The adipokines progranulin and omentin - novel regulators of basic ovarian cell functions.

The present study aimed to examine the effects of progranulin and omentin on basic ovarian cell functions. For this purpose, we investigated the effects of the addition of progranulin and omentin (0, 0.1, 1, or 10 ng/ml) on the viability, proliferation, apoptosis and steroidogenesis of cultured rabbit ovarian granulosa cells. To determine the importance of the interrelationships between granulosa cells and theca cells, we compared the influence of progranulin and omentin on progesterone and estradiol release in cultured granulosa cells and ovarian fragments containing both granulosa cells and theca cells. Cell viability, proliferation, cytoplasmic apoptosis and release of progesterone and estradiol were measured by Cell Counting Kit-8 (CCK-8), BrdU incorporation, cell death detection, and ELISA. Both progranulin and omentin increased granulosa cell viability and proliferation and decreased apoptosis. Progranulin increased progesterone release by granulosa cells but reduced progesterone output by ovarian fragments. Progranulin decreased estradiol release by granulosa cells but increased it in ovarian fragments. Omentin reduced progesterone release in both models. Omentin reduced estradiol release by granulosa cells but promoted this release in ovarian fragments. The present observations are the first to demonstrate that progranulin and omentin can be direct regulators of basic ovarian cell functions. Furthermore, the differences in the effects of these adipokines on steroidogenesis via granulosa and ovarian fragments indicate that these peptides could target both granulosa and theca cells.

Dietary supplementation of Capsicum powder affects the growth, immunoglobulins, pro-inflammatory cytokines, adipokines, meat, and liver histology of aflatoxin B1 exposed broiler chickens.

The effects of dietary supplementation with Capsicum annuum fruit pericarp powder (CPP) and Capsicum annuum fruit seed powder (CSP) on the health and performance of broiler chickens exposed to aflatoxin B1 (AFB1) was investigated. Four dietary groups were established: CON (control), AFT (0.5 mg/kg AFB1), CPAF (0.5 g/kg CPP and 0.5 mg/kg AFB1), and CSAF (0.5 g/kg CSP and 0.5 mg/kg AFB1). The AFT group shows a significant (P < 0.05) reduction in the relative growth rate compared to CON, CPAF, and CSAF. In contrast, the latter two groups exhibit growth rates similar (P > 0.05) to CON. Additionally, immunoglobulin levels (IgG, IgM, and IgA) in the AFT group are significantly (P < 0.05) lower compared to the other treatment groups. Serum interleukin-6 levels in the CPAF and CSAF groups were similar (P > 0.05) to CON but higher (P < 0.05) than in AFT. Tumor necrosis factor-alpha levels were elevated (P < 0.05) in AFT compared to the other treatment groups. Interferon-gamma concentrations in AFT were significantly (P < 0.05) lower than in the other treatment groups. The liver histology reveals that the AFT treatment group has periportal hepatic inflammation. In contrast, the CPAF and CSAF treatment groups exhibit normal hepatic microanatomy. In conclusion, 0.5 g/kg CPAF dietary supplementation may help to ameliorate the adverse effects of AFB1 exposure on broiler chicken health, specifically the growth, immune parameters and liver histology.

Marcadores bioquímicos propuestos para el estudio de la sarcopenia / Proposed biochemical markers for the study of sarcopenia

La sarcopenia asociada a la edad es una condición clínica caracterizada por una disminución en la fuerza, calidad y cantidad de masa muscular así como también en la función muscular. Un biomarcador se define como una característica que es medible objetivamente y evaluable como indicador de un proceso biológico normal, patológico o respuesta terapéutica a una intervención farmacológica. Los marcadores bioquímicos propuestos para el estudio de la sarcopenia pueden ser categorizados en dos grupos. El primero de ellos evalúa el estatus musculoesquelético; este panel de marcadores está formado por miostatina/folistatina, procolágeno aminoterminal tipo III e índice de sarcopenia. El segundo grupo de marcadores bioquímicos evalúa factores causales, para lo cual se sugiere medir el factor de crecimiento insulino-símil tipo 1 (IGF-1), dehidroepiandrosterona (DHEAS), cortisol, facto-res inflamatorios [proteína C reactiva (PCR), interleuquina 6 (IL-6) y factor de necrosis tu-moral (TNF-a)]. Las recomendaciones realiza-das están basadas en la evidencia científica disponible en la actualidad y la disponibilidad de la metodología apropiada para cada uno de los biomarcadores. (AU)

