New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver?

Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.

Effects of Torulaspora delbrueckii co-fermented with Saccharomyces cerevisiae on physicochemical and aromatic profiles of blueberry fermented beverage.

To investigate the effects of mixed fermentation with T. delbrueckii on aroma profiles of blueberry fermented beverage, five fermentations were conducted: monoculture of T. delbrueckii and S. cerevisiae, respectively; co-inoculation of two strains; sequential inoculation of two strains at time intervals of 24 h and 48 h, respectively. Compared with pure S. cerevisiae fermentation, ethanol level was decreased by up to 1.1% vol., while total anthocyanins were increased by 27.7%-85.0% in mixed fermentations. Marker aroma compounds in different fermentations with relative odor activity values higher than 1were identified. T. delbrueckii significantly decreased volatile acid content (especially acetic acid) by 22.2%-83.3%. Ethyl 3-methylbutanoate, ethyl hexanoate and ethyl octanoate, in pure T. delbrueckii fermentation were significantly decreased, while their concentrations were increased by 1.6-4.4 folds in sequential fermentations. Besides, linalool, rose oxide, benzeneacetaldehyde were significantly increased by sequential fermentation, which was associated with the enhancement of fruity and sweet notes.

Organokines and Exosomes: Integrators of Adipose Tissue Macrophage Polarization and Recruitment in Obesity.

The prevalence of obesity is escalating and has become a worldwide health challenge coinciding with the development of metabolic diseases. Emerging evidence has shown that obesity is accompanied by the infiltration of macrophages into adipose tissue, contributing to a state of low-grade chronic inflammation and dysregulated metabolism. Moreover, in the state of obesity, the phenotype of adipose tissue macrophages switches from the M2 polarized state to the M1 state, thereby contributing to chronic inflammation. Notably, multiple metabolic organs (adipose tissue, gut, skeletal muscle, and the liver) communicate with adipose tissue macrophages via secreting organokines or exosomes. In this review, we systematically summarize how the organokines (adipokines, gut microbiota and its metabolites, gut cytokines, myokines, and hepatokines) and exosomes (adipocyte-, skeletal muscle-, and hepatocyte-derived exosomes) act as important triggers for macrophage recruitment in adipose tissue and adipose tissue macrophage polarization, thus providing further insight into obesity treatment. In addition, we also highlight the complex interaction of organokines with organokines and organokines with exosomes, revealing new paths in understanding adipose tissue macrophage recruitment and polarization.

Adipose endothelial cells mastering adipose tissues metabolic fate.

Dynamic communication within adipose tissue depends on highly vascularized structural characteristics to maintain systemic metabolic homoeostasis. Recently, it has been noted that adipose endothelial cells (AdECs) act as essential bridges for biological information transmission between adipose-resident cells. Hence, paracrine regulators that mediate crosstalk between AdECs and adipose stromal cells were summarized. We also highlight the importance of AdECs to maintain adipocytes metabolic homoeostasis by regulating insulin sensitivity, lipid turnover and plasticity. The differential regulation of AdECs in adipose plasticity often depends on vascular density and metabolic states. Although choosing pro-angiogenic or anti-angiogenic therapies for obesity is still a matter of debate in clinical settings, the growing numbers of drugs have been confirmed to play an anti-obesity effect by affecting vascularization. Pharmacologic angiogenesis intervention has great potential as therapeutic strategies for obesity.

A computational model of pig ventricular cardiomyocyte electrophysiology and calcium handling: Translation from pig to human electrophysiology.

