Expert Consensus on the Application of Stem Cells in Psoriasis Research and Clinical Trials.

Psoriasis is an immune-mediated, chronic, relapsing, inflammatory, systemic disease induced by individual-environmental interactions, and is often lifelong because of the difficulty of treatment. In recent years, a variety of targeted therapies, including biologics, have improved the lesions and quality of life of most psoriasis patients, but they still do not address the problem of relapse and may be associated with decreased efficacy or adverse events such as infections over time. Therefore, there is an urgent need for breakthroughs in psoriasis treatment and in relapse-delaying and non-pharmacologic strategies, and stem cell therapy for psoriasis has emerged. In recent years, research on stem cell therapy for psoriasis has received a lot of attention, however, there is no reference standard as well as consensus in this field of research. Therefore, according to the latest consensus and guidelines, combined with relevant literature reports, clinical practice experience and the results of discussions with experts, this consensus specifies the types of stem cells commonly used in the treatment of psoriasis, the methods, dosages, and routes of stem cell therapy for psoriasis, as well as the clinical evaluations (efficacy and safety) of stem cell therapy for psoriasis. In addition, this consensus also provides normative standards for the processes of collection, preparation, preservation and quality control of stem cells and their related products, as well as recommendations for the management of stem cells during infusion for the treatment of psoriasis. This consensus provides the latest specific reference standards and practice guidelines for the field of stem cell therapy for psoriasis.

Superimposed Electric Field Enhanced Electrospray for High-Throughput and Consistent Cell Encapsulation.

Cell encapsulation technology, crucial for advanced biomedical applications, faces challenges in existing microfluidic and electrospray methods. Microfluidic techniques, while precise, can damage vulnerable cells, and conventional electrospray methods often encounter instability and capsule breakage during high-throughput encapsulation. Inspired by the transformation of the working state from unstable dripping to stable jetting triggered by local electric potential, this study introduces a superimposed electric field (SEF)-enhanced electrospray method for cell encapsulation, with improved stability and biocompatibility. Utilizing stiffness theory, we quantitatively analyze the stability of the electrospray, whose stiffness is five times stronger under conical confinement. The SEF technique enabled rapid, continuous production of ∼300 core-shell capsules per second in an aqueous environment, significantly improving cell encapsulation efficiency. Our method demonstrated remarkable potential as exemplified in two key applications: 1) a 92-fold increase in human-derived induced pluripotent stem cells (iPSCs) expansion over 10 days, outperforming traditional 2D cultures in both growth rate and pluripotency maintenance, and 2) the development of liver capsules for steatosis modeling, exhibiting normal function and biomimetic lipid accumulation. The SEF-enhanced electrospray method presents a significant advancement in cell encapsulation technology. It offers a more efficient, stable, and biocompatible approach, opening new possibilities in clinical transplantation, drug screening, and cell therapy. This article is protected by copyright. All rights reserved.

ZnO/g-C3N4 photocatalyst activated by low-pressure ultraviolet for restoring the SWASV signals: A fast pretreatment method for electrochemically detecting Cd2+ and Pb2+ in soil extracts.

Soil organic matter (SOM) significantly impacts the detection accuracy of Cd2+ and Pb2+ using square wave anodic stripping voltammetry (SWASV) due to the complexation of SOM to heavy metal ions (HMIs), thereby attenuating SWASV signals. This study explored an effective pretreatment method that combined low-pressure ultraviolet (LPUV) photolysis with the ZnO/g-C3N4 photocatalyst, activating the photocatalyst to generate highly oxidative •OH radicals and O2•- radicals, which effectively disrupted this complexation, consequently restoring the electroactivity of HMIs and achieving high-fidelity SWASV signals. The parameters of the LPUV-ZnO/g-C3N4 photocatalytic system were meticulously optimized, including the pH of photolysis, duration of photolysis, g-C3N4 mass fraction, and concentration of the photocatalyst. Furthermore, the ZnO/g-C3N4 photocatalyst was thoroughly characterized, with an in-depth investigation on the synergistic interaction between ZnO and g-C3N4 and the mechanisms contributing to the restoration of SWASV signals. This synergistic interaction effectively separated charge carriers and reduced charge transfer resistance, enabling photogenerated electrons (e-) from the conduction band of g-C3N4 to be quickly transferred to the conduction band of ZnO, preventing the recombination of e- and hole (h+) and generating more radicals to disrupt complexation and restore the SWASV signals. Finally, the analysis of HMIs in real soil extracts using the proposed pretreatment method demonstrated high detection accuracy of 94.9% for Cd2+ and 99.8% for Pb2+, which validated the feasibility and effectiveness of the proposed method in environmental applications.

