Self-assembling peptides are biomedical materials with unique structures that are formed in response to various environmental conditions. Governed by their physicochemical characteristics, the ...peptides can form a variety of structures with greater reactivity than conventional non-biological materials. The structural divergence of self-assembling peptides allows for various functional possibilities; when assembled, they can be used as scaffolds for cell and tissue regeneration, and vehicles for drug delivery, conferring controlled release, stability, and targeting, and avoiding side effects of drugs. These peptides can also be used as drugs themselves. In this review, we describe the basic structure and characteristics of self-assembling peptides and the various factors that affect the formation of peptide-based structures. We also summarize the applications of self-assembling peptides in the treatment of various diseases, including cancer. Furthermore, the in-cell self-assembly of peptides, termed reverse self-assembly, is discussed as a novel paradigm for self-assembling peptide-based nanovehicles and nanomedicines.
Di-n-butyl phthalate (DBP), a well-known endocrine disruptor, causes male reproductive dysfunction. To understand the underlying mechanisms, we performed histological, endocrinological, and ...biochemical analyses and assessed the expression of genes involved in spermatogenesis and sperm function according to OECD test guideline 407. Following 28 days of administration of the lowest observed adverse effect level dose of DBP to mice, no significant changes in body weight, testis and epididymis weights and histology, serum testosterone level, or testicular daily sperm production were found. Nonetheless, the motility of the epididymal sperm of the DBP group was significantly decreased together with an increase in the incidence of bent tails and abnormal heads. In the testes of the DBP group, lipid peroxidation (LPO) level was significantly increased and testicular Bcl-2 mRNA level was significantly decreased together with an increase in the Bax/Bcl-2 mRNA ratio. In the testes of the DBP group, levels of Prnd mRNA and protein and Pou4f1 mRNA, an activator of the Prnd promotor, were significantly decreased. Of note, prion-like protein doppel (PRND) was significantly decreased together with decreased PRND immunoreactivity in the head, midpiece, and tail of sperm. In the testes of the DBP group, levels of Sox9, Sgp1, and Sgp2 mRNA, which are functional Sertoli cell markers, were significantly decreased. Level of Amh mRNA, a Sertoli cell immaturity marker, was significantly increased together with that of Inha mRNA, suggesting deregulation of the brain-gonadal axis. Together, our findings suggest that DBP at present dosage may potentiate LPO generation and Sertoli cell immaturity via downregulation of Sox9 and disruption of the Pou4f1-Prnd gene network in post-meiotic germ cells without visible changes in spermatogenesis or testosterone level. This may result in structural and functional abnormalities in spermatozoa. Additionally, our findings suggest that assessment of the male reproductive toxicity of phthalate ester plasticizers based on conventional OECD test guidelines should be reconsidered.
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●DBP increased ROS damage in testis and potentiate apoptotic gene network in testis.●DBP deregulated Sox9 and increased Sertoli cell immaturity and inhibin in testis.●DBP at LOAEL dose increased structural abnormalities and impaired sperm motility.●Prion like protein doppel reduction by DBP is coupled with sperm abnormality.●Functional and structural abnormality of sperm should be addressed in OECD TG407.
The disease-associated scrapie prion protein (PrP
Sc
), the sole biochemical entity of prions, is formed from the cellular prion protein (PrP
C
) by conformational conversion. Previously, plasminogen ...was shown to interact with multiple PrP species. Hence, plasminogen was utilized not only to enrich the disease-associated PrP isoforms but also to stimulate the formation of PrP
Sc
. Here, we report that incubation of prion-infected cultured cells with the peptides composed of unique YRG/YKRG motifs derived from plasminogen increased a marginal level of PrP
Sc
. This phenomenon is attributed to enrichment of PrP
Sc
by the plasminogen-derived peptide because incubation of the YRG peptide with cell lysate containing PrP
Sc
resulted in an increase of their association, although this interaction was feasible only under a limited condition. The peptides did not increase PrP
Sc
production in protein misfolding cyclic amplification assay, an in vitro reaction of PrP
C
conversion to PrP
Sc
. Taken together, the results of this study suggest that the stimulatory activity of plasminogen in PrP
Sc
formation is not conserved in the plasminogen-derived YRG/YKRG peptides that can physically associate with PrP
Sc
.
Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of ...inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.
