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Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Animales , Humanos , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Lesión Renal Aguda/metabolismo , Riñón/metabolismo , Transducción de Señal , Estrés OxidativoRESUMEN
BACKGROUND: Chemotherapeutic insensitivity remains a big challenge in prostate cancer treatment. Recently, increasing evidence has indicated that KLF4 plays a key role in prostate cancer. However, the potential biological role of KLF4 in Chemotherapeutic insensitivity of prostate cancer is still unknown. METHODS: The role of KLF4 in cisplatin-induced apoptosis was detected by western blotting and a cell counting kit (CCK8). The potential molecular mechanism of KLF4 in regulating prostate cancer chemosensitivity was investigated by RNA sequencing analysis, q-RT-PCR, western blotting and chromatin immunoprecipitation (ChIP). The expression level of KLF4 mediated by miR-32-5p was confirmed by bioinformatic analysis and luciferase assays. RESULTS: Here, we found that KLF4 was induced by cisplatin in prostate cancer cells and that the increase in KLF4 promoted cell apoptosis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of BIK, facilitating its transcription. Additionally, we also found that the gene encoding KLF4 was a direct target of miR-32-5p. The downregulation of miR-32-5p in response to cisplatin treatment promoted KLF4 expression, which resulted in a increase in the chemosensitivity of prostate cancer. CONCLUSION: Thus, our data revealed that KLF4 is an essential regulator in cisplatin-induced apoptosis, and the miR-32-5p-KLF4-BIK signalling axis plays an important role in prostate cancer chemosensitivity.
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Proteínas Reguladoras de la Apoptosis/genética , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Factores de Transcripción de Tipo Kruppel/genética , Proteínas de la Membrana/genética , MicroARNs/genética , Neoplasias de la Próstata/patología , Regulación hacia Arriba/efectos de los fármacos , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Resistencia a Antineoplásicos/genética , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales , Células PC-3 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Regulación hacia Arriba/genéticaRESUMEN
The secretion and quality control of glycosylphosphatidylinositol-anchored proteins (GPI-APs) necessitates post-attachment remodeling initiated by the evolutionarily conserved PGAP1, which deacylates the inositol in nascent GPI-APs. Impairment of PGAP1 activity leads to developmental diseases in humans and fatality and infertility in animals. Here, we present three PGAP1 structures (2.66-2.84 Å), revealing its 10-transmembrane architecture and product-enzyme interaction details. PGAP1 holds GPI-AP acyl chains in an optimally organized, guitar-shaped cavity with apparent energetic penalties from hydrophobic-hydrophilic mismatches. However, abundant glycan-mediated interactions in the lumen counterbalance these repulsions, likely conferring substrate fidelity and preventing off-target hydrolysis of bulk membrane lipids. Structural and biochemical analyses uncover a serine hydrolase-type catalysis with atypical features and imply mechanisms for substrate entrance and product release involving a drawing compass movement of GPI-APs. Our findings advance the mechanistic understanding of GPI-AP remodeling.
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Inositol , Proteínas de la Membrana , Animales , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Inositol/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Hidrolasas , Control de Calidad , Glicosilfosfatidilinositoles/químicaRESUMEN
Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.
