Chalcomoracin promotes apoptosis and endoplasmic reticulum stress in hepatocellular carcinoma cells.

Chalcomoracin (CMR), a Diels-Alder adduct obtained from mulberry leaves, demonstrated wide-spectrum anti-cancer activity. Herein, we aimed to explore the function of CMR and how it works in hepatocellular carcinoma (HCC). Human HCC cell lines Hep3B and SNU-387 were cultured and treated with various concentrations of CMR (1.5, 3, and 6 µM). Subsequently, the effects of CMR on cell viability, colony formation, apoptosis, migration, and invasion abilities were studied in vitro. Furthermore, the levels of endoplasmic reticulum (ER) stress-related proteins and mitogen-activated protein kinase (MAPK) pathway-related proteins in cells under CMR exposure were detected using western blot. Experiments in vivo were conducted to examine the effects of CMR on tumor growth in HCC. CMR administration inhibited the viability and clonogenic, migration, and invasion abilities, as well as promoted cell apoptosis and ER stress in Hep3B and SNU-387 cells. In addition, CMR treatment reduced the phosphorylation levels of ERK, P38, and JNK in the MAPK pathway. Moreover, an in vivo study showed that CMR administration could inhibit tumorigenesis and MAPK pathway activity in HCC. Our data indicate that CMR has the potential to inhibit the development of HCC, potentially through the inhibition of the MAPK pathway. These findings suggest that CMR may have promising applications as an anticancer agent in future therapeutics for HCC.

Metabolic dysfunction-associated fatty liver disease increases the risk of complications after radical resection in patients with hepatocellular carcinoma.

BACKGROUND AND AIMS: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) in hepatocellular carcinoma (HCC) patients is increasing, yet its association with postoperative complications of HCC remains unclear. The aim of this study was to investigate the impact of MAFLD on complications after radical resection in HCC patients. METHODS: Patients with HCC who underwent radical resection were included. Patients were stratified into MAFLD group and non-MAFLD group. Clinical features and post-hepatectomy complications were compared between the two groups, and logistic regression analysis was used to determine independent risk factors associated with post-hepatectomy complications. RESULTS: Among the 936 eligible patients with HCC who underwent radical resection, concurrent MAFLD was diagnosed in 201 (21.5%) patients. Compared to the non-MAFLD group, the MAFLD group exhibited a higher incidence of complications, including infectious and major complications after radical resection in HCC patients. The logistic regression analysis found that MAFLD was an independent risk factor for complications, including infectious and major complications in HCC patients following radical resection (OR 1.565, 95%CI 1.109-2.343, P = 0.012; OR 2.092, 95%CI 1.386-3.156, P < 0.001; OR 1.859, 95% CI 1.106-3.124, P = 0.019; respectively). Subgroup analysis of HBV-related HCC patients yielded similar findings, and MAFLD patients with type 2 diabetes mellitus (T2DM) exhibited a higher incidence of postoperative complications compared to those without T2DM (all P < 0.05). CONCLUSIONS: Concurrent MAFLD was associated with an increased incidence of complications after radical resection in patients with HCC, especially MAFLD with T2DM.

Impact of MAFLD on the complications after hepatectomy in patients with HBV-related hepatocellular carcinoma.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a term that was proposed in 2020 by a group of international experts. However, the impact of MAFLD on complications after hepatectomy in patients with hepatocellular carcinoma is not clear. The aim of this study is to explore the influence of MAFLD on the complications after hepatectomy in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). Patients with HBV-HCC who underwent hepatectomy between January 2019 and December 2021 were consecutively enrolled. The predictors of complications after hepatectomy in HBV-HCC patients were retrospectively analyzed. Among the 514 eligible HBV-HCC patients, 117 (22.8%) were diagnosed with concurrent MAFLD. Post hepatectomy complications occurred in 101 patients (19.6%), including 75 patients (14.6%) with infectious complications and 40 patients (7.8%) with major complications. Univariate analysis showed that MAFLD was not the risk factor for complications after hepatectomy in patients with HBV-HCC (P > .05). However, univariate and multivariate analysis revealed that lean-MAFLD was an independent risk factor for post hepatectomy complications in patients with HBV-HCC (odds ratio 2.245; 95% confidence interval 1.243-5.362, P = .028). Similar results were found in the analysis of predictors for infectious and major complications after hepatectomy in patients with HBV-HCC. MAFLD commonly coexists with HBV-HCC and is not directly associated with complications after hepatectomy, but lean-MAFLD is an independent risk factor for post hepatectomy complications in patients with HBV-HCC.

