Diet-induced Obesity: Pathophysiology, Consequences and Target Specific Therapeutic Strategies.

Diet has emerged as a pivotal factor in the current time for diet-induced obesity (DIO). A diet overloaded with fats and carbohydrates and unhealthy dietary habits contribute to the development of DIO through several mechanisms. The prominent ones include the transition of normal gut microbiota to obese microbiota, under-expression of AMPK, and abnormally high levels of adipogenesis. DIO is the root of many diseases. The present review deals with various aspects of DIO and its target proteins that can be specifically used for its treatment. Also, the currently available treatment strategies have been explored. It was found that the expression of five proteins, namely, PPARγ, FTO, CDK4, 14-3-3 ζ protein, and Galectin-1, is upregulated in DIO. They can be used as potential targets for drug-designing studies. Thus, with these targets, the treatment strategy for DIO using natural bioactive compounds can be a safer alternative to medications and bariatric surgeries.

Does Eta Protein Differentiate Rheumatoid Arthritis from Psoriatic Arthritis?

AIM: The clinical symptoms and laboratory markers of Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) can be very similar, so making a differential diagnosis between these two diseases is often difficult. Serological parameters to be used in differential diagnosis can guide the clinician. This study aimed to investigate the usability of 14-3-3η (eta) protein as a biomarker in the differential diagnosis of PsA and RA, and the relationships between eta protein and disease activity scores and joint erosions in PsA and RA. METHODS: 54 PsA patients, 53 RA patients, and 56 healthy individuals were included in this study. The ELISA (Enzyme-Linked ImunoSorbent Assay) kit was used as a quantitative sandwich enzyme immunoassay technique to detect human eta protein levels. Receiver- operating Characteristic (ROC) curves analysis was used to determine the sensitivity and specificity of the eta protein. RESULTS: Eta protein levels were found to be significantly higher in the RA group than in the PsA [B: -0.341, OR (95% CI): 0.711 (0.556-0.909), p: 0.007] and control [B: -0.225, OR (95% CI): 0.798 (0.641-0.995), p: 0.045] groups. Eta protein median values were significantly higher in patients with joint erosion than in those without [ß= 0.151, OR (95% CI): 1.163 (1.003-1.349), p: 0.046]. CONCLUSION: Eta protein levels are higher in the serum of RA patients than PsA and are associated with joint erosion. Eta protein may be a potential biomarker in the differential diagnosis of RA and PsA. It may represent a possible therapeutic step in the pathophysiological pathways in the development of joint erosion.

Hiding in plain sight: Complex interaction patterns between Tau and 14-3-3ζ protein variants.

Tau protein is an intrinsically disordered protein that plays a key role in Alzheimer's disease (AD). In brains of AD patients, Tau occurs abnormally phosphorylated and aggregated in neurofibrillary tangles (NFTs). Together with Tau, 14-3-3 proteins - abundant cytosolic dimeric proteins - were found colocalized in the NFTs. However, so far, the molecular mechanism of the process leading to pathological changes in Tau structure as well as the direct involvement of 14-3-3 proteins are not well understood. Here, we aimed to reveal the effects of phosphorylation by protein kinase A (PKA) on Tau structural preferences and provide better insight into the interaction between Tau and 14-3-3 proteins. We also addressed the impact of monomerization-inducing phosphorylation of 14-3-3 at S58 on the binding to Tau protein. Using multidimensional nuclear magnetic resonance spectroscopy (NMR), chemical cross-linking analyzed by mass spectrometry (MS) and PAGE, we unveiled differences in their binding affinity, stoichiometry, and interfaces with single-residue resolution. We revealed that the interaction between 14-3-3 and Tau proteins is mediated not only via the 14-3-3 amphipathic binding grooves, but also via less specific interactions with 14-3-3 protein surface and, in the case of monomeric 14-3-3, also partially via the exposed dimeric interface. In addition, the hyperphosphorylation of Tau changes its affinity to 14-3-3 proteins. In conclusion, we propose quite complex interaction mode between the Tau and 14-3-3 proteins.

14-3-3 η ETA protein as a potential marker of joint damage in gout.

