Wenshen Xiaozheng Tang alleviates fibrosis in endometriosis by regulating differentiation and paracrine signaling of endometrium-derived mesenchymal stem cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation. AIMS OF THE STUDY: The aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs. MATERIALS AND METHODS: The nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator. RESULTS: WXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis. CONCLUSION: WXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis.

SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1.

Selective serotonin reuptake inhibitors (SSRIs) have shown promise in cancer therapy, particularly for hepatocellular carcinoma (HCC), but their molecular targets and mechanisms remain unclear. Here, we show that SSRIs exhibit significant anti-HCC effects independent of their classical target, the serotonin reuptake transporter (SERT). Using global inverse gene expression profiling, drug affinity responsive target stability assays, and in silico molecular docking, we demonstrate that citalopram targets glucose transporter 1 (GLUT1), resulting in reduced glycolytic flux. A mutant GLUT1 variant at the citalopram binding site (E380) diminishes the drug's inhibitory effects on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth of GLUT1high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis reveals that SSRI use correlates with a lower risk of metastasis among patients with HCC. Our study describes a role for SSRIs in cancer metabolism, establishing a rationale for their repurposing as potential anti-cancer drugs for HCC.

Removal of acetyl-rich impurities from chitosan using liquefied dimethyl ether.

Chitosan, recognized for its excellent biodegradability, biocompatibility, and antibacterial properties, has several potential applications, particularly in the biomedical field. However, its widespread use is hindered by inherent limitations such as low mechanical strength and safety concerns arising from a low degree of deacetylation and the presence of impurities. This study aimed to introduce an innovative purification method for chitosan via liquefied dimethyl ether (DME) extraction. The proposed technique effectively addresses the challenges associated with chitosan by facilitating deacetylation and impurity removal. Liquefied DME is emerging as the extraction solvent of choice owing to its advantages, such as low boiling point, safety, and environmental sustainability. The degree of deacetylation of chitosan was extensively evaluated using thermogravimetric-differential thermal analysis, Fourier transform infrared spectroscopy, X-ray diffraction, intrinsic viscosity measurements, solid-state nuclear magnetic resonance spectroscopy and X-ray photoelectron spectroscopy, and elemental analysis. The solubility of chitosan in liquefied DME was investigated using Hansen solubility parameters. This study contributes to the improvement of the safety profile of chitosan, thereby expanding its potential applications in various fields. The use of liquefied DME as an extraction solvent proved to be efficient in addressing the existing challenges and is consistent with the principles of safety and environmental sustainability.

Inactivated vaccine dosage and serum IgG levels correlate with persistent COVID-19 infections in hematologic malignancy patients during the Omicron Surge in China.

PURPOSE: The essence of this scholarly work was to carefully outline the key factors intensifying the virulence and protracted contagion of COVID-19, particularly among individuals afflicted with hematologic malignancies (HM), in an epoch predominantly governed by the Omicron variant. METHODS: Adults with HM diagnosed with COVID-19 from November 2022 to February 2023 were monitored in this retrospective study. Patient blood samples yielded biochemical data, and COVID-19 was confirmed through RNA or antigen testing. The factors affecting severity and infection duration were examined using both univariate and multivariate logistic regression analyses. For calculating the overall survival probabilities, the Kaplan-Meier product limit approach was employed. RESULTS: In the examined cohort, 133 individuals diagnosed with HM and concomitantly infected with COVID-19 were scrutinized. Of the participants, 29.3% (39 patients) were classified as Severe/Critical, while the other 70.7% (94 patients) were categorized as Non-severe. A significant difference was observed in vaccination status: 61.7% of patients in the Non-severe group had received at least a two-dose vaccine regimen, whereas 61.5% of the Severe/Critical group had either minimal or only one dose of vaccination. The data analysis revealed that elevated C-reactive protein levels (≥ 100 mg/L) significantly raised the risk of severe/critical conditions in HM patients with COVID-19, as determined by advanced multivariate logistic regression. The odds ratio was 3.415 with a 95% confidence interval of 1.294-9.012 (p = 0.013). Patients who continued to have positive nucleic acid tests and ongoing symptoms beyond 30 days were categorized as having a persistent infection, whereas those who achieved infection control within this timeframe were categorized as having infection recovery. Of the HM cohort, 11 did not survive beyond 30 days after diagnosis. The results from a competing risk model revealed that increased interleukin-6 levels (HR: 2.626, 95% CI: 1.361-5.075; p = 0.004) was significantly associated with persistent infection. Conversely, receiving more than two vaccine doses (HR: 0.366, 95% CI: 0.158-0.846; p = 0.019), and having high IgG levels (≥ 1000 mg/dl) (HR: 0.364, 95% CI: 0.167-0.791; p = 0.011), were associated with infection recovery. There was a notable disparity in survival rates between patients with persistent infections and infection recovery, with those in the non-persistent group demonstrating superior survival outcomes (P < 0.001). CONCLUSIONS: In conclusion, the study determined that HM patients with COVID-19 and increased C-reactive protein levels had a higher likelihood of severe health outcomes. Persistent infection tended to be more prevalent in those with vaccine dosages (< 2 doses), lower IgG levels, and higher interleukin-6 levels.

