Deciphering m6A methylation in monocyte-mediated cardiac fibrosis and monocyte-hitchhiked erythrocyte microvesicle biohybrid therapy.

Rationale: Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates the role of m6A modification enzymes METTL3 and METTL14 in these responses and explores a novel therapeutic strategy targeting these modifications to mitigate cardiac remodeling and fibrosis. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from patients with ventricular septal defects (VSD) who developed conduction blocks post-occluder implantation. The expression of METTL3 and METTL14 in PBMCs was measured. METTL3 and METTL14 deficiencies were induced to evaluate their effect on angiotensin II (Ang II)-induced myocardial inflammation and fibrosis. m6A modifications were analyzed using methylated RNA immunoprecipitation followed by quantitative PCR. NF-κB pathway activity and levels of monocyte migration and fibrogenesis markers (CXCR2 and TGF-ß1) were assessed. An erythrocyte microvesicle-based nanomedicine delivery system was developed to target activated monocytes, utilizing the METTL3 inhibitor STM2457. Cardiac function was evaluated via echocardiography. Results: Significant upregulation of METTL3 and METTL14 was observed in PBMCs from patients with VSD occluder implantation-associated persistent conduction block. Deficiencies in METTL3 and METTL14 significantly reduced Ang II-induced myocardial inflammation and fibrosis by decreasing m6A modification on MyD88 and TGF-ß1 mRNAs. This disruption reduced NF-κB pathway activation, lowered CXCR2 and TGF-ß1 levels, attenuated monocyte migration and fibrogenesis, and alleviated cardiac remodeling. The erythrocyte microvesicle-based nanomedicine delivery system effectively targeted inflamed cardiac tissue, reducing inflammation and fibrosis and improving cardiac function. Conclusion: Inhibiting METTL3 and METTL14 in monocytes disrupts the NF-κB feedback loop, decreases monocyte migration and fibrogenesis, and improves cardiac function. Targeting m6A modifications of monocytes with STM2457, delivered via erythrocyte microvesicles, reduces inflammation and fibrosis, offering a promising therapeutic strategy for cardiac remodeling associated with device implantation.

Subgroups of relational job characteristics and their differences in turnover intention and subjective well-being among nurses: a latent profile analysis.

OBJECTIVE: Relational job characteristics include perceived social worth and perceived social influence. Good relational job characteristics mean that nurses have high prosocial behavior. The purpose of this study was to explore the potential profile of nurses' relational job characteristics, influencing factors and their differences in turnover intention and subjective well-being, thus finding the most suitable clinical relationship job characteristics. METHODS: A cross-sectional survey was conducted among 1013 clinical nurses using the general demographic data questionnaire, Relational Job Characteristics scale, Turnover Intention Questionnaire and Campbell index of well-being. A latent profile analysis was performed to explore relational job characteristics latent profiles. Multinomial logistic regression analysis was conducted to examine the predictors of profile membership, and a one-way analysis of variance was applied to compare the turnover intention and subjective well-being in each latent profile. RESULTS: Five latent profiles were identified and labeled 'High prosocial job characteristics' profile (20.7%), 'Moderate prosocial job characteristics' profile (41.7%), 'High social worth-low social impact perceived' profile (6.3%), 'Low social worth-high social impact perceived' profile (18.8%) and 'Low prosocial job characteristics' profile (12.5%). Factors affecting the different types of nurse relationship job characteristics include age, marital status, hospital department, nursing years, professional title and hospital position. Among them, chief nurse, nurses with more than 20 years of nursing experience and obstetrics and gynecology nurses were more likely to be 'high prosocial job characteristics' profile. The turnover intention of nurses in 'high prosocial job characteristics' profile was significantly lower than that of other profiles, and their subjective well-being was significantly higher than that of other profiles. CONCLUSION: Improving nurses' perception of social worth and social impact on clinical work can improve nurses' prosocial behavior and subjective well-being, and reduce their turnover intention. Nursing managers or policy makers can formulate targeted intervention measures according to the influencing factors of potential profiles.

Electron stochastic acceleration in laboratory-produced kinetic turbulent plasmas.

