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1.
Sci Rep ; 14(1): 12917, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38839811

ABSTRACT

Allii Macrostemonis Bulbus (AMB) is a traditional Chinese medicine with medicinal and food homology. AMB has various biological activities, including anti-coagulation, lipid-lowering, anti-tumor, and antioxidant effects. Saponins from Allium macrostemonis Bulbus (SAMB), the predominant beneficial compounds, also exhibited lipid-lowering and anti-inflammatory properties. However, the effect of SAMB on atherosclerosis and the underlying mechanisms are still unclear. This study aimed to elucidate the pharmacological impact of SAMB on atherosclerosis. In apolipoprotein E deficiency (ApoE-/-) mice with high-fat diet feeding, oral SAMB administration significantly attenuated inflammation and atherosclerosis plaque formation. The in vitro experiments demonstrated that SAMB effectively suppressed oxidized-LDL-induced foam cell formation by down-regulating CD36 expression, thereby inhibiting lipid endocytosis in bone marrow-derived macrophages. Additionally, SAMB effectively blocked LPS-induced inflammatory response in bone marrow-derived macrophages potentially through modulating the NF-κB/NLRP3 pathway. In conclusion, SAMB exhibits a potential anti-atherosclerotic effect by inhibiting macrophage foam cell formation and inflammation. These findings provide novel insights into potential preventive and therapeutic strategies for the clinical management of atherosclerosis.


Subject(s)
Atherosclerosis , Foam Cells , Inflammation , Saponins , Animals , Foam Cells/drug effects , Foam Cells/metabolism , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Saponins/pharmacology , Mice , Inflammation/drug therapy , Inflammation/pathology , Allium/chemistry , Male , Apolipoproteins E/deficiency , Diet, High-Fat/adverse effects , NF-kappa B/metabolism , Mice, Inbred C57BL , Lipoproteins, LDL/metabolism
2.
Nat Commun ; 15(1): 4755, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38834568

ABSTRACT

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Macrophages , Mice, Knockout , Non-alcoholic Fatty Liver Disease , Sphingosine , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Male , Macrophages/metabolism , Macrophages/drug effects , Humans , Mice , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Liver/metabolism , Liver/pathology , Liver/drug effects , Mice, Inbred C57BL , Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism , Aryl Hydrocarbon Receptor Nuclear Translocator/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Liver Cirrhosis/genetics , Disease Models, Animal
3.
Dev Cell ; 2024 May 05.
Article in English | MEDLINE | ID: mdl-38723629

ABSTRACT

In mice, skin-resident type 2 innate lymphoid cells (ILC2s) exhibit some ILC3-like characteristics. However, the underlying mechanism remains elusive. Here, we observed lower expression of the ILC2 master regulator GATA3 specifically in cutaneous ILC2s (cILC2s) compared with canonical ILC2s, in line with its functionally divergent role in transcriptional control in cILC2s. Decreased levels of GATA3 enabled the expansion of RORγt fate-mapped (RORγtfm+) cILC2s after postnatal days, displaying certain similarities to ILC3s. Single-cell trajectory analysis showed a sequential promotion of the RORγtfm+ cILC2 divergency by RORγt and GATA3. Notably, during hair follicle recycling, these RORγtfm+ cILC2s accumulated around the hair follicle dermal papilla (DP) region to facilitate the process. Mechanistically, we found that GATA3-mediated integrin α3ß1 upregulation on RORγtfm+ cILC2s was required for their positioning around the DP. Overall, our study demonstrates a distinct regulatory role of GATA3 in cILC2s, particularly in promoting the divergence of RORγtfm+ cILC2s to facilitate hair follicle recycling.

