BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α.

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

miR-214-3p Targets ß-Catenin to Regulate Depressive-like Behaviors Induced by Chronic Social Defeat Stress in Mice.

ß-Catenin has been implicated in major depressive disorder (MDD), which is associated with synaptic plasticity and dendritic arborization. MicroRNAs (miRNA) are small noncoding RNAs containing about 22 nucleotides and involved in a variety of physiological and pathophysiological process, but their roles in MDD remain largely unknown. Here, we investigated the expression and function of miRNAs in the mouse model of chronic social defeat stress (CSDS). The regulation of ß-catenin by selected miRNA was validated by silico prediction, target gene luciferase reporter assay, and transfection experiment in neurons. We demonstrated that the levels of miR-214-3p, which targets ß-catenin transcripts were significantly increased in the medial prefrontal cortex (mPFC) of CSDS mice. Antagomir-214-3p, a neutralizing inhibitor of miR-214-3p, increased the levels of ß-catenin and reversed the depressive-like behavior in CSDS mice. Meanwhile, antagomir-214-3p increased the amplitude of miniature excitatory postsynaptic current (mEPSC) and the number of dendritic spines in mPFC of CSDS mice, which may be related to the elevated expression of cldn1. Furthermore, intranasal administered antagomir-214-3p also significantly increased the level of ß-catenin and reversed the depressive-like behaviors in CSDS mice. These results may represent a new therapeutic target for MDD.

Active Heme Metabolism Suppresses Macrophage Phagocytosis via the TLR4/Type I IFN Signaling/CD36 in Uterine Endometrial Cancer.

BACKGROUND: Uterine endometrial cancer (UEC) is a common gynecological estrogen-dependent carcinoma, usually accompanied by intermenstrual bleeding. Active heme metabolism frequently plays an increasingly important role in many diseases, especially in cancers. Tumor-associated macrophages (TAMs) are the major population in the immune microenvironment of UEC. However, the roles of heme metabolisms in the crosstalk between UEC cells (UECCs) and macrophages are unclear. MATERIALS AND METHODS: In our study, by using TCGA database analysis, integration analysis of the protein-protein interaction (PPI) network and sample RNA transcriptome sequencing were done. The expression level of both heme-associated molecules and iron metabolism-related molecules were measured by quantitative real-time polymerase chain reaction. Heme level detection was done through dehydrohorseradish peroxidase assay. In addition to immunohistochemistry, phagocytosis assay of macrophages, immunofluorescence staining, intracellular ferrous iron staining, as well as enzyme-linked immune sorbent assay were performed. RESULTS: In the study, we verified that heme accumulation in UECCs is apparently higher than in endometrial epithelium cells. Low expression of succinate dehydrogenase B under the regulation of estrogen contributes to over-production of succinate and heme accumulation in UECC. More importantly, excessive heme in UECCs impaired macrophage phagocytosis by regulation of CD36. Mechanistically, this process is dependent on toll-like receptor (TLR4)/type I interferons alpha (IFN Iα) regulatory axis in macrophage. CONCLUSION: Collectively, these findings elucidate that active heme metabolism of UECCs directly decreases phagocytosis by controlling the secretion of TLR4-mediated IFN Iα and the expression of CD36, and further contributing to the immune escape of UEC.

Heme metabolism and HO-1 in the pathogenesis and potential intervention of endometriosis.

Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase-1 (HO-1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO-1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti-inflammatory, and anti-proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

Active Estrogen-Succinate Metabolism Promotes Heme Accumulation and Increases the Proliferative and Invasive Potential of Endometrial Cancer Cells.

Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that the expression of aminolevulinate delta synthase 1 (ALAS1) and solute carrier family member 38 (SLC25A38) in UEC tissues is significantly higher than that in normal tissues. Further analysis showed that estrogen and succinate increased the expression of ALAS1 and SLC25A38 in uterine endometrial cancer cells (UECC), and the administration of succinate upregulated the level of the estrogen receptor (ER). Silencing nuclear receptor coactivator 1 (NCOA1) reversed the effects of estrogen and succinate via downregulation of ALAS1 expression. Additionally, exposure of UECC to heme increased cell viability and invasiveness, while silencing the NCOA1 gene weakened this effect. These findings revealed that estrogen and succinate can synergistically increase the expression of ALAS1 and SLC25A38 via the ERß/NCOA1 axis, promoting heme accumulation and increasing the proliferative and invasive potential of UECC.

Glucose transporters: Important regulators of endometrial cancer therapy sensitivity.

