Membrane-Active All-Hydrocarbon-Stapled α-Helical Amphiphilic Tat Peptides: Broad-Spectrum Antibacterial Activity and Low Incidence of Drug Resistance.

Multidrug resistance against conventional antibiotics has dramatically increased the difficulty of treatment and accelerated the need for novel antibacterial agents. The peptide Tat (47-57) is derived from the transactivating transcriptional activator of human immunodeficiency virus 1, which is well-known as a cell-penetrating peptide in mammalian cells. However, it is also reported that the Tat peptide (47-57) has antifungal activity. In this study, a series of membrane-active hydrocarbon-stapled α-helical amphiphilic peptides were synthesized and evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The impact of hydrocarbon staple, the position of aromatic amino acid residue in the hydrophobic face, the various types of aromatic amino acids, and the hydrophobicity on bioactivity were also investigated and discussed in this study. Among those synthesized peptides, analogues P3 and P10 bearing a l-2-naphthylalanine (Φ) residue at the first position and a Tyr residue at the eighth position demonstrated the highest antimicrobial activity and negligible hemolytic toxicity. Notably, P3 and P10 showed obviously enhanced antimicrobial activity against multidrug-resistant bacteria, low drug resistance, high cell selectivity, extended half-life in plasma, and excellent performance against biofilm. The antibacterial mechanisms of P3 and P10 were also preliminarily investigated in this effort. In conclusion, P3 and P10 are promising antimicrobial alternatives for the treatment of the antimicrobial-resistance crisis.

Interlayer and Phase Engineering Modifications of K-MoS2@C Nanoflowers for High-Performance Degradable Zn-Ion Batteries.

2D transition metal dichalcogenides (TMDs) have garnered significant interest as cathode materials for aqueous zinc-ion batteries (AZIBs) due to their open transport channels and abundant Zn2+ intercalation sites. However, unmodified TMDs exhibit low electrochemical activity and poor kinetics owing to the high binding energy and large hydration radius of divalent Zn2+. To overcome these limitations, an interlayer engineering strategy is proposed where K+ is preintercalated into K-MoS2 nanosheets, which then undergo in situ growth on carbon nanospheres (denoted as K-MoS2@C nanoflowers). This strategy stimulates in-plane redox-active sites, expands the interlayer spacing (from 6.16 to 9.42 Å), and induces the formation of abundant MoS2 1T-phase. The K-MoS2@C cathode demonstrates excellent redox activity and fast kinetics, attributed to the potassium ions acting as a structural "stabilizer" and an electrostatic interaction "shield," accelerating charge transfer, promoting Zn2+ diffusion, and ensuring structural stability. Meanwhile, the carbon nanospheres serve as a 3D conductive network for Zn2+ and enhance the cathode's hydrophilicity. More significantly, the outstanding electrochemical performance of K-MoS2@C, along with its superior biocompatibility and degradability of its related components, can enable an implantable energy supply, providing novel opportunities for the application of transient electronics.

The light-harvesting chlorophyll a/b-binding proteins of photosystem II family members are responsible for temperature sensitivity and leaf color phenotype in albino tea plant.

