Association between human herpesvirus 8 and lipid profile in northwest China: A cross-sectional study.

Human herpesvirus 8 (HHV-8) infection shows obvious regional and ethnic differences. Although studies have shown that these differences may be associated with lipid metabolism, to date, no large-scale studies have explored this. This study explored the seropositivity rate of HHV-8 among 2516 residents from 10 regions of northwest China and then the correlates of HHV-8 infection with lipid profile. The HHV-8 serological positivity rate was 15.6% among all residents. The HHV-8 seroprevalence ranged 11.2-27.6% among different ethnicities. Across different BMI levels, the positive rates of HHV-8 were 27.6%, 16.9%, and 13.6% for a BMI < 18.5, 18.5-24.9, and ≥25, respectively. HHV-8 seropositivity rate was lower for hypertensive people (12.6%) than for non-hypertensive people (16.7%). Univariate logistic regression analyses revealed that age, hypertension, systolic blood pressure, BMI, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) significantly correlated with HHV-8 seropositivity (p < 0.05). Multivariate logistic regression analysis after adjusting for confounding factors showed that HDL-C (odds ratio [OR]: 0.132, 95% confidence interval [CI], 0.082-0.212; p < 0.001) and BMI (OR: 0.959, 95% CI 0.933-0.986; p = 0.003) were associated with HHV-8 seropositivity. Subgroup analyses concerning ethnicity, sex, or age demonstrated a consistent relationship with HDL-C. The results of HHV-8 seropositivity and BMI were inconsistent in the subgroups. However, Spearman's correlation analysis between HHV-8 serum antibody titer and HDL-C levels showed no linear relationship among HHV-8 seropositive individuals (ρ = -0.080, p = 0.058). HHV-8 serum antibody titers were also not significantly correlated with BMI (ρ = -0.015, p = 0.381). Low HDL-C levels may be an independent risk factor for HHV-8 infection, but there is no significant correlation between HDL-C levels and HHV-8 antibody titers.

Autophagic degradation of CDK4 is responsible for G0/G1 cell cycle arrest in NVP-BEZ235-treated neuroblastoma.

BACKGROUND: CDK4 is highly expressed and associated with poor prognosis and decreased survival in advanced neuroblastoma (NB). Targeting CDK4 degradation presents a potentially promising therapeutic strategy compared to conventional CDK4 inhibitors. However, the autophagic degradation of the CDK4 protein and its anti-proliferation effect in NB cells has not been mentioned. RESULTS: We identified autophagy as a new pathway for the degradation of CDK4. Firstly, autophagic degradation of CDK4 is critical for NVP-BEZ235-induced G0/G1 arrest, as demonstrated by the overexpression of CDK4, autophagy inhibition, and blockade of autophagy-related genes. Secondly, we present the first evidence that p62 binds to CDK4 and then enters the autophagy-lysosome to degrade CDK4 in a CTSB-dependent manner in NVP-BEZ235 treated NB cells. Similar results regarding the interaction between p62 and CDK4 were observed in the NVP-BEZ235 treated NB xenograft mouse model. CONCLUSIONS: Autophagic degradation of CDK4 plays a pivotal role in G0/G1 cell cycle arrest in NB cells treated with NVP-BEZ235.

Ultra-Weak Polarization-Strain Coupling Effect Boosts Capacitive Energy Storage.

In pulse power systems, multilayer ceramic capacitors (MLCCs) encounter significant challenges due to the heightened loading electric field (E), which can lead to fatigue damage and ultrasonic concussion caused by electrostrictive strain. To address these issues, an innovative strategy focused on achieving an ultra-weak polarization-strain coupling effect is proposed, which effectively reduces strain in MLCCs. Remarkably, an ultra-low electrostrictive coefficient (Q33) of 0.012 m4 C-2 is achieved in the composition 0.55(Bi0.5Na0.5)TiO3-0.45Pb(Mg1/3Nb2/3)O3, resulting in a significantly reduced strain of 0.118% at 330 kV cm-1. At the atomic scale, the local structural heterogeneity leads to an expanded and loose lattice structure, providing ample space for large ionic displacement polarization instead of lattice stretching when subjected to the applied E. This unique behavior not only promotes energy storage performance (ESP) but also accounts for the observed ultra-low Q33 and strain. Consequently, the MLCC device exhibits an impressive energy storage density of 14.6 J cm-3 and an ultrahigh efficiency of 93% at 720 kV cm-1. Furthermore, the superior ESP of the MLCC demonstrates excellent fatigue resistance and temperature stability, making it a promising solution for practical applications. Overall, this pivotal strategy offers a cost-effective solution for state-of-the-art MLCCs with ultra-low strain-vibration in pulse power systems.

