FXR controls duodenogastric reflux-induced gastric inflammation through negatively regulating ER stress-associated TNXIP/NLPR3 inflammasome.

Duodenogastric reflux (DGR) is closely associated with gastric inflammation and tumorigenesis; however, the precise mechanism is unclear. Hence, we aim to clarify this molecular mechanism and design an effective therapeutic strategy based on it. The present study found that DGR induced TXNIP/NLRP3 inflammasome activation and triggered pyroptosis in gastric mucosa in vitro and in vivo, in which endoplasmic reticulum (ER) stress via PERK/eIF2α/CHOP signaling was involved. Mechanistically, farnesoid X receptor (FXR) antagonized the DGR-induced PERK/eIF2α/CHOP pathway and reduced TXNIP and NLRP3 expression. Moreover, FXR suppressed NLRP3 inflammasome activation by physically interacting with NLRP3 and caspase-1. Administration of the FXR agonist OCA protected the gastric mucosa from DGR-induced barrier disruption and mucosal inflammation. In conclusion, our study demonstrates the involvement of TXNIP/NLRP3 inflammasome-mediated pyroptosis in DGR-induced gastric inflammation. FXR antagonizes gastric barrier disruption and mucosal inflammation induced by DGR. Restoration of FXR activity may be a therapeutic strategy for DGR-associated gastric tumorigenesis.

USP50 regulates NLRP3 inflammasome activation in duodenogastric reflux-induced gastric tumorigenesis.

Duodenogastric reflux (DGR) has been linked to the onset of gastric cancer (GC), although the precise mechanism is yet obscure. Herein, we aimed to investigate how refluxed bile acids (BAs) and macrophages are involved in gastric carcinogenesis. In both active human bile reflux gastritis and the murine DGR model, ubiquitin specific protease 50 (USP50) was dramatically raised, and macrophages were the principal leukocyte subset that upregulated USP50 expression. Enhancing USP50 expression amplified bile acid-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and subsequent high-mobility group box protein 1 (HMGB1) release, while USP50 deficiency resulted in the reversed alteration. Mechanistically, USP50 interacted with and deubiquitinated apoptosis-associated speck-like protein containing CARD (ASC) to activate NLRP3 inflammasome. The release of HMGB1 contributes to gastric tumorigenesis by PI3K/AKT and MAPK/ERK pathways. These results may provide new insights into bile reflux-related gastric carcinogenesis and options for the prevention of DGR-associated GC.

USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A.

In the current study, we have shown that USP51 promotes colorectal cancer stemness and chemoresistance, and high expression of USP51 predicts survival disadvantage in colorectal cancer patients. Mechanically, USP51 directly binds to Elongin C (ELOC) and forms a larger functional complex with VHL E3 ligase (USP51/VHL/CUL2/ELOB/ELOC/RBX1) to regulate the ubiquitin-dependent proteasomal degradation of HIF1A. USP51 efficiently deubiquitinates HIF1A and activates hypoxia-induced gene transcription. Conversely, the activation of HIF1A under hypoxia transcriptionally upregulates the expression of USP51. Thus, USP51 and HIF1A form a positive feedback loop. Further, we found that the SUMOylation of ELOC at K32 inhibits its binding to USP51. SUMO-specific protease 1 (SENP1) mediates the deSUMOylation of ELOC, promoting the binding of USP51 to ELOC and facilitating the deubiquitination and stabilization of HIF1A by USP51. Importantly, USP51 plays a crucial role in promoting the HIF1A and SENP1-dependent proliferation, migration, stemness, and chemoresistance under hypoxia in colorectal cancer. Together, our data revealed that USP51 is an oncogene stabilizing the pro-survival protein HIF1A, offering a potential therapeutic target for colorectal cancer.

3-Bromopyruvate overcomes cetuximab resistance in human colorectal cancer cells by inducing autophagy-dependent ferroptosis.

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide. Cetuximab, in combination with chemotherapy, is effective for treating patients with wild-type KRAS/BRAF metastatic CRC (mCRC). However, intrinsic or acquired drug resistance often limits the use of cetuximab. In this study, we investigated the potential of co-treatment with 3-Bromopyruvate (3-BP) and cetuximab to overcome cetuximab resistance in CRC, both in vitro and in vivo. Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines with intrinsic cetuximab resistance (DLD-1 (KRASG13D/-) and HT29 (BRAFV600E)) and in a cetuximab-resistant cell line derived from Caco-2 with acquired resistance (Caco-2-CR). Further analysis revealed that co-treatment induced ferroptosis, autophagy, and apoptosis. Mechanistically, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1 (KRASG13D/-), HT29 (BRAFV600E), and Caco-2-CR cells. In conclusion, our findings suggest that co-treatment with 3-BP and cetuximab could be a promising strategy to overcome cetuximab resistance in human CRC.