INTRODUCTION: Light-harvesting chlorophyll a/b-binding (LHCB) protein complexes of photosystem II are integral to the formation of thylakoid structure and the photosynthetic process. They play an important role in photoprotection, a crucial process in leaf development under low-temperature stress. Nonetheless, potential key genes directly related to low-temperature response and albino phenotype have not been precisely identified in tea plant. Moreover, there are no studies simultaneously investigating multiple albino tea cultivars with different temperature sensitivity. OBJECTIVES: The study aimed to clarify the basic characteristics of CsLHCB gene family members, and identify critical CsLHCB genes potentially influential in leaf color phenotypic variation and low-temperature stress response by contrasting green and albino tea cultivars. Concurrently, exploring the differential expression of the CsLHCB gene family across diverse temperature-sensitive albino tea cultivars. METHODS: We identified 20 putative CsLHCB genes according to phylogenetic analysis. Evolutionary relationships, gene duplication, chromosomal localization, and structures were analyzed by TBtools; the physiological and biochemical characteristics were analyzed by protein analysis websites; the differences in coding sequences and protein accumulation in green and albino tea cultivars, gene expression with maturity were tested by molecular biology technology; and protein interaction was analyzed in the STRING database. RESULTS: All genes were categorized into seven groups, mapping onto 7 chromosomes, including three tandem and one segmental duplications. They all own a conserved chlorophyll A/B binding protein domain. The expression of CsLHCB genes was tissue-specific, predominantly in leaves. CsLHCB5 may play a key role in the process of leaf maturation and senescence. In contrast to CsLHCB5, CsLHCB1.1, CsLHCB2, and CsLHCB3.2 were highly conserved in amino acid sequence between green and albino tea cultivars. In albino tea cultivars, unlike in green cultivars, the expression of CsLHCB1.1, CsLHCB1.2, and CsLHCB2 was down-regulated under low-temperature stress. The accumulation of CsLHCB1 and CsLHCB5 proteins was lower in albino tea cultivars. Greater accumulation of CsLHCB2 protein was detected in RX1 and RX2 compared to other albino cultivars. CONCLUSIONS: CsLHCB1.1, CsLHCB1.2, and CsLHCB2 played a role in the response to low-temperature stress. The amino acid sequence site mutation of CsLHCB5 would distinguish the green and albino tea cultivars. The less accumulation of CsLHCB1 and CsLHCB5 had a potential influence on albino leaves. Albino cultivars more sensitive to temperature exhibited lower CsLHCB gene expression. CsLHCB2 may serve as an indicator of temperature sensitivity differences in albino tea cultivars. This study could provide a reference for further studies of the functions of the CsLHCB family and contribute to research on the mechanism of the albino in tea plant.

The Antimicrobial, Hemostatic, and Anti-Adhesion Effects of a Peptide Hydrogel Constructed by the All-d-Enantiomer of Antimicrobial Peptide Jelleine-1.

Peptide hydrogels are believed to be potential biomaterials with wide application in the biomedical field because of their good biocompatibility, injectability, and 3D printability. Most of the previously reported polypeptide hydrogels are composed of l-peptides, while the hydrogels formed by self-assembly of d-peptides are rarely reported. Herein, a peptide hydrogel constructed by D-J-1, which is the all-d-enantiomer of antimicrobial peptide Jelleine-1 (J-1) is reported. Field emission scanning electron microscope (FE-SEM) and rheologic study are performed to characterize the hydrogel. Antimicrobial, hemostatic, and anti-adhesion studies are carried out to evaluate its biofunction. The results show that D-J-1 hydrogel is formed by self-assembly and cross-linking driven by hydrogen bonding, hydrophobic interaction, and π-π stacking force of aromatic ring in the structure of D-J-1. It exhibits promising antimicrobial activity, hemostatic activity, and anti-adhesion efficiency in a rat sidewall defect-cecum abrasion model. In addition, it also exhibits good biocompatibility. Notably, D-J-1 hydrogel shows improved in vitro and in vivo stability when compared with its l-enantiomer J-1 hydrogel. Therefore, the present study will provide new insight into the application of d-peptide hydrogel, and provides a new peptide hydrogel with antibacterial, hemostatic, and anti-adhesion efficacy for clinical use.

Anthocyanin metabolism and its differential regulation in purple tea (Camellia sinensis).

Tea plants (Camellia sinensis) typically contain high-flavonoid phytochemicals like catechins. Recently, new tea cultivars with unique purple-colored leaves have gained attention. These purple tea cultivars are enriched with anthocyanin, which provides an interesting perspective for studying the metabolic flux of the flavonoid pathway. An increasing number of studies are focusing on the leaf color formation of purple tea and this review aims to summarize the latest progress made on the composition and accumulation of anthocyanins in tea plants. In addition, the regulation mechanism in its synthesis will be discussed and a hypothetical regulation model for leaf color transformation during growth will be proposed. Some novel insights are presented to facilitate future in-depth studies of purple tea to provide a theoretical basis for targeted breeding programs in leaf color.

Instruments to Assess Cognitive Reserve Among Older Adults: a Systematic Review of Measurement Properties.

