synthesis-of-strong-adhesive-hydrogel-gelatin-o-nitrosobenzaldehyde

Synthesis of Strong Adhesive Hydrogel, Gelatin O-Nitrosobenzaldehyde

Adhesive materials have become popular biomaterials in the field of biomedical and tissue engineering. In our previous work, we presented a new material - ...

Zhejiang University School of Medicine

Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases

Liver cirrhosis is a chronic liver disease caused by chronic liver injury, which activates hepatic stellate cells (HSCs) and the secretion of extracellular matrix (ECM). Cirrhosis accounts for an extensive level of morbidity and mortality worldwide, largely due to lack of effective treatment options. In this study, we have constructed a fusion protein containing matrix metal-loproteinase 8 (MMP-8) and the human growth factor mutant 1K1 (designated cMMP8-1K1) and delivered it into hepatocytes and in vivo and in cell culture via intravenous injection of fusion protein-harboring adenovirus. In doing so, we found that the cMMP8-1K1 fusion protein promotes the proliferation of hepatocytes, likely resulting from the combined inhibition of type I collagen secretion and the degradation of the ECM in the HSCs. This fusion protein was also observed to ameliorate liver cirrhosis in our mouse model. These changes appear to be linked to changes in downstream gene expression. Taken together, these results suggest a possible strategy for the treatment of liver cirrhosis and additional work is warranted. 

Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation.

Gallbladder neuroendocrine neoplasm (GB-NEN) is a relatively rare neoplasm, accounting for 0.5% of all neuroendocrine neoplasm cases and 2.1% of gallbladder cancers. Because of the limited understanding of GB-NEN, the aim of this study was to explore the clinicopathology and survival of GB-NEN patients selected from the Surveillance, Epidemiology, and End Results (SEER) database.

Clinicopathological features and survival for gallbladder NEN: a population-based study.

In most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma.

Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the underlying molecular mechanisms. : A novel hub miR-378a-3p was identified based on miRNA microarray and bioinformatics analysis. The abnormal expression of miR-378-3p was validated in different HCC patient cohorts and sorafenib-resistant (SR) HCC cell lines. The functional role of miR-378a-3p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays  and . Interactions among miR-378a-3p, LXRα, and IGF1R were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-378a-3p and its targets were evaluated in HCC samples. HCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of LXRα and its downstream miR-378a-3p. : miR-378a-3p expression was frequently reduced in established sorafenib-resistant HCC cell lines. The decreased miR-378a-3p levels correlated with poor overall survival of HCC patients following sorafenib treatment. miR-378a-3p overexpression induced apoptosis in SR HCC cells, whereas miR-378a-3p silencing exerted the opposite effects. IGF1R was identified as a novel target of miR-378a-3p. Furthermore, the primary miR-378 level was not consistent with its precursor miRNA level in SR HCC cells, which was attributed to the downregulation of exportin5 (XPO5) and subsequently reduced nuclear export of precursor miR-378 and restrained maturation of miR-378-3p. In this context, we combined an agonist GW3965 of liver X receptor alpha (LXRα), which functioned as a transcription activator of miRNA-378a, and its activation re-sensitized sorafenib-resistant cells to sorafenib treatment  and . : Our finding suggested decreased expression of XPO5 prevents maturation of miR-378a-3p, which leaded to the overexpression of IGF-1R and counteracted the effects of sorafenib-induced apoptosis. LXRα was able to activate miRNA-378a-3p transcription in HCC cells and could be a potential combinable treatment strategy with sorafenib to suppress HCC progression.

LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription.

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance significantly limits its therapeutic efficacy, and the mechanisms underlying resistance have not been fully clarified. Here we report that a circular RNA, circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib. Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm, which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation. Moreover, our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells. Using different HCC mouse models, we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.

CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.

Laparoscopic anatomical resection (LAR) is a highly challenging procedure. This study aimed to describe our experience of the LAR with an indocyanine green fluorescence negative staining (ICGNS) by the Glissonean pedicle transection (Takasaki) approach.

Laparoscopic anatomical portal territory hepatectomy using Glissonean pedicle approach (Takasaki approach) with indocyanine green fluorescence negative staining: how I do it.

Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (β integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination-independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment.

A tumor-suppressive circular RNA mediates uncanonical integrin degradation by the proteasome in liver cancer.

