Background The diagnosis of intrahepatic cholestasis of pregnancy (ICP) has traditionally relied on detecting elevated total bile acids. However, measuring total levels may not capture the full diagnostic picture. Mass spectrometry (MS) now allows precise measurement of individual bile acid subtypes. Yet, the clinical diagnostic value of this detailed profile remains unclear. This systematic review and meta-analysis therefore evaluates the diagnostic accuracy of MS-based bile acid analysis for ICP. Methodology Search Strategy and Study Selection: We systematically queried five databases: PubMed, Web of Science, the Cochrane Library, OVID, and CNKI. Our search strategy incorporated both keywords and Medical Subject Headings (MeSH) related to intrahepatic cholestasis of pregnancy, its diagnosis, and mass spectrometry. Two authors then independently screened the retrieved records, extracted the relevant data, and evaluated the risk of bias in the studies that were included. Statistical Synthesis The primary goal of our analysis was to determine how well mass spectrometry–based bile acid profiling identifies ICP. We therefore pooled the reported sensitivity and specificity from the selected studies. To present the overall diagnostic accuracy, we constructed a summary receiver operating characteristic (SROC) curve. All statistical work was completed using Stata 17.0, Review Manager 5.4, and Meta-Disc. Results The present systematic review and meta-analysis evaluated eight studies that focused on two clinical applications of mass spectrometry (MS) in bile acid profiling. For distinguishing ICP from healthy pregnancies (four studies), the assay showed excellent accuracy, with sensitivity at 0.95 (95% confidence interval [CI]: 0.89–0.98), and specificity at 0.95 (95% CI: 0.91–0.98). The diagnostic odds ratio was 332.18 (95% CI: 100.89–1093.71), and the area under the SROC curve reached 0.9860.In the comparison between ICP and asymptomatic hypercholanemia of pregnancy (four studies), the method continued to perform well, showing a sensitivity of 0.93 (95% CI: 0.86–0.97) and specificity of 0.92 (95% CI: 0.84–0.97). The diagnostic odds ratio was 156.54 (95% CI: 47.07–520.55), and the SROC area was 0.9735. Conclusion These findings demonstrate that mass spectrometry-based bile acid profiling provides reliable diagnostic performance for intrahepatic cholestasis of pregnancy, clearly distinguishing it from healthy pregnancies and from asymptomatic hypercholanemia of pregnancy (AHP). Moving forward, key priorities will involve confirming these results in larger, multi-center studies, creating unified international guidelines for clinical application, and resolving the recognized shortcomings of current diagnostic approaches for ICP.

BACKGROUND:Endothelial dysfunction is recognized as a crucial initiating factor for hypertension and associated cardiovascular/renal injury. Although MYDGF (myeloid-derived growth factor) is mainly derived from bone marrow cells, recent studies have also found the expression of MYDGF in different parenchymal cells. However, the expression pattern and the role of endothelial MYDGF in hypertension remain unclear. METHODS:Endothelial-specific knockout of MYDGF mice and recombinant MYDGF were used to examine the role of MYDGF in hypertension and associated cardiovascular/renal injury. RESULTS:Endothelial MYDGF was significantly downregulated in hypertensive mice. MYDGF deficiency in the endothelium aggravated endothelial dysfunction and cardiovascular/renal injury in hypertensive mice, which was attenuated by the overexpression of MYDGF or recombinant MYDGF. Functionally, MYDGF maintained endothelial homeostasis via pleiotropic protective effects, including anti-inflammation, antiapoptosis, inhibiting aberrant endothelial permeability and senescence, and inducing NO generation. Mechanistically, MYDGF promoted the activation of HMOX1 (heme oxygenase-1) transcription by mediating STAT3 (signal transducer and activator of transcription 3) phosphorylation, thereby reestablishing endothelial homeostasis. CONCLUSIONS:MYDGF governs endothelial homeostasis in hypertension through regulating HMOX1 expression. Targeting MYDGF may offer an innovative approach for treating hypertension and its cardiovascular complications.