The pig is commonly used as an experimental model of human heart disease, including for the study of mechanisms of arrhythmia. However, there exist differences between human and porcine cellular electrophysiology: The pig action potential (AP) has a deeper phase-1 notch, a longer duration at 50% repolarization, and higher plateau potentials than human. Ionic differences underlying the AP include larger rapid delayed-rectifier and smaller inward-rectifier K+-currents (IKr and IK1 respectively) in humans. AP steady-state rate-dependence and restitution is steeper in pigs. Porcine Ca2+ transients can have two components, unlike human. Although a reliable computational model for human ventricular myocytes exists, one for pigs is lacking. This hampers translation from results obtained in pigs to human myocardium. Here, we developed a computational model of the pig ventricular cardiomyocyte AP using experimental datasets of the relevant ionic currents, Ca2+-handling, AP shape, AP duration restitution, and inducibility of triggered activity and alternans. To properly capture porcine Ca2+ transients, we introduced a two-step process with a faster release in the t-tubular region, followed by a slower diffusion-induced release from a non t-tubular subcellular region. The pig model behavior was compared with that of a human ventricular cardiomyocyte (O'Hara-Rudy) model. The pig, but not the human model, developed early afterdepolarizations (EADs) under block of IK1, while IKr block led to EADs in the human but not in the pig model. At fast rates (pacing cycle length = 400 ms), the human cell model was more susceptible to spontaneous Ca2+ release-mediated delayed afterdepolarizations (DADs) and triggered activity than pig. Fast pacing led to alternans in human but not pig. Developing species-specific models incorporating electrophysiology and Ca2+-handling provides a tool to aid translating antiarrhythmic and arrhythmogenic assessment from the bench to the clinic.

High Serum Asprosin Levels Are Associated with Presence of Metabolic Syndrome.

OBJECTIVE: Asprosin, a new adipocytokine, has reportedly been associated with glucose release, dyslipidemia, and insulin resistance (IR). However, the relationship of asprosin with metabolic syndrome (MetS) remains unknown. This study aimed to investigate serum asprosin levels in MetS as well as their association with various metabolic parameters in humans. METHODS: A total of 131 consecutive patients with MetS, and 162 age-matched, healthy subjects were recruited for this study. Serum asprosin concentrations were determined using the enzyme-linked immunosorbent assay. Lipid profile, glucose, insulin, and inflammatory markers were also measured. RESULTS: Serum asprosin levels were higher in subjects with MetS (23.52 [16.70, 32.05] ng/mL) than in controls (16.70 [12.87, 22.38] ng/mL; P < 0.01), and they showed an increasing trend with increasing numbers of metabolic components (P for trend < 0.01). In all studied subjects, serum asprosin levels were positively correlated with body mass index, waist circumference, triglycerides, fasting plasma glucose, 2-hour plasma glucose, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) index, interleukin-6, and monocyte chemoattractant protein-1 and negatively correlated with high-density lipoprotein cholesterol (P < 0.05). In multiple linear regression, asprosin was independently and positively correlated with triglyceride and HOMA-IR (P < 0.05). Binary logistic regression revealed that asprosin was independently and positively correlated with the occurrence of MetS and IR, even after controlling for anthropometric variables, lipid profiles, and inflammatory markers. CONCLUSION: Asprosin is a potential metabolic-related adipokine and may be related to IR and MetS. This trial was registered with ChiCTR, ChiCTR1800018347.

Role of atrial arrhythmia and ventricular response in atrial fibrillation induced atrial remodelling.