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Tetrabenazina , Proteínas de Transporte Vesicular de Monoaminas , Humanos , Reserpina , Serotonina/metabolismo , Vesículas Sinápticas/metabolismo , Tetrabenazina/farmacología , Tetrabenazina/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
OBJECTIVE: To investigate the association between venous thromboembolism (VTE) and antidepressant use in an Asian population. METHODS: The authors conducted a nested case-control study of 1888 patients with VTE and 11,222 matched controls enrolled in the National Health Insurance Research Database in Taiwan from 2001 to 2009. The antidepressant exposure status and potential confounding factors were measured and included in the analyses. Conditional logistic regressions were applied to determine the effect of antidepressant use on VTE. RESULTS: We found a significant association of current antidepressant use with VTE in the total study sample (adjusted odds ratio [aOR], 1.59; 95% confidence interval (CI), 1.27-2.00). With regard to antidepressant classes and potency, we found that tricyclic antidepressants (aOR, 1.56; 95% CI, 1.11-2.18), serotonin 5-HT2A receptor blockers (aOR, 2.03; 95% CI, 1.27-3.24), and antidepressants with a low potency of serotonin reuptake inhibition (aOR, 1.57; 95% CI, 1.18-2.08) were associated with a significantly increased risk of VTE. When further stratifying by age, sex, and comorbid conditions, the VTE risk with antidepressant use was elevated among young and middle-aged adults, but not among the elderly. In addition, an elevated risk of VTE was observed in women and subjects without severe comorbid conditions, but not in men and subjects with severe comorbid conditions. CONCLUSIONS: There was a small increase in VTE risk with antidepressant use. The prescription of antidepressant drugs should be cautious, and especially, should be based on clinical evaluations of benefits and risks. The underlying mechanisms of the interaction between antidepressants and VTE warrant further investigation.
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Antidepresivos/efectos adversos , Tromboembolia Venosa/inducido químicamente , Adolescente , Inhibidores de Captación Adrenérgica/efectos adversos , Adulto , Factores de Edad , Antidepresivos/clasificación , Antidepresivos Tricíclicos/efectos adversos , Pueblo Asiatico , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Comorbilidad , Inhibidores de Captación de Dopamina/efectos adversos , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/efectos adversos , Oportunidad Relativa , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Medición de Riesgo , Factores de Riesgo , Antagonistas del Receptor de Serotonina 5-HT2/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Factores Sexuales , Taiwán/epidemiología , Factores de Tiempo , Tromboembolia Venosa/etnología , Adulto JovenRESUMEN
Holliday junction (HJ) is a four-way structured DNA intermediate in homologous recombination. In bacteria, the HJ-specific binding protein RuvA and the motor protein RuvB together form the RuvAB complex to catalyze HJ branch migration. Pseudomonas aeruginosa (P. aeruginosa, Pa) is a ubiquitous opportunistic bacterial pathogen that can cause serious infection in a variety of host species, including vertebrate animals, insects and plants. Here, we describe the cryo-Electron Microscopy (cryo-EM) structure of the RuvAB-HJ intermediate complex from P. aeruginosa. The structure shows that two RuvA tetramers sandwich HJ at the junction center and disrupt base pairs at the branch points of RuvB-free HJ arms. Eight RuvB subunits are recruited by the RuvA octameric core and form two open-rings to encircle two opposite HJ arms. Each RuvB subunit individually binds a RuvA domain III. The four RuvB subunits within the ring display distinct subdomain conformations, and two of them engage the central DNA duplex at both strands with their C-terminal ß-hairpins. Together with the biochemical analyses, our structure implicates a potential mechanism of RuvB motor assembly onto HJ DNA.
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Many eukaryotic receptors and enzymes rely on glycosylphosphatidylinositol (GPI) anchors for membrane localization and function. The transmembrane complex GPI-T recognizes diverse proproteins at a signal peptide region that lacks consensus sequence and replaces it with GPI via a transamidation reaction. How GPI-T maintains broad specificity while preventing unintentional cleavage is unclear. Here, substrates- and products-bound human GPI-T structures identify subsite features that enable broad proprotein specificity, inform catalytic mechanism, and reveal a multilevel safeguard mechanism against its promiscuity. In the absence of proproteins, the catalytic site is invaded by a locally stabilized loop. Activation requires energetically unfavorable rearrangements that transform the autoinhibitory loop into crucial catalytic cleft elements. Enzyme-proprotein binding in the transmembrane and luminal domains respectively powers the conformational rearrangement and induces a competent cleft. GPI-T thus integrates various weak specificity regions to form strong selectivity and prevent accidental activation. These findings provide important mechanistic insights into GPI-anchored protein biogenesis.