Classification of high-grade glioblastoma and single brain metastases using a new SCAT-inception model trained with MRI images.

Background and objectives: Glioblastoma (GBM) and brain metastasis (MET) are the two most common intracranial tumors. However, the different pathogenesis of the two tumors leads to completely different treatment options. In terms of magnetic resonance imaging (MRI), GBM and MET are extremely similar, which makes differentiation by imaging extremely challenging. Therefore, this study explores an improved deep learning algorithm to assist in the differentiation of GBM and MET. Materials and methods: For this study, axial contrast-enhanced T1 weight (ceT1W) MRI images from 321 cases of high-grade gliomas and solitary brain metastasis were collected. Among these, 251 out of 270 cases were selected for the experimental dataset (127 glioblastomas and 124 metastases), 207 cases were chosen as the training dataset, and 44 cases as the testing dataset. We designed a new deep learning algorithm called SCAT-inception (Spatial Convolutional Attention inception) and used five-fold cross-validation to verify the results. Results: By employing the newly designed SCAT-inception model to predict glioblastomas and brain metastasis, the prediction accuracy reached 92.3%, and the sensitivity and specificity reached 93.5 and 91.1%, respectively. On the external testing dataset, our model achieved an accuracy of 91.5%, which surpasses other model performances such as VGG, UNet, and GoogLeNet. Conclusion: This study demonstrated that the SCAT-inception architecture could extract more subtle features from ceT1W images, provide state-of-the-art performance in the differentiation of GBM and MET, and surpass most existing approaches.

Nuciferine alleviates collagen-induced arthritic in rats by inhibiting the proliferation and invasion of human arthritis-derived fibroblast-like synoviocytes and rectifying Th17/Treg imbalance.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation, posing challenges in the development of effective treatments. Nuciferine, an alkaloid found in lotus leaf, has shown promising anti-inflammatory and anti-tumor effects, yet its efficacy in RA treatment remains unexplored. This study investigated the antiproliferative effects of nuciferine on the MH7A cell line, a human RA-derived fibroblast-like synoviocyte, revealing its ability to inhibit cell proliferation, promote apoptosis, induce apoptosis, and cause G1/S phase arrest. Additionally, nuciferine significantly reduced the migration and invasion capabilities of MH7A cells. The therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis (CIA) rat model, where it markedly alleviated joint swelling, synovial hyperplasia, cartilage injury, and inflammatory infiltration. Nuciferine also improved collagen-induced bone erosion, decreased pro-inflammatory cytokines and serum immunoglobulins (IgG, IgG1, IgG2a), and restored the balance between T helper (Th) 17 and regulatory T cells in the spleen of CIA rats. These results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats.

Impact of therapeutic plasmapheresis on the duration of organ failure in patients with hypertriglyceridemia-associated acute pancreatitis.

