Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy.

Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of diabetic nephropathy (DN), and it is often accompanied by an increase in reactive oxygen species (ROS) production. However, the precise relationship between NFE2-related factor-2 (Nrf2), a key regulator of ROS balance, and ERS in DN remains elusive. This study aimed to investigate the impact of Nrf2 on ERS and its therapeutic potential in DN. Herein, ERS-related changes, including increased activating transcription factor-6 (ATF6), glucose-regulated protein 78 (GRP78), and transcription factor C/EBP homologous protein (CHOP) expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose cultured human renal proximal tubular (HK-2) cells. Nrf2 knockdown increased the sensitivity of HK-2 cells to ERS under high glucose conditions, underscoring the regulatory role of Nrf2 in ERS modulation. Notably, upregulating Nrf2 in ezetimibe-treated diabetic mice restored ERS markers and ameliorated albuminuria, glomerular hypertrophy, mesangial expansion, and tubulointerstitial fibrosis. Furthermore, the inhibition of ERS in HK-2 cells by the ROS scavenger, N-acetylcysteine, highlights the interplay between ROS and ERS. This study, for the first time, elucidates that the upregulation of Nrf2 may alleviate the negative influence of ROS-mediated ERS, presenting a promising therapeutic avenue for delaying the progression of DN. These findings suggest a potential strategy for targeting Nrf2 and ERS in developing novel therapeutic interventions for DN.

HDAC1 inhibits beige adipocyte-mediated thermogenesis through histone crotonylation of Pgc1a/Ucp1.

Obesity, one of the most serious public health issues, is caused by the imbalance of energy intake and energy expenditure. Increasing energy expenditure via induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Although histone modifications have been confirmed to regulate cellular energy metabolism, the involved biochemical mechanism of thermogenesis in adipose tissue is not completely understood. Herein, we report that class I histone deacetylases (HDAC) inhibitor MS275 increased PGC1α/UCP1 protein levels in inguinal white adipose tissue (iWAT) concomitant with elevated energy expenditure, reduced obesity and ameliorated glucose tolerance compared to control littermates. H3K18cr and H3K18ac levels were elevated after MS275 treatment. MS275 also promoted the transcription of Pgc1α and Ucp1 by enhancing the enrichment of H3K18cr and H3K18ac in the Pgc1α/Ucp1 enhancer and promoter, with a notable increase in H3K18cr. Mechanistically, the deletion of Hdac1 in beige adipocyte increases H3K18cr levels in enhancers and promoters of Pgc1α and Ucp1 genes, regulated the chromosomal state, thereby affecting the transcription of Pgc1α/Ucp1. Taken together, HDAC1 inhibits beige adipocyte-mediated thermogenesis through histone crotonylation of Pgc1a/Ucp1. This finding may provide a therapeutic strategy through increasing energy expenditure in obesity and related metabolic disorders.

Exploration of spatial heterogeneity of tumor microenvironment in nasopharyngeal carcinoma via transcriptional digital spatial profiling.

The heterogeneity of nasopharyngeal carcinoma (NPC) leads to mixed clinical outcomes. We collected 92 regions of interest from 41 biopsies of patients with untreated NPC and obtained their transcripts using GeoMx Digital Spatial Profiling (DSP) technology. Spatial heterogeneity was determined by measuring the expression of marker genes in tumor cell-enriched (PanCK-expressing), immune cell-enriched (CD45-expressing), and normal epithelial (Endo) regions. We screened 16 prognostic markers in tumor cell-enriched regions and 4 prognostic markers in immune cell-enriched regions. The levels of CD8+ T follicular helper T cells, activated NK cells, and M0 macrophage contents were higher in tumor cell-enriched regions than in immune cell-enriched regions. Conversely, plasma cell and M2 macrophage levels were lower. The follicular helper T cells in tumor cell-enriched regions were negatively correlated with resting NK cells and positively correlated with activated NK cells. In immune cell-enriched regions, this relationship was reversed. We also explored the heterogeneity of HLA gene families, immune checkpoints, and metabolism-related genes in the three regions. In tumor cell-enriched regions, we obtained 19 prognosis-related metabolism genes via univariate cox analysis. We used multiplex immunofluorescence to verify the elevated expression of SLC8A1 and MDH1 in immune cell-enriched regions and tumor cell-enriched regions, respectively, both of which were associated with prognosis of NPC. In conclusion, we explored the spatial heterogeneity of the NPC tumor environment and found specific diagnostic and prognostic markers that can be used to differentiate tumor cell-enriched regions from immune cell-enriched regions in NPC.

