Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions.

For an efficacious vaccine immunogen, influenza hemagglutinin (HA) needs to maintain a stable quaternary structure, which is contrary to the inherently dynamic and metastable nature of class I fusion proteins. In this study, we stabilized HA with three substitutions within its pH-sensitive regions where the refolding starts. An X-ray structure reveals how these substitutions stabilize the intersubunit ß-sheet in the base and form an interprotomeric aliphatic layer across the stem while the native prefusion HA fold is retained. The identification of the stabilizing substitutions increases our understanding of how the pH sensitivity is structurally accomplished in HA and possibly other pH-sensitive class I fusion proteins. Our stabilization approach in combination with the occasional back mutation of rare amino acids to consensus results in well-expressing stable trimeric HAs. This repair and stabilization approach, which proves broadly applicable to all tested influenza A HAs of group 1 and 2, will improve the developability of influenza vaccines based on different types of platforms and formats and can potentially improve efficacy.

Analysis of the Chloroplast Genome of Ficus simplicissima Lour Collected in Vietnam and Proposed Barcodes for Identifying Ficus Plants.

Ficus simplicissima Lour. is an Asian species of fig tree in the family Moraceae. The chloroplast (cp) genome of F. simplicissima m3 was sequenced using the Pacbio sequel platform. The F. simplicissima cpDNA has a size of 160,321 bp in length, of which GC content accounts for 36.13%. The cp genome of F. simplicissima consists of a single large copy (LSC) with a size of 91,346 bp, a single small copy (SSC) with a size of 20,131 bp, and a pair of inverted repeats with a size of 24,421 to 24,423 bp. The cp genome of F. simplicissima has 127 genes, including 85 protein-coding genes, eight rRNA genes, and 34 tRNA genes; 92 simple sequence repeats and 39 long repeats were detected in the cpDNA of F. simplicissim. A comparative cp genome analysis among six species in the Ficus genus indicated that the genome structure and gene content were highly conserved. The non-coding regions show more differentiation than the coding regions, and the LSC and SSC regions show more differences than the inverted repeat regions. Phylogenetic analysis supported that F. simplicissima m3 had a close relationship with F. hirta. The complete cp genome of F. simplicissima was proposed as a chloroplast DNA barcoding for genus-level in the Moraceae family and the psbA-trnH gene region for species-level identification.

Impact of antimicrobial stewardship intervention in clean and clean-contaminated surgical procedures at a Vietnamese national hospital.

OBJECTIVES: We investigated the characteristics of prophylactic antimicrobial use in clean and clean-contaminated surgical procedures and assessed the efficacy of a prophylactic antimicrobial stewardship intervention at Thong Nhat Hospital, Ho Chi Minh City, Vietnam. METHODS: A cross-sectional study was conducted on 354 patients who underwent either clean or clean-contaminated surgical procedures at Thong Nhat Hospital. Eligible patients were classified with respect to three periods of intervention from 2017 to 2020. Data collection included surgical procedures, patient characteristics, and prophylactic antimicrobial usage. We determined the efficacy of antimicrobial stewardship intervention based on comparisons among the primary outcome (the appropriateness of prophylactic antimicrobials) and secondary outcomes (postoperative antimicrobial prophylaxis (AP) prolongation, length of postoperative hospital stay, and cost of antimicrobials). RESULTS: The mean age of patients in periods 1, 2, and 3 was 54.5 ± 16.6, 50.2 ± 16.5, and 52.8 ± 17.3 years, respectively, with an overall male/female ratio of 1.1/1. No significant differences were detected in basic patient characteristics during the three periods. Majority of the surgical procedures were clean (56%-59%) and scheduled (85%-86%). Prophylactic antimicrobial stewardship intervention enhanced AP appropriateness (by 12.7%, 12.7%, and 39.0% in periods 1, 2, and 3, respectively, p < 0.001), decreased postoperative prophylactic antimicrobial duration [3.0 (0-6), 1.5 (0-5), and 0.0 (0-1) days, respectively, p < 0.001], and reduced average antimicrobial expenses (p < 0.001). CONCLUSIONS: The prophylactic antimicrobial stewardship interventions introduced at Thong Nhat Hospital had several positive impacts on the appropriateness of prophylactic antimicrobial use and treatment costs.