Renal fibrosis is a common outcome of chronic kidney disease (CKD), forming a fibrotic niche characterized by fibroblast activation and vascular rarefaction. Currently, there are no effective treatment strategies targeting fibrotic niche. Here, we show that chimeric antigen receptor-modified M2 macrophages (CAR-M2) targeting FAP and secreting interleukin (IL)-4 are delivered via an injectable HAMA-CS hydrogel beneath the renal subcapsule and attenuate renal fibrosis while promoting renal revascularization. The single-cell RNA sequencing reveals the heterogeneity and interaction of stroma and endothelial cells (ECs). A fibrosis-related Cxcr2+ EC subset is identified, and its specific depletion effectively mitigates renal fibrosis. Further results reveal that CAR-M2 can release matrix metalloproteinase 2 (MMP2) in close proximity to activate retinoid X receptor alpha (Rxra) in the Cxcr2+ ECs and further triggers its mitochondrial autophagy, leading to apoptosis. Our research provides innovative strategies and proof of principle for the immunotherapy of organ fibrosis.

BACKGROUND:Chronic thromboembolic pulmonary hypertension is characterized by proximal pulmonary artery obstruction and distal microvasculopathy. However, the mechanisms driving this dual-compartment pulmonary vascular remodeling remain unclear. METHODS:Male Sprague-Dawley rats were injected with gelatin sponge combined with SU5416 as a secondary insult. Hemodynamics, echocardiography, and pulmonary vascular remodeling were evaluated to investigate the development of chronic thromboembolic pulmonary hypertension. Single-cell RNA sequencing of rat lung tissue was conducted to elucidate the molecular mechanisms underlying pulmonary vascular remodeling. The results were validated by immunofluorescence and cell-based experiments. RESULTS:The optimal size range of gelatin sponge for large pulmonary artery obstruction was 710 to 1000 µm, which synergized with a low dose of SU5416 (10 mg/kg) to induce significant increases in right ventricular systolic pressure and right ventricular hypertrophy at 5 weeks. The model exhibited persistent elastic pulmonary artery obstruction and remodeling, along with significant wall thickening and muscularization of pulmonary microvessels. Single-cell transcriptomic analysis revealed a significant reduction in microvascular endothelial cells and an increase in smooth muscle cells in the chronic thromboembolic pulmonary hypertension rats. STAT3, EGR1, and HIF1A were identified as key genes driving aberrant smooth muscle cell proliferation. The Sell (encoding L-selectin)-Podxl (encoding PODXL, podocalyxin) ligand-receptor pair was found specifically in diseased rats and mediated immune cell-endothelial cell interactions. L-selectin promoted neutrophil adhesion and dysfunction in pulmonary arterial and microvascular endothelial cells, both of which were reversed by PODXL knockdown. CONCLUSIONS:Our new model recapitulates human chronic thromboembolic pulmonary hypertension pathophysiology and is useful for understanding pulmonary microvasculopathy. Sell-Podxl is a previously unrecognized link between inflammation and vascular remodeling, offering a potential therapeutic target.

Osteoporosis, characterized by reduced bone mass and increased fracture risk, underscores the urgent need for novel anabolic therapies. G protein-coupled receptors (GPCRs) are major drug targets, but the functions of adhesion GPCRs (aGPCRs) in bone remain largely unexplored. G-protein coupled receptor 125 (Gpr125) is an orphan aGPCR, and its role in osteoblast-mediated bone formation is entirely unknown. We employed lentiviral-mediated knockdown and overexpression of Gpr125 in primary mouse calvarial osteoblasts and bone marrow stromal cells (BMSCs). Osteogenic and adipogenic differentiation were assessed by staining and marker analysis. Transcriptomic profiling (RNA-seq) and pathway analysis were used to identify downstream mechanisms, validated by rescue experiments with Gper1 overexpression, PI3K/AKT inhibitors (LY294002), and Wnt/β-catenin activation (Wnt3a CM). The osteogenic role of Gpr125 was tested in ovariectomized and aged mouse osteoporosis models via osteoblast-targeted adeno-associated virus (AAV) delivery. Gpr125 was highly expressed in osteoblasts, peaking during differentiation. Its knockdown severely impaired osteogenesis while promoting adipogenesis in vitro. Conversely, its overexpression enhanced bone formation. RNA-seq identified G protein-coupled estrogen receptor 1 (Gper1) as the key downstream target. We defined a novel signaling axis where Gpr125 upregulates Gper1, which activates PI3K/AKT signaling, leading to β-catenin stabilization and osteogenic transcription. Rescue experiments established a strict hierarchy: Gper1 overexpression fully rescued the osteogenic defect caused by Gpr125 loss, but not Gpr125 expression itself. PI3K inhibition blocked Gpr125-induced β-catenin activation and osteogenesis. β-catenin activation partially rescued osteogenesis but failed to restore upstream signaling. Critically, osteoblast-specific Gpr125 overexpression in vivo effectively ameliorated bone loss and reduced marrow adiposity in both postmenopausal and senile osteoporosis mouse models. Our study unveils a complete Gpr125-Gper1-PI3K/AKT-β-catenin signaling axis essential for osteoblast differentiation and bone formation. This work identifies the aGPCR Gpr125 as a novel positive regulator of bone anabolism and proposes the Gpr125-Gper1 axis as a promising therapeutic target for developing new treatments against osteoporosis.