4.
Aesthetic Plast Surg ; 2024 May 10.
Article in English | MEDLINE | ID: mdl-38727847

ABSTRACT

BACKGROUND: The mechanism underlying the formation of upper eyelid creases has been the subject of extensive study and ongoing debate. This research aims to elucidate the principles of upper eyelid creases formation, leveraging the membrane bending theory from engineering mechanics. METHODS: We developed an anatomical model of the eyelid and implemented the finite element analysis. Preprocessing and mesh division were conducted using HyperMesh, followed by computational analysis with Abaqus. This approach enabled the observation of dynamic changes in the upper eyelid during eye opening and closing. RESULTS: The study reveals that natural upper eyelid crease formation is influenced by multiple factors. These include the softer texture of the upper eyelid skin and the suborbicularis oculi fat, reduced rigidity at the eyelid crease, optimal contraction force of the upper eyelid, and the strategic placement of the pre-tarsal fat pad just above the eyelid crease. CONCLUSIONS: Ultimately, our findings demonstrate the effectiveness of finite element analysis, grounded in membrane bending theory, in elucidating the dynamics of upper eyelid crease formation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

6.
Eur J Med Chem ; 271: 116451, 2024 May 05.
Article in English | MEDLINE | ID: mdl-38691892

ABSTRACT

The potent antibacterial activity and low resistance of antimicrobial peptides (AMPs) render them potential candidates for treating multidrug-resistant bacterial infections. Herein, a minimalist design strategy was proposed employing the "golden partner" combination of arginine (R) and tryptophan (W), along with a dendritic structure to design AMPs. By extension, the α/ε-amino group and the carboxyl group of lysine (K) were utilized to link R and W, forming dendritic peptide templates αRn(εRn)KWm-NH2 and αWn(εWn)KRm-NH2, respectively. The corresponding linear peptide templates R2nKWm-NH2 and W2nKRm-NH2 were used as controls. Their physicochemical properties, activity, toxicity, and stability were compared. Among these new peptides, the dendritic peptide R2(R2)KW4 was screened as a prospective candidate owing to its preferable antibacterial properties, biocompatibility, and stability. Additionally, R2(R2)KW4 not only effectively restrained the progression of antibiotic resistance, but also demonstrated synergistic utility when combined with conventional antibiotics due to its unique membrane-disruptive mechanism. Furthermore, R2(R2)KW4 possessed low toxicity (LD50 = 109.31 mg/kg) in vivo, while efficiently clearing E. coli in pulmonary-infected mice. In conclusion, R2(R2)KW4 has the potential to become an antimicrobial regent or adjuvant, and the minimalist design strategy of dendritic peptides provides innovative and encouraging thoughts in designing AMPs.


Subject(s)
Anti-Bacterial Agents , Arginine , Microbial Sensitivity Tests , Tryptophan , Tryptophan/chemistry , Tryptophan/pharmacology , Animals , Arginine/chemistry , Arginine/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Mice , Antimicrobial Peptides/chemistry , Antimicrobial Peptides/pharmacology , Antimicrobial Peptides/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Cell Membrane/drug effects , Dose-Response Relationship, Drug , Bacterial Infections/drug therapy , Humans , Escherichia coli/drug effects
7.
Sci Bull (Beijing) ; 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38734583

ABSTRACT

Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation. Identifying molecular glues is challenging. There is a scarcity of target-specific upregulating molecular glues, which are highly anticipated for numerous targets, including P53. P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases, whereas deubiquitinases (DUBs) remove polyubiquitination conjugates to counteract these E3 ligases. Thus, small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination. Here, using small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB, USP7, and elevate the P53 level. Among the molecular glues, bromocriptine (BC) is an FDA-approved drug with the most robust effects. BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7. Consistent with P53 upregulation in cancer cells, BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model. In summary, we established a potential screening platform and identified potential molecular glues upregulating P53. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.

8.
Food Res Int ; 187: 114462, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38763689

ABSTRACT

The risk of tuna adulteration is high driven by economic benefits. The authenticity of tuna is required to protect both consumers and tuna stocks. Given this, the study is designed to identify species-specific peptides for distinguishing three commercial tropical tuna species. The peptides derived from trypsin digestion were separated and detected using ultrahigh-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS) in data-dependent acquisition (DDA) mode. Venn analysis showed that there were differences in peptide composition among the three tested tuna species. The biological specificity screening through the National Center for Biotechnology Information's Basic Local Alignment Search Tool (NCBI BLAST) revealed that 93 peptides could serve as potential species-specific peptides. Finally, the detection specificity of species-specific peptides of raw meats and processed products was carried out by multiple reaction monitoring (MRM) mode based on a Q-Trap mass spectrometer. The results showed that three, one and two peptides of Katsuwonus pelamis, Thunnus obesus and Thunnus albacores, respectively could serve as species-specific peptides.