Cognitive reserve explains the differences in the susceptibility to cognitive impairment related to brain aging, pathology, or insult. Given that cognitive reserve has important implications for the cognitive health of typically and pathologically aging older adults, research needs to identify valid and reliable instruments for measuring cognitive reserve. However, the measurement properties of current cognitive reserve instruments used in older adults have not been evaluated according to the most up-to-date COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN). This systematic review aimed to critically appraise, compare, and summarize the quality of the measurement properties of all existing cognitive reserve instruments for older adults. A systematic literature search was performed to identify relevant studies published up to December 2021, which was conducted by three of four researchers using 13 electronic databases and snowballing method. The COSMIN was used to assess the methodological quality of the studies and the quality of measurement properties. Out of the 11,338 retrieved studies, only seven studies that concerned five instruments were eventually included. The methodological quality of one-fourth of the included studies was doubtful and three-seventh was very good, while only four measurement properties from two instruments were supported by high-quality evidence. Overall, current studies and evidence for selecting cognitive reserve instruments suitable for older adults were insufficient. All included instruments have the potential to be recommended, while none of the identified cognitive reserve instruments for older adults appears to be generally superior to the others. Therefore, further studies are recommended to validate the measurement properties of existing cognitive reserve instruments for older adults, especially the content validity as guided by COSMIN.Systematic Review Registration numbers: CRD42022309399 (PROSPERO).

Diagnostic Accuracy of Mobile Health-Based Audiometry for the Screening of Hearing Loss in Adults: A Systematic Review and Meta-Analysis.

Background: Hearing loss is one of the most prevalent chronic health conditions. Traditional pure tone audiometry (PTA) is the gold standard for hearing loss screening, but is not widely available outside specialized clinical centers. Mobile health (mHealth)-based audiometry could improve access and cost-effectiveness, but its diagnostic accuracy varies widely between studies. Therefore, we aimed to evaluate the diagnostic accuracy of mHealth-based audiometry for hearing loss screening in adults compared with traditional PTA. Methods: Ten English and Chinese databases were searched from inception until April 30, 2022. Two researchers independently selected studies, extracted data, and appraised methodological quality. The bivariate random-effects model was adopted to estimate the pooled sensitivity and specificity for each common threshold (i.e., the threshold to define mild or moderate hearing loss). The hierarchical summary receiver operating characteristic model was used to assess the area under the receiver operating characteristic curve (AUC) across all thresholds. Results: Twenty cohort studies were included. Only one study (n = 109) used the mHealth-based speech recognition test (SRT) as the index test. Nineteen studies (n = 1,656) used mHealth-based PTA as the index test, and all of them were included in the meta-analysis. For detecting mild hearing loss, the pooled sensitivity and specificity were 0.91 (95% confidence interval [CI] 0.80-0.96) and 0.90 (95% CI 0.82-0.94), respectively. For detecting moderate hearing loss, the pooled sensitivity and specificity were 0.94 (95% CI 0.87-0.98) and 0.87 (95% CI 0.79-0.93), respectively. For all PTA thresholds, the AUC was 0.96 (95% CI 0.40-1.00). Conclusions: mHealth-based audiometry provided good diagnostic accuracy for screening both mild and moderate hearing loss in adults. Given its high diagnostic accuracy, accessibility, convenience, and cost-effectiveness, it shows enormous potential for hearing loss screening, particularly in primary care sites, low-income regions, and settings with in-person visit limitations. Further work should evaluate the diagnostic accuracy of the mHealth-based SRT tests.

Small Molecular Mimetics of Antimicrobial Peptides as a Promising Therapy To Combat Bacterial Resistance.

Clinically, antibiotics are widely used to treat infectious diseases; however, excessive drug abuse and overuse exacerbate the prevalence of drug-resistant bacterial pathogens, making the development of novel antibiotics extremely difficult. Antimicrobial peptide (AMP) is one of the most promising candidates for overcoming bacterial resistance owing to its unique structure and mechanism of action. This study examines the development of small molecular mimetics of AMPs over the past two decades. These mimetics can selectively disrupt membranes, which are the characteristic antibacterial mechanism of AMPs. In addition, the advantages and disadvantages of small AMP mimetics are discussed. The small molecular mimetics of AMPs are anticipated to garner interest and investment in discovering new antibiotics. This Perspective will assist in revitalizing the golden age of antibiotics in the current era of combating bacterial resistance.

Fat-to-muscle ratio as a predictor for dyslipidaemia in transitional-age youth.

