Clinical Outcomes of Concomitant Coronary Artery Bypass Grafting During Ventricular Septal Myectomy.

BACKGROUND: The clinical characteristics and survival outcomes of patients who underwent concomitant coronary artery bypass grafting during septal myectomy have not been well studied. METHODS AND RESULTS: We reviewed patients who underwent both septal myectomy and coronary artery bypass grafting from 2009 to 2020. Causes of concomitant grafting and their impact on survival were analyzed. The median follow-up period was 5.1 years. A total of 320 patients underwent both grafting and myectomy. Of these, 69.7% and 28.1% underwent grafting attributed to atherosclerotic coronary artery disease and myocardial bridging, respectively. Patients who underwent grafting for coronary artery disease tended to be older, had a longer bypass time, and required more grafts compared with patients undergoing procedures because of myocardial bridging (all P<0.05). Postoperatively, the left ventricular outflow gradient significantly decreased from 85.4 mm Hg to 12.8 mm Hg (P<0.001) without perioperative death. The cumulative survival rates were 96.2% and 97.6% at 5 years in the coronary artery disease and myocardial bridging groups, respectively, and they were comparable to that of general myectomy cohort (hazard ratio [HR], 1.06 [95% CI, 0.47-2.36], P=0.895 and HR 0.75 [95% CI, 0.23-2.46], P=0.636, respectively). Sudden death accounted for 45.5% (5 of 11) of postoperative mortality. Analysis of composite end point events showed decreased morbidity with at least one arterial graft in the overall cohort (HR, 0.47 [95% CI, 0.23-0.94], P=0.034). CONCLUSIONS: Concomitant grafting in septal myectomy was found to be a safe procedure. Patients who underwent such surgery experienced favorable postoperative outcomes comparable to those who underwent septal myectomy alone, with a 5-year survival rate of >95% and improved functional class of >90%.

Iridoids and lignans from Valeriana officinalis and their bioactivities.

Seven undescribed iridoids, identified as valeriridoids A-E (compounds 1, 5, 18, 19a, 19b, 20a, and 20b), were isolated from the roots and rhizomes of Valeriana officinalis L., along with sixteen known iridoids and nine known lignans. The structures were elucidated using NMR and MS spectroscopy, and the absolute configurations of the undescribed iridoids were determined through ECD calculations. Valeriridoids D and E were found to be epimeric and scalemic mixtures, which were successfully resolved through a chiral column. These isolated iridoids were evaluated for their antiproliferative activities, with valeriridoid A, jatamanvaltrates P, and Q showing significant effects against human non-small cell lung cancer cells, with IC50 values of 14.68, 8.77, and 10.07 µM, respectively. Furthermore, the antihyperglycemic properties of the compounds were investigated in insulin-resistant human hepatoblastoma cells induced by palmitic acid treatment, revealing that valeriridoid A, jatamanvaltrates P, and Q at a concentration of 10 µM led to a notable increase in glucose consumption.

Heterogeneity of hepatocellular carcinoma that responds differently to combination therapy with TACE and Sorafenib as determined by digital spatial gene expression profiling.

BACKGROUND: The combination of Sorafenib and transcatheter arterial chemoembolization (TACE) exhibits limited efficacy in the treatment of certain advanced hepatocellular carcinomas (HCC), and the molecular mechanisms underlying resistance to this combination remain unclear. OBJECTIVE: This study aims to underscore the distinctive contribution of GeoMx DSP technology in elucidating the molecular intricacies of HCC resistance to the Sorafenib and TACE combination. METHODS: Patients with advanced HCC during the waiting period before liver transplantation were classified into sensitive and resistant groups based on their response to Sorafenib and TACE combination therapy. Employing GeoMx DSP technology for comprehensive gene expression profiling, we identified pivotal molecular targets linked to resistance against combination therapy. RESULTS: The investigation scrutinized intra-tumoral and inter-individual variances, unveiling a spectrum of crucial molecular targets, such as PLG, PLVAP, immunoglobulin genes, ORM1, and NR4A1, among others. Additionally, we explored signaling pathways associated with treatment responsiveness, including the PPAR signaling pathway. Notably, we emphasized the significance of the immune microenvironment characterized by heightened SPP1 expression in HCC resistance to combination therapy. In the resistant group, SPP1+ tumor-associated macrophage (TAM) infiltration was notably pronounced (p = 0.037), while T-cell depletion showed a mitigated presence (p = 0.013). CONCLUSION: The study reveals intra- and inter-individual heterogeneity in HCC that is differentially responsive to the combination of Sorafenib and TACE, highlighting multiple key molecular targets associated with treatment resistance. The immune microenvironment is important, and in particular, SPP1+ TAM infiltration may play a key role. Meanwhile, the introduction of immunotherapy in patients resistant to combination therapy may lead to positive results.

