Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.

Ts2O mediated deoxygenative C2-dithiocarbamation of quinoline N-oxides with CS2 and amines.

A general, efficient and practical protocol for Ts2O promoted deoxygenative dithiocarbamation of quinoline N-oxides with in situ generated dithiocarbamic acids from CS2 and amines is reported. The reaction proceeded well under transition-metal free conditions to obtain a variety of novel quinoline-dithiocarbamate compounds with wide functional group tolerance and good to high yields.

Impact of high-altitude acclimatization and de-acclimatization on the intestinal microbiota of rats in a natural high-altitude environment.

Introduction: Intestinal microorganisms play an important role in the health of both humans and animals, with their composition being influenced by changes in the host's environment. Methods: We evaluated the longitudinal changes in the fecal microbial community of rats at different altitudes across various time points. Rats were airlifted to high altitude (3,650 m) and acclimatized for 42 days (HAC), before being by airlifted back to low altitude (500 m) and de-acclimatized for 28 days (HADA); meanwhile, the control group included rats living at low altitude (500 m; LA). We investigated changes in the gut microbiota at 12 time points during high-altitude acclimatization and de-acclimatization, employing 16S rRNA gene sequencing technology alongside physiological indices, such as weight and daily autonomous activity time. Results: A significant increase in the Chao1 index was observed on day 14 in the HAC and HADA groups compared to that in the LA group, indicating clear differences in species richness. Moreover, the principal coordinate analysis revealed that the bacterial community structures of HAC and HADA differed from those in LA. Long-term high-altitude acclimatization and de- acclimatization resulted in the reduced abundance of the probiotic Lactobacillus. Altitude and age significantly influenced intestinal microbiota composition, with changes in ambient oxygen content and atmospheric partial pressure being considered key causal factors of altitude-dependent alterations in microbiota composition. High-altitude may be linked to an increase in anaerobic bacterial abundance and a decrease in non-anaerobic bacterial abundance. Discussion: In this study, the hypobaric hypoxic conditions at high-altitude increased the abundance of anaerobes, while reducing the abundance of probiotics; these changes in bacterial community structure may, ultimately, affect host health. Overall, gaining a comprehensive understanding of the intestinal microbiota alterations during high-altitude acclimatization and de-acclimatization is essential for the development of effective prevention and treatment strategies to better protect the health of individuals traveling between high- and low-altitude areas.

The impact of ageing mechanisms on musculoskeletal system diseases in the elderly.

Ageing is an inevitable process that affects various tissues and organs of the human body, leading to a series of physiological and pathological changes. Mechanisms such as telomere depletion, stem cell depletion, macrophage dysfunction, and cellular senescence gradually manifest in the body, significantly increasing the incidence of diseases in elderly individuals. These mechanisms interact with each other, profoundly impacting the quality of life of older adults. As the ageing population continues to grow, the burden on the public health system is expected to intensify. Globally, the prevalence of musculoskeletal system diseases in elderly individuals is increasing, resulting in reduced limb mobility and prolonged suffering. This review aims to elucidate the mechanisms of ageing and their interplay while exploring their impact on diseases such as osteoarthritis, osteoporosis, and sarcopenia. By delving into the mechanisms of ageing, further research can be conducted to prevent and mitigate its effects, with the ultimate goal of alleviating the suffering of elderly patients in the future.

Novel SERS Probe Based on Ag Nanobean/Cu Foam for Deep-Sea Extreme Environment Biomolecule Detection.

Here, we report on progress made in coupling advances in surface-enhanced Raman scattering (SERS) techniques with a deep-ocean deployable Raman spectrometer. Our SERS capability is provided by development of a Cu foam-loaded silver-nanobean (Ag/Cu foam) which we have successfully coupled to the tip of a Raman probe head capable of insertion into deep-sea sediments and associated fluids. Our purpose is to expand the range of molecular species which can be detected in deep-sea biogeochemical environments, and our initial targets are a series of amino acids reportedly found in pore waters of seep locations. Our work has progressed to the point of a full dock-based end-to-end test of the essential ship tether-ROV-deep-sea Raman system. We show here the initial results from this test as the essential requirement before at sea full ocean depth deployment. We describe in detail the procedures for preparing the Ag/Cu foam bean and demonstrate in our end-to-end test that this, when coupled to the spectrometer probe tip, yields a SERS signal enhancement of 1.2 × 106 for test molecules and detection of amino acids at 10-6 M levels consistent with reported levels of natural occurrence. Each nanobean unit is for single-use sensing since invasion of the sample fluid into the Ag/Cu foam matrix is not reversible. We describe techniques for bean rotation/replacement at depth to allow for multiple analyses at several locations during each ROV dive.

