Potential adverse events associated with sphingosine-1-phosphate (S1P) receptor modulators in patients with multiple sclerosis: an analysis of the FDA adverse event reporting system (FAERS) database.

Objective: Sphingosine-1-phosphate receptor (S1PR) modulators have recently attracted increasing attention for the treatment of multiple sclerosis (MS). Despite their preference in the clinic, multiple adverse events (AEs) continue to be reported every year. This study aimed to investigate the potential AEs as well as related important medical events (IMEs) signal associated with S1PR modulators, including fingolimod, siponimod and ozanimod in a real-world study using the FDA Adverse Event Reporting System (FAERS) database. Methods: All data were collected from the FAERS database, spanning from the fourth quarter of 2010(2010Q4) to the second quarter of 2023 (2023Q2). Potential AE and IME signals of S1PR modulators were identified based on a disproportionality analysis using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and the bayesian confidence propagation neural network of information components (IC). Results: Overall, 276,436 reports of fingolimod, 20,972 reports of siponimod and 10,742 reports of ozanimod were analyzed from the FAERS database. Among reports, females were more prone to develop AEs (73.71% for females vs. 23.21% for males), and more than 50% of patients suffered from AEs were between 18 and 64 years. Subsequently, we investigated the top 20 AEs associated with the signal strength of S1PR modulators at the preferred term (PT) level, and identified 31 (8 vs. 11 vs. 12, respectively) unlabeled risk signals such as thrombosis, uterine disorder and reproductive system and breast disorders. Furthermore, we discovered that the S1PR modulator reported variations in the possible IMEs, and that the IMEs associated with ocular events were reported frequently. It's interesting to note that infection and malignancy are prominent signals with both fingolimod and siponimod in the top 20 PTs related to mortality reports. Conclusion: The present investigation highlights the possible safety risks associated with S1PR modulators. The majority of AEs are generally consistent with previous studies and are mentioned in the prescribing instructions, however, several unexpected AE signals have also been observed. Ozanimod showed the lowest signal intensity and a better safety profile than the other S1PR modulators. Due to the short marketing time of drugs and the limitations of spontaneous reporting database, further research is required to identify potential AEs related to S1PR modulators.

Transcriptome sequencing and metabolome analysis reveal the molecular mechanism of Salvia miltiorrhiza in response to drought stress.

Salvia miltiorrhiza is commonly used as a Chinese herbal medicine to treat different cardiovascular and cerebrovascular illnesses due to its active ingredients. Environmental conditions, especially drought stress, can affect the yield and quality of S. miltiorrhiza. However, moderate drought stress could improve the quality of S. miltiorrhiza without significantly reducing the yield, and the mechanism of this initial drought resistance is still unclear. In our study, transcriptome and metabolome analyses of S. miltiorrhiza under different drought treatment groups (CK, A, B, and C groups) were conducted to reveal the basis for its drought tolerance. We discovered that the leaves of S. miltiorrhiza under different drought treatment groups had no obvious shrinkage, and the malondialdehyde (MDA) contents as well as superoxide dismutase (SOD) and peroxidase (POD) activities dramatically increased, indicating that our drought treatment methods were moderate, and the leaves of S. miltiorrhiza began to initiate drought resistance. The morphology of root tissue had no significant change under different drought treatment groups, and the contents of four tanshinones significantly enhanced. In all, 5213, 6611, and 5241 differentially expressed genes (DEGs) were shared in the A, B, and C groups compared with the CK group, respectively. The results of KEGG and co-expression analysis showed that the DEGs involved in plant-pathogen interactions, the MAPK signaling pathway, phenylpropanoid biosynthesis, flavonoid biosynthesis, and plant hormone signal transduction responded to drought stress and were strongly correlated with tanshinone biosynthesis. Furthermore, the results of metabolism analysis indicated that 67, 72, and 92 differentially accumulated metabolites (DAMs), including fumarate, ferulic acid, xanthohumol, and phytocassanes, which were primarily involved in phenylpropanoid biosynthesis, flavonoid biosynthesis, and diterpenoid biosynthesis pathways, were detected in these groups. These discoveries provide valuable information on the molecular mechanisms by which S. miltiorrhiza responds to drought stress and will facilitate the development of drought-resistant and high-quality S. miltiorrhiza production.