The origin of energetic charged particles in universe remains an unresolved issue. Astronomical observations combined with simulations have provided insights into particle acceleration mechanisms, including magnetic reconnection acceleration, shock acceleration, and stochastic acceleration. Recent experiments have also confirmed that electrons can be accelerated through processes such as magnetic reconnection and collisionless shock formation. However, laboratory identifying stochastic acceleration as a feasible mechanism is still a challenge, particularly in the creation of collision-free turbulent plasmas. Here, we present experimental results demonstrating kinetic turbulence with a typical spectrum k-2.9 originating from Weibel instability. Energetic electrons exhibiting a power-law distribution are clearly observed. Simulations further reveal that thermal electrons undergo stochastic acceleration through collisions with multiple magnetic islands-like structures within the turbulent region. This study sheds light on a critical transition period during supernova explosion, where kinetic turbulences originating from Weibel instability emerge prior to collisionless shock formation. Our results suggest that electrons undergo stochastic acceleration during this transition phase.

Low-intensity pulsed ultrasound improves myocardial ischaemia‒reperfusion injury via migrasome-mediated mitocytosis.

During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis-mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low-intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI-induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome-dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F-actin pathway. Meanwhile, F-actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS-induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome-dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non-invasive treatment for MIRI.

HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice.

Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno-associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.

Hyperexcitation of the glutamatergic neurons in lateral hypothalamus induced by chronic pain contributes to depression-like behavior and learning and memory impairment in male mice.

Chronic pain can induce mood disorders and cognitive dysfunctions, such as anxiety, depression, and learning and memory impairment in humans. However, the specific neural network involved in anxiety- and depression-like behaviors and learning and memory impairment caused by chronic pain remains poorly understood. In this study, behavioral test results showed that chronic pain induced anxiety- and depression-like behaviors, and learning and memory impairment in male mice. c-Fos immunofluorescence and fiber photometry recording showed that glutamatergic neurons in the LH of mice with chronic pain were selectively activated. Next, the glutamatergic neurons of LH in normal mice were activated using optogenetic and chemogenetic methods, which recapitulates some of the depressive-like behaviors, as well as memory impairment, but not anxiety-like behavior. Finally, inhibition of glutamatergic neurons in the LH of mice with chronic pain, effectively relieved anxiety- and depression-like behaviors and learning and memory impairment. Taken together, our findings suggest that hyperexcitation of glutamatergic neurons in the LH is involved in depression-like behavior and learning and memory impairment induced by chronic pain.

Nano co-delivery of doxorubicin and plumbagin achieves synergistic chemotherapy of hepatocellular carcinoma.

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.

Integrative analyses of multi-omics data constructing tumor microenvironment and immune-related molecular prognosis model in human colorectal cancer.

The increasing prevalence and incidence of colorectal cancer (CRC), particularly in young adults, underscore the imperative to comprehend its fundamental mechanisms, discover novel diagnostic and prognostic markers, and enhance therapeutic strategies. Here, we integrated multi-omics data, including gene expression, somatic mutation data and DNA methylation data, to unravel the intricacies of tumor microenvironment (TME) in CRC and search for novel prognostic markers. By calculating the immune score for each patient from the expression profile, we delineated the differential immune cell fraction, constructed an immune-related multi-omics atlas, and identified molecular characteristics. The entire colorectal dataset (n = 343) was randomly divided into training (n = 249) and testing datasets (n = 94). We screened 144 immune-related genes, 6 mutant genes, and 38 methylation probes associated with overall survival (OS). These makers were then incorporated into a 10-gene prognostic model using Lasso and Cox regression in the training dataset, and the model's performance was evaluated in an independent validation dataset. The model exhibited satisfactory results (average concordance index [C-index] = 0.77), with the average 1-year, 3-year, and 5-year AUCs being 0.79, 0.76, and 0.76 in the training dataset and 0.74, 0.80, and 0.90 in the testing dataset. Furthermore, the prognostic model demonstrated applicability in guiding chemotherapy for CRC patients and exhibited a degree of pan-cancer utility in risk stratification. In conclusion, our integrated analysis of multi-omics data revealed immune-related genetic and epigenetic characteristics of the TME. We propose an integrative prognostic model that can stratify risk and guide chemotherapy for CRC patients. The generalizability of the model in risk stratification across different cancer types was validated in Pan-Cancer cohort.

Prevalence and risk factors of postoperative delirium in tumor patients after free flap reconstruction: A systematic review and meta-analysis of case-control studies.

