Zingiber officinale promotes autophagy and apoptosis in human oral cancer through the C/EBP homologous protein.

The rhizome of Zingiber officinale (Z. officinale), commonly known as ginger, has been characterized as a potential drug candidate due to its antitumor effects. However, the chemotherapeutic effect of ginger on human oral cancer remains poorly understood. In this study, we examined the effects of an ethanol extract of Z. officinale rhizomes (ZOE) on oral cancer and identified the components responsible for its pharmacological activity. ZOE exerts its inhibitory activity in oral cancer by inducing both autophagy and apoptosis simultaneously. Mechanistically, ZOE-induced autophagy and apoptosis in oral cancer are attributed to the reactive oxygen species (ROS)-mediated endoplasmic reticulum stress response. Additionally, we identified two active components of ZOE, 1-dehydro-6-gingerdione and 8-shogaol, which were sufficient to stimulate autophagy initiation and apoptosis induction by enhancing CHOP expression. These results suggest that ZOE and its two active components induce ROS generation, upregulate CHOP, initiate autophagy and apoptosis, and hold promising therapeutics against human oral cancer.

BRAFV600E and TERT promoter C228T mutations on ThyroSeq v3 analysis of delayed skin metastasis from papillary thyroid cancer: a case report and literature review.

BACKGROUND: Skin metastasis from papillary thyroid cancer (PTC) is a rare entity that can occur up to decades after treatment of the primary tumor. Here, we present a patient who developed skin metastasis 10 years after treatment of her primary tumor and describe the molecular findings of the metastatic lesion. CASE PRESENTATION: A 44-year-old female with a history of PTC who underwent a total thyroidectomy and radioactive iodine (RAI) treatment 10 years ago presented with a 1.3-cm skin lesion along the prior thyroidectomy scar. A biopsy revealed metastatic PTC, and the patient underwent surgical excision of the lesion. ThyroSeq molecular testing showed the copresence of BRAFV600E mutation and TERT promoter C228T mutation. The patient subsequently received one round of adjuvant RAI therapy. CONCLUSIONS: A high index of suspicion is warranted in patients with a history of PTC who develop a skin lesion, even several years after remission of the primary disease. In patients with high-risk mutations, such as BRAFV600E and TERT promoter C228T mutations, long-term surveillance of disease recurrence is particularly important.

Comparison of arthroscopic primary and revision Bankart repair for capsulolabral restoration: a matched-pair analysis.

INTRODUCTION: There have been no previous studies comparing serial radiologic results between primary and revision Bankart repair despite the significance of capsulolabral height and slope restoration. The purpose of this study was (1) to compare serially the height and slope of the repaired labrum in the early postoperative period among primary and revision Bankart repair groups, and (2) to compare clinical outcomes between the two groups. MATERIALS AND METHODS: This study included each 24 patients who underwent arthroscopic primary Bankart repair (Group A) and revision Bankart repair (Group B) matched by age, sex, and glenoid defect ratio. Postoperative serial radiologic assessment of the repaired labral height and slope was proceeded using magnetic resonance imaging (MRI) or computed tomographic arthrography (CTA) at 3 weeks and 6 months. RESULTS: There were no significant differences in labral height and slope at 3 weeks and 6 months postoperatively in Group A. However, significant reductions in labral height and slope were evident between 3 weeks and 6 months postoperatively in Group B (P < 0.05). Group A yielded superior results to Group B with respect to labral height and slope at each time point (P < 0.05) in between-group analyses. The clinical outcomes were not significantly different between the two groups except for the patients' return to their premorbid sports activity level (P = 0.024). CONCLUSIONS: The height and slope of the repaired capsulolabral structures in the early postoperative period after arthroscopic revision Bankart repair group were significantly lower than those of the primary Bankart repair group. Also the reduction of labral height and slope was significant in the revision Bankart repair group over time. Nonetheless, clinical outcomes did not differ significantly except return to premorbid sports activity level at final follow-up.

A Simple, Selective, and General Catalyst for Ring Closing Depolymerization of Polyesters and Polycarbonates for Chemical Recycling.