INTRODUCTION: The aim of the study is to investigate serum levels of 14-3-3 η (ETA) protein in patients with gout and possible relations with joint damage. METHOD: This cross-sectional study included 43 gout patients and 30 control patients. RESULTS: Serum 14-3-3 η protein levels were significantly higher in gout patients (median [IQR], 3.1 [2.0] vs 2.2 [1.0], p = 0.007). In subgroup analyses of gout patients, serum 14-3-3 η protein levels did not differ between patients with and without a flare, tophaceous disease, elevated CRP and serum uric acid levels and a history of chronic kidney disease; however, were significantly higher in the patients with erosions (Median [IQR], 4.1 [2.7] vs 2.7 [1.5], p = 0.002). According to ROC curve, serum 14-3-3 η protein had 86.0% sensitivity and 30% specifity at a cut-off point of 1.7 ng/mL and had 74.7% sensitivity and 43.3% specifity at a cut-off point of 2.0 ng/mL. CONCLUSION: Our results demonstrated elevated levels of 14-3-3 η protein in gout patients which is more prominent in patients with erosive changes, implying role of 14-3-3 η protein in inflammatory and structural damage related pathways and suggesting a potential as a marker for disease severity.

14-3-3η Proteins as a Diagnostic Marker, Disease Activation Indicator, and Lymphoma Predictor in Patients with Primary Sjögren Syndrome.

BACKGROUND: Primary Sjögren syndrome (PSS) is a chronic, autoimmune, and lymphoproliferative disease of the connective tissue. In patients with PSS, the risk of developing B-cell non-Hodgkin lymphoma (NHL) increases dramatically, with a prevalence of approximately 5%. The 14-3-3 protein isoforms are phospho-serin/phospho-threonine binding proteins associated with many malignant diseases. This study aimed to evaluate the relationship between disease activity parameters and markers predicting lymphoma development in patients with PSS and 14-3-3η proteins. METHODS: This study was designed as an analytical case-control study. A total of 57 PSS patients and 54 healthy volunteers were included in the study. The European League Against Rheumatism (EULAR) Sjögren syndrome disease activity index (ESSDAI) was used to assess systemic disease activity in PSS. Receiver operating characteristic (ROC) analysis was used to test the diagnostic accuracy measures of the analytical results. Multivariable linear regression analysis was used to evaluate the effects of independent variables on the 14-3-3η protein. RESULTS: The 14-3-3η protein serum levels were found to be significantly higher in PSS (2.72 [2.04-4.07]) than healthy controls (1.73 [1.41-2.43]) (P<0.0001). A significant relationship was found between 14-3-3η protein levels and ESSDAI group (ß=0.385, 95%CI=0.318-1.651, P=0.005), hypocomplementemia (C3 or C4) (ß=0.223, 95% CI=0.09-1.983, P=0.048) and purpura (ß=0.252, 95% CI=0.335-4.903, P=0.022), which are accepted as lymphoma predictors. A significant correlation was found between PSS disease activity score ESSDAI and 14-33η protein (ß=0.496, 95% CI=0.079-0.244, P=0.0002). CONCLUSION: 14-3-3η proteins are potential candidates for diagnostic marker, marker of disease activity, and predictor of lymphoma in PSS patients.

A possible mechanism to the antidepressant-like effects of 20 (S)-protopanaxadiol based on its target protein 14-3-3 ζ.

Background: Ginsenosides and their metabolites have antidepressant-like effects, but the underlying mechanisms remain unclear. We previously identified 14-3-3 ζ as one of the target proteins of 20 (S)-protopanaxadiol (PPD), a fully deglycosylated ginsenoside metabolite. Methods: Corticosterone (CORT) was administered repeatedly to induce the depression model, and PPD was given concurrently. The tail suspension test (TST) and the forced swimming test (FST) were used for behavioral evaluation. All mice were sacrificed. Golgi-cox staining, GSK 3ß activity assay, and Western blot analysis were performed. In vitro, the kinetic binding analysis with the Biolayer Interferometry (BLI) was used to determine the molecular interactions. Results: TST and FST both revealed that PPD reversed CORT-induced behavioral deficits. PPD also ameliorated the CORT-induced expression alterations of hippocampal Ser9 phosphorylated glycogen synthase kinase 3ß (p-Ser9 GSK 3ß), Ser133 phosphorylated cAMP response element-binding protein (p-Ser133 CREB), and brain-derived neurotrophic factor (BDNF). Moreover, PPD attenuated the CORT-induced increase in GSK 3ß activity and decrease in dendritic spine density in the hippocampus. In vitro, 14-3-3 ζ protein specifically bound to p-Ser9 GSK 3ß polypeptide. PPD promoted the binding and subsequently decreased GSK 3ß activity. Conclusion: These findings demonstrated the antidepressant-like effects of PPD on the CORT-induced mouse depression model and indicated a possible target-based mechanism. The combination of PPD with the 14-3-3 ζ protein may promote the binding of 14-3-3 ζ to p-GSK 3ß (Ser9) and enhance the inhibition of Ser9 phosphorylation on GSK 3ß kinase activity, thereby activating the plasticity-related CREB-BDNF signaling pathway.

Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein.

In this work, a series of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein were designed and synthesized for treatment of liver cancer. After structural optimization for several rounds, C11 displayed a relatively better affinity with 14-3-3η, as well as the best inhibitory activities against several typical human liver cancer cell lines, including Bel-7402, SMMC-7721, SNU-387, Hep G2 and Hep 3B cells. Compound C11 also displayed best inhibitory activity against chemotherapy-resistant Bel-7402/5-Fu cells. Besides, C11 was rather safe against hERG and possessed moderate T1/2 and CL values in liver microsomes. In anti-proliferation, trans-well and cell apoptosis assays, C11 also showed its huge potential as a potent antitumor agent. Then, Western blot assay was conducted, following analyzed by molecular docking, the anti-proliferative mechanisms of this small-molecule inhibitor were revealed. Moreover, C11 was demonstrated to induce G1-S phase cell cycle arrest in liver cancer cells.

14-3-3η protein is associated with disease activity and osteoporosis in patients with rheumatoid arthritis.

Introduction: This study was designed to explore the potential association of serum 14-3-3η protein level with disease activity and bone mineral density (BMD) in Egyptian patients with rheumatoid arthritis (RA). Patients were recruited from the outpatient clinic at Mansoura University Hospital. Material and methods: One hundred eighty-eight patients with RA and 192 matched controls were enrolled. The rheumatoid arthritis activity parameters were evaluated in RA patients. Bone mineral density was measured. Serum levels of 14-3-3η protein and IL-6 were estimated for all participants by enzyme-linked immunosorbent assays (ELISA). Results: Rheumatoid arthritis patients had a significantly higher median serum 14-3-3η protein level compared to matched controls (p ≤ 0.05). Serum level of 14-3-3η protein was significantly correlated with DAS28-ESR (p ≤ 0.05) and serum IL-6 level (p ≤ 0.05). The rheumatoid arthritis-osteoporosis group had significantly higher serum 14-3-3η protein than the RA-osteopenia group and RA-control group. Similarly, the difference of the serum 14-3-3η protein between the RA-osteopenia group and the RA-control group was significant. In the linear regression analysis, the strongest factors that were associated with BMD in RA patients were the serum level of 14-3-3η protein (p ≤ 0.05), IL-6 (p ≤ 0.05) and DAS28-ESR (p ≤ 0.05). Conclusions: Serum level of 14-3-3η protein was significantly elevated in RA patients compared to controls and is significantly correlated with parameters of activity disease. The RA-osteoporosis group had significantly higher serum 14-3-3η protein than the RA-osteopenia group and RA-control group. Serum 14-3-3η protein can be a promising biomarker to reflect RA activity and predict presence of osteoporosis in RA patients.

Identification and confirmation of 14-3-3 ζ as a novel target of ginsenosides in brain tissues.

BACKGROUND: Ginseng can help regulate brain excitability, promote learning and memory, and resist cerebral ischemia in the central nervous system. Ginsenosides are the major effective compounds of Ginseng, but their protein targets in the brain have not been determined. METHODS: We screened proteins that interact with the main components of ginseng (ginsenosides) by affinity chromatography and identified the 14-3-3 ζ protein as a potential target of ginsenosides in brain tissues. RESULTS: Biolayer interferometry (BLI) analysis showed that 20(S)-protopanaxadiol (PPD), a ginseng saponin metabolite, exhibited the highest direct interaction to the 14-3-3 ζ protein. Subsequently, BLI kinetics analysis and isothermal titration calorimetry (ITC) assay showed that PPD specifically bound to the 14-3-3 ζ protein. The cocrystal structure of the 14-3-3 ζ protein-PPD complex showed that the main interactions occurred between the residues R56, R127, and Y128 of the 14-3-3 ζ protein and a portion of PPD. Moreover, mutating any of the above residues resulted in a significant decrease of affinity between PPD and the 14-3-3 ζ protein. CONCLUSION: Our results indicate the 14-3-3 ζ protein is the target of PPD, a ginsenoside metabolite. Crystallographic and mutagenesis studies suggest a direct interaction between PPD and the 14-3-3 ζ protein. This finding can help in the development of small-molecular compounds that bind to the 14-3-3 ζ protein on the basis of the structure of dammarane-type triterpenoid.

