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Wound healing requires cells that increase both collagen production as a result of inflammatory events and regeneration of epithelial tissue. The Plantago species of herbs have been used in traditional treatment of skin disorders and infectious diseases, and digestive, respiratory, reproductive and circulatory conditions. We investigated the efficacy of different concentrations of Plantago lanceolata L. extract (PLE) for wound healing owing to its anti-inflammatory, anti-bacterial, anti-fungal, anti-oxidant, anti-ulcerative, analgesic and immunomodulatory properties. We used 72 mice in four groups of 18. An excisional 1 cm wound was created in the skin on the back of the mice in all groups. An ointment containing 10% PLE was applied to the wound in group 1, an ointment containing 20% PLE was applied in group 2 and vaseline was applied in group 3. In group 4, no treatment was applied to the wound. On days 7, 14, and 21 of the experiment, six animals in each group were sacrificed after the wounds were photographed and specimens from the wound sites were examined. On day 14, epithelialization was more prominent in group 2, while vascularization and collagen deposition was more advanced in groups 1 and 2 compared to the other groups. Immunohistochemical examination revealed that TGF-β1 expression was elevated on day 14 in all groups; however, this elevation was more limited in groups 1 and 2 than in groups 3 and 4. Although ANGPT-2 expression increased in groups 1 and 4 on day 14, it decreased significantly in groups 2 and 3. We found that different concentrations of PLE exhibited positive effects on wound healing. Application of 10% PLE ointment may be a useful strategy for wound healing.  相似文献   
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Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC50 values in the range of 0.2–15.5 μm were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro1; 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structure-function relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease.  相似文献   
15.
We investigated the effects of lipopolysachharide (LPS) on functional and structural properties of the blood-brain barrier (BBB) during pentylenetetrazole (PTZ)-induced epileptic seizures in rats. Arterial blood pressure was significantly elevated during epileptic seizures irrespective of LPS pretreatment. Plasma levels of interleukin (IL)-1, interleukin (IL)-6, nitric oxide (NO) and malondialdehyde (MDA) increased while catalase concentrations decreased in animals treated with LPS, PTZ and LPS plus PTZ. The significantly increased BBB permeability to Evans blue (EB) dye in the cerebral cortex, diencephalon and cerebellum regions of rats by PTZ-induced seizures was markedly reduced upon LPS pretreatment. Immunoreactivity for tight junction proteins, zonula occludens-1 and occludin, did not change in brain vessels of animals treated with PTZ and LPS plus PTZ. Glial fibrillary acidic protein immunoreactivity was increased in LPS, but not in PTZ and LPS plus PTZ. These results indicate that LPS pretreatment reduces the passage of EB dye bound to albumin into the brain, at least partly, by increasing plasma NO and IL-6 levels during PTZ-induced epileptic seizures. We suggest that LPS may provide protective effects on the BBB integrity during epileptic seizures through transcellular pathway, since the paracellular route remained unaffected by LPS and LPS plus PTZ.  相似文献   
16.
Two lichen metabolites, rhizonaldehyde ( 1 ) and rhizonyl alcohol ( 2 ), were isolated from the acetone extract of Lobaria pulmonaria by chromatographic methods, and their chemical structures were determined by UV/VIS, IR, and 1D‐ and 2D‐NMR spectroscopic methods. The gastroprotective and in vivo antioxidant activities of extracts of L. pulmonaria and its metabolites, 1 and 2 , were investigated in indomethacin‐induced ulcer models in rats. The gastric lesions were significantly reduced by acetone, hexane, and CHCl3 extracts, with 75.3–41.5% inhibition. Rhizonyl alcohol ( 2 ) significantly reduced the gastric lesions with an inhibition rate of 84.6–42.8%, whereas rhizonaldehyde ( 1 ) significantly increased the gastric lesions. Antioxidant parameters and myeloperoxidase activities were also evaluated in the gastric tissues of the rats. Indomethacin caused oxidative stress, which resulted in lipid peroxidation in gastric tissues by decreasing the levels of the antioxidants as compared to healthy rat tissues. In contrast to indomethacin, all extracts and rhizonyl alcohol ( 2 ) caused a significant decrease in lipid peroxidation levels and an increase in antioxidant parameters, superoxide dismutase, glutathione peroxidase, and glutathione‐S‐transferase, and reduced glutathione in gastric tissues. The administration of rhizonyl alcohol ( 2 ) also resulted in a decrease in gastric myeloperoxidase activity increased by indomethacin. The gastroprotective effect of rhizonyl alcohol ( 2 ) can be attributed to its antioxidant properties and its suppressing effect on neutrophil infiltration into gastric tissues.  相似文献   
17.