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Aminoaciltransferasas , Glicosilfosfatidilinositoles , Humanos , Catálisis , Dominio Catalítico , LigandosRESUMEN
Iron deficiency is prevalent in women and patients with chronic kidney disease (CKD). Iron deficiency is not only related to anemia but contributes to adverse consequences for the kidney as well. Whether iron status is associated with renal outcomes after considering sex and anemia in patients with CKD stage 1-4 is unclear. Thus, we investigated the association of iron or iron saturation with renal outcomes in a CKD cohort. During a follow-up of 8.2 years, 781 (31.2%) patients met the composite renal outcome of renal replacement therapy and a 50% decline in renal function. In linear regression, iron was associated with sex, hemoglobin (Hb), and nutritional markers. In a fully adjusted Cox regression model, the male patients with normal iron had a significantly decreased risk of renal outcomes (hazard ratio (HR) 0.718; 95% confidence interval (CI) 0.579 to 0.889), but the female patients did not exhibit this association. The non-anemic patients (Hb ≥ 11 g/dL) had a decreased risk of renal outcomes (HR 0.715; 95% CI 0.568 to 0.898), but the anemic patients did not. In the sensitivity analysis, transferrin saturation (TSAT) showed similar results. When comparing iron and TSAT, both indicators showed similar prognostic values. In conclusion, iron deficiency, indicated by either iron or iron saturation, was associated with poor renal outcomes in the male or non-anemic patients with CKD stage 1-4.
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Non-insulin-based insulin resistance (IR) indices serve as the indicators of metabolic syndrome (MetS) but have limited value for predicting clinical outcomes. Whether the obesity paradox affects the predictive value of these indicators in patients with chronic kidney disease (CKD) remains unknown. We investigated whether MetS and non-insulin-based IR indices can predict all-cause mortality and renal outcomes in a prospective observational study with stage 1-4 CKD Asians (N = 2,457). These IR indices were associated with MetS. A Cox regression model including body mass index (BMI) revealed an association between MetS and renal outcomes. Among the IR indices, only high triglyceride-glucose (TyG) index was associated with adverse renal outcomes: the hazard ratio of Q4 quartile of the TyG index was 1.38 (1.12-1.70). All-cause mortality was marginally associated with MetS but not high IR indices. Low TyG and TyG-BMI indices as well as low BMI and triglyceride were paradoxically associated with increased risks of clinical outcomes. The triglyceride-to-high-density lipoprotein cholesterol ratio and metabolic score for IR indices were not associated with clinical outcomes. In conclusion, MetS and TyG index predict renal outcome and obesity paradox affects the prediction of IR indices in patients with stage 1-4 CKD.
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Kt/V and URR (urea reduction ratio) measurements represent dialysis adequacy. Single-pool Kt/V is theoretically a superior method and is recommended by the Kidney Disease Outcomes Quality Initiative guidelines. However, the prognostic value of URR compared with Kt/V for all-cause mortality is unknown. The effect modifiers and cut-off values of the two parameters have not been compared. We investigated 2615 incident hemodialysis patients with URR of 72% and Kt/V (Daugirdas) of 1.6. The average patient age was 59 years, 50.7% were female, and 1113 (40.2%) died within 10 years. URR and Kt/V were both positively associated with nutrition factors and female sex and negatively associated with body weight and heart failure. In Cox regression mod-els for all-cause mortality, the hazard ratios (HRs) of high URR groups (65-70%, 70-75%, and > 75%) and the URR < 65% group were 0.748 (0.623-0.898), 0.693 (0.578-0.829), and 0.640 (0.519-0.788), respectively. The HRs of high Kt/V groups (Kt/V 1.2-1.4, 1.4-1.7, and > 1.7) and the Kt/V < 1.2 group were 0.711 (0.580-0.873), 0.656 (0.540-0.799), and 0.623 (0.498-0.779), respec-tively. In subgroup analysis, Kt/V was not associated with all-cause mortality in women. The prognostic value of URR for all-cause mortality is as great as that of Kt/V. URR > 70% and Kt/V > 1.4 were associated with a higher survival rate. Kt/V may have weaker prognostic value for women.