Human umbilical cord mesenchymal stem cells alleviate fatty liver ischemia-reperfusion injury by activating autophagy through upregulation of IFNγ.

Liver ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of liver transplantation, and extended criteria donors (e.g., steatosis donor livers) are considered to be more sensitive to ischemia-reperfusion injury in liver transplantation. Currently, the application of human umbilical cord mesenchymal stem cells (hMSCs) has great promise in the treatment of various injuries in the liver. This study aimed to investigate the therapeutic role and mechanism of hMSCs in fatty liver IRI. After more than 8 weeks of high-fat chow feeding, we constructed a fatty liver mouse model and established ischemic injury of about 70% of the liver. Six hours after IRI, liver injury was significantly alleviated in hMSCs-treated mice, and the expression levels of liver enzyme, inflammatory factor TNF-α, and apoptotic proteins were significantly lower than those of the control group, which were also significant in pathological sections. Transcriptomics analysis showed that IFNγ was significantly upregulated in the hMSCs group. Mechanistically, IFNγ, which activates the MAPK pathway, is a potent agonist that promotes the occurrence of autophagy in hepatocytes to exert a protective function, which was confirmed by in vitro experiments. In summary, hMSCs treatment could slow down IRI in fatty liver by activating autophagy through upregulation of IFNγ, and this effect was partly direct.

Evaluation of liver regeneration after hemi-hepatectomy by combining computed tomography and post-operative liver function.

Background: Accurate evaluation of postoperative liver regeneration is essential to prevent postoperative liver failure. Aims: To analyze the predictors that affect liver regeneration after hemi-hepatectomy. Method: Patients who underwent hemi-hepatectomy in Hangzhou First People's Hospital and Hangzhou Shulan Hospital from January 2016 to December 2021 were enrolled in this study. The regeneration index (RI) was calculated by the following equation: RI = [(postoperative total liver volume {TLVpost} - future liver remnant volume {FLRV}/FLRV] × 100 %. Hepatic dysfunction was defined according to the "TBilpeak>7" standard, which was interpreted as (peak) total bilirubin (TBil) >7.0 mg/dL. Good liver regeneration was defined solely when the RI surpassed the median with hepatic dysfunction. Logistic regression analyses were performed to estimate prognostic factors affecting liver regeneration. Result: A total of 153 patients were enrolled, with 33 in the benign group and 120 patients in the malignant group. In the entire study population, FLRV% [OR 4.087 (1.405-11.889), P = 0.010], international normalized ratio (INR) [OR 2.763 (95%CI, 1.008-7.577), P = 0.048] and TBil [OR 2.592 (95%CI, 1.177-5.710), P = 0.018] were independent prognostic factors associated with liver regeneration. In the benign group, only the computed tomography (CT) parameter FLRV% [OR, 11.700 (95%CI, 1.265-108.200), P = 0.030] predicted regeneration. In the malignant group, parenchymal hepatic resection rate (PHRR%) [OR 0.141 (95%CI, 0.040-0.499), P = 0.002] and TBil [OR 3.384 (95%CI, 1.377-8.319), P = 0.008] were independent prognostic factors. Conclusion: FLRV%, PHRR%, TBil and INR were predictive factors associated with liver regeneration.

Impact of preoperative infection on the outcomes of liver transplant recipients: a national propensity score-matched retrospective cohort study in China.

