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Influence of Imidazole-Dipeptides on Cognitive Status and Preservation in Elders: A Narrative Review.
Nutrients
Nobutaka Masuoka, Chenxu Lei, Haowei Li +1 more
The worldwide increase in the number of patients with dementia is becoming a growing problem, while Alzheimer's disease (AD), a primary neurodegenerative disorder, accounts for more than 70% of all dementia cases. Research on the prevention or reduction of AD occurrence through food ingredients has been widely conducted. In particular, histidine-containing dipeptides, also known as imidazole dipeptides derived from meat, have received much attention. Imidazole dipeptides are abundant in meats such as poultry, fish, and pork. As evidenced by data from recent human intervention trials conducted worldwide, daily supplementation of carnosine and anserine, which are both imidazole dipeptides, can improve memory loss in the elderly and reduce the risk of developing AD. This article also summarizes the latest researches on the biochemical properties of imidazole dipeptides and their effects on animal models associated with age-related cognitive decline. In this review, we focus on the results of human intervention studies using supplements of poultry-derived imidazole dipeptides, including anserine and carnosine, affecting the preservation of cognitive function in the elderly, and discuss how imidazole dipeptides act in the brain to prevent age-related cognitive decline and the onset of dementia.
Enhanced angiogenic effects of RGD, GHK peptides and copper (II) compositions in synthetic cryogel ECM model.
Mater Sci Eng C Mater Biol Appl
Mohamed Zoughaib, Duong Luong, Ruslan Garifullin +3 more
Synthetic oligopeptides are a promising alternative to natural full-length growth factors and extracellular matrix (ECM) proteins in tissue regeneration and therapeutic angiogenesis applications. In this work, angiogenic properties of dual and triple compositions containing RGD, GHK peptides and copper (II) ions (Cu2+) were for the first time studied. To reveal specific in vitro effects of these compositions in three-dimensional scaffold, adamantyl group bearing peptides, namely Ada-Ahx-GGRGD (1) and Ada-Ahx-GGGHK (2), were effectively immobilized in bioinert pHEMA macroporous cryogel via host-guest β-cyclodextrin-adamantane interaction. The cryogels were additionally functionalized with Cu2+ via the formation of GHK-Cu complex. Angiogenic responses of HUVECs grown within the cryogel ECM model were analyzed. The results demonstrate that the combination of RGD with GHK and further with Cu2+ dramatically increases cell proliferation, differentiation, and production of a series of angiogenesis related cytokines and growth factors. Furthermore, the level of glutathione, a key cellular antioxidant and redox regulator, was altered in relation to the angiogenic effects. These results are of particular interest for establishing the role of multiple peptide signals on regeneration related processes and for developing improved tissue engineering materials.
Vasopressin Administration Is Associated With Rising Serum Lactate Levels in Patients With Sepsis.
J Intensive Care Med
Kristen A Severson, Laura Ritter-Cox, Jesse D Raffa +2 more
Vasopressin is used in conjunction with norepinephrine during treatment of patients with septic shock. Serum lactate is often used in monitoring of patients with sepsis; however, its importance as a therapeutic target is unclear. The objective of this study is to examine the relationship of vasopressin use on serum lactate levels in patients with sepsis.
Blockade of bradykinin receptors or angiotensin II type 2 receptor prevents paclitaxel-associated acute pain syndrome in mice.
Eur J Pain
Graziele C Zanata, Larissa G Pinto, Nicole R da Silva +7 more
Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin-kallikrein and renin-angiotensin systems in P-APS in mice.
Determination of the immunostimulatory drug-glucosoaminyl-muramyl-dipeptide-in human plasma using HPLC-MS/MS and its application to a pharmacokinetic study.