BACKGROUND: Postoperative delirium is a severe complication of flap transplantation surgery, adversely affecting surgical prognoses. The intricate pathophysiology of postoperative delirium renders the elucidation of its risk factors challenging. This research aims to delineate the prevalence and the specific risk factors of postoperative delirium in patients with cancer undergoing free flap reconstruction through a systematic review and meta-analysis to enlighten proactive prevention measures. METHODS: The researchers systematically queried both the international and Chinese databases. Searches were performed for publications from inception until September 14, 2023, using the terms "free tissue flaps," "delirium," "neoplasms," and "risk factors." Data synthesis and statistical analysis were conducted using Stata SE (version 15.0) to calculate the combined effect size for identified risk factors. Reported outcomes included weighted mean differences or odds ratios with their respective 95% confidence intervals. RESULTS: Twelve case-control studies were included (ntotal = 3,256). Among them, 515 patients developed postoperative delirium after free flap surgery, compared with 2,741 patients who did not. The outcomes suggest that the risk factors include but are not limited to age, male, late neoplasm staging, use of hypnotic or antipsychotic, history of background diseases, psychiatric review, tracheotomy, and impaired wound healing. In contrast, early neoplasm staging and others are the protective factors with statistical significance. Multivariate analysis further identified significant correlations between preoperative albumin, perioperative blood transfusion, sleep disturbance, postoperative visual analog scale, postoperative albumin, smoking, and the appearance of postoperative delirium. CONCLUSION: The determined risk factors were grouped into preoperative, intraoperative, and postoperative categories substantiated by current data to present instructions for postoperative delirium prevention.

Effects of lower limb length discrepancy on spinopelvic compensation following total hip arthroplasty in patients with developmental dysplasia of the hip.

BACKGROUND: Limited research has examined the impact of lower limb length discrepancy (LLLD) alteration on spinopelvic compensation in individuals with developmental dysplasia of the hip (DDH). This study aimed to investigate the effects of LLLD on spinopelvic compensation following total hip arthroplasty (THA) and elucidate the complex biomechanical adaptations in the spinopelvic structures. METHODS: A retrospective review of DDH patients undergoing THA from January 2014 to December 2021 categorized individuals with Crowe type I and II into the low dislocation group (LDG, n = 94) and those with Crowe type III and IV into the high dislocation group (HDG, n = 43). Demographic data, as well as preoperative, postoperative, and last follow-up imaging data, including lower limb length (LLL), sacral obliquity (SO), iliac obliquity (IO), hip obliquity (HO), Cobb angle, apical vertebral translation (AVT), and coronal decompensation (CD), were collected for analysis. RESULTS: Patients in the LDG had a significantly higher surgical age and shorter disease duration (P<0.05). In LDG, patients exhibited substantial postoperative reductions in LLLD, SO, IO, and HO (P<0.05), while Cobb Angle, AVT, and CD showed no statistically significant changes (P>0.05). The variation in LLLD correlated significantly with the variations in SO, IO, and HO (P<0.05). Postoperative outcomes in the HDG demonstrated marked decreases in LLLD, SO, IO, HO, and CD (P<0.05), with no significant change in Cobb angle and AVT (P>0.05). The variation in LLLD correlated significantly with the variations in SO, IO, HO, and CD (P<0.05). CONCLUSIONS: THA effectively reduces LLLD in patients with DDH, and the variation in LLLD correlates meaningfully with the recovery of spinopelvic compensatory mechanisms.

Challenging of ECMO application in pediatric restrictive cardiomyopathy: case report of a novel TNNI3 variant.