Subject(s)
Peptides , Species Specificity , Tuna , Animals , Peptides/analysis , Mass Spectrometry/methods , Chromatography, High Pressure Liquid/methods , Seafood/analysis , Food Contamination/analysis , Fish Proteins/analysis
9.
Eur J Med Chem ; 273: 116519, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38795519

ABSTRACT

Anticancer peptides (ACPs) have regarded as a new generation of promising antitumor drugs due to the unique mode of action. The main challenge is to develop potential anticancer peptides with satisfied antitumor activity and low toxicity. Here, a series of new α-helical anticancer peptides were designed and synthesized based on the regular repeat motif KLLK. The optimal peptides 14E and 14Aad were successfully derived from the new short α-helical peptide KL-8. Our results demonstrated that 14E and 14Aad had good antitumor activity and low toxicity, exhibiting excellent selectivity index. This result highlighted that the desirable modification position and appropriate hydrophobic side-chain structure of acidic amino acids played critical roles in regulating the antitumor activity/toxicity of new peptides. Further studies indicated that they could induce tumor cell death via the multiple actions of efficient membrane disruption and intracellular mechanisms, displaying apparent superiority in combination with PTX. In addition, the new peptides 14E and 14Aad showed excellent antitumor efficacy in vivo and low toxicity in mice compared to KL-8 and PTX. Particularly, 14Aad with the longer side chain at the 14th site exhibited the best therapeutic performance. In conclusion, our work provided a new avenue to develop promising anticancer peptides with good selectivity for tumor therapy.

10.
Cell Prolif ; : e13679, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38801100

ABSTRACT

Uncovering mechanisms of endogenous regeneration and repair through resident stem cell activation will allow us to develop specific therapies for injuries and diseases by targeting resident stem cell lineages. Sox9+ stem cells have been reported to play an essential role in acute kidney injury (AKI). However, a complete view of the Sox9+ lineage was not well investigated to accurately elucidate the functional end state and the choice of cell fate during tissue repair after AKI. To identify the mechanisms of fate determination of Sox9+ stem cells, we set up an AKI model with prostaglandin E2 (PGE2) treatment in a Sox9 lineage tracing mouse model. Single-cell RNA sequencing (scRNA-seq) was performed to analyse the transcriptomic profile of the Sox9+ lineage. Our results revealed that PGE2 could activate renal Sox9+ cells and promote the differentiation of Sox9+ cells into renal proximal tubular epithelial cells and inhibit the development of fibrosis. Furthermore, single-cell transcriptome analysis demonstrated that PGE2 could regulate the restoration of lipid metabolism homeostasis in proximal tubular epithelial cells by participating in communication with different cell types. Our results highlight the prospects for the activation of endogenous renal Sox9+ stem cells with PGE2 for the regenerative therapy of AKI.

11.
Sensors (Basel) ; 24(7)2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38610295

ABSTRACT

In recent years, hydroacoustic transducers made of PZT/epoxy composites have been extensively employed in underwater detection, communication, and recognition for their high energy conversion efficiency. Despite the ease with which these transducers can be formed into complex shapes, their lack of mechanical flexibility limits their versatility across various sizes of underwater vehicles. This study introduces a novel flexible piezoelectric composite hydroacoustic transducer (FPCHT) based on a 1-3 PZT-5A/silicone rubber composite and an island-bridge flexible electrode, which can break the limitations of existing hydroacoustic transducers that do not have flexibility. The finite element method is used to optimize the structural parameters of high-performance 1-3 FPC. A large-sized (187 mm × 47 mm × 5.12 mm) FPC is fabricated using an improved cutting-filling method and packaged into the FPCHT. Compared with the planar rigid PZT/epoxy composite hydroacoustic transducer (RPCHT) of the same size, the TVR (186.5 db) of the FPCHT has increased by about 7 dB, indicating that it has better acoustic radiation performance and electroacoustic conversion efficiency. Furthermore, its electroacoustic performance exhibits excellent stability under different bending states. Therefore, the FPCHT with high electroacoustic performance is an ideal substitute for the existing RPCHT and promotes the development of hydroacoustic transducers towards flexibility and portability.