BACKGROUND: Impact of preoperative infection on liver transplantation (LT) needs further investigation. MATERIALS AND METHODS: From 1 January 2015 to 31 December 2022, 24 122 eligible patients receiving LT were enrolled from the China Liver Transplant Registry database. The outcomes of LT were compared after using the propensity score-matched analysis. RESULTS: Compared to the noninfection group, patients in the infection group were more likely to have postoperative effusion, infection, abdominal bleeding, and biliary complications (all P <0.01), and they had shorter 30-day, 90-day survival, and overall survival (all P <0.01). Cox proportional hazards regression analysis revealed that MELD score and cold ischemia time were risk factors for the overall survival in the infection group (both P <0.05). Besides, compared to the nonpulmonary group, patients in the pulmonary group were more likely to have postoperative effusion and infection (both P <0.0001), and less likely to have postoperative abscess and early allograft dysfunction (both P <0.05). Patients in the nonabdominal group also had a higher proportion of postoperative infection than those in the abdominal group ( P <0.05). Furthermore, compared to the number=1 group, patients in the number ≥2 group were more prone to postoperative effusion and infection (both P <0.01), and they also had shorter 30-day and 90-day survival (both P <0.05). CONCLUSION: Preoperative infection can result in a higher incidence of early postoperative complications and shorter survival in liver transplant recipients. The types and number of infection sites will also influence the prognosis of liver transplant recipients.

Chemical Constituents from Berchemia polyphylla var. Leioclada.

One previously undescribed naphthoquinone-benzisochromanquinone dimer berpolydiquinone A (1), along with two previously undescribed naphthoquinone-anthraquinone dimers berpolydiquinones B and C (2-3), and one previously undescribed dimeric naphthalene berpolydinaphthalene A (4), were isolated from the stems and leaves of Berchemia polyphylla var. leioclada. The chemical structures of these compounds were determined using high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS), spectroscopic data, the exciton chirality method (ECM), and quantum chemical calculation. Notably, compounds (1-2 and 5) are dimeric quinones that share the same naphthoquinone moiety, specifically identified as 2-methoxystypandron. Compound (4) is a derivative of dimeric naphthalene with a symmetrical structure, which is a new structure type isolated from B. polyphylla var. leioclada for the first time. These findings suggest that B. polyphylla var. leioclada serves as a significant reservoir of structurally diverse phenolic compounds. This study provides a scientific foundation for regarding B. polyphylla var. leioclada as a potential source of "Tiebaojin".

Analysis and evaluation of patient-specific three-dimensional printing in complex septal myectomy.

OBJECTIVES: This study aimed to assess the effectiveness of three-dimensional printing (3DP) in patients with complex hypertrophic cardiomyopathy requiring combined transaortic and transapical septal myectomy. METHODS: We created 3DP models for 7 patients undergoing this surgery approach between June and October 2022 using silicone-like resin and conducted mock operations. The models were compared with echocardiography to identify abnormal muscle bundles and heart structures. These patients were then compared with a 1:2 matched group without 3DP, considering age, sex and additional operations. RESULTS: The models mostly presenting with midventricular obstruction showed high consistency with original computed tomography data (r = 0.978, P < 0.001). 3DP identified more abnormal muscle bundles than echocardiography, primarily between the interventricular septum and apex. Excised specimens in mock operations mirrored those in actual myectomies. While cardiopulmonary bypass time was not significantly different, a near-20-min decrease was observed in the 3DP group (135.5 ± 31.1 vs 154.4 ± 36.6 min, P = 0.054). CONCLUSIONS: While no significant differences in surgical outcomes were observed, 3DP appeared to enhance the visualization and understanding of spatial structures (average Likert scale score 4.0), potentially contributing to surgical proficiency (overall rating score 3.9). The use of 3DP may offer additional value in the preparation and execution of operations for complex hypertrophic cardiomyopathy cases.

Anthraquinone-benzisochromanquinone dimers from the stems and leaves of Berchemia polyphylla.

Three new anthraquinone-benzisochromanquinone dimers polyphylldiquinones A-C (1-3), along with three known analogs floribundiquinone A-B (4-5) and 7-dehydroxyventiloquinone H (6), were isolated from the stems and leaves of Berchemia polyphylla. The chemical structures and absolute configurations of these compounds were determined using HR-ESI-MS, spectroscopic data, and electronic circular dichroism. Notably, compounds (1-5) are dimeric quinones that share the same benzisochromanquinone moiety, specifically identified as 7-dehydroxyventiloquinone H (6), which was the first time to report as a natural product. Compounds 1-2 and compounds 4-5 are two pairs of atropisomers respectively.

Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases.

Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.

Mitral annular calcification in obstructive hypertrophic cardiomyopathy: Incidence, risk factors, and prognostic value after myectomy.