Genome assembly of Ottelia alismoides, a multiple-carbon utilisation aquatic plant.

OBJECTIVES: Ottelia Pers. is in the Hydrocharitaceae family. Species in the genus are aquatic, and China is their centre of origin in Asia. Ottelia alismoides (L.) Pers., which is distributed worldwide, is a distinguishing element in China, while other species of this genus are endemic to China. However, O. alismoides is also considered endangered due to habitat loss and pollution in some Asian countries. Ottelia alismoides is the only submerged macrophyte that contains three carbon dioxide-concentrating mechanisms, i.e. bicarbonate (HCO3-) use, crassulacean acid metabolism and the C4 pathway. In this study, we present its first genome assembly to help illustrate the various carbon metabolism mechanisms and to enable genetic conservation in the future. DATA DESCRIPTION: Using DNA and RNA extracted from one O. alismoides leaf, this work produced ∼ 73.4 Gb HiFi reads, ∼ 126.4 Gb whole genome sequencing short reads and ∼ 21.9 Gb RNA-seq reads. The de novo genome assembly was 6,455,939,835 bp in length, with 11,923 scaffolds/contigs and an N50 of 790,733 bp. Genome assembly completeness assessment with Benchmarking Universal Single-Copy Orthologs revealed a score of 94.4%. The repetitive sequence in the assembly was 4,875,817,144 bp (75.5%). A total of 116,176 genes were predicted. The protein sequences were functionally annotated against multiple databases, facilitating comparative genomic analysis.

Integrative multi-omics profiling in human decedents receiving pig heart xenografts.

In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.

Ultrasound-guided stellate ganglion block benefits the postoperative recovery of patients undergoing laparoscopic colorectal surgery: a single-center, double-blinded, randomized controlled clinical trial.

BACKGROUND: With the increasing prevalence of colorectal cancer (CRC), optimizing perioperative management is of paramount importance. This study investigates the potential of stellate ganglion block (SGB), known for its stress response-mediating effects, in improving postoperative recovery. We postulate that preoperative SGB may enhance the postoperative recovery of patients undergoing laparoscopic CRC surgery. METHODS: We conducted a randomized controlled trial of 57 patients undergoing laparoscopic colorectal cancer surgery at a single center. Patients, aged 18-70 years, were randomly assigned to receive either preoperative SGB or standard care. SGB group patients received 10 mL of 0.2% ropivacaine under ultrasound guidance prior to surgery. Primary outcome was time to flatus, with secondary outcomes encompassing time to defecation, lying in bed time, visual analog scale (VAS) pain score, hospital stays, patient costs, intraoperative and postoperative complications, and 3-year mortality. A per-protocol analysis was used. RESULTS: Twenty-nine patients in the SGB group and 28 patients in the control group were analyzed. The SGB group exhibited a significantly shorter time to flatus (mean [SD] hour, 20.52 [9.18] vs. 27.93 [11.69]; p = 0.012), accompanied by decreased plasma cortisol levels (mean [SD], postoperatively, 4.01 [3.42] vs 7.75 [3.13], p = 0.02). Notably, postoperative pain was effectively managed, evident by lower VAS scores at 6 h post-surgery in SGB-treated patients (mean [SD], 4.70 [0.91] vs 5.35 [1.32]; p = 0.040). Furthermore, patients in the SGB group experienced reduced hospital stay length (mean [SD], day, 6.61 [1.57] vs 8.72 [5.13], p = 0.042). CONCLUSIONS: Preoperative SGB emerges as a promising approach to enhance the postoperative recovery of patients undergoing laparoscopic CRC surgery. CLINICAL TRIAL REGISTRATION: ChiCTR1900028404, Principal investigator: Xia Feng, Date of registration: 12/20/2019.

Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation.

Glycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. Furthermore, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics.