Value of serum collagen triple helix repeat containing-1(CTHRC1) and 14-3-3η protein compared to anti-CCP antibodies and anti-MCV antibodies in the diagnosis of rheumatoid arthritis.

INTRODUCTION: Serological markers are important in the diagnosis of rheumatoid arthritis (RA) and other connective tissues diseases This study explored the clinical value of collagen triple helix repeat containing-1 (CTHRC1) and 14-3-3η protein, compared to routine markers, in the diagnosis of RA. METHODS: We recruited 103 RA patients, 105 non-RA patients (osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus) and 59 healthy controls. CTHRC1, 14-3-3η, anti-cyclic citrullinated peptide antibody (anti-CCP), anti-mutated citrullinated vimentin antibody (anti-MCV), rheumatoid factor and erythrocyte sedimentation rate (ESR) levels were measured, and their diagnostic value for RA evaluated and compared. RESULTS: All laboratory indices were elevated in RA (P < 0.05). Of these, anti-MCV had the highest sensitivity (86.4%) and anti-CCP the highest specificity (94.5%). The areas under the curve (AUC) of CTHRC1, 14-3-3η, anti-CCP, anti-MCV, rheumatoid factor and ESR were 0.84, 0.81, 0.89, 0.91, 0.85 and 0.77 respectively (all P < 0.01). Anti-CCP and anti-MCV were the most valuable in the diagnosis of RA. The combination of anti-CCP and anti-MCV had the maximum Youden index, followed by the combination of anti-CCP and 14-3-3η. Binary logistic regression analysis showed that 14-3-3η had the largest odds ratio value (95% CI) at 5.1 (2.1-12.5) for RA. CONCLUSION: CTHRC1 and 14-3-3η are promising serological indicators of RA, and when combined with anti-CCP, anti-MCV and ESR, can improve the diagnosis of this disease.

Genomics Links Inflammation With Neurocognitive Impairment in Children Living With Human Immunodeficiency Virus Type-1.

BACKGROUND: We identified host single-nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children. METHODS: Whole-exome sequencing (WES) was performed on 217 PHIV with cognitive score for age (CSA) < 70 and 247 CSA ≥ 70 (discovery cohort [DC]). SNVs identified in DC were evaluated in 2 validation cohorts (VC). Logistic regression was used to estimate adjusted odds ratios (ORs) for NCI. A human microglia NLRP3 inflammasome assay characterized the role of identified genes. RESULTS: Twenty-nine SNVs in 24 genes reaching P ≤ .002 and OR ≥ 1.5 comparing CSA < 70 to CSA ≥ 70 were identified in the DC, of which 3 SNVs were identified in VCs for further study. Combining the 3 cohorts, SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (P < .0001); RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (P < .0001 and P < .001, respectively). Knockdown of CCRL2 led to decreased microglial release of IL-1ß following exposure to ssRNA40 while knockdown of RETREG1 and YWHAH resulted in increased IL-1ß release. CONCLUSIONS: Using WES and 2 VCs, and gene silencing of microglia we identified 3 genetic variants associated with NCI and inflammation in HIV-infected children.

