Abstract We previously isolated rat 14.7K-interacting protein-2 (rFIP-2) from the rat-wounded pulp. The protein, homologous to human FIP-2, is known as optineurin and was initially identified as a ...novel tumor necrosis factor-α (TNFα)-inducible protein, and more recently, as an autophagy receptor. However, the biological role of optineurin in dental pulp remains elusive. We hypothesized that optineurin has a crucial role in regulating molecular processes during pulp inflammatory responses induced by TNF-α. We examined the kinetics of optineurin expression in pulp inflammation. Optineurin localization and expression were examined using rat pulp fibroblasts. The cells were treated with pharmacological inhibitors for TNF-α-induced inflammatory signals or with hydrogen peroxide as apoptotic stimuli. Stable optineurin-knockdown cells (OPTN-KD cells) were established by transfecting normal rat kidney cells with a vector expressing optineurin-specific small interfering RNA. Cell proliferation and the profiles of cytokines and intracellular signaling molecules were examined using OPTN-KD cells stimulated by TNF-α. Optineurin was localized in the cytoplasm and then translocated into the nucleus upon apoptotic stimuli. Optineurin expression was increased by TNF-α and decreased by a specific inhibitor of c-Jun N-terminal kinase. The OPTN-KD cells secreted smaller amounts of monocyte chemotactic protein-1 (MCP-1) and intracellular MCP-1 mRNA, and cell proliferation was significantly increased. Apoptosis-related signaling molecules were down-regulated in OPTN-KD cells. These results demonstrated that optineurin is a crucial molecule mediated by TNF-α, which induces the production of inflammatory factors and apoptosis signaling, suggesting the presence of signaling interactions between optineurin and a transcription factor for MCP-1.
Mechanical stress results in differential gene expression that is critical to convert the stimulus into biochemical signals. Under physiological stress such as occlusal force, human periodontal ...ligament fibroblasts (HPLF) are associated with homeostasis of periodontal tissues however the changes in response to mechanotransduction remain uncharacterized. We hypothesized that cyclic tension-responsive (CT) genes may be used to identify a set of fundamental pathways of mechanotransduction. Our goal was to catalogue CT genes in cultured HPLF. HPLF were subjected to cyclic tension up to 16
h, and total RNA was isolated from both tension-loaded and static HPLF. The oligonucleotide arrays analysis revealed significant changes of mRNA accumulation for 122 CT genes, and their kinetics were assigned by the
K-means clustering methods. Ingenuity Pathway Analysis was completed for HPLF mechanotransduction using 50 CT genes. This analysis revealed that cyclic tension immediately down-regulated all nuclear transcription factors except
v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) reacting as an early responsive gene. In turn, transcription factors such as
tumor protein p53 binding protein 2 (TP53BP2), and extra-nuclear molecules such as
adrenergic receptor β2 (ADRB2) were up-regulated after 1–2
h, which may result in fundamental HPLF functions to adapt to cyclic tension. Subsequent inhibition assays using Y27632, a pharmacologic inhibitor of Rho-associated kinase (ROCK), suggested that HPLF has both ROCK-dependent and ROCK-independent CT genes. Mechanical stress was found to effect the expression of numerous genes, in particular, expression of an early responsive gene; FOS initiates alteration of HPLF behaviors to control homeostasis of the periodontal ligament.
In the original publication of the article, one of the author name was published incorrectly as “Keisuke Yamashairo” and correct name should be “Keisuke Yamashiro”.
Abstract
We have recently identified lipopolysaccharide tumor-induced tumor necrosis factor α factor (LITAF) as a novel transcription factor controlling necrosis factor (TNF)-α expression in the ...human monocytic cell line, THP-1. To characterize the human (h) LITAF promoter, we isolated a 1.2-kb DNA fragment and followed this by a screening of human genomic DNA with a hLITAF cDNA probe. A 34-bp sequence domain located from nucleotides −74 to −43 in the hLITAF promoter exhibited the highest basal reporter gene activity; however, the activity was not elevated by lipopolysaccharide (LPS) stimulation. The sequence domain included a consensus sequence for hepatocyte nuclear factor (HNF)-3α, regulating the transcription of many kinds of genes. Interestingly, the DNA sequence position between −542 and −538 in the hLITAF promoter contained the CTCCC motif, which has been reported to act as a specific binding site for hLITAF protein. Electrophoretic mobility shift assays demonstrated that LPS induced the binding of THP-1 nuclear factors to a 22 bp probe containing the CTCCC motif. In addition, hLITAF mRNA and nuclear hLITAF protein increased significantly in the THP-1 cells immediately after LPS stimulation. These results suggest that the consensus sequence for HNF-3α, or a nuclear binding protein to the CTCCC motif, may play an important role in regulating LPS-dependent LITAF transcription.