UBE2C enhances temozolomide resistance by regulating the expression of p53 to induce aerobic glycolysis in glioma.

UBE2C is overexpressed in gliomas, and its overexpression has been reported to be correlated with the drug resistance of gliomas to some extent. In this study, we explore the role of UBE2C in regulating temozolomide (TMZ) resistance in glioma and investigate the underlying mechanisms involved. Twenty normal brain tissues and 100 glioma tissues from 50 TMZ-resistant patients and 50 TMZ-sensitive patients are included in this study. TMZ-resistant cell lines are constructed to explore the role of UBE2C in regulating glioma cell viability and TMZ resistance. Our results show that both the mRNA and protein levels of UBE2C are significantly elevated in the brain tissues of glioma patients, especially in those of TMZ-resistant patients. Consistently, UBE2C expression is markedly upregulated in TMZ-resistant cell lines. Overexpression of UBE2C rescues glioma cells from TMZ-mediated apoptosis and enhances cell viability. In contrast, downregulation of UBE2C expression further enhances TMZ function, increases cell apoptosis and decreases cell viability. Mechanistically, UBE2C overexpression decreases p53 expression and enhances aerobic glycolysis level by increasing ATP level, lactate production, and glucose uptake. Downregulation of p53 level abolishes the role of UBE2C downregulation in inhibiting TMZ resistance and aerobic glycolysis in glioma cells. Moreover, an animal assay confirms that downregulation of UBE2C expression further suppresses tumor growth in the context of TMZ treatment. Collectively, this study reveals that downregulation of UBE2C expression enhances the sensitivity of glioma cells to TMZ by regulating the expression of p53 to inhibit aerobic glycolysis.

[Spatial-temporal Evolution and Quantitative Attribution of Habitat Quality in Typical Karst Counties of Guizhou Plateau].

The purpose of this study was to reveal the spatial and temporal evolution patterns of habitat quality in karst counties of Guizhou plateau and its driving factors and to provide scientific basis for balanced ecological conservation and sustainable development of karst regions. Using DEM data, meteorological data, socio-economic data, and four periods of land use data in 1989, 2003, 2010, and 2020, the InVEST model was used to analyze the spatial and temporal evolution characteristics of habitat quality in Puding County from 1989 to 2020 and to quantitatively detect the driving forces of its spatial divergence. The results were as follows:① Arable land and forest land were the main land use types in Puding County, which constituted the surface cover landscape matrix. Land use changes from 2003-2010 were the most significant, among which forest land had the largest increase of 86.42%; arable land was the most severely lost land use type, with an area decrease of 157.57 km2, mainly flowing to forest land and construction land. ② From 1989 to 2020, the average value of habitat quality index in Puding County increased from 0.60 to 0.73. Spatially, the distribution pattern of "high-low-high" was generally from northeast to southwest, with the high value areas of habitat quality mainly distributed in the woodland and grassland areas in the northeast and the low value areas concentrated in the construction land in the central and south areas. ③ Land use type was the primary factor affecting the spatial and temporal distribution of habitat quality, with an explanation of 91.00%. In the interaction detection, the interaction of any two influencing factors was greater than that of individual factors alone, and the interaction between land use type and average annual precipitation was the strongest, reaching 96.00%; the interaction with lithological factors reached 94.00%, with natural and human factors jointly dominating the spatial and temporal changes in habitat quality. From the results of this study, we concluded that the habitat quality of Puding County was generally good from 1989 to 2020, and the relationship between land use type changes and habitat quality was close. Optimizing the land use structure and reducing the influence of human activities are important to improve the habitat quality of Puding County.

Factors influencing spontaneous hypothermia after emergency trauma and the construction of a predictive model.

