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Wang K, Mitoh Y, Horie K, Yoshida R. Exploring the Role of Ccn3 in Type III Cell of Mice Taste Buds. J Neurochem 2025; 169:e16291. [PMID: 39709613 DOI: 10.1111/jnc.16291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/22/2024] [Accepted: 12/04/2024] [Indexed: 12/24/2024]
Abstract
Different taste cells express unique cell-type markers, enabling researchers to distinguish them and study their functional differentiation. Using single-cell RNA-Seq of taste cells in mouse fungiform papillae, we found that Cellular Communication Network Factor 3 (Ccn3) was highly expressed in Type III taste cells but not in Type II taste cells. Ccn3 is a protein-coding gene involved in various biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Therefore, in this study, we aimed to explore the expression and function of Ccn3 in mouse taste bud cells. Using reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry (IHC), we confirmed that Ccn3 was predominantly expressed in Type III taste cells. Through IHC, quantitative real-time RT-PCR, gustatory nerve recordings, and short-term lick tests, we observed that Ccn3 knockout (Ccn3-KO) mice did not exhibit any significant differences in the expression of taste cell markers and taste responses compared to wild-type controls. To explore the function of Ccn3 in taste cells, bioinformatics analyses were conducted and predicted possible roles of Ccn3 in tissue regeneration, perception of pain, protein secretion, and immune response. Among them, an immune function is the most plausible based on our experimental results. In summary, our study indicates that although Ccn3 is strongly expressed in Type III taste cells, its knockout did not influence the basic taste response, but bioinformatics provided valuable insights into the possible role of Ccn3 in taste buds and shed light on future research directions.
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Affiliation(s)
- Kuanyu Wang
- Department of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yoshihiro Mitoh
- Department of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kengo Horie
- Department of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Ryusuke Yoshida
- Department of Oral Physiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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2
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Bhasne K, Bogoian-Mullen A, Clerico EM, Gierasch LM. The Hsc70 system maintains the synaptic SNARE protein SNAP-25 in an assembly-competent state and delays its aggregation. J Biol Chem 2024; 300:108001. [PMID: 39551143 PMCID: PMC11697113 DOI: 10.1016/j.jbc.2024.108001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/01/2024] [Accepted: 11/10/2024] [Indexed: 11/19/2024] Open
Abstract
The complex mechanism of synaptic vesicle fusion with the plasma membrane for neurotransmitter release is initiated by the formation of the SNARE complex at the presynaptic terminal of the neuron. The SNARE complex is composed of four helices contributed by three proteins: one from syntaxin (localized at the plasma membrane), one from synaptobrevin (localized at the synaptic vesicle), and two from the intrinsically disordered and aggregation-prone synaptosomal-associated 25 kDa protein (SNAP-25), which is localized to the plasma membrane by virtue of palmitoylation of cysteine residues. The fusion process is tightly regulated and requires the constitutively expressed Hsp70 chaperone (Hsc70) and its J-protein co-chaperone CSPα. We hypothesize that Hsc70 and CSPα cooperate to chaperone SNAP-25, disfavoring its aggregation and keeping it in a folding state competent for SNARE complex formation. To test this hypothesis, we used a bottom-up approach and studied the interaction between Hsc70 and CSPα with SNAP-25 in vitro. We showed that the aggregation of SNAP-25 is delayed in the presence of Hsc70 and CSPα. Using a peptide array that spans the sequence of SNAP-25, we identified three potential Hsc70-interacting sequences and designed peptides containing these sequences to test binding in solution. We characterized the interaction of SNAP-25-derived peptides with Hsc70 and CSPα using a combination of biochemical and biophysical techniques, including native-PAGE, binding affinity by fluorescence anisotropy, ATPase-activity of Hsc70, and NMR. We have identified an Hsc70 binding site within SNAP-25 that is likely to represent the site used in the cell to facilitate SNARE complex formation.
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Affiliation(s)
- Karishma Bhasne
- Department of Biochemistry & Molecular Biology, University of Massachusetts, Amherst Massachusetts, USA
| | - Antonia Bogoian-Mullen
- Department of Biochemistry & Molecular Biology, University of Massachusetts, Amherst Massachusetts, USA
| | - Eugenia M Clerico
- Department of Biochemistry & Molecular Biology, University of Massachusetts, Amherst Massachusetts, USA.
| | - Lila M Gierasch
- Department of Biochemistry & Molecular Biology, University of Massachusetts, Amherst Massachusetts, USA; Department of Chemistry, University of Massachusetts, Amherst Massachusetts, USA.
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Liu H, Dang R, Zhang W, Hong J, Li X. SNARE proteins: Core engines of membrane fusion in cancer. Biochim Biophys Acta Rev Cancer 2024:189148. [PMID: 38960006 DOI: 10.1016/j.bbcan.2024.189148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/23/2024] [Accepted: 06/27/2024] [Indexed: 07/05/2024]
Abstract
Vesicles are loaded with a variety of cargoes, including membrane proteins, secreted proteins, signaling molecules, and various enzymes, etc. Not surprisingly, vesicle transport is essential for proper cellular life activities including growth, division, movement and cellular communication. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) mediate membrane fusion of vesicles with their target compartments that is fundamental for cargo delivery. Recent studies have shown that multiple SNARE family members are aberrantly expressed in human cancers and actively contribute to malignant proliferation, invasion, metastasis, immune evasion and treatment resistance. Here, the localization and function of SNARE proteins in eukaryotic cells are firstly mapped. Then we summarize the expression and regulation of SNAREs in cancer, and describe their contribution to cancer progression and mechanisms, and finally we propose engineering botulinum toxin as a strategy to target SNAREs for cancer treatment.
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Affiliation(s)
- Hongyi Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China
| | - Ruiyue Dang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China
| | - Jidong Hong
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
| | - Xuejun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China.
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4
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Guo N, Yu L. SIP30 involvement in vesicle exocytosis from PC12 cells. Biochem Biophys Rep 2024; 37:101614. [PMID: 38188363 PMCID: PMC10770524 DOI: 10.1016/j.bbrep.2023.101614] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024] Open
Abstract
SNAP25 (synaptosome-associated protein of 25 kDa) is a core SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) protein; and the interaction between SNAP25 and other SNARE proteins is essential for synaptic vesicle exocytosis. Identified as a SNAP25 interacting protein, SIP30 (SNAP25 interacting protein at 30 kDa) has been shown to modulate neuropathic pain behavior, and is potentially involved in the cellular process of vesicle exocytosis. Previous study demonstrated that using a vesicle secretion assay in PC12 cells, anti-SIP30 siRNA reduced vesicle exocytosis. We investigated vesicle exocytosis from PC12 cells with FM1-43 fluorescence dye, and demonstrated that anti-SIP30 siRNA reduced the pool of releasable vesicles and the rate of vesicle exocytosis, without affecting the endocytosis and recycling of the exocytosed vesicles. The results show that SIP30 is involved in vesicle exocytosis, suggesting a potential mechanism of SIP30 modulation of neuropathic pain.