Various molecular and cellular processes are involved in renal fibrosis, such as oxidative stress, inflammation, endothelial cell injury, and apoptosis. Heat shock proteins (HSPs) are implicated in the progression of chronic kidney disease (CKD). Our aim was to evaluate changes in urine and serum HSP levels over time and their relationships with the clinical parameters of CKD in children. In total, 117 children with CKD and 56 healthy children were examined. The CKD group was followed up prospectively for 24 months. Serum and urine HSP27, HSP40, HSP47, HSP60, HSP70, HSP72, and HSP90 levels and serum anti-HSP60 and anti-HSP70 levels were measured by ELISA at baseline, 12 months, and 24 months. The urine levels of all HSPs and the serum levels of HSP40, HSP47, HSP60, HSP70, anti-HSP60, and anti-HSP70 were higher at baseline in the CKD group than in the control group. Over the months, serum HSP47 and HSP60 levels steadily decreased, whereas HSP90 and anti-HSP60 levels steadily increased. Urine HSP levels were elevated in children with CKD; however, with the exception of HSP90, they decreased over time. In conclusion, our study demonstrates that CKD progression is a complicated process that involves HSPs, but they do not predict CKD progression. The protective role of HSPs against CKD may weaken over time, and HSP90 may have a detrimental effect on the disease course.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12192-021-01239-9.  相似文献   
18.
Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity.  相似文献   
19.

The metabolic syndrome (MetS) and pathologies associated with metabolic dysregulations a worldwide growing problem. Our previous study demonstrated that pioglitazone (PGZ) has beneficial effects on metabolic syndrome associated disturbances in the heart. However, mechanism mediating the molecular alterations of Ubiquitin proteasome system (UPS) and autophagy has not been investigated in rat pancreas with metabolic syndrome. For this reason, we first aimed to detect whether MetS effects on the expression of UPS (p97/VCP, SVIP, Ubiquitin) and autophagic (p62, LC3) proteins in rat pancreas. The second aim of the study was to find impact of pioglitazone on the expression of UPS and autophagic proteins in MetS rat pancreas. To answer these questions, metabolic syndrome induced rats were used as a model and treated with pioglitazone for 2 weeks. Pancreatic tissue injuries, fibrosis and lipid accumulation were evaluated histopathologically in control, MetS and MetS-PGZ groups. Apoptosis and cell proliferation of pancreatic islet cells were assessed in all groups. UPS and autophagic protein expressions of pancreas in all groups were detected by using immunohistochemistry, double-immunfluorescence and Western blotting. Compared with the controls, the rat fed with high sucrose exhibited signs of metabolic syndrome, such as higher body weight, insulin resistance, higher triglyceride level and hyperglycaemia. MetS rats showed pancreatic tissue degeneration, fibrosis and lipid accumulation when their pancreas were examined with Hematoxilen-eozin and Mallory trichrome staining. Metabolic, histopathologic parameters and cell proliferation showed greater improvement in MetS-PGZ rats and pioglitazone decreased apoptosis of islet cells. Moreover, SVIP, ubiquitin, LC3 and p62 expressions were significantly increased while only p97/VCP expression was significantly decreased in MetS-rat pancreas compared to control. PGZ treatment significantly decreased the MetS-induced increases in autophagy markers. Additionally, UPS and autophagy markers were found to colocalizated with insulin and glucagon. Colocalization ratio of UPS markers with insulin showed significant decrease in MetS rats and PGZ increased this ratio, whereas LC3-insulin colocalization displayed significant increase in MetS rats and PGZ reversed this effect. In conclusion, PGZ improved the pancreatic tissue degeneration by increasing the level of p97/VCP and decreasing autophagic proteins, SVIP and ubiquitin expressions in MetS-rats. Moreover, PGZ has an effect on the colocalization ratio of UPS and autophagy markers with insulin.

