Solvatochromic sensors detect proteome aggregation in stressed liver tissues with hepatic cancer and cirrhosis.

Protein misfolding and aggregation involve complex cellular processes with clinical implications in various diseases. However, the detection of aggregated proteomes without defined 3-D structures in a complex biological milieu is challenging. This study utilizes chromone scaffold-based environment-sensitive fluorophores P1 and P2 to detect misfolded and aggregated proteome in stressed liver cells and the liver tissues diseased patients. The reported crystallization induced emission probes (P1 and P2) exhibit both polarity and viscosity sensitivity, with emission intensity and wavelength linearly correlated to viscosity and polarity. Meanwhile, P1 and P2 selectively and generally fluoresce upon binding to various aggregated proteins. In hepatic cells, P2 outperforms P1 in detecting stress-induced global proteome aggregation. In mouse liver tissue upon drug-induced injury, the fluorescence intensity of P2 correlated with the severity of liver injury, serving as an earlier indicator for liver stress prior to ALT/AST increase. The quantification of emission wavelength reveals lower micro-environmental polarity in liver-injury tissue. In patient-derived tissues with hepatic cancer and cirrhosis, P1 and P2 also report on the presence of aggregated proteome. Together, the reported solvatochromic proteome aggregation sensors can detect hepatic proteome aggregation and analyze its local polarity in cultured cell lines, animal model tissues, and human clinical samples.

Case Report: An Undefined Liver Lesion in a Young Man With Severe Aplastic Anemia: A Teachable Moment.

In this work, we reported a young man complaining of asthenia and intermittent fever for 10 days, and an ultrasound showed an undefined lesion on his liver. Facing the patient's situation with severe agranulocytosis, anemia, and thrombocytopenia, we passed through a tough diagnostic process for choosing an appropriate treatment for him with an ambiguous result of pathological biopsy. The undefined liver lesion was successfully solved by withdrawing the androgen for observation, without lobectomy. The lesion gradually diminished over 2 years of follow-up.

Wedelolactone alleviates acute pancreatitis and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis.

Acute pancreatitis (AP) is an inflammatory disorder associated with multiple organ failure. Pyroptosis and ferroptosis are two newly recognized cell death, and whether pyroptosis and ferroptosis are involved in AP remain largely elusive. The nature compound Wedelolactone (Wed) exhibits strong anti-inflammatory and antioxidant activities, the present study aims to investigate the effect of Wed on AP and unravel whether Wed could protect against AP and relevant lung injury against pyroptosis and ferroptosis. Our results showed that the pyroptosis inhibitor disulfiram or ferroptosis inhibitor ferrostatin-1 significantly alleviated AP and associated lung injury in the taurocholate or caerulein-induced murine AP model. Administration with Wed ameliorated AP and lung injury as evidenced by improved pathological injuries, reduced serum pancreatic digestive enzymes, and proinflammatory cytokines. The in vivo and in vitro data demonstrated that Wed broadly inhibited caspase1/caspase11 activation, reduced mature interleukin-1ß (IL-1ß) and N-terminal domain of gasdermin D (GSDMD-N) level. The oxidative stress and lipid peroxidation were also suppressed along with the up-regulation of the ferroptosis antagonism marker glutathione peroxidase-4 (GPX4) in Wed treatment group. Wed promoted the transcriptional activity and the selenium sensitivity of GPX4. Moreover, the protective effects of Wed in caerulein-stimulated pancreatic acinar cells were markedly abrogated by the down-regulation of GPX4. Collectively, our data suggest that pyroptosis and ferroptosis play crucial roles in AP. Wed mitigated AP and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis.

A case of primary hepatic extranodal marginal zone B-cell mucosa-associated lymphoid tissue (MALT) lymphoma treated by radiofrequency ablation (RFA), and a literature review.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is an extremely rare liver malignancy that usually lacks characteristic imaging findings and which is often misdiagnosed. We report a 63-year-old woman diagnosed with primary hepatic extranodal marginal zone B-cell lymphoma, MALT type. The patient underwent needle biopsy and radiofrequency ablation (RFA), and showed no signs of relapse during the 12-month postoperative follow-up. This case stresses the rarity of primary hepatic MALT-type lymphoma and the unique and effective treatment for this patient. Our patient received RFA, which showed good efficacy and which provides a new option for the treatment of hepatic MALT lymphoma. We also present our findings from a systematic review to improve the current understanding of this disease.