Naringin Inhibits the Proliferation, Migration, Invasion and Epithelial-to-Mesenchymal Transition of Gastric Cancer Cells via the PI3K/AKT Signaling Pathway.

Background: Gastric cancer is a common malignant tumor of the human digestive system. Currently, the treatment of gastric cancer is still dominated by radiotherapy, chemotherapy and surgery. Although the treatment is very effective, we are also trying to find new treatment methods. Traditional Chinese Medicine (TCM) may play an important role in the treatment of gastric cancer. Study Objective: The aim of this study is to explore the effects of naringin on the proliferation, migration, invasion and apoptosis of gastric cancer and its potential mechanisms. Methods: MGC803 and MKN45 viability were detected by MTT assay. The effects of naringin on cell cloning, migration and invasion were determined by colony formation assay, cell scratch test and transwell assay (ThermoFisher Scientific™, Waltham, Massachusetts USA), respectively. Cell cycle and apoptosis were assayed by flow cytometry. Associated proteins were measured using Western blot and immunohistochemistry (IHC). The experimental results were further verified in nude mice. Setting: This study was carried out in Department of Experimental Animal Center of Xi'an Jiaotong University and the Translation Medicine Center of the First Affiliated Hospital of Xi'an Jiaotong University in China. Results: Cells remained mainly in G0/G1 phase and apoptosis was increased. The nude mouse model showed that naringin treatment could inhibit the growth of tumors in nude mice. Cell scratch tests and transwell assay showed that the invasion and migration abilities of the gastric cancer cell line were significantly reduced after naringin treatment. Western blot showed that the expression of Vimentin, Zeb1 and P-AKT was downregulated and that E-cadherin was upregulated after naringin treatment. Conclusion: Naringin can block the cell-cycle, induce cancer cell apoptosis, and inhibit the epithelial mesenchymal transition (EMT) process by inhibiting the PI3K-AKT/Zeb1 pathway in gastric cancer cells. Therefore, naringin can inhibit the development of gastric cancer.

DFNA5 inhibits colorectal cancer proliferation by suppressing the mTORC1/2 signaling pathways via upregulation of DEPTOR.

The human deafness, autosomal dominant 5 gene (DFNA5), a newly discovered executor of pyroptosis, has been strongly implicated in the tumorigenesis of several human cancers. However, an understanding of the functional role of DFNA5 in the development and progression of colorectal cancer (CRC) is limited. In this study, we demonstrated that DFNA5 was downregulated in CRC tissues. Ectopic expression of DFNA5 inhibited tumor cell growth in vitro, retarded tumor formation in vivo, and blocked a cell-cycle transition from the G0/G1 to the S phase, whereas a DFNA5 knockdown promoted cell proliferation. Western blotting showed that the levels of cell cycle-related proteins, including cyclin D1, cyclin E, CDK2, and p21, were accordingly altered upon DFNA5 overexpression or DFNA5 knockdown. Mechanistic studies indicated that DFNA5 exerted its tumor suppressor functions by antagonizing mTORC1/2 signaling via upregulation of DEPTOR. In addition, blockage of mTORC1/2 signaling by Torin-1 abolished the accelerative proliferation by DFNA5 knockdown. In conclusion, these results indicated that DFNA5 inhibits the proliferation and tumor formation of colon cancer cells by suppressing mTORC1/2 signaling.

A pan-cancer analysis of molecular characteristics and oncogenic role of gasdermins.

BACKGROUND: The gasdermins (GSDMs) family is proposed to be pore-forming effector proteins that cause cell membrane permeabilization and pyroptosis. Despite our increasing knowledge of GSDMD, GSDME and GSDMB, the biological functions and the regulation of GSDM expression and activation remain elusive for most GSDMs. In this study, we analyzed the molecular characteristics and oncogenic role of GSDM family genes systematically. METHODS: TCGA, CCLE, cBioPortal, GEPIA, CellMiner and BioGRID databases were utilized in this study. Immunohistochemical analysis and a series of in vitro experiments were conducted. RESULTS: We found that, in cancer, GSDM genes and their expressions extensively changed, which were associated with patient survival. The expression of GSDMs was widely associated with cancer-related pathways, drug resistance, immune subtypes, tumor microenvironment and cancer cell stemness. However, an intra- and inter-cancer heterogeneity was discovered regarding the corresponding GSDM gene. We found that GSDMA and GSDMB regulated drug resistance to the opposite direction of GSDME. In colorectal cancer, GSDME might be a positive regulator in cell invasion and metastasis through cell migration and angiogenesis, while GSDMA, GSDMB and GSDMD might be a negatively regulator of cell migration. CONCLUSIONS: GSDM family genes might play important roles in cancer other than pyroptosis. We suggest more efforts be made to investigate the GSDM family and each GSDM gene be studied as an entity in each type of cancer.