Background: Restrictive cardiomyopathy (RCM) represents a rare cardiovascular disorder stemming from filament-associated genes. Nonetheless, treating RCM presents considerable challenges, particularly concerning device implantation and mechanical support. Furthermore, elucidating the molecular function of specific variants holds promise in benefiting patients and enhancing prognosis, given the significant heterogeneity among RCM variants. Case presentation: The proband, an eight-year-old female, was admitted to our hospital post cardiopulmonary resuscitation due to sudden cardiac arrest. Echocardiography revealed bilateral atrial enlargement. Whole-exome sequencing uncovered a novel heterozygous mutation (c.509G>A, p.R170Q) in TNNI3. Evaluation using the MutationTaster application deemed c.509G>A pathogenic (probability = 0.99). Following clinical manifestations, imaging assessments, and genetic screening, the proband received an RCM diagnosis. ECMO was recommended along with continuous renal replacement therapy. However, persistent atrial flutter ensued post-ECMO withdrawal. Attempts to restore cardiac rhythm with cardioversion, metoprolol, and amiodarone proved futile. Subsequent heart failure led to the patient's demise due to cardiac shock. Based on crystal protein structural analysis, we observed that cTnI-R170Q and R170W exerted similar impacts on protein structural stability and formation. However, both differed significantly from cTnI-R170G, primarily influencing amino acid regions 32-79 and 129-149, involved in TnC and actin binding. Therefore, cTnI-R170Q was revealed to induce RCM via the same molecular mechanism as cTnI-R170W. Conclusion: Managing RCM remains a critical challenge. This study underscores the discouragement of device implantations for cardiac pump functional support in RCM, particularly for non-short-term scheduled HTx. Additionally, considering catheter ablation for atrial fibrosis-induced AFs is recommended. Mechanistically, cTnI-R170Q primarily diminishes troponin-actin interactions and destabilizes thin filaments.

Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine ß-Synthase Mediated IL-6/STAT3 Inactivation.

Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine ß-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using ß-cell lines (MIN6, ß-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of ß-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.

Wutou decoction alleviates arthritis inflammation in CIA mice by regulating Treg cell stability and Treg/Th17 balance via the JAK2/STAT3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Wutou Decoction (WTD) is a classic traditional Chinese medicine formula, which has shown clinical efficacy in treating rheumatoid arthritis (RA). The Treg stability and Th17/Treg imbalance is an important immunological mechanism in RA progression. Whether WTD regulates CD4+ T cell subsets has not been thoroughly investigated yet. AIM OF THE STUDY: This study aimed to explore the potential role and mechanisms of WTD in regulating the diminished stability of Treg cells and the imbalance of CD4+ T cell subsets via in vivo and in vitro experiments. MATERIALS AND METHODS: Firstly, the therapeutic effects of WTD on the collagen-induced arthritis (CIA) mouse and its potential regulatory function on CD4+ T cell subsets were evaluated in vivo. Animal specimens were collected after 31 days of treatment with WTD. The anti-arthritic and anti-inflammatory effects of WTD were assessed through arthritis scoring, body weight, spleen index, serum IL-6 levels, and micro-PET/CT imaging. Gene enrichment analysis was performed to evaluate the activation T cell-related signaling pathway. Flow cytometry was used to determine the proportions of CD4+ T cell subsets in vitro and in vitro. Additionally, ELISA was used to assess the secretion of IL-10 and TGF-ß by Treg cells under inflammatory conditions. The suppressive function of Treg cells on cell proliferation under inflammatory conditions was examined using CFSE labeling. Immunofluorescence staining was performed to detect the phosphorylation levels of STAT3 in CD4+ T cells from mouse spleen tissues. Western blotting was used to evaluate the phosphorylation levels of JAK2/STAT3 in Treg cells. RESULTS: WTD significantly alleviated joint inflammation in CIA mice. WTD reduced serum IL-6 levels in CIA mice, improved their body weight and spleen index. WTD treatment inhibited the activation of CD4+ T cell subgroup-related signaling in the joint tissues of CIA mice. In vitro and in vitro experiments showed that WTD increased the proportion of Treg cells and decreased the proportion of Th17 cells in CIA mice spleen. Furthermore, WTD promoted the secretion of IL-10 and TGF-ß by Treg cells and enhanced the inhibitory capacity of Treg cells on cell proliferation under inflammatory conditions. Immunofluorescence detected decreased STAT3 phosphorylation levels in CD4+ T cells from CIA mice spleen, while western blotting revealed a decrease in JAK2/STAT3 phosphorylation levels in Treg cells in vitro. CONCLUSIONS: Inhibiting JAK2/STAT3 phosphorylation is a potential mechanism through which WTD improves Treg cell stability, balances CD4+ T cell subsets, and attenuates RA joint inflammation.

Natural MOF-Like Photocatalytic Nanozymes Alleviate Tumor Pressure for Enhanced Nanodrug Penetration.