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Affiliation(s)
- Ning Guo
- Department of Genetics, and Center of Alcohol & Substance Use Studies, Rutgers University, Piscataway, NJ, 08854, USA
| | - Lei Yu
- Department of Genetics, and Center of Alcohol & Substance Use Studies, Rutgers University, Piscataway, NJ, 08854, USA
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Li Y, Dang Q, Shen Y, Guo L, Liu C, Wu D, Fang L, Leng Y, Min W. Therapeutic effects of a walnut-derived peptide on NLRP3 inflammasome activation, synaptic plasticity, and cognitive dysfunction in T2DM mice. Food Funct 2024; 15:2295-2313. [PMID: 38323487 DOI: 10.1039/d3fo05076a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
NLRP3 inflammasome activation plays a key role in the development of diabetes-induced cognitive impairment. However, strategies to inhibit NLRP3 inflammasome activation remain elusive. Herein, we evaluated the impact of a walnut-derived peptide, TWLPLPR (TW-7), on cognitive impairment in high-fat diet/streptozotocin-induced type 2 diabetes mellitus (T2DM) mice and explored its underlying mechanisms in high glucose-induced HT-22 cells. In the Morris water maze test, TW-7 alleviated cognitive deficits in mice; this was confirmed at the level of synaptic structure and dendritic spine density in the mouse hippocampus using transmission electron microscopy and Golgi staining. TW-7 increased the expression of synaptic plasticity-related proteins and suppressed the NEK7/NLRP3 inflammatory pathway, as determined by western blotting and immunofluorescence analysis. The mechanism of action of TW-7 was verified in an HT-22 cell model of high glucose-induced insulin resistance. Collectively, TW-7 could regulate T2DM neuroinflammation and synaptic function-induced cognitive impairment by inhibiting NLRP3 inflammasome activation and improving synaptic plasticity.
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Affiliation(s)
- Yanru Li
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Qiao Dang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Yue Shen
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Linxin Guo
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Chunlei Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Dan Wu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Li Fang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Yue Leng
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, P. R. China.
| | - Weihong Min
- College of Food and Health, Zhejiang A & F University, Hangzhou 311300, P.R. China.
- National Grain Industry (High-Quality Rice Storage in Temperate and Humid Region) Technology Innovation Center, Hangzhou 311300, China
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Shu J, Peng F, Li J, Liu Y, Li X, Yuan C. The Relationship between SNAP25 and Some Common Human Neurological Syndromes. Curr Pharm Des 2024; 30:2378-2386. [PMID: 38963116 DOI: 10.2174/0113816128305683240621060024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/15/2024] [Accepted: 05/22/2024] [Indexed: 07/05/2024]
Abstract
Over the years, research on the pathogenesis of neurological diseases has progressed slowly worldwide. However, as the incidence rate continues to increase and the disease gradually develops, early diagnosis and treatment have become a top priority. SANP25, a protein present on the presynaptic membrane and involved in neurotransmitter release, is closely related to the loss or abnormal expression of synapses and neurons. SNAP25 deficiency can lead to synaptic disorders and inhibit neurotransmitter release. Therefore, a large amount of literature believes that SNAP25 gene mutation is a risk factor for many neurological diseases. This review used advanced search on PubMed to conduct extensive article searches for relevant literature. The search keywords included SNAP25 and Alzheimer's disease, SNAP25 and Parkinson's disease, and so on. After reading and summarizing the previous papers, the corresponding conclusions were obtained to achieve the purpose of the review. The deficiency or variation of SNAP25 might be related to the onset of schizophrenia, epilepsy, attention deficit/hypoactivity disorder, bipolar disorder effective disorder, and autism. SNAP25 has been found to be used as a neuropathological marker for neurological diseases, which could be the target of diagnosis or treatment of Alzheimer's disease and Parkinson's disease. Cerebrospinal Fluid (CSF) or blood has been found to enable more effective drug development.
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Affiliation(s)
- Jie Shu
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China
| | - Fan Peng
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China
| | - Jing Li
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China
| | - Yuhang Liu
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China
| | - Xiaolan Li
- College of Basic Medicine, The Second People's Hospital of China Three Gorges University, Yichang 443002, China
- Department of Gynecology, The Second People's Hospital of Yichang, Hubei, China
| | - Chengfu Yuan
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, China
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Vinci M, Costanza C, Galati Rando R, Treccarichi S, Saccone S, Carotenuto M, Roccella M, Calì F, Elia M, Vetri L. STXBP6 Gene Mutation: A New Form of SNAREopathy Leads to Developmental Epileptic Encephalopathy. Int J Mol Sci 2023; 24:16436. [PMID: 38003627 PMCID: PMC10670990 DOI: 10.3390/ijms242216436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Syntaxin-binding protein 6 (STXBP6), also known as amysin, is an essential component of the SNAP receptor (SNARE) complex and plays a crucial role in neuronal vesicle trafficking. Mutations in genes encoding SNARE proteins are often associated with a broad spectrum of neurological conditions defined as "SNAREopathies", including epilepsy, intellectual disability, and neurodevelopmental disorders such as autism spectrum disorders. The present whole exome sequencing (WES) study describes, for the first time, the occurrence of developmental epileptic encephalopathy and autism spectrum disorders as a result of a de novo deletion within the STXBP6 gene. The truncated protein in the STXBP6 gene leading to a premature stop codon could negatively modulate the synaptic vesicles' exocytosis. Our research aimed to elucidate a plausible, robust correlation between STXBP6 gene deletion and the manifestation of developmental epileptic encephalopathy.
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Affiliation(s)
- Mirella Vinci
- Oasi Research Institute-IRCCS, 94018 Troina, Italy; (M.V.); (R.G.R.); (S.T.); (M.E.); (L.V.)
| | - Carola Costanza
- Department of Psychology, Educational Science and Human Movement, University of Palermo, 90141 Palermo, Italy; (C.C.); (M.R.)
| | - Rosanna Galati Rando
- Oasi Research Institute-IRCCS, 94018 Troina, Italy; (M.V.); (R.G.R.); (S.T.); (M.E.); (L.V.)
| | - Simone Treccarichi
- Oasi Research Institute-IRCCS, 94018 Troina, Italy; (M.V.); (R.G.R.); (S.T.); (M.E.); (L.V.)
| | - Salvatore Saccone
- Department Biological, Geological and Environmental Sciences, University of Catania, Via Androne 81, 95124 Catania, Italy;
| | - Marco Carotenuto
- Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy;
| | - Michele Roccella
- Department of Psychology, Educational Science and Human Movement, University of Palermo, 90141 Palermo, Italy; (C.C.); (M.R.)
| | - Francesco Calì
- Oasi Research Institute-IRCCS, 94018 Troina, Italy; (M.V.); (R.G.R.); (S.T.); (M.E.); (L.V.)
| | - Maurizio Elia
- Oasi Research Institute-IRCCS, 94018 Troina, Italy; (M.V.); (R.G.R.); (S.T.); (M.E.); (L.V.)
| | - Luigi Vetri
- Oasi Research Institute-IRCCS, 94018 Troina, Italy; (M.V.); (R.G.R.); (S.T.); (M.E.); (L.V.)