A prelacrimal approach technique to overcome the limitation of the narrow lacrimal recess.

PURPOSE: The distance between the anterior wall of the maxillary sinus and the nasolacrimal duct has been classified into three types by Simmen, in which type I (< 3 mm) is the least feasible for a prelacrimal approach. The aim of our study is to present a surgical technique which overcomes the anatomical limitation of the narrow lacrimal recess (type I) in the management of inverted papilloma in the maxillary sinus. METHODS: Case series. RESULTS: Eight patients with type I lacrimal recess underwent surgical resection for inverted papilloma in the maxillary sinus via a prelacrimal approach. The technique is described in detail in the article and essentially involves exposure of the nasolacrimal duct using a diamond burr. Complete tumor excision was achieved in all cases through this access, with no significant intra-operative complications. CONCLUSIONS: This prelacrimal approach technique is safe and effective for the management of inverted papilloma in maxillary sinuses with a type I lacrimal recess configuration.

Customizable live-cell imaging chambers for multimodal and multiplex fluorescence microscopy.

Using multiple imaging modalities while performing independent experiments in parallel can greatly enhance the throughput of microscopy-based research, but requires the provision of appropriate experimental conditions in a format that meets the optical requirements of the microscope. Although customized imaging chambers can meet these challenges, the difficulty of manufacturing custom chambers and the relatively high cost and design inflexibility of commercial chambers has limited the adoption of this approach. Herein, we demonstrate the use of 3D printing to produce inexpensive, customized, live-cell imaging chambers that are compatible with a range of imaging modalities, including super-resolution microscopy. In this approach, biocompatible plastics are used to print imaging chambers designed to meet the specific needs of an experiment, followed by adhesion of the printed chamber to a glass coverslip, producing a chamber that is impermeant to liquids and that supports the growth and imaging of cells over multiple days. This approach can also be used to produce moulds for casting microfluidic devices made of polydimethylsiloxane. The utility of these chambers is demonstrated using designs for multiplex microscopy, imaging under shear, chemotaxis, and general cellular imaging. Together, this approach represents an inexpensive yet highly customizable approach for producing imaging chambers that are compatible with modern microscopy techniques.

The conserved regulatory RNA RsaE down-regulates the arginine degradation pathway in Staphylococcus aureus.

RsaE is a regulatory RNA highly conserved amongst Firmicutes that lowers the amount of mRNAs associated with the TCA cycle and folate metabolism. A search for new RsaE targets in Staphylococcus aureus revealed that in addition to previously described substrates, RsaE down-regulates several genes associated with arginine catabolism. In particular, RsaE targets the arginase rocF mRNA via direct interactions involving G-rich motifs. Two duplicated C-rich motifs of RsaE can independently downregulate rocF expression. The faster growth rate of ΔrsaE compared to its parental strain in media containing amino acids as sole carbon source points to an underlying role for RsaE in amino acid catabolism. Collectively, the data support a model in which RsaE acts as a global regulator of functions associated with metabolic adaptation.

Finding sRNA-associated phenotypes by competition assays: An example with Staphylococcus aureus.

Bacteria optimize their fitness in response to a changing environment by tight regulation of gene expression. Regulation can be controlled at both transcriptional and post-transcriptional levels via key players such as sigma factors, regulatory proteins and regulatory RNAs. The identification of phenotypes associated with gene deletions is the established method for finding gene functions but may require testing many conditions for each studied mutant. As regulatory RNAs often contribute to fine-tuning gene expression, phenotypes associated with their inactivation are often weak and difficult to detect. Nevertheless, minor phenotypes conferring modest advantages, may allow bacteria to emerge after some generations under selective pressure. A strategy employing DNA barcodes can be used to perform competition experiments between mutants and to monitor fitness associated with mutations in different growth conditions. We combined this strategy with deep sequencing to study regulatory RNAs in Staphylococcus aureus, a major opportunistic pathogen.