Efficacy of different indocyanine green doses in fluorescent laparoscopic cholecystectomy: A prospective, randomized, double-blind trial.

BACKGROUND AND OBJECTIVES: Intraoperative bile duct injury is a significant complication in laparoscopic cholecystectomy (LC). Near-infrared fluorescence cholangiography (NIFC) can reduce this complication. Therefore, determining the optimal indocyanine green (ICG) dosage for effective NIFC is crucial. This study aimed to determine the optimal ICG dosage for NIFC. METHODS: This was a prospective, randomized, double-blind clinical trial at a single tertiary referral center, including 195 patients randomly assigned to three groups: lower dose (0.01 mg/BMI) ICG (n = 63), medium dose (0.02 mg/BMI) ICG (n = 68), and higher dose (0.04 mg/BMI) ICG (n = 64). Surgeon satisfaction and detection rates for seven biliary structures were compared among the three dose groups. RESULTS: Demographic parameters did not significantly differ among the groups. The medium dose (72.1%) and higher dose ICG groups (70.3%) exhibited superior visualization of the common hepatic duct compared to the lower dose group (41.3%) (p < 0.001). No differences existed between the medium and higher dose groups. Similar trends were observed for the common bile duct and cystic common bile duct junction. CONCLUSIONS: In patients undergoing fluorescent laparoscopic cholecystectomy, the 0.02 mg/BMI dose of indocyanine green demonstrated better biliary structure detection rates than the 0.01 mg/BMI dose and was non-inferior to the 0.04 mg/BMI dose.

Benthic clade II-type nitrous oxide reducers suppress nitrous oxide emissions in shallow lakes.

Shallow lakes, recognized as hotspots for nitrogen cycling, contribute to the emission of the potent greenhouse gas nitrous oxide (N2O), but the current emission estimates for this gas have a high degree of uncertainty. However, the role of N2O-reducing bacteria (N2ORB) as N2O sinks and their contribution to N2O reduction in aquatic ecosystems in response to N2O dynamics have not been determined. Here, we investigated the N2O dynamics and microbial processes in the nitrogen cycle, which included both N2O production and consumption, in five shallow lakes spanning approximately 500 km. The investigated sites exhibited N2O oversaturation, with excess dissolved N2O concentrations (ΔN2O) ranging from 0.55 ± 0.61 to 53.17 ± 15.75 nM. Sediment-bound N2O (sN2O) was significantly positively correlated with the nitrate concentration in the overlying water (p < 0.05), suggesting that nitrate accumulation contributes to benthic N2O generation. High N2O consumption activity (RN2O) corresponded to low ΔN2O. In addition, a significant negative correlation was found between RN2O and nir/nosZ, showing that bacteria encoding nosZ contributed to N2O consumption in the benthic sediments. Redundancy analysis indicated that benthic functional genes effectively reflected the variations in RN2O and ∆N2O. qPCR analysis revealed that the clade II nosZ gene was more sensitive to ΔN2O than the clade I nosZ gene. Furthermore, four novel genera of potential nondenitrifying N2ORB were identified based on metagenome-assembled genome analysis. These genera, which are affiliated with clade II, lack genes responsible for N2O production. Collectively, benthic N2ORB, especially for clade II-type N2ORB, harnesses N2O consumption activity leading to low N2O emissions from shallow lakes. This study advances our knowledge of the role of benthic clade II-type N2ORB in regulating N2O emissions in shallow lakes.

The exploration of surgery and survival prediction in patients with peritoneal metastasis from gastric adenocarcinoma based on the SEER database.