The association among 14-3-3η protein, inflammation, bone remodeling and osteoporosis in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the correlation among 14-3-3η protein, inflammation, bone remodeling and osteoporosis in patients with rheumatoid arthritis. METHODS: In this cross-sectional study, the RA patients treated in our hospital were analyzed between January 2015 and November 2019. Bone mineral density was measured using dual energy X-ray absorptiometry, and at the beginning of the study, serum samples were collected and the level of 14-3-3η, TNF-α, and IL-6 was tested using the quantitative enzyme-linked immunosorbent assay, and I-CTX and PINP were measured using automatic electrochemical luminescence immune-analyzer for all the participants. RESULTS: In the current study, 285 patients with rheumatoid arthritis were enrolled and assigned into normal, osteopenia, and osteoporotic group respectively. The level of 14-3-3η and IL-6 presented with the highest value in the osteoporosis group, but the lowest value in the normal group, and there were significant differences in the level of 14-3-3η and IL-6 among the groups (p<0.05), and there was positive correlation between 14-3-3η and IL-6 (p<0.05). There were significant differences in PINP and I-CTX among the three groups (p<0.05), and a significantly positive correlation between I-CTX and 14-3-3η (p<0.05) and a significantly negative correlation between PINP and 14-3-3η (p<0.05) were found. CONCLUSION: There was a significant correlation among 14-3-3η protein, inflammation, bone remodeling and osteoporosis in patients with rheumatoid arthritis, the influence of 14-3-3η on osteoporosis may be contributed to its adjusting inflammation and bone remodeling.

Heat shock protein 90 alpha and 14-3-3η in postmenopausal osteoporotic rats with varying levels of serum FSH.

PURPOSE: This study compared the severity of osteoporosis and screened differentially expressed proteins in postmenopausal osteoporotic rats with varying levels of serum follicle stimulating hormone (FSH). METHODS: Thirty-six Sprague Dawley female rats were divided into four groups: sham operation (sham) group, ovariectomy (OVX) group, FSH and ovariectomy (OVX + FSH) group, and Leuprorelin (LE) and ovariectomy group (OVX + LE). Body weight, serum estradiol, FSH, tartrate-resistant acid phosphatase, alkaline phosphatase, and bone mineral density were measured. We randomly selected six rats each from the OVX and OVX + FSH groups to detect differentially expressed proteins by data-independent acquisition, and we verified the results in the remaining six rats by enzyme-linked immunosorbent assay (ELISA). RESULTS: Nineteen proteins were upregulated and 36 proteins were downregulated in the OVX + FSH group. The expression of heat shock protein 90 alpha (Hsp90α) and 14-3-3η protein was significantly different between the OVX and OVX + FSH groups, and both were linearly correlated with bone trabecular area. Results were verified by ELISA and were found to be consistent with the results of data-independent acquisition. DISCUSSION: In rats with high serum FSH, expression of Hsp90α protein was increased and expression of 14-3-3η protein was decreased. Both changes in protein expression were strongly correlated with bone trabecular area.

Serum 14-3-3η protein is associated with clinical and serologic features of Sjögren's syndrome in patients with systemic lupus erythematosus: a cross-sectional analysis.

INTRODUCTION/OBJECTIVES: Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) may coexist and carry a higher risk for future comorbidities. Although 14-3-3η protein is recently a known diagnostic marker in rheumatoid arthritis (RA), its role has not been investigated in SLE. The aim of this study was to compare serum 14-3-3η protein level in SLE and RA patients and to examine its association with clinical and laboratory features in SLE patients. METHODS: Eighty-four SLE patients and 39 RA patients were included. Sociodemographic, SLE disease activity index (SLEDAI), and damage index were assessed for SLE patients. Data about secondary SS were collected. 14-3-3η was measured by ELISA; titres above 0.19 ng/ml were considered positive. RESULTS: Serum 14-3-3η protein in SLE was significantly lower than in RA (0.37 ± 0.09 vs 1.5 ± 0.51; p < 0.001). 14-3-3η protein level was comparable between SLE patients with and without arthritis (0.29 ± 0.8 vs 0.15 ± 0.08 respectively; p = 0.20). Serum 14-3-3η protein level was higher in SLE with secondary SS features compared to those without (0.22 ± 0.10 IU/ml vs 0.11 ± 0.04 IU/ml; respectively, p < 0.001). There were no differences in 14-3-3η positivity for other lupus criteria or correlation of 14-3-3η titer with SLEDAI. 14-3-3η protein at 1.11 ng/mL yield a secondary SS diagnostic accuracy of 71%. CONCLUSIONS: Serum 14-3-3η protein level is high in SLE-associated SS. The 14-3-3η protein level was able to distinguish patients with secondary SS among patients with SLE. Studying the role of 14-3-3η protein in Sjögren's syndrome would be considered in further larger scale studies to confirm the impact of any association. Key Points • Serum 14-3-3η protein level is significantly higher in systemic lupus patients with secondary Sjögren's syndrome (SS) in comparison to those without. • Serum 14-3-3η protein can be used as a useful marker to distinguish patients with secondary SS among patients with systemic lupus. • 14-3-3η protein level shows no difference between systemic lupus patients with and without arthritis.

