MED26-containing Mediator may orchestrate multiple transcription processes through organization of nuclear bodies.

Mediator is a coregulatory complex that plays essential roles in multiple processes of transcription regulation. One of the human Mediator subunits, MED26, has a role in recruitment of the super elongation complex (SEC) to polyadenylated genes and little elongation complex (LEC) to non-polyadenylated genes, including small nuclear RNAs (snRNAs) and replication-dependent histone (RDH) genes. MED26-containing Mediator plays a role in 3' Pol II pausing at the proximal region of transcript end sites in RDH genes through recruitment of Cajal bodies (CBs) to histone locus bodies (HLBs). This finding suggests that Mediator is involved in the association of CBs with HLBs to facilitate 3' Pol II pausing and subsequent 3'-end processing by supplying 3'-end processing factors from CBs. Thus, we argue the possibility that Mediator is involved in the organization of nuclear bodies to orchestrate multiple processes of gene transcription.

Serum Angiopoietin-2 Levels Predict the Development of Hepatocellular Carcinoma following Hepatitis C Virus Eradication Using Direct-Acting Antiviral Agents.

INTRODUCTION: Our previous studies showed that serum angiopoietin-2 (Ang-2) and C-X-C motif chemokine ligand 10 (CXCL10) levels predicted improvement in liver fibrosis following sustained virological response (SVR) of hepatitis C virus (HCV) obtained with administration of with direct-acting antiviral agents (DAAs). These levels were evaluated retrospectively as predictive indicators of hepatocellular carcinoma (HCC) development following SVR. METHODS: We enrolled individuals from a historical cohort of 89 chronic HCV patients without history of HCC at baseline and with SVR following DAA therapy and had baseline serum levels of Mac-2 binding protein glycosylation isomer ≥2.0 cut-off index (C.O.I.). RESULTS: Multivariate analyses revealed that only the Ang-2 level at 24 weeks following the end of treatment (EOT24W) was significantly related to HCC development (hazard ratio 2.27; p = 0.003). This result was reproduced in individuals without history of HCC and with advanced liver fibrosis (M2BPGi level ≥3.3 C.O.I. at baseline). Time-dependent receiver operating characteristic curve analyses for the future risk of developing HCC within 5 years of follow-up (5y-HCC) showed the best cut-off Ang-2 level at the EOT24W was 2,780 pg/mL, and significantly stratified the cumulative incidence of HCC (≥2,780 vs. < 2,780 pg/mL, 5y-HCC: 45.5 vs. 8.2%, p < 0.001). CONCLUSIONS: At the EOT24W, serum Ang-2 level predicts the likelihood of developing HCC following SVR to DAA therapy.

Serum inducible protein 10 kDa/C-X-C motif chemokine 10 levels predict regression of M2BPGi-based liver fibrosis after hepatitis C virus eradication by direct-acting antiviral agents.

AIM: It is desirable to identify predictors of regression of liver fibrosis after achieving sustained virological response by anti-hepatitis C virus (anti-HCV) therapy. We retrospectively investigated the serum interferon-γ inducible protein 10 kDa (IP-10) level as a predictive indicator of regression of liver fibrosis after successful hepatitis C virus eradication by direct-acting antiviral agents (DAAs) therapy. METHODS: The study participants were recruited from a historical cohort of 116 chronically hepatitis C virus-infected patients who had achieved sustained virological response by DAAs therapy and whose serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at baseline (before DAAs therapy) were ≥2.0 cut-off index. We defined patients with M2BPGi levels <1.76 and ≥1.76 cut-off index at 2 years after the end of treatment (EOT) as the regression (n = 71) and non-regression (n = 45) groups, respectively. RESULTS: Multivariate analyses revealed that the albumin-bilirubin score at baseline, and albumin-bilirubin score, Fibrosis-4 index at 24 weeks after the EOT, and serum IP-10 change from baseline to 24 weeks after the EOT (IP-10 change) were significantly associated with regression of M2BPGi-based liver fibrosis. In addition, IP-10 change was significantly associated with regression of M2BPGi-based liver fibrosis by a multivariate analysis, even when the serum M2BPGi levels were aligned by propensity score matching and in patients with advanced M2BPGi-based liver fibrosis: M2BPGi levels ≥3.3 cut-off index at baseline. CONCLUSIONS: Serum IP-10 change from baseline to 24 weeks after the EOT is a feasible predictor of regression of M2BPGi-based liver fibrosis after achieving sustained virological response with DAA therapy.