Emodin Protects Against Acute Pancreatitis-Associated Lung Injury by Inhibiting NLPR3 Inflammasome Activation via Nrf2/HO-1 Signaling.

AIM: Lung injury is a common complication of acute pancreatitis (AP), which leads to the development of acute respiratory distress syndrome and causes high mortality. In the present study, we investigated the therapeutic effect of emodin on AP-induced lung injury and explored the molecular mechanisms involved. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were randomly divided into AP (n=24) and normal (n=6) groups. Rats in the AP group received a retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and then randomly assigned to untreated, emodin, combined emodin and ML385, and dexamethasone (DEX) groups. Pancreatic and pulmonary injury was assessed using H&E staining. In in vitro study, rat alveolar epithelial cell line L2 cells were exposed to lipopolysaccharide and treated with emodin. Nrf2 siRNA pool was applied for the knockdown of Nrf2. The contents of the pro-inflammatory cytokines in the bronchoalveolar lavage fluid and lung were determined using enzyme-linked immunosorbent assay. The expressions of related mRNAs and proteins in the lung or L2 cells were detected using real-time polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence. KEY FINDINGS: Emodin administration alleviated pancreatic and pulmonary injury of rats with AP. Emodin administration suppressed the production of proinflammatory cytokines, downregulated NLRP3, ASC and caspase-1 expressions and inhibited NF-κB nuclear accumulation in the lung. In addition, Emodin increased Nrf2 nuclear translocation and upregulated HO-1 expression. Moreover, the anti-inflammatory effect of emodin was blocked by Nrf2 inhibitor ML385. CONCLUSION: Emodin effectively protects rats against AP-associated lung injury by inhibiting NLRP3 inflammasome activation via Nrf2/HO-1 signaling.

MiR-3196, a p53-responsive microRNA, functions as a tumor suppressor in hepatocellular carcinoma by targeting FOXP4.

Increasing evidences demonstrate that miRNAs play an important role in development and progression of hepatocellular carcinoma (HCC). Recent studies indicate that miR-3196 regulates tumorigenesis in breast and lung cancer. However, its role and regulatory mechanism remains unknown in hepatocellular carcinoma. Here, we found that miR-3196 was downregulated in HCC tissues and decreased miR-3196 was correlated with tumor size (P=0.0297) and TNM stage (P=0.034). Forced miR-3196 suppressed HCC cell growth and chemoresistance in vivo and in vitro. Further mechanistic studies revealed that the tumor suppressor p53 transcriptionally upregulated miR-3196 expression by binding to its promoter region in HCC cells. Additional, we also found that FOXP4 was a downstream target of miR-3196 and increased miR-3196 inhibited FOXP4 expression which led to HCC growth suppression and cell apoptosis increase. Collectively, our data shed a new role of miR-3196 in HCC and indicates that p53-dependent, miR-3196-medicated FOXP4 pathway inhibits the tumorigenesis of HCC.

Long Non-Coding RNA Linc-USP16 Functions As a Tumour Suppressor in Hepatocellular Carcinoma by Regulating PTEN Expression.

BACKGROUND/AIMS: Recent evidence has indicated the crucial regulatory roles of long non-coding RNAs (lncRNAs) in tumour biology. In hepatocellular carcinoma (HCC), aberrant expression of lncRNAs plays an essential role in HCC tumourigenesis. However, the potential roles and regulatory mechanisms of the novel human lncRNA, Linc-USP16, in HCC are unclear. METHODS: To investigate the function of Linc-USP16 in HCC, we first analysed the expression levels of Linc-USP16 in HCC patient tissues and cell lines via q-RT-PCR and established overexpressed or knockdown HCC cell lines. RESULTS: Here, we found that Linc-USP16 expression was significantly down-regulated in HCC patient tissues and cell lines. Further functional experiments suggested that Linc-USP16 could directly increase PTEN expression by acting as a competing endogenous RNA (ceRNA) for miR-21 and miR-590-5p. These interactions led to repression of AKT pathway and inhibition of HCC cell proliferation and migration. CONCLUSION: Thus, our data showed that Linc-USP16, as a tumour suppressor, plays an important role in HCC pathogenesis and provides a new therapeutic strategy for HCC treatment.

