Sex-specific resting state brain network dynamics in patients with major depressive disorder.

Sex-specific neurobiological changes have been implicated in Major Depressive Disorder (MDD). Dysfunctions of the default mode network (DMN), salience network (SN) and frontoparietal network (FPN) are critical neural characteristics of MDD, however, the potential moderating role of sex on resting-state network dynamics in MDD has not been sufficiently evaluated. Thus, resting-state functional magnetic resonance imaging (fMRI) data were collected from 138 unmedicated patients with first-episode MDD (55 males) and 243 healthy controls (HCs; 106 males). Recurring functional network co-activation patterns (CAPs) were extracted, and time spent in each CAP (the total amount of volumes associated to a CAP), persistence (the average number of consecutive volumes linked to a CAP), and transitions across CAPs involving the SN, DMN and FPN were quantified. Relative to HCs, MDD patients exhibited greater persistence in a CAP involving activation of the DMN and deactivation of the FPN (DMN + FPN-). In addition, relative to the sex-matched HCs, the male MDD group spent more time in two CAPs involving the SN and DMN (i.e., DMN + SN- and DMN-SN + ) and transitioned more frequently from the DMN + FPN- CAP to the DMN + SN- CAP relative to the male HC group. Conversely, the female MDD group showed less persistence in the DMN + SN- CAP relative to the female HC group. Our findings highlight that the imbalance between SN and DMN could be a neurobiological marker supporting sex differences in MDD. Moreover, the dominance of the DMN accompanied by the deactivation of the FPN could be a sex-independent neurobiological correlate related to depression.

The degradation of TGR5 mediated by Smurf1 contributes to diabetic nephropathy.

The multiple roles of TGR5 in the regulation of glucose metabolism, inflammation, and oxidative stress have drawn attention as therapeutic candidates for diabetes-related kidney disease. However, diabetes induces downregulation of renal TGR5 protein expression, and the regulatory mechanisms have not been clarified. Here, we identify that Smurf1, an E3 ubiquitin ligase, is a critical interactor of TGR5 and mediates the ubiquitination and proteasomal degradation of TGR5 under high glucose stimulation in glomerular mesangial cells. Genetic deficiency of Smurf1 restores TGR5 protein expression and attenuates renal injuries in diabetic mice. Mechanistically, Smurf1 interacts with the TGR5 ICL2 region by its HECT domain and induces K11/K48-linked polyubiquitination of TGR5 at K306 residue. Moreover, restoration of TGR5 protects db/db mice from diabetic nephropathy. These observations elucidate the critical role of Smurf1 in regulating TGR5 stability, suggesting that pharmacological targeting of the interaction between Smurf1 and TGR5 could serve as a promising therapeutic strategy against diabetic nephropathy.

Fraxin represses NF-κB pathway via inhibiting the activation of epidermal growth factor receptor to ameliorate diabetic renal tubulointerstitial fibrosis.

Renal tubulointerstitial fibrosis (RIF), featured by epithelial-to-mesenchymal-transition (EMT) of renal tubular epithelial cells and collagen deposition in the renal interstitial region, is the main pathological change of diabetic nephropathy (DN). Fraxin, the main active component of Fraxinus rhynchophylla Hance with anti-inflammatory activity, has been demonstrated to ameliorate glomerulosclerosis. However, the regulatory role of Fraxin on diabetic RIF remains unclear. In this study, we investigated the renal protective benefits of Fraxin against diabetic RIF and elucidated its mechanisms. In vitro, Fraxin inhibited the abnormal expression of EMT-related markers and proinflammatory cytokines, improved cellular morphology, and subsequently reduced the extracellular matrix (ECM) production in high glucose (HG)-induced NRK-52E cells. In vivo, Fraxin effectively ameliorated renal function, inhibited the abnormal expression of EMT-related markers and proinflammatory cytokines, and reduced ECM deposition in renal tubule interstitium in db/db mice. Notably, Fraxin could directly bind to epidermal growth factor receptor (EGFR), which contributed to the inhibition of EGFR phosphorylation and counteracted the activation of c-Src/NF-κB pathway, eventually ameliorating RIF. Thus, Fraxin may be a potential drug candidate for treating DN.