External electric field driven conformation transition between lithium salts and electride-like molecules: intriguing NLO switches in Li@corannulene.

The external electric field has emerged as a powerful tool for building molecular switches with excellent properties. In this work, we investigate the impact of an external electric field on the transition between lithium salt and electride-like molecule conformations in Li@corannulene. Remarkably, the distance between the Li atom and the corannulene bottom displays a sharp increase under the influence of an external electric field strength of F-z = 110 × 10-4 a.u. As the external electric field strength increases, the Li atom brings about different directions of charge transfer (CT). The natural population analysis (NPA) charge and the molecular electrostatic potential (ESP) results show that the intermolecular CT occurs from the Li atom to the corannulene with the F-z ranging from 0 to 100 × 10-4 a.u. Interestingly, when the external electric field reaches F-z = 110 × 10-4 a.u., the CT is oriented from the corannulene to the Li atom. Moreover, electron localization function (ELF) basins are presented under an F-z of 110 × 10-4 a.u., which indicates that Li@corannulene exhibits electride-like (e-⋯[Li@corannulene]+) molecules and lithiation salt (Li+[corannulene]-) under an F-z of 0 to 100 × 10-4 a.u. Significantly, the differences in charge transfer also contribute to a significant improvement in hyperpolarizabilities (ßtot) during the conformation transition from lithiation salt (Li+[corannulene]-) to electride-like (e-⋯[Li@corannulene]+) molecules. This study explores the potential of Li@corannulene as a promising second-order NLO material, and the external electric field provides an efficient strategy for designing and developing NLO switching devices.

Primary Intrahepatic Mesothelioma: Case Series and Systematic Review of Literature.

BACKGROUND: Primary intrahepatic mesothelioma (PIHMM) has been rarely reported. Its typical clinical presentation, radiological features and pathology have not been defined. Here, we aimed to summarize its diagnosis and treatment. METHODS: We conducted a retrospective analysis of three cases of PIHMM in the First Affiliated Hospital of Zhejiang University School of Medicine and reviewed the current literature to investigate the clinical and pathological characteristics and prognosis of PIHMM. RESULTS: Based on our case series and the literature, the mean age of PIHMM was 59.7 (41-83) years. Most patients present with nonspecific symptoms such as abdominal pain, fever, weight loss and weakness. On imaging, PIHMM usually presented as a solid, heterogeneous soft tissue mass with irregular margins and significant enhancement of the margins in the arterial phase. Immunohistochemical markers such as calretinin, cytokeratin (CK)5/6, D2-40, WT-1, mesothelin CK and vimentin may be useful for diagnosis. The 3-year relapse-free survival rate (RFS) was 51.85%, the 3-year overall survival (OS) rate was 83.33% and the 3-year postoperative overall survival rate was 100%. CONCLUSION: PIHMM can only be diagnosed by careful postoperative pathology, because of its nonspecific clinical presentations, serological indicators or imaging features. Immunohistochemical staining is very useful to distinguish this tumor from other liver tumors. Surgery is the mainstay of treatment.

Resveratrol attenuates non-steroidal anti-inflammatory drug-induced intestinal injury in rats in a high-altitude hypoxic environment by modulating the TLR4/NFκB/IκB pathway and gut microbiota composition.