BACKGROUND: Mitral annular calcification (MAC) is a risk factor for cardiac surgery, but there is limited study on the prognosis value and the impact for valve function of MAC based on computed tomography (CT) diagnosis after myectomy for hypertrophic obstructive cardiomyopathy (OHCM). METHODS: Consecutive OHCM patients underwent septal myectomy were compared according to the existence of MAC and its severity in preoperative CT scans. The survival data were evaluated and compared by Kaplan Meier analysis and log rank test. Cox regression analysis was used to evaluate the impact of MAC on endpoint events. RESULTS: From the entire cohort of 1035 patients, 10.8% had MAC. In multivariate regression, female (OR = 2.23), age (OR = 1.07), aortic annular calcification (OR = 2.52), aortic calcification (OR = 2.56), systolic anterior motion of the mitral valve (SAM) (OR = 0.42), mitral valve thickening (OR = 2.13), and tricuspid regurgitation (OR = 3.12) were independent predictors of MAC. All-cause mortality (3.57% vs. 1.08%, p = 0.031), major adverse cardiovascular and cerebrovascular events (MACCE) (23.32% vs. 13.65%, p = 0.014), recurrent MR > 2+ (8.04% vs. 2.49%, p = 0.001) and NYHA III-IV (11.61% vs. 5.53%, p = 0.012) were more frequent in OHCM patients with MAC after myectomy. MAC was discovered to be an independent predictor of postoperative recurrent MR > 2+ after other risk factors were taken into account (HR 2.47, 95% CI 1.08-5.67, p = 0.0329). Moderate-to-severe MAC was an independent risk factor (HR 2.03, 95% CI 1.09-3.75, p = 0.0244) for long-term major adverse cardiovascular and cerebrovascular events (MACCE). CONCLUSION: MAC was detected in one-tenth of OHCM patients in preoperative CT scanning and is mainly associated with aging and atherosclerosis. OHCM patients with MAC had a worse prognosis and more recurrent mitral valve regurgitation than those without MAC after septal myectomy.

Garbractin A, a Polycyclic Polyprenylated Acylphloroglucinol with a 4,11-dioxatricyclo[4.4.2.01,5]Dodecane Skeleton from Garcinia bracteata Fruits.

Garbractin A (1), a structurally complicated polycyclic polyprenylated acylphloroglucinol (PPAP) with an unprecedented 4,11-dioxatricyclo[4.4.2.01,5] dodecane skeleton, was isolated from the fruits of Garcinia bracteata, along with five new biosynthetic analogues named garcibracteatones A-E (2-6). Their structures containing absolute configurations were revealed using spectroscopic data, the residual dipolar coupling-enhanced NMR approach, and quantum chemical calculations. The antihyperglycemic effect of these PPAPs (1-6) was evaluated using insulin-resistant HepG2 cells (IR-HepG2 cells) induced through palmitic acid (PA). Compounds 1, 3, and 4 were found to significantly promote glucose consumption in the IR-HepG2 cells and, therefore, may hold potential as candidates for treating hyperglycemia.

Identification of a brand intratumor microbiome signature for predicting prognosis of hepatocellular carcinoma.

PURPOSE: Given that prognosis of hepatocellular carcinoma (HCC) differs dramatically, it is imperative to uncover effective and available prognostic biomarker(s). The intratumor microbiome plays a significant role in the response to tumor microenvironment, we aimed to identify an intratumor microbiome signature for predicting the prognosis of HCC patients accurately and investigate its possible mechanisms subsequently. METHODS: The TCGA HCC microbiome data (TCGA-LIHC-microbiome) was downloaded from cBioPortal. To create an intratumor microbiome-related prognostic signature, univariate and multivariate Cox regression analyses were used to quantify the association of microbial abundance and patients' overall survival (OS), as well as their diseases specific survival (DSS). The performance of the scoring model was evaluated by the area under the ROC curve (AUC). Based on the microbiome-related signature, clinical factors, and multi-omics molecular subtypes on the basis of "icluster" algorithm, nomograms were established to predict OS and DSS. Patients were further clustered into three subtypes based on their microbiome-related characteristics by consensus clustering. Moreover, deconvolution algorithm, weighted correlation network analysis (WGCNA) and gene set variation analysis (GSVA) were used to investigate the potential mechanisms. RESULTS: In TCGA LIHC microbiome data, the abundances of 166 genera among the total 1406 genera were considerably associated with HCC patients' OS. From that filtered dataset we identified a 27-microbe prognostic signature and developed a microbiome-related score (MRS) model. Compared with those in the relatively low-risk group, patients in higher-risk group own a much worse OS (P < 0.0001). Besides, the time-dependent ROC curves with MRS showed excellent predictive efficacy both in OS and DSS. Moreover, MRS is an independent prognostic factor for OS and DSS over clinical factors and multi-omics-based molecular subtypes. The integration of MRS into nomograms significantly improved the efficacy of prognosis prediction (1-year AUC:0.849, 3-year AUC: 0.825, 5-year AUC: 0.822). The analysis of microbiome-based subtypes on their immune characteristics and specific gene modules inferred that the intratumor microbiome may affect the HCC patients' prognosis via modulating the cancer stemness and immune response. CONCLUSION: MRS, a 27 intratumor microbiome-related prognostic model, was successfully established to predict HCC patients overall survive independently. And the possible underlying mechanisms were also investigated to provide a potential intervention strategy.