System analysis of Huang-Lian-Jie-Du-Tang and their key active ingredients for overcoming CML resistance by suppression of leukemia stem cells.

BACKGROUND: BCR-ABL1-based resistance to imatinib, mainly resulting from BCR-ABL1 mutations, is largely solved after second- and third-generation tyrosine kinase inhibitors (TKIs) are discovered. Nonetheless, imatinib resistance without BCR-ABL1 mutations, including intrinsic resistance induced by stem cells within chronic myeloid leukemia (CML), remains the major clinical challenge for many patients. PURPOSE: To study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang (HLJDT) against BCR-ABL1-independent CML resistance to therapeutics, and then explore its mechanism of against CML drug resistance. METHODS: Cytotoxicity of HLJDT and its active ingredients in BCR-ABL1-independent imatinib resistance cells was analyzed through MTT assay. The cloning ability was measured through soft agar assay. Monitoring therapeutic effect on Xenografted mice CML model by in vivo imaging technology and mice survival time. Predicting the potential target protein binding sites by the technology of photocrosslinking sensor chip, molecular space simulation docking, and use Surface Plasmon Resonance (SPR) technology . Flow cytometry to detect the ratio of stem progenitor cells (CD34+). Constructing bone marrow transplantation mice CML leukemia model, detect the effects on leukemia stem cells LSK (Lin-\ Sca-1+ \C-kit+) self-renewal. RESULTS: Treatment with HLJDT, berberine and baicalein inhibited cell viability and colony formation of BCR-ABL1-independent imatinib-resistant cells in vitro while prolonging survival in mouse with CML xenografts and transplatation CML-like mouse models in vivo. JAK2 and MCL1were identified as targets of berberine and baicalein. JAK2 and MCL1 are involved in multi-leukemia stem cell-related pathways. Moreover, the ratio of CD34+ cells in resistant CML cells is higher than in treatment-sensitive CML cells. Treatment with BBR or baicalein partially suppressed CML leukemic stem cells (LSCs) self-renewal in vitro and in vivo. CONCLUSION: From the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.

PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration.

A large proportion of patients with chronic myeloid leukemia (CML; 20%-50%) develop resistance to imatinib in a BCR-ABL1-independent manner. Therefore, new therapeutic strategies for use in this subset of imatinib-resistant CML patients are urgently needed. In this study, we used a multi-omics approach to show that PPFIA1 was targeted by miR-181a. We demonstrate that both miR-181a and PPFIA1-siRNA reduced the cell viability and proliferative capacity of CML cells in vitro, as well as prolonged the survival of B-NDG mice harboring human BCR-ABL1-independent imatinib-resistant CML cells. Furthermore, treatment with miR-181a mimic and PPFIA1-siRNA inhibited the self-renewal of c-kit+ and CD34+ leukemic stem cells and promoted their apoptosis. Small activating (sa)RNAs targeting the promoter of miR-181a increased the expression of endogenous primitive miR-181a (pri-miR-181a). Transfection with saRNA 1-3 inhibited the proliferation of imatinib-sensitive and -resistant CML cells. However, only saRNA-3 showed a stronger and more sustained inhibitory effect than the miR-181a mimic. Collectively, these results show that miR-181a and PPFIA1-siRNA may overcome the imatinib resistance of BCR-ABL1-independent CML, partially by inhibiting the self-renewal of leukemia stem cells and promoting their apoptosis. Moreover, exogenous saRNAs represent promising therapeutic agents in the treatment of imatinib-resistant BCR-ABL1-independent CML.

