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1.
Sci Rep ; 14(1): 4799, 2024 02 27.
Article de Anglais | MEDLINE | ID: mdl-38413690

RÉSUMÉ

Research on amateur mountaineers is scarce, and this study aims to delve into the emotional experiences of ten amateur mountaineers during their ascent using the "Befindlichkeitsskala" (BFS) and Lake Louise Acute Mountain Sickness scoring system (LLS). These subjects were exposed to altitudes of 3140 m, 4300 m, and 5276 m, respectively. We found that LLS scores were negatively correlated with positive emotions (ß = -27.54, p < 0.05) and positively correlated with negative emotions (ß = 21.97, p < 0.05). At an altitude of 4300 m, individuals with AMS exhibited significant differences in depression, anger, excitement, and inactivity compared to climbers without AMS. Upon returning to 3140 m after completing the climb, significant differences were observed in emotions such as happiness, calmness, anger, excitement, and depression. Throughout the three-day climb, noteworthy differences emerged in activity, happiness, calmness, inactivity, positive emotions (p < 0.01), negative emotions, and overall emotional scores (p < 0.05). Our study suggests a decline in the emotional well-being of amateur climbers with increasing altitude, highlighting AMS as a pivotal predictive factor for emotional experiences while climbing.


Sujet(s)
Mal de l'altitude , Humains , Mal de l'altitude/psychologie , Maladie aigüe , Altitude , Émotions , Bonheur
2.
Theranostics ; 8(1): 199-211, 2018.
Article de Anglais | MEDLINE | ID: mdl-29290802

RÉSUMÉ

Rationale: HSV is one of the most widespread human viral pathogens. HSV-1 infects a large portion of the human population and causes severe diseases. The current clinical treatment for HSV-1 is based on nucleoside analogues, the use of which is limited due to drug resistance, side effects and poor bioavailability. AMPs have been identified as potential antiviral agents that may overcome these limitations. Therefore, we screened anti-HSV-1 peptides from a scorpion-derived AMP library and engineered one candidate into a histidine-rich peptide with significantly improved antiviral activity and development potential. Methods: A venomous gland cDNA library was constructed from the scorpion Euscorpiops validus in the Yunnan Province of China. Six putative AMPs were characterized from this cDNA library, and the synthesized peptides were screened via plaque-forming assays to determine their virucidal potential. Time of addition experiments according to the infection progress of HSV-1 were used to identify the modes of action for peptides of interest. The histidine-rich modification was designed based on structural analysis of peptides by a helical wheel model and CD spectroscopy. Peptide cellular uptake and distribution were measured by flow cytometry and confocal microscopy, respectively. Results: The peptide Eval418 was found to have high clearance activity in an HSV-1 plaque reduction assay. Eval418 exhibited dose-dependent and time-dependent inactivation of HSV-1 and dose-dependent inhibition of HSV-1 attachment to host cells. However, Eval418 scarcely suppressed an established HSV-1 infection due to poor cellular uptake. We further designed and modified Eval418 into four histidine-rich derivative peptides with enhanced antiviral activities and lower cytotoxicities. All of the derivative peptides suppressed established HSV-1 infections. One of these peptides, Eval418-FH5, not only had strong viral inactivation activity and enhanced attachment inhibitory activity but also had high inhibitory activity against intracellular HSV-1, which was consistent with its improved intracellular uptake and distribution as confirmed by confocal microscopy and flow cytometry. Conclusion: We successfully identified an anti-HSV-1 peptide, Eval418, from a scorpion venom peptide library and designed a histidine-rich Eval418 derivative with significantly improved potential for further development as an anti-HSV-1 drug. This successful modification can provide a design strategy to improve the bioavailability, cellular distribution and antiviral activity of peptide agents.