More than 30 cases of synovial sarcoma are sequenced on all organs of cBioPortal database, but it has not yet been reported before. Here, we reported a case of a 66-year-old male patient with an upper abdominal pain for half a month and a previous history of oral cancer. During this hospitalization, the patient underwent laparoscopic exploration followed by open pancreaticoduodenectomy. The histopathological diagnosis was pancreatic synovial sarcoma (PSS), and we further performed whole exome sequencing for this patient. We found that there are many copy number variations (CNV) of exon gene in all the 24 chromosomes, of which chr1, chr2, chr4 have the most exon gene amplification and chr21, chr22, chrY have the most exon gene deletion. Besides, GO (Gene Ontology) analysis showed that many driver-genes are related to chromosome or chromatin organization while KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis demonstrated that many driver-genes are enriched in the cancer-related pathways. Furthermore, we found mutations or CNV of the five vital driver-genes in the results of sequencing, including  Of them,  and  in exon 1 are both in-frame mutations. By exploring the pathogenic genes of PSS, we have found some vital gene mutations and better understood the pathogenesis to promote the targeted treatment of primary PSS.

Whole-exon sequencing insights into pancreatic synovial sarcoma: a case report.

This study was designed to evaluate the safety and effectiveness of a two-hand technique combining harmonic scalpel (HS) and laparoscopic Peng's multifunction operative dissector (LPMOD) in patients who underwent laparoscopic hemihepatectomy (LHH).

Safety and effectiveness evaluation of a two-handed technique combining harmonic scalpel and laparoscopic Peng's multifunction operative dissector in laparoscopic hemihepatectomy.

Altered metabolic patterns in tumor cells not only meet their own growth requirements but also shape an immunosuppressive microenvironment through multiple mechanisms. Noncoding RNAs constitute approximately 60% of the transcriptional output of human cells and have been shown to regulate numerous cellular processes under developmental and pathological conditions. Given their extensive action mechanisms based on motif recognition patterns, noncoding RNAs may serve as hinges bridging metabolic activity and immune responses. Indeed, recent studies have shown that microRNAs, long noncoding RNAs and circRNAs are widely involved in tumor metabolic rewiring, immune cell infiltration and function. Hence, we summarized existing knowledge of the role of noncoding RNAs in the remodeling of tumor metabolism and the immune microenvironment, and notably, we established the TIMELnc manual, which is a free and public manual for researchers to identify pivotal lncRNAs that are simultaneously correlated with tumor metabolism and immune cell infiltration based on a bioinformatic approach.

Noncoding RNAs link metabolic reprogramming to immune microenvironment in cancers.

Inflammatory bowel disease (IBD) is a chronic, immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier. Due to the poor remission effect and severe adverse events associated with current clinical medications, IBD remains an incurable disease. Here, we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating. The molecular coating is composed of o-nitrobenzaldehyde (NB)-modified Gelatin (GelNB), which can strongly bond with -NH on the intestinal surface of tissue to form a thin biophysical barrier. We found that this molecular coating was able to stay on the surface of the intestine for long periods of time, effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora. In addition, our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration, but also achieved a better outcome of IBD by reducing intestinal inflammation. Moreover, the  experiments showed that the GelNB was better than the classic clinical medication-mesalazine. Therefore, our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.

GelNB molecular coating as a biophysical barrier to isolate intestinal irritating metabolites and regulate intestinal microbial homeostasis in the treatment of inflammatory bowel disease.

Article	Year
Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation. Drug design, development and therapy\| PubMed ID: 26527860	2015
Clinicopathological features and survival for gallbladder NEN: a population-based study. Endocrine connections\| PubMed ID: 31398710	2019
The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine\| PubMed ID: 31918403	2020
LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription. Theranostics\| PubMed ID: 32754282	2020
CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal transduction and targeted therapy\| PubMed ID: 33361760	2020
Laparoscopic anatomical portal territory hepatectomy using Glissonean pedicle approach (Takasaki approach) with indocyanine green fluorescence negative staining: how I do it. HPB : the official journal of the International Hepato Pancreato Biliary Association\| PubMed ID: 33593657	2021
A tumor-suppressive circular RNA mediates uncanonical integrin degradation by the proteasome in liver cancer. Science advances\| PubMed ID: 33762338	2021
Whole-exon sequencing insights into pancreatic synovial sarcoma: a case report. Gland surgery\| PubMed ID: 34164326	2021
Safety and effectiveness evaluation of a two-handed technique combining harmonic scalpel and laparoscopic Peng's multifunction operative dissector in laparoscopic hemihepatectomy. World journal of surgical oncology\| PubMed ID: 34218803	2021
Noncoding RNAs link metabolic reprogramming to immune microenvironment in cancers. Journal of hematology & oncology\| PubMed ID: 34654454	2021
GelNB molecular coating as a biophysical barrier to isolate intestinal irritating metabolites and regulate intestinal microbial homeostasis in the treatment of inflammatory bowel disease. Bioactive materials\| PubMed ID: 35510173	2023

Yuelong Liang

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