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Fallo Renal Crónico , Diálisis Renal , Humanos , Femenino , Persona de Mediana Edad , Masculino , Pronóstico , Estudios de Seguimiento , Taiwán/epidemiología , Diálisis Renal/métodos , UreaRESUMEN
BACKGROUND: The association between autoimmune diseases and schizophrenia has rarely been systematically investigated. AIMS: To investigate the association between schizophrenia and a variety of autoimmune diseases and to explore possible gender variation in any such association. METHOD: Taiwan's National Health Insurance Research Database was used to identify 10 811 hospital in-patients with schizophrenia and 108 110 age-matched controls. Univariate and multiple logistic regression analyses were performed, separately, to evaluate the association between autoimmune diseases and schizophrenia. We applied the false discovery rate to correct for multiple testing. RESULTS: When compared with the control group, the in-patients with schizophrenia had an increased risk of Graves' disease (odds ratio (OR) = 1.32, 95% CI 1.04-1.67), psoriasis (OR = 1.48, 95% CI 1.07-2.04), pernicious anaemia (OR = 1.71, 95% CI 1.04-2.80), celiac disease (OR = 2.43, 95% CI 1.12-5.27) and hypersensitivity vasculitis (OR = 5.00, 95% CI 1.64-15.26), whereas a reverse association with rheumatoid arthritis (OR = 0.52, 95% CI 0.35-0.76) was also observed. Gender-specific variation was found for Sjögren syndrome, hereditary haemolytic anaemia, myasthenia gravis, polymyalgia rheumatica and dermatomyositis. CONCLUSIONS: Schizophrenia was associated with a greater variety of autoimmune diseases than was anticipated. Further investigation is needed to gain a better understanding of the aetiology of schizophrenia and autoimmune diseases.
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Enfermedades Autoinmunes/epidemiología , Esquizofrenia/epidemiología , Adulto , Distribución por Edad , Anciano , Enfermedades Autoinmunes/psicología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Análisis de Regresión , Distribución por Sexo , Factores Socioeconómicos , Taiwán/epidemiologíaRESUMEN
A high ultrafiltration rate (UFR) is associated with increased mortality in hemodialysis patients. However, whether a high UFR itself or heart failure with fluid overload followed by a high UFR causes mortality remains unknown. In this study, 2615 incident hemodialysis patients were categorized according to their initial cardiothoracic ratios (CTRs) to assess whether UFR was associated with mortality in patients with high or low CTRs. In total, 1317 patients (50.4%) were women and 1261 (48.2%) were diabetic. During 2246 (1087−3596) days of follow-up, 1247 (47.7%) cases of all-cause mortality were noted. UFR quintiles 4 and 5 were associated with higher risks of all-cause mortality than UFR quintile 2 in fully adjusted Cox regression analysis. As the UFR increased by 1 mL/kg/h, the risk of all-cause mortality increased 1.6%. Subgroup analysis revealed that in UFR quintile 5, hazard ratios (HRs) for all-cause mortality were 1.91, 1.48, 1.22, and 1.10 for CTRs of >55%, 50−55%, 45−50%, and <45%, respectively. HRs for all-cause mortality were higher in women and patients with high body weight. Thus, high UFRs may be associated with increased all-cause mortality in incident hemodialysis patients with a high CTR, but not in those with a low CTR.
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Eukaryotic cells are coated with an abundance of glycosylphosphatidylinositol anchor proteins (GPI-APs) that play crucial roles in fertilization, neurogenesis, and immunity. The removal of a hydrophobic signal peptide and covalent attachment of GPI at the new carboxyl terminus are catalyzed by an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among all eukaryotes. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GPI-T at a global 2.53-Å resolution, revealing an equimolar heteropentameric assembly. Structure-based mutagenesis suggests a legumain-like mechanism for the recognition and cleavage of proprotein substrates, and an endogenous GPI in the structure defines a composite cavity for the lipid substrate. This elongated active site, stemming from the membrane and spanning an additional ~22-Å space toward the catalytic dyad, is structurally suited for both substrates which feature an amphipathic pattern that matches this geometry. Our work presents an important step towards the mechanistic understanding of GPI-AP biosynthesis.