Glucose is of great importance in cancer cellular metabolism. Working together with several glucose transporters (GLUTs), it provides enough energy for biological growth. The main glucose transporters in endometrial cancer (EC) are Class 1 (GLUTs 1-4) and Class 3 (GLUTs 6 and 8), and the overexpression of these GLUTs has been observed. Apart from providing abundant glucose uptake, these highly expressed GLUTs also participate in the activation of many crucial signaling pathways concerning the proliferation, angiogenesis, and metastasis of EC. In addition, overexpressed GLUTs may also cause endometrial cancer cells (ECCs) to be insensitive to hormone therapy or even resistant to radiotherapy and chemoradiotherapy. Therefore, GLUT inhibitors may hopefully become a sensitizer for EC precision-targeted therapies. This review aims to summarize the expression regulation, function, and therapy sensitivity of GLUTs in ECCs, aiming to provide a new clue for better diagnosis and treatment of EC.

A LIGHT-HVEM/LTßR axis contributes to the fibrosis of intrauterine adhesion.

Intrauterine adhesion (IUA) is a fibrotic disease, with complex and multifactorial process, causing menstrual disorders, pregnancy loss or infertility. LIGHT (also named TNFSF14), mainly expressed by immune cells, has been reported to be associated with tissue fibrosis. However, the features of immunocyte subsets, the expression and roles of LIGHT and its receptor HVEM (herpes virus entry mediator) and LTßR (lymphotoxin beta receptor) in IUA remain largely unknown. Compared with the control group, we observed increased ratios of CD45+ cells, neutrophils, T cells, macrophages and decreased natural killer cells proportion, and high LIGHT expression on CD4+ T cells and macrophages in IUA endometrium. Further analysis showed there was a positive correlation between upregulated profibrotic factors (e.g., ɑ-smooth muscle actin, transforming growth factor ß1) and HVEM in IUA endometrial tissue. More importantly, recombinant human LIGHT protein directly up-regulated the expression of HVEM, LTßR, profibrotic and proinflammatory factors expression in human endometrial stromal cells. These findings reveal abnormal changes of immune cell subsets proportion and the overexpression of LIGHT-HVEM/LTßR axis in IUA endometrium, should contribute to inflammation and fibrosis formation of IUA.

DTL promotes melanoma progression through rewiring cell glucose metabolism.

Background: To investigate the role of DTL in the development of skin cutaneous melanoma (SKCM) and possible mechanisms. Methods: We examined the expression of DTL in SKCM in The Cancer Genome Atlas (TCGA) and Oncomine database and analyzed the relationship between DTL expression and melanoma prognosis. Furthermore, we silenced the DTL gene by RNA interference in A375 cells and investigated the effect of DTL silencing on the biological function of melanoma cells. Results: The expression of DTL in SKCM was upregulated in the tumor tissues compared with the paired normal tissues. Survival analysis showed that higher DTL expression in SKCM patients was associated with poor clinical outcome compared with the lower DTL expression group. Silencing of DTL in A375 cells significantly inhibited the melanoma cell growth and proliferation ability, and also significantly decreased the total glucose consumption and lactate production. Gene set enrichment analysis (GSEA) showed that MYC targets gene set pathway was highly enriched in the DTL high expression group. The expression levels of some MYC targets-related oncogenes, including c-MYC, HK1, HK2, PGK1, ENO1, LDHA, IDH1, ACLY, and HMGCR, were reduced in the A375 cells with knockdown DTL and upregulated in SKCM tissues with high DTL expression, and there was a positive correlation between them. Conclusions: An important role is played by DTL in promoting melanoma cell growth and glucose metabolism, possibly through activation of the MYC target pathway.

Deficiency of Glycosylated α-Dystroglycan in Ventral Hippocampus Bridges the Destabilization of Gamma-Aminobutyric Acid Type A Receptors With the Depressive-like Behaviors of Male Mice.

BACKGROUND: Depression is a common psychiatric disorder associated with defects in GABAergic (gamma-aminobutyric acidergic) neurotransmission. α-Dystroglycan (α-DG), a cell adhesion molecule known to be essential for skeletal muscle integrity, is also present at inhibitory synapses in the central nervous system and forms a structural element in certain synapses. However, the role of α-DG in the regulation of depressive-like behaviors remains largely unknown. METHODS: Depressive-like behaviors were induced by chronic social defeat stress in adult male mice. Surface protein was extracted by a biotin kit, and the expression of protein was detected by Western blotting. Intrahippocampal microinjection of the lentivirus or adeno-associated virus or agrin intervention was carried out using a stereotaxic instrument and followed by behavioral tests. Miniature inhibitory postsynaptic currents were recorded by whole-cell patch-clamp techniques. RESULTS: The expression of α-DG and glycosylated α-DG in the ventral hippocampus was significantly lower in chronic social defeat stress-susceptible male mice than in control mice, accompanied by a decreased surface expression of GABAA receptor γ2 subunit and reduced GABAergic neurotransmission. RNA interference-mediated knockdown of Dag1 increased the susceptibility of mice to subthreshold stress. Both in vivo administration of agrin and overexpression of like-acetylglucosaminyltransferase ameliorated depressive-like behaviors and restored the decrease in surface expression of GABAA receptor γ2 subunit and the amplitude of miniature inhibitory postsynaptic currents in chronic social defeat stress-exposed mice. CONCLUSIONS: Our findings demonstrate that glycosylated α-DG plays a role in the pathophysiological process of depressive-like behaviors by regulating the surface expression of GABAA receptor γ2 subunit and GABAergic neurotransmission in the ventral hippocampus.