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the most widely used anti-inflammatory medications, but their long-term use can cause damage to the gastrointestinal tract(GIT). One of the risk factors for GIT injury is exposure to a high-altitude hypoxic environment, which can lead to damage to the intestinal mucosal barrier. Taking NSAIDs in a high-altitude hypoxic environment can exacerbate GIT injury and impact gut microbiota. The aim of this study is to investigate the mechanisms by which resveratrol (RSV) intervention alleviates NSAID-induced intestinal injury in a high-altitude hypoxic environment, as well as its role in regulating gut microbiota. METHODS: Aspirin was administered orally to rats to construct a rat model of intestinal injury induced by NSAIDs. Following the induction of intestinal injury, rats were administered RSV by gavage, and the expression levels of TLR4, NF-κB,IκB as well as Zonula Occludens-1 (ZO-1) and Occludin proteins in the different treatment groups were assessed via Western blot. Furthermore, the expression of the inflammatory factors IL-10, IL-1ß, and TNF-α was evaluated using Elisa.16sRNA sequencing was employed to investigate alterations in the gut microbiota. RESULTS: The HCk group showed elevated expression of TLR4/NF-κB/IκB pathway proteins, increased expression of pro-inflammatory factors IL-1ß and TNF-α, decreased expression of the anti-inflammatory factor IL-10, and expression of intestinal mucosal barrier proteins ZO-1 and Occludin. The administration of NSAIDs drugs in the plateau hypoxic environment exacerbates intestinal inflammation and damage to the intestinal mucosal barrier. After treatment with RSV intervention, the expression of TLR4/NF-κB/IκB signaling pathway proteins would be reduced, thereby lowering the expression of inflammatory factors in the HAsp group. The results of HE staining directly show the damage to the intestines and the repair of intestinal mucosa after RSV intervention. 16sRNA sequencing results show significant differences (P<0.05) in Ruminococcus, Facklamia, Parasutterella, Jeotgalicoccus, Coprococcus, and Psychrobacter between the HCk group and the Ck group. Compared to the HCk group, the HAsp group shows significant differences (P<0.05) in Facklamia, Jeotgalicoccus, Roseburia, Psychrobacter, and Alloprevotella. After RSV intervention, Clostridium_sensu_stricto bacteria significantly increase compared to the HAsp group. CONCLUSION: Resveratrol can attenuate intestinal damage caused by the administration of NSAIDs at high altitude in hypoxic environments by modulating the TLR4/NF-κB/IκB signaling pathway and gut microbiota composition.

Neuronal repair after spinal cord injury by in vivo astrocyte reprogramming mediated by the overexpression of NeuroD1 and Neurogenin-2.

BACKGROUND: As a common disabling disease, irreversible neuronal death due to spinal cord injury (SCI) is the root cause of functional impairment; however, the capacity for neuronal regeneration in the developing spinal cord tissue is limited. Therefore, there is an urgent need to investigate how defective neurons can be replenished and functionally integrated by neural regeneration; the reprogramming of intrinsic cells into functional neurons may represent an ideal solution. METHODS: A mouse model of transection SCI was prepared by forceps clamping, and an adeno-associated virus (AAV) carrying the transcription factors NeuroD1 and Neurogenin-2(Ngn2) was injected in situ into the spinal cord to specifically overexpress these transcription factors in astrocytes close to the injury site. 5-bromo-2´-deoxyuridine (BrdU) was subsequently injected intraperitoneally to continuously track cell regeneration, neuroblasts and immature neurons marker expression, neuronal regeneration, and glial scar regeneration. In addition, immunoprotein blotting was used to measure the levels of transforming growth factor-ß (TGF-ß) pathway-related protein expression. We also evaluated motor function, sensory function, and the integrity of the blood-spinal cord barrier(BSCB). RESULTS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord was achieved by specific AAV vectors. This intervention led to a significant increase in cell regeneration and the proportion of cells with neuroblasts and immature neurons cell properties at the injury site(p < 0.0001). Immunofluorescence staining identified astrocytes with neuroblasts and immature neurons cell properties at the site of injury while neuronal marker-specific staining revealed an increased number of mature astrocytes at the injury site. Behavioral assessments showed that the intervention did not improve The BMS (Basso mouse scale) score (p = 0.0726) and gait (p > 0.05), although the treated mice had more sensory sensitivity and greater voluntary motor ability in open field than the non-intervention mice. We observed significant repair of the BSCB at the center of the injury site (p < 0.0001) and a significant improvement in glial scar proliferation. Electrophysiological assessments revealed a significant improvement in spinal nerve conduction (p < 0.0001) while immunostaining revealed that the levels of TGF-ß protein at the site of injury in the intervention group were lower than control group (p = 0.0034); in addition, P70 s6 and PP2A related to the TGF-ß pathway showed ascending trend (p = 0.0036, p = 0.0152 respectively). CONCLUSIONS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord after spinal cord injury can reprogram astrocytes into neurons and significantly enhance cell regeneration at the injury site. The reprogramming of astrocytes can lead to tissue repair, thus improving the reduced threshold and increasing voluntary movements. This strategy can also improve the integrity of the blood-spinal cord barrier and enhance nerve conduction function. However, the simple reprogramming of astrocytes cannot lead to significant improvements in the striding function of the lower limbs.