Predictive value of circulating tumor cell counts during the treatment of cancer: interactions with the blood microenvironment.

OBJECTIVE: This study aimed to evaluate the prognostic value of circulating tumor cell (CTC) in tumor patients during treatment. METHODS: This study retrospectively analyzed clinical data obtained from 174 cancer patients during treatment. The relationship between the CTC counts and clinicopathological variables was analyzed. A ROC curve was applied to determine the optimal cut-off values and assess the predictive ability of the prognostic indicators. The overall survival (OS) for different prognostic factors was calculated using the Kaplan-Meier method, and the difference between the survival curves was then compared using the log-rank test. Cox regression model was used to investigate the effect of independent factors on patients' survival. RESULTS: The CTC-positive rate was positively correlated with the clinicopathological variables of TNM stage, tumor differentiation, serum CEA level, and ki-67%. In the differential analysis of hematological microenvironment parameters in CTC-positive and CTC-negative samples, the complete blood count, blood biological chemistry, tumor markers (CEA, CA19-9, CA72-4), and lymphocyte subpopulation were statistically significant. The results of the ROC curve analysis indicated that the serum CEA level was the best diagnostic indicator to discriminate the CTC count in tumor patients. Additionally, the results of the univariate and multivariate analyses of OS in relation to clinical variables revealed that the CTC counts were an independent prognostic factor for unfavorable OS. CONCLUSION: The CTC counts in patients with tumors undergoing treatment were significantly correlated with hematological microenvironment parameters. The detection of CTCs may therefore be used as an indicator of tumor prognosis.

The third inactivated vaccine booster dramatically enhanced SARS-CoV-2 antibody responses and did not influence the profile of prothrombotic antibody.

The purpose of this study is to investigate the production of both severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific antibodies and autoantibodies in serum following the third booster vaccination of the inactivated COVID-19 vaccine, and to study the effect of B cell subsets with CD27 and CD38 phenotypes in peripheral blood on antibody production. Routine blood indexes, SARS-CoV-2 antibodies, platelet factor 4 and seven antiphospholipid antibodies were detected both before and 2 months after vaccination in the medical staff of the Zhongnan Hospital of Wuhan University. Peripheral blood B cell subtypes were detected before vaccination. Following immunization, the positive rate of anti-N-S1 immunoglobulin (IgG) had increased from 24.8% to 91.3% and the average antibody concentration had increased by 11 times. The positive rate of neutralizing antibody had increased from 24.8% to 91.3%, the average antibody concentration had increased by 12 times, and the primary increased anti-S1 IgG subtype was that of IgG1. Peripheral blood CD27 + CD38+ B cells were positively correlated with antibody levels after vaccination and were a predictor of the antibody response. In addition, although some indicators showed slight absolute changes, the blood parameters and antiphospholipid antibodies of most volunteers were normal both before and after COVID-19 inactivated vaccine inoculation, and there was no statistical difference in abnormal rates either before or after inoculation. Antibodies in vivo were increased after vaccination with the inactivated vaccine, and IgG1 was the main subtype involved in response to the vaccine. Vaccination with the inactivated COVID-19 vaccine did not appear to affect thrombus-related autoantibodies.

Cuproptosis related genes associated with Jab1 shapes tumor microenvironment and pharmacological profile in nasopharyngeal carcinoma.