Mitochondrial dysfunction is widely considered one of the key initiating factors leading to Parkinson's disease (PD). Mitophagy plays a critical role in maintaining mitochondrial homeostasis. Complement C1q-binding protein (C1QBP) plays a crucial role in regulating mitophagy and maintaining mitochondrial homeostasis. This study aims to investigate the role of C1QBP in the pathogenesis of PD by employing bidirectional modulation of C1QBP expression in the PD models. Our results showed reduced C1QBP expression in PD models. C1QBP deficiency aggravated motor dysfunction and dopaminergic neuron degeneration induced by MPTP, while its overexpression exerts protective effects. Mechanistically, C1QBP ameliorates MPP+-induced mitochondrial dysfunction, thereby attenuating neuronal loss. Furthermore, C1QBP promotes mitophagy to maintain mitochondrial homeostasis in PD models. However, these neuroprotective effects of C1QBP were abolished upon UNC-51-Like Kinase 1 (ULK1) knockdown. Collectively, our study has identified C1QBP as a novel guardian for dopaminergic neurons in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.

To investigate the effects of BBR on ferroptosis and osteogenic differentiation in rat bone marrow mesenchymal stem cells (BMSCs) under high-glucose conditions and to explore the potential involvement of related molecular pathways. Rat BMSCs were isolated, cultured, and characterized in vitro. The optimal concentration of BBR was determined using the cell counting kit-8 assay. Intracellular ferroptosis markers were quantified using specific biochemical assay kits. The expression of ferroptosis-related genes and proteins was analyzed by real-time quantitative polymerase chain reaction and Western blotting. Osteogenic differentiation potential was assessed through alkaline phosphatase staining, alkaline phosphatase activity assay, alizarin red S staining, and RT-qPCR for osteogenesis-related genes. Cell migration capacity was evaluated by a scratch wound healing assay. The involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) signaling pathway was examined using RT-qPCR and Western blotting. High-glucose stimulation induced ferroptosis in rat BMSCs. BBR treatment dose-dependently inhibited ferroptosis while concurrently promoting osteogenic differentiation. The anti-ferroptotic and pro-osteogenic effects of BBR were found to be associated with changes in the Nrf2/HO-1/GPX4 signaling pathway and were partially reversed by co-treatment with a specific Nrf2 inhibitor. BBR inhibits ferroptosis and promotes osteogenic differentiation, effects that are associated with the Nrf2/HO-1/GPX4 signaling pathway.

Achieving precise delivery has always been a key challenge in the development of nanomedicine to treat cancer. Intelligent stimulus-responsive nanocarriers imbued with fascinating features such as excellent targeting ability, high drug loading capacity, and targeted on-demand release emerging as an attractive tool in cancer therapy. Given the intricacy of the dynamic intracellular and extracellular environment of tumor, different strategies can be employed to design responsive nanomaterials to make them activable upon internal bio-stimuli (pH, redox, and enzymes) or external stimuli (ultrasound, light, temperature, and magnetic), respectively. Simultaneously, by virtue of precisely release at tumor-specific sites, smart nanocarriers have enabled remarkable progress in therapeutics delivery for cancer treatment. In this review, we outline emerging design concepts for elaborately creating novel nanocarriers that respond to internal or external stimuli. And we define critical steps along with the road of preclinical development and propose suggestions to circumvent the obstacle in technology and fabrication for clinical translation. Furthermore, future opportunities across cancer therapy are explored.

