Apoptotic signaling pathways in bone metastatic lung cancer: a comprehensive analysis.

This review provides a comprehensive analysis of apoptotic signaling pathways in the context of bone metastatic lung cancer, emphasizing the intricate molecular mechanisms and microenvironmental influences. Beginning with an overview of apoptosis in cancer, the paper explores the specific molecular characteristics of bone metastatic lung cancer, highlighting alterations in apoptotic pathways. Focused discussions delve into key apoptotic signaling pathways, including the intrinsic and extrinsic pathways, and the roles of critical molecular players such as Bcl-2 family proteins and caspases. Microenvironmental factors, such as the tumor microenvironment, extracellular matrix interactions, and immune cell involvement, are examined in depth. The review also addresses experimental approaches and techniques employed in studying apoptotic signaling, paving the way for a discussion on current therapeutic strategies, their limitations, and future prospects. This synthesis contributes a holistic understanding of apoptosis in bone metastatic lung cancer, offering insights for potential therapeutic advancements.

Association of dietary overall antioxidant intake with all-cause and cause-specific mortality among adults with depression: evidence from NHANES 2005-2018.

Higher intakes of individual antioxidants such as vitamins A, C, and E have been linked to mortality in the general population, but the association of overall antioxidant intake with mortality especially in depressed adults remains unclear. We aimed to investigate whether the dietary overall antioxidant intake is associated with all-cause and cause-specific mortality among depressed adults. This study included 3051 US adults with depression, who participated in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Patient Health Questionnaire-9 (PHQ-9) was used to define depression and evaluate depression severity. The dietary antioxidant quality score (DAQS) and dietary antioxidant index (DAI) were calculated based on the intakes of vitamins A, C, and E, zinc, selenium, and magnesium. A higher DAQS and DAI were significantly associated with lower depression scores (PHQ-9) (all P-trend < 0.05). For individual antioxidants, significant negative associations of vitamins A and E with all-cause mortality were observed. For overall antioxidant intake, the DAQS and DAI were inversely associated with all-cause and cancer mortality. Compared with participants in the lowest categories of DAQS and DAI, the corresponding HRs (95% CIs) in the highest categories were 0.63 (0.42-0.93) and 0.70 (0.49-0.98) for all-cause mortality and 0.39 (0.17-0.87) and 0.43 (0.21-0.88) for cancer mortality, respectively. The overall dietary antioxidant intake was beneficially associated with all-cause and cancer mortality in depressed adults. These findings suggest that comprehensive dietary antioxidant intake may improve depressive symptoms and lower mortality risk among adults with depression.

Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity.

In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f (MY-1121) exhibited low nanomolar IC50 values ranging from 0.089 to 0.238 µM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f (MY-1121) could bind to the colchicine binding site of ß-tubulin and directly act on ß-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f (MY-1121) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f (MY-1121) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities.

Topical tranexamic acid in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly: A protocol for systematic review and meta-analysis.

BACKGROUND: Numerous studies have demonstrated that the use of tranexamic acid (TXA) intravenously minimizes bleeding, lowers transfusion rates, and does not raise the risk of complications during major orthopedic surgery. Concerning the effectiveness of the topical application, there are, nevertheless, inconsistent findings. We aimed to develop a protocol for systematic review and meta-analysis on the benefits and safety of topical TXA in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly. METHODS: PubMed, Embase, and the Cochrane Library will all be searched for randomized controlled trials published from the database inception to October 15, 2022. The primary outcomes will be intraoperative blood loss, hidden blood loss, total blood loss, transfusion rate, transfusion units, operative time, thromboembolic events, and mortality. The risk of bias will be evaluated using the Cochrane risk of bias assessment tool. Review Manager 5.3 will be used for the analysis. RESULTS: The effects and safety of topical TXA in intramedullary nailing for the treatment of intertrochanteric fractures in the elderly will be quantified in this study. CONCLUSIONS: The study's findings will assist doctors in determining if topical TXA use is secure and efficient.