Background: Nasopharyngeal carcinoma (NPC) is the most common subcategory of head and neck squamous cell carcinoma (HNSCC). This study focused on the roles of cuproptosis related genes and Jab1 in the tumor microenvironment of NPC and HNSCC. Methods: Differential expression analysis of Jab1 and cuproptosis related genes in tumor cell enriched region (PanCK-expressing) and immune cell enriched region (CD45-expressing) of NPC microenvironment were performed by packages of R software. Survival analysis was performed using the survival and survminer packages. Corrplot package was used for correlation analysis. ConsensusClusterPlus package was used for cluster clustering among different regions of NPC, and functional enrichment analysis was performed using GSVA, GSEABase, clusterProfiler, org.Hs.eg.db and enrichplot packages. The pRRophetic package was used to predict drug sensitivity in NPC and HNSCC. Results: Relationships exist between cuproptosis related genes and Jab1 in the NPC microenvironment. The expression of cuproptosis related genes and Jab1 differed between tumor cell enriched region and immune cell enriched region. AKT inhibitor VIII, Doxorubicin, Bleomycin and Etoposide showed higher sensitivity to tumor cell than immune cell. In the high Jab1 group, higher expression of ATP7A, DBT, DLD and LIAS were associated with better prognosis of HNSCC patients. In contrast, in the low Jab1 group, higher expression of these genes is associated with worse prognosis of HNSCC patients. Conclusions: Prognostic cuproptosis related genes and Jab1 provided a basis for targeted therapy and drug development.

Pan-cancer analyses of Jab1/COPS5 reveal oncogenic role and clinical outcome in human cancer.

Jab1/COPS5 is associated with the progression of some cancers, however, its role in most cancers is still unclear.This study systematically explored the action and clinical application value of Jab1/COPS5 in different tumors based on large clinical data. We first identified by differential and survival analysis that Jab1/COPS5 was highly expressed as a high-risk gene in most cancers and was closely related to prognostic survival of patients based on the TCGA, GEO and CPTAC databases. Mutation analysis suggested that missense mutations were the main mutation type of Jab1. TMB and MSI were positively correlated with Jab1/COPS5 in most tumors, and patients with Jab1/COPS5 mutations had a poorer prognosis in prostate adenocarcinoma. By immune infiltration analysis, Jab1/COPS5 expression was positively correlated with the infiltration of CD8+ T cells in thymoma and uveal melanoma, and Jab1/COPS5 expression in testicular germ cell tumors was negatively correlated with the infiltration of cancer-associated fibroblasts. Correlation and enrichment analysis suggested that ARMC1, TCEB1 and UBE2V2 were positively correlated with Jab1/COPS5 expression and involved in multiple biological effects. In summary, this study systematically investigated the role of Jab1/COPS5 in different tumors, providing a theoretical basis for Jab1/COPS5 as a new biomarker in unresearched cancers and paving the way for targeted therapy and drug development.

COVID-19 and Cancer: Discovery of Difference in Clinical Immune Indexes.

OBJECTIVE: This study explored the consistency and differences in the immune cells and cytokines between patients with COVID-19 or cancer. We further analyzed the correlations between the acute inflammation and cancer-related immune disorder. METHODS: This retrospective study involved 167 COVID-19 patients and 218 cancer patients. COVID-19 and cancer were each further divided into two subgroups. Quantitative and qualitative variables were measured by one-way ANOVA and chi-square test, respectively. Herein, we carried out a correlation analysis between immune cells and cytokines and used receiver operating characteristic (ROC) curves to discover the optimal diagnostic index. RESULTS: COVID-19 and cancers were associated with lymphopenia and high levels of monocytes, neutrophils, IL-6, and IL-10. IL-2 was the optimal indicator to differentiate the two diseases. Compared with respiratory cancer patients, COVID-19 patients had lower levels of IL-2 and higher levels of CD3+CD4+ T cells and CD19+ B cells. In the subgroup analysis, IL-6 was the optimal differential diagnostic parameter that had the ability to identify if COVID-19 patients would be severely affected, and severe COVID-19 patients had lower levels of lymphocyte subsets (CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+T cells, and CD19+ B cells) and CD16+CD56+ NK cells and higher level of neutrophils. There were significant differences in the levels of CD3+CD4+ T cells and CD19+ B cells between T1-2 and T3-4 stages as well as IL-2 and CD19+ B cells between N0-1 and N2-3 stages while no significant differences between the metastatic and nonmetastatic cancer patients. Additionally, there were higher correlations between IL-2 and IL-4, TNF-α and IL-2, TNF-α and IL-4, TNF-α and IFN-γ, and CD16+CD56+NK cells and various subsets of T cells in COVID-19 patients. There was a higher correlation between CD3+CD4+ T cells and CD19+ B cells in cancer patients. CONCLUSION: Inflammation associated with COVID-19 or cancer had effects on patients' outcomes. Accompanied by changes in immune cells and cytokines, there were consistencies, differences, and satisfactory correlations between patients with COVID-19 and those with cancers.

