Identification of the feature genes involved in cytokine release syndrome in COVID-19.

OBJECTIVE: Screening of feature genes involved in cytokine release syndrome (CRS) from the coronavirus disease 19 (COVID-19). METHODS: The data sets related to COVID-19 were retrieved using Gene Expression Omnibus (GEO) database, the differentially expressed genes (DEGs) related to CRS were analyzed with R software and Venn diagram, and the biological processes and signaling pathways involved in DEGs were analyzed with GO and KEGG enrichment. Core genes were screened using Betweenness and MCC algorithms. GSE164805 and GSE171110 dataset were used to verify the expression level of core genes. Immunoinfiltration analysis was performed by ssGSEA algorithm in the GSVA package. The DrugBank database was used to analyze the feature genes for potential therapeutic drugs. RESULTS: This study obtained 6950 DEGs, of which 971 corresponded with CRS disease genes (common genes). GO and KEGG enrichment showed that multiple biological processes and signaling pathways associated with common genes were closely related to the inflammatory response. Furthermore, the analysis revealed that transcription factors that regulate these common genes are also involved in inflammatory response. Betweenness and MCC algorithms were used for common gene screening, yielding seven key genes. GSE164805 and GSE171110 dataset validation revealed significant differences between the COVID-19 and normal controls in four core genes (feature genes), namely IL6R, TLR4, TLR2, and IFNG. The upregulated IL6R, TLR4, and TLR2 genes were mainly involved in the Toll-like receptor signaling pathway of the inflammatory pathway, while the downregulated IFNG genes primarily participated in the necroptosis and JAK-STAT signaling pathways. Moreover, immune infiltration analysis indicated that higher expression of these genes was associated with immune cell infiltration that mediates inflammatory response. In addition, potential therapeutic drugs for these four feature genes were identified via the DrugBank database. CONCLUSION: IL6R, TLR4, TLR2, and IFNG may be potential pathogenic genes and therapeutic targets for the CRS associated with COVID-19.

Effect and mechanism of Hashimoto thyroiditis on female infertility: A clinical trial, bioinformatics analysis, and experiments-based study.

Diagnosing Hashimoto thyroiditis (HT) relies on thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) titers. The influence of these antibodies on female infertility remains a subject of debate. This study aims to explore the effect and mechanism of HT on female infertility. First, a single-center cross-sectional study was conducted to investigate whether TgAb and TPOAb are the key factors leading to female infertility. Second, bioinformatic analysis was performed to investigate the potential target molecules and pathways. Third, in vivo experiments were performed to explore the effects of elevated TgAb levels on embryo implantation in a mouse model of autoimmune thyroiditis (AIT). Four hundred and five infertile women and 155 healthy controls were enrolled in the cross-sectional study. Results indicated that the TPOAb titer was associated with female infertility, while the TgAb titer showed no significant association. The increased levels of TgAb and TPOAb are not significantly correlated with anti-Mullerian hormone. Bioinformatic analysis indicated that the common target molecules for HT and female infertility include interleukin (IL)-6, IL-10, matrix metalloproteinase 9, and tumor necrosis factor, suggesting potential regulation through multiple signaling pathways such as HIF-1, VEGF, MAPK, and Th17 cell differentiation. A certain dose of porcine thyroglobulin can successfully establish a mouse model of AIT. In this mouse model, embryo implantation and ovarian reserve remain unaffected by elevated TgAb levels. In conclusion, the serum TPOAb titer was associated with infertility due to female factors but the TgAb titer showed no significant association. A simple increase in serum TgAb titer does not affect embryo implantation and ovarian reserve in the AIT model.

Drugs for the treatment of postmenopausal symptoms: Hormonal and non-hormonal therapy.