Sujet(s)
Antiviraux/composition chimique , Antiviraux/pharmacologie , Herpèsvirus humain de type 1/effets des médicaments et des substances chimiques , Venins de scorpion/composition chimique , Scorpions/composition chimique , Animaux , Peptides antimicrobiens cationiques/composition chimique , Peptides antimicrobiens cationiques/pharmacologie , Chine , Banque de peptides
3.
Toxins (Basel) ; 8(5)2016 04 27.
Article de Anglais | MEDLINE | ID: mdl-27128943

RÉSUMÉ

Hepatitis B virus (HBV) infection is a major worldwide health problem which can cause acute and chronic hepatitis and can significantly increase the risk of liver cirrhosis and primary hepatocellular carcinoma (HCC). Nowadays, clinical therapies of HBV infection still mainly rely on nucleotide analogs and interferons, the usage of which is limited by drug-resistant mutation or side effects. Defensins had been reported to effectively inhibit the proliferation of bacteria, fungi, parasites and viruses. Here, we screened the anti-HBV activity of 25 scorpion-derived peptides most recently characterized by our group. Through evaluating anti-HBV activity and cytotoxicity, we found that BmKDfsin4, a scorpion defensin with antibacterial and Kv1.3-blocking activities, has a comparable high inhibitory rate of both HBeAg and HBsAg in HepG2.2.15 culture medium and low cytotoxicity to HepG2.2.15. Then, our experimental results further showed that BmKDfsin4 can dose-dependently decrease the production of HBV DNA and HBV viral proteins in both culture medium and cell lysate. Interestingly, BmKDfsin4 exerted high serum stability. Together, this study indicates that the scorpion defensin BmKDfsin4 also has inhibitory activity against HBV replication along with its antibacterial and potassium ion channel Kv1.3-blocking activities, which shows that BmKDfsin4 is a uniquely multifunctional defensin molecule. Our work also provides a good molecule material which will be used to investigate the link or relationship of its antiviral, antibacterial and ion channel-modulating activities in the future.


Sujet(s)
Antiviraux/pharmacologie , Défensines/pharmacologie , Virus de l'hépatite B/effets des médicaments et des substances chimiques , Scorpions , Réplication virale/effets des médicaments et des substances chimiques , Animaux , Survie cellulaire/effets des médicaments et des substances chimiques , ADN viral/effets des médicaments et des substances chimiques , Érythrocytes/effets des médicaments et des substances chimiques , Hémolyse/effets des médicaments et des substances chimiques , Cellules HepG2 , Antigènes de surface du virus de l'hépatite B/métabolisme , Antigènes e du virus de l'hépatite virale B/métabolisme , Virus de l'hépatite B/physiologie , Humains
4.
Mol Ther Nucleic Acids ; 5: e295, 2016 Mar 15.
Article de Anglais | MEDLINE | ID: mdl-26978579

RÉSUMÉ

Hepatitis B virus (HBV) infection is a major cause of chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma, all of which are severe threats to human health. However, current clinical therapies for HBV are limited by potential side effects, toxicity, and drug-resistance. In this study, a cell-penetrating peptide-conjugated peptide nucleic acid (PNA), Tat-PNA-DR, was designed to target the direct repeat (DR) sequences of HBV. Tat-PNA-DR effectively inhibited HBV replication in HepG2.2.15 cells. Its anti-HBV effect relied on the binding of Tat-PNA-DR to the DR, whereby it suppressed the translation of hepatitis B e antigen (HBeAg), HBsAg, HBV core, hepatitis B virus x protein, and HBV reverse transcriptase (RT) and the reverse transcription of the HBV genome. Furthermore, Tat-PNA-DR administered by intravenous injection efficiently cleared HBeAg and HBsAg in an acute hepatitis B mouse model. Importantly, it induced an 80% decline in HBV DNA in mouse serum, which was similar to the effect of the widely used clinical drug Lamivudine (3TC). Additionally, a long-term hydrodynamics HBV mouse model also demonstrated Tat-PNA-DR's antiviral effect. Interestingly, Tat-PNA-DR displayed low cytotoxicity, low mouse acute toxicity, low immunogenicity, and high serum stability. These data indicate that Tat-PNA-DR is a unique PNA and a promising drug candidate against HBV.