Prion diseases are neurodegenerative disorders in humans and animals for which no therapies are currently available. Here, we report that
Valeton (Zingiberaceae) (
) extract was partly effective in ...decreasing prion aggregation and propagation in both in vitro and in vivo models.
extract inhibited self-aggregation of recombinant prion protein (PrP) in a test tube assay and decreased the accumulation of scrapie PrP (PrP
) in ScN2a cells, a cultured neuroblastoma cell line with chronic prion infection, in a concentration-dependent manner.
extract also modified the course of the disease in mice inoculated with mouse-adapted scrapie prions, completely preventing the onset of prion disease in three of eight mice. Biochemical and neuropathological analyses revealed a statistically significant reduction in PrP
accumulation, spongiosis, astrogliosis, and microglia activation in the brains of mice that avoided disease onset. Furthermore, PrP
accumulation in the spleen of mice was also reduced.
extract precluded prion infection in cultured cells as demonstrated by the modified standard scrapie cell assay. This study suggests that
extract could contribute to investigating the modulation of prion propagation.
Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP
Sc
) that forms insoluble amyloids to impair brain ...function. PrP
Sc
interacts with the non-pathogenic, cellular prion protein (PrP
C
) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrP
Sc
but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC
50
= 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC
50
= 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrP
Sc
in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.
Many questions surround the underlying mechanism for the differential metabolic processing observed for the prion protein (PrP) in healthy and prion-infected mammals. Foremost, the physiological ...α-cleavage of PrP interrupts a region critical for both toxicity and conversion of cellular PrP (PrP
) into its misfolded pathogenic isoform (PrP
) by generating a glycosylphosphatidylinositol (GPI)-anchored C1 fragment. During prion diseases, alternative β-cleavage of PrP becomes prominent, producing a GPI-anchored C2 fragment with this particular region intact. It remains unexplored whether physical up-regulation of α-cleavage can inhibit disease progression. Furthermore, several pieces of evidence indicate that a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 play a much smaller role in the α-cleavage of PrP
than originally believed, thus presenting the need to identify the primary protease(s) responsible. For this purpose, we characterized the ability of plasmin to perform PrP α-cleavage. Then, we conducted functional assays using protein misfolding cyclic amplification (PMCA) and prion-infected cell lines to clarify the role of plasmin-mediated α-cleavage during prion propagation. Here, we demonstrated an inhibitory role of plasmin for PrP
formation through PrP α-cleavage that increased C1 fragments resulting in reduced prion conversion compared with non-treated PMCA and cell cultures. The reduction of prion infectious titer in the bioassay of plasmin-treated PMCA material also supported the inhibitory role of plasmin on PrP
replication. Our results suggest that plasmin-mediated endoproteolytic cleavage of PrP may be an important event to prevent prion propagation.
The conversion of the normal cellular prion protein (PrP
C
) to the misfolded pathogenic scrapie prion protein (PrP
Sc
) is the biochemical hallmark of prion replication. So far, various chemical ...compounds that inhibit this conformational conversion have been identified. Here, we report the novel anti-prion activity of SGI-1027 and its meta/meta analogue (M/M), previously known only as potent inhibitors of DNA methyltransferases (DNMTs). These compounds effectively decreased the level of PrP
Sc
in cultured cells with permanent prion infection, without affecting PrP
C
at the transcriptional or translational levels. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a PrP aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded PrP aggregates, implying that binding of these compounds hinders the PrP conversion process. A series of binding and docking analyses demonstrated that both SGI-1027 and M/M directly interacted with the C-terminal globular domain of PrP
C
, but only SGI-1027 bound to a specific region of PrP
C
with high affinity, which correlates with its potent anti-prion efficacy. Therefore, we report SGI-1027 and related compounds as a novel class of potential anti-prion agents that preferentially function through direct interaction with PrP
C
.
A novel activity of DNMT inhibitor SGI-1027 was discovered to suppress the pathogenic process of prion. The direct binding of SGI-1027 to prion protein with a normal conformation was discovered to suppress the formation of misfolded prion proteins.
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Abstract Branched polyamines are effective in inhibiting prions in a cationic surface charge density dependent manner. However, toxicity associated with branched polyamines, in general, often hampers ...the successful application of the compounds to treat prion diseases. Here, we report that constitutively maintained cationic properties in branched polyamines reduced the intrinsic toxicity of the compounds while retaining the anti-prion activities. In prion-infected neuroblastoma cells, quaternization of amines in polyethyleneimine (PEI) and polyamidoamine (PAMAM) dendrimers markedly increased the nontoxic concentration ranges of the compounds and still supported, albeit reduced, an appreciable level of anti-prion activity in clearing prions from the infected cells. Furthermore, quaternized PEI was able to degrade prions at acidic pH conditions and inhibit the in vitro prion propagation facilitated by conversion of the normal prion protein isoform to its misfolded counterpart, although such activities were decreased by quaternization. Quaternized PAMAM was least effective in degrading prions but efficiently inhibited prion conversion with the same efficacy as unmodified PAMAM. Our results suggest that quaternization represents an effective strategy for developing nontoxic branched polyamines with potent anti-prion activity. This study highlights the importance of polyamine structural control for developing polyamine-based anti-prion agents and understanding of an action mechanism of quaternized branched polyamines.
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