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Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.

Asunto(s)

Artritis Reumatoide , Desoxiglucosa , Dexametasona , Glucosa , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Animales , Glucosa/metabolismo , Dexametasona/farmacología , Dexametasona/uso terapéutico , Ratones , Desoxiglucosa/farmacología , Inflamación/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Polímeros/química , Ácido Hialurónico/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Masculino , Humanos , Proliferación Celular/efectos de los fármacos

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JOURNAL/nrgr/04.03/01300535-202501000-00031/figure1/v/2024-05-14T021156Z/r/image-tiff Early identification and treatment of stroke can greatly improve patient outcomes and quality of life. Although clinical tests such as the Cincinnati Pre-hospital Stroke Scale (CPSS) and the Face Arm Speech Test (FAST) are commonly used for stroke screening, accurate administration is dependent on specialized training. In this study, we proposed a novel multimodal deep learning approach, based on the FAST, for assessing suspected stroke patients exhibiting symptoms such as limb weakness, facial paresis, and speech disorders in acute settings. We collected a dataset comprising videos and audio recordings of emergency room patients performing designated limb movements, facial expressions, and speech tests based on the FAST. We compared the constructed deep learning model, which was designed to process multi-modal datasets, with six prior models that achieved good action classification performance, including the I3D, SlowFast, X3D, TPN, TimeSformer, and MViT. We found that the findings of our deep learning model had a higher clinical value compared with the other approaches. Moreover, the multi-modal model outperformed its single-module variants, highlighting the benefit of utilizing multiple types of patient data, such as action videos and speech audio. These results indicate that a multi-modal deep learning model combined with the FAST could greatly improve the accuracy and sensitivity of early stroke identification of stroke, thus providing a practical and powerful tool for assessing stroke patients in an emergency clinical setting.

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Nanozymes are a class of nanomaterials with enzyme-like activity that can mimic the catalytic properties of natural enzymes. The small size, high catalytic activity, and strong stability of nanozymes compared to those of natural enzymes allow them to not only exist in a wide temperature and pH range but also maintain stability in complex environments. Recently developed single-atom nanozymes have metal active sites composed of a single metal atom fixed to a carrier. These metal atoms can act as independent catalytically active centers. Metal single-atom nanozymes have a homogeneous single-atom structure and a suitable coordination environment for stronger catalytic activity and specificity than traditional nanozymes. The antioxidant metal single-atom nanozymes with the ability of removing reactive oxygen species (ROS) can simulate superoxidase dismutase, catalase, and glutathione peroxidase to show different effects in vivo. Furthermore, due to the similar structure of antioxidant enzymes, a metal single-atom nanozyme often has multiple antioxidant activities, and this synergistic effect can more efficiently remove ROS related to oxidative stress. The versatility of single-atom nanozymes encompasses a broad spectrum of biomedical applications such as anti-oxidation, anti-infection, immunomodulatory, biosensing, bioimaging, and tumor therapy applications. Herein, the nervous, circulatory, digestive, motor, immune, and sensory systems are considered in order to demonstrate the role of metal single-atom nanozymes in biomedical antioxidants.

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The present study identified the protective effects of garlic oligo/poly-saccharides of different chain lengths against dextran sulfate sodium (DSS)-induced colitis in mice and elucidated the structure-function relationships. The results showed that oral intake of garlic oligo/poly-saccharides decreased disease activity index, reduced colon shortening and spleen enlargement, and ameliorated pathological damage in the mouse colon. The dysregulation of colonic pro/anti-inflammatory cytokines was significantly alleviated, accompanied by up-regulated antioxidant enzymes, blocked TLR4-MyD88-NF-κB signaling pathway, enhanced intestinal barrier integrity, and restored SCFA production. Garlic oligo/poly-saccharides also reversed gut microbiota dysbiosis in colitic mice by expanding beneficial bacteria and suppressing the growth of harmful bacteria. High-molecular-weight polysaccharides exhibited stronger alleviating effects on DSS-induced colitic symptoms in mice than low-molecular-weight oligo/poly-saccharides did, probably due to their greater ability to be fermented in the colon. Taken together, this study demonstrated the anti-inflammatory effects of garlic oligo/poly-saccharides and revealed that high-molecular-weight polysaccharide fractions were more effective in alleviating DSS-induced colitis.