Background: As one of the most common diseases in terms of cancer-related mortality worldwide, gastric adenocarcinoma (GA) frequently develops peritoneal metastases (PMs) in advanced stages. Systemic therapy or optimal supportive care are recommended for advanced GA; however, patients frequently develop drug resistance. Surgical resection is not recommended for stage IV patients, and there have been some controversies regarding the role of it in GA patients with PMs. The aim of the study was to preliminarily evaluate the possible effect of surgical treatments on patients with only PMs from GA. Methods: Data were collected from the Surveillance, Epidemiology and End Results (SEER) database (year 2000-2022). A propensity score matching (PSM) was performed to reduce the influence of selection bias and confounding variables on comparisons. Then Cox proportional hazard regression, Kaplan-Meier analysis, and log-rank test were performed to assess the efficacy of surgical treatment in patients with PMs from GA. Results: A total of 399 patients diagnosed with PMs from GA were enrolled for our analysis, of which, 180 (45.1%) patients did not receive surgery and 219 (54.9%) patients received surgery. Multivariate Cox regression analysis before PSM indicated higher rates of overall survival (OS) outcome for patients who had received surgery [hazard ratio (HR) =0.4342, 95% confidence interval (CI): 0.3283-0.5742, P<0.001]. After PSM, a total of 172 patients were enrolled, with 86 in each group. Multivariate Cox analysis showed that surgery was the independent factor reflecting patients' survival (HR =0.4382, 95% CI: 0.3037-0.6324, P<0.001). Subgroup survival analysis revealed that surgery may bring advantages to patients with grades I-IV, stages T1-T4, stage N0, and tumor size less than 71 mm (P<0.05). We also found that the OS of chemotherapy patients who had undergone surgery was better than that of chemotherapy patients who had not undergone surgery (P<0.01). Conclusions: Based on the SEER database, surgery has better OS for patients only with PMs from GA. Patients without lymph node metastasis and those who received chemotherapy before may benefit from surgery. These specific groups of patients may have surgery as an option to improve the prognosis.

The aging lung: microenvironment, mechanisms, and diseases.

With the development of global social economy and the deepening of the aging population, diseases related to aging have received increasing attention. The pathogenesis of many respiratory diseases remains unclear, and lung aging is an independent risk factor for respiratory diseases. The aging mechanism of the lung may be involved in the occurrence and development of respiratory diseases. Aging-induced immune, oxidative stress, inflammation, and telomere changes can directly induce and promote the occurrence and development of lung aging. Meanwhile, the occurrence of lung aging also further aggravates the immune stress and inflammatory response of respiratory diseases; the two mutually affect each other and promote the development of respiratory diseases. Explaining the mechanism and treatment direction of these respiratory diseases from the perspective of lung aging will be a new idea and research field. This review summarizes the changes in pulmonary microenvironment, metabolic mechanisms, and the progression of respiratory diseases associated with aging.

Efficient synthesis of SCF3-containing 3-alkenylquinoxalinones via three-component radical cascade reaction.

An efficient and practical method for the synthesis of 3-alkenylquinoxalinones containing the SCF3 group has been readily developed through a three-component radical cascade reaction involving quinoxalinones, alkynes and AgSCF3. The reaction was found to be compatible with a variety of substrates and exhibited a high functional group tolerance and complete E-selectivity. The preliminary study suggests the involvement of a SCF3 radical in the transformation.

Significance of immunoglobulins synthesis with central nervous system involvement in Neuro-Behçet's disease.