Isolation and antihyperglycemic effects of garcibractinols A-H, intricate polycyclic polyprenylated acylphloroglucinols from the fruits of Garcinia bracteata.

Eight previously undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) were isolated from the fruits of Garcinia bracteata and named garcibractinols A-H. Garcibractinols A-F (compounds 1-6) were bicyclic polyprenylated acylphloroglucinols (BPAPs) sharing a rare bicyclo[4.3.1]decane core. On the other hand, garcibractinols G and H (compounds 7 and 8) shared an unprecedented BPAP skeleton bearing a 9-oxabicyclo[6.2.1]undecane core. The structures andabsolute configurations of compounds 1-8 were determined by spectroscopic analysis,single-crystal X-ray diffraction analysis, and quantum chemical calculation. The breakage of the C-3/C-4 linkage through the retro-Claisen reaction was a key step in the biosynthesis of compounds 7 and 8. The antihyperglycemic effects of the eight compounds were evaluated in insulin-resistant HepG2 cells. At a concentration of 10 µM, compounds 2 and 5-8 significantly increased the glucose consumption in the HepG2 cells. Furthermore, compound 7 was more effective than metformin (which was used as a positive control) in promoting glucose consumption in the cells. The findings of this study suggest that compounds 2 and 5-8 have anti-diabetic effects.

Circulating miR-141 as a potential biomarker for diagnosis, prognosis and therapeutic targets in gallbladder cancer.

MicroRNA-141(miR-141) has been reported to play vital roles in the regulation of carcinogenesis and cancer progression. However, the biological function of miR-141 in GBC has received less attention. The aim of this study was to estimate the potential value of the expression level of miR-141 as a diagnostic and prognostic blood-based biomarker in gallbladder cancer (GBC) patients. Meanwhile, to explore its biological role in GBC cells. RT-PCR was employed to confirm the expression of miR-141 in ten paired tissue samples (10 GBC tissues and 10 adjacent normal gallbladder tissues), GBC cell lines and peripheral blood specimens from 98 GBC patients and 60 healthy controls. MTT assay was used to evaluate the GBC cells proliferation and flow cytometry was used to detect the cell apoptosis. Receiver operating characteristic curve analysis and the area under the curve (AUC) were used to evaluate the value of miR-141 plasma levels for GBC diagnosis. Finally, clinicopathological and survival data of all GBC patients were collected and analyzed. Here, we confirmed that the expression of miR-141 were upregulated in primary gallbladder cancer cells and tissues compared with human gallbladder epithelial cells and adjacent normal tissues (P < 0.0001). Meanwhile, we found that downregulated expression of miR-141 by miR-141 inhibitor could induce apoptosis and inhibit proliferation of GBC cells. Additionally, elevated plasma miR-141 expression was also detected in the peripheral blood of GBC patients compared with healthy controls (P < 0.0001). The AUC value of miR-141 for GBC diagnosis was 0.894 (95% CI 0.843-0.945), which was more valuable than those including carcinoembryonic antigen (CEA) (0.713, 95% CI 0.633-0.793), carbohydrate antigen 125 (CA125) (0.837, 95% CI 0.776-0.899) and carbohydrate antigen 19-9 (CA19-9) (0.869, 95% CI 0.813-0.924). The high expression level of miR-141 in plasma was significantly associated with tumor invasion (P = 0.008), lymph node metastasis (P < 0.0001) and advanced pathologic tumor/node/metastasis (pTNM) stage (P = 0.009). More importantly, high plasma miR-141 expression was an independent prognostic factor for predicting poorer long-term survival in GBC patients. Elevated expression of circulating miR-141 in peripheral blood might be a potential novel biomarker for diagnosis and prognosis of GBC patients. Downregulated expression of miR-141 could inhibit proliferation and induce apoptosis of GBC cells, that provide a potential therapeutic target for GBC.