The impact of metabolic dysfunction-associated fatty liver disease on the prognosis of patients with hepatocellular carcinoma after radical resection.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is recently proposed an entity by a group of international experts. However, the impact of MAFLD on the prognosis of patients with hepatocellular carcinoma (HCC) is not clear. The aim of this study was to explore the influence of MAFLD for the prognosis of HCC after radical resection. METHODS: HCC patients who received radical resection were enrolled. The recurrence-free survival (RFS) and overall survival (OS) were compared between MAFLD and non-MAFLD. RESULTS: A total of 576 HCC patients were included, and among them 114 (19.8%) met the diagnostic criteria of MAFLD. The median RFS was 34.0 months in the MAFLD group and 19.0 months in the non-MAFLD group. The 1-, 3-, and 5-year RFS rates were 64.9%, 49.1% and 36.1% in the MAFLD group, which were higher than those of the non-MAFLD group (59.4%, 35.3% and 26.5%, respectively, P = 0.01). The mean OS was 57.0 months in the MAFLD group and 52.2 months in the non-MAFLD group. There was no statistical difference in OS rate between the MAFLD group and non-MAFLD group. Similar results were found in HBV-related HCC patients in the subgroup analysis. Univariate analysis revealed that MAFLD was a protective factor for RFS in HCC patients after radical resection (P < 0.05), and there was no association between MAFLD and OS rate (P > 0.05). Multivariate analysis demonstrated that MAFLD was not an independent protective factor for HCC patients with radical resection. CONCLUSIONS: MAFLD improves RFS rate in HCC patients with radical resection, but is not an independent protective factor and not associated with OS rate.

Targeting TBK1 attenuates ocular inflammation in uveitis by antagonizing NF-κB signaling.

Uveitis with complex pathogenesis is a kind of eye emergency involving refractory and blinding inflammation. Dysregulation of TANK binding kinase 1 (TBK1), which plays an important role in innate immunity, often leads to inflammatory diseases in various organs. However, the role of TBK1 in uveitis remains elusive. In this study, we identified that the mRNA expression level of TBK1 and its phosphorylation level were significantly increased in peripheral blood mononuclear cells (PBMCs) of patients with uveitis. Consistent with this, the expression of Tbk1 was elevated in the ocular tissues of uveitis rats and primary peritoneal macrophages while its phosphorylation levels, which present activation forms, were upregulated as well, accompanied by an increase in the level of nuclear factor-κB (NF-κB) and proinflammatory cytokines. In addition, inhibition of TBK1 may effectively reduce the inflammatory response of uveitis rats by blocking NF-κB entry into the nucleus and impeding the initiation of NLRP3 inflammasome- and caspase-1-mediated pyroptosis pathways.

Ratiometric fluorescence enzyme-linked immunosorbent assay based on carbon dots@SiO2@CdTe quantum dots with dual functionalities for alpha-fetoprotein.

Molecular tags such as fluorophores are increasingly being replaced with nanoparticles thanks to their superior optical properties, substantial chemical stability, and stability against photobleaching. Herein, we innovatively constructed a new ratiometric fluorescence enzyme-linked immunosorbent assay (RF-ELISA) for the screening of alpha-fetoprotein (AFP) in early hepatocellular carcinoma in vitro diagnostics using carbon dots@SiO2@CdTe quantum dots (CDs@SiO2@CdTe QDs). Carbon dots with blue fluorescence were initially encapsulated into SiO2 nanospheres through the typical Stöber method. Thereafter, CdTe QDs with red fluorescence were modified onto the surface of CDs@SiO2 nanospheres. Dual-emission nanotags with blue and red fluorescent signals were utilized to design a RF-ELISA method for the determination of AFP on the anti-AFP capture antibody-coated microplate using glucose oxidase (GOx)-labeled anti-AFP secondary antibody. After the formation of the sandwiched immunocomplex, GOx catalyzed glucose to generate hydrogen peroxide (H2O2), which could quench the red fluorescence of CdTe QDs on the surface of nanotags. Meanwhile, the encapsulated carbon dots in the nanotags could still maintain the initial blue fluorescence intensity. The ratio between red fluorescence intensity and blue-emission intensity could be used for the quantitative monitoring of AFP concentration under optimum conditions. The experimental results indicated that CDs@SiO2@CdTe QDs-based RF-ELISA could exhibit a good fluorescence signal with a dynamic linear range of 0.05-60 ng mL-1 at a low detection limit of 8.7 pg mL-1. Moreover, the fluorescence color of the solution including CDs@SiO2@CdTe QDs changed from pink to purple to blue with the increasing AFP level when viewed by the naked eye. Good reproducibility, high specificity, and acceptable stability were achieved for the analysis of target AFP. Importantly, the accuracy of ratiometric fluorescence immunoassay was evaluated to determine human serum samples, giving well-matched results relative to commercially usable human AFP ELISA method.

The Trend of Drug Therapy on Uveitic Macular Edema: A Bibliometric Analysis of the 100 Most Cited Articles.