Asunto(s)

Antiinflamatorios , Colitis , Sulfato de Dextran , Fructanos , Ajo , Microbioma Gastrointestinal , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Ajo/química , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Fructanos/farmacología , Fructanos/química , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Relación Estructura-Actividad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Peso Molecular , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos

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OBJECTIVE: Observational studies have reported that major depressive disorder (MDD) is associated with sedentary behavior (SB) and multiple chronic pain (MCP), but their associations remain unclear. Mendelian randomization analysis was used to assess the association. METHODS: Single nucleotide polymorphisms (SNPs) associated with MCP, SB [time spent watching television (Tel), using a computer (Com), or driving (Dri)], and MDD were collected from genome-wide association studies and screened as instrumental variants with a threshold of 1 × 10-5. Mendelian randomization was performed to examine their associations. Sensitivity analyses were conducted to evaluate robustness. RESULTS: MCP was associated with a higher risk of MDD [odds ratio (OR) inverse variance weighting (IVW) = 1.88; 95% confidence interval (CI), 1.64-2.15; P = 4.26 × 10-8), and causally related to SB (Tel: ORIVW = 1.23; 95% CI, 1.19-1.26; P = 6.02 × 10-38) (Dri: ORIVW = 1.05; 95% CI, 1.03-1.08; P = 3.92 × 10-5). Causality of SB on MCP was detected for Tel (ORIVW = 1.46; 95% CI, 1.39-1.53; P = 1.40 × 10-54) and Com (ORIVW = 0.88; 95% CI, 0.83-0.93; P = 2.50 × 10-6). No association was observed for SB on MDD. There is currently insufficient evidence to support that leisure activities are a mediating factor in MCP-induced MDD. CONCLUSION: There are complex relationships among MCP, SB, and MDD. More research and learning about potential relationships and mechanisms among these phenotypes should be supplied.

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Accurate tumor detection is crucial for the early discovery and subsequent treatment of small neoplastic foci. Molecular imaging, which combines non-invasiveness, high specificity, and strong sensitivity, excels in diagnosing early tumors and stands out among tumor diagnosis methods. Here, we introduced a dual-modal imaging probe capable of actively targeting tumor cells, suitable for both near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI). Dendritic mesoporous silica was used as a carrier for the probe, encapsulating Ag2S quantum dots (QDs) for NIR fluorescence imaging. Additionally, the probe conjugated the MRI contrast agent Gd-DOTA and cetuximab, which targeted EGFR on the tumor cell membrane surface, to achieve dual-modal imaging in the tumor area. This strategy provided a methodology for the accurate diagnosis of early-stage tumor lesions and guides precise lesion resection during surgery, offering significant potential for clinical application.

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Although the Omicron variant has been associated with greater transmissibility and tropism of the upper respiratory tract, the clinical and pathogenic features of patients infected with the Omicron variant during an outbreak in China have been unclear. Adults with COVID-19 were retrospectively enrolled from seven medical centers in Guangzhou, China, and clinical information and specimens ( BALF, sputum, and throat swabs) from participants were collected. Conventional detection methods, metagenomics next-generation sequencing (mNGS), and other methods were used to detect pathogens in lower respiratory tract samples. From December 2022 to January 2023, we enrolled 836 patients with COVID-19, among which 56.7% patients had severe/critical illness. About 91.4% of patients were infected with the Omicron strain (BA.5.2). The detection rate of possible co-infection pathogens was 53.4% by mNGS, including Klebsiella pneumoniae (16.3%), Aspergillus fumigatus (12.2%), and Pseudomonas aeruginosa (11.8%). The co-infection rate was 19.5%, with common pathogens being Streptococcus pneumoniae (11.5%), Haemophilus influenzae (9.2%), and Adenovirus (6.9%). The superinfection rate was 75.4%, with common pathogens such as Klebsiella pneumoniae (26.1%) and Pseudomonas aeruginosa (19.4%). Klebsiella pneumoniae (27.1%% vs 6.1%, P < 0.001), Aspergillus fumigatus (19.6% vs 5.3%, P = 0.001), Acinetobacter baumannii (18.7% vs 4.4%, P = 0.001), Pseudomonas aeruginosa (16.8% vs 7.0%, P = 0.024), Staphylococcus aureus (14.0% vs 5.3%, P = 0.027), and Streptococcus pneumoniae (0.9% vs 10.5%, P = 0.002) were more common in severe cases. Co-infection and superinfection of bacteria and fungi are common in patients with severe pneumonia associated with Omicron variant infection. Sequencing methods may aid in the diagnosis and differential diagnosis of pathogens. IMPORTANCE: Our study has analyzed the clinical characteristics and pathogen spectrum of the lower respiratory tract associated with co-infection or superinfection in Guangzhou during the outbreak of the Omicron strain, particularly after the relaxation of the epidemic prevention and control strategy in China. This study will likely prompt further research into the specific issue, which will benefit clinical practice.

