The innate immune system is an ancient and primary component system that rapidly reacts to defend the body against external pathogens. C1 is the initial responder of classical pathway of the innate ...immune system. C1 is comprised of C1q, C1r, and C1s. Among them, C1q is known to interact with diverse ligands, which can perform various functions in physiological and pathophysiological conditions. Because C1q participates in the clearance of pathogens, its interaction with novel receptors is expected to facilitate apoptosis induction, which could prevent the onset or progression of neurodegenerative diseases and could delay the aging process. Because senescence-associated secreting phenotype determinants are generally inflammatory cytokines or immune factors to activate immune cells. In the central nervous system, C1q has diverse neuroprotective roles against pathogens and inflammation. Most of neurodegenerative diseases show region specific pathology feature in the brain. It has been suggested the evidences that the active site and amount of C1q may be disease specific. This review considers currently the emerging and under-recognized roles of C1q in neurodegeneration and highlights the need for further research to clarify these roles. Future studies on the roles of C1q in regulating disease progression should consider these aspects, including the age-dependent onset time of each neurodegenerative disease progression.
Cognitive impairment is a serious condition that begins with amnesia and progresses to cognitive decline, behavioral dysfunction, and neuropsychiatric impairment. In the final stage, dysphagia and ...incontinence occur. There are numerous studies and developed drugs for cognitive dysfunction in neurodegenerative diseases, such as Alzheimer’s disease (AD); however, their clinical effectiveness remains equivocal. To date, attempts have been made to overcome cognitive dysfunction and understand and delay the aging processes that lead to degenerative and chronic diseases. Cognitive dysfunction is involved in aging and the disruption of inflammation and innate immunity. Recent reports have indicated that the innate immune system is prevalent in patients with AD, and that peripheral neutrophil markers can predict a decline in executive function in patients with mild cognitive impairment (MCI). Furthermore, altered levels of pro-inflammatory interleukins have been reported in MCI, which have been suggested to play a role in the peripheral immune system during the process from early MCI to dementia. Neutrophils are the first responders of the innate immune system. Neutrophils eliminate harmful cellular debris via phagocytosis, secrete inflammatory factors to activate host defense systems, stimulate cytokine production, kill pathogens, and regulate extracellular proteases and inhibitors. This review investigated and summarized the regulation of neutrophil function during cognitive impairment caused by various degenerative diseases. In addition, this work elucidates the cellular mechanism of neutrophils in cognitive impairment and what is currently known about the effects of activated neutrophils on cognitive decline.
Metabolic homeostasis is important for maintaining a healthy lifespan. Lipid metabolism is particularly necessary for the maintenance of metabolic energy sources and their storage, and the structure ...and function of cell membranes, as well as for the regulation of nutrition through lipogenesis, lipolysis, and lipophagy. Dysfunctional lipid metabolism leads to the development of metabolic disorders, such as atherosclerosis, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). Furthermore, dyslipidaemia causes inflammatory responses and foam cell formation. Mechanistic target of rapamycin (mTOR) signalling is a key regulator of diverse cellular processes, including cell metabolism and cell fate. mTOR complex 1 (mTORC1) is involved in lipid metabolism and immune responses in the body. Therefore, the mTORC1 signalling pathway has been suggested as a potential therapeutic target for the treatment of metabolic disorders. In this review, we focus on the roles of mTORC1 in lipid metabolism and inflammation, and present current evidence on its involvement in the development and progression of metabolic disorders.
Among autophagy-related molecules, p62/SQSTM1 is an adaptor for identifying and delivering intracellular cargo for degradation. Since ubiquitination is reversible, it has a switch role in autophagy. ...Ubiquitination is also involved in regulating autophagy in a timely manner. This study aimed to elucidate how p62-mediated autophagy is regulated in human endothelial cells and macrophages under atherosclerotic conditions, focusing on the lysosomal and proteasomal pathways. Co-cultured HUVECs and THP-1 cells were exposed to oxLDL (50 μg/mL) and autophagy was assessed. To downregulate p62, siRNA was administered, and the E3 ligases were inhibited by Heclin or MLN4924 treatment under the condition that cellular inflammatory processes were stimulated by oxLDL simultaneously initiated autophagy. Downregulating p62 induced an alternative degradation system, and the E3 ligases were found to be involved in the progression of atherosclerosis. Collectively, the present study demonstrated that the endothelial lipid accumulation under atherosclerotic conditions was caused by lysosomal dysfunction associated with autophagy.
Vessel damage by oxidized low-density lipoprotein (oxLDL) increases reactive oxygen species (ROS) and the membrane receptor cluster of differentiation 36 (CD36), involving various vascular ...pathological processes. In this study, the role of apoptosis signal-regulating kinase 1 (ASK1) as a cellular effector via the oxLDL-CD36 signaling axis, and its related mechanism as a downstream responder of CD36, was investigated in senescent human aortic endothelial cells (HAECs). To inhibit oxLDL-triggered vascular damage, HAECs and monocytes were treated with the CD36-neutralizing antibody or the ASK1 inhibitor NQDI-1. The oxLDL-triggered increases in ROS and CD36 elevated active ASK1 in the senescent HAECs. The ROS increase induced apoptosis, whereas CD36 neutralization or ASK1 inhibition protected against cell death. The blocking of CD36 increased senescent HAEC autophagy. In monocytes, oxLDL also induced CD36 expression and autophagy, the latter of which still occurred following ASK1 inhibition but not after CD36 neutralization. These findings suggest that oxLDL exposure activates ASK1, as a CD36 downstream responder, to accelerate apoptosis, particularly in senescent HAECs. ASK1’s involvement in monocytic autophagy was due to endoplasmic reticulum stress resulting from the oxLDL load, suggesting that oxLDL loading on aged vessels causes atherosclerotic endothelial dysfunction mediated by active ASK1.
