Modeling of antibody responses to COVID-19 vaccination in patients with rheumatoid arthritis.

To construct a model of the antibody response to COVID-19 vaccination in patients with rheumatoid arthritis (RA), and to identify clinical factors affecting the antibody response. A total of 779 serum samples were obtained from 550 COVID-19-naïve RA patients who were vaccinated against COVID-19. Antibody titers for the receptor binding domain (anti-RBD) and nucleocapsid (anti-N) were measured. The time from vaccination, and the log-transformed anti-RBD titer, were modeled using a fractional polynomial method. Clinical factors affecting antibody responses were analyzed by a regression model using generalized estimating equation. The anti-RBD titer peaked at about 2 weeks post-vaccination and decreased exponentially to 36.5% of the peak value after 2 months. Compared with the first vaccination, the 3rd or 4th vaccinations shifted the peaks of anti-RBD antibody response curves significantly upward (by 28-fold [4-195] and 32-fold [4-234], respectively). However, there was no significant shift in the peak from the 3rd vaccination to the 4th vaccination (p = 0.64). Multivariable analysis showed that sulfasalazine increased the vaccine response (by 1.49-fold [1.13-1.97]), but abatacept or JAK inhibitor decreased the vaccine response (by 0.13-fold [0.04-0.43] and 0.44-fold [0.26-0.74], respectively). Age was associated with lower ln [anti-RBD] values (coefficient: - 0.03 [- 0.04 to - 0.02]). In conclusion, the anti-RBD response of RA patients peaked at 2 weeks after COVID-19 vaccination, and then decreased exponentially, with the maximum peak increase observed after the 3rd vaccination. The antibody response was affected by age and the medications used to treat RA.

COVID-19 infection and efficacy of vaccination in patients with rheumatic diseases during Omicron outbreak in South Korea: a prospective cohort study.

OBJECTIVES: This study aims to investigate COVID-19 epidemiological data in patients with autoimmune inflammatory rheumatic diseases (AIRDs) during Omicron wave and to identify clinical factors associated with infection, including COVID-19 vaccination. METHODS: This prospective longitudinal study was performed between January and October 2022 in South Korea. Patients were classified into AIRD and non-AIRD groups according to their underlying diseases. COVID-19 status, date of confirmed infection and vaccination status were captured from the patient survey and national database. The COVID-19 incidence during the study period was examined and compared between the two groups. The effect of clinical factors on the infection rate was analysed in the AIRD group. RESULTS: A total of 1814 patients (1535 and 279 in the AIRD and non-AIRD groups, respectively) were analysed. During the study period, 857 COVID-19 cases were reported in 834 patients (46.0%). The infection rates in the AIRD and non-AIRD groups were comparable. In the AIRD group, older age (≥70 years) and glucocorticoid use were significantly associated with a lower rate of COVID-19 infection. The third booster vaccination significantly lowered the incidence of COVID-19 (adjusted HR 0.85 (95% CI 0.73 to 0.99)), and the prophylactic effect was more evident in patients aged <70 years (0.81 (95% CI 0.69 to 0.95), p value for interaction 0.036). CONCLUSION: The risk of SARS-CoV-2 infection with the Omicron variant did not increase in patients with AIRDs. The third booster vaccination regimen decreased the infection rate in patients aged <70 years.

Cereblon Deficiency Contributes to the Development of Elastase-Induced Emphysema by Enhancing NF-κB Activation.

Cereblon (CRBN) has been shown to play an essential role in regulating inflammatory response and endoplasmic reticulum stress, thus mediating the development of various diseases. However, little is known about the roles of CRBN in chronic obstructive pulmonary disease (COPD) pathogenesis. We found that the protein levels of CRBN in lung homogenates from patients with COPD were lower than those from never smokers and smokers. The CRBN protein level was positively correlated with the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). To investigate the role of CRBN in modulating elastase-induced emphysema, we used Crbn knockout (KO) mice. Elastase-induced emphysematous changes were significantly aggravated in Crbn KO mice. Neutrophil infiltration, lung cell injury, and protein leakage into the bronchoalveolar space were more severe in Crbn KO mice than in wild-type (WT) mice. Furthermore, Crbn KO resulted in the elevated release of neutrophilic chemokines and inflammatory cytokines in lung epithelial cells and macrophages. The transcriptional activity of nuclear factor-κB (NF-κB) was significantly increased in Crbn knocked-down cells. In conclusion, Crbn deficiency might be involved in the development of emphysema by enhancing NF-κB activation, suggesting that targeting CRBN might be an effective therapeutic approach for the treatment of COPD.