Macrophage-Targeted GSH-Depleting Nanocomplexes for Synergistic Chemodynamic Therapy/Gas Therapy/Immunotherapy of Intracellular Bacterial Infection.

Intracellular pathogens can survive inside the macrophages to protect themselves from eradication by the innate immune system and conventional antibiotics, resulting in severe bacterial infections. In this work, an antibiotic-free nanocomplex (HA/GA-Fe@NO-DON), exhibiting macrophage-targeted synergistic gas therapy (nitric oxide, NO)/chemodynamic therapy/immunotherapy, was reported. HA/GA-Fe nanoparticles were synthesized by the strong coordination interactions among carboxyl groups of hyaluronic acid (HA), polyphenol groups of gallic acid (GA), and Fe(II) ions. The hydrophobic glutathione (GSH)-responsive NO donor (NO-DON) was encapsulated in HA/GA-Fe nanoparticles to form the final nanocomplexes (HA/GA-Fe@NO-DON). HA on the nanocomplexes guides the macrophage-specific uptake and intracellular accumulation. After the uptake, HA/GA-Fe@NO-DON nanocomplexes could not only generate highly toxic hydroxyl radicals (•OH) by the Fenton reaction and GSH depletion but also release NO when stimulated by intracellular GSH. Meanwhile, the nanocomplexes could trigger an efficient proinflammation immune response to reinforce the antibacterial activity. This work presents the development of antibiotic-free macrophage-targeted HA/GA-Fe@NO-DON nanocomplexes as an effective adjuvant nanomedicine with synergistic gas therapy/chemodynamic therapy/immunotherapy for eliminating intracellular bacterial infection.

N-level complex helical structure modeling method.

This paper primarily explores the modeling method of n-level complex helical structures with coal mining machine cables as the research object. The paper first elaborately introduces the modeling method of n-level helix curves based on parametric equations and coordinate transformations, and compensates for the n-level helix curves with corrected pitch, which can obtain more accurate n-level helix curves and improve the accuracy of n-level helix curves modeling. Subsequently, based on this high-precision n-level helix curves modeling method, the paper elaborates on the method of solving pitch and twisting radius of multi-layer helical structure. Calculation scripts were written based on the above methods, which can be used to batch calculate the twisting radius and pitch of each layer structure in multi-layer structures when satisfying the conditions of in-layer tangency, inter-layer tangency, and extrusion deformation, and retain the actual results through logical judgment. Then, based on the above two methods, the paper developed a modeling method for braided structures based on piecewise functions containing fifth-order polynomials, which can effectively avoid the problem of insufficiently dense arrangement of braided lines and easy interference in traditional methods. Finally, a set of modeling tools was developed using C# and Python in Grasshopper to implement the modeling algorithm. Taking the MCPT-1.9/3.3 3120 + 170 + 4 * 10 coal mining machine cable as an example. The cable was modeled using both the method proposed in this paper and the traditional method. Comparative data shows that the method proposed in this paper can reduce errors by 3.31E6 times in the second-level and above helical structures. In addition this paper compares the standard line length, measured line length, and the line length established by the proposed model, showing that the relative errors are both less than 0.1941%. This paper provides a new, systematic, high-precision, and full-process cable modeling method, in which all parameters except the process parameters are accurately solved by equations. It lays a theoretical foundation for the high-precision simulation and intelligent sensing cables, which is of great significance for improving the safety, stability, and efficient development of the coal mining industry. The research results of the paper can not only be applied to the modeling of coal mining machine cables but also can be extended to the modeling of other complex multi-layer helical structures.