  相似文献   
20.
Tissue transglutaminase (tTG) has been implicated in the pathogenesis of Parkinson disease (PD). However, exactly how tTG modulates the structural and functional properties of α-synuclein (α-syn) and contributes to the pathogenesis of PD remains unknown. Using site-directed mutagenesis combined with detailed biophysical and mass spectrometry analyses, we sought to identify the exact residues involved in tTG-catalyzed cross-linking of wild-type α-syn and α-syn mutants associated with PD. To better understand the structural consequences of each cross-linking reaction, we determined the effect of tTG-catalyzed cross-linking on the oligomerization, fibrillization, and membrane binding of α-syn in vitro. Our findings show that tTG-catalyzed cross-linking of monomeric α-syn involves multiple cross-links (specifically 2-3). We subjected tTG-catalyzed cross-linked monomeric α-syn composed of either wild-type or Gln → Asn mutants to sequential proteolysis by multiple enzymes and peptide mapping by mass spectrometry. Using this approach, we identified the glutamine and lysine residues involved in tTG-catalyzed intramolecular cross-linking of α-syn. These studies demonstrate for the first time that Gln79 and Gln109 serve as the primary tTG reactive sites. Mutating both residues to asparagine abolishes tTG-catalyzed cross-linking of α-syn and tTG-induced inhibition of α-syn fibrillization in vitro. To further elucidate the sequence and structural basis underlying these effects, we identified the lysine residues that form isopeptide bonds with Gln79 and Gln109. This study provides mechanistic insight into the sequence and structural basis of the inhibitory effects of tTG on α-syn fibrillogenesis in vivo, and it sheds light on the potential role of tTG cross-linking on modulating the physiological and pathogenic properties of α-syn.Parkinson disease (PD)2 is a progressive movement disorder that is caused by the loss of dopaminergic neurons in the substantia nigra, the part of the brain responsible for controlling movement. Clinically, PD is manifested in symptoms that include tremors, rigidity, and difficulty in initiating movement (bradykinesia). Pathologically, PD is characterized by the presence of intraneuronal, cytoplasmic inclusions known as Lewy bodies (LB), which are composed primarily of the protein “α-synuclein” (α-syn) (1) and are seen in the post-mortem brains of PD patients with the sporadic or familial forms of the disease (2). α-Syn is a presynaptic protein of 140 residues with a “natively” unfolded structure (3). Three missense point mutations in α-syn (A30P, E46K, and A53T) are associated with the early-onset, dominant, inherited form of PD (4, 5). Moreover, duplication or triplication of the α-syn gene has been linked to the familial form of PD, suggesting that an increase in α-syn expression is sufficient to cause PD. Together, these findings suggest that α-syn plays a central role in the pathogenesis of PD.The molecular and cellular determinants that govern α-syn oligomerization and fibrillogenesis in vivo remain poorly understood. In vitro aggregation studies have shown that the mutations associated with PD (A30P, E46K, and A53T) accelerate α-syn oligomerization, but only E46K and A53T α-syn show higher propensity to fibrillize than wild-type (WT) α-syn (6-8). This suggests that oligomerization, rather than fibrillization, is linked to early-onset familial PD (9). Our understanding of the molecular composition and biochemical state of α-syn in LBs has provided important clues about protein-protein interactions and post-translational modifications that may play a role in modulating oligomerization, fibrillogenesis, and LB formation of the protein. In addition to ubiquitination (10), phosphorylation (11, 12), nitration (13, 14), and C-terminal truncation (15, 16), analysis of post-mortem brain tissues from PD and Lewy bodies in dementia patients has confirmed the colocalization of tissue transglutaminase (tTG)-catalyzed cross-linked α-syn monomers and higher molecular aggregates in LBs within dopaminergic neurons (17, 18). Tissue transglutaminase catalyzes a