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Musuroglu Keloglan S, Sahin L, Kocahan S, Annac E, Tirasci N, Pekmezekmek AB. Effect of caffeine on hippocampal memory and levels of gene expression in social isolation stress. Int J Dev Neurosci 2023; 83:641-652. [PMID: 37575074 DOI: 10.1002/jdn.10292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/06/2023] [Accepted: 07/21/2023] [Indexed: 08/15/2023] Open
Abstract
BACKGROUND Caffeine (Cf) antagonizes the adenosine receptors and has neuroprotective properties. The effect of Cf has been seen on stress-induced deficits of cognitive. In this study, we have investigated the effect of Cf on learning and memory functions induced by social isolation (SI) stress. MATERIALS AND METHODS In the present study, 21-day-old Wistar albino male rats (n = 28) were divided into four groups: the control (C), the SI, the Cf, and the social isolation + caffeine (SICf). Cf (0.3 g/L) was added to the drinking water of the experimental animals for 4 weeks. The learning and memory functions were assessed using the Morris Water Maze Test (MWMT). Following, was performed histopathological evaluation and determined hippocampal gene expression levels by RT-qPCR. RESULTS According to MWMT findings, the time spent in the quadrant where the platform removed was decreased in the SI group compared with the C (p < 0.05). Histological evaluation showed morphological changes in SI by irregular appearance, cellular edema, and dark pycnotic appearance of nuclei in some neurons. However, it was observed that the histological structure of most of the neurons in the SICf group was similar to the C and Cf groups. Hippocampal SNAP25 expression was decreased in the Cf and SICf groups than in the C group (p < 0.05). The GFAP expression was increased in the SICf group than in the C group (p < 0.05). NR2A increased in the SI and SICf groups compared with C and Cf groups (p < 0.05). NR2B expression decreased in the Cf group compared with C and SI groups (p < 0.05). CONCLUSIONS SI impaired spatial memory and causes morphological changes in adolescent rats, but this effect of isolation was not seen in Cf-treated animals. The effects of SI on NR2A, Cf on NR2B, and SNAP25 are remarkable. Here, we propose that the impaired effect of SI on spatial memory may be mediated by NR2A, but further studies are needed to explain this effect.
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Affiliation(s)
| | - Leyla Sahin
- Department of Physiology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Sayad Kocahan
- Department of Physiology, Faculty of Gulhane Medicine, Health Sciences University, Ankara, Turkey
| | - Ebru Annac
- Department of Histology and Embryology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey
| | - Nurhan Tirasci
- Department of Zootechnics and Animal Nutrition, Institute of Health Sciences, Fırat University, Elazig, Turkey
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Borsuk DJ, Studniarek A, Park JJ, Marecik SJ, Mellgren A, Kochar K. Use of Botulinum Toxin Injections for the Treatment of Chronic Anal Fissure: Results From an American Society of Colon and Rectal Surgeons Survey. Am Surg 2023; 89:346-354. [PMID: 34092078 DOI: 10.1177/00031348211023446] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Chronic anal fissure (CAF) is commonly treated by colorectal surgeons. Pharmacological treatment is considered first-line therapy. An alternative treatment modality is chemical sphincterotomy with injection of botulinum toxin (BT). However, there is a lack of a consensus on the BT administration procedure among colorectal surgeons. METHODS A national survey approved by the American Society of Colon and Rectal Surgeons (ASCRS) Executive Council was sent to all members. An eight-question survey was sent via ASCRS email correspondence between December 2019 and February 2020. Questions were derived from available meta-analyses and expert opinions on BT use in CAF patients and included topics such as BT dose, injection technique, and concomitant therapies. The survey was voluntary and anonymous, and all ASCRS members were eligible to complete it. Responses were recorded and analyzed via an online survey platform. RESULTS 216 ASCRS members responded to the survey and 90% inject 50-100U of BT. Most procedures are performed under MAC anesthesia (56%). A majority of respondents (64%) inject into the internal sphincter and a majority (53%) inject into 4 quadrants in the anal canal circumference. Some respondents perform concomitant manual dilatation (34%) or fissurectomy (38%). Concomitant topical muscle relaxing agents are not used uniformly among respondents. DISCUSSION Injection of BT for CAF is used commonly by colorectal surgeons. There is consensus on BT dosage, administration site, technique, and the use of monitored anesthesia care.
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Affiliation(s)
- Daniel J Borsuk
- Division of Colon and Rectal Surgery, 21886Advocate Lutheran General Hospital, Park Ridge, IL, USA
| | - Adam Studniarek
- Division of Colon and Rectal Surgery, 21886Advocate Lutheran General Hospital, Park Ridge, IL, USA.,Division of Colon and Rectal Surgery, 14681University of Illinois at Chicago, Chicago, IL, USA
| | - John J Park
- Division of Colon and Rectal Surgery, 21886Advocate Lutheran General Hospital, Park Ridge, IL, USA
| | - Slawomir J Marecik
- Division of Colon and Rectal Surgery, 21886Advocate Lutheran General Hospital, Park Ridge, IL, USA
| | - Anders Mellgren
- Division of Colon and Rectal Surgery, 14681University of Illinois at Chicago, Chicago, IL, USA
| | - Kunal Kochar
- Division of Colon and Rectal Surgery, 21886Advocate Lutheran General Hospital, Park Ridge, IL, USA
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Reynolds HM, Wen T, Farrell A, Mao R, Moore B, Boyden SE, Bayrak-Toydemir P, Nicholas TJ, Rynearson S, Holt C, Miller C, Noble K, Bentley D, Palmquist R, Ostrander B, Manberg S, Bonkowsky JL, Shayota BJ, Jenkins SM. Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome. Cold Spring Harb Mol Case Stud 2022; 8:a006242. [PMID: 36379720 PMCID: PMC9808558 DOI: 10.1101/mcs.a006242] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al., Lancet Neurol 14: 420 [2015]; Finsterer, Orphanet J Rare Dis 14: 57 [2019]; Prior and Ghosh, J Child Neurol 36: 610 [2021]). The SNAP25-related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novo SNAP25 c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reported SNAP25 variant phenotype, and paves a foundation for personalized management for CMS18.
