Integrated analysis revealed hypoxia signatures and LDHA related to tumor cell dedifferentiation and unfavorable prognosis in pancreatic adenocarcinoma: Hypoxia in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by analyzing single-nucleus RNA sequencing of 43, 817 tumor cells from 15 PDAC tumors and non-tumor, we find that hypoxia signatures were heterogeneous across samples and were potential regulators for tumor progression and more aggressive phenotype. Hypoxia-high PDAC tends to present a basal/squamous-like phenotype and has significantly increased outgoing signaling, which enhances tumor cell stemness and promotes metastasis, angiogenesis, and fibroblast differentiation in PDAC. Hypoxia is related to an extracellular matrix enriched microenvironment, and increased possibility of TP53 mutation in PDAC. TP63 is a specific marker of squamous-like phenotype, and presents elevated transcriptome levels in most hypoxia PDAC tumors. In summary, our research highlights the potential linkage of hypoxia, tumor progression and genome alteration in PDAC, leading to further understand of the formation of inter-tumoral and intra-tumoral heterogenous in PDAC. Our study extends the understanding of the diversity and transition of tumor cells in PDAC, which provides insight into future PDAC management.

Ergothioneine inhibits the progression of osteoarthritis via the Sirt6/NF-κB axis both in vitro and in vivo.

Osteoarthritis (OA), which is a major cause of serious arthralgia and disability among the elderly, has long plagued numerous populations. However, the specific molecular mechanisms involved in the etiology of OA are unclear. SIRT6 plays a critical function in the development of several inflammatory and aging-associated diseases. A study by D'Onofrio demonstrates that ergothioneine (EGT) is an effective activator of SIRT6. As revealed by previous reports, EGT exerts beneficial effects on the mouse body, including resistance to oxidation, tumor, and inflammation. Therefore, this work attempted to identify the inflammatory resistance of EGT and explore its effects on the incidence and development of OA. Mouse chondrocyte stimulation using varying levels of EGT and 10 ng/mL IL-1ß. According to in vitro experiments, EGT significantly reduced the decomposition of collagen II and aggrecan in OA chondrocytes, as well as inhibited the overexpression of PGE2, NO, IL-6, TNF-α, iNOs, COX-2, MMP-13, and ADAMTS5. In the present work, EGT hindered the NF-κB activity by activating the SIRT6 pathway in OA chondrocytes, which in turn, significantly attenuated the inflammatory response resulting from IL to 1ß. The inhibitory effect of EGT on the progression of OA was demonstrated by the mouse DMM model experiment. Thus, this study revealed that EGT was effective in anti-OA treatment.

MOF-Derived MnO/C Nanocomposites for High-Performance Supercapacitors.

As ordered porous materials, metal-organic frameworks (MOFs) have attracted tremendous attention in the field of energy conversion and storage due to their high specific surface area, permanent porosity, and tunable pore sizes. Here, MOF-derived MnO/C nanocomposites with regular octahedral shape were synthesized using a Mn-based analogue of the MIL-100 framework (Mn-MIL-100, MIL: Matérial Institut Lavoisier) as the precursor. Using aberration-corrected environmental transmission electron microscopy (ETEM), MnO nanocages with a diameter of approximately 20 nm were recognized in the MnO/C nanocomposites fabricated, dispersed in a microporous carbon matrix homogeneously. The nanocages are composed of MnO nanoparticles with a diameter of approximately 2 nm and with a single crystal structure. The specific surface area of the as-prepared MnO/C octahedra decreases to 256 m2 g-1 from 507 m2 g-1 of the Mn-MIL-100 precursor, whereas the total pore volume increases to 0.245 cm3 g-1, which is approximately 29% higher than that of the precursor (0.190 cm3 g-1). Additionally, when utilized as an electrode for supercapacitors, the MOF-derived MnO/C nanocomposite demonstrates a towering specific capacitance of 421 F g-1 at 0.5 A g-1 and good cycle stability (94%) after 5000 cycles. Our work reveals that the MnO nanoparticles in MOF-derived MnO/C nanocomposites exhibit nanocage structure characteristics, which might be inherited from the Mn-MIL-100 precursor with analogous supertetrahedron units.

Linalool inhibits the progression of osteoarthritis via the Nrf2/HO-1 signal pathway both in vitro and in vivo.

Osteoarthritis (OA) is a chronic injury of joints, which is characterized by the destruction and degeneration of articular cartilage. Currently, there is a lack of effective treatments for OA. Linalool is a natural compound with anti-inflammatory effects in various diseases. However, the anti-inflammatory effect of linalool in the development of osteoarthritis remains unclear. This study aimed to investigate the anti-inflammatory effect of linalool on IL-1ß-induced mouse chondrocytes, as well as its protective effect on joints in a mouse model of OA. Mouse chondrocytes were co-treated with 10 ng/mL IL-1ß and different concentration gradients of linalool. These in vitro experiments demonstrated that linalool could inhibit the expression of Interleukin-1ß (IL-1ß)-induced inflammatory factors, such as nitric oxide synthase, cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Furthermore, linalool reduced the catabolism of the extracellular matrix (ECM) by inhibiting the expression of matrix metalloproteinase-13 (MMP-13) and thrombospondin motif-5 (ADAMTS5) while upregulating the expression of type II collagen (COL II) and aggrecan. Regarding the mechanism of OA, it was observed that linalool inhibited the signal transduction of nuclear factor kappa B (NF-κB) by activating the nuclear factor-erythroid 2-related factor-2 (Nrf2) in chondrocytes. The inhibitory effect of linalool on the development of OA was demonstrated by the mouse DMM model experiment. The results suggested that linalool may be a potential drug for the treatment of OA.