CtDNA's prognostic value in patients with early-stage colorectal cancer after surgery: A meta-analysis and systematic review.

BACKGROUND: Circulating tumor DNA (ctDNA) positivity has been shown to suggest the presence of minimally residual tumor cells in numerous investigations. We aimed to assess the prognostic value of ctDNA positivity for recurrence-free survival in patients with early-stage colorectal cancer after radical surgery and following adjuvant chemotherapy. METHODS: We systematically reviewed studies published in English until August 15, 2022, concerning ctDNA and tumor-node-metastasis I to III colorectal cancer after surgery, and quantified the correlation between ctDNA positivity and early-stage (tumor-node-metastasis stage I-III) colorectal cancer using meta-analysis methods. RESULTS: In total, the meta-analysis comprised 1713 patients from 6 studies. Patients with ctDNA-positive colorectal cancer after surgery had a significantly higher risk of recurrence than patients with ctDNA-negative colorectal cancer (hazard ratio 4.64, 95% confidence interval 2.17-9.92, z = 3.96; P < .001). After adjuvant chemotherapy, patients who were ctDNA-positive had a significantly higher risk of recurrence than those who were ctDNA-negative (hazard ratio 7.27, 95% confidence interval 4.50-11.75, z = 8.1; P < .001). CONCLUSIONS: CtDNA positivity may potentially be a predictor for early-stage colorectal tumor recurrence following surgery and adjuvant chemotherapy.

CD8+ T cell trajectory subtypes decode tumor heterogeneity and provide treatment recommendations for hepatocellular carcinoma.

Introduction: Mounting evidence has revealed that the interactions and dynamic alterations among immune cells are critical in shaping the tumor microenvironment and ultimately map onto heterogeneous clinical outcomes. Currently, the underlying clinical significance of immune cell evolutions remains largely unexplored in hepatocellular carcinoma (HCC). Methods: A total of 3,817 immune cells and 1,750 HCC patients of 15 independent public datasets were retrieved. The Seurat and Monocle algorithms were used to depict T cell evolution, and nonnegative matrix factorization (NMF) was further applied to identify the molecular classification. Subsequently, the prognosis, biological characteristics, genomic variations, and immune landscape among distinct clusters were decoded. The clinical efficacy of multiple treatment approaches was further investigated. Results: According to trajectory gene expression, three heterogeneous clusters with different clinical outcomes were identified. C2, with a more advanced pathological stage, presented the most dismal prognosis relative to C1 and C3. Eight independent external cohorts validated the robustness and reproducibility of the three clusters. Further explorations elucidated C1 to be characterized as lipid metabolic HCC, and C2 was referred to as cell-proliferative HCC, whereas C3 was defined as immune inflammatory HCC. Moreover, C2 also displayed the most conspicuous genomic instability, and C3 was deemed as "immune-hot", having abundant immune cells and an elevated expression of immune checkpoints. The assessments of therapeutic intervention suggested that patients in C1 were suitable for transcatheter arterial chemoembolization treatment, and patients in C2 were sensitive to tyrosine kinase inhibitors, while patients in C3 were more responsive to immunotherapy. We also identified numerous underlying therapeutic agents, which might be conducive to clinical transformation in the future. Conclusions: Our study developed three clusters with distinct characteristics based on immune cell evolutions. For specifically stratified patients, we proposed individualized treatment strategies to improve the clinical outcomes and facilitate the clinical management.

Fluid shear stress induces cell migration via RhoA-YAP1-autophagy pathway in liver cancer stem cells.