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Affiliation(s)
- Hayley M Reynolds
- University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
| | - Ting Wen
- University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
- ARUP Laboratories, Salt Lake City, Utah 84108, USA
| | - Andrew Farrell
- Department of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, Utah 84112, USA
| | - Rong Mao
- University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
- ARUP Laboratories, Salt Lake City, Utah 84108, USA
| | - Barry Moore
- Department of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, Utah 84112, USA
| | - Steven E Boyden
- Department of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, Utah 84112, USA
| | - Pinar Bayrak-Toydemir
- University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
- ARUP Laboratories, Salt Lake City, Utah 84108, USA
| | - Thomas J Nicholas
- Department of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, Utah 84112, USA
| | - Shawn Rynearson
- Department of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, Utah 84112, USA
| | - Carson Holt
- Department of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, Utah 84112, USA
| | | | | | - Dawn Bentley
- Division of Neonatology, Department of Pediatrics University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
| | - Rachel Palmquist
- Division of Pediatric Neurology, Department of Pediatrics University of Utah School of Medicine, Salt Lake City, Utah 84113, USA
| | - Betsy Ostrander
- Division of Pediatric Neurology, Department of Pediatrics University of Utah School of Medicine, Salt Lake City, Utah 84113, USA
| | - Stephanie Manberg
- Division of Pediatric Neurology, Department of Pediatrics University of Utah School of Medicine, Salt Lake City, Utah 84113, USA
| | - Joshua L Bonkowsky
- Division of Pediatric Neurology, Department of Pediatrics University of Utah School of Medicine, Salt Lake City, Utah 84113, USA
- Center for Personalized Medicine, Primary Children's Hospital, Salt Lake City, Utah 84108, USA
| | - Brian J Shayota
- Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
| | - Sabrina Malone Jenkins
- Division of Neonatology, Department of Pediatrics University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
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Ochneva A, Zorkina Y, Abramova O, Pavlova O, Ushakova V, Morozova A, Zubkov E, Pavlov K, Gurina O, Chekhonin V. Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders. Int J Mol Sci 2022; 23:14498. [PMID: 36430976 PMCID: PMC9695177 DOI: 10.3390/ijms232214498] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/07/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022] Open
Abstract
Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation of protein aggregates in brain tissues, may be a possible cause behind the development of psychiatric disorders. Proteinopathies are known to be the main cause of neurodegeneration, but much less attention is given to the role of protein impairments in psychiatric disorders' pathogenesis, such as depression and schizophrenia. For this reason, the aim of this review was to discuss the potential contribution of protein illnesses in the development of psychopathologies. The first part of the review describes the possible mechanisms of disruption to protein folding and aggregation in the cell: endoplasmic reticulum stress, dysfunction of chaperone proteins, altered mitochondrial function, and impaired autophagy processes. The second part of the review addresses the known proteins whose aggregation in brain tissue has been observed in psychiatric disorders (amyloid, tau protein, α-synuclein, DISC-1, disbindin-1, CRMP1, SNAP25, TRIOBP, NPAS3, GluA1, FABP, and ankyrin-G).
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Affiliation(s)
- Aleksandra Ochneva
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
- Healthcare Department, Mental-Health Clinic No. 1 Named after N.A. Alexeev of Moscow, 117152 Moscow, Russia
| | - Yana Zorkina
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
- Healthcare Department, Mental-Health Clinic No. 1 Named after N.A. Alexeev of Moscow, 117152 Moscow, Russia
| | - Olga Abramova
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
- Healthcare Department, Mental-Health Clinic No. 1 Named after N.A. Alexeev of Moscow, 117152 Moscow, Russia
| | - Olga Pavlova
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
| | - Valeriya Ushakova
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
- Healthcare Department, Mental-Health Clinic No. 1 Named after N.A. Alexeev of Moscow, 117152 Moscow, Russia
- Department of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Anna Morozova
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
- Healthcare Department, Mental-Health Clinic No. 1 Named after N.A. Alexeev of Moscow, 117152 Moscow, Russia
| | - Eugene Zubkov
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
| | - Konstantin Pavlov
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
- Healthcare Department, Mental-Health Clinic No. 1 Named after N.A. Alexeev of Moscow, 117152 Moscow, Russia
| | - Olga Gurina
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
| | - Vladimir Chekhonin
- Department Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia
- Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
- National University of Science and Technology “MISiS”, Leninskiy Avenue 4, 119049 Moscow, Russia
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Özdemir Ç, Şahin N, Edgünlü T. Vesicle trafficking with snares: a perspective for autism. Mol Biol Rep 2022; 49:12193-12202. [PMID: 36198849 DOI: 10.1007/s11033-022-07970-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 09/21/2022] [Indexed: 11/30/2022]
Abstract
Vesicle-mediated membrane traffic is the mechanism fundamental to many biological events, especially the release of neurotransmitters. The main proteins of the mechanism that mediates membrane fusion in vesicle-mediated membrane traffic are N-ethylmaleimide sensitive factor (NSF) supplemental protein (SNAP) receptor (SNAREs) proteins. SNAREs are classified into vesicle-associated SNAREs (vesicle-SNAREs/v-SNAREs) and target membrane-associated SNAREs (target-SNARE/t-SNAREs). Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by many symptoms, especially complications in social communication and stereotypical behaviours. Defects in synaptogenesis and neurotransmission, oxidative stress, and developmental defects in the early stages of development are defined in the pathogenesis of the disease. SNARE proteins are on the basis of synaptogenesis and neurotransmission. Although the formation mechanisms and underlying causes of the SNARE complex are not fully understood, expression differences, polymorphisms, abnormal expressions or dysfunctions of the proteins that make up the SNARE complex have been associated with many neurodevelopmental diseases, including autism. Further understanding of SNARE mechanisms is crucial both for understanding ASD and for developing new treatments. In this review, the formation mechanisms of the SNARE complex and the roles of various factors involved in this process are explained. In addition, a brief evaluation of clinical and basic studies on the SNARE complex in autism spectrum disorders was made.
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Affiliation(s)
- Çilem Özdemir
- Department of Medical Biology, Health Sciences Institution, Muğla Sıtkı Koçman University, Mugla, Turkey
| | - Nilfer Şahin
- Department of Child and Adolescent Mental Health Diseases School of Medicine, Muğla Sıtkı Koçman University, Mugla, Turkey
| | - Tuba Edgünlü
- Department of Medical Biology, School of Medicine, Muğla Sıtkı Koçman University, 48000, Mugla, Turkey.
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Karmakar S, Ghosh T, Sankhla A, Bhattacharjee S, Katiyar V. Insulin biomolecular condensate formed in ionic microenvironment modulates the structural properties of pristine and magnetic cellulosic nanomaterials. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2022.119580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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An Shen Ding Zhi Ling Ameliorates the Symptoms of Attention Deficit Hyperactivity Disorder via Modulating Brain-Derived Neurotrophic Factor-Related Signaling Pathways. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5471586. [PMID: 35911131 PMCID: PMC9334057 DOI: 10.1155/2022/5471586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 06/16/2022] [Indexed: 11/18/2022]
Abstract
Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder. It may impact the cognitive and social functions throughout childhood and determine adult outcomes. Dopamine (DA) deficiency theory is the pathogenesis of ADHD that is recognized by most international literature. Existing studies have shown that DA deficiency is caused by the abnormal function of the DA transporter and an imbalance in the DA receptor functionality. Recent clinical and experimental studies have found that the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway acts a pivotal part in DA vesicle circulation and ADHD pathogenesis. An Shen Ding Zhi Ling (ASDZL) is a traditional Chinese medicine (TCM) prescription, which was widely prescribed to treat ADHD in Jiangsu, China, but its therapeutic mechanism is unclear. Therefore, we constructed a spontaneously hypertensive rat (SHR) model to explain its mechanism. SHRs were randomly assigned to four groups: SHR model group (vehicle), methylphenidate hydrochloride group (MPH), ASDZL group, and 7,8-dihydroxyflavone group (7,8-DHF). At the same time, the above groups were given continuous medication for four weeks. The results show that ASDZL, MPH, and 7,8-DHF group could significantly improve the spatial memory of SHRs in the Morris water maze tests. ASDZL increased the levels of BDNF, TrkB, p75 neurotrophin receptor (p75), C-Jun N-terminal kinases 1 (JNK1), and nuclear factor kappa B (NF-κB) in the prefrontal cortex (PFC) and hippocampus synaptosome of SHRs. The results of this study suggest that ASDZL can relieve the symptoms of ADHD in SHRs by regulating the balance between the BDNF/TrkB signaling pathway (promoting vesicle circulation) and the BDNF/P75/JNK1/NF-κB signaling pathway (inhibiting vesicle circulation) within the PFC and hippocampus synaptosome to increase the DA concentration in the synaptic cleft. The BDNF/TrkB signal pathway within the PFC and hippocampus synaptosome was activated by 7,8-DHF to increase DA concentration in the synaptic cleft. Whether 7,8-DHF can activate or inhibit the BDNF/P75 signaling pathway remains unclear.