The clinical efficacy of combined ESA and Roxadustat treatment for renal anemia in hemodialysis patients with secondary hyperparathyroidism: A case series.

RATIONALE: Pharmacological mechanism of Roxadustat in the treatment of renal anemia. PATIENT CONCERNS: To investigate the efficacy and safety of combined Roxadustat and erythropoiesis stimulator (ESA) treatment of renal anemia in hemodialysis patients with secondary hyperparathyroidism. DIAGNOSES: A retrospective analysis was conducted on hemodialysis patients with renal anemia and secondary hyperparathyroidism treated with ESAs alone, who were admitted to our hospital from March 2022 to December 2022. INTERVENTIONS: The patients were treated with Roxadustat combined with ESAs for 3 months, during which oral iron supplementation was given, and the changes in Hb levels and laboratory-related indicators before and after the combined treatment were analyzed. OUTCOMES: The results showed that a total of 13 patients received combination therapy, with a significant increase in Hb compared to ESAs alone (t = -3.955, P = .002). The Hb qualification rate was 38.46%, and the ∆Hb response rate was 76.92%. The parathyroid hormone significantly decreased with a statistically significant difference (Z = -2.062b, P = .039). Hemoglobin (RBC), total iron binding capacity, and serum ferritin (male) were significantly increased compared to ESAs alone. Total cholesterol and low-density lipoprotein were significantly lower than ESAs alone. The differences in the changes in the above indicators were statistically significant (P < .05). There was no statistically significant difference in changes in other laboratory-related indicators (P > .05). No adverse reactions were observed during the combined treatment of 13 patients. LESSONS SUBSECTIONS: The combination of Roxadustat and ESAs can effectively improve renal anemia in hemodialysis patients with secondary hyperparathyroidism, as well as improve indicators of hyperparathyroidism and blood lipid levels with high levels of safety. This combined treatment thus provides a new and safe treatment method for these patients.

Prognostic Nutritional Index (PNI) as an Independent Predictor of 3-Year Postoperative Mortality in Elderly Patients with Hip Fracture: A Post hoc Analysis of a Prospective Cohort Study.

OBJECTIVE: The prognostic nutritional index (PNI) has been reported as a significant predictor in various diseases. However, the prognostic value of the PNI in geriatric hip fracture patients has not been thoroughly evaluated. This study aimed to investigate the association between admission PNI and 3-year mortality in those patients. METHODS: In this post hoc analysis, we included patients aged ≥65 years who underwent surgery for hip fracture between 2018 and 2019. The admission PNI was calculated as serum albumin (g/L) +5 × total lymphocyte count (×109/L). Patients were categorized into four groups based on PNI quartiles (≤ 43.55, 43.55-46.55, 46.55-49.20, and >49.20, respectively). The median follow-up duration was 3.1 years. Cox proportional hazards models were used to calculate the hazard ratio (HR). Receiver operating characteristic curve (ROC) was conducted for using PNI to predict mortality. RESULTS: Of the 942 eligible patients, 190 (20.2%) patients died during the follow-up. Compared to patients in the first quartile (Q1), those in the second (Q2), third (Q3), and fourth (Q4) quartiles had significantly lower mortality risks (HRs 0.50, 95% CI 0.35-0.74; 0.41, 95% CI 0.26-0.64; and 0.26, 95% CI 0.15-0.45, respectively). The optimal cutoff of PNI for predicting mortality was set as 45.275 (sensitivity, 0.674; specificity, 0.692; area under the curve (AUC), 0.727). Patients with higher PNI (>45.275) had a significant lower mortality risk (HR 0.39, 95% CI 0.28-0.55) compared to those with lower PNI (≤ 45.275). CONCLUSION: PNI is a reliable and independent predictor of 3-year mortality after hip fracture surgery in the elderly.

Adapting cytoskeleton-mitochondria patterning with myocyte differentiation by promyogenic PRR33.