BACKGROUND: Although dyslipidaemia may have a crucial impact on cardiovascular health in adults, there is a lack of specific data in transitional-age youth. Therefore, this study attempted to evaluate the association of dyslipidaemia with fat-to-muscle ratio (FMR), and establish FMR thresholds for diagnosing dyslipidaemia in transitional-age youth. METHODS: One thousand six hundred sixty individuals aged 16 to 24 years from the baseline of a subcohort in the Northwest China Natural Population Cohort: Ningxia Project were analysed. Anthropometric characteristics were gauged by a bioelectrical impedance analyser, and dyslipidaemia components were measured using a Beckman AU480 chemistry analyser. Additionally, this study used logistic regression to estimate the risk of dyslipidaemia based on FMR quintiles, and calculate the gender-specific ideal cut-off values of dyslipidaemia and its components by the receiver operating characteristic (ROC) curve. RESULTS: Of the 1660 participants, aged 19.06 ± 1.14 years, 558 males and 1102 females. The prevalence of dyslipidaemia was 13.4% and was significantly associated with FMR quintiles among all participants (P < 0.05). The ideal values of FMR in diagnosing dyslipidaemia were 0.2224 for males and 0.4809 for females, while males had a higher AUC than females (0.7118 vs. 0.6656). Meanwhile, high FMR values were significantly associated with adverse outcomes of dyslipidaemia, hypercholesterolemia and hypertriglyceridaemia (P < 0.05). CONCLUSIONS: The FMR was positively correlated with the prevalence of dyslipidaemia. The FMR can be used as an effective body composition index for diagnosing dyslipidaemia, especially in males, and preventive strategies should be initiated in transitional-age youth to decrease obesity-related dyslipidaemia.

A carrier-free, dual-functional hydrogel constructed of antimicrobial peptide Jelleine-1 and 8Br-cAMP for MRSA infected diabetic wound healing.

Bacterial infection and local growth factor deficiency are two of the major causes of the nonunion of diabetic wounds. Antimicrobial peptides (AMPs) are believed to be alternatives to antibiotics against drug-resistant bacterial infections. 8-Bromoadenosine-3', 5'-cyclic monophosphate (8Br-cAMP) can promote cells to secrete growth factors and accelerate cell proliferation. In the present study, we constructed a hydrogel with antimicrobial peptide Jelleine-1 (J-1) and 8Br-cAMP without any other gelators or chemical crosslinking agents. The hydrogel was proved to promote the secretion of transforming growth factor-ß (TGF-ß) and vascular endothelial growth factor-A (VEGFA) in vitro and in vivo. Notably, it exhibited potent potential for wound healing in methicillin-resistant Staphylococcus aureus (MRSA) infected diabetic wounds. This would be attributed to the retention of AMPs and 8Br-cAMP on the wound site by the hydrogel system. In addition, the hydrogel also showed good biodegradability, proper stability, and good biocompatibility. This study would shed light on the development of carrier-free and multifunctional hydrogel for wound healing. STATEMENT OF SIGNIFICANCE: Bacterial infection and local growth factor deficiency are two of the major causes for the nonunion of refractory wounds. In the present study, an injectable carrier-free hydrogel was constructed of a natural antimicrobial peptide J-1 and 8Br-cAMP by eco-friendly physical crosslinking without any other gelators or chemical crosslinking agents. The hydrogel exhibited excellent antimicrobial activity and was proved to promote the secretion of TGF-ß and VEGFA in vitro and in vivo. Correspondingly, the hydrogel showed exceptionally wound healing effects in the wound model of MRSA infected diabetic rats. This study would provide an alternative strategy or a potential hydrogel dressing for the treatment of chronic or refractory wounds.

An Injectable Peptide Hydrogel Constructed of Natural Antimicrobial Peptide J-1 and ADP Shows Anti-Infection, Hemostasis, and Antiadhesion Efficacy.

Postoperative adhesion is a common complication of abdominal surgery, which always has many adverse effects in patients. At present, there is still a lack of effective treatment measures and materials to prevent adhesion in the clinics. Herein, we report the potential use of J-1-ADP hydrogel formed by natural antimicrobial peptide jelleine-1 (J-1) self-assembling in adenosine diphosphate (ADP) sodium solution to prevent postsurgery adhesion formation. J-1-ADP hydrogel was found to have good antimicrobial activity against the bacteria and fungi tested and can be used to prevent tissue infection, which was thought to be one of the incitements of adhesion. Due to ADP being a platelet-activating factor, J-1-ADP hydrogel showed significant hemostatic activity in vitro verified by whole blood coagulation, plasma coagulation, platelet activation, and platelet adhesion assays. Further, it showed potent hemostatic activity in a mouse liver hemorrhage model. Bleeding was believed to be a cause of the formation of postsurgery adhesion. J-1-ADP hydrogel had a significant antiadhesion effect in a rat side wall defect-cecum abrasion model. In addition, it had good biocompatibility and degradation properties. So the present study may provide an alternative strategy for designing antimicrobial peptide hydrogel material to prevent postoperative adhesion formation in the clinic.