The ability to efficiently and selectively process mixed polymer waste is important to address the growing plastic waste problem. Herein, we report that the combination of ZnCl2 and an additive amount of poly(ethylene glycol) under vacuum can readily and selectively depolymerize polyesters and polycarbonates with high ceiling temperatures (Tc >200 °C) back to their constitute monomers. Mechanistic experiments implicate a random chain scission mechanism and a catalyst structure containing one equivalent of ZnCl2 per ethylene glycol repeat unit in the poly(ethylene glycol). In addition to being general for a wide variety of polyesters and polycarbonates, the catalyst system could selectively depolymerize a polyester in the presence of other commodity plastics, demonstrating how reactive distillation using the ZnCl2 /PEG600 catalyst system can be used to separate mixed plastic waste.

Validation of CDr15 as a new dye for detecting neutrophil extracellular trap.

Neutrophil extracellular trap (NET) is one of the first-line defenses against microbes. Under certain circumstances, however, it also plays an aggravating factor in diverse inflammation-related diseases including cancers and vascular diseases. Our aim is to develop a new method to detect NET in cells and tissues using a DNA-specific fluorescence probe CDr15. CDr15 was characterized to be impermeable to the cell membranes and to emit a strong fluorescence in association with extracellular DNAs in NET. Due to these properties, CDr15 was successfully shown to quantify NETs in vitro and to be applicable for real-time monitoring NET formation in PMA-stimulated neutrophils. Even in formaldehyde-fixed tumor specimens, CDr15 could detect NETs spreading around cancer cells. Compared with DAPI and SYTOX DNA dyes, CDr15 showed a lower level of background fluorescence and a higher specificity in NET detection. Based on these results, we propose CDr15 as a novel marker of NET to be applicable in experimental and clinical studies.

Indoxyl sulfate-induced TNF-α is regulated by crosstalk between the aryl hydrocarbon receptor, NF-κB, and SOCS2 in human macrophages.

Indoxyl sulfate (IS) is a uremic toxin associated with increased prevalence of cardiovascular diseases (CVDs) in patients with chronic kidney disease. Despite the crucial role of uremia-related immune dysfunction, a majority of studies attempting to elucidate its pathogenic role in CVD have focused on IS-mediated endothelial dysfunction. Thus, we investigated the underlying molecular mechanisms involved in IS-induced production of TNF-α, a major cardiotoxic cytokine, by human macrophages. We found that crosstalk between the aryl hydrocarbon receptor (AhR), NF-κB, and the suppressor of cytokine signaling (SOCS)2 is important for TNF-α production in IS-stimulated human macrophages. IS-activated AhR rapidly associates with the p65 NF-κB subunit, resulting in mutual inhibition of AhR and NF-κB and inhibition of TNF-α production at an early time point. Later, this repression of TNF-α production is alleviated when SOCS2, a negative modulator of NF-κB, is directly induced by IS-activated AhR. In addition, once free of inhibition, activated AhR induces TNF-α expression by interacting with AhR binding sites in the TNF-α gene. Lastly, we confirmed decreased AhR and increased SOCS2 expression in monocytes of patients with end-stage renal disease, indicating the activation of AhR. Taken together, our results suggest that IS-induced TNF-α production in macrophages is regulated through a complicated mechanism involving interaction of AhR, NF-κB, and SOCS2.-Kim, H. Y., Yoo, T.-H., Cho, J.-Y., Kim, H. C., Lee, W.-W. Indoxyl sulfate-induced TNF-α is regulated by crosstalk between the aryl hydrocarbon receptor, NF-κB, and SOCS2 in human macrophages.

Brefeldin A-sensitive ER-Golgi vesicle trafficking contributes to NLRP3-dependent caspase-1 activation.