Background: Macular edema is the most common cause of impaired vision due to uveitis. Although various medications are available, not all uveitis patients with macular edema are satisfied with the treatment results. Therefore, solving this gap becomes the utmost concern worldwide. This study attempted to use bibliometric analysis to compare the valuable information in the top 100 highly cited studies in the field of drug therapy for uveitic macular edema (UME) and then determine the research hot spots and trends in this field. Methods: In this study, the Science Citation Index Expanded (SCIE) of Web of Science (WOS) was used to collect the top 100 most cited studies on UME and analyze the literature from different countries/regions, institutions, and journals. The visualization knowledge maps is generated by VOSviewer and Citespace software. Results: The top 100 highly cited studies are from 34 countries/regions. The United States has the largest number of publications, followed by the England, Spain and Germany. The top three institutions publishing highly cited literature are all from the England: University of London, University College London, and Moorfields Eye Hospital NHS Foundation Trust. Ophthalmology is the most widely published journal with 14 papers. The total number of citations is 1,371, meaning that Ophthalmology is the most authoritative journal in the field of UME drug therapy. The top two articles with the most cited times are from the United States, accounting for 36.5% of the total cited times of the top 10 articles. Keywords were divided into three clusters: the corticosteroid administration pathway, biological agents, and clinical trials. Uveitis, cystoid macular edema, efficacy, dexamethasone, and triamcinolone acetonide appeared more frequently in keywords. Researches on local and long-acting drug has gradually becoming the hot spots and trends. Conclusion: This study concludes that bibliometric analysis can intuitively and quickly obtain the frontiers and hot spots of research in the field of UME drug therapy. Corticosteroid administration, biological agents, and clinical trials are considered the potential focus of future research.

Antiviral Therapy Improves Survival in Hepatocellular Carcinoma with Microvascular Invasion: A Propensity Score Analysis.

BACKGROUND AND AIMS: To investigate the effect of postoperative adjuvant antiviral therapy (AVT) on hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) with microvascular invasion (MVI) after R0 liver resection. METHODS: A total of 1008 patients with HBV-related HCC with MVI were recruited, which comprises 378 non-AVT groups and 630 AVT groups. Propensity score matching (PSM) was developed to reduce any bias in patient selection. Independent risk factors were identified by Cox regression analysis. RESULTS: After PSM, the 1-, 3-, and 5-year overall survival rates in the AVT group and non-AVT group were 89.2%, 62.4%, 42.1%, and 73.3%, 46.3%, 22.1%, (p < 0.01), respectively. The 1-, 3-, and 5-year recurrence-free survival rates in the AVT group and non-AVT group were 52.5%, 30.4%, 22.1%, and 46.3%, 26.8%, 13.2% (p = 0.02), respectively. Multivariate Cox analysis revealed that postoperative adjuvant AVT was the independent protective factor associated with mortality (HR = 0.55, 95%CI = 0.46-0.67, p < 0.01) and tumor recurrence (HR = 0.81, 95%CI = 0.69-0.96, p = 0.01). CONCLUSIONS: Among patients who underwent curative hepatectomy for HBV-related HCC with MVI, postoperative adjuvant AVT was the independent protective factor associated with mortality and tumor recurrence. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC with MVI, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

Discovery of Novel Genetic Risk Loci for Acute Central Serous Chorioretinopathy and Genetic Pleiotropic Effect With Age-Related Macular Degeneration.

BACKGROUND: Central serous chorioretinopathy (CSC) is a severe and heterogeneous chorioretinal disorder. Shared clinical manifestations between CSC and age-related macular degeneration (AMD) and the confirmation of CFH as genetic risk locus for both CSC and AMD suggest possible common pathophysiologic mechanisms between two diseases. METHODS: To advance the understanding of genetic susceptibility of CSC and further investigate genetic pleiotropy between CSC and AMD, we performed genetic association analysis of 38 AMD-associated single nucleotide polymorphisms (SNPs) in a Chinese CSC cohort, consisting of 464 patients and 548 matched healthy controls. RESULTS: Twelve SNPs were found to be associated with CSC at nominal significance (p < 0.05), and four SNPs on chromosomes 1, 4, and 15 showed strong associations whose evidences surpassed Bonferroni (BF)-corrected significance [rs1410996, odds ratios (OR) = 1.47, p = 2.37 × 10-5; rs1329428, OR = 1.40, p = 3.32 × 10-4; rs4698775, OR = 1.45, p = 2.20 × 10-4; and rs2043085, OR = 1.44, p = 1.91 × 10-4]. While the genetic risk effects of rs1410996 and rs1329428 (within the well-established locus CFH) are correlated (due to high LD), rs4698775 on chromosome 4 and rs2043085 on chromosome 15 are novel risk loci for CSC. Polygenetic risk score (PRS) constructed by using three independent SNPs (rs1410996, rs4698775, and rs2043085) showed highly significant association with CSC (p = 2.10 × 10-7), with the top 10% of subjects with high PRS showing 6.39 times higher risk than the bottom 10% of subjects with lowest PRS. Three SNPs were also found to be associated with clinic manifestations of CSC patients. In addition, by comparing the genetic effects (ORs) of these 38 SNPs between CSC and AMD, our study revealed significant, but complex genetic pleiotropic effect between the two diseases. CONCLUSION: By discovering two novel genetic risk loci and revealing significant genetic pleiotropic effect between CSC and AMD, the current study has provided novel insights into the role of genetic composition in the pathogenesis of CSC.