AIMS: No studies have assessed the specific contributions of atrial fibrillation (AF)-related atrial vs. associated ventricular arrhythmia to remodelling. This study assessed the roles of atrial arrhythmia vs. high ventricular rate in AF-associated remodelling. METHODS AND RESULTS: Four primary dog-groups (12/group) were subjected to 3-week pacing: 600-b.p.m. atrial tachypacing maintaining AF [AF w/o- atrioventricular block (AVB)]; atrial tachypacing with atrioventricular-node ablation (AF+AVB) and ventricular-demand pacing (80 b.p.m.); 160-b.p.m. ventricular-tachypacing (V160) reproducing the response rate during AF; and sinus rhythm with AVB/ventricular-pacing at 80-b.p.m. (control group). At terminal study, left-atrial (LA) effective refractory period (ERP) was reduced equally in both AF groups (w/o-AVB and AF+AVB). AF-inducibility was increased strongly in AF groups (w/o-AVB and AF+AVB) and modestly in V160. AF duration was significantly increased in AF w/o-AVB but not in AF+AVB or V160. Conduction velocity was decreased in AF w/o-AVB, to a greater extent than in AF+AVB and V160. Atrial fibrous-tissue content was increased in AF w/o-AVB, AF+AVB and V160, with collagen-gene up-regulation only in AF w/o-AVB. Connexin43 gene expression was reduced only in AF w/o-AVB. An additional group of 240-b.p.m. ventricular tachypacing dogs (VTP240; to induce heart failure) was studied: vs. other tachypaced groups, VTP240 caused greater fibrosis, but no change in LA-ERP or AF-inducibility. VTP240 also increased AF duration, strongly decreased left ventricular ejection fraction, and was the only group with LA natriuretic-peptide activation. CONCLUSION: The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodelling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodelling and novel considerations for ventricular rate-control.

Inositol Trisphosphate Receptors and Nuclear Calcium in Atrial Fibrillation.

RATIONALE: The mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca2+ regulates gene expression, but the nature and significance of nuclear Ca2+-changes in AF are largely unknown. OBJECTIVE: To elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca2+ ([Ca2+]Nuc) and CaMKII (Ca2+/calmodulin-dependent protein kinase-II)-related signaling. METHODS AND RESULTS: Atrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing [600 bpm × 1 week]). [Ca2+]Nuc and cytosolic [Ca2+] ([Ca2+]Cyto) were recorded via confocal microscopy. Diastolic [Ca2+]Nuc was greater than [Ca2+]Cyto under control conditions, while resting [Ca2+]Nuc was similar to [Ca2+]Cyto; both diastolic and resting [Ca2+]Nuc increased with AF. IP3R (Inositol-trisphosphate receptor) stimulation produced larger [Ca2+]Nuc increases in AF versus control cardiomyocytes, and IP3R-blockade suppressed the AF-related [Ca2+]Nuc differences. AF upregulated nuclear protein expression of IP3R1 (IP3R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca2+]Nuc changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP3R knockdown with short-interfering RNA directed against IP3R1. Nuclear/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP3R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP3R1-expression was significantly increased, with decreased nuclear/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP3R1 upregulation and nuclear diastolic Ca2+-loading. CONCLUSIONS: AF increases atrial-cardiomyocyte nucleoplasmic [Ca2+] by IP3R1-upregulation involving miR-26a, leading to enhanced IP3R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation. Graphic Abstract: A graphic abstract is available for this article.

Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation-remodeled hearts.

Atrial fibrillation (AF) alters atrial cardiomyocyte (ACM) Ca2+ handling, promoting ectopic beat formation. We examined the effects of AF-associated remodeling on Ca2+-related action potential dynamics and consequences for AF susceptibility. AF was maintained electrically in dogs by right atrial (RA) tachypacing. ACMs isolated from AF dogs showed increased Ca2+ release refractoriness, spontaneous Ca2+ spark frequency, and cycle length (CL) threshold for Ca2+ and action potential duration (APD) alternans versus controls. AF increased the in situ CL threshold for Ca2+/APD alternans and spatial dispersion in Ca2+ release recovery kinetics, leading to spatially discordant alternans associated with reentrant rotor formation and susceptibility to AF induction/maintenance. The clinically available agent dantrolene reduced Ca2+ leak and CL threshold for Ca2+/APD alternans in ACMs and AF dog right atrium, while suppressing AF susceptibility; caffeine increased Ca2+ leak and CL threshold for Ca2+/APD alternans in control dog ACMs and RA tissues. In vivo, the atrial repolarization alternans CL threshold was increased in AF versus control, as was AF vulnerability. Intravenous dantrolene restored repolarization alternans threshold and reduced AF vulnerability. Immunoblots showed reduced expression of total and phosphorylated ryanodine receptors and calsequestrin in AF and unchanged phospholamban/SERCA expression. Thus, along with promoting spontaneous ectopy, AF-induced Ca2+ handling abnormalities favor AF by enhancing vulnerability to repolarization alternans, promoting initiation and maintenance of reentrant activity; dantrolene provides a lead molecule to target this mechanism.

