ABHD12 contributes to tumorigenesis and sorafenib resistance by preventing ferroptosis in hepatocellular carcinoma.

Sorafenib induces ferroptosis, making it a useful treatment against advanced liver hepatocellular carcinoma (LIHC). However, sorafenib resistance is extremely common among LIHC patients. Here, we used a comprehensive approach to investigate the effects of ABHD12, which regulates tumorigenesis and sorafenib resistance in LIHC. We validated ABHD12 expression was upregulated in LIHC tissue, which correlated with worse overall survival and related to tumor size or stage. ABHD12 facilitated a pro-tumorigenic phenotype involving increased cell proliferation, migration, and clonogenicity as well as sorafenib resistance. Knockout of ABHD12 sensitized liver cancer cells to sorafenib-induced ferroptosis. Co-delivery of sorafenib and ABHD12 inhibitor into a nude mouse model enhanced therapeutic efficacy for LIHC. Our study demonstrates that ABHD12 contributes to tumor growth and sorafenib resistance in liver cancer, which indicate the promising potential of ABHD12 in diagnosis and prognosis as well as highlight the potential therapeutic applications for co-delivery of sorafenib and ABHD12 inhibitor.

Effects of prenatal single and mixed bisphenol exposure on bone mineral density in preschool children: A population-based prospective cohort study.

Exposure to bisphenols can affect bone mineral density (BMD) in animals and humans. However, the effects of maternal exposure to bisphenols during pregnancy on bone health in preschool children remain unknown. We aimed to assess the effects of prenatal exposure to single and multiple bisphenols on bone health in preschool children. A total of 230 mother-child pairs were included in this study. Generalized linear regression, restricted cubic spline (RCS), principal component analysis (PCA), and Bayesian kernel machine regression (BKMR) were utilized to assess the relationship between bisphenol levels and bone health in preschool children. Each natural log (Ln) unit increase in tetrabromobisphenol A was related to a 0.007 m/s (95 % CI: -0.015, 0.000) decrease in Ln-transformed speed of sound (SOS) among girls. Decreased BMD Z scores in preschool children were found only in the high bisphenol S exposure group (ß = -0.568; 95 % CI: -1.087, -0.050) in boys. The risk of low BMD (BMDL) was significantly higher in the middle-exposure group (OR = 4.695; 95 % CI: 1.143, 24.381) and high-exposure group of BPS (OR = 6.165, 95 % CI: 1.445, 33.789) compared with the low-exposure group in boys. In girls, the risk of BMDL decreased with increasing bisphenol A concentration (OR = 0.413, 95 % CI: 0.215, 0.721). RCS analysis revealed a U-shaped nonlinear correlation between BPB concentration and BMDL in girls (P-overall = 0.011, P-nonlinear = 0.009). In PCA, a U-shaped dose-response relationship was found between PC2 and the risk of BMDL (P-overall = 0.048, P-nonlinear = 0.032), and a significant association was only noted in girls when stratified by sex. The BKMR model revealed a horizontal S-shaped curve relationship between bisphenol mixtures and BMDL in girls. The results indicated that prenatal exposure to single and mixed bisphenols can affect BMD in preschool children, exerting nonmonotonic and child sex-specific effects.

Which one is better for refractory/relapsed acute B-cell lymphoblastic leukemia: Single-target (CD19) or dual-target (tandem or sequential CD19/CD22) CAR T-cell therapy?

CD19 chimeric antigen receptor (CAR) T-cell therapy has shown great success against B-cell acute lymphoblastic leukemia (B-ALL). Tandem and sequential CD19/CD22 dual-target CAR T-cell therapies have been developed to reduce the possibility of CD19-negative relapse; however, the superior strategy is still uncertain. This study screened 219 patients with relapsed/refractory B-ALL who were enrolled in clinical trials of either CD19 (NCT03919240) or CD19/CD22 CAR T-cell therapy (NCT03614858). The complete remission (CR) rates in the single CD19, tandem CD19/CD22, and sequential CD19/CD22 groups were 83.0% (122/147), 98.0% (50/51), and 95.2% (20/21), respectively (single CD19 vs. tandem CD19/CD22, P = 0.006). Patients with high-risk factors achieved a higher rate of CR in the tandem CD19/CD22 group than in the single CD19 group (100.0% vs. 82.4%, P = 0.017). Tandem CD19/CD22 CAR T-cell therapy was one of the significant favorable factors in the multivariate analysis of the CR rate. The incidence of adverse events was similar among the three groups. Multivariable analysis in CR patients showed that a low frequency of relapse, a low tumor burden, minimal residual disease-negative CR and bridging to transplantation were independently associated with better leukemia-free survival. Our findings suggested that tandem CD19/CD22 CAR T-cell therapy obtains a better response than CD19 CAR T-cell therapy and a similar response to sequential CD19/CD22 CAR T-cell therapy.