This article presents a WR-4 band (170–260 GHz) H-plane diplexer based on the SU-8 micromachining process with a dual-mode resonator structure. The proposed diplexer features two fourth-order bandpass filters, achieving passbands of 215–218 and 221–224 GHz. This proposed design employs dual-mode rectangular waveguide resonators, and a non-resonant junction is formed by three non-resonant node resonators connecting the two passbands. The entire diplexer used for measurement includes the designed diplexer and three bends and requires only two SU-8 chips fabricated via a three-layer process to form the entire circuit. In addition, the preparation process of the SU-8 chips, the existing challenges, and the corresponding approaches are described in detail. Moreover, a fixture with upper and lower clamping blocks is designed to ensure measurement accuracy. The measured return loss values of the entire fabricated device in the two channels are about 12 dB and their center frequency shift values in the high-frequency direction are ∼1.5 and 1 GHz for the lower and higher bands, respectively. The good agreement between measurement and simulation results can be attributed to the high-precision fabrication process and carefully optimized design.

Angiogenesis is crucial to improving neurovascular remodeling poststroke. Therein, the transformation of endothelial cells (ECs) to tip cells is essential in initiating angiogenesis. Mitochondrial damage in ECs poststroke and associated metabolic disorder are key factors repressing angiogenesis, but the mechanisms are unknown. Here, we designed an Arg-Gly-Asp peptide (RGD)-modified, mitochondria-enriched, and extracellular vesicle mimetics (mitoEVMs) platform for mitochondrial transfer. RGD mediated the mesenchymal stem cell-derived mitochondria transfer to ECs around the lesion targetedly. We found MSC-derived mitochondria promoted tip cell transition and further stimulated angiogenesis after stroke, alleviated brain atrophy, and improved functional rehabilitation. We noticed mitochondrial transfer rescued mitochondrial function in ECs and reprogrammed glutathione metabolism to activate the mTORC1 pathway, upregulated the expression of p4E-BP1 and VEGFR2, and ultimately facilitated tip cell transition. Our work elucidates the mechanism of MSC-derived mitochondrial transfer in poststroke treatment and proposes a potential approach for rehabilitation after stroke.

BACKGROUND:Diffuse pulmonary lymphangiomatosis (DPL) is a rare pulmonary disorder, which affects the lymphatic channels from the mediastinum to the pleura. DPL is often misdiagnosed or missed due to the lack of clear specificity and definitive medical therapies. In most cases, the disease progresses to chronic morbidity or even death. CASE PRESENTATION:Here, we have reported a case of DPL in a 17-year-old boy who presented with hemoptysis and progressive breathlessness. The diagnosis was confirmed based on the typical imaging features observed through high-resolution computed tomography, chest magnetic resonance imaging, and lymphangiography. Furthermore, we have presented the genetic characteristics of the patient and his parents and discovered the following heterozygous variants of BCL6: NM_001706: exon5: c. A463G (p.M155V) and ATM: NM_000051: exon3: c.A107G (p.D36G). The patient underwent treatment with sirolimus for 2 months; his clinical symptoms disappeared completely, and the mediastinum soft mass shrank dramatically. CONCLUSIONS:Early diagnosis of DPL is challenging for clinicians, and imaging plays an important role in determining the location and severity of the disease. The gene mutation detected in this study may facilitate the pathogenesis of DPL. Sirolimus can prevent further disease progression in the short term, which may be an effective and safe therapeutic alternative for treating DPL.