Sarcopenia is a progressive and generalized skeletal muscle disorder defined by decrease in the strength, quality and quantity of muscle mass as well as in muscle function. A biomarker is defined as a feature objectively measured and evaluated as an indicator of a normal biologic process, a pathogenic process or a pharmacologic response to therapeutic intervention. The biochemical markers proposed for the study of sarcopenia may be classified in two groups. The first group evaluates the musculoskeletal status, made up by myostatin/follistatin, N-terminal Type III Procollagen and the sarcopenia index. The second evaluates causal factors, where the measurement of the following is suggested: hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate (DHEAS), cortisol, inflammatory factors [C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a)]. The recommendations made are based on scientific evidence currently available and the appropriate methodology availability for each biomarker. (AU)

Resveratrol and Dulaglutide ameliorate adiposity and liver dysfunction in rats with diet-induced metabolic syndrome: Role of SIRT-1 / adipokines / PPARγ and IGF-1.

BACKGROUND: Adiposity and non-alcoholic fatty liver disease (NAFLD) are common characteristics of metabolic syndrome (MS). Understanding the underlying pathogenesis is crucial for the development of new remedies. Resveratrol controls obesity and glycemic disorders in patients with MS. OBJECTIVES: This study aimed to evaluate the effect of resveratrol and dulaglutide on adipose tissues and liver in rats with MS, declaring their possible mechanisms. METHODS: Rats allocated as Control, MS (induced by a high fat/ high sucrose diet for eight weeks), MS + Resveratrol (30 mg/kg/day orally), and MS + Dulaglutide (0.6 mg/kg twice weekly SC); drugs administration was in the last four weeks. Serum biochemical measurements were done. Liver and visceral fat were processed for biochemistry, histopathology, and immunohistochemistry. RESULTS: MS results demonstrated significantly increased systolic and diastolic blood pressure, anthropometric measurements, serum levels of alanine aminotransferase (ALT), glycemic indices, and lipids with decreased HDL-C. Tissue levels of leptin, malondialdehyde (MDA), and TNF-α reactivity significantly increased. Expression of adiponectin, PPARγ, and insulin growth factor-1 (IGF-1) decreased. Also, Western blotting mRNA gene expression of liver SIRT-1 was down-regulated. Resveratrol and dulaglutide significantly and effectively reversed MS complexity, ameliorating all findings, particularly NAFLD and adiposity-induced inflammation. Resveratrol significantly appears superior to dulaglutide regarding the effects on hemodynamics, lipids, adipokines, IGF-1 levels, and adipocyte size. Parallel, dulaglutide has more influence on glycemic control. CONCLUSION: Protective effects of the drugs may be through correlations between SIRT-1/adipokines/IGF-1 and PPARγ, improving the cross-talk between insulin resistance, obesity markers, liver dysfunction, and TNF-α. Promising multi-beneficial therapies of resveratrol or dulaglutide in MS are recommended clinically for this purpose. Showing the Experimental Design.

Effect of nicotinamide N-methyltransferase on lipid accumulation in 3T3-L1 adipocytes.