Biomed Chromatogr
Natalia E Moskaleva, Pavel A Markin, Roman M Kuznetsov +2 more
GMDP (glucosoaminyl-muramyl-dipeptide), a synthetic analog of the peptidoglycan fragment of the bacterial cell wall, is an active component of the immunomodulatory drug Licopid. But the pharmacokinetic parameters of GMDP in humans after oral administration have not been investigated yet. The present study aimed at developing and validating a sensitive LC-MS/MS method for the analysis of GMDP in human plasma. The sample was prepared by solid-phase extraction using Strata-X 33 μm polymeric reversed-phase 60 mg/3 mL cartridges Phenomenex (Torrance, CA, USA). The analytes were separated using an Acquity UPLC BEN C18 column, 1.7 μm 2.1 × 50 mm Waters (Milford, USA). GMDP and internal standard growth hormone releasing peptide-2 (pralmorelin) were ionized in positive electrospray ionization mode and detected in multiple reaction monitoring mode. The developed method was validated within a linear range of 50-3000 pg/mL for GMDP. Accuracy for all analytes, given as the deviation between the nominal and measured concentration and assay variability , ranged from 1.61 to 3.02% and from 0.89 to 1.79%, respectively, for both within- and between-run variabilities. The developed and validated HPLC-MS/MS method was successfully used to obtain the plasma pharmacokinetic profiles of GMDP distribution in human plasma.
Direct evidence for binding of aluminum to NAP anti-amyloid peptide and its analogs.
Eur J Mass Spectrom (Chichester)
Ancuta-Veronica Lupaescu, Ionel Humelnicu, Brindusa Alina Petre +2 more
NAP (NAPVSIPQ) is a small peptide derived from the activity-dependent neuroprotective protein (ADNP), which provides neuroprotection against amyloid-β peptide toxicity associated with Alzheimer disease. Several metal ions are able to promote the formation of amyloid-β peptide oligomers and protofibrils in human brain tissue. Although the relationship between metal ions and amyloid-β peptide peptides is extensively investigated, that with the NAP peptide is less understood. Nevertheless, our previous research revealed unexpected iron binding to NAP peptide and its analogs. However, a link between aluminum ions, Alzheimer disease and amyloid-β peptide or NAP peptides still remains controversial. Therefore, we have investigated the possible binding of aluminum ions to NAP peptide and its four analogs. Indeed, MALDI-ToF mass spectrometry (MS), including MS/MS study, and Fourier transform infrared (FT-IR) spectroscopy revealed an unexpected pattern of aluminum ion binding to both NAP peptide and its analogs. Our results have been discussed with respect to NAP protection against Alzheimer disease-related neurotoxicity.
Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer-Its Comparative Expression, Processing and Signaling in Mammalian CNS.
Int J Mol Sci
Alexander Beletskiy, Ekaterina Chesnokova, Natalia Bal
A number of studies performed on rodents suggest that insulin-like growth factor 2 (IGF-2) or its analogs may possibly be used for treating some conditions like Alzheimer's disease, Huntington's disease, autistic spectrum disorders or aging-related cognitive impairment. Still, for translational research a comparative knowledge about the function of IGF-2 and related molecules in model organisms (rats and mice) and humans is necessary. There is a number of important differences in IGF-2 signaling between species. In the present review we emphasize species-specific patterns of IGF-2 expression in rodents, humans and some other mammals, using, among other sources, publicly available transcriptomic data. We provide a detailed description of Igf2 mRNA expression regulation and pre-pro-IGF-2 protein processing in different species. We also summarize the function of IGF-binding proteins. We describe three different receptors able to bind IGF-2 and discuss the role of IGF-2 signaling in learning and memory, as well as in neuroprotection. We hope that comprehensive understanding of similarities and differences in IGF-2 signaling between model organisms and humans will be useful for development of more effective medicines targeting IGF-2 receptors.
EDR Peptide: Possible Mechanism of Gene Expression and Protein Synthesis Regulation Involved in the Pathogenesis of Alzheimer's Disease.