Autophagy-Related Gene WD Repeat Domain 45B Promotes Tumor Proliferation and Migration of Hepatocellular Carcinoma through the Akt/mTOR Signaling Pathway.

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor. It has been found that autophagy plays a role both as a tumor promoter and inhibitor in HCC carcinogenesis. However, the mechanism behind is still unveiled. This study aims to explore the functions and mechanism of the key autophagy-related proteins, to shed light on novel clinical diagnoses and treatment targets of HCC. Bioinformation analyses were performed by using data from public databases including TCGA, ICGC, and UCSC Xena. The upregulated autophagy-related gene WDR45B was identified and validated in human liver cell line LO2, human HCC cell line HepG2 and Huh-7. Immunohistochemical assay (IHC) was also performed on formalin-fixed paraffin-embedded (FFPE) tissues of 56 HCC patients from our pathology archives. By using qRT-PCR and Western blots we found that high expression of WDR45B influenced the Akt/mTOR signaling pathway. Autophagy marker LC3- II/LC3-I was downregulated, and p62/SQSTM1 was upregulated after knockdown of WDR45B. The effects of WDR45B knockdown on autophagy and Akt/mTOR signaling pathways can be reversed by the autophagy inducer rapamycin. Moreover, proliferation and migration of HCC can be inhibited after the knockdown of WDR45B through the CCK8 assay, wound-healing assay and Transwell cell migration and invasion assay. Therefore, WDR45B may become a novel biomarker for HCC prognosis assessment and potential target for molecular therapy.

Pathologic Characteristics of Digestive Tract and Liver in Patients with Coronavirus Disease 2019.

With the high prevalence of coronavirus disease-2019 (COVID-19), there has been increasing understanding of the pathologic changes associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review summarizes the pathologic changes in the digestive system and liver associated with COVID-19, including the injuries induced by SARS-CoV2 infection of GI epithelial cells and the systemic immune responses. The common digestive manifestations associated with COVID-19 include anorexia, nausea, vomiting, and diarrhea; the clearance of the viruses in COVID-19 patients with digestive symptoms is usually delayed. COVID-19-associated gastrointestinal histopathology is characterized by mucosal damage and lymphocytic infiltration. The most common hepatic changes are steatosis, mild lobular and portal inflammation, congestion/sinusoidal dilatation, lobular necrosis, and cholestasis.

Associations between neonicotinoids metabolites and hematologic parameters among US adults in NHANES 2015-2016.

Hematologic parameters are important indicators for monitoring the physiological changes and human health. Neonicotinoids (NEOs) exhibit toxic effects and can affect hematologic parameters. However, the effects of exposure to NEOs metabolites on hematologic parameters in the general population remain unknown. We examined the relationship between NEOs metabolites and hematologic parameters using a cross-sectional study design in 1397 adults of the National Health and Nutrition Examination Survey (NHANES) 2015-2016. The levels of NEOs metabolites in urine and hematologic makers were measured. Multivariate linear regression models were performed to examine the relationship between exposure to NEOs metabolites and hematologic parameters. Detectable urine levels of clothianidin (CLO) was inversely associated with hematocrit (ß = - 0.689; 95% CI: - 1.335, - 0.042). Detectability of 5-hydroxy-imidacloprid (HIMI) was inversely correlated with basophil percentage (ß = - 0.093; 95% CI: - 0.180, - 0.007). N-Desmethyl-acetamiprid (NDE) was related to reduced white blood cells (WBC) (ß = - 0.419; 95% CI: - 0.764, - 0.074) and neutrophil counts (ß = - 0.349; 95% CI: - 0.623, - 0.074). Imidacloprid-equivalent total neonicotinoids (IMIeq) was negatively related to red blood cells (RBC) (ß = - 0.058; 95% CI: - 0.097, - 0.020), hemoglobin (ß = - 0.149; 95% CI: - 0.282, - 0.015), and hematocrit (ß = - 0.484; 95% CI: - 0.855, - 0.113). We also observed that exposure to NEOs metabolites was sex specifically related to hematologic alterations. For example, IMIeq was associated with reduced basophil counts (ß = - 0.016; 95% CI: - 0.028, - 0.003), basophil percentage (ß = - 0.092; 95% CI: - 0.169, - 0.016), RBC (ß = - 0.097; 95% CI: - 0.156, - 0.038), hemoglobin (ß = - 0.200; 95% CI: - 0.355, - 0.045), and hematocrit (ß = - 0.605; 95% CI: - 1.111, - 0.098) only in males. These results provide the first evidence that exposure to NEOs metabolites can disturb hematologic homeostasis in the general population, and the effects may be sex specific.