Ginsenoside Rb1 promotes the activation of PPARα pathway via inhibiting FADD to ameliorate heart failure.

PURPOSE: Ginsenoside Rb1 (GRb1), a dammarane-type triterpene saponin compound mainly distributed in ginseng (Panax ginseng), has been demonstrated to ameliorate cardiovascular diseases. However, it remains unclear whether GRb1 alleviates heart failure (HF) by maintaining cardiac energy metabolism balance. Therefore, this work aimed to investigate the cardiac benefits of GRb1 against cardiac energy deficit and explore its mechanism of action. METHODS AND RESULTS: Isoproterenol (ISO) induced HF Sprague-Dawley rats were administrated with GRb1 or fenofibrate for 6 weeks. ISO-induced primary neonatal rat cardiomyocytes (NRCMs) were used as the in vitro model. In vivo, GRb1 significantly improved the structural and metabolic disorder, as demonstrated by the restoration of cardiac function, inhibition of cardiac hypertrophy and fibrosis, and increased adenosine triphosphate (ATP) generation. In vitro, GRb1 effectively protected mitochondrial function and scavenged excessive reactive oxygen species. Moreover, in ISO-induced NRCMs, GRb1 significantly inhibited the abnormal upregulation of Fas-associated death domain (FADD), promoted transcriptional activation of peroxisome proliferator-activated receptor-alpha (PPARα), improved the aberrant expression of cardiac energy metabolism-related enzymes and cardiac fatty acid oxidation, and subsequently increased the synthesis of ATP. Noticeably, GRb1 could inhibit the increased binding between FADD and PPARα, which contributed to the activation of PPARα. Furthermore, GRb1 strengthened the thermal stabilization of FADD and might bind to FADD directly. CONCLUSIONS: Collectively, it's part of the in-depth mechanism of GRb1's cardio-protection that GRb1 could directly bind to FADD and counteract its negative role in the transcription of PPARα thus ameliorating cardiac energy derangement and HF.

Single-cell resolution reveals RalA GTPase expanding hematopoietic stem cells and facilitating of BCR-ABL1-driven leukemogenesis in a CRISPR/Cas9 gene editing mouse model.

BCR-ABL oncogene-mediated Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) is suggested to originate from leukemic stem cells (LSCs); however, factors regulating self-renewal of LSC and normal hematopoietic stem cells (HSCs) are largely unclear. Here, we show that RalA, a small GTPase in the Ras downstream signaling pathway, has a critical effect on regulating the self-renewal of LSCs and HSCs. A RalA knock-in mouse model (RalARosa26-Tg/+) was initially constructed on the basis of the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) assay to analyze normal hematopoietic differentiation frequency using single-cell resolution and flow cytometry. RalA overexpression promoted cell cycle progression and increased the frequency of granulocyte-monocyte progenitors (GMPs), HSCs and multipotent progenitors (MPPs). The uniform manifold approximation and projection (UMAP) plot revealed heterogeneities in HSCs and progenitor cells (HSPCs) and identified the subclusters of HSCs and GMPs with a distinct molecular signature. RalA also promoted BCR-ABL-induced leukemogenesis and self-renewal of primary LSCs and shortened the survival of leukemic mice. RalA knockdown prolonged survival and promoted sensitivity to imatinib in a patient-derived tumor xenograft model. Immunoprecipitation plus single-cell RNA sequencing of the GMP population confirmed that RalA induced this effect by interacting with RAC1. RAC1 inhibition by azathioprine effectively reduced the self-renewal, colony formation ability of LSCs and prolonged the survival in BCR-ABL1-driven RalA overexpression CML mice. Collectively, RalA was detected to be a vital factor that regulates the abilities of HSCs and LSCs, thus facilitating BCR-ABL-triggered leukemia in mice. RalA inhibition serves as the therapeutic approach to eradicate LSCs in CML.