Prognostic impact of serum soluble PD-1 and ADV score for living donor liver transplantation in patients with previously untreated hepatocellular carcinoma.

PURPOSE: The programmed death protein 1 (PD-1) pathway is the critical mechanism in development of hepatocellular carcinoma (HCC). The present study analyzed the prognostic impact of pretransplant serum soluble PD-1 (sPD-1) concentration and α-FP-des-γ-carboxyprothrombin-tumor volume (ADV) score in patients with previously untreated HCC undergone liver transplantation (LT). METHODS: This retrospective single-center study enrolled 100 patients with HCC who underwent living donor LT from 2010 to 2016. Concentrations of sPD-1 were measured in stored serum samples. RESULTS: Receiver operating characteristic curve analysis of 2-year tumor recurrence resulted in an sPD-1 cutoff of 177.1 µg/mL, which was associated with higher rates of tumor recurrence (P = 0.022), but not with overall patient survival (P = 0.460). The derived cutoff for pretransplant ADV score was 5.4log, which was associated with higher tumor recurrence rate (P < 0.001) and lower overall patient survival rate (P < 0.001). Both sPD-1 of >177.1 µg/mL (hazard ratio [HR], 2.26; P = 0.020) and pretransplant ADV score of >5.4log (HR, 3.56; P < 0.001) were independent risk factors for posttransplant HCC recurrence. The combination of these 2 factors enabled the stratification of patients into 3 groups, with groups having 0, 1, and 2 risk factors differing significantly in the prognosis of tumor recurrence (P < 0.001) and overall patient survival (P = 0.006). CONCLUSION: Both sPD-1 concentration and ADV score have prognostic impacts in patients who underwent LT for untreated HCCs. These factors, both individually and combined, can help in predicting posttransplant prognosis.

Cereblon contributes to the development of pulmonary fibrosis via inactivation of adenosine monophosphate-activated protein kinase α1.

Pulmonary fibrosis is a progressive and lethal lung disease characterized by the proliferation and differentiation of lung fibroblasts and the accumulation of extracellular matrices. Since pulmonary fibrosis was reported to be associated with adenosine monophosphate-activated protein kinase (AMPK) activation, which is negatively regulated by cereblon (CRBN), we aimed to determine whether CRBN is involved in the development of pulmonary fibrosis. Therefore, we evaluated the role of CRBN in bleomycin (BLM)-induced pulmonary fibrosis in mice and in transforming growth factor-beta 1 (TGF-ß1)-induced differentiation of human lung fibroblasts. BLM-induced fibrosis and the mRNA expression of collagen and fibronectin were increased in the lung tissues of wild-type (WT) mice; however, they were significantly suppressed in Crbn knockout (KO) mice. While the concentrations of TGF-ß1/2 in bronchoalveolar lavage fluid were increased via BLM treatment, they were similar between BLM-treated WT and Crbn KO mice. Knockdown of CRBN suppressed TGF-ß1-induced activation of small mothers against decapentaplegic 3 (SMAD3), and overexpression of CRBN increased it. TGF-ß1-induced activation of SMAD3 increased α-smooth muscle actin (α-SMA) and collagen levels. CRBN was found to be colocalized with AMPKα1 in lung fibroblasts. CRBN overexpression inactivated AMPKα1. When cells were treated with metformin (an AMPK activator), the CRBN-induced activation of SMAD3 and upregulation of α-SMA and collagen expression were significantly suppressed, suggesting that increased TGF-ß1-induced activation of SMAD3 via CRBN overexpression is associated with AMPKα1 inactivation. Taken together, these data suggest that CRBN is a profibrotic regulator and maybe a potential target for treating lung fibrosis.