GM-Pep: A High Efficiency Strategy to De Novo Design Functional Peptide Sequences.

Although peptides are regarded as ideal therapeutic agents, only a small proportion of the marketed drugs are peptides. In the past decade, pharmacists have paid great attention to the development of peptide therapeutics. Except a few approved chemically/rationally designed peptides, most attempts failed due to unsatisfactory efficacy or safety. Luckily, computation methods, such as artificial intelligence, have been utilized to accelerate the discovery of therapeutic peptides by predicting the activity, toxicity, and absorption, distribution, metabolism, and excretion of polypeptides. Usually, a specific biological activity of a peptide could be accurately determined by an interest-oriented binary classification constructed of a positive set and another un-experimentally validated negative set regardless of other characteristics, which suggests that it could be challenging to realize the comprehensive evaluation of the research object in the early stage of drug research and development. Herein, we proposed an integrated method (GM-Pep) that contained a conditional variational autoencoder model (CVAE) and a positive sample training multiclassifier (Deep-Multiclassifier) to effectively generate a single bioactive peptide sequence without toxicity and referential side effects. The results showed that our Deep-Multiclassifier model gave a sequence accuracy of up to 96.41% [toxicity (94.48%), antifungal (96.58%), antihypertensive (97.18%), and antibacterial (96.91%), respectively]. The properties of Deep-Multiclassifier and CVAE were validated through 12 first synthesized antibacterial peptides or compared to random peptides. The source code and data sets are available at https://github.com/TimothyChen225/GM-Pep.

The Relationship Between Sleep Disturbance and Apolipoprotein E ε4 in Adults With Mild Cognitive Impairment and Alzheimer's Disease Dementia: An Integrative Review.

BACKGROUND: Apolipoprotein E ε4 (APOE ε4) was shown to be a risk factor for mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. When coupled with sleep disturbance, APOE ε4 posed additional risks to cognitive impairment. But the literature on the association between sleep disturbance and the APOE ε4 status of persons who are cognitively impaired has not yet been systematically examined. OBJECTIVES: To explore and synthesize the relationship between sleep disturbance and APOE ε4 status of adults with MCI and AD. METHODS: An integrative review was guided by Whittemore and Knafl's methodology. Systematic searches identified studies with multiple sources published before May 20, 2021. A matrix and narrative synthesis was employed to organize and synthesize the findings. Joanna Briggs Institute (JBI) Critical Appraisal tools (2020) were used to evaluate the quality of the selected studies. RESULTS: A total of 7 studies were included. APOE ε4 was associated with poor sleep quality in terms of the deterioration of nighttime total sleep time, 24-hour total sleep time, rapid eye movement, sleep efficiency, sleep latency, and wake after sleep onset in a population with MCI or AD. The interacted and adjusted relationship between sleep disturbance and APOE ε4 on the progression of cognitive decline was inconsistent. CONCLUSIONS: There is evidence to support an association between sleep disturbance and APOE ε4 in individuals with cognitive impairment, but a further examination of the relationship between sleep parameters and APOE ε4 is warranted, especially as the causal or dose-response relationship remains unclear.

Association of Serum Vitamin D and Estradiol Levels with Metabolic Syndrome in Rural Women of Northwest China: A Cross-Sectional Study.

Objectives: We aimed to determine the association of serum vitamin D and estradiol levels with metabolic syndrome (MS) in rural women of northwest China. Methods: This research is a cross-sectional study. MS was defined according to the updated China Diabetes Society (CDS) criteria. Fasting serum 25-hydroxyvitamin D [25(OH)D] and estradiol levels were measured using a chemiluminescence immunoassay. Differences between variables were analyzed using the chi-square test and t-test. Logistic regression analysis models were used to estimate the odds ratios (ORs) and 95% confidence intervals. Results: In total, 1893 women participated, of whom 641 (33.9%) had MS. The serum levels of 25(OH)D and estradiol were higher in the non-MS group. There was no significant association between 25(OH)D and estradiol levels. After adjusting for potential confounders, we compared first, second, and third quartiles with the highest quartile. Adjusted ORs for MS with respect to 25(OH)D level quartiles were 1.555, 1.281, and 1.568, respectively. Adjusted ORs for MS with respect to estradiol level quartiles were 0.671, 0.785, and 0.996, respectively. In the vitamin D-deficient (VD-deficient) group, adjusted ORs for MS with respect to estradiol level quartiles were 0.635, 0.753, and 0.918, respectively. Conclusions: There is a negative correlation between MS and vitamin D level and a positive correlation between MS and estradiol level. Low estradiol concentrations increased the risk of MS in the VD-deficient group. The results suggest a potential synergism between low 25(OH)D concentration and estradiol in MS in women.