Postmenopausal symptoms are systemic symptoms associated with estrogen deficiency after menopause. At present, treatments for postmenopausal symptoms include hormonal therapy (HT) and non-HT. However, the optimal regimen for balancing the benefits and risks remains unclear. This article reviewed the characteristics, regimens, and side effects of drugs used in hormonal and non-HT. However, HT is still the most effective treatment with safety in early initiation since menopause onset. Nevertheless, it is essential to evaluate the risks of related chronic diseases and customize individualized treatments. Possible estetrol preparations and more types of Tissue Selective Estrogen Complex formulations are potential directions of drug development in the future of HT. Regarding non-HT, fezolinetant, currently in phase III clinical trials, is poised to become a first-in-class therapy for vasomotor symptoms. Ospemifene, dehydroepiandrosterone (DHEA), and vaginal lasers can also be used for moderate-to-severe genitourinary syndrome of menopause. Recent data suggest a superior efficacy and safety of vaginal lasers, but more validated evidence of long-term tolerability is needed to respond to the United States Food and Drug Administration warning. Herbal medication commonly used in Asia is effective in alleviating menopausal symptoms; however, its adverse effects still require more detailed reports and standardized observation methods. This review contributes to a better understanding of drugs for the treatment of postmenopausal symptoms and provides useful information for clinical drug selection.

The role of placental aging in adverse pregnancy outcomes: A mitochondrial perspective.

Premature placental aging is associated with placental insufficiency, which reduces the functional capacity of the placenta, leading to adverse pregnancy outcomes. Placental mitochondria are vital organelles that provide energy and play essential roles in placental development and functional maintenance. In response to oxidative stress, damage, and senescence, an adaptive response is induced to selectively remove mitochondria through the mitochondrial equivalent of autophagy. However, adaptation can be disrupted when mitochondrial abnormalities or dysfunctions persist. This review focuses on the adaptation and transformation of mitochondria during pregnancy. These changes modify placental function throughout pregnancy and can cause complications. We discuss the relationship between placental aging and adverse pregnancy outcomes from the perspective of mitochondria and potential approaches to improve abnormal pregnancy outcomes.

Plasma-derived exosomal immunoglobulins IGHV4-4 and IGLV1-40 as new non-small cell lung cancer biomarkers.

Exosomal proteins represent valuable research directions in the liquid biopsy of lung cancer (LC). Immunoglobulin subtypes, immunoglobulin molecules with different domains in variable regions, are products of B cell responses to different tumor antigens and are associated with tumor incidence and development. The plasma of patients with LC should theoretically contain a large number of B cell-derived exosomes that specifically recognize tumor antigens. This paper intended to assess the value of the proteomic screening of plasma exosomal immunoglobulin subtypes for diagnosing non-small cell LC (NSCLC). The plasma exosomes of NSCLC patients and healthy control participants (HCs) were isolated using ultracentrifugation. Label-free proteomics was employed to assess the differentially expressed proteins (DEPs), while the biological characteristics of the DEPs were analyzed using GO enrichment. The immunoglobulin content in the top two fold change (FC) values of the DEPs and the immunoglobulin with the lowest P-value were verified using an enzyme-linked immunosorbent assay (ELISA). The differentially expressed immunoglobulin subtypes verified via ELISA were selected to statistically analyze the receiver operating characteristic curve (ROC), after which the diagnostic values of the NSCLC immunoglobulin subtypes were determined via the ROC area under the curve (AUC). The plasma exosomes of the NSCLC patients contained 38 DEPs, of which 23 were immunoglobulin subtypes, accounting for 60.53%. The DEPs were mainly related to the binding between immune complexes and antigens. The ELISA results showed significant differences between the immunoglobulin heavy variable 4-4 (IGHV4-4) and immunoglobulin lambda variable 1-40 (IGLV1-40) in the LC patients and HCs. Compared with the HCs, the AUCs of IGHV4-4, IGLV1-40, and a combination of the two in diagnosing NSCLC were 0.83, 0.88, and 0.93, respectively, while the AUCs for non-metastatic cancer were 0.80, 0.85, and 0.89. Moreover, their diagnostic values for metastatic cancer compared to non-metastatic cancer displayed AUCs of 0.71, 0.74, and 0.83, respectively. When IGHV4-4 and IGLV1-40 were combined with serum CEA to diagnose LC, the AUC value increased, exhibiting values of 0.95, 0.89, and 0.91 for the NSCLC, non-metastatic, and metastatic groups, respectively. Plasma-derived exosomal immunoglobulins containing IGHV4-4 and IGLV 1-40 domains can provide new biomarkers for diagnosing NSCLC and metastatic patients.

Update on hormone therapy for the management of postmenopausal women.

