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Introduction: Zifanocycline (KBP-7072) is a novel aminomethylcycline antibiotic with a broad spectrum of antibacterial activity. This study determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of zifanocycline in mice and the optimal PK/PD index for efficacy against Acinetobacter baumannii in a neutropenic murine thigh infection model., Methods: Zifanocycline PK properties were characterized in plasma after single-dose subcutaneous injection in healthy mice at doses of 1, 4, 16, 64, and 256 mg/kg. PK/PD analyses were performed with zifanocycline against 8 clinical A. baumannii isolates in a neutropenic murine thigh infection model., Results: Plasma total and free drug C max , AUC 0-inf , and AUC 0-24 increased with dose, where C max of total drug was 0.12-25.2 mg/L, AUC 0-inf was 1.13-234 h*mg/L, AUC 0-24 was 1.09-225 h*mg/L, and free drug C max was 0.03-5.68 mg/L, AUC 0-inf was 0.25-52.6 h*mg/L, and AUC 0-24 was 0.25-50.5 h*mg/L. MICs of zifanocycline against A. baumannii ranged from 0.06 to 0.5 mg/L, with significant activity against all 8 strains. Average daily doses of zifanocycline to achieve a static, 1-log 10 kill, and 2-log 10 kill effect were projected to be 6.92, 9.63, and 13.22 mg/kg, and the mean fAUC/MIC ratios were 6.91, 9.10, and 12.60, respectively. AUC/MIC was the optimal PK/PD index of zifanocycline against A. baumannii., Conclusion: The in vivo efficacy results and PK/PD analyses support the design of optimal dosing regimens in clinical studies and assist with determining clinical breakpoints for zifanocycline., Competing Interests: Declaration of competing interest All authors were employees of KBP Biosciences USA, Inc., Princeton, NJ (Ying Chen, Jay Zhang) or KBP Biosciences Co., Ltd., Jinan, China (Li Li, Xiaojuan Tan, Tian Zhou, Shuangshuang Chi, Yuanju Zhu, Qingmei Liu) when the PK/PD studies were conducted, and this manuscript is being prepared, otherwise there was no reported conflict of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Systemic Sclerosis (SSc) is an autoimmune disease characterized by vascular and immune system dysfunction, along with tissue fibrosis. Our previous study found GRB2 was downregulated by salvianolic acid B, a small molecule drug that attenuated skin fibrosis of SSc., Objectives: Here we aim to investigate the role of GRB2 in SSc., Methods: The microarray data of SSc skin biopsies in Caucasians were obtained from the Gene Expression Omnibus (GEO) database. The expression of GRB2 was further detected in Chinese SSc and healthy controls. Bleomycin (BLM)-induced skin fibrosis mice were used to explore how GRB2 downregulation affected fibrosis. The apoptosis of EA.hy926 endothelial cells was induced by H 2 O 2 and apoptosis ratio was measured by flow cytometric. Transcriptome and phosphoproteomic analyses were performed to explore the regulated pathway., Results: The expression of GRB2 was significantly enhanced in SSc patient skin, 1.51-fold in Caucasians and 1.40-fold in Chinese. Double immunofluorescence staining showed the endothelial cells of SSc patient's skin highly expressed GRB2. The in vivo study revealed that GRB2 knockdown alleviated skin fibrosis and apoptosis of endothelial cells in BLM mouse skin. The in vitro study showed that GRB2 downregulation inhibited the apoptosis of EA.hy926 and protected them from H 2 O 2 -induced hyperpermeability. Moreover, transcriptome and phosphoproteomic analysis suggested the focal adhesion pathway was enriched in GRB2 siRNA transfected endothelial cells., Conclusions: Our results demonstrated GRB2 highly expressed in endothelial cells of SSc skin, and inhibiting GRB2 could effectively attenuate BLM-induced skin fibrosis and endothelial cell apoptosis. GRB2 is expected to be a new therapeutic target for SSc., Competing Interests: Conflict of Interest The authors have no conflict of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

PPARγ full agonists, thiazolidinediones (TZDs), have been known as a class of most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, recently their therapeutic benefits have been compromised by several undesirable side effects. In this study, a host-based repurposing strategy and in combination with comprehensive biological evaluations were synergistically employed to seek for potent PPARγ ligands, which led to the identification of an anti-thrombotic drug, dicoumarol (Dic), as the novel and safer selectively PPARγ modulator (SPPARγM) with advantages over current TZD drugs. The results in vitro showed that Dic had a potent binding affinity and weakly agonistic activity for PPARγ and its downstream key genes. Moreover, in diabetic model, it significantly reduced blood glucose without leading to the weight gain of both body and main organ tissues. Further mechanistic