5.
J Biol Chem ; 290(38): 23254-63, 2015 Sep 18.
Article de Anglais | MEDLINE | ID: mdl-26251517

RÉSUMÉ

Viral infection is an early stage of its life cycle and represents a promising target for antiviral drug development. Here we designed and characterized three peptide inhibitors of hepatitis C virus (HCV) infection based on the structural features of the membrane-associated p7 polypeptide of HCV. The three peptides exhibited low toxicity and high stability while potently inhibiting initial HCV infection and suppressed established HCV infection at non-cytotoxic concentrations in vitro. The most efficient peptide (designated H2-3), which is derived from the H2 helical region of HCV p7 ion channel, inhibited HCV infection by inactivating both intracellular and extracellular viral particles. The H2-3 peptide inactivated free HCV with an EC50 (50% effective concentration) of 82.11 nm, which is >1000-fold lower than the CC50 (50% cytotoxic concentration) of Huh7.5.1 cells. H2-3 peptide also bound to cell membrane and protected host cells from viral infection. The peptide H2-3 did not alter the normal electrophysiological profile of the p7 ion channel or block viral release from Huh7.5.1 cells. Our work highlights a new anti-viral peptide design strategy based on ion channel, giving the possibility that ion channels are potential resources to generate antiviral peptides.


Sujet(s)
Antiviraux/pharmacologie , Hepacivirus/métabolisme , Hépatite C/traitement médicamenteux , Canaux ioniques/composition chimique , Peptides/pharmacologie , Protéines virales/composition chimique , Libération de particules virales/effets des médicaments et des substances chimiques , Antiviraux/composition chimique , Cellules HeLa , Hepacivirus/génétique , Hépatite C/génétique , Hépatite C/métabolisme , Humains , Peptides/composition chimique
6.
Small ; 11(21): 2543-54, 2015 Jun 03.
Article de Anglais | MEDLINE | ID: mdl-25626995

RÉSUMÉ

A novel dual-pH sensitive charge-reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(L-lysine)-block-poly(L-leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3-dimethylmaleic anhydride to form ß-carboxylic amide, making the polypeptides self-assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell-penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH-sensitive ß-carboxylic amides.


Sujet(s)
Antinéoplasiques/administration et posologie , Antinéoplasiques/pharmacocinétique , Systèmes de délivrance de médicaments , Nanoparticules/composition chimique , Peptides/composition chimique , Transport nucléaire actif , Noyau de la cellule/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Doxorubicine/administration et posologie , Doxorubicine/pharmacocinétique , Vecteurs de médicaments/composition chimique , Cellules HeLa , Humains , Concentration en ions d'hydrogène , Micelles , Peptides/synthèse chimique , Polylysine/composition chimique , Multimérisation de protéines , Produits du gène tat du virus de l'immunodéficience humaine/composition chimique
7.
Antiviral Res ; 102: 1-10, 2014 Feb.
Article de Anglais | MEDLINE | ID: mdl-24315793

RÉSUMÉ

Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen that causes severe diseases, but there are not effective and safe drugs in clinical therapy besides acyclovir (ACV) and related nucleoside analogs. In this study, two new venom peptides from the scorpion Heterometrus petersii were identified with effective inhibitory effect on HSV-1 infection in vitro. Both Hp1036 and Hp1239 peptides exhibited potent virucidal activities against HSV-1 (EC50=0.43±0.09 and 0.41±0.06µM, respectively) and effective inhibitory effects when added at the viral attachment (EC50=2.87±0.16 and 5.73±0.61µM, respectively), entry (EC50=4.29±0.35 and 4.32±0.47µM, respectively) and postentry (EC50=7.86±0.80 and 8.41±0.73µM, respectively) steps. Both Hp1036 and Hp1239 peptides adopted α-helix structure in approximate membrane environment and resulted in the destruction of the viral morphology. Moreover, Hp1036 and Hp1239 peptides entered Vero cells and reduced the intracellular viral infectivity. Taken together, Hp1036 and Hp1239 peptides are two anti-viral peptides with effective inhibitory effect on multiple steps of HSV-1 life cycle and therefore are good candidate for development as virucides.