Peripherally inserted central catheter versus totally implanted venous port for delivering medium- to long-term chemotherapy: A cost-effectiveness analysis based on propensity score matching.

BACKGROUND: Peripherally inserted central catheters (PICCs) and totally implanted vascular access ports (PORTs) have been widely used for medium- to long-term chemotherapy. PICCs are associated with lower insertion cost, but higher complication rates than PORTs. However, there is a paucity of cost-effectiveness comparisons between the devices. We aimed to compare the cost-effectiveness of PICCs and PORTs for medium- to long-term chemotherapy from catheter insertion to removal. METHODS: A cost-effectiveness analysis was conducted based on propensity score matching (PSM) from the hospital perspective. Data were collected from a retrospective cohort study. The total cost outcome comprised insertion, maintenance, removal and complication costs. The effectiveness outcome was the complication-free rate. The primary and supplemental outcomes were cost-effectiveness ratios (CERs) and incremental cost-effectiveness ratios (ICERs). RESULTS: A total of 1050 patients (after PSM for 417 patients) were included. The average total cost for 3-6 month ($603.55 ± 78.68 vs $1270.21 ± 128.84), 6-9 month ($731.40 ± 42.97 vs $1414.48 ± 155.43), and 9-12 month ($966.83 ± 53.78 vs $1587.76 ± 160.56) dwell times were all significantly lower for PICCs than for PORTs (p < 0.001). PICCs were associated with significantly lower complication-free rates than PORTs during the 3-6 month (65.22% vs 90.58%, p < 0.001), 6-9 month (53.33% vs 91.80%, p < 0.001), and 9-12 month (44.44% vs 88.46%, p = 0.015) dwell times. Ultimately, PICCs were associated with lower CERs than PORTs for the 3-6 month (928.54 vs 1395.84) and 6-9 month (1380.00 vs 1537.48) but higher CER for the 9-12 month (2197.34 vs 1804.27) dwell times. ICERs were 2564.08 and 1751.49 with dwell times of 3-6 months and 6-9 months, respectively. CONCLUSION: This study provided economic evidence that informs vascular access device choice for medium- to long-term chemotherapy. For 3-9 month dwell times, PICCs were more cost-effective than PORTs. Furthermore, ICERs were applied and the choice was determined by willingness-to-pay. For 9-12 month dwell times, PORTs might be more cost-effective than PICCs, and studies with larger sample size would be needed to verify this finding in the future.

The effects of incorporation of the counterparts and mimics of L-lysine on the antimicrobial activity, hemolytic activity, cytotoxicity and tryptic stability of antimicrobial peptide polybia-MPII.

Due to the limited effects of conventional antibiotics on the increasing emergence of drug-resistant bacteria and fungi, novel antimicrobial agents were urgently needed to alleviate this phenomenon. Nowadays, antimicrobial peptides are believed to be a promising candidate for a new generation of antimicrobial drugs. Antimicrobial peptide polybia-MPII (MPII) was first isolated from the venom of the social wasp Polybia paulista with a broad spectrum of antimicrobial activity. In the present study, the counterparts and mimics of cationic amino acids of Lys, such as Arg, His, Orn, Dab and Dap were employed to substitute Lys in the sequence of MPII. The effects of the incorporation of these amino acids on its antimicrobial activity, hemolytic activity, cytotoxicity, enzyme stability and therapeutic potential were explored. Our results showed that although the incorporation of Arg could improve its antimicrobial activity, there is no improvement in enzyme stability. The incorporation of His makes MPII exert its antimicrobial activity in a pH-dependent manner. Notably, incorporating Dap could effectively decrease its hemolytic activity and cytotoxicity and enhance its enzyme stability against trypsin. In conclusion, this study would provide an effective strategy to improve the bioavailability and metabolic stability of AMPs while decrease their hemolytic activity and cytotoxicity.