Current clinical treatments for skin scars primarily reduce vascular density in situ. But, outcomes remain unsatisfactory due to limited understanding of scar vascular structure, endothelial cell (EC) heterogeneity, and functional changes. Through dermatoscopy, scanning electron microscopy, and immunofluorescence staining, our study revealed substantial vascular remodeling in scars, including increased neovascularization density, branching complexity, and incomplete vascular wall coverage. Single‐cell sequencing constructed an EC atlas of scar patients, identifying upregulated ATP synthesis, decomposition, and oxidative phosphorylation in scar ECs—characteristics resembling tumor vasculature. Notably, a subset of ECs with high neuropilin‐1 (NRP1) expression exhibited mesenchymal characteristics. In vitro experiments demonstrated that NRP1 knockdown blocked the transforming growth factor‐beta (TGF‐β)/SMAD family member 2 (SMAD2) signaling pathway and mitigated endothelial‐to‐mesenchymal transition (EndMT). Importantly, NRP1 inhibition reduced EndMT, restored normal vascular function and structure, and prevented scar formation in mice. Based on these findings, a functional hydrogel spray was developed using an NRP1‐targeting peptide, effectively preventing scar formation by promoting vascular normalization.

Objectives:Sarcopenia is an important indicator affecting the prognosis of patients with end-stage liver disease. The purpose of this review is to systematically review all relevant studies to evaluate the impact of sarcopenia on the prognosis of patients with ACLF. Methods:We systematically searched PubMed, Web of Science, Embase, the Cochrane Library, China Biomedical Literature Service System (CINAHL), China National Knowledge Infrastructure (CNKI), the WeiPu (VIP) and the Wanfang database for relevant articles published on or before August 1, 2024. Two independent reviewers conducted literature screening against predefined inclusion/exclusion criteria. Results:The systematic review included 12 cohort studies, with a total of 2,505 participants. Of these, 11 studies (2,072 participants) met the criteria for inclusion in the meta-analysis. The meta-analysis demonstrated that sarcopenia is significantly associated with an increased mortality risk in patients with ACLF [HR = 1.27, 95%CI (1.05, 1.54), p < 0.00001]. Subgroup analyses showed that the mortality risk was significantly increased in the subgroup of study with the outcome of short-term mortality [HR = 1.54, 95%CI (1.14, 2.08)], and prospective study [HR = 2.16, 95%CI (1.30, 3.60)]. Conclusion:The meta-analysis of 11 studies (2,072 participants) revealed a significant association between sarcopenia and elevated mortality risk in ACLF patients. However, these findings should be interpreted with caution due to the limited number of included studies and higher heterogeneity in the analysis. Systematic review registration:CRD42023441039.

Although emerging studies highlight the pivotal role of podocyte senescence in the pathogenesis of diabetic kidney disease (DKD) and aging-related kidney diseases, therapeutic strategies for preventing podocyte senescence are still lacking. Here, we identified a previously unrecognized role of GPR124, a novel adhesion G protein-coupled receptor, in maintaining podocyte structure and function by regulation of cellular senescence in DKD. Podocyte GPR124 was significantly reduced in db/db diabetic (a type 2 diabetic mouse model) and streptozocin-induced diabetic mice (a type 1 diabetic model), which was further confirmed in kidney biopsies from patients with DKD. The level of GPR124 in glomeruli was positively correlated with the estimated glomerular filtration rate and negatively correlated with serum creatinine levels. Podocyte-specific deficiency of GPR124 significantly aggravated podocyte injury and proteinuria in the two models of diabetic mice. Moreover, GPR124 regulated podocyte senescence in both diabetic and aged mice. Mechanistically, GPR124 directly bound with vinculin and negatively regulated focal adhesion kinase (FAK) signaling, thereby mediating podocyte senescence and function. Importantly, overexpression of GPR124 or pharmacological inhibition of FAK protected against podocyte senescence and injury under diabetic conditions. Our studies suggest that targeting GPR124 may be an innovative therapeutic strategy for patients with DKD and aging-related kidney diseases.