Molecules
Vladimir Khavinson, Natalia Linkova, Ekaterina Kozhevnikova +1 more
The EDR peptide (Glu-Asp-Arg) has been previously established to possess neuroprotective properties. It activates gene expression and synthesis of proteins, involved in maintaining the neuronal functional activity, and reduces the intensity of their apoptosis in in vitro and in vivo studies. The EDR peptide interferes with the elimination of dendritic spines in neuronal cultures obtained from mice with Alzheimer's (AD) and Huntington's diseases. The tripeptide promotes the activation of the antioxidant enzyme synthesis in the culture of cerebellum neurons in rats. The EDR peptide normalizes behavioral responses in animal studies and improves memory issues in elderly patients. The purpose of this review is to analyze the molecular and genetics aspects of the EDR peptide effect on gene expression and synthesis of proteins involved in the pathogenesis of AD. The EDR peptide is assumed to enter cells and bind to histone proteins and/or ribonucleic acids. Thus, the EDR peptide can change the activity of the MAPK/ERK signaling pathway, the synthesis of proapoptotic proteins (caspase-3, p53), proteins of the antioxidant system (SOD2, GPX1), transcription factors PPARA, PPARG, serotonin, calmodulin. The abovementioned signaling pathway and proteins are the components of pathogenesis in AD. The EDR peptide can be AD.
The Therapeutic Potential of Carnosine/Anserine Supplementation against Cognitive Decline: A Systematic Review with Meta-Analysis.
Biomedicines
Giuseppe Caruso, Justyna Godos, Sabrina Castellano +6 more
Carnosine is a natural occurring endogenous dipeptide that was proposed as an anti-aging agent more than 20 years ago. Carnosine can be found at low millimolar concentrations at brain level and different preclinical studies have demonstrated its antioxidant, anti-inflammatory, and anti-aggregation activity with neuroprotective effects in animal models of Alzheimer's disease (AD). A selective deficit of carnosine has also been linked to cognitive decline in AD. Different clinical studies have been conducted to evaluate the impact of carnosine supplementation against cognitive decline in elderly and AD subjects. We conducted a systematic review with meta-analysis, in accordance with the PRISMA guidelines coupled to the PICOS approach, to investigate the therapeutic potential of carnosine against cognitive decline and depressive symptoms in elderly subjects. We found five studies matching the selection criteria. Carnosine/anserine was administered for 12 weeks at a dose of 1 g/day and improved global cognitive function, whereas no effects were detected on depressive symptoms. These data suggest a preliminary evidence of clinical efficacy of carnosine against cognitive decline both in elderly subjects and mild cognitive impairment (MCI) patients, although larger and long-term clinical studies are needed in MCI patients (with or without depression) to confirm the therapeutic potential of carnosine.
TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone.
Front Cell Neurosci
Cong Zheng, Guiqin Chen, Yang Tan +11 more
Dopaminergic neurons loss is one of the main pathological characters of Parkinson's disease (PD), while no suitable neuroprotective agents have been in clinical use. Thyrotropin-releasing hormone (TRH) and its analogs protect neurons from ischemia and various cytotoxins, but whether the effect also applies in PD models remain unclear. Here, we showed that Taltirelin, a long-acting TRH analog, exhibited the neuroprotective effect in both cellular and animal models of PD. The in vitro study demonstrated that Taltirelin (5 μM) reduced the generation of reactive oxygen species (ROS) induced by MPP+ or rotenone, alleviated apoptosis and rescued the viability of SH-SY5Y cells and rat primary midbrain neurons. Interestingly, SH-SY5Y cells treated with Taltirelin also displayed lower level of p-tau (S396) and asparagine endopeptidase (AEP) cleavage products, tau N368 and α-synuclein N103 fragments, accompanied by a lower intracellular monoamine oxidase-B (MAO-B) activity. In the subacute MPTP-induced and chronic rotenone-induced PD mice models, we found Taltirelin (1 mg/kg) significantly improved the locomotor function and preserved dopaminergic neurons in the substantia nigra (SN). In accordance with the in vitro study, Taltirelin down-regulated the levels of p-tau (S396), p-α-synuclein (S129) tau N368 and α-synuclein N103 fragments in SN and striatum. Together, this study demonstrates that Taltirelin may exert neuroprotective effect via inhibiting MAO-B and reducing the oxidative stress and apoptosis, preventing AEP activation and its subsequent pathological cleavage of tau and α-synuclein, thus provides evidence for Taltirelin in protective treatment of PD.
Potent antibacterial activity of MSI-1 derived from the magainin 2 peptide against drug-resistant bacteria.
Theranostics
Lingman Ma, Xin Xie, Hanhan Liu +6 more
The structural modification of existing AMPs is an effective strategy to develop antimicrobial agents with high-efficiency, low-cost and low-toxicity antimicrobial agents. Methods: Here, we truncated 14-amino-acids at the N-terminus of MSI-78 to obtain MSI and further modified MSI to obtain four peptide analogs: MSI-1, MSI-2, MSI-3 and MSI-4. These peptide mutants were evaluated regarding their antibacterial activity against various sensitive or resistant bacteria; toxicity against mammalian cells or mice; and stability against violent pH, temperature variations and high NaCl concentrations. Finally, we also elucidated the possible mechanisms underlying its mode of action. Results: The results showed that MSI-1 and MSI-3 displayed activity that was superior to that of MSI-78 with MICs of 4-16 μg/ml and MBCs of 8-64 μg/ml, respectively, especially against drug-resistant bacteria, due to the increase in percent helicity and amphiphilicity. However, MSI-3, with higher hydrophobicity and antibacterial activity, had a relatively higher hemolysis rate and toxicity than MSI-1. MSI-1 exerted rapid bactericidal activity and effectively improved the survival rate and wound closure in penicillin-resistant E. coli-infected mice by eliminating bacterial counts in mouse organs or subeschar, further inhibiting the systemic dissemination of bacteria. Additionally, MSI-1 displayed perfect stability against violent pH, temperature variations and high NaCl concentrations and has the ability to circumvent the development of drug resistance. In terms of the mode of action, we found that at the super-MIC level, MSI-1 exhibited direct antimicrobial activity by disrupting the integrity of the bacterial cell membrane, while at the sub-MIC level, it bound to bacterial DNA to inhibit DNA replication and protein expression and ultimately disrupted bacterial biological function. Conclusions: This novel peptide MSI-1 could be a potential candidate for drug development against infection induced by drug-resistant bacteria.
Development of Antimicrobial Stapled Peptides Based on Magainin 2 Sequence.
Molecules
Motoharu Hirano, Chihiro Saito, Hidetomo Yokoo +4 more
Magainin 2 (Mag2), which was isolated from the skin of the African clawed frog, is a representative antimicrobial peptide (AMP) that exerts antimicrobial activity via microbial membrane disruption. It has been reported that the helicity and amphipathicity of Mag2 play important roles in its antimicrobial activity. We investigated and recently reported that 17 amino acid residues of Mag2 are required for its antimicrobial activity, and accordingly developed antimicrobial foldamers containing α,α-disubstituted amino acid residues. In this study, we further designed and synthesized a set of Mag2 derivatives bearing the hydrocarbon stapling side chain for helix stabilization. The preferred secondary structures, antimicrobial activities, and cell-membrane disruption activities of the synthesized peptides were evaluated. Our analyses revealed that hydrocarbon stapling strongly stabilized the helical structure of the peptides and enhanced their antimicrobial activity. Moreover, peptide 2 stapling between the first and fifth position from the N-terminus showed higher antimicrobial activity than that of Mag2 against both gram-positive and gram-negative bacteria without exerting significant hemolytic activity. To investigate the modes of action of tested peptides 2 and 8 in antimicrobial and hemolytic activity, electrophysiological measurements were performed.
Hydrogels based on low-methoxyl amidated citrus pectin and flaxseed gum formulated with tripeptide glycyl-l-histidyl-l-lysine improve the healing of experimental cutting wounds in rats.
Int J Biol Macromol
Alla Synytsya, Pavla Poučková, Marie Zadinová +5 more
Hydrogels based on natural and modified polysaccharides represent growing group of suitable matrices for the construction of effective wound healing materials. Bioactive tripeptide glycyl-l-histidyl-l-lysine and amino acid α-l-arginine are known to accelerate wound healing and skin repair. In this study, hydrogels based on low-methoxyl amidated citrus pectin or flaxseed gum were prepared and used for the transport of these healing agents to the experimental cutting wounds affected by extensive skin damage. Fourier-transform infrared spectroscopy, rheology, differential scanning calorimetry, scanning electron microscopy, swelling and release tests confirmed that these hydrogels differed in structure and physical properties. The cationic tripeptide was found to bind to carboxylic groups in LMA pectin, and the C3OH hydroxyl and ring oxygen O5 are involved in this interaction. The pectin hydrogel showed high viscosity and strong elastic properties, while the flaxseed gum hydrogel was characterised as a viscoelastic system of much lower viscosity. The former hydrogel released the drugs very slowly, while the latter hydrogel demonstrated zero order releasing kinetics optimal for drug delivery. In the in vivo wound healing testing on rats, both polysaccharide hydrogels improved the healing process mediated by the mentioned biomolecules. The tripeptide applied in the hydrogels showed significantly higher healing degree and lower healing time than in the control animals without treatment and when it was applied in an aqueous solution. Despite the absence of a synergistic effect, the mixture of the tripeptide and α-l-arginine in the hydrogels was also quite effective in wound healing. According to histological analysis, complete healing was achieved only when using the tripeptide in the flaxseed gum hydrogel. These observations might have an important prospect in clinical application of polysaccharide hydrogels.
Blockade of RANKL/RANK signaling pathway by epigallocatechin gallate alleviates mast cell-mediated inflammatory reactions.
Int Immunopharmacol
Hee-Yun Kim, Ho-Geun Kang, Sun-Young Nam +2 more
Receptor activator of NF-κB ligand (RANKL) as an osteoclast differentiation factor induces inflammatory reactions via production of thymic stromal lymphopoietin (TSLP). Epigallocatechin gallate (EGCG) is the major and the most active compound in green tea and has anti-inflammatory, anti-cancer, anti-oxidant, and neuroprotective effects. However, the effect and molecular mechanisms of EGCG are still unknown in RANKL-induced inflammatory reactions. Here we investigated the immuno-regulatory effects and its molecular mechanisms of epigallocatechin gallate (EGCG) in RANKL-stimulated human mast cell line, HMC-1 cells. In this study, EGCG prevented expression of PI3 Kinase and phosphorylation of mitogen-activated protein (MAP) Kinases in RANKL-stimulated HMC-1 cells. EGCG prevented caspase-1 activity and decreased transcriptional activity of nuclear factor (NF)-κB by suppressing inhibitory protein κBα phosphorylation in RANKL-stimulated HMC-1 cells. EGCG has been shown to prevent production and mRNA expression of TSLP, interleukin (IL)-1β, IL-6, and IL-8 by RANKL without cytotoxicity. Furthermore, EGCG prevented degranulation of mast cell in RANKL-stimulated HMC-1 cells. Overall, these results suggest that EGCG acts as a natural agent for preventing and treating RANKL-mediated inflammatory diseases by targeting PI3 Kinase, MAP Kinase, caspase-1, and NF-κB signaling cascade in mast cells.
Evaluation of Elafin Immunohistochemical Expression as Marker of Cervical Cancer Severity.
Acta Cytol
Adhemar Longatto-Filho, José Humberto Fregnani, Allini Mafra da Costa +5 more
The main risk factor for the development of cervical cancer (CC) is persistent infection by human papillomavirus (HPV) oncogenic types. In order to persist, HPV exhibits a plethora of immune evasion mechanisms. PI3/Elafin (Peptidase Inhibitor 3) is an endogenous serine protease inhibitor involved in epithelial protection against pathogens. PI3/Elafin's role in CC is still poorly understood.