This study aimed to investigate spontaneous hypothermia among emergency trauma patients and develop a predictive model. A cohort of 162 emergency trauma patients was categorized into hypothermic (n = 61) and control (n = 101) groups, with trauma severity assessed using the modified Glasgow Coma Scale (GCS). Univariate analysis revealed significant differences between the groups in trauma severity, posture, garment wetness, warming measures, pre-hospital fluid resuscitation, and modified GCS scores (P < 0.05). The hypothermic group exhibited lower prothrombin time compared to the control group (P < 0.05). A logistic regression model was constructed, expressed as Y = 25.76 - 1.030X 1 + 0.725X 2 + 0.922X 3 - 0.750X 4 - 0.57X 6, and its fit was evaluated using the Hosmer-Lemeshow test. The receiver operating characteristic curve demonstrated an area under the curve of 0.871, with 81.2% sensitivity and 79.5% specificity. The Youden index identified the optimal predictive cut-off at its highest (0.58). Validation results included 86.21% sensitivity, 82.93% specificity, and 84.29% accuracy. Risk factors for spontaneous hypothermia after emergency trauma encompassed trauma severity, posture during consultation, clothing dampness upon admission, warming measures during transfer, pre-hospital fluid resuscitation, and modified GCS scores. The risk prediction model demonstrated high accuracy, enabling effective assessment of spontaneous hypothermia risk in emergency trauma patients and facilitating preventive measures.

Pollutant removal in an experimental bioretention cell situated in a northern Chinese sponge city.

To assess the viability and effectiveness of bioretention cell in enhancing rainwater resource utilization within sponge cities, this study employs field monitoring, laboratory testing, and statistical analysis to evaluate the water purification capabilities of bioretention cell. Findings indicate a marked purification impact on surface runoff, with removal efficiencies of 59.81% for suspended solids (SS), 39.01% for chemical oxygen demand (COD), 37.53% for ammonia nitrogen (NH3-N), and 30.49% for total phosphorus (TP). The treated water largely complies with rainwater reuse guidelines and tertiary sewage discharge standards. Notably, while previous research in China has emphasized water volume control in sponge city infrastructures, less attention has been given to the qualitative aspects and field-based evaluations. This research not only fills that gap but also offers valuable insights and practical implications for bioretention cell integration into sponge city development. Moreover, the methodology and outcomes of this study serve as a benchmark for future sponge city project assessments, offering guidance to relevant authorities.

Resolving neuroinflammatory and social deficits in ASD model mice: Dexmedetomidine downregulates NF-κB/IL-6 pathway via α2AR.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals' daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.

Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening.

Hand, foot, and mouth disease (HFMD) is a common pediatric illness mainly caused by enteroviruses, which are important human pathogens. Currently, there are no available antiviral agents for the therapy of enterovirus infection. In this study, an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed. Using this screening system, we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, exhibits potential inhibitory effects against various enteroviruses that cause HFMD, such as EV-A71, CV-A10, CV-B3 and CV-A16. Further investigations revealed that FAN targets the early stage of the enterovirus life cycle. Through the selection of FAN-resistant EV-A71 viruses, we demonstrated that the VP1 protein could be a potential target of FAN, as two mutations in VP1 (E145G and V258I) resulted in viral resistance to FAN. Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.

Relationship between chorioamnionitis or funisitis and lung injury among preterm infants: meta-analysis involved 16 observational studies with 68,397 participants.