Endoplasmic reticulum (ER)-Golgi vesicle trafficking plays a pivotal role in the conventional secretory pathway of many cytokines; however, the precise release mechanism of a major inflammasome mediator, IL-1ß, is not thought to follow the conventional ER-Golgi route and remains elusive. Here, we found that perturbation of ER-Golgi trafficking by brefeldin A (BFA) treatment attenuated nucleotide-binding oligomerization domain-like receptor family, pyrin-domain-containing 3 (NLRP3) inflammasome activation in mouse bone marrow-derived macrophages (BMDMs). BFA treatment inhibited NLRP3-mediated inflammasome assembly and caspase-1 activation but did not block IL-1ß secretion from BMDMs following BFA administration after NLRP3 inflammasome activation. Consistently, short-hairpin RNA-dependent knockdown of BFA-inhibited guanine nucleotide-exchange protein 1 (BIG1), a molecular target of BFA and an initiator of Golgi-specific vesicle trafficking, abolished NLRP3-dependent apoptosis-associated speck-like protein containing a caspase-recruitment domain oligomerization and caspase-1 activation in BMDMs. Similarly, knockdown of Golgi-specific BFA-resistance guanine nucleotide exchange factor 1, another target of BFA, clearly attenuated NLRP3-mediated caspase-1 activation in BMDMs. Mechanistically, inhibition of BIG1-mediated vesicle trafficking did not impair NLRP3-activating signal 2-promoted events, such as potassium efflux and mitochondrial rearrangement, but caused significant impairment of signal 1-triggered priming steps, including NF-κB-mediated pathways. These data suggest that BFA-targeted vesicle trafficking at the Golgi contributes to activation of the NLRP3 inflammasome signaling.-Hong, S., Hwang, I., Gim, E., Yang, J., Park, S., Yoon, S.-H., Lee, W.-W., Yu, J.-W. Brefeldin A-sensitive ER-Golgi vesicle trafficking contributes to NLRP3-dependent caspase-1 activation.

CD4+ /CD8+ T-cell ratio correlates with the graft fate in pig-to-non-human primate islet xenotransplantation.

BACKGROUND: Xenogeneic islet transplantation using porcine pancreata has been a promising option for substituting human islet transplantation. Moreover, recent advances in pre-clinical results have put islet xenotransplantation closer to the possibility of clinical application. While preparing for the era of clinical xenotransplantation, developing non-invasive immune monitoring method which could predict the graft fate could benefit the patient. However, there are few reports showing predictive immune parameters associated with the fate of the graft in islet xenotransplantation. METHODS: The absolute number and ratio of T-cell subsets have been measured via flow cytometry from the peripheral blood of 16 rhesus monkeys before and after porcine islet xenotransplantation. The correlation between the graft survival and the absolute number or ratio of T cells was retrospectively analyzed. RESULTS: The ratio of CD4+ versus CD8+ T cells was significantly reduced due to CD8+ effector memory cells' increase. Correlation analyses revealed that CD4+ /CD8+ , CD4+ /CD8+ naïve, CD4+ naïve/CD8+ naïve, and CD4+ central memory/CD8+ naïve cell ratios negatively correlated with the duration of graft survival. Conversely, further analyses discovered strong, positive correlation of CD4+ /CD8+ cell ratios within the early graft-rejected monkeys (≤60 days). CONCLUSIONS: This retrospective study demonstrated that CD4+ /CD8+ ratios correlated with graft survival, especially in recipients which rejected the graft in early post-transplantation periods. CD4+ /CD8+ ratios could be used as a surrogate marker to predict the graft fate in pig-to-NHP islet xenotransplantation.

Human Cytomegalovirus (HCMV)-infected Astrocytoma Cells Impair the Function of HCMV-specific Cytotoxic T Cells.