Connexin32 Promotes the Activation of Foxo3a to Ameliorate Diabetic Nephropathy via Inhibiting the Polyubiquitination and Degradation of Sirt1.

Aims: Renal oxidative stress (OSS) is the leading cause of diabetic nephropathy (DN). The silent information regulator 1/forkhead boxo3a (Sirt1/Foxo3a) pathway plays an essential role in regulating the antioxidant enzyme system. In this study, we aimed to investigate the mechanism of connexin32 (Cx32) on the antioxidant enzyme system in DN. Results: In this study, Cx32 overexpression significantly reduced reactive oxygen species generation and effectively inhibited the excessive production of extracellular matrix such as fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1) in high-glucose (HG)-induced glomerular mesangial cells. In addition, Cx32 overexpression reversed the downregulation of Sirt1, and promoted the nuclear transcription of Foxo3a, subsequently activating the antioxidant enzymes including catalase and manganese superoxide dismutase (MnSOD), however, Cx32 knockdown showed the opposite effects. A further mechanism study showed that Cx32 promoted the autoubiquitination and degradation of Smad ubiquitylation regulatory factor-1 (Smurf1), thereby reducing the ubiquitination of Sirt1 at Lys335 and the degradation of Sirt1. Moreover, the in vivo results showed that adenovirus-mediated Cx32 overexpression activated the Sirt1/Foxo3a pathway, and inhibited OSS in the kidney tissues, eventually improving the renal function and glomerulosclerosis in diabetic mice. Innovation: This study highlighted the antioxidant role of Cx32-Sirt1-Foxo3a axis to alleviate DN, which is a new mechanism of Cx32 alleviating DN. Conclusion: Cx32 alleviated DN via activating the Sirt1/Foxo3a antioxidant pathway. The specific mechanism was that Cx32 upregulated the Sirt1 expression through reducing the ubiquitination of Lys335 of Sirt1 by inhibiting Smurf1. Antioxid. Redox Signal. 39, 241-261.

Fyn deficiency inhibits oxidative stress by decreasing c-Cbl-mediated ubiquitination of Sirt1 to attenuate diabetic renal fibrosis.

OBJECTIVE: Oxidative stress (OS) is the main cause leading to diabetic renal fibrosis. Recently, Fyn was paid much attention on OS and emerged as a pivotal player in acute kidney injury, while whether Fyn regulates oxidative stress in chronic diabetes nephropathy (DN) has not been clarified yet. The purpose of this study was to identify the role of Fyn in DN and elucidated its regulatory mechanism. METHODS: The db/db mice and littermate control C57BKS/J mice were injected by tail vein with Fyn interfering adenovirus or Fyn overexpressing adenovirus to investigate the role of Fyn in vivo. Primary glomerular mesangial cells (GMCs) were used for in vitro studies. RESULTS: Fyn was up-regulated in high glucose (HG)-induced GMCs and kidneys of diabetic mice. Additionally, Fyn knockdown reduced the level of OS in HG-induced GMCs and kidneys of diabetic mice, thereby ameliorating diabetic renal fibrosis. While overexpression of Fyn significantly increased the level of OS in GMCs and kidney tissues, resulting in renal damage. Moreover, Fyn deficiency exerted antioxidant effects by activating the Sirt1/Foxo3a pathway. Mechanistically, Fyn facilitated the combination of c-Cbl and Sirt1 by phosphorylating c-Cbl at Tyr731, which triggered K48-linked polyubiquitination of Sirt1 at Lys377 and Lys513 by c-Cbl and promoted Sirt1 degradation, impairing the antioxidant effects of Foxo3a. CONCLUSIONS: Fyn deficiency promoted Foxo3a nuclear transcription via reducing the ubiquitination of Sirt1 by c-Cbl, thereby alleviating renal oxidative damage in diabetic mice. These results identified Fyn as a potential therapeutic target against DN.

The ubiquitination of CKIP-1 mediated by Src aggravates diabetic renal fibrosis (original article).