Background
This retrospective, multicenter study evaluated the effect of pemafibrate treatment on liver function and fibrosis by liver function tests (LFTs) and various fibrotic biomarkers including ...FibroScan in non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia.
Methods
A total of 138 NAFLD patients treated with pemafibrate at three hospitals between September 2018 and April 2021 were included. To evaluate the effect of pemafibrate treatment, FibroScan-aspartate aminotransferase (FAST) score, a novel index of steatohepatitis that can be calculated based on the aspartate aminotransferase (AST) value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) was used.
Results
Serum TG levels were significantly decreased 4 weeks after pemafibrate treatment (
p
= 0.003). The levels of AST (
p
= 0.038), alanine aminotransferase (ALT) (
p
= 0.003), and gamma-glutamyl transferase (GGT) (
p
= 0.047) also significantly diminished 12 weeks after pemafibrate administration compared to before administration (
p
< 0.05). However, serum HDL-cholesterol (
p
= 0.193), LDL-cholesterol (
p
= 0.967), and eGFR (
p
= 0.909) levels were not significantly altered 12 weeks after pemafibrate administration. In addition, the fibrosis biomarkers’ Type IV collagen (
p
= 0.753) and FIB-4 index (
p
= 0.333) did not significantly differ, while Autotaxin (
p
= 0.006) and the AST-to-platelet ratio index (APRI) (
p
= 0.003) significantly decreased 48 weeks after pemafibrate administration. No significant reductions in LSM (
p
= 0.959) and CAP (
p
= 0.266) were detected using FibroScan 48 weeks after pemafibrate administration. FAST score was significantly improved (
p
= 0.0475).
Conclusion
Pemafibrate improved LFTs, including fibrotic biomarkers and FAST score, due to the hepatic anti-inflammatory effect, suggesting that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.
Although there have been advances in the prevention and diagnosis of hepatocellular carcinoma (HCC) in recent years, many HCC patients are still diagnosed with advanced stage. Systemic therapy is ...indicated for unresectable HCC (uHCC) with major vascular invasion and/or extrahepatic metastases, and the atezolizumab plus bevacizumab (atezo/bev) combination is currently recommended as first-line treatment for uHCC. Recently, sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reportedly associated with prognosis in uHCC patients treated with sorafenib or lenvatinib. There are few reports on muscle strength assessments, including grip strength (GS), despite their importance in accurate sarcopenia diagnosis, and furthermore, there is no evidence regarding atezo/bev therapy. In this study, we investigated whether sarcopenia affects the clinical outcome of atezo/bev therapy. This study included 64 uHCC patients on atezo/bev therapy and assessed their GS and SMI, and SMI was measured using bioelectrical impedance analysis (BIA). We diagnosed sarcopenia based on GS and BIA-SMI and compared the clinical outcomes in the sarcopenia and non-sarcopenia groups. Of these patients, 28 had sarcopenia, and 36 had non-sarcopenia. Adverse events (AEs) frequently occurred, and the albumin-bilirubin score significantly decreased after atezo/bev therapy in the sarcopenia group than in the non-sarcopenia group. The median progression-free survival was 4.7 (0.4-26.4) and 10.6 (1.1-24.5) months in the sarcopenia and non-sarcopenia groups, respectively. The median overall survival (OS) was 12.6 (1.4-27.7) months in the sarcopenia group and was not reached in the non-sarcopenia group, indicating a significant difference in the Kaplan-Meier survival curves for both groups (
< 0.01). In multivariate analysis, sarcopenia was significantly associated with OS. In conclusion, sarcopenia was significantly associated with poor clinical outcomes based on the occurrence of AEs and decreased liver function in uHCC patients on atezo/bev therapy. GS and SMI are important parameters for accurately diagnosing sarcopenia.