BACKGROUND: Human cytomegalovirus (HCMV) infection in glioblastoma multiforme (GBM) is associated with a poor prognosis and may affect the pathogenesis of GBM. In this study, we investigated the role of HCMV-infected astrocytoma cells in impairing the activity of cytotoxic T lymphocytes (CTLs) specific to the HCMV protein. METHODS: CTLs specific to HCMV immediate early (IE)-1 were expanded from peripheral blood mononuclear cells of healthy donors by stimulating CD8+ T lymphocytes with U373MG cells (ATCC HTB-17: male) expressing HCMV IE-1. The death rate of the target and the effector cells was determined by the total count of the remaining respective cells after the interaction of them. RESULTS: The death rate of the target cells by CTLs increased depending on HLA restriction and the effector:target (E:T) ratio. The death rate of effector cells in the HCMV-infected U373MG cell culture was 37.1% on day 4 post-infection. The removal of the culture supernatant from HCMV-infected U373MG cells prior to adding the effector cells increased target cell death from 8.4% to 40.8% at E:T = 1:1, but not at E:T = 3:1. The transfer of cells from a 24-hour co-culture of the HCMV-infected U373MG cells and CTLs to HCMV IE-1-expressing target cells resulted in decreasing the cell death rate of the target cells from 31.1% to 13.0% at E:T = 1:1, but not at E:T = 3:1. HCMV infection of U373MG cells decreases the activity of CTLs specific to HCMV when the number of CTLs is low. CONCLUSION: These results suggest that HCMV could impair CTL activity and facilitate glioblastoma growth unchecked by CTLs.

Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow.

Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide.

Beijing urban particulate matter-induced injury and inflammation in human lung epithelial cells and the protective effects of fucosterol from Sargassum binderi (Sonder ex J. Agardh).

Particulate matter (PM) air pollution has gradually become a widespread problem in East Asia. PM may cause unfamiliar inflammatory responses, oxidative stress, and pulmonary tissue damage, and a comprehensive understanding of the underlying mechanisms is required in order to develop effective anti-inflammatory agents. In this study, fine dust collected from Beijing, China (CPM) (size < PM13 with majority < PM2.5) was evaluated for its oxidative stress- and inflammation-inducing effects, which cause cell damage, in A459 human lung epithelial cells. Oxidative stress was marked by an increase in intracellular ROS levels and the production of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and heme oxygenase-1 (HO-1). Upon induction of oxidative stress, a marked increase was observed in the expression of key inflammatory mediators such as COX-2 and PGE2 and the pro-inflammatory cytokines TNF-α and IL-6 via NF-kB and MAPK pathways. Cellular damage was marked by a reduction in viability, increased lactate dehydrogenase (LDH) release, formation of apoptotic and necrotic bodies, accumulation of sub-G1 phase cells, and DNA damage. Apoptosis was found to be mediated via the activation of caspases through the mitochondria-mediated pathway. Fucosterol, purified from the brown alga Sargassum binderi (Sonder ex J. Agardh) by bio-assay-guided fractionation and purification, exhibited potential therapeutic effects against CPM-induced detrimental effects. Further studies could focus on developing fucosterol, in forms such as steroidal inhalers, against PM-induced pulmonary tissue inflammation.

Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation.

The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4(+) T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4(+) T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell-specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4(+) T-cell activation via epigenetic regulation of Kv1.3 expression.

Pseudolaric Acid B Induces Growth Inhibition and Caspase-Dependent Apoptosis on Head and Neck Cancer Cell lines through Death Receptor 5.

Pseudolaric Acid B (PAB), diterpenoid isolated from the root bark of Pseudolarix kaempferi Gordon tree (Pinaceae), exhibits an anti-proliferative and apoptotic activity in various cancer cell lines but to date, the effects of PAB on head and neck cancer (HNC) cell lines remain to be elucidated. In this study, we showed that PAB significantly inhibited the viability and caspase-dependent apoptosis in HN22 cell line. PAB-induced apoptosis is through inducing death receptor 5 (DR5) together with the increase in the expression of cleaved caspase-8. It also inhibited the proliferations and induced apoptosis through DR5 in other three HNC cell lines (HSC3, Ca9.22, and HSC4). Extending our in vitro findings, we found that ethanol extract of Pseudolarix kaempferi (2.5 mg/kg/day) reduced tumor growth in a xenograft model bearing HN22 cell line without any change in body weight. DR5 were also found to be increased in tumors tissue of PAB-treated mice without any apparent histopathological changes in liver or kidney tissues. Taken together, PAB may be a potential lead compound for chemotherapeutic agents against head and neck cancer.

Long-Term Oncologic Outcomes of Laparoscopic Sentinel Node Navigation Surgery in Early Gastric Cancer: A Single-Center, Single-Arm, Phase II Trial.