Effects of prenatal exposure to bisphenols on newborn leucocyte telomere length: a prospective birth cohort study in China.

Telomere length (TL) at birth is related to diseases that may arise in the future and long-term health. Bisphenols exhibit toxic effects and can cross the placenta barrier. However, the effects of prenatal exposure to bisphenols on newborn TL remain unknown. We aimed to explore the effects of prenatal exposure to bisphenols (i.e., bisphenol A [BPA], bisphenol B [BPB], bisphenol F [BPF], bisphenol S [BPS] and tetrabromobisphenol A [TBBPA]) on relative TL in newborns. A total of 801 mother-infant pairs were extracted from the Guangxi Zhuang Birth Cohort. The relationship between bisphenol levels in maternal serum and relative TL in cord blood was examined by generalized linear models and restricted cubic spline (RCS) models. After adjusting for confounders, we observed a 3.19% (95% CI: -6.08%, -0.21%; P = 0.037) reduction in relative cord blood TL among mothers ≥ 28 years old, with each onefold increase in BPS. However, in each onefold increase of TBBPA, we observed a 3.31% (95% CI: 0.67%, 6.01%; P = 0.014) increase in relative cord blood TL among mothers < 28 years old. The adjusted RCS models revealed similar results (P overall < 0.05, P non-linear > 0.05). This study was the first to establish a positive association between serum TBBPA levels and relative TL in newborns born to young mothers. However, BPS levels were inversely correlated with TL in fetus born to old mothers. The results suggested that the fetus of old pregnant women may be more sensitive to BPS exposure. Moreover, BPS exposure early in life may accelerate aging or increase the risk of developing BPS-related diseases in later life.

[Expression of Th17 and IL-23 in Peripheral Blood and Their Relationship with Immunophenotype in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To observe the expression of helper T cells 17(Th17), interleukin 23 (IL-23) in peripheral blood in patients with acute myeloid leukemia (AML), to analyze the relationship between Th17, IL-23 in peripheral blood and immunophenotype. METHODS: 105 patients with AML in the hospital from January 2019 to January 2021 were prospectively selected as the research subjects, the expression of Th17 and IL-23 in peripheral blood of patients with AML was detected by flow cytometry; immunophenotype was detected and counted. The relationship between the expression of Th17, IL-23 in peripheral blood and immunophenotype of AML patients was analyzed. Draw ROC curve and analyze the predictive value of Th17 and IL-23 expression in peripheral blood to immunophenotype. RESULTS: The immunophenotype results of AML patients showed that myeloid antigen, lymphoid antigen and hematopoietic stem/progenitor cell marker antigen were positive expressed for various antigens in 105 AML patients, in myeloid antigens, CD13+ accounted for the highest proportion (93.33%), in lymphoid antigens, CD56+ accounted for the highest proportion (32.38%), and in hematopoietic stem/progenitor cell marker antigens, CD38+ accounted for the highest proportion (68.57%). The expression of Th17 in peripheral blood of AML patients with CD56+, CD7+, CD34+ and human leukocyte antigen DR+(HLA-DR+) were higher than that of AML patients with CD56-, CD7-, CD34-, HLA-DR-, the expression of IL-23 in peripheral blood of AML patients with CD56+, CD34+ and HLA-DR+ were higher than that of AML patients with CD56-, CD34-, HLA-DR-, the differences were statistically significant (P<0.05); compared the expression of Th17 and IL-23 in peripheral blood between other antibody positive and negative patients, there was no statistical significant difference (P>0.05). Logistic regression analysis showed that the high expression of Th17 in patients with AML was related to the positive expression of CD56, CD7, CD34 and HLA-DR in the detection of immunophenotype, the high expression of IL-23 was related to the positive expression of CD56, CD34 and HLA-DR in the detection of immunophenotype. The ROC curve showed that the AUC of expression levels of Th17 and IL-23 in peripheral blood alone and in combination for predicting CD56+, CD34+, HLA-DR+ and Th17 in peripheral blood for predicting CD7+ were mostly 0.5-0.7, which had certain predictive value, but the predictive performance was low. CONCLUSION: Myeloid antigen, lymphoid antigen and hematopoietic hematopoietic stem/progenitor cell marker antigen are positive expressed for various antigens in AML patients, the high expression of Th17 in peripheral blood of AML patients is related to the positive expression of CD56, CD7, CD34 and HLA-DR in detection of immunophenotyping, the high expression of IL-23 is related to the positive expression of CD56, CD34 and HLA-DR in the detection of immunophenotype.