12.
Int J Infect Dis ; 144: 107045, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38604470

ABSTRACT

BACKGROUND: The course of organ dysfunction (OD) in Corona Virus Disease 2019 (COVID-19) patients is unknown. Herein, we analyze the temporal patterns of OD in intensive care unit-admitted COVID-19 patients. METHODS: Sequential organ failure assessment scores were evaluated daily within 2 weeks of admission to determine the temporal trajectory of OD using group-based multitrajectory modeling (GBMTM). RESULTS: A total of 392 patients were enrolled with a 28-day mortality rate of 53.6%. GBMTM identified four distinct trajectories. Group 1 (mild OD, n = 64), with a median APACHE II score of 13 (IQR 9-21), had an early resolution of OD and a low mortality rate. Group 2 (moderate OD, n = 140), with a median APACHE II score of 18 (IQR 13-22), had a 28-day mortality rate of 30.0%. Group 3 (severe OD, n = 117), with a median APACHR II score of 20 (IQR 13-27), had a deterioration trend of respiratory dysfunction and a 28-day mortality rate of 69.2%. Group 4 (extremely severe OD, n = 71), with a median APACHE II score of 20 (IQR 17-27), had a significant and sustained OD affecting all organ systems and a 28-day mortality rate of 97.2%. CONCLUSIONS: Four distinct trajectories of OD were identified, and respiratory dysfunction trajectory could predict nonpulmonary OD trajectories and patient prognosis.


Subject(s)
COVID-19 , Intensive Care Units , Multiple Organ Failure , Organ Dysfunction Scores , SARS-CoV-2 , Humans , COVID-19/mortality , COVID-19/complications , COVID-19/physiopathology , Male , Female , Middle Aged , Multiple Organ Failure/mortality , Multiple Organ Failure/etiology , Aged , APACHE , Hospitalization , Hospital Mortality
13.
Molecules ; 29(6)2024 Mar 11.
Article in English | MEDLINE | ID: mdl-38542876

ABSTRACT

Endothelial inflammation is a multifaceted physiological process that plays a pivotal role in the pathogenesis and progression of diverse diseases, encompassing but not limited to acute lung infections like COVID-19, coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders such as depression. This inflammatory response is characterized by augmented expression of adhesion molecules and secretion of pro-inflammatory cytokines. In this study, we discovered that saponins from Allium macrostemon bulbs (SAMB) effectively inhibited inflammation in human umbilical vein endothelial cells induced by the exogenous inflammatory mediator lipopolysaccharide or the endogenous inflammatory mediator tumor necrosis factor-α, as evidenced by a significant reduction in the expression of pro-inflammatory factors and vascular cell adhesion molecule-1 (VCAM-1) with decreased monocyte adhesion. By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway's inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation.


Subject(s)
Acute Lung Injury , Chive , Drugs, Chinese Herbal , Saponins , Humans , Animals , Mice , NF-kappa B/metabolism , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/metabolism , Saponins/pharmacology , Lipopolysaccharides/toxicity , Inflammation/drug therapy , Inflammation/prevention & control , Human Umbilical Vein Endothelial Cells , Tumor Necrosis Factor-alpha/pharmacology , Acute Lung Injury/drug therapy , Inflammation Mediators/metabolism
14.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 38(3): 315-323, 2024 Mar 15.
Article in Chinese | MEDLINE | ID: mdl-38500425