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Although the recombinant zoster vaccine (RZV) has demonstrated efficacy in reducing the risk of herpes zoster (HZ) for individuals aged 50 years and older, its effectiveness in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. This study was conducted to assess the effect of RZV on the risk of HZ in COPD patients. A multi-institutional propensity score-matched retrospective cohort study was conducted using the TriNetX Research network, including individuals aged 40 years or older with COPD from January 1, 2018, to December 31, 2022. Patients with a history of HZ or prior zoster vaccination were excluded. The primary outcome was HZ occurrence, with secondary outcomes including severe and nonsevere HZ. After propensity score matching, each 17 431 patients receiving RZV and unvaccinated patients were included. The vaccinated group had a significantly lower risk of HZ compared to the unvaccinated group (HR, 0.62; [95% confidence intervals] 95% CI, 0.51-0.75, p < 0.01). Similar risk reductions were observed for nonsevere HZ (HR, 0.61; 95% CI, 049-0.75, p < 0.01) and severe HZ (HR, 0.53; 95% CI, 0.38-0.73, p < 0.01). Further subgroup analyses demonstrated consistent risk reductions across age (50-59, 60-69, 70-79, and ≥80 years), sex, and comorbidities, except for individual aged 40-49 years. This study confirms the effectiveness of RZV in reducing HZ risk in patients with COPD aged 50 years and older, supporting its administration in this population. However, vaccination rates remain low, highlighting the need for improved vaccination strategies in this high-risk group. Efforts to enhance vaccine uptake are warranted to reduce HZ morbidity.

Asunto(s)

Vacuna contra el Herpes Zóster , Herpes Zóster , Puntaje de Propensión , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Masculino , Femenino , Anciano , Herpes Zóster/prevención & control , Estudios Retrospectivos , Persona de Mediana Edad , Vacuna contra el Herpes Zóster/inmunología , Vacuna contra el Herpes Zóster/administración & dosificación , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Anciano de 80 o más Años , Adulto , Vacunación

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Inhibitors of α-amylase have been developed to regulate postprandial blood glucose fluctuation. The enzyme inhibition arises from direct or indirect inhibitor-enzyme interactions, depending on inhibitor structures. However, an ignored factor, substrate, may also influence or even decide the enzyme inhibition. In this work, it is innovatively found that the difference in substrate enzymolysis modes, i.e., structural composition and concentration of α-1,4-glucosidic bonds, triggers the diversity in inhibitor-enzyme aggregating behaviors and α-amylase inhibition. For competitive inhibition, there exists an equilibrium between α-amylase-substrate catalytic affinity and inhibitor-α-amylase binding affinity; therefore, a higher enzymolysis affinity and concentration of α-1,4-glucosidic structures interferes the balance, unfavoring inhibitor-enzyme aggregate formation and thus weakening α-amylase inhibition. For uncompetitive inhibition, the presence of macromolecular starch is necessary instead of micromolecular GalG2CNP, which not only binds with active site but with an assistant flexible loop (involving Gly304-Gly309) near the site. Hence, the refined enzyme structure due to the molecular flexibility more likely favors the inhibitor binding with the non-active loop, forming an inhibitor-enzyme-starch ternary aggregate. Conclusively, this study provides a novel insight into the evaluation of α-amylase inhibition regarding the participating role of substrate in inhibitor-enzyme aggregating interactions, emphasizing the selection of appropriate substrates in the development and screening of α-amylase inhibitors.