investigations revealed that Dic possessed such desired pharmacological properties mainly through effectively inhibiting the phosphorylation of PPARγ-Ser273 and selectively regulating the expressions of insulin-sensitive and resistance genes. Finally, the docking studies on the analysis of the potent binding mode of Dic with PPARγ revealed a remarkable difference on interaction region compared with other developed PPARγ agonists, which not only gave a proof of concept for the abovementioned mechanism but also provided the molecular basis for the discrimination of Dic from other PPARγ ligands, especially TZD drugs. Taken together, our findings suggested that Dic could serve as a new and promising candidate with good therapeutic index for treating T2DM, especially for those T2DM patients with thrombosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purposes: To quantitatively predict central lymph node metastasis (CLNM) risks by comparing the clinicopathological features of different multifocal manifestations in papillary thyroid carcinomas (PTC) patients., Methods: A total of 998 PTC patients from three medical centers were retrospectively analyzed., Results: PTC patients with multifocal lesions in at least one thyroid lobe (MF group) yielded significantly higher CLNM rates than those with unifocal lesions in one or both lobes (UF group). Multifocality in at least one lobe rather than bilateral presence was confirmed to be an independent risk factor of CLNM for PTC patients. Four (age, gender, maximum tumor diameter, and thyroid capsular invasion (TCI)) and three (age, gender, and TCI) factors were proven to be independent risk factors of CLNM for patients within UF and MF groups, respectively. Predictive nomograms were established for these patients based on their respective high-risk factors. The accuracy and validity of these newly-created models were verified using C-index and calibration curves. Patients within UF and MF groups possessing significantly different CLNM risks based on individualized nomogram risk scores were further classified into different subgroups. A detailed CLNM risk stratification flow chart covering all PTC patients was then established., Conclusion: A meticulous evaluating system that quantifiesCLNM risk for PTC patients with unifocal lesions in one or both lobes and multifocal lesions in at least one lobe was established., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Genetic factors play a key role in the pathogenesis of autoimmune diseases, whereas the disease-causing variants remain largely unknown. Herein, we performed an exome-wide association study of systemic sclerosis in a Han Chinese population. In the discovery stage, 527 patients with systemic sclerosis and 5,024 controls were recruited and genotyped. In the validation study, an independent sample set of 479 patients and 1,096 controls were examined. In total, we found that four independent signals reached genome-wide significance. Among them, rs7574865 (P combined  = 3.87 × 10 -12 ) located within signal transducer and activator of transcription 4 gene was identified previously using samples of European ancestry. Additionally, another signal including three SNPs in linkage disequilibrium might be unreported susceptibility loci located in the epidermis differentiation complex region. Furthermore, two SNPs located within exon 3 of IGHM (rs45471499, P combined  = 1.15 × 10 -9 ) and upstream of LRP2BP (rs4317244, P combined  = 4.17 × 10 -8 ) were found. Moreover, rs4317244 was identified as an expression quantitative trait locus for LRP2BP that regulates tight junctions, cell cycle, and apoptosis in endothelial cell lines. Collectively, our results revealed three signals associated with systemic sclerosis in Han Chinese and suggested the importance of LRP2BP in systemic sclerosis pathogenesis. Given the limited sample size and discrepancies between previous results and our study, further studies in multiethnic populations are required for verification., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Andrastones are unusual 6,6,6,5-tetracyclic meroterpenoids that are rarely found in nature. Previously, three andrastones were obtained from the rice static fermentation extract of the deep-sea-derived fungus Penicillium allii-sativi MCCC 3A00580. Inspired by one strain many compounds (OSMAC) approach, the oat static fermentation on P. allii-sativi was conducted. As a result, 14 andrastones were isolated by UV-guided isolation. The chemical structures of the nine new compounds (1-9) was established by comprehensive analysis of the NMR, MS, ECD, and X-ray crystallography and the five known ones (10-14) were assigned by comparing their NMR, MS, and OR data with those reported in literature. Compound 1 bears a novel hemiketal moiety while 2 is the first example