Drug Survival Outcomes Associated with the Real-World Use of Ixekizumab, Secukinumab, Guselkumab, and Adalimumab for the Treatment of Plaque Psoriasis in China: A 52-Week Single-Center Retrospective Study.

Background: Data pertaining to biologic agents used for treating psoriasis in real-world settings are lacking at present. To compare drug survival at 52 weeks for a range of biologics used to treat psoriasis under real-world conditions. Methods: This was a retrospective, single-center, observational study of a cohort of patients diagnosed with plaque psoriasis treated using ixekizumab, secukinumab, guselkumab, or adalimumab between January 2020 and December 2021. Baseline demographic characteristics, duration of psoriasis, and prior biological treatments for all patients were recorded. Drug survival rates were analyzed in different patient groups using Kaplan-Meier curves and Log rank tests. Results: In total, this study included 386 plaque psoriasis patients, of whom 70, 175, 36, and 105 were, respectively, treated using ixekizumab, secukinumab, guselkumab, and adalimumab. Over a 52-week period, the overall cumulative drug survival rates for ixekizumab, secukinumab, guselkumab, and adalimumab were 67.1%, 63.0%, 72.2%, and 37.1%, respectively. Lack of efficacy was the primary cause of discontinuation for these biologic therapies, followed by economic burden and adverse event incidence. Conclusion: These results suggest that guselkumab exhibited superior drug survival, drug survival outcomes for ixekizumab and secukinumab were comparable, and significantly better than those of adalimumab in China. Preventing a loss of drug efficacy represents a primary approach to improving biologic drug survival in psoriasis patients.

Heme oxygenase 1: a novel oncogene in multiple gynecological cancers.

Heme oxygenase 1 (HO-1), also known as heat shock protein 32 (HSP32), is a stress-inducible enzyme. In the past, it was believed to participate in maintaining cell homeostasis, reducing oxidative stress damage and exerting anti-apoptotic effects. When exposed to noxious stimulation, the expression of HO-1 in the body will increase, antagonizing these oxidative stresses and protecting our bodies. Recently, many studies showed that HO-1 was also highly-expressed in multiple gynecological cancers (such as ovarian cancer, cervical cancer and endometrial cancer), suggesting that it should be closely related to cell proliferation, metastasis, immune regulation and angiogenesis as an oncogene. This review summarizes the different effects of HO-1 under normal and diseased conditions with a brief discussion of its implications on the diagnosis and treatment of gynecological cancers, aiming to provide a new clue for prevention and treatment of diseases.

Transcription Factor TWIST1 Integrates Dendritic Remodeling and Chronic Stress to Promote Depressive-like Behaviors.

BACKGROUND: Deficiency in neuronal structural plasticity is involved in the development of major depressive disorder. TWIST1, a helix-loop-helix transcription factor that is essential for morphogenesis and organogenesis, is normally expressed at low levels in mature neurons. However, it is poorly understood what role TWIST1 plays in the brain and whether it is involved in the pathophysiology of depression. METHODS: Depressive-like behaviors in C57BL/6J mice were developed by chronic social defeat stress. Genetic and pharmacological approaches were used to investigate the role of the TWIST1-miR-214-PPAR-δ signaling pathway in depressive-like behaviors. Molecular biological and morphological studies were performed to define the molecular mechanisms downstream of TWIST1. RESULTS: The expression of TWIST1 was positively correlated with depressive behaviors in humans and mice. Chronic stress elevated TWIST1 expression in the medial prefrontal cortex of mice, which was reversed by fluoxetine treatment. While the overexpression of TWIST1 increased susceptibility to stress, the knockdown of TWIST1 prevented the defective morphogenesis of dendrites of pyramidal neurons in layer II/III of the medial prefrontal cortex and alleviated depressive-like behaviors. Mechanistically, this prodepressant property of TWIST1 was mediated, at least in part, through the repression of miR-214-PPAR-δ signaling and mitochondrial function, which was also mimicked by genetic and pharmacological inhibition of PPAR-δ. CONCLUSIONS: These results suggest that TWIST1 in the medial prefrontal cortex mediates chronic stress-induced dendritic remodeling and facilitates the occurrence of depressive-like behavior, providing new information for developing drug targets for depression therapy.