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15
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Downregulation of CRTC1 Is Involved in CUMS-Induced Depression-Like Behavior in the Hippocampus and Its RNA Sequencing Analysis. Mol Neurobiol 2022; 59:4405-4418. [PMID: 35556215 DOI: 10.1007/s12035-022-02787-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
Chronic stress is an important risk factor for mood disorders including depression. The decreased level of CREB (cAMP-responsive element binding)-regulated transcription coactivator 1 (CRTC1) expression in hippocampus may be involved in depression-like behavior in some stress-induced depression models. But the mechanism of CRTC1 in mediating depression-like behavior remains unknown. In this study, chronic unpredictable mild stress (CUMS)-treated mice showed depression-like behavior accompanied by the downregulation of CRTC1 in the hippocampus. Adeno-associated virus (AAV)-CRTC1-mediated overexpression of CRTC1 in the hippocampus by stereotactic brain injection could significantly prevent depression-like behavior in CUMS-treated mice. The above data reveal that the downregulation of hippocampal CRTC1 expression participates in CUMS-induced depression-like behavior. In order to explore the key targets regulated by CRTC1, AAV-mediated CRTC1 short hairpin (shRNA) was constructed to achieve knockdown of CRTC1 in the hippocampus, and then the hippocampi were collected for RNA-sequencing (RNA-seq). The RNA-seq data show that upregulated genes were enriched in stress and immune system-associated GO terms and pathways such as response to stress and external stimulus and regulation of immune response and that downregulated genes were enriched in neural activity such as synaptic transmission and cognitive behavior. We further provided RT-qPCR data that the inflammation-related factors including Gpr84, Tlr2, Lyz2, and Icam1 were significantly upregulated in the hippocampus of both CUMS- and CRTC1 shRNA-induced models, some of them were also validated in protein levels by Western blotting. We propose a hypothesis that CUMS induces downregulation of CRTC1, which might lead to depression-like behavior via neuroinflammation pathway. This study provides new explanation for the inflammatory hypothesis of depression and some clues for exploring the molecular mechanism of CRTC1 regulation.
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Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
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Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
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17
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Karmakar S, Sankhla A, Katiyar V. Supramolecular organization of Cytochrome-C into quantum-dot decorated macromolecular network under pH and thermal stress. Int J Biol Macromol 2021; 193:1623-1634. [PMID: 34742836 DOI: 10.1016/j.ijbiomac.2021.10.225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/30/2021] [Accepted: 10/30/2021] [Indexed: 12/12/2022]
Abstract
The holo form of Cytochrome-C which is involved in the electron transfer chain of aerobic and anaerobic respiration remains structurally intact by its complex with heme. However, when a prolonged thermal and pH stress was applied, heme was found to abruptly dissociate from the holo protein, resulting in complete collapse of the three-dimensional functional structure. Interestingly, two distinct structures were formed as the consequence of the dissociation event: (i) A macromolecular amyloid-network formed by the collapsed protein fragments, generated by self-oxidation, and (ii) Fe-containing Quantum-Dots (FeQDs) with 2-3 nm diameter formed by heme reorganization. Further adding to intrigue, the FeQDs were re-adsorbed on the surface of the amyloid network leading to FeQD-decorated macromolecular amyloid matrix. The heme-interactant Met80, constituting the amyloidogenic region, initiates the amylogenic cascade, and gradual exposure of Trp59 synergistically emit intrinsic fluorescence alongside FeQDs. The development of the aforementioned events were probed through a multitude of biophysical, chemical and computational analyses like ThT/ANS/intrinsic fluorescence assays, CD-spectroscopy, FETEM/STEM/elemental mapping, Foldamyloid/Foldunfold/Isunstruct/H-protection/LIGplot analyses, etc. The FeQD-decorated amyloid-network was found to exhibit gel-like property, which supported the growth of BHK-21 fibroblast without cytotoxicity. Further studies on FeQD-decorated Cytochrome C amyloid network might open possibilities to design advanced biomaterial for diverse biological applications.
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Affiliation(s)
- Srijeeb Karmakar
- Department of Bioscience and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
| | - Arjun Sankhla
- Department of Chemical Engineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
| | - Vimal Katiyar
- Department of Chemical Engineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
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Proteomic Analysis of Human Serum for Patients at Different Pathological Stages of Hepatic Fibrosis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:3580090. [PMID: 34877354 PMCID: PMC8645358 DOI: 10.1155/2021/3580090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022]
Abstract
Background Hepatic fibrosis is a severe liver disease that has threatened human health for a long time. In order to undergo timely and adequate therapy, it is important for patients to obtain an accurate diagnosis of fibrosis. Laboratory inspection methods have been efficient in distinguishing between advanced hepatic fibrosis stages (F3, F4), but the identification of early stages of fibrosis has not been achieved. The development of proteomics may provide us with a new direction to identify the stages of fibrosis. Methods We established serum proteomic maps for patients with hepatic fibrosis at different stages and identified differential expression of proteins between fibrosis stages through ultra-high-performance liquid chromatography tandem mass spectrometry proteomic analysis. Results From the proteomic profiles of the serum of patients with different stages of liver fibrosis, a total of 1,338 proteins were identified. Among three early fibrosis stages (control, F1, and F2), 55 differential proteins were identified, but no proteins simultaneously exhibited differential expression between control, F1, and F2. Differential proteins were detected in the comparison between different fibrosis stages. Significant differences were found between advanced fibrosis stages (F2-vs.-F3 and F3-vs.-F4) through a series of statistical analysis, including hierarchical clustering, Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes pathway, and protein-protein interaction network analysis. The differential proteins identified by GO annotation were associated with biological processes (mainly platelet degranulation and cell adhesion), molecular functions, and cellular components. Conclusions All potential biomarkers identified between the stages of fibrosis could be key points in determining the fibrosis staging. The differences between early stages may provide a useful reference in addressing the challenge of early fibrosis staging.
