Weighted gene co-expression network analysis identifies specific modules and hub genes related to Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. This study aims to screen specific modules and key genes related to PD. METHODS: Gene expression profile data GSE6613 and GSE22491 were downloaded from the Gene Expression Omnibus database. The significantly differentially expressed genes (DEGs) in different datasets were screened, followed by gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The Weighted Gene Co-expression Network Analysis (WGCNA) was used to screen disease-related modules that are significantly stable across datasets. The protein-protein interaction network was constructed using the DEGs in the stable module obtained and preservation modules. Finally, the hub genes directly related to PD were screened. RESULTS: A total of 179 DEGs with the same significant difference direction were screened. The enrichment analysis of GO and KEGG pathways showed that 20 significantly related GO biological processes and 9 KEGG signaling pathways were screened. A total of three highly conservative modules were detected in the WGCNA network. Finally, three significant PD-related KEGG pathways screened from the Comparative Toxicogenomics Database were identified, including neuroactive ligand-receptor interaction (CRHR2, CTSG, GRIN1, GRIN2D, LPAR4 and P2RX3), amyotrophic lateral sclerosis (BCL2, GRIN1 and GRIN2D) and alcoholism (CAMKK2, GRIN1, GRIN2D and SLC18A2). Key genes, such as SLC18A2, GRIN1 and GRIN2D, may be potential candidate genes for PD progression. CONCLUSIONS: Our findings indicate that SLC18A2, GRIN1 and GRIN2D may play an important role in the pathogenesis of PD.

Is skeletal muscle loss associated with chemoradiotherapy toxicity in nasopharyngeal carcinoma patients? A prospective study.

BACKGROUND: Our study explored to investigate whether skeletal muscle loss before concurrent chemoradiotherapy (CCRT) can predict treatment-related toxicity in this population. METHODS: Computed tomography (CT) scan of the third lumbar were used to assess and calculate the SMA (skeletal muscle area), SMI (skeletal muscle index), SMD (skeletal muscle density), SMG (skeletal muscle gauge) and estimate LBM (lean body mass). Handgrip strength (HGS) and daily walk speed were evaluated. Predictive factors linked to toxicity were assessed by logistic regression models and adjusted odds ratios (OR) of treatment toxicity were reported. RESULTS: A total of 82 patients were evaluated (67.1% males, 45.7 ± 10.7 years). Skeletal muscle loss was not associated with severe radiotherapy toxicity. In males, sarcopenia increases the risk of dose-limiting toxicity (DLT) (OR: 4.00, 95% CI = 1.20-13.36, p = 0.024). DLT is associated with reduced SMA (OR: 0.97, 95% CI = 0.94-1.00, p = 0.041), SMI (OR: 0.91, 95% CI = 0.84-0.99, p = 0.042) and LBM (OR: 0.90, 95% CI = 0.81-0.99, p = 0.041). Reduced HGS was significantly associated with grade 3-4 leukopenia (OR: 0.92, 95% CI = 0.86-0.98, p = 0.007), and was associated with any grade 3-4 toxicity (OR: 0.94, 95% CI = 0.89-0.99, p = 0.013). There is a strong correlation between LBM and HGS (Pearson's r = 0.71, p < 0.001). CONCLUSIONS: Skeletal muscle loss was not associated with severe radiation oral mucositis and dermatitis but associated with any grade 3-4 toxicity and severe gastrointestinal reactions in NPC patients. In males, sarcopenia before treatment is predictive of DLT. Increased HGS is independently associated with a reduced risk of hematological toxicity.

ACOX1 destabilizes p73 to suppress intrinsic apoptosis pathway and regulates sensitivity to doxorubicin in lymphoma cells.

Lymphoma is one of the most curable types of cancer. However, drug resistance is the main challenge faced in lymphoma treatment. Peroxisomal acyl-CoA oxidase 1 (ACOX1) is the rate-limiting enzyme in fatty acid ß-oxidation. Deregulation of ACOX1 has been linked to peroxisomal disorders and carcinogenesis in the liver. Currently, there is no information about the function of ACOX1 in lymphoma. In this study, we found that upregulation of ACOX1 promoted proliferation in lymphoma cells, while downregulation of ACOX1 inhibited proliferation and induced apoptosis. Additionally, overexpression of ACOX1 increased resistance to doxorubicin, while suppression of ACOX1 expression markedly potentiated doxorubicin-induced apoptosis. Interestingly, downregulation of ACOX1 promoted mitochondrial location of Bad, reduced mitochondrial membrane potential and provoked apoptosis by activating caspase-9 and caspase-3 related apoptotic pathway. Overexpression of ACOX1 alleviated doxorubicin-induced activation of caspase-9 and caspase-3 and decrease of mitochondrial membrane potential. Importantly, downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. Also, overexpression of ACOX1 significantly reduced stability of p73 protein thereby reducing p73 expression. Thus, our study indicated that suppression of ACOX1 could be a novel and effective approach for treatment of lymphoma. [BMB Reports 2019; 52(9): 566-571].