OBJECTIVES: Demyelination and immunocyte-infiltrated lesions have been found in neuro-Behçet's disease (NBD) pathology. Lacking satisfying laboratory biomarkers in NBD impedes standard clinical diagnostics. We aim to explore the ancillary indicators for NBD diagnosis unveiling its potential etiology. METHODS: 28 NBD with defined diagnosis, 29 patients with neuropsychiatric lupus erythematosus, 30 central nervous system idiopathic inflammatory demyelination diseases (CNS-IIDD), 30 CNS infections, 30 cerebrovascular diseases, and 30 noninflammatory neurological diseases (NIND) were retrospectively enrolled. Immunoglobulins (Ig) in serum and cerebral spinal fluid (CSF) were detected by immunonephelometry and myelin basic protein (MBP) by quantitative enzyme-linked immunosorbent assay. RESULTS: IgA index is almost twice enhanced in NBD than NIND with an accuracy of 0.8488 in differential diagnosis, the sensitivity and specificity of which were 75.00 % and 90.00 % when the cutoff was > 0.6814. The accuracy of CSF Ig and quotient of Ig all exceed 0.90 in discerning NBD with damaged and intact blood-brain barrier (BBB). Clustering analyses divided NBD into two different phenotypes: one with BBB damage has lower Ig synthesis, the other with extra-synthesis in parenchymal sites but with intact BBB. MBP index is significantly correlated with kappa (KAP) index and lambda (LAM) index (r = 0.358, 0.575, P < 0.001), hinting the NBD pathogenesis of CNS demyelination in triggering excessive intrathecal Ig productions and humoral responses. CONCLUSIONS: IgA index acts as a potential diagnostic indicator in differentiating NBD from NIND and CNS-IIDD. Excessive immunoglobulin production induced by CNS inflammation and demyelination might be latent immunopathogenesis of NBD.

Key phytochemicals contributing to the bitterness of quinoa.

Despite its nutritional components and potential health benefits, the bitterness of quinoa seed limits its utilization in the food industry. Saponins are believed to be the main cause of the bitterness, but it is still uncertain which specific compound is responsible. This study aimed to isolate the main components contributing to the bitterness in quinoa seed by solvent extraction and various column chromatography techniques guided by sensory evaluation. Five compounds were identified by mass spectrometry and nuclear magnetic resonance analyses, with the dose-over-threshold factors from 29.03 to 198.89. The results confirmed that triterpenoids are responsible for the bitter taste in quinoa seed, with phytolaccagenic acid derivatives being the primary contributor. Additionally, kaempferol 3-O-(2″, 6″-di-O-α-rhamnopyranosyl)-ß-galactopyranoside (namely mauritianin), was demonstrated for the first time to be associated with the bitterness of quinoa. This study could provide new insight into the bitter compound identification in quinoa.

The Essential Role of PGF2α/PTGFR in Molding Endometrial Breakdown and Vascular Dynamics, Regulated by HIF-1α in a Mouse Menstrual-like Model.

In women of childbearing age, extensive decidualization, shedding and remodeling of the endometrium during the menstrual cycle are fundamental for successful pregnancy. The role of prostaglandins (PGs) in menstruation has long been proposed in humans, and the rate-limiting enzyme cyclooxygenase was shown to play a key role in endometrial breakdown and shedding in a mouse menstrual-like model in our previous study. However, the specific types of PGs involved and their respective roles remain unclear. Therefore, our objective was to investigate the mechanism through which PGs regulate endometrial disintegration. In this study, the microscopy was observed by HE; the protein levels of prostaglandins E1 (PGE1), prostaglandins E2 (PGE2), prostaglandin F2α (PGF2α) and Prostaglandin I2 (PGI2) were detected by ELISA; the mRNA level of Pfgfr2, Vascular Endothelial Growth Factor(Vegf), Angiostatin and Hypoxia inducible factor-1α (Hif1α) were examined by real-time PCR; PTGFR Receptor (PTGFR), VEGF, Angiostatin and HIF-1α protein levels were investigated by western blotting; the locations of protein were observed by Immunohistochemistry; HIF-1α binding PTGFR promoter was detected by Chromatin Immunoprecipitation (ChIP) and real-time PCR. We found that the concentrations of PGE1, PGE2, and PGF2α all increased significantly during this process. Furthermore, Ptgfr mRNA increased soon after Progesterone (P4) withdrawal, and PTGFR protein levels increased significantly during abundant endometrial breakdown and shedding processes. PTGFR inhibitors AL8810 significantly suppressed endometrial breakdown and shedding, promoted Angiostatin expression, and reduced VEGF-A expressions and vascular permeability. And HIF-1α and PTGFR were mainly located in the luminal/gland epithelium, vascular endothelium, and pre-decidual zone. Interestingly, HIF-1α directly bound to Ptgfr promoter. Moreover, a HIF-1α inhibitor 2-methoxyestradiol (2ME) significantly reduced PTGFR expression and suppressed endometrial breakdown which was in accord with PTGFR inhibitor's effect. Similar changes occurred in human stromal cells relevant to menstruation in vitro. Our study provides evidence that PGF2α/PTGFR plays a vital role in endometrial breakdown via vascular changes that are regulated by HIF-1α during menstruation.