Dynamic polysaccharide/platelet-rich plasma hydrogels with synergistic antibacterial activities for accelerating infected wound healing.

Platelet-rich plasma (PRP) has been recognized as an effective therapy in regenerative medicine and surgery, which can reduce the risk of antibiotic abuse and promote the healing of infected wounds. Recent advances in PRP-based treatments have focused on the controlled release of growth factors in PRP with biocompatible hydrogels and antimicrobial promotion by introducing hydrogel components or antibiotics, while the inherent antimicrobial activity of PRP is mostly neglected or sacrificed. Here, we demonstrate the combination of an antimicrobial polysaccharide, carboxymethyl chitosan, and PRP to construct an antimicrobial hydrogel via dynamic bonding with oxidized chondroitin sulfate. Significant inhibitory effects against Staphylococcus aureus and Escherichia coli (95 % of inhibition rate) are achieved through the synergistic contributions of the polysaccharide and PRP. Additionally, the resulting hydrogel promotes the migration of NIH-3T3 fibroblasts and collagen deposition by approximately 1.7 and 1.8 times, respectively, thereby accelerating the healing process of infected wounds. This work may bring new perspectives for potent applications of PRP-based hydrogel dressings for antibiotic-free management of infected wounds.

Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS).

OBJECTIVE: FAS gene defects lead to autoimmune lymphoproliferative syndrome (ALPS), which is often inherited in an autosomal dominant and rarely in an autosomal recessive manner. We report a case of a newborn girl with novel compound heterozygous variants in FAS and reveal the underlying mechanism. METHODS: Whole-exome sequencing (WES) was used to identify pathogenic variants. Multiparametric flow cytometry analysis, phosflow analysis, and FAS-induced apoptosis assays were used to explore the effects of the variants on FAS expression, apoptosis, and immunophenotype. The HEK293T cells were used to assess the impact of the variants on protein expression and FAS-induced apoptosis. RESULTS: The patient was born with hepatosplenomegaly, anemia, and thrombocytopenia. She also experienced COVID-19, rotavirus infection, herpes simplex virus infection, and severe pneumonia. The proportion of double-negative T cells (DNTs) was significantly elevated. Novel FAS compound heterozygous variants c.310T > A (p.C104S) and c.702_704del (p.T235del) were identified. The apoptotic ability of T cells was defective, and FAS expression on the surface of T cells was deficient. The T235del variant decreased FAS expression, and the C104S protein remained in the endoplasmic reticulum (ER) and could not translocate to the cell surface. Both mutations resulted in loss-of-function in terms of FAS-induced apoptosis in HEK293T cells. The DNTs were mainly terminally differentiated T (TEMRA) and CD45RA+HLA-DR+, with high expression of CD85j, PD-1, and CD57. The percentage of Th1, Tfh, and autoreactive B cells were significantly increased in the patient. The abnormal immunophenotyping was partially attenuated by sirolimus treatment. CONCLUSIONS: We identified two variants that significantly affect FAS expression or localization, leading to early disease onset of in the fetus. Abnormalities in the mTOR pathway are associated with a favorable response to sirolimus.

CARD9 promotes cholangiocarcinoma by regulating the IL-17A/Hedgehog and the THEM4/AKT/mTOR signaling pathways.