Mechanistic study of base-pairing small regulatory RNAs in bacteria.

In all three kingdoms of life, RNA is not only involved in the expression of genetic information, but also carries out extremely diverse cellular functions. This versatility is essentially due to the fact that RNA molecules can exploit the power of base pairing to allow them to fold into a wide variety of structures through which they can perform diverse roles, but also to selectively target and bind to other nucleic acids. This is true in particular for bacterial small regulatory RNAs that act by imperfect base-pairing with target mRNAs, and thereby control their expression through different mechanisms. Here we outline an overview of in vivo and in vitro approaches that are currently used to gain mechanistic insights into how these sRNAs control gene expression in bacteria.

Novel Multivalent Wound-Healing Ointment Provides Bioburden Control and Moisture Management: A Retrospective Registry Data Analysis.

OBJECTIVE: The purpose of this retrospective registry data analysis was to explore the effectiveness of a novel multivalent topical ointment (Terrasil Infection Control Wound Care Ointment; Aspiera Medical, Woonsocket, Rhode Island), containing a patented mineral complex and 0.2% benzethonium chloride in the treatment of nonhealing acute and chronic wounds. DESIGN: Aspiera Medical designed a registry to capture physician experiences and treatment results with Terrasil Infection Control Wound Care Ointment. Physicians were asked to enter deidentified patient data into an online registry. SETTING: Wound clinics in the United States were asked to participate in the registry. PATIENTS: Physicians at 4 wound clinics treated 30 patients (26 of whom completed the treatment) with various chronic wounds that had persisted for an average of 6 months and entered treatment data into the registry. INTERVENTIONS: Patients applied the ointment according to physician orders. Concurrent treatments used by patients included offloading, compression wraps, and dressings, such as collagen and calcium alginate. Patients were treated until complete wound closure or lost to follow-up. MAIN OUTCOME MEASURES: Physicians calculated each patient's percentage wound reduction at each visit. MAIN RESULTS: Thirty patients were entered into the registry. Pretreatment and posttreatment measurements were available for 26 of them. Patients achieved an average surface area reduction of 84% in a mean of 23 days' treatment. CONCLUSION: The antimicrobial and moisturizing ointment studied appears to be effective in promoting wound closure in a variety of acute and chronic wounds. Wounds studied included diabetic foot ulcers, venous leg ulcers, venous stasis ulcers, surgical infections, burns, and insect bites. The results of this registry data analysis will be used to inform planned clinical trials.

Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost.

Advanced therapies such as bioengineered skin substitutes (BSS) and dehydrated human amnion/chorion membrane (dHACM) have been shown to promote healing of chronic diabetic ulcers. An interim analysis of data from 60 patients enrolled in a prospective, randomised, controlled, parallel group, multi-centre clinical trial showed that dHACM (EpiFix, MiMedx Group Inc., Marietta, GA) is superior to standard wound care (SWC) and BSS (Apligraf, Organogenesis, Inc., Canton, MA) in achieving complete wound closure within 4-6 weeks. Rates and time to closure at a longer time interval and factors influencing outcomes remained unassessed; therefore, the study was continued in order to achieve at least 100 patients. With the larger cohort, we compare clinical outcomes at 12 weeks in 100 patients with chronic lower extremity diabetic ulcers treated with weekly applications of Apligraf (n = 33), EpiFix (n = 32) or SWC (n = 35) with collagen-alginate dressing as controls. A Cox regression was performed to analyse the time to heal within 12 weeks, adjusting for all significant covariates. A Kaplan-Meier analysis was conducted to compare time-to-heal within 12 weeks for the three treatment groups. Clinical characteristics were well matched across study groups. The proportion of wounds achieving complete closure within the 12-week study period were 73% (24/33), 97% (31/32), and 51% (18/35) for Apligraf, EpiFix and SWC, respectively (adjusted P = 0·00019). Subjects treated with EpiFix had a very significant higher probability of their wounds healing [hazard ratio (HR: 5·66; adjusted P: 1·3 x 10(-7) ] compared to SWC alone. No difference in probability of healing was observed for the Apligraf and SWC groups. Patients treated with Apligraf were less likely to heal than those treated with EpiFix [HR: 0·30; 95% confidence interval (CI): 0·17-0·54; unadjusted P: 5·8 x 10(-5) ]. Increased wound size and presence of hypertension were significant factors that influenced healing. Mean time-to-heal within 12 weeks was 47·9 days (95% CI: 38·2-57·7) with Apligraf, 23·6 days (95% CI: 17·0-30·2) with EpiFix group and 57·4 days (95%CI: 48·2-66·6) with the SWC alone group (adjusted P = 3·2 x 10(-7) ). Median number of grafts used per healed wound were six (range 1-13) and 2·5 (range 1-12) for the Apligraf and EpiFix groups, respectively. Median graft cost was $8918 (range $1,486-19,323) per healed wound for the Apligraf group and $1,517 (range $434-25,710) per healed wound in the EpiFix group (P < 0·0001). These results provide further evidence of the clinical and resource utilisation superiority of EpiFix compared to Apligraf for the treatment of lower extremity diabetic wounds.

Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann-Pick type C disease.

Niemann-Pick Type C (NPC) disease is caused by a deficiency of either NPC1 or NPC2. Loss of function of either protein results in the progressive accumulation of unesterified cholesterol in every tissue leading to cell death and organ damage. Most literature on NPC disease focuses on neurological and liver manifestations. Pulmonary dysfunction is less well described. The present studies investigated how Npc1 deficiency impacts the absolute weight, lipid composition and histology of the lungs of Npc1(-/-) mice (Npc1(nih)) at different stages of the disease, and also quantitated changes in the rates of cholesterol and fatty acid synthesis in the lung over this same time span (8 to 70days of age). Similar measurements were made in Npc2(-/-) mice at 70days. All mice were of the BALB/c strain and were fed a basal rodent chow diet. Well before weaning, the lung weight, cholesterol and phospholipid (PL) content, and cholesterol synthesis rate were all elevated in the Npc1(-/-) mice and remained so at 70days of age. In contrast, lung triacylglycerol content was reduced while there was no change in lung fatty acid synthesis. Despite the elevated PL content, the composition of PL in the lungs of the Npc1(-/-) mice was unchanged. H&E staining revealed an age-related increase in the presence of lipid-laden macrophages in the alveoli of the lungs of the Npc1(-/-) mice starting as early as 28days. Similar metabolic and histologic changes were evident in the lungs of the Npc2(-/-) mice. Together these findings demonstrate an intrinsic lung pathology in NPC disease that is of early onset and worsens over time.

A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers.

Venous leg ulcers produce significant clinical and economic burdens on society and often require advanced wound therapy. The purpose of this multicenter, randomized, controlled study is to evaluate the safety and efficacy of one or two applications of dehydrated human amnion/chorion membrane allograft and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. The primary study outcome was the proportion of patients achieving 40% wound closure at 4 weeks. Of the 84 participants enrolled, 53 were randomized to receive allograft and 31 were randomized to the control group of multilayer compression therapy alone. At 4 weeks, 62% in the allograft group and 32% in the control group showed a greater than 40% wound closure (p = 0.005), thus showing a significant difference between the allograft-treated groups and the multilayer compression therapy alone group at the 4-week surrogate endpoint. After 4 weeks, wounds treated with allograft had reduced in size a mean of 48.1% compared with 19.0% for controls. Venous leg ulcers treated with allograft had a significant improvement in healing at 4 weeks compared with multilayer compression therapy alone.

Orthodontic Treatment for Borderline Class III Malocclusion in Adults: Nonextraction Treatment with Anterior Bite Turbo: A Case Report.