The Regiocontrollable Enantioselective Synthesis of Chiral Trifluoromethyl-Containing Spiro-Pyrrolidine-Pyrazolone Compounds via Amino-Regulated 1,3-Proton Migration Reaction.

An amino-controlled regiodivergent asymmetric synthesis of CF3-containing spiro-pyrrolidine-pyrazolone compounds is described. With alkaloid-derived squaramide as catalyst, the 1,3-dipolar cycloaddition of α,ß-unsaturated pyrazolone with diethyl 2-((2,2,2-trifluoroethyl)imino) malonate offered adducts in excellent yields, dr, and ee. While the cyclohexanediamine-derived squaramide was employed, the reaction afforded a series of structure isomers through a switched umpolung reaction.

Contribution of the µ opioid receptor and enkephalin to the antinociceptive actions of endomorphin-1 analogs with unnatural amino acid modifications in the spinal cord.

Endomorphin analogs containing unnatural amino acids have demonstrated potent analgesic effects in our previous studies. In the present study, the differences in antinociception and the mechanisms thereof for analogs 1-3 administered intracerebroventricularly and intrathecally were explored. All analogs at different routes of administration produced potent analgesia compared to the parent peptide endomorphin-1. Multiple antagonists and antibodies were used to explore the mechanisms of action of these analogs, and it was inferred that analogs 1-3 stimulated the µ opioid receptor to induce antinociception. Moreover, the antibody data suggested that analog 2 may induce the release of immunoreactive [Leu5]-enkephaline and [Met5]-enkephaline to produce a secondary component of antinociception at the spinal level and analog 3 may stimulate the the release of immunoreactive [Met5]-enkephaline at the spinal level. Finally, analogs 2 and 3 produced no acute tolerance in the spinal cord. We hypothesize that the unique characteristics of the endomorphin analogs result from their capacities to stimulate the release of endogenous antinociceptive substances.

An optimized analog of antimicrobial peptide Jelleine-1 shows enhanced antimicrobial activity against multidrug resistant P. aeruginosa and negligible toxicity in vitro and in vivo.

Due to the threat of escalating multi-drug resistant gram-negative bacteria to human health and life, novel antimicrobial agents against gram-negative pathogens are urgently needed. As antimicrobial peptides are not prone to induce bacteria resistance, they are believed to be one kind of promising class of potential antimicrobial agent candidates to combat multi-drug resistant bacteria for long-term use. Jelleine-1, first isolated from the royal jelly of honeybees, is a typical amphiphilic antimicrobial peptide and shows broad antimicrobial spectrum and negligible toxicity. To promote its antimicrobial activity and extend its potential of clinical use against multi-drug resistant gram-negative bacteria, novel analogs of jelleine-1 were designed, synthesized and their antimicrobial functions and toxicity were examined in this study. Our results showed that fine tuning of the cationic charge, polarity, and basicity of the sequence through amino acids substitution at position 3, 5, 7 and maintaining position 1, 4, 6, 8 unchanged could improve the bioactivity of jelleine-1 significantly. Meanwhile, we also found that the substitution of phenylalanine by tryptophan also could improve the antimicrobial activity of jelleine-1. Among all the analogs, analog 15, which is enriched in arginine and leucine, showed the most potent antimicrobial activity against both gram-negative and gram-positive bacteria, especially to multi-drug resistant Pseudomonas aeruginosa in vivo and in vitro. In addition, analog 15 also showed potent inhibition of the formation of multi-drug resistant P. aeruginosa biofilm and negligible toxicity, which was certified by MTT, hemolysis, blood assay, and biochemical analysis.

Catalytic Asymmetric Construction of Tertiary Carbon Centers Featuring an α-Difluoromethyl Group with CF2H-CH2-NH2 as the "Building Block".

We report here for the first time a novel difluoromethylated ketimine building block condensed by thioisatin and difluoroethylamine, offering efficient access to a broad range of enantioenriched products bearing difluoroethylamine units (27 examples, ≤98% yield, >99% ee) in the presence of quinine-derived squaramide. Further transformation of the intermediate would generate a variety of versatile functional blocks like α-difluoromethyl amines, ß-amino acid, and ß-diamine with retention of the enantiomeric excess at the difluoromethyl-bound carbon.