Cholangiocarcinoma (CCA) is a highly lethal malignant tumor originating from the bile duct, and its underlying mechanisms are not fully understood. In order to identify key genes in CCA, we downloaded gene expression data from public GSE76297, GSE26566 and TCGA-CHOL datasets. CARD9 was selected as a CCA-related gene from the datasets. Its expression was identified in the CCA tissues via PCR, western blot and immunohistochemistry assays. The loss-and-gain function assay of CARD9 was conducted in CCA cell lines (QBC939 and RBE) and nude mice. This study found a significant upregulation of CARD9 in CCA tissues, which is associated with poor prognosis in patients. Overexpression of CARD9 promotes proliferation and invasion of QBC939 and RBE cells, enhances the growth and development in CCA mouse models, and reduces sensitivity to chemotherapy drugs for CCA. Mechanistically, CARD9 activates the NF-κB and NLRP3 inflammatory signaling pathways, induces excessive release of various inflammatory factors, and triggers a cascade reaction of interleukin-17 (IL-17A). IL-17A promotes the stability of IHH mRNA by regulating HuR, enhances IHH transcription, and activates the Hedgehog signaling pathway to accelerate the progression of CCA. In addition, CARD9 promotes proliferation and invasion of CCA cells by interacting with THEM4, thereby facilitating AKT and mTOR phosphorylation, and accelerating the progression of CCA. Overall, these data suggest that CARD9 is involved in the progression of CCA by regulating the IL-17A/Hedgehog and the THEM4/AKT/mTOR signaling pathways. Therefore, CARD9 may serve as a novel therapeutic target for CCA treatment.

Construction of Solution Processable NUS-8/PANI Nanosheets via Template-Directed Polymerization for Ultratrace Gas Sensing.

The advancement of wireless gas sensing signifies a substantial leap forward in gas detection and intelligent monitoring technologies. This necessitates stringent design criteria for gas sensitive materials with good solution processability, conductivity, and porosity, whose design and synthesis remain challenging yet highly sought-after. Herein, the fabrication of NUS-8/polyaniline (PANI) nanosheets is presented with excellent solution processability, high porosity, triboelectric property, and superior electrical conductivity via a template-directed polymerization strategy. Solution processable NUS-8 nanosheets, synthesized directly by a "one-pot" approach, serve as templates to enhance the "on-site" polymerization of aniline, resulting in the formation of PANI layer on NUS-8 nanosheets with a thickness of 7 nm. The resultant NUS-8/PANI nanosheets exhibit outstanding solution processability, and a film conductivity of 8.6 S m-1. The solution processability enables the facile fabrication of homogeneous and compact NUS-8/PANI films and thus their integration onto electronic devices targeted for multifunctional sensing. The NUS-8/PANI coated sensors demonstrate sensitive and selective detection at room temperature toward ultratrace ammonia with a detection limit of 120 ppb. A wireless sensing system based on the NUS-8/PANI-coated sensor is capable to monitor the spoilage process of meat. This study paves novel avenues for designing and synthesizing gas-sensitive materials for practical applications.

Lanthanum chloride exerts therapeutic potential for chronic kidney disease by suppressing nanohydroxyapatite-induced mitophagy and mitochondria-mediated apoptosis.

OBJECTIVE: To investigate the protective effect of lanthanum chloride on kidney injury in chronic kidney disease and its mechanism. METHODS: 1. Patients with CKD stage 2-5 were selected to analyze the effect of lanthanum-containing preparations on CKD. 2. Sixty healthy male Wistar rats were randomly divided into control group, model group, lanthanum chloride groups (0.03 ng/kg, 0.1 ng/kg, 0.3 ng/kg, q.3d., i.v.), and lanthanum carbonate group (0.3 g/kg, q.d., p.o.). The model group was given 2 % adenine suspension (200 mg/kg, q.d., p.o.) for the first two weeks, followed by adenine (200 mg/kg, b.i.d., p.o.) for 2 weeks, and all animals were sacrificed after eight weeks of administration. 3. The serum and kidneys of rats in each group were collected to detect the oxidative stress indicators and the expressions of LC3B-Ⅱ/Ⅰ, p62, Bcl-2, Bax, Caspase-3 and Cleaved Caspase-3. 4. Human renal tubular epithelial cells (HK-2 cells) were divided into control group, model group, lanthanum chloride group, pyrophosphate (PPI) group, chloroquine (CQ) group, rapamycin group, doxorubicin (DOX) group and N-acetyl-L-cysteine (NAC) group. The mitochondrial status, mitophagy and apoptosis levels were detected. RESULTS: 1.Lanthanum-containing preparations can significantly reduce the biochemical indexes of kidney injury in patients with CKD. 2. In the model group, the glomerular and renal tubular edema, the mitochondria were short and round, and the expression of LC3B-Ⅱ/Ⅰ and Bax increased, while the expression of P62, Bcl-2 and Caspase-3 decreased, and there was a significant improvement in the administration group, especially the 0.1 ng/kg group and lanthanum carbonate group. 3. In the HK-2 cell model group, mitochondrial membrane potential decreased, morphology changed and the results were reversed by lanthanum chloride. CONCLUSION: Lanthanum chloride may alter the morphology of nano-hydroxyapatite, thereby inhibiting its induced mitophagy and mitochondria-mediated apoptosis, and ultimately improve CKD renal injury effectively.