BACKGROUND: Chorioamnionitis (CA) can cause multiple organ injuries in premature neonates, particularly to the lungs. Different opinions exist regarding the impact of intrauterine inflammation on neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD). We aim to systematically review the relationship between CA or Funisitis (FV) and lung injury among preterm infants. METHODS: We electronically searched PubMed, EMbase, the Cochrane library, CNKI, and CMB for cohort studies from their inception to March 15, 2023. Two reviewers independently screened literature, gathered data, and did NOS scale of included studies. The meta-analysis was performed using RevMan 5.3. RESULTS: Sixteen observational studies including 68,397 patients were collected. Meta-analysis showed CA or FV increased the lung injury risk (OR = 1.43, 95%CI: 1.06-1.92). Except for histological chorioamnionitis (HCA) (OR = 0.72, 95%CI: 0.57-0.90), neither clinical chorioamnionitis (CCA) (OR = 1.86, 95%CI: 0.93-3.72) nor FV (OR = 1.23, 95%CI: 0.48-3.15) nor HCA with FV (OR = 1.85, 95%CI: 0.15-22.63) had statistical significance in NRDS incidence. As a result of stratification by grade of HCA, HCA (II) has a significant association with decreased incidence of NRDS (OR = 0.48, 95%CI: 0.35-0.65). In terms of BPD, there is a positive correlation between BPD and CA/FV (CA: OR = 3.18, 95%CI: 1.68-6.03; FV: OR = 6.36, 95%CI: 2.45-16.52). Among CA, HCA was positively associated with BPD (OR = 2.70, 95%CI: 2.38-3.07), whereas CCA was not associated with BPD (OR = 2.77, 95%CI: 0.68-11.21). HCA and moderate to severe BPD (OR = 25.38, 95%CI: 7.13-90.32) showed a positive correlation, while mild BPD (OR = 2.29, 95%CI: 0.99-5.31) did not. CONCLUSION: Currently, evidence suggests that CA or FV increases the lung injury incidence in premature infants. For different types of CA and FV, HCA can increase the incidence of BPD while decreasing the incidence of NRDS. And this "protective effect" only applies to infants under 32 weeks of age. Regarding lung injury severity, only moderate to severe cases of BPD were positively correlated with CA.

Low pressure reversibly driving colossal barocaloric effect in two-dimensional vdW alkylammonium halides.

Plastic crystals as barocaloric materials exhibit the large entropy change rivalling freon, however, the limited pressure-sensitivity and large hysteresis of phase transition hinder the colossal barocaloric effect accomplished reversibly at low pressure. Here we report reversible colossal barocaloric effect at low pressure in two-dimensional van-der-Waals alkylammonium halides. Via introducing long carbon chains in ammonium halide plastic crystals, two-dimensional structure forms in (CH3-(CH2)n-1)2NH2X (X: halogen element) with weak interlayer van-der-Waals force, which dictates interlayer expansion as large as 13% and consequently volume change as much as 12% during phase transition. Such anisotropic expansion provides sufficient space for carbon chains to undergo dramatic conformation disordering, which induces colossal entropy change with large pressure-sensitivity and small hysteresis. The record reversible colossal barocaloric effect with entropy change ΔSr ~ 400 J kg-1 K-1 at 0.08 GPa and adiabatic temperature change ΔTr ~ 11 K at 0.1 GPa highlights the design of novel barocaloric materials by engineering the dimensionality of plastic crystals.

Global, regional, and national burden of diet high in processed meat from 1990 to 2019: a systematic analysis from the global burden of disease study 2019.

Objective: The objective of this study is to explore the prevalence and attributable burden of diet high in processed meat (DHIPM) in global, regional, and national level due to the burden caused by unhealthy dietary pattern worldwide. Design: Cross-sectional study. Materials and design: All the data involved in this research were obtained from Global Burden of Diseases Study 2019. DisMod-MR 2.1, a Bayesian meta-regression tool, was used to estimate the prevalence, which was measured by summary exposure value (SEV) and attributable burden of DHIPM. The Spearman rank order correlation method was performed to measure the correlation between sociodemographic index (SDI) and the prevalence as well as attributable burden. The estimated annual percentage change (EAPC) was calculated to demonstrate the temporal trends. Results: Globally, there were 304.28 thousand deaths and 8556.88 disability-adjusted life years (DALYs) caused by DHIPM in 2019 and increased by 34.63 and 68.69%, respectively. The prevalence had decreased slightly from 1990 to 2019, however increased in most regions and countries, especially in middle SDI regions, despite the implicitly high prevalence in high SDI regions. Countries with higher SDI values were facing higher prevalence and attributable burden of DHIPM while developing countries were observed with severer temporal trends. Compared with women, men had suffered from lower exposure level however graver attributable burden of DHIPM in the past three decades. Conclusion: The progress of continuous urbanization allowed increasingly severe prevalence and attributable burden of DHIPM, thus the challenge to alleviate this trend was acute. Effective measures such as education on beneficial dietary pattern and supplement on healthy food were urgently required, especially in developing regions and countries.