GGA (geranylgeranoic acid) is a natural polyprenoic acid, derivatives of which has been shown to prevent second primary hepatoma. GGA induces mitochondria-mediated PCD (programmed cell death), which ...may be relevant to cancer prevention. To gain further insights into GGA-induced PCD, autophagy processes were examined in human hepatoma-derived HuH-7 cells. Treatment of HuH-7/GFP (green fluorescent protein)-LC3 cells with GGA induced green fluorescent puncta in the cytoplasm within 30 min and their massive accumulation at 24 h. After 15 min of GGA treatment, a burst of mitochondrial superoxide production occurred and LC3β-I was appreciably converted into LC3β-II. GGA-induced early stages of autophagy were unequivocally confirmed by electron-microscopic observation of early/initial autophagic vacuoles. On the other hand, LC3β-II as well as p62/SQSTM1 (sequestosome 1) continuously accumulated and co-localized in the cytoplasmic puncta after GGA treatment. Furthermore, GGA treatment of HuH-7/mRFP (monomeric red fluorescent protein)-GFP-LC3 cells showed yellow fluorescent puncta, whereas glucose deprivation of the cells gave red fluorescent puncta. These results strongly suggest that GGA induces the initial phase of autophagy, but blocks the maturation process of autolysosomes or late stages of autophagy, insomuch that GGA provides substantial accumulation of autophagosomes under serum-starvation conditions in human hepatoma cells.
EB-TACE has recently been performed because of its lower hepatotoxicity compared to cTACE in less advanced HCC. However, local recurrence at the tumor margins is often observed after DEB-TACE. cTACE ...involves filling the intratumoral sinusoids with lipiodol-containing anticancer drugs and accumulating in the drainage area, which is the first site of HCC recurrence. The aim of this study is to evaluate the therapeutic effect of DEB-TACE followed by cTACE in HCC patients. Between 2014 and 2020, 65 patients with Barcelona clinic liver cancer (BCLC) stage B (intermediate stage) of HCC were enrolled and divided into two groups: one group received DEB-TACE followed by cTACE (cTACE group) and the other group received only DEB-TACE (non-cTACE group). Sixty-five patients were medically followed. The median observation time was 14 ± 13.1 months after the first DEB-TACE and outcomes were analyzed for multiple factors. Results: The complete response rate was significantly higher in the cTACE group than in the non-TACE group. The analysis showed that the only factor that increased the CR rate in the cTACE group was the total tumor number (less than four). The OS rate of CR patients was higher than that of non-CR patients in the cTACE group. Adverse events in the cTACE group included severe thrombocytopenia but only in one of twenty-seven patients. Conclusions: The combined therapy with DEB-TACE followed by cTACE may be a new effective therapeutic strategy for the intermediate stage of HCC patients.
Bone turnover markers (BTMs) are useful parameters for assessing fracture risk and unlike bone mineral density (BMD), can be measured at any institution. However, BTM values have not been established ...in patients post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the practicality of BTMs in patients who underwent allo-HSCT by measuring levels of the serum bone resorption marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), and the bone formation marker, bone-specific alkaline phosphatase (BAP), together with BMD, 1 month before and 6 months after allo-HSCT. Patients were classified into either the alendronate group (
n
= 14) if alendronate treatment (35 mg orally per week) was administered before allo-HSCT or within 1 month after allo-HSCT, or the control group (
n
= 16), in which patients did not receive alendronate treatment. Despite the high frequency of corticosteroids users in the alendronate group (71.4 vs. 18.9%;
p
< 0.01), the mean percentage changes in BMD at the lumbar spine (− 2.9 vs. − 3.1%;
p
= 0.44) and femoral neck (− 3.2 vs. − 4.1%;
p
= 1.00), TRACP-5b levels (− 4.8 vs. 9.9%;
p
= 0.45), and BAP levels (6.9 vs. 1.0%;
p
= 0.85) during 6 months did not differ significantly between the alendronate and control groups. Additionally, the percentage changes in BMD at the lumbar spine were negatively associated with the TRACP-5b levels 6 months after allo-HSCT (
p
= 0.03,
r
= 0.40). Our results indicate the possible effectiveness of alendronate treatment in allo-HSCT patients. BTM levels could be useful to monitor the BMD changes.
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