Nicotinamide N-methyltransferase (NNMT) is a methylase, and its expression is positively correlated with obesity and insulin resistance. This study aims to detect the effects of NNMT on lipid accumulation, triglyceride content, adipocyte differentiation-related transcription factors, genes related to lipid metabolism, adipokine expression, and autophagy in adipocytes. Lentivirus vectors and eukaryotic expression plasmids were used to interfere with NNMT expression. The Oil Red O method was used to detect lipid accumulation, and colorimetry was used to detect triglyceride levels. The transcription of adipocyte differentiation-related transcription factors (PPARγ, C/EBPα, and SREBP1), lipid metabolism-related genes (FABP4, FAS, FATP1 [SLC27A1], and LPL), adipokines (ADIPOQ and LEP) and autophagy-related genes (Beclin1, ATG7, ATG12, and ATG14) was detected by quantitative real-time polymerase chain reaction (RT-qPCR), and the protein expressions of PPARγ, ADIPOQ, LC3I, LC3II, Beclin1, and P62 were detected by western blot analysis. Compared with the control group, the knockdown of NNMT expression reduced lipid accumulation and triglyceride content in 3T3-L1 cells. The transcription of PPARγ, C/EBPα, SREBP1, FABP4, FASN, FATP1, LPL, Beclin1, ATG7, ATG12, and ATG14 decreased, while ADIPOQ and LEP transcription increased. The expression of PPARγ, LC3I/II, and Beclin1 proteins also decreased, while ADIPOQ and P62 protein expression increased. The over-expression NNMT group showed experimental results opposite to those described above. Interference with the expression of NNMT affects lipid accumulation, triglyceride content after cell differentiation, adipocyte differentiation-related transcription factors, genes related to lipid metabolism, the expression of adipokines, and autophagy in adipocytes.

Asprosin Exerts Pro-Inflammatory Effects in THP-1 Macrophages Mediated via the Toll-like Receptor 4 (TLR4) Pathway.

Adipose tissue is a dynamic endocrine organ, secreting a plethora of adipokines which play a key role in regulating metabolic homeostasis and other physiological processes. An altered adipokine secretion profile from adipose tissue depots has been associated with obesity and related cardio-metabolic diseases. Asprosin is a recently described adipokine that is released in response to fasting and can elicit orexigenic and glucogenic effects. Circulating asprosin levels are elevated in a number of cardio-metabolic diseases, including obesity and type 2 diabetes. In vitro studies have reported pro-inflammatory effects of asprosin in a variety of tissues. The present study aimed to further elucidate the role of asprosin in inflammation by exploring its potential effect(s) in THP-1 macrophages. THP-1 monocytes were differentiated to macrophages by 48 h treatment with dihydroxyvitamin D3. Macrophages were treated with 100 nM recombinant human asprosin, 100 ng/mL lipopolysaccharide (LPS), and 10 µM caffeic acid phenethyl ester (CAPE; an inhibitor of NFκB activation) or 1 µM TAK-242 (a Toll-like receptor 4, TLR4, inhibitor). The expression and secretion of pertinent pro-inflammatory mediators were measured by qPCR, Western blot, ELISA and Bioplex. Asprosin stimulation significantly upregulated the expression and secretion of the pro-inflammatory cytokines: tumour necrosis factor α (TNFα), interleukin-1ß (IL-1ß), IL-8 and IL-12 in vitro. This pro-inflammatory response in THP-1 macrophages was partly attenuated by the treatments with CAPE and was significantly inhibited by TAK-242 treatment. Asprosin-induced inflammation is significantly counteracted by TLR4 inhibition in THP-1 macrophages, suggesting that asprosin exerts its pro-inflammatory effects, at least in part, via the TLR4 signalling pathway.

C1q/tumor necrosis factor-related protein-3 improves microvascular endothelial function in diabetes through the AMPK/eNOS/NO· signaling pathway.