calcium-dependent transamidating reaction involving glutamine and lysine residues, which results in the formation of a covalent cross-link via ε-(γ-glutamyl) lysine bonds (Fig. 2F). To date, seven different isoforms of tTGs have been reported, of which only tTG2 seems to be expressed in the human brain (19), whereas tTG1 and tTG3 are more abundantly found in stratified squamous epithelia (20). Subsequent immuno-histochemical, colocalization, and immunoprecipitation studies have shown that the levels of tTG and cross-linked α-syn species are increased in the substantia nigra of PD brains (17). These findings, combined with the known role of tTG in cross-linking and stabilizing bimolecular assemblies, led to the hypothesis that tTG plays an important role in the initiation and propagation of α-syn fibril formation and that it contributes to fibril stability in LBs. This hypothesis was initially supported by in vitro studies demonstrating that tTG catalyzes the polymerization of the α-syn-derived non-amyloid component (NAC) peptide via intermolecular covalent cross-linking of residues Gln79 and Lys80 (21) and by other studies suggesting that tTG promotes the fibrillization of amyloidogenic proteins implicated in the pathogenesis of other neurodegenerative diseases such as Alzheimer disease, supranuclear palsy, Huntington disease, and other polyglutamine diseases (22-24). However, recent in vitro studies with full-length α-syn have shown that tTG catalyzes intramolecular cross-linking of monomeric α-syn and inhibits, rather than promotes, its fibrillization in vitro (25, 26). The structural basis of this inhibitory effect and the exact residues involved in tTG-mediated cross-linking of α-syn, as well as structural and functional consequences of these modifications, remain poorly understood.Open in a separate windowFIGURE 2.tTG-catalyzed cross-linking of α-syn involves one to three intramolecular cross-links. A-C, MALDI-TOF/TOF analysis of native (—) and cross-linked (- - -) α-syn, showing that most tTG-catalyzed cross-linking products of WT or disease-associated mutant forms of α-syn are intramolecularly linked (predominant peak with two cross-links), and up to three intramolecular cross-links can occur (left shoulder). The abbreviations M and m/cl are used to designate native and cross-linked α-synuclein, respectively. D and E, kinetic analysis of α-syn (A30P) cross-linking monitored by MALDI-TOF and SDS-PAGE. F, schematic depiction of the tTG-catalyzed chemical reaction (isodipeptide formation) between glutamine and lysine residues.In this study, we have identified the primary glutamine and lysine residues involved in tTG-catalyzed, intramolecularly cross-linked monomeric α-syn and investigated how cross-linking these residues affects the oligomerization, fibrillization, and membrane binding of α-syn in vitro. Using single-site mutagenesis and mass spectrometry applied to exhaustive proteolytic digests of native and cross-linked monomeric α-syn, we identified Gln109 and Gln79 as the major tTG substrates. We demonstrate that the altered electrophoretic mobility of the intramolecularly cross-linked α-syn in SDS-PAGE occurs as a result of tTG-catalyzed cross-linking of Gln109 to lysine residues in the N terminus of α-syn, which leads to the formation of more compact monomers. Consistent with previous studies, we show that intramolecularly cross-linked α-syn forms off-pathway oligomers that are distinct from those formed by the wild-type protein and that do not convert to fibrils within the time scale of our experiments (3-5 days). We also show that membrane-bound α-syn is a substrate of tTG and that intramolecular cross-linking does not interfere with the ability of monomeric α-syn to adopt an α-helical conformation upon binding to synthetic membranes. These studies provide novel mechanistic insight into the sequence and structural basis of events that allow tTG to inhibit α-syn fibrillogenesis, and they shed light on the potential role of tTG-catalyzed cross-linking in modulating the physiological and pathogenic properties of α-syn.  相似文献   
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