The impact of hydroxybutyl chitosan and 5-fluorouracil on the procedure of endoscopic endonasal dacryocystorhinostomy.

PURPOSE: To investigate the effects of hydroxybutyl chitosan (HBCS) with and without 5-fluorouracil (5-FU) during endoscopic endonasal dacryocystorhinostomy (Endo-DCR). In addition, the present study observed the impact of HBCS and 5-FU on the functions of the nasal mucosal cell population in vivo. METHODS: Patients were randomized into HBCS (group A), HBCS combined with 5-FU (group B), and gelatin sponge control group (group C). 16S rRNA high-throughput sequencing technology examined the conjunctival sac and nasal flora changes. In addition, CCK8, cell scratching, and flow cytometry were used to investigate the effects of HBCS and 5-FU on the nasal mucosal cell populations. RESULTS: Subjects in groups A, B, and C had anastomotic areas of 21.83 ± 12.69 mm2, 21.57 ± 14.53 mm2, and 12.45 ± 8.16 mm2, respectively (P = 0.0359). Group A had less severe epiphora than the other two groups at 1-, 2-, and 12-week postoperative follow-up (P < 0.05). Complications around the anastomosis in group A were the least severe of the three groups (P = 0.0259). After surgery, the proportion of pathogenic bacteria in the conjunctival sac and nasal cavity was higher in groups A and B than in healthy adults. At the 2-week follow-up, the structure of nasal flora in group A was more similar to that of the healthy adults compared to group B. CONCLUSION: Intraoperative use of HBCS at the anastomose improves the postoperative outcome of En-DCR. 5-FU cannot give better postoperative results in En-DCR and is detrimental to the normalization of the postoperative flora in patients with chronic dacryocystitis. At the cellular level, both HBCS and 5-FU inhibit the migration of nasal mucosal cell populations, and 5-FU inhibits proliferation but does not promote apoptosis.

Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.

PURPOSE: The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s Project Optimus initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed. METHODS: Model-predicted outcomes for each clinically relevant end point, informed by ER modeling, are converted to a CUS using a user-defined utility function. Thereafter, individual CUS is integrated into a single score with user-defined weighting for each end point. The user-defined weighting feature allows the user to incorporate expert knowledge/understanding into weighing the product's benefit versus risk profile. RESULTS: To validate the framework, data were leveraged from over 50 oncology programs from 2019 to 2023 on the basis of FDA new drug application/biologics license application review packages and/or related literature studies. Five representative cases were selected for in-depth evaluation. Results showed that the optimal benefit-risk ratio (highest CUS) was consistently observed at PK exposures synonymous with recommended doses. A recurring theme across cases was a greater emphasis on safety over efficacy in oncology drug dose determination. CONCLUSION: The ER-based CUS framework offers a strategic tool to navigate the complexities of dose selection in oncology programs. It serves as a pillar to the importance of integrative data analysis, aligning with the vision of Project Optimus, and demonstrates its potential in guiding dose optimization by balancing therapeutic benefits against risk.

Network Pharmacology and in vitro Experimental Verification on Intervention of Oridonin on Non-Small Cell Lung Cancer.