The repair of vascular endothelial cell dysfunction is an encouraging approach for the treatment of vascular complications associated with diabetes. It has been demonstrated that members of C1q/tumor necrosis factor-related protein (CTRP) family may improve endothelial function. Nevertheless, the protective properties of CTRPs in diabetic microvascular complications continue to be mostly unknown. Here, we demonstrate that the C1q-like globular domain of CTRP3, CTRP5, and CTRP9 (gCTRP3, 5, 9) exerted a vasorelaxant effect on the microvasculature, of which gCTRP3 was the most powerful one. In a murine model of type 2 diabetes mellitus, serum gCTRP3 level and endothelial function decreased markedly compared with controls. Two weeks of gCTRP3 treatment (0.5 µg/g/d) enhanced endothelium-dependent relaxation in microvessels, increased nitric oxide (NO·) production, and reduced retinal vascular leakage. In addition, Western blotting in human retinal microvascular endothelial cells indicated that gCTRP3 triggered AMP-activated protein kinase-α (AMPKα), hence increasing the endothelial NO synthase (eNOS) level and NO· production. In addition, incubation with gCTRP3 in vitro ameliorated the endothelial dysfunction induced by high glucose in the branch of the mesenteric artery. Blockade of either eNOS or AMPKα completely abolished the effects of gCTRP3 described above. Taken together, we demonstrate for the first time that gCTRP3 improves impaired vasodilatation of microvasculature in diabetes by ameliorating endothelial cell function through the AMPK/eNOS/NO· signaling pathway. This finding may suggest an effective intervention against diabetes-associated microvascular complications.

The Effect of TLR Agonists and Myokines on Secretory Activity of Adipogenically Differentiated MSC Cultures.

We studied the effect of bacterial pathogen-associated molecular patterns and myokines on the secretion of adipokines by mesenchymal stem cells (MSC) and products of their adipogenic differentiation. The secretion of adiponectin, adipsin, leptin, and insulin by adipogenically differentiated cell cultures was quantitatively determined using multiplex ELISA. MSC obtained from the stromal vascular fraction of human subcutaneous adipose tissue were shown to secrete a known adipokine adipsin. The ability of white adipocytes to secrete significant amounts of insulin (in vitro) has been shown for the first time. Control cultures of white adipocytes secreted much higher levels of adiponectin, leptin, and insulin when compared to other adipocytes cultures. On the other hand, beige and brown adipocyte cultures secreted more adipsin than white adipocyte cultures. The influence of myokine ß-aminoisobutyric acid on the secretion of adipsin in MSC, white, beige, and brown adipocytes was also studied.

CTRP6(C1q/Tumor Necrosis Factor (TNF)-related protein-6) alleviated the sevoflurane induced injury of mice central nervous system by promoting the expression of p-Akt (phosphorylated Akt).

Postoperative cognitive impairment and nervous system damage caused by anesthetics seriously affect patient's postoperative recovery. Recent study has revealed that CTRP6 could alleviate apoptosis, inflammation and oxidative stress of nerve cells, thereby relieving nervous system damage induced by cerebral ischemia reperfusion. However, whether CTRP6 could relieve sevoflurane induced central nervous system injury is unclear. We stimulated C57BL/6 mice with sevoflurane and injected CTRP6 overexpression adenovirus vector. Next, H&E staining and TUNEL assays were performed to examine the effect of CTRP6 on sevoflurane induced injury of central nervous system. Finally, we isolated primary nerve cells of hippocampus. Flow cytometry and commercial kits were used for the detection of apoptosis and ROS levels of these cells. Western blotting was used for the detection of the expression level of p-Akt in central nervous tissues and primary cells. Results showed that sevoflurane induced injury and apoptosis of central nervous tissues. Overexpression of CTRP6 relieved apoptosis and injury of these tissues. CTRP6 inhibited the expression of cleaved caspase-3 and cleaved PARP in these tissues. Sevoflurane promoted apoptosis of primary cells and enhanced the expression of ROS and MDA in these cells. Overexpression of CTRP6 alleviated apoptosis and suppressed production of ROS and MDA in these cells. In addition, CTRP6 also enhanced the expression of p-Akt in primary cells. Taken together, our results suggested that CTRP6 relieved sevoflurane induced injury of central nervous tissues by promoting the expression of p-Akt. Therefore, the targeted drug of CTRP6 should be explored for the remission of these symptoms.

No evidence for change in expression of TBC1D1 and TBC1D4 genes in cultured human adipocytes stimulated by myokines and adipokines.