Renal chronic inflammation is an important hallmark of diabetic renal fibrosis. Casein kinase 2 interacting protein 1 (CKIP-1) performs a nephroprotective role in the pathogenesis of diabetic nephropathy (DN), which is dramatically decreased in diabetic kidneys. However, whether CKIP-1 regulates inflammation to ameliorate renal fibrosis remains unclear and it is interesting to clarify the degradation mechanism of CKIP-1. Here, we identified CKIP-1 expression was down-regulated in diabetic kidneys and knockout (KO) of CKIP-1 increased c-Jun expression and extra cellular matrix (ECM) in kidneys of normal mice, and knockout (KO) of CKIP-1 further exacerbated renal inflammatory fibrosis in diabetic mice. Moreover, the activated Src kinase interacted with CKIP-1 at Lys252 and increased K48 linked polyubiquitination and proteasome degradation of CKIP-1 in HG induced GMCs and diabetic kidneys. Mechanistically, Src facilitating the binding of c-Cbl with CKIP-1 by promoting the phosphorylation of c-Cbl, thereby increasing Cbl-mediated ubiquitination of CKIP-1 to down-regulate CKIP-1 protein expression. Thus, our study highlighted the anti-inflammation role of CKIP-1 and clarified the mechanism of CKIP-1 degradation in DN.

Discovery of the oncogenic MDM2, a direct binding target of berberine and a potential therapeutic, in multiple myeloma.

Recent studies have suggested the potency of berberine (BBR) for multiple cancer treatments, including multiple myeloma (MM). However, the direct target and underlying mechanism of BBR remain largely understood in MM. Here, we demonstrated that BBR inhibited cell proliferation and acted synergistically with bortezomib in MM.1S cells. BBR treatment induced MM cell cycle arrest by downregulating several cell cycle-related proteins. Murine double minute 2 (MDM2) as a BBR-binding protein was identified by surface plasmon resonance image (SPRi) analysis and molecular docking. Overexpression of MDM2 is associated with MM progression and a poor prognosis. Knockdown MDM2 by siRNA transfection can repress MM malignant progression and attenuate the BBR sensitivity to MM.1S cells. BBR treatment induced the degradation of MDM2 through the ubiquitin-proteasome system and reactivated P53/P21 in MM cells. Overall, our data has illustrated that MDM2, as a binding protein of BBR for the first time, may serve as a potential therapeutic option for MM.

Fraxin Promotes the Activation of Nrf2/ARE Pathway via Increasing the Expression of Connexin43 to Ameliorate Diabetic Renal Fibrosis.

Diabetic nephropathy (DN) is quickly becoming the largest cause of end-stage renal disease (ESRD) in diabetic patients, as well as a major source of morbidity and mortality. Our previous studies indicated that the activation of Nrf2/ARE pathway via Connexin43 (Cx43) considerably contribute to the prevention of oxidative stress in the procession of DN. Fraxin (Fr), the main active glycoside of Fraxinus rhynchophylla Hance, has been demonstrated to possess many potential pharmacological activities. Whereas, whether Fr could alleviate renal fibrosis through regulating Cx43 and consequently facilitating the activation of Nrf2/ARE pathway needs further investigation. The in vitro results showed that: 1) Fr increased the expression of antioxidant enzymes including SOD1 and HO-1 to inhibit high glucose (HG)-induced fibronectin (FN) and inflammatory cell adhesion molecule (ICAM-1) overexpression; 2) Fr exerted antioxidant effect through activating the Nrf2/ARE pathway; 3) Fr significantly up-regulated the expression of Cx43 in HG-induced glomerular mesangial cells (GMCs), while the knock down of Cx43 largely impaired the activation of Nrf2/ARE pathway induced by Fr; 4) Fr promoted the activation of Nrf2/ARE pathway via regulating the interaction between Cx43 and AKT. Moreover, in accordance with the results in vitro, elevated levels of Cx43, phosphorylated-AKT, Nrf2 and downstream antioxidant enzymes related to Nrf2 were observed in the kidneys of Fr-treated group compared with model group. Importantly, Fr significantly improved renal dysfunction pathological changes of renal fibrosis in diabetic db/db mice. Collectively, Fr could increase the Cx43-AKT-Nrf2/ARE pathway activation to postpone the diabetic renal fibrosis and the up-regulation of Cx43 is probably a novel mechanism in this process.