MicroRNA-205-5p regulates the chemotherapeutic resistance of hepatocellular carcinoma cells by targeting PTEN/JNK/ANXA3 pathway.

Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system, and patients with advanced HCC have a poor outlook, partly due to resistance to chemotherapeutic drugs. Previous studies have implicated microRNAs in the regulation of chemoresistance, and we have previously shown that microRNA (miR)-205-5p is down-regulated in multiple hepatoma cell lines. Here, we investigate whether miR-205-5p is involved in chemotherapeutic resistance in HCC. Expression of miR-205-5p was measured by real-time quantitative reverse transcription PCR and cell viability was determined using a CCK-8 cell viability assay. Expression of proteins in the PTEN/JNK/ANXA3 pathway were assessed via Western blotting. We found that miR-205-5p expression was down-regulated in all HCC cell lines investigated. In addition, miR-205-5p expression was upregulated by 5-fluorouracil (5-Fu) treatment in Bel-7402 (Bel) cells. Interestingly, miR-205-5p expression was increased in multidrug-resistant Bel-7402/5-Fu (Bel/Fu) cells, compared with Bel cells. We next demonstrated that sensitivity to 5-Fu was increased in Bel/Fu cells after treatment with a miR-205-5p inhibitor. Similarly, increased resistance to 5-Fu was observed in Bel cells after transfection with a miR-205-5p mimic. We injected nude mice with Bel/5-Fu cells to promote tumor growth, and found that co-treatment with a miR-205-5p antagomir and 5-Fu slowed tumor growth more than either treatment alone. Finally, we found that these effects were all associated with changes in the PTEN/JNK/ANXA3 pathway. In conclusion, inhibition of miR-205-5p may reverse chemotherapeutic resistance to 5-Fu, and this may occur via the PTEN/JNK/ANXA3 pathway.

Activated δ­opioid receptors inhibit hydrogen peroxide­induced apoptosis in liver cancer cells through the PKC/ERK signaling pathway.

Apoptotic liver cancer cells have important roles in liver tumorigenesis and liver cancer progression. Recent studies have shown that δ­opioid receptors are highly expressed in human liver and liver cancer cells. The present study aimed to investigate the role of activated δ­opioid receptors on human liver cancer cell apoptosis and its interrelation with the mitochondria and the protein kinase C/extracellular­signal­regulated kinase (PKC/ERK) signaling pathway. H2O2 was used to induce apoptosis in human liver cancer cells. During apoptosis, mitochondrial transmembrane potentials were observed to decrease, cytochrome c expression was found to increase and B cell lymphoma 2 (Bcl­2) expression decreased. These findings suggested that H2O2­induced apoptosis was mediated through the mitochondrial pathway. Of note, activated δ­opioid receptors were observed to inhibit H2O2­induced apoptosis in human liver cancer cells. Following δ­opioid receptor activation, the number of apoptotic liver cancer cells decreased, mitochondrial transmembrane potentials were restored, cytoplasmic cytochrome c and Bcl­2­associated X protein expression decreased and Bcl­2 expression increased. These data suggested that δ­opioid receptor activation inhibited mitochondria­mediated apoptosis. In addition, activation of δ­opioid receptors was observed to increase the expression of PKC and ERK in human liver cancer cells. Furthermore, upon inhibition of the PKC/ERK signaling pathway, the protective effect associated with the δ­opioid receptor on liver cancer cell apoptosis was inhibited, which was not associated with the status of δ­opioid receptor activation. These findings suggested that the PKC/ERK signaling pathway has an important role in δ­opioid receptor­mediated inhibition of apoptosis in human liver cancer cells.