TBC1D1 and TBC1D4 proteins play analogous, but not identical role in governing insulin-signalling pathway. Little is known about changes in expression levels of TBC1D1 and TBC1D4 genes in mammals, including humans. Number of factors were studied, but data remain controversial. The aim of this study was to evaluate the effect of selected cytokines, adipokines and myokines with known or putative insulin sensitivity regulation activity (adiponectin, irisin, omentin, interleukin 6, leptin, resistin, and tumour necrosis factor) on TBC1D1 and TBC1D4 expression levels in cultured differentiated human adipocytes. No significant differences were found between the adipocytes treated with different stimuli and this effect was determined not dose dependent. It is reasonable to conclude that relative shortage of data showing no change in TBC1D1 and TBC1D4 from literature results from publication bias; therefore, our finding provides additional insight into the role of both genes.

CTRP12 Alleviates Isoproterenol Induced Cardiac Fibrosis via Inhibiting the Activation of P38 Pathway.

C1q/tumor necrosis factor (TNF)-related protein 12 (CTRP12) plays a crucial part in cardiovascular diseases especially the coronary artery disease. Nonetheless, it is unrevealed that whether the CTRP12 participates in the progress of cardiac fibrosis. In this study, we investigated whether CTRP12 regulates pathological myocardial fibrosis. We isolated neonatal rat cardiac fibroblasts were cultured with recombination CTRP12 followed by stimulating with Isoproterenol (ISO, 100 µM) for 24 h. Then the adenovirus were used to achieve the CTRP12-overexpressed fibroblasts. In vivo, the C57/B6 mice were subjected to recombinant human CTRP12 (0.2 µg/g/d) for 2 weeks after injected with Isoproterenol (ISO, 10 mg/kg/d for 3 d then 5 mg/kg/d for 11 d, subcutaneously (s.c.), 2 weeks) and mice were also subjected to adenovirus with P38 overexpressing system to explore the mechanism. As a result, CTRP12 significantly inhibit the transformation of cardiac fibroblasts to myofibroblasts and the transcription of cardiac fibrosis-related proteins induced by ISO in vitro. The administration of CTRP12 can effectively reduce the cardiac fibrosis and enhance the cardiac function in mice hearts. The treatment with CTRP12 did not change the expression level of phosphorylated (p)-smad2, smad4, p-extracellular regulated protein kinases 1/2 and c-Jun N-terminal kinase 1/2, but it suppressed the activation of p38. Cardiac overexpression of p38 could abolish this kind of cardioprotective effects by CTRP12. In summary, the CTRP12 protect against the ISO induced cardiac fibrosis via suppressing the p38 signal pathway.

Adipokine-Modulated Immunological Homeostasis Shapes the Pathophysiology of Inflammatory Bowel Disease.

Inflammatory colon diseases, which are a global health concern, include a variety of gastrointestinal tract disorders, such as inflammatory bowel disease and colon cancer. The pathogenesis of these colon disorders involves immune alterations with the pronounced infiltration of innate and adaptive immune cells into the intestines and the augmented expression of mucosal pro-inflammatory cytokines stimulated by commensal microbiota. Epidemiological studies during the past half century have shown that the proportion of obese people in a population is associated with the incidence and pathogenesis of gastrointestinal tract disorders. The advancement of understanding of the immunological basis of colon disease has shown that adipocyte-derived biologically active substances (adipokines) modulate the role of innate and adaptive immune cells in the progress of intestinal inflammation. The biomedical significance in immunological homeostasis of adipokines, including adiponectin, leptin, apelin and resistin, is clear. In this review, we highlight the existing literature on the effect and contribution of adipokines to the regulation of immunological homeostasis in inflammatory colon diseases and discuss their crucial roles in disease etiology and pathogenesis, as well as the implications of these results for new therapies in these disorders.

Effects of adipokine administration to the hypothalamic preoptic area on body temperature in rats.