Identification of STAT3 as a biomarker for cellular senescence in liver fibrosis: A bioinformatics and experimental validation study.

BACKGROUND: Cellular senescence is associated with a dysregulated inflammatory response, which is an important driver of the development of liver fibrosis (LF). This study aimed to investigate the effect of cellular senescence on LF and identify potential key biomarkers through bioinformatics analysis combined with validation experiments in vivo and in vitro. METHODS: The Gene Expression Omnibus (GEO) database and GeneCards database were used to download the LF dataset and the aging-related gene set, respectively. Functional enrichment analysis of differential genes was then performed using GO and KEGG. Hub genes were further screened using Cytoscape's cytoHubba. Diagnostic values for hub genes were evaluated with a receiver operating characteristic (ROC) curve. Next, CIBERSORTx was used to estimate immune cell types and ratios. Finally, in vivo and in vitro experiments validated the results of the bioinformatics analysis. Moreover, molecular docking was used to simulate drug-gene interactions. RESULTS: A total of 44 aging-related differentially expressed genes (AgDEGs) were identified, and enrichment analysis showed that these genes were mainly enriched in inflammatory and immune responses. PPI network analysis identified 6 hub AgDEGs (STAT3, TNF, MMP9, CD44, TGFB1, and TIMP1), and ROC analysis showed that they all have good diagnostic value. Immune infiltration suggested that hub AgDEGs were significantly associated with M1 macrophages or other immune cells. Notably, STAT3 was positively correlated with α-SMA, COL1A1, IL-6 and IL-1ß, and was mainly expressed in hepatocytes (HCs). Validation experiments showed that STAT3 expression was upregulated and cellular senescence was increased in LF mice. A co-culture system of HCs and hepatic stellate cells (HSCs) further revealed that inhibiting STAT3 reduced HCs senescence and suppressed HSCs activation. In addition, molecular docking revealed that STAT3 was a potential drug therapy target. CONCLUSIONS: STAT3 may be involved in HCs senescence and promote HSCs activation, which in turn leads to the development of LF. Our findings suggest that STAT3 could be a potential biomarker for LF.

An effective treatment for diabetic foot necrosis with traditional Chinese and Western medicine: a case report.

Patients with diabetes who undergo a kidney transplant are at a great risk of undergoing amputations, usually associated with severe infection and necrosis. The treatment of severe diabetic foot necrosis is challenging in clinic, and the function of the limb is often hugely compromised. A 74-year-old male who had been diagnosed with severe post-renal transplant diabetic foot necrosis refused the option of below-knee amputation from previous surgeons, and requested to keep his left foot. The patient was treated with integrated traditional Chinese medicine (TCM) and Western medicine, with positive results. TCM therapeutic principles included 'clearing heat, removing toxicity, regulating Qi, resolving dampness, activating stagnant blood and nourishing yin as well as tonifying Qi and blood'. Treatment with Western medicine included wound debridement, internal fixation or joint fusion, and use of insulin, antibiotics and vasodilators. The patient was treated with a staged and diverse approach (i.e., a combination of TCM and Western medicine, surgical management and education for diabetic foot care), which ultimately helped the patient achieve limb salvage and regain normal function. A combination therapy of Western medicine and TCM may be a promising approach to heal diabetic foot ulcers.

Adhesive polydopamine-based photothermal hybrid hydrogel for on-demand lidocaine delivery, effective anti-bacteria, and prolonged local long-lasting analgesia.