Difficulty of nanomedicines to effectively penetrate the tumor core and achieve effective killing of tumor stem cells is an important factor leading to recurrence, metastasis and drug resistance of tumors. Strategies based on the tumor microenvironment offer new perspectives and approaches to address the challenges associated with deep tumor treatment. Here, we designed novel MgF2@L-Arg nanoparticles (ML NPs) by integrating basic L-arginine into MgF2. Under the endogenous acid gradient within the tumor, ML NPs selectively protonate their proximal amines, leading to spatial charge asymmetry. This promotes the sustained diffusion and permeation of ML NPs deep into the tumor, achieving a penetration distance of up to 197 μm. Moreover, aside from enabling synergistic effects in sonodynamic therapy (SDT) and gas therapy, ML NPs can reduce the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and heat shock protein 70 (HSP 70) within tumor cells, induce immunogenic cell death, and bind to the co-stimulatory molecule LFA-1 on the surface of tumor cells, thereby enhancing the specific cytotoxicity of CD8+ T cells. This mechanism significantly improves the immune response against cancer cells and effectively suppresses tumor metastasis. Our research proposes a viable new strategy for the deep penetration of nanoparticles into tumors and for effective deep tumor treatment, demonstrating the tremendous potential of such materials in enhancing anti-tumor efficacy.

The associations between LDH and non-alcoholic fatty liver disease (NAFLD), as well as advanced hepatic fibrosis (AHF), have not been explored. This study aims to investigate the association between log-transformed LDH levels and the prevalence of NAFLD and AHF. In this cross-sectional study, after applying specific criteria for inclusion and exclusion, a total of 7,316 individuals were chosen from the 59,842 participants for the final analysis. LDH levels were measured using an enzymatic rate method. A fatty liver index (FLI) greater than or equal to 60 and an NAFLD fibrosis score (NFS) higher than 0.676 were found to be indicative of hepatic steatosis and advanced hepatic fibrosis. Both weighted multivariable linear and logistic regression analyses were used to finish the study. Moreover, additional analyses were performed utilizing weighted stratified analysis and weighted smoothed curve fitting using the generalized additive model (GAM). Following data analysis, the multivariable regression model 3 showed a significant association between the elevated log-transformed LDH levels and AHF (OR: 3.087, 95

Background:The morphological differences in the pulmonary vascular tree between chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease (CTED) are not yet fully understood. This study aimed to use artificial intelligence (AI) segmentation technology to identify morphological markers that can be used to differentiate CTEPH from CTED using computed tomography pulmonary angiography (CTPA). Methods:We conducted a retrospective cohort study with consecutive patients diagnosed with CTEPH, CTED, and control subjects at the China-Japan Friendship Hospital from January 2019 to October 2023. The study involved the automatic quantification of the pulmonary blood volume (BV), tortuosity, and fractal dimension (FD) from CTPA images using an AI workstation. These morphological metrics were compared among the three groups using the Kruskal-Wallis test. Correlations between these metrics and the hemodynamic parameters were evaluated using Spearman's rank correlation coefficients. Additionally, a receiver operating characteristic (ROC) curve analysis was conducted to assess the discriminative ability of pulmonary artery tortuosity to differentiate between each pair of groups. Results:A total of 190 participants [57 years, interquartile range (IQR), 49-65 years, 97 men], including 116 CTEPH patients, 54 CTED patients, and 20 controls, were enrolled in this study. Pulmonary artery tortuosity in the control, CTED, and CTEPH groups showed a progressively increasing trend [1.07 (IQR, 1.06-1.10) vs. 1.10 (IQR, 1.07-1.14) vs. 1.14 (IQR, 1.10-1.18), P<0.01]. The area under the curve (AUC) values of pulmonary arterial tortuosity for differentiating between the CTEPH patients and controls, CTED patients and controls, and CTEPH patients and CTED patients were 0.859, 0.712, and 0.663, respectively. There was a positive correlation between pulmonary artery tortuosity and mean pulmonary arterial pressure (mPAP) (r=0.44, P<0.01), and pulmonary vascular resistance (PVR) (r=0.47, P<0.01). Additionally, the volume of the small- and medium-sized pulmonary arteries was significantly higher in the CTED patients than the CTEPH patients (P<0.01). The pulmonary arterial FD among the three groups was comparable (P=0.36). Conclusions:Pulmonary arterial tortuosity on CTPA had auxiliary diagnostic value in differentiating between CTEPH patients and controls, but its value in differentiating between CTED and CTEPH patients requires further study. The reduced volume of small- and medium-sized pulmonary arteries in CTEPH patients could indicate impaired pulmonary hemodynamics.