SARS-CoV-2-specific immune response in COVID-19 convalescent individuals.

We collected blood from coronavirus disease 2019 (COVID-19) convalescent individuals and investigated SARS-CoV-2-specific humoral and cellular immunity in these discharged patients. Follow-up analysis in a cohort of 171 patients at 4-11 months after the onset revealed high levels of IgG antibodies. A total of 78.1% (164/210) of the specimens tested positive for neutralizing antibody (NAb). SARS-CoV-2 antigen peptide pools-stimulated-IL-2 and -IFN-γ response can distinguish COVID-19 convalescent individuals from healthy donors. Interestingly, NAb survival was significantly affected by the antigen peptide pools-stimulated-IL-2 response, -IL-8 response, and -IFN-γ response. The antigen peptide pools-activated CD8+ T cell counts were correlated with NAb. The antigen peptide pools-activated natural killer (NK) cell counts in convalescent individuals were correlated with NAb and disease severity. Our data suggested that the development of NAb is associated with the activation of T cells and NK cells. Our work provides a basis for further analysis of the protective immunity to SARS-CoV-2 and for understanding the pathogenesis of COVID-19. It also has implications for the development of an effective vaccine for SARS-CoV-2 infection.

Analysis of Lymphocyte Subpopulations and Cytokines in COVID-19-Associated Pneumonia and Community-Acquired Pneumonia.

BACKGROUND: The 2019 novel coronavirus SARS-CoV-2 caused large outbreaks of COVID-19 worldwide. COVID-19 resembles community-acquired pneumonia (CAP). Our aim was to identify lymphocyte subpopulations to distinguish between COVID-19 and CAP. METHODS: We compared the peripheral blood lymphocytes and their subsets in 296 patients with COVID-19 and 130 patients with CAP. Parameters for independent prediction of COVID-19 were calculated by logistic regression. RESULTS: The main lymphocyte subpopulations (CD3+CD4+, CD16+CD56+, and CD4+/CD8+ ratio) and cytokines (TNF-α and IFN-γ) of COVID-19 patients were significantly different from that of CAP patients. CD16+CD56+%, CD4+/CD8+ratio, CD19+, and CD3+CD4+ were identified as predictors of COVID-19 diagnosis by logistic regression. In addition, the CD3+CD4+counts, CD3+CD8+ counts, andTNF-α are independent predictors of disease severity in patients. CONCLUSIONS: Lymphopenia is an important part of SARS-CoV-2 infection, and lymphocyte subsets and cytokines may be useful to predict the severity and clinical outcomes of the disease.

Development and validation of immune inflammation-based index for predicting the clinical outcome in patients with nasopharyngeal carcinoma.