Development of a Novel Rat Intervertebral Disc Degeneration Model by Surgical Multifidus Resection-Induced Instability.

OBJECTIVE: This study aimed to investigate whether surgical resection of multifidus in rats could generate a reliable model of intervertebral disc degeneration (IVDD). METHODS: Instability of the lumbar spine in Sprague-Dawley rats was induced by multifidus resection. Longissimus changes were examined by hematoxylin and eosin staining and immunohistochemistry. Specific protein and mRNA changes in the nucleus pulposus (NP) were quantified by Western blot and reverse transcription-polymerase chain reaction. Bone alterations were assessed using X-ray imaging, and disc changes were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. RESULTS: Fat infiltration and increased tumor necrosis factor-α expression in the longissimus were detected following surgery. Reverse transcription-polymerase chain reaction and Western blot results demonstrated that the inflammation and catabolism in the NP were increased after the surgical intervention. Moreover, X-ray imaging showed that the disc height had decreased and bone spurs had formed at the vertebral rims. Histological analyses further revealed degeneration of the annulus fibrosus, endplate, and NP. Furthermore, in contrast to the sham group, the collagen II expression was reduced, while matrix metalloproteinase-13 was increased in the surgery group. CONCLUSIONS: Surgical resection of the multifidus in rats resulted in a reproducible IVDD model. Because the present procedure does not impart direct injury to the intervertebral disc, it can better imitate the pathological states in humans. Therefore, our rat multifidus resection model might help us further understand the intrinsic pathophysiology of IVDD.

Expressional and functional characteristics of checkpoint kinase 1 as a prognostic biomarker in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most common pathological subtype of liver cancer and is the third leading cause of cancer death worldwide. Checkpoint kinase 1 (CHEK1), an essential serine/threonine kinase that regulates the cell cycle, is reported to be associated with carcinogenesis. However, the biological role and clinical significance of CHEK1 in HCC are still incompletely known. Methods: In this research, CHEK1 messenger RNA (mRNA) levels in various liver hepatocellular carcinoma (LIHC) cohorts from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were evaluated. The Kaplan-Meier database was applied to identify the correlation between survival time and CHEK1 expression in patients with HCC. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanism of CHEK1 in HCC, and NetworkAnalyst v. 3.0 (https://www.networkanalyst.ca/) was used to construct the regulatory networks of CHEK1 in HCC. Discriminant Regulon Expression Analysis (DoRothEA) was used to detect the activity of transcriptional factors (TFs) in gene-enriched cells (EC) with CHEK1 coexpression. In vitro experiments were conducted to investigate the effects of CHEK1 on the biological function of HCC cells. Results: The CHEK1 mRNA level was overexpressed in HCC, and increased CHEK1 expression correlated with poor survival outcomes. The homo sapiens-microRNA-195 (hsa-miR-195) may have contributed to the upregulation of CHEK1 in HCC. GSEA and NetworkAnalyst v. 3.0 showed that CHEK1 played a crucial part in tumor proliferation of HCC and may be regulated by TF E2F1. DoRothEA showed increased transcriptional activity of E2F1 in gene-EC with CHEK1 coexpression. Moreover, experiments of cell function showed that the knockdown of CHEK1 weakened the aggressive behavior and proliferation of HCC cells. Overexpression of E2F1 increased the proliferation and invasion of HCC cells in vitro, while the silencing of CHEK1 dampened cell invasion induced by E2F1 overexpression. Conclusions: These results identified the prognostic significance and expression characteristics of CHEK1 in HCC through bioinformatics analysis and experimental verification. This lays the foundation for further research on the diagnosis and treatment of HCC.

H2AFZ Is a Prognostic Biomarker Correlated to TP53 Mutation and Immune Infiltration in Hepatocellular Carcinoma.

H2A family member Z (H2AFZ) is a highly conserved gene encoding H2A.Z.1, an isoform of histone variant H2A.Z, and is implicated in cancer. In this study, we report that overexpression of H2AFZ is associated with tumor malignancy and poor prognosis in HCC patients. Functional network analysis suggested that H2AFZ mainly regulates cell cycle signaling and DNA replication via pathways involving several cancer-related kinases and transcription factor E2F1. Further studies revealed that H2AFZ overexpression is regulated by TP53 mutation and led to an attenuation of rapid proliferation phenotype and aggressive behavior in HCC cells. Moreover, we found that H2AFZ was related to immune infiltrations and was co-expressed with immune checkpoint genes, including CD274 (PD-L1), CTLA-4, HAVCR2 (TIM3), LAG3, PDCD1 (PD-1), and TIGIT (VSIG9) in HCC, indicating that H2AFZ-overexpressed HCC patients may be sensitive to immune checkpoint blockades (ICBs). Integrated analysis suggested that H2AFZhigh/TP53mut patients had the shortest OS and PFS time, but most likely to respond to ICBs. These findings indicate that the H2AFZ possesses potential value as a novel prognostic indicator for HCC patients and is correlated with immune infiltration in HCC, laying a foundation for future study of HCC investigation and intervention.

Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis.

Bladder cancer (BLCA) remains the leading cause of cancer-related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2-box (CAGGTG) of PARD3 promoter-proximal. Inhibition of GSK-3ß promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936-1356 aa) and ZO-1 (1372-1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK-3ß/Snail/Par3/ZO-1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA.