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Cognition Enhancers
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Ramneek Kaur, Rashi Rajput, Sachin Kumar, Harleen Kaur, R. Rachana, Manisha Singh
Like PKC, there are many other proteins that have a C1 domain. Many proteins including mammalian uncoordinated (Munc)-13 family proteins (Wojcik and Brose, 2007) and rat sarcoma guanyl releasing protein 1 (Lorenzo et al., 2000) binds to 1,2-diacylglycerol and have homologous domains. These listed proteins are present in neurons and contribute in the growth of dendrites and release of synaptic vesicles. Therefore, they cannot be disregarded as a prospective target for various cognition enhancers and bryostatin; then, there are numerous isoforms of Munc13. Munc13 isoform is present in Purkinje and cerebellum granule cells, where it helps in controlling the motor learning. Munc13-1 is the profuse isoform which is present throughout the brain and is a prospective target of cognition enhancers as it is a synaptic vesicle C which colocalizes with the presynaptic marker synaptophysin (Augustin et al., 2001) and therefore, it is well-located to alter the synaptic efficiency. It was observed that phorbol dibutyrate binds to Munc13 and decreases the energy barrier for fusion of synaptic vesicle (Basu et al., 2007). Phorbol esters and diacylglycerol (DAG) increases the release of neurotransmitters in the hippocampal neurons; Munc13 (but not PKC) is the protein which is accountable of causing this effect (Rhee et al., 2002).
Defining in vitro topical antimicrobial and antibiofilm activity of epoxy-tigliane structures against oral pathogens
Published in Journal of Oral Microbiology, 2023
Wenya Xue, Manon F. Pritchard, Saira Khan, Lydia C. Powell, Joana Stokniene, Jingxiang Wu, Nicholas Claydon, Paul Reddell, David W. Thomas, Katja E. Hill
In peri-implantitis, extracellular matrix (ECM) remodeling will occur following surgical debridement [32]. EBC-1013, being a PKC activator (and potentially other C1 domain-containing proteins), exhibits immunomodulatory activity [15]. Interestingly, in diabetic skin wounds, EBC-1013 was able to induce a local inflammatory response, with Tnf, Il1b, Il6, Il36g, and Cxcl2 induction and polymorphonuclear leukocyte (PMNL) recruitment, as well as reorganization and remodeling of the extracellular matrix, and wound re-epithelialization. The immunostimulatory activity of EBC-1013 contrasts with the immunomodulatory activities of peptides such as pleurocidin [33], and essential oils (already in use in dentistry) [34], which inhibit inflammatory responses by suppressing the production of important mediators of pro-inflammatory pathways [35–37]. Innate immune induction by EBC-1013 induced healing in 6/7 diabetic wounds, compared to only 1/7 of untreated wounds. The induction of a rapidly resolving local innate immune response, combined with rapid remodeling at the implant/host interface, may contribute to the removal of biofilm persister cells from the sites of debridement.
A novel compound heterozygous mutation in DGKE in a Chinese patient causes atypical hemolytic uremic syndrome
Published in Hematology, 2020
Jitong Li, Yinsen Song, Yaodong Zhang, Hongjiang Li, Ming Tian, Di Li, Shufeng Zhang, Guanghai Cao, Cuihua Liu
DGKE protein model predictions were performed by using the Phyre2 online tool. The C1 domain was modeled based on the c2e73A (the phorbol esters/diacylglycerol binding domain of protein kinase C gamma) template with a confidence score of 98.39, identity of 26% and coverage residues of aa 55-117 (10%) of the DGKE amino acid sequence. The integrated DAGKc, DAGKa and LC domains were modeled based on the c2qv7A (diacylglycerol kinase DgkB in complex with ADP and Mg) template with a confidence score of 100, identity of 18% and coverage residues aa 213-563 (61%) of the DGKE amino acid sequence. The 3D models were visualized with PyMOL software. The position of the residue that is altered as a result of the M1 mutation (p.C77W) is marked in pink, and the position of the residues that are altered as a consequence of the M2 mutation (p.C264Yfs*27) is marked in light green. The C1 (58-108 aa), DAGKc (219-350 aa), DAGKa (369-524 aa) and LC (548-563 aa) domains are colored blue, purple, orange and red, respectively, and the other resides of the indicated models are marked in black.
RAP GTPases and platelet integrin signaling
Published in Platelets, 2019
Lucia Stefanini, Wolfgang Bergmeier
The C-terminal regulatory domain of CALDAG-GEFI [24] includes a pair of highly sensitive calcium ion (Ca2+)-binding EF hand domains (KD~80 nM) [27] and an atypical C1 domain. The EF hand domains provide remarkable sensitivity toward minor changes in the cytoplasmic Ca2+ concentration [28], which in resting platelets was measured at ~20–50 nM. The C1 domain is considered atypical because, unlike the prototypical C1 domain of protein kinase C (PKC), it has weak affinity for the second messenger diacylglycerol (DAG) [29]. Accordingly, DAG does not affect the subcellular localization or the activity of CALDAG-GEFI [30, 31] and platelets lacking functional CALDAG-GEFI in humans or mice respond normally to stimulation with DAG mimetics [11, 32]. However, the C1 domain is important for optimal CALDAG-GEFI function in platelets in vivo [20] and our ongoing studies suggest that this domain is important for the association of CalDAG-GEFI to the plasma membrane (unpublished data). When platelets encounter an injury, Ca2+ mobilization from the endoplasmic reticulum is the most rapid intracellular response to agonist receptor engagement by either exposed components of the extracellular matrix or by locally generated soluble agonists. Our current working model is that Ca2+ binding to the EF hands ensures the near-immediate activation of CALDAG-GEFI catalytic activity. The C1 domain, while it does not affect the catalytic activity per se, enhances the GEF efficiency of CALDAG-GEFI [20] by driving its localization to the inner leaflet of the plasma membrane (unpublished data), where RAP is enriched due to its post-translational modifications (see below for details). Both these regulatory mechanisms contribute to the efficient and very rapid activation of RAP.