Inflammation indicators, such as systemic inflammation response index (SIRI), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), are associated with poor prognosis in various solid cancers. In this study, we investigated the predictive value of these inflammation indicators in nasopharyngeal carcinoma (NPC). This retrospective study involved 559 patients with NPC and 500 patients with chronic rhinitis, and 255 NPC patients were followed up successfully. Continuous variables and qualitative variables were measured by t test and chi-square test, respectively. The optimal cut-off values of various inflammation indicators were determined by receiver operating characteristic (ROC) curve. Moreover, the diagnostic value for NPC was decided by the area under the curves (AUCs). The Kaplan-Meier methods and the log-rank test were used to analyse overall survival (OS) and disease-free survival (DFS). The independent prognostic risk factors for survival and influencing factors of side effects after treatment were analysed by Cox and logistic regression analysis, respectively. Most haematological indexes of NPC and rhinitis were significantly different between the two groups, and PLR was optimal predictive indicators of diagnosis. In the multivariable Cox regression analysis, PLR, WBC, RDW, M stage and age were independent prognostic risk factors. Many inflammation indicators that affected various side effects were evaluated by logistic regression analysis. In conclusion, the combined inflammation indicators were superior to single haematological indicator in the diagnosis and prognosis of NPC. These inflammation indicators can be used to supply the current evaluation system of the TNM staging system to help predict the prognosis in NPC patients.

Can routine laboratory tests discriminate SARS-CoV-2-infected pneumonia from other causes of community-acquired pneumonia?

BACKGROUND: The clinical presentation of SARS-CoV-2-infected pneumonia (COVID-19) resembles that of other etiologies of community-acquired pneumonia (CAP). We aimed to identify clinical laboratory features to distinguish COVID-19 from CAP. METHODS: We compared the hematological and biochemical features of 84 patients with COVID-19 at hospital admission and 221 patients with CAP. Parameters independently predictive of COVID-19 were calculated by multivariate logistic regression. The receiver operating characteristic (ROC) curves were generated and the area under the ROC curve (AUC) was measured to evaluate the discriminative ability. RESULTS: Most hematological and biochemical indexes of patients with COVID-19 were significantly different from patients with CAP. Nine laboratory parameters were identified to be predictive of a diagnosis of COVID-19. The AUCs demonstrated good discriminatory ability for red cell distribution width (RDW) with an AUC of 0.87 and hemoglobin with an AUC of 0.81. Red blood cell, albumin, eosinophil, hematocrit, alkaline phosphatase, and mean platelet volume had fair discriminatory ability. Combinations of any two parameters performed better than did the RDW alone. CONCLUSIONS: Routine laboratory examinations may be helpful for the diagnosis of COVID-19. Application of laboratory tests may help to optimize the use of isolation rooms for patients when they present with unexplained febrile respiratory illnesses.

Prognostic Value of Clinical Biochemistry-Based Indexes in Nasopharyngeal Carcinoma.

Inflammation and nutritional status have significant effects on the prognosis of cancer patients. This study investigated the predictive value of clinical biochemistry-based indexes in nasopharyngeal carcinoma (NPC). This retrospective study included 559 NPC patients and 500 patients with chronic rhinitis. Continuous variables were measured by t-test. The area under curves (AUC) was used to determine the diagnostic and prognostic value for NPC. Kaplan-Meier methods and the log-rank test were used to analyze overall survival (OS) and disease-free survival (DFS) of the patients. Cox and logistic regression analysis were used to analyze the independent prognostic risk factors for survival and influencing factors of side effects after treatment, respectively. The study results revealed that most indexes of NPC and rhinitis were significantly different between the two groups. In the survival analysis, the systemic inflammation score (SIS), prognostic nutritional index (PNI), albumin/globulin ratio (AGR), albumin (ALB), urea nitrogen (BUN) and creatinine (CREA) had significant influence on the OS and DFS. AGR was the optimal prognostic indicator for NPC. Among these indexes, SIS, AGR, BUN and CERA were independent prognostic factors of OS, AGR and PNI were independent prognostic factors of DFS. Most indexes were risk factors of side effects occurred in radiotherapy. In conclusion, the clinical biochemistry-based indexes, are reliable and of low-cost, therefore, they can be used in predicting diagnosis, prognosis and treatment plans of NPC.

Bioinspired red blood cell membrane-encapsulated biomimetic nanoconstructs for synergistic and efficacious chemo-photothermal therapy.