The Pyroptosis-Related Gene Prognostic Index Associated with Tumor Immune Infiltration for Pancreatic Cancer.

Pancreatic cancer (PC) is one of the most fatal malignancies. Pyroptosis, a type of inflammatory cell death, likely plays a critical role in the development and progression of tumors. However, the relationship between pyroptosis-related genes (PRGs) and prognosis and immunity to PC is not entirely clear. This study, aimed at identifying the key PRGs in PC, highlights their prognostic value, immune characteristics, and candidate drugs for therapies. We screened 47 differentially expressed PRGs between PC and normal pancreas tissues from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Afterwards, a pyroptosis-related gene prognostic index (PRGPI) was constructed based on eight PRGs (AIM2, GBP1, HMGB1, IL18, IRF6, NEK7, NLRP1 and PLCG1) selected by univariate and multivariate Cox regression analysis and LASSO regression analysis, and verified in two external datasets from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) databases. We found that the PC patients in the PRGPI-defined subgroups not only reflected significantly different levels of infiltration in a variety of immune cells, such as M1 macrophages, but also showed differential expression in genes of the human leukocyte antigen (HLA) family and immune checkpoints. Additionally, molecular characteristics and drug sensitivity also stayed close to the PRGPI risk scores. Therefore, PRGPI may serve as a valuable prognostic biomarker and may potentially provide guidance toward novel therapeutic options for PC patients.

Decrease of CD38 expression is linked to increase of solitary plasmacytoma pathological grade: a single institution experience from China.

INTRODUCTION: Solitary plasmacytoma (SP) is a rare plasma cell disorder characterized by localized neoplastic proliferation of monoclonal plasma cell. Due to its rarity, further understanding of the spectrum of its clinicopathologic features is needed. METHODS: A retrospective analysis of cases from a single institution was conducted. Clinical characteristics of the patients were collected; histopathological and semi-quantitative immunohistochemical analyses were performed. RESULTS: Thirteen cases were identified from our pathology archives, including 4 cases of solitary plasmacytoma of bone (SPB) (30.8%) and 9 extraosseous plasmacytoma (EP) (69.2%). The mean age of EP is a decade older than SPB. There is no gender disparity. The most common sites involved are the vertebrae and nasopharynx. Histologically, the tumors can be classified into two grades based on degree of differentiation. Immunohistochemically the tumor cells express CD38, CD138, MUM-1, and exhibit light chain restriction. Ki-67 proliferation index is 30%. In situ hybridization for Epstein-Barr virus-encoded small RNAs (EBER) is negative in six cases tested. Semi-quantitative immunohistochemical analysis showed decreased integrated optical density (IOD) of CD38 in neoplastic cells. IgH gene rearrangement was identified in two cases. CONCLUSION: SP is a rare plasmacytoid neoplasm that occurs more frequently in older patients. Diagnosis requires a systematic clinical approach combined with the pathological characteristics of plasmacytoid morphology, immunophenotype and light chain restriction. There are more cases of EP than SPB in our series, which is in contrast to that reported in literature. Results from this study suggest that CD38 is a potential immunohistochemical marker associated with prognosis of SP. Further studies with more cases and longer term follow-up may provide more definitive information on risk of progression from SP to multiple myeloma (MM).

Single and mixed effects of prenatal exposure to multiple bisphenols on hemoglobin levels and the risk of anemia in pregnant women.