Coordinated cytoskeleton-mitochondria organization during myogenesis is crucial for muscle development and function. Our understanding of the underlying regulatory mechanisms remains inadequate. Here, we identified a novel muscle-enriched protein, PRR33, which is upregulated during myogenesis and acts as a promyogenic factor. Depletion of Prr33 in C2C12 represses myoblast differentiation. Genetic deletion of Prr33 in mice reduces myofiber size and decreases muscle strength. The Prr33 mutant mice also exhibit impaired myogenesis and defects in muscle regeneration in response to injury. Interactome and transcriptome analyses reveal that PRR33 regulates cytoskeleton and mitochondrial function. Remarkably, PRR33 interacts with DESMIN, a key regulator of cytoskeleton-mitochondria organization in muscle cells. Abrogation of PRR33 in myocytes substantially abolishes the interaction of DESMIN filaments with mitochondria, leading to abnormal intracellular accumulation of DESMIN and mitochondrial disorganization/dysfunction in myofibers. Together, our findings demonstrate that PRR33 and DESMIN constitute an important regulatory module coordinating mitochondrial organization with muscle differentiation.

Association of baseline blood pressure and outcomes in etiology subtypes of large vessel occlusion stroke: Data from ANGEL-ACT registry.

BACKGROUND: Blood pressure (BP) management at the initial stage of stroke caused by large-vessel occlusion (LVO) remains challenging. We assessed the association between baseline BP and clinical and safety outcomes of endovascular treatment (EVT) in different stroke etiologies. METHODS: Patients with acute ischemic stroke and anterior circulation LVO were screened from a prospective, multicenter registry of EVT from November 2017 to March 2019. The primary outcome was poor 90-day outcome (modified Rankin Scale score 3-6). The safety outcome was 24 h post-procedure parenchymal hematoma (PH). The Trial of Org 101072 in Acute Stroke Treatment criteria were used for etiologic stroke classification. Restricted cubic spline and binary logistic regression analysis were performed to examine the association between study outcomes and natural log-transformed BP. RESULTS: In subgroup analyses, a U-shaped correlation existed between baseline mean arterial pressure (MAP) and poor outcome in large-artery atherosclerosis stroke only. Higher MAP was an independent risk factor compared with a central reference value (≥ 133 mm Hg vs 96-115 mm Hg; adjusted OR [aOR], 2.50; 95 % CI, 1.09 to 5.71, P = 0.030). Whereas elevated MAP was associated with PH (aOR, 1.58; 95 % CI 1.04 to 2.39, P = 0.030 for a ln10-unit increase in natural log-transformed MAP) in the range <110 mm Hg exclusively for cardioembolic stroke. CONCLUSION: Whether it is cause or epiphenomenon, baseline BP was associated with 90-day outcome in large-artery atherosclerosis stroke, whereas in cardioembolic stroke baseline BP was correlated with post-procedure PH within a certain range. Identifying these features based on etiological subtypes may offer a reference for BP management in acute LVO stroke.

Associations of oxidative stress markers with the prevalence of sarcopenia in the United States general population.

OBJECTIVE: The purpose of the present study was to examine the association of oxidative stress markers with sarcopenia in the general United States population under the age of 60. METHODS: We used the National Health and Nutrition Examination Survey data from 2011‒2014 and performed Restricted Cubic Spline (RCS) plots, weighted multivariable logistic regression analysis to calculate ratio ratios and 95% Confidence Intervals, and subgroup analysis based on age, sex, hypertension, diabetes mellitus, and body mass index stratification to determine the association of markers of oxidative stress with the prevalence of sarcopenia. RESULTS: The present analysis included a total of 8,782 participants. Firstly, the RCS plots showed a roughly L-shaped curve association of total bilirubin and serum iron with a prevalence of sarcopenia. Secondly, albumin was negatively and linearly associated with the risk of sarcopenia. Finally, with the increase in gamma-glutamyl transferase, the prevalence of sarcopenia showed a trend of first rising and then declining as a result of the iron increase. CONCLUSIONS: We demonstrated a nonlinear association between markers of oxidative stress and sarcopenia. The need to focus more on levels of oxidative stress in the body could provide better prevention strategies for sarcopenia.

Bufalin-Loaded Multifunctional Photothermal Nanoparticles Inhibit the Anaerobic Glycolysis by Targeting SRC-3/HIF-1α Pathway for Improved Mild Photothermal Therapy in CRC.