Fluid shear stress (FSS) regulates the metastasis of hepatocellular carcinoma (HCC), but the role of the RhoA-YAP1-autophagy pathway in HCC remains unclear. Due to the core role of liver cancer stem cells (LCSCs) in HCC metastasis and recurrence, we explored the RhoA-YAP1-autophagy pathway in LCSCs under FSS. Our results indicate that LCSCs have stronger proliferation and cell spheroidization abilities. FSS (1 dyn/cm2) upregulated the migration of LCSCs and autophagy protein markers, inducing LC3B aggregation and autophagosome formation in LCSCs. Mechanistically, FSS promoted YAP1 dephosphorylation and transport to the nucleus, which is mediated by RhoA, inducing autophagy. Finally, inhibition of autophagy suppressed cell migration in LCSCs under FSS. In conclusion, FSS promoted the migration of LCSCs via the RhoA-YAP1-autophagy pathway.

Regulator of G-protein signaling 14 protects the liver from ischemia-reperfusion injury by suppressing TGF-ß-activated kinase 1 activation.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Regulator of G-protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates the G-protein and mitogen-activated protein kinase (MAPK) signaling pathways. However, the role of RGS14 in hepatic IRI remains unclear. APPROACH AND RESULTS: We found that RGS14 expression increased in mice subjected to hepatic ischemia-reperfusion (IR) surgery and during hypoxia reoxygenation in hepatocytes. We constructed global RGS14 knockout (RGS14-KO) and hepatocyte-specific RGS14 transgenic (RGS14-TG) mice to establish 70% hepatic IRI models. Histological hematoxylin and eosin staining, levels of alanine aminotransferase and aspartate aminotransferase, expression of inflammatory factors, and apoptosis were used to assess liver damage and function in these models. We found that RGS14 deficiency significantly aggravated IR-induced liver injury and activated hepatic inflammatory responses and apoptosis in vivo and in vitro. Conversely, RGS14 overexpression exerted the opposite effect of the RGS14-deficient models. Phosphorylation of TGF-ß-activated kinase 1 (TAK1) and its downstream effectors c-Jun N-terminal kinase (JNK) and p38 increased in the liver tissues of RGS14-KO mice but was repressed in those of RGS14-TG mice. Furthermore, inhibition of TAK1 phosphorylation rescued the effect of RGS14 deficiency on JNK and p38 activation, thus blocking the inflammatory responses and apoptosis. CONCLUSIONS: RGS14 plays a protective role in hepatic IR by inhibiting activation of the TAK1-JNK/p38 signaling pathway. This may be a potential therapeutic strategy for reducing incidences of hepatic IRI in the future.

Caspase-1 Inhibitor Reduces Pyroptosis Induced by Brain Death in Kidney.

Brain death (BD) induces an organ-level inflammatory response. However, the underlying mechanisms have not been fully elucidated. Here, we investigated the role of caspase-1-mediated pyroptosis in BD-induced kidney injury in rats. A BD model was established in Sprague-Dawley rats. The rats were intravenously injected with Z-YVAD-FMK 1 h before BD, and sham-operated rats served as controls. After 0, 1, 2, 4, and 6 h of BD, renal injury, and renal expression of the nod-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, caspase-11, gasdermin D (GSDMD), IL-1ß, and IL-18 were assessed using quantitative reverse transcriptase-polymerase chain reaction, western blotting, and immunohistochemistry. Blood urea nitrogen and serum creatinine levels were measured. Additionally, renal tubular epithelial cells (NRK-52E) were subjected to 3 h of hypoxia followed by 6 h of reoxygenation and incubated with Z-YVAD-FMK before hypoxia and reoxygenation. Caspase-11 was knocked-down using small interfering RNA technology. Cell viability and levels of pyroptosis-associated proteins were assessed thereafter. NLRP3, caspase-1, GSDMD, IL-1ß, and IL-18 expression levels were upregulated in BD rats. Treatment with Z-YVAD-FMK reduced mRNA and protein levels of caspase-1, GSDMD, IL-1ß, and IL-18, improved renal function, and alleviated renal injury. Z-YVAD-FMK efficaciously reduced pyroptosis effects in kidneys in BD rats. Thus, it could be considered as a therapeutic target for BD-induced kidney injury.

miR­140­5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1.