INTRODUCTION: Bisphenols have endocrine-disrupting effects, which may disrupt hemoglobin (Hb) homeostasis and lead to anemia. However, the effects of bisphenols on anemia remain unknown. Therefore, we assessed the effects of single- and multiple-exposure to bisphenols on Hb levels and anemia of pregnant women. METHODS: The study involved 2035 pregnant women from Guangxi Zhuang Birth Cohort in China. Generalized linear regression, principal component analysis (PCA), quantile g-computation (Qgcomp), and Bayesian kernel machine regression (BKMR) were performed to examine the effects of serum bisphenols on Hb levels and the risk of anemia. RESULTS: After adjustment, elevated bisphenol A (BPA) levels were correlated with decreased Hb concentrations (ß = -0.51; 95%CI: -0.92, -0.10) in the first trimester, and these correlations were more sensitive in mothers of males. Compared with the low-exposure group, bisphenol B (BPB) levels in the high-exposure group led to a 1.52 g/L (95%CI: -3.01, -0.03) decrease in Hb levels in the second trimester; tetrabromobisphenol A (TBBPA) levels in the high-exposure group led to a higher the risk of anemia in the third trimester (OR = 1.46; 95%CI: 1.07, 1.99); bisphenol F (BPF) in the high-exposure group led to lower Hb levels (ß = -2.42; 95%CI:-4.69, -0.14) in mothers of male fetuses in the third trimester. Qgcomp showed that elevated levels of bisphenol mixture was correlated with (ß = -1.42; 95%CI: -2.61, -0.24) decrease in Hb levels in the second trimester. PCA revealed a negative association between PC2 and Hb levels in the first trimester (ß = -0.89; 95%CI: -1.61, -0.17). Similarly, a negative relationship was observed between PC1 and Hb levels in the third trimester among mothers with male fetuses (ß = -1.00; 95%CI: -1.94, -0.06). CONCLUSIONS: Prenatal exposure to single and mixed bisphenols may decrease Hb levels and increase the risk of anemia during pregnancy, the associations may be greater in mothers with male fetuses than those with female fetuses.

Prenatal exposure to bisphenols and risk of preterm birth: Findings from Guangxi Zhuang birth cohort in China.

Preterm birth (PTB), a serious adverse birth outcome, is the leading cause of perinatal mortality and morbidity. Bisphenols induce endocrine disruption that spreads across the placenta, which may affect fetal growth and development. However, the effects of bisphenols on PTB, particularly their combined effects, remain unknown. This study investigated the association between prenatal bisphenol exposure and PTB. Study participants were 2023 mother-infant pairs that were selected from the Guangxi Zhuang Birth Cohort. Maternal serum bisphenol levels were measured using ultrahigh performance liquid chromatography-tandem mass spectrometry, and pregnancy outcomes were obtained from medical records. Multivariate logistic regression, restricted cubic spline, principal component analysis (PCA), quantile g-computation (Qgcomp), and Bayesian kernel machine regression (BKMR) were used to examine the association between serum bisphenol levels and PTB. Ln-transformed BPA concentrations were associated with an increased risk of PTB only in female infants (OR = 1.30, 95% CI: 1.02, 1.64). Ln-transformed bisphenol F (BPF) concentrations were positively associated with the risk of PTB (OR = 1.73, 95% CI: 1.18, 2.55). Inverse U-shaped relationships were observed between bisphenol B (BPB), bisphenol S (BPS), and tetrabromobisphenol A (TBBPA) levels and the risk of PTB (P-overall < 0.05, P-non-linear < 0.05). After sex stratification, the association between BPA analogs and PTB was only observed in males. In Qgcomp analysis, bisphenol mixtures were related to an increased risk of PTB (OR = 1.52, 95% CI: 1.04, 2.21), with BPF (43.7%), BPS (29.6%) and BPA (26.8%) having the greatest positive contribution. Results indicate that prenatal exposure to bisphenol mixtures might increase the risk of PTB, which might be primarily driven by BPA, BPF and BPS. There may also be sex-specific and nonmonotonic dose-dependent effects.

Prognostic Value of Immune-Related Multi-IncRNA Signatures Associated With Tumor Microenvironment in Esophageal Cancer.