Kinetics of HBcrAg and HBsAg using highly sensitive iTACT assays in chronic hepatitis B patients with HBsAg seroclearance.

Two novel assays have been developed, iTACT-hepatitis B core-related antigen (iTACT-HBcrAg) and iTACT-hepatitis B surface antigen (iTACT-HBsAg) assays. We investigated the longitudinal profiles of iTACT-HBcrAg- and -HBsAg in patients with HBsAg seroclearance (SC) (<0.05 IU/mL). This study comprises 60 HBV-infected patients with HBsAg SC, 27 in chronic hepatitis/liver cirrhosis (CH/LC) group and 33 in inactive carrier (IC) group. Longitudinal profiles of iTACT-HBcrAg and -HBsAg were examined using stored serum samples. The median period from HBsAg SC to iTACT-HBcrAg loss or to the last observation was longer in the CH/LC group than the IC group (39 vs. -3 months, p = 0.004), but this tendency was not observed in that by iTACT-HBsAg. Comparing the times of iTACT-HBcrAg and -HBsAg loss, the rate of patients who lost HBcrAg first was significantly higher in the IC group (p = 0.008). The cumulative incidence rate of iTACT-HBcrAg loss after HBsAg SC was higher in the IC group that the CH/LC group (p = 0.002). Patients in the CH/LC group had higher rates of detectable iTACT-HBcrAg than those in the IC group after HBsAg SC, suggesting that the presence of HBcrAg possibly contribute to the progression of chronic hepatitis B.

Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression.

Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.

Blocking neddylation elicits antiviral effect against hepatitis B virus replication.

BACKGROUND: Hepatitis B Virus (HBV) is the most common cause of chronic liver disease worldwide. The mechanisms that regulate HBV viral replication remain poorly defined. Here, we show that blocking of the neddylation elicits antiviral effect against HBV replication, indicating that NEDD8 supports viral production. METHODS AND RESULTS: To explore role of neddylation, HBV-replicating HepG2.2.15.7 cells and HBV-infected HepG2-hNTCP-30 cells were treated with siNEDD8 and MLN4924, a potent and selective NEDD8-activating enzyme inhibitor. Cell viability, intracellular and extracellular HBV DNA, covalently closed circular DNA (cccDNA), HBsAg, HBeAg, and HBcrAg were measured to assess the consequences of the various treatments on viral replication. Our data showed that HBV infection increased NEDD8 expression in human liver cell lines. Symmetrically, NEDD8 knockdown by siRNA or MLN4924 treatments decreased HBV replication in HepG2.2.15.7 and HepG2-hNTCP-30 cells. Notably, HBsAg, and HBeAg secretions were strongly suppressed in the culture supernatants, but not the HBcrAg. These results indicate that the suppression of NEDD8 decreases HBV replication. However, cccDNA steady level confirms once again its persistence and longevity in chronic infection. CONCLUSION: The manipulation of the neddylation pathway can thus provide new tools interfering with HBV persistence as well as novel therapeutic strategies against chronic hepatitis B.

Serum angiopoietin-2 levels predict regression of Mac-2 binding protein glycosylation isomer-based liver fibrosis after hepatitis C virus eradication by direct-acting antiviral agents.

AIM: It is desirable to identify predictors of regression of liver fibrosis after achieving a sustained virologic response (SVR) by direct-acting antiviral agents (DAAs) to antihepatitis C virus (HCV) therapy. Here, we retrospectively investigated the serum angiopoietin-2 (Ang-2) level as a predictive indicator of regression of liver fibrosis after successful HCV eradication by DAA therapy. METHODS: The study subjects were recruited from a historical cohort of 109 chronically HCV-infected patients who had achieved SVR by DAA therapy and whose serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at baseline (before DAA therapy) were ≥2.0 the cut-off index (COI). We defined patients with M2BPGi levels <1.76 and ≥1.76 COI at 2 years after the end of treatment (EOT) as the regression (R, n = 69) and nonregression (NR, n = 40) groups, respectively. RESULTS: Multivariate analyses revealed that the Ang-2 level at baseline and the Ang-2 level, albumin-bilirubin score, and FIB-4 index at 24 weeks after the EOT were significantly associated with regression of M2BPGi-based liver fibrosis. Receiver operating characteristic curve analyses showed that the Ang-2 level at 24 weeks after the EOT had the largest area under the curve values (0.859). The same results were obtained even when the serum M2BPGi levels were aligned by propensity score matching and in patients with advanced M2BPGi-based liver fibrosis: M2BPGi levels ≥3.3 COI at baseline. CONCLUSIONS: The serum Ang-2 level at 24 weeks after the EOT is a feasible predictor of regression of M2BPGi-based liver fibrosis after achieving SVR by DAA therapy.