BACKGROUND: Plasmapheresis is widely used for severe hypertriglyceridemia-associated acute pancreatitis (HTG-AP) to remove excessive triglycerides from plasma. This study aimed to evaluate whether plasmapheresis could improve the duration of organ failure in HTG-AP patients. METHODS: We analyzed a cohort of patients from a multicenter, prospective, long-running registry (the PERFORM) collecting HTG-AP patients admitted to the study sites within 72 h from the onset of symptoms. This study was based on data collected from November 2020 to March 2023. Patients who had organ failure at enrollment were involved in the analyses. The primary outcome was time to organ failure resolution within 14 days. Multivariable Cox regression model was used to evaluate the association between plasmapheresis and time to organ failure resolution. Directed acyclic graph (DAG) was used to identify potential confounders. RESULTS: A total of 122 HTG-AP patients were included (median [IQR] sequential organ failure assessment (SOFA) score at enrollment, 3.00 [2.00-4.00]). Among the study patients, 46 underwent plasmapheresis, and 76 received medical treatment. The DAG revealed that baseline serum triglyceride, APACHE II score, respiratory failure, cardiovascular failure, and renal failure were potential confounders. After adjusting for the selected confounders, there was no significant difference in time to organ failure resolution between patients undergoing plasmapheresis and those receiving exclusive medical treatment (HR = 1.07; 95%CI 0.68-1.68; P = 0.777). Moreover, the use of plasmapheresis was associated with higher ICU requirements (97.8% [45/46] vs. 65.8% [50/76]; OR, 19.33; 95%CI 2.20 to 169.81; P = 0.008). CONCLUSIONS: In HTG-AP patients with early organ failure, plasmapheresis was not associated with accelerated organ failure resolution compared to medical treatment but may be associated with more ICU admissions. TRIAL REGISTRATION: The PERFORM study was registered in the Chinese Clinical Trial Registry (ChiCTR2000039541). Registered 30 October 2020.

Early prediction and prevention of infected pancreatic necrosis.

Approximately 20%-30% of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis (IPN), a highly morbid and potentially lethal complication. Early identification of patients at high risk of IPN may facilitate appropriate preventive measures to improve clinical outcomes. In the past two decades, several markers and predictive tools have been proposed and evaluated for this purpose. Conventional biomarkers like C-reactive protein, procalcitonin, lymphocyte count, interleukin-6, and interleukin-8, and newly developed biomarkers like angiopoietin-2 all showed significant association with IPN. On the other hand, scoring systems like the Acute Physiology and Chronic Health Evaluation II and Pancreatitis Activity Scoring System have also been tested, and the results showed that they may provide better accuracy. For early prevention of IPN, several new therapies were tested, including early enteral nutrition, antibiotics, probiotics, immune enhancement, etc., but the results varied. Taken together, several evidence-supported predictive markers and scoring systems are readily available for predicting IPN. However, effective treatments to reduce the incidence of IPN are still lacking apart from early enteral nutrition. In this editorial, we summarize evidence concerning early prediction and prevention of IPN, providing insights into future practice and study design. A more homogeneous patient population with reliable risk-stratification tools may help find effective treatments to reduce the risk of IPN, thereby achieving individualized treatment.

Gastrodin Attenuates Colitis and Prevents Tumorigenesis in Mice by Interrupting TLR4/MD2/NF-ΚB Signaling Transduction.

INTRODUCTION: Chronic inflammation is one of the causative factors for tumorigenesis. Gastrodin is a main active ingredient isolated from Gastrodia elata Blume, a famous medicinal herb with a long edible history. AIM: This study aimed to explore the effects of gastrodin on colitis-associated carcinogenesis (CRC) in mice and to elucidate its potential molecular mechanisms. METHODS: Balb/c mice were induced with azoxymethane (AOM) and dextran sulfate sodium (DSS) for 12 weeks. Gastrodin (50 mg/kg) was administered via oral gavage three times per week until the end of the experiment. Disease indexes, including body weight, bloody diarrhea, colon length, histopathological score, and tumor size, were measured. Tumor cell proliferation was evaluated by BrdU incorporation assay and tumor cell cytotoxicity was assessed by cell counting kit (CCK-8). The expression levels of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-ΚB) signaling molecules, NF-ΚB luciferase, and pro-inflammatory cytokines were determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunoblotting, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reporter gene assays. The binding affinity between gastrodin and myeloid differentiation protein-2 (MD2) was analyzed by molecular docking and cellular thermal shift assay (CETSA). RESULTS: Gastrodin administration was demonstrated to mitigate various CRC-related symptoms in mice, including weight loss, diarrhea, and tissue abnormalities. Notably, gastrodin suppressed tumor cell growth during colitis- associated tumorigenesis, resulting in fewer and smaller adenomas in the colon. Unlike irinotecan, a broadspectrum antitumor drug, gastrodin did not exhibit apparent cytotoxicity in various colorectal adenocarcinoma cell lines. Additionally, gastrodin downregulated TLR4/NF-ΚB signaling molecules and pro-inflammatory mediators in mice and macrophages. Molecular docking and CETSA experiments suggested that gastrodin binds to the MD2 protein, potentially interfering with the recognition of lipopolysaccharide (LPS) by TLR4, leading to NF-ΚB pathway inhibition. CONCLUSION: This study provides evidence for the first time that gastrodin attenuated colitis and prevented colitisrelated carcinogenesis in mice, at least partially, by diminishing tumor-promoting cytokines through the interruption of TLR4/MD2/NF-ΚB signaling transduction.