Retrusive upper lips, retroclined upper incisors, a shorter midface, and a larger maxillary-mandibular difference are the characteristics of borderline Class III malocclusion. Individuals with borderline Class III malocclusion frequently exhibit certain morphologic, dental, and skeletal traits, which should aid in the diagnosis of the condition. To report the case of a 22-year-old Vietnamese woman who complained of having tense front teeth and lacking confidence when smiling. Medical history did not find anything strange, there was root canal treatment of the first premolar on the left of the upper jaw, asymmetrical concave chin, and right deviation. Orthodontic camouflage treatment using anterior bite turbos in combination with early light short Class III elastics and box elastics was proposed since the patient declined to have orthognathic surgery. In just 10 months of treatment, a Class I molar and canine relationship was created, an anterior crossbite was corrected via mandibular retraction, and severe skeletal malocclusions were successfully treated without orthognathic surgery. Smiling currently showcases the patient's maxillary incisors more prominently, and her lower lip fullness has diminished, giving her a more attractive smile and a significant improvement to her facial profile.

Clinical performance of computer-aided design/computer-aided manufacture lithium disilicate ceramic endocrown restorations: A 2-year study.

Context: Optimal restoration methods for endodontically treated teeth (ETTs) have always remained an ongoing discussion among physicians in this day and age. ETTs have a tendency to fracture when chewing, compared to initial teeth. From the perspective of biology, preserving and restoring tooth structure is critical to maintaining biomechanical, functional, and esthetic harmony. Dental bonding techniques have lessened the necessity for post-and-core restorations in ETTs with severe substance loss. A minimally invasive endodontic restoration technique called "endocrown" was initially introduced by Bindl and Mörmann in 1999. Aims: The aim of the study was to clinically evaluate all-ceramic mandibular molar endocrowns made using computer-aided design/computer-aided manufacturing (CAD/CAM) following 2 years of follow-up. Subjects and Methods: This unblinded study contains 56 patients with 56 mandibular molars, which had severe substance loss. After teeth preparation, lithium disilicate ceramic endocrowns were manufactured with the CEREC CAD/CAM system, and cementation was performed using a composite luting agent. The endocrowns were assessed using the modified United States Public Health Service criteria at baseline, 6 months, 1 year, and 2 years following placement. Patient satisfaction was evaluated using a questionnaire. Statistical Analysis Used: This study used descriptive statistics, including mean, standard deviation, and 95% confidence intervals. Data were processed using STATA version 14.0 (StataCorp LLC, USA). Results: Two endocrowns (3.6%) failed throughout the period of observation. The high clinical rating criteria (96.4%, count of 54) and the increased satisfaction percentage (94.6%, count of 53) remained practically stable during the follow-up assessments at 6 months and after 1-2 years. Conclusions: Endocrown offers a less invasive treatment option that may be a better method for endodontically treated mandibular molars. With contemporary CAD/CAM technology and new materials, time in the chair and esthetics optimally improved, bringing satisfaction to the patient.

The Applicability of the Moyers, Tanaka-Johnston, and Gross-Hasund Analysis and a New Formula for the Vietnamese Population.

Aim: Our aim is to determine the applicability of other analyses and develop a new formula appropriate for the Vietnamese population. Materials and Methods: A cross-sectional descriptive analysis was conducted on a total of 120 dental arch samples (18-25 years old, 60 males, and 60 females) with <5 mm of tooth crowding, complete teeth on the dental arch, no missing teeth, and no fillings on the mesial or distal sides. Each study sample will be imprinted and measured using conventional as well as digital methods. Result: There was a significant discrepancy between the overall mesiodistal width from canine to second premolar in the maxilla and mandibular measured with electronic calipers on the cast model and the values calculated by the Moyer, Tanaka - Johnston, Gross - Hasund formulae in the mandibular, and measured by digital scanning and results calculated by the Gross-Hasund formula for maxilla and mandibular and the Moyers, Tanaka-Johnston formula for mandibular. The values obtained were compared with those calculated using the Moyers, Tanaka-Johnston, and Gross-Hasund formulae for the mandibular. Additionally, measurements were taken by digital scanning, and the results were calculated using the Gross-Hasund formula for both the maxilla and mandibular, and the Moyers and Tanaka-Johnston formulae for the mandibular. When used to estimate space analysis in the Vietnamese population, the estimation formula for each gender had greater accuracy and reliability than other widely used methods. Conclusions: As the central incisor and first molar are the first permanent teeth to erupt, the mesiodistal width may be readily measured. This new formula may be used to predict the width in the early stages of the mixed dentition.