BACKGROUND: Sentinel node navigation surgery (SNNS) in early gastric cancer (EGC) is technically feasible according to previous literature, however its long-term oncologic safety has not been reported. METHODS: A single-center, single-arm, phase II trial was conducted to determine the oncologic outcomes of laparoscopic sentinel node (SN) biopsy in clinical stage T1N0M0 gastric cancer patients. Cases with positive SNs on intraoperative pathologic examination underwent conventional gastrectomy with radical lymphadenectomy (SN-positive group), whereas those with negative SNs underwent laparoendoscopic-limited gastric resections without further lymph node dissections (SN-negative group). The primary endpoint was 3-year relapse-free survival. RESULTS: Between July 2010 and April 2013, 113 patients were enrolled, with 100 patients being included in the final analysis. SNs were detected in 99 patients. The mean number of identified SNs was 6.1 ± 3.9. Eleven patients were included in the SN-positive group and 89 in the SN-negative group. After a median follow-up period of 46.4 months, four patients died and three showed cancer recurrence. All recurrences occurred on the remnant stomach after endoscopic submucosal resection or wedge resection in the SN-negative group. The 3-year relapse-free and overall survival rates were 96.0% (95% confidence interval [CI] 92.2-100.0%) and 98.0% (95% CI 95.2-100.0%), respectively. CONCLUSIONS: Our results indicate that laparoscopic SNNS may be oncologically safe in EGC. Limited gastric resections should be carefully performed to prevent local recurrence in SN-negative cases. A randomized controlled trial is needed based on the present study.

Apoptotic and antiproliferative properties of 3ß-hydroxy-Δ5-steroidal congeners from a partially purified column fraction of Dendronephthya gigantea against HL-60 and MCF-7 cancer cells.

Organisms belonging to the genus Dendronephthya are among a group of marine invertebrates that produce a variety of terpenoids with biofunctional properties. Many of these terpenoids have been proven effective as anticancer drugs. Here, we report the antiproliferative effect of 3ß-hydroxy-Δ5-steroidal congeners against the proliferation of HL-60 human leukemia cells and MCF-7 human breast cancer cells. The sterol-rich fraction (DGEHF2-1) inhibited the growth of HL-60 and MCF-7 cells with IC50 values of 13.59 ± 1.40 and 29.41 ± 0.87 µg ml-1 respectively. Treatment with DGEHF2-1 caused a dose-dependent increase in apoptotic body formation, DNA damage and the sub-G1 apoptotic cell population. Moreover, DGEHF2-1 downregulated the expression of Bcl-xL while upregulating Bax, caspase-9, and PARP cleavage in both HL-60 and MCF-7 cells. The steroid fraction was found to act via the mitochondria-mediated apoptosis pathway. Identification of the sterols was performed via gas chromatography-tandem mass spectrometry analysis. Studying the mechanism of the anticancer effect caused by these sterol derivatives could lead to the identification of other natural products with anticancer properties.

Anti-inflammatory potential of alginic acid from Sargassum horneri against urban aerosol-induced inflammatory responses in keratinocytes and macrophages.

The airborne particulate pollutants originating in the deserts of Mongolia and China which becomes contaminated with industrial effluents and traffic emissions while moving with the wind currents towards East Asia has recently become a serious environmental and health issue in the region. They cause asthma, collateral lung tissue damage, oxidative stress, allergic reactions, and inflammation. The current study was undertaken to evaluate the protective effects of alginate extracted from the invasive alga Sargassum horneri (SHA) against fine dust collected from Beijing, China (Chinese fine dust; CFD). It was found that CFD induces inflammation in HaCaT keratinocytes and inhibits macrophage activation. All of the particulate matter (PM) comprising CFD was < PM13 majority being < PM2.5 which is defined for mineral elements and polycyclic aromatic hydrocarbons. SHA attenuated PGE2 levels in CFD-induced HaCaT keratinocytes. The IC50 for SHA was 36.63 ±â€¯4.11 µg mL-l. SHA also reduced the levels of COX-2, IL-6, and TNF-α, and inhibited certain key molecular mediators of the NF-κB and MAPK pathways in keratinocytes. SHA substantially reduced the levels of CFD-derived metal ions like Pb2+ and Ca2+ in keratinocytes attributable to its metal ion chelating properties. CFD-induced HaCaT keratinocyte culture media increased inflammatory responses in RAW 264.7 macrophages. These cells presented with increased levels of NO, iNOS, COX-2, PGE2, and pro-inflammatory cytokines. It was found that the aforementioned effects could be reversed in RAW 264.7 macrophages when keratinocytes were treated with SHA. Therefore, SHA could be used against fine dust-induced inflammation in keratinocytes.