Recently, the fabrication of nanotechnology-based co-delivery systems has garnered enormous interest for efficacious cancer therapy. However, these systems still face certain challenges such as codelivery of drugs with different chemistries, inadequate loading efficiency, immune rejection resulting in rapid clearance and substantially poor bioavailability in vivo. To address the challenges, we have developed a biomimetic and stable design based on bovine serum albumin (BSA) nanoparticles that are encapsulated with a hydrophilic photothermal agent, indocyanine green (ICG), as well as a hydrophobic agent, gambogic acid (GA), via the desolvation method. Furthermore, these nanoconstructs have been coated with the red blood cell membranes (RBCm), which exhibit pronounced long-term circulation in addition to avoiding premature leakage of drugs. RBCm-coated BSA nanoparticles show a higher affinity towards both GA and ICG (RmGIB NPs), resulting in high loading efficiencies of 24.3 ±â€¯1.2 % and 25.0 ±â€¯1.2 %, respectively. Moreover, the bio-efficacy investigations of these biomimetic constructs (RmGIB NPs) in cells in vitro as well as in tumor-bearing mice in vivo confirm augmented inhibition, demonstrating potential synergistic chemo-photothermal therapeutic efficacy. Altogether, we provide an efficient delivery platform for designing and constructing BSA nanovehicles toward synergistic and effective co-delivery of therapeutics.

A novel "on-off-on" fluorescence assay for the discriminative detection of Cu(ii) and l-cysteine based on red-emissive Si-CDs and cellular imaging applications.

Copper ions (Cu2+) and l-cysteine (l-Cys) in the human body always play critical roles in various physiological processes, while abnormal Cu2+ and l-Cys concentrations in the biological system lead to many diseases. In this manuscript, Si-doped carbon dots (Si-CDs) with near-infrared fluorescence were designed for the detection of Cu2+ and l-Cys through the fluorescence "on-off-on" mode. The carbon dots exhibited not only excellent optical merits including good stability against photobleaching and high chemical stability, but also superior biological compatibility. Interestingly, due to the abundant amino groups distributed on the surface of Si-CDs, they could bind to copper ions to form cupric amine complexes and then quench the fluorescence of Si-CDs due to an electron transfer process. In addition, upon the addition of l-Cys, the FL intensity of Si-CDs could be effectively recovered accompanied with complexation between Cu2+ and the functional groups in l-Cys, due to which Cu2+ was removed from the surface of Si-CDs. Notably, as far as we know, these are the first red-emitting carbon dots for copper ion and l-Cys assays in water samples and human plasma samples. Furthermore, this strategy was successfully applied to the determination of Cu2+ and l-Cys in living systems, demonstrating great practicability in biomedical applications.

RNA-Seq analysis of peripheral blood mononuclear cells reveals unique transcriptional signatures associated with radiotherapy response of nasopharyngeal carcinoma and prognosis of head and neck cancer.

Radiotherapy is the main treatment for nasopharyngeal carcinoma (NPC); however, radioresistance limits the therapeutic efficacy and prognosis of patients with NPC. Here, we plan to identify the genes involved in radiotherapy response. Peripheral blood mononuclear cells (PBMC) from three paired NPC patients with pre-radiotherapy and post-radiotherapy were extracted. Next-generation deep sequencing was then performed to identify the PBMCs transcripts profiles in response to radiotherapy. Data of gene chip GSE48501 was obtained from Gene Expression Omnibus (GEO) database. The gene integration of differentially expressed genes identified from RNA-Seq data and gene chip was performed using "RobustRankAggreg" package. RNA-Seq data from 44 normal and 519 Head and neck squamous cell carcinoma (HNSCC) tissues (downloaded from TCGA) was integrated into the analysis to further support our study. Cox regression was used to identify risk factors impacting survival. Total of 45 genes were identified to be associated with radiotherapy response. Significantly enriched Gene Ontology (GO) terms and pathways were enriched. Univariate and multivariate analysis suggested the dysregulated genes, CHAC2, CLEC9A, GNG10, JCHAIN, KLRB1, NOG, OLR1, PRELID2, SYT1, VWCE, ZNF443 were associated with survival in HNSCC patients. Our data provide an overview of the profiles of radiotherapy-associated genes, which will facilitate future investigations into the function of radiotherapy resistance.