The effects of adipokine administration to the hypothalamic preoptic area (POA), which is one of the body temperature (BT) regulation centers in the central nervous system, on BT were investigated in male Wistar rats. BT was measured in conscious rats using telemetry. Insulin-like growth factor-1 (IGF-1), interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 and lipocalin-2 produced hyperthermia, and the effects induced by IL-1ß (25 ng) and IGF-1 (5 µg) were sustainable and remarkable. IL-6 did not show any significant effect. The IGF-1-induced effect was inhibited by pretreatment with IGF binding protein 3 (IGFBP3) or NVP-AEW541 (NVP, a selective inhibitor of type 1 IGF receptor tyrosine kinase, IGF1R TK). NVP-induced inhibition was observed only in the early phase of IGF-1-induced hyperthermia. In addition, IGF-1 increased the IL-1ß concentration in the microdialysate of POA perfusion, but did not increase the IL-1ß concentration in the plasma or the PGE2 concentration in the microdialysate. These findings suggested that IGF-1 produced hyperthermia, which was mediated, at least a part, through an increased IL-1ß concentration after activation of IGF1R TK in the POA, and the IGF-IGFBP system possibly participates in BT homeostasis in the POA.

Adipokines and Inflammation Alter the Interaction Between Rheumatoid Arthritis Synovial Fibroblasts and Endothelial Cells.

Objective: The long-distance migration of rheumatoid arthritis synovial fibroblasts (RASFs) in the severe combined immunodeficiency (SCID) mouse model of rheumatoid arthritis (RA) suggests that an interaction between RASFs and endothelial cells (EC) is critical in this process. Our objective was to assess whether immunomodulatory factors such as adipokines and antirheumatic drugs affect the adhesion of RASFs to ECs or the expression of surface molecules. Methods: Primary ECs or human umbilical vein endothelial cell (HUVEC) and primary RASFs were stimulated with adiponectin (10 µg/mL), visfatin (100 ng/mL), and resistin (20 ng/mL) or treated with methotrexate (1.5 and 1,000 µM) and the glucocorticoids prednisolone (1 µM) and dexamethasone (1 µM), respectively. The expression of adhesion molecules was analyzed by real-time polymerase chain reaction. The interaction of both cell types was analyzed under static (cell-to-cell binding assay) and dynamic conditions (flow-adhesion assay). Results: Under static conditions, adipokines increased mostly binding of RASFs to EC (adiponectin: 40%, visfatin: 28%, tumor necrosis factor α: 49%). Under flow conditions, visfatin increased RASF adhesion to HUVEC (e.g., 0.5 dyn/cm2: 75.2%). Reduced adhesion of RASFs to E-selectin was observed after treatment with dexamethasone (e.g., 0.9 dyn/cm2: -40%). In ECs, tumor necrosis factor α (TNF-α) increased expression of intercellular adhesion molecule 1 (20-fold) and vascular cell adhesion molecule 1 (77-fold), whereas P-selectin was downregulated after stimulation with TNF-α (-6-fold). Conclusion: The adhesion of RASFs to EC was increased by visfatin under static and flow conditions, whereas glucocorticoids were able to decrease adhesion to E-selectin. The process of migration and adhesion of RASFs to ECs could be enhanced by adipokines via adhesion molecules and seems to be targeted by therapeutic intervention with glucocorticoids.

Omentin-1 attenuates adipose tissue inflammation via restoration of TXNIP/NLRP3 signaling in high-fat diet-induced obese mice.