Sujet(s)
Peptides antimicrobiens cationiques/pharmacologie , Antiviraux/pharmacologie , Herpèsvirus humain de type 1/effets des médicaments et des substances chimiques , Venins de scorpion/pharmacologie , Animaux , Chlorocebus aethiops , Herpèsvirus humain de type 1/physiologie , Humains , Tests de sensibilité microbienne , Scorpions , Cellules Vero , Pénétration virale/effets des médicaments et des substances chimiques , Réplication virale/effets des médicaments et des substances chimiques
8.
J Biol Chem ; 287(36): 30181-90, 2012 Aug 31.
Article de Anglais | MEDLINE | ID: mdl-22791717

RÉSUMÉ

Hepatitis B virus (HBV) is a noncytopathic human hepadnavirus that causes acute, chronic hepatitis and hepatocellular carcinoma (HCC). As the clinical utility of current therapies is limited, new anti-HBV agents and sources for such agents are still highly sought after. Here, we report that Mucroporin-M1, a scorpion venom-derived peptide, reduces the amount of extracellular HBsAg, HBeAg, and HBV DNA productions of HepG2.2.15 cells in a dose-dependent manner and inhibits HBV capsid DNA, HBV intracellular RNA replication intermediates and the HBV Core protein in the cytoplasm of HepG2.2.15 cells. Using a mouse model of HBV infection, we found that HBV replication was significantly inhibited by intravenous injection of the Mucroporin-M1 peptide. This inhibitory activity was due to a reduction in HBV promoter activity caused by a decrease in the binding of HNF4α to the precore/core promoter region. Furthermore, we confirmed that Mucroporin-M1 could selectively activate mitogen-activated protein kinases (MAPKs) and lead to the down-regulation of HNF4α expression, which explains the decreased binding of HNF4α to the HBV promoter. Moreover, when the protein phosphorylation activity of the MAPK pathway was inhibited, both HNF4α expression and HBV replication recovered. Finally, we proved that treatment with the Mucroporin-M1 peptide increased phosphorylation of the MAPK proteins in HBV-harboring mice. These results implicate Mucroporin-M1 peptide can activate the MAPK pathway and then reduce the expression of HNF4α, resulting in the inhibition of HBV replication in vitro and in vivo. Our work also opens new doors to discovering novel anti-HBV agents or sources.


Sujet(s)
Antiviraux/pharmacologie , Virus de l'hépatite B/physiologie , Hépatite B/traitement médicamenteux , Facteur nucléaire hépatocytaire HNF-4/biosynthèse , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Peptides/pharmacologie , Venins de scorpion/pharmacologie , Réplication virale/effets des médicaments et des substances chimiques , Animaux , Capside/métabolisme , ADN viral/biosynthèse , ADN viral/génétique , Modèles animaux de maladie humaine , Régulation de l'expression des gènes , Cellules HepG2 , Hépatite B/génétique , Hépatite B/métabolisme , Antigènes de surface du virus de l'hépatite B/génétique , Antigènes de surface du virus de l'hépatite B/métabolisme , Antigènes e du virus de l'hépatite virale B/génétique , Antigènes e du virus de l'hépatite virale B/métabolisme , Facteur nucléaire hépatocytaire HNF-4/génétique , Humains , Souris , Souris de lignée BALB C , Phosphorylation/effets des médicaments et des substances chimiques , Phosphorylation/génétique , Réplication virale/physiologie
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