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White DN, Stowell MHB. Room for Two: The Synaptophysin/Synaptobrevin Complex. Front Synaptic Neurosci 2021; 13:740318. [PMID: 34616284 PMCID: PMC8488437 DOI: 10.3389/fnsyn.2021.740318] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/18/2021] [Indexed: 12/01/2022] Open
Abstract
Synaptic vesicle release is regulated by upwards of 30 proteins at the fusion complex alone, but disruptions in any one of these components can have devastating consequences for neuronal communication. Aberrant molecular responses to calcium signaling at the pre-synaptic terminal dramatically affect vesicle trafficking, docking, fusion, and release. At the organismal level, this is reflected in disorders such as epilepsy, depression, and neurodegeneration. Among the myriad pre-synaptic proteins, perhaps the most functionally mysterious is synaptophysin (SYP). On its own, this vesicular transmembrane protein has been proposed to function as a calcium sensor, a cholesterol-binding protein, and to form ion channels across the phospholipid bilayer. The downstream effects of these functions are largely unknown. The physiological relevance of SYP is readily apparent in its interaction with synaptobrevin (VAMP2), an integral element of the neuronal SNARE complex. SNAREs, soluble NSF attachment protein receptors, comprise a family of proteins essential for vesicle fusion. The complex formed by SYP and VAMP2 is thought to be involved in both trafficking to the pre-synaptic membrane as well as regulation of SNARE complex formation. Recent structural observations specifically implicate the SYP/VAMP2 complex in anchoring the SNARE assembly at the pre-synaptic membrane prior to vesicle fusion. Thus, the SYP/VAMP2 complex appears vital to the form and function of neuronal exocytotic machinery.
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Affiliation(s)
- Dustin N. White
- MCD Biology, University of Colorado Boulder, Boulder, CO, United States
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Cross-fostering alleviates depression-like behavior mediated by EAAT2 and SNARE complex in prenatal stress offspring rat. Pharmacol Biochem Behav 2021; 210:173269. [PMID: 34487773 DOI: 10.1016/j.pbb.2021.173269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 11/20/2022]
Abstract
Previous studies have shown that prenatal stress (PS) can potentially contribute to depression-like behavior in offspring and that this effect may be moderated by cross-fostering. However, the underlying mechanism of this effect remains to be determined. This study aimed to determine the effect of cross-fostering on the expression of EAAT2 and the SNARE complex in the hippocampus and the prefrontal cortex of PS offspring rats and to demonstrate functional effects on depression-like behavior. The impacts of cross-fostering were functionally assessed using the sucrose preference test (SPT), the forced swimming test (FST) and the elevated plus maze (EPM). Quantitative real-time PCR was used to determine changes in the expression of EAAT2 and SNAREs mRNA in the hippocampus and the prefrontal cortex of offspring rats. PS offspring rats showed significantly decreased sucrose preference and prolonged immobility time, while cross-fostering effectively increased sucrose preference and shorten the time of immobility. The expression of EAAT2 mRNA in PS offspring rats was markedly reduced, whilst the core mRNA expression of the SNARE complex increased. Our results provide strong evidence demonstrating that cross-fostering can alleviate depression-like behavior and regulate the abnormal expression levels of EAAT2 mRNA and SNARE complex in the hippocampus and the prefrontal cortex of PS offspring rats. Our findings contribute to further understanding of the pathogenesis of PS-induced depression and may help to inform the future development of novel treatment approaches.
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Jęśko H, Wieczorek I, Wencel PL, Gąssowska-Dobrowolska M, Lukiw WJ, Strosznajder RP. Age-Related Transcriptional Deregulation of Genes Coding Synaptic Proteins in Alzheimer's Disease Murine Model: Potential Neuroprotective Effect of Fingolimod. Front Mol Neurosci 2021; 14:660104. [PMID: 34305524 PMCID: PMC8299068 DOI: 10.3389/fnmol.2021.660104] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/31/2021] [Indexed: 12/11/2022] Open
Abstract
Alzheimer's disease (AD) induces time-dependent changes in sphingolipid metabolism, which may affect transcription regulation and neuronal phenotype. We, therefore, analyzed the influence of age, amyloid β precursor protein (AβPP), and the clinically approved, bioavailable sphingosine-1-phosphate receptor modulator fingolimod (FTY720) on the expression of synaptic proteins. RNA was isolated, reverse-transcribed, and subjected to real-time PCR. Expression of mutant (V717I) AβPP led to few changes at 3 months of age but reduced multiple mRNA coding for synaptic proteins in a 12-month-old mouse brain. Complexin 1 (Cplx1), SNAP25 (Snap25), syntaxin 1A (Stx1a), neurexin 1 (Nrxn1), neurofilament light (Nefl), and synaptotagmin 1 (Syt1) in the hippocampus, and VAMP1 (Vamp1) and neurexin 1 (Nrxn1) in the cortex were all significantly reduced in 12-month-old mice. Post mortem AD samples from the human hippocampus and cortex displayed lower expression of VAMP, synapsin, neurofilament light (NF-L) and synaptophysin. The potentially neuroprotective FTY720 reversed most AβPP-induced changes in gene expression (Cplx1, Stx1a, Snap25, and Nrxn1) in the 12-month-old hippocampus, which is thought to be most sensitive to early neurotoxic insults, but it only restored Vamp1 in the cortex and had no influence in 3-month-old brains. Further study may reveal the potential usefulness of FTY720 in the modulation of deregulated neuronal phenotype in AD brains.
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Affiliation(s)
- Henryk Jęśko
- Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Iga Wieczorek
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Przemysław Leonard Wencel
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | | | - Walter J. Lukiw
- LSU Neuroscience Center, Departments of Neurology and Ophthalmology, Louisiana State University School of Medicine, New Orleans, LA, United States
| | - Robert Piotr Strosznajder
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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Li Y, Wang C, Wang P, Li X, Zhou L. Effects of febrile seizures in mesial temporal lobe epilepsy with hippocampal sclerosis on gene expression using bioinformatical analysis. ACTA EPILEPTOLOGICA 2020. [DOI: 10.1186/s42494-020-00027-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractBackgroundTo investigate the effect of long-term febrile convulsions on gene expression in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and explore the molecular mechanism of MTLE-HS.MethodsMicroarray data of MTLE-HS were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between MTLE-HS with and without febrile seizure history were screened by the GEO2R software. Pathway enrichment and gene ontology of the DEGs were analyzed using the DAVID online database and FunRich software. Protein–protein interaction (PPI) networks among DEGs were constructed using the STRING database and analyzed by Cytoscape.ResultsA total of 515 DEGs were identified in MTLE-HS samples with a febrile seizure history compared to MTLE-HS samples without febrile seizure, including 25 down-regulated and 490 up-regulated genes. These DEGs were expressed mostly in plasma membrane and synaptic vesicles. The major molecular functions of those genes were voltage-gated ion channel activity, extracellular ligand-gated ion channel activity and calcium ion binding. The DEGs were mainly involved in biological pathways of cell communication signal transduction and transport. Five genes (SNAP25, SLC32A1, SYN1, GRIN1,andGRIA1) were significantly expressed in the MTLE-HS with prolonged febrile seizures.ConclusionThe pathogenesis of MTLE-HS involves multiple genes, and prolonged febrile seizures could cause differential expression of genes. Thus, investigations of those genes may provide a new perspective into the mechanism of MTLE-HS.