Management of hepatitis B virus (HBV) reactivation in patients with resolved HBV infection based on a highly sensitive HB core-related antigen assay.

AIMS: To prevent hepatitis B virus (HBV) reactivation-related hepatitis, we examined the clinical usefulness of a highly sensitive HB core-related antigen (iTACT-HBcrAg) assay in patients with resolved HBV infection after nucleos(t)ide analog (NA) treatment for HBV reactivation. METHODS: We retrospectively analyzed 27 patients with resolved HBV infection who experienced HBV reactivation (defined as HBV DNA levels of 1.3 log IU/ml or more), and who received systemic chemotherapies for hematological malignancies between 2008 and 2020. iTACT-HBcrAg, HBsAg-HQ, and antibodies against hepatitis B surface antigen (anti-HBs) were measured using samples stored after HBV reactivation. The lower limit of quantification for iTACT-HBcrAg was 2.0 log U/ml. RESULTS: HBV reactivation was diagnosed at a median HBV DNA level of 1.8 log IU/ml, and then all patients received NA treatment. No patient had HBV-related hepatitis with a median maximum HBV DNA level of 2.0 log IU/ml. The positivities of iTACT-HBcrAg and HBsAg-HQ were 96% and 52% after HBV reactivation, respectively. Of 25 patients with detectable iTACT-HBcrAg at the initiation of NA treatment, 17 (68%) achieved iTACT-HBcrAg loss. Median durations from NA treatment to HBV DNA loss and iTACT-HBcrAg loss or the last follow-up were 35 and 175 days, respectively. Recurrence of HBV reactivation after NA cessation was not observed in seven of eight patients who achieved iTACT-HBcrAg loss or seropositive for anti-HBs during follow-up, except for one without anti-HBs after allogeneic transplantation. CONCLUSIONS: iTACT-HBcrAg could be a potential surrogate marker for diagnosing early-stage HBV reactivation as well as safe cessation of NA treatment in patients with resolved HBV infection after HBV reactivation.

Clinical efficacy of a novel, high-sensitivity HBcrAg assay in the management of chronic hepatitis B and HBV reactivation.

BACKGROUND & AIMS: A fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg) has been developed. We demonstrate the clinical utility of iTACT-HBcrAg for monitoring chronic hepatitis B (CHB) and for the early detection of HBV reactivation. METHODS: After fundamental assessments, the clinical performance of iTACT-HBcrAg was compared with other HBV markers. i) Serial sera, available from 161 HBeAg-negative patients with CHB and persistently undetectable HBV DNA, were measured by iTACT-HBcrAg and a conventional HBcrAg assay (G-HBcrAg). ii) Serial sera from 13 HBV-reactivated patients were measured by iTACT-HBcrAg and an ultra-high-sensitivity HBsAg immune complex transfer-chemiluminescent enzyme immunoassay (lower limit of detection; 0.0005 IU/ml, ICT-CLEIA) to compare HBV DNA detection. iii) To elucidate the various HBcrAg components detected by iTACT-HBcrAg, OptiPrep density gradient centrifugation analysis was performed on sera obtained before and after HBV reactivation. RESULTS: The analytical performance of iTACT-HBcrAg was satisfactory. The sensitivity of iTACT-HBcrAg (2.1 Log U/ml) was approximately 10-fold greater than that of G-HBcrAg (2.8 Log U/ml). i) HBcrAg was detectable in the sera of 97.5% (157/161) of patients with CHB by iTACT-HBcrAg, of whom 75.2% (121/161) had ≥2.8 Log U/ml HBcrAg and 22.4% (36/161) had 2.1-2.8 Log U/ml HBcrAg, which was undetectable by G-HBcrAg. ii) 9 and 2 of 13 HBV-reactivated patients were HBcrAg-positive by iTACT-HBcrAg before and at HBV DNA positivity, respectively; 7 and 4 were HBcrAg-positive by iTACT-HBcrAg before and at HBsAg-positivity by ICT-CLEIA, respectively. iii) The HBcrAg detected by iTACT-HBcrAg before HBV reactivation was contained in empty particles (22 KDa precore protein). CONCLUSIONS: iTACT-HBcrAg could be used to better monitor responses to anti-HBV treatments in HBeAg-negative patients and for the early detection of HBV reactivation. LAY SUMMARY: A fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg) has been developed. iTACT-HBcrAg can be used to monitor HBeAg-negative patients with chronic hepatitis B, as well as for the early detection of HBV reactivation. iTACT-HBcrAg could be used as a general marker of disease progression and treatment response.