Considering the astonishing prevalence of localized pain affecting billions of patients worldwide, the development of advanced analgesic formulations or delivery systems to achieve clinical applicability is of great significance. In this study, an integrated PDA-based LiH@PDA@Ag@PAA@Gelatin system was designed for sustained delivery of lidocaine hydrochloride (LiH). By optimizing the preparation process and formulation of the hydrogel, the hydrogel exhibited superior mechanical properties, reversibility, adhesion strength, and self-healing attributes. Moreover, PDA@Ag nanoparticles were evenly dispersed within the hydrogel, and the optimized PDA@Ag@PAA@Gelatin showed a higher photothermal conversion efficiency than that of pure PDA. Importantly, LiH@PDA@Ag@PAA@Gelatin could effectively capture and eradicate bacteria through the synergistic interaction between near-infrared (NIR), PDA, Ag and LiH. In vitro and in vivo tests demonstrated that LiH@PDA@Ag@PAA@Gelatin exhibited higher drug delivery efficiency compared to commercial lidocaine patches. By evaluating the mechanical pain withdrawal threshold of the spared nerve injury (SNI) model in rats, it was proven that LiH@PDA@Ag@PAA@Gelatin enhanced and prolonged the analgesic effect of LiH. Furthermore, LiH@PDA@Ag@PAA@Gelatin induced by NIR possessed excellent on-demand photothermal analgesic ability. Therefore, this study develops a convenient method for preparing localized analgesic hydrogel patches, providing an important step towards advancing PDA-based on-demand pain relief applications.

Screening for early rheumatoid arthritis using high-frequency ultrasound, serum RANKL, and OPG detection.

OBJECTIVE: To conduct a comparative study of high-frequency ultrasound and magnetic resonance imaging (MRI) combined with serum RANKL and OPG detection, and assess the efficacy of high-frequency ultrasound with RANKL and OPG detection in screening early rheumatoid arthritis (RA). METHOD: High-frequency ultrasound and MRI were performed on both carpal joints of 60 patients with early RA, and the frequencies of synovitis, joint effusion, tenosynovitis, and bone erosion detected by high-frequency ultrasound and MRI were observed. The serum levels of receptor activator for nuclear factor-κB ligand (RANKL) and osteoclastogenesis inhibitory factor (OPG) were also detected. The serum levels of RANKL and OPG were also detected in 80 normal healthy examinees. The data were recorded and statistically analyzed. RESULTS: The detection rates of carpal synovitis, joint effusion, tenosynovitis, and bone erosion in RA patients by high-frequency ultrasound were 81.66%, 69.16%, 63.33%, and 1.66%, respectively, while the detection rates by MRI were 80.00%, 71.66%, 65.00%, and 15.00%, respectively. There was no significant difference between high-frequency ultrasound and MRI in the detection rates of carpal synovitis, joint effusion, and tenosynovitis in RA patients (P > 0.05), while the detection rate of bone erosion by high-frequency ultrasound was significantly lower than that by MRI. The serum levels of RANKL and OPG in RA patients were 231.47 and 68.71, respectively, while the serum levels of RANKL and OPG in normal healthy examinees were 123.51 and 385.05, respectively. The serum RANKL levels of RA patients were significantly higher than those of healthy examinees, while the serum OPG levels of RA patients were significantly lower than those of healthy examinees, which were statistically significant (P < 0.01). The AUC values of the ROC curves obtained by high-frequency ultrasound and MRI combined with serum RANKL and OPG detection in Synovitis modeling were 0.955 and 0.954, respectively. The AUC values of the ROC curves obtained from the joint fusion modeling using high-frequency ultrasound and MRI combined with serum RANKL and OPG detection were 0.949 and 0.950, respectively. The AUC values of the ROC curves obtained from modeling Tenosynovitis using high-frequency ultrasound and MRI combined with serum RANKL and OPG detection were 0.941 and 0.949, respectively. The AUC values of ROC curves obtained by combining high-frequency ultrasound and MRI with serum RANKL and OPG detection in Bone erosion modeling were 0.908 and 0.923, respectively. CONCLUSION: High-frequency ultrasound combined with serum RANKL and OPG detection has comparable effects to MRI on screening early RA, providing a safe, simple, and cost-effective screening method for the early detection of RA patients. Key Points • High-frequency ultrasound and MRI can effectively detect early lesions of the wrist joints in RA patients. • Ultrasound diagnosis has the advantages of being quick, inexpensive, and repeatable, making it the preferred choice of imaging examination for RA patients at an early stage.