Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

Abstract Sepsis-associated encephalopathy (SAE) is a complication of sepsis that has high morbidity rates. Long-lasting depression is a major mental health disorder in patients with SAE that results in a substantial decrease in quality of life and economic burden. However, the underlying mechanism of SAE is unclear, and effective treatments are not available. In the current study, we explored the role of apoptosis and necroptosis related to depression in sepsis. In a mouse model of cecal ligation and puncture (CLP), we detected mental impairments by the open field test, elevated-plus maze and forced swimming test on the fourteenth day. Moreover, apoptosis- and necroptosis-associated proteins and morphological changes were examined in the hippocampus of the septic mice. These mice showed depression-like behaviors at 14 days after CLP, with substantial increases in neuronal apoptosis and necroptosis. Importantly, we found that apoptosis and necroptosis were related according to Ramsay’s rule in the brains of the septic mice. Inhibiting the function of MD2, the crosstalk mediator of apoptosis and necroptosis, in neurons effectively reduced neuronal loss and alleviated depression-like behaviors in the septic mice. These results suggest that neuronal death in the hippocampus contributes to the mental impairments in SAE and that inhibiting neuronal MD2 is a new strategy for treatment of mental health issues in sepsis by inhibiting necroptosis and apoptosis.

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Men’s mental health: Connection to urologic health

Canadian Urological Association Journal ◽

10.5489/cuaj.2312 ◽

2014 ◽

Vol 8 (7-8) ◽

pp. 153 ◽

Cited By ~ 4

Author(s):

Andrew Matthew ◽

Dean Elterman

Keyword(s):

Mental Health ◽

Mental Health Disorder ◽

Leadership Role ◽

Health Issues ◽

Psychological Care ◽

Health Concerns ◽

Mental Health Issues ◽

Significant Burden ◽

Male Patients ◽

Healthy Behaviour

Historically, the specialty of urology has focussed on single-system diseases. In recent years, however, there has been increasing recognition of the interconnectivity between the various systems, such as cardiovascular disease, metabolic syndrome, erectile dysfunction, and prostate cancer. This constellation of disease/syndrome and dysfunction may place urologists at the centre of men’s overall health concerns. As urologists consider taking on a leadership role in men’s health, they should also consider their potential in helping men suffering from the significant burden of mental health disorder. Urologists may have a unique opportunity to identify mental health issues in their male patients, influence healthy behaviour change, and successfully refer men, who might otherwise not seek help, to appropriate medical/psychological care.

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Impact of COVID-19 pandemic on mental health of general population in Kashmir Valley, India

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20204895 ◽

2020 ◽

Vol 8 (11) ◽

pp. 4011

Author(s):

Feroz Ahmad Wani ◽

Rifat Jan ◽

Mudasir Ahmad

Keyword(s):

Mental Health ◽

Online Survey ◽

Risk Estimation ◽

Psychiatric Morbidity ◽

Female Gender ◽

Risk Groups ◽

Economic Losses ◽

High Morbidity ◽

Health Issues ◽

High Level

Background: The high morbidity and morbidity associated with epidemics and disasters and economic losses thereof is a high psychosocial risk. Estimation of the burden of mental health issues and recognition of various risk groups will lead to better allocation of resources to prevent the increased burden of psychiatric morbidity during the epidemic.Methods: This was an online survey conducted during COVID-19 pandemic based on self reporting DASS 21 scale.Results: Among the participants 49.5% had depression, 34.8% had anxiety and 22.3% had stress in varying severity from mild to extremely severe forms. Female gender, less age, high level of education and unemployment were the risk factors for increased psychiatric morbidity.Conclusions: There is a dire need to recognize the mental health threat due to COCID-19 pandemic and implement the steps to protect the vulnerable population from it.

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Inhibiting miR-22 Alleviates Cardiac Dysfunction by Regulating Sirt1 in Septic Cardiomyopathy

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.650666 ◽

2021 ◽

Vol 9 ◽

Author(s):

Runze Wang ◽

Yuerong Xu ◽

Wei Zhang ◽

Yexian Fang ◽

Tiqun Yang ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Cecal Ligation ◽

Control Group ◽

Autophagic Flux ◽

High Morbidity ◽

Sham Operation ◽

Septic Cardiomyopathy ◽

New Strategy ◽

Underlying Mechanisms

High morbidity and mortality are the most typical characteristics of septic cardiomyopathy. We aimed to reveal the role of miR-22 in septic cardiomyopathy and to explore the underlying mechanisms. miR-22 cardiac-specific knockout (miR-22cKO) mice and miR-22 cardiac-specific transgenic (miR-22cOE) mice were subjected to a cecal ligation and puncture (CLP) operation, while a sham operation was used in the control group. The echocardiogram results suggested that miR-22cKO CLP mice cardiac dysfunction was alleviated. The serum LDH and CK-MB were reduced in the miR-22cKO CLP mice. As expected, there was reduced apoptosis, increased autophagy and alleviated mitochondrial dysfunction in the miR-22cKO CLP mice, while it had contrary role in the miR-22cOE group. Inhibiting miR-22 promoted autophagy by increasing the LC3II/GAPDH ratio and decreasing the p62 level. Additionally, culturing primary cardiomyocytes with lipopolysaccharide (LPS) simulated sepsis-induced cardiomyopathy in vitro. Inhibiting miR-22 promoted autophagic flux confirmed by an increased LC3II/GAPDH ratio and reduced p62 protein level under bafilomycin A1 conditions. Knocking out miR-22 may exert a cardioprotective effect on sepsis by increasing autophagy and decreasing apoptosis via sirt1. Our results revealed that targeting miR-22 may become a new strategy for septic cardiomyopathy treatment.