Evaluation of Aortic Hemodynamics Using Four-Dimensional Flow of Magnetic Resonance Imaging in Rabbits with Liver Fibrosis.

BACKGROUND: Liver fibrosis (LF) precipitates systemic hemodynamic alterations, however, its impact on the aorta remaining undefined. PURPOSE: To assess aorta hemodynamics changes during LF development in a rabbit model. STUDY TYPE: Prospective, experimental. ANIMAL MODEL: Thirty 7-month-old male rabbits underwent bile duct ligation (BDL) to induce LF. FIELD STRENGTH/SEQUENCE: Biweekly four-dimensional (4D) flow imaging incorporating a 3D gradient-echo at 3.0 T scanner for 14 weeks post-BDL. ASSESSMENT: Histopathological exams for 2-5 rabbits were performed at each time point, following each MRI scan. LF was graded using the Metavir scale by a pathologist. 4D flow was analyzed by two radiologists using dedicated postprocessing software. They recorded 4D flow parameters at four aorta sections (aortic sinus, before and after bifurcation of aortic arch, and descending aorta). STATISTICAL TESTS: The linear mixed model; Bonferroni correction; Pearson correlation coefficient (r); receiver operating characteristic (ROC) curve; Delong test. The level of significance was set at P < 0.05. RESULTS: Following BDL, the wall shear stress (WSS) (0.23-0.32 Pa), energy loss (EL) (0.27-1.55 mW) of aorta significantly increased at the second week for each plane, peaking at the sixth week (WSS: 0.35-0.49 Pa, EL: 0.57-2.0 mW). So did the relative pressure difference (RPD) (second week: 1.67 ± 1.63 mmHg, sixth week: 2.43 ± 0.63 mmHg) in plane 2. Notably, the RPD in plane 2 at the second week displayed the highest area under ROC curve of 0.998 (specificity: 1, sensitivity: 0.967). LF were found at the second, fourth, and sixth week after BDL, with grade F2, F3, and F4, respectively. The RPD in plane 2 was most strongly correlated with the severity of LF (r = 0.86). DATA CONCLUSIONS: The occurrence of LF could increase WSS, EL, and RPD of aorta as early as the second week following BDL. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Retrospective analysis of laboratory results in 18 cases of severe asthma treated with omalizumab.

OBJECTIVE: The aim of this study was to explore the laboratory results in severe as asthma patients with omalizumab therapy and provide evidence for estimating omalizumab efficacy. METHODS: Retrospective study of 18 patients with severe asthma received omalizumab therapy in Shanghai General Hospital from 2020 to 2022 was performed. The basic data of patients were collected. The absolute number and the percentage of basophil and eosinophil in peripheral blood, total IgE level in serum, and as pulmonary function were detected at the beginning of treatment and 4 months after treatment. Differences between two groups were analyzed using Paired T test. RESULTS: The most common allergens collected from patients with moderate to severe asthma were dust mite (positive ratio 55.56%), mixed mold (16.67%), cat and dog dander, and Aspergillus fumigatus (11.11%). There was no significant difference in eosinophil and basophil counts in peripheral blood between the two groups. However, serum total IgE levels increased from (437.55±279.35) KU/L to (1071.42±721.28) KU/L (P=0.004), and FEV1/FVC ratio increased from (65.53±14.15)% to (73.91±13.63)% (P=0.005) after 4 months of treatment. CONCLUSIONS: The existing laboratory indicators for evaluation of omalizumab efficacy are still very limited, and new biomarkers need to be further developed. Elevated serum IgE levels at four weeks of treatment and FEV1/FVC may be potential indicators for omalizumab monitoring.

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/ß-Catenin signaling.