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Jęśko H, Cieślik M, Gromadzka G, Adamczyk A. Dysfunctional proteins in neuropsychiatric disorders: From neurodegeneration to autism spectrum disorders. Neurochem Int 2020; 141:104853. [PMID: 32980494 DOI: 10.1016/j.neuint.2020.104853] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/05/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023]
Abstract
Despite fundamental differences in disease course and outcomes, neurodevelopmental (autism spectrum disorders - ASD) and neurodegenerative disorders (Alzheimer's disease - AD and Parkinson's disease - PD) present surprising, common traits in their molecular pathomechanisms. Uncontrolled oligomerization and aggregation of amyloid β (Aβ), microtubule-associated protein (MAP) tau, or α-synuclein (α-syn) contribute to synaptic impairment and the ensuing neuronal death in both AD and PD. Likewise, the pathogenesis of ASD may be attributed, at least in part, to synaptic dysfunction; attention has also been recently paid to irregularities in the metabolism and function of the Aβ precursor protein (APP), tau, or α-syn. Commonly affected elements include signaling pathways that regulate cellular metabolism and survival such as insulin/insulin-like growth factor (IGF) - PI3 kinase - Akt - mammalian target of rapamycin (mTOR), and a number of key synaptic proteins critically involved in neuronal communication. Understanding how these shared pathomechanism elements operate in different conditions may help identify common targets and therapeutic approaches.
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Affiliation(s)
- Henryk Jęśko
- Department of Cellular Signalling, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106, Warsaw, Poland.
| | - Magdalena Cieślik
- Department of Cellular Signalling, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106, Warsaw, Poland.
| | - Grażyna Gromadzka
- Cardinal Stefan Wyszynski University, Faculty of Medicine. Collegium Medicum, Wóycickiego 1/3, 01-938, Warsaw, Poland.
| | - Agata Adamczyk
- Department of Cellular Signalling, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106, Warsaw, Poland.
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Li YC, Zheng XX, Xia SZ, Li Y, Deng HH, Wang X, Chen YW, Yue YS, He J, Cao YJ. Paeoniflorin ameliorates depressive-like behavior in prenatally stressed offspring by restoring the HPA axis- and glucocorticoid receptor- associated dysfunction. J Affect Disord 2020; 274:471-481. [PMID: 32663978 DOI: 10.1016/j.jad.2020.05.078] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 04/25/2020] [Accepted: 05/14/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Prenatal stress (PS) can increase the risk of nervous, endocrine and metabolic diseases and induce depression in offspring. Paeoniflorin (PA) is an amorphous glucoside isolated from the aqueous extract of roots of the peony plant (Paeonia lactiflora Pall.) and exerts various pharmacological effects in the nervous system. METHODS Male prenatally stressed offspring were used to investigate the antidepression-like effects and possible mechanism of PA. We measured animal behavior, HPA axis, Nissil staining, and Ng expression. Additionally, we assessed the modulation of hippocampal glucocorticoid receptors (GR) nuclear translocation and SNARE complex expression by western blotting. RESULTS The results showed that administration of PA (15, 30, and 60 mg/kg/day, i.g.) for 28 days markedly increased sucrose intake and decreased the immobility time and the total number of crossings, center crossings, rearing, and grooming in male PS offspring. Moreover, PA significantly reduced the serum corticosterone (CORT), adrenocorticotropin (ACTH), corticotropin-releasing hormone (CRH) and hippocampal glutamate (Glu) levels in male PS offspring, which were stimulated by an increase of GR nuclear translocation. Furthermore, PA markedly increased neurogranin (Ng) protein expression in the hippocampus CA3 region in offspring. PA also markedly decreased hippocampal Glu by inhibiting SNAP25, VAMP2, Syntaxin1a and related protein expression; SNARE complex formation; and EAAT2/3, NR1, NR2A, and FKBP5 protein expression. CONCLUSIONS Taken together, the results of this study show that PA has antidepression-like effects in male PS offspring, partially due to the HPA axis, GR dysfunction and Glu transport system.
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Affiliation(s)
- Ying Chun Li
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Xing Xing Zheng
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Si Zhe Xia
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Yang Li
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Huan Huan Deng
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Xing Wang
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Yi Wei Chen
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Yi Song Yue
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Jiao He
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China
| | - Yan Jun Cao
- Biomedicine Key Laboratory of Shaanxi Province, school of pharmacy, Northwest University, Xi'an, P.R. China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, P.R. China.
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Changes in the Expression of SNAP-25 Protein in the Brain of Juvenile Rats in Two Models of Autism. J Mol Neurosci 2020; 70:1313-1320. [PMID: 32367505 PMCID: PMC7399687 DOI: 10.1007/s12031-020-01543-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 04/13/2020] [Indexed: 12/13/2022]
Abstract
The results of genetic studies suggest a possible role for SNAP-25 polymorphism in the development of autism spectrum disorders (ASDs); however, there are no data available on whether changes in SNAP-25 expression also affect animals in rodent models of ASD. The aim of the present study was to explore this issue. The studies included 1-month-old rats representing valproic acid (VPA)- and thalidomide (THAL)-induced models of autism. Their mothers received single doses of VPA (800 mg/kg) or THAL (500 mg/kg) per os on the 11th day of gestation. SNAP-25 protein content in the cerebellum, hippocampus, and frontal lobe was determined using Western blotting, while changes of mRNA levels of Snap25 gene were determined using real-time polymerase chain reaction. Compared to controls, SNAP-25 content was decreased by approximately 35% in all brain structures tested, in both males and females, exclusively in the VPA group. In contrast to this, Snap25 expression, studied in males, was increased in the hippocampus and cerebellum in both, VPA- and THAL-treated rats. We discuss the compliance of these results with the hypothesized role of SNAP-25 in the pathophysiology of ASD and the adequacy of the experimental models used.
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26
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Yin K, Li Y, Ma Z, Yang Y, Zhao H, Liu C, Jin M, Wudong G, Sun Y, Hang T, Zhang H, Wang F, Wen Y. SNAP25 regulates the release of the Rabies virus in nerve cells via SNARE complex-mediated membrane fusion. Vet Microbiol 2020; 245:108699. [PMID: 32456820 DOI: 10.1016/j.vetmic.2020.108699] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/20/2020] [Accepted: 04/20/2020] [Indexed: 11/16/2022]
Abstract
Recent studies have reported that host proteins regulate Rabies virus (RABV) infection via distinct mechanisms. The abnormal neural function caused by RABV infection is related to the abnormal synaptic signal transmission in which the RABV glycoprotein (G) is involved. In the present study, two recombinant Rabies viruses (rRABVs), namely rSAD-SAD-Flag-G and rSAD-CVS-Flag-G, were established and rescued based on rSAD and verified by indirect fluorescence assay (IFA), and western blotting (WB). To investigate how the G protein interacts with synaptosomal-associated protein 25 (SNAP25), primary neuronal cells (PNC) of embryonic mice were cultured and infected with rRABVs. Immunoprecipitation (IP) and LC-MS/MS analysis of glycoprotein-binding proteins, which were flag tagged, were carried out to determine the interaction of G protein and soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins (SNARE) complex in PNC. G protein and the SNARE member SNAP25 were co-expressed in HEK293 cells or primary neuronal cells to investigate their colocalization. Knockdown of SNAP25 with small interfering RNA (siRNA) was conducted on mNA cells, and rRABV replication was observed by IFA, qRT-PCR, and virus titration. The results indicated that rRABVs were successfully rescued and grew well in PNC. Flag-tag IP and confocal microscopy demonstrated that SNAP25 works together with G protein and colocalizes with G on the cytomembrane of HEK293 cells. The downregulation of SNAP25, using RNA interference, resulted in a significant decrease in the number of viral mRNAs, viral proteins, and virus particles. Furthermore, the regression of SNAP25 did not affect the initial infection of the virus but reduced the infectivity of progeny virions.