Cone Beam CT Assessment of Mandibular Foramen and Mental Foramen Positions as Essential Anatomical Landmarks: A Retrospective Study in Vietnam.

INTRODUCTION: The mandibular foramen (MnF) and the mental foramen (MF) are essential anatomical landmarks that should be considered before any surgical procedures in the mandible. This study aimed to investigate the characteristics of the MnF and MF in relation to adjacent anatomical structures, as well as age and gender differences, using cone beam computed tomography (CBCT) projections. METHODS: The study was conducted from August 2023 to January 2024 at the Can Tho University of Medicine and Pharmacy Hospital, Vietnam. In this retrospective study, 50 CBCT images of Vietnamese patients were randomly taken for various clinical purposes. Furthermore, relevant data, such as gender and age groups, were selected to evaluate the correlations, along with specific inclusion criteria. Patients within the age range of 18-69 with a symmetrical mandible were included. RESULTS: The distance of the MnF-MN was 29.6±5.0 mm (right) and 30.1±4.6 mm (left) in males and 25.0±4.2 mm (right) and 26.3±5.0 mm (left) in females. The distance of the MnF-posterior border of the ramus (P) was 16.2±3.6 mm (right) and 15.0±2.3 mm (left) in males. For females, it was 17.1±2.9 mm (right) and 13.8±1.7 mm (left). The distance of the MF-body mandible (MB) was 15.4±2.4 mm (right) and 15.6±2.0 mm (left) in males and 14.0±2.1 mm (right) and 14.3±1.6 mm (left) in females. The distance of the MF-mandibular midline (MM) was 27.0±2.6 mm (right) and 27.0±2.9 mm (left) in males and 25.3±2.0 mm (right) and 25.1±2.2 mm (left) in females. These distances showed statistically significant differences depending on gender (P<0.05). CONCLUSION: It can be said that CBCT provides comprehensive information about the MnF and the MF for dentists in research and clinical practice.

Polythiophene-wrapped Chitosan Nanofibrils with a Bouligand Structure toward Electrochemical Macroscopic Membranes.

Exploring structural biomimicry is a great opportunity to replicate hierarchical frameworks inspired by nature in advanced functional materials for boosting new applications. In this work, we present the biomimetic integration of polythiophene into chitosan nanofibrils in a twisted Bouligand structure to afford free-standing macroscopic composite membranes with electrochemical functionality. By considering the integrity of the Bouligand structure in crab shells, we can produce large, free-standing chitosan nanofibril membranes with iridescent colors and flexible toughness. These unique structured features lead the chitosan membranes to host functional additives to mimic hierarchically layered composites. We used the iridescent chitosan nanofibrils as a photonic platform to investigate the host-guest combination between thiophene and chitosan through oxidative polymerization to fabricate homogeneous polythiophene-wrapped chitosan composites. This biomimetic incorporation fully retains the twisted Bouligand organization of nanofibrils in the polymerized assemblies, thus giving rise to free-standing macroscopic electrochemical membranes. Our further experiments are the modification of the biomimetic polythiophene-wrapped chitosan composites on a glassy carbon electrode to design a three-electrode system for simultaneous electrochemical detection of uric acid, xanthine, hypoxanthine, and caffeine at trace concentrations.

Design and Preclinical Evaluation of a Nanoparticle Vaccine against Respiratory Syncytial Virus Based on the Attachment Protein G.