Effects of immunopotentiators on biochemical parameters, proinflammatory cytokine, and nonspecific immune responses in Shaoxing ducklings.
Poult Sci
Tiantian Gu, Guoqin Li, Xinsheng Wu +6 more
Antibiotics are one of the most important medical discoveries of the 20th century and will remain an essential tool for treating animal and human diseases in the 21st century. However, misuse of antibiotics imperils the development of animal husbandry and human health all over the world, and it is important to find reliable alternatives to antibiotics to reduce the use of antibiotics. In this study, 22 potential immunopotentiators were screened on the levels of apoptosis and inflammatory factor in duck embryo fibroblast cells (DEFs). The results indicated that interferon (IFN)-β and tumor necrosis factor-α gene transcriptions were significantly upregulated, while interleukin (IL)-2 and Bcl2 mRNA levels were significantly decreased during 22 immunopotentiators treatment. Besides, the expression level of IL-1β mRNA showed significant increase during dihydromyricetin, chlorogenic acid, naringin, imiquimod, thymopentin, β-D-Glucan, astragalus polysacharin, astragalus saponin I, astragalus flavone, curcumin, CpG-DNA-2, and LPS treatment. And the level of caspase 3 protein was significantly upregulated with treating chlorogenic acid, β-D-Glucan, astragalus polysacharin, astragalus flavone, curcumin, CpG-DNA-2, chicken IgG, LPS, and poly(I:C). These results indicated that chlorogenic acid, β-D-Glucan, astragalus flavone, CpG-DNA-2, and chicken IgG have the positive immune regulation effects on duck DEFs. Thus, the 5 immunopotentiators were chosen to further verify their immunomodulatory function in vivo. The results showed that the activity of serum AST was significantly downregulated during all immunopotentiators treatments excepting for β-D-Glucan, and the activities of serum IL12p40, IL-1β, IFN-α, and IFN-β were significantly increased compared with the control group. Five immunopotentiators also induced the duck's pattern recognition receptors and inflammatory factor gene expression. In addition, 5 immunopotentiators could facilitate the contents of serum caspase 3, iNOSm and COX2 and reduce the Bcl2. These results suggested that these 5 immunopotentiators could enhance duck innate immune responses. Taken together, our study not only screened out 5 kinds of duck innate immune immunopotentiators but also initially clarified their underlying mechanism of action, which provide a new insight for the development of efficient approaches to prevent the duck disease from pathogen infections.
Vasopressin and post-traumatic stress disorder.
Stress
Eszter Sipos, Bibiána Török, István Barna +2 more
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with a wide range of behavioral disturbances and serious consequences for both patient and society. One of the main reasons for unsuccessful therapies is insufficient knowledge about its underlying pathomechanism. In the search for centrally signaling molecules that might be relevant to the development of PTSD we focus here on arginine vasopressin (AVP). So far AVP has not been strongly implicated in PTSD, but different lines of evidence suggest a possible impact of its signaling in all clusters of PTSD symptomatology. More specifically, in laboratory rodents, AVP agonists affect behavior in a PTSD-like manner, while significant reduction of AVP signaling in the brain e.g. in AVP-deficient Brattleboro rats, ameliorated defined behavioral parameters that can be linked to PTSD symptoms. Different animal models of PTSD also show alterations in the AVP signaling in distinct brain areas. However, pharmacological treatment targeting central AVP receptors via systemic routes is hampered by possible side effects that are linked to the peripheral action of AVP as a hormone. Indeed, the V1a receptor, the most common receptor subtype in the brain, is implicated in vasoconstriction. Thus, systemic treatment with V1a receptor antagonists would be implicated in hypotonia. This implies that novel treatment concepts are needed to target AVP receptors not only at brain level but also in distinct brain areas, to offer alternative treatments for PTSD.
