deciphering the mechanism of adiponectin function. In this study, Human Embryonic Kidney-293 (HEK-293) cells were cultured under normal and high-glucose condition, with and without APN (1, 10, and 100 ng/mL) for 48 hours. mTOR protein expression was evaluated by western blot analysis, and SIRT1 protein was assessed using ELISA method. To evaluate hyperglycaemia-mediated cytotoxicity, cell viability was determined using MTT assay. Data showed that APN in high dose (100 ng/mL) significantly reduced the expression of mTOR and p-mTOR, increased SIRT1 protein, and also improved cell viability compared with the control high glucose (p ≤ 0.05). According to this results, APN can be useful in preventing renal cell damage, by affecting on the expression of mTOR and SIRT1 proteins, as well as increasing the survival of kidney cells in hyperglycaemia conditions. SIGNIFICANCE OF THE STUDY: Adiponectin triggered mTOR/p-mTOR/SIRT1 pathway and decreased cell death in human kidney cells. Our findings provide preliminary experimental data that support further studies on the potential therapeutic role of adiponectin in diabetes and diabetic-induced metabolic complications., (© 2019 John Wiley & Sons, Ltd.)

Recurrent spontaneous abortion is associated with abnormal maternal tolerance to the semi-allogenic fetus, wherein the Th17/Treg axis plays a crucial role. Adiponectin (APN) is an adipocytokine that is shown to be a novel negative T-cell regulator and induce immune tolerance. The CBA/J × DBA/2 mating was used as an abortion-prone model to investigate whether the addition of recombinant adiponectin (rAPN) improves the pregnancy outcome. Recombinant adiponectin therapy reduced the abortion rate in abortion-prone model. It skewed the ability of serum cytokine production toward a Treg bias and induced APN production. Flow cytometry revealed that rAPN administration expanded the splenic CD4+CD25+ regulatory T-cell (Treg) population and reduced the Th17 cell populations in CBA/J × DBA/2 matings. RT-PCR revealed that rAPN administration induced the expression of AdipoR1 and AdipoR2 mRNA at the maternofetal interface. Recombinant adiponectin administration induced FoxP3 and reduced RORγt expressions at the maternofetal interface. In vitro experiment also showed that rAPN treatment enhanced the FoxP3 mRNA and protein expression and decreased the RORγt expression in splenic lymphocytes of abortion-prone mice. Blocking the different signal transduction pathways downstream of APN, p38MAPK inhibitor (SB203580) and STAT5 inhibitor (Pimozide) could abrogate the regulatory effect of rAPN on FoxP3 and RORγt expression, while STAT3 inhibitor (Stattic) and AMPK inhibitor (p5499) did not exert any influence. Thus, the current results demonstrated that rAPN therapy improves pregnancy outcome in a murine model of abortion by expanding the Treg cell population and function and decreasing the Th17 cell population and function via a p38MAPK-STAT5 pathway., (© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

There are very limited clinically viable treatment options for acute liver failure, a life-threatening condition that rapidly progresses to loss of liver function. In this study, we aim to evaluate the therapeutic potential of UCBP for acute liver failure induced in a rat model by D-galactosamine (GalN). F344 rats were randomly divided into two groups (control and UCBP-treated) after GalN injection. The therapeutic effects of UCBP were evaluated based on survival rate, H&E staining, TUNEL, PCNA staining, and in vivo BrdU labeling. Hepatocyte proliferation and the therapeutic mechanisms of UCBP were examined with BrdU and Western blot assay in vitro. The survival rate in the UCBP-treated group was found to be increased compared to the control group (85 vs 55%, P = 0.029). UCBP treatment significantly decreased apoptosis and increased cell proliferation. These effects may be secondary to specific bioactive molecules in UCBP. In vitro experiments revealed that adiponectin is one of the key biologically active components of UCBP in facilitating this result and promoting hepatocyte proliferation. Furthermore, this effect is mediated by p38/ERK mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, this uncomplicated and clinically accessible approach may serve as effective bridge therapy for acute liver failure.