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide. Hence, for a better understanding of tumor microenvironment and to seek for novel molecular targets for esophageal cancer, we performed related studies on two histopathological subtypes of esophageal cancer: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Bioinformatic analyses were conducted based on the RNA-seq, genomic mutation, and clinical data from TCGA and GEO cohorts. We clustered patients into high-immunity and low-immunity groups through the ssGSEA results. The ESTIMATE algorithm was used to evaluate the tumor microenvironment. Patients with high immunity in both ESCC and EAC had lower tumor purity and poor survival. Subsequently, CIBERSORT was performed to learn about the detailed difference of tumor-infiltrating lymphocytes (TILs) between high- and low-immunity patients. Specific increase of M2 macrophages and decrease of activated dendric cells can be observed in ESCC and EAC, respectively. The most enriched functions and pathways of high-immunity patients were immunoglobulin complex, MHC class II protein complex, and allograft rejection according to the GO terms and KEGG. Two prognostic immune-related multi-lncRNA risk models were constructed and validated by ROC curve and PCA in ESCC and EAC. High-risk patients in both subtypes had poor survival, advanced clinical characteristics, and higher drug susceptibility except cisplatin and sorafenib. In addition, the tumor mutation burden (TMB) was positively correlated with the risk level in the ESCC and EAC and showed distinct differences between the two subtypes. In summary, we comprehensively analyzed the tumor microenvironment for two subtypes of esophageal cancer, identified two multi-lncRNA signatures predictive for the prognosis, and explored the possibility of the signatures to forecast drug susceptibility as well as TMB for the first time. The findings may serve as a conceptual basis for innovative strategy of individualized immunotherapy for esophageal cancer.

Quenching effects of (-)-Epigallocatechin gallate for singlet oxygen production and its protection against oxidative damage induced by Ce6-mediated photodynamic therapy in vitro.

BACKGROUND: Singlet oxygen (1O2) is highly reactive to biological components such as lipids, proteins and DNA, which induces oxidative damage to cells and tissues. Natural antioxidants may function as 1O2 quencher to prevent 1O2 involved photosensitized oxidation in biological system. METHODS: Time-resolved measurement of 1O2 luminescence was employed to evaluate the 1O2 quenching abilities of natural antioxidants in air-statured phosphate buffered saline (PBS), including (-)-Epigallocatechin gallate (EGCG), Proanthocyanidins, L-carnosine and Vitamin C. The 1O2 quenching effects and rate constant of EGCG were investigated by detecting the absorption, fluorescence and 1H-NMR spectroscopy and 1O2 luminescence decay curves, respectively. In addition, the protective activity of EGCG against 1O2 oxidative damage caused by Ce6-mediated photodynamic therapy (PDT) was verified in cells. RESULTS: EGCG, proanthocyanidins, L-carnosine and Vitamin C efficiently quenched 1O2 luminescence at 1270 nm. The triplet-state quenching rate constants of EGCG for Rose Bengal (RB), Chlorin e6, AlPcS and HiPorfin are 2.21 × 109, 4.90 × 108, 3.30 × 108, 1.78 × 109 M-1s-1, while the 1O2 quenching rate constants are 2.80 × 108, 1.50 × 108, 1.30 × 108, 1.70 × 108 M-1s-1, respectively. Furthermore, EGCG could effectively quench 1O2 production to prevent NIH/3T3 cells oxidative damage induced by Ce6-mediated PDT. CONCLUSIONS: EGCG is an efficient quencher for both triplet-state photosensitizers and 1O2. The quenching ability of EGCG during photosensitization for selected photosensitizers is: RB > HiPorfin > Ce6 > AlPcS. EGCG could be used to protect normal cells and tissue against oxidative damage.

LRRK2 is a candidate prognostic biomarker for clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC), derived from renal tubular epithelial cells, is the most common malignant tumor of the kidney. The study of key genes related to the pathogenesis of ccRCC has become important for gene target therapy. METHODS: Bioinformatics analysis of The Cancer Genome Atlas (TCGA), the NCBI Gene Expression Omnibus (GEO) database, USUC Xena database, cBioPortal for Cancer Genomics, and MethSurv were performed to examine the aberrant genetic pattern and prognostic significance of leucine-rich repeat kinase 2 (LRRK2) expression and its relationship to clinical parameters. Immunohistochemistry and Western blot were performed to verify LRRK2 expression. The regulation of ccRCC tumor cell lines proliferation by LRRK2 was examined by CCK8 assay. RESULTS: Bioinformatics analysis showed that LRRK2 expression was up-regulated and largely correlated with DNA methylation in ccRCC. The up-regulation of LRRK2 was confirmed in ccRCC tissue immunohistochemically and by protein analysis. The level of expression was related to gender, pathological grade, stage, and metastatic status of ccRCC patients. Meanwhile, Kaplan-Meier analysis showed that high expression of LRRK2 correlates to a better prognosis; knockdown of LRRK2 expression attenuated the proliferation ability of ccRCC tumor cell lines; protein-protein interaction network analysis showed that LRRK2 interacts with HIF1A and EGFR. CONCLUSION: We found that LRRK2 may play an important role in the tumorigenesis and progression of ccRCC. Our findings provided a potential predictor and therapeutic target in ccRCC.