Sulforaphane alleviates ethanol-mediated central inhibition and reverses chronic stress-induced aggravation of acute alcoholism via targeting Nrf2-regulated catalase expression.

Acute ethanol intoxication by excessive drinking is an important cause of alcohol-induced death. Stress exposure has been identified as one risk factor for alcohol abuse. Previous reports indicated that stressors may augment inhibitory effects of alcohol, but the underlying mechanism remains unknown. Here, we reported that chronic unpredictable stress increased the sensitivity to the acute ethanol intoxication in mice via impairing nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-catalase signaling. Nrf2 activity regulates the expression of catalase, a key antioxidant enzyme that mediates ethanol oxidation in the brain. Pharmacological blockade of catalase or Nrf2 activity significantly aggravated acute ethanol intoxication. Sulforaphane, a cruciferous vegetable-derived activator of Nrf2, significantly attenuated acute ethanol intoxication. Furthermore, the stress-induced aggravation of acute alcoholism was rapidly reversed by sulforaphane. Our findings suggest that Nrf2 may function as a novel drug target for the prevention of acute alcoholism, especially in psychiatric patients, by controlling catalase-mediated ethanol oxidation.

Gephyrin Palmitoylation in Basolateral Amygdala Mediates the Anxiolytic Action of Benzodiazepine.

BACKGROUND: Benzodiazepines (BZDs) have been used to treat anxiety disorders for more than five decades as the allosteric modulator of the gamma-aminobutyric acid A receptor (GABAAR). Little is known about other mechanisms of BZDs. Here, we describe how the rapid stabilization of postsynaptic GABAAR is essential and sufficient for the anxiolytic effect of BZDs via a palmitoylation-dependent mechanism. METHODS: Palmitoylated proteins in the basolateral amygdala (BLA) of rats with different anxious states were assessed by a biotin exchange protocol. Both pharmacological and genetic approaches were used to investigate the role of palmitoylation in anxiety behavior. Electrophysiological recording, reverse transcription polymerase chain reaction, Western blotting, and coimmunoprecipitation were used to investigate the mechanisms. RESULTS: Highly anxious rats were accompanied by the deficiency of gephyrin palmitoylation and decreased the synaptic function of GABAAR in the BLA. We then identified that the dysfunction of DHHC12, a palmitoyl acyltransferase that specifically palmitoylates gephyrin, contributed to the high-anxious state. Furthermore, diazepam, as an anxiolytic drug targeting GABAARs, was found to increase gephyrin palmitoylation in the BLA via a GABAAR-dependent manner to activate DHHC12. The anxiolytic effect of diazepam was nearly abolished by the DHHC12 knockdown. Specifically, similar to the effect of BZD, the overexpression of DHHC12 in the BLA exerted a significant anxiolytic action, which was prevented by flumazenil. CONCLUSIONS: Our results support the view that the strength of inhibitory synapse was controlled by gephyrin palmitoylation in vivo and proposes a previously unknown palmitoylation-centered mode of BZD's action.

[A scanning electron microscopic study of root surface following mini-implant anchorage for maxillary incisors intrusion].

PURPOSE: To establish an animal model for maxillary incisors intrusion with mini-implant as the anchorage and study the effect on the surface morphology of cementum after the force had been given. METHODS: 9 dogs were selected and randomly divided into 5 groups, group I was the control group(1 dog) with no force given; groups II,III,IV,V were experimental groups (2 dogs each). Mini-implants were inserted into the labial alveolar bone between the roots of second and third maxillary incisors on both sides, 100 gram force was imposed on the first and the second incisors on both sides.The animals were sacrificed at the end of 1, 2, 4,12 weeks (activation for 4 weeks,then retention for 8 weeks after force removal) respectively after activation.Scanning electron microscopy was used to examine the surface of the cementum. RESULTS: In group II, the surfaces of root tip had a little scratch, which was small,confined. In group III, near the apical 1/3 of root, lacunas were fused, but no dentin exposed. In group IV, at the junction of the apical 1/3 and the middle 1/3 of the root, lacunas went deep into the dentin,which were wide and serious. In group V, the surfaces of lacunas were low ,smooth and even. CONCLUSIONS: As the intrusion goes on, the area of absorption expands from the root tip to neck. Root resorption increases with the duration of the applied force prolonged and repair of the cementum occurs at the resorbed area after force removal.