IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα

Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B (IκBα) and then activate nuclear factor kappa-B (NF-κB). Inhibition of IKKβ has been a therapeutic strategy for inflammatory and autoimmune diseases. Here we report that IKKβ is constitutively activated in healthy donors and healthy Ikkβ C46A (cysteine 46 mutated to alanine) knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation. These indicate that IKKβ activation probably plays homeostatic role instead of causing inflammation. Compared to Ikkβ WT littermates, lipopolysaccharides (LPS) could induce high mortality rate in Ikkβ C46A mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5' adenosine monophosphate-activated protein kinase (p-AMPK) expression. We then demonstrated that IKKβ kinase domain (KD) phosphorylates AMPKα1 via interacting with residues Thr183, Ser184, and Thr388, while IKKβ helix-loop-helix motifs is essential to phosphorylate IκBα according to the previous reports. Kinase assay further demonstrated that IKKβ simultaneously catalyzes phosphorylation of AMPK and IκBα to mediate homeostasis. Accordingly, activation of AMPK rather than inhibition of IKKβ could substantially rescue LPS-induced mortality in Ikkβ C46A mice by rebuilding the homeostasis. We conclude that IKKβ activates AMPK to restrict inflammation and IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Expressions of interleukin 6, interleukin 8 and interleukin 10 in the peripheral blood of patients with diffuse large B-cell lymphoma and their clinical significances / 白血病·淋巴瘤

Objective:To explore expressions of interleukin 6 (IL-6), interleukin 8 (IL-8) and interleukin 10 (IL-10) in the peripheral blood of patients with diffuse large B-cell lymphoma (DLBCL) and their clinical significances.Methods:The clinical data of 78 newly diagnosed patients with DLBCL from March 2018 to March 2021 in the First Affiliated Hospital of Xiamen University were retrospectively analyzed, and 58 healthy people receiving physical examination during the same period were taken as the healthy controls. The expressions levels of IL-6, IL-8 and IL-10 in peripheral blood were tested by using cytometric bead array (CBA), and the association of the levels of IL-6, IL-8 and IL-10 with clinical characteristics, disease staging and prognosis was analyzed.Results:The expression levels of IL-6, IL-8 and IL-10 in DLBCL group were higher than those in the healthy control group [(171.81±70.91) pg/ml vs. (2.71±0.28) pg/ml, (47.95±13.04) pg/ml vs. (3.69±0.47) pg/ml, (38.02±10.35) pg/ml vs. (1.77±0.23) pg/ml], and differences were statistically significant ( t values were 2.38, 3.39, 3.50, all P<0.05). In DLBCL group, the expression levels of IL-6, IL-8 and IL-10 in patient with bone marrow invasion, international prognostic index (IPI) 3-5 scores and clinical staging Ⅲ-Ⅳ were higher than those in patients with bone marrow non-invasion, IPI 1-2 scores and clinical stagingⅠ-Ⅱ(all P<0.05). There was a relationship between the expression levels of IL-6 and IL-8, IL-6 and IL-10, IL-8 and IL-10 in peripheral blood of DLBCL patients ( r2 value was 0.93, 0.89, 0.89, respectively; all P < 0.05). Among patients with high expressions of IL-6, IL-8 and IL-10, the proportion of patients not receiving remission after 6 cycles of treatment in clinical staging Ⅲ-Ⅳ was higher than that of patients with high expressions of IL-6, IL-8 and IL-10 alone or any two of them, and differences were statistically significant (all P < 0.05). Conclusions:There is a high correlation of IL-6, IL-8 and IL-10 expression levels; the increasing expression levels of them may predict the later disease stage and poor prognosis for DLBCL patients.

The Current Situation of Hospice Care and Influencing Factors in 235 Cases / 中国医学伦理学

Objective:To survey the level of hospice care and the influencing factors in Shaanxi province. Methods:Interview and return visit method was used to investigate. Results:In total 235 patients, 37. 02% patients received hos-pice care. There is not significant difference between hospice users and no hospice users in sex and geographic differ-ences. There was significant difference between hospice users and no hospice users in personal ages, and in gap between urban and rural areas. and in medical payment, and in basic lesions. Malignant tumor patients receive hospice care most-ly. No patient received hospice care patients with acute trauma. The effect of ages on hospice is maximum ( OR =2. 877). Basic lesions is an important cause of influence whether patients receiving hospice care services(OR=1. 569). Conclusion:The level of hospice care is low in Shaanxi. The age and basic lesions is influencing factors of hospice care. The geographic differences has no effect on hospice care.

Approximate entropy analysis of fetal heart rate variability and its application in the diagnosis of fetal distress / 生物医学工程学杂志

To introduce approximate entropy (ApEn) in the analysis of fetal heart rate variability (FHRV) and to discuss the relationship between the ApEn values and perinatal outcomes, 67 computerized cardiotocographs were recorded. Approximate entropy and index in time domain were used to analyze FHRV. After childbirth, the neonatal Apgar scores were recorded and umbilical cord arterial blood gas analyses were performed. The results showed the ApEn values of FHRV were correlated with pH, Pco2, Po2, HCO3-, ABE, SO2 and neonatal Apgar scores (r = 0.51, -0.29, 0.49, 0.29, 0.45, 0.56, 0.28, respectively, P < 0.05). The ApEn values for acidotic fetuses (pH less than 7.20) were significantly different from those of normal fetuses (P < 0.01), however the time domain parameters of FHRV were unable to identify the difference. The results suggest that the ApEn values of FHRV are closely related to the fetal hypoxia and acidemia. Thus the ApEn analysis appears to be useful for improving the sensitivity in the diagnosis of fetal distress.

Effect of psychological intervention on the anxious reaction of perioperative patients with esophageal and cardiac carcinoma / 中国医学伦理学

We investigated the psychological condition of 70 inpatients who had esophageal and cardiac carcinoma before radical operation with Hamilton Anxiety Scales.For the patients with anxiety,we carried out psychological intervention before operation which includes general care,follow-up,collective psychotherapy,keep disease condition individually and so on.The results showed the treatment had great benefit to most of the patients.