Integration of multiomics analyses reveals unique insights into CD24-mediated immunosuppressive tumor microenvironment of breast cancer.

BACKGROUND: Tumor immunotherapy brings new light and vitality to breast cancer patients, but low response rate and limitations of therapeutic targets become major obstacles to its clinical application. Recent studies have shown that CD24 is involved in an important process of tumor immune regulation in breast cancer and is a promising target for immunotherapy. METHODS: In this study, singleR was used to annotate each cell subpopulation after t-distributed stochastic neighbor embedding (t-SNE) methods. Pseudo-time trace analysis and cell communication were analyzed by Monocle2 package and CellChat, respectively. A prognostic model based on CD24-related genes was constructed using several machine learning methods. Multiple quantitative immunofluorescence (MQIF) was used to evaluate the spatial relationship between CD24+PANCK+cells and exhausted CD8+T cells. RESULTS: Based on the scRNA-seq analysis, 1488 CD24-related differential genes were identified, and a risk model consisting of 15 prognostic characteristic genes was constructed by combining the bulk RNA-seq data. Patients were divided into high- and low-risk groups based on the median risk score. Immune landscape analysis showed that the low-risk group showed higher infiltration of immune-promoting cells and stronger immune reactivity. The results of cell communication demonstrated a strong interaction between CD24+epithelial cells and CD8+T cells. Subsequent MQIF demonstrated a strong interaction between CD24+PANCK+ and exhausted CD8+T cells with FOXP3+ in breast cancer. Additionally, CD24+PANCK+ and CD8+FOXP3+T cells were positively associated with lower survival rates. CONCLUSION: This study highlights the importance of CD24+breast cancer cells in clinical prognosis and immunosuppressive microenvironment, which may provide a new direction for improving patient outcomes.

PFKFB3-mediated glycolysis in hepatic stellate cells promotes liver regeneration.

Hepatic stellate cells (HSCs) perform a significant function in liver regeneration (LR) by becoming active. We propose to investigate if activated HSCs enhance glycolysis via PFKFB3, an essential glycolytic regulator, and whether targeting this pathway could be beneficial for LR. The liver and isolated HSCs of mice subjected to 2/3 partial hepatectomy (PHx) exhibited a significant rise in PFKFB3 expression, as indicated by quantitative RT-PCR analyses and Western blotting. Also, the primary HSCs of mice subjected to PHx have a significant elevation of the glycolysis level. Knocking down PFKFB3 significantly diminished the enhancement of glycolysis by PDGF in human LX2 cells. The hepatocyte proliferation in mice treated with PHx was almost completely prevented when the PFKFB3 inhibitor 3PO was administered, emerging that PFKFB3 is essential in LR. Furthermore, there was a decline in mRNA expression of immediate early genes and proinflammatory cytokines. In terms of mechanism, both the p38 MAP kinase and ERK1/2 phosphorylation in LO2 cells and LO2 proliferation were significantly reduced by the conditioned medium (CM) obtained from LX2 cells with either PFKFB3 knockdown or inhibition. Compared to the control group, isolated hepatocytes from 3PO-treated mice showed decreased p38 MAP kinase and ERK1/2 phosphorylation and proliferation. Thus, LR after PHx involves the activation of PFKFB3 in HSCs, which enhances glycolysis and promotes lactate production, thereby facilitating hepatocyte proliferation via the p38/ERK MAPK signaling pathway.

Platelet-rich plasma (PRP) in nerve repair.