GW4064 enhances the chemosensitivity of colorectal cancer to oxaliplatin by inducing pyroptosis.

Repeated and long-term oxaliplatin therapy leads to drug resistance and severe adverse events, which limit its clinical use. These difficulties highlight the importance of identifying potent and specific drug combinations to enhance the antitumor effects of oxaliplatin. The farnesoid X receptor (FXR) deficiency in colorectal cancer (CRC) suggests that restoring FXR function might be a promising strategy for CRC treatment. A drug combination study showed that the GW4064 acted synergistically with oxaliplatin in colon cancer cells. The combination of oxaliplatin plus GW4064 inhibited cell growth and colony formation, induced apoptosis and pyroptosis in vitro, and slowed tumor growth in vivo. Mechanistically, GW4064 enhanced the chemosensitivity of cells to oxaliplatin by inducing BAX/caspase-3/GSDME-mediated pyroptosis. Furthermore, the combination of oxaliplatin and GW4064 synergistically inhibited STAT3 signaling by restoring SHP expression. Our study revealed that GW4064 could enhance the antitumor effects of oxaliplatin against CRC, which provides a novel therapeutic strategy based on a combinational approach for CRC treatment.

Depression and anxiety before and after limb length discrepancy correction in patients with unilateral developmental dysplasia of the hip.

OBJECTIVE: Limb length discrepancy (LLD) is common in patients with developmental dysplasia of the hip (DDH) and may influence the psychological status of these patients. The present study aims to investigate depression and anxiety in DDH patients with different extents of LLD and to assess the effect of LLD correction on these two psychological factors. METHODS: 161 patients with DDH were recruited and divided into two groups based on whether they could perceive LLD preoperatively. The patients who could not perceive LLD were assigned to group N, and those who could perceive LLD were assigned to group P. Depression/anxiety, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and LLD were assessed one week before, six months and two years after total hip arthroplasty (THA). RESULTS: Depression and anxiety were significantly higher in group P patients compared to group N patients. The patients in group N presented significant improvement in depression and anxiety six months after arthroplasty, while DDH patients in group P did two years after arthroplasty. Correlation analyses revealed their improvement was associated with pain relief and improved hip function in both groups of patients and was also related to changes in the perception of LLD in group P patients. CONCLUSIONS: Depression and anxiety levels were higher in DDH patients with perceived LLD. Their improvement was related to pain relief and improved hip function following THA. In DDH patients with perceived LLD, a change in the perception of LLD also played a part in their improvement.

Ulnar Rotation Osteotomy for Congenital Radial Head Dislocation.

PURPOSE: To evaluate an ulnar rotation osteotomy for congenital anterior dislocation of the radial head. METHODS: Nine patients (5 boys and 4 girls aged 6 to 13 years) with congenital anterior dislocation of the radial head were treated with ulnar rotation osteotomy. Magnetic resonance imaging of the elbow showed the proximal radioulnar joint on the anterior-lateral side of the ulna rather than on the lateral side in patients with congenital anterior dislocation of the radial head. On the basis of this finding, we performed an osteotomy on the ulna and laterally rotated the proximal radioulnar joint achieving radial head reduction and restoring the anatomical relationship between the radial head and the capitellum. Clinical and radiographical evaluation of the elbow was performed before surgery and at postoperative follow-up. RESULTS: All patients were followed for 13 to 45 months after surgery. Elbow radiography showed that the radiocapitellar joint was reduced in all patients at the last follow-up visit and that the carrying angle was decreased relative to that in the preoperative condition. Elbow stability and the range of elbow flexion motion were improved at the last follow-up. We did not observe ulnar osteotomy site nonunion or elbow osteoarthritis in these patients. Furthermore, radial head dislocation did not recur. CONCLUSIONS: At early follow-up, ulnar rotation osteotomy was a safe and effective method for the treatment of congenital anterior dislocation of the radial head. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.