Distinct stress-related medial prefrontal cortex activation in women with depression with and without childhood maltreatment.

BACKGROUND: Emerging evidence has highlighted the moderating effect of childhood maltreatment (CM) in shaping neurobiological abnormalities in major depressive disorder (MDD). However, whether neural mechanisms underlying stress sensitivity in MDD are affected by the history of CM is unclear. METHODS: Two hundred and thirteen medication-free female participants were recruited for a functional magnetic resonance imaging study assessing the effects of psychosocial stress on neural responses. The Montreal Imaging Stress Task was administrated to 44 female MDD patients with CM (MDD/CM), 32 female MDD patients without CM (MDD/noCM), 43 female healthy controls (HCs) with CM (HC/CM), and 94 female HCs without CM (HC/noCM). A CM (CM, noCM) × diagnosis (MDD, HC) whole-brain voxel-wise analysis was run to assess putative group differences in neural stress responses. RESULTS: A significant CM × Diagnosis interaction emerged in the medial prefrontal cortex (mPFC). Bonferroni-corrected simple effects analysis clarified that (1) the MDD/CM group had less mPFC deactivation than the HC/CM group, (2) the MDD/noCM group exhibited greater mPFC deactivation than the HC/noCM group, and (3) the MDD/CM group exhibited less mPFC deactivation relative to the MDD/noCM group. In addition, the mPFC-seed psychophysiological interaction analysis revealed that individuals in the CM groups had significantly greater stress-related mPFC-left superior frontal gyrus and mPFC-right posterior cerebellum connectivity relative to the noCM groups. CONCLUSIONS: Findings highlight distinct neural abnormalities in MDD depending on prior CM history, particularly potentiated stress-related mPFC recruitment among MDD individuals reporting CM. Moreover, CM history was generally associated with the disruption in functional connectivity centered on the mPFC.

Targeting SOS1 overcomes imatinib resistance with BCR-ABL independence through uptake transporter SLC22A4 in CML.

Resistance to the BCR-ABL inhibitor imatinib mesylate poses a major problem for the treatment of chronic myeloid leukemia. Imatinib resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, sometimes there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent imatinib mesylate resistance remains to be elucidated. SOS1, a guanine nucleotide exchange factor for Ras protein, affects drug sensitivity and resistance to imatinib. The depletion of SOS1 markedly inhibits cell growth either in vitro or in vivo and significantly increases the sensitivity of chronic myeloid leukemia cells to imatinib. Furthermore, LC-MS/MS and RNA-seq assays reveal that SOS1 negatively regulates the expression of SLC22A4, a member of the carnitine/organic cation transporter family, which mediates the active uptake of imatinib into chronic myeloid leukemia cells. HPLC assay confirms that intracellular accumulation of imatinib is accompanied by upregulation of SLC22A4 through SOS1 inhibition in both sensitive and resistant chronic myeloid leukemia cells. BAY-293, an inhibitor of SOS1/Ras, was found to depress proliferation and colony formation in chronic myeloid leukemia cells with resistance and BCR-ABL independence. Altogether these findings indicate that targeting SOS1 inhibition promotes imatinib sensitivity and overcomes resistance with BCR-ABL independence by SLC22A4-mediated uptake transport.

Potential structural trait markers of depression in the form of alterations in the structures of subcortical nuclei and structural covariance network properties.