Omentin-1 is an adipokine expressed by the adipose tissue and is reduced in obesity. This study was designed to calculate the protective efficiency and mechanism of omentin-1 against inflammation of the adipose tissue in obese mice. A transgenic mouse model with omentin-1 protein overexpression was established by crossing omentin-1 transgenic mice with Fabp4-Cre mice. Obesity was induced in the mice by feeding them a high-fat diet for 10 weeks. Fabp4-Cre-mediated overexpression of omentin-1 significantly increased serum omentin-1 level, serum anti-inflammatory factor levels, and expression of M2-specific mRNAs; inhibited body weight and adipose tissue weight gain; improved glucose tolerance, insulin tolerance, and insulin sensitivity; decreased serum levels of insulin and proinflammatory factors, adipocyte size, and expression of M1-specific mRNAs; suppressed macrophage infiltration; downregulated expression of proinflammatory factors; upregulated expression of anti-inflammatory factors; and inhibited thioredoxin-interacting protein (TXNIP)/NOD-like receptor 3 (NLRP3) signaling in the adipose tissue of obese mice. An NLRP3 inhibitor (20 mg/kg MCC950) exhibited the same effects as overexpression of omentin-1. Pretreatment with omentin-1 inhibited lipopolysaccharide-induced inflammation via TXNIP/NLRP3 signaling in RAW 264.7 macrophages. These findings suggest that omentin-1 suppresses adipose tissue inflammation in obese mice, at least partly, via inhibiting the TXNIP/NLRP3 signaling pathway.

C1q/TNF-related protein 6 (CTRP6) attenuates renal ischaemia-reperfusion injury through the activation of PI3K/Akt signalling pathway.

C1q/TNF-related protein 6 (CTRP6) is a member of the CTRP family that has been reported to exhibit a nephroprotective effect. However, the role of CTRP6 in renal ischaemia/reperfusion (I/R) injury (IRI) remains unclear. In the present study, we aimed to explore the protective effect of CTRP6 in renal IRI and the potential mechanism. We found that CTRP6 expression was markedly decreased in the kidneys of mice subjected to I/R and HK-2 cells in response to hypoxia/reoxygenation (H/R) stimulation. Recombinant CTRP6 protein protected against renal I/R injury by the reduction of blood urea nitrogen (BUN) and creatinine levels. The increased production of ROS and malondialdehyde (MDA), as well the decreased activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) caused by H/R induction were mitigated by CTRP6 in HK-2 cells. The caspase-3 activity and apoptotic rate were both decreased in CTRP6-overexpressing HK-2 cells. In addition, we also found that knockdown of CTRP6 aggravated H/R-caused oxidative stress and cell apoptosis in HK-2 cells. Moreover, CTRP6 overexpression enhanced the H/R-stimulated activation of PI3K/Akt pathway in HK-2 cells. Inhibition of PI3K reversed the nephroprotective effects of CTRP6 in HK-2 cells. Taken together, CTRP6 exerted protective effects against H/R-caused oxidative injury in HK-2 cells via activating the PI3K/Akt pathway.

The protective role of omentin-1 in IL-1ß-induced chondrocyte senescence.

Osteoarthritis is a common type of degenerative joint disease. Inflammation-related chondrocyte senescence plays a major role in the pathogenesis of osteoarthritis. Omentin-1 is a newly identified anti-inflammatory adipokine involved in lipid metabolism. In this study, we examined the biological function of omentin-1 in cultured chondrocytes. The presence of omentin-1 potently suppresses IL-1ß-induced cellular senescence as revealed by staining with senescence-associated beta-galactosidase (SA-ß-Gal). At the cellular level, omentin-1 attenuates IL-1ß-induced G1 phase cell-cycle arrest. Mechanistically, we demonstrate that omentin-1 reduced IL-1ß-induced expression of senescent factors including caveolin-1, p21, and PAI-1 as well as p53 acetylation through ameliorating SIRT1 reduction. Notably, silencing of SIRT1 abolishes IL-1ß-induced senescence along with the induction of p21 and PAI-1, suggesting that the action of omentin-1 in chondrocytes is dependent on SIRT1. Collectively, our results revealed the molecular mechanism through which the adipokine omentin-1 exerts a beneficial effect, thereby protecting chondrocytes from senescence. Thus, omentin-1 could have clinical implication in the treatment of osteoarthritis.

The Effects of Progranulin in a Rat Model of Acute Myocardial Ischemia/Reperfusion are Mediated by Activation of the P13K/Akt Signaling Pathway.

BACKGROUND Progranulin is an adipokine, encoded by the progranulin (GRN) gene. Progranulin is expressed in atherosclerosis, but its effects in cardiac ischemia and reperfusion injury are unknown. Therefore, this study aimed to investigate the effects of progranulin in a rat model of acute myocardial ischemia/reperfusion (MI/R) injury in vivo. MATERIAL AND METHODS The model of acute MI/R injury was established in male Wistar rats by ligation of the left anterior descending (LAD) coronary artery for 30 minutes and reperfusion for 60 minutes. Before modeling, one group was treated with progranulin (0.03 µg/kg), and one group was treated with the P13K/Akt inhibitor, LY294002 (3 mg/kg). Left ventricular function (LV) was monitored, including the LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), and changes in LV pressure. At the end of the study, blood and myocardial tissue were examined. Cardiac biochemical markers, histopathology, gene expression, and apoptosis were analyzed. RESULTS Progranulin improved cardiac function following acute MI/R injury and significantly improved recovery of cardiac contractility and LVSP. Progranulin significantly reduced myocyte apoptosis, inflammation, and tissue edema, and was highly expressed in cardiac tissue following MI/R injury. The cardioprotective effect of progranulin was reduced by blocking the P13K/Akt signaling pathway. CONCLUSIONS In the rat model of acute MI/R injury, progranulin had a protective effect on cardiac function and morphology, associated with activation of the P13K/Akt signaling pathway. The mechanisms of the anti-apoptotic, anti-inflammatory, and inotropic effects of progranulin in the setting of acute MI/R injury require further in vivo studies.

Vaspin protects mouse mesenchymal stem cells from oxidative stress-induced apoptosis through the MAPK/p38 pathway.

The aim of the work was to study the influence of vaspin on oxidative stress-induced apoptosis of mouse mesenchymal stem cells (MSCs). MSCs originated from bone marrow of C57BL/6 mouse were treated with vaspin and/or H2O2 in a dose-dependent manner. Cellular viability detected by CCK-8 and cell apoptosis studied by flow cytometry and TUNEL assay were observed in these cells. The protein expressions of PI3K, p-PI3K, Akt, p-Akt, T-ERK1/2, p-ERK1/2, p38, p-p38, JNK, and p-JNK were tested by Western blot. Vaspin had no significant effect on cellular viability, but significantly reduced H2O2-induced apoptosis. Western blot assay showed that pretreatment with vaspin promoted the activation of p-p38. Inhibition of p38 by SB203580 suppressed the protective effect of vaspin on oxidative stress-induced apoptosis. Vaspin inhibits oxidative stress-induced apoptosis of MSCs via the activation of MAPK/p38 signaling pathway. These findings indicate that vaspin is prone to osteoporosis protection.

Adipokines Regulate the Expression of Tumor-Relevant MicroRNAs.

BACKGROUND: Increasing prevalence of obesity requires the investigation of respective comorbidities, including tumor diseases like colorectal, renal, post-menopausal breast, prostate cancer, and leukemia. To date, molecular mechanisms of the malignant transformation of these peripheral tissues induced by obesity remain unclear. Adipose tissue secretes factors with hormone-like functions, the adipokines, and is therefore categorized as an endocrine organ. Current research demonstrates the ability of adipose tissue to alter DNA methylation and gene expression in peripheral tissues, probably affecting microRNA (miR) expression. METHODS: Literature was analyzed for adipokine-regulated miRs. Many of these adipokine upregulated or downregulated miRs exert either oncogenic or anti-tumoral potential. RESULTS: The three selected and analyzed adipokines, adiponectin, leptin, and resistin, induce more strongly oncogenic miRs and simultaneously reduce anti-tumoral miRs than vice versa. This effect is not only true for the pure number of regulated miRs, it is also the case by consideration of the abundance of the respective miR expression based on actual data sets derived from next-generation sequencing. CONCLUSION: The link of obesity and cancer is analyzed under the aspect of adipokine-regulated miRs. At the same time the impact of miR abundance is considered as a regulatory variable. This context offers new strategies for tumor therapy and diagnostics.