ABSTRACT

Objective: To explore the molecular mechanism of miR-515-5p in inhibiting chondrocyte apoptosis and alleviating inflammatory response in osteoarthritis (OA). Methods: Human cartilage cell line C28/I2 was cultured in vitro and treated with 10 ng/mL interleukin 1ß (IL-1ß) for 24 hours to construct an in vitro OA model. C28/I2 cells were transfected with miR mimics, mimics negative control (NC), over expression (oe)-NC, and oe-Toll-like receptor 4 (TLR4), respectively, and then treated with 10 ng/mL IL-1ß for 24 hours to establish OA model. Cell proliferation capacity was detected by cell counting kit 8 and 5-Ethynyl-2'-deoxyuridine, cell apoptosis and cell cycle were detected by flow cytometry, and B-cell lymphoma 2 protion (Bcl-2), Bcl-2-associated X protein (Bax), cleaved-Caspase-3, TLR4, myeloid differentiation primary response gene 88 (MyD88), p65 and phosphorylated p65 (p-p65) protein expression levels were detected by Western blot. Real-time fluorescence quantitative PCR was used to detect mRNA expression levels of miR-515-5p and TLR4, and ELISA was used to detect pro-inflammatory factor prostaglandin E2 (PGE2), tumor necrosis factor α (TNF -α), and IL-6 levels in cell supernatant. The potential binding sites between miR-515-5p and TLR4 were predicted by BiBiServ2 database, and the targeting relationship between miR-515-5p and TLR4 was verified by dual luciferase reporting assay. Results: After the treatment of C28/I2 cells with IL-1ß, the expressions of miR-515-5p and Bcl-2 protein and the proliferation ability of C28/I2 cells significantly reduced. The expression levels of Bax and cleaved-Caspase-3 protein, the levels of pro-inflammatory factors (PGE2, TNF-α, IL-6) in the supernatant of C28/I2 cells, and the apoptosis of C28/I2 cells significantly increased. In addition, the proportion of the cells at S phase and G 2 phase decreased significantly, and the proportion of cells at G 1 phase increased significantly, suggesting that the cell cycle was blocked after IL-1ß treatment. After transfection with miR mimics, the expression level of miR-515-5p in the cells significantly up-regulated, partially reversing the apoptosis of OA chondrocytes induced by IL-1ß, and alleviating the cycle arrest and inflammatory response of OA chondrocytes. After treating C28/I2 cells with IL-1ß, the mRNA and protein levels of TLR4 significantly increased. Overexpression of miR-515-5p targeted inhibition of TLR4 expression and blocked activation of MyD88/nuclear factor κB (NF-κB) pathway. Overexpression of TLR4 could partially reverse the effect of miR mimics on IL-1ß-induced apoptosis and inflammation of OA chondrocytes. Conclusion: miR-515-5p negatively regulates the expression of TLR4, inhibits the activation of MyD88/NF-κB pathway and apoptosis of OA chondrocytes, and effectively alleviates the inflammatory response of the cells.


Subject(s)
MicroRNAs , Osteoarthritis , Humans , Adaptor Proteins, Signal Transducing/metabolism , Apoptosis , bcl-2-Associated X Protein/metabolism , Caspase 3/genetics , Caspase 3/metabolism , Chondrocytes/metabolism , Dinoprostone/metabolism , Interleukin-1beta/pharmacology , Interleukin-1beta/metabolism , Interleukin-6/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , NF-kappa B/metabolism , Osteoarthritis/metabolism , RNA, Messenger , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolism
15.
J Med Chem ; 67(8): 6365-6383, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38436574

ABSTRACT

Antimicrobial peptides (AMPs) have emerged as promising agents to combat the antibiotic resistance crisis due to their rapid bactericidal activity and low propensity for drug resistance. However, AMPs face challenges in terms of balancing enhanced antimicrobial efficacy with increased toxicity during modification processes. In this study, de novo d-type ß-hairpin AMPs are designed. The conformational transformation of self-assembling peptide W-4 in the environment of the bacterial membrane and the erythrocyte membrane affected its antibacterial activity and hemolytic activity and finally showed a high antibacterial effect and low toxicity. Furthermore, W-4 displays remarkable stability, minimal occurrence of drug resistance, and synergistic effects when combined with antibiotics. The in vivo studies confirm its high safety and potent wound-healing properties at the sites infected by bacteria. This study substantiates that nanostructured AMPs possess enhanced biocompatibility. These advances reveal the superiority of self-assembled AMPs and contribute to the development of nanoantibacterial materials.