Betatrophin knockdown induces beiging and mitochondria biogenesis of white adipocytes.

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.

Serum CCN3 levels are increased in type 2 diabetes mellitus and associated with obesity, insulin resistance and inflammation.

BACKGROUD: CCN3 is a novel adipokine and has emerged as a potential metabolic regulator. However, information regarding the role of CCN3 in type 2 diabetes mellitus (T2DM) remains unclear. This study measured for the first time serum CCN3 levels in T2DM and explored the correlations between its serum levels and various metabolic parameters in humans. METHODS: A total of 219 newly diagnosed T2DM (nT2DM) patients and 205 healthy control subjects, matched for age and sex ratio, were enrolled. Circulating CCN3 and TNF-α, IL-6 and MCP-1 were measured by ELISA. The anthropometric assessment and biochemical evaluation were done in all subjects. OGTT were performed in 34 healthy individuals to investigate the association of CCN3 with glucose. RESULTS: Serum CCN3 levels were significantly higher in nT2DM patients compared to those of the healthy controls (6.71[4.88, 8.56] vs. 4.51[3.55, 5.99] ng/ml, P < 0.01). Serum CCN3 positively correlated with BMI, WC, FAT%, TG, FPG, 2 h-PG, HbA1c, FIns, HOMA-IR, hs-CRP and TNF-α, IL-6 and MCP-1, but negatively with HOMA-ß in all individuals (P < 0.05). Multiple linear regression analysis indicated that BMI, HOMA-IR, TNF-α and MCP-1 were independently associated with CCN3. Multivariate logistic regression analysis demonstrated that CCN3 was correlated with nT2DM. Finally, area under ROC curve of CCN3 (gender and age adjusted) for predicting the presence of nT2DM was 0.725(95% CI: 0.676-0.773). After an oral glucose challenge, there was no obvious change in the circulating levels of CCN3 as compared to 0 min (P > 0.05). CONCLUSIONS: Elevation of CCN3 in nT2DM supports the hypothesis that CCN3 may serve as a risk factor associated with the pathogenesis of T2DM.

JAZF1, a relevant metabolic regulator in type 2 diabetes.

Excessive adiposity and metabolic inflammation are the key risk factors of type 2 diabetes mellitus (T2DM). Juxtaposed with another zinc finger gene 1 (JAZF1) has been identified as a novel transcriptional cofactor, with function of regulating glucose and lipid homeostasis and inflammation. JAZF1 is involved in metabolic process of T2DM via interaction with several nuclear receptors and protein kinases. Additionally, increasing evidence from genome-wide association studies (GWAS) has shown that JAZF1 polymorphisms are closely associated with T2DM. In this review, we have updated the latest research advances on JAZF1 and discussed its regulatory network in T2DM. The association between JAZF1 polymorphisms and T2DM is discussed as well. The information provided is of importance for guiding future studies as well as for the design of JAZF1-based T2DM therapy.

Serum zinc-α2-glycoprotein levels are elevated and correlated with thyroid hormone in newly diagnosed hyperthyroidism.

BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. METHODS: A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. RESULTS: The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). CONCLUSION: We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. TRIAL REGISTRATION: ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.

Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling.