ß-Asarone increases doxorubicin sensitivity by suppressing NF-κB signaling and abolishes doxorubicin-induced enrichment of stem-like population by destabilizing Bmi1.

BACKGROUND: Lymphoma is one of the most common hematologic malignancy. Drug resistance is the main obstacle faced in lymphoma treatment. Cancer stem cells are considered as the source of tumor recurrence, metastasis and drug resistance. The ß-Asarone, a low-toxicity compound from the traditional medical herb Acorus calamus, has been shown to act as an anti-cancer reagent in various cancer types. However, the anti-cancer activities of ß-Asarone in lymphoma have not been shown. METHODS: Cell counting assay was used to evaluate Raji cell proliferation. CCK8 assay was used to evaluate the cell viability. Annexin-V/PI staining and flow cytometry analysis were used to evaluate apoptosis. ALDEFLUOR assay was used to evaluate the stem-like population. Luciferase reporter assay was used to examine the activation of NF-κB signaling. Western blot and polymerase chain reaction (PCR) were used to determine the expression of interested genes. RESULTS: We showed that ß-Asarone inhibited proliferation and induced apoptosis in Raji lymphoma cells in a dose-dependent manner. Additionally, ß-Asarone functioned as a sensitizer of doxorubicin and resulted in synergistic effects on inhibition of proliferation and induction of apoptosis when combined with doxorubicin treatment. Interestingly, we found that ß-Asarone also reduced the stem-like population of Raji lymphoma cells in a dose-dependent manner, and suppressed the expression of c-Myc and Bmi1. Importantly, ß-Asarone abolished doxorubicin-induced enrichment of the stem-like population. In the mechanism study, we revealed that ß-Asarone suppressed not only basal NF-κB activity but also Tumor necrosis factor α (TNF-α) induced NF-κB activity. Moreover, blocking NF-κB signaling inactivation was critical for ß-Asarone induced apoptosis and inhibition of proliferation, but not for the effect on ß-Asarone reduced stem-like population. In fact, ß-Asarone suppressed stem-like population by destabilizing Bmi1 via a proteasome-mediated mechanism. CONCLUSIONS: Our data suggested the application of ß-Asarone to lower the toxic effect of doxorubicin and increase the sensitivity of doxorubicin in clinical treatment. More importantly, our data revealed a novel role of ß-Asarone which could be used to eliminate stem-like population in lymphoma, implying that ß-Asarone might reduce relapse and drug resistance.

Determination of freely dissolved polycyclic aromatic hydrocarbons in human serum using core-shell Fe3O4@polyacrylate magnetic microspheres by exclusive volume effect.

Freely dissolved concentration is an important parameter for evaluating the bioavailability of compounds. Negligible-depletion solid-phase microextraction (nd-SPME) has been widely used for the determination of freely dissolved compounds but suffered from long equilibrium time. Multifunctional mesoporous composite microspheres have large specific surface area and therefore extraction equilibrium could be reached in a short time. In this study, a novel method was developed for quick determination of freely dissolved polycyclic aromatic hydrocarbons (PAHs) in human serum using core-shell polyacrylate-ferriferous oxide magnetic microspheres (Fe3O4@PA). Mass transfer of PAHs from sample solution to Fe3O4@PA was greatly increased owing to unique properties including large surface area (58.5 m2 g-1), high pore volume (0.10 cm3 g-1) and thin coating layer (50 nm). Freely dissolved PAHs can be selectively extracted because of the mesoporous structure of PA coating layer with uniform pore size of 7.08 nm. However, bound forms of PAHs would not be able to access into pore channels due to size exclusion. In comparison with long equilibration time (139 h) by nd-SPME, equilibrium can be reached within 29 min (t90%) using Fe3O4@PA as novel sorbents. The sorption coefficients (log KBSA) of PAHs to bull serum albumin (BSA) ranged from 3.36 to 4.87, which are consistent with the values measured by nd-SPME (log KBSA = 3.64-5.12). Finally, the freely dissolved PAHs (Cfree) measured by the proposed method (0.69-1.92 µg L-1) have a good agreement with that by nd-SPME (0.56-2.11 µg L-1), indicating that it is feasible for rapid determination of free forms of compounds in real samples by Fe3O4@PA.