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Renal macrophages (RMs) participate in tissue homeostasis, inflammation and repair. RMs consist of embryo-derived (EMRMs) and bone marrow-derived RMs (BMRMs), but the fate, dynamics, replenishment, functions and metabolic states of these two RM populations remain unclear. Here we investigate and characterize RMs at different ages by conditionally labeling and ablating RMs populations in several transgenic lines. We find that RMs expand and mature in parallel with renal growth after birth, and are mainly derived from fetal liver monocytes before birth, but self-maintain through adulthood with contribution from peripheral monocytes. Moreover, after the RMs niche is emptied, peripheral monocytes rapidly differentiate into BMRMs, with the CX3CR1/CX3CL1 signaling axis being essential for the maintenance and regeneration of both EMRMs and BMRMs. Lastly, we show that EMRMs have a higher capacity for scavenging immune complex, and are more sensitive to immune challenge than BMRMs, with this difference associated with their distinct glycolytic capacities. Renal macrophages (RMs) can be of bone marrow or embryonic origin, but their abundance, fate and metabolic profiles in physiological and pathogenic settings are still unclear. Here the authors show, by characterizing these two RMs in multiple transgenic mouse lines, that they exhibit distinct dynamics, homeostasis, immune activity, and metabolic properties.

Metabolomic profiling can aid in understanding crucial biological processes in cancer development and progression and can also yield diagnostic biomarkers. Desorption electrospray ionization coupled to mass spectrometry imaging (DESI-MSI) has been proposed as a potential adjunct to diagnostic surgical pathology, particularly for prostate cancer. However, due to low resolution sampling, small numbers of mass spectra, and little validation, published studies have yet to test whether this method is sufficiently robust to merit clinical translation. We used over 900 spatially resolved DESI-MSI spectra to establish an accurate, high-resolution metabolic profile of prostate cancer. We identified 25 differentially abundant metabolites, with cancer tissue showing increased fatty acids (FAs) and phospholipids, along with utilization of the Krebs cycle, and benign tissue showing increased levels of lyso-phosphatidylethanolamine (PE). Additionally, we identified, for the first time, two lyso-PEs with abundance that decreased with cancer grade and two phosphatidylcholines (PChs) with increased abundance with increasing cancer grade. Importantly, we developed and internally validated a multivariate metabolomic classifier for prostate cancer using 534 spatial regions of interest (ROIs) in the training cohort and 430 ROIs in the test cohort. With excellent statistical power, the training cohort achieved a balanced accuracy of 97% and validation on testing data set demonstrated 85% balanced accuracy. Given the validated accuracy of this classifier and the correlation of differentially abundant metabolites with established patterns of prostate cancer cell metabolism, we conclude that DESI-MSI is an effective tool for characterizing prostate cancer metabolism with the potential for clinical translation.

The aim of our study is to investigate whether adjunct neuromuscular electrical stimulation (NMES) therapy improves functional performance outcomes in children with cerebral palsy (CP) who have received botulinum toxin (BTX) injections. We searched the PubMed, Cochrane Library, CINAHL, EMBASE, and Scopus databases for randomized controlled trials studying the effects of NMES after BTX injection in children with CP from database inception to July 3, 2024. Two independent reviewers extracted data, and risks of bias were assessed using the PEDro scale for randomized controlled trials. We included 5 randomized controlled trials in this meta-analysis. NMES treatment following BTX injection resulted in greater functional performance outcomes compared with BTX injections alone (standardized mean difference = 0.57; 95% CI = 0.22 to 0.92). However, NMES following BTX injections did not significantly improve spasticity outcomes (standardized mean difference = 0.28; 95% CI = − 0.21 to 0.76). Despite including only a small number of trials, the present analysis demonstrated that NMES is an effective adjunct to BTX injections for managing CP in children. Further research must be conducted to refine these therapies, ensure better outcomes, and alleviate the burdens faced by individuals with CP.

Photobiomodulation (PBM) has been emerging as a promising alternative therapy in dentistry. However, various parameters of PBM are used in different studies, and there is limited cumulative data on PBM for improving bone formation in clinical trials. The aim of this review was to evaluate the effectiveness of PBM in the process of bone remodeling in dentistry using randomized controlled trials. Initially, a total of 1,011 articles published from January 2008 to December 2021 were retrieved from five electronic databases (PubMed, Scopus, Cochrane Library, EMBASE, and CINAHL). After a two-step review, nine articles met the inclusion criteria. The parameter of PBM, group, treatment sessions, assessment times and outcomes of the included studies were reviewed. Eighty-nine percent of the studies revealed positive effects on bone formation between the laser group and the control group. Only one article reported that light-emitting diode did not significantly enhance osteogenesis. Additionally, the present study shows that Gallium aluminum arsenide of near infrared (NIR) laser with continuous mode is the most commonly used form of PBM. The biostimulatory effects are dependent on several parameters, with wavelength and dose being more important than others. Based on this review, it is suggested that the NIR range and an appropriate dose of PBM could be used to increase the efficiency of stimulating bone healing and remodeling. However, standardization of treatment protocols is needed to clarify therapeutic strategies in dentistry.