Human respiratory syncytial virus (RSV) poses a significant human health threat, particularly to infants and the elderly. While efficacious vaccines based on the F protein have recently received market authorization, uncertainties remain regarding the future need for vaccine updates to counteract potential viral drift. The attachment protein G has long been ignored as a vaccine target due to perceived non-essentiality and ineffective neutralization on immortalized cells. Here, we show strong G-based neutralization in fully differentiated human airway epithelial cell (hAEC) cultures that is comparable to F-based neutralization. Next, we designed an RSV vaccine component based on the central conserved domain (CCD) of G fused to self-assembling lumazine synthase (LS) nanoparticles from the thermophile Aquifex aeolicus as a multivalent antigen presentation scaffold. These nanoparticles, characterized by high particle expression and assembly through the introduction of N-linked glycans, showed exceptional thermal and storage stability and elicited potent RSV neutralizing antibodies in a mouse model. In conclusion, our results emphasize the pivotal role of RSV G in the viral lifecycle and culminate in a promising next-generation RSV vaccine candidate characterized by excellent manufacturability and immunogenic properties. This candidate could function independently or synergistically with current F-based vaccines.

Potential biological functions and future perspectives of sialylated milk oligosaccharides.

Sialyllactoses (SLs) primarily include sialylated human milk oligosaccharides (HMOs) and bovine milk oligosaccharides (BMOs). First, the safety assessment of 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL) revealed low toxicity in various animal models and human participants. SLs constitute a unique milk component, highlighting the essential nutrients and bioactive components crucial for infant development, along with numerous associated health benefits for various diseases. This review explores the safety, biosynthesis, and potential biological effects of SLs, with a specific focus on their influence across various physiological systems, including the gastrointestinal system, immune disorders, rare genetic disorders (such as GNE myopathy), cancers, neurological disorders, cardiovascular diseases, diverse cancers, and viral infections, thus indicating their therapeutic potential.

3'-Sialyllactose protects against LPS-induced endothelial dysfunction by inhibiting superoxide-mediated ERK1/2/STAT1 activation and HMGB1/RAGE axis.

AIM: Endothelial hyperpermeability is an early stage of endothelial dysfunction associated with the progression and development of atherosclerosis. 3'-Sialyllactose (3'-SL) is the most abundant compound in human milk oligosaccharides, and it has the potential to regulate endothelial dysfunction. This study investigated the beneficial effects of 3'-SL on lipopolysaccharide (LPS)-induced endothelial dysfunction in vitro and in vivo. MAIN METHODS: We established LPS-induced endothelial dysfunction models in both cultured bovine aortic endothelial cells (BAECs) and mouse models to determine the effects of 3'-SL. Western blotting, qRT-PCR analysis, immunofluorescence staining, and en face staining were employed to clarify underlying mechanisms. Superoxide production was measured by 2',7'-dichlorofluorescin diacetate, and dihydroethidium staining. KEY FINDINGS: LPS significantly decreased cell viability, whereas 3'-SL treatment mitigated these effects via inhibiting ERK1/2 activation. Mechanistically, 3'-SL ameliorated LPS-induced ROS accumulation leading to ERK1/2 activation-mediated STAT1 phosphorylation and subsequent inhibition of downstream transcriptional target genes, including VCAM-1, TNF-α, IL-1ß, and MCP-1. Interestingly, LPS-induced ERK1/2/STAT1 activation leads to the HMGB1 release from the nucleus into the extracellular space, where it binds to RAGE, while 3'-SL suppressed EC hyperpermeability by suppressing the HMGB1/RAGE axis. This interaction also led to VE-cadherin endothelial junction disassembly and endothelial cell monolayer disruption through ERK1/2/STAT1 modulation. In mouse endothelium, en face staining revealed that 3'-SL abolished LPS-stimulated ROS production and VCAM-1 overexpression. SIGNIFICANCE: Our findings suggest that 3'-SL inhibits LPS-induced endothelial hyperpermeability by suppressing superoxide-mediated ERK1/2/STAT1 activation and HMGB1/RAGE axis. Therefore, 3'-SL may be a potential therapeutic agent for preventing the progression of atherosclerosis.