Ischemia/reperfusion (I/R)­induced liver injury remains a primary concern in liver transplantation and hepatectomy. Previous studies have indicated that microRNAs (miRs) are involved in multiple pathophysiological processes, including liver I/R. miR­140­5p reportedly inhibits inflammatory responses and apoptosis in several diseases; however, the role of miR­140­5p in liver I/R remains unknown. The present study aimed to investigate the potential role and mechanism of miR­140­5p on liver I/R injury. Mouse liver I/R and mouse AML12 cell hypoxia/reoxygenation (H/R) models were established. miR­140­5p mimics, inhibitor or agonists were used to overexpress or inhibit miR­140­5p in vitro and in vivo. Reverse transcription­quantitative polymerase chain reaction was used to detect miR­140­5p expression. Liver and cell injury were evaluated using several biochemical assays. The association between miR­140­5p and calpain­1 (CAPN1) was confirmed using a dual­luciferase reporter assay. The results revealed that miR­140­5p expression was decreased in the mouse model of liver I/R injury and AML12 cells subjected to H/R, while overexpressed miR­140­5p reduced liver injury in vivo and cell injury in vitro. In addition, CAPN1 was determined to be a target of miR­140­5p; overexpressed CAPN1 abrogated the effect of miR­140­5p on H/R­induced cell injury. The present study indicated that miR­140­5p protected against liver I/R by targeting CAPN1, which may provide a novel therapeutic target for liver I/R injury.

Interaction analysis of gene variants related to one-carbon metabolism with chronic hepatitis B infection in Chinese patients.

BACKGROUND: The risk of chronic hepatitis B (CHB) infection is influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by polymorphic variants in one-carbon metabolism genes. In the present study, we investigated the relationship between polymorphisms belonging to the one-carbon metabolic pathway and CHB infection. METHODS: A case-control study using 230 CHB patients and 234 unrelated healthy controls was carried out to assess the genetic association of 24 single nucleotide polymorphisins (SNPs) determined by mass spectrometry. RESULTS: Three SNPs, comprising rs10717122 and rs2229717 in serine hydroxymethyltransferase1/2 (SHMT2) and rs585800 in betaine-homocysteine S-methyltransferase (BHMT), were associated with the risk of CHB. Patients with DEL allele, DEL.DEL and DEL.T genotypes of rs10717122 had a 1.40-, 2.00- and 1.83-fold increased risk for CHB, respectively. Cases inheriting TA genotype of rs585800 had a 2.19-fold risk for CHB infection. The T allele of rs2229717 was less represented in the CHB cases (odds ratio = 0.66, 95% confidence interval = 0.48-0.92). The T allele of rs2229717 was less in patients with a low hepatitis B virus-DNA level compared to the control group (odds ratio = 0.49, 95% confidence interval = 0.25-0.97) and TT genotype of rs2229717 had a significant correlation with hepatitis B surface antigen level (p = 0.0195). Further gene-gene interaction analysis showed that subjects carrying the rs10717122 DEL.DEL/DEL.T and rs585800 TT/TA genotypes had a 2.74-fold increased risk of CHB. CONCLUSIONS: The results of the present study suggest that rs10717122, rs585800 and rs2229717 and gene-gene interactions of rs10717122 and rs585800 affect the outcome of CHB infection, at the same time as indicating their usefulness as a predictive and diagnostic biomarker of CHB infection.

hMex-3A is associated with poor prognosis and contributes to the progression of hepatocellular carcinoma.