to possess a novel tetrahydrofuran moiety via C-7 and C-15. All isolates were tested for anti-allergic bioactivity. Compound 10, 3-deacetylcitreohybridonol, significantly decreased degranulation with the IC 50 value of 14.8 μM, compared to that of 92.5 μM for the positive control, loratadine. Mechanism study indicated 10 could decrease the generation of histamine and TNF-α by reducing the accumulation of Ca 2+ in RBL-2H3 cells. These findings indicate andrastones could be potential to discover new anti-allergic candidate drugs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To compare two different laser sources, a KTP laser with a wavelength of 532 nm and a Nd:YAG laser with a wavelength of 1064 nm, to investigate the relation between laser source and bleaching gel during laser irradiation., Methods: Extracted human teeth were stained and randomly divided into six groups. Two in-office bleaching gels, Beyond and Opalescence Boost, were applied to stained teeth and then irradiated at either 532 nm or 1064 nm. The temperature change of pulp chamber was measured. The color change (ΔE*) was evaluated at the following time points: immediately after bleaching, 7, 14 and 30 days after the end of bleaching., Results: Boost irradiated by KTP laser showed the higher temperature increase when compared with Beyond irradiated KTP and Nd:YAG. Boost irradiated by Nd:YAG presented lower temperature increase than by KTP. All groups showed a certain color change. After bleaching, Nd:YAG laser irradiation did not increase the ΔE* value significantly compared with gels without laser (p >  0.05). At each time point, Boost activated by KTP laser showed higher ΔE* value compared with other groups (p < 0.05), but decreased significantly 15 days after the end of bleaching. The other groups showed a relatively small change in ΔE* value after 30 days (p > 0.05)., Conclusions: KTP laser achieved better results than the Nd:YAG laser regarding tooth color change when associated with the Opalescence Boost bleaching gels., (Copyright © 2020. Published by Elsevier B.V.)

Background: Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation and fibrosis. Our previous research found Disabled-2 (DAB2) expression was significantly downregulated by salvianolic acid B, a small molecular medicine which attenuated experimental skin fibrosis of SSc. These suggest that DAB2 plays an important role in SSc skin fibrosis, but the role of DAB2 in SSc remains unclear., Objectives: To investigate the role of DAB2 in SSc., Methods: DAB2 expression level was detected in the skin and peripheral blood mononuclear cells of SSc patients. Bleomycin (BLM)-induced SSc mice and primary SSc skin fibroblasts were used to investigate the effect of DAB2 downregulation on fibrosis. RNA-seq transcriptome analysis was performed to underlie the mechanism of DAB2 in fibroblasts., Results: DAB2 expression was enhanced in SSc lesion skin and was positively correlated with fibrotic genes, such as α-SMA and PAI-1. The in vivo study revealed that DAB2 downregulation alleviated skin fibrosis, alleviating skin thickness and reducing collagen deposition, and DAB2 knockdown ameliorated the inflammatory cell infiltration. The in vitro study showed that DAB2 knockdown reduced extracellular matrix genes and proteins expression. Moreover, Transcriptome analysis revealed TGF-β and focal adhesion signaling pathways were the main downregulated pathways involved in DAB2 siRNA treated fibroblasts., Conclusions: Taken together, our results revealed that DAB2 was increased in SSc skin, and DAB2 downregulation inhibited BLM-induced mouse skin fibrosis and SSc skin fibroblasts activation. DAB2 played an important role in the pathogenesis of SSc and DAB2 modulation may represent a potential therapeutic method for SSc., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

Epigenetic modifications, including DNA methylation, play an important role in the pathogenesis of autoimmune diseases. In this study, we characterized the DNA methylome in primary T cells of patients with systemic sclerosis. Genome-wide DNA methylation assays of CD4 + and CD8 + T cells from 24 systemic sclerosis patients and 24 matched controls were conducted and differentially methylated regions were validated. In the discovery stage, we found that hypomethylation of genes involved in the type I IFN signaling pathway was significantly enriched in both CD4 + (P = 7.59 × 10 -6 ) and CD8 + (P = 2.10 × 10 -8 ) differentially methylated regions. In the validation stage, we confirmed these changes for five type I IFN-associated genes. In addition, protein levels of both type I IFN-α (P < 0.0001) and β (P = 0.002) were significantly elevated in the sera of systemic sclerosis patients. Moreover, significant associations between type I IFN-α/β protein levels with the DNA