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BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) results in significant neurological deficits, and microglia play the critical role in regulating the immune microenvironment and neurological recovery. Protein lactylation has been found to modulate the function of immune cells. Therefore, this study aimed to elucidate the effects of glycolysis-derived lactate on microglial function and its potential neuroprotective mechanisms via lactylation after SCI. METHODS: Single-cell RNA sequencing (scRNA-seq) data were obtained from figshare to analyze cellular and molecular alterations within the spinal cord post-SCI, further focusing on the expression of microglia-related genes for cell sub-clustering, trajectory analysis, and glycolysis function analysis. We also evaluated the expression of lactylation-related genes in microglia between day 7 after SCI and sham group. Additionally, we established the mice SCI model and performed the bulk RNA sequencing in a time-dependent manner. The expression of glycolysis- and lactylation-related genes was evaluated, as well as the immune infiltration analysis based on the lactylation-related genes. Then, we investigated the bio-effects of lactate on the inflammation and polarization phenotype of microglia. Finally, adult male C57BL/6 mice were subjected to exercise first to increase lactate level, before SCI surgery, aiming to evaluate the protective effects of lactate-mediated lactylation of microglia-related proteins on SCI. RESULTS: scRNA-seq identified a subcluster of microglia, recombinant chemokine C-X3-C-motif receptor 1+ (CX3CR1+) microglia, which is featured by M1-like phenotype and increased after SCI. KEGG analysis revealed the dysfunctional glycolysis in microglia after SCI surgery, and AUCell analysis suggested that the decreased glycolysis an increased oxidative phosphorylation in CX3CR1+ microglia. Differential gene analysis suggested that several lactylation-related genes (Fabp5, Lgals1, Vim, and Nefl) were downregulated in CX3CR1+ microglia at day 7 after SCI, further validated by the results from bulk RNA sequencing. Immunofluorescence staining indicated the expression of lactate dehydrogenase A (LDHA) in CX3CR1+ microglia also decreased at day 7 after SCI. Cellular experiments demonstrated that the administration of lactate could increase the lactylation level and inhibit the pro-inflammatory phenotype in microglia. Functionally, exercise-mediated lactate production resulted in improved locomotor recovery and decreased inflammatory markers in SCI mice compared to SCI alone. CONCLUSIONS: In the subacute phase of SCI, metabolic remodeling in microglia may be key therapeutic targets to promote nerve regeneration, and lactate contributed to neuroprotection after SCI by influencing microglial lactylation and inflammatory phenotype, which offered a novel approach for therapeutic intervention.

Asunto(s)

Ácido Láctico , Ratones Endogámicos C57BL , Microglía , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Ratones , Masculino , Ácido Láctico/metabolismo , Análisis de Secuencia de ARN/métodos , Fármacos Neuroprotectores/farmacología , Glucólisis/efectos de los fármacos , Glucólisis/fisiología

RESUMEN

Multiple resonance (MR) boron-nitrogen doped polycyclic aromatic hydrocarbons (BN-PAHs) showed compelling thermally activated delayed fluorescence (TADF), surpassing those of their hydrocarbon analogs. However, the structural variety of π-extended BN-PAHs remains narrow. In this study, we synthesized three double helical BN-doped nanographenes (BN-NGs), 2a-2c, via the π-extension of the MR core. During the formation of 2a, a nanographene with one heptagon (1a) was obtained, whereas subsequent dehydrocyclization of the [6]helicene units within 2b-2c led to heptagon structures, yielding other two BN-NGs containing double heptagons (1b-1c). These BN-NGs (2a-2c and 1a-1c) showed pronounced redshifts of 100-190 nm compared to the parent MR core while preserving the TADF characteristics and prolonging the delayed fluorescence lifetime to the millisecond level. Furthermore, the integration of heptagon ring into 1a-1c expanded the conjugation, reduced the oxidation potentials, and yielded a more flexible framework compared to those of 2a-2c. The enantiomers of 2a-2c, 1a, and 1c were resolved and their chiroptical properties were studied. Notably, 1a and 1c exhibited the increased chiroptical dissymmetry factors.