Background The histone methyltransferase SMYD3 (SET and MYND domain containing 3) is critical for vascular homeostasis and may be implicated in pathological angiogenesis. However, its mechanism remains elusive, and targeted inhibitors are in early-stage development. We aim to clarify whether SMYD3 regulates angiogenesis and develop novel molecules targeting SMYD3. Methods Expression profile of SMYD3 under pro-angiogenic conditions was characterized by bioinformatics analysis and endothelial cell (EC) validation. The effects of SMYD3 knockdown, knockdown-overexpression, and overexpression on angiogenesis were validated, including Matrigel neovascularization, aortic ring sprouting, and EC tube formation. Regarding molecule development, virtual screening, structural modifications, molecular docking, inhibition screening of EC proliferation, and SMYD3 enzyme activity and cellular thermal shift assays were employed. A novel molecule ZYZ329 was identified and evaluated in angiogenesis. Mechanistic studies involved genetic approaches and the mitochondrial reactive oxygen species (mROS) scavenger MitoQ (Mitoquinone mesylate). Finally, a murine hindlimb ischemia model and rat skin healing model were established to evaluate ZYZ329 on pathological and physiological angiogenesis. Results SMYD3 was upregulated in endothelial cells under ischemic, hypoxic, and VEGF-stimulated conditions. And SMYD3 gene knockdown, overexpression after knockdown, and overexpression regulated the angiogenesis capacity of endothelial cells. After virtual screening and structural modifications, the novel molecule ZYZ329 was developed for dual inhibition of EC proliferation (IC 50  = 6.147 μM) and SMYD3 enzymatic function (IC 50  = 0.419 μM). The ZYZ329 engaged SMYD3 in cells, and exhibited a certain degree of selectivity for SMYD3. Moreover, ZYZ329 significantly attenuated pathological angiogenesis in a dose-dependent manner. Mechanistically, genetic or pharmacological inhibition of SMYD3 impaired HIF-1α stabilization and downstream VEGFA production. SMYD3 genetic perturbation modulated mROS without affecting apoptosis in hypoxic endothelial cell. MitoQ intervention confirmed that moderate SMYD3-driven mROS elevation regulates the HIF-1α/VEGFA axis in angiogenesis. In hindlimb ischemia model, ZYZ329 significantly impaired blood flow recovery and post-ischemic angiogenesis, demonstrating superior efficacy to EPZ031686. However, ZYZ329 had no significant effect on physiological angiogenesis. Conclusions SMYD3 drives angiogenesis partially via the mROS/HIF-1α/VEGFA axis. We developed a novel molecule ZYZ329, which potently suppresses pathological angiogenesis. This offers potential therapeutic target and lead structures for treating angiogenesis-related diseases. Graphical Abstract

Background: Sagittal alignment in the lumbar spine is essential for spinal stability and functionality, with significant implications in surgical planning for spinal deformity correction. However, standardized lumbar partitioning, particularly identifying a critical sagittal alignment zone, remains underdefined. This study aims to establish a reliable lumbar partition to guide surgical decisions and optimize clinical outcomes. Methods: A systematic review of four major biomedical databases yielded 32 studies, of which 4 met the inclusion criteria. Studies on asymptomatic adults with segmental lordosis data stratified by pelvic incidence were analyzed. Lumbar lordosis values were converted to percentages, allowing for cross-study comparison. Sensitivity analysis and bias assessment were performed to ensure methodological rigor. Results: The findings identified the L3–L5 interval, especially around the L4 vertebra, as a critical biomechanical zone across various populations and pelvic incidence groups. Individuals with higher pelvic incidence had concentrated lordosis in lower segments, while those with lower pelvic incidence had greater lordosis in upper segments, underscoring the L3–L5 region’s stability as a surgical reference. Conclusions: The L3–L5 interval serves as a key partition zone for sagittal alignment, providing a stable reference for lumbar spine fusion. These findings offer a foundational clinical reference, potentially improving alignment outcomes and reducing postoperative complications.