It has been proposed recently that major depressive disorder (MDD) could represent an adaptation to conserve energy after the perceived loss of an investment in a vital source, such as group identity, personal assets, or relationships. Energy conserving behaviors associated with MDD may form a persistent marker in brain regions and networks involved in cognition and emotion regulation. In this study, we examined whether subcortical regions and volume-based structural covariance networks (SCNs) have state-independent alterations (trait markers). First-episode drug-naïve currently depressed (cMDD) patients (N = 131), remitted MDD (RD) patients (N = 67), and healthy controls (HCs, N = 235) underwent structural magnetic resonance imaging (MRI). Subcortical gray matter volumes (GMVs) were calculated in FreeSurfer software, and group differences in GMVs and SCN were analyzed. Compared to HCs, major findings were decreased GMVs of left pallidum and pulvinar anterior of thalamus in the cMDD and RD groups, indicative of a trait marker. Relative to HCs, subcortical SCNs of both cMDD and RD patients were found to have reduced small-world-ness and path length, which together may represent a trait-like topological feature of depression. In sum, the left pallidum, left pulvinar anterior of thalamus volumetric alterations may represent trait marker and reduced small-world-ness, path length may represent trait-like topological feature of MDD.

Sustained Attention Deficits in Adults With Juvenile-Onset Type 1 Diabetes Mellitus.

OBJECTIVE: This study aimed to investigate whether patients with juvenile-onset type 1 diabetes mellitus (T1DM) have poorer sustained attention than their counterparts with adult-onset T1DM, and whether there is a relationship between diabetes-related variables and sustained attention. METHODS: This study included 76 participants with juvenile-onset T1DM, 68 participants with adult-onset T1DM, and 85 healthy controls (HCs). All participants completed the Sustained Attention to Response Task, Beck Depression Inventory-II, and the Chinese version of the Wechsler Adult Intelligence Scale. RESULTS: The juvenile-onset group showed more omission errors (p = .007) than the adult-onset group and shorter reaction time (p = .005) than HCs, whereas the adult-onset group showed no significant differences compared with HCs. Hierarchical linear regression analysis revealed that the age of onset was associated with omission errors in T1DM participants (ß = -0.275, t = -2.002, p = .047). In the juvenile-onset group, the omission error rate were associated with the history of severe hypoglycemia (ß = 0.225, t = 1.996, p = .050), whereas reaction time was associated with the age of onset (ß = -0.251, t = -2.271, p = .026). Fasting blood glucose levels were significantly associated with reaction time in both the juvenile-onset and adult-onset groups (ß = -0.236, t = -2.117, p = .038, and ß = 0.259, t = 2.041, p = .046, respectively). CONCLUSIONS: Adults with juvenile-onset T1DM have sustained attention deficits in contrast to their adult-onset counterparts, suggesting that the disease adversely affects the developing brain. Both the history of severe hypoglycemia and fasting blood glucose levels are factors associated with sustained attention impairment. Early diagnosis and treatment in juvenile patients are required to prevent the detrimental effects of diabetes.

The MAOA Gene Influences the Neural Response to Psychosocial Stress in the Human Brain.

The stress response is regulated by many mechanisms. Monoamine oxidase A (MAOA) has been related to many mental illnesses. However, few studies have explored the relationship between MAOA and acute laboratory-induced psychosocial stress with functional magnetic resonance imaging (fMRI). In the current study, the Montreal Imaging Stress Task (MIST) and fMRI were used to investigate how MAOA influences the stress response. Increased cortisol concentrations were observed after the task; functional connectivity between the bilateral anterior hippocampus and other brain regions was reduced during stress. MAOA-H allele carriers showed greater deactivation of the right anterior hippocampus and greater cortisol response after stress than did MAOH-L allele carriers. Hippocampal deactivation may lead to disinhibition of the hypothalamic-pituitary-adrenal (HPA) axis and the initiation of stress hormone release under stress. Our results suggest that the MAOA gene regulates the stress response by influencing the right anterior hippocampus.