Absence of association between pretransplant serum soluble programmed death protein-1 level and prognosis following living donor liver transplantation in patients with hepatocellular carcinoma.

ABSTRACT: Programmed death protein 1 (PD-1) pathway is one of the most critical mechanisms in tumor biology of hepatocellular carcinoma (HCC). The study aimed to assess the prognostic influence of pretransplant serum soluble PD-1 (sPD-1) in patients undergoing liver transplantation for treatment of HCC.Data from 229 patients with HCC who underwent living donor liver transplantation between January 2010 and December 2015 were retrospectively evaluated. Stored serum samples were used to measure sPD-1 concentrations.Overall survival (OS) and disease-free survival (DFS) rates were 94.3% and 74.5% at 1 year; 78.2% and 59.2% at 3 years; and 75.4% and 55.5% at 5 years, respectively. Prognostic analysis using pretransplant serum sPD-1 with a cut-off of 93.6 µg/mL (median value of the study cohort) did not have significant prognostic influence on OS (P = .69) and DFS (P = .26). Prognostic analysis using sPD-1 with a cut-off of 300 µg/mL showed similar OS (P = .46) and marginally lower DFS (P = .070). Combination of Milan criteria and sPD-1 with a cutoff of 300 µg/mL showed similar outcomes of OS and DFS in patients within and beyond Milan criteria. Multivariate analysis revealed that only Milan criteria was an independent prognostic for OS and DFS, but pretransplant sPD1 with a cut-off of 300 µg/mL did not become a prognostic factor.The results of this study demonstrate that pretransplant serum sPD-1 did not show significant influences on post-transplant outcomes in patients with HCC. Further large-scale, multicenter studies are necessary to clarify the role of serum sPD-1 in liver transplantation recipients.

Self-luminescent photodynamic therapy using breast cancer targeted proteins.

Despite the potential of photodynamic therapy (PDT), its comprehensive use in cancer treatment has not been achieved because of the nondegradable risks of photosensitizing drugs and limits of light penetration and instrumentation. Here, we present bioluminescence (BL)-induced proteinaceous PDT (BLiP-PDT), through the combination of luciferase and a reactive oxygen species (ROS)-generating protein (Luc-RGP), which is self-luminescent and degradable. After exposure to coelenterazine-h as a substrate for luciferase without external light irradiation, Luc-RGP fused with a small lead peptide-induced breast cancer cell death through the generation of BL-sensitive ROS in the plasma membrane. Even with extremely low light energy, BLiP-PDT exhibited targeted effects in primary breast cancer cells from patients and in in vivo tumor xenograft mouse models. These findings suggest that BLiP-PDT is immediately useful as a promising theranostic approach against various cancers.

Cereblon Deletion Ameliorates Lipopolysaccharide-induced Proinflammatory Cytokines through 5'-Adenosine Monophosphate-Activated Protein Kinase/Heme Oxygenase-1 Activation in ARPE-19 Cells.

Cereblon (CRBN), a negative modulator of AMP-activated protein kinase (AMPK), is highly expressed in the retina. We confirmed the expression of CRBN in ARPE-19 human retinal cells by Western blotting. We also demonstrated that CRBN knock-down (KD) could effectively downregulate IL-6 and MCP-1 protein and gene expression in LPS-stimulated ARPE-19 cells. Additionally, CRBN KD increased the phosphorylation of AMPK/acetyl-coenzyme A carboxylase (ACC) and the expression of heme oxygenase-1 (HO-1) in ARPE-19 cells. Furthermore, CRBN KD significantly reduced LPS-induced nuclear translocation of NF-κB p65 and activation of NF-κB promoter activity. However, these processes could be inactivated by compound C (inhibitor of AMPK) and zinc protoporphyrin-1 (ZnPP-1; inhibitor of HO-1). In conclusion, compound C and ZnPP-1 can rescue LPS-induced levels of proinflammatory cytokines (IL-6 and MCP-1) in CRBN KD ARPE-19 cells. Our data demonstrate that CRBN deficiency negatively regulates proinflammatory cytokines via the activation of AMPK/HO-1 in the retina.