Altered ethanolamine plasmalogen and phosphatidylethanolamine levels in blood plasma of patients with bipolar disorder.

AIM: Ethanolamine-containing phospholipids are synthesized in endoplasmic reticulum (ER) and mitochondria. ER stress and mitochondrial dysfunction have been implicated in bipolar disorder (BP). In this study, we aimed to examine the relationship of ethanolamine plasmalogen (PLE) and phosphatidylethanolamine (PTE) levels in blood plasma with BP. METHODS: Plasma PLE and PTE levels were compared between 34 patients with BP (DSM-IV) and 38 healthy control participants matched for age, sex, and ethnicity (Japanese). Furthermore, the relationships of plasma PLE and PTE levels with clinical variables were explored. RESULTS: Plasma PLE levels were significantly lower in patients with BP than in healthy controls (P = 0.0033). In subgroup analyses, plasma PLE levels were significantly lower in patients with BP type I (BP I) than in healthy controls (P = 0.0047); furthermore, plasma PTE levels were significantly lower in patients with BP I than in controls (P = 0.016) and patients with BP type II (BP II) (P = 0.010). Receiver-operating characteristic curve analysis revealed that the discriminatory power of plasma PTE levels for distinguishing between BP I and II was fair (area under the curve = 0.78; P = 0.0095). There were no significant correlations of plasma PLE or PTE levels with depression or manic symptoms in patients. CONCLUSIONS: Plasma PLE and PTE levels were associated with BP I, but not with BP II. Moreover, plasma PTE levels differed between patients with BP I and II. Our findings highlight the importance of ethanolamine phospholipids in the pathophysiology of BP, especially BP I.

Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome.

Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P < 7.66 × 10-9). Cis-only analysis revealed additional 580 SNP-protein pairs with FDR < 0.01 (nominal P < 2.13 × 10-5). pQTL SNPs were more likely, compared to non-pQTL SNPs, to be a disease/trait-associated variants identified by previous genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans.

Factors associated with longitudinal changes in serum concentrations of Mac-2 binding protein: A prospective 3-year observational study.

BACKGROUND AND AIMS: Mac-2 binding protein (M2BP) plays an important role in cell adhesion. In a recent cross-sectional study we reported that serum M2BP concentrations may reflect silent atherosclerosis. The aim of the present prospective follow-up study was to investigate possible relationships between changes in concentrations of M2BP and other factors over a >3-year period. METHODS AND RESULTS: The present study enrolled subjects who visited Enshu hospital from 2014 to 2015 for a periodic physical check-up and then attended for another physical check-up after >3 years (n = 174). Factors affecting changes in M2BP concentrations were investigated at both baseline and follow-up. Subjects with liver dysfunction, a history of hepatic disease, malignant neoplasm, or cardiovascular events at baseline were excluded. Univariate and multivariate regression analyses showed that changes in serum M2BP concentrations during the follow-up period were significantly associated with changes in low-density lipoprotein cholesterol (LDL-C), triglyceride, and oxidative stress marker derivatives of reactive oxygen metabolites (d-ROM) concentrations. Moreover, the increase in LDL-C was significantly greater in subjects in whom M2BP concentrations increased during the follow-up period. Logistic regression analysis with an endpoint of increased M2BP revealed that increased LDL-C was an independent determinant of an increase in M2BP during the follow-up period. CONCLUSION: During the observation period of >3 years, serum M2BP concentrations were increased in subjects who also exhibited increases in levels of metabolic parameters, especially LDL-C, and the oxidative stress marker d-ROM. These results support that serum M2BP reflects one of the contributors to the progression of silent atherosclerosis.

Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection.

BACKGROUND & AIMS: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. METHODS: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). RESULTS: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10-8). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. CONCLUSIONS: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.

Novel monitoring of hepatitis B reactivation based on ultra-high sensitive hepatitis B surface antigen assay.

BACKGROUND & AIMS: Occult hepatitis B virus (HBV) infection should be evaluated before systemic chemotherapy to prevent HBV reactivation-related hepatitis. We investigated HBV reactivation using high sensitivity HB surface antigen (HBsAg) chemiluminescent enzyme immunoassay (HBsAg-HQ) and ultra-high sensitive HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA). METHODS: Of 120 HBV-resolved patients with haematological malignancy receiving systemic chemotherapy from 2012 to 2015 in our hospital, 13 patients had HBV DNA reactivation (in 12/13 patients HBV DNA became quantifiable) according to HBV DNA monitoring. These patients were applied for Architect HBsAg-QT (detection limit:50 mIU/mL), HBsAg-HQ (5 mIU/mL) and ICT-CLEIA (0.5 mIU/mL) using stored samples. RESULTS: When HBV DNA was firstly quantifiable by regular HBV DNA monitoring, HBsAg-QT was detected in 1/12 patients (8%), HBsAg-HQ was detected in 4/12 patients (33%) and ICT-CLEIA was detected in all 12 patients (100%), suggesting that the sensitivity of ICT-CLEIA was comparable to that of HBV DNA quantification. Interestingly, two patients were HBsAg positive by ICT-CLEIA before HBV DNA became detectable. Median difference of detectable point between HBV DNA and ICT-CLEIA was zero (range from -28 to 56 days), while median delay by HBsAg-QT or HBsAg-HQ was 52.5 days after HBV DNA became detectable. Although anti-HBs titres were high (131.9 mIU, 80.4 mIU) in two patients with escape mutations (Saa126V, Saa145R), HBsAg by ICT-CLEIA and HBV DNA were detectable concurrently. CONCLUSIONS: ICT-CLEIA is a novel assay for HBV monitoring to prevent hepatitis caused by HBV reactivation.

Biochemical markers subtyping major depressive disorder.

The pathophysiology of major depressive disorder (MDD) remains elusive, and there is no established biochemical marker used in the daily clinical setting. This situation may result in part from the heterogeneity of MDD, which might include heterogeneous subgroups with different biological mechanisms. In this review, we discuss three promising biological systems/markers to potentially subtype MDD: the dopamine system, the hypothalamic-pituitary-adrenal axis, and chronic inflammatory markers. Several lines of evidence suggest that a facet of MDD is a dopamine agonist-responsive subtype. Focusing on the hypothalamic-pituitary-adrenal axis, depressive spectrum disorders show hypercortisolism to hypocortisolism, which could be detected by hormonal challenge tests, such as the dexamethasone/corticotrophin-releasing hormone test. Finally, accumulating evidence suggests that at least some MDD patients show characteristics similar to those of chronic inflammatory diseases, including neuroinflammatory markers and reduced tryptophan due to the increased activation of the tryptophan-kynurenine pathway. Future studies should examine the inter-relations between these systems/markers to subtype and integrate the pathophysiology of MDD.

Personality in remitted major depressive disorder with single and recurrent episodes assessed with the Temperament and Character Inventory.