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BACKGROUND: This study was to investigate the application value of whole-body dynamic 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging in recurrent anastomotic tumors of digestive tract after gastric and esophageal cancer surgery. Postoperative patients with gastric and esophageal cancer have a high risk of tumor recurrence, and traditional imaging methods have certain limitations in early detection of recurrent tumors. Whole-body dynamic 18F-FDG PET/CT imaging, due to its high sensitivity and specificity, can provide comprehensive information on tumor metabolic activity, which is expected to improve the early diagnosis rate of postoperative recurrent tumors, and provide an important reference for clinical treatment decision-making. AIM: To investigate the clinical value of whole-body dynamic 18F-FDG PET/CT imaging in differentiating anastomotic recurrence and inflammation after the operation of upper digestive tract tumors. METHODS: A retrospective analysis was performed on 53 patients with upper digestive tract tumors after operation and systemic dynamic 18F-FDG PET/CT imaging indicating abnormal FDG uptake by anastomosis, including 29 cases of gastric cancer and 24 cases of esophageal cancer. According to the follow-up results of gastroscopy and other imaging examinations before and after PET/CT examination, the patients were divided into an anastomotic recurrence group and anastomotic inflammation group. Patlak multi-parameter analysis software was used to obtain the metabolic rate (MRFDG), volume of distribution maximum (DVmax) of anastomotic lesions, and MRmean and DVmean of normal liver tissue. The lesion/background ratio (LBR) was calculated by dividing the MRFDG and DVmax of the anastomotic lesion by the MRmean and DVmean of the normal liver tissue, respectively, to obtain LBR-MRFDG and LBR-DVmax. An independent sample t test was used for statistical analysis, and a receiver operating characteristic curve was used to analyze the differential diagnostic efficacy of each parameter for anastomotic recurrence and inflammation. RESULTS: The dynamic 18F-FDG PET/CT imaging parameters MRFDG, DVmax, LBR-MRFDG, and LBR-DVmax of postoperative anastomotic lesions in gastric cancer and esophageal cancer showed statistically significant differences between the recurrence group and the inflammatory group (P < 0.05). The parameter LBR-MRFDG showed good diagnostic efficacy in differentiating anastomotic inflammation from recurrent lesions. In the gastric cancer group, the area under the curve (AUC) value was 0.935 (0.778, 0.993) when the threshold was 1.83, and in the esophageal cancer group, the AUC value was 1. When 86 is the threshold, the AUC value is 0.927 (0.743, 0.993). CONCLUSION: Whole-body dynamic 18F-FDG PET/CT imaging can accurately differentiate the diagnosis of postoperative anastomotic recurrence and inflammation of gastric cancer and esophageal cancer and has the potential to be an effective monitoring method for patients with upper digestive tract tumors after surgical treatment.

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Purpose: At present, we have entered the era of using biological agents and small molecule targeted drugs to treat diseases. Although there have been many reports of biological agents treating pityriasis rubra pilaris recently, the clinical application of the JAK inhibitors in the treatment of pityriasis rubra pilaris has been rarely reported, and there is a lack of evidence on the safety and efficacy of these drugs. We explore the use of the JAK inhibitor tofacitinib in the treatment of pityriasis rubra pilaris with significant efficacy and no significant side effects, providing new ideas for the clinical treatment of pityriasis rubra pilaris. Methods: We cover a case of pityriasis rubra pilaris treated with the JAK inhibitor tofacitinib, which showed significant efficacy without any adverse effects. Results: This case report showed that the JAK inhibitor tofacitinib had significant clinical efficacy in the treatment of pityriasis rubra pilaris. We speculated that the treatment of pityriasis rubra pilaris with the JAK inhibitors may be related to blocking the activation of the JAK/STAT pathway, thereby blocking the high expression of cytokines IL-17, IL-12/IL-23, IL-23, TNF-α. Conclusion: The JAK inhibitor tofacitinib can become a new option for treating pityriasis rubra pilaris.

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Methicillin-resistant Staphylococcus aureus (MRSA) is a highly infectious pathogen that poses a serious threat to human life and health. This study aimed to provide a scientific basis for the rational clinical use of antimicrobial drugs for treating MRSA infections and inform the development of preventive and control measures by analyzing the clinical distribution and resistance characteristics of MRSA in a hospital in Hebei China. To accomplish this, bacterial identification and drug sensitivity experiments were performed with 1858 Staphylococcus aureus (S. aureus) strains collected from a hospital from January 2018 to December 2022 using a phoenixTM-100 bacterial identification drug sensitivity analyzer. The experimental data were analyzed using WHONET 5.6 software, and the MRSA strains detected were analyzed for their clinical distribution and drug resistance. Of the 1858 S. aureus strains isolated, 429 were MRSA. Sputum samples had the highest MRSA detection rates (52.45%). Critical care medicine had the highest rate of MRSA (12.59%), followed by dermatology (9.79%). MRSA resistance to tetracycline increased by 13.9% over 5 years; resistance to quinupristin/dalfopristin also increased but remained low (1.9%). Resistance decreased to gentamicin, rifampicin, ciprofloxacin, and cotrimoxazole, though most significantly to erythromycin and clindamycin, exceeding 77% and 83%, respectively. No strains were resistant to vancomycin, teicoplanin, or linezolid, and drug resistance was most prevalent in patients ≥ 60 years old. This study will aid in improving the diagnosis and treatment of MRSA infections.