Subject(s)
Anti-Bacterial Agents , Antimicrobial Peptides , Hemolysis , Microbial Sensitivity Tests , Nanofibers , Tryptophan , Nanofibers/chemistry , Tryptophan/chemistry , Tryptophan/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Antimicrobial Peptides/chemistry , Antimicrobial Peptides/pharmacology , Antimicrobial Peptides/chemical synthesis , Hemolysis/drug effects , Animals , Humans , Mice
16.
Adv Mater ; : e2400436, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38514194

ABSTRACT

Linear d-glucans are natural polysaccharides of simple chemical structure. They are comprised of d-glucosyl units linked by a single type of glycosidic bond. Noncovalent interactions within, and between, the d-glucan chains give rise to a broad variety of macromolecular nanostructures that can assemble into crystalline-organized materials of tunable morphology. Structure design and functionalization of d-glucans for diverse material applications largely relies on top-down processing and chemical derivatization of naturally derived starting materials. The top-down approach encounters critical limitations in efficiency, selectivity, and flexibility. Bottom-up approaches of d-glucan synthesis offer different, and often more precise, ways of polymer structure control and provide means of functional diversification widely inaccessible to top-down routes of polysaccharide material processing. Here the natural and engineered enzymes (glycosyltransferases, glycoside hydrolases and phosphorylases, glycosynthases) for d-glucan polymerization are described and the use of applied biocatalysis for the bottom-up assembly of specific d-glucan structures is shown. Advanced material applications of the resulting polymeric products are further shown and their important role in the development of sustainable macromolecular materials in a bio-based circular economy is discussed.

17.
Eur J Med Chem ; 269: 116337, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38537511

ABSTRACT

The global issue of antibiotic resistance is increasingly severe, highlighting the urgent necessity for the development of new antibiotics. Brevicidine, a natural cyclic lipopeptide, exhibits remarkable antimicrobial activity against Gram-negative bacteria. In this study, a comprehensive structure-activity relationship of Brevicidine was investigated through 20 newly synthesized cyclic lipopeptide analogs, resulting in the identification of an optimal linear analog 22. The sequence of analog 22 consisted of five d-amino acids and four non-natural amino acid 2,5-diaminovaleric acid (Orn) and conjugated with decanoic acid at N-terminal. Compared to Brevicidine, analog 22 was easier to synthesize, and exerted broad spectrum antimicrobial activity and excellent stability (t1/2 = 40.98 h). Additionally, analog 22 demonstrated a rapid bactericidal effect by permeating non-specifically through the bacterial membranes, thereby minimizing the likelihood of inducing resistance. Moreover, it exhibited remarkable efficacy in combating bacterial biofilms and reversing bacterial resistance to conventional antibiotics. Furthermore, it effectively suppressed the growth of bacteria in vital organs of mice infected with S. aureus ATCC 25923. In conclusion, analog 22 may represent a potential antimicrobial peptide for further optimization.