14-3-3η Protein in Rheumatoid Arthritis: Promising Diagnostic Marker and Independent Risk Factor for Osteoporosis.

BACKGROUND: Early identification and disease monitoring are challenges facing rheumatologists in the management of rheumatoid arthritis (RA). METHODS: We utilized enzyme-linked immunosorbent assay (ELISA) to determine 14-3-3η and anticyclic citrullinated peptide antibody (anti-CCP) levels, with rheumatoid factor (RF) level detected by rate nephelometry. The diagnostic value of each index was determined via receiver operating characteristic (ROC) curve, and the association between 14-3-3η and osteoporosis was assessed using multiple logistic regression analysis. RESULTS: Serum levels of 14-3-3η were 3.26 ng per mL in patients with RA. These levels were helpful in identifying patients with the disease, with the area under the curve (AUC) being 0.879 and 0.853, respectively, from all healthy control individuals and patients with RA. Combining 14-3-3η with RF or anti-CCP increased the diagnostic rate. Logistic regression analysis identified 14-3-3η as an independent risk factor for RA-related osteoporosis (odds ratio [OR], 1.503; 95% confidence interval [CI], 1.116-2.025; P <.01). CONCLUSIONS: Serum 14-3-3η detection by itself or combined with other serum indices was helpful in differentiating patients with RA. Also, it was a promising biomarker for disease monitoring in RA.

14-3-3η Protein in serum and synovial fluid correlates with radiographic damage and progression in a longitudinal evaluation of patients with established rheumatoid arthritis.

Objectives: The aim of the study is to examine the association between 14-3-3η protein levels in both serum and synovial fluid (SF) with various parameters in a longitudinal cohort of patients with established rheumatoid arthritis (RA).Methods: Serum and SF samples were obtained from RA patients and 14-3-3η levels were measured. Radiological damage and progression were evaluated using Sharp/van der Heijde score (SHS) at study entry and at 2-years follow-up.Results: A total of 39 RA patients were included with a mean disease duration of 9.6 ± 8 years. Levels of 14-3-3η were two-fold higher in SF than in serum (mean of 3.7 versus 1.7 ng/mL, respectively). While no significant association was found between 14-3-3η levels with disease activity or other laboratory assessments, both serum and SF 14-3-3η levels positively correlated with radiographic damage at baseline (SHS; p < .001). SF, but not serum, 14-3-3η levels correlated with absolute progression (p < .03).Conclusion: 14-3-3η levels are significantly higher in RA SF than in serum in an established RA cohort. Serum and SF 14-3-3η levels correlate with radiographic damage at baseline and at 2-years follow-up. This study further substantiates the utility of 14-3-3η as a biomarker for mechanistic joint damage in established RA.

14-3-3η protein: a promising biomarker for rheumatoid arthritis.

Effective management of rheumatoid arthritis (RA) depends on early identification followed by timely invention and proper monitoring of treatment responses which remain challenges facing rheumatologists for lacking biomarkers of high sensitivity and specificity. 14-3-3η has been reported to be a novel RA-related biomarker inducing the expression of multiple factors mediating the pathogenesis of RA, and increasing the diagnostic capture when combined with rheumatoid factor and anticyclic citrullinated peptide antibody. Besides, elevated serum 14-3-3η was relevant to more serious joint erosion and worse therapy outcomes. Here, we summarized the emerging knowledge regarding the roles 14-3-3η plays in RA and its clinical implications as diagnostic, prognostic and therapeutic response surrogate as well as potential drug target for RA.

Clinical significance of detecting HLA-DR, 14-3-3η protein and d-dimer in the diagnosis of rheumatoid arthritis.

AIM: To investigate the clinical significance of detecting several biomarkers collectively in the diagnosis of rheumatoid arthritis (RA). METHODS: 128 RA patients, 174 non-RA patients and 80 healthy controls were enrolled. HLA-DR4 and HLA-DR53 were detected by the PCR-SSP method, 14-3-3η protein, anti-CCP and anti-Sa were detected by ELISA and DD was detected by latex immunoturbidimetric assay. RESULTS: The positive rates of HLA-DR4, HLA-DR53, 14-3-3η protein, anti-CCP and anti-Sa were obviously higher in the RA group (43.8, 38.3, 51.6, 80 and 40.6%, respectively); anti-CCP was of highest sensitivity (79.68%), highest specificity (97.5%) and Youden index (0.77). The AUC of 14-3-3η protein, DD, anti-CCP, anti-Sa were 0.813, 0.859, 0.930, 0.861, respectively. CONCLUSION: All biomarkers were strongly correlated risk factors for RA; the combination of multiple biomarkers might be of help for diagnostic and therapeutic strategies in RA of recent onset.