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Glicosilfosfatidilinositoles , Proteínas , Microscopía por Crioelectrón , Retículo Endoplásmico/metabolismo , Glicosilfosfatidilinositoles/química , Humanos , Señales de Clasificación de ProteínaRESUMEN
The incidence of hepatic steatosis is increasing globally, and it is important to identify those at risk to prevent comorbidities. Complete blood count is a simple, convenient, and inexpensive laboratory examination which can be used to obtain white blood cell (WBC) and platelet counts. The aims of this study were to investigate the relationships between WBC and platelet counts with hepatic steatosis, and whether WBC and platelet counts were associated with the severity of hepatic steatosis. We enrolled 1969 participants residing in southern Taiwan who took part in a health survey from June 2016 to September 2018 in this cross-sectional study. None of the participants were heavy alcohol users or had a history of hepatitis B or C. We collected laboratory data, and the severity of hepatic steatosis was determined by abdominal ultrasound. The overall prevalence rate of hepatic steatosis was 42.0%. There were significant trends of stepwise increases in WBC count (p < 0.001) corresponding to the severity of hepatic steatosis. After multivariable linear regression analysis, hepatic steatosis was significantly associated with high WBC count (coefficient ß, 0.209; 95% confidence interval (CI), 0.055 to 0.364; p = 0.008) and high platelet count (coefficient ß, 12.213; 95% CI, 6.092 to 18.334; p < 0.001); also, higher WBC counts corresponded with the severity of hepatic steatosis.
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Krüppel-like factor 4 (KLF4), a key transcription factor, acts as a multifunctional player involved in the progression of numerous aggressive cancers. The proteasome-dependent pathway is one of the main modalities in controlling KLF4 abundance at a posttranslational level. Although some of the ubiquitin ligases have been identified, the deubiquitinases of KLF4 and the regulatory function remain unexplored. Here, by screening ubiquitin-specific proteases that may interact with KLF4, we found ubiquitin-specific peptidase 10 (USP10) as a deubiquitinating enzyme for KLF4. Forced expression of USP10 remarkably increases KLF4 protein level by blocking the latter degradation, whereas the depletion of USP10 promotes KLF4 degradation and thus enhances tumorigenesis. Loss of USP10 in mice downregulates KLF4 expression and accelerates KrasG12D-driven lung adenocarcinoma initiation and progression. In addition, our data revealed that KLF4 can facilitate the transcription of tumor suppressor TIMP3 by directly binding to the TIMP3 promoter. Clinically, reduction of USP10 expression, concomitant with decreased KLF4 and TIMP3 abundance in carcinoma tissue, predicts poor prognosis of lung cancer patient. Taken together, our results demonstrate that USP10 is a critical regulator of KLF4, pinpointing USP10-KLF4-TIMP3 axis as a promising therapeutic target in lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Pulmonares/metabolismo , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Células A549 , Animales , Carcinogénesis , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/fisiología , Masculino , Ratones , Ratones Noqueados , Ratones Desnudos , UbiquitinaciónRESUMEN
BACKGROUND: The capacity to regulate emotion is important for individuals' ability to adapt to society, the long-term lack of which can lead to related emotional disorders. However, evaluating whether an emotion-regulation strategy is appropriate requires consideration of the individual's distinct culture and situation. In this study, we compared the anger regulation strategies employed in various interpersonal situations by psychiatric outpatients and a community control group in Taiwan. METHODS: We surveyed 150 psychiatric outpatients (mean age = 45.30, SD = 12.48, 73.3% female) and 150 community controls (mean age = 45.05, SD = 12.24, 73.3% female) congruent in age and sex. Participants evaluated their emotion regulation in two interpersonal contexts by completing a set of questionnaires related to a recent incident of anger they experienced with family and friends, respectively. RESULTS: Outpatients used the emotion-regulation strategies of cognitive reappraisal and expressive suppression equally in various relationships; while the community control group made more use of cognitive reappraisal to regulate anger, which arose in their relationships with both family and friends. Relationship intimacy influenced the strategy adopted, and the community control group was more likely to use suppression to regulate anger towards friends than family members, which reflected a cultural belief-maintaining harmony in social relationships. LIMITATIONS: Context-specific emotion regulation was assessed via a retrospective self-report measure, which is subject to recall bias. CONCLUSIONS: Our findings highlight the importance of considering interpersonal contexts when studying emotion regulation and developing psychological interventions that target anger or other negative emotion regulation.