Purpose: Compared with traditional photothermal therapy (PTT, >50°C), mild PTT (≤45°C) is a promising strategy for tumor therapy with fewer adverse effects. Unfortunately, its anti-tumor efficacy is hampered by thermoresistance induced by overexpression of heat shock proteins (HSPs). In our previous study, we found bufalin (BU) is a glycolysis inhibitor that depletes HSPs, which is expected to overcome thermotolerance of tumor cells. In this study, BU-loaded multifunctional nanoparticles (NPs) were developed for enhancing the mild PTT of colorectal cancer (CRC). Methods: Fe3O4 NPs coated with the polydopamine (PDA) shell modified with polyethylene glycol (PEG) and cyclic arginine-glycyl-aspartic peptide (cRGD) for loading BU (Fe3O4@PDA-PEG-cRGD/BU NPs) were developed. The thermal variations in Fe3O4@PDA-PEG-cRGD/BU NPs solution under different conditions were measured. Glycolysis inhibition was evaluated by measuring the glucose uptake, extracellular lactate, and intracellular adenosine triphosphate (ATP) levels. The cellular cytotoxicity of Fe3O4@PDA-PEG-cRGD/BU NPs was analyzed using a cell counting kit-8 assay, Calcein-AM/PI double staining, and flow cytometry in HCT116 cells. The magnetic resonance imaging (MRI) performance and anti-tumor therapeutic efficacy of Fe3O4@PDA-PEG-cRGD/BU NPs were evaluated in HCT116-tumor bearing mice. Results: Fe3O4@PDA-PEG-cRGD/BU NPs had an average diameter of 260.4±3.5 nm, the zeta potential of -23.8±1.6 mV, the drug loading rate of 1.1%, which had good thermal stability, photothermal conversion efficiencies and MRI performance. In addition, the released BU not only killed tumor cells but also interfered with glycolysis by targeting the steroid receptor coactivator 3 (SRC-3)/HIF-1α pathway, preventing intracellular ATP synthesis, and combating HSP-dependent tumor thermoresistance, ultimately strengthening the thermal sensitivity toward mild PTT both in vitro and in vivo. Conclusion: This study provides a highly effective strategy for enhancing the therapeutic effects of mild PTT toward tumors.

Targeted-lung delivery of bardoxolone methyl using PECAM-1 antibody-conjugated nanostructure lipid carriers for the treatment of lung inflammation.

The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.

ERα Coregulator TRIM28 Promotes Breast Cancer Progression by Activating the AKT/GSK3ß Pathway.

Estrogen receptor α (ERα) promotes the growth and survival of ER-positive breast cancer (BC) cells. ER regulates ER expression target genes by directly binding to specific estrogen response elements, upon activation by estrogens. In this study, 106 proteins interacting with endogenous chromatin-bound ER in a BC cell line MCF7 were identified using the RIME method. The interactome data showed that the tripartite motif containing 28 (TRIM28) is the most significantly enriched ER-associated protein. This study provides evidence that TRIM28 expression improves ER transcriptional activity and promotes the BC cells proliferation, migration, and invasion of BC cells. The high expression of TRIM28 is associated with poor clinical outcomes in patients with ER-positive BC. Mechanistic experiments indicate that TRIM28 expression activates the AKT/GSK3ß pathway. To conclude, TRIM28 acts as a regulatory protein of ER and AKT signaling; therefore, it can be a target for the therapeutic interventions of BC.

Endoscopic polidocanol foam sclerobanding for the treatment of grade II-III internal hemorrhoids: A prospective, multi-center, randomized study.