Platelet-rich plasma (PRP) has the capability of assisting in the recovery of damaged tissues by releasing a variety of biologically active factors to initiate a hemostatic cascade reaction and promote the synthesis of new connective tissue and revascularization. It is now widely used for tissue engineering repair. In addition, PRP has demonstrated nerve repair and pain relief, and has been studied and applied to the facial nerve, median nerve, sciatic nerve, and central nerve. These suggest that PRP injection therapy has a positive effect on nerve repair. This indicates that PRP has high clinical value and potential application in nerve repair. It is worthwhile for scientists and medical workers to further explore and study PRP to expand its application in nerve repair, and to provide a more reliable scientific basis for the opening of a new approach to nerve repair.

A colorimetric sensor based on 4-MPBA Au@AgNPs for accurately identification of EnshiYulu tea grade.

Enshi Yulu green tea (ESYL) is the most representative traditional steamed green tea in Enshi, Hubei. Different ESYL grades exhibit distinct flavors, tastes, and prices. In this study, a visual sensor based on 4-MPBA Au@AgNPs was developed for the rapid and accurate identification of ESYL grades. The recognition mechanism involved the binding of 4-MPBA Au@AgNPs with polyphenolic compounds in ESYL to form borate esters and the conversion of Ag+ to Ag0, with the generated Ag0 depositing on the surface of 4-MPBA Au@AgNPs. The results showed that the sensor can amplify the color differences of different grades of ESYL. The visual results were also validated by the partial least squares discriminant analysis model, demonstrating an enhancement in recognition accuracy from 68.2 % to 95.5 % compared to the original extraction solution. The colorimetric sensor developed in this study is expected to provide a new approach for traceability research of other foods.

A photo-responsive self-healing hydrogel loaded with immunoadjuvants and MoS2 nanosheets for combating post-resection breast cancer recurrence.

Tumor recurrence after surgical resection remains a significant challenge in breast cancer treatment. Immune checkpoint blockade therapy, as a promising alternative therapy, faces limitations in combating tumor recurrence due to the low immune response rate. In this study, we developed an implantable photo-responsive self-healing hydrogel loaded with MoS2 nanosheets and the immunoadjuvant R837 (PVA-MoS2-R837, PMR hydrogel) for in situ generation of tumor-associated antigens at the post-surgical site of the primary tumor, enabling sustained and effective activation of the immune response. This PMR hydrogel exhibited potential for near-infrared (NIR) light response, tissue adhesion, self-healing, and sustained adjuvant release. When implanted at the site after tumor resection, NIR irradiation triggered a photothermal effect, resulting in the ablation of residual cancer cells. The in situ-generated tumor-associated antigens promoted dendritic cell (DC) maturation. In a mouse model, PMR hydrogel-mediated photothermal therapy combined with immune checkpoint blockade effectively inhibited the recurrence of resected tumors, providing new insights for combating post-resection breast cancer recurrence.

Nanofiber Peptides for Bacterial Trapping: A Novel Approach to Antibiotic Alternatives in Wound Infections.

The pervasive employment of antibiotics has engendered the advent of drug-resistant bacteria, imperiling the well-being and health of both humans and animals. Infections precipitated by such multi-resistant bacteria, especially those induced by methicillin-resistant Staphylococcus aureus (MRSA), pervade hospital settings, constituting a grave menace to patient vitality. Antimicrobial peptides (AMPs) have garnered considerable attention as a potent countermeasure against multidrug resistant bacteria. In preceding research endeavors, an insect-derived antimicrobial peptide is identified that, while possessing antimicrobial attributes, manifested suboptimal efficacy against drug-resistant Gram-positive bacteria. To ameliorate this issue, this work enhances the antimicrobial capabilities of the initial ß-hairpin AMPs by substituting the structural sequence of the original AMPs with variant lengths of hydrophobic amino acid-hydrophilic amino acid repeat units. Throughout this endeavor, this work has identified a number of peptides that possess highly effective antibacterial characteristics against a wide range of bacteria. Additionally, some of these peptides have the ability to self-assemble into nanofibers, which then build networks in a distinctive manner to capture bacteria. Consequently, they represent prospective antibiotic alternatives for addressing wound infections engendered by drug-resistant bacteria.