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Many studies have uncovered the essential role of ZBTB7A in regulating tumourigenesis. However, its functional significance in cell responses to endoplasmic reticulum stress (ER stress) remains poorly understood. Here we report that ZBTB7A functions as an important prosurvival factor in osteosarcoma cells undergoing pharmacological ER stress-induced by tunicamycin (TM) or thapsigargin (TG). The downregulation of ZBTB7A expression by ER stress promoted cell apoptosis in vitro and in vivo. ZBTB7A expression levels were increased in osteosarcoma tissues and elevated ZBTB7A was associated with osteosarcoma metastasis. Further mechanistic studies revealed that miR-663a induced by ER stress directly bound to the 3'UTR of ZBTB7A and contributed to ER stress-induced ZBTB7A downregulation in osteosarcoma cells. Additionally, our data revealed that ZBTB7A bound to the promoter of LncRNA GAS5 and transcriptionally suppressed LncRNA GAS5 expression, leading to a decline in ER stress-induced cell apoptosis. Collectively, our findings reveal the prosurvival role of ZBTB7A in osteosarcoma adaptation to ER stress and suggest that the miR-663a-ZBTB7A-LncRNAGAS5 pathway is essential for the survival of human osteosarcoma cells under ER stress.
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Apoptosis/fisiología , Proteínas de Unión al ADN/fisiología , Estrés del Retículo Endoplásmico/fisiología , MicroARNs/fisiología , Osteosarcoma/metabolismo , ARN Largo no Codificante/metabolismo , Factores de Transcripción/fisiología , Línea Celular Tumoral , Humanos , Osteosarcoma/genéticaRESUMEN
Bipolar disorder (BD) is highly heritable and well known for its recurrent manic and depressive episodes. The present study focused on manic episode in BD patients and aimed to investigate state-specific transcriptome alterations between acute episode and remission, including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and micro-RNAs (miRNAs), using microarray and RNA sequencing (RNA-Seq) platforms. BD patients were enrolled with clinical information, and peripheral blood samples collected at both acute and remission status spanning for at least 2 months were confirmed by follow-ups. Symptom severity was assessed by Young Mania Rating Scale. We enrolled six BD patients as the discovery samples and used the Affymetrix Human Transcriptome Array 2.0 to capture transcriptome data at the two time points. For replication, expression data from Gene Expression Omnibus that consisted of 11 BD patients were downloaded, and we performed a mega-analysis for microarray data of 17 patients. Moreover, we conducted RNA sequencing (RNA-Seq) in additional samples of 7 BD patients. To identify intraindividual differentially expressed genes (DEGs), we analyzed data using a linear model controlling for symptom severity. We found that noncoding genes were of majority among the top DEGs in microarray data. The expression fold change of coding genes among DEGs showed moderate to high correlations (â¼0.5) across platforms. A number of lncRNAs and two miRNAs (MIR181B1 and MIR103A1) exhibited high levels of gene expression in the manic state. For coding genes, we reported that the taste function-related genes, including TAS2R5 and TAS2R3, may be mania state-specific markers. Additionally, four genes showed a nominal p-value of less than 0.05 in all our microarray data, mega-analysis, and RNA-Seq analysis. They were upregulated in the manic state and consisted of MS4A14, PYHIN1, UTRN, and DMXL2, and their gene expression patterns were further validated by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR). We also performed weight gene coexpression network analysis to identify gene modules for manic episode. Genes in the mania-related modules were different from the susceptible loci of BD obtained from genome-wide association studies, and biological pathways in relation to these modules were mainly related to immune function, especially cytokine-cytokine receptor interaction. Results of the present study elucidated potential molecular targets and genomic networks that are involved in manic episode. Future studies are needed to further validate these biomarkers for their roles in the etiology of bipolar illness.