Wound closure is a critical step in postoperative wound recovery. Substantial advancements have been made in many different means of facilitating wound closure, including the use of tissue adhesives. ...Compared to conventional methods, such as suturing, tissue bioadhesives better accelerate wound closure. However, several existing tissue adhesives suffer from cytotoxicity, inadequate tissue adhesive strength, and high costs. In this study, a series of bioadhesives was produced using non-swellable spider silk-derived silk fibroin protein and an outer layer of swellable polyethylene glycol and tannic acid. The gelation time of the spider silk-derived silk fibroin protein bioadhesive is less than three minutes and thus can be used during rapid surgical wound closure. By adding polyethylene glycol (PEG) 2000 and tannic acid as co-crosslinking agents to the N-Hydroxysuccinimide (NHS), and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) reaction, the adhesive strength of the bioadhesive became 2.5 times greater than that of conventional fibrin glue adhesives. Silk fibroin bioadhesives do not show significant cytotoxicity in vitro compared with other bioadhesives. In conclusion, silk fibroin bioadhesive is promising as a new medical tool for more effective and efficient surgical wound closure, particularly in bone fractures.
The present study aimed to assess the changes in blood factors and ultrasound measures of atherosclerosis burden patient with mild cognitive impairment (MCI) and dementia. Peripheral blood samples ...and ultrasonography findings were obtained for 53 enrolled participants. Flow cytometry was used to evaluate levels of activated platelets and platelet-leukocyte aggregates (PLAs). The number of platelets expressing p-selectin was correlated with intima media thickness (IMT) and plaque number in both the MCI and dementia groups. The number of platelets expressing p-selectin glycoprotein ligand (PSGL) was strongly correlated with IMT in patients with MCI, whereas the number of platelets expressing PGSL was correlated with plaque number rather than IMT in patients with dementia. PLAs was associated with both IMT and plaque number in patients with MCI but not in those with dementia. Our findings demonstrate that alterations in IMT and plaque number are associated with an increased risk of cognitive decline as well as conversion from MCI to dementia and that blood factor analysis may aid to detect the severity of cognitive decline.
Suppressor of cytokine signaling (SOCS) proteins are primarily feedback inhibitors of cytokine signaling. The two conserved domains of SOCS proteins have distinct functions. Src homology 2 (SH2) ...domain inhibits cytokine receptor, while SOCS box acts as an E3 ubiquitin ligase. SOCS2, a cytokine signaling suppressor, has been primarily implicated in regulating inflammatory conditions in neuronal diseases. However, SOCS proteins have been suggested to play diverse roles in healthy and diseased nervous system including neurodegenerative disorders. In this study, SOCS2 was found to be upregulated in Huntington’s disease and was substantially induced in extended polyglutamine (polyQ)-expressing striatal cells. The induced level was augmented under aging conditions. In extended polyQ-expressing cells, downregulated SOCS2 improved autophagic dysfunction rather than altered inflammatory conditions. Overall, we suggest that SOCS2 involves in regulating autophagy by functioning as an E3 ligase in extended polyQ conditions, and consequently regulates cell damage and cell death type.
•SOCS2 expression was substantially induced and secreted into serum of HD mice.•SOCS2 was stimulated in extended polyQ striatal cells and augmented with age.•Downregulated SOCS2 alleviated autophagic dysfunction in extended polyQ cells.
The harmful cellular environment leads to brain damage, and each brain subregion exhibits a differential vulnerability to its effects. This study investigated the causes of selectively striatal cell ...loss in systemic 3-nitropropionic acid (3-NP) infused mice.
This study was performed in the neuronal cell line, primary neuron, cultured mouse brain, and mice brain tissues. The 3-NP solution was delivered using an osmotic mini-pump system for 7 days. ROS in brain tissue were detected and evaluated with the signals of CM-H2DCFDA for total cellular ROS and MitoSOX Red for mitochondrial ROS. Cellular ROS and the functional status of mitochondria were assessed with a detection kit and analyzed using flow cytometry. To quantify oxidative damaged DNA, apurinic/apyrimidinic (AP) site numbers in DNA were measured. The protein expression level was assessed using Western blotting, and immunohistochemistry was performed. Cleaved caspase-3 activities were measured by using an enzyme-linked immunosorbent assay (ELISA) kit.
By 3-NP, mitochondrial dysfunction was higher in the striatum than in the cortex, and mitochondria-derived ROS levels were higher in the striatum than in the cortex. However, autophagy that may restore the energy depletion resulting from mitochondrial dysfunction occurred comparably less in the striatum than in the cortex. Inhibition of ASK1 by NQDI1 regulates MAPK signaling, apoptosis, and autophagy. Regulated autophagy of the cortex improved non-cell autonomously striatal damaged condition.
This study illustrated that the different vulnerabilities of the brain subregions, striatum or cortex, against 3-NP are rooted in different mitochondria-derived ROS amounts and autophagic capacity.
•3NP infusion induced more mitochondrial dysfunction but less autophagy in the striatum.•ASK1 inhibition prevented apoptotic MAPKinase pathway and controlled autophagy.•ASK1 inhibitor regulated autophagy of the cortex but not of the damaged striatum.•ASK1 inhibition restored BDNF of the striatum and synaptic connections.
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