In oncological nanomedicine, overcoming the dual-phase high interstitial pressure in the tumor microenvironment is pivotal for enhancing the penetration and efficacy of nanotherapeutics. The elevated tumor interstitial solid pressure (TISP) is largely attributed to the overaccumulation of collagen in the extracellular matrix, while the increased tumor interstitial fluid pressure (TIFP) stems from the accumulation of fluid due to the aberrant vascular architecture. In this context, metal-organic frameworks (MOFs) with catalytic efficiency have shown potential in degrading tumor interstitial components, thereby reducing interstitial pressure. However, the potential biotoxicity of the organic components of MOFs limits their clinical translation. To circumvent this, a MOF-like photocatalytic nanozyme, RPC@M, using naturally derived cobalt phytate (CoPA) and resveratrol (Res) is developed. This nanozyme not only facilitates the decomposition of water in the tumor interstitium under photoactivation to reduce TIFP, but also generates an abundance of reactive oxygen species through its peroxidase-like activity to exert cytotoxic effects on tumor cells. Moreover, Res contributes to the reduction of collagen deposition, thereby lowering TISP. The concurrent diminution of both TISP and TIFP by RPC@M leads to enhanced tumor penetration and potent antitumor activity, presenting an innovative approach in constructing tumor therapeutic nanozymes from natural products.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

Low-intensity pulsed ultrasound protects from inflammatory dilated cardiomyopathy through inciting extracellular vesicles.

AIMS: CD4+ T cells are activated during inflammatory dilated cardiomyopathy (iDCM) development to induce immunogenic responses that damage the myocardium. Low-intensity pulsed ultrasound (LIPUS), a novel physiotherapy for cardiovascular diseases, has recently been shown to modulate inflammatory responses. However, its efficacy in iDCM remains unknown. Here, we investigated whether LIPUS could improve the severity of iDCM by orchestrating immune responses and explored its therapeutic mechanisms. METHODS AND RESULTS: In iDCM mice, LIPUS treatment reduced cardiac remodelling and dysfunction. Additionally, CD4+ T cell inflammatory responses were suppressed. LIPUS increased Treg cells while decreasing Th17 cells. LIPUS mechanically stimulates endothelial cells, resulting in increased secretion of extracellular vesicles (EVs), which are taken up by CD4+ T cells and alter their differentiation and metabolic patterns. Moreover, EVs selectively loaded with microRNA (miR)-99a are responsible for the therapeutic effects of LIPUS. The hnRNPA2B1 translocation from the nucleus to the cytoplasm and binding to caveolin-1 and miR-99a confirmed the upstream mechanism of miR-99a transport. This complex is loaded into EVs and taken up by CD4+ T cells, which further suppress mTOR and TRIB2 expression to modulate cellular differentiation. CONCLUSION: Our findings revealed that LIPUS uses an EV-dependent molecular mechanism to protect against iDCM progression. Therefore, LIPUS is a promising new treatment option for iDCM.

Multi-cohort validation: A comprehensive exploration of prognostic marker in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common form of RCC. It is characterized by resistance to traditional radiotherapy and chemotherapy, as well as an unfavorable clinical prognosis. Although TYMP is implicated in the advancement of tumor progression, the role of TYMP in ccRCC is still not understood. Heightened TYMP expression was identified in ccRCC through database mining and confirmed in RCC cell lines. Indeed, TYMP knockdown impacted RCC cell proliferation, migration, and invasion in vitro. TYMP showed a positive correlation with clinicopathological parameters (histological grade, pathological stage). Moreover, patients with high TYMP expression were indicative of poor prognosis in TCGA-ccRCC and external cohorts. The results of single-cell analysis showed that the distribution of TYMP was predominantly observed in monocytes and macrophages. Furthermore, there is a significant association between TYMP and immune status. Methylation analysis further elucidated the relationship between TYMP expression and multiple methylation sites. Drug sensitivity analysis unveiled potential pharmaceutical options. Additionally, mutation analyses identified an association between TYMP and the ccRCC driver genes like BAP1 and ROS1. In summary, TYMP may serve as a reliable prognostic indicator for ccRCC.

Plasma Concentration of Posaconazole in Septic Shock Patients with Continuous Renal Replacement Therapy: A Case Report.