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Affiliation(s)
- Kun Yin
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China; State Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Economic Animals and Plants, Chinese Academy of Agricultural Sciences CAAS, Changchun, Jilin 130112, China; The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Yiming Li
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Zipeng Ma
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Yang Yang
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Hongzhe Zhao
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Chunyu Liu
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Ming Jin
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Gaowa Wudong
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Yuming Sun
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Tianyu Hang
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - He Zhang
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China
| | - Fengxue Wang
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China.
| | - Yongjun Wen
- College of Veterinary Medicine, Key Laboratory for Clinical Diagnosis and Treatment of Animal Diseases of Ministry of Agriculture, Inner Mongolia Agricultural University, Inner Mongolia Autonomous Region, Huhhot 010018, China; State Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Economic Animals and Plants, Chinese Academy of Agricultural Sciences CAAS, Changchun, Jilin 130112, China
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27
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Network-based identification of genetic factors in ageing, lifestyle and type 2 diabetes that influence to the progression of Alzheimer's disease. INFORMATICS IN MEDICINE UNLOCKED 2020. [DOI: 10.1016/j.imu.2020.100309] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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28
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Zhao Y, Sharfman NM, Jaber VR, Lukiw WJ. Down-Regulation of Essential Synaptic Components by GI-Tract Microbiome-Derived Lipopolysaccharide (LPS) in LPS-Treated Human Neuronal-Glial (HNG) Cells in Primary Culture: Relevance to Alzheimer's Disease (AD). Front Cell Neurosci 2019; 13:314. [PMID: 31354434 PMCID: PMC6635554 DOI: 10.3389/fncel.2019.00314] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/26/2019] [Indexed: 12/19/2022] Open
Abstract
Trans-synaptic neurotransmission of both electrical and neurochemical information in the central nervous system (CNS) is achieved through a highly interactive network of neuron-specific synaptic proteins that include pre-synaptic and post-synaptic elements. These elements include a family of several well-characterized integral- and trans-membrane synaptic core proteins necessary for the efficient operation of this complex signaling network, and include the pre-synaptic proteins: (i) neurexin-1 (NRXN-1); (ii) the synaptosomal-associated phosphoprotein-25 (SNAP-25); (iii) the phosphoprotein synapsin-2 (SYN-2); and the post-synaptic elements: (iv) neuroligin (NLGN), a critical cell adhesion protein; and (v) the SH3-ankyrin repeat domain, proline-rich cytoskeletal scaffolding protein SHANK3. All five of these pre- and post-synaptic proteins have been found to be significantly down-regulated in primary human neuronal-glial (HNG) cell co-cultures after exposure to Bacteroides fragilis lipopolysaccharide (BF-LPS). Interestingly, LPS has also been reported to be abundant in Alzheimer's disease (AD) affected brain cells where there are significant deficits in this same family of synaptic components. This "Perspectives" paper will review current research progress and discuss the latest findings in this research area. Overall these experimental results provide evidence (i) that gastrointestinal (GI) tract-derived Gram-negative bacterial exudates such as BF-LPS express their neurotoxicity in the CNS in part through the directed down-regulation of neuron-specific neurofilaments and synaptic signaling proteins; and (ii) that this may explain the significant alterations in immune-responses and cognitive deficits observed after bacterial-derived LPS exposure to the human CNS.
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Affiliation(s)
- Yuhai Zhao
- LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Anatomy and Cell Biology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Nathan M. Sharfman
- LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Vivian R. Jaber
- LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Walter J. Lukiw
- LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
- Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
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29
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Avcil M, Akman G, Klokkers J, Jeong D, Çelik A. Efficacy of bioactive peptides loaded on hyaluronic acid microneedle patches: A monocentric clinical study. J Cosmet Dermatol 2019; 19:328-337. [DOI: 10.1111/jocd.13009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 01/07/2023]
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30
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Wang X, Zhang J, Zhou L, Xu B, Ren X, He K, Nie L, Li X, Liu J, Yang X, Yuan J. Long-term iron exposure causes widespread molecular alterations associated with memory impairment in mice. Food Chem Toxicol 2019; 130:242-252. [PMID: 31136779 DOI: 10.1016/j.fct.2019.05.038] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/09/2019] [Accepted: 05/24/2019] [Indexed: 12/14/2022]
Abstract
Limited literature available indicates the neurotoxic effects of excessive iron, however, a deep understanding of iron neurotoxicity needs to be developed. In this study, we evaluated the toxic effects of excessive iron on learning and cognitive function in long-term iron exposure (oral, 10 mg/L, 6 months) of mice by behavioral tests including novel object recognition test, step-down passive avoidance test and Morris water maze test, and further analyzed differential expression of hippocampal proteins. The behavioral tests consistently showed that iron treatment caused cognitive defects of the mice. Proteomic analysis revealed 66 differentially expressed hippocampal proteins (30 increased and 36 decreased) in iron-treated mice as compared with the control ones. Bioinformatics analysis showed that the dysregulated proteins mainly included: synapse-associated proteins (i.e. synaptosomal-associated protein 25 (SNAP25), complexin-1 (CPLX1), vesicle-associated membrane protein 2 (VAMP2), neurochondrin (NCDN)); mitochondria-related proteins (i.e. ADP/ATP translocase 1 (SLC25A4), 14-3-3 protein zeta/delta (YWHAZ)); cytoskeleton proteins (i.e. neurofilament light polypeptide (NEFL), tubulin beta-2B chain (TUBB2B), tubulin alpha-4A chain (TUBA4A)). The findings suggest that the dysregulations of synaptic, mitochondrial, and cytoskeletal proteins may be involved in iron-triggered memory impairment. This study provides new insights into the molecular mechanisms of iron neurotoxicity.
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Affiliation(s)
- Xian Wang
- Department of Occupational and Environmental Health and Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, PR China; Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Jiafei Zhang
- Department of Occupational and Environmental Health and Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, PR China; Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Li Zhou
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Benhong Xu
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Xiaohu Ren
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Kaiwu He
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Lulin Nie
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Xiao Li
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China
| | - Jianjun Liu
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China.
| | - Xifei Yang
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, Guangdong, PR China.
| | - Jing Yuan
- Department of Occupational and Environmental Health and Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, PR China.
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