Dehydrocostus Lactone Induces Apoptosis and Cell Cycle Arrest through Regulation of JAK2/STAT3/PLK1 Signaling Pathway in Human Esophageal Squamous Cell Carcinoma Cells.

BACKGROUND: Dehydrocostus lactone (DEH), one of the sesquiterpene lactones, has shown extensive pharmaceutical activities, including anti-cancer activity. However, its effects on human esophageal squamous cell carcinoma (ESCC) cells are still unknown. OBJECTIVE: To investigate the effect of DEH on ESCC cells and the underling molecular mechanisms. METHODS: The cell proliferation was tested using CCK-8 and colony formation assay. Apoptosis was analyzed by flow cytometry, hoechst staining and caspase-3 activity assay. Cell cycle was analyzed by flow cytometry. IL-6 (STAT3 activator) was used to activate JAK2/STAT3 pathway. Immunofluorescence assay was performed to detect intracellular location of STAT3. SiRNA transfection was performed to knock down the expression of PLK1. The protein expression was analyzed by western blotting assay. RESULT: DHE treatment significantly reduced the viability of ESCC cells through apoptosis induction and cell cycle arrest. Furthermore, DHE treatment significantly inhibited the phosphorylation of JAK2 and STAT3. IF assay showed that the distribution of STAT3 in the nucleus was decreased by DHE treatment. In addition, coculture with IL-6 significantly prevented the inhibition of phosphorylation of JAK2 and STAT3 by DHE treatment and partly reversed the effect of DHE on ESCC cells. Moreover, DHE treatment significantly down-regulated the expression of PLK1, which was partly reversed by IL-6 coculture. Finally, knock down of PLK1 using siRNA reduced the viability of ESCC cells and induced apoptosis and cell cycle arrest Conclusion: Our study demonstrated that DHE has a potent anti-cancer effect on ESCC cells through apoptosis induction and cell cycle arrest via JAK2/STAT3/PLK signaling pathway.

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most devastating stroke subtype, with a poor prognosis and few proven treatments. Neuroinflammation is associated with ICH-induced brain injury and unfavorable outcomes. There is growing evidence that Dickkopf (DKK) 3 plays a key role in the adaptive anti-inflammatory and neuroprotective responses following intracerebral hemorrhage. This study aimed to evaluate the protective effects of DKK3 against brain edema and neuroinflammation in a mice model of ICH. METHODS: Male, adult CD1 mice were subjected to sham or ICH surgery using a collagenase injection model. ICH animals received either recombinant DKK3, Kremen-1 siRNA, or DVL-1 siRNA. The neurobehavioral deficits were evaluated at 24 h, 72 h, and 28 days after ICH induction. Western blot and immunofluorescence were employed to examine the expression and localization of DKK3, Kremen-1, Dishevelled-1 (DVL-1), c-JUN N-terminal kinase (JNK), Activator protein-1 (AP-1), cleaved caspase-1, NF-κB, and IL-1ß in the brain. RESULTS: The expression of endogenous DKK3 and DVL-1 was transiently decreased after ICH compared to that in the sham group. Compared to the mice of ICH, exogenous rDKK3 administration reduced the brain water content and affected the neurological functions in ICH mice. Moreover, DKK3 was colocalized with Kremen-1 in microglia. Using a Kremen-1 or DVL-1 siRNA-induced in vivo knockdown approach, we demonstrated that the effects of DKK3 against ICH were mediated, at least partly, by the Kremen-1 and DVL-1 pathways. CONCLUSIONS: DKK3 improves the neurological outcomes, potentially by decreasing JNK/AP-1-mediated inflammation, thereby ameliorating the short- and long-term sequelae after ICH.

Dracorhodin perchlorate induces apoptosis and G2/M cell cycle arrest in human esophageal squamous cell carcinoma through inhibition of the JAK2/STAT3 and AKT/FOXO3a pathways.