Aims: Heart failure (HF) produces left atrial (LA)-selective fibrosis and promotes atrial fibrillation. HF also causes adrenergic activation, which contributes to remodelling via a variety of signalling molecules, including the exchange protein activated by cAMP (Epac). Here, we evaluate the effects of Epac1-signalling on LA fibroblast (FB) function and its potential role in HF-related atrial remodelling. Methods and results: HF was induced in adult male mongrel dogs by ventricular tachypacing (VTP). Epac1-expression decreased in LA-FBs within 12 h (-3.9-fold) of VTP onset. The selective Epac activator, 8-pCPT (50 µM) reduced, whereas the Epac blocker ESI-09 (1 µM) enhanced, collagen expression in LA-FBs. Norepinephrine (1 µM) decreased Epac1-expression, an effect blocked by prazosin, and increased FB collagen production. The ß-adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (ß2-AR-blocker), but not by CGP (ß1-AR-blocker). ß-AR-activation with isoproterenol decreased collagen expression, an effect mimicked by the ß2-AR-agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-ß1, known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3-inhibitor SIS3. To evaluate effects on atrial fibrosis in vivo, mice subjected to myocardial infarction (MI) received the Epac-activator Sp-8-pCPT or vehicle for 2 weeks post-MI; Sp-8-pCPT diminished LA fibrosis and attenuated cardiac dysfunction. Conclusions: HF reduces LA-FB Epac1 expression. Adrenergic activation has complex effects on FBs, with α-AR-activation suppressing Epac1-expression and increasing collagen expression, and ß2-AR-activation having opposite effects. Epac1-activation reduces cardiac dysfunction and LA fibrosis post-MI. Thus, Epac1 signalling may be a novel target for the prevention of profibrillatory cardiac remodelling.

Perivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword.

Perivascular adipose tissue (PVAT), the adipose tissue that surrounds most of the vasculature, has emerged as an active component of the blood vessel wall regulating vascular homeostasis and affecting the pathogenesis of atherosclerosis. Although PVAT characteristics resemble both brown and white adipose tissues, recent evidence suggests that PVAT develops from its own distinct precursors implying a closer link between PVAT and vascular system. Under physiological conditions, PVAT has potent anti-atherogenic properties mediated by its ability to secrete various biologically active factors that induce non-shivering thermogenesis and metabolize fatty acids. In contrast, under pathological conditions (mainly obesity), PVAT becomes dysfunctional, loses its thermogenic capacity and secretes pro-inflammatory adipokines that induce endothelial dysfunction and infiltration of inflammatory cells, promoting atherosclerosis development. Since PVAT plays crucial roles in regulating key steps of atherosclerosis development, it may constitute a novel therapeutic target for the prevention and treatment of atherosclerosis. Here, we review the current literature regarding the roles of PVAT in the pathogenesis of atherosclerosis.

Zinc alpha2 glycoprotein protects against obesity-induced hepatic steatosis.

BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation. METHODS: ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes. RESULTS: ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes. CONCLUSIONS: Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.

Ginsenoside improves papillary thyroid cancer cell malignancies partially through upregulating connexin 31.

Connexin 31 (Cx31) is considered a suppressor for many tumors. Ginsenoside (Rg1) is a traditional Chinese herb that is widely acknowledged due to its anti-tumor characteristics. However, limited studies have focused on the role of Rg1 in papillary thyroid cancer (PTC) cells. In the current study, we found that the expression of Cx31 in thyroid cancer tissues and thyroid cancer cell lines was significantly lower than that in normal thyroid epithelial tissues and cell lines. Overexpression of Cx31 reduced thyroid cancer cell proliferation, migration and invasion. Furthermore, we found that Rg1 significantly enhanced the expression of Cx31. Moreover, the proliferation and migration of IHH-4 and BCPAP cells were significantly reduced by Rg1 treatment. In contrast, the silencing of Cx31 enhanced the expression of Ki67 and proliferating cell nuclear antigen (PCNA). Meanwhile, treatment with Rg1 significantly decreased the protein levels of Ki67 and PCNA, but these effects could be abolished by transfection with si-Cx31. In summary, we provide novel evidence that the expression of Cx31 was decreased in thyroid cancer cells, but Rg1 treatment could significantly enhance the expression of Cx31 thereby suppressing thyroid cancer cell proliferation and migration.