OBJECTIVE: To explore the key target molecules and potential mechanisms of oridonin against non-small cell lung cancer (NSCLC). METHODS: The target molecules of oridonin were retrieved from SEA, STITCH, SuperPred and TargetPred databases; target genes associated with the treatment of NSCLC were retrieved from GeneCards, DisGeNET and TTD databases. Then, the overlapping target molecules between the drug and the disease were identified. The protein-protein interaction (PPI) was constructed using the STRING database according to overlapping targets, and Cytoscape was used to screen for key targets. Molecular docking verification were performed using AutoDockTools and PyMOL software. Using the DAVID database, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. The impact of oridonin on the proliferation and apoptosis of NSCLC cells was assessed using cell counting kit-8, cell proliferation EdU image kit, and Annexin V-FITC/PI apoptosis kit respectively. Moreover, real-time quantitative PCR and Western blot were used to verify the potential mechanisms. RESULTS: Fifty-six target molecules and 12 key target molecules of oridonin involved in NSCLC treatment were identified, including tumor protein 53 (TP53), Caspase-3, signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase kinase 8 (MAPK8), and mammalian target of rapamycin (mTOR). Molecular docking showed that oridonin and its key target molecules bind spontaneously. GO and KEGG enrichment analyses revealed cancer, apoptosis, phosphoinositide-3 kinase/protein kinase B (PI3K/Akt), and other signaling pathways. In vitro experiments showed that oridonin inhibited the proliferation, induced apoptosis, downregulated the expression of Bcl-2 and Akt, and upregulated the expression of Caspase-3. CONCLUSION: Oridonin can act on multiple targets and pathways to exert its inhibitory effects on NSCLC, and its mechanism may be related to upregulating the expression of Caspase-3 and downregulating the expressions of Akt and Bcl-2.

Macrophage Membrane Spontaneously Encapsulated Cyclodextrin-Based Nanomedicines for Improving Lipid Metabolism and Inflammation in Atherosclerosis.

Atherosclerosis is a persistent inflammatory condition of the blood vessels associated with abnormalities in lipid metabolism. Development of biomimetic nanoplatforms provides an effective strategy. Herein, inspired by the peptide CLIKKPF spontaneously coupling to phosphatidylserine (PS) on the inner leaflet of cell membranes specifically, MM@NPs were constructed by macrophage membrane spontaneous encapsulation of cyclodextrin-based nanoparticles modified with the peptide CLIKKPF and loaded with the hydrophobic compound resveratrol. MM@NPs could be specifically phagocytized by the activated endothelium with the overexpressed VCAM-1 for enhancing target delivery into the pathological lesion. Additionally, for the ApoE-/- mice, MM@NPs provide comprehensive treatment efficiency in reducing oxidant stress, alleviating the inherent inflammation, and decreasing cholesterol deposition, subsequently resulting in the atherosclerotic plaque regression. Therefore, MM@NPs could be one possible candidate for improving lipid metabolism and inflammation in atherosclerosis.

The clinical effect of endoscopic and open surgery in the treatment of thyroid cancer and their effect on the blood coagulation state: a comparative study.

Purpose: This study was performed to compare the therapeutic efficacy of endoscopic surgery and open surgery and their effects on postoperative blood coagulation state in patients with thyroid cancer, and to provide evidence for the prevention measurement of thrombosis in the perioperative period. Methods: One hundred patients with thyroid cancer who received treatment in our hospital from January 2021 to December 2021, were randomly divided into an endoscopic group and an open surgery group, with 50 patients in each group. The patients in the open surgery group were treated by traditional open surgery, while patients in the endoscopic group accepted endoscopic surgery. The clinically therapeutic effect and blood coagulation of the 2 groups were compared. Results: Intraoperative blood loss and length of hospital stay were lower, and operative time was longer in the endoscopic group than in the open surgery group (P < 0.05). The 24-hour postoperative fibrinogen and D-dimer levels were higher in both groups than in the preoperative period, while PT was shorter (P < 0.05). There were no significant differences in postoperative complications and follow-up between the 2 groups (P > 0.05), but the incidence of complications, postoperative metastases, and thrombosis was relatively low in the endoscopic group. Conclusion: In the treatment of patients with thyroid cancer, endoscopic surgery has the advantages of less blood loss, fewer complications, and so on. Endoscopic and open surgery can lead to a hypercoagulable state, but the effect of endoscopic surgery is better than that of open surgery.

Vitamin D receptor attenuates carbon tetrachloride-induced liver fibrosis via downregulation of YAP.

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl4) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.

scRNA-seq reveals the landscape of immune repertoire of PBMNCs in iMCD.