Dracorhodin perchlorate (DP), a synthetic analogue of the anthocyanin red pigment dracorhodin, has been shown to exert various pharmacological effects, including anticancer activity. However, its effects on human esophageal squamous cell carcinoma (ESCC) cells have not been previously investigated, and the molecular mechanisms underlying its anticancer activity remain unclear. In the present study, it was demonstrated that DP significantly reduced the viability of ESCC cells compared with that noted in normal human liver LO2 cells. Treatment with DP induced G2/M phase cell cycle arrest through upregulation of p21 and p27, and downregulation of cyclin B1 and Cdc2. Furthermore, DP treatment induced caspase­dependent apoptosis, which could be reversed by exposure to Z­VAD­FMK, a caspase inhibitor. Western blotting demonstrated that DP induced apoptosis through extrinsic and intrinsic pathways by upregulating death receptor 4 (DR4), DR5, cleaved caspase­3/­7/­9 and cleaved poly (ADP­ribose) polymerase (PARP), and by decreasing total PARP, total caspase­3/7, Bcl­2 and caspase­9/­10. Moreover, DP treatment decreased the phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), AKT, and forkhead box O3a (FOXO3a) in ESCC cells, indicating that the activity of the JAK2/STAT3 and AKT/FOXO3a signaling pathways was inhibited. Therefore, DP is a promising therapeutic agent for ESCC.

High Trophinin-Associated Protein Expression Is an Independent Predictor of Poor Survival in Liver Cancer.

BACKGROUND: Trophinin-associated protein (TROAP) is a cytoplasmic protein that functions as an adhesion molecule in processes such as embryo implantation, spindle formation, and cancer. OBJECTIVE: To evaluate the relationship of TROAP expression in hepatocellular carcinoma (HCC) tissue with clinicopathologic parameters and survival time in liver cancer patients based on an analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data. METHODS: RNA-sequencing (RNA-Seq) expression data and clinical information were downloaded for the TCGA-LIHC cohort. Associations between TROAP expression in HCC tissues and clinical parameters were evaluated by Chi-square tests. Differences in survival between high and low expression groups (median expression cutoff) from Cox regression analysis were compared, and P values were calculated by a log-rank test. Kaplan-Meier curves were compared with the log-rank test. RESULTS: Analysis of RNA-Seq gene expression data for 373 patients with primary tumors revealed overexpression of TROAP in liver cancer. High TROAP expression was associated with survival status (P = 0.015), T stage (P = 0.049), clinical stage (P = 0.048), and gender (P = 0.033). Patients with high TROAP-expressing liver cancers had a shorter median overall survival of 3.83 years compared with 5.80 years for patients with low TROAP-expressing liver cancers (P = 0.00422). Multivariate analysis identified TROAP expression as an independent prognostic variable for overall survival in liver cancer patients. CONCLUSION: TROAP expression is an independent predictor of poor survival in liver cancer.

Isoalantolactone induces apoptosis through reactive oxygen species-dependent upregulation of death receptor 5 in human esophageal cancer cells.

Esophageal cancer is the eighth most prevalent cancer and has high mortality in our society. Isoalantolactone, extracted from Inula helenium L, has shown potent anticancer effects on a variety of cancers. However, its effect on human esophageal cancer, and the underlying molecular mechanism, remain to be investigated. In the present study, we demonstrated that isoalantolactone induced apoptosis in esophageal cancer cells. Treatment with isoalantolactone activated caspases-3, -7, and -10, and upregulated death receptor (DR)5. Furthermore, DR5 knockdown partially reversed the effect of isoalantolactone. These results indicated the extrinsic apoptosis was induced by isoalantolactone. In addition, intracellular reactive oxygen species (ROS) were significantly elevated after treatment with isoalantolactone. N-Acetylcysteine, an ROS scavenger, blocked both the apoptosis and decreased cell viability caused by isoalantolactone. In vivo, significant suppression of tumor growth by isoalantolactone was observed in an ECA109 cell xenograft mouse model. Isoalantolactone showed no obvious adverse effects on mouse weight and histology of heart, liver, spleen, lung, and kidney. In conclusion, our results revealed that isoalantolactone induced apoptosis through the extrinsic pathway via upregulation of DR5 and elevation of ROS in human esophageal cancer cells. Isoalantolactone, therefore, could be a potential candidate in developing anticancer agents for esophageal cancer patients.