methylation status as well as the expression profiles of these IFN-associated genes were confirmed. In conclusion, the type I IFN pathway is dysfunctional at the epigenetic level in systemic sclerosis patients, indicating that hypomethylation and upregulation of type I IFN-associated genes might be critical in systemic sclerosis pathogenesis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation and fibrosis. Our previous research has indicated that Sirtuin1 (Sirt1) plays a role in the regulation of TNF-α-induced inflammation; however, whether Sirt1 may inhibit the progress of SSc by blocking inflammation remains unknown., Objective: We aimed to investigate the function of Sirt1 in SSc., Methods: The function and its mechanism of Sirt1 were evaluated in fibroblasts or scleroderma mice. The expression of Sirt1 and cytokines was analyzed using real-time PCR, western blot, ELISA and immunohistochemistry., Results: We determined that fibroblasts of SSc patients were activated to exhibit inflammation. Sirt1, activated by resveratrol (Res), ameliorated cutaneous inflammation and fibrosis in bleomycin (BLM)-induced scleroderma mice. An improvement in mammalian target of rapamycin (mTOR) was identified in the fibroblasts of SSc patients and the skin lesions of BLM mice. Rapamycin, an mTOR specific inhibitor, substantially inhibited the induced inflammation and fibrosis. The enhancement of mTOR expression in the skin lesions of the BLM-treated mice was significantly inhibited by Sirt1 activation. However, in both the BLM-treated cells and mice, Res exerted an inhibitory function on the expression of inflammatory factors, and collagen was diminished following mTOR knockdown. These findings suggest that Res may inhibit inflammation and fibrosis via mTOR., Conclusion: The modulation of Sirt1 activity may represent a potential therapeutic method for SSc. The mechanism may involve the inhibition of mTOR phosphorylation, whereas mTOR activity was shown to be a pathogenic culprit of SSc., (Copyright © 2017. Published by Elsevier B.V.)

GNB2L1 is an intercellular scaffold protein of the Trp-Asp (WD) repeat protein family, and has been reported to play suppressive roles in the progression of gastric cancer. However, the regulatory mechanisms of GNB2L1 in gastric cancer still remain largely elusive. In the present study, we found that OGT was capable to interact with GNB2L1 directly and modify GNB2L1 with O-GlcNAcylation in gastric cancer, and this O-GlcNAcylation hindered the inhibition of GNB2L1 on migration of gastric cancer cells. Moreover, O-GlcNAcylation regulated the degradation instead of the synthesis of GNB2L1 in gastric cancer, and our data suggested the O-GlcNAcylation on GNB2L1 influenced its stability directly. In addition, the clinical data revealed the negative correlation of the protein level instead of the mRNA level of GNB2L1 with OGT expression, and showed that OGT reversed the inhibition of GNB2L1 on metastasis, and worsened the prognosis of GNB2L1(High) patients. In summary, this study indicated the O-GlcNAcylation on GNB2L1 reversed its inhibition on gastric tumour metastasis via promoting its degradation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Gastric cancer is one of the most prevailing cancers with high morbidity and mortality. Limitations in the current diagnosis and therapy, specially lacking of specific molecular therapeutic targets, ask for the development of new strategies. Aptamer, a newly developed adaptive molecule, could be used in clinical detection and therapy because of its high affinity and specificity. As no aptamer has ever been developed in preventing gastric cancer so far, we were the first who cloned such an aptamer specifically targeting gastric cancer. The aptamer was selected by systematic evolution of ligands by exponential enrichment with gastric cancer cell-line HGC-27 as target cell line and immortalized gastric epithelial cell-line GES-1 as control cell line. The affinity and specificity of candidate aptamers were examined by flow cytometry, confocal imagining and aptamer-based histochemistry staining. After 19 cycles of systematic evolution of ligands by exponential enrichment and subsequent cloning and sequencing, an aptamer with the highest affinity and specificity (nominated as AGC03) among candidates was screened out from a random single-stranded DNA pool. Moreover, AGC03 could not only specifically bind to gastric cancer cells (the equilibrium dissociation constant value was 16.49 ± 0.40 nM) in vitro, but also recognize cancer cells in human cancer tissue. Our most important finding is that AGC03 could even be internalized into cells automatically. In conclusion, we obtained a novel aptamer specifically targeting gastric cancer,which is an effective tool for both gastric cancer diagnosis and drug delivery.