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This study explored the intersection of race, gender, and sexuality as they pertain to experiences of Asian American female sexual minority (AAFSM) students attending Midwestern universities in the United States through an intersectional lens. The study utilized intersectionality as a theoretical framework, a data generation tool, and a methodological approach to guide the study. The results showed that the participants experienced constructed objectifications, which included gendered, racial, and sexual objectification. The findings also revealed that participants' race, gender, and sexual orientation were contextualized based on the situation. Further, participants devalued their Asianness, womanhood, and LGBTQness owing to the lack of positive representation in the curriculum. The analyzed data can be best categorized as the lack of intersectional representations in curricula, contextualized race, gender, and sexuality, and reported experiences of constructed objectifications. Discussions provided an inclusive campus environment for participants who were AAFSMs. These discussions also provided meaningful suggestions for educators, administrators, policymakers, and stakeholders to foster an equal and equitable educational environment for students with multiple marginalized identities.

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BACKGROUND: The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. METHODS: The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF-α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. RESULTS: The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF-α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF-α, thereby exerting chondroprotective effects. CONCLUSION: TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.

Asunto(s)

Exosomas , Células Madre Mesenquimatosas , Osteoartritis , Factor de Necrosis Tumoral alfa , Exosomas/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratones , Osteoartritis/terapia , Osteoartritis/metabolismo , Tejido Adiposo/citología , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Cartílago Articular/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células Cultivadas , Humanos

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Hepatic ischemia‒reperfusion injury is a common injury in liver surgery and liver transplantation that can lead to liver function damage, including oxidative stress, apoptosis, autophagy and inflammatory reactions. Pyroptosis is a type of inflammatory programmed cell death that has been implicated in ischemia‒reperfusion injury-associated inflammatory reactions. Although circular RNAs can regulate cell death in hepatic ischemia‒reperfusion injury, their relationship with pyroptosis remains unclear. Therefore, this study aimed to investigate the effect of circular RNA on pyroptosis in hepatic ischemia‒reperfusion injury. We constructed a mouse hepatic ischemia‒reperfusion injury model for circular RNA sequencing and obtained 40 circular RNAs with significant differential expression, of which 39 were upregulated and 1 was downregulated. Subsequently, the endogenous competitive RNA network was constructed using TarBase, miRTarBase, TargetScan, RNAhybrid, and miRanda. Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology functional analyses of downstream target genes revealed that circRNA-Phf21a_0002 might affect pyroptosis by regulating the mTOR signaling pathway and Bach1 by sponging let-7b-5p. The overexpression plasmid upregulated the expression of circRNA-Phf21a_0002 in a hypoxia/reoxygenation model, which aggravated pyroptosis in AML12 cells and apoptosis and necrosis of hepatocytes. Next, we investigated the underlying mechanism and found that circRNA-Phf21a_0002 enabled the expression of Bach1 through sponging of let-7b-5p. The aggravation of pyroptosis via overexpression of circRNA-Phf21a_0002 was reversed by let-7b-5p mimics in hypoxia/reoxygenation-subjected AML12 cells. Collectively, our study clarifies that circRNA-Phf21a_0002 aggravates the pyroptosis of hepatocytes related to ischemia-reperfusion by sponging let-7b-5p. These findings provide new molecular mechanisms and novel biomarkers for follow-up treatment.

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The present study aimed to prepare polysaccharides from the pomace of Polygonatum rhizome and characterize their structural features and biological activities. After hot water extraction and DEAE-52 cellulose fractionation, a neutral polysaccharide (PKP) was obtained with 91.85% sugars and 0.45% proteins. Structural characterization indicated that PKP contained a main fraction with a molecular weight of 4.634 × 103 Da and was composed of →1)-ß-D-Fruf-(2→ and →6)-ß-D-Fruf-(2→ residues. PKP was a semi-crystalline polymer, and the Congo red assay suggested the presence of triple-helix structure in PKP. PKP exhibited moderate radical scavenging activity (including 15.55% inhibition of DPPH, 21.48% inhibition of ABTS, and 22.52% inhibition of ·OH) and could effectively protect MRC-5 cells from H2O2-induced oxidative damage at 0.01 mg/mL through inhibiting apoptosis, decreasing SA-ß-galactosidase activity, and downregulating the expression levels of p16 and p53. Therefore, PKP could be used in functional foods and pharmaceuticals as an antioxidant. This study provides an attractive method for utilizing polysaccharides from waste materials.