: Pulmonary vascular endotheliitis, perivascular inflammation, and immune activation are observed in COVID-19 patients. While the initial SARS-CoV-2 infection mainly infects lung epithelial cells, whether it also infects endothelial cells (ECs) and to what extent SARS-CoV-2-mediated pulmonary vascular endotheliitis is associated with immune activation remain to be determined. : To address these questions, we studied SARS-CoV-2-infected ( ) mice, a severe COVID-19 mouse model, as well as lung samples from SARS-CoV-2-infected nonhuman primates (NHP) and patient deceased from COVID-19. We used immunostaining, RNAscope, and electron microscopy to analyze the organs collected from animals and patient. We conducted bulk and single cell (sc) RNA-seq analyses, and cytokine profiling of lungs or serum of the severe COVID-19 mice. : We show that SARS-CoV-2-infected mice develop severe COVID-19, including progressive body weight loss and fatality at 7 days, severe lung interstitial inflammation, edema, hemorrhage, perivascular inflammation, systemic lymphocytopenia, and eosinopenia. Body weight loss in mice correlated with the severity of pneumonia, but not with brain infection. We also observed endothelial activation and dysfunction in pulmonary vessels evidenced by the up-regulation of VCAM1 and ICAM1 and the downregulation of VE-cadherin. We detected SARS-CoV-2 in capillary ECs, activation and adhesion of platelets and immune cells to the vascular wall of the alveolar septa, and increased complement deposition in the lungs, in both COVID-19-murine and NHP models. We also revealed that pathways of coagulation, complement, K-ras signaling, and genes of ICAM1 and VCAM1 related to EC dysfunction and injury were upregulated, and were associated with massive immune activation in the lung and circulation. : Together, our results indicate that SARS-CoV-2 causes endotheliitis via both infection and infection-mediated immune activation, which may contribute to the pathogenesis of severe COVID-19 disease.

CXCL8-CXCR1/CXCR2 signaling pathways might form complex crosstalk among different cell types within the ovarian tumor microenvironment, thereby modulating the behaviors of different cells. This study aimed to investigate the expression pattern of CXCL8 in the ovarian tumor microenvironment and its impact on both endothelial-to-mesenchymal transition (EndMT) and ferroptosis of endothelial cells. The human monocytic cell line THP-1 and the human umbilical vein endothelial cell line PUMC-HUVEC-T1 were used to conduct in vitro studies. Erastin was used to induce ferroptosis. Results showed that tumor-associated macrophages are the major source of CXCL8 in the tumor microenvironment. CXCL8 treatment promoted the nucleus entrance of NF-κB p65 and p65 phosphorylation via CXCR2 in endothelial cells, suggesting activated NF-κB signaling. Via the NF-κB signaling pathway, CXCL8 enhanced TGF-β1-induced EndMT of PUMC-HUVEC-T1 cells and elevated their expression of SLC7A11 and GPX4. These trends were drastically weakened in groups with CXCR2 knockdown or SB225002 treatment. TPCA-1 reversed CXCL8-induced upregulation of SLC7A11 and GPX4. CXCL8 protected endothelial cells from erastin-induced ferroptosis. However, these protective effects were largely canceled when CXCR2 was knocked down. In summary, CXCL8 can activate the NF-κB signaling pathway in endothelial cells in a CXCR2-dependent manner. The CXCL8-CXCR2/NF-κB axis can enhance EndMT and activate SLC7A11 and GPX4 expression, protecting endothelial cells from ferroptosis.

Preclinical mouse models that recapitulate some characteristics of coronavirus disease (COVID-19) will facilitate focused study of pathogenesis and virus–host responses. Human agniotensin-converting enzyme 2 (hACE2) serves as an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect people via binding to envelope spike proteins. Herein we report development and characterization of a rapidly deployable COVID-19 mouse model. C57BL/6J (B6) mice expressing hACE2 in the lung were transduced by oropharyngeal delivery of the recombinant human adenovirus type 5 that expresses hACE2 (Ad5-hACE2). Mice were infected with SARS-CoV-2 at Day 4 after transduction and developed interstitial pneumonia associated with perivascular inflammation, accompanied by significantly higher viral load in lungs at Days 3, 6, and 12 after infection compared with Ad5-empty control group. SARS-CoV-2 was detected in pneumocytes in alveolar septa. Transcriptomic analysis of lungs demonstrated that the infected Ad5-hACE mice had a significant increase in IFN-dependent chemokines Cxcl9 and Cxcl10, and genes associated with effector T-cell populations including Cd3 g, Cd8a, and Gzmb. Pathway analysis showed that several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the data set, including cytokine–cytokine receptor interaction, the chemokine signaling pathway, the NOD-like receptor signaling pathway, the measles pathway, and the IL-17 signaling pathway. This response is correlative to clinical response in lungs of patients with COVID-19. These results demonstrate that expression of hACE2 via adenovirus delivery system sensitized the mouse to SARS-CoV-2 infection and resulted in the development of a mild COVID-19 phenotype, highlighting the immune and inflammatory host responses to SARS-CoV-2 infection. This rapidly deployable COVID-19 mouse model is useful for preclinical and pathogenesis studies of COVID-19.