Objective: This study aims to evaluate the impact of continuous renal replacement therapy (CRRT) on the plasma concentrations of Posaconazole in critically ill patients. Case presentation: In this study, we reported a patient with septic shock, cardiac arrest, and Multiple Organ Dysfunction Syndrome showed improvement following anti-infective treatment with Posaconazole. The patient's condition improved after Posaconazole was administered for anti-infective treatment. The concentration of Posaconazole was measured during CRRT. The results showed that the trough concentrations of Posaconazole were 1.9mg/L and 0.8mg/L on the 7th and 11th days of CRRT, respectively. The peak concentrations of Posaconazole were 6.6 mg/L and 4.3 mg/L on the 7th and 11th days of CRRT. On the first and second day after the discontinuation of CRRT, the trough concentrations of Posaconazole were 0.7 mg/L and 0.8 mg/L, and the peak concentrations were 2.6 mg/L and 2.2 mg/L. These results indicated that the trough and peak concentrations of Posaconazole were not significantly different before and after CRRT. No adverse reactions occurred during the follow-up. Conclusion: Posaconazole plasma concentrations remained stable during and after CRRT, suggesting that dose adjustments are not necessary in these clinical settings.

Long non-coding RNA PXN-AS1 promotes glutamine synthetase-mediated chronic myeloid leukemia BCR::ABL1-independent resistance to Imatinib via cell cycle signaling pathway.

BACKGROUND: Chronic myeloid leukemia (CML) is a common hematological malignancy, and tyrosine kinase inhibitors (TKIs) represent the primary therapeutic approach for CML. Activation of metabolism signaling pathway has been connected with BCR::ABL1-independent TKIs resistance in CML cells. However, the specific mechanism by which metabolism signaling mediates this drug resistance remains unclear. Here, we identified one relationship between glutamine synthetase (GS) and BCR::ABL1-independent Imatinib resistance in CML cells. METHODS: GS and PXN-AS1 in bone marrow samples of CML patients with Imatinib resistance (IR) were screened and detected by whole transcriptome sequencing. GS expression was upregulated using LVs and blocked using shRNAs respectively, then GS expression, Gln content, and cell cycle progression were respectively tested. The CML IR mice model were established by tail vein injection, prognosis of CML IR mice model were evaluated by Kaplan-Meier analysis, the ratio of spleen/body weight, HE staining, and IHC. PXN-AS1 level was blocked using shRNAs, and the effects of PXN-AS1 on CML IR cells in vitro and in vivo were tested the same as GS. Several RNA-RNA tools were used to predict the potential target microRNAs binding to both GS and PXN-AS1. RNA mimics and RNA inhibitors were used to explore the mechanism through which PXN-AS1 regulates miR-635 or miR-635 regulates GS. RESULTS: GS was highly expressed in the bone marrow samples of CML patients with Imatinib resistance. In addition, the lncRNA PXN-AS1 was found to mediate GS expression and disorder cell cycle in CML IR cells via mTOR signaling pathway. PXN-AS1 regulated GS expression by binding to miR-635. Additionally, knockdown of PXN-AS1 attenuated BCR::ABL1-independent Imatinib resistance in CML cells via PXN-AS1/miR-635/GS/Gln/mTOR signaling pathway. CONCLUSIONS: Thus, PXN-AS1 promotes GS-mediated BCR::ABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway.

Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis.

Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), a process associated with ferroptosis. Ginsenoside Rb1 (GRb1), a major active component extracted from Panax ginseng, inhibits HSC activation. However, the potential role of GRb1 in mediating HSC ferroptosis remains unclear. This study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro, using CCl4-induced liver fibrosis mouse model and primary HSCs, LX-2 cells. The findings revealed that GRb1 effectively inactivated HSCs in vitro, reducing alpha-smooth muscle actin (α-SMA) and Type I collagen (Col1A1) levels. Moreover, GRb1 significantly alleviated CCl4-induced liver fibrosis in vivo. From a mechanistic standpoint, the ferroptosis pathway appeared to be central to the antifibrotic effects of GRb1. Specifically, GRb1 promoted HSC ferroptosis both in vivo and in vitro, characterized by increased glutathione depletion, malondialdehyde production, iron overload, and accumulation of reactive oxygen species (ROS). Intriguingly, GRb1 increased Beclin 1 (BECN1) levels and decreased the System Xc-key subunit SLC7A11. Further experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by GRb1. Moreover, BECN1 could directly interact with SLC7A11, initiating HSC ferroptosis. In conclusion, the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in vitro. Overall, this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation, at least partly through its modulation of BECN1 and SLC7A11.