Hormone therapy (HT) has been used in postmenopausal women for decades in clinical practice. With further analysis and newer studies, the benefits and risks of HT have been repeatedly verified and discussed. HT is recommended for the treatment of vasomotor symptoms (VMS), genitourinary syndrome of menopause (GSM) and the prevention of osteoporosis. However, the precise association between HT and the risks of cardiovascular diseases, venous thromboembolism, neurodegenerative diseases, breast cancer, and endometrial cancer remains controversial. Therefore, determining how to take advantage of and control the risks of HT by adjusting the initiation time, regimen, and duration is crucial. Recent studies have indicated that HT is not related to the risk of all-cause, cardiovascular, or breast cancer mortality although it might increase the incidence of some chronic diseases. For symptomatic postmenopausal women under the age of 60 without contraindications, early initiation of HT is safe and probably has a mortality benefit over the long term. Initiating HT close to menopause at the lowest effective dose is more likely to have maximal benefits and the lowest risks. Transdermal and vaginal HT may have a lower risk, but recent evidence suggests additional clinical benefits of oral HT formulations in relieving VMS and preventing osteoporosis. The pooled cohort risk equation for atherosclerotic cardiovascular disease (ASCVD) and the free app named Menopro can be used to perform individual risk assessments. In addition, Chinese herbal medicines have benefits in alleviating hot flashes, depression, and menopausal symptoms, although further data are needed to strongly support their efficacy. Acupuncture and electroacupuncture have definite efficacy in the treatment of postmenopausal symptoms with few adverse effects, so they are a reasonable option as an alternative therapy for high-risk women. This review discusses the history of, guidelines on, and strategies for HT in order to make suggestions based on the most up-to-date evidence for the management of postmenopausal women.

Development and Validation of a Hypoxia-related Prognostic Model for Ovarian Cancer.

BACKGROUND: The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopathological features and genomics. METHODS: We identified hypoxia-related differentially expressed genes (DEGs) between OC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression (GTEx). LASSO Cox regression analysis was applied for building a prognostic model in the TCGA-GTEx cohorts, and its predictive value was validated in the GEO-OC cohort. Functional enrichment analysis was performed to investigate the underlying mechanisms. By constructing a hypoxia model of the SKOV3 cell line and applying qRT-PCR, we investigated the relationship between hypoxia with two novel genes in the prognostic model (ISG20 and ANGPTL4). RESULTS: Twelve prognostic hypoxia-related DEGs were identified, and nine of them were selected to establish a prognostic model. OC patients were stratified into two risk groups, and the high-risk group showed reduced survival time compared to the low-risk group upon survival analysis. Univariate and multivariate Cox regression analysis demonstrated that the risk score was an independent risk factor for overall survival. The biological function of the identified prognostic hypoxia-related gene signature was involved in immune cell infiltration. Low expression of ISG20 was observed in the CoCl2-mimicked hypoxic SKOV3 cell line and negatively correlated with HIF-1α. CONCLUSION: Our findings showed that this hypoxia-related gene signature could serve as a satisfactory prognostic classifier for OC and will be beneficial to the research and development of targeted therapeutic strategies.

Immunopotentiator thymosin alpha-1 attenuates inflammatory pain by modulating the Wnt3a/ß-catenin pathway in spinal cord.

The mechanism of inflammatory pain involves the central nervous system (CNS) and the immune system. It is reported that immunopotentiator thymosin alpha-1 (Tα1) can reduce inflammation, protect neurons and strengthen the immune function. However, the roles of Tα1 in inflammatory pain still remain unclear. In this study, we found Tα1 can attenuate the complete Freund's adjuvant (CFA)-induced mechanical allodynia and heat hyperalgesia. Meanwhile, it reduced the upregulation of CFA-induced inflammatory mediators (interferon (IFN)-γ, tumor necrosis factor-α and brain-derived neurotrophic factor). In addition, we found the Wnt3a/ß-catenin pathway was activated in spinal cord after the injection of CFA, paralleling with pain hypersensitivity. However, Tα1 reversed this status. In summary, Tα1 could attenuate inflammatory pain by modulating the Wnt3a/ß-catenin pathway. It might be related to the downregulation of inflammatory mediators.