AIM: Previous studies consistently reported increased harm avoidance (HA) assessed with the Temperament and Character Inventory (TCI) in patients with major depressive disorder (MDD). However, such findings may have been related with depression severity and number of depressive episodes. The aims of the present study were twofold: to examine TCI personality profile in remitted MDD (DSM-IV) patients and to compare TCI personality between MDD patients with single episode (SGL-MDD) and those with recurrent episodes (REC-MDD) in order to elucidate personality profile associated with recurrence. METHODS: TCI was administered to 86 outpatients with remitted SGL-MDD (12 male and 17 female patients; mean age 43.2 ± 12.1 years) and REC-MDD (26 male and 31 female patients; 40.3 ± 11.6 years), and 529 healthy controls (225 men and 304 women; 43.4 ± 15.5 years), matched for age, sex and education years. Logistic regression analyses were performed in which single/recurrent episodes of depression were the dependent variable and age, sex, age of onset, family history of psychiatric disease and TCI scores were entered as possible predictors. RESULTS: The remitted MDD patients had significantly higher scores on HA (P < 0.001) and lower scores on self-directedness (P < 0.001), compared with the controls. HA (P = 0.03), its subscore, fatigability (P = 0.03), and family history of psychiatric disease were found to be positive predictors for recurrence. CONCLUSION: There are differences in personality profile between remitted MDD patients and controls, and between remitted REC-MDD and SGL-MDD patients, suggesting that they are trait markers. HA and fatigability might be useful to assess risk for recurrence of depression.

Effects of Herbal Tea (Non-Camellia sinensis) on Glucose Homeostasis and Serum Lipids in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

CONTEXT: Hyperglycemia and hyperlipidemia increase the risk for diabetes and its complications, atherosclerosis, heart failure, and stroke. Identification of safe and cost-effective means to reduce risk factors is needed. Herbal teas may be a vehicle to deliver antioxidants and polyphenols for prevention of complications. OBJECTIVE: This systematic review and meta-analysis were conducted to evaluate and summarize the impact of herbal tea (non-Camellia sinensis) on glucose homeostasis and serum lipids in individuals with type 2 diabetes (T2D). DATA SOURCES: PubMed, FSTA, Web of Science, CINAHL, MEDLINE, and Cochrane Library databases were searched from inception through February 2023 using relevant keyword proxy terms for diabetes, serum lipids, and "non-Camellia sinensis" or "tea." DATA EXTRACTION: Data from 14 randomized controlled trials, totaling 551 participants, were included in the meta-analysis of glycemic and serum lipid profile end points. RESULTS: Meta-analysis suggested a significant association between drinking herbal tea (prepared with 2-20 g d-1 plant ingredients) and reduction in fasting blood glucose (FBG) (P = .0034) and glycated hemoglobin (HbA1c; P = .045). In subgroup analysis based on studies using water or placebo as the control, significant reductions were found in serum total cholesterol (TC; P = .024), low-density lipoprotein cholesterol (LDL-C; P = .037), and triglyceride (TG; P = .043) levels with a medium effect size. Meta-regression analysis suggested that study characteristics, including the ratio of male participants, trial duration, and region, were significant sources of FBG and HbA1c effect size heterogeneity; type of control intervention was a significant source of TC and LDL-C effect size heterogeneity. CONCLUSIONS: Herbal tea consumption significantly affected glycemic profiles in individuals with T2D, lowering FBG levels and HbA1c. Significance was seen in improved lipid profiles (TC, TG, and LDL-C levels) through herbal tea treatments when water or placebo was the control. This suggests water or placebo may be a more suitable control when examining antidiabetic properties of beverages. Additional research is needed to corroborate these findings, given the limited number of studies.

Blood mRNA expression levels of glucocorticoid receptors and FKBP5 are associated with depressive disorder and altered HPA axis.

BACKGROUND: While depression has been associated with alterations in the hypothalamic-pituitary adrenal (HPA) axis function, there is still controversy regarding the nature and extent of the dysfunction, such as in the debate about hypercortisolism vs. hypocortisolism. It may therefore be necessary to understand whether and how HPA axis function in depression is linked to mRNA expression of key genes regulating this system. METHODS: We studied 163 depressed outpatients, most of whom were chronically ill, and 181 healthy controls. Blood mRNA expression levels of NR3C1 (including GRα, GRß, and GR-P isoforms), FKBP4, and FKBP5 were measured at baseline. HPA axis feedback sensitivity was measured by the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test. The association between mRNA expression levels and HPA axis feedback sensitivity was examined. RESULTS: Compared to controls, patients showed significantly higher expression of GRα and lower expression of FKBP5, and higher post-Dex cortisol levels, even after controlling for age and sex. FKBP5 expression was significantly positively correlated with cortisol levels in patients, while GRα expression was significantly negatively correlated with cortisol levels in controls. LIMITATIONS: Most patients were taking psychotropic medications. The large number of correlation tests may have caused type I errors. CONCLUSIONS: The tripartite relationship between depression, mRNA expression of GR and FKBP5, and HPA axis function suggests that the altered gene expression affects HPA axis dysregulation and, as a result, impacts the development and/or illness course of depressive disorder. The combination of increased GRα expression and decreased FKBP5 expression may serve as a biomarker for chronic depression.