COVID-19 and inflammatory bowel disease: A pathophysiological assessment.

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has led to the ongoing global pandemic. Although most patients experience no or only mild symptoms, some patients can develop severe illness, such as progressive pneumonia, acute respiratory distress syndrome, secondary hemophagocytic lymphohistiocytosis and multiple organ failure caused by cytokine release syndrome. A majority of COVID-19 patients also develop gastrointestinal symptoms. These can present special challenges to the management of patients with inflammatory bowel disease (IBD) due to potential interactions between the immune response related to SARS-CoV-2 infection and dysregulated immunity associated with IBD. In this context, the pathogenesis of COVID-19 is reviewed in order to address these questions regarding immune interactions between COVID-19 and IBD.

[CpG ODN synergistically promotes proliferation and migration of mouse RAW264.7 macrophages induced by lipopolysaccharide].

Objective To investigate the effects of CpG oligodeoxynucleotide (CpG ODN) on the proliferation and migration of macrophages induced by lipopolysaccharide (LPS) and its mechanism. Methods In vitro inflammatory cell model was established by 1 mg/L LPS added into the culture medium of mouse RAW264.7 macrophages. CCK-8 assay was performed to assess the effect of CpG ODN (500 nmol/L) on the proliferation of macrophages induced by LPS; TranswellTM assay was used to measure the effect of CpG ODN (500 nmol/L) on the migration of macrophages induced by LPS. Western blot analysis was performed to detect the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK), c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases (ERK) and nuclear factor kappa-B subunits 65 (NF-κBp65). The specific inhibitors for p38MAPK (SB203580), JNK (SP600125), ERK (PD98059) and NF-κBp65 (BAY11-7082) were used to further explore the possible mechanism underlying the effects of CpG ODN. Real-time PCR was used to detect the role of CpG ODN in LPS-induced transcription of COX2 and MCP-1 in macrophages. Results CpG ODN synergistically enhanced the proliferation and migration of LPS-stimulated macrophages and promoted the transcription of COX2 and MCP-1. It also selectively enhanced the phosphorylation of JNK and ERK proteins in MAPK signaling pathway. To blockage JNK and ERK signaling pathways with its specific inhibitors dramatically inhibited the effects of CpG ODN. Conclusion CpG ODN can synergistically promote the proliferation and migration of LPS-stimulated macrophages through JNK and ERK pathway as well as the transcription of COX2 and MCP-1.

CpG-Oligodeoxynucleotides Alleviate Tert-Butyl Hydroperoxide-Induced Macrophage Apoptosis by Regulating Mitochondrial Function and Suppressing ROS Production.

Oxidative stress and mitochondrial dysfunction are related to disease pathogenesis. Oligodeoxynucleotide containing CpG motifs (CpG ODN) demonstrate possibilities for immunotherapy applications. The aim of the present work is to explore the underlying mechanism of the cytoprotective function of CpG ODN by employing the oxidative stress modulation in immune cells. We used the imaging flow cytometry to demonstrate that tert-butyl hydroperoxide (t-BHP) induces mitochondrial-mediated apoptosis and ROS production in RAW264.7 cells. After pretreatment with CpG ODN, the percentage of apoptotic cells and ROS production was both markedly reduced. The decrease in mitochondrial membrane potential (MMP) induced by t-BHP was partially reversed by CpG ODN. The t-BHP induced upregulation of the expression of apoptosis-related proteins (cleaved-caspase 3, cleaved-caspase 9, cleaved-PARP, and bax) was notably decreased in the presence of CpG ODN. Furthermore, we found that CpG ODN enhanced phosphorylation of ERK1/2 and Akt to inhibit ROS production. In conclusion, the protective effect of CpG ODN in mitigation of t-BHP-induced apoptosis is dependent on the reduction of ROS.