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Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.658677 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qing Yu ◽

Liying Zou ◽

Xiu Yuan ◽

Fang Fang ◽

Feng Xu

Keyword(s):

Liver Injury ◽

Western Blotting ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Early Stage ◽

Morphological Changes ◽

Cecal Ligation ◽

Injury Model ◽

Associated Proteins

Background: Liver injury is one of the serious complications of sepsis. Previous studies suggested that dexmedetomidine (DEX) could alleviate cecal ligation and puncture (CLP)-induced liver injury. However, it is unclear whether the protective effect of DEX on sepsis-induced liver injury is related to autophagy.Methods: Mice (n = 105) were randomly divided into the following groups: (i) CON group (Sham); (ii) CLP group (CLP-induced liver injury + saline); (iii) CLP + DEX group (CLP-induced liver injury + DEX). Mouse models of sepsis-induced liver injury were established using CLP. DEX or normal saline was administered by intraperitoneal injection at 0, 2, and 4 h after CLP surgery. The mortality rate within 120 h was calculated. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and inflammatory cytokines were measured at 6, 12, and 24 h in each group. Hematoxylin and eosin staining assay was carried out to detect the morphological changes of mouse liver cells in each group. The levels of autophagy-associated proteins LC3II, Beclin-1, p62, and LAMP-2 were detected in three groups of mice using western blotting. The expression of LC3II was detected using immunofluorescence. Transmission electron microscopy (TEM) of liver tissue was used to observe autophagosomes and autophagosome–lysosomes. Lastly, the effect of DEX on the AMPK/SIRT1 pathway-associated protein levels were detected using western blotting. Meanwhile, we used L0-2 cells infected with mRFP-GFP-LC3 adenovirus to further analyze the role of SIRT1 in DEX-induced autophagy in liver injury model in vitro.Results: DEX significantly improved the survival rate of septic mice at the early stage and ameliorated the pathology of sepsis-induced liver injury. The level of autophagy-associated proteins, phosphorylated (p)-AMPK/AMPK, and SIRT1 in the liver of CLP-induced sepsis mice peaked at 12 h post-CLP and decreased significantly at 24 h. In the CLP + DEX group, the levels of autophagy-associated proteins, p-AMPK/AMPK, and SIRT1 increased, whereas inflammatory cytokines decreased at 24 h. The autophagosome structure was clearly observed at different time points in the CLP + DEX group. In the in vitro hepatocyte injury model, the SIRT1 inhibitor significantly increased intracellular ROS levels and reversed the effect of DEX on autophagy flux.Conclusion: We demonstrated a novel mechanism in which DEX protects against CLP-induced liver injury. DEX enhances autophagy, which alleviates the inflammatory responses in CLP-induced liver injury by regulating the SIRT1/AMPK pathway.

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Serinc2 deficiency causes susceptibility to sepsis-associated acute lung injury

10.21203/rs.3.rs-907860/v1 ◽

2021 ◽

Author(s):

Shuai Mao ◽

Jian Lv ◽

Meng Chen ◽

Ningning Guo ◽

Yu Fang ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Responses ◽

Cecal Ligation ◽

Underlying Mechanism ◽

Raw264.7 Cells ◽

Inflammatory Factors ◽

High Morbidity ◽

Positive Staining ◽

Protective Effects

Abstract Background Severe sepsis and its subsequent complications cause high morbidity and mortality rates worldwide. Lung is one of the most vulnerable organs sensitive to sepsis-associated inflammatory storm, and usually develops into acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). The pathogenesis of sepsis-associated ALI is accompanied by coordinated transmembrane signal transduction and subsequent programmed cell death; however, the underlying mechanism remains largely unclear. Results Here we find that the expression of serine incorporator 2 (Serinc2), a protein involved in phosphatidylserine synthesis and membrane incorporation, is upregulated in cecal ligation and puncture (CLP)-induced ALI. Furthermore, serinc2-knockout (KO) mouse line is generated by CRISPR-cas9 approach. Compared with wildtype mice, the Serinc2-KO mice exhibit exacerbated ALI-related pathologies after CLP. The expressions of pro-inflammatory factors, including IL1β, IL6, TNFα, and MCP1, are significantly enhanced by Serinc2 deficiency, concurrent with over-activation of STAT3, p38 and ERK pathways. Conversely, Serinc2 overexpression in RAW264.7 cells significantly suppresses the inflammatory responses induced by lipopolysaccharide (LPS). Serinc2 KO aggravates CLP-induced apoptosis as evidenced by increases in TUNEL-positive staining, Bax expression, and Caspase-3 cleavage and decreases in BCL-2 expression and Akt phosphorylation, whereas these changes are suppressed by Serinc2 overexpression in LPS-treated RAW264.7 cells. Moreover, administration of AKTin, an inhibitor of Akt, abolishes the protective effects of Serinc2 overexpression against inflammation and apoptosis. Conclusions Our findings demonstrate a protective role of Serinc2 in the lung through activating the Akt pathway, and provide novel insight into the pathogenesis of sepsis-induced ALI.

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