Hepatitis B Prophylaxis after Liver Transplantation in Korea: Analysis of the KOTRY Database.

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population. METHODS: Korean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis. RESULTS: The study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence. CONCLUSION: Combination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval.

Correction: Kim, Y. K. et al. Tussilagone Inhibits the Inflammatory Response and Improves Survival in CLP-Induced Septic Mice. Int. J. Mol. Sci. 2017, 18, 2744.

We wish to make the following corrections to this paper [...].

Cereblon deficiency confers resistance against polymicrobial sepsis by the activation of AMP activated protein kinase and heme-oxygenase-1.

Cereblon (CRBN) has a pleiotropic role in important cellular processes and is a potential therapeutic target in several diseases, including mental retardation, cancer, and metabolic disorders. The role of CRBN in polymicrobial sepsis induced by cecal ligation and puncture (CLP) was investigated using CRBN-deficient (KO) mice. Survival following CLP was significantly higher in KO mice compared to wild-type (WT) controls (50% vs 0% at day 6 after CLP). The improved survival of KO mice was accompanied by reduced peripheral blood bacterial load and lung injury. Serum tumor necrosis factor (TNF)-α and high mobility group box 1 (HMGB1) concentrations were significantly lower in KO mice than in WT mice. Peritoneal macrophages from KO mice with CLP-induced septic mouse had higher levels of activation of AMPK and heme oxygenase-1 (HO-1). Forced expression of CRBN in macrophage of KO mice suppressed activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and HO-1 and augmented expression of TNF-α and HMGB1 as inhibition of AMPK by compound C. These studies demonstrate the contribution of CRBN expression to the pathogenesis of CLP-induced sepsis and peritoneal macrophage responses and suggest a novel therapeutic modality for polymicrobial sepsis.

Advanced glycation end products promote triple negative breast cancer cells via ERK and NF-κB pathway.

Advanced glycation end products (AGEs) are harmful compounds generated by nonspecific glycation of proteins and lipids. The accumulation of AGEs is associated with various diseases, including breast cancer. AGEs have been shown to promote a breast cancer cell line by enhancing proliferation, invasion and migration. In this study, we investigated the effect and associated mechanism of AGEs on triple negative breast cancer cells. AGEs enhanced the proliferation, tumorigenicity, invasion and migration of primary breast cancer cells. AGEs also enhanced the RNA and protein expression of matrix metalloproteinase (MMP)-9 and its gelatinase activity. Enhanced MMP-9 expression was mediated by extracellular-signal regulated kinase (ERK) and nuclear factor kappa B (NF-κB) pathways. Moreover, inhibitors of ERK and NF-κB signaling attenuated the effect of AGEs on tumorigenicity, invasion and migration of primary breast cancer cells. Taken together, we suggest that AGEs directly promote primary breast cancer cells via the ERK and NF-κB pathway, which may lead to advanced therapeutic modalities of breast cancer.

Tussilagone Inhibits the Inflammatory Response and Improves Survival in CLP-Induced Septic Mice.

Tussilagone, extracted from Tussilago farfara is an oriental medicine used for asthma and bronchitis. We investigated its mechanism of action, its inhibitory effects on lipopolysaccharide-induced inflammation in macrophages, and its impact on viability in a cecal ligation and puncture (CLP)-induced mouse model of sepsis. Tussilagone suppressed the expression of the inflammatory mediators, nitric oxide and prostaglandin E2, and the inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1), in lipopolysaccharide-stimulated RAW 264.7 cells and peritoneal macrophages. Tussilagone also reduced the activation of the mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) involved in the activation of various inflammatory mediators in activated macrophages. Moreover, tussilagone administration (1 mg/kg and 10 mg/kg) produced decreased mortality and lung injury in CLP-activated septic mice. Augmented expression of cyclooxygenase (COX)-2 and TNF-α in pulmonary alveolar macrophages of septic mice were attenuated by tussilagone administration. Tussilagone also suppressed the induction of nitric oxide, prostaglandin E2, TNF-α and HMGB1 in the serum of the septic mice. Overall, tussilagone exhibited protective effects against inflammation and polymicrobial sepsis by suppressing inflammatory mediators possibly via the inhibition of NF-κB activation and the MAP kinase pathway. These results suggest the possible use of tussilagone for developing novel therapeutic modalities for sepsis and other inflammatory diseases.