BACKGROUND: HMex-3A, an RNA-binding protein, was found to be associated with tumorigenesis. However, the roles of hMex-3A in hepatocellular carcinoma (HCC) progression remained unclear. METHODS: The different expression of hMex-3A between HCC tissues and non-tumor tissues was evaluated using The Cancer Genome Atlas database. Thereafter, the hMex-3A expression was evaluated in HCC tissues using Western blotting and qRT-PCR. Immunohistochemistry was performed to investigate the association between hMex-3A level and clinicopathological features including prognosis in HCC patients. In addition, we used si-hMex-3A to knockdown hMex-3A in HCC cells to test Cell Counting Kit-8, colony formation, cell migration and invasion. RESULTS: The hMex-3A expression was significantly elevated in HCC tissues. Analysis of the clinicopathological parameters suggested that hMex-3A expression was significantly associated with pathological grade (P = 0.019) and TNM stage (P = 0.001) in HCC. Moreover, univariate and multivariate Cox-regression analyses revealed that high hMex-3A expression (HR = 1.491, 95% CI: 1.107-2.007; P = 0.009) was an independent risk factor for overall survival in HCC patients. Finally, we confirmed that si-hMex-3A could significantly inhibit HCC cell proliferation, migration, and invasion in vitro. CONCLUSIONS: HMex-3A may contribute to the progression of HCC and might be used as a novel therapeutic target and prognostic marker in HCC.

Tripartite Motif-Containing 27 Attenuates Liver Ischemia/Reperfusion Injury by Suppressing Transforming Growth Factor ß-Activated Kinase 1 (TAK1) by TAK1 Binding Protein 2/3 Degradation.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (I/R) injury, which mainly involves inflammatory responses and apoptosis, is a common cause of organ dysfunction in liver transplantation (LT). As a critical mediator of inflammation and apoptosis in various cell types, the role of tripartite motif-containing (TRIM) 27 in hepatic I/R injury remains worthy of study. APPROACH AND RESULTS: This study systemically evaluated the putative role of TRIM27/transforming growth factor ß-activated kinase 1 (TAK1)/JNK (c-Jun N-terminal kinase)/p38 signaling in hepatic I/R injury. TRIM27 expression was significantly down-regulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Subsequently, using global Trim27 knockout mice (Trim27-KO mice) and hepatocyte-specific Trim27 transgenic mice (Trim27-HTG mice), TRIM27 functions to ameliorate liver damage, reduce the inflammatory response, and prevent cell apoptosis. In parallel in vitro studies, activating TRIM27 also prevented H/R-induced hepatocyte inflammation and apoptosis. Mechanistically, TRIM27 constitutively interacted with the critical components, TAK1 and TAK1 binding protein 2/3 (TAB2/3), and promoted the degradation of TAB2/3, leading to inactivation of TAK1 and the subsequent suppression of downstream JNK/p38 signaling. CONCLUSIONS: TRIM27 is a key regulator of hepatic I/R injury by mediating the degradation of TAB2/3 and suppression of downstream TAK1-JNK/p38 signaling. TRIM27 may be a promising approach to protect the liver against I/R-mediated hepatocellular damage in transplant recipients.

[Meta-analysis of direct anterior approach and other approaches for hemiarthroplasty in elderly patients with femoral neck fracture].

OBJECTIVE: To systematically evaluate the clinical efficacy of high-quality direct anterior approach (DAA) and other approaches for the treatment of elderly patients with femoral neck fracture. METHODS: Literatures published in English or Chinese about the direct anterior approach and other approaches for hemiarthroplasty in femoral neck fracture were searched on Cochrane Library, PubMed, EMBASE, Web of science, Wanfang, CNKI databases from their establishment to May 2019. According to the inclusion and exclusion criteria, two researchers independently screened the literatures, and extracted the data. The quality of RCT were evaluated by Cochrane Risk of Bias Assessment Tool, and non-RCT were evaluated by the NOS scale. Meta-analysis was performed using the RevMan 5.3 software. RESULTS: A total of 9 articles were included with 901 cases, in which 429 cases used DAA, and 472 used other approaches. DAA had a significantly lower dislocation rate compared to subgroup of posterior and posterolateral approach [OR=0.19, 95%CI (0.06, 0.61), P=0.005]. No significant differences were found between DAA group and subgroup of direct lateral and anterolateral approach[OR=1.08, 95%CI(0.20, 5.76), P=0.93]. Also there were no relevant differences between the DAA group and control in infection rate[OR=1.07, 95%CI(0.47, 2.43), P=0.88], perioperative fracture rate[OR=0.95, 95%CI(0.36, 2.50), P=0.92], re operation rate[OR=0.76, 95%CI(0.30, 1.89), P=0.55], overall complication rate [OR=0.88, 95%CI (0.63, 1.22), P=0.44], mortality [OR=1.33, 95%CI (0.84, 2.11), P=0.23], operative time[MD=1.43, 95%CI(-5.85, 8.71), P=0.70]. CONCLUSION: The current evidenceindicates that the DAA was associated with a significantly lower dislocation rate compared to posterior capsular approaches for hemiarthroplasty. There was no significant difference in dislocation rate with the lateral and anterolateral approach.