Inflammatory bowel disease (IBD) is characterized by persistent damage to the intestinal barrier and excessive inflammation, leading to increased intestinal permeability. Current treatments of IBD primarily address inflammation, neglecting epithelial repair. Our previous study has reported the therapeutic potential of notoginsenoside R1 (NGR1), a characteristic saponin from the root of Panax notoginseng, in alleviating acute colitis by reducing mucosal inflammation. In this study we investigated the reparative effects of NGR1 on mucosal barrier damage after the acute injury stage of DSS exposure. DSS-induced colitis mice were orally treated with NGR1 (25, 50, 125 mg·kg-1·d-1) for 10 days. Body weight and rectal bleeding were daily monitored throughout the experiment, then mice were euthanized, and the colon was collected for analysis. We showed that NGR1 administration dose-dependently ameliorated mucosal inflammation and enhanced epithelial repair evidenced by increased tight junction proteins, mucus production and reduced permeability in colitis mice. We then performed transcriptomic analysis on rectal tissue using RNA-sequencing, and found NGR1 administration stimulated the proliferation of intestinal crypt cells and facilitated the repair of epithelial injury; NGR1 upregulated ISC marker Lgr5, the genes for differentiation of intestinal stem cells (ISCs), as well as BrdU incorporation in crypts of colitis mice. In NCM460 human intestinal epithelial cells in vitro, treatment with NGR1 (100 µM) promoted wound healing and reduced cell apoptosis. NGR1 (100 µM) also increased Lgr5+ cells and budding rates in a 3D intestinal organoid model. We demonstrated that NGR1 promoted ISC proliferation and differentiation through activation of the Wnt signaling pathway. Co-treatment with Wnt inhibitor ICG-001 partially counteracted the effects of NGR1 on crypt Lgr5+ ISCs, organoid budding rates, and overall mice colitis improvement. These results suggest that NGR1 alleviates DSS-induced colitis in mice by promoting the regeneration of Lgr5+ stem cells and intestinal reconstruction, at least partially via activation of the Wnt/ß-Catenin signaling pathway. Schematic diagram of the mechanism of NGR1 in alleviating colitis. DSS caused widespread mucosal inflammation epithelial injury. This was manifested by the decreased expression of tight junction proteins, reduced mucus production in goblet cells, and increased intestinal permeability in colitis mice. Additionally, Lgr5+ ISCs were in obviously deficiency in colitis mice, with aberrant down-regulation of the Wnt/ß-Catenin signaling. However, NGR1 amplified the expression of the ISC marker Lgr5, elevated the expression of genes associated with ISC differentiation, enhanced the incorporation of BrdU in the crypt and promoted epithelial restoration to alleviate DSS-induced colitis in mice, at least partially, by activating the Wnt/ß-Catenin signaling pathway.

Magnetic modulation of lysosomes for cancer therapy.

Lysosomes play a central role in biochemical signal transduction and oxidative stress in cells. Inducing lysosome membrane penetration (LMP) to cause lysosomal-dependent cell death (LCD) in tumor cells is an effective strategy for cancer therapy. Chemical drugs can destroy the stability of lysosomes by neutralizing protons within the lysosomes or enhancing the fragility of the lysosomal membranes. However, there remain several unsolved problems of traditional drugs in LMP induction due to insufficient lysosomal targeting, fast metabolism, and toxicity in normal cells. With the development of nanotechnology, magnetic nanoparticles have been demonstrated to target lysosomes naturally, providing a versatile tool for lysosomal modulation. Combined with excellent tissue penetration and spatiotemporal manipulability of magnetic fields, magnetic modulation of lysosomes progresses rapidly in inducing LMP and LCD for cancer therapy. This review comprehensively discussed the strategies of magnetic modulation of lysosomes for cancer therapy. The intrinsic mechanisms of LMP-induced LCD were first introduced. Then, the modulation of lysosomes by diverse physical outputs of magnetic fields was emphatically discussed. Looking forward, this review will shed the light on the prospect of magnetic modulation of lysosomes, inspiring future research of magnetic modulation strategy in cancer therapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Onosma glomeratum Y. L. Liu polysaccharide alleviates LPS-induced pulmonary inflammation via NF-κB signal pathway.