Subject(s)
Antimicrobial Peptides , Staphylococcus aureus , Animals , Mice , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Bacteria , Gram-Negative Bacteria , Lipopeptides/pharmacology , Microbial Sensitivity Tests
18.
J Biomater Appl ; 38(9): 989-999, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38427917

ABSTRACT

In this study, dissolving microneedles (MNs) using polyvinyl alcohol (PVA) and poly (1-vinylpyrrolidone-co-vinyl acetate) (P(VP-co-VA)) as matrix materials were developed for transdermal delivery of rizatriptan benzoate (RB) for acute migraine treatment. In-vitro permeation studies were conducted to assess the feasibility of the as-fabricated dissolving MNs to release RB. Drug skin penetration were tested by Franz diffusion cells, showing an increase of the transdermal flux compared to passive diffusion due to the as-fabricated dissolving MNs having a sufficient mechanical strength to penetrate the skin and form microchannels. The pharmacological study in vivo showed that RB-loaded dissolving MNs significantly alleviated migraine-related response by up-regulating the level of 5-hydroxytryptamine (5-HT) and down-regulating the levels of calcitonin gene-related peptide (CGRP) and substance P (SP). In conclusion, the RB-loaded dissolving MNs have advantages of safety, convenience, and high efficacy over conventional administrations, laying a foundation for the transdermal drug delivery system treatment for acute migraine.


Subject(s)
Drug Delivery Systems , Migraine Disorders , Triazoles , Tryptamines , Humans , Skin , Administration, Cutaneous , Migraine Disorders/drug therapy , Needles
19.
Front Oncol ; 14: 1344050, 2024.
Article in English | MEDLINE | ID: mdl-38511144

ABSTRACT

Abstract: To explore the impact of different imaging classifications of prostate cancer (PCa) with extracapsular extension (EPE) on positive surgical margins (PSM) after laparoscopic radical prostatectomy. Methods: Clinical data were collected for 114 patients with stage PT3a PCa admitted to Ningbo Yinzhou No. 2 Hospital from September 2019 to August 2023. Radiologists classified the EPE imaging of PCa into Type I, Type II, and Type III. A chi-square test or t-test was employed to analyze the factors related to PSM. Multivariate regression analysis was conducted to determine the factors associated with PSM. Receiver operating characteristic curve analysis was used to calculate the area under the curve and evaluate the diagnostic performance of our model. Clinical decision curve analysis was performed to assess the clinical net benefit of EPE imaging classification, biopsy grade group (GG), and combined model. Results: Among the 114 patients, 58 had PSM, and 56 had negative surgical margins. Multivariate analysis showed that EPE imaging classification and biopsy GG were risk factors for PSM after laparoscopic radical prostatectomy. The areas under the curve for EPE imaging classification and biopsy GG were 0.677 and 0.712, respectively. The difference in predicting PSM between EPE imaging classification and biopsy GG was not statistically significant (P>0.05). However, when used in combination, the diagnostic efficiency significantly improved, with an increase in the area under the curve to 0.795 (P<0.05). The clinical decision curve analysis revealed that the clinical net benefit of the combined model was significantly higher than that of EPE imaging classification and biopsy GG. Conclusions: EPE imaging classification and biopsy GG were associated with PSM after laparoscopic radical prostatectomy, and their combination can significantly improve the accuracy of predicting PSM.

20.
Eur J Med Chem ; 268: 116276, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38452726

ABSTRACT

The emergence of bacterial resistance has posed a significant challenge to clinical antimicrobial treatment, rendering commonly used antibiotics ineffective. The development of novel antimicrobial agents and strategies is imperative for the treatment of resistant bacterial infections. Antimicrobial peptides (AMPs) are considered a promising class of antimicrobial agents due to their low propensity for resistance and broad-spectrum activity. Anoplin is a small linear α-helical natural antimicrobial peptide that was isolated from the venom of the solitary wasp Anplius samariensis. It exhibits rich biological activity, particularly broad-spectrum antimicrobial activity and low hemolytic activity. Over the past three decades, more than 40 research publications on anoplin have been made available online. This review focuses on the advancements of anoplin in antimicrobial research, encompassing its sources, characterization, antimicrobial activity, influencing factors and structural modifications. The aim is to provide assistances for the development of new antimicrobial agents that can combat bacterial resistance.


Subject(s)
Anti-Infective Agents , Bacterial Infections , Humans , Antimicrobial Cationic Peptides/pharmacology , Antimicrobial Cationic Peptides/chemistry , Anti-Infective Agents/chemistry , Wasp Venoms/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria , Microbial Sensitivity Tests
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