TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder

AbstractInflammation and abnormalities in Toll-like receptor (TLR) expression and activation have been linked to major depressive disorder (MDD). However, negative regulators of TLR pathways have not been previously investigated in this context. Here, we sought to investigate the association of depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17), with mRNA expression levels of negative regulators of the TLR pathway, including SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2 and TNFAIP3, in peripheral blood mononuclear cells (PBMCs) from 100 patients with MDD and 53 healthy controls, before and after treatment with antidepressants. Positive regulators of the TLR4 pathway, including Pellino 1, TRAF6 and IRAK1, were also investigated. Among all patients, MyD88s, and TNFAIP3 mRNAs were expressed at lower levels in PBMCs from patients with MDD. Multiple linear regression analyses revealed that TNFAIP3 mRNA expression before treatment was inversely correlated with severity of depression and effectively predicted improvement in HAMD-17 scores. Among 79 treatment-completers, only TNFAIP3 mRNA was significantly increased by treatment with antidepressants for 4 weeks. Treatment of human monocytes (THP-1) and mouse microglia (SIM-A9) cell lines with fluoxetine significantly increased TNFAIP3 mRNA expression and suppressed IL-6 levels. The suppressive effect of fluoxetine on IL-6 was attenuated by knockdown of TNFAIP3 expression. These findings suggest that both dysfunction of the negative regulatory system in patients with MDD and antidepressant treatment exert anti-inflammatory effects, at least in part through increased expression of the TNFAIP3 gene. They also indicate that modulating expression of the TNFAIP3 gene to rebalance TLR-mediated inflammatory signaling may be potential therapeutic strategy for treating MDD

RBBP6 interactome : RBBP6 isoform 3/DWNN and Nek6 interaction is critical for cell cycle regulation and may play a role in carcinogenesis

RBBP6 is a multidomain protein, with four splice variants translated into four functional isoforms. RBBP6 isoform 1 has been reported to interact with TP53 and pRb as well as with proteins that regulate transcriptional response to tumorigenesis such as HDM2, ZBTB38, YBX1 and NEK6. Experimental validation of isoforms 2 and 4 is yet to be conducted. The third isoform, consisting of only the DWNN domain and a short unordered c terminus, has been shown to be down-regulated in several human cancers and demonstrated as a regulator of G2/M cell cycle arrest. A number of studies have supported the role of DWNN in cell cycle regulation, however, its mechanism in these processes remains obscure. Posttranslational modification of DWNN could be critical for its function and this study was formulated to understand how the DWNN regulates the cell cycle. Our study identified 12 cell cycle-related proteins interacting with DWNN using various bioinformatics tools. We also identified 10 ubiquitin ligases that interact with DWNN. The most relevant interacting partner, the cell cycle regulator Nek6, has been reported to interact with DWNN during the cell cycle. It was therefore critical to interrogate the interaction between Nek6 and DWNN by homology modelling and docking. The DWNN mutants had a reduced affinity for NEK6 with at least one of the mutants having changes that affect at least one phosphorylation site. It is likely that NEK6 promotes cell proliferation by phosphorylating DWNN. This work suggests that DWNN co-regulates RNA splicing, ubiquitination, and cell cycle control. DWNN may therefore, be targeted for novel anticancer therapies through cell cycle regulation.Supplementary Material: Fig. S1. Comparison of the Ramachandran plots for Nek 7 as determined by crystallography and the Nek6 models using Nek 7 as a templateFig. S2. Structure of wild-type RBBP5 isoform 3 compared to mutant forms of the protein: (A) The wild type RBBP6 isoform 3 structure as determined by NMR. The protein has 7 Beta sheets and one alpha helix. (B) A 3D model of the S25A mutant of RBBP6 isoform 3 and (C) the 3D model of the T49A mutant of RBBP6 isoform 3, show that the amino acid substitutions in the mutant proteins had no significant effect on the overall structure of the protein. Like the wild type protein, the mutants all contain 7 Beta sheets and one alpha helixThe South African Medical Research Council (SAMRC) and the National Research Foundation (NRF).https://http//www.elsevier.com/locate/imuhj2021Obstetrics and Gynaecolog

The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: An In Vitro and In Vivo Comparison Study with Herceptin

HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used for in vitro analysis. The in vivo effect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer

Effect of Supplementation of Tanshinone IIA and Sodium Tanshinone IIA Sulfonate on the Anticancer Effect of Epirubicin: An In Vitro Study

Tanshinone IIA (Tan IIA) and sodium tanshinone IIA sulfonate (STS) were found to have protective effects on cardiomyocyte against adriamycin-induced damage and may be used clinically. It is unclear whether the supplementation of STS or Tan IIA would affect the anticancer activity of anthracycline. To evaluate the effect of Tan IIA or STS on the anticancer of epirubicin, the cell viability, apoptosis, Akt expression, and uptake of epirubicin after supplementation of Tan IIA or STS in the epirubicin-treated BT-20 cells were measured and compared. Tan IIA inhibited BT-20 cell growth and induced apoptosis in a time- and dose-dependent manner. When Tan IIA was used with epirubicin, an increase of BT-20 cells apoptosis was accompanied by the decreasing phosphorylation of Akt. STS had no effect on the cell viability of BT-20 cells. However, when used with epirubicin, STS decreased the epirubicin-induced cytotoxicity and apoptosis in BT-20 cells. The antagonistic effect of STS on epirubicin-induced cytotoxicity in BT-20 cells occurred concomitantly with the reduced epirubicin uptake and the increased phosphorylation of Akt. STS decreased the uptake of epirubicin in BT-20 cells and blocked epirubicin-induced apoptosis through activation of Akt