Synaptopodin-2 promotes hepatocellular carcinoma metastasis via calcineurin-induced nuclear-cytoplasmic translocation.

Hepatocellular carcinoma (HCC), a type of malignant liver tumor, has a grim prognosis. As a functional protein, synaptopodin-2 (SYNPO2) has been associated with malignancy; however, the expression profile and function of SYNPO2 in HCC remains unknown. Herein, we revealed that SYNPO2 was transcriptionally downregulated in HCC tissues from both The Cancer Genome Atlas cohort and our cohort, and was also decreased at the translational level as determined by western blotting and immunohistochemical staining. Furthermore, reduced SYNPO2 expression correlated significantly with short overall survival and recurrence free survival of HCC patients. Restoring SYNPO2 expression inhibited the proliferation and aggressiveness of hepatocarcinoma cells. Mechanistically, increasing the ratio of cytoplasmic SYNPO2 to nuclear SYNPO2 was positively associated with recurrence rate in HCC patients; calcineurin (CaN) activity positively correlated with cytoplasmic SYNPO2 levels in HCC tissues; and nuclear-cytoplasmic translocation of SYNPO2 was induced by CaN to facilitate metastasis of HCC through assembly of peripheral actin bundles. In short, our findings uncover a novel role of SYNPO2 in HCC metastasis via the CaN/SYNPO2/F-actin axis, and indicate that SYNPO2 may serve as a possible prognostic marker and novel therapeutic target.

Six-Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia-Reperfusion Injury by Suppressing Transforming Growth Factor-ß-Activated Kinase 1.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six-transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R-induced liver damage remains largely unclear. APPROACH AND RESULTS: In the present study, we found that Steap3 expression was significantly up-regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3-KO) mice, hepatocyte-specific Steap3 transgenic (Steap3-HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3-KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3-HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor-ß-activated kinase 1 (TAK1) activation and downstream c-Jun N-terminal kinase (JNK) and p38 signaling during hepatic I/R injury. CONCLUSIONS: Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1-dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.

Targeting BET Proteins With a PROTAC Molecule Elicits Potent Anticancer Activity in HCC Cells.

Background and Aim: Bromodomain and extraterminal domain (BET) family proteins are epigenetic regulators involved in human malignances. Targeting BET proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer therapeutics. BET proteins have been found to be overexpressed in HCC cells and tumor tissues. However, the biological activity of BET-PROTACs in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated anti-HCC activity of BETd-260, a BET-PROTAC molecule using in vitro and in vivo models. Methods: BETd-260-mediated anti-HCC activity was investigated by cell viability, apoptosis assays. Efficacy was examined with a cell lines-derived HCC xenograft model in mice. Anticancer mechanism was investigated by RT-PCR, western blotting and immunohistochemical staining. Results: BETd-260 potently suppressed cell viability and robustly induced apoptosis in HCC cells. BETd-260 reciprocally modulated the expression of several apoptotic genes in HCC cells, i.e., suppressing the expression of anti-apoptotic Mcl-1, Bcl-2, c-Myc, and X-linked inhibitor of apoptosis (XIAP), whereas increasing the expression of pro-apoptotic Bad. BETd-260 treatment led to disruption of mitochondrial membrane integrity, and triggered apoptosis via intrinsic signaling in HCC cells. BETd-260 triggered apoptosis in HCC xenograft tissue and profoundly inhibited the growth of HCC xenograft tumors in mice. Conclusion: Our data suggest that pharmacological targeting of BET for degradation may be a novel therapeutic strategy for the treatment of HCC.