Novel Findings of Retinal and Choroidal Features Utilizing Optical Coherence Tomography Angiography Analysis in Patients With Autoimmune Posterior Uveitis.

Purpose: To analyze the quantitative parameters acquired by optical coherence tomography angiography (OCTA) in patients with autoimmune posterior uveitis. Methods: OCTA images of 65 eyes affected with uveitis and 65 normal control (NC) eyes were obtained. The central macular thickness (CMT), retinal thicknesses, foveal avascular zone (FAZ) area, foveal density 300 µm (FD300), and vascular density (VD) were compared among acute uveitic eyes, chronic uveitic eyes, and NC eyes. VDs were evaluated in the choriocapillaris, outer retina, optic disk, whole and parafovea superficial capillary plexus (SCP), and whole and parafovea deep capillary plexus (DCP). Correlation analysis was used to analyze the relationship between LogMAR best-corrected visual acuity (BCVA) and quantitative parameters from OCTA. Results: Compared with NC eyes, the CMT and retinal thicknesses were increased significantly in eyes with uveitis (p < 0.05, respectively). No significant difference was observed in the FAZ area. FD300, VDs in the optic disk, SCP, and DCP both in whole image and parafovea, choriocapillaris were significantly decreased in uveitis eyes (p < 0.05, respectively) compared with NC eyes, only the acute group had decreased VD of the outer retina and choriocapillaris compared with the NC group (p < 0.05). Moreover, quantitative parameters of OCTA showed a significant correlation with LogMAR BCVA in the patients with uveitis. Whole VD DCP was the best predictive factor for BCVA in the patients with uveitis. Conclusion: Quantitative measurement by OCTA is a promising strategy for objective assessment of autoimmune posterior uveitis.

Selective aminolysis of acetylated lignin: Toward simultaneously improving thermal-oxidative stability and maintaining mechanical properties of polypropylene.

Even with outstanding radical capturing ability, the utilization of lignin as a natural antioxidant in polypropylene (PP) still has been pended. Usually, the compatibility of its blends is improved based on the reaction of hydroxyl content, thus leading to the decreasing content of phenolic hydroxyl (Ph-OH) group and inferior thermal-oxidative stability of lignin blends. Here, the selective aminolysis of acetylated Kraft lignin (pyr-KL) was investigated, which structures were characterized using FTIR, 31P-NMR and GPC. The Ph-OH group of acetylated KL could be released by the addition of pyrrolidine; however the aliphatic hydroxyl group is still blocked. With the control of reaction conditions, the highest oxidation induction time of pyr-KL/PP (0.5wt% loading) reaches up to 22.6min, almost 2.6 times than that of pure PP. More importantly, the mechanical properties of PP were also maintained under the loading of pyr-KL, which is much better than that of curde KL/PP.

Focal adhesion molecule Kindlin-1 mediates activation of TGF-ß signaling by interacting with TGF-ßRI, SARA and Smad3 in colorectal cancer cells.

Kindlin-1, an integrin-interacting protein, has been implicated in TGF-ß/Smad3 signaling. However, the molecular mechanism underlying Kindlin-1 regulation of TGF-ß/Smad3 signaling remains elusive. Here, we reported that Kindlin-1 is an important mediator of TGF-ß/Smad3 signaling by showing that Kindlin-1 physically interacts with TGF-ß receptor I (TßRI), Smad anchor for receptor activation (SARA) and Smad3. Kindlin-1 is required for the interaction of Smad3 with TßRI, Smad3 phosphorylation, nuclear translocation, and finally the activation of TGF-ß/Smad3 signaling pathway. Functionally, Kindlin-1 promoted colorectal cancer (CRC) cell proliferation in vitro and tumor growth in vivo, and was also required for CRC cell migration and invasion via an epithelial to mesenchymal transition. Kindlin-1 was found to be increased with the CRC progression from stages I to IV. Importantly, raised expression level of Kindlin-1 correlates with poor outcome in CRC patients. Taken together, we demonstrated that Kindlin-1 promotes CRC progression by recruiting SARA and Smad3 to TßRI and thereby activates TGF-ß/Smad3 signaling. Thus, Kindlin-1 is a novel regulator of TGF-ß/Smad3 signaling and may also be a potential target for CRC therapeutics.