Indigenous Case of Disseminated Histoplasmosis, Taiwan

We report the first indigenous case of disseminated histoplasmosis in Taiwan diagnosed by histopathology of bone marrow, microbiologic morphology, and PCR assay of the isolated fungus. This case suggests that histoplasmosis should be 1 of the differential diagnoses of opportunistic infections in immunocompromised patients in Taiwan

Pioglitazone, a PPAR-γ Activator, Stimulates BKCa but Suppresses IKM in Hippocampal Neurons

Pioglitazone (PIO), a thiazolidinedone, was reported to stimulate peroxisome proliferator-activated receptor-γ (PPAR-γ) with anti-inflammatory, anti-proliferative, anti-diabetic, and antidepressive activities. However, whether this compound exerts any perturbations on Ca2+-activated K+ and M-type K+ currents in central neurons remains largely unresolved. In this study, we investigated the effects of PIO on these potassium currents in hippocampal neurons (mHippoE-14). In whole-cell current recordings, the presence of PIO (10 μM) increased the amplitude of Ca2+-activated K+ current [IK(Ca)] in mHippoE-14 cells. PIO-induced stimulation of IK(Ca) observed in these cells was reversed by subsequent addition of paxilline, yet not by TRAM-39 or apamin. In inside-out current recordings, PIO applied to the bath concentration-dependently increased the activity of large-conductance Ca2+-activated K+ (BKCa) channels with an EC50 value of 7.6 μM. Its activation of BKCa channels in mHippoE-14 cells was voltage-dependent and accompanied by both a lengthening in mean open time and a shortening in slow component of mean closed time. The activation curve of BKCa channels after addition of PIO was shifted to less depolarized potential without any change in the gating charge. PIO also suppressed the amplitude of M-type K+ currents inherently in mHippoE-14 neurons. Taken together, in addition to its agonistic action on PPAR-γ, PIO-induced perturbation of these potassium channels may be responsible for its widely pharmacological actions on hippocampal neurons

Cardiovascular Outcomes in Acute Coronary Syndrome and Malnutrition: A Meta-Analysis of Nutritional Assessment Tools

Background: There is emerging evidence that malnutrition is associated with poor prognosis among patients with acute coronary syndrome (ACS). // Objectives: This study seeks to elucidate the prognostic impact of malnutrition in patients with ACS and provide a quantitative review of most commonly used nutritional assessment tools. // Methods: Medline and Embase were searched for studies reporting outcomes in patients with malnutrition and ACS. Nutritional screening tools of interest included the Prognostic Nutrition Index, Geriatric Nutritional Risk Index, and Controlling Nutritional Status. A comparative meta-analysis was used to estimate the risk of all-cause mortality and cardiovascular events based on the presence of malnutrition and stratified according to ACS type, ACS intervention, ethnicity, and income. // Results: Thirty studies comprising 37,303 patients with ACS were included, of whom 33.5% had malnutrition. In the population with malnutrition, the pooled mortality rate was 20.59% (95% CI: 14.95%-27.67%). Malnutrition was significantly associated with all-cause mortality risk after adjusting for confounders including age and left ventricular ejection fraction (adjusted HR: 2.66, 95% CI: 1.78-3.96, P = 0.004). There was excess mortality in the group with malnutrition regardless of ACS type (P = 0.132), ethnicity (P = 0.245), and income status (P = 0.058). Subgroup analysis demonstrated no statistically significant difference in mortality risk between individuals with and without malnutrition (P = 0.499) when using Controlling Nutritional Status (OR: 7.80, 95% CI: 2.17-28.07, P = 0.011), Geriatric Nutritional Risk Index (OR: 4.30, 95% CI: 2.78-6.66, P < 0.001), and Prognostic Nutrition Index (OR: 4.67, 95% CI: 2.38-9.17, P = 0.023). // Conclusions: Malnutrition was significantly associated with all-cause mortality risk following ACS, regardless of ACS type, ethnicity, and income status, underscoring the importance of screening and interventional strategies for patients with malnutrition

Synergistic Apoptosis-Inducing Antileukemic Effects of Arsenic Trioxide and Mucuna macrocarpa

The objective of this study was to examine the potential of enhancing the antileukemic activity of arsenic trioxide (ATO) by combining it with a folk remedy, crude methanolic extract of Mucuna macrocarpa (CMEMM). Human leukemia cells HL-60, Jurkat, and Molt-3 were treated with various doses of ATO, CMEMM, and combinations thereof for 24 and 48 h. Results indicated that the combination of 2.5 μM ATO and 50 μg/mL CMEMM synergistically inhibited cell proliferation in HL-60 and Jurkat cell lines. Apoptosis triggered by ATO/CMEMM treatment was confirmed by accumulation of cells in the sub-G1 phase in cell cycle analyses, characteristic apoptotic nuclear fragmentation, and increased percentage of annexin V-positive apoptotic cells. Such combination treatments also led to elevation of reactive oxygen species (ROS). The antioxidants N-acetyl cysteine (NAC), butylated hydroxytoluene, and α-tocopherol prevented cells from ATO/CMEMM-induced apoptosis. The ATO/CMEMM-induced activation of caspase-3 and caspase-9 can be blocked by NAC. In summary, these results suggest that ATO/CMEMM combination treatment exerts synergistic apoptosis-inducing effects in human leukemic cells through a ROS-dependent mechanism and may provide a promising antileukemic approach in the future