As a traditional Chinese medicinal and edible homologous plant, Onosma glomeratum Y. L. Liu has been used for treating lung diseases in Tibet. In this study, a pectin polysaccharide, OGY-LLPA, with a molecular weight of 62,184 Da, was isolated and characterized by GC-MS and NMR analysis. It mainly consists of galacturonic acid (GalA), galactose (Gal), rhamnose (Rha), and arabinose (Ara), with a linear main chain of galacturonic acid (homogalacturonan, HG) inserted by part of rhamnose galacturonic acid (rhamnogalacturonan, RG), attaching with arabinogalactan (AG) branches at RG-I. Both in the LPS-induced A549 cell model and LPS-induced pneumonia mouse model, OGY-LLPA demonstrated strong anti-inflammatory effects, even comparable to DEX, indicating its potential as an anti-pneumonia candidate agent. Moreover, low-dose OGY-LLPA alleviated LPS-induced pulmonary inflammation by inhibiting the NF-κB signaling pathway. Overall, these findings could not only contribute to the utilization of Onosma glomeratum Y. L. Liu., but also provides a theoretical basis for the treatment of inflammation-related diseases.

Nutrition therapy in critically ill patients with severe acute pancreatitis.

A significant proportion of patients (10%-20%) with acute pancreatitis develop severe acute pancreatitis characterized by pancreatic necrosis, systemic inflammation, and organ failure, commonly requiring intensive care unit (ICU) admission. In this specific population, nutrition therapy is more challenging than that in the general ICU population, primarily because of inevitable gastrointestinal involvement by pancreatic inflammation. In this review, we discussed several key aspects of nutrition therapy in this population, including key pathophysiology that may impede nutrition therapy, the timing and implementation of enteral nutrition and parenteral nutrition, the importance of specific nutrient supplements, and the long-term outcomes that may be addressed by nutrition therapy.

Research on Alternating Current Field Measurement Method for Buried Defects of Titanium Alloy Aircraft Skin.

Titanium alloys are extensively used in the manufacturing of key components in aerospace engines and aircraft structures due to their excellent properties. However, aircraft skins in harsh operating environments are subjected to long-term corrosion and pressure concentrations, which can lead to the formation of cracks and other defects. In this paper, a detection probe is designed based on the principle of alternating current field measurement, which can effectively detect both surface and buried defects in thin-walled titanium alloy plates. A finite element simulation model of alternating current field measurement detection for buried defects in thin-walled TC4 titanium alloy plates is established using COMSOL 5.6 software. The influence of defect length, depth, and excitation frequency on the characteristic signals is investigated, and the detection probe is optimized. Simulation and experimental results demonstrate that the proposed detection probe exhibits high detection sensitivity to varying lengths and depths of buried defects, and can detect small cracks with a length of 3 mm and a burial depth of 2 mm, as well as deep defects with a length of 10 mm and a burial depth of 4 mm. The feasibility of this probe for detecting buried defects in titanium alloy aircraft skin is confirmed.

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.

A Lysosome-Targeted Magnetic Nanotorquer Mechanically Triggers Ferroptosis for Breast Cancer Treatment.

Targeting ferroptosis has attracted exponential attention to eradicate cancer cells with high iron-dependent growth. Increasing the level of intracellular labile iron pool via small molecules and iron-containing nanomaterials is an effective approach to induce ferroptosis but often faces insufficient efficacy due to the fast drug metabolism and toxicity issues on normal tissues. Therefore, developing a long-acting and selective approach to regulate ferroptosis is highly demanded in cancer treatment. Herein, a lysosome-targeted magnetic nanotorquer (T7-MNT) is proposed as the mechanical tool to dynamically induce the endogenous Fe2+ pool outbreak for ferroptosis of breast cancer. T7-MNTs target lysosomes via the transferrin receptor-mediated endocytosis in breast cancer cells. Under the programmed rotating magnetic field, T7-MNTs generate torques to trigger endogenous Fe2+ release by disrupting the lysosomal membrane. This magneto-mechanical manipulation can induce oxidative damage and antioxidant defense imbalance to boost frequency- and time-dependent lipid peroxidization. Importantly, in vivo studies show that T7-MNTs can efficiently trigger ferroptosis under the magnetic field and play as a long-acting physical inducer to boost ferrotherapy efficacy in combination with RSL3. It is anticipated that this dynamic targeted strategy can be coupled with current ferroptosis inducers to achieve enhanced efficacy and inspire the design of mechanical-based ferroptosis inducers for cancer treatment.

GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals.

Arteriovenous malformations (AVMs) are fast-flow vascular malformations and refer to important causes of intracerebral haemorrhage in young adults. Getting deep insight into the genetic pathogenesis of AVMs is necessary. Herein, we identified two vital missense variants of G protein-coupled receptor (GPCR) associated sorting protein 1 (GPRASP1) in AVM patients for the first time and congruously determined to be loss-of-function variants in endothelial cells. GPRASP1 loss-of-function caused endothelial dysfunction in vitro and in vivo. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral haemorrhage, AVMs and exhibited vascular anomalies in multiple organs. GPR4 was identified to be an effective GPCR binding with GPRASP1 to develop endothelial disorders. GPRASP1 deletion activated GPR4/cAMP/MAPK signalling to disturb endothelial functions, thus contributing to vascular anomalies. Mechanistically, GPRASP1 promoted GPR4 degradation. GPRASP1 enabled GPR4 K63-linked ubiquitination, enhancing the binding of GPR4 and RABGEF1 to activate RAB5 for conversions from endocytic vesicles to endosomes, and subsequently increasing the interactions of GPR4 and ESCRT members to package GPR4 into multivesicular bodies or late endosomes for lysosome degradation. Notably, the GPR4 antagonist NE 52-QQ57 and JNK inhibitor SP600125 effectively rescued the vascular phenotype caused by endothelial Gprasp1 deletion. Our findings provided novel insights into the roles of GPRASP1 in AVMs and hinted at new therapeutic strategies.

Blockade of CCR5 suppresses paclitaxel-induced peripheral neuropathic pain caused by increased deoxycholic acid.

Paclitaxel leads to peripheral neuropathy (paclitaxel-induced peripheral neuropathy [PIPN]) in approximately 50% of cancer patients. At present, there are no effective treatment strategies for PIPN, the mechanisms of which also remain unclear. In this study, we performed microbiome and metabolome analysis of feces and serum from breast cancer patients with different PIPN grades due to paclitaxel treatment. Our analysis reveals that levels of deoxycholic acid (DCA) are highly increased because of ingrowth of Clostridium species, which is associated with severe neuropathy. DCA, in turn, elevates serum level of C-C motif ligand 5 (CCL5) and induces CCL5 receptor 5 (CCR5) overexpression in dorsal root ganglion (DRG) through the bile acid receptor Takeda G-protein-coupled receptor 5 (TGR5), contributing to neuronal hyperexcitability. Consistent with this, administration of CCR5 antagonist maraviroc suppresses the development of neuropathic nociception. These results implicate gut microbiota/bile acids/CCR5 signaling in the induction of PIPN, thus suggesting a target for PIPN treatment.

SLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling.

White adipose tissue browning can promote lipid burning to increase energy expenditure and improve adiposity. Here, we show that Slc35d3 expression is significantly lower in adipose tissues of obese mice. While adipocyte-specific Slc35d3 knockin is protected against diet-induced obesity, adipocyte-specific Slc35d3 knockout inhibits white adipose tissue browning and causes decreased energy expenditure and impaired insulin sensitivity in mice. Mechanistically, we confirm that SLC35D3 interacts with the NOTCH1 extracellular domain, which leads to the accumulation of NOTCH1 in the endoplasmic reticulum and thus inhibits the NOTCH1 signaling pathway. In addition, knockdown of Notch1 in mouse inguinal white adipose tissue mediated by orthotopic injection of AAV8-adiponectin-shNotch1 shows considerable improvement in obesity and glucolipid metabolism, which is more pronounced in adipocyte-specific Slc35d3 knockout mice than in knockin mice. Overall, in this study, we reveal that SLC35D3 is involved in obesity via NOTCH1 signaling, and low adipose SLC35D3 expression in obesity might be a therapeutic target for obesity and associated metabolic disorders.