Thymopentin improves the survival of septic mice by promoting the production of 15-deoxy-prostaglandin J2 and activating the PPARγ signaling pathway.
FASEB J
Ye Zhang, Xue Yang, Wenchao Yan +13 more
Sepsis, a systemic inflammatory response syndrome (SIRS) caused by infection, is a major public health concern with limited therapeutic options. Infection disturbs the homeostasis of host, resulting in excessive inflammation and immune suppression. This has prompted the clinical use of immunomodulators to balance host response as an alternative therapeutic strategy. Here, we report that Thymopentin (TP5), a synthetic immunomodulator pentapeptide (Arg-Lys-Asp-Val-Tyr) with an excellent safety profile in the clinic, protects mice against cecal ligation and puncture (CLP)-induced sepsis, as shown by improved survival rate, decreased level of pro-inflammatory cytokines and reduced ratios of macrophages and neutrophils in spleen and peritoneum. Regarding mechanism, TP5 changed the characteristics of LPS-stimulated macrophages by increasing the production of 15-deoxy-Δ12,14 -prostaglandin J2 (15-d-PGJ2). In addition, the improved effect of TP5 on survival rates was abolished by the peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662. Our results uncover the mechanism of the TP5 protective effects on CLP-induced sepsis and shed light on the development of TP5 as a therapeutic strategy for lethal systemic inflammatory disorders.
Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia-Reperfusion in Rats.
Genes (Basel)
Ivan B Filippenkov, Vasily V Stavchansky, Alina E Denisova +8 more
Cerebral ischaemia is the most common cause of impaired brain function. Biologically active peptides represent potential drugs for reducing the damage that occurs after ischaemia. The synthetic melanocortin derivative, ACTH(4-7)PGP (Semax), has been used successfully in the treatment of patients with severe impairment of cerebral blood circulation. However, its molecular mechanisms of action within the brain are not yet fully understood. Previously, we used the transient middle cerebral artery occlusion (tMCAO) model to study the damaging effects of ischaemia-reperfusion on the brain transcriptome in rats. Here, using RNA-Seq analysis, we investigated the protective properties of the Semax peptide at the transcriptome level under tMCAO conditions. We have identified 394 differentially expressed genes (DEGs) (>1.5-fold change) in the brains of rats at 24 h after tMCAO treated with Semax relative to saline. Following tMCAO, we found that Semax suppressed the expression of genes related to inflammatory processes and activated the expression of genes related to neurotransmission. In contrast, ischaemia-reperfusion alone activated the expression of inflammation-related genes and suppressed the expression of neurotransmission-related genes. Therefore, the neuroprotective action of Semax may be associated with a compensation of mRNA expression patterns that are disrupted during ischaemia-reperfusion conditions.
A role for CIM6P/IGF2 receptor in memory consolidation and enhancement.
Elife
Xiao-Wen Yu, Kiran Pandey, Aaron C Katzman +1 more
Cation-independent mannose-6-phosphate receptor, also called insulin-like growth factor two receptor (CIM6P/IGF2R), plays important roles in growth and development, but is also extensively expressed in the mature nervous system, particularly in the hippocampus, where its functions are largely unknown. One of its major ligands, IGF2, is critical for long-term memory formation and strengthening. Using CIM6P/IGF2R inhibition in rats and neuron-specific knockdown in mice, here we show that hippocampal CIM6P/IGF2R is necessary for hippocampus-dependent memory consolidation, but dispensable for learning, memory retrieval, and reconsolidation. CIM6P/IGF2R controls the training-induced upregulation of de novo protein synthesis, including increase of Arc, Egr1, and c-Fos proteins, without affecting their mRNA induction. Hippocampal or systemic administration of mannose-6-phosphate, like IGF2, significantly enhances memory retention and persistence in a CIM6P/IGF2R-dependent manner. Thus, hippocampal CIM6P/IGF2R plays a critical role in memory consolidation by controlling the rate of training-regulated protein metabolism and is also a target mechanism for memory enhancement.