MicroRNA-223-3p levels in serum-derived extracellular vesicles predict regression of M2BPGi-based liver fibrosis after hepatitis C virus eradication by direct-acting antiviral agents.

BACKGROUND: We retrospectively investigated microRNA (miRNA) levels in serum-derived extracellular vesicles (EVs) as predictive indicators for regression of liver fibrosis, after achievement of a sustained virological response (SVR) by direct-acting antiviral (DAA) therapy for chronic hepatitis C (CHC). METHODS: The study subjects were recruited from a historical cohort of 108 CHC patients whose pretreatment serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels were ≥ 2.0 cut-off index (COI). We classified patients with M2BPGi levels < 1.76 and ≥ 1.76 COI at 2 years after the end of treatment (EOT) into the regression and non-regression groups, respectively. Eleven of the patients were assigned to the discovery set, and we comprehensively investigated the miRNAs contained in serum-derived EVs at 24 weeks after the EOT (EOT24W), using RNA sequencing. The remaining 97 patients were assigned to the validation set, and reproducibility was verified by quantitative real-time PCR. RESULTS: Through analysis of the discovery and validation sets, we identified miR-223-3p and miR-1290 as candidate predictors. Subsequently, we analyzed various clinical data, including these candidate miRNAs. Multivariate analyses revealed that the levels of miR-223-3p at EOT24W were significantly associated with regression of M2BPGi-based liver fibrosis (Odds ratio: 1.380; P = 0.024). Consistent results were obtained, even when the serum M2BPGi levels were aligned by propensity score matching and in patients with advanced M2BPGi-based liver fibrosis (pretreatment M2BPGi levels ≥ 3.3 COI). CONCLUSIONS: The miR-223-3p level in serum-derived EVs at EOT24W is a feasible predictor of regression of M2BPGi-based liver fibrosis after achievement of an SVR by DAA therapy.

Application of a newly developed high-sensitivity HBsAg chemiluminescent enzyme immunoassay for hepatitis B patients with HBsAg seroclearance.

We modified and automated a highly sensitive chemiluminescent enzyme immunoassay (CLEIA) for surface antigen (HBsAg) detection using a combination of monoclonal antibodies, each for a specific epitope of HBsAg, and by improving an earlier conjugation technique. Of 471 hepatitis B virus (HBV) carriers seen in our hospital between 2009 and 2012, 26 were HBsAg seronegative as determined by the Abbott Architect assay. The Lumipulse HBsAg-HQ assay was used to recheck those 26 patients who demonstrated seroclearance by the Abbott Architect assay. The performance of the Lumipulse HBsAg-HQ assay was compared with that of a quantitative HBsAg detection system (Abbott Architect) and the Roche Cobas TaqMan HBV DNA assay (CTM) (lower limit of detection, 2.1 log copies/ml) using blood serum samples from patients who were determined to be HBsAg seronegative by the Abbott Architect assay. Ten patients had spontaneous HBsAg loss. Of 8 patients treated with nucleotide analogues (NAs), two were HBsAg seronegative after stopping lamivudine therapy and 6 were HBsAg seronegative during entecavir therapy. Eight acute hepatitis B (AH) patients became HBsAg seronegative. Of the 26 patients, 16 were HBsAg positive by the Lumipulse HBsAg-HQ assay but negative by the Abbott Architect assay. The differences between the two assays in terms of detectable HBsAg persisted over the long term in the spontaneous loss group (median, 10 months), the NA-treated group (2.5 months), and the AH group (0.5 months). In 9 patients, the Lumipulse HBsAg-HQ assay detected HBsAg when HBV DNA was negative by the CTM assay. HBsAg was also detected by the Lumipulse HBsAg-HQ assay in 4 patients with an anti-HBs concentration of >10 mIU/ml, 3 of whom had no HBsAg escape mutations. The automatic, highly sensitive HBsAg CLEIA Lumipulse HBsAg-HQ is a convenient and precise assay for HBV monitoring.