Upregulation of Mcl-1 inhibits JQ1-triggered anticancer activity in hepatocellular carcinoma cells.

Bromodomains and extra-terminal (BET) proteins inhibitors are promising cancer therapeutic agents. However, tumor cells often develop resistance to BET inhibitors, greatly limiting their therapeutic potential. To study the mechanism underlying the resistance of BET inhibitors in hepatocellular carcinoma (HCC) cells, we herein investigated the impact of BET inhibitor JQ1 on the gene expression of Bcl-2 family members by RNA sequencing analysis, and found that acute treatment with JQ1 triggered upregulation of Mcl-1 in HCCLM3 and BEL7402 cell lines. This JQ1-triggered Mcl-1 upregulation was further confirmed by quantitative reverse transcription polymerase chain reaction and western blotting analysis, both at mRNA and protein levels. Inhibition of Mcl-1 by RNA interference dramatically enhanced JQ1-triggered caspase-3 activation, cleavage of poly (ADP-ribose) polymerase and apoptotic cell death induction in multiple HCC cell lines. Moreover, JQ1 in combination with cyclin-dependent kinase inhibitor flavopiridol at a subtoxic concentration that reduced expression of Mcl-1, triggered massive apoptotic cell death in HCCLM3 and BEL7402 cell lines. Together, these data suggest that Mcl-1 is a major contributor to BET inhibitor-resistance in HCC cells, and that combining drugs capable of down-regulating Mcl-1 may promote therapeutic potential in human HCC.

Inhibition of Endoplasmic Reticulum Stress Alleviates Lung Injury Induced by Brain Death.

Brain death (BD) can induce inflammation and injury of organs. Endoplasmic reticulum (ER) stress is associated with a variety of diseases. However, little is known about how ER stress is implicated in brain death (BD)-induced lung injury. In this study, a stable BD rat model was constructed to investigate the role of ER stress on BD-induced lung injury. H&E staining demonstrated that BD can induce lung injury in rats. The results of Western blot and immunohistochemistry showed that apoptosis was observed in the lung tissues of BD rats. And the level of GRP78, p-PERK, p-eIF2α, CHOP, and Caspase-12 was highly expressed in BD rats compared with the control group. Inhibition of ER stress with salubrinal reduced the BD-induced lung inflammation. Moreover, BD-induced increase of NF-κB activity was lowered by inhibition of ER stress. These results suggested that inhibition of ER stress alleviates BD-induced lung inflammation by regulating NF-κB signaling pathway.

Polymorphisms and expression pattern of circular RNA circ-ITCH contributes to the carcinogenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks the sixth most common cancer and the third cause of cancer-related mortality worldwide. Recent studies identified that circ-ITCH Suppresses mutiple cancers proliferation via inhibiting the Wnt/beta-Catenin pathway. In current study, conducted a genetic association study together with epidemiological follow-up study to delineate the role of circ-ITCH in the development and progression of HCC. we found rs10485505 (adjusted OR =1.18; 95% CI=1.06-1.31; P value =3.1×10-3) and rs4911154 (adjusted OR =1.27; 95% CI=1.14-1.43; P value =3.7×10-5) were significantly associated with increased HCC risk. The expression level of circ-ITCH was significantly lower in HCC tissues, compared with that in adjacent tissues (P value < 0.001). Cox regression analysis indicated that high expression of circ-ITCH was associated with favorable survival of HCC (HR=0.45; 95% CI=0.29-0.68; P value < 0.001). These results indicate that circ-ITCH may have an inhibitory effect on HCC, and could serve as susceptibility and prognostic biomarkers for HCC patients.