BACKGROUND: Endoscopic rubber band ligation (ERBL) is a nonsurgical technique for the treatment of symptomatic internal hemorrhoids but is limited by recurrence and post-procedural pain. AIM: To evaluate satisfaction, long-term recurrence, and post-procedural pain in managing internal hemorrhoids using a combination of polidocanol foam sclerotherapy and ERBL. METHODS: This was a prospective, multicenter, randomized study. A total of 195 consecutive patients diagnosed with grade II-III internal hemorrhoids were enrolled from four tertiary hospitals and randomly divided into a cap-assisted endoscopic polidocanol foam sclerobanding (EFSB) or an ERBL group. All patients were followed-up for 12 months. Symptom-based severity and post-procedural pain were assessed using a hemorrhoid severity score (HSS) and a visual analog scale (VAS). Continuous variables were reported as medians and interquartile range. RESULTS: One hundred and ninety-five patients were enrolled, with 98 in the EFSB group. HSS was lower in the EFSB group than in the ERBL group at 8 weeks [4.0 (3.0-5.0) vs 5.0 (4.0-6.0), P = 0.003] and 12-month [2.0 (1.0-3.0) vs 3.0 (2.0-3.0), P < 0.001] of follow-up. The prolapse recurrence rate was lower in the EFSB group at 12 months (11.2% vs 21.6%, P = 0.038). Multiple linear regression analysis demonstrated that EFSB treatment [B = -0.915, 95% confidence interval (CI): -1.301 to -0.530, P = 0.001] and rubber band number (B = 0.843, 95%CI: 0.595-1.092, P < 0.001) were negatively and independently associated with the VAS score 24 hours post-procedure. The median VAS was lower in the EFSB group than in the ERBL [2.0 (1.0-3.0) vs 3.0 (2.0-4.0), P < 0.001]. CONCLUSION: Cap-assisted EFSB provided long-term satisfaction and effective relief from the recurrence of prolapse and pain 24 hours post-procedure.

GO/MoS2@PVA composite membrane-based optical fiber Mach-Zehnder interferometer for humidity sensing and its non-contact sensing application.

A humidity sensor based on an optical fiber Mach-Zehnder interferometer (MZI) coated with a GO/MoS2@PVA composite membrane was investigated for non-contact sensing. MoS2 was used as a nanospacer to enhance the humidity-sensitive properties of GO, and the adhesion and stability of the composite membrane on the fiber surface could be increased by PVA. The proposed sensor shows a maximum sensitivity of 0.26 dB/%RH with average response and recovery times of 1.62 and 1.11 s, respectively. In non-contact sensing applications, the sensor can effectively recognize a maximum distance of 10 mm for the proximity of a human finger with a distance variation interval of 3 mm. The proposed sensor is expected to be applied in non-contact distance detection and localization or as a non-contact human-computer interaction panel.

Circulating Cell-Free DNA Promotes Inflammation in Patients with Dermatomyositis with Anti-NXP2 Antibodies via the cGAS/STING Pathway.

OBJECTIVES: Dermatomyositis (DM) is a rare type I interferon (IFN-I)-driven autoimmune disease, and anti-nuclear matrix protein 2 (NXP2) antibody is related to severe muscle disease and poor prognosis. Circulating cell-free DNA (ccf-DNA), including ccf-mitochondrial DNA and ccf-nuclear DNA, activates cGAS/STING pathway to induce IFN-I production in autoimmune diseases. We investigated whether serum-derived ccf-DNA played a pathogenic role on skeletal muscle in anti-NXP2 antibody-positive DM. METHODS: Serum ccf-DNA levels were measured, and correlations between ccf-DNA and clinicopathological indicators were performed. RNA sequencing, immunofluorescence, western blotting and RT-qPCR were performed on skeletal muscle samples. The serum-induced expression of p-STING in C2C12 cells was assessed in vitro. RESULTS: We found that increased ccf-DNA levels were positively correlated with MYOACT scores in anti-NXP2 antibody-positive DM. RNA sequencing and immunofluorescence results revealed that the cytosolic DNA-sensing pathway was upregulated and that increased cytosolic dsDNA was colocalised with cGAS in skeletal muscle in anti-NXP2 antibody-positive DM. Western blot analysis revealed activation of the cGAS/STING pathway in patients with perifascicular atrophy (PFA) but not in patients without PFA. RT-qPCR showed increased IFN-I scores in both patients with PFA and patients without PFA. Sera from patients with PFA increased p-STING expression in C2C12 cells, and DNase I treatment and STING inhibitor efficiently inhibited p-STING expression, respectively. CONCLUSIONS: Increased ccf-DNA levels may be potential biomarkers for monitoring disease activity in anti-NXP2 antibody-positive DM. Activation of the cGAS/STING pathway is associated with PFA. Our findings identify the pathogenic role of ccf-DNA on skeletal muscle via the cGAS/STING pathway.