The etiology of idiopathic multicentric Castleman disease (iMCD) is poorly understood, and the identification of targetable disease mediators remains an unmet clinical need. Thus, we firstly employed single-cell RNA sequencing (scRNA-seq) to elucidate the landscape of the immune repertoire of peripheral blood mononuclear cells (PBMNCs) in iMCD and to identify additional driver cytokines/cells/pathways to address IL-6 blockade-refractory cases. We revealed that the inflammatory cytokine storm observed in iMCD was a significant phenomenon pervasive across all immune cells. B-plasma cell subsets was the main source of IL-6. The IL-6 signaling pathway was significantly activated across a spectrum of immune cells. Systemic upregulation of CXCL13 is mainly driven by peripheral helper T (Tph) and regulatory T (Treg) cells. Notably, a significant positive interaction was observed between CXCL13-expressing T cells and IL-6 signaling-activated B cells. This study provides an immune perspective on PBMNCs in iMCD at the single-cell level, unveiling pathways or targets characterized by atypical inflammatory expression that could potentially serve as promising candidates for therapeutic intervention in iMCD.

Red Blood Cell Membrane Spontaneously Coated Nanoprodrug Based on Phosphatidylserine for Antiatherosclerosis Applications.

Atherosclerosis (AS) is characterized by the accumulation of lipids within the walls of coronary arteries, leading to arterial narrowing and hardening. It serves as the primary etiology and pathological basis for cardiovascular diseases affecting the heart and brain. However, conventional pharmacotherapy is constrained by inadequate drug delivery and pronounced toxic side effects. Moreover, the inefficacy of nanomedicine delivery systems in controlling disease progression may be attributed to nonspecific clearance by the mononuclear phagocyte system. Thus, a biomimetic platform spontaneously enveloped by red blood cell membrane is exploited for anti-atherosclerosis applications, offering favorable biocompatibility. The CLIKKPF polypeptide is introduced to develop red blood cell membrane spontaneously encapsulated nanotherapeutics only through simple coincubation. Given the functional modifications, RBC@P-LVTNPs is beneficial to facilitate the target drug delivery to the atherosclerotic lesion, responding precisely to the pathological ROS accumulation, thereby accelerating the on-demand drug release. Both in vivo and in vitro results also confirm the significant therapeutic efficacy and favorable biocompatibility of the biomimetic nanomedicine delivery system, thus providing a promising candidate for nanotherapeutics against AS.

Tracheoplasty should be proactively considered in the surgical strategy for treating the ring-sling complex.

OBJECTIVE: To examine the safety and effectiveness of proactive tracheoplasty for pediatric ring-sling complex. METHODS: We retrospectively collected data from 304 children who were diagnosed with a ring-sling complex and underwent surgery at 3 cardiac centers in China between January 2010 and June 2023. The children were categorized into 3 surgical groups: concurrent sling and tracheal surgery (group A; n = 258), staged sling and tracheal surgery (group B; n = 25), and sling-only surgery (group C; n = 21). We compared perioperative clinical characteristics, tracheal morphology changes, and outcomes across the 3 groups. RESULTS: The median age of the children was 1.2 years (interquartile range, [IQR], 0.7-1.9 years). The anomalous tracheobronchial arborization rates were higher in group A (52.5%) and group B (60.0%) compared to group C (15.0%). The preoperative narrow-wide ratio (NWR) was lower in groups A and B than in group C, with values of 0.44 (IQR, 0.35-0.52), 0.44 (IQR, 0.33-0.59), and 0.68 (IQR, 0.54-0.72), respectively (P < .001). Preoperative subcarina angles were similar among the groups (P = .54). After specific surgeries, the NWR and subcarina angle were improved significantly in groups A and B but not in group C. There were 7 in-hospital deaths and 2 postdischarge deaths. Respiratory symptoms improved in groups A and B, but 7 children in group C remained in respiratory dysfunction. Six children presented with residual stenosis of the left pulmonary artery. CONCLUSIONS: Concurrent sling and tracheal surgeries for children with the ring-sling complex are safe and effective and are especially preferable for those with NWR ≤0.6, long-segment or diffuse tracheal stenosis, anomalous tracheobronchial arborization, and pronounced respiratory symptoms.

Continuous therapy in HHV-8 negative Multicentric Castleman Disease and prolonged progression-free survival.

The optimal treatment endpoints and duration of continuous therapy for multicentric Castleman disease (MCD) remain controversial. We retrospectively analyzed data from 123 patients with Human Herpesvirus (HHV)-8 negative MCD. We demonstrated that continuous therapy significantly enhanced progression-free survival (PFS) in patients who achieved an optimal response after initial treatment. These findings underscore the critical role of continuous therapy in HHV-8 negative MCD. Further studies with larger cohorts are required to validate these findings.