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Background and objectives: Exosomes, which are small nanoscale vesicles capable of secretion, have garnered significant attention in recent years because of their therapeutic potential, particularly in the context of kidney diseases. Notably, human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) are emerging as promising targeted therapies for renal conditions. The aim of this study was to investigate the therapeutic effects of hucMSC-Exos on diabetic kidney disease (DKD) both in vivo and in vitro. Additionally, this study seeks to elucidate cellular and molecular differentials, as well as the expression of relevant signaling pathways, through single-cell RNA sequencing. This endeavor was designed to enhance our understanding of the connection between hucMSC-Exos and the pathogenesis of DKD. Methods and results: The study commenced with the extraction and characterization of hucMSC-Exos, including the determination of their concentrations. Animal experiments were conducted to evaluate the therapeutic potential of hucMSC-Exos in a DKD mouse model. Subsequently, single-cell sequencing was employed to investigate the molecular mechanisms underlying the efficacy of extracellular vesicles in ameliorating DKD. These findings were further substantiated by cell-based experiments. Importantly, the results indicate that hucMSC-Exos can impede the progression of DKD in mice, with macrophage activation playing a pivotal role in this process. Conclusions: The in vivo experiments conclusively established hucMSC-Exos as a pivotal component in preserving renal function and retarding the progression of DKD. Our utilization of single-cell sequencing technology, in conjunction with in vivo and in vitro experiments, provides compelling evidence that M2 macrophages are instrumental in enhancing the amelioration of diabetic nephropathy.

RESUMEN

Background: As constituents of the reticuloendothelial system, the spleen and bone marrow (BM) have been recognized as integral components of the systemic inflammatory response in cancer contexts, thereby serving as predictive indicators for assessing cancer prognosis. Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) has attained widespread utilization for staging, assessing treatment response, and prognostication in lymphoma patients. Several investigations have proposed that focal increased 18F-FDG uptake in the BM or spleen may correlate with malignant involvement in lymphoma. However, scant data exist regarding the implications of diffuse BM and splenic uptake. This study aimed to explore the relationships between metabolic parameters of the spleen and BM on 18F-FDG PET/CT and inflammatory markers, and to assess their prognostic value in patients with lymphoma. Methods: A retrospective analysis was conducted on 118 patients newly diagnosed with malignant lymphoma, who underwent 18F-FDG PET/CT and exhibited diffuse increased splenic or BM uptake in 18F-FDG PET/CT imaging. The mean standardized uptake value (SUV) of the spleen, BM, and liver was calculated. The association between metabolic variables and systemic inflammatory markers was investigated, and the prognostic significance of clinicopathological and PET parameters was assessed using overall survival (OS) and progression-free survival (PFS). Results: A statistically significant correlation was found between the spleen-to-liver SUV ratio (SLR) and inflammatory markers such as C-reactive protein (r=0.264, P=0.007) and platelet-to-lymphocyte ratio (r=0.227, P=0.021). No significant correlation was observed between BM-to-liver SUV ratio (BLR) and hematologic parameters, while concordance analysis revealed a fair agreement between BLR and bone marrow biopsy (BMB) (Cohen's Kappa-κ =0.271, P=0.002). In patients with aggressive non-Hodgkin lymphoma, both SLR [P=0.017, HR 2.715, 95% confidence interval (CI): 0.875-8.428] and BLR (P=0.044, HR 0.795, 95% CI: 0.348-1.813) were significantly linked to OS, while SLR (P=0.019, HR 2.223, 95% CI: 1.139-4.342) emerged as a significant prognostic factor for PFS. Conclusions: This study highlighted that diffuse increased splenic 18F-FDG uptake in lymphoma patients was closely associated with inflammation, whereas diffuse BM uptake was likely attributable to BM infiltration rather than inflammatory changes. Furthermore, both parameters held promise as prognostic indicators for patients with aggressive lymphoma.