Influence of psychosocial stress on activation in human brain regions: moderation by the 5-HTTLPR genetic locus.

Variants of the serotonin transporter linked polymorphic region (5-HTTLPR) of the serotonin transporter gene SLC6A4 have been related with the onset of depression, anxiety, and other mental disorders. Homozygotes for the short 5-HTTLPR variant, referred to as the SS genotype, have greater cortisol responses to experimentally induced psychosocial stress. In the current study, we used functional magnetic resonance imaging (fMRI) to compare regional brain activations across 5-HTTLPR genotypes in subjects performing the Montreal Imaging Stress Task (MIST). Subjects with an SS genotype had significant greater increases in cortisol concentrations after the task than subjects with at least one long 5-HTTLPR allele. Additionally, relative to L carriers, the SS group had greater activation in the dorsomedial prefrontal cortex(dmPFC), dorsal anterior cingulate cortex, anterior insula.

Neuroticism modulates neural activities of posterior cingulate cortex and thalamus during psychosocial stress processing.

OBJECTIVE: Individuals with higher neuroticism are vulnerable to stress and are prone to develop depression, however, the neural mechanisms underlying it have not been clarified clearly. METHOD: The Montreal Imaging Stress Task (MIST) was administered to 148 healthy adults during functional magnetic resonance imaging (fMRI). Whole-brain voxel-wise regression analyses were used to detect associations of neuroticism with neural activity involved in perceiving and processing psychosocial stress. In addition, two-sample t-tests were conducted between the high-neurotic and low-neurotic group in order to supplement the results found in regression analyses. RESULTS: Higher neuroticism scores were associated with higher activities in the posterior cingulate cortex (PCC)/precuneus and thalamus (p < 0.05, false discovery rate correction). Moreover, two sample t-tests also revealed that the high-neurotic group had higher neural stress responses in precuneus and bilateral thalamus in comparison to the low-neurotic group (p < 0.05, false discovery rate correction). LIMITATIONS: Our study mainly recruited young adults, which may limit the generalizability of our findings. CONCLUSIONS: Our findings highlight the crucial role of PCC/precuneus and thalamus in the association between neuroticism and stress and may provide insight into the cognitive model of depression.

State-independent and -dependent structural alterations in limbic-cortical regions in patients with current and remitted depression.

BACKGROUND: The high recurrence of major depressive disorder (MDD) may derive from underlying state-independent structural alterations. METHODS: First-episode drug-naïve currently depressed (cMDD) patients (N = 97), remitted depressed (RD) patients (N = 72), and healthy controls (HCs, N = 100) underwent structural magnetic resonance imaging (MRI). Group differences in cortical thickness (CT), surface area (SA), and local gyrification index (lGI) were analyzed in FreeSurfer. RESULTS: Both groups of depressed patients had significantly decreased CT, relative to HCs, in the left precentral gyrus and significantly increased lGI values in the left superior frontal gyrus (SFG) indicative of state-independent alterations. Relative to HCs, the cMDD group had decreased CT of the SFG, caudal middle frontal gyrus (MFG), posterior cingulate cortex (PCC), and lateral occipital regions as well as increased SA or lGI of the superior temporal gyrus, precuneus, and pericalcarine, whereas the RD group had increased SA or lGI of the SFG, caudal MFG, and supramarginal gyrus; these alterations appeared to be state-dependent. SA or lGI values of the fusiform gyrus, inferior temporal gyrus, and superior parietal lobule differed between the cMDD and RD groups, consistent with state-dependent alterations. Beck depression inventory scores correlated with CT or lGI values of the caudal MFG, lateral occipital cortex in depressed patients. LIMITATIONS: The structural features of several subcortical limbic regions were not analyzed. CONCLUSIONS: Left precentral gyrus CT and left SFG gyrification alterations may represent state-independent alterations in MDD.