Elevated serum 14-3-3η protein may be helpful for diagnosis of early rheumatoid arthritis associated with secondary osteoporosis in Chinese population.

Osteoporosis (OP) is one of the signs of bone damage in rheumatoid arthritis (RA). The 14-3-3η protein is an inflammatory protein, which has been reported to be associated with rheumatoid arthritis (RA). This is to determine the serum levels of 14-3-3η protein, evaluate its diagnostic value in early RA, and clear out its significance in RA with secondary osteoporosis. Two hundred fifty-nine RA patients and 80 age and sex-matched healthy controls were included. Assays of serum 14-3-3η protein were done for all participants by enzyme-linked immunosorbent assay (ELISA). Dual-energy X-ray absorptiometry (DEXA) was used to measure bone mineral density (BMD). Serum 14-3-3η protein level was significantly high in RA (2.49/4.72), compared with controls (P < 0.0001). Positive rate of 14-3-3η protein in RA was 97.3%, which was higher than that in controls (χ 2 = 276.641, P < 0.0001). Serum 14-3-3η protein level in early RA was significantly higher than that in established RA (3.91/4.82 vs 2.01/3.29, Z = 2.624, P < 0.05). The positive rate among three groups (normal control, early RA group, established RA group) differed from each other (χ 2 = 131.396, P < 0.0001). Results of ROC curve indicated the cutoff point of 14-3-3η protein for diagnosis of early RA was 0.879 ng/ml (P < 0.0001). Linear correlation analysis found that serum 14-3-3η protein positively correlated with VAS and HAQ (P < 0.0001), negatively correlated with BMD at lumbar spine and femur in RA (P < 0.0001). Serum 14-3-3η protein among groups of bone mass normal (2.73/3.79), osteopenia (3.15/4.86), and osteoporosis (6.34/6.42) was different in early RA patients (χ 2 = 7.974, P < 0.05). Serum 14-3-3η protein levels increase significantly in patients with RA (especially in early RA). There are close relationships between serum 14-3-3η protein and clinical symptoms and osteoporosis in patients with RA.

Role of 14-3-3η protein on cardiac fatty acid metabolism and macrophage polarization after high fat diet induced type 2 diabetes mellitus.

Diabetic cardiomyopathy (DCM), a metabolic disorder, is one of the leading causes of mortality around the world and its pathogenesis involves cardiac inflammation and altered metabolic profile. Altered fatty acid metabolism during DCM can cause macrophage polarization in which inflammatory M1 phenotype dominates over the anti-inflammatory M2 phenotype. Hence, it is essential to identify a specific target, which could revert the metabolic profile and thereby reducing the M1 macrophage polarization. 14-3-3η protein has several cellular protective functions especially in the heart as plenty of reports available in various animal models of heart failure including diabetes mellitus. However, its role in the cardiac fatty acid metabolism and macrophage polarization remains unidentified. The present study has been designed to delineate the effect of cardiospecific dominant negative mutation of 14-3-3η protein (DN14-3-3) on various lipid metabolism related marker proteins expressions and cardiac macrophage phenotype in high fat diet (HFD) fed mice. Feeding HFD for 12 weeks has produced significant increase in body weight in the DN14-3-3 (TG) mice than C57BL6/J (WT) mice. Western blotting and immunohistochemical staining analysis of the heart tissue has revealed an increase in the expression of markers of cardiac fatty acid synthesis related proteins in addition to the reduced expression of fatty acid oxidation related proteins in TG mice fed HFD than WT mice fed HFD. Furthermore, the M1 macrophage marker proteins were increasingly expressed while M2 markers expressions were reduced in the hearts of TG mice fed HFD. In conclusion, our current study has identified that there is a definite role for the 14-3-3η protein against the pathogenesis of heart failure via regulation of cardiac fatty acid metabolism and macrophage polarization.