Sargassum horneri (Turner) C. Agardh ethanol extract inhibits the fine dust inflammation response via activating Nrf2/HO-1 signaling in RAW 264.7 cells.

BACKGROUND: Among the different kinds of pollution, air pollution continues to increase globally. East Asia is considered to be significantly affected. As a result, the populations in these regions face serious health issues including respiratory disorders. This study investigated the impact of fine dust (FD) particles (CRM No. 28) on macrophage cells as a model for alveolar lung cells. METHODS: The research focused on inflammation and oxidative stress induced by FD and Sargassum horneri (Turner) C. Agardh ethanol extract (SHE) as a potential treatment. S. horneri is a type of brown algae that has demonstrated anti-inflammatory effects against RAW 264.7 macrophages in previous studies. MTT, Griess, ELISA, western blotting, and mRNA expression analyses using PCR techniques were used in this study. RESULTS: The optimum FD concentration was determined to be 125 µg mL- 1. FD particles stimulated inflammatory mediators production (iNOS, COX-2, and PGE2) and pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), leading to NO production. These mediators were dose-dependently downregulated by treatment with SHE. IL-6 and TNF-α were identified as biomarkers for FD. SHE treatment induced HO-1 and Nrf2 activity in a dose-dependent manner under FD stimulation. This confirmed the cytoprotective effect against oxidative stress induced via FD. Furthermore, treatment of the cells with a p38 MAPK inhibitor (SB202190) induced FD-stimulated NO production. CONCLUSIONS: The results suggest that SHE increases macrophage cellular resistance to FD-induced inflammation and oxidative stress, probably via the p38 MAPK pathway and Nrf2/HO-1 expression.

Preferential Induction of the T Cell Auxiliary Signaling Molecule B7-H3 on Synovial Monocytes in Rheumatoid Arthritis.

B7-H3, a newly identified B7 family member, has functional duality as a co-stimulator and co-inhibitor that fine-tunes T cell-mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Further, monocytes play crucial roles in the pathophysiology of various inflammatory disorders including autoimmune diseases; however, the immunological role of B7-H3 in rheumatoid arthritis (RA) has not been defined. Thus, we aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments reveal that surface B7-H3 has an inhibitory effect on IFN-γ production in CD4 memory cells. Moreover, surface B7-H3 expression on synovial monocytes inversely correlates with RA clinical parameters. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles affecting RA pathogenesis.

Imaging of Myocardial Ischemia-Reperfusion Injury Using Sodium [18F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans.

Positron emission tomography (PET)/computed tomography (CT) using sodium [18F]fluoride (Na[18F]F) has been proven to be a promising hot-spot imaging modality for myocardial infarction (MI). We investigated Na[18F]F uptake in ischemia-reperfusion injury (IRI) of rats and humans. Sodium [18F]fluoride PET/CT was performed in Sprague-Dawley rats that had IRI surgery, and it readily demonstrated prominent Na[18F]F uptake in the infarct area post-IRI. Sodium [18F]fluoride uptake was matched with negative 2,3,5-triphenyl-2 H-tetrazolium chloride staining results, accompanied by myocardial apoptosis and associated with positive calcium staining results. Furthermore, area at risk was negative for Na[18F]F uptake. Cyclosporine A (CysA) treatment reduced standardized uptake value of 18F over the infarct area, and a significant decrease in infarct size was also observed by the CysA treatment. In humans, Na[18F]F PET/CT readily demonstrated increased Na[18F]F uptake in the 2 patients with MI post-percutaneous coronary intervention. In conclusion, this study sheds light on the potential utility of Na[18F]F PET/CT as a hot-spot imaging modality for myocardial IRI.