Naringin Decreases TNF-α and HMGB1 Release from LPS-Stimulated Macrophages and Improves Survival in a CLP-Induced Sepsis Mice.

Naringin, a flavanone glycoside extracted from various plants, has a wide range of pharmacological effects. In the present study, we investigated naringin's mechanism of action and its inhibitory effect on lipopolysaccharide-induced tumor necrosis factor-alpha and high-mobility group box 1 expression in macrophages, and on death in a cecal ligation and puncture induced mouse model of sepsis. Naringin increased heme oxygenase 1 expression in peritoneal macrophage cells through the activation of adenosine monophosphate-activated protein kinase, p38, and NF-E2-related factor 2. Inhibition of heme oxygenase 1 abrogated the naringin's inhibitory effect on high-mobility group box 1 expression and NF-kB activation in lipopolysaccharide-stimulated macrophages. Moreover, mice pretreated with naringin (200 mg/kg) exhibited decreased sepsis-induced mortality and lung injury, and alleviated lung pathological changes. However, the naringin's protective effects on sepsis-induced lung injury were eliminated by zinc protoporphyrin, a heme oxygenase 1 competitive inhibitor. These results revealed the mechanism underlying naringin's protective effect in inflammation and may be beneficial for the treatment of sepsis.

Crotamine stimulates phagocytic activity by inducing nitric oxide and TNF-α via p38 and NFκ-B signaling in RAW 264.7 macrophages.

Crotamine is a peptide toxin found in the venom of the rattlesnake Crotalus durissus terrificus and has antiproliferative, antimicrobial, and antifungal activities. Herein, we show that crotamine dose-dependently induced macrophage phagocytic and cytostatic activity by the induction of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α). Moreover, the crotamineinduced expression of iNOS and TNF-α is mediated through the phosphorylation of p38 and the NF-κB signaling cascade in macrophages. Notably, pretreatment with SB203580 (a p38-specific inhibitor) or BAY 11-7082 (an NF-κB inhibitor) inhibited crotamine-induced NO production and macrophage phagocytic and cytotoxic activity. Our results show for the first time that crotamine stimulates macrophage phagocytic and cytostatic activity by induction of NO and TNF-α via the p38 and NF-κB signaling pathways and suggest that crotamine may be a useful therapeutic agent for the treatment of inflammatory disease. [BMB Reports 2016; 49(3): 185-190].

Berberine protects 6-hydroxydopamine-induced human dopaminergic neuronal cell death through the induction of heme oxygenase-1.

Berberine (BBR) is one of the major alkaloids and has been reported to have a variety of pharmacologic effects, including inhibition of cell cycle progression. Here, we investigated the mechanisms of BBR protection of neuronal cells from cell death induced by the Parkinson's disease-related neurotoxin 6-hydroxydopamine (6-OHDA). Pretreatment of SH-SY5Y cells with BBR significantly reduced 6-OHDAinduced generation of reactive oxygen species (ROS), caspase-3 activation, and subsequent cell death. BBR also upregulated heme oxygenase-1 (HO-1) expression, which conferred protection against 6-OHDA-induced dopaminergic neuron injury and besides, effect of BBR on HO-1 was reversed by siRNA-Nrf2. Furthermore, BBR induced PI3K/Akt and p38 activation, which are involved in the induction of Nrf2 expression and neuroprotection. These results suggest that BBR may be useful as a therapeutic agent for the treatment of dopaminergic neuronal diseases.